CN110872271A

CN110872271A - Salt of cyclohexane derivative

Info

Publication number: CN110872271A
Application number: CN201811007871.0A
Authority: CN
Inventors: 黄悦; 郑飞; 傅啸云; 唐春兰; 朱丹
Original assignee: SHANGHAI JINGXIN BIOLOGICAL MEDICAL CO Ltd; Zhejiang Jingxin Pharmaceutical Co Ltd
Current assignee: SHANGHAI JINGXIN BIOLOGICAL MEDICAL CO Ltd; Zhejiang Jingxin Pharmaceutical Co Ltd
Priority date: 2018-08-30
Filing date: 2018-08-30
Publication date: 2020-03-10

Abstract

The invention relates to a cyclohexane derivative N' - [ trans-4- [2- [7- (benzo [ b ]) as shown in a formula I]Thiophene) -7-piperazinyl]Ethyl radical]Cyclohexyl radical]-sulfates of N, N-dimethylurea and crystalline forms thereof. In vivo experiments of the sulfate also prove that the sulfate has high bioavailability and quick in vivo effect, and is an ideal salt base of the compound shown in the formula I.

Description

Salt of cyclohexane derivative

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a salt of a cyclohexane derivative for treating mental diseases and a preparation method thereof.

Background

The present inventors have disclosed in CN106518841A compound 1 having the structural formula of formula I, whose chemical name is N '- [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea the cyclohexane derivative represented by the structural formula of formula I, N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea, has D2/D3 antagonistic activity and 5-hydroxytryptamine absorption inhibitory activity as well as anti-schizophrenic activity, and in particular, has high selectivity of D3/D2 receptor and less side effects.

In order to improve the in vivo pharmacokinetic properties of the compound, a more preferred form of the compound, such as a salt of the compound of formula I, is highly desirable.

Disclosure of Invention

Based on the existing compound shown in the formula I, the inventor develops the following salt of the compound shown in the formula I, and the salt has the advantages of quick in-vivo effect and high bioavailability. Specifically, the present invention provides the following technical solutions.

The invention provides a salt of cyclohexane derivative N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethyl urea shown as a formula I, wherein the salt contains an anion, and the anion is sulfate

In one embodiment, the salt of the invention wherein the stoichiometry of the compound of formula I and anion is 1: 1.

In one embodiment, the salt of the invention, wherein the sulfate salt of the compound of formula I is of formula II:

in one embodiment, the salt of the invention has an X-ray powder diffraction spectrum using CuK α radiation at 2 θ at least at diffraction peaks at 6.719 ° soil 0.2 °, 15.927 ° ± 0.2 °, 17.257 ° ± 0.2 °, 17.781 ° ± 0.2 °, 18.294 ° ± 0.2 °, 18.863 ° soil 0.2 °, 21.464 ° ± 0.2 °, 21.711 ° ± 0.2 ° and 23.806 ° ± 0.2 °, preferably at least at 6.719 ° ± 0.02 °, 15.927 ° ± 0.02 °, 17.257 ° ± 0.02 °, 17.781 ° ± 0.02 °, 18.294 ° ± 0.02 °, 18.863 ° ± 0.02 °, 21.464 ° ± 0.02 °, 21.711 ° ± 0.02 ° and 23.806 ° ± 0.02 °.

In one embodiment, the salts of the present invention further exhibit diffraction peaks at 2 Θ values of 9.858 ° ± 0.2 °, 14.437 ° ± 0.2 °, 15.240 ° ± 0.2 °, 20.792 ° ± 0.2 °, 23.204 ° ± 0.2 ° and 27.023 ° ± 0.2 °; preferably, it also has diffraction peaks at 2 θ values of 9.858 ° ± 0.02 °, 14.437 ° ± 0.02 °, 15.240 ° ± 0.02 °, 20.792 ° ± 0.02 °, 23.204 ° ± 0.02 ° and 27.023 ° ± 0.02 °.

In one embodiment, the salt of the invention wherein it further has diffraction peaks at 2 Θ values of 7.195 ° ± 0.2 °, 7.947 ° ± 0.2 °, 12.610 ° soil 0.2 °, 13.414 ° ± 0.2 °, 14.823 ° soil 0.2 °, 20.187 ° ± 0.2 °, 22.207 ° ± 0.2 °, 22.741 ° ± 0.2 °, 24.552 ° ± 0.2 °, 25.532 ° ± 0.2 °, 26.631 ° soil 0.2 °, 27.515 ° soil 0.2 °, 28.190 ° ± 0.2 °, 28.563 ° ± 0.2 °, 29.829 ° ± 0.2 °, 32.993 ° ± 0.2 °, 34.360 ° ± 0.2 ° and 36.462 ° ± 0.2 °; preferably, it also has diffraction peaks at 2 θ values of 7.195 ° ± 0.02 °, 7.947 ° ± 0.02 °, 12.610 ° ± 0.02 °, 13.414 ° ± 0.02 °, 14.823 ° ± 0.02 °, 20.187 ° ± 0.02 °, 22.207 ° ± 0.02 °, 22.741 ° ± 0.02 °, 24.552 ° ± 0.02 °, 25.532 ° ± 0.02 °, 26.631 ° ± 0.02 °, 27.515 ° ± 0.02 °, 28.190 ° ± 0.02 °, 28.563 ° ± 0.02 °, 29.829 ° ± 0.02 °, 32.993 ° ± 0.02 °, 34.360 ° ± 0.02 ° and 36.462 ° ± 0.02 °.

In one embodiment, the salt of the invention has an XRPD pattern as shown in figure 3A.

In one embodiment, the salt of the invention has an endothermic peak at 195.1 ℃ in DSC analysis.

In one embodiment, a salt of the invention has a DSC profile as shown in figure 3B.

In one embodiment, the salt of the invention, in TGA analysis, loses up to 0.43% weight at 150 ℃.

In one embodiment, the TGA profile of the salt of the invention is shown in figure 3C.

The present invention also provides a process for preparing the sulfate salt of the compound of formula I, comprising the steps of: the compound shown in the formula I reacts with sulfuric acid in an organic solvent to obtain the sulfate of the compound shown in the formula I.

In one embodiment, the reaction molar ratio of the compound of formula I to sulfuric acid is 1: 1-1: 2; preferably, the molar ratio is 1: 1-1: 1.1.

In one embodiment, the organic solvent is selected from isopropanol, ethyl acetate, acetonitrile, toluene, or a mixture of two or more thereof.

The invention also provides a pharmaceutical composition for treating or improving schizophrenia, psychotic disorder, confusion, mood disorder, bipolar disorder, depression, phobia, obsessive-compulsive disorder, anxiety disorder or cognitive disorder, which comprises the sulfate and pharmaceutical excipients.

The sulfate of the compound of the formula I has high crystallinity, small TGA weight loss and higher and unique DSC endothermic signal, and in vivo experiments prove that the sulfate has quick in vivo effect and high bioavailability.

Drawings

FIG. 1 is an X-ray powder diffraction pattern (XPRD pattern) of the free base of a compound of formula I according to one embodiment of the present invention.

FIG. 2A is an X-ray powder diffraction pattern (XPRD pattern) of the hydrochloride salt of the compound of formula I according to one embodiment of the present invention.

FIG. 2B is a Differential Scanning Calorimetry (DSC) plot of the hydrochloride salt of the compound of formula I in one embodiment of the present invention. The abscissa is temperature (. degree. C.); the ordinate represents the heat flow rate (W/g).

Figure 2C is a thermogravimetric analysis (TGA) of the hydrochloride salt of the compound of formula I in one embodiment of the present invention.

FIG. 3A is an X-ray powder diffraction pattern (XPRD pattern) of a sulfate salt of a compound of formula I, in one embodiment of the present invention.

FIG. 3B is a Differential Scanning Calorimetry (DSC) plot of the sulfate salt of the compound of formula I in one embodiment of the present invention. The abscissa is temperature (. degree. C.); the ordinate represents the heat flow rate (W/g).

FIG. 3C is a thermogravimetric analysis (TGA) plot of the sulfate salt of the compound of formula I in one embodiment of the present invention.

FIG. 4A is an X-ray powder diffraction pattern (XPRD pattern) of a phosphate salt of a compound of formula I, in one embodiment of the present invention.

FIG. 4B is a Differential Scanning Calorimetry (DSC) plot of the phosphate salt of a compound of formula I in one embodiment of the invention. The abscissa is temperature (. degree. C.); the ordinate represents the heat flow rate (W/g).

FIG. 4C is a thermogravimetric analysis (TGA) plot of the phosphate salt of the compound of formula I in one embodiment of the present invention.

FIG. 5A is an X-ray powder diffraction pattern (XPRD pattern) of the maleate salt of the compound of formula I in one embodiment of the present invention.

Figure 5B is a Differential Scanning Calorimetry (DSC) plot of the maleate salt of the compound of formula I in one embodiment of the present invention. The abscissa is temperature (. degree. C.); the ordinate represents the heat flow rate (W/g).

Figure 5C is a thermogravimetric analysis (TGA) of the maleate salt of the compound of formula I in one embodiment of the present invention.

FIG. 5D is a drawing of the maleate salt of the compound of formula I in one embodiment of the present invention₁H-NMR chart.

FIG. 6A is an X-ray powder diffraction pattern (XPRD pattern) of the tartrate salt of the compound of formula I, in one embodiment of the present invention.

Figure 6B is a Differential Scanning Calorimetry (DSC) plot of the tartrate salt of the compound of formula I in one embodiment of the present invention. The abscissa is temperature (. degree. C.); the ordinate is the heat flow (W/g) and thermogravimetric analysis (TGA) plots.

FIG. 7A is an X-ray powder diffraction pattern (XPRD pattern) of the fumarate salt of a compound of formula I in one embodiment of the present invention.

Figure 7B is a Differential Scanning Calorimetry (DSC) plot of the fumarate salt of a compound of formula I in one embodiment of the invention. The abscissa is temperature (. degree. C.); the ordinate is the heat flow (W/g) and thermogravimetric analysis (TGA) plots.

FIG. 8A is an X-ray powder diffraction pattern (XPRD pattern) of the citrate salt of the compound of formula I, in one embodiment of the present invention.

Figure 8B is a Differential Scanning Calorimetry (DSC) plot of the citrate salt of the compound of formula I in one embodiment of the present invention. The abscissa is temperature (. degree. C.); the ordinate is the heat flow (W/g) and thermogravimetric analysis (TGA) plots.

FIG. 9A is an X-ray powder diffraction pattern (XPRD pattern) of the glycolate salt of the compound of formula I, in one embodiment of the invention.

FIG. 9B is a Differential Scanning Calorimetry (DSC) plot of the glycolate salt of the compound of formula I in one embodiment of the invention. The abscissa is temperature (. degree. C.); the ordinate is the heat flow (W/g) and thermogravimetric analysis (TGA) plots.

FIG. 10A is an X-ray powder diffraction pattern (XPRD pattern) of the malate salt of a compound of formula I, in one embodiment of the invention.

Figure 10B is a Differential Scanning Calorimetry (DSC) plot of the malate salt of the compound of formula I in one embodiment of the present invention. The abscissa is temperature (. degree. C.); the ordinate is the heat flow (W/g) and thermogravimetric analysis (TGA) plots.

FIG. 11A is an X-ray powder diffraction pattern (XPRD pattern) of a lactate salt of a compound of formula I in one embodiment of the present invention.

FIG. 11B is a Differential Scanning Calorimetry (DSC) plot of the lactate salt of the compound of formula I in one embodiment of the present invention. The abscissa is temperature (. degree. C.); the ordinate is the heat flow (W/g) and thermogravimetric analysis (TGA) plots.

FIG. 12A is an X-ray powder diffraction pattern (XPRD pattern) of the succinate salt of the compound of formula I in one embodiment of the present invention.

Figure 12B is a differential scanning calorimetry trace (DSC plot) of the succinate salt of the compound of formula I in one embodiment of the present invention. The abscissa is temperature (. degree. C.); the ordinate is the heat flow (W/g) and thermogravimetric analysis (TGA) plots.

FIG. 13A is an X-ray powder diffraction pattern (XPRD pattern) of the adipate salt of the compound of formula I in one embodiment of the invention.

FIG. 13B is a Differential Scanning Calorimetry (DSC) plot of the adipate salt of the compound of formula I in one embodiment of the invention. The abscissa is temperature (. degree. C.); the ordinate is the heat flow (W/g) and thermogravimetric analysis (TGA) plots.

FIG. 14A is an X-ray powder diffraction pattern (XPRD pattern) of the p-toluenesulfonic acid salt of the compound of formula I according to one embodiment of the present invention.

FIG. 14B is a Differential Scanning Calorimetry (DSC) plot of the p-toluenesulfonate salt of the compound of formula I in one embodiment of the present invention. The abscissa is temperature (. degree. C.); the ordinate is the heat flow (W/g) and thermogravimetric analysis (TGA) plots.

FIG. 15A is an X-ray powder diffraction pattern (XPRD pattern) of a mesylate salt of a compound of formula I, according to one embodiment of the invention.

Figure 15B is a differential scanning calorimetry trace (DSC plot) of the mesylate salt of the compound of formula I in one embodiment of the invention. The abscissa is temperature (. degree. C.); the ordinate is the heat flow (W/g) and thermogravimetric analysis (TGA) plots.

FIG. 16A is an X-ray powder diffraction pattern (XPRD pattern) of a hydrobromide salt of the compound of formula I in one embodiment of the present invention.

Figure 16B is a Differential Scanning Calorimetry (DSC) plot of the hydrobromide salt of the compound of formula I in one embodiment of the present invention. The abscissa is temperature (. degree. C.); the ordinate is the heat flow (W/g) and thermogravimetric analysis (TGA) plots.

Detailed Description

The invention is further illustrated by the following examples. It is to be understood that these examples are for illustrative purposes only and are not limiting upon the present invention. Various changes or modifications thereof, which may occur to those skilled in the art based on the teachings of the present invention, are within the scope of the present invention.

N' - [ trans-4- [2- [7- (benzo [ b ]) of the invention]Thiophene) -7-piperazinyl]Ethyl radical]Cyclohexyl radical]X-ray powder diffractogram of crystalline form of various salts of N, N-dimethylurea, expressed as diffraction peak position, i.e. diffraction angle 2 theta (°), interplanar spacing

Diffraction peak relative intensity (I/I0).

The term "relative intensity" refers to the ratio of the intensity of the other peak to the intensity of the peak having the highest intensity when the intensity of the peak having the highest intensity among all diffraction peaks of an X-ray powder diffraction pattern is 100%.

The term "substantially the same" means that at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern appear in the exemplary X-ray powder diffraction spectrum given in figure 1.

Examples

Reagent: the reactants and the catalyst used in the embodiment of the invention are chemically pure, and can be directly used or simply purified according to the requirement; the organic solvent and the like are analytically pure and are directly used. The reagents were purchased from Shanghai chemical reagent company, China medicine (group).

Amorphous forms of the compounds of formula I are prepared according to the methods reported in the prior art such as example 5 in CN106518841A, and are not limited thereto.

X-ray powder diffraction:

the X-ray powder diffraction analysis is carried out on an X-ray powder diffractometer produced by PANALYTACAL by adopting CuK α rays, the test power is 45kV multiplied by 40mA, the step width is 0.02 degrees, and the theta-2 theta continuous scanning of the scanning range is 3-40 degrees (2 theta).

Differential Scanning Calorimetry (DSC) characterization:

the measurement was carried out by using a Q2000/2500 differential scanning calorimeter of TA under the condition that the protective gas was nitrogen, the temperature rise rate was 10 ℃/min, and the temperature gradually increased from 25 ℃ to the set end point.

Thermogravimetric analysis (TGA):

the measurement was carried out by using a Q5000/5500 thermogravimetric analyzer manufactured by TA under the condition that the protective gas is nitrogen, the temperature rise rate is 10 ℃/min, and the temperature gradually rises from room temperature to a set terminal point.

Content detection method (HPLC):

chromatographic conditions

Solution preparation

Diluent (blank solution) acetonitrile/water 1/1(V/V)

Test solution: precisely weighing 5mg of a sample, placing the sample in a 10ml measuring flask, adding 2ml of methanol for dissolving, adding a diluent (blank solution) for constant volume, and uniformly mixing to obtain the product.

Ion chromatograph test (IC) conditions (salt formation molar ratio test):

example 1: preparation and identification of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (compound of formula I) free base crystal form A

Preparation of example 5 for free base reference CN 106518841A.

Preparation of 1-benzo [ b ] thiophene-4-piperazine hydrochloride

A mixture of 7.20g of 7-bromobenzo [ b ] thiophene, 19.9g of piperazine anhydride, 4.70g of sodium tert-butoxide, 0.32g of (R) - (+) -2, 2 '-bis (diphenylphosphino) -1, 1' -Binaphthyl (BINAP), 0.63g of dipalladium tris (dibenzylideneacetone) and 150ml of toluene was refluxed for 1 hour under a nitrogen atmosphere. 150ml of water was poured into the reaction solution, followed by extraction with 100ml of X3 ethyl acetate, washing with water, drying over anhydrous magnesium sulfate, and evaporation of the solvent under reduced pressure (0.01MPa, 45 ℃ C.). The residue was purified by silica gel column chromatography (dichloromethane: methanol: 25% ammonia 100: 10: 1) to give 4.60g of 1-benzo [ b ] thiophen-4-yl-piperazine as a yellow oil. 2ml of concentrated hydrochloric acid were added to a methanol solution (25ml) containing 4.6g of 1-benzo [ b ] thiophen-4-yl-piperazine and the solvent was evaporated under reduced pressure (0.01MPa, 45 ℃). Ethyl acetate (50ml) was added to the residue, and the precipitated crystals were filtered, dissolved in 15ml of methanol under reflux and then cooled to room temperature (25 ℃ C.) to be recrystallized to obtain 1-benzo [ b ] thiophen-4-yl-piperazines hydrochloride as colorless needle crystals.

Preparation of trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl-carbamic acid tert-butyl ester

2.54g (10mmol) of 1-benzo [ b ] thiophene-4-piperazine hydrochloride and 2.40g (10mmol) of trans-2- {1- [4- (N-tert-butoxycarbonyl) amino ] cyclohexyl } -acetaldehyde are dissolved in 120ml of dichloromethane, 1.40ml (10mmol) of triethylamine are added at room temperature (25 ℃ C. + -2 ℃ C.) and stirred slowly for 10 minutes, then 3.16g (14.8mmol) of sodium triacetoxyborohydride are added stepwise, the reaction is stirred further at room temperature for 24 hours, and after the reaction has ended 120ml of a 10% sodium bicarbonate solution is added. The reaction system is directly extracted and separated, the organic phase is dried by anhydrous sodium sulfate, finally, the organic phase is filtered and steamed to dryness, and the solid is refluxed, dissolved and cooled to room temperature (25 +/-2 ℃) by 15ml of ethyl acetate to be crystallized to obtain 3.70g of target product.

Preparation of trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexylamine

In an ice-water bath, 4.43g of trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl-carbamic acid tert-butyl ester was placed in a reaction flask, 80ml of an ethyl acetate solution of saturated hydrogen chloride was added, and a deprotection reaction was carried out by stirring for 8 hours to give a white precipitate, to obtain 3.42g of the hydrochloride of the title compound. The solid was added to 50ml of a methylene chloride solution, 50ml of a saturated sodium bicarbonate solution was stirred for half an hour, followed by liquid-separation extraction, and the organic phase was concentrated (0.01MPa, 40 ℃ C.) to obtain 3.30g of the objective product.

Preparation of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea

1.73g of trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexaneamine are dissolved in 50ml of dichloromethane, 1.40ml of triethylamine are added, followed by 5.50mmol of N, N-diformylcarbonyl chloride. Stirred at room temperature (25 ℃ C. + -. 2 ℃ C.) for 48 hours. After the reaction, 50ml of water was added for extraction and separation, the organic phase was concentrated (0.01MPa, 45 ℃ C.), and the objective fraction was collected by column chromatography (400 mesh silica gel type) with methanol/dichloromethane at 1: 10 and concentrated to obtain 1.89g of an amorphous objective product.

Preparation and identification of free base crystal form a:

dissolving 200mg of the amorphous product in ethyl acetate, refluxing and dissolving at 77 ℃, cooling to room temperature (20-25 ℃), stirring for 1h, performing suction filtration, and recrystallizing to obtain a crystal form, namely a crystal form A of free base of the compound shown as the formula I, wherein an X-ray diffraction pattern (XRPD) of the crystal form A is shown as figure 1; the solubility of free base form a in water is about 0.031 mg/ml.

Example 2: preparation and characterization of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (hydrochloride salt of compound of formula I)

Preparation of salt: the free base product from example 1, 200mg, and 1.05 molar ratio of hydrochloric acid in toluene (tolumen) was stirred in a vortex at room temperature for 3 days and dried under vacuum at 50 ℃ for 3 days. It is in crystalline form, designated as the hydrochloride form B of the compound of formula I.

FIG. 2A shows the powder X-ray diffraction pattern (XRPD), and the corresponding spacing values at 2 θ are provided in Table 1

Characteristic peak of (2).

Table 1 XRPD diffraction peak data for hydrochloride form B

As to the hydrochloride form B of the compound of formula I, the solubility in water is greater than 4.6 mg/ml; the DSC results in FIG. 2B show an endothermic peak at 278.2 deg.C for the sample; the TGA of figure 2C shows that the sample had 0.49% weight loss when heated to 150 ℃. The HPLC/IC measurement corresponds to a 1: 1 stoichiometry (base: hydrochloric acid).

Example 3: preparation and characterization of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (sulfate salt of compound of formula I)

Preparation of sulfate salt (a): the product from example 1, 200mg to 1.05 molar ratio of sulfuric acid in ethyl acetate (EtOAc), was vortexed at room temperature for 4 days and dried under vacuum at 50 ℃ for 3 days to give the product as a crystalline form, designated as the sulfate salt of the compound of formula I, form a.

FIG. 3A shows the powder X-ray diffraction pattern (XRPD), and the corresponding spacing values at 2 θ are provided in Table 2

Characteristic peak of (2).

Table 2 XRPD diffraction peak data for sulfuric acid form a

As to the sulfate salt form a of the compound of formula I, the solubility in water is greater than 8.0 mg/ml; the DSC results in FIG. 3B show that the sample has an endothermic peak at 195.1 ℃; the TGA of figure 3C shows that the sample had 0.43% weight loss when heated to 150 ℃. The HPLC/IC measurement corresponds to a 1: 1 stoichiometry (base: sulfuric acid).

Preparation of sulfate salt (b): the product from example 1, 200mg and 1.05 molar ratio of sulfuric acid in Isopropylamine (IPA) was stirred for 4 days at room temperature and dried under vacuum at 50 ℃ for 3 days to give it as a crystalline form substantially identical to the X-ray diffraction pattern (XRPD), DSC pattern and TGA pattern of the sulfate salt form a of the compound of formula I above.

Preparation of sulfate salt (c): the product from example 1, 200mg and 1.05 molar ratio of sulfuric acid in Acetonitrile (ACN), was vortexed at room temperature for 4 days and dried under vacuum at 50 ℃ for 3 days to give a crystalline form which is substantially the same as the X-ray diffraction pattern (XRPD), DSC profile and TGA profile of the sulfate salt form a of the compound of formula I above.

Preparation of sulfate salt (d): the product from example 1, 200mg and 1.05 molar ratio of sulfuric acid in Toluene (Toluene), was stirred for 4 days at room temperature and dried under vacuum at 50 ℃ for 3 days to give it as a crystalline form, which has essentially the same X-ray diffraction pattern (XRPD), DSC pattern and TGA pattern as the sulfate salt form A of the compound of formula I described above.

Example 4: preparation and characterization of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (phosphate salt of a compound of formula I)

Preparation of phosphate (a): the product from example 1, 200mg to 1.05 molar ratio of phosphoric acid, was vortexed in ethyl acetate (EtOAc) at room temperature for 5 days to give the product in crystalline form, designated as the phosphate form a of the compound of formula I.

FIG. 4A shows the powder X-ray diffraction pattern (XRPD), and the corresponding spacing values at 2 θ are provided in Table 3

Characteristic peak of (2).

Table 3 XRPD diffraction peak data for phosphate form a

With respect to the phosphate form a of the compound of formula I, the solubility in water is greater than 7.6 mg/ml; the DSC results in FIG. 4B show that the sample has an endothermic peak at 213.9 ℃; the TGA of figure 4C shows that the sample had 0.7% weight loss when heated to 150 ℃. The HPLC/IC measurement corresponds to a 1: 1 stoichiometry (base: phosphoric acid).

Preparation of phosphate (b): the product from example 1, 200mg and 1.05 molar ratio of phosphoric acid in Isopropylamine (IPA) was stirred for 5 days at room temperature in a mixed vortex and was obtained in crystalline form, substantially identical to the X-ray diffraction pattern (XRPD), DSC profile and TGA profile of the phosphate salt form a of the compound of formula I above.

Preparation of phosphate (c): the product from example 1, 200mg and 1.05 molar ratio of phosphoric acid in Acetone (Acetone) was vortexed at room temperature for 5 days to give it as a crystalline form, which is substantially the same as the X-ray diffraction pattern (XRPD), DSC profile and TGA profile of the phosphate salt form a of the compound of formula I above.

Preparation of phosphate (d): the product from example 1, 200mg and 1.05 molar ratio of phosphoric acid, in Acetonitrile (ACN), was vortexed at room temperature for 5 days to give a crystalline form that was substantially identical to the X-ray diffraction pattern (XRPD), DSC pattern, and TGA pattern of the phosphate salt form a of the compound of formula I above.

Preparation of phosphate (e): the product from example 1, obtained as a crystalline form with substantially the same X-ray diffraction pattern (XRPD), DSC profile and TGA profile as phosphate form a of the compound of formula I above, was stirred in Toluene (Toluene) at room temperature for 5 days with stirring in a molar ratio of 200mg to 1.05 phosphoric acid.

Example 5: preparation and characterization of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (maleate salt of compound of formula I)

Preparation of maleate salt (a): the product from example 1, 200mg and 1.05 molar ratio of maleic acid in Acetone (Acetone) was stirred in a vortexing manner at room temperature for 5 days to give it in crystalline form, designated as the maleate salt of the compound of formula I, crystalline form a.

FIG. 5A shows the powder X-ray diffraction pattern (XRPD), and the corresponding spacing values at 2 θ are provided in Table 4

Characteristic peak of (2).

Table 4 XRPD diffraction peak data for maleate form a

(ii) a solubility in water of greater than 2.6mg/ml for the maleate salt form a of the compound of formula I; the DSC results of FIG. 5B show that the sample has an endothermic peak at 191.8 ℃; the TGA of figure 5C shows that the sample had 0.41% weight loss when heated to 150 ℃.₁H-NMR corresponds to 1: 1 stoichiometry (base: maleic acid) and the results are shown in FIG. 5D.

Preparation of maleate salt (b): the product from example 1, 200mg and 1.05 mole ratio maleic acid in Isopropylamine (IPA) was stirred at room temperature for 5 days in the form of crystalline form substantially the same as the X-ray diffraction pattern (XRPD), DSC pattern and TGA pattern for crystalline form a of the maleate salt of the compound of formula I above.

Preparation of maleate salt (c): the product from example 1, 200mg and 1.05 mole ratio of maleic acid in ethyl acetate (EtOAc) was stirred for 5 days at room temperature with vortexing and was obtained in crystalline form, substantially identical to the X-ray diffraction pattern (XRPD), DSC pattern and TGA pattern of maleate form a of the compound of formula I above.

Preparation of maleate salt (d): the product from example 1, 200mg and 1.05 molar ratio of maleic acid in Acetonitrile (ACN) was vortexed at room temperature for 5 days to give a crystalline form that was substantially the same as the X-ray diffraction pattern (XRPD), DSC pattern, and TGA pattern of crystalline form a of the maleate salt of the compound of formula I above.

Preparation of maleate salt (e): the product from example 1, obtained in crystalline form with 200mg and 1.05 molar ratio of maleic acid in Toluene (tolumen) and stirred for 5 days at room temperature, was substantially identical to the X-ray diffraction pattern (XRPD), DSC pattern and TGA pattern of the maleate salt form a of the compound of formula I above.

Comparative example 1: preparation and characterization of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (tartrate salt of compound of formula I)

Preparation of tartrate salt: the product from example 1, 200mg, was stirred with 1 molar ratio of tartaric acid in Acetone (Acetone) for 5 days at room temperature. It is in the form of a crystalline form, designated tartrate form a of the compound of formula I.

With respect to the tartrate form a of the compound of formula I, figure 6A shows a powder X-ray diffraction pattern (XRPD); the DSC results of FIG. 6B show that the sample has an endothermic peak at 169.8 ℃; the TGA of figure 6B shows that the sample had a 5.5% weight loss when heated to 150 ℃.₁H-NMR corresponds to 1: 1 stoichiometry (base: tartaric acid).

Comparative example 2: preparation and characterization of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (fumarate salt of a compound of formula I)

Preparation of fumarate salt: 200mg of the product from example 1 were stirred in Acetone (Acetone) with 1 molar ratio of fumaric acid for 5 days at room temperature. It is in crystalline form, designated as fumarate salt form a of the compound of formula I.

With respect to the tartrate form a of the compound of formula I, figure 7A shows a powder X-ray diffraction pattern (XRPD); the DSC results of FIG. 7B show that the sample has an endothermic peak at 200.3 ℃; the TGA of figure 7B shows that the sample had 0.9% weight loss when heated to 150 ℃.₁H-NMR corresponds to 1: 1 stoichiometry (base: fumaric acid).

Comparative example 3: preparation and characterization of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (citrate salt of a compound of formula I)

Preparation of citrate salt: the product from example 1, 200mg, was stirred with 1 molar ratio of citric acid in ethyl acetate (EtOAc) for 5 days at room temperature. It is in the form of a crystalline form, designated citrate form a of the compound of formula I.

With respect to the tartrate form a of the compound of formula I, figure 8A shows a powder X-ray diffraction pattern (XRPD); the DSC results of FIG. 8B show that the sample has an endothermic peak at 126.8 ℃; the TGA of figure 8B shows that the sample had a 2.6% weight loss when heated to 140 ℃.₁H-NMR corresponds to 1: 1 stoichiometry (base: citric acid).

Comparative example 4: preparation and characterization of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (glycolate salt of the compound of formula I)

Preparation of glycolate: the product from example 1, 200mg, was stirred with 1 molar ratio of glycolic acid in Isopropylamine (IPA) for 5 days at room temperature. It is in the form of a crystalline form designated as the glycolate salt of the compound of formula I crystalline form a.

With respect to the glycolate salt form a of the compound of formula I, fig. 9A shows a powder X-ray diffraction pattern (XRPD); the DSC results of FIG. 9B show that the sample has an endothermic peak at 129.2 ℃; the TGA of figure 9B shows that the sample had 11.9% weight loss when heated to 120 ℃.₁H-NMR corresponds to 1: 1 stoichiometry (base: glycolic acid).

Comparative example 5: preparation and characterization of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (malate salt of compound of formula I)

Preparation of malate: the product from example 1, 200mg, was stirred with 1 molar ratio of L-malic acid in Acetone (Acetone) for 5 days at room temperature. It is in the form of a crystalline form, designated as malate form a of the compound of formula I.

With respect to the malate salt form a of the compound of formula I, fig. 10A shows a powder X-ray diffraction pattern (XRPD); the DSC results of figure 10B show that the sample has two endothermic peaks at 140.4 and 155.0 ℃; the TGA of figure 10B shows that the sample had 8.8% weight loss when heated to 140 ℃.₁H-NMR corresponds to 1: 1 stoichiometry (base: malic acid).

Comparative example 6: preparation and characterization of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (DL-lactate salt of a compound of formula I)

Preparation of lactate: the product from example 1, 200mg, was stirred with 1 molar ratio of DL-lactic acid in ethyl acetate (EtOAc) for 5 days at room temperature. It is in the form of a crystalline form, designated as malate form a of the compound of formula I.

With respect to the malate salt form a of the compound of formula I, fig. 11A shows a powder X-ray diffraction pattern (XRPD); the DSC results of FIG. 11B show that the sample has an endothermic peak at 106.9 ℃; the TGA of fig. 11B shows that the sample had 1.7% weight loss when heated to 100 ℃.₁H-NMR corresponds to 1: 1 stoichiometry (base: lactic acid).

Comparative example 7: preparation and characterization of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (succinate salt of compound of formula I)

Preparation of succinate salt: the product from example 1, 200mg, was stirred with 1 molar ratio of succinic acid in ethyl acetate (EtOAc) at room temperature for 5 days. It is in crystalline form, designated as succinate form a of the compound of formula I.

With respect to succinate form a of the compound of formula I, figure 12A shows a powder X-ray diffraction pattern (XRPD); the DSC results of figure 12B show that the sample has an endothermic peak at 152.0 ℃; the TGA of figure 12B shows that the sample had a 2.3% weight loss when heated to 150 ℃.₁H-NMR corresponds to 1: 1 stoichiometry (base: succinic acid).

Comparative example 8: preparation and characterization of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (adipate salt of a compound of formula I)

Preparation of adipate salt: the product from example 1, 200mg, was stirred with 1 molar ratio of adipic acid in ethyl acetate (EtOAc) for 5 days at room temperature. It is in crystalline form, designated adipate form a of the compound of formula I.

With respect to form a of the adipate salt of the compound of formula I, fig. 13A shows a powder X-ray diffraction pattern (XRPD), and the TGA of fig. 13B shows a 1.0% weight loss of the sample when the sample is heated to 150 ℃; the DSC results in FIG. 13B show that the sample has an endothermic peak at 115.0 ℃.₁H-NMR satisfied 1: 1 stoichiometric amount (base: adipic acid).

Comparative example 9: preparation and identification of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (p-toluenesulfonate salt of the compound of formula I)

Preparation of p-toluenesulfonate salt: the product from example 1, 200mg, was stirred with 1 molar ratio of p-toluenesulfonic acid in ethyl acetate (EtOAc) for 5 days at room temperature. It is in the form of a crystalline form designated as p-toluenesulfonate form a of the compound of formula I.

With respect to crystalline form A of the p-toluenesulfonate salt of the compound of formula I, FIG. 14A shows a powder X-ray diffraction pattern (XRPD); the DSC results of FIG. 14B show that the sample has an endothermic peak at 205.6 ℃; TGA of 14B showed 0.8% weight loss of the sample when the sample was heated to 150 ℃.₁H-NMR corresponds to 1: 1 stoichiometry (base: p-toluenesulfonic acid).

Comparative example 10: preparation and characterization of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (mesylate salt of compound of formula I)

Preparation of mesylate: the product from example 1, 200mg, was stirred with 1 molar ratio of methanesulfonic acid in Isopropylamine (IPA) for 5 days at room temperature. It is in crystalline form, designated as mesylate form a of the compound of formula I.

With respect to the mesylate salt form a of the compound of formula I, figure 15A shows a powder X-ray diffraction pattern (XRPD); the DSC results of FIG. 15B show that the sample has an endothermic peak at 211.1 ℃; the TGA of figure 15B shows that the sample had 3.0% weight loss when heated to 150 ℃.₁H-NMR corresponds to 1: 1 stoichiometry (base: methanesulfonic acid).

Comparative example 11: preparation and characterization of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea (the hydrobromide salt of the compound of formula I)

Preparation of a hydrobromide salt: the product from example 1, 200mg, was stirred with 1 molar hydrobromic acid in ethyl acetate (EtOAc) for 5 days at room temperature. It is in the form of a crystalline salt, designated as hydrobromide form a of the compound of formula I.

With respect to the hydrobromide salt form a of the compound of formula I, figure 16A shows a powder X-ray diffraction pattern (XRPD); the DSC results in FIG. 16B show that the sample has an endothermic peak at 249.6 ℃; the TGA of figure 16B shows that the sample had 1.4% weight loss when heated to 150 ℃.₁H-NMR corresponds to 1: 1 stoichiometry (base: hydrobromic acid).

Analysis of the XRPD, DSC and TGA profiles of the above salts and crystalline forms, combined with a safety rating based on higher crystallinity, less TGA weight loss, higher and unique DSC endotherm, may lead to the preferred hydrochloride, sulfate, phosphate and maleate salts of the compounds of formula I.

Example 6

This experiment performed preliminary studies on the absorption process and characteristics of the compound of formula I and its salts in rats. Pharmacokinetic studies were performed on SD rats with a single gavage of 1mg/kg of a compound of formula I and its salt (calculated as the base concentration in the salt form).

The experimental method comprises the following steps:

SD rats were administered 1mg/kg of the free base of example and its salt (including the free base of example 1, the hydrochloride of example 2, the sulfate of example 3, and the phosphate of example 4) in a single gavage, respectively. Each group had 4 male rats. The concentration of the compound of formula I in the plasma was measured and pharmacokinetic parameters were calculated from the concentration-time curve and the results obtained are shown in Table 5.

Table 5 plasma pharmacokinetic parameters after gavage of 1mg/kg of a salt of a compound of formula I (analyzed using a non-compartmental model) (Mean ± SD, n ═ 6)

As can be seen in table 5, the bioavailability of the sulfate salt is relatively high compared to the hydrochloride salt; the shorter Tmax of the sulfate salt is a relatively fast onset in vivo compared to the compound of formula I and its hydrochloride and phosphate salts.

Claims

1. A salt of cyclohexane derivative N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -7-piperazinyl ] ethyl ] cyclohexyl ] -N, N-dimethylurea shown in formula I,

the salt comprises an anion which is a sulfate salt

2. The salt of claim 1, wherein the stoichiometry of the compound of formula I and anion is 1: 1.

3. The salt of claim 1, the sulfate salt of the compound of formula I is of formula II:

4. the salt of claim 1 having an X-ray powder diffraction spectrum using CuK α radiation expressed in degrees 2 θ with diffraction peaks at least 6.719 ° ± 0.2 °, 15.927 ° ± 0.2 °, 17.257 ° ± 0.2 °, 17.781 ° ± 0.2 °, 18.294 ° ± 0.2 °, 18.863 ° ± 0.2 °, 21.464 ° ± 0.2 °, 21.711 ° ± 0.2 ° and 23.806 ° ± 0.2 °.

5. The salt of claim 4, which further exhibits diffraction peaks, in terms of 2 Θ, at 9.858 ° ± 0.2 °, 14.437 ° ± 0.2 °, 15.240 ° ± 0.2 °, 20.792 ° ± 0.2 °, 23.204 ° ± 0.2 ° and 27.023 ° ± 0.2 °.

6. The salt of claim 5, which further exhibits diffraction peaks at 2 Θ values at 7.195 ° ± 0.2 °, 7.947 ° ± 0.2 °, 12.610 ° ± 0.3 °, 13.414 ° ± 0.2 °, 14.823 ° ± 0.2 °, 20.187 ° ± 0.2 °, 22.207 ° ± 0.2 °, 22.741 ° ± 0.2 °, 24.552 ° ± 0.2 °, 25.532 ° ± 0.2 °, 26.631 ° ± 0.2 °, 27.515 ° ± 0.2 °, 28.190 ° ± 0.2 °, 28.563 ° ± 0.2 °, 29.829 ° ± 0.2 °, 32.993 ° ± 0.2 °, 34.360 ° ± 0.2 ° and 36.462 ° ± 0.3 °; preferably, the XRPD pattern is as shown in figure 3A.

7. A salt of a compound of formula I according to claim 1, having an endothermic peak at 195.1 ℃ in DSC analysis; preferably, the DSC profile is as shown in figure 3B; in TGA analysis, the weight loss at 150 ℃ reaches 0.43%; preferably, the TGA profile is as shown in figure 3C.

8. A process for preparing a salt of a compound of formula I as claimed in claims 1-7, comprising the steps of: the compound of the formula I reacts with sulfuric acid in an organic solvent to obtain the sulfate of the compound shown in the formula I.

9. The method according to claim 8, wherein the reaction molar ratio of the compound of formula I and sulfuric acid is 1: 1-1: 2; preferably, the molar ratio is 1: 1-1: 1.1; wherein the organic solvent is selected from isopropanol, ethyl acetate, acetonitrile, toluene or a mixture of two or more of the above.

10. A pharmaceutical composition for treating or ameliorating schizophrenia, psychotic disorders, confusion, mood disorders, bipolar disorder, depression, phobias, obsessive-compulsive disorders, anxiety disorders or cognitive disorders, which comprises a salt according to claims 1-7 and a pharmaceutical excipient.