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WO2023121251A1 - Composés inhibiteurs doubles de l'egfr et de l'hdac et leur utilisation médicale - Google Patents

Composés inhibiteurs doubles de l'egfr et de l'hdac et leur utilisation médicale Download PDF

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Publication number
WO2023121251A1
WO2023121251A1 PCT/KR2022/020882 KR2022020882W WO2023121251A1 WO 2023121251 A1 WO2023121251 A1 WO 2023121251A1 KR 2022020882 W KR2022020882 W KR 2022020882W WO 2023121251 A1 WO2023121251 A1 WO 2023121251A1
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Prior art keywords
amino
phenyl
methylmethylsulfonamido
oxoheptyl
hydroxyamino
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English (en)
Korean (ko)
Inventor
유형철
김재선
이윤진
서행란
김지희
송연화
남재경
이해준
임지웅
이주영
최광현
강희근
김선주
백민정
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Korea Institute of Radiological and Medical Sciences
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Korea Institute of Radiological and Medical Sciences
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—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
    • C07D239/28—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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

Definitions

  • the present disclosure relates to compounds for the treatment or alleviation of fibrosis.
  • the present disclosure also relates to the pharmaceutical use of a compound according to the present disclosure for the treatment or alleviation of fibrosis. That is, the present disclosure relates to methods for the treatment of fibrosis or relief of symptoms of fibrosis.
  • Fibrosis can affect various organs such as the heart, liver, lungs, skeletal muscle, kidneys, blood vessels, and more.
  • fibrosis can be classified into skeletal muscle tissue (dystrophic muscle disease), heart and vascular tissue (myocardial infarction), liver tissue (non-alcoholic fatty liver disease/cirrhosis), lung tissue (idiopathic pulmonary fibrosis), and kidney tissue (chronic kidney disease). /renal fibrosis).
  • HDAC histone deacetylase
  • the problem to be solved by the present disclosure is to provide a compound effective for the treatment or alleviation of fibrosis or a pharmaceutical composition containing such a compound as an active ingredient. That is, the problem to be solved by the present disclosure is to find a component effective for the treatment or alleviation of fibrosis and to provide a medicinal use thereof.
  • the present disclosure provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 independently of each other are hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
  • R 4 is hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl;
  • n 0, 1, 2, 3, or 4;
  • R 5 and R 6 independently represent hydrogen, C 1 -C 6 alkyl substituted with hydroxamic acid, or C 2 -C 6 alkene substituted with hydroxamic acid.
  • R 5 and R 6 are each independently hydrogen, -C 1 ⁇ C 6 alkyl-C(O)N(OH)H, or -C 2 ⁇ C 6 alkene-C(O )N(OH)H.
  • the compounds according to the present invention may be used as pharmaceutically acceptable salts. Indeed, in one aspect of the present invention, salts of compounds according to Formula 1 may be preferred over the respective free bases, since, for example, such salts impart greater stability or solubility to the molecule and thus the dosage form. This is because it promotes the formulation of Rho.
  • compounds according to Formula 1 may function as compounds with basic functional groups.
  • the pharmaceutically acceptable salt of Formula 1 is an acid addition salt.
  • Pharmaceutically acceptable acid addition salts are formed from acids which form non-toxic salts. For example, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulphate, nitrate, phosphate, hydrogen phosphate ( hydrogen phosphate, acetate, maleate, malate, fumarate, malonate, lactate, tartrate, citrate , formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate ), benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate, methanesulphonic, ethanesulphonic ), p-toluenesulphonic, and isethionat
  • pharmaceutically acceptable salt refers to a salt that retains the desired biological activity of a subject compound and exhibits minimal undesirable toxic effects.
  • pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or separately by reacting the purified compound in its free acid or free base form with a suitable base or acid separately.
  • the term “pharmaceutically acceptable” means generally considered safe for such use, officially approved for such use by a national or state regulatory agency, or approved by the U.S. Pharmacopoeia or veterinary , more particularly suitable for use in pharmaceutical preparations listed in other pharmacopeias generally recognized for use in humans.
  • alkyl refers to a saturated straight-chain or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms (unless the number of carbon atoms is specifically limited). "Lower alkyl” means a straight chain or branched alkyl having 1 to 4 carbon atoms.
  • saturated straight-chain alkyls are -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n- decyl, while saturated branched alkyl is -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3- Methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-
  • C 1-6 when described as “C 1-6 ”, “C1-6”, or “C1-C6”, it means that the number of carbon atoms is 1 to 6.
  • C1-C6 alkyl means an alkyl having 1 to 6 carbon atoms.
  • alkenyl means a saturated straight-chain or branched non-cyclic hydrocarbon containing from 2 to 10 carbon atoms and at least one carbon-carbon double bond.
  • Representative straight-chain and branched (C 2 -C 10 ) alkenyls are -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl , -3-methyl-1-butenyl, -2-methyl-2-butenic, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3 -Hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3octenyl, -1-nonenyl,
  • alkoxy means -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -O(CH 2 ) 3 CH 3 , -O(CH 2 ) 4 CH 3 , -O-(alkyl), including -O(CH 2 ) 5 CH 3 , and the like, wherein alkyl is as defined above.
  • lower alkoxy means -O-(lower alkyl), wherein lower alkyl is as defined above.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
  • haloalkyl As used herein, the terms "haloalkyl”, “haloalkoxy”, “haloalkenyl” or “haloalkynyl” refer to an alkyl, alkoxy, alkenyl or alkynyl group in which one or more hydrogen atoms are replaced by halogen atoms, respectively. .
  • haloalkyl is -CF 3 , -CHF 2 , -CH 2 F, -CBr 3 , -CHBr 2 , -CH 2 Br, -CC1 3 , -CHC1 2 , -CH 2 CI, -CI 3 , -CHI 2 , -CH 2 I, -CH 2 -CF 3 , -CH 2 -CHF 2 , -CH 2 -CH 2 F, -CH 2 -CBr 3 , -CH 2 -CHBr 2 , -CH 2 -CH 2 Br, -CH 2 -CC1 3 , -CH 2 -CHC1 2 , -CH 2 -CH 2 CI, -CH 2 -CI 3 , -CH 2 -CHI 2 , -CH 2 -CH 2 I, and the like include that wherein alkyl and halogen are as defined above.
  • the term "compound of the present disclosure” or “compound according to an aspect of the present invention” is meant to encompass a compound according to Formula 1 and pharmaceutically acceptable salts thereof, unless otherwise specified. .
  • compound of Formula 1(s) is also meant to include compounds of Formula 1 as well as clathrates, hydrates, solvates, or polymorphs (polymorphs) thereof.
  • polymorph refers to a solid crystal form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical and/or spectral properties. Differences in terms of physical properties include, but are not limited to, stability (e.g. heat or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). It doesn't. Differences in stability may be due to chemical reactivity changes (e.g. differential oxidation such as faster discoloration when composed of one polymorph than when composed of another polymorph) or mechanical properties (e.g.
  • kinetically Tablet fragments stored as the preferred polymorph may be thermodynamically converted to a more stable polymorph) or both (tablets of one polymorph are more susceptible to degradation at high humidity).
  • Other physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form solvates, or may be more difficult to filter or wash, than another polymorph, eg, due to its shape or particle size distribution.
  • solvent compound refers to a compound of the present invention comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and can be administered in very small amounts to humans.
  • hydrate refers to a compound of the present invention that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate refers to a compound of the present invention in the form of a crystal lattice containing spaces (eg, channels) in which guest molecules (eg, solvent or water) are confined.
  • the compound of Formula 1 is isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2 -(N-methylmethylsulfonamido)phenyl)amino)pyrimidine-5-carboxylate or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention provides a pharmaceutical composition for treating, improving or preventing fibrosis, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another aspect of the present invention is also a treatment for fibrosis, comprising administering a therapeutically or prophylactically effective amount of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment, improvement or prevention of fibrosis.
  • Methods of treatment, improvement or prevention are provided. That is, the present disclosure provides a pharmaceutical use of the compound of Formula 1 or a pharmaceutically acceptable salt thereof for treating, improving or preventing fibrosis.
  • prevention includes prevention of recurrence, expansion or development of fibrosis in a patient (subject).
  • treatment includes eradication, elimination, or control of fibrosis, and minimizing or delaying the spread of fibrosis.
  • fibrosis is cardiac, liver, lung, skeletal muscle, kidney, or vascular fibrosis.
  • the fibrosis is liver or pulmonary fibrosis.
  • the fibrosis is pulmonary fibrosis.
  • the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present disclosure is generally administered in a therapeutically or prophylactically effective amount.
  • the compound(s) of the present invention can be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in a dosage effective for the intended treatment.
  • An effective dosage is generally from about 0.01 to about 50 mg/kg of body weight/day, preferably from about 0.05 to about 20 mg/kg/day, in single or divided administration. Dosage levels below the lower end of this range may be suitable depending on the age, species, and disease or condition being treated. In other cases, still larger doses can be used without detrimental side effects. Larger doses may be divided into several smaller doses for administration throughout the day. Methods for determining the appropriate dosage are well known in the art.
  • the present disclosure also provides a composition, preferably a pharmaceutical composition, comprising a compound of the present disclosure (a compound of Formula 1 above, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient.
  • the active ingredient described herein can be administered as follows.
  • the active ingredient according to the present invention may be administered intranasally, and nasal administration may be particularly preferable for the pharmaceutical use of the present disclosure.
  • nasal administration is a concept including conventional inhalant administration.
  • intranasal administration is meant delivery of a composition into the nose and nasal cavities through one or both of the nose or nasal passages, and includes delivery by a spray mechanism or droplet mechanism or delivery by aerosolization of an active ingredient.
  • Administration of the composition by inhalation may be through the nose or mouth via delivery by a nebulizer or droplet mechanism.
  • compositions of the present invention may be formulated by methods well known to those skilled in the art, for example, with representative solubilizing, diluting, or dispersing substances such as saline, preservatives such as benzyl alcohol. , absorption enhancers and the like, but is not limited thereto.
  • a liquid pharmaceutical composition may be prepared by the same method as an oral administration composition described later.
  • Such nasal administration may be performed using an intranasal delivery device well known in the art to which the present invention pertains, and propellants such as fluorocarbon and hydrofluoroalkane may be used in such a device.
  • propellants such as fluorocarbon and hydrofluoroalkane may be used in such a device.
  • the compound of the present invention can be administered orally, and oral is a concept including swallowing.
  • Oral administration allows the compounds of the present invention to enter the gastrointestinal tract or be directly absorbed from the mouth into the bloodstream, eg, by buccal or sublingual administration.
  • compositions suitable for oral administration may be in solid, liquid, gel, or powder form, and may have formulations such as tablets, lozenges, capsules, granules, powders, and the like. .
  • compositions for oral administration may optionally be enteric coated and exhibit delayed or sustained release through the enteric coating. That is, the composition for oral administration according to the present invention may be a formulation having an immediate or modified release pattern.
  • Liquid formulations may include solutions, syrups and suspensions, and such liquid compositions may be contained in soft or hard capsules.
  • Such formulations may include a pharmaceutically acceptable carrier such as water, ethanol, polyethylene glycol, cellulose, or oil.
  • the formulation may also contain one or more emulsifying and/or suspending agents.
  • the amount of active ingredient drug may be present from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight of the total weight of the tablet.
  • Tablets may also contain a disintegrant comprising from about 0.5% to about 35% by weight, more usually from about 2% to about 25% by weight of the dosage form.
  • disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.
  • Suitable glidants included for making into tablets may be present in amounts from about 0.1% to about 5% by weight, and include talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like. It can be used as a lubricant, but the present invention is not limited to these types of additives.
  • Gelatin polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. may be used as a binder for preparing tablets.
  • Mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc. may be used as suitable diluents for preparing tablets, but the present invention is not limited to these types of additives. .
  • the solubilizing agent that may be included in the tablet may be used in an amount of about 0.1% to about 3% by weight based on the total weight of the tablet, for example, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, Diethylene glycol monoethyl ether, dimethylisosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR TM (Nikkol), oleyl ester, Gelucire TM , caprylic/caprylic mono/ Diglyceride, sorbitan fatty acid ester, Solutol HS TM and the like can be used in the pharmaceutical composition according to the present invention, but the present invention is not limited to the specific types of these solubilizing agents.
  • Compounds of the present invention may be administered directly into the bloodstream, muscle, or intestine.
  • Suitable methods for parenteral administration include intravenous, intramuscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial injection, and the like.
  • Suitable devices for parenteral administration include injectors (including needle and needleless syringes) and infusion methods.
  • compositions for parenteral administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
  • parenteral formulations are liquid compositions, and these liquid compositions are aqueous solutions containing the active ingredient, salt, buffer, tonicity agent and the like according to the present invention.
  • Parenteral formulations may also be prepared in dried form (eg lyophilized) or as sterile non-aqueous solutions. These formulations may be used with a suitable vehicle such as sterile water. Solubility-enhancing agents may also be used in the preparation of parenteral solutions.
  • Compounds according to the present disclosure are useful for the treatment, amelioration or prevention of fibrosis. That is, the present disclosure provides a pharmaceutical use for treating, ameliorating or preventing fibrosis of a compound according to the present disclosure. Another aspect of the present disclosure provides a method for treating or alleviating fibrosis comprising administering to a subject (preferably a human) in need thereof a therapeutically or prophylactically effective amount of a compound according to the present disclosure.
  • Step 1 Preparation of N-(2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide (1-1)
  • step 1 The material from step 1 (3 g, 7.88 mmol), 4-amino-2-methoxybenzoic acid (1.32 g, 7.88 mmol) and para-toluenesulfonic acid (1.50 g, 7.88 mmol) in isopropyl alcohol (240 mL) The mixture was stirred at reflux for 6 hours. The reaction mixture was concentrated and extracted with dichloromethane and water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was recrystallized from dichloromethane and cyclohexane to give the title compound (1.26 g, %).
  • O-benzylhydroxylamine hydrochloride salt (1.07 g, 6.73 mmol), 7-((tert-butoxycarbonyl)amino)heptanoic acid (1.50 g, 6.11 mmol), 1-ethyl-3-(3-dimethylamino) Diisopropylethylamine (4.2 mL, 24.40 mmol) in dichloromethane (30 mL) mixture of propyl) carbodiimide (EDC, 1.76 g, 9.17 mmol) and hydroxybenzotriazole (HOBt, 1.24 g, 9.17 mmol) was added and stirred overnight.
  • EDC propyl carbodiimide
  • HOBt hydroxybenzotriazole
  • the reaction mixture was diluted with dichloromethane and washed sequentially with water, 1N HCl aqueous solution, and NaHCO3 aqueous solution.
  • the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated.
  • the residue was purified by column chromatography to give the title compound (1.0 g, 47%).
  • Step 5 N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(tri Preparation of fluoromethyl) pyrimidin-2-yl) amino) benzamide (1-5)
  • Step 6 N-(7-(hydroxyamino)-7-oxoheptyl)-2-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5 Preparation of -(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (1-6)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-2-fluorobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-2-fluoro-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino) Preparation of -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (2-2)
  • Step 3 2-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5 Preparation of -(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (2-3)
  • Step 1 Preparation of 4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid ( 3-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-aminobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(tri Preparation of fluoromethyl) pyrimidin-2-yl) amino) benzamide (3-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoro Preparation of methyl) pyrimidin-2-yl) amino) benzamide (3-3)
  • Step 1 3-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzo
  • ripe acid (4-1) 3-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzo
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-3-methoxy-benzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-3-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino) Preparation of -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (4-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 N-(7-(hydroxyamino)-7-oxoheptyl)-3-methoxy-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5 Preparation of (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (4-3)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-3-fluoro-benzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-3-fluoro-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino) Preparation of -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (5-2)
  • Step 3 3-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)-5 Preparation of -(trifluoromethyl)pyrimidin-2-yl)amino)benzamide (5-3)
  • Example 6 Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-3-methoxyphenyl)amino)-4-((2-(N-methyl Preparation of methylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate
  • Step 1 Preparation of isopropyl 2-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidine-5-carboxylate (6-1)
  • Step 2 4-((5-(isopropylcarbonyl)-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-methoxybenzo Preparation of ripe acid (6-2)
  • Step 3 Isopropyl 2-((4-((7-((benzyloxy)amino)-7-oxoheptyl)carbamoyl)-3-methoxyphenyl)amino)-4-((2-(N- Preparation of methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate (6-3)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 2.
  • Step 4 Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-3-methoxyphenyl)amino)-4-((2-(N-methylmethyl Preparation of sulfonamido) phenyl) amino) pyrimidine-5-carboxylate (6-4)
  • Example 7 Isopropyl 2-((3-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methyl Preparation of methylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate
  • Step 1 2-Fluoro-4-((5-(isopropylcarbonyl)-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)benzo Preparation of ripe acid (7-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-2-fluorobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 Isopropyl 2-((4-((7-((benzyloxy)amino)-7-oxoheptyl)carbamoyl)-3-fluorophenyl)amino)-4-((2-(N- Preparation of methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate (7-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 Isopropyl 2-((3-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethyl Preparation of sulfonamido) phenyl) amino) pyrimidine-5-carboxylate (7-3)
  • Example 8 Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethylsulfonamido) Preparation of phenyl) amino) pyrimidine-5-carboxylate
  • Step 1 Preparation of 4-((5-(isopropylcarbonyl)-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid ( 8-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-aminobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 Isopropyl 2-((4-((7-((benzyloxy)amino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethylsulfonamido Preparation of )phenyl)amino)pyrimidine-5-carboxylate (8-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethylsulfonamido)phenyl Preparation of )amino)pyrimidine-5-carboxylate (8-3)
  • Example 9 Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-2-methoxyphenyl)amino)-4-((2-(N-methyl Preparation of methylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate
  • Step 1 4-((5-(isopropylcarbonyl)-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxybenzo Manufacture of ripe acid (9-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-3-methoxybenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 Isopropyl 2-((4-((7-((benzyloxy)amino)-7-oxoheptyl)carbamoyl)-2-methoxyphenyl)amino)-4-((2-(N- Preparation of methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate (9-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 Isopropyl 2-((4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)-2-methoxyphenyl)amino)-4-((2-(N-methyl) Preparation of sulfonamido) phenyl) amino) pyrimidine-5-carboxylate (9-3)
  • Example 10 Isopropyl 2-((2-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methyl Preparation of methylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate
  • Step 1 3-Fluoro-4-((5-(isopropylcarbonyl)-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)benzo Preparation of ripe acid (10-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-3-fluorobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 Isopropyl 2-((4-((7-((benzyloxy)amino)-7-oxoheptyl)carbamoyl)-2-fluorophenyl)amino)-4-((2-(N- Preparation of methylmethylsulfonamido) phenyl) amino) pyrimidine-5-carboxylate (10-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 Isopropyl 2-((2-fluoro-4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)phenyl)amino)-4-((2-(N-methylmethyl Preparation of sulfonamido) phenyl) amino) pyrimidine-5-carboxylate (10-3)
  • Step 1 Preparation of 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-fluorobenzoic acid (11 -One)
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)- Preparation of 5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-fluorobenzamide (11-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-fluoro-N-(7- Preparation of (hydroxyamino) -7-oxoheptyl) benzamide (11-3)
  • Example 12 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-(7 Preparation of (hydroxyamino)-7-oxoheptyl)benzamide
  • Step 1 Preparation of 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-fluorobenzoic acid (12 -One)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-2-fluorobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrid Preparation of midin-2-yl) amino) -2-fluorobenzamide (12-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-(7- Preparation of (hydroxyamino) -7-oxoheptyl) benzamide (12-3)
  • Example 13 2-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrid Preparation of midin-2-yl) amino) benzamide
  • Step 1 Preparation of 2-fluoro-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid (13-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-2-fluorobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-2-fluoro-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino) Preparation of pyrimidin-2-yl) amino) benzamide (13-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 2-Fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)-4-((4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidine Preparation of -2-yl) amino) benzamide (13-3)
  • Example 14 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of )-7-oxoheptyl)benzamide
  • Step 1 Preparation of 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid (14-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-aminobenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrid Preparation of midin-2-yl) amino) benzamide (14-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of -7-oxoheptyl)benzamide (14-3)
  • Example 15 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of )-7-oxoheptyl)-3-methoxybenzamide
  • Step 1 Preparation of 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxybenzoic acid ( 15-1)
  • the title compound was obtained by a method similar to the step 2 synthesis method of Example 1, using 4-amino-3-methoxybenzoic acid instead of 4-amino-2-methoxybenzoic acid.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrid Preparation of midin-2-yl) amino) -3-methoxybenzamide (15-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of -7-oxoheptyl) -3-methoxybenzamide (15-3)
  • Example 16 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of )-7-oxoheptyl)-2-methoxybenzamide
  • Step 1 Preparation of 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-2-methoxybenzoic acid ( 16-1)
  • the title compound was obtained using a method similar to the step 2 synthesis method of Example 1 above.
  • Step 2 N-(7-((benzyloxy)amino)-7-oxoheptyl)-4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrid Preparation of midin-2-yl) amino) -2-methoxybenzamide (16-2)
  • the title compound was obtained by a method similar to the synthesis method in Step 5 of Example 1, using 7-amino-N-(benzyloxy)heptanamide hydrochloride salt (1-4) and the materials of Step 1.
  • Step 3 4-((5-chloro-4-((2-(N-methylmethylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-N-(7-(hydroxyamino) Preparation of -7-oxoheptyl) -2-methoxybenzamide (16-3)
  • the compound used in the experiment was prepared at the highest concentration of 1 ⁇ M and was sequentially diluted 3-fold. Concentrations of 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, and 0.05 nM were used. Staurosporine was used as a control material to confirm the enzymatic reaction conditions. The concentration of ATP used in the reaction was the concentration corresponding to Km for each protein.
  • Substrates to be used for the reaction were mixed in assay buffer, a reaction buffer solution (composition: 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01%, Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO) was prepared by mixing. Cofactors required for substrate reaction were added. After each enzyme was added to the substrate mixture, the test substance was treated by concentration and the reaction was initiated by treatment with 33 P-ATP. After the reaction for 2 hours, the kinase activity was analyzed by measuring and analyzing the amount of remaining radioactivity after passing through the P81 Filter plate. The kinase activity inhibitory activity results for the compounds of the invention are shown in Table 1.
  • Enzyme activity inhibition was confirmed using purified human-derived HDAC 1, 2, 3, 4, and 6 proteins and substrates for HDAC. Two compounds were prepared at concentrations of 1000, 100, 10, and 1 nM. As a substrate, fluorescently labeled HDAC class 2a was used at a concentration of 20 ⁇ M. Trichostatin A was used as a control material for confirmation of the enzyme reaction conditions. After mixing the enzyme, compound, and substrate, the reaction was carried out at room temperature for 30 minutes, and the degree of inhibition of HDAC activity was relatively analyzed by measuring the final fluorescence value. HDAC activity inhibitory activity results for the compounds of the invention are shown in Figure 1.
  • H&E Hematoxylin and Eosin staining method
  • Mouse tissues were first fixed in 10% neutral formalin for 5 days and then made into paraffin blocks. As a process of removing paraffin penetrating into tissue, xylene was reacted, followed by reaction in 100, 95, 70, and 50% ethanol solutions for 3 minutes, respectively. After the 50% ethanol process was completed, it was washed with running water for 10 minutes. The hematoxylin solution was reacted for 2 minutes to stain the nuclei, and washed with running water for 10 minutes. Then, the cytoplasm was stained by reacting with an eosin solution for 30 seconds, and 50, 70, 95, and 100% ethanol were reacted for 1 minute each. Finally, after reacting with the xylene solution, a drop of the mounting solution was applied, and the cover slide was covered and observed under a microscope.
  • Mouse tissues were first fixed in 10% neutral formalin for 5 days and then made into paraffin blocks. In order to remove paraffin in the tissue, it was reacted with xylene, reacted with 100, 95, 70, and 50% ethanol solutions for 3 minutes each, and after the last process was finished, washed with running water for 10 minutes. First, Bouin's Solution was reacted in a water bath at 60 ° C for 60 minutes, and after the reaction, it was washed with running water for 10 minutes. After washing, Weigert's hematoxylin A and B solutions were mixed in a 1:1 ratio and reacted for 10 minutes.
  • the Biebrich Scarlet-Acid Fuschin solution was reacted for 3 minutes and rinsed once with tertiary distilled water. Then, the reaction was carried out in Phosphotumstic/Phosphomolydic acid for 20 minutes and aniline blue for 30 minutes without washing. After the last dyeing process was finished, it was rinsed 3 times with tertiary distilled water and reacted in 1% acetic acid solution for 1 minute. After dehydration through 95 and 100% ethanol solutions, xylene solution was finally finished, a drop of mounting solution was dropped, and a cover slide was covered and observed under a microscope.
  • the positive control material (Nintedanib) and the compound of Example 8 were found to significantly inhibit radiation-induced pulmonary fibrosis.

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Abstract

La présente divulgation concerne un composé utile pour le traitement ou le soulagement de la fibrose, en particulier la fibrose pulmonaire et son utilisation médicale.
PCT/KR2022/020882 2021-12-21 2022-12-20 Composés inhibiteurs doubles de l'egfr et de l'hdac et leur utilisation médicale Ceased WO2023121251A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009112490A1 (fr) * 2008-03-11 2009-09-17 Cellzome Limited Sulfonamides en tant qu'inhibiteurs de zap-70
US20110028405A1 (en) * 2007-12-20 2011-02-03 Richard John Harrison Sulfamides as zap-70 inhibitors
US20120172385A1 (en) * 2009-09-11 2012-07-05 Richard John Harrison Ortho substituted pyrimidine compounds as jak inhibitors
US20200190068A1 (en) * 2017-08-28 2020-06-18 Zhihong Chen Substituted pyrimidines, pharmaceutical compositions and therapeutic methods thereof
CN113754591A (zh) * 2020-06-05 2021-12-07 山东大学 一种hdac、jak和bet三靶点抑制剂及其制备方法和应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110028405A1 (en) * 2007-12-20 2011-02-03 Richard John Harrison Sulfamides as zap-70 inhibitors
WO2009112490A1 (fr) * 2008-03-11 2009-09-17 Cellzome Limited Sulfonamides en tant qu'inhibiteurs de zap-70
US20120172385A1 (en) * 2009-09-11 2012-07-05 Richard John Harrison Ortho substituted pyrimidine compounds as jak inhibitors
US20200190068A1 (en) * 2017-08-28 2020-06-18 Zhihong Chen Substituted pyrimidines, pharmaceutical compositions and therapeutic methods thereof
CN113754591A (zh) * 2020-06-05 2021-12-07 山东大学 一种hdac、jak和bet三靶点抑制剂及其制备方法和应用

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