WO2021025448A1 - Nouveau composé pour inhiber l'histone acétyltransférase p300 et composition antifibrotique le comprenant - Google Patents

Nouveau composé pour inhiber l'histone acétyltransférase p300 et composition antifibrotique le comprenant Download PDF

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WO2021025448A1
WO2021025448A1 PCT/KR2020/010304 KR2020010304W WO2021025448A1 WO 2021025448 A1 WO2021025448 A1 WO 2021025448A1 KR 2020010304 W KR2020010304 W KR 2020010304W WO 2021025448 A1 WO2021025448 A1 WO 2021025448A1
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group
integer
fibrosis
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halogen
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윤호근
손명현
박수연
홍정연
이수연
권영주
나영화
황수연
신재호
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리퓨어생명과학 주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms

Definitions

  • the present invention is a novel compound for inhibiting histone acetyltransferase p300 (histone acetyltransferase p300); Antifibrotic composition comprising the novel compound; And to various uses thereof.
  • Tissues contain well-ordered populations of cells that are bound to the extracellular matrix and are surrounded by a network of blood vessels.
  • Fibrosis or fibrosis is an abnormal accumulation of the collagen matrix following inflammation or injury that changes the structure and function of various tissues.
  • excessive accumulation of fibrous connective tissue such as a collagen matrix that replaces normal tissue, is the most etiological factor.
  • Progressive fibrosis occurring in the kidneys, liver, fat, lungs, heart, bones or bone marrow, and skin is a major cause of death or pain.
  • pulmonary fibrosis which is fibrosis occurring in the lungs, refers to a disease that induces tissue fibrosis as chronic inflammatory cells infiltrate the alveolar wall of the lung tissue, causing severe structural mutations in the lung tissue. Once fibrosis progresses due to some reason, the lung tissue is hardened and the alveolar wall thickens, reducing the amount of oxygen supplied by the blood, thereby making breathing difficult.
  • the treatment of pulmonary fibrosis discovered in the early stages of progression includes treatment with steroid drugs such as steroids (Steroid), azathioprine, and cyclophosphamide, and antioxidants such as acetylcysteine. And treatment methods using growth factors such as cytokines (Cytokine) and IFN- ⁇ (Interferon- ⁇ ). Treatment methods using steroid drugs and antioxidants have been studied and reported continuously since 2000, but have not yet been proven for clear drug efficacy, and long-term administration results in systemic side effects or side effects that develop resistance. It has been reported to do.
  • steroid drugs such as steroids (Steroid), azathioprine, and cyclophosphamide
  • antioxidants such as acetylcysteine.
  • growth factors such as cytokines (Cytokine) and IFN- ⁇ (Interferon- ⁇ ).
  • Treatment methods using steroid drugs and antioxidants have been studied and reported continuously since 2000, but have not yet been proven for clear drug
  • the treatment through growth factor administration is a treatment that has received a lot of attention in recent years, and it is a relatively fundamental approach using'interferon', which suppresses the production of TGF- ⁇ (Transforming growth factor- ⁇ ), which is known as an important factor in pulmonary fibrosis. .
  • TGF- ⁇ Transforming growth factor- ⁇
  • various types of treatments such as injection or aerosol methods have been reported because of fewer side effects and excellent efficacy compared to treatments using steroid drugs and antioxidants.
  • the therapeutic efficacy of a single component such as interferon may be temporary, and this may only show efficacy in some patients, requiring continuous research and clinical trials.
  • An object of the present invention is to provide a novel compound capable of inhibiting histone acetyltransferase (HAT) p300.
  • Another object of the present invention is to provide a composition for preventing, improving or treating diseases related to HAT p300, including a novel compound that inhibits HAT p300.
  • Another object of the present invention is to provide a method for preventing, improving or treating diseases related to HAT p300 by using a novel compound that inhibits HAT p300.
  • n are each independently an integer of 1 to 4.
  • R 1 is selected from the group consisting of a substituted or unsubstituted C 3 to C 40 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C 6 to C 14 aryl group, and a heteroaryl group having 5 to 14 nuclear atoms. Is a substituent;
  • p is an integer from 1 to 3
  • q is an integer from 0 to 3 but p + q does not exceed 4;
  • R 2 is halogen, and when there are a plurality of R 2 , they are the same as or different from each other;
  • r is an integer from 0 to 5;
  • R a , R b , R c , and R d are each independently (1) hydrogen; (2) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl Or; (3) R b and R c together with the N atom to which they are attached may form a substituted heterocyclyl.
  • the substitution is -C(O)OR a , wherein R a may be hydrogen or a C 1-6 alkyl group, more preferably a carboxyl group, but is not limited thereto.
  • cycloalkyl group of the present invention means a monovalent substituent derived from a monocyclic or polycyclic non-aromatic hydrocarbon having 3 to 40 carbon atoms, unless otherwise stated.
  • examples of such cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, and adamantine, but are not limited thereto.
  • heterocycloalkyl group of the present invention, unless otherwise stated, includes 1 to 3 heteroatoms selected from N, O, P, or S, and the remaining ring atoms are C, a monovalent monovalent monovalent monovalent of 3 to 20 ring atoms It means a cyclic system.
  • One or more hydrogen atoms in the heterocycloalkyl group may be optionally substituted.
  • the heterocycloalkyl group include, but are not limited to, pyrrolidine, pyrazolidine, imidazolidine, piperidine, or piperazine.
  • aryl group of the present invention refers to a mono- or poly-cyclic carbocyclic ring system having 6 to 14 carbon atoms, which has one or more fused or non-fused aromatic rings, unless otherwise stated, and aryl Examples of examples include phenyl, naphthyl, tetrahydronaphthyl, indenyl and andracenyl, but are not limited thereto.
  • heteroaryl group of the present invention, unless otherwise stated, is one or more selected from O, N and S, for example, a 5 to 14 membered monocyclic or bicyclic containing 1 to 4 heteroatoms. It means more than a click aromatic group.
  • Examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, benzo[d]oxazolyl, isoxazolyl, oxazolopyridinyl, pyrazolyl, triazolyl, thia Zolyl, benzo[d]thiazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, naphthooxazolyl, and similar groups. It is not limited to these.
  • bicyclic heteroaryl examples include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, iso Quinolinyl, purinyl, puropyridinyl, and groups similar thereto, but are not limited thereto.
  • halogen of the present invention means fluorine, chlorine, bromine or iodine unless otherwise stated.
  • alkyl of the present invention means a linear or branched saturated monovalent hydrocarbon radical, and the alkyl may be optionally substituted with one or more substituents described in the present invention.
  • alkyl are, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t -Butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms) may be included.
  • the "pharmaceutically acceptable salt” of the present invention has low toxicity to the human body and should not adversely affect the biological activity and physicochemical properties of the parent compound.
  • the pharmaceutically acceptable salt may be an acid addition salt of a pharmaceutically acceptable free acid and a basic compound of Formula 1, but is not limited thereto.
  • Preferred salt forms of the compounds of the present invention include salts with inorganic acids or organic acids.
  • inorganic acid hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, and the like may be used.
  • organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, Oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, and the like can be used.
  • Organic bases that can be used to prepare an organic base addition salt are tris(hydroxymethyl)methylamine, dicyclohexylamine, and the like.
  • Amino acids that can be used in the preparation of amino acid addition salts are natural amino acids such as alanine and glycine. It will be apparent to those of ordinary skill in the art that other acids or bases in addition to the inorganic acids, organic acids, organic bases and amino acids exemplified above may be used.
  • the salt of the present invention can be prepared by a conventional method.
  • it can be prepared by dissolving the compound of Formula 1 in a water-miscible solvent such as methanol, ethanol, acetone, and 1,4-dioxane, and then adding a free acid or a free base to crystallization.
  • a water-miscible solvent such as methanol, ethanol, acetone, and 1,4-dioxane
  • optical isomer of the present invention may have an asymmetric carbon center, it is an R or S isomer or a racemic compound, and all optical isomers and mixtures that can be formed by the compound of the present invention are included in the scope of the present invention.
  • the compound may be a compound represented by the following Formula 2:
  • R 1 , R 2 and R 3 are the same as defined in Formula 1 above.
  • n and n may each independently be an integer of 1 or 2.
  • R 1 is a C 3 to C 40 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C 6 to C 14 aryl group, and a heteroaryl group having 5 to 14 nuclear atoms.
  • It may be a substituent selected from the group consisting of, preferably a heterocycloalkyl group having 5 to 7 nuclear atoms including 1 or 2 N atoms; C 6 ⁇ C 10 aryl group; And it may be any one substituent selected from the group consisting of a heteroaryl group having 5 to 10 nuclear atoms containing 1 or 2 S atoms, more preferably a piperidinyl group, a pyridinyl group, a phenyl group or a thiophenyl group.
  • I can.
  • the substituent of R 1 preferably the C 6 ⁇ C 14 aryl group of R 1 may be unsubstituted or substituted with at least one kind of -(COO(R 4 ));
  • R 4 is hydrogen or a C 1 to C 4 alkyl group, preferably hydrogen; When there is a plurality of R 4 , they may be the same or different from each other.
  • p may be an integer of 1 or 2, preferably an integer of 1.
  • q may be an integer of 0 or 1, preferably an integer of 1.
  • r may be an integer of 1 or 2, preferably an integer of 1.
  • R 3 may be a halogen or cyano group.
  • m and n are each independently an integer of 1 or 2;
  • R 1 is a substituent selected from the group consisting of a substituted or unsubstituted heterocycloalkyl group having 5 to 7 nuclear atoms, a C 6 to C 14 aryl group, and a heteroaryl group having 5 to 14 nuclear atoms;
  • p is an integer of 1 or 2;
  • q is an integer from 0 to 2;
  • R 2 is halogen;
  • R 3 may be a substituent selected from the group consisting of halogen, cyano group, C 1 to C 5 alkylcarbonyl group and carbamoyl group.
  • m and n are each independently an integer of 1 or 2;
  • R 1 is a heterocycloalkyl group having 5 to 7 nuclear atoms, a C 6 to C 8 aryl group, or a heteroaryl group having 5 to 14 nuclear atoms;
  • p is an integer of 1 or 2;
  • q is an integer from 0 to 2;
  • r is an integer of 1 or 2;
  • R 2 is halogen;
  • R 1 may be unsubstituted or substituted with at least one kind of -(COO(R 4 ));
  • R 4 is hydrogen or a C 1 to C 4 alkyl group, and when a plurality of R 4 is present, they may be the same or different from each other.
  • m and n are each independently an integer of 1 or 2; r is an integer of 1 or 2; R 1 is a substituent selected from a heterocycloalkyl group having 5 to 7 nuclear atoms or a C 6 to C 8 aryl group; R 2 is halogen; R 3 is a halogen or cyano group; The aryl group of R 1 is substituted with -(COO(R 4 )); R 4 may be hydrogen or a C 1 to C 4 alkyl group.
  • the compound of the present invention may be at least one selected from the group consisting of the following compounds, but is not limited thereto:
  • the compound may be any one of the following compounds, but is not limited thereto:
  • a compound for inhibiting histone acetyltransferase p300 represented by Formula 1 is provided.
  • the compound, histone acetyltransferase p300, and the like are the same as described in the above compound, and thus are omitted to avoid excessive complexity of the specification.
  • compositions for preventing, improving or treating a histone acetyltransferase p300-related disease is provided.
  • composition of the present invention comprises a pharmaceutical composition; Food composition; Or it can be used as a cosmetic composition.
  • the composition of the present invention includes a novel compound represented by Formula 1 of the present invention, a pharmaceutically acceptable salt thereof, an optical isomer, a hydrate, and a compound selected from solvates as an active ingredient. Accordingly, since the composition of the present invention contains a novel compound that very effectively inhibits HAT p300 as an active ingredient, the histone acetyltransferase p300-related disease in which HAT p300 is increased, for example, prevention, improvement or The therapeutic effect can be exerted.
  • the compound corresponding to the active ingredient is the same as described for the compound, and thus is omitted to avoid excessive complexity of the specification.
  • the histone acetyltransferase p300-related disease of the present invention can prevent all diseases caused by excessively increasing the expression level of histone acetyltransferase or excessively increasing its activity compared to the normal control without disease.
  • the "fibrosis” of the present invention is a disease in which abnormal generation, accumulation and deposition of extracellular matrix by fibroblasts occurs, and the collagen matrix is abnormally accumulated due to damage or inflammation that may change the structure and function of various tissues. Fibrosis of all organs may be included as long as possible organs, preferably fibrosis occurring in at least one organ selected from the group consisting of kidney, liver, lung, heart, bone or bone marrow and skin, but is limited thereto. It is not.
  • fibrosis is a phenomenon in which the expression of genes related to fibrosis, for example, collagen, is promoted by TGF- ⁇ (Transforming growth factor- ⁇ ) whose expression level is increased through the acetylase p300. It may be induced by or may be induced due to the absence of an enzyme capable of recovering cells from damage in which fibrosis may be induced, but is not limited thereto.
  • the fibrosis of the present invention includes pulmonary fibrosis, uterine fibrosis, myelofibrosis, liver fibrosis, heart fibrosis, multiple sclerosis, kidney fibrosis, Kidney fibrosis, and cystic fibrosis.
  • Cystic fibrosis), neutropenia, skeletal muscle fibrosis, skin sclerosis, dermatomyositis, mediastinal fibrosis, and spleen fibrosis caused by sickle cell anemia may be at least one selected from the group consisting of, and preferably pulmonary fibrosis. However, it is not limited thereto.
  • pulmonary fibrosis refers to the development of scarred (fibrous) tissue due to the formation or development of excessive fibrous connective tissue in the lung (fibrosis).
  • pulmonary fibrosis is a chronic disease that causes swelling and scarring of alveoli and interstitial tissues of the lungs.
  • Such scar tissue replaces healthy tissue and causes inflammation, and chronic inflammation can be identified as a precursor to fibrosis. Due to such damage to the lung tissue, the lung may become stiff, and the individual may have difficulty in self-breathing.
  • pulmonary fibrosis is Idiopathic Pulmonary Fibrosis, Nonspecific Interstitial Pneumonia, Acute Interstitial Pneumonia, Idiopathic Organizing Pneumonia, and Respiratory Bronchitis-related Respiratory Bronchiolitis Associated Interstitial Lung, Desquamative Interstitial Pneumonia, Lymphoid Interstitial Pneumonia, Interstitial Pulmonary Fibrosis and Diffuse Pulmonary Fibrosis, preferably idiopathic pulmonary fibrosis. May be, but is not limited thereto.
  • the pulmonary fibrosis of the present invention is caused by various causes, for example, microscopic damage to the lungs induced by inhalation of fine particles (asbestos, stone dust, metal dust, particles present in cigarette smoke, silica dust, etc.) can do.
  • pulmonary fibrosis may occur as a side effect of other diseases (autoimmune diseases, viral or bacterial infections, etc.), and cytotoxic agents (such as bleomycin, busulfan, and methotrexate); Antibiotics (such as nitrofurantoin and sulfasalazine); Arrhythmia treatment (amiodarone and tocainide, etc.); Anti-inflammatory drugs (such as gold and penicylamine); It may be caused by certain drugs such as illegal drugs (drugs, cocaine, heroin, etc.), and in the case of idiopathic pulmonary fibrosis, it may be caused by an unknown cause other than this cause.
  • diseases autoimmune diseases, viral or bacterial infections, etc.
  • cytotoxic agents such as bleomycin, busulfan, and methotrexate
  • Antibiotics such as nitrofurantoin and sulfasalazine
  • Arrhythmia treatment amiodarone and tocainide, etc.
  • Anti-inflammatory drugs such as gold and pen
  • the "prevention" of the present invention is limited to any action that can inhibit or delay symptoms caused by acetyltransferase p300-related diseases, such as fibrosis, using the composition of the present invention. Can be included without.
  • treatment of the present invention is any action that enables or benefit from an acetyltransferase p300-related disease, such as fibrosis, using the composition of the present invention, without limitation. Can be included.
  • the "improvement" of the present invention may be included without limitation, as long as the symptoms caused by acetyltransferase p300 related diseases, for example fibrosis, are improved or beneficially changed using the composition of the present invention.
  • the pharmaceutical composition of the present invention is not limited thereto, but is formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods.
  • the pharmaceutical composition is for intratracheal administration or inhalation administration; Or it may be formulated to be used as an injection, but is not limited thereto.
  • the active ingredient is formulated for inhalation administration so that it can reach the target organ in a yield suitable for prevention or treatment.
  • the pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier When the pharmaceutically acceptable carrier is administered orally, a binder, a lubricant, a disintegrant, an excipient, a solubilizing agent, a dispersing agent, a stabilizer, a suspending agent, a coloring agent, a fragrance, etc. may be used.
  • a buffering agent, a preservative Painless agents, solubilizers, isotonic agents, stabilizers, etc. may be mixed and used, and in the case of topical administration, a base agent, an excipient, a lubricant, a preservative, and the like may be used.
  • the formulation of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
  • a pharmaceutically acceptable carrier as described above.
  • it when administered orally, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc.In the case of injections, it can be prepared in unit dosage ampoules or multiple dosage forms. have. Others, solutions, suspensions, tablets, capsules, can be formulated as sustained-release preparations.
  • examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , Methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like may be used.
  • fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like may additionally be included.
  • the route of administration of the pharmaceutical composition of the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, Includes sublingual or rectal. Oral or parenteral administration is preferred.
  • the parenteral of the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or injection techniques.
  • the pharmaceutical composition of the present invention can also be administered in the form of suppositories for rectal administration.
  • the pharmaceutical composition of the present invention depends on a number of factors including the activity of the specific compound used, age, weight, general health, sex, formulation, time of administration, route of administration, excretion rate, drug formulation and the severity of the specific disease to be prevented or treated. It may vary in various ways, and the dosage of the pharmaceutical composition varies depending on the patient's condition, weight, degree of disease, drug form, route and duration of administration, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg/day kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be divided several times. The above dosage does not in any way limit the scope of the present invention.
  • the pharmaceutical composition according to the present invention may be formulated as a pill, dragee, capsule, liquid, gel, syrup, slurry, or suspension.
  • the food composition of the present invention is prepared in the form of a beverage
  • various flavoring agents or natural carbohydrates, etc. as an additional component like a normal beverage.
  • natural carbohydrates monosaccharides such as glucose, disaccharides such as fructose, and common sugars such as sucrose and polysaccharides, dextrins, cyclodextrins, and sugar alcohols such as xylitol, sorbitol, and erythritol are used.
  • natural carbohydrates monosaccharides such as glucose, disaccharides such as fructose, and common sugars such as sucrose and polysaccharides, dextrins, cyclodextrins, and sugar alcohols such as xylitol, sorbitol, and erythritol are used.
  • sugar alcohols such as xylitol, sorbitol, and erythritol
  • the flavoring agent may be a natural flavoring agent (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and a synthetic flavoring agent (saccharin, aspartame, etc.).
  • a natural flavoring agent for example, rebaudioside A, glycyrrhizin, etc.
  • a synthetic flavoring agent sacharin, aspartame, etc.
  • the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, A pH adjuster, a stabilizer, a preservative, a glycerin, an alcohol, a carbonation agent used in carbonated beverages, and the like may be further included.
  • the ingredients included in the food composition of the present invention may be used independently or in combination. Although the ratio of the additive does not correspond to the core element of the present invention, it may be selected from 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.
  • the cosmetic composition of the present invention is a lotion, nutritional lotion, nutritional essence, massage cream, beauty bath water additive, body lotion, body milk, bath oil, baby oil, baby powder, shower gel, shower cream, sunscreen lotion, sunscreen cream , Suntan cream, skin lotion, skin cream, sunscreen cosmetics, cleansing milk, depilatory makeup, face and body lotion, face and body cream, skin whitening cream, hand lotion, hair lotion, cosmetic cream, jasmine oil, bath Manufactured in the form of soap, water soap, beauty soap, shampoo, hand sanitizer (hand cleaner), medicinal soap, medical use, cream soap, facial wash, body cleaner, scalp cleaner, hair rinse, makeup soap, tooth whitening gel, toothpaste, etc. Can be.
  • the composition of the present invention may further include a solvent commonly used in the manufacture of cosmetic compositions, or an appropriate carrier, excipient, or diluent.
  • the type of solvent that can be further added to the cosmetic composition of the present invention is not particularly limited, but, for example, water, saline, DMSO, or a combination thereof may be used.
  • excipients or diluents purified water, oil, wax, fatty acids, fatty alcohols, fatty acid esters, surfactants, humectants, thickeners, antioxidants, viscosity stabilizers, chelating agents, buffers, lower alcohols, etc. Included, but not limited to.
  • whitening agents, moisturizing agents, vitamins, sunscreen agents, perfumes, dyes, antibiotics, antibacterial agents, and antifungal agents may be included as needed.
  • Hydrogenated vegetable oil, castor oil, cottonseed oil, olive oil, palm seed oil, jojoba oil, and avocado oil may be used as the oil of the present invention, and waxes include beeswax, spermaceti, carnauba, candelilla, montan, ceresin, liquid paraffin , Lanolin can be used.
  • Stearic acid, linoleic acid, linolenic acid, and oleic acid may be used as the fatty acid of the present invention, and as fatty acid alcohols, cetyl alcohol, octyl dodecanol, oleyl alcohol, panthenol, lanolin alcohol, stearyl alcohol, hexadecanol
  • fatty acid ester isopropyl myristate, isopropyl palmitate, and butyl stearate
  • surfactant cationic surfactants, anionic surfactants, and nonionic surfactants known in the art can be used, and surfactants derived from natural products are preferred as far as possible.
  • hygroscopic agents, thickeners, antioxidants, and the like which are widely known in the cosmetic field, may be included, and the types and amounts thereof are as known in the art.
  • a method for preventing, improving or treating a histone acetyltransferase p300-related disease comprising the steps of administering the composition of the present invention to a target individual is provided.
  • histone acetyltransferase p300-related diseases, prevention, improvement, treatment, compounds, and compositions are the same as those previously described in the present specification, and are omitted to avoid excessive complexity of the specification.
  • the "individual” is an individual suspected of developing a histone acetyltransferase p300-related disease
  • the suspected individual of the histone acetyltransferase p300-related disease is a mouse including a human who has or may develop the disease
  • It means a mammal, including livestock, etc., but includes without limitation the fusion protein of the present invention or an individual treatable with the composition comprising the same.
  • the method of the present invention may include administering the active ingredient in a pharmaceutically effective amount.
  • the appropriate total daily use amount may be determined by the treating physician within the range of correct medical judgment, and may be administered once or in several divided doses.
  • a specific therapeutically effective amount for a specific patient is a specific composition, including the type and degree of reaction to be achieved, whether other agents are used in some cases, the patient's age, weight, general health status, It is preferable to apply differently according to various factors including sex and diet, administration time, administration route and secretion rate of the composition, treatment period, drugs used with or concurrently with the specific composition, and similar factors well known in the medical field.
  • the "combination" of the present invention refers to simultaneous, separate or sequential administration.
  • the interval between administrations of the second component should be such that the beneficial effects of the combination are not lost.
  • the dosage of the fusion protein of the present invention may be about 0.0001 ⁇ g to 500 mg per 1 kg of the patient's body weight, but is not limited thereto.
  • the present invention relates to a novel compound that enables additional hydrogen bonding with a specific amino acid position of the HAT p300 through structural analysis of histone acetyltransferase (HAT) p300, and the novel compound of the present invention Has remarkably excellent inhibitory effect on the activity of HAT p300, so it can be used very effectively in the prevention, improvement or treatment of diseases related to the activation of HAT p300, such as fibrosis.
  • HAT histone acetyltransferase
  • HAT histone acetyltransferase
  • GCN5 histone acetyltransferase GCN5; FIG. 2 in tissues of idiopathic pulmonary fibrosis according to an embodiment of the present invention.
  • PCAF P300/CBP-associated factor; FIG. 3 expression levels were confirmed through immunohistochemical staining.
  • FIG. 6 shows a HAT p300 domain and a substrate inhibitor Lys-CoA molecular model using molecular docking simulation according to an embodiment of the present invention.
  • FIG. 7 shows the results of analysis of major residues involved in the binding between the HAT p300 domain and the substrate inhibitor Lys-CoA molecule using molecular docking simulation according to an embodiment of the present invention.
  • a compound selected from the compound represented by the following Formula 1, a pharmaceutically acceptable salt thereof, an optical isomer, a hydrate, and a solvate is provided:
  • R 1 is selected from the group consisting of a substituted or unsubstituted C 3 to C 40 cycloalkyl group, a heterocycloalkyl group having 5 to 7 nuclear atoms, a C 6 to C 14 aryl group, and a heteroaryl group having 5 to 14 nuclear atoms.
  • R 2 is halogen, and when there are a plurality of R 2 , they are the same as or different from each other;
  • the prevention, improvement or treatment of p300-related diseases comprising as an active ingredient a compound selected from the compound represented by Formula 1, its pharmaceutically acceptable salt, optical isomer, hydrate and solvate Provides a way.
  • Tissues obtained from patients with idiopathic pulmonary fibrosis or normal people were fixed with 10% formalin, embedded in paraffin, and a 7 ⁇ m-thick section was attached to the slide. Then, after deparaffinizing the section using xylene, ethanol was treated in the order of high concentration to low concentration, and p300 (histone acetyltransferase p300), GCN5 (histone acetyltransferase GCN5), and PCAF (P300/CBP-associated factor). After performing immunostaining using a specific antibody, the expression level of each protein was measured using an optical microscope, and the results are shown in FIGS. 1 to 3.
  • p300 As shown in FIGS. 1 to 3, among histone acetyltransferase (hereinafter referred to as'HAT') p300, GCN5 and PCAF, p300 increased in tissues of patients with idiopathic pulmonary fibrosis compared to tissues obtained from normal subjects. I confirmed that it was done.
  • 'HAT' histone acetyltransferase
  • p300 is present at a higher level than that of normal tissues, so when specifically inhibiting the expression or function of p300, fibrosis is effectively suppressed. It can be seen that it can be cured.
  • candidate substances 1 to 14 inhibited the activity of HAT by 80% or more, but candidate substances 15 to 67, HAT-25, HAT-26 and HAT-28 showed an efficiency of inhibiting the activity of HAT from 20% to 20%. It was only 50%.
  • Candidates 1 to 14 having good HAT inhibition efficiency in [2-1] were diluted at concentrations of 0.5 ⁇ M, 1 ⁇ M, 10 ⁇ M and 100 ⁇ M. Then, the degree of inhibition of HAT activity was confirmed in the same manner as in [2-1], and the results are shown in FIG. 5 and Table 1.
  • Candidate substance One 2 3 4 5 6 7 8 9 10 11 12 13 14 IC 50 ( ⁇ M) 50.84 44.09 28.9 12.12 32.4 10.14 27.65 35.52 9.01 13.12 41.67 0.953 32.84 35.82
  • candidate material 12 As shown in FIG. 5 and Table 1, the IC 50 of candidate 12 (HAT-12) among candidate substances 1 to 14 was confirmed to be 0.953.
  • candidate material 12 is as shown in Formula 3 below.
  • Synthesis Examples 1 to 19 having the above characteristics to further increase HAT p300 inhibitory activity were prepared as follows.
  • Yellow solid compound 4 was obtained using 5-chlorovanillin (1.00 g, 5.36 mmol) and ethyl 3-(chloromethyl)benzoate (1.06 g, 5.36 mmol) (1.18 g, 63.1%).
  • White solid compound 7 was obtained using 5-chlorovanillin (1.00 g, 5.36 mmol) and ethyl 3-(bromomethyl)benzonitrile (1.05 g, 5.36 mmol) (1.30 g, 80.5%).
  • a white solid compound 8 was obtained using 5-bromovanillin (1.00 g, 4.33 mmol) and ethyl 3-(bromomethyl)benzonitrile (0.85 g, 4.33 mmol) (1.53 g, 83.8%).
  • White solid compound 10 was obtained by using 5-chlorovanillin (1.00 g, 5.36 mmol) and ethyl 3-fluorobenzyl chloride (0.78 g, 5.36 mmol) (1.15 g, 72.8%).
  • Vanillin (1.00 g, 6.57 mmol) and 3-methoxybenzyl chloride (1.03 g, 6.57 mmol) were used to obtain a yellow semi-solid compound 11 (1.48 g, 99.6%).
  • White solid compound 12 was obtained using 5-chlorovanillin (0.18 g, 0.96 mmol) and 4-(chloromethyl)benzamide (0.16 g, 0.96 mmol) (0.22 g, 73.2%).
  • White solid compound 13 was obtained by using 5-bromovanillin (0.18 g, 0.79 mmol) and 4-(chloromethyl)benzamide (0.13 g, 0.79 mmol) (0.20 g, 73.2%).
  • White solid compound 14 was obtained by using 5-idovanillin (0.26 g, 0.94 mmol) and 4-(chloromethyl)benzamide (0.16 g, 0.94 mmol) (0.28 g, 72.4%).
  • White solid compound 16 was obtained by using 5-bromovanillin (0.18 g, 0.79 mmol) and 3-(chloromethyl)benzamide (0.13 g, 0.79 mmol) (0.20 g, 73.2%).
  • White solid compound 17 was obtained by using 5-idovanillin (0.26 g, 0.94 mmol) and 3-(chloromethyl)benzamide (0.16 g, 0.94 mmol) (0.28 g, 72.4%).
  • Synthesis Example 1 of a brown syrup was obtained using compound 2 (208 mg, 0.59 mmol) and 1-(2-aminoethyl) piperidine (75 mg, 0.59 mmol) (260 mg, 95.4%).
  • Synthesis Example 2 of a brown syrup was obtained using compound 3 (205 mg, 0.51 mmol) and 1-(2-aminoethyl) piperidine (55 mg, 0.51 mmol) (260 mg, 99.6%).
  • Synthesis Example 3 of yellow syrup was obtained using compound 4 (200 mg, 0.57 mmol) and 1-(2-aminoethyl) piperidine (73.5 mg, 0.57 mmol) (275 mg, quantitative).
  • Synthesis Example 4 of yellow syrup was obtained using compound 5 (200 mg, 0.51 mmol) and 1-(2-aminoethyl) piperidine (65.2 mg, 0.51 mmol) (252 mg, 98.2%).
  • Synthesis Example 5 of yellow syrup was obtained by using compound 6 (200 mg, 0.45 mmol) and 1-(2-aminoethyl) piperidine (58.3 mg, 0.45 mmol) (238 mg, 93.0%).
  • Synthesis Example 6 of a yellow syrup was obtained using compound 7 (200 mg, 0.66 mmol) and 1-(2-aminoethyl) piperidine (85.0 mg, 0.66 mmol) (273 mg, quantitative).
  • Synthesis Example 8 of a yellow syrup was obtained using compound 9 (200 mg, 0.51 mmol) and 1-(2-aminoethyl) piperidine (65.2 mg, 0.51 mmol) (245 mg, 95.7%).
  • Synthesis Example 9 of a yellow syrup was obtained using compound 10 (200 mg, 0.68 mmol) and 1-(2-aminoethyl) piperidine (87.0 mg, 0.68 mmol) (267 mg, 97.2%).
  • Synthesis Example 12 of a brown syrup was obtained using compound 11 (200 mg, 0.72 mmol) and 2-2 (aminoethyl) thiophene (91.9 mg, 0.72 mmol) (280 mg, quantitative).
  • Synthesis Example 14 as a pink solid was obtained using compound 12 (100 mg, 0.31 mmol) and 1-(2-aminoethyl) piperidine (40.1 mg, 0.31 mmol) (132 mg, 98.6%).
  • Synthesis Example 15 as a pale yellow solid was obtained using compound 13 (100 mg, 0.27 mmol) and 1-(2-aminoethyl) piperidine (35.2 mg, 0.27 mmol) (123 mg, 97.3%).
  • Synthesis Example 18 of foamy semi-solid was obtained using compound 15 (100 mg, 0.31 mmol) and 2-(2-aminoethyl) thiophene (39.8 mg, 0.31 mmol) (93 mg, 69.3%).
  • the degree of inhibition of HAT p300 activity of Synthesis Examples 1 to 19 corresponded to 50% on average.
  • the degree of inhibition of HAT p300 activity of 80% was almost similar to that of candidate material 12 (HAT 12).
  • HAT p300 activity was inhibited by 90% or more.
  • the novel synthetic compound according to the present invention is improved so that additional hydrogen bonding with R1410, T1411, W1466, and Y1467 of HAT p300 can occur, thereby more effectively inhibiting the activity of HAT p300, through which HAT p300 It can be seen that it can be used very effectively in the prevention, improvement or treatment of diseases related to
  • the present invention relates to a novel compound that enables additional hydrogen bonding with a specific amino acid position of the HAT p300 through structural analysis of histone acetyltransferase (HAT) p300, and the novel compound of the present invention Has remarkably excellent inhibitory effect on the activity of HAT p300, so it can be used very effectively in the prevention, improvement or treatment of diseases related to the activation of HAT p300, such as fibrosis.
  • HAT histone acetyltransferase

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Abstract

La présente invention concerne un nouveau composé permettant la formation d'une liaison hydrogène supplémentaire avec une position d'acide aminé spécifique dans l'histone acétyltransférase (HAT) p300 par l'analyse structurale de HAT p300. Le nouveau composé selon la présente invention a un excellent effet inhibiteur sur l'activité de HAT p300 et peut être utilisé de manière très efficace dans la prévention, le soulagement ou le traitement de maladies associées à l'activation de HAT p300, telles que la fibrose.
PCT/KR2020/010304 2019-08-05 2020-08-05 Nouveau composé pour inhiber l'histone acétyltransférase p300 et composition antifibrotique le comprenant WO2021025448A1 (fr)

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