WO2017135786A1 - Nouveau composé amide et son utilisation - Google Patents

Nouveau composé amide et son utilisation Download PDF

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WO2017135786A1
WO2017135786A1 PCT/KR2017/001288 KR2017001288W WO2017135786A1 WO 2017135786 A1 WO2017135786 A1 WO 2017135786A1 KR 2017001288 W KR2017001288 W KR 2017001288W WO 2017135786 A1 WO2017135786 A1 WO 2017135786A1
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phenyl
pyrazole
methyl
carboxamido
carbamoyl
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PCT/KR2017/001288
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English (en)
Korean (ko)
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장성연
이혁
김성환
김범태
김성수
허정녕
임환정
임승길
강명모
노경태
이경로
최지원
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연세대학교 산학협력단
한국화학연구원
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Publication of WO2017135786A1 publication Critical patent/WO2017135786A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to novel compounds that can be usefully used for the prevention or treatment of bone diseases and uses thereof.
  • Bone formation and bone resorption are largely caused by the interaction of three cells: chondrocytes, osteoblasts and osteoclasts. .
  • osteoclasts are derived from hematopoietic stem cells and are responsible for uptake of aged bone.
  • Osteoblasts are cells derived from bone marrow stromal cells and play a major role in bone formation.
  • Osteoclasts differentiate RAW264.7 monocytes from mice into multinucleated osteoclasts by the receptor activator of nuclear factor ⁇ B (RANK) ligand (RANKL).
  • RANK nuclear factor ⁇ B
  • MAPK mitogen-activated protein kinase
  • NF- ⁇ B transcription factor NF- ⁇ B
  • RANKL when RANKL binds to RANK, it promotes the activity of TRAF6 (tumor necrosis factor receptor-associated factor 6), thereby promoting the activity of transcription factors such as MAPK or NF- ⁇ B, AP-1, NFATc1 (Lee ZH, Kim).
  • TRAF6 tumor necrosis factor receptor-associated factor 6
  • HH. Signal trasduction by receptor activator of nuclear factor kappa B in osteoclasts.Biochem Biophys Res Commun. 2003 May 30, 305, 211-4). Therefore, blocking of signaling pathways activated by RANKL has been recognized as one of the therapeutic approaches for the treatment of bone diseases including osteoporosis.
  • osteoblasts originate from mesenchymal stem cells, and mineralization such as calcium formation by osteoblast differentiation not only maintains bone strength, but also plays an important role in the homeostasis of calcium and hormone metabolism throughout the body.
  • Calcium formation by osteoblast differentiation is regulated by vitamin D and parathyroid hormone
  • bone formation by osteoblast differentiation is bone morphogenetic protein (BMP), Wnt MAP kinase in cells.
  • BMP bone morphogenetic protein
  • Wnt MAP kinase Wnt MAP kinase in cells.
  • Alkaline phosphatase associated with differentiation of osteoblasts by cross-talk of various signaling systems such as calcineurin-caldomulin kinase, NF- ⁇ B, and AP-1.
  • osteopontin, osteocalcin, type I collagen and the like related to mineralization are synthesized (Pittenger, MF; Mackay, AM; Beck, S. C; Craig, S .; Marshak, DR, Multilineage potential of Adult Human Mesenchymal Stem Cells.Science 1999, 284, 143-147). That is, compounds that promote the activity of alkaline phosphatase may promote the differentiation of osteocytes and may be a target of therapeutic agents for bone diseases.
  • bone formation is continuously controlled by bone resorption by osteoclasts and bone remodeling by an equal action of bone formation by osteoblasts. maintain.
  • excessive activity of osteoclasts or deactivation of osteoblasts may cause imbalances in the remodeling process of bone formation, which may cause bone disease by breaking the balance between osteoclasts and osteoblasts in vivo.
  • Osteoporosis a representative example of bone disease
  • Osteoporosis is a condition in which bone balance decreases due to a loss in the balance between bone formation and bone absorption, and the risk of fracture is continuously increased due to the degeneration of the microstructure of bone tissue. This is a reduced state and the balance of aggregate formation is broken so that osteoclasts occur in an increased state than osteoblasts.
  • Normal bone inside has a dense structure like a mesh, but in the case of osteoporosis, the gap between bone microstructures becomes thinner and the microstructure becomes thinner and weaker, which increases the risk of bone fractures even after a small impact. It is classified as elderly osteoporosis, which occurs gradually in men and women over 70 years of age and causes progressive bone loss of the pelvis and vertebra, and secondary osteoporosis due to diseases, drugs, alcohol, smoking, or accidents, regardless of age.
  • Osteoporosis is currently one of the most important social problems in the United States, causing about 260,000 women every year, with about 12% to 20% of deaths. Aging and postmenopausal women's osteoporosis and osteoporosis fractures cause serious problems in an aging society and women's social participation.
  • Materials currently used for the treatment of osteoporosis include estrogen, androtic anagolic ateroids, calcium preparations, phosphates, fluorides, ipriflavones, and vitamin D3.
  • Estrogens inhibit osteoblastic cell death, increase cell survival, and promote osteoclast cell death to decrease cell survival, which is somewhat effective in treating menopausal symptoms and maintaining bone mineral density. There are side effects that cause back.
  • as a drug for inhibiting the activity of osteoclasts to inhibit bone destruction or to increase the activity of bone regeneration units through the proliferation of osteoblasts calcitonin, para-acid hormone, bisphosphonate preparations, and the like.
  • existing osteoporosis therapeutic agents cause many side effects when administered for a long time. Therefore, there is a need for the development of safe prophylactic and therapeutic agents that have a long-term effect of increasing bone mineral density and have fewer side effects.
  • the present inventors have diligently researched to find novel substances that can effectively treat bone diseases while reducing side effects of conventional bone diseases such as the use of therapeutic agents for osteoporosis. It was confirmed that the prophylactic and therapeutic effect was completed the present invention.
  • One object of the present invention is to provide a series of novel amide compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof.
  • Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of bone diseases comprising the compound, its stereoisomers, or pharmaceutically acceptable salts thereof as an active ingredient.
  • a pharmaceutical composition comprising a compound represented by Formulas 1 to 3, stereoisomers thereof, or a pharmaceutically acceptable salt thereof according to the present invention
  • FIGS. 1 to 18 are diagrams showing examples of the compound represented by Formula 1 according to an embodiment of the present invention.
  • 19 to 24 are diagrams showing examples of the compound represented by Formula 2 according to an embodiment of the present invention.
  • 25 to 32 are diagrams showing examples of the compound represented by Formula 3 according to an embodiment of the present invention.
  • 33 is a view showing the results of mineralization assay of the compounds according to the embodiment of the present invention.
  • 34A and 34B show mineralization assay results of compounds according to an embodiment of the present invention.
  • ALP alkaline phosphatase
  • 36 is a diagram showing a numerical comparison of ALP assay results of the compounds according to the embodiment of the present invention. Compounds that are 120% or more of KY-06003 are marked in red.
  • FIG. 37 is a diagram showing a numerical comparison of the results of mineralization assay of the compounds according to the embodiment of the present invention. Compounds that are 120% or more of KY-06003 are marked in red.
  • 38A to 38D illustrate ALP assay results of OVX-injected compounds of compounds according to an embodiment of the present invention.
  • 39 is a view showing the results of mineralization assay of the compound injected OVX of the compound according to the embodiment of the present invention.
  • FIG. 40 is a diagram showing an example of a method for preparing a compound represented by Formula 1 of the present invention.
  • 41 is a diagram showing an example of a method for preparing a compound represented by Formula 2 of the present invention.
  • FIG. 42 is a diagram showing an example of a method for preparing a compound represented by Formula 3 of the present invention.
  • 43 is a diagram showing the recovery effect on the Wnt signaling system by the compound of the present invention.
  • 44A to 44J show ELISA binding assay results for the compounds of the present invention.
  • 45 is a diagram showing a result of SPR binding assay of a compound of the present invention.
  • 46 is a diagram showing the effect on the bone density of the compound of the present invention.
  • FIG. 47 is a diagram showing the effect on the bone area and the bone circumference of the compound of the present invention.
  • 48 is a diagram showing the effect on the bone cross-sectional thickness and bone surface area of the compound of the present invention.
  • the present invention is a compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 to R 3 are each independently hydrogen, halogen, —SO 3 H, C 1-4 alkyl, C 6-10 aryl, or two adjacent substituents connected to each other and fused together with a thiophene ring to which they are bonded; Form hetero aryl,
  • the aryl is unsubstituted or from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 fluorinated alkyl, C 1-4 fluorinated alkoxy, cyano, carboxamido and acetamino May be substituted with any one or more substituents selected;
  • R 4 is hydrogen, halogen, —CO 2 (C 0-4 alkyl), —CO 2 (C 6-10 aryl), or —CONHW, wherein W is a protected or unprotected amino acid;
  • R 5 is C 1-4 alkyl, or unsubstituted or substituted C 6-10 aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, or C 3-10 cycloalkyl,
  • W ' is a protected or unprotected amino acid
  • n is an integer of 0-3.
  • R 1 to R 3 are each independently hydrogen, chloro, bromo, -SO 3 H, cyano, methyl, phenyl, or R 1 and R 2 are linked to each other to form benzothiophene together with the thiophene ring to which they are bonded.
  • the phenyl may be unsubstituted or substituted with any one or more substituents selected from the group consisting of fluoro, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, aminoformyl and acetamino;
  • R 4 is hydrogen, fluoro, —CO 2 H, —CO 2 CH 3 , —CO 2 C 2 H 5 , or —CONHW, wherein W is isoleucine, protected or unprotected with methyl;
  • R 5 is propyl, cyclopropyl, benzodioxolyl, or unsubstituted or substituted phenyl, pyridinyl, piperidinyl or cyclohexyl,
  • the phenyl, pyridinyl, piperidinyl and cyclohexyl may be unsubstituted or benzyl, benzyloxy, morpholinyl, -CONH (CH 2 ) 2 morpholinyl, -CONH (CHCH 3 ) CONH (CH 2 ) 2 morpholi Nyl, fluoro, chloro, bromo, methyl, trifluoromethyl, thiophenyl, -CONH 2 , -CONHCH 3 , -CONHC 2 H 5 , -SO 2 NH 2 , -CH 2 CO 2 H, -CH 2 CO 2 CH 3 , -COCH 3 , -CO 2 H, -CO 2 CH 3 , -CO 2 C 2 H 5 , -CO 2 (tert-butyl), -SO 3 H, phenoxy, sulfofenoxy, and -CONHW 'may be substituted with any one or more substituents selected from the
  • W is tryptophan, alanine, aspartic acid, phenylalanine, tyrosine, valine, isoleucine, leucine or methionine, protected or unprotected with methyl or tert-butyl;
  • n can be zero or one.
  • the present invention provides a compound represented by the following formula (2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 6 is C 6-10 aryl, 3 to 10 membered heterocycloalkyl, or (3 to 10 membered heterocycloalkyl) (C 1-4 alkyl),
  • the aryl and heterocycloalkyl are unsubstituted or C 1-4 halogenated alkyl, -CO (C 6-10 aryl), -CO ( 1-4 alkyl), -CONH (C 6-10 aryl), -SO 2 (C 6-10 aryl unsubstituted or substituted with C 1-4 alkyl), (C 6-10 aryl) (C 1-4 alkyl), -CO 2 (C 0-4 alkyl), halogen, C 1- 4 alkoxy, C 6-10 aryloxy, 5-10 membered heteroaryl, or -CONHW '', which may be substituted with any one or more substituents selected from the group consisting of:
  • R 7 is hydrogen, C 6-10 aryloxy, -CONH (C 1-4 alkylene) (3 to 10 membered heterocycloalkyl), -CO 2 (C 0-4 alkyl), or -CONHW '',
  • Each of W ′′ is an independently protected or unprotected amino acid.
  • R 6 is phenyl, piperidinyl, or piperidinylmethyl
  • phenyl and piperidinyl are unsubstituted or trifluoromethyl, trifluoromethoxy, -CO 2 H, -CO 2 CH 3 , -CO 2 (phenyl), -CONH (phenyl), halogen, C 1- 4 may be substituted with any one or more substituents selected from the group consisting of alkoxy, benzyl, imidazolyl, tosyl, or phenoxy;
  • R 7 is hydrogen, phenoxy, -CONH (CH 2 ) 2 (morpholinyl), -CO 2 H, -CO 2 CH 3 or -CONHW '',
  • the W ′′ may be tryptophan, protected with or without methyl, but is not limited thereto.
  • the present invention provides a compound represented by the following formula (3), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • Z is -CO 2 H, -CO 2 (C 1-4 alkyl), -CONH (C 1-4 alkyl), hydroxy, C 1-4 alkyl, C 1-4 halogenated alkyl, C 3-8 cycloalkyl , 3 to 10 membered heterocycloalkyl, C 6-10 aryl or 5 to 10 membered heteroaryl,
  • the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted, hydroxy, C 1-4 alkyl, C 1-4 halogenated alkyl, C 6-10 aryloxy, (C 6-10 aryl) (C 1 -4 alkyl), (C 6-10 aryl) (C 1-4 alkyl) oxy, -CONH (C 0-4 alkyl), 3 to 10 membered heterocycloalkyl, and - (C 0-4 alkylene) CO Can be substituted with any one or more substituents selected from the group consisting of 2 (C 0-4 alkyl);
  • R 8 and R 9 are each independently hydrogen, — (C 0-4 alkylene) CO 2 (C 0-4 alkyl), —CONH (C 0-4 alkyl), or halogen;
  • R 10 and R 11 are each independently hydrogen or halogen.
  • Z is -CO 2 H, -CO 2 C 2 H 5 , -CONH 2 , -CONHCH 3 , hydroxy, methyl, propyl, trifluoroalkyl, or hydroxy, bromo, trifluoroalkyl, phenoxy, Unsubstituted or substituted with any one or more substituents selected from the group consisting of phenylethyl, benzyl, benzyloxy, morpholinyl, -CONHCH 3 , -CO 2 H, -CO 2 CH 3 , and -CO 2 C 2 H 5 Cyclopropyl, piperidinyl, morpholinyl, indolyl, indazolyl, phenyl or pyridinyl;
  • R 8 and R 9 are each independently hydrogen, —CO 2 H, —CH 2 CO 2 H, —CH 2 CO 2 CH 3 , —CO 2 CH 3 , —CO 2 C 2 H 5 , chloro, bromo, -CONHCH 3 , -CH 2 CONH 2 , or -CONH 2 ;
  • R 10 and R 11 may each independently be hydrogen or fluoro.
  • the compounds represented by Formulas 1 to 3 of the present invention may be used in the form of a pharmaceutically acceptable salt.
  • salts are acid addition salts formed with pharmaceutically acceptable free acids.
  • pharmaceutically acceptable salt of the present invention is any concentration of the compound which is relatively nontoxic to the patient and has a harmless effective action, and the side effects caused by the salt do not degrade the beneficial efficacy of the compound represented by the formula (I). Means any organic or inorganic addition salt.
  • the compounds of the present invention may be used alone or in combination or in combination with other pharmaceutically active compounds.
  • Pharmaceutically acceptable salts of the compounds represented by Formulas 1 to 3 of the present invention refer to salts prepared according to methods conventional in the art, and such preparation methods are known to those skilled in the art.
  • the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable inorganic and organic acids and bases.
  • Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
  • a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
  • organic acids and inorganic acids may be used as the free acid
  • hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like may be used as the inorganic acid
  • methanesulfonic acid, p-toluenesulfonic acid, acetic acid, and trifluoroacetic acid may be used as the organic acid.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate.
  • the metal salt it is particularly suitable to prepare sodium, potassium, or calcium salt, but is not limited thereto.
  • Corresponding silver salts may also be obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
  • Pharmaceutically acceptable salts of the compounds represented by formulas (1) to (3) include salts of acidic or basic groups which may be present in the compound of formula (I), unless otherwise indicated.
  • pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group
  • other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfates, hydrogen sulphates, phosphates, hydrogen phosphates , Dihydrogenphosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts; It can be prepared through the method.
  • any salts of the compounds represented by the formulas (1) to (3) of the present invention any salts of the compounds that exhibit biological activities equivalent to those of the compounds may be used without limitation.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of bone diseases comprising a compound represented by the formula (1) to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a method for preventing or treating bone disease, comprising administering the pharmaceutical composition to a subject in need thereof.
  • bone disease refers to a condition or disease that results from excessive production and / or migration of osteoclasts or a condition or disease in which bone mass is required or required by promoting osteoblast activity.
  • Bone loss disorders refers to a condition or a disease in which a decrease in bone mass accompanied by symptoms such as a decrease in bone density and deterioration of bone tissue occurs. Rheumatoid arthritis, but is not limited thereto.
  • the composition of the present invention can be used for the prophylactic treatment of osteoporosis or osteopenia.
  • osteoporosis used in the present invention refers to a state in which bone fracture may occur due to a decrease in bone mass and qualitative change
  • osteoporosis refers to an initial symptom of osteoporosis.
  • it is classified as osteopenia in case of -1.0 to -2.5 and osteoporosis in case of -2.5 or more based on bone density (T).
  • the term "prophylaxis or treatment of bone disease” includes the prevention and complete or partial treatment of said bone disease achieved by administering a composition according to the invention to a subject. It also includes reducing or improving symptoms of bone disease, alleviating the pain of the symptoms, reducing the incidence of bone disease, or any other change in the patient that increases the outcome of treatment.
  • the term "individual" means any animal, including humans, who may or may have a bone disease.
  • the composition of the present invention can be administered to an individual to effectively prevent or treat the bone disease.
  • the composition of the present invention can be administered in parallel with existing therapeutic agents for bone disease.
  • the term "administration" means introducing a predetermined substance into a patient in an appropriate manner, and the route of administration of the composition of the present invention may be administered via any general route as long as it can reach the target tissue. Can be. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, nasal administration, pulmonary administration, rectal administration, but is not limited thereto.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to the medical treatment and not causing side effects, wherein the effective dose level is the sex, age and weight of the patient. , Factors such as health status, type of disease, severity, drug activity, drug sensitivity, method of administration, time of administration, route of administration, and rate of release, duration of treatment, combination or drug used, and other medical fields. It can be easily determined by those skilled in the art according to known factors.
  • the active substance can be administered at a dose of about 0.01 mg / kg / day to 1000 mg / kg / day. In the case of oral administration, a range of 50 to 500 mg / kg may be suitable and may be administered at least once a day.
  • the pharmaceutical composition of the present invention may contain 0.001 to 1% by weight of the compound represented by Formula 1 to 3, stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition for preventing or treating bone diseases according to the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent in addition to the active ingredient described above.
  • a pharmaceutically acceptable carrier means to exhibit properties that are not toxic to an individual such as a cell or human being exposed to the composition.
  • the carrier can be used without limitation so long as it is known in the art such as buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, bases, excipients, lubricants.
  • Carriers, excipients and diluents that may be included in the pharmaceutical compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium Silicates, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • composition of the present invention when formulating the composition of the present invention, it can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used.
  • a solid preparation such as tablets, pills, powders, granules, capsules and the like.
  • Such solid preparations are prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, or lactose, gelatin and the like in addition to the composition.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups.In addition to the commonly used simple diluents, water and liquid paraffin, various excipients such as wetting agents, flavoring agents, preservatives, etc. Can be.
  • the oral composition may be formulated to coat the active agent or to protect it from degradation in the stomach.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • As the base of the suppository utopsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • carbohydrates such as glucose, sucrose, dextran, antioxidants such as ascorbic acid, glutathione, chelating substances, small molecule proteins or other stabilizers can be used.
  • compositions of the present invention may be administered by any device in which the active substance may migrate to target cells.
  • Preferred modes of administration and preparations are intravenous, subcutaneous, intradermal, intramuscular, injectable and the like.
  • Injections include non-aqueous solvents such as aqueous solvents such as physiological saline solution and ring gel solution, vegetable oils, higher fatty acid esters (e.g., oleic acid, etc.), and alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.).
  • Stabilizers e.g.
  • Preservatives eg, mercury nitrate, chimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc. may be included.
  • compositions of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is determined by the condition and weight of the patient, Depending on the extent, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.
  • Wnt signaling is required for skeletal development, adult skeletal homeostasis, and bone aggregate formation.
  • Wnt proteins are involved in various signaling pathways (Box1), but it is believed that most of the Wnt signaling system's action on the skeletal system is explained by the canonical wnt-beta-catenin signaling pathway.
  • betacatenin is released from the complex and is not subject to proteolysis.
  • Stabilization of betacatenin induces the transfer of betacatenin into the nucleus and induces osteoblast differentiation by controlling transcription of genes such as WISP1 and RUNX2 in conjunction with transcription factors (TCF-4 or LEF-1).
  • Adipogenesis is inhibited by inhibiting adipogenic factors such as C / EBP ⁇ (CCAAT / enhancer binding protein ⁇ ) and PPAR- ⁇ (peroxisome proliferator activated receptor ⁇ ).
  • Wnt signaling systems are also important in the inhibition of osteoclast formation and bone resorption. Inhibition of osteoclast formation by Wnt is reported to be due to the induction of the expression of osteoprotegerin (also known as TNF receptor superfamily member 11B), which binds to RANKL and inhibits osteoclast formation. .
  • the mechanical load activates the Wnt signaling system in cells of the osteoblast lineage, suggesting that the action of Wnt may be involved in linking mechanical forces to assimilation of the skeletal system.
  • This mechanism is associated with the inhibition of sclerostin, a Wnt antagonist preferentially expressed by epidemiological osteoblasts. Inhibition of sclerostin is particularly present in sites that are subject to high loads in bone, which promotes Wnt signaling and bone formation. In contrast, sclerostin is increased by no-load of the skeletal system, which causes bone loss due to increased bone resorption and reduced bone formation. This mechanism is thought to be related to the development of osteoporosis of disuse, which results in decreased bone mass due to continued bed rest and nerve damage. Insoluble
  • Antagonists that interact with Wnt and LRP-5-LRP-6 co-receptors include sclerostin and Dickkopf-related protein 1 (Dkk-1).
  • Sclerostine encoded by SOST is mainly expressed by osteoblasts, which binds to the LRP5-LRP6 co-receptor and interferes with Wnt signaling.
  • sclerostin inhibits osteoblast formation and bone formation in vitro and in vivo.
  • Sclerostine expression is inhibited by mechanical compression and parathyroid hormone (PTH) in osteoblasts and osteocytes. In patients with hyperparathyroidism, lower levels of sclerostin than those with normal parathyroid function can be observed. .
  • PTH parathyroid hormone
  • Osteopenia is caused by decreased osteoblast count and bone formation.
  • recently developed antibodies against sclerostin have demonstrated that sclerostin is prevented from binding to the Lrp-5-Lrp-6 co-receptor, thereby enhancing the Wnt signal and increasing bone density and bone mass.
  • Monoclonal Anti-body (Ab) against sclerostin is the main competitor.
  • the problems of Monoclonal Ab are as follows.
  • Carboxylic acid compound (40 mg, 0.1 mmol), methylamine (3.0 equiv), EDCI (1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide; 3.0 equiv), HOBt (N-hydroxybenzotriaxole; 3.0 equiv) in 7 mL vials, DIPEA (N, N-diisopropylethylamine; 3.0 equivalents) was dissolved in dimethylformamide (DMF; 0.3 M) and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted three times with H 2 O / EA mixed solvent and the organic layer was washed with saturated sodium carbonate. The organic layer was dried over MgSO 4 , the solvent was concentrated under reduced pressure, and silica gel column was performed to obtain the title compound (36 mg, 89%).
  • DIPEA N, N-diisopropylethylamine; 3.0 equivalents
  • the ester compound (200 mg, 0.43 mmol) in a 7 mL vial was dissolved in LiOH (5.0 equiv), THF / H 2 O / MeOH mixed solvent, and then stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, and acid-base extraction was performed. The water layer was washed with ether, adjusted to pH 3 by adding 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (178 mg, 94%).
  • Example 14 3- (3- (N- Profile Sulpa Mole ) Benzamido ) Benzoic acid (3- (3- (N-propylsulfamoyl) benzamido) benzoic acid); KY-06430
  • the ester compound (100 mg, 0.4 mmol) was dissolved in a THF / H 2 O / MeOH mixed solvent in a 7 mL round bottom flask, and LiOH (30 mg, 0.8 mmol) was added thereto and stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, 15 mL of water was added, 1N HCl was added, and extracted three times with EA (30 mL) at pH 2. The organic layer was dried over MgSO 4 to afford the title compound (133 mg, 95%).
  • Example 21 N- (3- (2- (methylamino) -2-oxoethyl) phenyl) -3- (N-phenylsulfamoyl) benzamide (N- (3- (2- (methylamino) -2-oxoethyl ) phenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06437
  • Example 24 3- (N- (4- (benzyloxy) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (N- (4- (benzyloxy) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06440
  • Example 25 3- (3- (N- (1- Benzylpiperidine -4- days) Sulfa Mole ) Benzamido ) Benzoic acid (3- (3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) benzamido) benzoic acid); KY-06442
  • Example 26 3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (N- (1-benzylpiperidin-4- yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06443
  • Example 27 3- (3- (N- (4- Morpholinophenyl ) Sulfa Mole ) Benzamido ) Benzoic acid (3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido) benzoic acid); KY-06445
  • Example 30 3- (N- (1H-indol-5-yl) Sulfa Mole ) -N- (3- ( Methylcarbamoyl ) Phenyl) benzamide (3- (N- (1H-indol-5-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06448
  • Example 31 3- (3- (N- (1H-indol-6-yl) Sulfa Mole ) Benzamido ) Benzoic acid (3- (3- (N- (1H-indol-6-yl) sulfamoyl) benzamido) benzoic acid); KY-06449
  • Example 32 3- (N- (1H-indol-6-yl) Sulfa Mole ) -N- (3- ( Methylcarbamoyl ) Phenyl) benzamide (3- (N- (1H-indol-6-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06450
  • Example 33 3- (3- (N- (3,5- Bis (trifluoromethyl) phenyl ) Sulfa Mole ) Benzamido ) Benzoic acid (3- (3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) benzamido) benzoic acid); KY-06451
  • Example 34 3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (N- (3,5- bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06452
  • Example 35 3-((3-((3- Carboxyphenyl ) Cabamo ) Phenyl) Sulfonamido ) Benzoic acid (3-((3-((3-carboxyphenyl) carbamoyl) phenyl) sulfonamido) benzoic acid); KY-06453
  • the ester compound (200 mg, 0.43 mmol) in a 7 mL vial was dissolved in LiOH (5.0 equiv), THF / H 2 O / MeOH mixed solvent, and stirred at room temperature for 6 hours. After completion of the reaction, the solvent was removed and acid-base extraction was performed. The water layer was washed with ether, adjusted to pH 3 by adding 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (178 mg, 94%).
  • Example 36 Ethyl 3-((2,4- Difluoro -5- ( Phenylcarbamoyl ) Phenyl) Sulfonamido ) Benzoate (ethyl 3-((2,4- difluoro -5- (phenylcarbamoyl) phenyl) sulfonamido) benzoate); KY-06454
  • sulfonyl chloride compound (2.59 mmol, 860 mg) was dissolved in methylene chloride (MC, 9 mL), followed by ethyl 3-aminobenzoate (1.0 equiv., 0.38 mL), DIPEA (1.5 equiv., 0.68 mL) was added and stirred at room temperature for 2 days. After completion of the reaction, the mixture was extracted three times with H 2 O / EA mixed solvent and the organic layer was dried over MgSO 4 . After silica gel column was concentrated under reduced pressure, solidified with MC / ether / hexane and filtered through a sinter to give the title compound (128 mg, 11%) as a yellow solid compound.
  • MC methylene chloride
  • DIPEA 1.5 equiv., 0.68 mL
  • Example 37 3-((2,4- Difluoro -5- ( Phenylcarbamoyl ) Phenyl) Sulfonamido ) Benzoic acid (3-((2,4-difluoro-5- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid); KY-06455
  • Example 38 Ethyl 3- (4-fluoro-3- (N-phenylsulfamoyl) benzamido ) Benzoate (ethyl 3- (4- fluoro -3- (N- phenylsulfamoyl ) benzamido ) benzoate); KY-06456
  • acyl chloride compound (1.3 mmol, 346 mg) was dissolved in MC (1.5 mL) in a 25 mL round bottom flask, ethyl 3-aminobenzoate (0.95 equiv., 209 mg, 1.24 mmol), DIPEA (0.95) in a 7 mL vial. Equivalent weight, 0.218 mL, 1.24 mmol) and MC (1.5 mL) were stirred together. The mixture contained in a 7 mL vial was slowly added to a 25 mL round bottom flask, and the 7 mL vial was further added with MC (0.5 mL), followed by stirring at 0 ° C. for 30 minutes.
  • Example 39 3- (4- Fluoro -3- (N- Phenylsulfamoyl ) Benzamido ) Benzoic acid (3- (4-fluoro-3- (N-phenylsulfamoyl) benzamido) benzoic acid); KY-06457
  • Example 40 Ethyl 3- (2,4-difluoro-5- (N-phenylsulfamoyl) benzamido ) Benzoate (ethyl 3- (2,4- difluoro -5- (N- phenylsulfamoyl ) benzamido ) benzoate); KY-06458
  • acyl chloride compound (1.4 mmol, 392.5 mg) was dissolved in MC (1.5 mL) in a 25 mL round bottom flask, ethyl 3-aminobenzoate (0.95 equiv., 224 mg, 1.33 mmol), DIPEA (0.95) in a 7 mL vial. Equivalent, 0.234 mL, 1.33 mmol) and MC (1.5 mL) were stirred together. The mixture contained in a 7 mL vial was slowly added to a 25 mL round bottom flask, and the 7 mL vial was further added with MC (0.5 mL), followed by stirring at 0 ° C. for 30 minutes.
  • Example 41 3- (2,4- Difluoro -5- (N- Phenylsulfamoyl ) Benzamido ) Benzoic acid (3- (2,4-difluoro-5- (N-phenylsulfamoyl) benzamido) benzoic acid); KY-06459
  • the ester compound (230 mg, 0.49 mmol) was dissolved in THF (1.5 mL) in a 7 mL vial and stirred.
  • H 2 O (1.5 mL) and MeOH (1.0 mL) were added by syringe, and LiOH (12.6 mg, 2.0 equiv., 0.30 mmol) was added thereto, and the mixture was stirred at room temperature for 24 hours.
  • Example 42 methyl 3- (3- (N- (2-phenoxyphenyl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- (2- phenoxyphenyl ) sulfamoyl ) benzamido ) benzoate); KY-06462
  • Example 43 methyl 3- (3- (N- (3-phenoxyphenyl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- (3- phenoxyphenyl ) sulfamoyl ) benzamido ) benzoate); KY-06463
  • Example 44 methyl 3- (3- (N- (4-phenoxyphenyl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- (4- phenoxyphenyl ) sulfamoyl ) benzamido ) benzoate); KY-06464
  • Example 45 methyl 3- (3- (N- (4- ( Benzyloxy ) Phenyl) Sulfa Mole ) Benzamido ) Benzoate (methyl 3- (3- (N- (4- ( benzyloxy ) phenyl) sulfamoyl ) benzamido ) benzoate); KY-06465
  • Example 46 methyl 3- (3- (N- (pyridin-2-yl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- ( pyridin -2- yl ) sulfamoyl ) benzamido ) benzoate); KY-06466
  • Example 47 methyl 3- (3- (N- (pyridin-3-yl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- ( pyridin -3- yl ) sulfamoyl ) benzamido ) benzoate); KY-06467
  • Example 48 methyl 3- (3- (N-propylsulfamoyl) benzamido) benzoate (methyl 3- (3- (N-propylsulfamoyl) benzamido) benzoate); KY-06468
  • Example 49 methyl 3- (3- (N-cyclopropylsulfamoyl) benzamido) benzoate (methyl 3- (3- (N- cyclopropylsulfamoyl ) benzamido ) benzoate); KY-06469
  • Example 50 methyl 3- (3- (N-methylsulfamoyl) benzamido) benzoate (methyl 3- (3- (N-methylsulfamoyl) benzamido) benzoate); KY-06470
  • Example 51 methyl 3- (3- (N- (4-morpholinophenyl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- (4- morpholinophenyl ) sulfamoyl ) benzamido ) benzoate); KY-06471
  • Example 52 methyl 3- (3- (N- (1H-indol-5-yl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- (1H- indol -5- yl ) sulfamoyl ) benzamido ) benzoate); KY-06472
  • Example 53 methyl 3- (3- (N- (1H-indol-6-yl) sulfamoyl) benzamido ) Benzoate (methyl 3- (3- (N- (1H- indol -6- yl ) sulfamoyl ) benzamido ) benzoate); KY-06473
  • Example 54 methyl 3- (3- (N- (3,5- Bis (trifluoromethyl) phenyl ) Sulfa Mole ) Benzamido ) Benzoate (methyl 3- (3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) benzamido) benzoate); KY-06474
  • Example 55 methyl 3- (3- (N- (1- Benzylpiperidine -4- days) Sulfa Mole ) Benzamido ) Benzoate (methyl 3- (3- (N- (1- benzylpiperidin -4- yl ) sulfamoyl ) benzamido ) benzoate); KY-06475
  • Example 56 methyl 3-((3-((3- ( Methoxycarbonyl ) Phenyl) Cabamo ) Phenyl) Sulfonamido ) Benzoate (methyl 3-((3-((3- (methoxycarbonyl) phenyl) carbamoyl) phenyl) sulfonamido) benzoate); KY-06476
  • a carboxylic acid compound (2.2 g, 10 mmol) was added to thionyl chloride (20 mL) and refluxed for 16 hours. After completion of the reaction, thionyl chloride was removed, aminobenzoate (1.69 g, 9 mmol, 0.9 sugar) and DIPEA (1.6 mL) were dissolved in MC (8 mL), followed by stirring at 0 ° C. 3-chlorosulfonyl benzoyl chloride was dissolved in MC (8 mL) and added slowly. After stirring for 30 minutes at 0 ° C., the mixture was extracted with distilled water and MC, dried over MgSO 4 , and separated by silica gel column to obtain the title compound.
  • Example 58 methyl 3- Bromo -5- (3- (N-phenylsulfamoyl) benzamido) benzoate (methyl 3- bromo -5- (3- (N- phenylsulfamoyl ) benzamido ) benzoate); KY-06478
  • Example 59 methyl 3- Bromo -5- ((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoate (methyl 3- bromo -5-((3- ( phenylcarbamoyl ) phenyl) sulfonamido ) benzoate); KY-06479
  • Example 60 3- Bromo -5- (3- (N- Phenylsulfamoyl ) Benzamido ) Benzoic acid (3- bromo -5- (3- (N-phenylsulfamoyl) benzamido) benzoic acid); KY-06480
  • the ester compound (100 mg, 0.2 mol) was added to a 7 mL vial with LiOH (20 equivalents) and THF / H 2 O / MeOH mixed solution as a solvent and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and acid-base extraction was performed. The water layer was washed with ether, adjusted to pH 3 by adding 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (95 mg, 98%).
  • Example 61 3- Bromo -5-((3- ( Phenylcarbamoyl ) Phenyl) Sulfonamido ) Benzoic acid (3- bromo -5-((3- (phenylcarbamoyl) phenyl) sulfonamido) benzoic acid); KY-06481
  • the ester compound (100 mg, 0.2 mol) was added to a 7 mL vial with LiOH (20 equivalents) and THF / H 2 O / MeOH mixed solution as a solvent and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and acid-base extraction was performed. The water layer was washed with ether, adjusted to pH 3 by adding 1N HCl, and extracted with EA. The organic layer was dried over MgSO 4 to give the title compound (85 mg, 83%).
  • Example 64 methyl 3-((1-oxo-1,2,3,4- Tetrahydroisoquinoline ) -7- Sulfonamido ) Benzoate (methyl 3-((1- oxo -1,2,3,4- tetrahydroisoquinoline ) -7-sulfonamido) benzoate); KY-06484
  • Example 65 3- (N- (2- ( Phenylamino ) Phenyl) Sulfa Mole ) Benzoic acid (3- (N- (2- (phenylamino) phenyl) sulfamoyl) benzoic acid); KY-06486
  • the amine compound (300 mg, 1.6 mmol) was dissolved in pyridine (4.0 mL) in a 7 mL vial and stirred for 30 minutes.
  • 3- (chlorosulfonyl) benzoic acid (379 mg, 1.0 equiv) was added slowly.
  • the pyridine was removed under reduced pressure, extracted three times with 1N HCl / EA mixed solution, the organic layer was dried over MgSO 4 , the solvent was concentrated under reduced pressure, and a silica gel column was performed to obtain the title compound (167 mg, 28%). Obtained.
  • Example 66 3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide (3- (N- (1-benzylpiperidin-4- yl) sulfamoyl) -N- (3- (methylcarbamoyl) phenyl) benzamide); KY-06489
  • Example 67 1- (4-Fluorophenyl) -N- (3- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (1- ( 4-fluorophenyl) -N- (3- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06490
  • Example 68 1- (4-fluorophenyl) -N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (1- (4-fluorophenyl ) -N- (3-sulfamoylphenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06491
  • Example 69 3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid (3- (1- (4- fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid); KY-06492
  • Example 70 methyl 3- (1- (4- Fluorophenyl ) -3- (thiophen-2-yl) -1H- Pyrazole -4- Carcassamido ) Benzoate (methyl 3- (1- (4- fluorophenyl ) -3- ( thiophen -2- yl ) -1H-pyrazole-4-carboxamido) benzoate); KY-06493
  • Example 71 N- (3-carbamoylphenyl) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (N- (3-carbamoylphenyl ) -1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06494
  • Example 72 1- (4-Fluorophenyl) -N- (4- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide (1- ( 4-fluorophenyl) -N- (4- (methylcarbamoyl) phenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamide); KY-06496
  • Example 74 3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid (3- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1 H-pyrazole-4-carboxamido) benzoic acid); KY-06498
  • Example 78 3- (N- (1- Benzylpiperidine -4- days) Sulfa Mole ) -N- (3- Carbamoylphenyl ) Benzamide (3- (N- (1-benzylpiperidin-4-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06504
  • Example 80 3- (N- (1H- Indazole -5 days) Sulfa Mole ) -N- (3- Carbamoylphenyl ) Benzamide (3- (N- (1H-indazol-5-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06506
  • Example 81 3- (N- (1H- Indazole -6- days) Sulfa Mole ) -N- (3- Carbamoylphenyl ) Benzamide (3- (N- (1H-indazol-6-yl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06507
  • Example 83 2,4-difluoro-N- (3- (methylcarbamoyl) phenyl) -5- (N-phenylsulfamoyl) benzamide (2,4-difluoro-N- (3- (methylcarbamoyl) phenyl ) -5- (N-phenylsulfamoyl) benzamide); KY-06509
  • Example 84 3- (N- (3,5-bis (trifluoromethyl) phenyl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide (3- (N- (3,5-bis (trifluoromethyl ) phenyl) sulfamoyl) -N- (3-carbamoylphenyl) benzamide); KY-06510
  • Example 85 4- Fluoro -N- (3- ( Methylcarbamoyl ) Phenyl) -3- (N- Phenylsulfamoyl ) Benzamide (4-fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N-phenylsulfamoyl) benzamide); KY-06511
  • Example 87 Ethyl 3-((5-((3- ( Ethoxycarbonyl ) Phenyl) Cabamo )-2- Fluorophenyl Sulfonamido) benzoate (ethyl 3-((5-((3- ( ethoxycarbonyl ) phenyl) carbamoyl ) -2-fluorophenyl) sulfonamido) benzoate); KY-06513
  • Example 88 3-((5-((3- Carboxyphenyl ) Cabamo )-2- Fluorophenyl ) Sulfonamido ) Benzoic acid (3-((5-((3-carboxyphenyl) carbamoyl) -2-fluorophenyl) sulfonamido) benzoic acid); KY-06514
  • Example 89 4-fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N- (3- (methylcarbamoyl) phenyl) sulfamoyl) benzamide (4-fluoro-N- (3- (methylcarbamoyl) phenyl) -3- (N- (3- (methylcarbamoyl) phenyl) sulfamoyl) benzamide); KY-06515
  • Example 90 Ethyl 3- ((2-fluoro-5- (phenylcarbamoyl) phenyl) sulfonamido ) Benzoate (ethyl 3-((2- fluoro -5- ( phenylcarbamoyl ) phenyl) sulfonamido ) benzoate); KY-06516
  • Example 98 4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzoic acid (4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1 H-pyrazole-4-carboxamido) benzoic acid); KY-06524
  • Example 99 4- (5-((3- Phenoxyphenyl ) Cabamo ) Thiazol-2-yl) benzoic acid (4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoic acid); KY-06525
  • Example 100 methyl (4- (5-((3- Phenoxyphenyl ) Cabamo ) Thiazol-2-yl) Benzoyl ) -D- Tryptophanate (methyl (4- (5-((3- phenoxyphenyl ) carbamoyl ) thiazol -2- yl ) benzoyl ) -D-tryptophanate); KY-06527
  • Example 101 (4- (5-((3- Phenoxyphenyl ) Cabamo ) Thiazol-2-yl) Benzoyl ) -D-tryptophan (4- (5-((3-phenoxyphenyl) carbamoyl) thiazol-2-yl) benzoyl) -D-tryptophan; KY-06528
  • Example 102 methyl (3- (3- (5- Chlorothiophene -2-yl) -1-phenyl-1H- Pyrazole -4- Carcassamido ) Benzoyl) -L-tryptophanate (methyl (3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophanate); KY-06529
  • Example 103 (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophan ((3- (3- ( 5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-tryptophan); KY-06530
  • Example 104 methyl (3- (3- (5- Chlorothiophene -2-yl) -1-phenyl-1H- Pyrazole -4- Carcassamido ) Benzoyl) -D-alanine (methyl (3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D-alaninate); KY-06531
  • Example 105 (3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D-alanine ((3- (3- ( 5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -D-alanine); KY-06532
  • Example 106 Dimethyl (3- (3- (5- Chlorothiophene -2-yl) -1-phenyl-1H- Pyrazole -4- Carcassamido ) Benzoyl) -L-aspartate (dimethyl (3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartate); KY-06533
  • Example 107 (3- (3- (5-Chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartic acid ((3- (3- (5-chlorothiophen-2-yl) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) -L-aspartic acid); KY-06534
  • Example 108 4- (1- (4-fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid (4- (1- (4- fluorophenyl) -3- (thiophen-2-yl) -1H-pyrazole-4-carboxamido) benzenesulfonic acid); KY-06535
  • Example 109 Ethyl (3- (3- (5- Chlorothiophene -2-yl) -1-phenyl-1H- Pyrazole -4- Carcassamido ) Benzoyl) glycinate (ethyl (3- (3- (5- chlorothiophen -2- yl ) -1-phenyl-1H-pyrazole-4-carboxamido) benzoyl) glycinate); KY-06536

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Abstract

La présente invention concerne un nouveau composé amide qui peut être utilisé pour la prévention ou le traitement d'une maladie osseuse, et son utilisation.
PCT/KR2017/001288 2016-02-05 2017-02-06 Nouveau composé amide et son utilisation WO2017135786A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20160015230 2016-02-05
KR10-2016-0015230 2016-02-05

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Publication Number Publication Date
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109970654A (zh) * 2019-05-21 2019-07-05 郑州大学 一系列取代2-苯基吡唑衍生物及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004043951A1 (fr) * 2002-10-24 2004-05-27 Carex S.A. Composes et compositions de modulation
WO2007087427A2 (fr) * 2006-01-25 2007-08-02 Synta Pharmaceuticals Corp. Composes thiazole et thiadiazole destines a des utilisations associees a une inflammation et au système immunitaire
US20080119402A1 (en) * 2003-09-22 2008-05-22 Jie Zheng Compositions and methods for the inhibition of dishevelled proteins
US8969339B2 (en) * 2003-09-22 2015-03-03 Enzo Biochem, Inc. Compositions and methods for bone formation and modeling

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8597949B2 (en) * 2007-07-28 2013-12-03 The University Of Chicago Methods and compositions for modulating RAD51 and homologous recombination
CN103889953B (zh) * 2011-07-01 2016-06-08 巴鲁﹒S﹒布隆伯格研究所 作为防乙型肝炎病毒感染的抗病毒剂的氨磺酰苯甲酰胺衍生物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004043951A1 (fr) * 2002-10-24 2004-05-27 Carex S.A. Composes et compositions de modulation
US20080119402A1 (en) * 2003-09-22 2008-05-22 Jie Zheng Compositions and methods for the inhibition of dishevelled proteins
US8969339B2 (en) * 2003-09-22 2015-03-03 Enzo Biochem, Inc. Compositions and methods for bone formation and modeling
WO2007087427A2 (fr) * 2006-01-25 2007-08-02 Synta Pharmaceuticals Corp. Composes thiazole et thiadiazole destines a des utilisations associees a une inflammation et au système immunitaire

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YOKOOJI, A.: "Palladium-catalyzed direct arylation of thiazoles with aryl bromides", TETRAHEDRON, vol. 59, no. 30, 2003, pages 5685 - 5689, XP004437442, DOI: doi:10.1016/S0040-4020(03)00879-2 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109970654A (zh) * 2019-05-21 2019-07-05 郑州大学 一系列取代2-苯基吡唑衍生物及其制备方法和应用

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