WO2018080269A1 - 알라닌 및 프롤린 아미노산의 기능적 유도체 화합물 및 이를 포함하는 약학적 조성물 - Google Patents

알라닌 및 프롤린 아미노산의 기능적 유도체 화합물 및 이를 포함하는 약학적 조성물 Download PDF

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WO2018080269A1
WO2018080269A1 PCT/KR2017/012108 KR2017012108W WO2018080269A1 WO 2018080269 A1 WO2018080269 A1 WO 2018080269A1 KR 2017012108 W KR2017012108 W KR 2017012108W WO 2018080269 A1 WO2018080269 A1 WO 2018080269A1
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Prior art keywords
benzyl
compound
oxy
formula
pyrrolidine
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English (en)
French (fr)
Korean (ko)
Inventor
박기덕
반용선
이종승
이경태
배애님
연슬기
강용구
박종현
김시원
장보고
최지원
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Amtixbio Co Ltd
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Amtixbio Co Ltd
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Priority to CA3041985A priority Critical patent/CA3041985C/en
Priority to JP2019545217A priority patent/JP7061317B2/ja
Priority to BR112019008577-7A priority patent/BR112019008577B1/pt
Priority to EP17865577.5A priority patent/EP3533782A4/en
Priority to CN201780067547.5A priority patent/CN110325509B/zh
Priority to KR1020207007595A priority patent/KR20200066610A/ko
Priority to US16/346,028 priority patent/US20200199065A1/en
Priority to AU2017351906A priority patent/AU2017351906B2/en
Priority to CN202310670949.1A priority patent/CN116836083A/zh
Application filed by Amtixbio Co Ltd filed Critical Amtixbio Co Ltd
Priority to KR1020187033364A priority patent/KR102099980B1/ko
Publication of WO2018080269A1 publication Critical patent/WO2018080269A1/ko
Anticipated expiration legal-status Critical
Priority to US18/918,365 priority patent/US20250034082A1/en
Priority to US18/918,533 priority patent/US20250034085A1/en
Priority to US18/918,511 priority patent/US20250034084A1/en
Priority to US18/918,493 priority patent/US20250034083A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P3/00—Fungicides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a benzyloxybenzyl aminyl amino acid derivative having an amino acid as a functional group and an antifungal pharmaceutical composition comprising the same as an active ingredient.
  • Cryptococcus neoformans is a biliary homogeneous pathogen that causes meningitis in a weakened immunity group and is known to kill more than 600,000 people worldwide every year due to fungal infectious meningitis.
  • Cryptococcosis only limited treatment is available for the treatment of cryptococcosis.
  • Antifungal agents developed to date can be classified into antifungal agents having chemically azole structures and antifungal agents having viaazole structures.
  • the azole antifungal agents include ketoconazole, fluconazole, itraconazole, and voriconazole, and the non-solvent antifungal agents include terbinafine and flucytosine. ), Amphotericin B and caspofungin are representative drugs.
  • Ketoconazole, fluconazole, itraconazole, voriconazole, and allylamines-based naphthypine and terbinafine having an azole structure have similar mechanisms of action.
  • Both classes of antifungal agents inhibit the enzymes necessary for the conversion of lanosterol to ergosterol, a major component of fungal cell membranes.
  • the azole antifungal agent inhibits microsomal enzymes, and the allylamine antifungal agent inhibits squalene epoxidase, thereby exhibiting the above effects.
  • Flucytosine is a metabolic antagonist that inhibits nucleic acid synthesis, and has antifungal action by uncompromising antagonism of fungal RNA and DNA synthesis, and shows antifungal action, and has a polyene structure. Binds to ergosterol inside the fungal cell membrane to induce depolarization of the cell membrane, forms pores, and causes loss of intracellular contents, thereby exhibiting antifungal action.
  • Caspofungin an antifungal agent of the Echinocandins family, reversibly inhibits the formation of fungal cell walls and differs from the antifungal agents acting on the cell membranes in that they act on the cell walls.
  • azole drugs may cause hepatitis death when used in patients with reduced liver function, hepatic function tests must be performed prior to administration. Flucytosine has been reported to be dose-dependently inhibiting myelosuppression, hepatotoxicity, and small intestinal colitis, and this side effect increases when renal function is lowered. Therefore, monitoring renal function of patients is very important. It is also contraindicated in pregnant women. Representative toxicity of amphotericin B is glomerular neotoxicity following renal artery contraction, which is dose dependent, resulting in an increased incidence of permanent renal insufficiency at lifetime cumulative doses of 4-5 g or more.
  • nephrotoxicity such as excessive loss of potassium, magnesium, and bicarbonate due to tubular toxicity and a decrease in hematopoietic hormone production may occur.
  • acute reactions may cause symptoms such as thrombophlebitis, chills, tremors and hyperventilation.
  • the antifungal agents developed in the past have various side effects according to the types of drugs, and thus, there is a demand for the development of new therapeutic agents that can lower the side effects and enhance the antifungal effect.
  • Another object of the present invention is to provide an antifungal pharmaceutical composition
  • an antifungal pharmaceutical composition comprising the benzyloxybenzyl aminyl amino acid derivative of the present invention, salts and / or solvates thereof as an active ingredient.
  • Another object of the present invention is to provide an antifungal pesticide preparation comprising the benzyloxybenzyl aminyl amino acid derivative of the present invention, salts and / or solvates thereof as an active ingredient.
  • Another object of the present invention is to provide an antifungal agent for animals comprising the benzyloxybenzyl aminyl amino acid derivative, salt and / or solvate active ingredient of the present invention.
  • Another object of the present invention is to provide an antifungal composition
  • an antifungal composition comprising the benzyloxybenzylamiminyl amino acid derivative, salts and / or solvates thereof of the present invention.
  • the present invention provides a benzyloxybenzylamine amino acid derivative represented by the following [Formula 1], pharmaceutically acceptable salts, and / or solvates thereof.
  • R 4, R 5, R 6, R 7 and R 8 are the same or different from each other, each independently hydrogen, C 1- 7 alkyl, hydroxy, halogen, halogenated C 1- 7 alkyl, C 1- 7 alkyloxy, and is selected from C 1- 7 halogenated alkyloxy, Y is selected from the following [formula 2] to [formula 4],
  • R 1 and R 3 are the same or different from each other, each independently hydrogen or C 1- 7 alkyl,
  • R 2 is C 1-7 alkyl.
  • the halogen may be selected from fluoro, chloro, bromo and iodo,
  • the C 1- 6 alkyl is a straight chain, it may be in a crushed or cyclic alkyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec- butyl, t- butyl, pentyl, hexyl, heptyl And octyl.
  • the alkyloxy group of C 1-7 may be selected from methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy and octyloxy.
  • the halogenated C 1 - 7 alkyl-difluoro-methyl, trifluoromethyl, deployment Oro ethyl, trifluoro ethyl, trifluoropropyl, tri be selected from heptyl as cyclohexyl and trifluoromethyl as a pentyl, trifluoromethyl fluoro Can and
  • the halogenated C 1 - 7 alkyloxy is difluoromethyl methyloxy, as methyloxy, deployment as a trifluoroacetic Oro ethyloxy, trifluoroacetic ethyloxy, trifluoroacetic propyloxy, pentyloxy, trifluoroacetate trifluoroacetic hexyloxy Ci and trifluoroheptyloxy.
  • R 4, R 5 , R 6, R 7 and either one of R 8 is C 1- 7 alkyl, hydroxy, halogen, halogenated C 1 - 7 alkyl, C 1 7 is alkyloxy and halogenated C 1 -7 alkyloxy and the other four can be hydrogen.
  • the pharmaceutically acceptable salt is not particularly limited as long as it is commonly used in the art, and specific examples thereof include inorganic acids or carboxylic acids such as hydrochloric acid, bromic acid, sulfonic acid, amido sulfuric acid, phosphoric acid, or nitric acid, or The salt may be formed using an organic acid such as sulfonic acid, but is not limited thereto.
  • carboxylic acid may include acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, succinic acid, propionic acid, glycolic acid, stearic acid and lactic acid, and the like.
  • Ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid and naphthalenedisulfonic acid may be included, but the kind of the carboxylic acid and sulfonic acid is not limited to the above compounds.
  • Benzyloxybenzylamiminyl amino acid derivatives represented by [Formula 1] effectively work to inhibit or kill the growth of fungi. Therefore, the composition comprising the benzyloxybenzyl aminyl amino acid derivative represented by the above [Formula 1] as an active ingredient can be usefully used as a pharmaceutical composition for preventing or treating mycosis. In addition, it can be prepared and used as a pharmaceutical composition for co-administration with existing drugs.
  • the fungus is not limited so long as it is a disease caused by fungi.
  • the fungus is, for example, Candida, Sfortricum, Malassezia, Cryptococcus, Aspergillus, Alveolar, and Mucolis but not limited thereto.
  • the fungal disease may be a disease caused by the genus Candida, Sfortricum, Malassezia, Cryptococcus, Aspergillus, Alveolar fungus or Mucolis.
  • Examples include meningitis, cutaneous candidiasis, mucosal candidiasis, visceral candidiasis, urinary candidiasis, candida endocarditis, oropharyngeal candidiasis, candidiasis endophthalmitis, candidiasis sepsis, ringworm, striae, fungal abscess, fungal granulomas , Purulent granulomas, madura fungus, alveolar pneumonia, systemic Cryptococcus, skin mucosa, Cryptococcosis, Aspergillosis, sinus, hemoptysis, allergy, true pulmonary tuberculosis, pulmonary fibrosis, alveolar cyst, chronic fever, cough, Sputum, phlegm and
  • Benzyloxybenzylamiminyl amino acid derivatives according to the present invention can be prepared by a method comprising the following steps.
  • R 1 is hydrogen or C 1- 7 alkyl
  • R 2 is a C 1- 7 alkyl.
  • an amine group of an amino acid selected from the following [Formula 5] to [Formula 7] is protected with an amine protecting group.
  • the amine protecting group can be used as long as it is commonly used for amine protection.
  • the amino acid protected by the amine group is reacted with the benzylamine derivative to prepare a benzyloxybenzyl aminylamino acid derivative in which the amine group of the amino acid is protected by a protecting group.
  • the reaction can be made in one step or two steps. When the reaction is one step, the amino acid protected amine group may be reacted with a benzyloxybenzylamine derivative. When the reaction is two steps, the amino acid protected amine group is reacted with 4-hydroxybenzylamine to amino acid. After preparing a 4-hydroxybenzyl aminyl amino acid derivative in which the amine group is protected with a protecting group, it may be reacted with the benzyl bromide derivative.
  • the amine protecting group can be removed using a conventional amine removal method, and treated with perchloric acid in the present invention.
  • Benzyloxybenzylamiminyl amino acid derivatives according to the present invention may have a primary, secondary or tertiary amine of an amino acid residue.
  • an alkylation reaction may be performed to introduce an alkyl group.
  • the benzyloxybenzyl aminyl amino acid derivative or a pharmaceutically acceptable salt thereof is mixed into a conventional carrier, adjuvant or diluent and formulated in a conventional formulation method to prepare a form suitable for oral or parenteral administration.
  • a conventional carrier, adjuvant or diluent is mixed into a conventional carrier, adjuvant or diluent and formulated in a conventional formulation method to prepare a form suitable for oral or parenteral administration.
  • the carrier, adjuvant or diluent may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, poly Vinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • conventional fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like may be further included, and lubricants such as magnesium styrate and talc may be further added.
  • oral administration it may be prepared in the form of tablets, capsules, solutions, syrups, suspensions, and the like.
  • parenteral administration it may be prepared in the form of injections for abdominal cavity, subcutaneous, muscle, or transdermal, or external preparations. Can be.
  • the pharmaceutical composition inhibits or kills the growth of fungi, and is effective in daily use of the benzyloxybenzylamiminyl amino acid derivative of Formula 1 or a pharmaceutically acceptable salt thereof in the pharmaceutical composition.
  • the dosage ranges from 0.01 to 1,000 mg / day in adults, but the dosage may vary depending on the patient's age, weight, sex, dosage form, health condition and degree of disease. It may be administered in divided doses once or several times a day.
  • Benzyloxybenzylamiminyl amino acid derivatives according to the present invention exhibit excellent drug resistance in ADME / Tox test evaluation and have excellent antifungal activity, and have been found in conventional antifungal agents such as hepatotoxicity, nephrotoxicity, neurotoxicity, rash, edema and myelosuppression. Since there are no side effects or can be greatly alleviated, it can be usefully applied as a treatment for new fungal infections.
  • Candida albicans ( Candida ) of the compounds of the present invention albicans SC5314, ATCC), Candida Gras Braga other (Candida glabrata BG2, ATCC), Cryptococcus neoformans var.grubii H99 , ATCC and inhibitory activity against Aspergillus fumigatus strains compared to amphotericin B (AmpB) and fluconazole (FCZ) .
  • KDS1087 represents Compound 22
  • KDS1090 represents Compound 26
  • KDS1092 represents Compound 29.
  • KDS1087, KDS1090, KDS1092, AmpB, and FCZ are indicated from the left side of the bar graph.
  • FIG. 2 compares Compound 22 (1087), Compound 26 (1090) and Compound 28 (1092) MIC test results of the present invention against various species of Aspergillus pumigatus strains with amphotericin B (AMB). (Mean value). The compound of the present invention showed higher inhibitory activity than amphotericin B.
  • KDS1087, KDS1090, KDS1092, and AmpB are indicated from the left side of the bar graph.
  • FIG. 3 shows the mean values of Compound 22 (1087), Compound 26 (1090) and Compound 28 (1092) MIC test results of the various Candida albican strains. From the left side of the bar graph in the figure are KDS1087, KDS1090 and KDS1092.
  • Figure 4 shows the results of applying a compound of the present invention (compound 26) against phytopathogenic fungi, very good inhibitory activity.
  • FIG. 5 compares the inhibitory activity of various compounds of the present invention against pathogenic fungi with propiconazole, defenoconazole and fludioxonil.
  • reaction scheme for preparing the compound of the present invention is as follows. Numerals not used with the alphabetic alphabet in the following schemes represent the compound numbers prepared in the present invention. That is, 1 represents compound 1:
  • a benzyloxybenzyl aminyl amino acid derivative whose amino acid is a primary amine structure was alkylated to give a secondary amine structure.
  • the compound of Synthesis Example 4 1.0 equiv
  • iodomethane (10 equiv) were dissolved in tetrahydrofuran and slowly added dropwise sodium hydride (10 equiv) at 0 ° C. for 24 hours at room temperature. Reacted. After the reaction was completed, the reaction mixture was extracted with methylene chloride, dried with a desiccant (sodium sulfate), and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography.
  • the purified compound was dissolved in methylene chloride and then stirred with 6.0-10.0 equivalents of 4.0M hydrochloric acid. After completion of the reaction, the mixture was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to obtain a benzyloxybenzyl aminyl amino acid derivative including a secondary amine structure.
  • a benzyloxybenzyl aminyl amino acid derivative whose amino acid is a primary amine structure was alkylated to form a tertiary amine structure.
  • the compound of Synthesis Example 4 (1.0 equivalent) was dissolved in methanol, and then formaldehyde (37% by weight solution) and 10% palladium catalyst were added sequentially, and reacted at room temperature for 18 hours. After the reaction, the catalyst was removed by filtration through celite, and the filtrate was evaporated under reduced pressure. The reaction mixture was recrystallized from methanol / diethyl ether to give the desired compound.
  • the purified product was dissolved in a dimethyl chloride solvent, added 4.0M hydrochloric acid (6.0-10.0 equiv) and stirred at room temperature, and then concentrated in vacuo. The obtained residue was separated and purified via chromatography using silica gel.
  • Test Example 1 antifungal activity assay ( MIC analysis)
  • MIC human pathogenic fungi in vitro Antimicrobial activity
  • Antifungal activity assay was performed by inoculating 5 ⁇ 10 2 to 2.5 ⁇ 10 cell / mL inoculated bacterial solution to a 2-fold dilution series of the sample solution to be tested according to the National Committee for Clinical Laboratory Standard (NCCLS) method of the US.
  • NCLS National Committee for Clinical Laboratory Standard
  • Candida was cultured for 48 hours and Cryptococcus neoformans strains were incubated for 72 hours, and then examined by visual observation.
  • amphotericin B amphotericin B
  • fluconazole which are known to have excellent antifungal inhibitory activity with human toxicity
  • RPMI-1640 powder (Sigma; R1383-1L) was first added to 900 ml distilled water to prepare the medium. Next, 34.5 g of MOPS was added to the final concentration of 0.165 M, and then 100 ml of 20% glucose was added thereto, and then adjusted to pH 7 using NaOH. Next, the filter was stored in refrigerated conditions at 4 degrees Celsius and then used for the next experiment.
  • FIG. 2 shows Compound 22 (1087), Compound 26 (1090) and Compound 28 (1092) MIC of the present invention for several species of Aspergillus pumigatus (KCCM32791, KCCM60031, KCCM60293, KCCM60036, KCCM60031, and KCCM60027).
  • the test results are shown in comparison with amphotericin B (AMB) (indicated average value).
  • AMB amphotericin B
  • the compound of the present invention showed higher inhibitory activity than amphotericin B.
  • FIG. 3 shows Compound 22 (1087), Compound 26 (1090), and Compound 28 (1092) of the present invention against several species of Candida albicans (KCCM11282, KCCM11474, KCCM12552, KCCM12554, KCCM50235, KCCM50539, KCCM50582, KCCM50573, KCCM12556).
  • the average value of the MIC test results is shown.
  • the compound of the present invention in application to Cryptococcus neoformus, Candida glabrata, Candida albican and the like, has a synergistic effect when used in combination with commercially available itraconazole and voriconazole as an antifungal agent. It was confirmed (results not shown). This suggests the possibility of co-administration with drugs that are particularly resistant to azole drugs.
  • Test Example 2 plant pathogenic fungi and Inhibitory activity against ringworm
  • Trichophyton tonsurans (KCCM60442), Trichophyton tonsurans (KCCM11866), Trichophyton rubrum (KCCM60450), Trichophyton mentagrophytes (KCCM11950), Trichophyton mentagrophytes (KCCM60449), and Trichophyton mentagrophytes (KCCM60444)
  • the strain is cultured in a YPD solid medium, the compound (Compound 26) of the present invention is added, and the inhibitory activity is observed.
  • the compounds of the present invention showed excellent inhibitory activity against these ringworm and athlete's foot fungi.
  • Test Example 3 Honey Bee Moth ( Galleria mellonella ) Insect Model vivo Drug efficacy evaluation using
  • Cryptococcus a pathogenic fungus Wild-type (H99S) strain of neoformans was inoculated in YPD (yeast extract, peptone and dextrose) liquid medium, and cultured for 16 hours, and washed twice in PBS (phosphate buffered saline) to prepare a final sample of 10 6 cells / ml.
  • YPD yeast extract, peptone and dextrose
  • PBS phosphate buffered saline
  • neoformans prepared for walking larvae Inject 4 ⁇ l of the suspension to infect 4000 cells of pathogen per larvae using a Hamilton autoinjector (PB600-1), a 100 ⁇ l syringe and a needle. Three hours after the pathogen infection, each drug (compound 18 of the invention) dilutions were injected in the same manner, followed by an additional two injections once every 24 hours. After the infection with C. neoformans, the group injected with PBS alone instead of the drug was tested as a positive control group, and the group with both PBS and infection and drug injection were tested as a negative control group. After infection and drug injection, the larvae were observed every day in an environment capable of maintaining sufficient humidity in a 37 ° C. incubator, and the survival level was recorded. The plot of survival was created using the Prism 6 program from GraphPad. The significance level with the control group was determined by using Long-rank (Mantel-Cox) method.
  • the larvae group fed with PBS after fungal infection dropped to 60% on the third day of infection, and all died on the seventh day of infection, but the larvae fed with the drug according to the present invention All survived on day 3 of infection and showed 50% survival on day 7 of infection. Therefore, the compound according to the present invention showed an antifungal effect in an animal model, and it was confirmed that the toxicity was very low.
  • the novel compound of the present invention may be usefully used for the development of antifungal agents.
  • it has a wide range of fungicidal activity, as well as the prevention and treatment of human infectious fungi. It can be used to develop antifungal or fungicidal preparations for the prevention and killing of animal infectious fungal diseases and phytopathogenic fungi.
  • it since it shows a synergistic effect when used with conventional antifungal formulations, it may be used in the development of co-administered formulations.

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BR112019008577-7A BR112019008577B1 (pt) 2016-10-28 2017-10-30 Compostos derivativos funcionais de aminoácidos prolina e alanina e composição farmacêutica compreendendo os mesmos
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US16/346,028 US20200199065A1 (en) 2016-10-28 2017-10-30 Functional derivative compounds of alanine and proline amino acids and pharmaceutical composition comprising same
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JP2019545217A JP7061317B2 (ja) 2016-10-28 2017-10-30 アラニンおよびプロリンアミノ酸の機能的誘導体化合物およびそれを含む薬学的組成物
US18/918,365 US20250034082A1 (en) 2016-10-28 2024-10-17 Functional derivative compounds of alanine and proline amino acids and pharmaceutical composition comprising same
US18/918,533 US20250034085A1 (en) 2016-10-28 2024-10-17 Composition and methods for preventing or treating phytopathogenic fungal infection
US18/918,511 US20250034084A1 (en) 2016-10-28 2024-10-17 Compositions and methods for preventing or treating mycosis
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US18/918,533 Division US20250034085A1 (en) 2016-10-28 2024-10-17 Composition and methods for preventing or treating phytopathogenic fungal infection
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110195999A1 (en) * 2003-09-30 2011-08-11 Kazutaka Nakamoto Novel antifungal agent containing heterocyclic compound
KR20130129203A (ko) * 2010-10-21 2013-11-27 바이엘 인텔렉쳐 프로퍼티 게엠베하 Ｎ-벤질 헤테로시클릭 카르복사미드
US20150284375A1 (en) * 2012-12-18 2015-10-08 Ajinomoto Co., Inc. Heterocyclic amide derivative and medicine containing same

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998006265A2 (en) * 1996-08-09 1998-02-19 Buckman Laboratories International, Inc. Treatment of fungal infections using a combination of an anti-fungal compound and an n-alkyl-heterocyclic compound, especially n-dodecyl-morpholine
GB0009055D0 (en) * 2000-04-13 2000-05-31 Novartis Ag Organic compounds
JP6413200B2 (ja) * 2013-10-25 2018-10-31 日本曹達株式会社 アミノピリジン誘導体および農園芸用殺菌剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110195999A1 (en) * 2003-09-30 2011-08-11 Kazutaka Nakamoto Novel antifungal agent containing heterocyclic compound
KR20130129203A (ko) * 2010-10-21 2013-11-27 바이엘 인텔렉쳐 프로퍼티 게엠베하 Ｎ-벤질 헤테로시클릭 카르복사미드
US20150284375A1 (en) * 2012-12-18 2015-10-08 Ajinomoto Co., Inc. Heterocyclic amide derivative and medicine containing same

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
BECK-SAGUE, C. M. ET AL., J. INFECT. DIS., vol. 167, 1993, pages 1247 - 1251
DATABASE CHEMICAL ABSTRACT 25 March 2014 (2014-03-25), Database accession no. 1573090-62-6 *
DATABASE Chemical Abstract 25 March 2014 (2014-03-25), retrieved from STN Database accession no. 1607122-04-2 *
DATABASE CHEMICAL ABSTRACT Database accession no. 1573521-13-7 *
DATABASE CHEMICAL ABSTRACT Database accession no. 1580733-69-2 *
DATABASE CHEMICAL ABSTRACT Database accession no. 1580938-24-4 *
DATABASE CHEMICAL ABSTRACT Database accession no. 1606837-63-1 *
DATABASE CHEMICAL ABSTRACT Database accession no. 1607121-83-4 *
DIAMOND, R. D., REV. INFECT. DIS., vol. 13, 1991, pages 480 - 486
KING, A. M. ET AL.: "Primary Amino Acid Derivatives: Substitution of the 4'-N'-betizylamide Site in (R)-N'-benzyl 2-ammo-3-methylbutanamide, (R)-N'-benzyl 2-amino-3,3-dimethylbutanamide, and (R)-N'-benzyl 2-amino-3-methoxypropionamide Provides Potent Anticonvulsants with Pain-attenuating Properties", JOURNAL OF MEDICINAL CHEMISTRY, vol. 54, no. 19, 2011, pages 6417 - 6431, XP055593795 *
LIU, K. K.-C. ET AL.: "Orally Active and Brain Permeable Proline Amides as Highly Selective 5HT2c Agonists for the Treatment of Obesity", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 20, no. 7, 2010, pages 2365 - 2369, XP026971079 *
PISA, D. ET AL., SCIENTIFIC REPORTS, vol. 5, pages 15015
STRENBERG, S., SCIENCE, vol. 266, 1994, pages 1632 - 1634

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