WO2023229295A1 - Composition pharmaceutique pour la prévention ou le traitement du cancer comprenant un dérivé de phénylpropène en tant que principe actif - Google Patents

Composition pharmaceutique pour la prévention ou le traitement du cancer comprenant un dérivé de phénylpropène en tant que principe actif Download PDF

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WO2023229295A1
WO2023229295A1 PCT/KR2023/006799 KR2023006799W WO2023229295A1 WO 2023229295 A1 WO2023229295 A1 WO 2023229295A1 KR 2023006799 W KR2023006799 W KR 2023006799W WO 2023229295 A1 WO2023229295 A1 WO 2023229295A1
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Prior art keywords
prop
amino
ethyl
biphenyl
phenyl
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PCT/KR2023/006799
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English (en)
Korean (ko)
Inventor
임춘영
민상현
김남희
황희종
오배준
홍은미
우서연
한예리
도현주
장태호
이슬
김남두
이지영
유지훈
이하연
김영규
박상욱
신선혜
차은주
황지선
서창훈
염영일
이동철
박경찬
김차연
구한
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재단법인 대구경북첨단의료산업진흥재단
한국생명공학연구원
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Publication of WO2023229295A1 publication Critical patent/WO2023229295A1/fr

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    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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Definitions

  • the present invention relates to a phenylpropine derivative and a pharmaceutical composition for the prevention or treatment of cancer containing the same as an active ingredient.
  • Liver cancer ranks 6th in incidence in Korea and 2nd in mortality among all cancers. It is a cancer with a high incidence and mortality rate and rapid metastasis to the lungs and bones. In addition, 70% of liver cancer surgery patients have a high recurrence rate, with recurrence within 5 years, and the treatment prognosis for relapsed liver cancer is also poor. For this reason, there is a need for the development of drugs that can effectively induce death and inhibition of proliferation of liver cancer cells.
  • lipids In addition to serving as energy storage, lipids also serve as building blocks for newly synthesized membranes. It has been proven through many recent studies that specific mutations occur in the lipid metabolism of cancer cells, and it has been reported that changes in the expression and activity of lipid metabolism enzymes occur due to the activation of oncogenic signals. This fact suggests that proteins involved in lipid metabolism can be used as excellent chemotherapy targets for cancer treatment.
  • Acetyl-CoA carboxylase is the rate-limiting enzyme in fatty acid synthesis.
  • Acetyl-CoA Carboxylase ACC
  • ACC Acetyl-CoA Carboxylase
  • beta-energy metabolism is regulated by promoting oxidation ( ⁇ -oxidation). This regulation of energy metabolism affects the proliferation and metastasis of cancer cells (WANG, Chao, et al. Expert Review of Anticancer Therapy, 2015, 15.6: 667-676).
  • the present inventors confirmed that the phenylpropine derivative of the present specification has an inhibitory activity on Acetyl-CoA Carboxylase (ACC), a rate-limiting enzyme in fatty acid synthesis involved in inhibiting the proliferation of cancer cells in human liver cancer cell lines, and proposed the present invention. Completed.
  • ACC Acetyl-CoA Carboxylase
  • the object of the present invention is to provide phenylpropine derivatives.
  • Another object of the present invention is to provide a novel pharmaceutical composition for preventing or treating cancer.
  • Another object of the present invention is to provide a novel health functional food composition for preventing or improving cancer.
  • the present invention provides a compound represented by the following formula (1), a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
  • n 1 or 2;
  • A is unsubstituted or substituted C6 aryl or 6-membered heteroaryl
  • the substituted C6 aryl or 6-membered heteroaryl is at least one selected from the group consisting of halogen, hydroxy, 6-membered heterocycloalkyl, C1-C10 alkylsulfonyl, C1-C10 alkyloxycarbonyl, carboxy, and sulfonamide. is substituted, or is substituted on two adjacent atoms to form an unsubstituted heterocycle of 5-6 atoms;
  • L is -CHR 1 -, -CHCH 2 - or -CH 2 CH 2 -,
  • R 1 is hydrogen or C1-C10 alkyl
  • B is -NR 2 X, -NX 2 or -OX
  • R 2 is hydrogen or C1-C10 alkyl
  • R 4 is unsubstituted or substituted C1-C10 alkyl, C1-C10 alkoxy, 6-membered heterocycloalkyl, C6-aryl or 6-membered heteroaryl,
  • the substituted C1-C10 alkyl, C1-C10 alkoxy, 6-membered heterocycloalkyl, C6 aryl or 6-membered heteroaryl is unsubstituted or substituted C1-C10 alkyl with one or more selected from the group consisting of hydroxy and C6 aryl. , C1-C10 alkyl carbonyl, unsubstituted or substituted with one or more halogens, halogen, hydroxy, Boc (tert-butyloxycarbonyl), C1-C10 alkoxy unsubstituted or substituted with C1-C10 alkoxy, C6 aryloxy. and C6 arylcarbonyl.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of cancer containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.
  • the present invention provides a health functional food composition for preventing or improving cancer containing the compound represented by Formula 1, an optical isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. provides.
  • the compound represented by Formula 1 described herein is expected to be useful in the prevention or treatment of cancer by confirming the ACC inhibitory activity involved in tumor proliferation and metastasis inhibition mechanisms.
  • alkylene alkenyl or “alkyl” include straight or branched chain hydrocarbon moieties, unless otherwise specified.
  • C1-C5alkyl means alkyl with a skeleton of 1 to 5 carbons. Specifically, C1-C5 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, etc. may include.
  • cycloalkyl includes carbocyclic groups containing carbon atoms.
  • C3-C8 cycloalkyl means cycloalkyl with a skeleton of 3 to 8 carbons.
  • C3-C8 cycloalkyl may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • heterocycle includes fully saturated or partially unsaturated heterocycloalkyl and heteroaryl.
  • heterocycloalkyl includes monovalent saturated moieties consisting of 1 to 3 rings containing 1, 2, 3 or 4 heteroatoms selected from N, O or S. Two or three rings may contain bridged, fused or spiro heterocycloalkyls.
  • heteroaryl refers to an aromatic ring having one or more aromatic rings containing 1, 2 or 3 ring heteroatoms selected from N, O or S or an aromatic ring of 2 or 3 fused rings. May contain radicals.
  • a compound represented by the following formula (1) a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
  • n 1 or 2;
  • A is unsubstituted or substituted C6 aryl or 6-membered heteroaryl
  • the substituted C6 aryl or 6-membered heteroaryl is at least one selected from the group consisting of halogen, hydroxy, 6-membered heterocycloalkyl, C1-C10 alkylsulfonyl, C1-C10 alkyloxycarbonyl, carboxy, and sulfonamide. is substituted, or is substituted on two adjacent atoms to form an unsubstituted heterocycle of 5-6 atoms;
  • L is -CHR 1 -, -CHCH 2 - or -CH 2 CH 2 -,
  • R 1 is hydrogen or C1-C10 alkyl
  • B is -NR 2 X, -NX 2 or -OX
  • R 2 is hydrogen or C1-C10 alkyl
  • R 4 is unsubstituted or substituted C1-C10 alkyl, C1-C10 alkoxy, 6-membered heterocycloalkyl, C6-aryl or 6-membered heteroaryl,
  • the substituted C1-C10 alkyl, C1-C10 alkoxy, 6-membered heterocycloalkyl, C6 aryl or 6-membered heteroaryl is unsubstituted or substituted C1-C10 alkyl with one or more selected from the group consisting of hydroxy and C6 aryl. , C1-C10 alkyl carbonyl, unsubstituted or substituted with one or more halogens, halogen, hydroxy, Boc (tert-butyloxycarbonyl), C1-C10 alkoxy unsubstituted or substituted with C1-C10 alkoxy, C6 aryloxy. and C6 arylcarbonyl.
  • n 1 or 2;
  • A is unsubstituted or substituted C6 aryl or 6-membered heteroaryl containing N
  • the substituted C6 aryl or 6-membered heteroaryl containing N is selected from the group consisting of halogen, hydroxy, 6-membered heterocycloalkyl, C1-C5 alkylsulfonyl, C1-C5 alkyloxycarbonyl, carboxy, and sulfonamide. is substituted with one or more atoms, or is substituted on two adjacent atoms to form a 5-atom unsubstituted heterocycle containing two O's;
  • L is -CHR 1 -, -CHCH 2 - or -CH 2 CH 2 -,
  • R 1 is hydrogen or C1-C5 alkyl
  • B is -NR 2 X, -NX 2 or -OX
  • R 2 is hydrogen or C1-C5 alkyl
  • R 4 is unsubstituted or substituted C1-C5alkyl, C1-C5alkoxy, 6-membered heterocycloalkyl, C6aryl or 6-membered heteroaryl,
  • the substituted C1-C5 alkyl, C1-C5 alkoxy, 6-membered heterocycloalkyl, C6 aryl or 6-membered heteroaryl is unsubstituted or substituted C1-C5 alkyl with one or more selected from the group consisting of hydroxy and C6 aryl. , C1-C5 alkylcarbonyl, unsubstituted or substituted with one or more halogens, halogen, hydroxy, Boc (tert-butyloxycarbonyl), C1-C5 alkoxy, unsubstituted or substituted with C1-C5 alkoxy, C6 aryloxy. and C6 arylcarbonyl, and a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment of the present invention is,
  • n 1 or 2;
  • A is unsubstituted or phenyl or pyridine
  • the substituted phenyl or pyridine is substituted with one or more selected from the group consisting of Cl, hydroxy, morpholine, methylsulfonyl, methyloxycarbonyl, carboxy and sulfonamide, or is substituted on two adjacent atoms to give 1 , forming 3-dioxole;
  • L is -CHR 1 -, -CHCH 2 - or -CH 2 CH 2 -,
  • R 1 is hydrogen or methyl
  • B is -NR 2 X, -NX 2 or -OX
  • R 2 is hydrogen or methyl
  • R 4 is unsubstituted or substituted methyl, methoxy, piperazine, morpholine, phenyl, pyridine or pyrimidine,
  • the substituted methyl, methoxy, piperazine, morpholine, phenyl, pyridine or pyrimidine is unsubstituted or substituted with one or more methyl selected from the group consisting of hydroxy and phenyl, unsubstituted or substituted with one or more F.
  • Boc tert-butyloxycarbonyl
  • methoxy, methoxy substituted with methoxy, phenyloxy and phenylcarbonyl A compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is provided.
  • One embodiment of the present invention is,
  • the compound represented by Formula 1 provides any one compound selected from the following compound group, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment of the present invention is,
  • a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • These cancers include lung cancer, non-small cell lung cancer (NSCL), bronchoalveolar cell lung cancer, ovarian cancer, colorectal cancer, melanoma, stomach cancer, gastrointestinal cancer, liver cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, and uterine cancer.
  • NCL non-small cell lung cancer
  • bronchoalveolar cell lung cancer ovarian cancer
  • colorectal cancer melanoma
  • stomach cancer gastrointestinal cancer
  • liver cancer gastrointestinal cancer
  • bone cancer pancreatic cancer
  • skin cancer head and neck cancer
  • skin or eye melanoma and uterine cancer.
  • rectal cancer colon cancer, breast cancer, uterine sarcoma, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, esophagus cancer, laryngeal cancer, small intestine cancer, thyroid cancer, parathyroid cancer, sarcoma of soft tissue, urethral cancer, penile cancer, prostate cancer It may be any one of cancer, multiple myeloma, chronic or acute leukemia, and preferably liver cancer.
  • One embodiment of the present invention is,
  • a pharmaceutical composition for preventing or treating diseases caused by ACC hyperactivation is provided.
  • the term "containing as an active ingredient” means containing in a dosage range that brings about the effect of preventing, improving, or treating cancer, and the dosage range may vary depending on the severity and formulation, and application. The number of times may vary depending on the age, weight, and constitution of the subject.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • the term "pharmaceutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment or improvement, and the effective dose level is determined by the type and severity of the individual, age, It can be determined based on factors including gender, drug activity, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. For example, effective amounts of 0.001 mg/kg to 100 mg/kg, 0.01 mg/kg to 10 mg/kg, or 0.1 mg/kg to 1 mg/kg are included.
  • the upper quantitative limit of the pharmaceutical composition of the present invention can be selected and implemented by a person skilled in the art within an appropriate range.
  • the pharmaceutical composition according to the present invention may contain an effective amount of the compound represented by Formula 1 alone or may include one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • the pharmaceutically acceptable carrier, excipient, or diluent refers to a substance that is physiologically acceptable and does not typically cause gastrointestinal upset, allergic reactions such as dizziness, or similar reactions when administered to humans.
  • the carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Examples include, but are not limited to, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be additionally included.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral dosage forms during clinical administration.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations contain one or more compounds and at least one excipient, such as starch, calcium carbonate, sucrose, or lactose ( It is prepared by mixing lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable esters such as ethyl oleate.
  • a pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration can be done by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. It depends on how you do it.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water along with a stabilizer or buffer to prepare a solution or suspension, which is administered in ampoule or vial unit dosage form.
  • a stabilizer or buffer to prepare a solution or suspension, which is administered in ampoule or vial unit dosage form.
  • the composition may be sterilized and/or contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and may be mixed, granulated, etc. using conventional methods. It can be formulated according to the coating or coating method.
  • prevention refers to the prevention of cancer symptoms in advance by suppressing or blocking the symptoms of cancer by administering, ingesting, or applying the pharmaceutical composition or health functional food of the present invention to an individual who is not suffering from cancer. This means preventing it from occurring.
  • treatment includes complete cure of cancer symptoms as well as partial cure, improvement, and relief of cancer symptoms as a result of administering the pharmaceutical composition of the present invention to an individual suffering from cancer.
  • the compound represented by Formula 1 can be used not only in the form of its pharmaceutically acceptable salt, but also in the form of isomers, solvates, hydrates, etc. that can be prepared therefrom.
  • 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 structural isomers such as tautomers and stereoisomers, and stereoisomers include R or S isomers (optical isomers, enantiomers) and geometric isomers (trans, cis) with an asymmetric carbon center. Everything is included.
  • all stereoisomers of the compound represented by Formula 1 and mixtures thereof are also included within the scope of the present invention.
  • 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.
  • the hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • the hydrate may contain more than 1 equivalent of water, preferably 1 to 5 equivalents of water.
  • Such hydrates can be prepared by crystallizing the compound represented by Formula 1 of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof from water or a solvent containing water.
  • 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.
  • the compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedio acids.
  • Non-toxic organic acids such as ate, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.
  • These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and nitrate.
  • the acid addition salt according to the present invention can be prepared by conventional methods, for example, the precipitate produced by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic acid or inorganic acid. It can be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.
  • an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc.
  • a pharmaceutical composition for the prevention or treatment of cancer containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient may be administered as an individual therapeutic agent, or It can be used in combination with other treatments in use, and the effect can be enhanced by combined administration.
  • a health functional food composition for preventing or improving cancer containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the term “improvement” means reducing or alleviating cancer symptoms by administering, ingesting, or applying the pharmaceutical composition or food composition of the present invention to a cancer-stricken individual.
  • health functional food refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body in accordance with the Health Functional Food Act, and the term “functional” refers to food that is related to the structure and function of the human body. It means ingestion for the purpose of controlling nutrients or obtaining useful health effects such as physiological effects.
  • the health functional food or health supplement food of the present invention obtained in this way is very useful because it can be consumed on a daily basis.
  • One embodiment of the present invention is a method for preventing cancer, comprising administering to a subject in need a compound represented by Formula 1 described herein, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof. Or provide a treatment method.
  • One embodiment of the present invention is a compound represented by Formula 1 described herein, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically thereof for producing a medicament used for the prevention or treatment of cancer.
  • the use of acceptable salts is provided.
  • UV detector 254nm
  • UV detector 254nm
  • UV detector 254nm
  • UV detector 254nm
  • UV detector 254nm
  • 4-(2-Aminoethyl)benzenesulfonamide (401 mg, 2.00 mmol) was dissolved in dimethylformamide, and then 3-phenylpropiolic acid (307 mg, 2.10 mmol), EDCI (576 mg, 3 mmol), and HOBt were added at room temperature. (368 mg, 2.40 mmol) and DIPEA (1.07 ml, 6.00 mmol) were added. After stirring at room temperature for 15 hours, distilled water was added dropwise to terminate the reaction, diluted with ethyl acetate, and washed with water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 40% ethyl acetate/hexane), and the target compound 3-phenyl-N-(4-sulfamoylphenethyl)propiolamide (450 mg, 68%, brown) was obtained. solid) was obtained.
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 50% ethyl acetate/hexane) to obtain the target compound 4-(2-((3-(4-(trifluoromethyl)phenyl)prop-2- Yin-1-yl)amino)ethyl)benzenesulfonamide (70 mg, 55%, yellow solid) was obtained.
  • the target compound 4-(2-((3-phenylprop-2-yn-1-yl)amino)ethyl)benzenesulfonamide was obtained in a similar manner to Example 3.
  • N-methyl-3-phenylprop-2-yn-1-amine 43 mg, 0.30 mmol was dissolved in dimethylformamide and then 4-(2-iodoethyl)benzenesulfonamide (31 mg) at room temperature. , 0.100 mmol), and DIPEA (0.026 ml, 0.150 mmol) were added. After heating to 60°C and heating and stirring for 15 hours, the reaction was terminated by adding distilled water, diluted with ethyl acetate, and washed with water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the target compound 4-(2-(bis(3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide was obtained in a similar manner to Example 1.
  • the target compound 4-(2-((3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide was obtained in a similar manner to Example 3.
  • the target compound 3-([1,1'-biphenyl]-4-yl)-N-(4-chlorophenethyl)prop-2-yn-1-amine was obtained in a similar manner to Example 3. .
  • Example 3 the target compound 3-([1,1'-biphenyl]-4-yl)-N-(3-([1,1'-biphenyl]-4-yl)prop -2-yn-1-yl)-N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)prop-2-yn-1-amine was obtained.
  • the target compound 3-([1,1'-biphenyl]-4-yl)-N-(2,2-diphenylethyl)prop-2-yn-1-amine was prepared in a manner similar to Example 3 above. Obtained.
  • the target compound 3-([1,1'-biphenyl]-4-yl)-N-(4-morpholinophenethyl)prop-2-yn-1-amine was obtained in a similar manner to Example 3. did.
  • Step 2 Preparation of 2-(1-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)-4-chlorophenol
  • the target compound 4-chloro-2-(1-((3-(4-methoxyphenyl)prop-2-yn-1-yl)amino)ethyl)phenol was obtained in a similar manner to Example 22.
  • Example 24 4-(2-((3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)(methyl)amino)ethyl)benzenesulfonamide manufacture of
  • the target compound 4-chloro-2-(1-((3-(4-methoxyphenyl)prop-2-yn-1-yl)(methyl)amino)ethyl)phenol was prepared in a manner similar to Example 31. Obtained.
  • Step 1 Preparation of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 10% ethyl acetate/hexane), and the target compound tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (0.72 g, 50% %, white solid) was obtained.
  • Step 2 Preparation of tert-butyl 4-(4-(3-hydroxyprop-1-yn-1-yl)phenyl)piperazine-1-carboxylate
  • the compound tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (0.72 g, 2.11 mmol) prepared in step 1 was dissolved in pyrrolidine and then dissolved in Pd(PPh 3 ) at room temperature. 4 (36 mg, 0.12 mmol) and propargyl alcohol (0.48 mL, 8.44 mmol) were added.
  • the reaction mixture was degassed using a nitrogen balloon and then stirred at room temperature for 30 minutes. It was then heated to 120 °C and heated and stirred for 8 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure.
  • the obtained residue was diluted in ethyl acetate and washed with water and salt water.
  • the residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 30% ethyl acetate/hexane) to produce the target compound tert-butyl 4-(4-(3-hydroxyprop-1-yn-1-yl)phenyl.
  • Piperazine-1-carboxylate (0.34 g, 51%, yellow solid) was obtained.
  • Step 3 Preparation of tert-butyl 4-(4-(3-oxoprop-1-yn-1-yl)phenyl)piperazine-1-carboxylate
  • Step 4 Preparation of tert-butyl 4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazine-1-carboxylate
  • the extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 5% methanol/dichloromethane), and the target compound tert-butyl 4-(4-(3-((4-hydroxyphenethyl)amino)prop- 1-In-1-yl)phenyl)piperazine-1-carboxylate (74 mg, 53%, white solid) was obtained.
  • the extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 30% ethyl acetate/hexane) to produce the target compound tert-butyl 4-(4-(3-((1-(5-chloro-2-hydroxyphenyl) )Ethyl)amino)prop-1-yn-1-yl)phenyl)piperazine-1-carboxylate (47 mg, 31%, white solid) was obtained.
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 5% methanol mixed solution (1% ammonia water)/dichloromethane) to produce the target compound 4-(2-((3-(4-(piperazine-1- Y)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol (6 mg, 19%, white solid) was obtained.
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 10% methanol/dichloromethane) to produce the target compound 4-(2-((3-(4-morpholinophenyl)prop-2-yn-1 -yl)amino)ethyl)phenol (40 mg, 46%, yellow solid) was obtained.
  • the target compound 4-(2-((3-(4-(pyridin-4-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol was obtained in a similar manner to Example 38. .
  • Example 39 the target compound 4-chloro-2-(1-((3-(4'-methoxy-[1,1'-biphenyl]-4-yl)prop-2-yne -1-yl)amino)ethyl)phenol was obtained.
  • Step 2 Preparation of 3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-ol
  • the obtained residue was diluted in ethyl acetate and washed with water and salt water.
  • the residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the obtained residue was separated and purified by silica gel chromatography (0-30% ethyl acetate/hexane) to obtain the target compound (0.19 g, 69%, white solid).
  • Step 3 Preparation of 3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)propiolaldehyde
  • Step 4 4-(2-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino) Manufacture of ethyl)phenol
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 50% ethyl acetate/hexane) to produce the target compound 4-(2-((3-(4'-(methoxymethoxy)-[1,1' -Biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol (63 mg, 87%, yellow solid) was obtained.
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 20% ethyl acetate/hexane) to produce the target compound 4-chloro-2-(1-((3-(4'-(methoxymethoxy)-[ 1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol (79 mg, 100%, colorless sticky liquid) was obtained.
  • the target compound 4-(2-((3-(4-(pyridin-3-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol was obtained in a similar manner to Example 38. .
  • the target compound 4-(2-((3-(4-(pyridin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol was obtained in a similar manner to Example 38. .
  • the target compound 4-(2-((3-(4-(pyrimidin-2-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol was obtained in a similar manner to Example 38. did.
  • Step 2 Preparation of 3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-ol
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 25% ethyl acetate/hexane) to produce the target compound 3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)propiol.
  • the aldehyde (0.24 g, 80%, yellow solid) was prepared.
  • Step 4 4-(2-((3-(4'-phenoxy-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol manufacturing
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 5% methanol/dichloromethane) to obtain the target compound 4-(2-((3-(4'-phenoxy-[1,1'-biphenyl] -4-yl)prop-2-yn-1-yl)amino)ethyl)phenol (55 mg, 80%, brown solid) was obtained.
  • the target compound 4-(2-((3-(4-(pyrimidin-5-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol was obtained in a similar manner to Example 38. did.
  • 1-(4-bromophenyl)piperazine (0.5 g, 2.07 mmol) was dissolved in acetonitrile, and then 2-iodopropane (0.84 g, 4.98 mmol) and potassium carbonate (0.57 g, 4.15 mmol) were dissolved in acetonitrile. ) was added. After heating to 65 °C and stirring for 3 hours and 30 minutes, distilled water was added dropwise to the mixture to terminate the reaction, followed by extraction with dichloromethane and washing with salt water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 70% ethyl acetate mixed solution (1% triethylamine)/hexane) to produce the target compound 1-(4-bromophenyl)-4-isopropylpiperazine. (0.50 g, 87%, white solid) was obtained.
  • Step 2 Preparation of 3-(4-(4-isopropylpiperazin-1-yl)phenyl)prop-2-yn-1-ol
  • the obtained residue was diluted in ethyl acetate and washed with water and salt water.
  • the residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 5% methanol/dichloromethane) to produce the target compound 3-(4-(4-isopropylpiperazin-1-yl)phenyl)prop-2-yne.
  • -1-ol (0.16 g, 36%, white solid) was obtained.
  • Step 4 Preparation of 4-(2-((3-(4-(4-isopropylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 100% ethyl acetate mixed solution (1% triethylamine)/hexane), and the target compound 4-(2-((3-(4-(4-iso) Propylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)phenol (25 mg, 34%, white solid) was obtained.
  • Example 61 1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazin-1-yl)ethane-1 -manufacture of
  • 1-(4-Bromophenyl)piperazine (0.5 g, 2.07 mmol) was dissolved in dichloromethane, and then acetylchloride (0.29 g, 3.73 mmol) and triethylamine (0.57 mL, 4.15 mmol) were added at 0 °C. was added. After stirring for 1 hour, distilled water was added dropwise to the mixture to terminate the reaction, extracted with dichloromethane, and washed with salt water.
  • the extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound 1-(4-(4-bromophenyl)piperazin-1-yl)ethan-1-one (0.56 g, 96%, white solid). was obtained.
  • Step 2 Preparation of 1-(4-(4-(3-hydroxyprop-1-yn-1-yl)phenyl)piperazin-1-yl)ethan-1-one
  • the obtained residue was diluted in ethyl acetate and washed with water and salt water.
  • the residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 5% methanol/dichloromethane) to produce the target compound 1-(4-(4-(3-hydroxyprop-1-yn-1-yl)phenyl. )piperazin-1-yl)ethan-1-one (0.14 g, 28%, brown solid) was obtained.
  • Step 3 Preparation of 3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)propiolaldehyde
  • Step 4 1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazin-1-yl)ethan-1-one manufacture of
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 5% methanol/dichloromethane) to produce the target compound 1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop- 1-yn-1-yl)phenyl)piperazin-1-yl)ethan-1-one (35 mg, 23%, yellow solid) was obtained.
  • Step 1 Preparation of tert-butyl (3-(4-(4-acetylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)(4-hydroxyphenethyl)carbamate
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 50% ethyl acetate/hexane) to produce the target compound tert-butyl (3-(4-(4-acetylpiperazin-1-yl)phenyl)prop- 2-yn-1-yl)(4-hydroxyphenethyl)carbamate (51 mg, 50%, white solid) was obtained.
  • Step 2 Preparation of tert-butyl (4-hydroxyphenethyl)(3-(4-(piperazin-1-yl)phenyl)prop-2-yn-1-yl)carbamate
  • Step 3 tert-Butyl (4-hydroxyphenethyl)(3-(4-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)phenyl)prop-2-yne -1-day) Preparation of carbamate
  • Step 4 2,2,2-trifluoro-1-(4-(4-(3-((4-hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazine -1-day) Preparation of ethane-1-one
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 5% methanol/dichloromethane), and the target compound 2,2,2-trifluoro-1-(4-(4-(3-((4- Hydroxyphenethyl)amino)prop-1-yn-1-yl)phenyl)piperazin-1-yl)ethan-1-one (7 mg, 17%, yellow sticky solid) was obtained.
  • Step 1 Preparation of (4'-(3-hydroxy-1-propyn-1-yl)-(1,1'-biphenyl)-4-yl)(phenyl)methanone
  • the obtained residue was diluted with dichloromethane and washed with water and salt water.
  • the residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the obtained residue was separated and purified by silica gel chromatography (0-50% ethyl acetate/hexane) to obtain the target compound (0.45 g, 49%, yellow solid).
  • Step 3 4-(2-((3-(4'-(hydroxy(phenyl)methyl)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl) Production of amino)ethyl)phenol
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 70% ethyl acetate/hexane) to produce the target compound 4-(2-((3-(4'-(hydroxy(phenyl)methyl)-[1, 1'-biphenyl]-4-yl)prop-2-yn-1-yl)amino)ethyl)phenol (29.4 mg, 49%, yellow solid) was obtained.
  • the extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 50% ethyl acetate/hexane) to obtain the target compound ((((4-hydroxyphenethyl)azanediyl)bis(prop-1-yne-3) ,1-diyl))bis([1,1'-biphenyl]-4',4-diyl))bis(phenylmethanone) (12.9 mg, 28%, yellow solid) was obtained.
  • the extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 50% ethyl acetate/hexane) to produce the target compound (4'-(3-((4-hydroxyphenethyl)amino)prop-1-yne- 1-yl)-[1,1'-biphenyl]-4-yl)(phenyl)methanone (8.6 mg, 12%, yellow solid) was obtained.
  • the obtained residue was separated and purified by silica gel chromatography (0 ⁇ 5% methanol/dichloromethane) to obtain the target compound 4-(2-((3-(4'-phenoxy-[1,1'-biphenyl] -4-yl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide (32 mg, 79%, white solid) was obtained.
  • Example 66 the target compound 4-(2-((3-(4'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)prop-2-yne -1-yl)amino)ethyl)benzenesulfonamide was obtained.
  • the residue of the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the obtained residue was separated and purified by silica gel chromatography (0-50% ethyl acetate/hexane) to obtain the target compound (0.4 g, 41%, yellow solid).
  • Step 4 Preparation of 4-(2-((3-(4-(4-benzylpiperazin-1-yl)phenyl)prop-2-yn-1-yl)amino)ethyl)benzenesulfonamide
  • Huh7 liver cancer cell line was obtained from ATCC and cultured in complete DMEM medium (Hyclone, UT, USA) containing 10% fetal bovine serum (FBS; HyClone, AUS) in an environment of 37°C, 5% CO 2 and 100% humidity. .
  • Cells were seeded in 6-well microtiter plates at a plating density of 200,000 cells/well, depending on the doubling time of the individual cell lines. After culturing for 24 hours before drug addition, the compound of the present invention was added to each well at a concentration of 10 ⁇ M, and a group treated with 0.1% DMSO was used as a control group, and the culture was incubated at 37°C for 1 hour.
  • Membranes were blocked in 5% BSA for 1 h at room temperature and incubated with the indicated antibodies overnight at 4 °C. Afterwards, the membrane was washed with TBS-T three times for 10 minutes each at room temperature, and then incubated with horseradish peroxidase-conjugated secondary antibody for 1 hour and 30 minutes at room temperature. After incubation, the membrane was washed with TBS-T for 1 hour at room temperature and confirmed using an enhanced chemiluminescence detection system (ECL). Immunoreactive protein band images were scanned and visual density was quantified using computer software (ImageJ software, version 1.37, Wayne Rasband, NIH, Bethesda, MD).
  • the compounds of the present invention especially the five examples compounds 34, 35, 43, 56, and 65 shown above, exhibit strong inhibitory activity with an expression change value of 20 times or more.
  • Example p-ACC activity Example p-ACC activity
  • Example p-ACC activity Example p-ACC activity
  • Example p-ACC activity Example p-ACC activity
  • Huh-7 (human, hepatocarcinoma) cells were cultured in a 15cm dish using DMEM medium (10% FBS, 10% P/S) , then 4 /C mouse (Orient bio., Busan, Korea) was transplanted into the right hip.
  • DMEM medium 10% FBS, 10% P/S
  • 4 /C mouse Orient bio., Busan, Korea
  • the size of the tumor grew to more than 300 mm 3 after administration of the cancer cells, it was divided into two groups: the solvent control group (Control) and the test substance group (Example 18 compound of the present invention).
  • Example 14 The cancer size reduction experiment of Example 14 was repeated three times, and as a result, it was confirmed that the cancer size was reduced by 55.31%, 37.64%, and 47.67%.

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Abstract

La présente invention concerne un dérivé de phénylpropène, et une composition pharmaceutique pour la prévention ou le traitement du cancer, comprenant le dérivé de phénylpropène en tant que principe actif. Le dérivé de phénylpropène selon la présente invention a été confirmé comme ayant une activité inhibitrice de l'ACC impliquée dans le mécanisme d'inhibition de la prolifération tumorale et des métastases.
PCT/KR2023/006799 2022-05-23 2023-05-18 Composition pharmaceutique pour la prévention ou le traitement du cancer comprenant un dérivé de phénylpropène en tant que principe actif WO2023229295A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0527458A1 (fr) * 1991-08-13 1993-02-17 Roche Diagnostics GmbH Nouveaux dérivés de 3,5-di-tert.butyl-4-hydroxyphényl, procédé pour leur préparation et compositions pharmaceutiques
WO2010081904A1 (fr) * 2009-01-19 2010-07-22 Glaxo Group Limited Dérivés de 4(1h)-pyridinone et leur utilisation comme agents antipaludiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0527458A1 (fr) * 1991-08-13 1993-02-17 Roche Diagnostics GmbH Nouveaux dérivés de 3,5-di-tert.butyl-4-hydroxyphényl, procédé pour leur préparation et compositions pharmaceutiques
WO2010081904A1 (fr) * 2009-01-19 2010-07-22 Glaxo Group Limited Dérivés de 4(1h)-pyridinone et leur utilisation comme agents antipaludiques

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE Registry 16 May 2019 (2019-05-16), ANONYMOUS : " 2-Propynamide, N-[2-[4-(aminosulfonyl)phenyl]ethyl]-3-(2-methoxyphenyl)- (CA INDEX NAME)", XP093112103, retrieved from stnEXT Database accession no. 2308935-75-1 *
DATABASE Registry 23 February 2006 (2006-02-23), ANONYMOUS : "Benzenesulfonamide, 4-[2-[(3-phenyl-2-propyn-1-yl)amino]ethyl]- (CA INDEX NAME)", XP093112106, retrieved from STNext Database accession no. 875002-40-7 *
MILNE KIRSTY; SUN JIANHUI; ZAAL ESTHER A.; MOWAT JENNA; CELIE PATRICK H.N.; FISH ALEXANDER; BERKERS CELIA R.; FORLANI GIUSEPPE; LO: "A fragment-like approach to PYCR1 inhibition", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 29, no. 18, 25 July 2019 (2019-07-25), Amsterdam NL , pages 2626 - 2631, XP085779561, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2019.07.047 *

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