CN113214172A - Preparation method of fluconazole intermediate reductive amination product - Google Patents
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Abstract
The invention discloses a preparation method of a fluconazole intermediate reductive amination product, belonging to the technical field of chemical synthesis. The structural formula of the product IM2 of the reductive amination of the fluconazole intermediate is shown in the specification. Experiments show that under the selected reaction conditions, the fluconazole intermediate is easy to prepare into the corresponding oxime pre-IM2, and the yield and the purity are higher than those of a literature method; Pd-C catalytic hydrogenation reduction is the best method for converting pre-IM2 into fluconazole intermediate reductive amination product IM2, and has the advantages of high yield, pure product and industrial production prospect.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of a fluconazole intermediate reductive amination product.
Background
Fungi are eukaryotic organisms with a rigid cell wall and a true nucleus, which survive in a parasitic or saprophytic manner. The fungi are of various kinds, and more than 300 kinds of fungi which are pathogenic to human are available.
Fungal infections pose a persistent and serious threat to human health and life. Statistically, more than 10 million people worldwide are infected with fungi each year, and over a million people die from fungal infections. At present, the medical treatment method for solving the fungal infection mainly adopts chemical treatment. The development of antifungal drugs can be roughly divided into 4 generations: 1930-1950 s, the 1 st generation of drugs on the market, represented by griseofulvin, nystatin and amphotericin B; the 2 nd generation is the 1960-1990 rd imidazole drugs including clotrimazole, miconazole, ketoconazole and econazole; triazole drugs marketed in the 1990's in the 3 rd generation, including fluconazole (fluconazole), itraconazole, and the like; the 4 th generation is echinocandin drug developed in the beginning of the 21 st century and caspofungin, micafungin and anidulafungin and the like which are subsequently marketed. The discovery of azole drugs shows that antifungal drugs develop in the direction of broad spectrum, high efficiency and low toxicity, and achieve good effects.
Fluconazole (structure shown in figure 4) is an important antifungal infection drug. The fluconazole has similar structural parts with voriconazole, raviconazole and posaconazole, and contains three parts of difluorophenyl, triazole and hydroxyethyl group, and the common structure is derived from fluconazole intermediates (the structure is shown in figure 4).
Two of the routes to fluconazole use the intermediate shown in figure 4 as important starting material. This intermediate is also used in the preparation of voriconazole.
The laboratory reduces fluconazole into alcohol, and the alcohol reacts with halogenated acid ester, succinic anhydride, halogenated alcohol and the like to synthesize some useful intermediates (the literature synthetic route of fluconazole is shown in figure 5 and figure 6), further derive a large amount of active molecules and show the potential of further development (see Chinese patent application No. 201811122153.8).
In order to design a new molecule for synthesis, the laboratory wishes to obtain the reductive amination product IM2 of the fluconazole intermediate (see fig. 7), and consults the literature find that the molecule does exist, but no synthetic method is found, and no commercial vendor sells the compound at home.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing a reductive amination product of a fluconazole intermediate.
Through research, the invention provides the following technical scheme:
a product of the reductive amination of a fluconazole intermediate, IM2, characterized by the following structural formula:
the preparation method of the reductive amination product of the fluconazole intermediate is characterized by comprising the following steps of:
1. reacting the fluconazole intermediate with hydroxylamine hydrochloride to prepare an intermediate Pre-IM 2;
2. reducing the intermediate Pre-IM2 to obtain a fluconazole intermediate reductive amination product IM 2;
preferably, the preparation method of the fluconazole intermediate reductive amination product comprises the following steps:
A. under the action of alkali, the fluconazole intermediate and hydroxylamine hydrochloride react in an organic solvent under the temperature control to prepare pre-IM 2; the organic solvent is methanol, ethanol, chloroform, acetonitrile or tetrahydrofuran; the alkali is sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, pyridine or 4-dimethylamino pyridine; the temperature is-10 ℃ to 80 ℃;
B. in the presence of Pd-C catalyst, pre-IM2 reacts with hydrogen in organic solvent, the temperature is controlled and the mixture is stirred, the paste obtained by post-treatment is dispersed and separated by adding solvent, and the product IM2 of the reductive amination of fluconazole intermediate is prepared. The organic solvent is methanol, ethanol, propanol, butanol, chloroform, ethyl acetate or tetrahydrofuran; the dispersing solvent is ethyl acetate, methanol, ethanol, petroleum ether, diethyl ether, methyl tert-butyl ether, n-hexane or cyclohexane; the temperature is 100-200 ℃;
more preferably, in the step a, the organic solvent is methanol; the base is pyridine; the temperature was 25 ℃ at room temperature and 70 ℃ in an oil bath.
More preferably, in the step B, the organic solvent is methanol; the dispersing solvent is ethyl acetate and petroleum ether; the temperature was 150 ℃.
The invention has the beneficial effects that:
1) the reductive amination product of the fluconazole intermediate provided by the invention takes the fluconazole intermediate as an initial raw material, and the carbonyl group of the fluconazole intermediate is oximated to obtain pre-IM 2; pre-IM2 reacts with hydrogen, and is reduced by Pd-C catalyst under heating and pressurizing to generate a product IM 2. The chemical structure of the product IM2 of the reductive amination of the fluconazole intermediate prepared by the invention1And (4) HNMR confirmation.
2) The preparation method of the intermediate pre-IM2 provided by the invention is improved as follows: the yield is improved from 60-70% in patent documents to more than 98% by changing the alkali NaOH used in the patent method into pyridine; the product produced by the patented process contains an orange-yellow impurity that is not visibly absorbed under UV, and the invention contains little impurity. Compared with the literature method, the method has the advantages of shorter reaction time, higher yield and less impurities. In addition, two configurational isomers of pre-IM2 are obtained by separation, and1and (4) HNMR characterization.
3) The product IM2 of the reductive amination of the fluconazole intermediate provided by the invention is an optimal method which is not reported in documents and is selected from a plurality of research methods, the post-treatment is simple and convenient, the yield is higher than 89%, the product purity is high, and the product can be directly used for the subsequent reaction. Although the reductive amination product IM2 of the fluconazole intermediate can be found in the literature, no synthetic method is available and no commercial product is available. The preparation method of the reductive amination product IM2 of the fluconazole intermediate provided by the research has very good industrialization prospect.
Drawings
FIG. 1 is a (E) -Pre-IM2 hydrogen spectrum;
FIG. 2 is a (Z) -pre-IM2 hydrogen spectrum;
FIG. 3 is an IM2 hydrogen spectrum;
FIG. 4 is a representative marketed drug containing fluconazole intermediate building blocks;
FIG. 5 is a representation of a literature synthetic route for fluconazole;
FIG. 6 is a representation of a literature synthetic route for fluconazole;
FIG. 7 is a contemplated synthetic route;
FIG. 8 is a hydrogen bond formed between pyridine as a base and its hydroxyl group and the N-1 atom of the triazole ring.
Detailed Description
The technical solution of the present invention is described in detail and completely with reference to the following embodiments, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The main reagents and instruments involved in the synthesis of the invention are: fluconazole intermediate (professor Zhou synd); methanol (Beijing YinoKai Tech Co., Ltd., > 99.9%); hydroxylamine hydrochloride (shanghai di bai biotechnology limited, AR); pyridine (Chuandong chemical industry, AR); 10% Pd/C (Tech, Inc., Yinaoka, Beijing); h2(pure hydrogen, jiekai gas control equipment limited); anhydrous sodium sulfate (chemical, AR, Chuandong); the other reagents are all commercial chemical pure or analytical pure products and are directly used without purification. Nuclear magnetic resonance apparatus (AV-600, Bruker, USA; TMS as internal standard); a magnetic stirring low-temperature constant-temperature water tank (PSL-1810, Shanghai Ailang instruments Co., Ltd.); a melting point tester (X-6, Beijing Fukai Instrument Co., Ltd.); high pressure reactor (agilawood pressure reducing valve); a rotary evaporator (R1001N, zheng cheng kou gong cao limited).
EXAMPLE 1 preparation of intermediate Oxime pre-IM2
To a 100mL pear-shaped flask was added fluconazole intermediate 6.695g (30mmol), methanol (MeOH)14mL, stirring at room temperature; adding hydroxylamine hydrochloride NH2OH & HCl2.502g (36mmol), stirring at room temperature; pyridine (Py)3.625mL (3.560g,45mmol) was added and stirring continued at room temperature; transferring the mixture into an oil bath, and carrying out reflux reaction. The progress of the reaction was checked by TLC and was completed after 2-2.5h of reflux.
Stopping stirring, taking out the reaction bottle from the oil bath pot, standing to room temperature, adding 50mL of pure water at one time, stirring, and standing; performing suction filtration, washing with water (15mL multiplied by 2), transferring to a culture dish, bundling, putting into a dryer, vacuumizing, and drying for 2 days; after weighing, the sample was transferred to a reagent bottle, and the bottle was sealed and stored in a freezer to obtain 7.012g of pre-IM2 (white solid) with a yield of 98.2%. The results of the multiple experiments are shown in Table 1.
TABLE 1 results of the Pre-IM2 Synthesis experiment
It was found experimentally that the fluconazole intermediate (white solid) slowly dissolved in methanol to become an opalescent turbid liquid; addition of NH2OH HCl, the system turned to a pale yellow solution after a while with stirring, no solid appeared. Py is added and stirred, and the system becomes slightly viscous; the reaction was stopped when the feed point became increasingly light throughout the reaction, after 2h it became very light and the reaction time was further extended. Standing at room temperature, adding water to precipitate a large amount of white solid. Carrying out suction filtration and washing to obtain a solid; after drying, white and glossy crystals were obtained.
To confirm the structure, 550mg of the obtained solid was taken, loaded by dry loading into a column having a height of about 75mm and an inner diameter of about 25mm, and eluted with an eluent of Petroleum Ether (PE): Ethyl Acetate (EA): 2:1 (v/v). On Thin Layer Chromatography (TLC) plates RfThe larger dots appear to be more concentrated, and RfThe spot concentrations with smaller values are smaller and they correspond to oximes of the Z/E configuration, respectively. Respectively receiving the eluents corresponding to the two points by using respectively weighed dry flasks, removing the solvent by rotary removal under reduced pressure, putting the flasks into a vacuum drier for 2 days, weighing again after constant weight, and measuring the mass fractions of the substances corresponding to the two points381mg (R) respectivelyfLarger dots, needle crystals) and 134mg (R)fDots of smaller value, flocculent crystals) in a mass ratio of 2.84: 1. After this time, 10mg of each solid sample was taken, dissolved in DMSO-d6 and tested1HNMR. The analysis of the spectrum shows that the required intermediate pre-IM2 is obtained.
The process of the patent document uses 1.5 equivalents of NaOH as base, and the solid obtained after completion of the reaction and work-up is orange and the yield can only reach 60% to 70%. The product produced by this process is said to contain an orange-yellow impurity that is not visibly absorbing under UV. Compared with a literature method, the experiment adopts pyridine as alkali, so that the yield is higher, and impurities are less; the reason why the final product did not give a 1:1 cis-trans isomer but a 2.84:1 ratio was probably because RfThe point corresponding to the larger value and the larger concentration is in Z configuration, and the hydroxyl group is supposed not to be free but to form hydrogen bond with the N-1 atom of the triazole ring beside the point (see figure 8), so that the molecule of the Z configuration product is more stable and has more thermodynamic advantage in oxime forming reaction.
Although both configurations of the product are present, the subsequent reduction is not affected (the reduction products are the same).
Melting point and spectral data are as follows:
(E)-pre-IM2
white flocculent crystal, m.p.174.8-175.6 deg.C
1HNMR(600MHz,DMSO-d6)δ11.58(s,1H,H-1),8.43(s,1H,H-2),7.92(s,1H,H-3),7.26(dt,J＝14.2, 8.7Hz,2H,H-4andH-5),7.10(dd,J＝11.6,5.1Hz,1H,H-6),5.28(s,2H,H-7).
(Z)-preIM2
White needle-like crystals m.p.136.1-136.9 deg.C
1HNMR(600MHz,DMSO-d6)δ12.15(s,1H,H-1),8.48(s,1H,H-2),7.83(s,1H,H-3),7.48(dd,J＝15.3, 8.4Hz,1H,H-4),7.23(dd,J＝14.5,5.5Hz,1H,H-5),7.06(t,J＝8.4Hz,1H,H-6),5.49(s,2H,H-7).
EXAMPLE 2 reduction of Oxime by AlNiCo/NaOH System
Adding pre-IM21mmol into a 350mL pressure-resistant bottle, adding methanol for dissolving, adding Al-Ni alloy, adding excessive 20% NaOH solution, immediately screwing a pressure-resistant bottle cap, quickly stirring, and controlling the reaction temperature. TLC monitored the progress of the reaction. After 6H of reaction, TLC showed a faint spot of product on the TLC plate beyond the starting spot, and 1 drop of reaction was mixed with 1 drop of 20% H2SO4After mixing, spotting and re-spreading, finding that a new spot still remains on the base line and belongs to the expression of the amine substance after salifying, and preliminarily confirming that the spot is an amine molecule and possibly a reduction product IM 2. The results of the multiple experiments are shown in Table 2.
TABLE 2 AlNiCo/NaOH systems reduction of oximes test results
NA indicates no significant change in the reaction system, TLC indicates no new spot was formed, and the same is followed
Experiments show that the Pre-IM2 is slowly dissolved in methanol and becomes a milky yellow solution after being stirred for 5 min; when the Al-Ni alloy is added and an excessive amount of NaOH solution is added, a large amount of bubbles are generated immediately, along with violent heat release, and when no bubbles are generated any more, the system becomes black turbid liquid. No matter whether the reaction system is heated or not, the reaction is carried out until gas is not generated and the reaction time is further prolonged, and the system properties are not obviously changed. The reaction was stopped. If the reaction system is heated and the reaction bottle is opened after the reaction system is sufficiently cooled, only Entry4 can smell weak amine substance odor, and the other phenomena are not obvious.
After several exploratory experiments, it was found that the reaction did not occur without increasing the temperature, and the reaction hardly occurred when the pressure of the reaction system was less than 2 atmospheres (atm). Found that 2g (aluminum-Ni alloy) of Pre-IM20.715g (3mmol) and Al-Ni alloyThe mass fraction of aluminum in the nickel alloy is 50 percent, and 55mmolH is generated after the aluminum is completely dissolved by NaOH2The reaction was carried out in a 350mL pressure bottle, and the best reaction effect was obtained by roughly calculating the pressure generated by this amount of hydrogen to be 4.5atm) and the amount of 8.837g of 20% NaOH solution (1.2 times the amount of Al in the alloy), and reacting with MeOH as a solvent at 65 ℃. And (3) removing metal Ni in the system by suction filtration, washing a filter cake by DCM, extracting the filtrate for multiple times by DCM, drying the extract, and carrying out rotary drying under reduced pressure to obtain 127mg (0.566mmol) of a product, wherein the yield is 18.9%, and the structure of the product is consistent with that of the product obtained by catalytic hydrogenation through follow-up TLC analysis.
Although this process gives products, it is inefficient in the synthesis of IM2, a key intermediate with a large demand. But also indicates a promising and more efficient method for the synthesis of IM2 by further catalytic hydrogenation reduction of pre-IM2, i.e. with a more active Pd-C catalyst and carrying out the reaction at higher hydrogen pressure and reaction temperature.
Example 3 HCOONH4Reduction of oximes by the Pd-C System
To a 100mL round bottom flask was added pre-IM21mmol, HCOONH45mmol, 5% Pd-C5 wt%, then adding 3mL of methanol, stirring at 30 ℃, gradually heating to 65 ℃, refluxing and stirring, and detecting the progress of the reaction by TLC. The results of the multiple experiments are shown in Table 3.
TABLE 3 HCOONH4Results of oxime reduction experiments in Pd-C system
The added materials turned into black turbid liquid, and undissolved HCOONH was observed4A crystal; whether heated to reflux or not,the reaction system has no obvious change, but after heating and refluxing for a period of time, white crystals are observed to be generated below the condensing tube, and the tendency of blocking the refluxing condensing tube is observed.
Literature reports of HCOONH4the/Pd-C system has good reduction capability and good effect in the reduction of certain compounds with simple structures. However, in the reduction of pre-IM2, no reaction occurred at room temperature (entry1), and the reaction produced a large number of impurity sites after the temperature was raised (entry2 and 3). After the temperature is raised, HCOONH is found4The sublimation occurs, and the solid is formed at the lower opening of the condensation pipe to block the condensation pipe, even if the reaction can be smoothly carried out, HCOONH4The "sublimation" of (A) also tends to be a negative factor in the scale-up of the synthesis.
Example 4 HCOONH4Reduction of oximes by the/Zn (powder) system
To a 100mL round bottom flask was added pre-IM21mmol, HCOONH43mmol and 2mmol of activated zinc powder, adding MeOH H1.8mL under stirring, stirring at room temperature (30 ℃) for reaction, gradually raising the temperature to 65 ℃ for reflux, and detecting the reaction progress by TLC. The results of the multiple experiments are shown in Table 4.
TABLE 4 HCOONH4Results of oxime reduction experiment in/Zn System
The added raw materials can not be completely dissolved, the system is grey turbid liquid, and undissolved HCOONH can be observed4And (4) crystals. After the reaction is carried out for a long time, the reaction system has no obvious change, and no new point exists in TLC detection.
This method has been successful in the literature, although the oxime successfully reduced in the literature has a relatively simple structure and relatively fixed reaction conditions (i.e., mostly MeOH as solvent, 2eq activated zinc powder, HCOONH)44 eq). The reason for the failure of this process may be that no nature of the bound reactants is foundThe suitable reduction conditions, especially the reaction solvent, reaction temperature, charge ratio, charge mode, etc., do not exclude the possibility that the system itself cannot reduce the reactant, and the method is still to be explored.
Example 5 NaBH4Systematic reduction of oximes
To a 50mL round bottom flask was added pre-im20.2381g (1mmol), solvent was added with stirring until the white solid just completely dissolved, with or without addition of catalyst (cat.) with stirring; followed by rapid addition of NaBH40.1513g (2mmol), the reaction was stirred at room temperature and the progress of the reaction was checked by TLC. The results of the multiple experiments are shown in Table 5.
TABLE 5 NaBH4Results of oxime reduction experiment of system
The white solid can be completely dissolved in the selected solvent to become a light yellow solution; the catalyst is different, and the phenomenon is different: adding NiCl2·6H2O、LiCl、AlCl3No obvious change after the treatment, adding I2The system turns brown after THF. Until the reaction is stopped, the state of each reaction system and the feeding are not obviously changed.
NaBH4Mainly used for the reduction of aldehyde ketone because the reduction capability is not strong enough. However, it has been found that carboxylic acid esters and the like can also be reduced if activators (usually anhydrous Lewis acids) are added, as can NaBH4The reducing power can be greatly enhanced under appropriate conditions. At the same time, NaBH has been reported4In I2In situ formation of BH in THF System3The THF complex also greatly enhances the reducibility of the system, and there are precedents for successful reduction of oximes.
The studies shown in Table 5 are all based on the literature reported enhancement of NaBH4Reductive Process, in the trial listed in Table 5, all reagents, catalysts and solvents were thoroughly dried (only NiCl)2·6H2With the exception of O, the water of crystallization was not removed by drying), and the peroxide was also removed beforehand with THF, but the reduction was unsuccessful. The possible reasons are that no reducing conditions, especially reaction solvent, reaction temperature, feeding ratio, feeding mode and the like are found, and the possibility that reactants cannot be reduced by the system per se is not eliminated.
Example 6H2Preparation of oxime-reductive amination product by Pd-C system reduction
Adding Pre-IM27.00g (30mmol) and MeOH10mL into a 250mL high-pressure reaction kettle, and stirring at room temperature; adding 10mL of methanol into a beaker, and slowly adding 10% of Pd-C0.700g; the 10% Pd/C in methanol solution was transferred to the autoclave by a dropper. Is filled into H2Ventilating for 3 times, and charging H2To a pressure value of 0.8 MPa. And (3) placing the high-pressure reaction kettle in a 150 ℃ oil bath kettle for reaction for 3.5h (heating for 1h, keeping the temperature for reaction for 1.5h, and cooling to room temperature for 1 h). After the reaction vessel was opened, TLC detection revealed that there was no Pre-IM 2. And (5) carrying out suction filtration and recovering the palladium-carbon. And (3) performing rotary evaporation to obtain a white paste, dispersing by using PE/EA (poly ethylene/ethylene) 20/1(v/v), precipitating a white solid, performing suction filtration, and performing vacuum drying to obtain IM26.00g with the yield of 89%. The product is very pure and can be used directly in the subsequent reaction. The results of the multiple experiments are shown in Table 6.
TABLE 6 IM2 results of the Synthesis experiment
Further purification of the product: to a 100mL pear flask, 500mg of pre-IM2 was added, 5mL of water was added, and stirring was performed to dissolve a white solid portion, followed by dropwise addition of 6NHCl to the solution until the pH of the solution became 1. With the addition of acid, the white solid further dissolved, and a small amount of undissolved white solid remained, and was filtered, and the filtrate wasTransferring to 250mL pear-shaped flask, adding 20% NaOH solution to adjust pH to 14, when pH is close to 14, a small amount of oil is generated on the liquid surface, performing DCM extraction (3X 10mL), collecting organic phase, and anhydrous Na2SO4Drying, transferring to a 100mL pear-shaped flask, and spin-drying the solvent in vacuum to obtain white crystals. The solid has high purity, and can be completely determined1Purity requirement of HNMR.
The melting point and spectral data for IM2 are as follows:
white solid, m.p.66.3-67.1 deg.C
1HNMR(600MHz,DMSO-d6)δ8.32(s,1H,H-1),7.90(s,1H,H-2),7.54(dd,J＝15.6,8.0Hz,1H,H-3), 7.14(d,J＝9.5Hz,1H,H-4),7.06(t,J＝8.3Hz,1H,H-5),4.47(t,J＝6.4Hz,1H,H-6),4.30(t,J＝6.8Hz,2H,H-7), 2.08(s,2H,H-8).
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (3)
1. A product of the reductive amination of a fluconazole intermediate, IM2, characterized by the following structural formula:
2. a process for the preparation of a product of the reductive amination of a fluconazole intermediate as claimed in claim 1, comprising the steps of: reacting the fluconazole intermediate with hydroxylamine hydrochloride to prepare an intermediate Pre-IM 2;
reducing the intermediate Pre-IM2 to obtain a fluconazole intermediate reductive amination product IM 2;
3. a process for the preparation of a product of the reductive amination of a fluconazole intermediate according to claim 2, characterized in that it comprises the following steps:
A. under the action of alkali, the fluconazole intermediate and hydroxylamine hydrochloride react in an organic solvent under the temperature control to prepare pre-IM 2; the organic solvent is methanol, ethanol, chloroform, acetonitrile or tetrahydrofuran; the alkali is sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, pyridine or 4-dimethylamino pyridine; the temperature is-10 ℃ to 80 ℃; the optimized reaction conditions are as follows: the solvent is methanol, the alkali is pyridine, the temperature is 25 ℃ firstly, then oil bath is carried out at 70 ℃, and stirring reaction is carried out.
B. In the presence of Pd-C catalyst, pre-IM2 reacts with hydrogen in organic solvent, the temperature is controlled and the mixture is stirred, the paste obtained by post-treatment is dispersed and separated by adding solvent, and the product IM2 of the reductive amination of fluconazole intermediate is prepared. The organic solvent is methanol, ethanol, propanol, butanol, chloroform, ethyl acetate or tetrahydrofuran; the dispersing solvent is ethyl acetate, methanol, ethanol, petroleum ether, diethyl ether, methyl tert-butyl ether, n-hexane or cyclohexane; the temperature is 100-200 ℃; the optimized reaction conditions are as follows: the solvent is methanol, the temperature is 150 ℃, and the precipitated solvent is ethyl acetate and petroleum ether.
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| US20150105373A1 (en) * | 2012-04-25 | 2015-04-16 | Takeda Pharmaceutical Company, Chuo-ku | Nitrogenated heterocyclic compound |
| US20180256572A1 (en) * | 2017-03-10 | 2018-09-13 | Vps-3, Inc. | Metalloenzyme inhibitor compounds |
| US20210371393A1 (en) * | 2018-04-18 | 2021-12-02 | Medshine Discovery Inc. | Benzopyrazole compound used as rho kinase inhibitor |
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