WO2021213111A1 - Inhibiteur de snail, dérivé de celui-ci, procédé de préparation correspondant, composition pharmaceutique et utilisation associées - Google Patents
Inhibiteur de snail, dérivé de celui-ci, procédé de préparation correspondant, composition pharmaceutique et utilisation associées Download PDFInfo
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- WO2021213111A1 WO2021213111A1 PCT/CN2021/082215 CN2021082215W WO2021213111A1 WO 2021213111 A1 WO2021213111 A1 WO 2021213111A1 CN 2021082215 W CN2021082215 W CN 2021082215W WO 2021213111 A1 WO2021213111 A1 WO 2021213111A1
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- 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
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- 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
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Definitions
- the present invention relates to a Snail inhibitor and its derivatives, preparation methods, pharmaceutical compositions and applications, in particular to a Snail inhibitor and its derivatives which can be prepared as drugs for the treatment and/or prevention of diseases related to Snail inhibition.
- a Snail inhibitor and its derivatives which can be prepared as drugs for the treatment and/or prevention of diseases related to Snail inhibition.
- Snail is a zinc finger transcription factor, which combines the zinc finger structure in the protein structure with the downstream target gene promoter with E-box (CAGGTG) as the core, participates in downstream gene transcription, inhibits the formation of chromatin structure and other processes to maintain the body Normal biological function. Under normal physiological conditions, the content of Snail protein in cells is very limited and maintained at an inactive low level.
- Snail mRNA When cells are stimulated by oxidative stress, the translation speed of Snail mRNA increases and the ability to enter the nucleus is enhanced; Snail mRNA accumulates in the nucleus to increase protein stability, thereby enhancing the transcriptional activity of downstream target genes and inhibiting the cell cycle. Multiple processes such as stagnation, apoptosis resistance, invasion and metastasis, and immune regulation have an impact. Therefore, ensuring that Snail's timely and appropriate regulation is necessary to ensure its normal function of transcription.
- Snail's transcription abnormality can be detected in many types of tumors, such as breast cancer, colon cancer, and lung cancer, and indicates a poor prognosis of the tumor.
- Snail can inhibit the transcription of cell cycle D2 (Cyclin D2), increase the expression of p21Cip1/WAF1, and promote the growth of tumor cells; it can also activate the p53-mediated apoptosis resistance pathway to inhibit tumor cell apoptosis.
- Snail as a key regulator of EMT (Mesenchymal Transformation), can accelerate tumor progression; it can also promote the expression of immunosuppressive factors, so that tumor cells can produce immune resistance. Therefore, Snail plays a central role in tumor progression.
- the first object of the present invention is to provide a Snail inhibitor and its derivatives
- the second object is to provide a method for preparing the Snail inhibitor and its derivatives
- the third object is to provide a Snail inhibitor and its derivatives.
- the fourth purpose of the pharmaceutical composition of the inhibitor and its derivatives is to provide the application of the Snail inhibitor and its derivatives in the preparation of drugs for the treatment and/or prevention of diseases related to Snail inhibition.
- the Snail inhibitor and its derivatives of the present invention have a structure of formula (I), and the derivatives are isomers, diastereomers, enantiomers, and mutual isomers of the Snail inhibitor.
- R 1 , R 2 or R 3 is R or -TWR 6 , or R 1 , R 2 or R 3 and the atoms between them together form a fused 5-8 membered unsaturated or partially unsaturated ring, and the ring Has 0-3 nitrogen, oxygen or sulfur ring heteroatoms; any substitutable ring carbon on the fused ring formed by R 2 and R 3 is halogen, oxo, -CN, -NO 2 , R 7 or -VR 6 substitution, any substitutable ring nitrogen on the fused ring formed by R 1 , R 2 or R 3 is substituted by R 4 ;
- Q is an aryl group, a heteroaryl group or a heterocyclic group, and the aryl group or heteroaryl group is substituted by one or more R 4 , wherein the aryl group is a 6-10 membered aryl group; the heteroaryl group is a five-membered group Or a six-membered heteroaryl group, and the ring has 1-4 nitrogen, oxygen or sulfur ring heteroatoms; the heterocyclic group is a 5-10 membered heterocyclic group, and the ring has 1-4 nitrogen, oxygen or Sulfur ring heteroatom;
- X is -O-, -S-, -SO-, -SO 2 -, -N(R 6 )SO 2 -, -SO 2 N(R 6 )-, -N(R 6 )-, -CO- , -CO 2 -, -N(R 6 )CO-, -N(R 6 )CO 2 -, -N(R 6 )CON(R 6 )-, -N(R 6 )SO 2 N(R 6 )-, -N(R 6 )N(R 6 )-, -CON(R 6 )-, -OCON(R 6 )-, -C(R 6 ) 2 O-, -C(R 6 ) 2 S -, -C(R 6 ) 2 SO-, -C(R 6 ) 2 SO 2 -, -C(R 6 ) 2 SO 2 N(R 6 )-, -C(R 6 ) 2 N(R 6 )-
- G is D-L-Z
- D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring
- the 5-7 membered monocyclic ring or 8-10 membered bicyclic ring is an aryl, heteroaryl, heterocyclic or carbocyclic group, wherein The heteroaryl or heterocyclic group has 1-4 nitrogen, oxygen or sulfur ring heteroatoms; any substitutable ring carbon on the ring is substituted by oxo, TR 5 or VWR 5 ; any one of the ring can be substituted
- the ring nitrogen of is replaced by R 7;
- L is a chemical bond, -O-, -S-, -SO-, -SO 2 -, -N(R 6 )SO 2 -, -SO 2 N(R 6 )-, -N(R 6 )-,- CO-, -CO 2 -, -N(R 6 )CO-, -N(R 6 )CO 2 -, -N(R 6 )CON(R 6 )-, -N(R 6 )SO 2 N( R 6 )-, -N(R 6 )N(R 6 )-, -CON(R 6 )-, -OCON(R 6 )-, -C(R 6 ) 2 O-, -C(R 6 ) 2 S-, -C(R 6 ) 2 SO-, -C(R 6 ) 2 SO 2 -, -C(R 6 ) 2 SO 2 N(R 6 )-, -C(R 6 ) 2 N( R 6 )
- Z is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring, and the 5-7 membered monocyclic ring or 8-10 membered bicyclic ring is an aryl, heteroaryl, heterocyclic or carbocyclic group, wherein The heteroaryl or heterocyclic group has 1-4 nitrogen, oxygen or sulfur ring heteroatoms; any substitutable ring carbon on the ring is substituted by oxo, -TR 5 or -VWR 5 ; any one of the ring can be substituted by oxo, -TR 5 or -VWR 5 The substituted ring nitrogen is replaced by R 7;
- R is hydrogen or an optionally substituted group, and the optionally substituted group is a C 1 -C 6 aliphatic group, a C 1 -C 10 aryl group, and a 5-10 membered heteroaryl ring Or 5-10 membered heterocyclic ring;
- T is a chemical bond or a C 1-4 alkylene chain
- R 4 is hydrogen, C 1 -C 6 alkyl, cyano, halogen, halogenated C 1 -C 6 alkyl, hydroxyl, mercapto, C 1 -C 6 alkoxy, R 7 , -COR 7 , -CO 2 (substituted C 1 -C 6 aliphatic group), -CON(R 7 ) 2 or -SO 2 R 7 ;
- V is -O-, -S-, -SO-, -SO 2 -, -N(R 6 )SO 2 -, -SO 2 N(R 6 )-, -N(R 6 )-, -CO- , -CO 2 -, -N(R 6 )CO-, -N(R 6 )CO 2 -, -N(R 6 )CON(R 6 )-, -N(R 6 )SO 2 N(R 6 )-, -N(R 6 )N(R 6 )-, -C(O)N(R 6 )-, -OC(O)N(R 6 )-, -C(R 6) 2 O-, -C(R 6 ) 2 S-, -C(R 6 ) 2 SO-, -C(R 6 ) 2 SO 2 -, -C(R 6 ) 2 SO 2 N(R 6 )-, -C( R 6 ) 2 N(R
- R 6 is hydrogen or a substituted C 1 -C 4 aliphatic group, or two R 6 on the same nitrogen atom and the connected nitrogen atom form a 5-6 membered heterocyclic ring or heteroaromatic ring;
- R 7 is hydrogen or a substituted C 1 -C 6 aliphatic group, or two R 7 on the same nitrogen atom and the connected nitrogen atom form a 5-8 membered heterocyclic ring or heteroaromatic ring.
- Q is an aryl group, a heteroaryl group or a heterocyclic group, and the aryl group or heteroaryl group is substituted by one or more R 4 , wherein the aryl group is a phenyl group; the heteroaryl group is a pyrrolyl group or a pyrazolyl group , Imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; the heterocyclic group is piperidinyl, Morpholinyl or piperazinyl;
- G is DLZ, where L is a chemical bond, -NH- or -N(CH 3 )-.
- Q is an aryl group, a heteroaryl group, or a heterocyclic group, and the aryl group or heteroaryl group is substituted by one or more R 4 , wherein the aryl group is a phenyl group; the heteroaryl group is a pyridyl group;
- G is DLZ, where L is a chemical bond, -NH- or -N(CH 3 )-; Z is phenyl, pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl , Triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, morpholinyl, piperazinyl, piperidinyl or 1,4-oxazin-4-yl, the substituent R 7 is methyl Group, ethyl, tert-butyl, 1-2 halogens, trifluoromethyl, methoxy, tert-butoxycarbonyl, cyano, cyclopropyl or phenyl.
- the Snail inhibitor is any of the following compounds:
- the pharmaceutically acceptable salt is a salt formed by the Snail inhibitor with an acid or a base
- the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid , Naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid, the alkali contains alkaline metal cations, alkaline earth Inorganic base of metal cation or ammonium cation salt.
- the preparation method of the Snail inhibitor and its derivatives of the present invention is any one of the following methods:
- the corresponding acid or base solution is added to the solution of the compound having the structure of formula (I) prepared by any of the above methods, and the solvent is removed under reduced pressure after the salt is formed, to obtain the pharmaceutically acceptable salt of the Snail inhibitor .
- the pharmaceutical composition of the present invention comprises the Snail inhibitor and/or its derivative and a pharmaceutically acceptable carrier.
- the Snail inhibitor and its derivatives can be added with pharmaceutically acceptable carriers to prepare common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions, injections, and can be added with flavors, sweeteners, liquid or solid fillers Or diluents and other commonly used pharmaceutical excipients.
- Snail inhibitor and its derivatives of the present invention in the preparation of drugs for treating and/or preventing diseases related to Snail inhibition.
- composition of the present invention in the preparation of drugs for treating and/or preventing diseases related to Snail inhibition.
- the diseases related to Snail inhibition are lung cancer, melanoma, liver cancer, kidney cancer, leukemia, prostate cancer, thyroid cancer, skin cancer, pancreatic cancer, rectal cancer, colon cancer, ovarian cancer, testicular cancer, breast cancer, Bladder cancer, gallbladder cancer, myelodysplastic syndrome, lymphoma, esophageal cancer, gastrointestinal cancer, astrocytoma, neuroblastoma, glioma, schwannoma, mesothelioma, non-insulin-dependent Diabetes or autoimmune disease.
- This type of inhibitors and their derivatives and pharmaceutical compositions have a strong affinity with Snail protein. At nanomolar concentrations, they have a good affinity with Snail protein, which can effectively inhibit the activity of Snail and affect cells. It also has a good inhibitory effect. When the concentration is 1 ⁇ M, the cell inhibition rate can reach 99% or more;
- the prepared drugs have a wide range of targets, which can be used to treat and/or prevent a variety of diseases related to the inhibition of Snail activity;
- Figure 1 is a 1 H NMR spectrum of compound 1-1;
- Figure 2 is a mass spectrum of compound I-1.
- Formic acid and p-fluoroo-phenylenediamine come from Shanghai Bi De Pharmaceutical Technology Co., Ltd., Titan Technology Co., Ltd., and Saen Chemical Technology Co., Ltd.
- the HCT-116 colon cancer cell line was derived from Nanjing Anakang Biotechnology Co., Ltd.
- MST Microscale Thermophoresis
- compounds I-1, I-24 and I-42 all have affinity for Snail protein.
- the affinity is at the micromolar or even nanomolar concentration level, and the affinity is obvious, which is beneficial to Play an inhibitory role.
- Example 4 Determination of the anti-tumor activity of the compound in vitro
- the CCK-8 method was used to determine the inhibitory effect on the HCT-116 colon cancer cell line.
- the CCK-8 method uses a new water-soluble tetrazolium salt 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4- Disulfobenzene)-2H-tetrazole monosodium salt is a colorimetric detection product for rapid and highly sensitive detection of bacterial activity.
- This tetrazolium salt can be reduced to orange-yellow water-soluble by bacterial dehydrogenase in the presence of electronic carriers Formazan, the amount of formazan produced is directly proportional to the activity of the bacteria. The stronger the bacterial activity, the darker the color; the weaker the bacterial activity, the lighter the color. For the same bacteria, the intensity of the color is linearly related to the activity of the bacteria.
- Compound HCT-116 inhibition rate (%) Compound HCT-116 inhibition rate (%) I-1 99.7 I-26 99.8 I-5 83.5 I-27 90.8 I-6 70.9 I-28 85.8 I-8 64.3 I-29 90.9 I-12 99.6 I-30 99.8 I-13 99.7 I-31 98.8 I-15 99.8 I-35 99.7 I-18 86.2 I-37 99.7 I-24 98.9 I-38 82.6 I-25 99.1 I-41 83.4
Abstract
L'invention concerne un inhibiteur de Snail, un dérivé de celui-ci, un procédé de préparation correspondant, une composition pharmaceutique et une utilisation associées. L'inhibiteur de Snail a une structure de composé telle que représentée dans la formule (I). Le dérivé d'inhibiteur de Snail se rapporte à un isomère, un diastéréoisomère, un énantiomère, un tautomère, un solvate, un sel pharmaceutiquement acceptable, un promédicament ou un mélange associé du composé. Le composé et son dérivé peuvent inhiber l'activité de Snail et l'activité cellulaire, peuvent être utilisés pour préparer un médicament pour le traitement et/ou la prévention de maladies liées à l'inhibition de Snail. En outre, le procédé de préparation du composé est simple et pratique, le rendement est élevé, et le procédé peut être facilement mis à l'échelle.
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CN202010329903.XA CN113549057B (zh) | 2020-04-24 | 2020-04-24 | Snail抑制剂及其衍生物,制备方法、药物组合物和应用 |
CN202010329903.X | 2020-04-24 |
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Citations (5)
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CN1578663A (zh) * | 2001-09-14 | 2005-02-09 | 梅特希尔基因公司 | 组蛋白脱乙酰化酶抑制剂 |
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WO2009063054A1 (fr) * | 2007-11-16 | 2009-05-22 | 4Sc Ag | Nouveaux composés bifonctionnels qui inhibent les protéines kinases et les histones désacétylases |
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CN111187268A (zh) * | 2020-01-16 | 2020-05-22 | 中国药科大学 | 作为Snail抑制剂的化合物CYD19或可药用的盐及其制备方法、药物组合物和用途 |
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WO2009036057A1 (fr) * | 2007-09-10 | 2009-03-19 | Curis, Inc. | Agents antiprolifératifs contenant une fraction de liaison au zinc |
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CN1578663A (zh) * | 2001-09-14 | 2005-02-09 | 梅特希尔基因公司 | 组蛋白脱乙酰化酶抑制剂 |
CN1997649A (zh) * | 2004-03-26 | 2007-07-11 | 梅特希尔基因公司 | 组蛋白脱乙酰基酶的抑制剂 |
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