CN111377911B - Morpholine benzamide compound and application thereof - Google Patents
Morpholine benzamide compound and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of medical treatment, and particularly relates to a morpholine benzamide compound and application thereof, wherein the morpholine benzamide compound has a compound structure shown in a formula (A), and can be used for antidepressant drug treatment application,
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a novel morpholine benzamide compound, a preparation method thereof, a composition containing the compound and application of the compound.
Technical Field
The role of sigma-1 receptors (sigma-1 receptors), in particular the sigma-1 Receptor subtype, has been identified as an important target in the pathophysiology of neuropsychiatric diseases, drugs for the treatment of neuropsychiatric diseases, such as depression and anxiety ([ J)]Human Psychopharmacology: Clinical and Experimental,2010,25(3): 193-200). Brain-derived neurotrophic factor (BDNF) is the most widely studied neurotrophic factor in depression studies. In general, a decrease in BDNF levels is associated with the pathophysiology of depression, while upregulation is a feature of antidepressant therapy, and the sigma-1 receptor is involved in the upregulation of BDNF expression and the PLC γ/IP3/Ca activated by BDNF2+Enhancement of signal transduction pathways, and thus have therapeutic effectsPotential for treatment of depression ([ J)].Pharmacology&therapeutics,2010,127(3):271-282)。
WO2005089747A discloses azabicyclo derivatives having the chemical structure shown below, which act mainly on histamine H3 receptor and are useful in neurological disorders associated with cerebral aging,
among compounds having pharmacological activity to sigma-1 receptors, such as Imipramine (Imipramine) and fluvoxamine (fluvoxamine), although both have certain therapeutic effects on the treatment of depression, adverse reactions include gastrointestinal adverse reactions, dry mouth, lethargy, hypotension, accelerated heart rate, urinary retention, electrocardiographic changes, increased risk of suicide, and the like. Therefore, the screening of the sigma-1 receptor agonist which has high activity and can reduce serious adverse reactions and can be used as a medicament is still a hot spot of the current medical field, especially the research of depression.
Disclosure of Invention
The invention aims to provide a morpholine benzamide compound with pharmaceutical activity and application thereof in the field of medical treatment.
The invention provides a compound shown in a general formula (A), an enantiomer or a pharmaceutically acceptable salt thereof,
wherein:
X1is O or S;
R1and R2Each independently selected from hydrogen, halogen, hydroxy, amino, cyano, C substituted or unsubstituted by one or more halogen, hydroxy, amino1-5Alkyl of (a), C substituted or unsubstituted by one or more halogen, hydroxy, amino1-5Alkoxy group of (a);
y is selected from a substituent group shown in a formula (I), a formula (II), a formula (III) or a formula (IV):
X2is O or S, n is 0 or 1;
R3and R4Each independently selected from hydrogen, halogen, hydroxy, amino, cyano, C substituted or unsubstituted by one or more halogen, hydroxy, amino1-5Alkyl of (a), C substituted or unsubstituted by one or more halogen, hydroxy, amino1-5Alkoxy group of (2).
In a preferred embodiment of the present invention, the compound represented by the above general formula (a), enantiomer or pharmaceutically acceptable salt thereof is excluded:
when Y is selected from the substituent group shown in the formula (I), R1、R2、R3And R4As is the case with hydrogen.
In a further preferred embodiment variant of the invention:
when R is3When it is hydrogen, R4Preferably selected from halogen, hydroxy, amino, cyano, C substituted by one or more halogen, hydroxy, amino1-5Alkyl of R1And R2As defined above;
when R is3And R4When neither is hydrogen, R3And R4Each independently preferably selected from halogen, hydroxy, amino, cyano, C substituted or unsubstituted with one or more halogen, hydroxy, amino1-5Alkyl of R1And R2As defined above;
when R is3And R4When both are hydrogen, R1And R2As defined above, but R2Is not hydrogen.
In a further preferred embodiment variant of the invention:
when Y is selected from the substituent group shown in the formula (II), the formula (III) or the formula (IV), R2Hydrogen is preferred.
In a further preferred embodiment of the present invention, said C1-5The alkyl group is selected from methyl, ethyl, propyl,Butyl or pentyl; said C is1-5The alkoxy group of (a) is selected from methoxy, ethoxy, propoxy, butoxy or pentoxy; the halogen is selected from fluorine, chlorine, bromine or iodine.
In a further preferred embodiment of the present invention, the propyl group is selected from the group consisting of n-propyl (n-Pr, -CH)2CH2CH3) Or isopropyl ((i-Pr, -CH (CH)3)2) (ii) a The butyl is selected from n-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Or tert-butyl (t-Bu, -C (CH)3)3) (ii) a Said pentyl group is selected from n-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) Or 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3)。
In a further preferred embodiment of the present invention, the propoxy group is selected from the group consisting of 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2) (ii) a The butoxy group is selected from 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)3)3) (ii) a The pentoxy is selected from 1-pentoxy (n-pentoxy, -OCH)2CH2CH2CH2CH3) 2-pentyloxy (-OCH (CH)3)CH2CH2CH3) 3-pentyloxyRadical (-OCH (CH)2CH3)2) 2-methyl-2-butoxy (-OC (CH))3)2CH2CH3) 3-methyl-2-butoxy (-OCH (CH)3)CH(CH3)2) 3-methyl-l-butoxy (-OCH)2CH2CH(CH3)2) 2-methyl-l-butoxy (-OCH)2CH(CH3)CH2CH3)。
In a more preferred embodiment of the present invention, said C1-5Is preferably selected from C1-3Alkyl of (a), said C1-3The alkyl group is selected from methyl, ethyl, n-propyl (n-Pr, -CH)2CH2CH3) Or isopropyl ((i-Pr, -CH (CH)3)2)。
In a more preferred embodiment of the present invention, said C1-5Alkoxy of (A) is preferably C1-3Alkoxy of (a), said C1-3The alkoxy group of (A) is selected from methoxy (MeO, -OCH)3) Ethoxy (EtO, -OCH)2CH3) 1-propoxy (n-PrO, n-propoxy, -OCH)2CH2CH3) Or 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2)。
In a preferred further embodiment of the present invention, exemplary compounds of the compound represented by the general formula (a) are as follows:
table 1 illustrative Compounds of the Compound represented by the general formula (A)
The invention further provides a compound shown in the general formula (A), and a pharmaceutically acceptable salt of enantiomer, wherein the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, gluconate, saccharate, benzoate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate.
In a preferred embodiment of the present invention, the pharmaceutically acceptable salt is prepared from the compound represented by the general formula (a) and the corresponding acid.
The invention further provides a preparation method of the compound shown in the general formula (A), the enantiomer or the pharmaceutically acceptable salt thereof, which is specifically prepared by firstly synthesizing a benzoic acid parent body by the compound shown in the formula (a) and the compound shown in the formula (b) and then condensing the benzoic acid parent body with a nitrogen-containing structure.
Wherein Y is selected from a substituent group shown in a formula (I), a formula (II), a formula (III) or a formula (IV):
the reaction condition of the step 1 is carbonate and an organic solvent, and the heating reflux is carried out for 3-8 h, preferably 6 h;
the reaction conditions of the step 2 are strong alkali and organic solvent, and the heating reflux is carried out for 3-6 h, preferably 4 h;
and 3, reacting 4-Dimethylaminopyridine (DMAP), a carbodiimide condensing agent and an organic solvent at room temperature for 6-10 hours, preferably 8 hours.
In a preferred embodiment of the invention, the carbonate is selected from K2CO3Or Na2CO3Preferably K2CO3。
In a preferred embodiment of the invention, the strong base is selected from NaOH, KOH, LiOH, NaH, KH or LiH, preferably NaOH.
In a preferred embodiment of the present invention, the carbodiimide-based condensing agent is selected from the group consisting of Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC), and 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDCI).
In a preferred embodiment of the present invention, the carbodiimide-based condensing agent further includes a salt thereof, such as hydrochloride.
In a preferred embodiment of the invention, the organic solvent is selected from the group consisting of nitriles, ketones, N-Dimethylformamide (DMF), haloalkanes, C1-5Alcohols of (4).
In a preferred embodiment of the present invention, the organic solvent of step 1 is preferably a nitrile; the organic solvent of step 2 is preferably C1-5The alcohols of (1); the organic solvent of step 3 is preferably a haloalkane.
In a further preferred embodiment of the invention, the nitrile is selected from acetonitrile; the ketone is selected from acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one or hexan-3-one, preferably acetone; the alcohol is selected from methanol, ethanol, n-butanol or isobutanol, preferably methanol; the haloalkane is preferably dichloromethane or tetrachloromethane, preferably dichloromethane.
The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the general formula (a), an enantiomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In a preferred embodiment of the present invention, the pharmaceutical composition may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the present invention may be formulated for oral, buccal, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous) or rectal administration or for administration by inhalation or insufflation. The compounds of the present invention may also be formulated in sustained release dosage forms.
In a preferred embodiment of the invention, an effective amount of a compound of the invention is administered orally, e.g., with an inert diluent or in a carrier. According to some embodiments of the invention, the compounds of the invention may be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral treatment, the compounds of the present invention may be used with excipients and in the form of tablets, troches, capsules, suspensions, syrups and the like. According to an embodiment of the invention, the above-mentioned formulations should contain at least 0.5% (w/w) of the active compound of the invention, but may vary depending on the particular dosage form, wherein 4% to about 70% by weight of the unit is convenient. The amount of active compound in such pharmaceutical compositions should be such that a suitable dosage is achieved.
In a preferred embodiment of the invention, for oral administration, the active compounds according to the invention are formulated, for example, by customary means into tablets or capsules with pharmaceutically acceptable excipients, for example binding agents (for example starch, gelatin, polyvinylpyrrolidone or acacia), fillers (for example lactose, microcrystalline cellulose or calcium phosphate), lubricants (for example magnesium stearate, talc or silicon dioxide), disintegrants (for example potato starch or sodium starch glycolate) or wetting agents (for example sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may, for example, be presented as solutions, syrups or suspensions, or may be evaporated to a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (e.g. almond oil, oily esters or ethanol) and preservatives (e.g. methyl or propyl p-hydroxybenzoate).
In a preferred embodiment of the invention, when the active compounds of the invention are to be administered parenterally, the compounds provided herein may be combined with sterile water or an organic medium to form an injectable solution or suspension.
In a preferred embodiment of the invention, the active compounds of the invention may be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
The invention also provides the use of a compound of formula (a), an enantiomer or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating the sigma-1 receptor, wherein the medicament optionally comprises one or more additional agents which modulate the nervous system or ameliorate a psychotic disorder in a mammal.
In a preferred embodiment of the invention, the modulation comprises modulation of the agonistic activity of a receptor.
In a preferred embodiment of the present invention, the present invention also provides the use of a compound of formula (a), an enantiomer or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for the treatment of a neuropsychiatric disorder selected from schizophrenia, mania, anxiety or depression, preferably depression.
Advantageous technical effects of the invention
The compound provided by the invention has stronger affinity to sigma-1 receptors and smaller affinity to sigma-2 receptors, thereby showing specific high affinity to sigma-1 receptors; a mouse tail suspension immobility experiment model shows that the compound provided by the invention has stronger neuropsychiatric disease treatment activity, especially better anti-depression activity and good safety compared with the positive medicament S-38093, the compound in the comparative example 1, the compound in the comparative example 2 and fluoxetine and venlafaxine.
Examples
The following describes in detail embodiments of the present invention. The following examples are illustrative only and are not to be construed as limiting the invention. Unless otherwise indicated, all ratios, percentages, and the like referred to herein are by weight.
Synthetic examples
Example 1, (2, 6-Dimethylmorpholino) (4- (3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) phenyl) methanone (Compound 4)
7.6g of methyl 4-hydroxybenzoate, 15.0g of 1, 3-dibromopropane and 20.7g of potassium carbonate are taken, 50mL of acetone is added, and the mixture is heated and refluxed for reaction for 6 hours. TLC detection, after the reaction is finished, cooling to room temperature, evaporating the solvent, adding a proper amount of dichloromethane, washing with water, separating a water layer, adding anhydrous magnesium sulfate to an organic layer for drying, evaporating the solvent to obtain a light yellow oily substance, and performing column chromatography (eluent petroleum ether: ethyl acetate 5:1) to obtain 10.1g of a white solid, wherein the melting point is 126-.
② 9.5g of the product of the first step, 14.5g of anhydrous potassium carbonate, 50mL of acetonitrile and 4.7g of octahydro cyclopentane [ c ] pyrrole are heated and refluxed for 6 hours, cooled to room temperature, filtered, the solvent is evaporated to dryness, and column chromatography is carried out (eluent petroleum ether: ethyl acetate 1:1) to obtain 8.1g of light yellow oily matter with the yield of 76.4 percent.
Dissolving 7.6g of the product obtained in the second step in 75mL of methanol, slowly dropwise adding 50mL of 1mol/L sodium hydroxide solution, reacting at room temperature for 4h after dropwise adding, evaporating the methanol in the system under reduced pressure, adjusting the pH of the water phase to 5-6 by using 2mol/L hydrochloric acid solution, stirring at room temperature for 1h, carrying out suction filtration, washing the filter cake to be neutral by using water, and drying to obtain 6.1g of white solid with the yield of 84.7%.
And fourthly, taking 1.4g of the product in the third step, adding 0.44g of 2, 6-dimethylmorpholine, 0.014g of 4-Dimethylaminopyridine (DMAP), 1.9g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 30mL of Dichloromethane (DCM), reacting for 8 hours at room temperature, quenching the reaction by using 1mol/mL of sodium bicarbonate solution, separating to obtain an organic phase, extracting the aqueous phase for 2 times (50mL times) by using dichloromethane, combining the organic phases, drying by using anhydrous sodium sulfate, evaporating the solvent to obtain a yellow oily substance, and performing column chromatography (eluent dichloromethane: methanol ═ 30:1) to obtain 1.4g of a light yellow oily substance, wherein the yield is 77.8%.
1H NMR(400MHz,CDCl3)δ8.13-7.65(m,2H),7.29-6.84(m,2H),4.05(t,J＝11.6Hz,2H),3.63-3.59(m,4H),3.53-3.34(m,4H),3.01-2.63(m,2H),2.43(t,J＝12.2Hz,2H),2.19-1.99(m,2H),1.97-1.56(m,8H),1.53-1.30(m,2H).MS(ESI)m/z 359.2([M+H]+).
Example 2, (3, 5-Dimethylmorpholino) (4- (3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) phenyl) methanone (Compound 5)
The title compound 5 was prepared in the same manner as in example 1, substituting 3, 5-dimethylmorpholine for 2, 6-dimethylmorpholine in the fourth step.
1H NMR(400MHz,CDCl3)δ8.19-7.73(m,2H),7.38-6.86(m,2H),4.32-3.89(m,4H),3.76-3.68(m,2H),3.43-3.35(m,2H),3.02-2.68(m,2H),2.43(t,J＝12.3Hz,1H),2.20-1.98(m,2H),1.96-1.54(m,8H),1.55-1.30(m,2H),1.26(d,J＝9.8Hz,6H).MS(ESI)m/z 387.3([M+H]+).
Example 3, (2, 3-Dimethylmorpholino) (4- (3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) phenyl) methanone (Compound 6)
The title compound 6 was prepared in the same manner as in example 1, except that 2, 3-dimethylmorpholine was used instead of 2, 6-dimethylmorpholine in the fourth step.
1H NMR(400MHz,CDCl3)δ8.10-7.58(m,2H),7.47-6.76(m,2H),4.04(t,J＝11.8Hz,2H),3.97-3.86(m,1H),3.77-3.30(m,5H),3.01-2.70(m,2H),2.46-2.39(m,2H),2.23-2.00(m,2H),1.99-1.55(m,8H),1.58-1.31(m,2H),1.26(d,J＝9.9Hz,3H),1.13(d,J＝9.3Hz,3H).MS(ESI)m/z 387.3([M+H]+).
Example 4, (3-Fluoromorpholino) (4- (3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) phenyl) methanone (Compound 7)
The title compound 7 was obtained in the same manner as in example 1 except that 3-fluoromorpholine was used instead of 2, 6-dimethylmorpholine in the fourth step.
1H NMR(400MHz,CDCl3)δ8.12-7.66(m,2H),7.34-6.71(m,2H),6.21(d,J＝74.1,1H),4.28-3.89(m,4H),3.83-3.42(m,4H),2.98-2.73(m,2H),2.43(t,J＝8.7Hz,2H),2.17-1.98(m,2H),1.98-1.55(m,8H),1.55-1.27(m,2H).MS(ESI)m/z 377.2([M+H]+).
Example 5, (2-Fluoromorpholino) (4- (3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) phenyl) methanone (Compound 8)
The title compound 8 was prepared as in example 1, substituting 2, 6-dimethylmorpholine with 2-fluoromorpholine in the fourth step.
1H NMR(400MHz,CDCl3)δ8.11-7.56(m,2H),7.21-6.90(m,2H),6.58(dt,J＝74.3,9.9Hz,1H),4.05(t,J＝12.0Hz,2H),3.92-3.75(m,1H),3.72-3.41(m,5H),3.00-2.71(m,2H),2.43(t,J＝11.5Hz,2H),2.25-2.01(m,2H),2.00-1.55(m,8H),1.56-1.16(m,2H).MS(ESI)m/z 377.2([M+H]+).
Example 6, (4- (3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) phenyl) (3-hydroxymorpholino) methanone (Compound 9)
The title compound 9 was prepared as in example 1, substituting 3-hydroxymorpholine for 2, 6-dimethylmorpholine in the fourth step.
1H NMR(400MHz,CDCl3)δ8.26-7.53(m,2H),7.42-6.68(m,2H),5.43(t,J＝11.4Hz,1H),4.25-3.83(m,3H),3.78-3.43(m,5H),3.03-2.66(m,2H),2.43(t,J＝12.3Hz,2H),2.21-2.00(m,2H),1.99-1.56(m,9H),1.55-1.24(m,2H).MS(ESI)m/z 375.2([M+H]+).
Example 7, (4- (3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) phenyl) (2-hydroxymorpholino) methanone (Compound 10)
The title compound 10 was prepared in the same manner as in example 1, except that 2-hydroxymorpholine was used instead of 2, 6-dimethylmorpholine in the fourth step.
1H NMR(400MHz,CDCl3)δ8.05-7.73(m,2H),7.42-6.80(m,2H),5.31(t,J＝9.8Hz,1H),4.05(t,J＝12.1Hz,2H),3.74-3.40(m,6H),2.99-2.71(m,2H),2.43(t,J＝12.3Hz,2H),2.21-2.00(m,2H),1.99-1.55(m,8H),1.56-1.18(m,3H).MS(ESI)m/z 375.2([M+H]+).
Example 8, 4- (4- (3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) benzoyl) morpholin-3-one (Compound 11)
Title compound 11 was prepared as in example 1, substituting 3-morpholinone for 2, 6-dimethylmorpholine in the fourth step.
1H NMR(400MHz,CDCl3)δ8.01-7.77(m,2H),7.31-6.96(m,2H),4.71(s,2H),4.05(t,J＝12.0Hz,1H),3.76(t,J＝6.8Hz,2H),3.56-3.48(m,2H),3.08-2.65(m,2H),2.43(t,J＝9.1Hz,2H),2.25-2.02(m,2H),1.99-1.55(m,8H),1.55-1.31(m,2H).MS(ESI)m/z 373.2([M+H]+).
Example 9, 4- (4- (3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) benzoyl) morpholin-2-one (Compound 12)
Title compound 12 was prepared in the same manner as in example 1, except that 2-morpholone was used instead of 2, 6-dimethylmorpholine in the fourth step.
1H NMR(400MHz,CDCl3)δ8.33-7.56(m,2H),7.27-6.63(m,2H),4.46(t,J＝7.0Hz,2H),4.28(s,2H),4.05(t,J＝12.0Hz,2H),3.72(t,J＝7.0Hz,1H),3.54(t,J＝7.0Hz,1H),2.95-2.69(m,2H),2.43(t,J＝9.2Hz,2H),2.19-1.55(m,10H),1.54-1.29(m,2H).MS(ESI)m/z 373.2([M+H]+).
Example 10, (4- (3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) phenyl) (2- (hydroxymethyl) morpholino) methanone (Compound 13)
Title compound 13 was prepared according to the procedure of example 1 substituting 2- (hydroxymethyl) morpholine for 2, 6-dimethylmorpholine in the fourth step.
1H NMR(400MHz,CDCl3)δ8.18-7.66(m,2H),7.69-6.82(m,2H),4.05(t,J＝12.1Hz,2H),3.79-3.24(m,9H),3.03-2.69(m,2H),2.43(t,J＝12.3Hz,2H),2.20-2.00(m,2H),1.99-1.55(m,8H),1.55-1.21(m,3H).MS(ESI)m/z 389.2([M+H]+).
Example 11, (4- (3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) phenyl) (3- (hydroxymethyl) morpholino) methanone (Compound 14)
Title compound 14 was prepared as in example 1, substituting 3- (hydroxymethyl) morpholine for 2, 6-dimethylmorpholine in the fourth step.
1H NMR(400MHz,CDCl3)δ8.10-7.66(m,2H),7.46-6.82(m,2H),4.05(t,J＝12.1Hz,2H),3.89(dd,J＝19.8,3.0Hz,1H),3.74-3.43(m,7H),3.40-3.18(m,1H),2.97-2.73(m,2H),2.43(t,J＝12.3Hz,2H),2.20-1.55(m,10H),1.55-1.29(m,2H),1.19(s,1H).MS(ESI)m/z 389.2([M+H]+).
EXAMPLE 12 (4- (3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) phenyl) (octahydro-4H-benzo [ b ] [1,4] oxazin-4-yl) methanone (Compound 15)
The title compound 15 was prepared as in example 1, substituting octahydro-2H-1, 4-benzoxazine hydrobromide for 2, 6-dimethylmorpholine in the fourth step.
1H NMR(400MHz,CDCl3)δ8.32-7.63(m,2H),7.35-6.67(m,2H),4.05(t,J＝12.1Hz,2H),3.88-3.71(m,2H),3.69-3.46(m,2H),3.41-3.32(m,1H),3.16-3.06(m,1H),3.01-2.71(m,2H),2.43(t,J＝12.3Hz,2H),2.22-1.55(m,15H),1.55-1.30(m,4H),1.30-1.01(m,1H).MS(ESI)m/z 413.3([M+H]+).
Example 13, (4- (3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) -2-hydroxypropoxy) phenyl) (morpholino) methanone (Compound 16)
Putting 6.6g of 4-hydroxybenzoic acid, 18.5g of EDCI, 0.6g of DMAP and 70mL of dichloromethane into a 250mL reaction bottle, reacting at room temperature for 10min, adding 6.2g of morpholine, reacting at room temperature for 6h, detecting by TLC, adding 50mL of water into the reaction bottle after the reaction is finished, quenching the reaction, stirring at room temperature for 30min, standing and separating to obtain an organic phase, extracting the aqueous phase with dichloromethane for 2 times (50 mL/time), combining the organic phases, drying with anhydrous sodium sulfate, evaporating the solvent to obtain a light yellow solid, and performing column chromatography (eluent dichloromethane: methanol ═ 30:1) to obtain 8.2g of off-white solid with the yield of 82.8%.
② taking 7.8g of the product of the first step, 5.5g of epichlorohydrin and 20.7g of potassium carbonate, adding 150mL of acetonitrile, and heating and refluxing for reaction for 6 hours. TLC detection, after the reaction is finished, cooling to room temperature, evaporating the solvent to dryness, adding a proper amount of dichloromethane, washing with water, separating a water layer, adding anhydrous magnesium sulfate to an organic layer for drying, evaporating the solvent to dryness to obtain a light yellow oily substance, performing column chromatography separation (an eluent, petroleum ether, ethyl acetate, 3:1), and performing column chromatography to obtain a white solid, wherein the white solid is 7.3g, and the yield is 76.0%.
③ taking 1.9g of the product obtained in the second step, 4.1g of anhydrous potassium carbonate, 30mL of acetonitrile and 1.3g of octahydro cyclopentane [ c ] pyrrole, heating and refluxing for reaction for 6 hours, cooling to room temperature, filtering, evaporating the solvent to dryness, and separating by column chromatography (eluent petroleum ether: ethyl acetate 1:1) to obtain 2.2g of white solid with the yield of 72.4%.
1H NMR(400MHz,CDCl3)δ8.10-7.65(m,2H),7.44-6.76(m,2H),4.3.53-3.43(m,1H),4.27(dd,J＝19.8,9.0Hz,1H),3.91(dd,J＝19.8,9.0Hz,1H),3.72-3.37(m,8H),3.06-2.69(m,4H),2.23-2.04(m,2H),2.01(s,1H),1.99-1.55(m,6H),1.56-1.28(m,2H).MS(ESI)m/z 375.2([M+H]+).
Example 14, (4- (2-fluoro-3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) phenyl) (morpholino) methanone (Compound 17)
1.9g of the compound 16 prepared in example 13 was dissolved in 30mL of dichloromethane, cooled in an ice bath, 1.6g of diethylaminosulfur trifluoride (DAST) dissolved in 20mL of dichloromethane was slowly added dropwise thereto, after completion of the addition, the mixture was allowed to react at room temperature for 8 hours, the reaction was detected by TLC, 20mL of a saturated sodium bicarbonate solution was added dropwise thereto to quench the reaction, the reaction was stirred at room temperature for 10 minutes, and the mixture was allowed to stand for liquid separation to obtain an organic phase, the aqueous phase was extracted 2 times (30 mL/time) with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain a yellow oily substance, and column chromatography (eluent dichloromethane: methanol: 30:1) was performed to obtain 0.9g of a yellow oily substance with a yield of 47.9%.
1H NMR(400MHz,CDCl3)δ8.20-7.67(m,2H),7.30-6.85(m,2H),5.53-5.30(m,1H),4.41-3.97(m,2H),3.81-3.37(m,8H),3.28-2.80(m,4H),2.31-2.04(m,2H),2.02-1.55(m,6H),1.55-1.09(m,2H).MS(ESI)m/z 377.2([M+H]+).
Example 15, (4- (3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) phenyl) (morpholino) methanone (comparative example 1 compound)
The compound of comparative example 1 was prepared according to the method of example 1, substituting morpholine for 2, 6-dimethylmorpholine in the fourth step.
Example 16, (4- (3- (hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propoxy) phenyl) (3-methylmorpholino) methanone (comparative example 2 compound)
The compound of comparative example 1 was prepared according to the method of example 1, substituting 3-methylmorpholine for 2, 6-dimethylmorpholine in the fourth step.
Test examples
Control compound: s-38093 was prepared by reference to the method described in patent CN100577160C, specification examples 1 and 22: the compound of comparative example 1 was prepared according to method 15 described in the examples; the compound of comparative example 2 was prepared according to method 16 described in the examples;
example 17 assay of the Activity of the Compounds of the invention on the sigma 1receptor
(1) Preparation of sigma 1receptor membranes
Cutting off the head of a guinea pig, operating on ice, quickly taking a brain, combining tissues into a centrifuge tube, adding 0.01M Tris HCl solution and 0.32M sucrose solution, homogenizing for 3-4 s at 4 grades, homogenizing for 4 times, then adding 0.01M Tris HCl solution and 0.32M sucrose solution, adjusting to 10mL/g, adjusting the weight of a test tube after homogenizing by using a balance, and centrifuging for 10min at 1000R; adding 0.01M Tris HCl solution and 0.32M sucrose solution into the supernatant, adjusting to 2mL/g, 1000R, and centrifuging at 4 deg.C for 10 min; taking the supernatant, centrifuging at 4 ℃ for 25min at 11500R; adding 0.01M Tris HCl solution and 0.32M sucrose solution into the precipitate, adjusting to 3mL/g, incubating at 25 deg.C for 15min, 11500R, centrifuging at 4 deg.C for 25min, and storing the precipitate at-80 deg.C for use.
(2) Receptor binding assay materials
Isotope ligand [ 2 ]3H]- (+) -pentazocine (250. mu. Ci, NET-1056250UC) available from Perkinelmer; haloperidol, available from Sigma-Aldrich; GF/C glass fiber filter paper from Whatman; subpackaging a Tris inlet; PPO and POPOPOP are purchased from Shanghai reagent I factory; fat-soluble scintillation liquid; microbeta TriLux scintillation counter available from Perkinelmer.
(3) Experimental methods
1. Bradford method for quantitative determination of protein
Refer to kit instructions.
2. Preparation of homogenate
A: 0.01M Tris-HCl buffer, containing 0.32M sucrose solution, pH 7.4.
B: 0.01M Tris-HCl buffer, pH 7.4.
3. Receptor saturation binding assay.
(1) Dispersing the prepared membrane uniformly by using a proper amount of homogenate by using a homogenizer, and adding a proper amount of homogenate to form 50mL of membrane suspension for later use;
(2) adding 100 mu L of membrane preparation into each reaction tube;
(3) 100 μ L B solution was added to total binding Tubes (TB) and 100 μ L haloperidol (final concentration 10) was added to non-specific binding tubes (NB)-5M)；
(4) Isotope ligand is added into each reaction tube respectively3H]10 μ L of (+) -pentazocine with the final concentration of 32.00, 16.00, 8.00, 4.00, 2.00, 1.00, 0.50, 0.25nM in sequence;
(5) incubating each reaction tube at 25 ℃ for 3h, 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;
(6) and (5) putting the scintillation vial into a liquid scintillation counter for counting.
4、σ1Competitive receptor binding assays
(1) Firstly, dispersing the prepared membrane uniformly by using a proper amount of homogenate by using a homogenizer, and adding a proper amount of homogenate to form 50mL of membrane suspension for later use;
(2) adding 100 mu L of membrane preparation into each reaction tube;
(3) 100 μ L B solution was added to total binding Tubes (TB) and 100 μ L haloperidol (final concentration 10) was added to non-specific binding tubes (NB)-5M), test Compound specific binding tube (SB) 100. mu.L of test Compound (final concentration 10)-5M)；
(4) Each reaction tube was filled with 10. mu.L of radioligand [3H ] - (+) -pentazocine (final concentration: 4 nM);
(5) incubating each reaction tube at 25 ℃ for 3h, after the reaction is finished, rapidly filtering the combined ligand through decompression, leading Whatman test paper to be saturated by using 0.25% PEI solution 2h in advance, fully washing the mixed solution by using ice-cold test buffer solution, taking out the filter disc, putting the filter disc into a 2mL scintillation cup, adding 1mL toluene scintillation solution, and uniformly mixing;
(6) and (5) putting the scintillation vial into a liquid scintillation counter for counting.
5. Statistical processing of data
TB: summary and constants
NB: non-specific binding constant
SB: binding constant of compound
Inhibition (I%) (TB-SB) ÷ (TB-NB) × 100%;
calculation of IC for each Compound by logit method50；
Mapping by Scatchard to give the respective radioligands KdValue and Bmax；
Finally, the K of the compound to be determined is obtainediThe value:
Ki＝IC50÷(1+C/Kd)。
EXAMPLE 18 assay of the Activity of the Compounds of the invention on the sigma 2 receptor
(1) Preparation of sigma 2 receptor membranes
Cutting off the head of a guinea pig, operating on ice, quickly taking a brain, combining tissues into a centrifuge tube, adding 0.01M Tris HCl solution and 0.32M sucrose solution, homogenizing for 3-4 s at 4 grades, homogenizing for 4 times, then adding 0.01M Tris HCl solution and 0.32M sucrose solution, adjusting to 10mL/g, adjusting the weight of a test tube after homogenizing by using a balance, and centrifuging for 10min at 1000R; adding 0.01M Tris HCl solution and 0.32M sucrose solution into the supernatant, adjusting to 2mL/g, 1000R, and centrifuging at 4 deg.C for 10 min; centrifuging the supernatant at 11000R at 4 deg.C for 25 min; adding 0.01M Tris HCl solution and 0.32M sucrose solution into the precipitate, suspending for 30s, adjusting to 3mL/g, incubating at 25 deg.C for 15min, centrifuging at 11000g for 30min, collecting supernatant, storing at-20 deg.C for more than 12h, and incubating with 50mM Tris solution when in use.
(2) Receptor binding assay materials
Isotope ligand [ alpha ], [ alpha ] an3H]-DTG([3H]-DTG, 250. mu. Ci, NET-986250UC), available from Perkinelmer; DTG, available from Sigma-Aldrich; GF/C glassFiber filter paper, available from Whatman corporation; subpackaging a Tris inlet; PPO and POPOPOP are purchased from Shanghai reagent I factory; fat-soluble scintillation liquid; microbeta TriLux scintillation counter available from Perkinelmer.
(3) Experimental methods
1. Bradford method for quantitative determination of protein
Refer to kit instructions.
2. sigma-2 receptor competitive binding assays.
(1) Dispersing the prepared membrane uniformly by using a proper amount of homogenate by using a homogenizer, and adding a proper amount of homogenate to form 50mL of membrane suspension for later use;
(2) adding 100 mu L of membrane preparation and 100 mu L of homogenate into each reaction tube respectively;
(3) 100 μ L of the homogenate was added to total bound Tubes (TB) and 100 μ L of 5 μ M DTG (final concentration 0.5 x 10) was added to non-specific bound tubes (NB)-5M), test Compound specific binding tube (SB) 100. mu.L of test Compound (final concentration 10)-5M) and 100nM (+) -NANM for screening sigma-1 receptors;
(4) isotope ligand is added into each reaction tube respectively3H]DTG (final concentration 5nM, 2 parallel channels for each reaction channel, and ice for each channel when loaded);
(5) incubating each reaction tube at 25 ℃ for 120min, after the reaction is finished, rapidly filtering the combined ligand through decompression, soaking the whatman test paper in 0.5% PEI, fully washing the test paper with ice-cold test buffer solution, taking out the filter disc, placing the filter disc into a 2mL scintillation cup, adding 1mL toluene scintillation solution, and uniformly mixing;
(6) and (5) putting the scintillation vial into a liquid scintillation counter for counting.
5. Statistical processing of data
TB: summary and constants
NB: non-specific binding constant
SB: binding constant of compound
Inhibition (I%) (TB-SB) ÷ (TB-NB) × 100%;
calculation of IC for each Compound by logit method50；
Mapping by Scatchard to give the respective radioligands KdValue and Bmax；
Finally, the K of the compound to be determined is obtainediThe value:
Ki＝IC50÷(1+C/Kd)。
TABLE 2 Compound vs. sigma1Receptor and sigma2The affinity of the receptor (Ki values, nM,
)
the above experimental results show that: the compounds have better affinity to sigma 1 receptors and lower affinity to sigma 2 receptors, which shows that the compounds have better specificity to the sigma 1 receptors and can be used for improving central nervous system diseases, such as schizophrenia, mania, anxiety or depression.
Example 19 acute toxicity study
(1) Sequential limit test
The experimental method comprises the following steps: ICR mice, each half of male and female, were randomly divided into several groups of 5 mice each, 2000mg/kg of each compound and solvent group, and administered by gavage at 0.2ml/10 g. Observing the death condition of the animals within 3 days (if 3 or more than 3 animals survive within three days and the life state is not obviously abnormal, continuing to observe until the experiment is ended after 7 days, and if the animals die 3 or more than 3 animals within three days, determining the LD of the animals by adopting a half-lethal method50)。
(2) Half lethal dose assay
The experimental method comprises the following steps: ICR mice are divided into a plurality of groups of 5 mice in each group, wherein the groups are 1500mg/kg, 1000mg/kg and 500mg/kg of compounds and solvent groups, the groups are respectively administrated by intragastric administration according to 0.2ml/10g, and the death condition of the animals within 1-3 days is observed.
The experimental results are as follows: single-dose LD of mice of Compounds 5, 6 and 950Greater than 2000mg/kg, equivalent to or less than the positive control drug, and lessThe results are shown in Table 3.
TABLE 3 acute toxicity test results for preferred Compounds in vivo animal models
Example 20 mouse Tail suspension experiment
Experimental animals: healthy ICR mice, male, 22-40 g, were provided by Nanjing Qinglong mountain animal farming center.
The main reagents are as follows: s-38093, comparative example 1 compound, comparative example 2 compound, fluoxetine (commercially available), venlafaxine (commercially available).
An experimental instrument: stopwatch, self-made lever and observation glass device.
The experimental method comprises the following steps: mice of acceptable weight were selected and grouped several days prior to the experiment. The experiment is carried out in two days, the first day, the mice are placed on a lever for 6min, the immobility time of 4min is recorded, the mice with the immobility time of 60-180S are screened out, the mice in all levels are randomly grouped according to three levels of 60-90S, 90-120S and 120-180S, a blank control group (no administration, administration of a solvent with the same volume), a positive control group (administration of S-38093, a compound in a comparative example 1, a compound in a comparative example 2, fluoxetine and venlafaxine) and test drug administration groups (compounds 5, 6 and 9) are set, and each group is provided with 10 mice. The following day, the mice were gavaged (at a dose of 2.5, 5, 10, 20, 40, 80mg/kg), 1h after dosing, the tail of the mice was suspended on the lever for 6min, and the immobility time 4min after dosing was recorded (the immobility standard means that the mice stopped struggling on the lever or appeared in a swing state).
Data statistics processing: the Mean of the experimental data is represented by standard deviation (Mean plus or minus SD), and the comparison is carried out by using one-factor variance analysis; the results of each administration group were subjected to T-test with a blank control group to evaluate whether the test drug had antidepressant activity,*represents p<0.05，**Represents p<0.01, there was a significant difference.
The experimental results are as follows: compared with S-38093, the compound of comparative example 1, the compound of comparative example 2, fluoxetine and venlafaxine in a positive control group, the compounds 5, 6 and 9 of the invention have more remarkable anti-depression activity in a mouse tail suspension immobility model experiment, which shows that the compounds provided by the invention have more potential in anti-depression treatment, and the specific results are shown in Table 4.
TABLE 4 Effect of intragastric administration on mouse tail suspension immobility time (
n＝10)
EXAMPLE 21 preparation of tablets
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.
Although the present invention has been described in detail hereinabove, those skilled in the art will appreciate that various modifications and changes can be made thereto without departing from the spirit and scope of the invention. The scope of the invention is not limited by the detailed description set forth above but is intended to be encompassed by the claims.
Claims (11)
1. A compound represented by the general formula (A):
wherein, X1Is O or S;
R1selected from hydrogen; r2Selected from hydrogen, halogen, hydroxy;
y is selected from a substituent group shown in a formula (I), a formula (II), a formula (III) or a formula (IV):
X2is O or S, n is 0 or 1;
R3and R4Each independently selected from hydrogen, halogen, hydroxy, amino, cyano, C substituted or unsubstituted by one or more halogen, hydroxy, amino1-5Alkyl of (a), C substituted or unsubstituted by one or more halogen, hydroxy, amino1-5Alkoxy group of (a);
the compound represented by the general formula (A) or a pharmaceutically acceptable salt thereof is not included:
when Y is selected from the substituent group shown in the formula (I), R1、R2、R3And R4As is the case with hydrogen.
2. The compound of formula (A) or a pharmaceutically acceptable salt thereof according to claim 1,
when R is3When it is hydrogen, R4Selected from halogen, hydroxyl, amino, cyano, C substituted by one or more of halogen, hydroxyl, amino1-5Alkyl of R1And R2As defined in claim 1;
when R is3And R4When neither is hydrogen, R3And R4Each independently selected from halogen, hydroxy, amino, cyano, C substituted or unsubstituted by one or more of halogen, hydroxy, amino1-5Alkyl of R1And R2As defined in claim 1;
when R is3And R4When both are hydrogen, R1And R2As defined in claim 1, except that R2Is not hydrogen.
3. The compound of formula (A), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R is R when Y is selected from the group consisting of the substituents of formula (II), formula (III) or formula (IV)2Selected from hydrogen.
4. The compound of formula (a) or a pharmaceutically acceptable salt thereof according to claim 1, wherein C is1-5The alkyl group of (a) is selected from methyl, ethyl, propyl, butyl or pentyl; said C is1-5The alkoxy group of (a) is selected from methoxy, ethoxy, propoxy, butoxy or pentoxy; the halogen is selected from fluorine, chlorine, bromine or iodine.
5. The compound of formula (a) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (a) is selected from the group consisting of:
6. the compound of formula (a) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, gluconate, saccharate, benzoate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate.
7. A process for the preparation of a compound of formula (a) or a pharmaceutically acceptable salt thereof as claimed in claim 1, which comprises:
wherein Y is selected from a substituent group shown in a formula (I), a formula (II), a formula (III) or a formula (IV):
the reaction condition of the step 1 is that the heating reflux is carried out for 3-8 h under the condition that carbonate and an organic solvent exist;
the reaction condition of the step 2 is that the heating reflux is carried out for 3-6 h under the condition of strong alkali and organic solvent;
the reaction condition of the step 3 is that the reaction is carried out for 6-10 h at room temperature in the presence of 4-Dimethylaminopyridine (DMAP), a carbodiimide condensing agent and an organic solvent;
said carbonate is selected from K2CO3Or Na2CO3The strong base is selected from NaOH, KOH, LiOH, NaH, KH or LiH, the carbodiimide-based condensing agent is selected from Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC), 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDCI), and the organic solvent is selected from nitriles, ketones, N-Dimethylformamide (DMF), haloalkanes, C, and1-5the alcohols of (1);
n，R1、R2、R3、R4，X1、X2as defined in claim 1 or claim 2.
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (a) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9. Use of a compound of formula (a) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 8 for the manufacture of a medicament for the treatment of a neuropsychiatric disorder.
10. The use according to claim 9, wherein the neuropsychiatric disorder is selected from schizophrenia, mania, anxiety or depression.
11. Use according to claim 10, wherein the neuropsychiatric disorder is selected from depression.
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