WO2018004213A1 - Nouveau composé ayant une activité inhibitrice de smo et composition comprenant celui-ci en tant qu'ingrédient actif pour prévenir ou traiter le cancer - Google Patents

Nouveau composé ayant une activité inhibitrice de smo et composition comprenant celui-ci en tant qu'ingrédient actif pour prévenir ou traiter le cancer Download PDF

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WO2018004213A1
WO2018004213A1 PCT/KR2017/006692 KR2017006692W WO2018004213A1 WO 2018004213 A1 WO2018004213 A1 WO 2018004213A1 KR 2017006692 W KR2017006692 W KR 2017006692W WO 2018004213 A1 WO2018004213 A1 WO 2018004213A1
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cancer
quinazolin
dimethylmorpholino
formula
pyridin
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PCT/KR2017/006692
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Korean (ko)
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이경
고혁완
바타라이디팍
김민경
정주현
이한규
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동국대학교 산학협력단
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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention provides novel isoindolinone or quinazolinone derivative chemicals that act as SMO (smoothened) inhibitors to inhibit cancer caused by Hedgehog signaling hyperactivity. It relates to a pharmaceutical composition for the prevention or treatment of cancer diseases, including as an active ingredient.
  • Hedgehog is a protein that plays an important role in embryonic development and regulates proliferation, migration and differentiation in various organs including dorsal and embryonic axis formation, nervous system, musculoskeletal system, etc.
  • Hedgehog in the adult is involved in the maintenance of stem cells, abnormal abnormal activity in the adult tissue of the hedgehog causes a variety of cancers, such as basal cell carcinoma, brain cancer.
  • Hedgehog signaling abnormalities in the human developmental stage cause stillbirth or organ development disorders because they affect a wide range of processes from the beginning of fetal development to the end organ formation process.
  • hedgehog signaling activity is maintained only in some specific tissues, such as adult stem cells, in adults and is reduced in most tissue somatic cells.
  • excessive signaling activity caused by mutations of hedgehog signaling genes (Ptch, Smo, Sufu, Gli, etc.) at the somatic stage promotes cell proliferation and causes cancer.
  • Sonic Hedgehog There are three types of mammal hedgehogs, Sonic Hedgehog, Indian Hedgehog, and Desert hedgehog. The most studied among them is the Sonic Hedgehog (SHH) signaling pathway that can be expressed systemically.
  • SHH Sonic Hedgehog
  • the Sonic Hedgehog signaling pathway begins by the binding of Sonic Hedgehog to Patched1 (Ptch1), a 12-membrane-through receptor in the cell membrane, and Ptch1 inhibits SMO, a 7-membrane-type Gli protein-binding receptor.
  • Ptch1 When Sonic Hedgehog binds to, Ptch1 loses its action to inhibit SMO.
  • SMO is activated
  • Gli which is a transcription factor
  • the expression of the hedgehog target gene is activated.
  • the hedgehog acting as a ligand binds to the Ptch1 receptor present in the cell membrane and promotes the migration of SMO, another GPCR-like membrane transmembrane protein whose activity is inhibited by Phch1, to the primary ciliary, resulting in hedgehog signaling. It promotes the activity of the Gli transcription factor, a factor.
  • the way in which SMO modulates Gli transcription factor activity is by controlling the Sufu, which inhibits the migration of Gli transcription factors into the nucleus at the lower signaling stage by the hedgehog, or the stability of the Gli protein in the primary cilia. Increase the expression of the inactive Gli to the state of transcriptional activity to induce an increase in the expression of the gene hedge-hog acted by the Gli transcription factor to proceed the cell migration, proliferation and differentiation process.
  • cancers with hedgehog signaling include basal cell carcinoma, medulloblastoma, glioblastoma, breast cancer, prostate cancer, malignant melanoma, lung cancer, Pancreatic cancer.
  • hedgehog also acts as a factor regulating the function of stromal cells that regulate the microenvironment of cancer stem cells as well as cancer cells and cancer stem cells. Therefore, inhibiting hedgehog signaling is an attractive and effective as a number of target control drugs that can simultaneously control the growth of cancer cells at various stages as one drug.
  • the present invention has been made to solve the above problems in the prior art, the present inventors have made diligent efforts to develop an anticancer agent having an SMO inhibitory activity, as a result of confirming the excellent SMO inhibitory activity of the novel compounds according to the present invention The invention has been completed.
  • Another object of the present invention is to provide a novel compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer diseases comprising the novel compound of Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a novel compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • R1 is , or ego
  • R2 is or to be.
  • the present invention also provides a novel compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof.
  • R1 is Cl, , , , , , or ego;
  • R2 is , , , , , , , or to be.
  • the compound represented by Formula 1 may be selected from the group consisting of the following compounds.
  • the compound represented by Formula 2 may be selected from the group consisting of the following compounds.
  • the present invention also provides a pharmaceutical composition for preventing or treating cancer diseases comprising the compound of Formula 1 or Formula 2 as an active ingredient.
  • the present invention also provides a health functional food composition for improving cancer disease comprising the compound of Formula 1 or Formula 2 as an active ingredient.
  • the cancer is basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, chondroma, melanoma, small cell lung cancer, non-small cell lung cancer, B-cell lymphoma, multiple myeloma, brain cancer, esophageal cancer, breast cancer, ovary Cancer, stomach cancer, colorectal cancer, liver cancer, kidney cancer, head and neck cancer, mesothelioma, soft tissue sarcoma, osteosarcoma, testicular cancer, prostate cancer, pancreatic cancer, bone cancer, bone metastasis, acute leukemia, chronic leukemia, glioma, Hodgkins disease, cutaneous melanoma , Bladder cancer, endocrine cancer, parathyroid cancer, thyroid cancer, cervical cancer, endometrial cancer, ovarian cancer, skin cancer, renal cell carcinoma, pituitary adenoma, spinal axis tumor, uterine cancer, gastric cancer and
  • the composition may inhibit the hedgehog signaling pathway (Hedgehog signaling pathway).
  • the composition may inhibit SMO (Smoothened) activity.
  • the composition may inhibit Gli1 expression.
  • the composition may inhibit the hedgehog signaling pathway for the SMO (smoothened) variant (D477H).
  • the present invention also provides a method for treating a cancer disease comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound of Formula 1, Formula 2, or a pharmaceutically acceptable salt thereof. to provide.
  • the present invention provides a therapeutic use of cancer diseases of the pharmaceutical composition comprising a compound of Formula 1, Formula 2 or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a novel compound having an SMO inhibitory activity, and exhibits excellent anticancer effect through the regulation of the hedgehog signaling pathway and the inhibitory activity of SMO activity of isoindolinone derivatives and quinazolinone derivative compounds. Bar, there is an advantage that can prevent, ameliorate or treat cancer diseases.
  • Figure 2 is a diagram showing the IC 50 analyzed the degree of hedgehog signal inhibition of the four isoindolinone derivatives (Isoindolinone).
  • FIG. 3 is a diagram showing IC 50 of Hedgehog signal inhibition level of 22 quinazolinone derivatives.
  • FIG. 4 is a diagram showing representative examples (Compound 14 and Compound 20) of quinazolinone derivatives that inhibit Hedgehog signaling activated by SHh (Sonic Hedgehog) ligand.
  • FIG. 5 is a diagram showing a representative example of a quinazolinone derivative that inhibits signal transduction in the cells from which Ptch1 has been removed without the SHh ligand, thereby increasing Gli1 protein expression.
  • Figure 6 shows that Quinazolinone derivatives, like Vismodegib and Sonidegib, inhibit the migration of SMO proteins, which are sub-action genes of hedgehog signaling activity, to the cilia.
  • Figure 8 shows that Quinazolinone derivatives, like Vismodegib and Sonidegib, inhibit the process of Gli2, a downstream action transcription factor of hedgehog signaling activity, to the cilia.
  • Figure 9 is a comparison of the degree of inhibition of the hedgehog signaling pathway for SMO (D477H) variants that cause resistance to Vismodegib for Vismodegib, Sonidegib and Quinazolinone derivatives.
  • the present inventors when treated with the novel compound prepared in Example, based on the fact that it can inhibit hedgehog signaling, SMO inhibition, Gli transcription factor inhibition and SMO variant (D477H) inhibitory effect of the compound
  • the present invention was specifically confirmed, and based on this, the present invention was completed.
  • the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • R1 is , or ego
  • R2 is or to be.
  • Preferred examples of the compound represented by Formula 1 according to the present invention are as follows.
  • the present invention also provides a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof.
  • R1 is Cl, , , , , , or ego;
  • R2 is , , , , , , , or to be.
  • Preferred examples of the compound represented by Formula 2 according to the present invention are as follows.
  • the term "pharmaceutically acceptable” is suitable for use in contact with the tissue of a subject (eg, a human being) because the benefit / risk ratio is reasonable without excessive toxicity, irritation, allergic reactions or other problems or complications.
  • a compound or composition is within the scope of sound medical judgment.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide.
  • the acid addition salts according to the present invention can be dissolved in conventional methods, for example, by dissolving a compound represented by the formula (1) or (2) in an excess of an aqueous solution of an acid, which salt is a water miscible organic solvent such as methanol, ethanol, acetone or It can be prepared by precipitation with acetonitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.
  • an aqueous solution of an acid which salt is a water miscible organic solvent such as methanol, ethanol, acetone or It can be prepared by precipitation with acetonitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture and then drying or by suction filtration of the precipitated salt.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
  • the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).
  • the compound of Formula 1 or Formula 2 was found to inhibit the activity of most SMO, in particular, quinazoli represented by Compound 14 and Compound 20 In the case of the non-derivative compound, it was found that the SMO inhibitory activity was superior to that of the positive control Vismodegib (see Example 29).
  • the compound of Formula 1 or Formula 2 according to the present invention inhibits SMO (Smoothened) activity through the regulation of the hedgehog signaling pathway (Hedgehog signaling pathway), and inhibits the expression of the transcription factor Gli1 bar, anticancer activity is required It can be used for a variety of purposes and uses.
  • the present invention provides a composition for the prevention, improvement or treatment of cancer diseases containing the compound of Formula 1, Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient, the composition is a pharmaceutical composition and health function It may include all food compositions.
  • prevention means any action that inhibits or delays the onset of a cancer disease by administration of a pharmaceutical composition according to the invention.
  • treatment means any action that improves or advantageously changes to a cancer disease by administration of the pharmaceutical composition according to the present invention.
  • the cancer disease is basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, chondroma, melanoma, small cell lung cancer, non-small cell lung cancer, B-cell lymphoma, multiple myeloma, brain cancer, esophageal cancer, breast cancer, ovarian cancer, gastric cancer, Colorectal cancer, liver cancer, kidney cancer, head and neck cancer, mesothelioma, soft tissue sarcoma, osteosarcoma, testicular cancer, prostate cancer, pancreatic cancer, bone cancer, bone metastasis, acute leukemia, chronic leukemia, glioma, Hodgkins disease, cutaneous melanoma, bladder cancer, endocrine It may be at least one selected from cough cancer, parathyroid cancer, thyroid cancer, cervical cancer, endometrial cancer, ovarian cancer, skin cancer, renal cell carcinoma, pituitary adenoma, spinal axis tumor, uterine
  • diseases associated with hedgehog signaling pathway regulation are all considered to be included in cancer diseases that can be prevented or treated with a compound having the structure of Formula 1 or 2 of the present invention.
  • the cancer may be any cancer caused by hedgehog signaling hyperactivity.
  • the pharmaceutical composition when used in the form of a pharmaceutical composition, may contain a pharmaceutically effective amount of a compound of Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof. It may further comprise a pharmaceutically acceptable carrier, excipient or diluent comprising the composition containing as a component.
  • the pharmaceutically effective amount herein refers to an amount sufficient to prevent or treat the symptoms of cancer disease.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient.
  • the pharmaceutically acceptable carrier is commonly used in the formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose , Polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and the like.
  • it may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
  • 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.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level refers to the type of disease, the severity, the activity of the drug, It may be determined according to the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, factors including the drug used concurrently and other factors well known in the medical field.
  • the pharmaceutical compositions according to the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, weight of the patient, the absorption of the active ingredient in the body, the inactivation rate and excretion rate, the type of disease, the drug used in general 0.001 to 150 mg, preferably 0.01 to 100 mg, per kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day.
  • the dose may be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., the above dosage does not limit the scope of the present invention by any method.
  • the present invention provides a method for treating a cancer disease comprising administering the pharmaceutical composition to a subject.
  • subject means a subject in need of treatment for a disease, and more specifically, a mammal, such as a primate, mouse, dog, cat, horse and cow, which is human or non-human. .
  • the anticancer composition according to the present invention may be used in the form of a dietary supplement composition utilized in the manufacture of foods, such as a main ingredient, a subsidiary ingredient, a food additive, a functional food or a beverage, which are effective in improving cancer diseases. have.
  • the food means a natural product or processed product containing one or more nutrients, and preferably means a state in which it can be directly eaten through some processing process. It includes all additives, functional foods and drinks.
  • the food to which the composition according to the present invention can be added examples include various foods, beverages, gums, teas, vitamin complexes, and functional foods.
  • the food includes special nutritional products (e.g., formulated milk, young, infant food, etc.), processed meat products, fish products, tofu, jelly, noodles (e.g., ramen, noodles, etc.), breads, health supplements, seasoned foods ( For example, soy sauce, miso, red pepper paste, mixed soy sauce), sauces, sweets (e.g. snacks), candy, chocolates, gums, ice creams, dairy products (e.g.
  • the additive may be prepared by a conventional manufacturing method.
  • the functional food is a biological defense rhythm control, disease prevention and recovery of a food group or a food composition that has added value to the food by using physical, biochemical, biotechnological techniques, etc. to function and express the function of the food for a specific purpose. It means a food that is designed and processed to fully express the body control function on the living body, preferably, it may be a health functional food.
  • the functional food may include food acceptable food additives, and may further include appropriate carriers, excipients and diluents commonly used in the manufacture of functional foods.
  • the beverage refers to a generic term of drinking to quench thirst or enjoy a taste and includes a functional beverage.
  • the beverage includes, as an essential component, a composition containing a compound of Formula 1 or Formula 2 or a pharmaceutically acceptable salt thereof for the prevention or amelioration of cancer symptoms.
  • Various flavors or natural carbohydrates and the like may be included as additional ingredients.
  • foods containing the composition of the present invention in addition to those described above include flavors such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and fillers (such as cheese, chocolate), Pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like, which components may be independently or It can be used in combination.
  • flavors such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and fillers (such as cheese, chocolate), Pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like, which components may be independently or It can be used in combination.
  • the amount of the composition may comprise 0.001% to 90% by weight of the total food weight, preferably 0.1% to 40% by weight
  • the amount of the composition may comprise 0.001% to 90% by weight of the total food weight, preferably 0.1% to 40% by weight
  • it may be included in a ratio of 0.001g to 2g, preferably 0.01g to 0.1g based on 100ml, and may be less than the above range for long-term intake, but the active ingredient has no problem in terms of safety. Since it may be used in an amount greater than the above range because it is not limited to the above range.
  • An azeotropic mixture was prepared by refluxing a mixture of 3-bromo-2-methyl benzoic acid (2.00 g, 9.30 mmol), concentrated sulfuric acid (0.20 mL) and ethanol (3.00 ml) under benzene (10.0 mL) for 18 hours.
  • the reaction mixture was cooled to room temperature and washed with saturated sodium bicarbonate solution and water.
  • the organic phase was recovered, dried and concentrated.
  • the crude product was purified by flash column chromatography (Hex: EA 5: 1) to give a colorless liquid as 1.99 g (88.0%) of pure compound.
  • Step 3 Preparation of 4 - bromo- 2- (6-(( 2S, 6R ) -2,6 -dimethylmorpholino ) pyridin-3-yl) isoin dolin-1-one
  • Step 4 2- (6-(( 2S, 6R ) -2,6- dimethylmorpholino ) pyridin-3-yl) -4- (4- ( trifluoromethoxy ) phenyl) isoindolin-1- Manufacture of
  • step 3 4-bromo-2- (6-((2S, 6R) -2,6-dimethylmorpholino) pyridin-3-yl) isoindolin-1-one mixture (step 3), (4- ( Trifluoromethoxy) phenyl) methanediol (1.5 equiv) and 2 M aqueous sodium bicarbonate solution were sealed with a DME in a closed tube. The solution was bubbled under argon for 15 minutes and palladium catalyst (15.0 mg, 5 mol%) was added. The reaction solution was further bubbled under argon for 5 minutes, the sealed tube was heated to 130 ° C. overnight, then cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The combined organic phases were dried, filtered and concentrated. The crude product was purified by flash column chromatography to give pure compound.
  • a pure compound was prepared in the same manner as in Example 1, except that (2,4-difluorophenyl) methanediol was used instead of (4- (trifluoromethoxy) phenyl) methanediol of step 4. Got it.
  • Step 2 Ethyl 2- Methyl- 4 '-( trifluoromethoxy ) biphenyl- 3- carboxylate Produce
  • Step 3 Preparation of ethyl 2- ( bromomethyl ) -4 '-( trifluoromethoxy ) biphenyl- 3- carboxylate
  • Step 4 2- (6-(( 2S, 6R ) -2,6- dimethylmorpholino ) pyrimidin-4-yl) -4- (4- ( trifluoromethoxy ) phenyl) isoindolin- Preparation of 1-On
  • 3-Chloroanthranilic acid was sealed in a closed tube with orthoformate triethyl (1.2 equiv), 4-fluoroaniline (1.2 equiv) and THF, and the reaction mixture was heated to 110 ° C. for 18 hours. It was cooled to room temperature, saturated sodium bicarbonate solution was added, and the crude product was extracted with ethyl acetate. The combined organic phases were dried with magnesium sulfate, filtered and concentrated under reduced pressure, which was purified by flash column chromatography.
  • a pure compound was obtained in the same manner as in Example 5, except that 6-((2S, 6R) -2,6-dimethylmorpholino) pyridin-3-amine was used instead of 4-fluoroaniline.
  • a pure compound was obtained in the same manner as in Example 5, except that 6-((2S, 6R) -2,6-dimethylmorpholino) pyrimidin-4-amine was used instead of 4-fluoroaniline. .
  • Arylisatin (1 mmol) was dissolved in 5% NaOH (5 mL) and hydrogen peroxide (30% aqueous solution) (5 mL) was added drop-wise with stirring at room temperature. After stirring at 50 ° C. for 30 minutes, the solution was cooled to room temperature and acidified to pH 2 with 2N HCl solution. The white precipitate obtained was recovered and used directly in the next step. Trimethyl ortho formic acid (1.2 mmol), 4-morpholinoaniline (1.2 mmol) and THF were added together to the prepared acid and sealed in a sealed tube, and the resulting reaction mixture was heated to 110 ° C. for 18 hours.
  • a pure compound was obtained by the same method as Example 10, except that (3-methoxyphenyl) methanediol was used instead of phenylmethanediol of step 1.
  • Example 12 (Compound 12) 3- (4-morpholinophenyl) -8- (4- (trifluoromethoxy) Fe carbonyl) quinazolin -4 (3H) - Preparation of a whole
  • a pure compound was obtained by the same method as Example 10, except that (4- (trifluoromethoxy) phenyl) methanediol was used instead of phenylmethanediol of step 1.
  • Example 15 (Compound 15) 3- (6-(( 2S, 6R ) -2,6- dimethylmorpholino ) pyridin-3-yl ) -8- (4- (trifluoromethoxy) phenyl) quina Preparation of Zolin-4 (3H) -one
  • Example 16 (Compound 16) 3- (6-(( 2S, 6R ) -2,6- dimethylmorpholino ) pyridin-3 -yl) -8- (naphthalen-1-yl) quinazolin-4 ( Preparation of 3H) -one
  • Naphthalen-1-ylboronic acid was used in place of phenylmethanediol in step 1, and 6-((2S, 6R) -2,6-dimethylmorpholino) pyridine-3-in place of 4-morpholinoaniline in step 2 Except for using the amine was prepared in the same manner as in Example 10 to obtain a pure compound.
  • Example 17 (Compound 17) 3- (6-(( 2S, 6R ) -2,6- dimethylmorpholino ) pyridin-3-yl) -8-p-tolylquinazolin-4 (3H) -one Manufacture
  • 4-tolylmethanediol is used instead of phenylmethanediol of step 1, and 6-((2S, 6R) -2,6-dimethylmorpholino) pyridine-3-in place of 4-morpholinoaniline of step 2 Except for using the amine was prepared in the same manner as in Example 10 to obtain a pure compound.
  • Example 18 (Compound 18) 3- (6-(( 2S, 6R ) -2,6- dimethylmorpholino ) pyridin-3-yl) -8- (4-methoxyphenyl) quinazolin-4 ( Preparation of 3H) -one
  • Example 20 (Compound 20) 3- (6-(( 2S, 6R ) -2,6- dimethylmorpholino ) pyridin-3-yl) -8- (4-fluorophenyl) quinazolin-4 ( Preparation of 3H) -one
  • Example 21 (Compound 21) 3- (5-(( 2S, 6R ) -2,6- dimethylmorpholino ) pyridin-2-yl ) -8- (4- (trifluoromethoxy) phenyl) quina Preparation of Zolin-4 (3H) -one
  • Example 22 (Compound 22) 3- (6- (4 -methylpiperazin- 1 - yl) pyridin-3-yl) -8- (4- (trifluoromethoxy) phenyl) quinazolin-4 ( Preparation of 3H) -one
  • Example 26 (Compound 26) of 3- (3- (1H-imidazol-1-yl) propyl) -8- (4- ( pyrofluoromethoxy ) phenyl) quinazolin-4 (3H) -one Produce
  • NIH3T3 cells containing reporter plasmid (8xGliBS-luciferase) with luciferase bound to the Gli binding site, which is a specific nucleotide sequence where Gli, the final transcription factor of Hedgehog signaling, binds for gene expression.
  • reporter plasmid 8xGliBS-luciferase
  • 4x10 4 8xGliBS-luciferase NIH3T3 cells were cultured in 24 well plates, and then cultured for 30 hours in serum-free DMEM culture the following day to induce cilia formation. After cilia were formed, the hedgehog signal-inducing ligand, Sonic Hedgehog (Shh) -conditioned media, was treated with the compound and the activity was measured using the Dual-luciferase reporter assay system after 24 hours.
  • Ptch1 -/- dermal fibroblasts derived from mice from which the hedgehog signaling inhibitory gene Ptch1 was removed to demonstrate that the hedgehog activity-inhibiting effect of Compound 14 and Compound 20 occur specifically in hedgehog signaling.
  • Experiments were performed using mouse embryonic fibroblasts (MEFs). Ptch1 -/- dermal fibroblasts were treated with Vismodegib, Sonidegib, Compound 14 and Compound 20 (10 ⁇ M each) for 24 hours in cells where hedgehog signaling activity is always occurring even without Hhh as a ligand.
  • the amount of Gli1 protein whose expression was increased by signaling activity was measured by western blotting using Gli1-specific antibodies.
  • Smo-EGFP NIH3T3 cells were treated with serum-free DMEM to induce cilia formation, and then treated with hedgehog ligands and compounds (Vismodegib, Sonidegib, Compound 14 and Compound 20) simultaneously. After 24 hours of compound treatment, the cells were fixed with fixed solution (4% PFA), followed by fluorescence staining using an acetylated-tubulin (Ac-Tub) antibody that labeled the cilia, and then the degree of inhibition of migration to the cilia by Smo-EGFP was compared. It was.
  • hedgehog ligands and compounds (Vismodegib, Sonidegib, Compound 14 and Compound 20) simultaneously Treated. After 24 hours of compound treatment, the cells were fixed with fixed solution (4% PFA), followed by fluorescence staining using acetylated-tubulin (Ac-Tub) antibody and Gli2 antibody to label the cilia, and then the degree of migration of Gli2 to the cilia. It was.
  • Shh-conditioned media and 5 different concentrations of Vismodegib, Sonidegib, Compound 14, and Compound 20 were treated for 24 hours in NIH3T3 cells expressing Smo (D477H) mutations that induce steady-state Smo or Vismodegib drug resistance.
  • Gli1 mRNA expression was measured using a quantitative real-time PCR method to determine the degree of hedgehog signal inhibition by drug-resistant Smo mutant (Smo (D477H)).
  • the present invention relates to a novel compound having an SMO inhibitory activity, wherein the isoindolinone derivative and the quinazolinone derivative compound have excellent anticancer effects through the regulation of the hedgehog signaling pathway and the inhibitory activity of the SMO activity. It has been confirmed that it can be usefully used in the field of treatment of cancer diseases.

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Abstract

La présente invention concerne un nouveau composé ayant une activité inhibitrice de SMO, où le nouveau composé présente un excellent effet anticancéreux par l'intermédiaire des capacités d'isoindolinone et de composés dérivés de quinazolinone pour moduler la voie de signalisation hedgehog et inhiber l'activité de SMO, ce qui permet de prévenir, de soulager ou de traiter une maladie cancéreuse.
PCT/KR2017/006692 2016-06-28 2017-06-26 Nouveau composé ayant une activité inhibitrice de smo et composition comprenant celui-ci en tant qu'ingrédient actif pour prévenir ou traiter le cancer WO2018004213A1 (fr)

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KR1020160081189A KR101789430B1 (ko) 2016-06-28 2016-06-28 Smo 저해 활성을 갖는 신규 화합물 및 이를 유효성분으로 포함하는 암 예방 또는 치료용 조성물
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WO2021020363A1 (fr) 2019-07-29 2021-02-04 武田薬品工業株式会社 Composé hétérocyclique
US11071730B2 (en) 2018-10-31 2021-07-27 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11203591B2 (en) 2018-10-31 2021-12-21 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
CN114957219A (zh) * 2022-05-10 2022-08-30 苏州大学 一种靶向降解Gli1蛋白的降解剂及其制备方法和应用
US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof

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US11071730B2 (en) 2018-10-31 2021-07-27 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11203591B2 (en) 2018-10-31 2021-12-21 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
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US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof
WO2021020363A1 (fr) 2019-07-29 2021-02-04 武田薬品工業株式会社 Composé hétérocyclique
CN114957219A (zh) * 2022-05-10 2022-08-30 苏州大学 一种靶向降解Gli1蛋白的降解剂及其制备方法和应用
CN114957219B (zh) * 2022-05-10 2023-12-15 苏州大学 一种靶向降解Gli1蛋白的降解剂及其制备方法和应用

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