CN108440538B - Novel pyrroloimidazole derivative and preparation method and application thereof - Google Patents
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Abstract
The invention discloses a novel pyrroloimidazole derivative and a preparation method and application thereof, and relates to the field of organic synthesis and medicinal chemistry, wherein the derivative is a benzimidazole pyrrole compound shown in a general formula (I), and pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof; the novel pyrroloimidazole derivative has the advantages of simple synthesis method, high yield, good antibacterial activity on various fungi and wide application prospect in the aspect of antibacterial and anticancer activity.
Description
Technical Field
The invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to a pyrroloimidazole derivative for treating diseases of candida parapsilosis, sporotrichosis, saccharomyces cerevisiae aspergillus, candida albicans, candida glabrata, candida tropicalis, trichophyton rubrum, penicillium, trichophyton verrucosum, trichophyton purpurea, cryptococcus neoformans, candida krusei, epidermophyton floccosum and trichophyton gypseum, a preparation method thereof, a pharmaceutical composition containing the derivative and application thereof.
Background
Fungal infections are a common disease and multiple complications. In recent years, due to the increase of the incidence of consumptive diseases such as tumor, diabetes, AIDS and the like, and the large clinical use of broad-spectrum antibiotics, immunosuppressants, antitumor drugs and the like, the immunity of patients is reduced, so that the incidence of fungal infection, particularly deep fungal infection, is greatly increased, the mortality rate is increased, and the deep fungal infection becomes one of the main causes of death of cancer and patients with immunodeficiency diseases in recent years.
Antifungal medicines for treating and preventing deep fungal infection are mostly azole medicines, especially triazole medicines such as fluconazole, itraconazole, voriconazole and the like. However, these drugs have certain limitations, such as: fluconazole has poor effect on aspergillus, continuously generates drug-resistant strains, itraconazole has poor oral absorption, and voriconazole which is just clinically researched also has certain toxic and side effects. Therefore, the search for antifungal drugs with broad spectrum, high efficiency, low toxicity and high bioavailability for oral administration still has very important significance. Research shows that the compound containing the pyrroloimidazole fragment structure has good antifungal activity.
In recent decades, receptor cyclopropanation chemistry has made extensive progress and the synthesis of heterocyclic compounds by ring-expansion cycloaddition is a valuable synthetic strategy, particularly using transition metal-catalyzed intramolecular cycloaddition, allowing the formation of multiple chemical bonds and highly complex structures of the compound by a single reaction. Generally, transition metal-catalyzed cycloadditions involve a wide range of double dipoles including enolates, alkynyloxyethers, indoles, aldehydes, imines, pyridines, nitriles, nitrosobenzenes, benzothiazoles, and the like.
Lewis acid catalyzed cycloaddition of imines to cyclopropane has particularly broad applications, e.g., Kerr et al first report ytterbium triflate catalyzed [3+2 ] imine to three-membered ring]Performing cycloaddition reaction to synthesize pyrrolidine heterocyclic compounds; carriera and Lautens et al have demonstrated that 3-spirocyclopropyl-2-oxoindole reacts with imine [3+2 ] under the catalytic action of magnesium iodide]Performing cycloaddition reaction to synthesize pyrrolidine heterocyclic compounds; bertozzi et al utilize a Lewis acid MgI2And Et2AlI conducted a study of the cycloaddition reaction of an ethanone cyclopropane with an imine. Sunxeli et al studied the cycloaddition reaction of 1, 1-cyclopropane diesters with imines using Lewis acid scandium trifluoromethanesulfonate; matsubara et al utilize Ni (COD)2Cycloaddition reactions of cyclopropane compounds with imines were investigated.
The heterocyclic compound is synthesized by using cycloaddition reaction, the synthetic route is short, the atom economy is high, more and more attention is paid to the heterocyclic compound, and the unique reaction characteristic opens up a new field of view for searching novel heterocyclic compounds. The novel heterocyclic compound is also developed importantly in the field of pharmaceutical chemistry, and can be used for simply and efficiently constructing a fused cyclic compound by utilizing a cycloaddition reaction so as to realize large-scale drug substrate screening, thereby playing more and more important roles in the fields of medicine synthesis and pharmaceutical chemistry.
Disclosure of Invention
The invention aims to provide a benzimidazole pyrrole compound shown in a general formula (I) and a novel pyrrole imidazole derivative of pharmaceutically acceptable salt, enantiomer, diastereoisomer or racemate thereof.
Another object of the present invention is to provide a process for producing the derivative represented by the above general formula (I).
It is a further object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula (I) above or a pharmaceutically acceptable salt thereof.
Still another object of the present invention is to provide the use of the compound represented by the above general formula (I) for preparing a medicament for treating fungal infectious diseases such as candida parapsilosis, sporothrix, saccharomyces cerevisiae aspergillus, candida albicans, candida glabrata, candida tropicalis, trichophyton rubrum, penicillium, trichophyton verrucosum, trichophyton purpurea, cryptococcus neoformans, candida krusei, epidermophyton floccosum, trichophyton gypseum, and the like.
Still another object of the present invention is to provide the use of the above pharmaceutical composition in the preparation of a medicament for treating fungal infections such as candida parapsilosis, sporothrix, brewer's yeast aspergillus, candida albicans, candida glabrata, candida tropicalis, trichophyton rubrum, penicillium, trichophyton verrucosum, trichophyton purpurea, cryptococcus neoformans, candida krusei, epidermophyton floccosum, trichophyton gypseum, etc.
The above object of the present invention is achieved by the following technical solutions:
a novel pyrroloimidazole derivative is a benzimidazole compound shown in a general formula (I), and pharmaceutically acceptable salts, enantiomers, diastereoisomers or racemes; wherein:
R1each independently selected from: hydrogen, halogen, cyano, nitro, amino, hydroxy, hydroxymethyl, methoxy, trifluoromethyl, trifluoromethoxy, carboxy, C1-C6 straight or branched chainAlkyl of (a), C2-C6 linear or branched unsaturated hydrocarbyl, C1-C6 linear or branched alkoxy, C1-C6 linear or branched alkanoyl, or C1-C6 linear or branched alkylamino;
R2each independently selected from: halogen, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, phenyl, sulfonamide, naphthyl, biphenyl, C5-C12 heteroaryl, or C3-C12 heterocyclic group, wherein the heterocyclic group or the heteroaryl group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;
R3each independently selected from: mono-or di-substituted hydrogen, ester group, halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, methoxy, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated alkyl, C1-C6 linear or branched alkoxy, C1-C6 linear or branched alkanoyl, or C1-C6 linear or branched alkylamino.
Preferably, R in said formula (I)2Is substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C5-C12 heteroaryl, said heteroaryl containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen.
Preferably, R in said formula (I)1The substituents of (a) are each independently selected from: halogen, C1-C12 linear or branched alkyl, C1-C12 linear or branched alkoxy, C2-C12 linear or branched unsaturated alkyl, C3-C12 cyclic hydrocarbon, cyano, nitro, amino, hydroxyl, trifluoromethyl, trifluoromethoxy, carboxyl, sulfonamide and mercapto.
Preferably, R in said formula (I)4Is hydrogen, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated alkyl, C1-C6 linear or branched alkylamino.
In a preferred embodiment of the present invention, the benzimidazolopyrrole compounds include compounds represented by formula (II) 1 to 28, formula (III) 1a to 28a and formula (IV) 1b to 28 b:
in addition, in some preferred embodiments, the above-mentioned benzimidazolopyrrole compounds may have asymmetric centers, chiral axes and chiral planes, and may exist in the form of enantiomers, diastereomers, racemates and mixtures thereof.
The invention also provides a pharmaceutically acceptable salt of the compound of the general formula (I), which is: the compounds of the general formula (I) are reacted with inorganic or organic acids to form conventional non-toxic salts. For example, conventional non-toxic salts may be prepared by reacting a compound of formula (I) with inorganic acids including hydrochloric, hydrobromic, sulfuric, nitric, sulfamic and phosphoric acids, or organic acids including citric, tartaric, lactic, pyruvic, acetic, benzenesulfonic, p-toluenesulfonic, methanesulfonic, naphthalenesulfonic, ethanesulfonic, naphthalenedisulfonic, maleic, malic, malonic, fumaric, succinic, propionic, oxalic, trifluoroacetic, stearic, pamoic, hydroxymaleic, phenylacetic, benzoic, salicylic, glutamic, ascorbic, p-aminobenzenesulfonic, 2-acetoxybenzoic, and isethionic acids; or sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt formed by the compound of the general formula (I) and propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid after forming ester and then forming inorganic base; or methylamine salt, ethylamine salt or ethanolamine salt formed by the compound of the general formula (I) and organic base; or the compound of the general formula (I) forms ester with lysine, arginine and ornithine and then forms corresponding inorganic acid salt with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid and phosphoric acid or forms corresponding organic acid salt with formic acid, acetic acid, picric acid, methanesulfonic acid and ethanesulfonic acid.
The present invention provides a process for producing a benzimidazolopyrrole compound represented by the above general formula (I), which comprises the following steps:
wherein R is1、R2、R3And R4As claimed in any one of claims 1 to 5;
step a: the compound I1Dispersing in a solvent, and obtaining a compound Ia after the reaction is completed under the heating condition of heating or microwave heating, wherein the solvent is trimethyl orthoformate, triethyl orthoformate or an aqueous solution of formaldehyde;
step b: dispersing compound Ia in solvent, adding cyclopropane derivative and Lewis acid catalyst, heating to 140 deg.C for 12h or microwave heating to 135 deg.C for 1-2h to obtain compound IbWherein the solvent is 1, 2-dichloroethane; the Lewis acid is ytterbium trifluoromethanesulfonate;
step c: the compound IbDispersing in solvent, adding oxidant, and reacting at 0-40 deg.C for 12 hr to obtain compound IcWherein the solvent is dichloromethane, acetone or dimethyl sulfoxide (DMSO), and the oxidant is potassium permanganate or cupric salt;
step d: the compound IcDispersing in solvent, adding oxidant, and reacting for 8 hr under reflux condition to obtain compound IdWherein the solvent is dichloromethane, and the oxidant is 2, 3-dichloro-5, 6-dicyan p-benzoquinone or dibenzoyl peroxide.
In another aspect of the present invention, a pharmaceutical composition comprises a therapeutically effective amount of the above-described benzimidazolopyrrole compound, and a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, in combination with one or more pharmaceutically acceptable carriers.
In still another aspect of the present invention, the use of the above novel pyrroloimidazole derivatives in the preparation of a medicament for the treatment of fungal infection diseases; wherein the fungi include Candida parapsilosis, Sporothrix, Saccharomyces cerevisiae Aspergillus, Candida albicans, Candida glabrata, Candida tropicalis, Trichophyton rubrum, Penicillium, Trichophyton verrucosum, Trichophyton purpureus, Cryptococcus neoformans, Candida krusei, Epidermophyton floccosum or Trichophyton gypseum.
In still another aspect of the present invention, the use of the above pharmaceutical composition for the preparation of a medicament for the treatment of fungal infection diseases; wherein the fungi include Candida parapsilosis, Sporothrix, Saccharomyces cerevisiae Aspergillus, Candida albicans, Candida glabrata, Candida tropicalis, Trichophyton rubrum, Penicillium, Trichophyton verrucosum, Trichophyton purpureus, Cryptococcus neoformans, Candida krusei, Epidermophyton floccosum or Trichophyton gypseum.
Compared with the prior art, the invention has the beneficial effects that:
the invention utilizes cycloaddition reaction to synthesize the heterocyclic compound, has short synthetic route, simple and convenient synthetic method, high yield and high atom economy, and opens up a brand-new visual field for people to search for novel heterocyclic compounds in the fields of medicine synthesis and pharmaceutical chemistry.
Secondly, the novel pyrroloimidazole compounds have good bacteriostatic activity on candida parapsilosis, sporotrichosis, aspergillus cerevisiae, candida albicans, candida glabrata, candida tropicalis, trichophyton rubrum, penicillium, trichophyton verrucosum, trichophyton purpurea, cryptococcus neoformans, candida krusei, trichophyton floccosum, trichophyton gypseum and the like.
Detailed Description
The present invention will be described in further detail with reference to examples. It should be noted that the scope of the present invention is not limited by the embodiments, but is defined by the claims. The starting materials used in the present invention are not specifically described, and are all commercially available.
Example 1
Formula Ia1The synthesis preparation reaction formula is as follows:
the preparation method comprises the following steps: dissolving o-phenylenediamine (1.08g,10mmol) in 8ml trimethyl orthoformate, adding 46mg (1mmol) formic acid, microwave at 120 deg.C in 25ml microwave reaction tube for 60min, cooling to room temperature, adding 5% NaHCO3Quenching the solution, extracting and separating the solution by using ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, and performing spin drying to obtain a light yellow solid product 1.16g with the yield of 98%;1HNMR(400MHz,CDCl3,ppm)δ:8.40(d,J＝2Hz,1H),7.88(d,J＝8.0Hz,3H),7.17(d,J＝4.6Hz,1H)。
examples 2 to 9
With (I)2-I9) The compound is used as a raw material to prepare a product of a formula (I)a2-Ia9) Compound (target product is the formula (I) in Table 1a2)-(Ia9) The preparation procedure is the same as in example 1, the reaction formula is as follows:
in examples 2-9, the selection of each group of the product of the compound of formula (Ia), reagents for preparation and assay data are shown in Table 1.
TABLE 1
Example 10
Formula Ib1The synthesis preparation reaction formula is as follows:
the preparation method comprises the following steps: benzimidazole (0.36g,3mmol) was dissolved in 3ml12-dichloroethane, microwave in a 10ml microwave reaction tube at 135 ℃ for 40min, cooling to room temperature, suction-filtering with a suction-filtering funnel filled with diatomite, washing with ethyl acetate, then washing with saturated NaCl solution, extracting and separating with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, spin-drying, and separating by column chromatography (petroleum ether: ethyl acetate: 6: 1-3: 1) to obtain 0.56g of a light yellow viscous product with a yield of 94%;1HNMR(400MHz,CDCl3,ppm)δ:8.32(s,1H),7.97(d,J＝4.0Hz,1H),7.48(d,J＝8.0Hz,1H),7.36-7.30(m,2H),6.14-6.05(m,1H),5.41(d,J＝12.0Hz,1H),5.30(d,J＝16.0Hz,1H),5.10(dd,J1＝14.4Hz,J2＝7.2Hz,1H),3.72(s,3H),3.64(s,3H),3.29(t,J＝8.0Hz,1H),2.79-2.61(m,2H)。
examples 11 to 28
With (I)a1-Ia9) Compounds and (A)1-A10) The compound is used as a raw material to prepare a product of a formula (I)b2-Ib19) Compounds (target products are of formula (I) in Table 2b2)-(Ibx) Each compound) was prepared according to the same procedure as in example 10, with the following reaction scheme:
in examples 11 to 28, the selection of each group of the product of the compound of formula (Ib), and the reagents for preparation and the data for detection are shown in Table 2.
TABLE 2
Example 29
Formula Ic1The synthesis preparation reaction formula is as follows:
the preparation method comprises the following steps: a25 mL dry round bottom flask was taken and the starting material (0.31g, 1mmol) was dissolved in 8mL acetone under nitrogen, after which 3 equivalents of KMnO were added4And 2 equivalents of CuCl2Reacting for 8 hours at the temperature of 60 ℃; filtering with a suction filter funnel filled with diatomite, washing with ethyl acetate, and obtaining the yield of 95%;1HNMR(400MHz,CDCl3,ppm)δ:8.32(s,1H),7.97(d,J＝4.0Hz,1H),7.36-7.30(m,2H),6.14-6.05(m,1H),5.41(d,J＝12.0Hz,1H),5.30(d,J＝16.0Hz,1H),5.10(dd,J1＝14.4Hz,J2＝7.2Hz,1H),3.72(s,3H),3.64(s,3H),3.29(t,J＝8.0Hz,1H),2.79-2.61(m,2H)。
examples 30 to 47
With (I)b2-Ib18) The compound is used as a raw material to prepare a product of a formula (I)c1-Ic19) Compounds (target product is formula (I) in Table 3c2)-(Ic19) Each compound) was prepared according to the procedure of example 29, the reaction scheme being as follows:
in examples 30 to 47, the product was of the formula (I)c) The selection of each group of the compounds, the reagents for preparation and the detection data are shown in Table 3.
TABLE 3
Example 48
Formula Id1The synthesis preparation reaction formula is as follows:
the preparation method comprises the following steps: a25 mL dry round bottom flask was taken and the starting material (0.31g, 1mmol) was dissolved in 8mL cyclohexane under nitrogen, after which 2 equivalents of BPO were added and heated to 90 ℃ for 30 min. Cooling to room temperature, and column chromatography (petroleum ether: ethyl acetate: 10: 1-3: 1) to give 0.23g of a pale yellow viscous substance in 76% yield;1HNMR(400MHz,CDCl3,ppm)δ:7.86(d,J＝4.6Hz,1H),7.43-7.40(m,1H),7.36-7.42(m,1H),7.24-7.19(m,1H),6.79(t,J＝8.0Hz,1H),6.37(d,J＝8.0Hz,1H),5.66-5.45(m,2H),3.77(s,3H),3.56(s,3H)。
examples 49 to 66
With (I)c2-Ic18) The compound is used as a raw material to prepare a product of a formula (I)d1-Id19) Compounds (target products are of formula (I) in Table 4d2)-(Id19) Each compound) was prepared according to the same procedure as in example 48, having the following reaction scheme:
in examples 49-66, the products are of the formula (I)d) The selection of each group of the compounds, the reagents for preparation and the detection data are shown in Table 4.
TABLE 4
Example 67 in vitro antifungal Activity test
1. Experimental strains
Candida parapsilosis, Sporothrix, Saccharomyces cerevisiae, Candida albicans, Candida glabrata, Candida tropicalis, Trichophyton rubrum, Penicillium, Trichophyton verruciformis, Trichophyton purpureus, Cryptococcus neoformans, Candida krusei, Epidermophyton floccosum, and Trichophyton gypseum.
2. Reagent and material
Materials for test: improved martin culture medium, 96-well culture plate and DMSO.
Control drugs: fluconazole.
3. Experimental methods
(1) Preparation of antibacterial medicinal liquid
Dissolving the tested medicines in DMSO respectively to prepare a solution of 25.6g/L, and storing at the temperature below-20 ℃ for later use; before the test, the test solution refrigerated at low temperature is taken out, melted in a thermostat at 35 ℃, and diluted by 10 times by RPMI1640 for standby.
(2) Preparation of inoculum
Tested candidaThe strains (Candida parapsilosis, Candida albicans, Candida glabrata, Candida tropicalis) were inoculated on a modified Martin medium and suspended in sterile saline at 0.85% by mass. Counting spores with a hemocytometer, adjusting the bacterial content so that the colony-forming unit is 1X 106-5×106CFU/mL. Diluting with RPMI-1640 culture medium 200 times during inoculation, diluting 10 times, and adjusting CFU value to 0.5 × 103-6.0×103CFU/mL, spare.
(3) MIC plate preparation
A blank was prepared by adding 100. mu.L of RPMI-1640 culture medium to well No. 1 of a sterilized 96-well polyethylene plate under sterile conditions. 190 μ L of bacteria solution is added into No. 2 hole, and 100 μ L of prepared bacteria solution is added into No. 3-12 holes. Then 10. mu.L of the test solution was added to well No. 2, and the concentration in well No. 2-11 was diluted by 10-fold, so that the final concentration in each well was 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25mg/L, and no test solution was added to well No. 12 as a growth control. And (4) sealing each MIC plate, putting the MIC plate in a common air incubator at 35 ℃, and incubating for 24h to judge the result.
(4) Result judgment
The OD value of each well was measured at 620nm with a microplate reader, and the minimum concentration at which the OD value was decreased by 80% or more was taken as the MIC value. -128 mg/L when MIC values are higher than 128 mg/L; when the MIC value is lower than 0.25mg/L, the MIC value is less than or equal to 0.25 mg/L.
(5) Repeated observation and statistics
The test is repeated at least three times, when single jump of the MIC value occurs, the maximum bacteria-inhibiting concentration is recorded, and when two or more jump of the MIC value occurs, the test is carried out again.
4. Results of antifungal susceptibility test
The test compound is found to have broad-spectrum antifungal activity by primary MIC measurement, wherein the activity of the benzopyrrole compounds of example 11, example 13, example 16, example 21, example 23, example 26, example 33, example 34, example 49, example 51, example 65 and the like for inhibiting the fungi is more remarkable, and the MIC values of the test strains are all less than 20 mg/L.
Claims (7)
1. The pyrroloimidazole derivative is characterized by being represented by a general formula (I)b) A benzimidazole pyrrole compound and pharmaceutically acceptable salts thereof:
R1one independently selected from phenyl, biphenyl, methyl, ethyl, isopropyl, methoxy, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or naphthyl;
R2independently selected from one of vinyl, phenyl, biphenyl, p-tolyl, m-methoxyphenyl, o-fluorophenyl, m-fluorophenyl, p-methoxyphenyl, m-methoxyphenyl, p-nitrophenyl, m-trimethylphenyl, p-cyanophenyl, m-cyanophenyl, p-trifluoromethylphenyl or naphthyl;
R3independently selected from ester groups.
2. The pyrroloimidazole derivative of claim 1, wherein R is1Is one of methyl, ethyl, isopropyl, methoxy, fluorine, chlorine, bromine, nitro, cyano or trifluoromethyl.
3. A pyrroloimidazole derivative selected from a compound represented by any one of 1 to 28 in formula (II):
4. a process for producing a pyrroloimidazole derivative according to claim 1 or 2, which comprises the step represented by the formula (v);
wherein R is1、R2、R3As claimed in claim 1 or 2;
step a: the compound I1Dispersing in a solvent, and obtaining a compound Ia after the reaction is completed under the heating condition of heating or microwave heating, wherein the solvent is trimethyl orthoformate, triethyl orthoformate or an aqueous solution of formaldehyde;
step b: dispersing compound Ia in solvent, adding cyclopropane derivative
Reacting with Lewis acid catalyst at 140 deg.C for 12 hr or microwave heating to 135 deg.C for 1-2 hr to obtain the compound of formula (I)b) A compound shown in the specification;
wherein the solvent is 1, 2-dichloroethane, and the Lewis acid is ytterbium trifluoromethanesulfonate.
5. A pharmaceutical composition comprising a therapeutically effective amount of a pyrroloimidazole-derivative according to any one of claims 1 to 3, together with one or more pharmaceutically acceptable carriers.
6. Use of a pyrroloimidazole derivative according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment of fungal infectious diseases; wherein the fungus is selected from Candida parapsilosis, Sporothrix, Saccharomyces cerevisiae Aspergillus, Candida albicans, Candida glabrata, Candida tropicalis, Trichophyton rubrum, Penicillium, Trichophyton verrucosum, Trichophyton purpureus, Cryptococcus neoformans, Candida krusei, Epidermophyton floccosum and Trichophyton gypseum.
7. Use of the pharmaceutical composition of claim 5 for the manufacture of a medicament for the treatment of fungal infection; wherein the fungus is selected from Candida parapsilosis, Sporothrix, Saccharomyces cerevisiae Aspergillus, Candida albicans, Candida glabrata, Candida tropicalis, Trichophyton rubrum, Penicillium, Trichophyton verrucosum, Trichophyton purpureus, Cryptococcus neoformans, Candida krusei, Epidermophyton floccosum and Trichophyton gypseum.
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| GB913934A (en) * | 1958-03-03 | 1962-12-28 | Rohm & Haas | Condensed heterocyclic compounds |
| WO2006015191A2 (en) * | 2004-07-29 | 2006-02-09 | Threshold Pharmaceuticals, Inc. | Multicyclic lonidamine analogs |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB913934A (en) * | 1958-03-03 | 1962-12-28 | Rohm & Haas | Condensed heterocyclic compounds |
| WO2006015191A2 (en) * | 2004-07-29 | 2006-02-09 | Threshold Pharmaceuticals, Inc. | Multicyclic lonidamine analogs |
Non-Patent Citations (1)
| Title |
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| Domino Staudinger/aza-Wittig/Mannich Reaction: An Approach to Diversity of Di- and Tetrahydropyrrole Scaffolds;Anna S. Pavlova,et al.,;《 Chem. Eur. J.》;20161031;第22卷;第17967-17971页 * |
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