CN113979997A - N, N- (4-piperidyl, aryl) -3-aminophenol derivatives, pharmaceutical composition and application thereof - Google Patents

N, N- (4-piperidyl, aryl) -3-aminophenol derivatives, pharmaceutical composition and application thereof Download PDF

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CN113979997A
CN113979997A CN202111337681.7A CN202111337681A CN113979997A CN 113979997 A CN113979997 A CN 113979997A CN 202111337681 A CN202111337681 A CN 202111337681A CN 113979997 A CN113979997 A CN 113979997A
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汪亮亮
曹峰
蒋绚
张树群
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Abstract

The invention provides N, N- (4-piperidyl, aryl) -3-aminophenol derivatives, a pharmaceutical composition taking the derivatives as an active ingredient, a preparation method and application thereof, and belongs to the technical field of medicines. The N, N- (4-piperidyl, aryl) -3-aminophenol compound has obvious opioid receptor agonistic activity, has triple agonistic activity on MOR receptors, DOR receptors and KORs, and has higher agonistic activity on the MOR receptors and the DOR receptors than the KOR receptors.

Description

N, N- (4-piperidyl, aryl) -3-aminophenol derivatives, pharmaceutical composition and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to N, N- (4-piperidyl, aryl) -3-aminophenol derivatives, a preparation method thereof, a pharmaceutical composition using the compounds as active ingredients, and application thereof in preparing novel potent analgesic drugs.
Background
Opioid drugs target in vivo as opioid receptors, and are widely concerned in the fields of clinical medicine and public health due to their potent analgesic ability. Opioid drugs are often associated with side effects such as euphoria, physical dependence, respiratory depression and constipation, and thus finding safer and more effective analgesics is an important issue in the field of opioid research.
Opioid Receptors belong to the G Protein-Coupled Receptors (GPCRs) family A. To date, four Opioid Receptor subtypes have been cloned, the μ -Opioid receptors (Mu Opioid Receptor, MOR), the κ -Opioid receptors (Kappa Opioid Receptor, KOR), the δ -Opioid receptors (Delta Opioid Receptor, DOR), and the Nociceptin Opioid receptors (NOP).
MOR agonists such as morphine are potent analgesics for severe pain such as cancer pain, but are limited in use because of their serious side effects such as euphoria, physical dependence, respiratory depression and constipation. Activation of KOR agonists in vivo may produce a strong analgesic effect without the potential for abuse, but may produce serious adverse side effects such as dysphoria, water diuresis, salivation, vomiting, and sedation in non-human primates. The DOR agonist has weak analgesic activity, only aims at inflammatory pain, and has the main side effect of convulsion, but the targeted DOR agonist has not been clinically approved. A great deal of pharmacological evidence indicates that the fourth subtype NOP gene is significantly different from other opioid receptors. Animal model and clinical test results show that the combined administration of opioid receptor agonists of different subtypes can reduce the initiation of side effects in vivo. Therefore, the opioid receptor multi-agonist can simultaneously activate DOR/MOR/KOR to counteract the side effect generated by independently activating one subtype, can keep the analgesic effect and has higher respiratory safety and less abuse tendency.
At present, in the prior art, no novel N, N- (4-piperidyl, aryl) -3-aminophenol derivative is reported, and no pharmacological activity is reported.
Disclosure of Invention
The invention designs and synthesizes DOR, MOR and KOR triple agonists based on the crystal structures of opioid receptors DOR, MOR and KOR to obtain novel N, N- (4-piperidyl, aryl) -3-aminophenol derivatives, thereby improving the powerful analgesic capacity. The purpose is to provide an N, N- (4-piperidyl, aryl) -3-aminophenol compound with a general formula (1), a preparation method thereof, a pharmaceutical composition taking the compound as an active ingredient, and an application of the compound in preparing a potent analgesic.
In order to achieve the above purpose of the present invention, the present invention provides the following technical solutions:
an N, N- (4-piperidyl, aryl) -3-aminophenol derivative represented by the following general formula (1),
Figure BDA0003350914460000021
wherein n is 0,1, 2;
ar can be one of the following groups:
Figure BDA0003350914460000022
wherein W can be H, Me, Et, F, Cl, Br, I, CF3Group of Ph etc
R may be one of the following groups:
Figure BDA0003350914460000023
wherein R is1，R2,R3Independently of one another, may be H, Me, Et, F, Cl, Br, I, CF3Ph, etc., X, Y, Z may be C, N atoms independently of each other; the value of n' is 0-4;
the N, N- (4-piperidyl, aryl) -3-aminophenol derivative is applied to the preparation of the opioid receptor agonist.
The N, N- (4-piperidyl, aryl) -3-aminophenol derivatives are applied to the preparation of potent analgesic drugs.
The preparation method of the N, N- (4-piperidyl, aryl) -3-aminophenol derivative comprises the following steps:
Figure BDA0003350914460000031
(1) step1, 1, 2-dichloroethane is taken as a solvent, and 3-amino aniline and N-tert-butyloxycarbonyl-4-piperidone are subjected to reductive amination in the presence of sodium triacetoxyborohydride and glacial acetic acid to obtain a compound 31;
(2) step 2: using dichloromethane as a solvent, and reacting a compound 31 under the catalysis of 4-methyl benzenesulfonic acid pyridine and the protection of 3, 4-dihydro-2H-pyran to obtain a compound 32;
(3) step 3: taking toluene as a solvent, and carrying out a coupling reaction of a compound 32 and ArI catalyzed by bis (dibenzylideneacetone) palladium in the presence of sodium tert-butoxide and tri-tert-butylphosphine to obtain a compound 33;
wherein Ar is as defined above;
(4) step 4: using dichloromethane as a solvent, and removing a protecting group of the compound 33 by using trifluoroacetic acid to obtain a compound 34;
(5) step 5: taking N, N-dimethylformamide as a solvent, and carrying out reductive amination on the compound 34 in the presence of sodium triacetoxyborohydride and glacial acetic acid to obtain a compound 1;
wherein R is as defined above.
The compounds of the general formula 1 of the invention can be prepared by the above or similar preparation method, and corresponding starting materials are selected according to different substituents and different positions of the substituents. It will be appreciated by those skilled in the art that the above routes are useful for understanding the present invention, but do not limit the content of the present invention, and the variables are defined as mentioned in formula 1 unless otherwise specified.
The invention also provides a pharmaceutical composition, which comprises any one or any combination of the N, N- (4-piperidyl, aryl) -3-aminophenol derivatives and at least one pharmaceutically acceptable carrier.
The application of the pharmaceutical composition in preparing medicaments of opioid receptor agonists.
The application of the pharmaceutical composition in preparing analgesic drugs.
The method for preparing the pharmaceutical composition comprises the steps of firstly obtaining the compound according to the method for preparing the compound, and finally adding one or any combination of the prepared compounds into a pharmaceutically acceptable carrier to prepare the pharmaceutical composition.
The pharmaceutical composition comprises the compound of the general formula 1 or pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate thereof and pharmaceutically acceptable carrier or excipient.
According to the invention, the test of the agonistic activity of opioid receptors (MOR, DOR and KOR) proves that the N, N- (4-piperidyl, aryl) -3-aminophenol compound with the general formula 1 has good opioid receptor (MOR, DOR and KOR) triple agonistic activity, and the compound can be used for preparing a powerful analgesic.
Compared with the prior art, the invention has the following advantages:
1. the novel N, N- (4-piperidyl, aryl) -3-aminophenol derivatives are synthesized for the first time, novel compounds with good medicinal value are provided in the prior art, and the technical blank is filled.
2. The preparation method of the novel N, N- (4-piperidyl, aryl) -3-aminophenol derivative provided by the invention is simple and feasible, high in yield, environment-friendly and material-saving.
3. The novel N, N- (4-piperidyl, aryl) -3-aminophenol derivative provided by the invention has better triple agonistic activity on three types of opioid receptors, and particularly has agonistic activity on MOR and DOR up to the nM level.
4. The invention provides a brand-new medicine application of novel N, N- (4-piperidyl, aryl) -3-aminophenol derivatives, and provides a compound related to the invention for preparing a potent analgesic.
5. The invention provides a brand-new medicine application of a novel N, N- (4-piperidyl, aryl) -3-aminophenol derivative, and provides an application of the novel N, N- (4-piperidyl, aryl) -3-aminophenol derivative in preparing a medicine of an opioid receptor agonist.
Description of the drawings:
FIG. 1 is a schematic structural diagram of an N, N- (4-piperidyl, aryl) -3-aminophenol compound of the present invention:
FIG. 2 is a flow chart of the synthetic route of the present invention.
Detailed Description
The inventor has extensively and deeply studied and found a group of compounds with brand new structure, the derivatives can activate MOR, DOR, KOR opioid receptors, and EC of agonistic activity of some compounds50Values reached the nM range. The present invention has been completed based on this finding.
The present inventors have synthesized a series of candidate compounds with MOR, DOR, KOR opioid receptor agonistic activity. Through structural optimization design of the obtained candidate compounds, a batch of novel N, N- (4-piperidyl, aryl) -3-aminophenol compounds with agonistic activity on MOR, DOR and KOR opioid receptors are discovered, cellular level activity evaluation is carried out on the compounds, and a plurality of compounds have agonistic activity EC on MOR, DOR and KOR opioid receptors50Values reached the nM range. The following examples are provided to further illustrate the essence of the present invention, but are not intended to limit the present invention.
The following description will further explain the substance of the present invention by using the embodiments of the present invention with reference to the accompanying drawings, but the present invention is not limited thereto.
The following will describe the preparation of the compound of formula 1 according to the present invention with reference to specific examples, but these specific methods do not limit the present invention in any way. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
Example 1:
the synthesis general formula is as follows:
Figure BDA0003350914460000051
intermediate 31 synthesis:
to a reaction flask treated with anhydrous oxygen-free was added 3-aminophenol (5.0g, 45.9mmol, 1.0eq) dissolved in 1, 2-dichloroethane (150mL) with stirring at room temperature, followed by N-tert-butoxycarbonyl-4-piperidone (9.2g, 45.8mmol, 1.0eq), sodium triacetoxyborohydride (14.6g, 68.7mmol, 1.5eq) and glacial acetic acid (4.1mL, 68.7mmol, 1.5 eq). After 24h, quench by addition of 1N sodium hydroxide solution (76.1mL, 76.1mmol) and purify by column chromatography as in the general experimental procedure to give intermediate 31(9.9g, 74.7%).
Intermediate 32 synthesis:
compound 31(5.0g, 17.1mmol, 1.0eq) was added to a pressure-resistant flask treated with anhydrous oxygen-free water dissolved in ultra-dry dichloromethane (35mL) at room temperature with stirring, followed by the addition of pyridine 4-methylbenzenesulfonate (640.0mg, 1.7mmol, 0.1eq) and DHP (4.3g, 51.0mmol, 3.0 eq). The pressure bottle was sealed under argon protection, heated to 40 ℃ for 24h, cooled to room temperature, quenched with sodium bicarbonate solution, post-experimental treatment according to general experimental procedures, and purified by column chromatography to give intermediate 32(3.0g, 46.6%).
Synthesis of intermediate 33:
adding the intermediate 32(1.0eq) into a reaction tube subjected to anaerobic treatment, dissolving the intermediate in toluene at room temperature under stirring, sequentially adding sodium tert-butoxide (4.0eq), bis (dibenzylideneacetone) palladium (0.1eq), tri-tert-butylphosphine (428, 0.1eq) and aryl iodide ArI (1.4eq), sealing the reaction tube under the protection of argon, heating to 140 ℃, monitoring the completion of the reaction, cooling to room temperature, filtering with diatomite, concentrating, and purifying by column chromatography to obtain the intermediate 33.
Synthesis of intermediate 34:
adding the intermediate 33(1.0eq) into a reaction tube, dissolving in dichloroethane, cooling to 0 ℃, slowly adding trifluoroacetic acid (60.0eq) dropwise, moving to normal temperature, monitoring the completion of the reaction, adding sodium bicarbonate under ice bath to quench, carrying out post-experimental treatment according to general experimental operation, and purifying by column chromatography to obtain an intermediate 34.
Synthesis of final product 1:
the above intermediate 34(1.0eq) and N, N-dimethylformamide were added to a reaction flask subjected to anhydrous oxygen-free treatment, and isobutyraldehyde (1.0eq), sodium triacetoxyborohydride (1.5eq) and glacial acetic acid (1.5eq) were added in this order. After 24h, after monitoring the reaction, adding saturated sodium bicarbonate to quench, carrying out post-experimental treatment according to general experimental operation, and purifying by column chromatography to obtain the product 1.
Specific compounds were prepared as follows:
1. 3- ((1-Benzylpiperidin-4-yl) (pyridin-3-yl) amino) phenol (Compound 2) referring to the above synthetic general formulas Step 1-5, 3-iodopyridine was used in Step3 instead of ArI, and benzaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.92(q,J＝10.04Hz,2H),7.26(m,5H),7.09(m,J＝5.00Hz,2H),6.94(d,J＝7.47Hz,1H),6.57(d,J＝7.96Hz,1H),6.41(d,J＝7.73Hz,1H),6.21(s,1H),3.74(m,1H),3.53(s,2H),2.98(d,J＝11.31Hz,2H),2.14(t,J＝11.55Hz,2H),1.83(d,J＝12.05Hz,2H),1.54(q,J＝11.18Hz,2H).
2. 3- ((1-Phenylethylpiperidin-4-yl) (pyridin-3-yl) amino) phenol (Compound 3) referring to the above synthetic general formulas Step 1-5, 3-iodopyridine was used in Step3 instead of ArI, and phenylacetaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.95(q,J＝5.91Hz,2H),7.24(m,2H),7.12(m,5H),6.97(d,J＝7.36Hz,1H),6.58(d,J＝8.03Hz,1H),6.43(d,J＝7.80Hz,1H),6.31(s,1H),3.80(m,1H),3.12(d,J＝11.35Hz,2H),2.79(m,2H),2.63(m,2H),2.23(t,J＝11.56Hz,2H),1.92(d,J＝12.23Hz,2H),1.63(q,J＝11.42,2H).
3. 3- ((1- (2- (naphthalen-2-yl) ethyl) piperidin-4-yl) (pyridin-3-yl) amino) phenol (Compound 4) referring to the above synthetic general formulas Step 1-5, 3-iodopyridine was used in Step3 instead of ArI, and 2-naphthaleneacetaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ8.02(d,J＝13.91Hz,3H),7.83(d,J＝10.56Hz,1H),7.71(d,J＝8.07Hz,1H),7.46(m,2H),7.37(t,J＝6.36Hz,1H),7.31(d,J＝5.45Hz,1H),7.17(t,J＝7.95Hz,1H),7.09(m,1H),7.00(d,J＝7.95Hz,1H),6.68(d,J＝7.83Hz,1H),6.47(d,J＝7.70Hz,1H),6.43(s,1H),3.88(m,1H),3.31(m,2H),3.25(d,J＝11.13Hz,2H),2.79(t,J＝8.07Hz,2H),2.37(t,J＝12.54Hz,2H),1.98(d,J＝11.86Hz,2H),1.74(m,J＝9.35Hz,2H).
4. 3- ((1- (2-Fluorophenethyl) piperidin-4-yl) (pyridin-3-yl) amino) phenol (Compound 5) referring to the above synthetic general formulas Step 1-5, 3-iodopyridine was used instead of ArI in Step3, and 2-Fluorophenylacetaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.98(q,J＝5.46Hz,2H),7.14(m,4H),7.02(m,3H),6.64(d,J＝7.58Hz,1H),6.45(d,J＝7.80Hz,1H),6.37(s,1H),3.85(m,1H),3.19(d,J＝10.88Hz,2H),2.88(m,2H),2.69(m,2H),2.34(t,J＝13.32Hz,2H),1.97(m,2H),1.70(m,2H).
5. 3- ((1- (3-Fluorophenethyl) piperidin-4-yl) (pyridin-3-yl) amino) phenol (Compound 6) referring to the above synthetic general formulas Step 1-5, 3-iodopyridine was used instead of ArI in Step3, and 3-fluorobenzaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.97(q,J＝7.22Hz,2H),7.22(q,J＝7.67Hz,1H),7.12(m,2H),7.01(d,J＝7.20Hz,1H),6.94(d,J＝7.24Hz,1H),6.88(q,J＝5.34Hz,2H),6.63(d,J＝7.70Hz,1H),6.45(d,J＝7.70Hz,1H),6.35(s,1H),3.83(m,1H),3.14(d,J＝11.13Hz,2H),2.82(q,J＝5.34Hz,2H),2.66(q,J＝5.34Hz,2H),2.28(t,J＝11.13Hz,2H),1.95(d,J＝11.92Hz,2H),1.65(q,J＝11.37Hz,2H).
6. 3- ((1- (4-Fluorophenethyl) piperidin-4-yl) (pyridin-3-yl) amino) phenol (Compound 7) referring to the above synthetic general formulas Step 1-5, 3-iodopyridine was used instead of ArI in Step3, and 4-fluorobenzaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.97(q,J＝4.65Hz,2H),7.11(m,4H),6.94(m,3H),6.62(d,J＝7.95Hz,1H),6.45(d,J＝7.83Hz,1H),6.35(s,1H),3.83(m,1H),3.13(d,J＝11.25Hz,2H),2.78(m,J＝4.00Hz,2H),2.62(m,J＝5.40Hz,2H),2.26(t,J＝11.37Hz,2H),1.94(d,J＝12.10Hz,2H),1.64(q,J＝11.25Hz,2H).
7. 3- ((1- (4-Chlorophenylethyl) piperidin-4-yl) (pyridin-3-yl) amino) phenol (Compound 8) As shown in the above synthetic general formulas, Steps 1-5 were synthesized, using 3-iodopyridine instead of ArI in Step3, and 4-chlorophenylacetaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.98(q,J＝4.32Hz,2H),7.22(d,J＝8.19Hz,2H),7.11(m,J＝7.98Hz,4H),6.99(d,J＝8.81Hz,1H),6.64(d,J＝7.83Hz,1H),6.43(d,J＝7.83Hz,1H),6.37(s,1H),3.81(m,1H),3.08(d,J＝10.83Hz,2H),2.75(q,J＝5.34Hz,2H),2.58(q,J＝5.38Hz,2H),2.21(t,J＝11.55Hz,2H),1.93(d,J＝12.35Hz,2H),1.61(m,J＝11.04Hz,2H).
8. 3- ((1- (4-bromophenyl) piperidin-4-yl) (pyridin-3-yl) amino) phenol (Compound 9) referring to the above synthetic general formulas Step 1-5, 3-iodopyridine was used instead of ArI in Step3, and 4-bromobenzaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.97(q,J＝3.99Hz,2H),7.37(d,J＝8.19Hz,2H),7.11(m,2H),7.01(q,J＝7.99Hz,3H),6.61(d,J＝8.07Hz,1H),6.44(d,J＝7.83Hz,1H),6.35(s,1H),3.80(m,1H),3.09(d,J＝11.25Hz,2H),2.74(q,J＝5.34Hz,2H),2.59(q,J＝5.34Hz,2H),2.21(t,J＝11.55Hz,2H),1.92(d,J＝11.98Hz,2H),1.61(q,J＝11.25Hz,2H).
9. 3- (pyridin-3-yl (1- (4- (trifluoromethyl) phenethyl) piperidin-4-yl) amino) phenol (Compound 10) referring to the above synthetic general formulas Step 1-5, 3-iodopyridine was used in Step3 instead of ArI, and 4-trifluoromethylphenylacetaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ8.07(d,J＝2.69Hz,2H),7.61(d,J＝8.07Hz,2H),7.37(d,J＝7.83Hz,2H),7.22(m,2H),7.09(d,J＝8.22Hz,1H),6.76(d,J＝7.95Hz,1H),6.54(d,J＝7.95Hz,1H),6.50(s,1H),3.95(m,1H),3.24(d,J＝11.13Hz,2H),2.96(q,J＝5.30Hz,2H),2.78(q,J＝5.38Hz,2H),2.40(t,J＝11.49Hz,2H),2.04(d,J＝12.35Hz,2H),1.74(q,J＝11.13Hz,2H).
10. 3- ((1- (2- (pyridin-2-yl) ethyl) piperidin-4-yl) (pyridin-3-yl) amino) phenol (Compound 11) referring to the above synthetic general formulas Step 1-5, 3-iodopyridine was used in Step3 instead of ArI, and 2-pyridineacetaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ8.48(d,J＝3.42Hz,1H),7.98(m,2H),7.58(t,J＝7.27Hz,1H),7.12(m,4H),7.00(d,J＝7.46Hz,1H)6.61(d,J＝7.34Hz,1H),6.41(d,J＝7.58Hz,1H),6.36(s,1H),3.79(m,J＝5.50Hz,1H),3.08(d,J＝10.39Hz,2H),2.99(q,J＝6.85Hz,2H),2.79(q,J＝6.64Hz,2H),2.23(t,J＝11.31Hz,2H),1.91(d,J＝11.86Hz,2H),1.58(q,J＝10.45Hz,2H).
11. 3- (pyridin-3-yl (1- (2- (pyridine-3))-yl) ethyl) piperidin-4-yl) amino) phenol (compound 12) referring to the above synthetic general formulas Step 1-5, 3-iodopyridine was used in Step3 instead of ArI, and 3-pyridylacetaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ8.43(s,2H),8.00(d,J＝8.19Hz,2H),7.51(d,J＝7.21Hz,1H),7.21(t,J＝5.75Hz,1H),7.13(q,J＝7.50Hz,2H),7.02(d,J＝7.70Hz,1H),6.66(d,J＝7.58Hz,1H),6.42(d,J＝10.51Hz,2H),3.82(m,J＝5.35Hz,1H),3.08(d,J＝9.05Hz,2H),2.78(q,J＝4.36Hz,2H),2.62(q,J＝3.06Hz,2H),2.23(t,J＝12.34Hz,2H),1.94(d,J＝11.62Hz,2H),1.58(q,J＝10.79Hz,2H).
12. 3- (pyridin-3-yl (1- (2- (pyridin-4-yl) ethyl) piperidin-4-yl) amino) phenol (Compound 13) referring to the above synthetic general formulas Step 1-5, 3-iodopyridine was used in Step3 instead of ArI, and 4-pyridineacetaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ8.47(d,J＝4.89Hz,2H),8.01(d,J＝11.76Hz,2H),7.14(m,4H),7.04(d,J＝8.19Hz,1H),6.66(d,J＝6.97Hz,1H),6.44(d,J＝7.83Hz,1H),6.39(s,1H),3.85(m,1H),3.14(d,J＝13.33Hz,2H),2.83(q,J＝5.54Hz,2H),2.71(q,J＝5.09Hz,2H),2.32(t,J＝12.17Hz,2H),1.97(d,J＝12.47Hz,2H),1.64(q,J＝11.21Hz,2H).
13. 3- ((1-Phenylethylpiperidin-4-yl) (pyridin-2-yl) amino) phenol (Compound 14) referring to the above synthetic general formulas Step 1-5, 2-iodopyridine was used in Step3 instead of ArI, and phenylacetaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ8.11(d,J＝4.16Hz,1H),7.23(d,J＝7.08Hz,2H),7.17(m,5H),6.66(d,J＝7.70Hz,1H),6.52(m,2H),6.44(s,1H),6.02(d,J＝8.56Hz,1H),4.97(m,1H),3.22(d,J＝10.64Hz,2H),2.88(q,J＝5.05Hz,2H),2.75(q,J＝5.38Hz,2H),2.47(t,J＝11.43Hz,2H),1.93(d,J＝11.62Hz,2H),1.78(q,J＝10.69Hz,2H).
14. 3- ((1-Phenylethylpiperidin-4-yl) (pyridin-4-yl) amino) phenol (Compound 15) referring to the above synthetic general formulas Step 1-5, 4-iodopyridine was used in Step3 instead of ArI, and phenylacetaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ8.02(d,J＝5.99Hz,2H),7.22(m,5H),7.14(d,J＝7.83Hz,1H),6.83(d,J＝8.44Hz,1H),6.49(d,J＝8.44Hz,1H),6.39(d,J＝5.75Hz,2H),3.85(m,1H),3.08(d,J＝11.00Hz,2H),2.76(q,J＝5.42Hz,2H),2.59(q,J＝5.30Hz,2H),2.18(t,J＝11.49Hz,2H),1.89(d,J＝11.74Hz,2H),1.63(q,J＝11.13Hz,2H).
15. 3- (piperidin-4-yl (thien-3-yl) amino) phenol (Compound 16) according to the general formula for the synthesis described above, 16 was obtained in Step4 using 3-thienyliodo in Step3 instead of ArI.1H NMR(400MHz,MeOD-d4)δ7.36(dd,J1＝5.1,J2＝3.1Hz,1H),6.96(t,J＝8.2Hz,2H),6.84(dd,J1＝3.1,J2＝1.4Hz,1H),6.71(dd,J1＝5.2,J2＝1.4Hz,1H),6.26(ddd,J1＝7.9,J2＝5.0,J3＝2.2Hz,2H),6.19(t,J＝2.3Hz,1H),3.88(tt,J1＝11.9,J2＝3.7Hz,1H),3.07(dt,J1＝13.5,J2＝2.9Hz,2H),2.72(td,J1＝12.6,J2＝2.4Hz,2H),1.97(dd,J1＝12.9,J2＝3.2Hz,2H),1.42(qd,J1＝12.5,J2＝4.0Hz,2H).
16. 3- ((1-isobutylpiperidin-4-yl) (thiophen-3-yl) amino) phenol (compound 17): referring to the synthetic general formulas Step 1-5, 3-thiophene iodine is used in Step3 instead of ArI, and isobutyraldehyde is used in Step 5.1H NMR(400MHz,CDCl3)δ7.20(dd,J1＝4.7,J2＝3.5Hz,1H),7.02(t,J＝8.2Hz,1H),6.66(d,J＝4.9Hz,2H),6.27(ddd,J1＝10.1,J2＝7.9,J3＝2.2Hz,2H),6.10(t,J＝2.4Hz,1H),3.69(tt,J1＝11.9,J2＝3.8Hz,1H),2.96(dt,J1＝12.7,J2＝3.2Hz,2H),2.10(d,J＝7.1Hz,2H),2.03(td,J1＝12.1,J2＝2.3Hz,2H),1.89(dt,J1＝12.6,J2＝3.1Hz,3H),1.75(m,1H),1.60(qd,J1＝12.5,J2＝3.6Hz,2H),0.89(d,J＝6.8Hz,6H).
17. 3- ((1- (3-methyl-2-en-1-yl) piperidin-4-yl) (thiophen-3-yl) amino) phenol (compound 18): referring to the synthetic general formulas Step 1-5, 3-thiophene iodine is used in Step3 instead of ArI, and 3-methyl-2-enal is used in Step 5.1H NMR(400MHz,CDCl3)δ7.17(dd,J1＝5.0,J2＝3.1Hz,1H),7.04(t,J＝8.2Hz,1H),6.63(d,J＝5.1Hz,1H),6.61(dd,J1＝3.4,J2＝1.8Hz,1H),6.30(ddd,J1＝13.1,J2＝8.0,J3＝2.2Hz,2H),6.13(d,J＝2.3Hz,1H),5.22(t,J＝7.3Hz,1H),3.70(tt,J1＝11.9,J2＝3.8Hz,1H),3.02(d,J＝11.5Hz,2H),2.96–2.94(m,2H),2.09(t,J＝11.6Hz,2H),1.92(d,J＝12.2Hz,2H),1.68(s,3H),1.63(s,3H),1.57(td,J1＝13.2,J2＝12.7,4.0Hz,2H).
18. 3- ((1- (4-Fluorobenzyl) piperidin-4-yl) (thiophen-3-yl) amino) phenol (Compound 19) referring to the above synthetic general formulas Step 1-5, 3-thiophenediiodo was used in Step3 instead of ArI, and 4-fluorobenzaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.30–7.19(m,3H),6.98(dt,J1＝16.9,J2＝8.3Hz,3H),6.64(dd,J1＝7.3,J2＝4.0Hz,2H),6.24(ddd,J1＝18.3,J2＝8.1,J3＝2.3Hz,2H),6.04(t,J＝2.2Hz,1H),3.68(tt,J1＝11.8,J2＝3.9Hz,1H),3.45(s,2H),2.91(d,J＝11.5Hz,2H),2.07(t,J＝11.2Hz,2H),1.87(dt,J1＝12.9,J2＝2.9Hz,2H),1.53(qd,J1＝12.4,J2＝3.7Hz,2H).
19. 3- ((1- ((1H-pyrrol-2-yl) methyl) piperidin-4-yl) (thiophen-3-yl) amino) phenol (Compound 20) referring to the above synthetic general formulas Step 1-5, 3-thiophenediodine was used in Step3 instead of ArI, and 2-pyrrolecarboxaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ8.78(s,1H),7.23(dd,J1＝5.1,J2＝3.2Hz,1H),7.03(t,J＝8.2Hz,1H),6.71(q,J＝2.4Hz,1H),6.64(d,J＝5.0Hz,2H),6.28(td,J1＝8.2,J2＝2.1Hz,2H),6.13(d,J＝2.3Hz,1H),6.10(d,J＝2.9Hz,1H),6.05(d,J＝3.2Hz,1H),3.73(ddt,J1＝12.0,J2＝7.9,J3＝3.9Hz,1H),3.54(s,2H),2.98(d,J＝11.8Hz,2H),2.15(t,J＝12.0Hz,2H),1.93(d,J＝12.8Hz,3H),1.54(qd,J1＝12.7,J2＝3.4Hz,2H).
20. 3- ((1- (cyclopropylmethyl) piperidin-4-yl) (thiophen-3-yl) amino) phenol (Compound 21) referring to the synthetic general formulas Step 1-5 above, 3-thiophenediodine was used in Step3 instead of ArI, and cyclopropylcarboxaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.12(dd,J1＝5.2,J2＝3.1Hz,1H),7.03(t,J＝8.1Hz,1H)6.52(dd,J1＝5.2,J2＝1.4Hz,1H),6.40(d,J＝3.0Hz,1H),6.35(ddd,J1＝14.0,J2＝8.1,J3＝2.1Hz,2H),6.15(t,J＝2.3Hz,1H),3.69(tt,J1＝12.0,J2＝3.9Hz,1H),3.17(d,J＝11.6Hz,2H),2.23(d,J＝6.8Hz,2H),2.10(t,J＝11.6Hz,2H),1.95(d,J＝3.6Hz,2H),1.63(qd,J1＝12.5,J2＝3.8Hz,2H),0.81(dtt,J1＝12.0,J2＝7.0,J3＝3.5Hz,1H),0.47–0.42(m,2H),0.08(t,J＝5.0Hz,2H).
21. 3- ((1- (cyclobutylmethyl) piperidin-4-yl) (thiophen-3-yl) amino) phenol (Compound 22) referring to the general synthesis formulas Step 1-5 above, 3-thienyliodo was used in Step3 instead of ArI, and cyclobutylmethyl aldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.16(q,J＝2.67Hz,1H),7.01(t,J＝8.06Hz,1H),6.57(d,J＝4.64Hz,1H),6.48(d,J＝1.36Hz,1H),6.31(t,J＝7.86Hz,2H),6.16(s,1H),3.70(m,1H),3.01(d,J＝11.36Hz,2H),2.48(d,J＝6.25Hz,2H),2.22(t,J＝11.44Hz,2H),2.01(q,J＝8.32Hz,2H),1.91(d,J＝12.28Hz,2H),1.84(m,1H),1.73(m,2H),1.67(m,2H),1.63(m,2H).
22. 3- ((1- (Cyclopentylmethyl) piperidin-4-yl) (thiophen-3-yl) amino) phenol (Compound 23) referring to the above synthetic general formulas Step 1-5, 3-thiophenediiodo was used in Step3 instead of ArI, and cyclopentylaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.16(dd,J1＝5.1,J2＝3.1Hz,1H),7.03(t,J＝8.2Hz,1H),6.59(d,J＝5.1Hz,1H),6.51(d,J＝3.1Hz,1H),6.30(ddd,J1＝19.5,J2＝8.1,J3＝2.2Hz,2H),6.08(s,1H),3.68(tt,J＝11.8,3.8Hz,1H),3.02(d,J＝11.5Hz,2H),2.29(d,J＝6.9Hz,2H),2.06(t,J＝11.8Hz,2H),1.98(m,1H),1.89(d,J＝11.5Hz,2H),1.75(dd,J1＝12.0,J2＝6.6Hz,2H),1.60(m,2H),1.55(m,2H),1.45(m,2H),1.11(m,2H).
23. 3- ((1- (cyclohexylmethyl) piperidin-4-yl) (thiophen-3-yl) amino) phenol (Compound 24) referring to the above synthetic general formulas Step 1-5, 3-thiophenediodine was used in Step3 instead of ArI, and cyclohexylformaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.27(m,1H),7.02(t,J＝8.2Hz,1H),6.72(d,J＝3.2Hz,1H),6.69(d,J＝5.1Hz,1H),6.27(td,J1＝8.3,J2＝2.3Hz,2H),6.13(d,J＝2.5Hz,1H),3.69(tt,J1＝11.6,J2＝3.9Hz,1H),2.96(d,J＝11.5Hz,2H),2.11(d,J＝6.8Hz,2H),2.00(t,J＝11.8Hz,2H),1.89(d,J＝12.2Hz,2H),1.73–1.61(m,4H),1.60–1.50(m,2H),1.45–1.40(m,1H),1.19–1.09(m,4H),0.88–0.80(m,2H).
24. 3- ((1- (cycloheptylmethyl) piperidin-4-yl) (thiophen-3-yl) amino) phenol (Compound 25) referring to the synthetic general formulas Step 1-5 above, 3-thiophenediodine was used instead of ArI in Step3, and cycloheptylaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.21(m,1H),7.00(t,J＝7.98Hz,1H),6.65(d,J＝4.88Hz,2H),6.31(d,J＝7.64Hz,1H),6.25(d,J＝8.08Hz,1H),6.20(s,1H),3.71(m,1H),3.02(d,J＝10.88Hz,2H),2.20(d,J＝6.32Hz,2H),2.13(t,J＝11.34Hz,2H),1.90(d,J＝12.04Hz,2H),1.70(m,2H),1.61(m,2H),1.56(m,1H),1.52(m,2H),1.46(m,2H),1.35(m,2H),1.27(m,2H),1.11(q,J＝10.03Hz,2H).
25. 3- ((1-Benzylpiperidin-4-yl) (thiophen-3-yl) amino) phenol (Compound 26) referring to the above synthetic general formulas Step 1-5, 3-thiophenediodine was used in Step3 instead of ArI, and benzaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.24–7.20(m,5H),7.18(t,J＝4.1Hz,1H),6.98(t,J＝8.2Hz,1H),6.61(d,J＝4.2Hz,2H),6.23(ddd,J1＝16.3,J2＝8.1,J3＝2.2Hz,2H),6.02(d,J＝2.5Hz,1H),3.65(tt,J1＝11.9,J2＝3.8Hz,1H),3.47(s,2H),2.93(dd,J1＝9.0,J2＝6.1Hz,2H),2.07(t,J＝11.6Hz,2H),1.84(d,12.2Hz,2H),1.54(qd,J1＝12.5,J2＝3.7Hz,2H).
26. 3- ((1-Phenethylpiperidin-4-yl) (thien-3-yl) amino) phenol (Compound 27) referring to the above synthetic general formulas Step 1-5, 3-thienyliodo was used in Step3 instead of ArI, and phenylacetaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.23(d,J＝7.24Hz,2H),7.17(m,2H),7.13(d,J＝7.65Hz,2H),7.00(t,J＝8.09Hz,1H),6.62(d,J＝4.09Hz,2H),6.28(m,J＝4.01Hz,2H),6.17(s,1H),3.73(m,1H),3.12(d,J＝11.47Hz,2H),2.79(m,2H),2.63(m,2H),2.23(t,J＝11.61Hz,2H),1.94(d,J＝11.95Hz,2H),1.67(q,J＝11.25Hz,2H).
27. 3- ((1- (3-phenylpropyl) piperidin-4-yl) (thiophen-3-yl) amino) phenol (Compound 28) referring to the above synthetic general formulas Step 1-5, 3-thiophenediodine was used in Step3 instead of ArI, and phenylpropanal was used in Step 5.1H NMR(400MHz,CDCl3)δ7.25(d,J＝3.7Hz,1H),7.23(d,J＝7.4Hz,1H),7.19–7.09(m,4H),6.96(t,J＝8.1Hz,1H),6.61(dd,J1＝6.9,J2＝4.1Hz,2H),6.42(s,1H),6.38(dd,J1＝8.1,J2＝2.2Hz,1H),6.18(dd,J1＝8.2,J2＝2.1Hz,1H),3.82(t,J＝4.0Hz,1H),3.18(d,J＝11.6Hz,2H),2.62–2.55(m,4H),2.50(t,J＝12.2Hz,2H),1.95–1.88(m,4H),1.82(t,J＝12.7Hz,2H).
28. 3- ((1- (4-phenylbutyl) piperidin-4-yl) (thiophen-3-yl) amino) phenol (Compound 29) referring to the synthetic general formulas Step 1-5 above, 3-thiophenediodine was used instead of ArI in Step3, and 4-phenylbutanol was used in Step 5.1H NMR(400MHz,CDCl3)δ7.23(d,J＝7.44Hz,2H),7.16(m,2H),7.12(d,J＝8.32Hz,2H),7.01(t,J＝8.06Hz,1H),6.58(d,J＝4.36Hz,1H),6.52(d,J＝1.64Hz,1H),6.29(t,J＝6.68Hz,2H),6.12(s,1H),3.70(m,1H),3.02(d,J＝11.24Hz,2H),2.57(m,2H),2.38(m,2H),2.13(t,J＝11.60Hz,2H),1.91(d,J＝12.00Hz,2H),1.63(m,2H),1.56(m,2H),1.52(m,2H).
29. 3- ((1- (Cyclopentylmethyl) piperidin-4-yl) (pyridin-3-yl) amino) phenol (Compound 30) referring to the above synthetic general formulas Step 1-5, 3-iodopyridine was used instead of ArI in Step3, and cyclopentylaldehyde was used in Step 5.1H NMR(400MHz,CDCl3)δ7.97(q,J＝4.14Hz,2H),7.13(m,1H),7.08(t,J＝4.12Hz,1H),6.97(d,J＝7.68Hz,1H),6.60(d,J＝7.32Hz,1H),6.43(d,J＝7.84Hz,1H),6.34(s,1H),3.82(m,1H),3.12(d,J＝11.16Hz,2H),2.41(d,J＝6.72Hz,2H),2.24(t,J＝10.80Hz,2H),2.05(m,1H),1.91(d,J＝12.08Hz,2H),1.75(m,1H),1.69(m,1H),1.55(m,1H),1.49(m,1H),1.14(m,1H).
Example 2:
and (4) biological activity. Evaluation of the agonistic activity of the compounds of the invention at opioid receptors (MOR, DOR, KOR).
To evaluate the agonistic action of the compounds of the invention on opioid receptors (MOR, DOR, KOR)The invention uses DAGO (MOR agonist), DPDPDPE (DOR agonist) and U50488(KOR agonist) as positive control. EC of the Compound50The values were determined by concentration effect generation curve calculation.
1. Principles and methods of experimentation
The experimental principle is as follows: by establishing a cell line which co-transfers a target receptor and the G alpha 16, the activation of the receptor can cause the activation of the G alpha 16 protein, and further activates phospholipase C (PLC) to generate IP3 and DAG, IP3 can be combined with an IP3 receptor on an endoplasmic reticulum and mitochondria in a cell, thereby causing the release of intracellular calcium. Therefore, measurement of changes in intracellular calcium can be used as a means for detecting the activation state of a target receptor. Fluo-4/AM is a calcium fluorescent probe indicator used for measuring calcium ions, is used as a nonpolar fat-soluble compound, and after entering cells, under the action of cell lipolytic enzyme, an AM group is dissociated to release Fluo-4; since Fluo-4 is a polar molecule and does not readily pass through a lipid bilayer membrane, it can retain Fluo-4 in the cell for a long period of time. The level of activation of the G.alpha.protein can ultimately be reflected by measuring the intensity of the fluorescence that is excited. If the compound to be screened is capable of agonizing the target receptor, the calcium flux response can be greatly increased. Conversely, if the compound to be screened is capable of antagonizing the target receptor, the calcium flux response may be greatly reduced.
2. Results of the experiment
The agonistic activity of the N, N- (4-piperidinyl, aryl) -3-aminophenol compounds of the invention on the three subtypes MOR, DOR, KOR of opioid receptors is shown in Table 1 below.
TABLE 1 EC of agonistic Activity of Compounds of the invention on opioid receptors (MOR, DOR, KOR)50Value of
Figure BDA0003350914460000141
Figure BDA0003350914460000151
From the activity data in table 1, it can be found that the N, N- (4-piperidyl, aryl) -3-aminophenol derivatives of the invention show higher triple agonistic activity to three opioid receptors, especially the agonistic activity to MOR and DOR can reach nM level, and the related compounds can be used for preparing potent analgesic drugs.
Example 3:
preparation of tablets:
adding excipient into N, N- (4-piperidyl, aryl) -3-aminophenol derivative (any one or any combination of compounds 2-30) and its polymorph at a weight ratio of 1:5-1:10 to the excipient, granulating, and tabletting.
Example 4:
preparation of oral liquid preparation:
taking N, N- (4-piperidyl, aryl) -3-aminophenol derivatives (any one or any combination of compounds 2-30) and polymorphs thereof, and preparing the oral liquid according to a conventional oral liquid preparation method.
Example 5:
preparation of capsules, granules or medicinal granules:
adding excipient into N, N- (4-piperidyl, aryl) -3-aminophenol derivative (compound 2-30 or any combination thereof) and its polymorph at a weight ratio of 5:1, and making into capsule, granule or granule.

Claims (9)

1. An N, N- (4-piperidyl, aryl) -3-aminophenol derivative represented by the following general formula (1),
Figure FDA0003350914450000011
wherein n is 0,1, 2;
ar is one of the following groups:
Figure FDA0003350914450000012
wherein W is H, Me, Et, F, Cl, Br, I, CF3The radical Ph, is,
r is one of the following groups:
Figure FDA0003350914450000013
wherein R is1，R2,R3Are, independently of one another, H, Me, Et, F, Cl, Br, I, CF3,Ph；
X, Y and Z are mutually independent C and N atoms; n' is 0 to 4.
2. The N, N- (4-piperidinyl, aryl) -3-aminophenol derivative represented by the general formula (1) according to claim 1, characterized in that it is a compound represented by the following structural formula:
Figure FDA0003350914450000021
3. use of a N, N- (4-piperidinyl, aryl) -3-aminophenol derivative according to claim 1 or 2, for the preparation of a medicament for the preparation of an opioid receptor agonist.
4. Use of the N, N- (4-piperidinyl, aryl) -3-aminophenol derivatives according to claim 1 or 2 for the preparation of analgesic drugs.
5. A process for the preparation of an N, N- (4-piperidinyl, aryl) -3-aminophenol derivative according to claim 1, comprising the following synthetic scheme:
Figure FDA0003350914450000031
wherein, (1) Step1 is to obtain a compound 31 by reductive amination of 3-amino aniline and N-tert-butoxycarbonyl-4-piperidone in the presence of sodium triacetoxyborohydride and glacial acetic acid by taking 1, 2-dichloroethane as a solvent;
(2) step 2: using dichloromethane as a solvent, and reacting a compound 31 under the catalysis of 4-methyl benzenesulfonic acid pyridine and the protection of 3, 4-dihydro-2H-pyran to obtain a compound 32;
(3) step 3: taking toluene as a solvent, and carrying out a coupling reaction of a compound 32 and ArI catalyzed by bis (dibenzylideneacetone) palladium in the presence of sodium tert-butoxide and tri-tert-butylphosphine to obtain a compound 33;
wherein Ar is as defined in claim 1;
(4) step 4: using dichloromethane as a solvent, and removing a protecting group of the compound 33 by using trifluoroacetic acid to obtain a compound 34;
(5) step 5: taking N, N-dimethylformamide as a solvent, and carrying out reductive amination on the compound 34 in the presence of sodium triacetoxyborohydride and glacial acetic acid to obtain a compound 1;
wherein R is as defined in claim 1.
6. A pharmaceutical composition comprising any one or any combination of the N, N- (4-piperidinyl, aryl) -3-aminophenol derivatives of claim 1 or 2 and at least one pharmaceutically acceptable carrier.
7. Use of the pharmaceutical composition of claim 6 in the manufacture of a medicament for an opioid receptor agonist.
8. Use of the pharmaceutical composition of claim 6 for the preparation of an analgesic.
9. A process for preparing the pharmaceutical composition of claim 6, comprising the following synthetic route:
Figure FDA0003350914450000032
wherein, (1) Step1 is to obtain a compound 31 by reductive amination of 3-amino aniline and N-tert-butoxycarbonyl-4-piperidone in the presence of sodium triacetoxyborohydride and glacial acetic acid by taking 1, 2-dichloroethane as a solvent;
(2) step 2: using dichloromethane as a solvent, and reacting a compound 31 under the catalysis of 4-methyl benzenesulfonic acid pyridine and the protection of 3, 4-dihydro-2H-pyran to obtain a compound 32;
(3) step 3: taking toluene as a solvent, and carrying out a coupling reaction of a compound 32 and ArI catalyzed by bis (dibenzylideneacetone) palladium in the presence of sodium tert-butoxide and tri-tert-butylphosphine to obtain a compound 33;
wherein Ar is as defined in claim 1;
(4) step 4: using dichloromethane as a solvent, and removing a protecting group of the compound 33 by using trifluoroacetic acid to obtain a compound 34;
(5) step 5: taking N, N-dimethylformamide as a solvent, and carrying out reductive amination on the compound 34 in the presence of sodium triacetoxyborohydride and glacial acetic acid to obtain a compound 1;
wherein R is as defined in claim 1;
finally, one or any combination of the prepared compounds is added into a pharmaceutically acceptable carrier to prepare the pharmaceutical composition.
CN202111337681.7A 2021-11-12 2021-11-12 N, N- (4-piperidyl, aryl) -3-aminophenol derivatives, pharmaceutical composition and application thereof Pending CN113979997A (en)

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