WO2023229099A1 - Dérivé d'oxime de benzofuranyle hydroxyphénylméthanone et ses utilisations - Google Patents
Dérivé d'oxime de benzofuranyle hydroxyphénylméthanone et ses utilisations Download PDFInfo
- Publication number
- WO2023229099A1 WO2023229099A1 PCT/KR2022/010099 KR2022010099W WO2023229099A1 WO 2023229099 A1 WO2023229099 A1 WO 2023229099A1 KR 2022010099 W KR2022010099 W KR 2022010099W WO 2023229099 A1 WO2023229099 A1 WO 2023229099A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydroxyphenyl
- dibromo
- methanone oxime
- methyl
- ethylbenzofuran
- Prior art date
Links
- -1 Benzofuranyl hydroxyphenyl methanone oxime derivative Chemical class 0.000 title claims abstract description 163
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- 125000000217 alkyl group Chemical group 0.000 claims description 15
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- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to benzofuranyl hydroxyphenyl methanone oxime derivatives, and more particularly to benzofuranyl hydroxyphenyl methanone oxime derivatives and their use in inhibiting HSP47.
- HSP47 Heat shock protein 47 protein is a protein present in the endoplasmic reticulum induced by stress and acts as a chaperon protein for the formation of the three-dimensional structure of collagen and extracellular secretion.
- HSP47 has been reported to have increased expression in fibrosis of various tissues, such as liver cirrhosis, pulmonary fibrosis, keloid, hypertrophic scar, and glomerulosclerosis. According to the literature, it has been reported that inhibiting the HSP47 protein inhibits collagen secretion in cells that produce collagen. In addition, it has been reported that inhibition of HSP47 protein induces apoptosis of cells producing collagen (Ito S et. al ., 2017). These results show that inhibition of HSP47 protein is an effective and specific therapeutic target for fibrosis inhibition treatment.
- Fibrosis or fibrosis refers to the abnormal accumulation of collagen following damage or inflammation that changes the structure and function of various tissues. Regardless of where fibrosis occurs, most etiologies of fibrosis involve excessive accumulation of collagen that replaces normal tissue. Progressive fibrosis in the liver, lung, or skin is a disease with high unmet medical need for which there is no specific treatment to date.
- HSP47 has also been reported to be expressed in cancer cells, and it has been reported that increased expression of HSP47 facilitates the metastasis of many cancer cells and increases mortality. It has also been reported that cancer progression is suppressed when HSP47 expression is suppressed through genetic methods (Parveen A et. al., 2020).
- the problem to be solved by the present invention is to recognize that there is a close relationship between HSP47 and excessive accumulation of collagen, and to provide an HSP47 inhibitory substance that has therapeutic efficacy against diseases such as fibrosis and cancer by inhibiting the HSP47 protein.
- the problem of the present invention is to provide a pharmaceutical composition for preventing or treating HSP47-related diseases containing the benzofuranyl hydroxyphenyl methanone oxime derivative compound as an active ingredient.
- the problem of the present invention is to provide a method for preventing or treating HSP47-related diseases using the benzofuranyl hydroxyphenyl methanone oxime derivative compound.
- the problem of the present invention is to provide a use of the benzofuranyl hydroxyphenyl methanone oxime derivative compound for the prevention or treatment of HSP47-related diseases.
- the problem of the present invention is to provide a method for producing the benzofuranyl hydroxyphenyl methanone oxime derivative compound.
- a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is provided. .
- R 1 is hydrogen, C 1 -C 6 straight or branched chain alkyl, or halogen
- R 2 is hydrogen, C 1 -C 6 straight or branched chain alkyl, halogen, or SO 2 NR a R b ,
- R a and R b are independently hydrogen, C 1 -C 6 straight or branched chain alkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl substitution. is C 1 -C 3 alkyl, or
- R a and R b are linked to each other to form a 4- to 7-membered heterocycloalkyl containing 0 to 2 heteroatoms with N connected to SO 2 , wherein C forming the heterocycloalkyl is O. Substituted or not substituted,
- R 3 is hydrogen or halogen
- R 4 and R 5 are independently halogen
- R 6 is hydrogen or C 1 -C 6 straight or branched chain alkyl.
- a treatment for HSP47-related diseases comprising a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
- Pharmaceutical compositions for prophylaxis or treatment are provided.
- the use of the benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the above formula (I), its hydrate, its solvate or its pharmaceutically acceptable salt for the prevention or treatment of HSP47-related diseases provided.
- a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive is provided.
- novel benzofuranyl hydroxyphenyl methanone oxime derivative compound of the present invention was confirmed to exhibit excellent activity as an HSP47 inhibitor by effectively inhibiting HSP47 protein, a specific therapeutic target for fibrosis inhibition treatment, lung epithelial cells, and hepatic stellate cells. , it was confirmed to have excellent efficacy in suppressing collagen production in skin cells, and it was found that it can be used for the prevention or treatment of HSP47-related diseases.
- novel benzofuranyl hydroxyphenyl methanone oxime derivative compound of the present invention can be usefully used in the prevention or treatment of HSP47-related diseases in the medical and pharmaceutical fields.
- the present invention provides a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
- R 1 is hydrogen, C 1 -C 6 straight or branched chain alkyl, or halogen
- R 2 is hydrogen, C 1 -C 6 straight or branched chain alkyl, halogen, or SO 2 NR a R b ,
- R a and R b are independently hydrogen, C 1 -C 6 straight or branched chain alkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl substitution. is C 1 -C 3 alkyl, or
- R a and R b are linked to each other to form a 4- to 7-membered heterocycloalkyl containing 0 to 2 heteroatoms with N connected to SO 2 , wherein C forming the heterocycloalkyl is O. Substituted or not substituted,
- R 3 is hydrogen or halogen
- R 4 and R 5 are independently halogen
- R 6 is hydrogen or C 1 -C 6 straight or branched chain alkyl.
- R 1 may be hydrogen, methyl, or Cl.
- R 2 is hydrogen, methyl, Cl, or SO 2 NR a R b , where R a and R b are independently hydrogen, methyl, ethyl, propyl, hydroxyethyl, cyclopropyl, or It may be cyclopropylmethyl, or R a and R b may include N linked to SO 2 to form azetidinyl, pyrrolidinyl, morpholino, or piperazinone.
- R 3 may be hydrogen, Cl, or Br.
- R 4 and R 5 may independently be Br or I.
- R 6 may be hydrogen or methyl.
- benzofuranyl hydroxyphenyl methanone oxime derivative compounds according to the present invention are as follows:
- alkyl refers to a straight or branched chain saturated hydrocarbon, preferably C 1 -C 10 alkyl.
- the alkyl is methyl, ethyl, n -propyl, iso -propyl, n -butyl, iso -butyl, tert -butyl, n -pentyl, iso -pentyl, n -hexyl, 3-methylhexyl, 2, It includes, but is not limited to, 2-dimethylpentyl, 2,3-dimethylpentyl, n -heptyl, n -octyl, n -nonyl, and n -decyl.
- halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
- heteroatom means N, O or S.
- heterocycloalkyl refers to a non-aromatic carbocyclic ring containing one or more heteroatoms such as nitrogen, oxygen or sulfur within the cycloalkyl.
- the compound represented by Formula I according to the present invention can be prepared and used in the form of a prodrug, hydrate, solvate, and pharmaceutically acceptable salt to enhance in vivo absorption or increase solubility, so the above prodrug, Hydrates, solvates and pharmaceutically acceptable salts are also within the scope of the present invention.
- prodrug refers to a substance that is transformed in vivo into the parent drug. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be bioactive by oral administration, whereas the parent drug may not be. A prodrug may also have improved solubility in a pharmaceutical composition than the parent drug. For example, prodrugs may be in vivo hydrolyzable esters of compounds according to the invention and pharmaceutically acceptable salts thereof. Another example of a prodrug may be a short peptide (polyamino acid) in which the peptide is linked to an acid group that is metabolically converted to reveal the active site.
- polyamino acid polyamino acid
- hydrate refers to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or its salt.
- solvate refers to a compound of the invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.
- Preferred solvents therefor are solvents that are volatile, non-toxic, and/or suitable for administration to humans.
- isomers refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is structurally or sterically different.
- isomers include both structural isomers such as tautomers, and stereoisomers such as R or S isomers and geometric isomers (trans, cis) having an asymmetric carbon center. All these isomers and mixtures thereof are also included within the scope of the present invention.
- pharmaceutically acceptable salt refers to a salt form of a compound that does not cause significant irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound.
- the pharmaceutical salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, etc.
- Organic carboxylic acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicic acid, etc., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Acid addition salts formed by sulfonic acids and the like are included.
- carboxylic acid salts include metal or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N- Organic salts such as methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine are included.
- the compound of formula I according to the present invention can also be converted into its salt by conventional methods.
- the present invention provides a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the following formula (I), comprising the step of reacting the ketone compound of the formula (I-1) with hydroxylamine (H 2 NO-R 6 ) hydrochloride.
- a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the following formula (I) comprising the step of reacting the ketone compound of the formula (I-1) with hydroxylamine (H 2 NO-R 6 ) hydrochloride.
- R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are the same as those of Chemical Formula I above.
- This step is a step of condensing the ketone compound of Formula I-1 with hydroxylamine (H 2 NO-R 6 ) hydrochloride to convert the ketone group contained in the ketone compound of Formula I-1 into an oxime group (Synthetic Method A )am.
- the solvent used at this time may be an organic solvent used in the ketone-oxime condensation reaction, for example, ethanol may be used, but is not limited thereto.
- ketone compound of Formula I-1 the compound in which R 2 is SO 2 NR a R b is an amine compound (HNR a R b ) containing the desired substituent, a compound containing a -SO 2 Cl group (Compound A), and By reacting, ketone compound B containing the desired substituent (when R 2 is SO 2 NR a R b in Chemical Formula I-1) can be obtained. Afterwards, the oxime derivative of Formula I can be obtained by condensation of ketone compound B with hydroxylamine (H 2 NO-R 6 ) hydrochloride.
- Schemes 1 to 24 of the Examples are exemplified as methods for preparing the compound of Formula I of the present invention, and the preparation methods of Schemes 1 to 24 do not limit the method of preparing the compound of Formula I according to the present invention. It is obvious that the preparation methods of Schemes 1 to 24 are merely examples and can be easily modified by those skilled in the art depending on the specific substituent.
- the present invention also provides a method for preventing or treating HSP47-related diseases, comprising as an active ingredient a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
- a pharmaceutical composition for use comprising as an active ingredient a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
- the present invention also provides a method of administering a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a patient in need thereof, Provides a method of treating or preventing HSP47-related diseases.
- the present invention also provides the use of the benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the above formula (I), its hydrate, its solvate, or its pharmaceutically acceptable salt for the prevention or treatment of HSP47-related diseases.
- the HSP47-related disease may be fibrosis or cancer.
- the fibrosis may be one or more selected from the group consisting of cirrhosis, pulmonary fibrosis, keloid, hypertrophic scar, and renal fibrosis (glomerulosclerosis), and the cancer may include breast cancer, colon cancer, and cancer-related cancer. It may be one or more selected from the group consisting of fibrosis.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a benzofuranyl hydroxyphenyl methanone oxime derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
- the additive may include a pharmaceutically acceptable carrier or diluent, and can be used in oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, topical preparations, suppositories, and sterilization products according to conventional methods. It can be formulated in the form of an injectable solution.
- a pharmaceutically acceptable carrier or diluent such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, topical preparations, suppositories, and sterilization products according to conventional methods. It can be formulated in the form of an injectable solution.
- the pharmaceutically acceptable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, and microcrystalline. Contains cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It also includes diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
- Oral solid preparations include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, such as starch, calcium carbonate, sucrose, or lactose. ), gelatin, etc., and may include lubricants such as magnesium stearate and talc.
- Oral liquid preparations include suspensions, oral solutions, emulsions, syrups, etc., and may include diluents such as water and liquid paraffin, humectants, sweeteners, fragrances, and preservatives.
- Parenteral preparations include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, creams, freeze-dried preparations, and suppositories.
- Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, and vegetable oils such as olive oil. Includes injectable esters such as oil and ethyl oleate.
- injectable esters such as oil and ethyl oleate.
- As a base for suppositories witepsol, macrogol, tween 61, cacao, laurel, glycerogelatin, etc. can be used.
- the dosage of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, degree of disease, form of the active ingredient, route and period of administration, and can be appropriately adjusted depending on the patient.
- the active ingredient can be administered at a dose of 0.0001 to 1000 mg/kg per day, preferably 0.01 to 100 mg/kg, and the administration may be administered once a day or in divided doses.
- the pharmaceutical composition of the present invention may contain the active ingredient at a weight percentage of 0.001 to 90% based on the total weight of the composition.
- the pharmaceutical composition of the present invention is administered to mammals such as rats, mice, livestock, and humans by various routes, for example, orally, through the skin, abdominal cavity, rectum, or intravenously, into muscle, subcutaneously, intrauterine dura, or intracerebroventricularly. It can be administered by injection.
- Example 1 O-methyl hydroxylamine hydrochloride was used instead of hydroxylamine hydrochloride, and the target compound was obtained by treatment according to the synthesis method (Method A).
- Step 1) (Synthesis Method B [Method B])
- Compound B was treated using method A to obtain the target compound C.
- Compound 11-1 was treated using Synthesis Method A ( Method A ) to obtain the target compound.
- Compound 12-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.
- Compound 13-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.
- Compound 14-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.
- Compound 15-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.
- Compound 16-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.
- Compound 17-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.
- Compound 18-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.
- Compound 19-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.
- Compound 20-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.
- Compound 21-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.
- Compound 22-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.
- Compound 23-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.
- Compound 24-1 was treated according to Synthesis Method A ( Method A ) to obtain the target compound.
- Fibrils were formed by adding 180 ul of PBS (phosphate-buffered saline, pH 7.4) solution to 20 ul of collagen solution (UK) dissolved in an acidic solution, and this was measured at a wavelength of 340 nm.
- HSP47 activity was evaluated as the degree to which fibril formation was inhibited by adding HSP47 protein (GenScript US) at a concentration of 9.45 ⁇ g/ml. Test substances were included at concentrations of 100 ⁇ M to 1 ⁇ M, and the degree of HSP47 inhibition was expressed as a percentage.
- lung epithelial cells A549 cells
- liver stellate LX-2 cells Elabscience, CH
- skin KEL FIB ATCC, US
- TGF-beta After treatment with 10 ng/ml, the cells were incubated with the test substance for 24 hours. The cells were washed with PBS, fixed with Bouin's solution, and washed twice using distillation. After staining the fixed cells with Sirius red for 2 hours, changes in cell shape were observed, washed with HCl 0.01 N solution, and Sirius red bound to collagen was extracted with NaOH 0.1 N solution. and then quantified at a wavelength of 570 nm. The collagen production inhibition efficacy of each test substance is expressed as a percentage in Table 1 below.
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Abstract
La présente invention concerne un nouveau composé dérivé d'oxime de benzofuranyle hydroxyphénylméthanone utilisé en tant qu'inhibiteur de HSP47, des hydrates, des solvates ou des sels pharmaceutiquement acceptables de celui-ci. Il a été confirmé que le composé dérivé d'oxime de benzofuranyle hydroxyphénylméthanone selon la présente invention a une excellente activité en tant qu'inhibiteur de HSP47 par inhibition efficace de la protéine HSP47, qui est une cible thérapeutique spécifique pour un traitement d'inhibition de la fibrose, et a une excellente efficacité dans l'inhibition de la production de collagène dans des cellules tissulaires respectives, et peut ainsi être utilisé pour la prévention ou le traitement de maladies associées à HSP47. En conséquence, le nouveau composé dérivé d'oxime de benzofuranyle hydroxyphénylméthanone selon la présente invention peut être utilisé de manière efficace pour la prévention ou le traitement de maladies associées à HSP47 dans les domaines médicaux et pharmaceutiques.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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KR1020220063202A KR20230163654A (ko) | 2022-05-24 | 2022-05-24 | 벤조퓨라닐 히드록시페닐 메타논 옥심 유도체 및 이의 용도 |
KR10-2022-0063202 | 2022-05-24 |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2000018737A1 (fr) * | 1998-09-29 | 2000-04-06 | Shionogi & Co., Ltd. | Derives heterocycliques possedant une activite acaricide |
KR20050059343A (ko) * | 2001-04-19 | 2005-06-17 | 에-자이가부시기가이샤 | 2-이미노피롤리딘 유도체 |
WO2006084338A1 (fr) * | 2005-02-14 | 2006-08-17 | Bionomics Limited | Nouveaux inhibiteurs de polymérisation de la tubuline |
WO2018053587A1 (fr) * | 2016-09-21 | 2018-03-29 | Vectus Biosystems Limited | Compositions pour le traitement de l'hypertension et/ou de la fibrose |
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EP0388682A1 (fr) | 1989-03-15 | 1990-09-26 | Bayer Ag | Hétéroarylphényléthers substitués, procédés pour leur préparation et leur utilisation comme insecticides |
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2022
- 2022-05-24 KR KR1020220063202A patent/KR20230163654A/ko unknown
- 2022-07-12 WO PCT/KR2022/010099 patent/WO2023229099A1/fr unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2000018737A1 (fr) * | 1998-09-29 | 2000-04-06 | Shionogi & Co., Ltd. | Derives heterocycliques possedant une activite acaricide |
KR20050059343A (ko) * | 2001-04-19 | 2005-06-17 | 에-자이가부시기가이샤 | 2-이미노피롤리딘 유도체 |
WO2006084338A1 (fr) * | 2005-02-14 | 2006-08-17 | Bionomics Limited | Nouveaux inhibiteurs de polymérisation de la tubuline |
WO2018053587A1 (fr) * | 2016-09-21 | 2018-03-29 | Vectus Biosystems Limited | Compositions pour le traitement de l'hypertension et/ou de la fibrose |
Non-Patent Citations (2)
Title |
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CARAMELLA P, CELLERINO G, HOUK K N, ALBINI F MARINONE, SANTIAGO CIELO: "Selectivity in cycloadditions. 6. Cycloadditions of nitrile oxides to benzofuran", REGIOCHEMISTRY. J. ORG. CHEM., vol. 43, no. 15, 1 July 1978 (1978-07-01), pages 3006 - 3010, XP093112932 * |
ZHAO MINGMING, HE WEI, ZOU LIANG-HUA, WANG DAWEI, SUN TIAN-YU, XIA XIAO-FENG: "Iron-catalyzed hydrogen atom transfer induced cyclization of 1,6-enynes for the synthesis of ketoximes: a combined experimental and computational study", ORGANIC CHEMISTRY FRONTIERS, vol. 8, no. 3, 9 February 2021 (2021-02-09), pages 643 - 652, XP093112931, ISSN: 2052-4129, DOI: 10.1039/D0QO01341B * |
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