CN109761974B - 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonist and application thereof - Google Patents
1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonist and application thereof Download PDFInfo
- Publication number
- CN109761974B CN109761974B CN201910053921.7A CN201910053921A CN109761974B CN 109761974 B CN109761974 B CN 109761974B CN 201910053921 A CN201910053921 A CN 201910053921A CN 109761974 B CN109761974 B CN 109761974B
- Authority
- CN
- China
- Prior art keywords
- pyrido
- indole
- tetrahydro
- methyl
- triazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention relates to 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b]The indole TRPV1 antagonist or the pharmaceutically acceptable salt thereof has the following structural general formula:
in the formula, R is H, F, Cl, Br, I, CF3Methyl, isopropyl, tert-butyl, cyclopropyl, propenyl, ethynyl, hydroxy, phenoxy, acetyl or phenyl; n is 1,2 or 3; l is a triazolyl, tetrazolyl, ureido or thioureido group; ar is phenyl, pyridyl, isoquinolyl, quinolyl or pyrimidyl. The test shows that: the 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b]The indole compound has good TRPV1 inhibitory activity, and the activity of part of the compound is far higher than that of a TRPV1 receptor antagonist BCTC; there were few adverse effects of body temperature elevation compared to BCTC. The general formula 1,2,3, 4-tetrahydro-9 according to the invention is thereforeH-pyrido [3,4-b]The indole compound and the medicinal salt thereof are safe and effective and have stronger analgesic effect.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonists, a pharmaceutical preparation using the compounds as active ingredients, and application of the compounds in preparation of a pain treatment drug.
Background
Pain is a common symptom of many diseases, and approximately 5 million people suffer from a variety of pain each year. Currently, the analgesics most clinically used are mainly divided into two categories: one is a narcotic analgesic that directly activates opioid receptors, and the other is an antipyretic analgesic represented by non-steroidal anti-inflammatory drugs (NSAIDs). Although the clinical effects of the medicines are good, the side effects of the medicines are obvious, such as addiction to opioids, gastrointestinal side effects of non-steroidal anti-inflammatory drugs and the like. In addition, a large number of pains such as chronic and neuropathic pains cannot be effectively controlled using existing drugs.
In recent years, with the development of related disciplines and the application of new technologies, research on various receptors related to pain transduction and their selective ligands has been advanced. In 1997, David juliuus and his panelists successfully cloned transient receptor potential vanilloid 1(TRPV1, once referred to as capsaicin receptor or vanilloid receptor subtype 1), a breakthrough in the field of neurobiology and pain research. TRPV1 is widely distributed on primary sensory neurons such as the two-stage neurons without myelinated axons (C fibers), the intracellular sensory ganglia (dorsal root ganglia and trigeminal ganglia) and the subset of sensory neurons with thin myelinated axons (a δ fibers), and plays a critical role in the initiation of the neuroinflammatory response and in the transduction of pain. At present, TRPV1 has become an important novel analgesic target, and its antagonist can directly block receptor, inhibit the transmission of pain signal from peripheral nerve to central nerve, block various pathological states related to receptor, and has analgesic effect. Different from the traditional analgesic agent for blocking the transmission of pain, the TRPV1 antagonist acts on peripheral nociceptors, can directly block the perception of pain, and has more direct analgesic effect. The study of TRPV1 antagonists has become one of the most promising analgesic research directions today.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonists, which can be used for preparing novel analgesic drugs.
The invention also provides a preparation method of the 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonist, a pharmaceutical preparation taking the compound as an active ingredient, and application of the compound in preparation of a medicament for treating pain.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention synthesizes a series of 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonists shown in a general formula (I) or pharmaceutically acceptable salts thereof, and the specific structural general formula is as follows:
mother nucleus 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ]]In the indole, R on the left side is H, F, Cl, Br, I, CF3Aromatic or aliphatic (e.g., methyl, isopropyl, t-butyl, cyclopropyl, propenyl, ethynyl, hydroxy, phenoxy, acetyl or phenyl, etc.), n is 1,2 or 3 (i.e., the number of rings on the right can be varied, e.g., six-membered, seven-membered, eight-membered, etc.); l may be: groups such as triazolyl, tetrazolyl, ureido, or thioureido groups; ar can be a benzene ring or an aromatic heterocyclic group, such as phenyl, pyridyl, isoquinolyl, quinolyl or pyrimidyl and the like, and the position of a substituent on the aromatic can be changed.
Further, preferred compounds among the 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonists of the present invention described above include, but are not limited to, the following twenty compounds:
2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (1);
2- ((1- (isoquinolin-5-yl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (2);
2- ((1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (3);
2- ((1- (2-nitro-4-methylphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (4);
2- ((1- (3-chloro-4-methylphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (5);
2- ((1- (3-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (6);
2- ((1- (4-nitrophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (7);
2- ((1- (2,4, 6-trimethylphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (8);
2- ((1- (3, 4-dimethoxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (9);
2- ((1- (3-isopropylphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (10);
2- ((1- (4, 6-dimethylpyridinyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (11);
2- ((1- (2-chloropyridyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (12);
n- (4-bromophenyl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (13);
n- (isoquinolin-5-yl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (14);
n- (2-chloropyridin-3-yl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (15);
n- (2-chloro-4-methylphenyl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (16);
n- (4-tert-butylphenyl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (17);
n- (4-trifluoromethylphenyl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (18);
n- (2,4, 6-trichlorophenyl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (19) or
N- (2, 4-dimethylphenyl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (20).
The 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonist or a pharmaceutically acceptable salt thereof comprises an addition salt formed by the following acids: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzenesulfonic acid or succinic acid, and the like known to be acceptable.
The invention provides a compound preparation prepared by compounding the 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonist or pharmaceutically acceptable salt thereof with conventional auxiliary materials or carriers in the field. The preparation comprises a compound shown as a general formula (I) or a medicinal salt thereof as an effective component and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are those conventional in the pharmaceutical art and refer to one or more inert, non-toxic solid or liquid fillers, diluents, adjuvants and the like that do not adversely affect the active compound or the patient.
The dosage form of the compound preparation can be tablets, capsules, pills, suppositories, soft capsules, oral liquid, suspensions, injections and other pharmaceutically common dosage forms. Tablets and capsules for oral use contain conventional excipients such as fillers, diluents, lubricants, dispersants and binders. The various dosage forms of the compound preparation of the present invention can be prepared according to conventional methods well known in the pharmaceutical field.
The dosage of the above active ingredients may vary depending on the formulation. In general, amounts which have proven advantageous are, for achieving the desired result, from about 0.01 to 800mg, preferably from 0.1 to 80mg/kg, of the compound of the formula (I) per kg of compound to be administered per 24 hours. If necessary, it can be administered in the form of several single doses. However, if necessary, it may deviate from the above amounts depending on the type and body weight of the subject to be treated, the behavior of the individual on the drug, the nature and severity of the disease, the type of preparation and administration, and the time and interval of administration.
The invention also provides application of the 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonist or pharmaceutically acceptable salts thereof in preparing a medicament for treating pain.
The invention also provides the application of the compound preparation as an analgesic.
The preparation of the 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole compound is divided into the following two synthetic routes, wherein the synthetic routes of the 1,2, 3-triazole compounds such as the compounds (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11) and (12) are shown as follows:
the synthetic routes of urea compounds such as compounds (13), (14), (15), (16), (17), (18), (19), (20) are shown below:
the invention provides a 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole compound with a novel structure, which is obtained by modifying a common structural segment of a main active ingredient Evodiamine and rutaceae apine which have multiple biological activities such as analgesia, anti-inflammation, anti-diabetes, thermoregulation and the like related to TRPV1 activity when researching the traditional Chinese medicine fructus evodiae, and solves the problems of drug property, water solubility, oral bioavailability and the like of the traditional medicine through modification of a connecting arm and an aromatic region functional group and modification of an effective group. The 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole compounds have good TRPV1 inhibitory activity, and the activity of partial compounds is far higher than that of a TRPV1 receptor antagonist BCTC; there were few adverse effects of body temperature elevation compared to BCTC. Therefore, the general formula 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole compound and the medicinal salt thereof are safe and effective and have strong analgesic effect.
Detailed Description
The present invention will be further described with reference to the following examples. It should be noted that the following examples are only for illustration and are not intended to limit the present invention. Variations of the teachings of the present invention may be made by those skilled in the art without departing from the scope of the claims of the present application.
Example 1:
preparation of 2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (1)
(a) Preparation of 1-azido-4-chlorobenzene
Parachloroaniline (1.27g,10mmol) dissolved in 6mol/L HCl (10mL) in a round bottom flask under ice bath, NaNO was placed2(0.69g, 10mmol) was dissolved in 25ml of water and added dropwise to the reaction system. The mixture was stirred for 20min with NaN3(1.95g, 30mmol) was dissolved in 40ml of water and added dropwise. Stirring at room temperature for 2-4h, extracting with ethyl acetate (30ml × 2), mixing organic phases, washing with water (30ml × 3), and removing solvent by evaporation under reduced pressure to obtain 1-azido-4-chlorobenzene;
(b) preparation of 2- (prop-2-yn-1-yl) -2,3,4, 9-tetrahydro-9H-pyrido [3,4-b ] indole
1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ]]Indole (1.72g,10mmol), K2CO3(0.69g,0.5mmol) was dissolved in acetone (10ml) to obtain solution A. Bromopropyne (1.18g,10mmol) and KI (0.018g,0.01mmol) were dissolved in acetone (10ml) to obtain a solution B. Stirring the solution A, B for 45min, adding the solution B into the solution A dropwise, stirring for 12-24H, vacuum filtering, and removing solvent by evaporation under reduced pressure to obtain 2- (prop-2-yne-1-yl) -2,3,4, 9-tetrahydro-9H-pyrido [3,4-B ]]Indole;
(c) preparation of 2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (1)
1-azido-4-chlorobenzene (1.53g, 10mmol) was reacted with 2- (prop-2-yn-1-yl) -2,3,4, 9-tetrahydro-9H-pyrido [3,4-b ] indole (2.10g, 10mmol) in 75% methanol (40ml) with heating at 60 ℃ for 24-48H. Extraction with ethyl acetate (30ml × 2), combination of the organic phases, evaporation of the solvent under reduced pressure and column separation (DCM: MeOH ═ 20:1 by volume) gave compound 1 as a pale yellow solid in 83% yield. The experimental data are as follows:
C20H18ClN5,yield 83％,pale yellow solid,m.p＝237.0-237.2℃；1H NMR(DMSO,400MHz):δppm 10.69(s,1H,NH),8.82(s,1H,C＝CH),7.98(d,2H,J＝8.0Hz,Ar-H),7.66(d,2H,J＝8.0Hz,Ar-H),7.36(d,1H,J＝8.0Hz,Ar-H),7.27(d,1H,J＝8.0Hz,Ar-H),7.01(t,1H,J＝8.0Hz,Ar-H),6.94(t,1H,J＝8.0Hz,Ar-H),3.94(s,2H,CH2),3.70(s,2H,CH2),2.88(t,2H,J＝6.0Hz,CH2),2.72(t,2H,J＝6.0Hz,CH2)；HRMS m/z:[M+H]+364.1320(calcd.364.1323)。
example 2:
preparation of 2- ((1- (isoquinolin-5-yl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (2)
Referring to the preparation method in example 1, wherein p-chloroaniline was replaced with pentaaminoisoquinoline, compound 2 was prepared as a tan solid in 87% yield. The experimental data are as follows:
C23H20N6,yield 87％,brown yellow solid,m.p＝147.2-149.6℃；1H NMR(CDCl3,400MHz):δppm 9.33(s,1H,NH),8.70(s,1H,C＝CH),8.54(s,1H,Ar-H),8.09(d,1H,J＝12.0Hz,Ar-H),7.91(s,1H,Ar-H),7.73-7.63(m,2H,Ar-H),7.54(d,1H,J＝8.0Hz,Ar-H),7.44(d,1H,J＝12.0Hz,Ar-H),7.24(t,1H,J＝8.0Hz,Ar-H),7.10-7.01(m,2H,Ar-H),4.05(s,2H,CH2),3.79(s,2H,CH2),3.02(t,2H,J＝6.0Hz,CH2),2.86(t,2H,J＝6.0Hz,CH2)；HRMS m/z:[M+H]+381.1819(calcd.381.1822)。
example 3:
preparation of 2- ((1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (3)
Referring to the preparation method in example 1, wherein p-chloroaniline was replaced with o-chloroaniline, compound 3 was obtained as a pale yellow solid in a yield of 91.6%. The experimental data are as follows:
C20H18ClN5,yield 91.6％,pale yellow solid,m.p＝143.6-145.0℃；1H NMR(DMSO,400MHz):δppm 10.62(s,1H,NH),8.42(s,1H,C＝CH),7.68(d,1H,J＝8.0Hz,Ar-H),7.62(d,1H,J＝12.0Hz,Ar-H),7.52(t,2H,J＝10.0Hz,Ar-H),7.27(d,1H,J＝8.0Hz,Ar-H),7.18(t,1H,J＝12.0Hz,Ar-H),6.94-6.82(m,2H,Ar-H),3.87(s,2H,CH2),3.60(s,2H,CH2),2.79(t,2H,J＝8.0Hz,CH2),2.65(t,2H,J＝14.0Hz,CH2)；HRMS m/z:[M+H]+364.1319(calcd.364.1323)。
example 4:
preparation of 2- ((1- (2-nitro-4-methylphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (4)
Referring to the preparation method in example 1, wherein p-chloroaniline was replaced with 2-nitro-4-methylaniline, compound 4 was obtained as a tan solid in a yield of 92.0%. The experimental data are as follows:
C21H20N6O2,yield 92.0％,brown yellow solid,m.p＝128.7-129.4℃；1H NMR(DMSO,400MHz):δppm 10.73(s,1H,NH),8.60(s,1H,C＝CH),8.05(d,2H,J＝8.0Hz,Ar-H),7.74(s,2H,Ar-H),7.37(d,1H,J＝8.0Hz,Ar-H),7.28(d,1H,J＝8.0Hz,Ar-H),7.02(t,1H,J＝8.0Hz,Ar-H),6.95(t,1H,J＝8.0Hz,Ar-H),3.97(s,2H,CH2),3.71(s,2H,CH2),2.89(t,2H,J＝6.0Hz,CH2),2.74(t,2H,J＝6.0Hz,CH2),2.50(s,3H,CH3)；HRMS m/z:[M+H]+389.1719(calcd.389.1721).
example 5:
preparation of 2- ((1- (3-chloro-4-methylphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (5)
Referring to the preparation method in example 1, wherein p-chloroaniline was replaced with 3-chloro-4-methylaniline, compound 5 was obtained as a tan solid in a yield of 90.3%. The experimental data are as follows:
C21H20ClN5,yield 90.3％,brown yellow solid,m.p＝229.6-231.4℃；1H NMR(DMSO,400MHz):δppm 10.80(s,1H,NH),8.96(s,1H,C＝CH),8.16(s,1H,Ar-H),7.96(d,1H,J＝8.0Hz,Ar-H),7.67(d,1H,J＝8.0Hz Ar-H),7.47(d,1H,J＝8.0Hz,Ar-H),7.38(d,1H,J＝8.0Hz,Ar-H),7.12(t,1H,J＝8.0Hz,Ar-H),7.05(t,1H,J＝8.0Hz,Ar-H),4.05(s,2H,CH2),3.81(s,2H,CH2),3.48(s,3H,CH3),3.00(s,2H,CH2),2.84(s,2H,CH3)；HRMS m/z:[M+H]+378.1480(calcd.378.1480).
example 6:
preparation of 2- ((1- (3-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (6)
Referring to the preparation method in example 1, in which p-chloroaniline was replaced with m-fluoroaniline, compound 6 was obtained as a tan solid in a yield of 92.4%. The experimental data are as follows:
C20H18FN5,yield 92.4％,brown yellow solid,m.p＝196.1-198.2℃；1H NMR(DMSO,400MHz):δppm 10.68(s,1H,NH),8.86(s,1H,C＝CH),7.89-7.86(m,2H,Ar-H),7.64(d,1H,Ar-H),7.38-7.27(m,3H,Ar-H),7.03-6.92(m,2H,Ar-H),3.95(s,2H,CH2),3.71(s,2H,CH2),2.89(s,2H,CH2),2.73(s,2H,CH2)；HRMS m/z:[M+H]+348.1618(calcd.348.1619).
example 7:
preparation of 2- ((1- (4-nitrophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (7)
Referring to the preparation method in example 1, wherein p-chloroaniline was replaced with p-nitroaniline, compound 7 was obtained as a tan solid in 89.2% yield. The experimental data are as follows:
C20H18N6O2,yield 89.2％,brown yellow solid,m.p＝201.4-202.5℃；1H NMR(DMSO,400MHz):δppm 10.65(s,1H,NH),9.00(s,1H,C＝CH),8.44(d,2H,J＝12.0Hz,Ar-H),8.26(t,2H,J＝6.0Hz,Ar-H),7.36(d,1H,J＝8.0Hz Ar-H),7.26(d,1H,J＝6.0Hz,Ar-H),7.03-6.91(m,2H,Ar-H),3.97(s,2H,CH2),3.71(s,2H,CH2),2.90(t,2H,J＝8.0Hz,CH2),2.73(t,2H,J＝8.0Hz,CH2)；HRMS m/z:[M+H]+375.1558(calcd.375.1564).
example 8:
preparation of 2- ((1- (2,4, 6-trimethylphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (8)
Referring to the preparation method in example 1, in which p-chloroaniline was replaced with 2,4, 6-trimethylaniline, compound 8 was obtained as a pale yellow solid in a yield of 79.0%. The experimental data are as follows:
C23H25N5,yield 79.0％,pale yellow solid,m.p＝148.5-149.9℃；1H NMR(CDCl3,400MHz):δppm 8.56(s,1H,NH),7.56(s,1H,C＝CH),7.44(d,1H,J＝8.0Hz,Ar-H),7.23(s,1H,J＝12.0Hz,Ar-H),7.10-7.02(m,2H,Ar-H),6.98(s,2H,Ar-H),4.03(s,2H,Ar-H),3.73(s,2H,Ar-H),2.95(t,2H,J＝8.0Hz,CH2),2.84(t,2H,J＝8.0Hz,CH2),2.35(s,3H,CH3),3.85(s,6H,CH3)；HRMS m/z:[M+H]+372.2177(calcd.372.2183).
example 9:
preparation of 2- ((1- (3, 4-dimethoxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (9)
Referring to the preparation method in example 1, wherein p-chloroaniline was replaced with 3, 4-dimethoxyaniline, compound 9 was obtained as a tan solid in 87.1% yield. The experimental data are as follows:
C22H23N5O2,yield 87.1％,brown yellow solid,m.p＝180.9-181.6℃；1H NMR(DMSO,400MHz):δppm 10.70(s,1H,NH),8.75(s,1H,C＝CH),7.50-7.43(m,2H,Ar-H),7.37(d,1H,J＝12.0Hz,Ar-H),7.27(d,1H,J＝8.0Hz,Ar-H),7.13(d,1H,J＝12.0Hz,Ar-H),7.04-6.91(m,2H,Ar-H),3.94(s,2H,CH2),3.87(s,3H,CH3),3.82(s,3H,CH3),3.71(s,2H,CH2),2.91(t,2H,J＝6.0Hz,CH2),2.74(t,2H,J＝6.0Hz,CH2)；HRMS m/z:[M+H]+390.1922(calcd.390.1925).
example 10:
preparation of 2- ((1- (3-isopropylphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (10)
Referring to the preparation method in example 1, in which p-chloroaniline was replaced with m-isopropylaniline, compound 10 was obtained as a tan solid in 73.7% yield. The experimental data are as follows:
C23H25N5,yield 73.7％,brown yellow solid,m.p＝167.0-168.9℃；1H NMR(CDCl3,400MHz):δppm 8.57(s,1H,NH),7.94(s,1H,C＝CH),7.56(s,1H,Ar-H),7.45-7.36(m,3H,Ar-H),7.26-7.21(m,1H,Ar-H),7.05(t,2H,J＝12.0Hz,Ar-H),3.94(s,2H,CH2),3.68(s,2H,CH2),3.94(s,2H,CH2),2.82(s,2H,CH2),1.27(d,7H,J＝8.0Hz,CH-CH3)；HRMS m/z:[M+H]+372.2180(calcd.372.2183).
example 11:
preparation of 2- ((1- (4, 6-dimethylpyridinyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (11)
Referring to the preparation method in example 1, wherein p-chloroaniline was replaced with 2-amino-4, 6-dimethylpyridine, compound 11 was obtained as a yellow solid in 73.0% yield. The experimental data are as follows:
C21H22N6,yield 73.0％,yellow solid,m.p＝176.6-178.2℃；1H NMR(CDCl3,400MHz):δppm11.43(s,1H,NH),8.25(s,1H,C＝CH),7.38(s,1H,Ar-H),7.36-7.09(m,3H,Ar-H),6.93(s,1H,Ar-H),6.90(s,1H,Ar-H),3.67(s,2H,CH2),3.63(s,2H,CH2),2.85(s,2H,CH2),2.73(s,2H,CH2),2.49(s,3H,CH3),2.47(s,3H,CH3)；HRMS m/z:[M+H]+359.1974(calcd.359.1979).
example 12:
preparation of 2- ((1- (2-chloropyridyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (12)
Referring to the preparation method in example 1, wherein p-chloroaniline was replaced with 2-chloro-3-aminopyridine, cyan solid compound 12 was prepared in 74.2% yield. The experimental data are as follows:
C19H17ClN6,yield 74.2％,cyan solid,m.p＝155.4-157.3℃；1H NMR(CDCl3,400MHz):δppm11.23(s,1H,NH),8.37(s,1H,C＝CH),8.35-8.12(m,2H,Ar-H),7.63-7.21(m,3H,Ar-H),6.94-6.91(m,2H,Ar-H),3.65(s,2H,CH2),3.62(s,2H,CH2),2.81(s,2H,CH2),2.73(s,2H,CH2)；HRMS m/z:[M+H]+365.1273(calcd.365.1276).
example 13:
preparation of N- (4-bromophenyl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (13)
P-bromoaniline (1.72g,10mmol), 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole (1,72g,10 mmol), triethylamine (5.5ml, 40mmol) and triphosgene (100.9mg, 0.34mmol) were added to a reaction flask in this order under nitrogen atmosphere, reacted at room temperature for 24 hours, water was added to terminate the reaction, dichloromethane was extracted, the organic phases were combined, the solvent was evaporated under reduced pressure, and column chromatography (DCM: MeOH: 80:1, volume ratio) was performed to obtain brown solid compound 13 with a yield of 44.0%. The experimental data are as follows:
C18H16BrN3O,yield 44.0％,brown-solid；1H NMR(DMSO,400MHz):δppm 10.88(s,1H,NH),8.86(s,1H,NH),7.49(d,2H,J＝8.0Hz,Ar-H),7.43(t,3H,J＝8.0Hz,Ar-H),7.33(d,1H,J＝4.0Hz,Ar-H),7.05(t,1H,J＝8.0Hz,Ar-H),6.98(t,1H,J＝8.0Hz,Ar-H),4.70(s,2H,NCH2CH2),3.83(t,2H,J＝4.0Hz,NCH2CH2),2.78(t,2H,J＝4.0Hz,NCH2)；HRMS m/z:[M+H]+370.0549(calcd.370.0550)。
example 14:
preparation of N- (isoquinolin-5-yl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (14)
Referring to the preparation method in example 13, wherein p-bromoaniline was replaced with 5-aminoisoquinoline, compound 14 was obtained as a brown solid in 50.5% yield. The experimental data are as follows:
C21H18N4O,yield 50.5％,brown solid；1H NMR(DMSO,400MHz):δppm 10.93(s,1H,NH),9.31(s,1H,NH),8.97(s,1H,Isoquinoline),8.49(d,1H,J＝8.0Hz,Isoquinoline),7.93(d,1H,J＝8.0Hz,Isoquinoline),7.70(m,3H,J＝7.62-7.79Hz,Isoquinoline),7.45(d,1H,J＝12.0Hz,Ar-H),7.34(d,1H,J＝8.0Hz,Ar-H),7.00(m,2H,J＝7.67-7.70Hz,Ar-H),4.79(s,2H,NCH2CH2),3.94(t,2H,J＝8.0Hz,NCH2CH2),2.86(t,2H,J＝8.0Hz,NCH2).HRMS m/z:[M+H]+343.1551(calcd.343.1553)。
example 15:
preparation of N- (2-chloropyridin-3-yl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (15)
Referring to the preparation method in example 13, wherein p-bromoaniline was replaced with 2-chloro-3-aminopyridine, compound 15 was obtained as a brown solid in 49.0% yield. The experimental data are as follows:
C17H15ClN4O,yield 49％,white solid；1H NMR(DMSO,400MHz):δppm 10.92(s,1H,NH),8.56(s,1H,NH),8.18(m,1H,J＝8.17-8.19Hz,Ar-H),7.98(m,1H,J＝7.96-7.99Hz,Ar-H),7.38(m,3H,J＝7.31-7.44Hz,Pyridine),7.03(m,2H,J＝6.96-7.09Hz,Ar-H),4.73(s,2H,NCH2CH2),3.86(t,2H,J＝8.0Hz,NCH2CH2),2.81(t,2H,J＝6.0Hz,NCH2).HRMS m/z:[M+H]+327.1006(calcd.327.1007)。
example 16:
preparation of N- (3-chloro-4-methylphenyl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (16)
Referring to the preparation method in example 13, wherein p-bromoaniline was replaced with 3-chloro-4-methylaniline, compound 16 was obtained as a bright brown solid in a yield of 25.5%. The experimental data are as follows:
C19H18ClN3O,yield 25.5％,light-brown solid,1H NMR(DMSO,400MHz):δppm 10.92(s,1H,NH),8.86(s,1H,NH),7.66(s,1H,Ar-H),7.40(d,1H,J＝8.0Hz,Ar-H),7.36(d,1H,J＝8.0Hz,Ar-H),7.31(d,1H,J＝8.0Hz,Ar-H),7.19(d,1H,J＝8.0Hz,Ar-H),7.04(t,1H,J＝8.0Hz,Ar-H),6.96(t,1H,J＝8.0Hz,Ar-H),4.68(s,2H,NCH2CH2),3.82(t,2H,J＝4.0Hz,NCH2CH2),2.76(t,2H,J＝4.0Hz,NCH2),2.24(s,3H,Ar-CH3)；HRMS m/z:[M+H]+340.1209(calcd.340.1211)。
example 17:
preparation of N- (4-tert-butylphenyl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (17)
Referring to the preparation method in example 13, wherein p-bromoaniline was replaced with 4-tert-butylaniline, compound 17 was obtained as a brown solid in a yield of 23.5%. The experimental data are as follows:
C22H25N3O,yield 23.5％,light-brown solid；1H NMR(DMSO,400MHz):δppm 10.88(s,1H,NH),8.65(s,1H,NH),7.42(d,2H,J＝12.0Hz,Ar-H),7.38(s,1H,Ar-H),7.33(d,1H,J＝8.0Hz,Ar-H),7.26(d,1H,J＝8.0Hz,Ar-H),7.05(t,1H,J＝8.0Hz,Ar-H),6.98(t,1H,J＝8.0Hz,Ar-H),4.69(s,2H,NCH2CH2),3.83(t,2H,J＝4.0Hz,NCH2CH2),2.77(t,2H,J＝4.0Hz,NCH2),1.26(s,9H,C(CH3)3)；HRMS m/z:[M+H]+348.2068(calcd.348.2070)。
example 18:
preparation of N- (4-trifluoromethylphenyl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (18)
Referring to the preparation method in example 13, wherein p-bromoaniline was replaced with 4-trifluoromethylaniline, compound 18 was obtained as a white solid in 24.5% yield. The experimental data are as follows:
C19H16F3N3O,yield 24.5％,white solid；1H NMR(DMSO,400MHz):δppm 10.89(s,1H,NH),9.12(s,1H,NH),7.72(d,1H,J＝8.0Hz,Ar-H),7.60(d,1H,J＝8.0Hz,Ar-H),7.42(d,1H,J＝8.0Hz,Ar-H),7.31(d,1H,J＝8.0Hz,Ar-H),7.06(t,1H,J＝8.0Hz,Ar-H),6.89(t,1H,J＝8.0Hz,Ar-H),4.72(s,2H,NCH2CH2),3.86(t,2H,J＝4.0Hz,NCH2CH2),2.79(t,2H,J＝4.0Hz,NCH2)；HRMS m/z:[M+H]+360.1317(calcd.360.1318).
example 19:
preparation of N- (2,4, 6-trichlorophenyl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (19)
Referring to the preparation method in example 13, wherein p-bromoaniline was replaced with 2,4, 6-trichloroaniline, compound 19 was obtained as a bright yellow solid in 21.5% yield. The experimental data are as follows:
C18H14Cl3N3O,yield 21.5％,light-yellow solid；1H NMR(DMSO,400MHz):δppm 10.88(s,1H,NH),8.67(s,1H,NH),7.71(s,2H,Ar-H),7.42(d,1H,J＝8.0Hz,Ar-H),7.31(d,1H,J＝8.0Hz,Ar-H),7.05(t,1H,J＝8.0Hz,Ar-H),6.97(t,1H,J＝8.0Hz,Ar-H),4.69(s,2H,NCH2CH2),3.84(t,2H,J＝4.0Hz,NCH2CH2),2.79(t,2H,J＝4.0Hz,NCH2)；HRMS m/z:[M+H]+394.0273(calcd.394.0275).
example 20:
preparation of N- (2, 4-dimethylphenyl) -3, 4-dihydro-1H-pyrido [3,4-b ] indole-2 (9H) -amide (20)
Referring to the preparation method in example 13, wherein p-bromoaniline was replaced with 2, 4-dimethylaniline, compound 20 was obtained as a bright yellow solid in 26.4% yield. The experimental data are as follows:
C20H21N3O,yield 26.4％,light-brown solid；1H NMR(DMSO,400MHz):δppm 10.88(s,1H,NH),8.19(s,1H,NH),7.42(d,1H,J＝8.0Hz,Ar-H),7.32(d,1H,J＝8.0Hz,Ar-H),7.06(t,1H,J＝8.0Hz,Ar-H),6.99(d,1H,J＝8.0Hz,Ar-H),6.94(d,1H,J＝8.0Hz,Ar-H),4.68(s,2H,NCH2CH2),3.82(t,2H,J＝4.0Hz,NCH2CH2),2.77(t,2H,J＝4.0Hz,NCH2),2.25(s,3H,Ar-CH3),2.13(s,3H,Ar-CH3)；HRMS m/z:[M+H]+320.1756(calcd.320.1757).
example 21:
a tablet containing 2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole (Compound 1), the contents of each raw material in each tablet (0.1g) are as follows:
the preparation method of the tablet comprises the following steps: mixing the raw materials and the auxiliary materials according to a conventional method in the field, granulating, drying and tabletting to obtain the tablet. Application test: the following are the data from pharmacological experiments with some of the compounds of the invention:
1. antagonistic Activity screening of Compounds 1 to 20 of the present invention against TRPV1 receptor
By adopting an aequorin reporter gene detection technology, the cell strain stably co-expresses aequorin and a TRPV1 receptor. Intracellular Ca when the receptor is excited2+Increase in Ca2+Coelenterazine reconstitutes the photoprotein, producing a bioluminescent effect at 469 nm. By measuring the rapid chemiluminescent signal produced by the release of stimulated intracellular calcium, test samples can be screened for effects on the TRPV1 receptor.
The TRPV1 antagonistic activity screening experiment of the compound comprises the following steps: test compounds and capsaicin were brought to an initial concentration of 10mM in DMSO and diluted to a test concentration of 0.1mM in Try's solution, where the capsaicin was diluted to 250 nM. The initial concentration of calcium ion fluorescent probe was 5mM and was diluted to a concentration of 0.05mM with HBSS containing 33mg Pluronic F-127 per ml. Approximately 10000 HEK-293-TRPV1 cells per well were incubated at 37 ℃ with 10. mu.l of 0.05mM calcium ion fluorescent probe. After 20 minutes, 30. mu.l of HBSS containing 1% FBS was added and incubation was continued for 40 minutes. After 40 minutes, the HBSS and other fluids are aspirated from the wells and the wells are washed with Taiwan's solution, followed by 40 microliters of test compound at a concentration of 0.1mM per well. 3 duplicate wells were set for each compound, 3 of which were incubated at 37 ℃ for 30 minutes with only Tschmann's solution as a blank, and fluorescence intensity was measured at 488nm for excitation and 526nm for emission. Cells were then incubated at 37 ℃ for 30 minutes with 10. mu.l of capsaicin at a concentration of 250nM per well and fluorescence intensity was measured at an excitation wavelength of 488nM and an emission wavelength of 526 nM. The relative concentration of intracellular calcium ions is characterized by calculating the difference of fluorescence intensity before and after each group of capsaicin is added, so as to detect the antagonism degree of the compound on the capsaicin, and further detect the TRPV1 receptor of the compoundThe degree of antagonistic activity. Part of the compounds being at 10-5Antagonistic activity against TRPV1 receptor at mol dose results are shown in table 1.
Table 1 screening of partial compounds for TRPV1 receptor antagonistic activity
Note: inhibition rate (blank difference-experimental group difference)/blank difference 100%
Fluorescence intensity after adding capsaicin in blank group-fluorescence intensity before adding capsaicin in blank group
The difference between the experimental group and the fluorescence intensity after adding capsaicin-the fluorescence intensity before adding capsaicin
NE: the blank control group had an inhibition ratio of 0.
The test results in table 1 show that: the inhibition rates of tested compounds 1 to 20 on TRPV1 are all more than 50%, which indicates that the tested compounds have TRPV1 inhibitory activity.
2. Effect of Compounds 1 to 20 of the invention on three mouse pain models
The mouse licking experiment: mice were randomly grouped by weight, 6 per group. The oral gavage is carried out 30 minutes before the test, the dosage is 30mg/kg, and the blank group is provided with 0.5 percent CMC-Na with equal volume. For the test, 20. mu.L (1.6. mu.g/20. mu.L) of capsaicin was injected subcutaneously into the right dorsum of the mouse, and the total length of time (unit: sec) that the mouse licks the right foot within 5 minutes was recorded.
Mouse writhing experiment: mice were randomly grouped by weight, 6 per group. The oral gavage is carried out 30 minutes before the test, the dosage is 30mg/kg, and the blank group is provided with 0.5 percent CMC-Na with equal volume. When in test, the mouse is injected with 0.6 percent acetic acid solution in the abdominal cavity, and the times of writhing reaction (belly concave, hind limb stretching and hip lifting) of the mouse within 15 minutes are recorded.
Mouse tail-shortening experiment: mice were randomly grouped by weight, 6 per group. The tail end of the mouse tail is immersed in a hot water bath at 52 ℃, the tail contraction response time of the mouse is recorded, the two times of measurement are carried out at an interval of 10 minutes, the average value is used as the basic pain threshold of the mouse, and the time for immersing the mouse tail in the hot water does not exceed 12 seconds. 30 minutes after the basal pain threshold was determined, each group was orally gavaged at a dose of 30mg/kg, and the blank group was given an equal volume of 0.5% CMC-Na. After half an hour of administration, the basal pain threshold was measured and the tail-shortening response time was measured half an hour after administration, and the average value was the pain threshold after administration. The percent maximum analgesic effect (MPE%) for each group was calculated as (basal pain threshold-post-dose pain threshold)/(cut-off time-basal pain threshold) × 100, with a cut-off time of 12 seconds.
TABLE 2 analgesic Activity of partial Compounds in three mouse pain models
Note: t-test, p <0.05, p <0.01, p <0.001 compared to blank group. High potency selective TRPV1 antagonist BCTC: n- (4-tert-butylphenyl) -4- (3-chloropyridin-2-yl) piperazine-1-carboxamide
The test results in table 2 show that: in three analgesic models, partial compounds of the invention such as 1,5,6,7,13,18,19 and the like have very significant difference compared with a blank group, wherein the analgesic activity of the preferred compound 1 is superior to that of a positive control BCTC, and the compound has stronger analgesic effect.
3. Effect of Compounds 1 to 20 of the invention on mouse body temperature
Mice were randomly grouped by weight, 6 per group. Each group was orally administered at a dose of 30mg/kg by gavage, and the blank group was administered with 0.5% CMC-Na in an equal volume. Mouse body temperature was measured 0min, 30 min, 60 min, 90 min, 120 min after administration.
The test result shows that: compared with 0 minute after the positive control BCTC is administrated, the difference is very obvious; compared with 0 minute after the compound 1-5 test groups are administrated, the compound 1-5 test groups have no significant difference with the blank group, and the body temperature of the mouse has no obvious change. The partial compound of the invention is proved to have little influence on the body temperature of mice.
The pharmacological data show that the compound of the general formula (I) has stronger analgesic effect compared with positive control BCTC, and the preferable compound has almost no side effect of body temperature rise.
Claims (6)
1,2,3, 4-tetrahydro-9H-pyrido [3,4-b]The indole TRPV1 antagonist or the pharmaceutically acceptable salt thereof is characterized by specifically comprising the following compounds:
2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole;
2- ((1- (isoquinolin-5-yl) -1)H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole;
2- ((1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole;
2- ((1- (2-nitro-4-methylphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole;
2- ((1- (3-chloro-4-methylphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole;
2- ((1- (3-fluorophenyl) -1)H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole;
2- ((1- (4-Nitrophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole;
2- ((1- (2,4, 6-trimethylphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole;
2- ((1- (3, 4-dimethoxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole;
2- ((1- (3-isopropylphenyl))-1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole;
2- ((1- (4, 6-dimethylpyridinyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole;
2- ((1- (2-Chloropyridyl) -1H-1,2, 3-triazol-4-yl) methyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole.
2. The 1,2,3, 4-tetrahydro-9 of claim 1H-pyrido [3,4-b]An indole TRPV1 antagonist or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a salt with: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzenesulfonic acid or succinic acid.
3. The 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonist of claim 1 or a pharmaceutically acceptable salt thereof and auxiliary materials conventional in the art are compounded to prepare a compound preparation.
4. The compound preparation of claim 3, wherein the compound preparation is in the form of tablets, capsules, pills, suppositories, soft capsules, oral liquid, suspensions or injections.
5. The 1,2,3, 4-tetrahydro-9 of claim 1H-pyrido [3,4-b]The application of indole TRPV1 antagonist or pharmaceutically acceptable salt thereof in preparing a medicament for treating pain.
6. The use of the compound preparation of claim 3 in the preparation of an analgesic.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910053921.7A CN109761974B (en) | 2019-01-21 | 2019-01-21 | 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonist and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910053921.7A CN109761974B (en) | 2019-01-21 | 2019-01-21 | 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonist and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109761974A CN109761974A (en) | 2019-05-17 |
| CN109761974B true CN109761974B (en) | 2021-05-14 |
Family
ID=66454983
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910053921.7A Active CN109761974B (en) | 2019-01-21 | 2019-01-21 | 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonist and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109761974B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111454233B (en) * | 2020-05-08 | 2023-01-24 | 河南大学 | 4- (2- (pyrrolidine/piperidine-1-yl) benzyl) -piperazinylurea TRPV1 antagonist and preparation and application thereof |
| CN111423432B (en) * | 2020-05-11 | 2023-01-24 | 河南大学 | (S) -4/5-phenyl-2- (pyrrolidine-2-yl) thiazole TRPV1 antagonist and preparation and application thereof |
| CN113233996B (en) * | 2021-05-20 | 2022-05-20 | 河南大学 | Novel TRPV1 antagonistic/FAAH inhibition double-target drug, and preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004113300A1 (en) * | 2003-06-23 | 2004-12-29 | Ono Pharmaceutical Co., Ltd. | Novel tricyclic heterocycle compound |
| WO2006123242A1 (en) * | 2005-05-18 | 2006-11-23 | Pfizer Limited | 1, 2, 4 -triazole derivatives as vasopressin antagonists |
| CN101379041A (en) * | 2006-02-03 | 2009-03-04 | 赛诺菲-安万特 | Tricyclic n-heteroaryl-carboxamide derivatives containing a benzimidazole unit, method for preparing same and their therapeutic use |
| WO2009069132A2 (en) * | 2007-11-29 | 2009-06-04 | Ramot At Tel Aviv University Ltd. | Novel reverse transcriptase inhibitors |
| CN111454233A (en) * | 2020-05-08 | 2020-07-28 | 河南大学 | 4- (2- (pyrrolidine/piperidine-1-yl) benzyl) -piperazinylurea TRPV1 antagonist and preparation and application thereof |
-
2019
- 2019-01-21 CN CN201910053921.7A patent/CN109761974B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004113300A1 (en) * | 2003-06-23 | 2004-12-29 | Ono Pharmaceutical Co., Ltd. | Novel tricyclic heterocycle compound |
| WO2006123242A1 (en) * | 2005-05-18 | 2006-11-23 | Pfizer Limited | 1, 2, 4 -triazole derivatives as vasopressin antagonists |
| CN101379041A (en) * | 2006-02-03 | 2009-03-04 | 赛诺菲-安万特 | Tricyclic n-heteroaryl-carboxamide derivatives containing a benzimidazole unit, method for preparing same and their therapeutic use |
| WO2009069132A2 (en) * | 2007-11-29 | 2009-06-04 | Ramot At Tel Aviv University Ltd. | Novel reverse transcriptase inhibitors |
| CN111454233A (en) * | 2020-05-08 | 2020-07-28 | 河南大学 | 4- (2- (pyrrolidine/piperidine-1-yl) benzyl) -piperazinylurea TRPV1 antagonist and preparation and application thereof |
Non-Patent Citations (5)
| Title |
|---|
| Reaction of tetrahydro-β-carboline-1-carboxylic acid with isocyanates and isothiocyanates. Synthesis of 1-alkyl- or arylcarbamoyl-β-carbolines;Lopez-Rodriguez, Maria L. 等;《Heterocycles》;19941231;第37卷(第2期);化合物VIb * |
| RN：1022361-86-9;ACS;《STN Registry数据库》;20080525;化合物RN：1991560-79-2 * |
| RN：1923502-86-6;ACS;《STN Registry数据库》;20160102;化合物RN：1022361-86-9 * |
| RN：1991560-79-2;ACS;《STN Registry数据库》;20120912;化合物RN：1923502-86-6 * |
| Tetrahydro-β-carboline derivatives targeting fatty acid amide hydrolase (FAAH) and transient receptor potential (TRP) channels;Giorgio Ortar 等;《Bioorganic & Medicinal Chemistry Letters》;20121112;第23卷(第1期);第138-142页，尤其是第139图1，第140页表1，第138页左栏第1段 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109761974A (en) | 2019-05-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109761974B (en) | 1,2,3, 4-tetrahydro-9H-pyrido [3,4-b ] indole TRPV1 antagonist and application thereof | |
| US7312330B2 (en) | Bicycloheteroarylamine compounds as ion channel ligands and uses thereof | |
| TW539675B (en) | Novel 2,3-disubstituted-4(3H)-quinazolinones | |
| US7414131B2 (en) | Bicycloheteroarylamine compounds as ion channel ligands and uses thereof | |
| WO2016184434A1 (en) | Pyrido-azaheterecydic compound and preparation method and use thereof | |
| CN111454233B (en) | 4- (2- (pyrrolidine/piperidine-1-yl) benzyl) -piperazinylurea TRPV1 antagonist and preparation and application thereof | |
| PL184446B1 (en) | Substituted derivatives of imidazolydinodione-2,4, method of obtaining them and pharmaceutic preparation | |
| CN102731413A (en) | Urea compound and its preparation method, intermediate and use | |
| CN111423432B (en) | (S) -4/5-phenyl-2- (pyrrolidine-2-yl) thiazole TRPV1 antagonist and preparation and application thereof | |
| JP2009539889A (en) | Quaternary ammonium salt compounds of spirocyclopiperazines, process for their production and use | |
| TW200524599A (en) | Substituted tricyclic heterocycles and their uses | |
| RU2303037C2 (en) | Derivatives of pyridine and medicinal agent based on thereof possessing selective blocking activity with respect to subspecies of nmda-receptors | |
| CN113307791B (en) | Pyrimidylpiperazine urea TRPV1 antagonistic/MOR agonistic double-target compound and preparation method and application thereof | |
| JPS6322082A (en) | 1-(hydroxystiryl)-5h-2, 3-benzodiazepine derivative and its production, drug containing said derivative and its production | |
| CN107721919B (en) | Phenyl quinoline TRPV1 antagonist as well as preparation method and application thereof | |
| CN106117182B (en) | Quinazoline-N- phenethyl tetrahydroisoquinolicompounds compounds and its preparation method and application | |
| CN107827837B (en) | Sphingosine-1-phosphate receptor modulator compounds, and preparation method and application thereof | |
| TWI824251B (en) | Pyridinemorpholine compounds, their preparation methods and their applications | |
| JP6680888B2 (en) | Pyridinol derivative or pharmaceutically acceptable salt thereof and pharmaceutical composition containing the same as an active ingredient | |
| JP2024514015A (en) | Alkynylphenylbenzamide compounds and their uses | |
| US9593113B2 (en) | Imide and acylurea derivatives as modulators of the glucocorticoid receptor | |
| CN112457265A (en) | Tetrazole derivative, preparation method thereof, pharmaceutical composition containing tetrazole derivative and application of pharmaceutical composition | |
| JP6126078B2 (en) | 4-alkanoylamino-3-pyrazolone derivatives | |
| JP2022500458A (en) | Salts of substituted pyrolopyrimidine-based CDK inhibitors and their crystals and use | |
| CN115232126B (en) | Beta-carbolin-1, 2, 3-triazole compound, preparation method thereof and application of compound in resisting Alzheimer disease |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |