WO2013026264A1 - Cb1 acceptor inhibitor compound with nitrogen-containing aromatic ring having hydroxyl and use thereof - Google Patents

Abstract

Disclosed is a cannabinoid (CB1) acceptor inhibitor compound with nitrogen-containing aromatic ring having hydroxyl shown as general formula I and a physiologically acceptable salt and solvate thereof. Wherein each substituent definition is as described in the description. The compound can be used to prepare medicines for drug rehabilitation, losing weight and treating diabetes, etc.

Description

 Hydroxyl-containing nitrogen-containing aromatic ring-containing CB1 receptor inhibitor compound and use thereof

 The present invention relates to a CB1 receptor inhibitor, in particular to a low toxicity "multi-headed drug", a nitrogen-containing aromatic ring-containing CB1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group, and a physiologically acceptable salt thereof or Solvates, methods of preparing the CB1 receptor inhibitors, and pharmaceutical uses thereof. In particular, a low toxicity hydroxy or substituted hydroxypyridine diaryl substituted pyrazole derivative CB1 receptor inhibitor, a preparation method thereof and a medicament for the preparation of a drug for detoxification, weight loss, diabetes treatment, or prevention of cardiovascular diseases Application, and even all medical uses associated with CB 1 receptor inhibitors. Background technique

Rimonabant, the product of the French company Sanofi-Aventis, is the world's first and only CB1 receptor inhibitor ^[1 ' ^2] that has been on the market to date, and its medical effects involve the central nervous system and the periphery. The gastrointestinal system not only fights drug dependence (drug addiction), but also inhibits alcohol addiction or smoking addiction. It also increases the body's sensitivity to insulin, promotes glucose metabolism, helps in the treatment of diabetes, and suppresses appetite. At the same time, the high ester density cholesterol level in the patient is increased while the low fat density cholesterol level is lowered. Such a variety of pharmacological effects have aroused the strong interest of pharmacies and are generally optimistic about the drug market. However, shortly after listing in the European Union, it led to depression, and even the toxic side effects of suicide were valued in the United States, and gradually became apparent in the application of the European Union. Finally, it was released from the European Union in October 2008, similar to the Brinbaban (Surinabant). ) No further reports have been reported.

At the same time, high-efficiency compounds developed by companies in the United States, France, India, South Korea, and Hungary have been found to have the same central toxicity problems. The magical class (MJ-15) ^[3] invented in mainland China has not yet reported its entry into clinical research. The structural formula of Lee-15 is as follows:

Rimonabant Surinabant (MJ-15).

1

Confirmation 9 SUMMARY OF THE INVENTION

 One of the technical problems to be solved by the present invention is to provide a nitrogen-containing aromatic ring-containing CB1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group, in particular to provide a low toxicity "multi-headed drug" with a hydroxyl group or A diaryl-substituted pyrazole derivative CB1 receptor inhibitor which replaces a hydroxyl group-containing heterocyclic ring.

 The second technical problem to be solved by the present invention is a method for preparing a nitrogen-containing aromatic ring-containing CB1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group, that is, providing a low-toxic nitrogen-containing aromatic group having a hydroxyl group or a substituted hydroxyl group. Process for the preparation of a cyclic diaryl substituted pyrazole derivative CB1 receptor inhibitor.

 The third technical problem to be solved by the present invention is to provide a low toxicity group of a nitrogen-containing aromatic ring-containing CB1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group in all medical applications related to a CB1 receptor inhibitor, in particular It is used in the preparation of drugs for detoxification, weight loss, diabetes, treatment or prevention of cardiovascular diseases.

 The CB1 receptor inhibitors provided by the invention can be used for detoxification, weight loss and diabetes treatment, and they have sufficiently strong activity, and the toxicity is expected to be significantly lower than that of the magical class (MJ-15), and it is expected to overcome the existing CB1 receptor inhibition. The toxicity and side effects exhibited by the agent.

 The technical solution for accomplishing the above inventive task is: a low toxicity "multi-headed drug", a nitrogen-containing aromatic ring-containing CB1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group, and a physiologically acceptable salt or solvate thereof, The CB1 receptor inhibitor is a nitrogen-containing aromatic ring-containing CB1 receptor inhibitor having a hydroxyl group or a substituted hydroxyester group and a physiologically acceptable salt or solvate thereof. When the nitrogen-containing heterocycle is acridine, the formula is:

Formula I

The pyridine ring to the right of the above formula may be replaced by pyrrole, pyrazole, imidazole, azazo, anthracene, carbazole, etc., like pyridine, which are both nitrogen-containing aromatic rings; Substituted by pyrrole or N-substituted pyrrole; it may also be replaced by N-pyridine oxide.

Wherein 1 ^ ₈ is a linear, branched or cyclic hydrocarbon group or a hydrocarbon group having on the pyrazole ring; R ₂ and R ₃ on the pyrazole ring are the same or different and are phenyl or contain a halogen, dC ₃ linear or branched fluorenyl or decyloxy group, trifluoromethyl group, nitro group, phenyl group, etc. a phenyl group of any one, two or three substituents; wherein, preferably, p-bromo or p-chlorophenyl; R ₃ is preferably a 2,4-dichlorophenyl group.

The nitrogen-containing aromatic ring substituted by 0 is bonded to the 3-position amide group of the pyrazole ring substituted by R, R ₂ and R ₃ by a certain carbon atom on the ring through (CH ₂ ) _n ; The n in the range is 0-3;

 R4 is hydrogen, a straight chain, branched or cyclic saturated or unsaturated hydrocarbon group, or a hydrocarbon group containing one or more aromatic rings; an acyl group of a saturated or unsaturated aliphatic carboxylic acid; An acyl group of an aliphatic carboxylic acid substituted with a carboxyl group, a hydroxyl group or a decyloxy group (e.g., Y-hydroxy-butyryl group, β-methoxycarbonylpropionyl group); an acyl group of a substituted or unsubstituted aromatic carboxylic acid or a sulfonic acid; An acyl group of a family or an aromatic amino acid; when R4 contains an optically asymmetric center, its configuration includes both R and S possibilities.

In the above formula I, the substituent OR4 and the substituted carbazole-3-amide group of the CH _{2 n} chain

The relative position on the acridine ring may take all chemically reasonable possibilities: 3, 4, 5, or 6-OR4 substitution on the 2-(CH ₂ ) _n -NH-acridine ring; 3-(CH ₂ ) 2, 4, 5, or 6-OR4 substituent on the piperidine ring Soft _n -NH-; and the substituents on the 2 or 4- (CH _{2) n} -NH- Soft piperidine ring 3-OR4.

 The nitrogen-containing aromatic ring-containing CB1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group and a physiologically acceptable salt thereof may be: hydrochloride, hydrobromide, sulfate, hydrosulfate, dihydrogen phosphate Salt, methanesulfonate, monomethyl sulfate, maleate, fumarate, oxalate, naphthalene-2-sulfonate, gluconate, citrate, a isethionate, a p-toluenesulfonate, a 3,5-dimethylmonobenzylsulfonate, or a quaternary ammonium salt formed with a halogenated halogen, which is fluorine, chlorine, bromine, or iodine Alkane.

 The present invention includes, in addition to the compound expressed by the above formula, a complex obtained by mixing any two or more of the compounds in different ratios (or any ratio).

The main feature of the present invention is that, as part of the molecule, the compounds of the present invention all have a nitrogen-containing aromatic ring having a 3⁄4 group or a substituted hydroxy group, in the structure thereof, as compared with various CB1 receptor inhibitors which have been published in various countries in the world. Chemical structures with hydroxyl groups or derived therefrom (such as esters or ethers), in most cases, are much less toxic than without hydroxyl groups; their blood-brain barrier (BBB) permeability in humans is comparable to that of Sanofi, France -Aventis' products are different from rimonabant and can be adjusted by different ester groups to further reduce central toxicity. First, a hydroxy substitution of aminomethylpyridine is prepared. The preparation method can vary greatly depending on the position of the substitution. In the case of 2-hydroxy-4-aminomethylpyridine, 3-hydroxy-4-aminomethylpyridine, 2-hydroxy-5-aminomethylpyridine, all of them are derived from the corresponding pyridinaldehyde and are produced by hydroxylamine. , and then restore, as shown in Equation 1:

 Reaction Formula 1: Preparation of Hydroxyl Substituent of Aminomethylpyridine

 The resulting hydroxy substituted aminomethylpyridine is condensed with a rimonabant or a bromoethyl nucleus carboxylic acid under the action of a catalyst to give the corresponding hydroxypyridine condensation product. These condensates are treated with an aliphatic or aromatic acyl group to produce various esters, as shown in Reaction Scheme 2:

 Preparation of reaction formula 2, hydroxypyridine condensate and ethers and esters thereof

Formula: R^CH ₃ or C ₂ H _{5 ;} B ₄ is C1 or Br; is a various aliphatic, aromatic hydrocarbon group, acyl group or sulfonyl group.

 When R4 is a hydrocarbon group, the product is a variety of ethers. For the purpose of smoothing the alkylation, a phase transfer catalyst, such as the preparation of the compound ZH1 102-0-1, is sometimes used:

 Reaction Formula 3, Preparation of Methyl Ether When R4 is an acyl group, the product is a variety of esters. The acylating agent may be an acid halide, an acid anhydride or the like.

In order to prepare an ester of an amino acid, the amino acid used needs to be protected in advance, as shown in Reaction Scheme 4: 9

 Reaction formula 4, preparation of amino acid condensate

In the formula: Or C ₂ H _{5 ;} B ₄ is C1 or Br; PG is a protecting group; is a substituent at the alpha position of various amino acids, including aliphatic, such as a simple sulfhydryl group; aromatic, including benzyl, benzene ring Substituted benzyl, 2-thiophene-methylene and the like.

The nucleus of the double mother nucleus may be a by-product of the preparation of the condensed amide (as obtained in Example 3, ZH-1302-2-1), or via 2 equivalents of the core of rimonabant or bromideban The acid chloride of the carboxylic acid is reacted with the hydroxy substituent of the aminomethylpyridine, as in the reaction formula 5:

 Reaction formula 5, preparation of double mother core product

In the formula: ! ^ is 0 ₃ or C ₂ H ₅ ; B ₄ is C1 or Br. The low toxicity CB1 receptor inhibitor of the present invention and physiologically acceptable salts or solvates thereof can be applied to all medical aspects related to CB1 receptor inhibitors, including preparation of drug addiction drugs, weight loss drugs, and antidiabetic agents. Drug, treatment or prevention of cardiovascular disease drugs.

 The strategic idea of the invention:

Rimonabant is effective and active, and its IC _5Q value is as low as ΙΟηΜ. Among the various drugs that people actually use, the IC _5Q values of many varieties are measured in μΜ (that is, ΙΟΟΟηΜ). Applicant research Now, a compound having an IC _5Q value of 3, 517 nM (i.e., 3.5 μM) has reached 95% inhibition of the CB1 receptor at a concentration of ΙΟμΜ (see the inventor's previously patent ^[4] ). The reason for the elimination of rimonabant is that its central toxicity is too high. The strategic principle of the present invention is to pursue the highest drug-making properties, not the highest activity; in order to reduce toxicity, it is willing to sacrifice the efficacy to some extent.

This strategy was in the affirmative preliminary efficacy studies: In vitro activity of patent application by far lower than rimonabant, 1〇 _{5 ()} up to the value of the lead compound 228.7ηΜ ^{ZH-107-SR / S [} 5] In the mouse test, the weight loss of the compound was found to be half that of the same dose of rimonabant.

 ZH-107-S-R/S; IC50, 228.7ηΜ

The difference between Magical Class (MJ-15) and Rimonabant is the replacement of the latter piperidine ring with aromatic methylpyridine. Considering that the physiological toxicity of the aromatic ring itself is stronger than the ester ring in most cases, the inventors are concerned that the toxic side effects of MJ-15 on the central nervous system may be even stronger than that of rimonabant. It has been reported ^[3] that the in vitro activity of MJ-15 is even higher than that of rimonabant, but no further reports have been reported so far. Is it due to central toxicity?

Applicants of the present patent have considered possible metabolites of rimonabant in the human body in order to obtain a low toxicity lead compound. The applicant originally thought that: under the action of the drug P450 in vivo, the three hydroxylated metabolites of rimonabant should be non-toxic but not inhibiting, and the enantiomer of the metabolite should be non-toxic but still Strong activity. However, the results show that the pair of enantiomers of the 3-hydroxy derivative of rimonabant, (S)-5-(4-chlorophenyl) small (2,4-dichlorophenyl)-4-yl The keto-1H-pyrazole-3-carboxylic acid (3-hydroxypiperidin-1-yl)amide (ZH-101-S) and the R-enantiomer (ZH-101-R) all exhibit strong activity. Its IC _5Q values are 50.0nM and 68.8ηΜ ^{ί6], respectively} . This gives the inventor an important revelation: the introduction of a hydroxyl group into the molecule of a highly active CB1 receptor inhibitor, regardless of the orientation of the hydroxyl group, although the activity of the product is reduced. In this case, why not apply the same hydroxylation strategy to MJ-15?

 ZH-101-R ZH-101-S

IC ₅₀ 68.8nM IC ₅₀ 50.0nM What's more, Magic Class (MJ-15) - the most likely metabolic reaction is hydroxylation; the most likely hydroxylation site is the pyridine ring. Since the metabolic reaction itself is a detoxification process, the hydroxylated product should be non-toxic or at least significantly less toxic than its prototype MJ-15.

 The introduction of hydroxyl groups increases the hydrophilicity of the molecule, thereby reducing the permeability of the blood-brain barrier, allowing the drug to enter the central nervous system less; even if the entry is due to reduced lipophilicity, binding to the CB1 receptor there. Become more slack. These factors should weaken the side effects that cause depression. In contrast, less penetration of the blood-brain barrier means higher concentrations in the peripheral system and more action on the spinal cord and gastrointestinal nervous system. This may indicate a certain characteristic, such as showing better weight loss.

 The hydroxyl group itself generally reduces the toxicity of the drug and also increases the bioavailability of the drug.

 The applicant then introduced a hydroxyl group onto the pyridine ring of MJ-15, expecting to reduce its toxicity under the premise of sacrificing activity.

As expected, when the hydrogen on the pyridine ring was replaced by a hydroxy group, the resulting new compounds, such as (ΖΗ-Π02-0-0) and (ZH-1302-00), had IC _5Q values of 129.6 nM for CB1 receptor inhibition, respectively. And 71.4 nM, which is higher than the MJ-15 reported value of 1.39 nM (see Table 1 below), that is, the inhibitory activity is reduced, but still strong enough.

Applicants have further esterified the introduced hydroxyl groups. This strategy was used in the previously applied patent ^[5 ' ^{7) to} demonstrate outstanding results: the in vitro activity of the product is increased, even to the same level as rimonabant. Now, the hydroxypyridine condensate is esterified, for example, acetylated to give ZH-1302-0-1, and the aromatic benzoyl group is attached to obtain ZH-1302-2-2. The acyl group of the amino acid is attached to obtain (S)-ZH. - 1302-3-1 and so on. In vitro activity screening showed that they have high inhibition rates for the CB1 receptor.

 The inventor also put forward the concept of "multi-headed drug". For example, ZH-1302-2-2, once it enters the human body, is absorbed in the prototype and is bound to hydrolyze in the gastrointestinal tract, producing ZH-1302-0-0 and benzoic acid:

 ZH- 1302-2-2 ZH- 1302-0-0

ZH-1302-2-2 is a single compound that has been widely hydrolyzed in the gastrointestinal tract and has become a mixture of both ZH-1302-2-2 and ZH-1302-0-0 (used widely Benzoic acid as a preservative is not considered). The ratio of the two is equivalent to the molar ratio of absorbed and hydrolyzed by ZH-1302-2-2. ZH-1302-2-2 as an ester should be easier to penetrate the blood-brain barrier and act on the central nervous system; ZH-1302-0-0 as a hydroxy compound is the opposite, difficult to penetrate the blood-brain barrier , more on the peripheral system. Therefore, the pharmacological action of this compound of ZH-1302-2-2 is necessarily three The combined effect of the factors: the role of the prototype ZH-1302-2-2; the effect of the hydrolysate ZH-1302-0-0; and the molar ratio of ZH-1302-2-2 to ZH-1302-0-0 ( The ratio of the number). It is particularly worth mentioning that the molar ratio of ester to hydroxy compound can be adjusted; the method of adjustment is to change the ester group to change the rate at which the ester is absorbed in the gastrointestinal tract and the rate at which it is hydrolyzed. For example, the ratio of 2,4-dichlorobenzoate ZH-1302-2-5 absorbed by the prototype in the body to be hydrolyzed to ZH-1302-0-0 will obviously differ from ZH-1302-2-2. By adjusting this ratio, it is even possible to develop a series of new drugs with different effects: Some are mainly central; some are mainly peripheral.

Patent applicant previously proposed ^{[5 '7],} such compounds have called "single composite drug", meaning now borrow "reentry long sub-conductor Missiles", changed to "sub-conductor long drug "(Multiple Independently Taget Able Drugs), more precisely.

 The hydroxy ester of the present invention is a "multi-headed drug."

 Such "multiple-headed drugs" are also likely to have particularly advantageous absorption and distribution advantages in the body, and may also be more effective.

Applicants have further esterified the introduced hydroxyl groups with amino acids, especially natural amino acids. This strategy has also been applied to the previously applied patent ^[5 ' ^7] and has been successful. Nowadays, the hydroxypyridine derivative is used to obtain an ester of an amino acid, such as ZH-1302-3-1:

 ZH-1302-3-1

 Like the products of the second strategy above, they are also a type of "long-headed drug" that undergoes hydrolysis in the body. However, the introduction of amino acids creates three new features: First, the toxicity of a drug is not equal to the simple addition of its components, but it is of course related to its components. Nowadays, the use of non-toxic amino acids, even natural amino acids as human nutrients, may further reduce the toxicity of the whole drug. Second, the chirality of amino acids may increase the selectivity of drugs, and the selectivity is often increased. With a decrease in toxicity. (For example, dextro-phenanthrene has a good weight-loss effect while left-handed body damages the heart valve; dextrosalidomide sleeps while the left-handed body causes fetal malformation, etc.). Third, the above "multi-headed drug" ZH-1302-2-2 is generally neutral and has low solubility; once the amino acid product is salted (such as hydrochloride), it will not only exhibit good solubility, but also Positive ions. Its absorption, distribution, metabolism and excretion in the human body will be different from neutral molecules. This feature opens up a broader space for the selection of excellent compounds.

In summary, the present invention is characterized in that all of the inventive compounds have a nitrogen-containing aromatic ring; and the nitrogen-containing aromatic ring necessarily has a hydroxyl group or a substituted hydroxyl group (that is, a substituent such as an ester group or a decyloxy group). It is due to this hydroxyl In the presence, the toxicity of the compounds is greatly reduced; it is precisely because of the presence of substituted hydroxyl groups that they are "multi-headed drugs" whose function can be regulated.

 In summary, the present invention relates to and provides a novel class of low toxicity hydroxy substituted nitrogen-containing aromatic ring CB1 receptor inhibitors, and physiologically acceptable salts or solvent compounds thereof, processes for their preparation and use. Specifically disclosed a novel class of low toxicity amide derivatives of pyrazole-3-carboxylic acid and their salts and solvates; their synthetic routes, preparation procedures and processes; and their use alone or as a composite component One is used for all medical uses associated with high expression of CB1 receptors, especially for detoxification, smoking cessation, weight loss and diabetes treatment. DRAWINGS

Figure 1 is a graph showing the percentage inhibition of the CB1 receptor by the compound of the present invention at a concentration of 10 M.

 (0% means complete inhibition; 100% means no inhibitory activity; Rimonabant and MJ-15 are internal standards used, with reference to the results of the first screening method.)

Figure 2 is a graph showing the percentage inhibition of the CB1 receptor by the compound of the present invention at a concentration of 10 M.

 (0% means complete inhibition; 100% means no inhibitory activity; Rimonabant, ZH-105-R/S, ZH-501-S are the internal standards used, with reference to the results of the first screening method.)

Thank you: Figure 1 and Figure 2 above are freely determined by Shanghai National New Drug Screening Center. Patent applicants would like to thank Xie. detailed description

 This patent refers to the following documents:

 [1] Pyrazole derivatives, method of preparing them and pharmaceutical compositions in which they are present; Francis Barth; Pierre Casellas, et al; Sanofi, Paris, France;

USP 5,624,941.

 [2] Pyrazole-3 -carboxamide derivatives, process for their preparation and pharmaceutical compositions in which they are present; Francis Barth; Pierre Casellas, et al, Sanofi, Paris, France; USP 5,462,960.

 [3] Wilderness, a new cannabinoid receptor antagonist diet drug MJ15 preclinical toxicology and related mechanisms; PhD thesis; Institute of Pharmacology and Toxicology, Chinese Academy of Military Medical Sciences; May 28, 2008.

 [4] Fan Rulin, Feng Jianke, Wang Hua, Yao Hu, Yin Wentao; Chinese Patent, Application No. (201010187654.1): Low toxicity CB1 receptor inhibitor, its preparation method and its application in the preparation of drugs for detoxification, weight loss and treatment of diabetes.

[5] a) Fan Rulin, Yao Hu, Feng Jianke, Qiao Lin; Chinese Patent, Application No. (201 1 10092998.9): "Single Compound Drug": Chiral Nitrogen Heterocycle, Synthetic Method and Preparation of Low Toxicity CB 1 Application in receptor inhibitors; b) Fan Ru Lin, Yao Hu, Feng Jianke, Qiao Lin, Yuan Chen; PCT/CN2012/074015: Optically active low toxicity CB1 receptor inhibitors, preparation methods and uses thereof.

 [6]a) Fan Rulin, Zhou Xiaohong, Yao Hu, Wang Hua, Feng Jianke, Yin Wentao; Chinese Patent, Application No.

 (2011 10027174.3), chiral CB1 receptor inhibitor, preparation method and use thereof; b) Fan Rulin, Chen Zhiyuan, Yao Hu, Feng Jianke, Qiao Lin; PCT/CN2012/070538, Chiral low toxicity CB1 receptor inhibitor and Preparation methods and uses.

 [7] a) Fan Rulin, Feng Jianke, Wang Hua, Yao Hu, Qiao Lin; Chinese Patent, Application No. (201 110122819.1); 3-pyrazolecarboxylic acid amides, preparation methods thereof and their preparation as CB1 receptors Application in the drug. b) Fan Rulin, Feng Jianke, Wang Hua, Yao Hu, Qiao Lin; PCT/CN2011/082982: Low toxicity 3-pyrazolecarboxylic acid amide, its preparation method and its application in the preparation of a drug as a CB1 receptor inhibitor.

 Pharmacological experiment:

For the compounds of the present invention, the inventors determined their inhibition rates for the CB1 receptor and the IC _{5 of} some of the compounds, respectively. Values, and their inhibition rates for protein tyrosine phosphatase (PTP1B) were investigated to investigate their possible hypoglycemic effects. 1. Method for determining the in vitro activity of CB1 receptor

 The compounds of the invention were screened for in vitro activity according to two methods.

The first method was performed by a relevant US unit. The IC _5Q data of the compound for the CB1 receptor was determined as follows: First, the radioactive [3H]-limoma was dissolved in HEPES containing 0.25% BSA (pH 7.4). binding buffer at a concentration of 2-5 nM; protein into CHO cell membranes expressing CB1 3 μ _§ receptors have a small hole 96 to the test board; samples 1: 100 (weight ratio) was dissolved DMSO was added to these wells. The test plates were allowed to incubate for 1.5 hours at room temperature; the reaction mixture was transferred to a GF B filter plate using a Packard cell harvester to terminate the binding reaction. The filter plates were washed and the material on the plates was calculated using a Packard Top Count Scintillation Counter; non-specific connections were determined by adding an excess of 1000-fold non-radioactive limona; the specific linkage was subtracted from the total number of non-specific linkages. CPM was converted to percent inhibition based on total and non-specific connections; IC ₅₍₎ values were calculated using inhibition data and curves.

 The second method was completed by China National New Drug Screening Center. Experimental principle:

By establishing a cell line that co-transforms CB1 and Gal6, the receptor is activated to activate Gal6 protein, which in turn activates lipase C (PLC) to produce IP3 and DAG, and IP3 can interact with intracellular endoplasmic reticulum and mitochondria. The IP3 receptor binds, causing the release of intracellular calcium. Therefore, measuring changes in intracellular calcium can be used as a method of detecting the activation state of CB1. Fluo-4/AM is a calcium fluorescent probe indicator used to measure calcium ions as a non-polar, fat-soluble compound. Upon entry into the cell, the AM group dissociates and releases Fluo-4 under the action of cell lipolytic enzyme; since Fluo-4 is a polar molecule, it does not easily pass through the lipid bilayer membrane, which allows Fluo-4 to remain for a long time. Within the cell. Finally, the level of activation of the Get protein can be reflected by measuring the intensity of the excited fluorescence. If the screened compound is capable of antagonizing the CB1 receptor, the calcium flux reaction can be greatly reduced. Experimental steps:

 1. CHO cells stably expressing CB1/Gcd6 were seeded in 96-well plates and cultured overnight at 37 °C.

2. Aspirate the culture medium in the wells with the cells, add freshly prepared dye (HBS containing 2 μΜ of F1UO-4AM) to 40 μΐ/well, and incubate for 40 minutes at 37 ° C in an incubator.

3. Dilute and mix the drug to be tested with calcium buffer.

4. Discard the dye and wash it with freshly prepared calcium buffer. Replace with 50 μl of calcium buffer dissolved with the drug to be tested.

5. Using the Flex Station II instrument, the instrument will automatically add 25 μl of calcium buffer dissolved in CB1 receptor-known agonist at the 15th second, and finally read the fluorescence at 525 nm. Based on the same principle, if the selected compound binds to the receptor, it can cause a calcium flow reaction and thus be an agonist of the receptor; if the selected compound can inhibit the binding of the agonist to the receptor, it can be excited The calcium-induced reaction caused by the agent is greatly reduced, thereby exhibiting an antagonist of the CB1 receptor. The experimental setup instrument Flex Station was added to the 30 nM agonist CP55940 (25 μΙ/well). The reaction rate of the positive drug Rimonabant (10 u M ) was 0, and the DMSO (1 %) was 100%. The fitting rate of each compound at the CB1 receptor to CP55940 was obtained by fitting calculation using GraphPad Prism software. In order to correlate the results of the two different methods, the two methods are simultaneously applied to rimonabant, magic (MJ-15), ZH-112-00, ZH-1302-0-0, ZH-105- R/S, and ZH-501-S totaled 6 compounds, and the results are shown in Table 1.

The inhibitory activity of the compounds of the present invention on the CB1 receptor and the IC50 values are shown in Tables 2 to 4, and see Figure 1 and Figure 2. 2. Determination of inhibition rate of protein tyrosine phosphatase PTP1B (protein tyrosine phosphatase) PTP1B plays a very important role in regulating insulin sensitivity and fat metabolism through dephosphorylation of the insulin receptor. Therefore, selective, highly active PTP1B inhibitors are of great value in the treatment of diabetes and obesity.

 Experimental method for determination of inhibition rate of PTP 1 B:

Protein tyrosine phosphatase for screening PTP1B is a GST fusion protein expressed and purified from E. coli. Using the purple substrate pNPP, the inhibition of the activity of the recombinant enzyme by different compounds was observed to preliminarily evaluate the medicinal effects of the compound. PTP1B Hydrolyzed Substrate The product obtained from the phospholipid of pNPP has a strong light absorption at 405 nm. Therefore, the change in light absorption at 405 nm can be directly monitored to observe changes in the activity of the enzyme and the inhibition of the compound.

First, calculate the increment of light absorption intensity per unit time in the initial velocity of the enzyme (unit: mO.D. /min), which represents the initial velocity of the enzyme, and then calculate the inhibition rate of the enzyme activity of the sample according to formula 1 (%Inhibiti ₀ n) ,

%100% X -^DMSOSampleDMSOvvvInhibition formula 1

Which indicates the initial velocity of the dosing group, indicating the initial velocity of the DMS0 group (ie, the non-medicated group).

In the experiment, the pure compound concentration selected in the preliminary screening was 20 u g/ml (the crude extract was 100 g/ml), and three replicate wells were set. Samples with an initial screening inhibition rate of 50% or more continue to measure IC values.

 50

 The value of I (the concentration of the drug when the enzyme activity is inhibited by 50%) is the inhibition value (%Inhibition). The logarithm of the sample concentration X is calculated by the nonlinear fitting of Equation 2.

hXLoglCBo t tomTopBo t tomlnhibi tion*-+- +=) 50 (101% formula 2

 Where h represents the Hi l l coefficient.

In this patent, the IC50 values for the compounds are not included. The results of the measurement of the percentage of inhibition are shown in Table 5. Table 1. References for the two analytical methods: References for IC ₅ o values and percent inhibition for CB 1 receptors

Table 2, compound IC _{5-hydroxypyridine} for CB1 receptor. Value or percent inhibition Method 1: Data preparation method for membrane preparation 3 in combination with 3H-SR141716 2

Kd = 3. 1 nM Example ΙΟμ

 Concentration

 With people CB1 subject

 Next, right

 Structural combination

 CB-1 subject to

IC ₅₀ (nM)

 Body suppression

 Compound rate, % ICso

ZH- 1 102-0- 1 _o see 5911η

0

 N 129. 6 Figure 1 Μ

ZH-1202-0- 1 Not tested Not tested

0

 Set

ZH-1301-0-0 See 27630η Figure 1 Μ

ZH- 1302-0-0 3 71.4 See 902 Figure 2 nM ZH- 1402-0-0 25 See 2026 Figure 2 nM Table 3, IC _5Q values or percent inhibition of hydroxypyridyl ethers and esters for CB1 receptors

Table 4, IC _5Q values or percent inhibition of 4-ethylpyrazole-hydroxypyridyl esters for CB1 receptors

Note: Kd is the dissociation equilibrium constant (De-association) used to characterize the strength of the interaction of the reagent with the receptor or enzyme as a reference.

Table 5, Percent inhibition of PTP1B at a concentration of 20 H g/mL Patented compound number Screening list Result Deviation Remarks

 Bit number

 MJ-15 NC00152 86.88 4.69 Active

 120

 ZH- 1102-00 NC00152 84.55 2.28 Active

 121

 ZH- 1102-21 NC00152 80.58 11.23 Active

 122

 ZH- 1302-00 NC00152 82.59 1.40 Active

 123

 ZH- 1302-21 NC00152 88.73 8.73 Active

 124

 ZH- 1301-00 NC00152 90.69 0.1 1 Active

 132

 ZH-1301-1 1 NC00152 81.72 6.53 Active

 133

 ZH- 1301-23 NC00152 93.02 1.42 Active

 134

 ZH- 1301-24 NC00152 93.79 1.00 Active

 135

 ZH- 1301-25 NC00152 95.62 0.43 Active

 136

 ZH- 1301-26 NC00152 59.69 6.98 Active

 137

 ZH-1302-1 1 NC00152 2.51 0.51

 138

 ZH- 1302-22 NC00152 93.73 0.58 Active

 139

 ZH- 1302-23 NC00152 93.98 2.67 Active

 140

 ZH- 1302-24 NC00152 92.63 7.74 Active

 141

 ZH- 1302-25 NC00152 86.79 0.21 Active

 142

 ZH- 1302-26 NC00152 89.15 0.34 Active

 143

 ZH- 1402-00 NC00152 94.88 0.36 Active

 144

 ZH-1402-11 NC00152 71.80 0.48 Active

 145

 ZH- 1402-22 NC00152 84.34 1.27 Active

 146

 ZH- 1402-23 NC00152 94.24 0.23 Active

 147

ZH- 1302-31 NC00152 91.81 1.18 Active 150

 ZH- 1301-22 NC00152 93.15 0.25 Active

 151 Thanks: The above data is freely determined by Shanghai National New Drug Screening Center. Patent applicants would like to thank them. Synthesis example

 The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. In addition, it is to be understood that various modifications and changes may be made by those skilled in the art in the form of the present invention. Example 1: 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (2-hydroxypyridine-5-ammonia) Methyl)amide (ZH-1102-0-0) and 5-[5-(4-chlorophenyl) small (2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3- Amido]methyl-pyridin-2-yl-5-(4-chlorophenyl) small (2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate (ZH -1102-2-1)

 (A) Synthesis of 2-hydroxy-5-aminomethylpyridine

 920 mg (7.5 mmol) of 2-hydroxy-pyridine-5-formaldehyde was added to 25 mL of anhydrous methanol. The mixture was stirred magnetically to a paste. Hydroxylamine hydrochloride 625 mg (9.0 mmol) was added in ice-water bath and stirred at 10 Torr for 3 min. The solution was clarified and stirring was continued for 2.5 hours. TLC showed the reaction was complete.

10 mL of acetone was added to the reaction mixture, and the mixture was stirred for 10 min, and the solvent was evaporated at 45 ° C; the obtained solid was dissolved in 25 mL of anhydrous methanol, and then added with 10% Pd/C 180 mg, and stirred at room temperature overnight, TLC indicated The reaction is almost complete. The orange solution was filtered, concentrated to 6 mL, aqueous ammonia was added to pH=8, and the precipitated solid was filtered off. Purification by column chromatography with chloroform-methanol gradient elution, yield: 87.3%; Mp, 169-17rC _; ESI- MS m/z: 125.04 [M+H] ⁺ _; Ή-NMR (DMSO-d ₆ ): δ 3.48 (bs, 2H), 6.30 (d, lH), 7.25 (s, lH), 7.46 (s, 1H).

 (B) Synthesis of (ZH-1102-0-0) and (ZH-1102-2-1)

500 mg (about 4.0 mmol) 2-hydroxy 5-aminomethylpyridine, 1.37 g (3.6 mmol, 0.9 eq) of the parent carboxylic acid, 1.53 g (8 mmol) of EDC hydrochloride and 1.08 g (8 mmol) of HOBT. In a mL round bottom flask, a vacuum pump was used for 0.5 h, and then nitrogen gas was introduced. After repeating once, 5 mL of dry DMF was added thereto, and the mixture was stirred at room temperature for 10 hours. Add 25 mL of water; extract 3 times with ethyl acetate, 50 mL each time. The combined organic phases were washed twice with Na ₂ CO ₃ solution, 50 mL each time; and finally washed twice with 60 mL of brine. After drying over anhydrous sodium sulfate, the solvent was evaporated, and then purified. First eluted is a double condensate (ZH-1102-2-1) in which the hydroxyl group on the pyridine ring is also esterified (186 mg, p-aminomethylpyridinium) For pyridine, the yield was 5.5%; 'H-NMR (CDC1 ₃ , 400 MHz): δ, 2.40 (bs, 6H); 4.68 (d, 2H); 6.65

(m, 1H); 7.19 (m, 2H); 7.36-7.57 (m, 13H); 7.92 (bs, 1H). Then (ZH-1102-00) 580 mg, yield 30.3% for aminomethylpyridine; Mp, 257-260'C _; ESI-MS m/z: 487.10

[M+H] ⁺ ; NMR (CDC1 ₃ ): ^, 2.40 (s, 3H), 4.41 (bs, 2H); 6.61 (d, 1H); 7.09 (d, 2H); 7.34-7.31 (4H, m ), 7.40 (1H, s); 7.45 (lH, bs), _; 7.57 (d, 1H). In the same manner, 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-indazole-3-carboxylic acid chloride was used instead of the above 5- (4) -Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid chloride, which gives 5-(4-bromophenyl)-1-( 2, 4-Dichlorophenyl)-N-[(3-hydroxypyridin-4-yl)-methyl]-4-ethyl-1H-pyrazole-3-amide (ZH-1202-00).

Example 2: 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N-K2-hydroxypyridin-4-yl)-methyl1-4-methyl- 1H- Pyrazole-3-amide (ZH-1301-0-0)

(A) Synthesis of 2-hydroxy-4-aminomethylpyridine 2.0 g (16.25 mmol) of 2-hydroxy-4-carbaldehyde-pyridine was added to 40 mL of anhydrous methanol, stirred and dissolved; hydroxylamine hydrochloride 590 was added under ice cooling. Mg (8.50 mmol, 1.1 eq); After stirring for 5 min, stir at room temperature for 35 min.

TLC showed the reaction was complete. Acetone 5 mL was added to the reaction mixture, and after stirring for 10 min, the solvent was evaporated at 40 °C. The obtained solid was dissolved in anhydrous methanol (20 mL), Pd/C (10%) 500 mg was added, and hydrogen was stirred at room temperature for 24 h. TLC indicated that the reaction was substantially complete. Filtration gave a pale yellow solution. After concentration, silica gel column chromatography eluted with chloroform-methanol (10:1 5:1) to give an orange solid 500 mg (8.86 mmol, 54.5%). 2-hydroxy-4-aminomethylpyridine. MP, 275-276°C (hydrochloride); Ή NMR (400 MHz, DMSO-d ₆ , δ, ppm): δ, 3.86 (bs, 2H), 6.31 (1H, d, J=4.0 Hz, H -5), 6.42 (s, 1H), 7.40 (d, 1H), 8.66 (3H, N ⁺ H ₃ ), 11.69 (bs, 1H, OH).

 Synthesis of (B) (ZH-1301-0-0)

2-hydroxy 4-aminomethylpyridine 375 mg (3.05 mmol), EDC.HC1288 mg (1.5 mmol), DMAP 50 mg (0.41 mmol, and rimonabantine 1.2 g (3.15 mmol) added to 50 mL In a single-mouth bottle, vacuum was applied for 0.5 hours, and after filling with N _{2 ,} vacuum was further applied for 0.5 hour; 5 mL of dry DMF was poured into the bottle and reacted at room temperature for 24 hours, and TLC showed that the reaction was almost complete. 10 mL of water and 10 mL of methanol were added, and oil was used. Ether (50 mLX3) extraction to remove less polar After the compound, 60 mL X 2 then extracted with ethyl acetate, after washed with saturated aqueous sodium chloride solution in ethyl acetate extracts were dried over anhydrous Na ₂ S0 ₄ and concentrated to about lmL, into purified by silica gel column eluting with ethyl acetate : Petroleum ether (2:1) eluted to give l.lg compound in a yield of 80.8%. MP, 227-228 °C; 'H-NMR (CDC1 ₃ , 400 MHz): δ, 2.19 (s, 3H); 4.51 (bs, 2H); 6.30 (s, 1H), 6.54 (s, 1H); 7.09 (d, 2H); 7.29-7.45 (m, 6H); 12.80 (bs, 1H, OH).

 Example 3: 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N-[(3-hydroxyacridin-4-yl)-methylbu 4-methyl- 1H-pyrazole-3-amide (ZH-1302-0-0) and 3-[(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl- 1H-pyrazole-3-oxiranyl)pyridin-4-yl]-[ (5-(4-chlorophenyl) small (2,4-dichlorophenyl)-4-methyl-1H-pyrazole -3- Amido] Methide (Me-1) (ZH-1302-2-1)

Synthesis of (A) 3-hydroxy-4-aminomethylpyridine

 Add 950 mg (7.72 mmol) of 3-hydroxy-pyridine-4-carbaldehyde to 40 mL of anhydrous methanol and stir to dissolve. Add 590 mg (8.50 mmol, 1.1 eq) of hydroxylamine hydrochloride under ice-cooling, stir for 5 min. Stir at room temperature for 35 min,

TLC showed the reaction was complete.

5 mL of acetone was added to the reaction mixture, and after stirring for 10 min, the solvent was evaporated at 40 ° C. The obtained solid was dissolved in 20 mL of anhydrous methanol, and 10% Pd/C 150 mg was added thereto, and stirred at room temperature overnight, and TLC indicated that the reaction was substantially finished. The orange solution was filtered, and the solvent was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Mp, 209-211 ° C; NMR (400 MHz, DMSO-d ₆ - 5: 3.96 (s, 2H), 7.37 (s, lH), 8.06 (bs, 1H), 8.29 (s, 1H).

 (B) (ZH-1302-0-0) and (ZH-1302-2-1) synthesis

Add 3-hydroxy 4-aminomethylpyridine 224 mg (1.8 mmol), carboxylic acid 825 mg (2.2 mmol '1.2 eq), EDC.HCI 690 mg (3.6 mmol) and HOBT 486 mg to a 10 mL round bottom flask. Dry in vacuum for half an hour, pass nitrogen; repeat vacuum for half an hour. 2 mL of f-dried DMF was poured thereinto and stirred at room temperature for 10 hours. After the reaction, it was poured into 25 mL of ice water and extracted with 3×20 mL of chloroform; the combined organic phases were washed twice with Na ₂ C0 ₃ solution, 30 mL each time. After drying over anhydrous sodium sulfate, the solvent was evaporated and purified by column chromatography. First eluted is the double condensate ZH-1302-21, 168.6 mg, which is also esterified with a hydroxyl group on the acridine ring. The yield is 11% for the hydroxyaminomethyl group; Mp, 147-150 °C. 'H NMR (CDC1 ₃ ), δ: 2.37 (bs, 6H), 4.71 (d, 2H), 7,06 (d, 2H), 7.10 (d, 2H), 7.26-7.30 (9H, m), 7.42 ( s, 1H), 7.51 (bs, 1H), 8.52 (bs, 1H), 8.58 (s, lH) c then the expected compound (ZH-1302-0-0) 314.6mg, yield 36.5% Mp, 257-260 ° C. ESI-MS m/z: 487.10 [M+H] ⁺ ; NMR (400 MHz, CDC1 ₃ ), δ 2.40 (3H, bs); 4.41 (2H, d) _; (1H, d); 7.09 (2H, d); 7.34-7.31 (4H, m); 7.40 (1H, s) _; 7.45 (1H, bs), 7.57 (1H, d). (C) (ZH-1302-0-0) another preparation procedure

2-hydroxy 4-aminomethylpyridine 2.2 g ( 17.7 mmol), parent carboxylic acid 8.25 g (22 mmol, 1.2 eq), EDC.HC1 6.78 g (35.4 mmol) and DMAP 216 mg to 100 mL round bottom After drying in a flask for 1 hour under vacuum, dry DMF 1 mL and 40 mL of acetonitrile were added thereto, and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off, and 20 mL (40 mmol) of CH ₃ ONa / CH ₃ OH solution was slowly added to the mixture in an ice water bath to hydrolyze the double condensate. The inorganic salt was filtered off; 25 mL of ice water was added to the filtrate, and the product solid was precipitated; after stirring for 10 min, it was filtered and washed with water; and dried, and then added to ethyl acetate (80 mL), and filtered, and the filter cake was collected to obtain 4.0 g, yield 46.3%. .

 To the mother liquid obtained by the above filtration product, 25 mL of water was added, and extracted with 2x 50 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give a yellow solid (yield). The main component was still the desired condensate (ZH-1302-0-0), and the purity was not high.

 2-fold equivalent of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-indazole-3-carboxylic acid chloride with 3-hydroxy-4- The aminomethylpyridine reaction can be obtained in a high yield (ΖΗ-1302-2-1).

Example 4, 5[5-(4-Chlorophenyl)-1(2,4-dichlorophenyl) 4-methyl-1 H-pyrazole-3-amido)methyl]pyridine-2 - ki-methyl ether (ZH-1102-0-1)

The raw material (ZH1102-0-0) 146 mg (0.3 mmol) was suspended in 10 mL of dry acetonitrile, 276 mg (2.0 mmol) K ₂ C0 ₃ and 20 mg tetrabutylammonium bromide were added, and dimethyl sulfate was added dropwise. The ester was 100 μL (1.2 mmol) and stirred at 55 ° C for 1.5 hours. TLC showed the starting material disappeared. The solvent was evaporated, and purified by silica gel chromatography eluting eluting eluting with

ESI-MS m/z: 625.04 [M+H] ⁺ ; Ή-NMR (400 MHz, CDC1 ₃ , δ, ppm): δ , 2.34 (3Η, bs ) ; 3.48 (3H, bs); 4.30 (2H, d); 6.51 (lH, d); 7.03 (2H, d); 7.38-7.22 (7H, m). Example 5, 5[5-(4-chlorophenyl) small (2,4-dichlorophenyl) 4-methyl-1 H-pyrazole-3-amido)methyl]pyridin-2-yl -allyl ether (ZH-1102-0-3)

(ZH-1 102-0-0) 146 mg (0.3 mmol) was suspended in 10 mL of dry acetonitrile, 138 mg (1.0 mmol) K ₂ C0 ₃ and 20 mg KI were added, and allyl bromide 95 μL was added dropwise. (1.0 mmol), stirring at 55 ° C for 1.5 hours, TLC showed that the starting material disappeared. The solvent was evaporated, and purified directly on silica gel column eluting with petroleum ether: ethyl acetate (2:1) to give 138 mg Standard compound, yield 87.1% = ES1-MS m/z: 527.05 [M+H] ⁺ , Ή-NMR (400 MHz, CDC1 ₃ , 5, ppm): δ 2.35 (3H, brs); 4.32 (2H, d,); 4.51 (2H, d); 5.23-5.14 (2H, m); 5.89 (1H, m), _; 6.54 (1H, d,); 7.04 (2H, d); 7.29-7.25 (4H, m ); 7.37-7.36 (3H, m). Example 6, 5[5-(4-chlorophenyl) small (2,4-dichlorophenyl) 4-methyl-1H-pyrazole-3-amido)methyl]pyridin-2-yl- Acetate (ZH-1102-1-1)

(ZH-1102-0-0) 146 mg (0.3 mmol) was suspended in 5 mL of dry acetonitrile, 0.5 mL of acetic anhydride and 2 drops of pyridine were added and reacted at 55 ° C for 2 hours. TLC indicated the reaction was complete. After adding 20 mL of water and extracting with 20 mL of ethyl acetate, the organic layer was washed with 20 mL of NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ , and purified by silica gel column eluting with petroleum ether: ethyl acetate (2:1) Mg compound, yield 50.3% ESI-MS m/z: 529.03 [M+H]+, Ή-NMR (CDC1 ₃ ): δ, 2.33 (3Η, bs); 2.39 (3H, bs); 4.37 (2H, d); 6.58 (lH, d); 7.07 (2H, d), 7.42- 7.27 (6H, m); 7.54 (1H, dd). Example 7, 5[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl) 4-methyl-1H-pyrazole-3-amido)methyl]pyridine-2- Base-benzoate (ZH 1102-2-2)

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (2-hydroxypyridine-5-aminomethyl) Amide (ΖΗ-1102-0-0) 0.147g (0.3mmol) was dissolved in 10ml of CH ₂ Cl ₂ , cooled to 5 ° C in ice water, and 0.079 g (0.5 mmol) of benzoyl chloride was added dropwise in 2 ml of CH ₂ C1 ₂ To the solution, 0.103 g (1.00 mmol) of triethylamine was added, and the reaction was stirred. After the reaction of TLC was detected, the mixture was washed twice with 15 ml of water; the organic phase was washed with 15 ml of saturated NaCl solution; dried over anhydrous NaS04 and concentrated by filtration; Column chromatography gave 116.4 mg of a white solid, yield 65.5%. 'H-NMR CDCb): δ, 2.417 (3H, s) _; 4.699, (2H, d); 7.081-8.249 (15H, m) _; 8.474 (lH, s). Example 8, 5[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido)methyl]pyridine-2 -yl-2-chloro-benzoate (ZH1102-2-3)

 Using 2-chlorobenzoyl chloride instead of benzoyl chloride, it was obtained according to the preparation procedure of ZH-1102-2-2, yield 58.5%.

ESI-MS m/z: 625.04 [M+H] ⁺ ; Ή-NMR (400 MHz, CDCl ₃ , δ, ppm): δ' 2.37 (3Η, bs); 4.40 (2Η, d) _; 6.67 (1H, d); 7.07 (2H, d); 7.64-7.27 (10H, m); 7.90 (lH, m). Example 9, 5[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl) 4-methyl-1H-pyrazole-3-amido)methyl]pyridine-2- 4-chloro-benzoate (ZH1102-24) Dissolve 156 mg (1.0 mmol) of 4-chlorobenzoic acid in dry DCM ' Add (C0C1) ₂ 143 μί (1.5 eq) f Ρ 1 drop of DMF, react at room temperature for 1 hour, evaporate the solvent, add 2 mL DCM, steamed again. A pale yellow 4-chlorobenzoyl chloride crude product was obtained.

 The raw material (ZH-1102-0-0) 146 mg (0.3 mmol) was dissolved in 10 mL of dry DCM and added to 1.0 mL.

Et ₃ N, the above 4-chlorobenzoyl chloride (1.0 mmol) was added under cooling, and the mixture was allowed to react at room temperature for 1 hour, and TLC indicated that the reaction was completed. The solvent was evaporated, and purified by silica gel chromatography eluting eluting eluting with ESI-MS ητ/ζ: 625.04 [Μ+Η] _; Ή-NMR (400 MHz, CDC1 ₃ ): δ , 2.39 (3Η, bs); 4.65 (2H, d); 7.09 (2H, d); 7.16 ( lH,d); 7.54-7.27 (8H, m); 7.91 (1H, m); 8.12 (2H,d). Example 10, 5[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl) 4-methyl-1H-pyrazole-3-carboamine)methyl]pyridine-2 -yl-2,4-dichlorobenzoate (ZH-1102-2-5)

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyva-3-carboxylic acid (2-hydroxypyridine-5-aminomethyl) Amide

(ΖΗ-1102-0-0) 0.151g (0.31 mmol) dissolved in 10 ml of CH ₂ Cl ₂ , cooled to 5 ° C in ice-water bath, and added 2, 4-dichlorobenzoyl chloride 0.109 g (0.5 mmol) 2 ml of the solution in CH ₂ C1 ₂ , 0.107 g (1.02 mmol) of triethylamine was added, and the reaction was stirred. After the TLC detection reaction was completed, the reaction was washed twice with 15 ml of water; the organic phase was washed with 15 ml of saturated NaCl solution; After drying, it was concentrated by filtration; column chromatography gave 147.1 mg of white solid, yield 74.2%. 'H-NMRfCDC): δ, 2.414(3H, s); 4.695(2H,d); 7.079(2H,t); 7.101-7.568(9H,m); 7.918(lH,d); 8.105(lH,d );

8.475 (lH, s). Example 11 , 5[5-(4-chlorophenyl) small (2,4-dichlorophenyl) 4-methyl-1 H-pyrazole-3-amido)methyl]pyridin-2-yl -thiophene-2_carboxylate (ZH1102-2-6)

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (2-hydroxypyridin-5-aminomethyl) Amide (ΖΗ-1102-0-0) 0.155g (0.31 mmol) dissolved in 10 ml of CH ₂ Cl ₂ , cooled to 5 ° C in ice water, and added dropwise thiophene-2-carboxycarbonyl 0.075 g (0.5 mmol) in 2 ml CH ₂ C1 ₂ solution, 0.105 g (1.01 mmol) of triethylamine was added, and the reaction was stirred. After the TLC detection reaction was completed, the reaction was washed twice with 15 ml of water; the organic phase was washed with 15 ml of saturated NaCl solution; after drying without 7_KNaS04, Concentration by filtration; column chromatography gave 135.8 mg of white solid, yield 73.3%. 'H-NMR (CDC1 ₃ ): δ, 2.395 (3H, s); 4.660 (2H, d); 7.065-7.673 (10H, m); 7.887 (lH, d); 7.989 (lH, d); lH, s). Example 12: 4-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido-methyl]pyridine- 2-based acetate (ZH-1301-1-1) 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N-[(2-hydroxypyridin-4-yl)-methyl]-4-methyl-1H-pyridyl Oxazole-3-amide (ZH-1301-00) 244 1^ (0.5 010101) dissolved in dry 00^10 1^, added Et ₃ N 1.0 mL, added CH ₃ COCl (212 L, 3.0 mmol) under cooling The reaction was allowed to proceed at room temperature for 1 hour, and TLC showed the reaction was completed. The solvent was distilled off, and ethyl acetate (80 mL) was added, and the mixture was washed twice with 2×20 mL of water, and then washed once with 20 mL of saturated brine. After drying over anhydrous Na ₂ SO ₄ , it was concentrated to 1 mL, and purified by silica gel column to afford 120 mg of the desired compound (ZH-1301-1-1) with a yield of 45.3%.

MP, 122-126 ° C _; 'H-NMR (CDC1 ₃ , 400 MHz): δ, 2.41 (bs, 6H) ·. 4.68 (bs 2H) ; 7.09-7.34 (m, 8H) ; 7.46 (m, 2H ). Example 13: 4-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido-methyl]pyridine- 2-based benzoate (ZH-1301-2-2)

5-(4-Chlorophenyl) small (2,4-dichlorophenyl)-N-[(2-hydroxypyridin-4-yl)-methyl]-4-methyl-1H-pyrazole- 3-amide (ZH-1301-00), EDC HCl, DMAP, and benzoic acid were placed in a single-mouth bottle, and reacted after drying 24 . The procedure was the same as that of (ZH-1301-2-3), and the desired compound 150 mg was obtained in a yield of 60.0%. MP, 140- 143 °C _; 'H-NMR (CDC1 ₃ , 400 MHz): δ, 2.42 (s, 3H), 4.74 (bs, 2H); 7.08-7.65 (m,

 10H); 8.13-8.24 (m, 4H); 8.45 ( s, 1H). Example 14: 4-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido-methyl]pyridine- 2-based 2-chloro-benzoate (ZH-1301-2-3)

5-(4-Chlorophenyl) small (2,4-dichlorophenyl)-N-[(2-hydroxypyridin-4-yl)-methyl]-4-methyl-1H-pyrazole- 3-amide (ZH-1301-00) 244 mg (0.5 mmol), EDC HCl 288 mg (1.5 mmol), DMAP 50 mg, and 2-chlorobenzoic acid 156.6 mg (1.0 mmol) in a 50 mL single-mouth bottle Vacuum was applied for 0.5 hour, and after filling with N _{2 ,} vacuum was further applied for 0.5 hour; 8 mL of dry DCM was poured into the bottle, and reacted at room temperature for 24 hours, and TLC showed that the reaction was substantially complete. Most of the solvent was distilled off, ethyl acetate 50 mL and water 20 mL; The layers were separated, the aqueous layer was extracted with 30 mL of ethyl acetate once, and the organic layers were washed with saturated brine, dried over anhydrous Na ₂ S0 ₄ and dried After concentration to 1 mL, it was purified by silica gel column to give the desired product (ZH-1301-2-3) 200 mg, yield 63.9%. MP, 132-135 ° C _; 'H-NMRi CDCls, 400 MHz): (52.38 (s, 3H), 4.53 (bs, 2H); 7.08-7.81 (m, 12H); 7.91-8.42 (m, 2H). Example 15: 4-[5-(4-Chlorophenyl)-1 - (2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido-methyl]pyridine-2 Base - 4-chloro-benzoate (ZH- 1301- 2-4)

The preparation procedure is the same as that of (ZH-1301-2-3), and 4-chlorobenzoic acid is used instead of 2-chlorobenzoic acid as the acylating agent to obtain compound (ZH-1301-2-4) 180 mg, yield 57.5. %. MP, 133-135 ; Ή-NMR (CDCI ₃ +20% DMSO-d6, 400 MHz): 8, 2.25 (bs, 3H); 4.56 (bs, 2H); 7.01-8.19 (m, 14H). Example 16: 4-[5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-ylamido-methyl]pyridine- 2yl-2,4-dichlorobenzoate (ZH-1301-2-5)

The preparation procedure was the same as that of (ZH-1301-2-3), and 2-chlorobenzoic acid was replaced by 2,4-dichlorobenzoic acid as the acylating agent. The compound (ZH-1301-2-5) 200 mg was obtained in a yield of 60.6%. MP, 135-138 ° C _; 'H-NMR (CDC1 ₃ , 400 MHz): δ, 2.39 (bs, 3H); 4.55 (bs, 2H); 6.46 (s, 1H); 6.67 (s, 1H); 7.08- 7.47 (m, 8H); 7.55 (s, 1H); 7.81-7.92 (m, 2H). Example 17: 4-[5-(4-Chlorophenyl)-I-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido-methyl]pyridine- The preparation procedure of 2-yl-thiophene-2-carboxylate (ZH-1301- 2-6) is the same as that of (ZH-1301-2-3), and acylation is carried out by replacing 2-chlorobenzoic acid with 2-thiophenecarboxylic acid. The desired white product (ZH-1301- 2-6) 120 mg of compound was obtained in a yield of 56.2%. MP, 155-157 ° C; Ή-NMR (CDC1 ₃ , 400 MHz): δ, 2.40 (s, 3H); 4.72 (bs, 2H); 7.08-7.64 (m, 10H); 7.88 (s, 1H) ; 8.02 (bs, 1H); 8.42 (bs, 1H). Example 18: 4-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-ylamido-methyl]pyridine- 3-based acetate (ZH-1302-1-1)

5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N-[(3-hydroxypyridin-4-yl)-methyl]-4-methyl-1H-pyridyl Oxazole-3-amide (ZH-1302-0-0) 300 mg (0.615 mmol) Dissolved in 10 mL of dry DCM, added with 1.0 mL of EtjN, and then added CH ₃ COC1 220 L ( 3.1 mmol) ), raised to room temperature, and reacted for 0.5 h, TLC showed the reaction was complete. The solvent was evaporated, and purified by silica gel column chromatography to afford 190 mg of the desired product (ZH-1302-1-1). MP, 104-106'C; Ή-NMR (400 MHz, CDC1 ₃ ), δ, 2.36 (bs, 6Η), 4.57 (bs, 2H), 7.05-7.07 (d, 2H), 7.28-7.44 (m, 6H), 8.37-8.42 (ds, 2H). Example 19: 4 [5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido-methyl]pyridine-3 Benzobenzoate (ZH-1302-2-2) According to the preparation procedure of (ZH-1302-1-1), benzoyl chloride was used instead of acetyl chloride to obtain a pale yellow solid. MP,

141-143 °C _; 'H-NMR(400 MHZ, CDC1 ₃ ): δ> 2.33 (bs, 3H) , 4.65 (bs, 2H) , 7.05-7.07 (m, 2H) , 7.25-7.51 (m, 8H ), 7.65 (m, 1H), 8.22 (d, 2H), 8.50 (m, 2H). Example 20: 4-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido-methyl]pyridine- 3-yl-2-chloro-benzoate (ZH-1302-2-3)

 According to the preparation procedure of (ZH-1302-1-1), 2-chloro-benzoyl chloride was used instead of acetyl chloride to give a pale yellow solid.

MP, 140-141°C; 1H-NMR (400 MHz, CDC1 ₃ ): δ, 2.35 (s, 3H), 4.70 (bs, 2H), 7.06- 7.08 (m, 2H), 7.29-7.54 (m, 9H), 8.14 (d, 1H), 8.56 (m, 2H). Example 21: 4-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyridin-3-amido-methyl]pyridine- 3-based 4-chloro-benzoate (ZH-1302- 2-4)

 According to the preparation procedure of (ZH-1302-1-1), 4-chloro-benzoyl chloride was used instead of acetyl chloride to give a pale yellow solid.

MP, 148-149°C _; 'H-NMR(400 MHZ, CDC1 ₃ ): S, 2.33 (s, 3H) , 4,66 (bs, 2H) , 7.06- 7.08 (m, 2H) , 7.25-7.50 (m, 8H), 8.15 (d, 2H), 8.54 (m, 2H). Example 22: 4-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido-methyl]pyridine- 3-yl-2,4-dichlorobenzoate (ZH-1302-2-5)

(A) 2, 4-dichlorobenzoic acid 191.01 mg (1.0 mmol) in butyl-dried DCM 10 mL was added dropwise (C0C1) ₂ 142.7 μί and 1 D of DMF, and allowed to react at room temperature for 1 hour. The solvent was evaporated to dryness. A crude pale yellow 2,4-dichlorobenzoyl chloride was obtained. Used directly in the next step.

(B) The esterification reaction procedure was identical to that of the compound (ZH-1302-1-1), and TLC showed that the reaction was completed in 1 hour. Conventional workup and column chromatography gave the product as a pale yellow color (ZH-1302-2-4). MP, 134-136 ° C _; 'H-NMR (400 MHz, CDC1 ₃ ): δ, 2.34 (s, 3H) , 4.67 (bs, 2H) , 7.06-7.08 (m, 2H) , 7.25-7.48 (m , 7H), 7.55 (s, 1H), 8.11 (d, 1H), 8.53 (m, 2H). Example 23: 4-[5-(4-Chlorophenyl) _1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido-methyl]pyridine-3 -thiophene-2-carboxylate (ZH-1302-2-6)

5-(4-Chlorophenyl) small (2,4-dichlorophenyl)-N-[(3-hydroxyacridin-4-yl)-methyl]-4-methyl-lH4tt -3- Amide (ZH-1302-00) (244 mg, 0.5 mmol), EDC.HC 1192 mg (1.0 mmol), DMAP (20 mg) and 2- thiophenecarboxylic acid 128.2 mg (1 mmol) were placed in a 25 mL round bottom flask. After vacuuming for 15 min, nitrogen was introduced. Gas; so dry again. DCM 10 mL was injected and stirred overnight. TLC showed complete reaction. Purification by direct column chromatography eluting with EtOAc EtOAc (EtOAc:EtOAc) MP, 152- 153 ° C _; 'H-NMRi CDCb, 400 MHz): δ, 2.35 (s, 3H); 4.69 (bs, 2H); 7.08-7.71 (m, 10H); 8.04 (s, IH); 8.53 (s, 1H); 8.57 (s, 1H). Example 24: 4-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyridyl-3-amido-methyl]pyridine-3 Benzyl-2-amino-propionate (ZH-1302- 3-1)

 (A) 4-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-carbazole-3-amido-methyl]acridine- Preparation of 3-based 2-N-Boc-amino-propionate

 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N-[(3-hydroxypyridin-4-yl)-methyl]-4-methyl-1H-pyridyl Oxazol-3-amide (ZH-1302-00) 487.8 mg (1 mmol), EDC HC1287.7 mg (1.5 mmol), DMAP (25 mg) and N-Boc-L-alanine 378.4 mg (2 mmol) It was added to a 50 mL round bottom flask, and after evacuation for 15 min, nitrogen gas was introduced; the drying was repeated once. Inject DCM 10 mL and stir overnight. TLC showed the reaction was essentially complete. Purification by column chromatography, eluting with EtOAc EtOAc (EtOAc:EtOAc)

MP, 163-164 °C; 'H-NMR (CDC1 ₃ , 400 MHz): δ, 1.43 (bs, 9H); 1.49 (bs, 3H); 2.34 (b, 3H); 4.31 (bs, 1H); 4.59 (bs, 2H) ; 7.06 (m, 2H) ; 7.28-7.73 (m, 6H) ·' 8.45 (m, 2H).

 (B) Preparation of ZH- 1302- 3-1

The above N-Boc condensate was placed in 10 mL of a mixed solvent of CH3CN and water (4:1), and the pH was adjusted to 3-4 with 2N hydrochloric acid, and reacted at room temperature for 1 hour; poured into a buffer of 50 mL of PH7, under reduced pressure. under concentrated to about 10mL, extracted with ethyl acetate three times with 25 mL; the combined organic phases were washed with water, brine, dried and concentrated over anhydrous Na ₂ S0 _4. Purification by column chromatography gave the desired product (ZH-1302-3-1) 200 mg as a white solid. 'Η- NMR (400 MHz, CDC1 ₃ ): δ, 1,31 (d, 3Η); 2.34 (b, 3H); 3.81 (bs, 1H); 4.59 (bs, 2H) ; 7.01-7.08 (m, 2H); 7.26-7.72 (m, 6H); 8.40 (m, 2H). Example 25: 5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-N-[(3-hydroxypyridin-4-yl)-methyl1-4-ethyl- 1H-pyrazole-3-amide (ZH-1402-0-0)

3-hydroxy 4-aminomethylpyridine 200 mg (1.61 mmol), EDC HC1521 mg (2.72 mmol), DMAP 50 mg, and bromonabancarboxylic acid 600 mg (1.36 mmol) in a 50 mL single-mouth bottle, pumped After vacuuming for 0.5 hour, N _{2 was added} and vacuum was further applied for 0.5 hour; 5 mL of dry DMF was poured thereinto and reacted at room temperature for 12 hours, and TLC showed that the reaction was substantially complete. Add 10 mL of water and 10 mL of methanol, and extract with petroleum ether (50 mL X 3) to remove the less polar compound; After drying with ethyl acetate washed with 60 raL X 2 is extracted, the organic layer was washed with saturated brine and dried over anhydrous Na ₂ S0 _4; solvent was distilled off, and methanol was added 5 mL CH ₃ ONa 540 mg, stirred at room temperature for 1 hour. Add 20 mL of water and 50 mL of ethyl acetate;

After layering, the aqueous layer was extracted with 50 mL ethyl acetate. Combine all organic phases, wash with saturated brine, anhydrous

After drying over Na ₂ S0 ₄ , the solvent was evaporated and purified by silica gel column to yield the desired compound 400 mg, yield 53.8%. MP, 158-160 °C _; 'H-NMRiCDCls, 400 MHz): δ, 1.18 (t, 3H); 2.76 (bs, 2H) ; 4.57 (bs,

2); 7 01-7.44 (m, 7H); 7.91 (bs, 1H); 8.03 (bs, 1H); 8.34 (bs, 1H); 8.91 (s, 1H, OH). Example 26: 4-[5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-amido-methyl]pyridine- 3-yl-acetate (ZH-1402- 1- 1 )

5-(4-Bromophenyl) small (2,4-dichlorophenyl)-N-[(3-hydroxypyridin-4-yl)-methyl]-4-ethyl-1H-pyrazole- 3- carboxamide (ZH-1402-00) 273 mg ( 0.5 mmol) was dissolved in DCM 8 mL was added Et ₃ N 1 mL and CH ₃ COCl 177 L, was stirred for 1.5 hours. Filtration, the filtrate was directly passed through a silica gel column; eluted with 50 mL of petroleum ether and eluted with petroleum ether: ethyl acetate (1:1) to give a pale yellow solid, 120 mg, yield 40.8%.

 MP, 130-133

1H-NMR (CDC1 ₃ , 400 MHz): δ 1.22 (bs, 3Η); 2.39 (s, 3H); 2.79 (m, 2H); 4.59

 (bs, 2H); 7.02-7.04 (m, 2H); 7.29-7.48 (m, 6H); 8.39 (s, 1H); 8.45 (s,

 1H). Example 27: 4-[5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-isoethyl-1H-pyrazole-3-amido-methyl]pyridine_ 3-based monobenzoate (ZH-1402-2-2)

The preparation procedure was the same as that of (ZH-1402-1-1), replacing acetyl chloride with benzoyl chloride. A white solid of 80 mg was obtained in a yield of 51.7%. MP, 137-139 ° C _; ^! H-NMR (CDC1 ₃ , 400 MHz): δ, 1.19 (bs, 3H); 2.76 (bs,

2H); 4.70 (bs, 2H); 6.99-7.01 (m, 2H); 7.29-7.60 (m, 6H); 7.67 (bs, 1H);

8.13 (d, 2H); 8.23 (d, 2H); 8.56 (s, 1H); 8.60 (s, 1H). Example 28: 4-[5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-ylamide-methyl]pyridine-3 Base-o-chloro-benzoate (ZH-1402-2-3)

The preparation procedure was the same as that of (ZH-1402-1-1), and 2-chlorobenzoic acid was used instead of acetyl chloride. A pale yellow solid 190 mg was obtained in a yield of 50.4%. 63

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Claims

Rights request

 A low toxicity "multi-headed drug", a nitrogen-containing aromatic ring-containing CB 1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group, and a physiologically acceptable salt or solvate thereof, characterized in that the CB1 is subjected to The bulk inhibitor is a nitrogen-containing aromatic ring-containing CB1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group, and a physiologically acceptable salt or solvate thereof, and a general formula For:

The pyridine of the above formula I can be replaced by pyrrole, pyrazole, imidazole, azazo, anthracene, carbazole, etc., like pyridine, which are both nitrogen-containing aromatic rings; the pyridine ring is especially pyrrole Or replaced by an N-substituted pyrrole; it may also be replaced by an N-pyridine oxide;

 Among them, on the pyrazole ring! ^ is a linear, branched or cyclic hydrocarbon or alkoxy group;

R ₂ and R ₃ on the pyrazole ring are the same or different and are phenyl or contain a halogen, dC ₃ linear or branched alkyl or a decyloxy group, a trifluoromethyl group, a nitro group, a phenyl group, etc. a phenyl group of any one, two or three substituents;

The nitrogen-containing heterocyclic ring substituted by OR4 is bonded to the 3-position amide group of the pyrazole ring substituted by the above R ₂ and R ₃ by a certain carbon atom on the ring through (CH ₂ ) _n ; n is 0-3;

 R4 is hydrogen, a linear, branched or cyclic saturated or unsaturated hydrocarbon group, or a hydrocarbon group containing one or more aromatic rings; and R4 is an acyl group of a saturated or unsaturated aliphatic carboxylic acid; R4 is an acyl group of an aliphatic carboxylic acid substituted by a halogen, a carboxyl group, a hydroxyl group or a decyloxy group; R4 is an acyl group of a substituted or unsubstituted aromatic carboxylic acid or a sulfonic acid; and R4 is an aliphatic or aromatic amino acid. An acyl group; when it contains an optically asymmetric center, its configuration includes both R and S possibilities;

The two substituents -OR4 and -(CH ₂ ) _n -NH on the pyridine ring can take any chemically reasonable relative position for the nitrogen atom on the pyridine ring: 2-(CH ₂ ) _n -NH-acridine ring 3, 4, 5 on, or a substituted _{6-0; 3- (CH 2) -NH- 2} , 4, 5-substituted, 6-OR4 or on _n-pyridine ring; and 4- (CH _{2) n} -NH - 2 or 3-0 substitution on the pyridine ring.

The low toxicity "multi-headed drug" according to claim 1, a CB1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group, and a physiologically acceptable salt or solvate thereof, characterized in that The acyl group of the saturated or unsaturated aliphatic carboxylic acid includes: a formyl group, an acetyl group or an acryloyl group, and the "aliphatic carboxylic acid substituted by a halogen, a carboxyl group, a hydroxyl group or a decyloxy group" The acyl group includes: an acyl group of chloroacetic acid, a carboxyformyl group, a carboxypropionyl group, or a Y-hydroxybutyryl group; and the "acyl group of a substituted or unsubstituted aromatic carboxylic acid or a sulfonic acid" includes: , R ₂ , R _3- substituted pyrazole carboxylic acid (master nucleus in formula I), benzoyl, 2-thiophene, mono or polychloro substituted benzoyl, benzenesulfonyl, 0- or -naphthalenesulfonic acid The acyl group of the aliphatic or aromatic amino acid includes: an α-alanine acyl group, an α-phenylalanine acyl group or a β-(2-thienyl)-α-alanine acyl group.

The low toxicity "multi-headed drug" according to claim 1, which is a CB1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group, and a physiologically acceptable salt or solvate thereof, characterized in that And R is a methyl group or an ethyl group, and the R ₂ is a p-bromo or p-chlorophenyl group; and is a 2, 4-dichlorophenyl group.

 The nitrogen-containing heterocyclic CB1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group, and a physiologically acceptable salt or solvate thereof, according to claim 1, wherein the hydroxyl group or substituted hydroxyl group The nitrogen-containing aromatic ring is a pyridine ring having a hydroxyl group and an N-oxide thereof;

The structural formula of the preferred compounds of the invention is as follows:

ZH-1102-2-3 EN-1102-2-4 ZH-1102-2 -

 ZH-1302-3-1 ZH- 1402-0-0 EN-1402-1 -1

 ZH- 1402-2-2 ZH- 1402-2-3

The nitrogen-containing aromatic ring-containing CB1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group, and a physiologically acceptable salt or solvate thereof, according to claim 1, wherein the salt is a hydrochloride salt, Hydrobromide, sulfate, hydrosulfate, dihydrogen phosphate, methanesulfonate, monomethyl sulfate, maleate, fumarate, oxalate, naphthalene -2-sulfonate, gluconate, citrate, isethionate, p-toluenesulfonate, 3,5-dimethyl-benzylsulfonate, or a season formed with haloxime A hinge salt, which is a fluorine, chlorine, bromine, or iododecane hydrocarbon.

 The nitrogen-containing aromatic ring-containing CB 1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group, and a physiologically acceptable salt or solvate thereof, according to claim 1, wherein the hydroxyl group or the substituent is substituted A hydroxy-containing nitrogen-containing aromatic ring-containing CB 1 receptor inhibitor and a physiologically acceptable salt or solvate thereof, comprising a pharmaceutical composition comprising two or more kinds of the present invention in any ratio A combination of CB 1 receptor inhibitors.

 The "long-headed drug" of claim 1, a nitrogen-containing aromatic CB 1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group, and a physiologically acceptable salt or solvate thereof in the protein tyrosine phosphatase PTP1B is highly useful as a drug in the expression of related diseases.

 The "long-headed drug" of claim 1, a nitrogen-containing aromatic CB 1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group, and a physiologically acceptable salt or solvate thereof, for use as a medicament in the treatment of diabetes .

 9. A method of preparing a "multiple-headed drug" according to claim 1, a nitrogen-containing aromatic CB1 receptor inhibitor having a hydroxyl group or a substituted hydroxyl group, and a physiologically acceptable salt or solvate thereof - first preparing an aminomethyl group a hydroxy substitution of pyridine: from the corresponding hydroxypyridine formaldehyde, by the action of hydroxylamine, to produce hydrazine; to be reduced, to obtain a hydroxy substitution of aminomethylpyridine; and with the core of rimonabant or bromenaban The carboxylic acid is condensed by the action of a catalyst to obtain a corresponding hydroxypyridine condensation product;

 The condensate forms a corresponding ether on the hydroxyl group of the pyridine ring by various activators;

The condensate is treated with an aliphatic or aromatic acid halide to produce various esters; In order to prepare an ester of an amino acid, the amino acid used needs to be pre-protected, and the protective group is removed after the condensation is completed; the above-mentioned R, R ₂ , R ₃ substituted pyrocarboxylic acid condensate, that is, the condensate of the double mother nucleus, It is a by-product in the preparation of a condensed amide, and may be obtained by reacting 2 equivalents of a hydroxy group of a parent carboxylic acid of rimonabant or bromideban with a hydroxy substituent of aminomethylpyridine.

 10. The CB1 receptor inhibitor having a hydroxyl group or a substituted hydroxy group and a physiologically acceptable salt or solvate thereof, according to the claims, for the preparation of detoxification, weight loss, treatment of diabetes or cardiovascular diseases The application of the drug.