阅读说明：本技术 一种具有镇痛活性的萘酚衍生类化合物及其制备方法 (Naphthol derivative compound with analgesic activity and preparation method thereof ) 是由 王志强 伏鸿博 于 2020-12-29 设计创作，主要内容包括：本发明属于医药领域,涉及一种萘酚衍生类化合物及其在镇痛中的应用。所述的萘酚衍生类化合物结构式如式I所示：药理学研究表明,本发明制备的化合物发明的化合物具有良好的镇痛活性和较小的生物毒性,从而可以用于镇痛药物的制备。(The present invention belongs toIn the field of medicine, relates to a naphthol derivative compound and application thereof in analgesia. The structural formula of the naphthol derivative compound is shown as a formula I: pharmacological research shows that the compound prepared by the invention has good analgesic activity and smaller biotoxicity, so that the compound can be used for preparing analgesic drugs.)

1. A naphthol derivative compound, the chemical structural general formula of which is shown in formula I,

in the formula: r is selected from

2. The synthetic route of naphthol derivative compound of formula I according to claim 1 is:

3. the process for producing a naphthol-derived compound according to claim 1, which comprises the steps of: the compound II and the compound in the general formula III react for about two hours in a proper solvent under the action of sodium hydride at high temperature to prepare the target compound I.

4. The method of claim 3, wherein said suitable solvent in said step of synthesizing is selected from the group consisting of DMF, DMSO, DMAC and the like.

5. Use of a naphthol derivative according to claim 1 for analgesia.

6. Use according to claim 5, characterized in that the compound obtained according to the invention is used for the preparation of a medicament for analgesia.

Technical Field

The invention belongs to the field of medicines, and relates to a naphthol derivative compound with analgesic activity and a preparation method thereof

Background

Neuropathic Pain (Neuropathic Pain) is a Pain syndrome caused by primary injury or dysfunction of the nervous system, and is mainly manifested by hyperalgesia, allodynia, spontaneous Pain, and the like. The unclear pathogenesis of the neurogenic pain is one of the more serious clinical problems which afflict human beings at present. Many clinical symptoms are associated with or underlie neuropathic pain, such as diabetes, post-operative pain from amputation, lower back pain, cancer, chemical injury or toxins, other serious surgery, peripheral nerve damage caused by the compression of traumatic lesions, nutritional deficiencies, infections such as herpes zoster, HIV, etc.

Currently, there is no specific therapeutic drug for neuropathic pain, opioids and central nerve inhibitors are commonly used to control pain, and among all opioid analgesics, morphine is still the most widely used analgesic. But in addition to its therapeutic properties, it has several disadvantages including respiratory depression, decreased gastrointestinal motility causing constipation, nausea and vomiting. Tolerance and physical dependence also limit the clinical use of opioids. And the opioid analgesic is almost ineffective to part of the neurogenic pain, and the side effect of the drug acting on the central nervous system is large, so that the dosage of the drug is limited, and the drug cannot achieve the effective analgesic effect. And many anti-inflammatory drugs, particularly nonsteroidal anti-inflammatory drugs, cause gastrointestinal side effects, including ulceration and erosion of the gastrointestinal tract, especially when taken orally, which often become severe requiring hospitalization and can even be fatal. Therefore, it is very urgent to search for a drug acting on the spinal cord or peripheral sites and having no side effects on the central nervous system in the pathogenesis of neurogenic pain.

The invention creatively synthesizes the naphthol derivative compound, has high analgesic activity, good water solubility and low toxicity, so as to obtain a brand new compound which can be used for preparing analgesic drugs, and the prior art does not have reports of related structures.

Disclosure of Invention

Aiming at the problems, the invention aims to provide a preparation method and application of a naphthol derivative compound, and the compound prepared by the invention has good analgesic activity and smaller biotoxicity and can be used as a brand new compound for preparing analgesic drugs. In order to achieve the purpose, the invention adopts the following technical scheme.

A naphthol derivative compound has a structural general formula I as follows:

in the formula: r is selected from

Another objective of the invention is to provide a synthetic route of the naphthol derivative compound shown as formula I:

further, the synthesis method of the steps in the synthesis route is as follows:

the compound II and the compound in the general formula III react for about two hours in a proper solvent under the action of sodium hydride at high temperature to prepare the target compound I.

NMR data of part of the Compounds the following are:

compound 1:¹H-NMR(400MHz,CDCl₃)δ:1.14(t,12H),1.40-1.59(m,8H),1.71(m,2H),2.25(s,6H),2.51(t,2H),2.66(m,2H),2.89(q,8H),2.92(m,1H),3.35(t,1H),3.57(t,2H),4.16(t,2H),7.01(d,1H),7.23(s,1H),7.38(d,1H),7.48(s,1H),7.58(d,1H),7.69(d,1H).¹³C-NMR(125MHz,CDCl₃)δ:12.32,22.76,25.61,33.77,45.80,47.72,51.96,52.92,54.13,60.40,61.61,67.38,83.09,107.90,118.12,127.51,127.71,127.82,129.96,130.17,132.07,134.17,158.00；

compound 2:¹H-NMR(400MHz,CDCl₃)δ:1.37-1.62(m,18H),1.84-1.96(m,4H),2.29(s,6H),2.57-2.66(m,8H),2.76(t,2H),2.83(td,2H),2.94-3.06(m,2H),3.12(t,1H),3.51(t,2H),4.08(t,2H),6.98(dd,1H),7.22(dd,1H),7.25(t,1H),7.56-7.59(m,2H),7.78(dd,1H).¹³C-NMR(125MHz,CDCl₃)δ:24.43,25.29,25.5,31.23,45.46,49.41,52.51,53.81,54.45,57.71,66.66,67.23,77.76,112.61,114.38,125.88,126.61,127.85,128.6,132.67,133.24,134.44,158.45。

the naphthol derivative compound provided by the invention has high analgesic activity and low toxicity, and can be further studied.

The analgesic drug or the pharmaceutically acceptable salt or solvate thereof can be applied to analgesia, and particularly provides the application of a naphthol derivative compound in analgesia.

Compared with the prior art, the invention has the following beneficial effects:

the compound of the invention has high analgesic activity and low toxicity, and is expected to become an effective analgesic drug.

In conclusion, the naphthol derivative compound has good development prospect when being used for preparing analgesic drugs.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

Drawings

FIG. 1: influence of the compound on writhing frequency of acetic acid writhing method mice.

FIG. 2: effect of the compounds of the invention on the threshold of carrageenan-induced pain in rats.

Detailed Description

The following synthetic examples, biological test results, are used to further illustrate the invention, but are not meant to limit the invention.

Synthesis examples

Example 1 Synthesis of Compound II

6-methoxy-2-naphthoic acid (10.0g, 49.45mmol) and thionyl chloride (45mL, 62.2mmol) were reacted in dichloromethane (60mL) at reflux in the presence of a catalytic amount of N, N-dimethylformamide (0.5mL) for 4 hours. After completion of the reaction, the system was added to a well stirred solution of dimethylamine hydrochloride (10.1g, 123.87mmol) and triethylamine (17.4mL, 125.18mmol) in dichloromethane (50mL) while maintaining the temperature below 5 ℃. After the addition was complete, stirring was continued at 5-10 ℃ for 0.5 h. The reaction was quenched by the addition of water (100.0mL) and the organic layer was separated. The aqueous layer was extracted with dichloromethane (3X 50.0mL) and the combined organic phases were washed with water (2X 50.0 mL). The organic layer was dried over anhydrous sodium sulfate, and the organic layer was concentrated to obtain a crude product. Hexane (70.0mL) was added to the resulting crude and stirred at 25-30 ℃ for 0.5 hour. Then, filtration was carried out to give 2- (6-methoxynaphthalen-2-yl) -N, N-dimethylacetamide as an off-white solid in a yield of 11.11g, 92.3%.

¹H-NMR(400MHz,CDCl₃)δ:2.98(s,6H),3.81(s,3H),3.89(s,2H),7.05(d,1H),7.20(s,1H),7.40(d,1H),7.55(d,1H),7.66(s,1H),7.74(d,1H).¹³C-NMR(125MHz,CDCl₃)δ:36.74,42.39,56.08,106.60,116.32,126.35,126.89,127.05,129.60,131.29,133.38,134.15,156.99,173.77.LC-MS(ESI,pos,ion)m/z:244[M+H]。

A solution of Lithium Hexamethyldisilazide (LHMDS) (46.00mmol) in tetrahydrofuran was added to a well stirred solution of 2- (6-methoxynaphthalen-2-yl) -N, N-dimethylacetamide (11.11g, 45.66mmol) in tetrahydrofuran (100.0mL) maintaining the temperature at-60 ℃ to-70 ℃. The mixture was stirred for 30 minutes. Cyclohexanone (13.15mL, 127.29mmol) was added, maintaining the temperature at-60 ℃ to-70 ℃. After the reaction was completed, the temperature was raised to room temperature, and a saturated aqueous ammonium chloride solution was added. The pH was then adjusted to 4.0 by addition of dilute hydrochloric acid and the mixture was extracted with ethyl acetate (3X 150 mL). The combined organic extracts were washed with water and dried over anhydrous sodium sulfate. The extract was concentrated to give 2- (1-hydroxycyclohexyl) -2- (6-methoxynaphthalen-2-yl) -N, N-dimethylacetamide as a yellow solid in 13.44g, 86.2% yield.

¹H-NMR(400MHz,CDCl₃)δ:1.08(m,1H),1.26-1.37(m,4H),1.45-1.64(m,4H),1.92(t,2H),2.98(s,6H),3.80(s,3H),3.85(s,1H),7.05(d,1H),7.22(s,1H),7.25(d,1H),7.58(d,1H),7.72(d,1H),7.76(s,1H).¹³C-NMR(125MHz,CDCl₃)δ:23.06,25.61,35.06,36.72,56.08,58.27,72.87,107.12,116.50,125.87,129.53,129.94,130.00,130.13,131.91,134.59,158.15,170.67.LC-MS(ESI,pos,ion)m/z:342[M+H]。

A solution of borane (0.068mol) -tetrahydrofuran was added to a solution of 2- (1-hydroxycyclohexyl) -2- (6-methoxynaphthalen-2-yl) -N, N-dimethylacetamide (13.44g, 39.36mmol) in tetrahydrofuran (50mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 20 minutes and then heated under reflux for 3 hours. After completion of the reaction, 10% hydrochloric acid (25mL) was added and heated under reflux for 3 hours. The reaction mixture was cooled to 10 ℃ and then neutralized to pH 7.0 by the addition of 10% aqueous sodium hydroxide. The reaction was concentrated under reduced pressure to remove tetrahydrofuran, water (50mL) was added and the reaction mixture was extracted with toluene (3X 100 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated. Hexane (100mL) was added to the resulting crude product and stirred for 15 minutes. This was filtered to give 1- (2- (dimethylamino) -1- (6-methoxynaphthalen-2-yl) ethyl) cyclohex-1-ol as an off-white solid, 9.01g, yield 69.9%.

¹H-NMR(400MHz,CDCl₃)δ:1.40-1.56(m,8H),1.66(s,1H),1.73(t,2H),2.25(s,6H),2.65(m,1H),2.89-2.99(m,2H),3.81(s,3H),7.02(d,1H),7.19(s,1H),7.37(d,1H),7.52(s,1H),7.58(d,1H),7.69(d,1H).¹³C-NMR(125MHz,CDCl₃)δ:23.06,25.61,37.28,45.80,55.53,56.08,61.25,75.61,107.12,116.50,127.51,128.52,129.53,130.18,131.26,131.91,134.59,158.15.LC-MS(ESI,pos,ion)m/z:328[M+H].

1- (2- (dimethylamino) -1- (6-methoxynaphthalen-2-yl) ethyl) cyclohex-1-ol (9.01g, 27.51mmol) was dissolved in ethanol at normal pressure and 25 deg.C, 20% Pd/C (0.2g, 10% w/w) was added, nitrogen was replaced three times, hydrogen was replaced three times again, and stirring was carried out overnight. After completion of the reaction, the mixture was filtered through celite to remove the catalyst. The filtrate was concentrated to obtain a crude product. Hexane (50mL) was then added to the crude product and stirred for 1 hour. Filtration gave 6- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) naphthalen-2-ol (compound II) as an off-white solid, 7.73g, 89.7% yield.

¹H-NMR(400MHz,CDCl₃)δ:1.08(m,1H),1.26-1.37(m,4H),1.45-1.65(m,3H),1.67(s,1H),1.75(t,2H),2.25(s,6H),2.65(m,1H),2.88-2.99(m,2H),4.93(s,1H),7.00(d,1H),7.26(s,1H),7.35(d,1H),7.51(s,1H),7.57(d,1H),7.62(d,1H).¹³C-NMR(125MHz,CDCl₃)δ:23.06,25.61,37.28,45.80,55.53,61.25,75.61,110.29,118.42,127.35,128.15,128.44,130.36,130.61,132.82,134.68,155.38.LC-MS(ESI,pos,ion)m/z:314[M+H]。

Example 2 Synthesis of Compound 1

6- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) naphthalen-2-ol (7.73g, 24.66mmol) was gradually added to a suspension of sodium hydride (1.8g, 75.00mmol) in DMF (50mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours, and then 2-chloro-N, N-diethyl-1-amine (8.23g, 60.67mmol) was added to the system. After stirring at 100 ℃ for 2 hours and TLC detection of the reaction was complete, the reaction mixture was concentrated under reduced pressure and the crude product obtained was dissolved in dichloromethane (200mL), extracted with 2mol/L HCl (2 × 50mL), the aqueous phase was adjusted to pH 10 with 10% NaOH solution and then extracted with dichloromethane (2 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give compound 1 as an off-white solid, 10.74g, in 85.1% yield. LC-MS (ESI, pos, ion) M/z:512[ M + H ].

Example 3 Synthesis of Compound 2

6- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) naphthalen-2-ol (8.00g, 25.5mmol) was gradually added to a suspension of sodium hydride (1.8g, 75.00mmol) in DMF (50mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours, and then 1- (2-chloroethyl) piperidine (8.93g, 60.5mmol) was added to the system. After stirring at 100 ℃ for 2 hours and TLC detection of the reaction was complete, the reaction mixture was concentrated under reduced pressure and the crude product obtained was dissolved in dichloromethane (200mL), extracted with 2mol/L HCl (2 × 50mL), the aqueous phase was adjusted to pH 10 with 10% NaOH solution and then extracted with dichloromethane (2 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give compound 2 as an off-white solid, 11.56g, in 84.6% yield. LC-MS (ESI, pos, ion) M/z 536[ M + H ].

Example 4 Synthesis of Compound 3

6- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) naphthalen-2-ol (8.00g, 25.5mmol) was gradually added to a suspension of sodium hydride (1.8g, 75.00mmol) in DMF (50mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours, then 1- (2-chloroethyl) pyrrolidine (8.08g, 60.5mmol) was added to the system. After stirring at 100 ℃ for 2 hours and TLC detection of the reaction was complete, the reaction mixture was concentrated under reduced pressure and the crude product obtained was dissolved in dichloromethane (200mL), extracted with 2mol/L HCl (2 × 50mL), the aqueous phase was adjusted to pH 10 with 10% NaOH solution and then extracted with dichloromethane (2 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give compound 3 as an off-white solid, 11.42g, in 88.2% yield. LC-MS (ESI, pos, ion) M/z:508[ M + H ].

Example 5 Synthesis of Compound 4

6- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) naphthalen-2-ol (8.00g, 25.5mmol) was gradually added to a suspension of sodium hydride (1.8g, 75.00mmol) in DMF (50mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours, then 4- (2-chloroethyl) morpholine (9.05g, 60.5mmol) was added to the system. After stirring at 100 ℃ for 2 hours and TLC detection of the reaction was complete, the reaction mixture was concentrated under reduced pressure and the crude product obtained was dissolved in dichloromethane (200mL), extracted with 2mol/L HCl (2 × 50mL), the aqueous phase was adjusted to pH 10 with 10% NaOH solution and then extracted with dichloromethane (2 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give compound 4 as a pale yellow solid, 11.84g, yield 86.0%. LC-MS (ESI, pos, ion) M/z:540[ M + H ].

Test example 1 determination of analgesic Effect of Compound by acetate writhing test

The analgesic effect of the compound obtained by the present invention was evaluated by the acetate writhing method. ICR (CD-1) male mice (with the weight of 22-25 g) are randomly divided into a blank group, a positive group, a compound 1 group, a compound 2 group, a compound 3 group and a compound 4 group, and 6 mice are selected in each group. The blank mice were gavaged with 0.9% NaCl; aspirin 74mg.kg is administered by gastric lavage in positive group^-1(ii) a Test groups of compounds were administered at 100 mg/kg, respectively^-1The compounds 1 to 4 obtained by the invention are continuously administrated for 5 days. After 90min of the last administration, 0.2mL of 0.6% acetic acid solution is injected into the abdominal cavity of each mouse to prepare an acetic acid writhing experimental model. The number of writhing times of the mice within 15min after the intraperitoneal injection of the acetic acid solution is recorded, and the writhing inhibition rate is calculated, wherein the writhing inhibition rate (%) is (the average number of writhing of the model group-the average number of writhing of the experiment group) ÷ the number of writhing times of the model group multiplied by 100%.

The results in figure 1 show that the compounds 1-4 obtained by the invention have good analgesic effect on the animal torsion frequency of acute inflammatory pain caused by the acetic acid torsion method of mice, and the effects of the compounds 1 and 2 are obviously superior to those of positive medicaments.

Test example 2 Effect of the obtained Compound on the pain threshold of carrageenan-induced rats

Male Sprague-Dawley (SD) rats, weighing 230-270 g, were randomly divided into blank, positive, Compound 1, Compound 2, Compound 3 and Compound 4 groups of 6 rats each. The rats in the blank group were gavaged with 0.9% NaCl; aspirin 40mg.kg is administered by gastric lavage of positive group^-1(ii) a Compound experimental groups were administered at 40 mg/kg each^-1The compounds 1 to 4 obtained by the invention are continuously administrated for 5 days. 90min after the last administration, a model of acute inflammation in rats was prepared by injecting carrageenan (1% carrageenan in 0.9% NaCl, 0.1mL) intradermally into the plantar surface of the right hind paw of the rat. The mechanical paw withdrawal reflex threshold (MWT) of the rats was measured with an automatic pain measuring instrument 6 hours after the sole injection of carrageenan. The rat is placed in an organic glass cover, the bottom of the organic glass cover is a grid pad made of metal wires, the rat is allowed to adapt for 30min before testing, a von Frey filament is used for vertically stimulating the middle area of the bottom of the right hind paw of the rat, and when the rat has a definite reaction, the reading on a liquid crystal display is recorded, namely the mechanical paw withdrawal reflex threshold of the rat. The maximum application force is 55g, each test is at least 5min, and after the behavioral response (such as licking foot) caused by the stimulus completely disappears, the next stimulus is given. MWT is the average of two readings.

As shown in the results of FIG. 2, the compounds 1 to 4 obtained by the present invention all significantly increased the pain threshold of rats induced by carrageenan. The compound obtained by the invention has good analgesic effect.

Test example 3 test of acute toxicity of the obtained Compound

Kunming female mice (with the body weight of 18-22 g) were randomly divided into a blank group, a positive group, a compound 1 group, a compound 2 group, a compound 3 group and a compound 4 group, with 10 mice per group. The minimum dose lethal to all animals and the maximum dose not lethal to any animal is determined by increasing the injected dose several times. Animals were observed for 24 hours and mortality was recorded for each group of animals. Half the effective amount (ED 50) and half the lethal amount (LD 50) are used to indicate the safety of the drug. The smaller the ED50 of the drug, the larger the LD50, indicating that the drug is safer.

Table 1 test of acute toxicity of the resulting compounds.

As can be seen from the results in Table 1, the compounds 1 to 4 obtained by the present invention all have less biological toxicity.

Pharmacological screening and biological evaluation show that the compound obtained by the invention has good analgesic activity and smaller biotoxicity. Therefore, the compound provided by the invention has good analgesic activity and low toxicity, can be further researched in preclinical stage as an analgesic candidate drug, and can also be further researched as an analgesic lead compound.