CN118561729A - Synthetic method and application of nitro cyclic compound - Google Patents

Abstract

The present invention discloses a synthesis method of a nitrocyclic compound and its use, belonging to the field of chemical medicine. The present invention provides a nitrocyclic compound as shown in formula (I), or a pharmaceutically acceptable salt, prodrug, hydrate or solvate, crystal form, stereoisomer or isotope variant thereof, which can be used to prevent and inhibit abnormal proliferation of cancer cells, and to treat and/or prevent related diseases such as lung cancer and breast cancer.

Description

A method for synthesizing nitrocyclic compound and its application

Technical Field

The invention belongs to the field of chemical medicine, and specifically relates to a synthesis method of a nitrocyclic compound and application thereof.

Background Art

The bone marrow (BM) microenvironment confers growth, survival, and drug resistance to multiple myeloma (MM) cells (Chauhan et al., Cancer Cell 2009, 16: 309-323). BM hypoxia (low oxygenation) plays a role in promoting MM cell survival, drug resistance, migration, and metastasis. Therefore, new therapies that selectively target MM cells in the hypoxic BM environment could overcome conventional drug resistance.

Radiotherapy is an effective method for selectively targeting cancer cells, but when solid tumors grow beyond a critical diameter of 1-2 mm ³ (106 cells), diffusion restriction of oxygen and nutrients in peripherally located blood vessels leads to a necrotic core. The resulting activation of the hypoxia inducible factor (HIF) system mediates the expression of VEGF, erythropoietin, and factors that regulate glucose transport and glycolysis, such as GLUT-1 and GLUT-3. The induction of these genes drives vascular remodeling and a metabolic switch to aerobic glycolysis, which is integral to malignant transformation and progression. The presence of hypoxia predicts a poor response to radiotherapy due to the lack of superoxide, hydrogen peroxide, and hydroxyl radicals that oxidatively damage macromolecules such as lipids, proteins, and nucleic acids under hypoxic conditions.

Therefore, a hypoxia-selective epigenetic factor, RRX-001 is used as a radio- or chemosensitizer that can induce apoptosis and overcome bone marrow resistance. Once injected intravenously, it rapidly penetrates red blood cells (RBCs), where it forms a stable adduct with the hemoglobin β-chain cysteine 93 residue (Cys-β93) and reduces glutamate. RRx-001 is associated with pleiotropic effects, including upregulation of oxidative stress, epigenetic modulation, and polarization of macrophages to the M1 phenotype.

The structure of RRX-001 is

However, some radiosensitizers with a history of radiosensitization and potential radiosensitizers (including halogenated pyrimidines and other antimetabolites, cisplatin and 5-fluorouracil (5-FU), nitroimidazoles, and hypoxic cytotoxins (such as tilapazine and mitomycin-related quinone EO9 and porphyromycin) have been observed to have limited clinical efficacy and a large amount of normal tissue toxicity.

Therefore, there is a need to explore new compounds to better treat and prevent abnormal proliferation of cancer cells.

Summary of the invention

The novel cyclic nitro compounds of the present invention or having good pharmacodynamics/pharmacokinetic properties and pharmaceutically acceptable salts thereof, and their use in treating and preventing diseases related to abnormal proliferation of cancer cells such as lung cancer, breast cancer and the like.

One object of the present invention is to provide a nitrocyclic compound having a structure represented by the general formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance, or prodrug thereof:

Where:

Z is independently selected from carbonyl (-CO-) or sulfonyl (-SO ₂ -);

R ₁ is selected from alkenyl Alkynyl Acyl-C(=O)-R ₆ ,

R ₂ is selected from H, halogen (F, Cl, Br, I), cyano;

R ₃ and R ₄ are independently selected from H, C1-4 alkyl, halogen-substituted C1-4 alkyl, amine-substituted C1-4 alkyl, C3-6 cycloalkyl, C3-6 nitrogen heterocycle;

R ₅ is selected from H, C1-4 alkyl;

_R6 is selected from C1-4 alkyl.

In one embodiment of the present invention, R ₂ can specifically be H, F or cyano.

In one embodiment of the present invention, R ₃ and R ₄ are independently selected from: H, isobutyl group, pyridine ring.

In one embodiment of the present invention, R ₅ can specifically be H or methyl.

In one embodiment of the present invention, R ₆ can be specifically methyl.

In one embodiment of the present invention, the nitro cyclic compound of the structure represented by the above general formula (I) is specifically selected from:

In one embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic salt or an organic salt, the inorganic salt includes hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, acid phosphate; the organic salt is selected from acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, sulfonate, benzenesulfonate, salicylate.

The present invention also provides the use of the compound of the above general formula (I) or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance, prodrug in the preparation of a drug for inhibiting abnormal cell proliferation.

The present invention also provides the use of the compound of the above general formula (I) or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance, prodrug in the preparation of a drug for treating cancer.

In one embodiment of the present invention, the cancer includes: lung cancer, breast cancer, etc.

The present invention also provides a method for preparing the compound of general formula (I).

The present invention also provides a pharmaceutical composition comprising the above-mentioned compound of general formula (I) of the present invention or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance, prodrug, and a pharmaceutically acceptable carrier, excipient or diluent.

Among them, pharmaceutically acceptable carriers include: microspheres, nanoparticles and liposomes.

In one embodiment of the present invention, the dosage forms of the pharmaceutical composition include injection, lyophilized powder for injection, suspension, implant, embolic agent, capsule, tablet, pill and oral solution.

Beneficial effects:

The compounds of the present invention can be used as sensitizers for radiotherapy or chemotherapy, and the activity or selectivity compared to the positive control (RRx-001) is significantly improved, and can be used to treat and/or prevent abnormal proliferation of cancer cells related diseases, such as metabolic diseases such as lung cancer and breast cancer. In addition, the compounds of the present invention or their salts have almost no side effects and have good drug metabolism and pharmacokinetics. Therefore, the compounds designed by the present invention have good development and application prospects.

DETAILED DESCRIPTION

The technical solution of the present invention will be described in detail below in conjunction with embodiments.

In the present invention, "C3-C6 cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms.

In the present invention, "C3-C6 nitrogen heterocycle" refers to a nitrogen-containing heterocycle having 3 to 6 carbon atoms.

In the present invention, "substituted" means that one or more hydrogen atoms in the group are replaced by the same or different substituents.

"Administration" or "administering" a subject compound in the context of the present invention means providing the subject in need of treatment with a compound of the present invention.

The term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and have a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.

<Pharmaceutical Composition>

The present invention also provides a pharmaceutical composition comprising the above-mentioned compound of general formula (I) of the present invention or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance and a pharmaceutically acceptable carrier, excipient or diluent.

The compounds of the present invention or their pharmaceutically acceptable salts can be formulated into solid preparations for oral administration, including, but not limited to capsules, tablets, pills, powders, granules, etc. In these solid dosage forms, the compounds of the general formula (I) of the present invention are mixed as active ingredients with at least one conventional inert excipient (or carrier), for example, with sodium citrate or dicalcium phosphate. Or mixed with the following ingredients: (1) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (2) binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose, gum arabic, etc.; (3) humectants, such as glycerol, etc.; (4) disintegrators, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, etc.; (5) solubilizers, such as paraffin, etc.; (6) absorption accelerators, such as quaternary ammonium compounds, etc.; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate, etc.; (8) adsorbents, such as kaolin, etc.; (9) lubricants, such as talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc., or mixtures thereof. Capsules, tablets and pills may also contain buffers.

The solid dosage forms such as tablets, pills, capsules, pills and granules can be coated or microencapsulated with coating and shell materials such as enteric coatings and other materials known in the art. They can contain opacifiers, and the release of the active ingredient in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active ingredient can also be formed into microcapsules with one or more of the above-mentioned excipients.

The compounds of the present invention or their pharmaceutically acceptable salts can be formulated into liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, etc. In addition to the compound of formula (I) or its pharmaceutically acceptable salt as an active ingredient, the liquid dosage form may contain inert diluents conventionally used in the art, such as water and other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil, etc. or mixtures of these substances, etc. In addition to these inert diluents, the liquid dosage form of the present invention may also include conventional adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and spices, etc.

The suspending agent includes, for example, ethoxylated stearyl alcohol, polyoxyethylene sorbitol, and sorbitan, microcrystalline cellulose, agar, etc. or a mixture of these substances.

The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions. Suitable carriers, diluents, solvents, excipients include water, ethanol, polyols and suitable mixtures thereof.

The compound of the present invention or its pharmaceutically acceptable salt can be configured into dosage forms for topical administration, including ointments, powders, suppositories, drops, sprays and inhalants, etc. The compound of the present invention of general formula (I) or its pharmaceutically acceptable salt as an active ingredient is mixed with a physiologically acceptable carrier and optional preservatives, buffers, and propellants that may be required under sterile conditions.

The pharmaceutical composition of the present invention comprises a compound of the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, excipient, and diluent. When preparing the pharmaceutical composition, the compound of the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is usually mixed with a pharmaceutically acceptable carrier, excipient, or diluent. The content of the compound of the general formula (I) or a pharmaceutically acceptable salt thereof can be 0.01-1000 mg, for example 0.05-800 mg, 0.1-500 mg, 0.01-300 mg, 0.01-200 mg, 0.05-150 mg, 0.05-50 mg, etc.

The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The technical solution of the present invention will be described in detail below in conjunction with examples.

The following examples are provided to illustrate, but not to limit, the synthesis of compounds of formula (I). All temperatures are in degrees Celsius. All evaporations were performed under reduced pressure unless otherwise stated. Reagents were purchased from commercial suppliers and used without further purification unless otherwise stated. The structures of the final products, intermediates and starting materials were confirmed by standard analytical methods, such as elemental analysis, spectral feature analysis, such as MS, NMR. The abbreviations used are conventional in the art.

Example 1: 1-(3,3-Dinitroazetidin-1-yl)prop-2-en-1-one (1)

Preparation of 1-(tert-butyl)azetidin-3-yl methanesulfonate (intermediate a-2):

N,N-diisopropylethylamine (24 mL, 138 mmol) was added to a suspension of N-tert-butyl-3-hydroxyazetidine (10.0 g, 60.0 mmol) in dichloromethane (300 mL). After stirring at room temperature for 20 minutes, the clear solution was cooled to 0°C and methanesulfonyl chloride (5 mL, 66 mmol) was added dropwise. The reaction mixture was stirred for 1 hour while warming to room temperature. After the reaction was completed, it was concentrated under reduced pressure and the crude product was purified by column to obtain intermediate a-2. 5.9 g, yield: 37%. MS-ESI (m/z): 208.11 [M+1] ⁺

Preparation of (1-(tert-butyl)-3-nitroazetidin-3-yl)methanol (intermediate a-3):

Dissolve 1-(tert-butyl)azetidin-3-yl methanesulfonate (intermediate a-2) (5.8 g, 28.0 mmol) in water (100 mL), add sodium nitrate (2.4 g, 28.0 mmol) and formaldehyde (5 mL, 168 mmol) in turn, heat to 55 ° C for 4 hours, and after the reaction, concentrate under reduced pressure and purify by column to obtain intermediate a-3. 3.3 g, yield: 63%. MS-ESI (m/z): 189.14 [M+1] ⁺

Preparation of 1-(tert-butyl)-3,3-dinitroazetidine (intermediate a-4):

At 20-25°C, (1-(tert-butyl)-3-nitroazetidine-3-yl)methanol (3.0 g, 12.3 mmmol) was dissolved in water (150 mL), sodium hydroxide (1.7 g, 42.5 mmol) was slowly added and stirred at room temperature for 1-2 hours. The nitrate solution was cooled to 10°C. A solution of potassium ferrocyanide (0.4 g, 1.2 mmol) and sodium nitrite (3.4 g, 48.9 mmol) in water (40 mL) was added to the mixture. Sodium persulfate (4.1 g, 17.1 mmmol) was slowly added to the solution at a temperature of 10-15°C. The reaction was warmed to 20-25°C and reacted for 16 hours. The resulting orange/brown emulsion was extracted with dichloromethane (3X50 mL). The combined yellow/orange organic extracts _were dried over _Na2SO4 . The solvent was concentrated under reduced pressure and dried in vacuo to obtain intermediate a-4 as a light yellow solid, 2.1 g, yield: 83%. MS-ESI (m/z): 204.06 [M+1] ⁺ .

Preparation of 1-(3,3-dinitroazetidin-1-yl)ethane-1-one (intermediate a-5):

Acetic anhydride (3 mL) was added to 1-tert-butyl-3,3-dinitroazetidine (1.5 g, 7.4 mmol), and then trifluoride boron etherate (0.5 mL) was added dropwise. The solution was heated to 120-124 ° C and stirred for 12 hours. It was then concentrated under reduced pressure to obtain a black solid, which was recrystallized and washed with n-hexane/dichloromethane to obtain intermediate a-5. White crystals, 1.2 g, yield: 84.6%. MS-ESI (m/z): 190.03 [M+l] +

Preparation of 3,3-dinitroazetidine (intermediate a-6):

1-(3,3-Dinitroazetidin-1-yl)ethane-1-one (1.0 g, 5.3 mmmol) was added to a 5% HCl (10 mL) solution and refluxed for 4 hours. The solution was distilled under reduced pressure to remove the solvent to obtain intermediate a-6. White crystals, 0.76 g, yield: 97%. MS-ESI (m/z): 148.12 [M+1] ⁺

Preparation of 1-(3,3-dinitroazetidin-1-yl)prop-2-en-1-one (1):

3,3-Dinitroazetidine (150.0 mg, 1.0 mmmol) was dissolved in DMF (2 mL), triethylamine (185.7 mg, 2.0 mmmol) was added, and a solution of acryloyl chloride (138.0 mg, 1.53 mmmol) in DMF (1 mL) was added dropwise under ice bath. After the addition was completed, the mixture was reacted for 2 h under nitrogen protection at room temperature. The reaction was monitored by TLC to complete. Water (15 mL) was added dropwise to the reaction solution, and solids precipitated. The filter cake was washed with water and dried in a vacuum oven (45 ° C, 24 h) to obtain a white solid powder. The product was separated and purified by column chromatography [DCM: MeOH = 20: 1 (V/V)] to obtain 1-(3,3-dinitroazetidine-1-yl)prop-2-en-1-one (1) (30.3 mg), with a yield of 18.2%.

MS-ESI(m/z): 202.08[M+l] ⁺ .

¹ H NMR (400MHz, DMSO) δ6.36 (dd, J＝17.0, 10.2Hz, 1H), 6.13 (dd, J＝17.0, 2.3Hz, 1H), 5.67 (dd, J＝10.2, 2.3Hz, 1H ),5.09(br s,2H),4.81(br s,2H).

Using the corresponding intermediates instead of the synthetic raw materials of Example 1, Examples 2-5 (see Table 1) were synthesized according to the similar operation as Example 1 to obtain the desired products.

Table 1

Example 6 (E)-4-(Dimethylamino)-1-(3,3-dinitroazetidin-1-yl)but-2-en-1-one (6)

Preparation of (E)-4-(dimethylamino)but-2-enoic acid (b-2):

At room temperature, 20 ml of sodium hydroxide aqueous solution (1.0 mmol) was slowly added dropwise to a reaction bottle containing (E)-4-(dimethylamino)but-2-enoic acid methyl ester (1.0 g, 7.1 mmol). After the addition was completed, the reaction was stirred at room temperature for 1.5 h. After the reaction was completed, the aqueous layer was separated, neutralized with hydrochloric acid, and concentrated under reduced pressure. 7.0 ml of acetonitrile was added to the residue and stirred for 2.0 h. The mixture was filtered, and 2.0 ml of acetone was added to the filtrate. The mixture was stirred at room temperature overnight for crystallization to obtain (E)-4-(dimethylamino)but-2-enoic acid (0.46 g) with a yield of 45%. MS-ESI (m/z): 128.1 [Ml] ⁺

Preparation of (E)-4-(dimethylamino)but-2-enoyl chloride (b-3):

To a solution of (E)-4-(dimethylamino)but-2-enoic acid (400 mg, 2.2 mmol) in THF (16 mL) was added DMF (63.3 mg) and oxalyl chloride (267 mg, 2.1 mmol) under an ice bath at 0°C. The reaction solution was stirred at 20°C for 2 hours to obtain an orange mixture. TLC detected that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain (E)-4-(dimethylamino)but-2-enoyl chloride, which was directly carried out to the next step without purification.

Preparation of (E)-4-(dimethylamino)-1-(3,3-dinitroazetidin-1-yl)but-2-en-1-one (6):

The synthesis method refers to the synthesis of compound 1, wherein (E)-4-(dimethylamino)-1-(3,3-dinitroazetidine-1-yl)but-2-en-1-one (6) was obtained as a light yellow solid (52.9 mg) with a yield of 20.2%.

ESI-MS m/z: 259.1 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO) δ6.86 (m, 1H), 6.23 (d, J = 10.2Hz, 1H), 5.09 (br s, 2H), 4.81 (br s, 2H), 3.01 (d, J =5.6Hz,2H),2.20(s,6H).

Using (Z)-4-isocyano-6,6-dimethylhept-4-en-3-one as the starting material, the (Z)-2-isocyano-4,4-dimethylpent-2-enoyl chloride was synthesized according to the synthesis method from b-1 to b-3 in Example 2, and then it was synthesized with a-6 to obtain Example 7.

Use pyruvic acid to synthesize 2-oxopropanoyl chloride according to the synthesis method of b-3, and then synthesize it with compound a-6 according to the synthesis method of compound 1 to obtain Example 8.

The corresponding structures and characterization information of Examples 7-8 are shown in Table 2.

Table 2

Biological Examples:

Assay: Nitrocyclic inhibitors were screened on the human non-small cell lung cancer cell line A549 cells and the murine squamous cell carcinoma cell line SCC VII cells.

Experimental methods:

A549 cells, a human non-small cell lung cancer cell line (purchased from the Chinese Academy of Sciences Cell Bank) and SCC VII cells, a murine squamous cell carcinoma cell line (purchased from the American Type Culture Collection (ATCC, Rockville, MD, USA)), were cultured in DMEM (high glucose) medium containing 0.5 mg/ml G418 and 10% FBS at 37°C and 5% _CO2 . These cancer cell lines were split into 96 cell culture dishes at 2000 cells per well and treated with different concentrations of the test compound. After 24 hours of treatment with the test compound, cell proliferation was assessed using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) colorimetric assay. The absorbance of the formazan solution was measured spectrophotometrically at a wavelength of 570 nm. The optical density (OD) value measured by rFhe is proportional to the number of viable cells. For each combination of cell line, sample and sample concentration, the experiment was repeated twice.

Graphpad Prism5 software was used to calculate the _IC50 value according to the following formula.

The drug group refers to the group treated with the test compound according to the above method; the blank control group refers to the group with only culture medium, without cells and test compounds; the positive control group refers to the group with cells and culture medium, plus 0.5% DMSO, without test compounds.

Xm: the logarithmic value of the designed maximum concentration; i: the logarithmic value of each concentration multiple concentration; ΣP: the sum of the growth inhibition rates of each group; 0.5: empirical constant.

The _IC50 value was calculated based on the inhibition rate obtained by the above formula.

Experimental results:

The activity evaluation results are shown in Table 3 below:

Table 3 In vitro inhibition of A549 and SCC VII activity by a series of compounds

Note: RRx-001 is the most advanced active compound currently, and is selected as the reference compound for the compounds of the present invention.

The experimental results show that the compounds of the present invention have more efficient tumor cell inhibition activity and higher drug potential than RRx-001.

For compounds of the general formula (I), linking groups and substituent groups have an important influence on the pharmacodynamic properties of the compounds. Although the present disclosure has been described in some detail and with some particularity regarding several described embodiments, it is not intended that it should be limited to any such details or embodiments or any particular embodiment, but should be interpreted with reference to the appended claims so as to provide the broadest possible interpretation of such claims in view of the prior art, and therefore, effectively cover the intended scope of the present disclosure.

Claims (10)

1. A nitrocyclic compound having a structure represented by general formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, prodrug thereof:

Wherein:

Z is independently selected from carbonyl or sulfonyl;

r ₁ is selected from alkenyl Alkynyl groupAcyl-C (=o) -R ₆,

R ₂ is selected from H, halogen, cyano;

R ₃、R₄ is independently selected from H, C-4 alkyl, halogen substituted C1-4 alkyl, amino substituted C1-4 alkyl, C3-6 cycloalkyl, C3-6 azacyclic;

R ₅ is selected from H, C-4 alkyl;

R ₆ is selected from C1-4 alkyl.

2. The nitrocyclic compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, prodrug thereof, wherein R ₂ is specifically selected from H, F or cyano; r ₃、R₄ is specifically selected from the group consisting of: H. isobutyl and pyridine rings; r ₅ is specifically selected from: H. a methyl group; r ₆ is in particular methyl.

3. The nitrocyclic compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, or prodrug thereof, wherein the compound specifically comprises:

4. A nitrocyclic compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, prodrug thereof, wherein the pharmaceutically acceptable salt is an inorganic or organic salt, and the inorganic salt comprises hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, acid phosphate; the organic salt is selected from acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, sulfonate, benzenesulfonate, salicylate.

5. Use of a nitrocyclic compound of any one of claims 1-4, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, prodrug thereof, for the manufacture of a medicament for inhibiting CB1 signaling.

6. Use of a nitrocyclic compound of any one of claims 1-4, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, prodrug thereof, in the manufacture of a medicament for use in treating a metabolic-related disorder; the metabolism related diseases include lung cancer and breast cancer.

7. A pharmaceutical composition comprising a nitrocyclic compound of any one of claims 1-4, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label, prodrug thereof, and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 7, wherein the pharmaceutically acceptable carrier comprises: microspheres, nanoparticles, and liposomes.

9. The pharmaceutical composition of claim 7, further comprising an excipient or diluent.

10. The pharmaceutical composition according to claim 7, wherein the dosage form of the pharmaceutical composition comprises injection, freeze-dried powder for injection, suspension, implant, suppository, capsule, tablet, pill and oral liquid.