WO2017152725A1 - 一种视黄酸类化合物、其制备方法、中间体及应用 - Google Patents
一种视黄酸类化合物、其制备方法、中间体及应用 Download PDFInfo
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- 0 C#Cc1cc(****2)c2cc1 Chemical compound C#Cc1cc(****2)c2cc1 0.000 description 4
- QWTNPBRQEVADNI-UHFFFAOYSA-N CC(C)(CC=C(c1ccccc1)c1c2)c1ccc2C#CN Chemical compound CC(C)(CC=C(c1ccccc1)c1c2)c1ccc2C#CN QWTNPBRQEVADNI-UHFFFAOYSA-N 0.000 description 1
- WFHXMNBJFLDEHK-UHFFFAOYSA-N CC(C)(CCC(C)(C)c1c2)c1ccc2C#Cc1ccc(C(O)=O)c(N)c1 Chemical compound CC(C)(CCC(C)(C)c1c2)c1ccc2C#Cc1ccc(C(O)=O)c(N)c1 WFHXMNBJFLDEHK-UHFFFAOYSA-N 0.000 description 1
- UWOLDXNTPFGPSN-UHFFFAOYSA-N CC(C)(CCC(C)(C)c1c2)c1ccc2C#Cc1ccc(C(O)=O)nc1 Chemical compound CC(C)(CCC(C)(C)c1c2)c1ccc2C#Cc1ccc(C(O)=O)nc1 UWOLDXNTPFGPSN-UHFFFAOYSA-N 0.000 description 1
- WHRYBDJOWNPYQZ-UHFFFAOYSA-N CC(C)(CCC(C)(C)c1c2)c1ccc2C#Cc1ncc(C(OC)=O)nc1 Chemical compound CC(C)(CCC(C)(C)c1c2)c1ccc2C#Cc1ncc(C(OC)=O)nc1 WHRYBDJOWNPYQZ-UHFFFAOYSA-N 0.000 description 1
- GBXMWWXATCVPPW-UHFFFAOYSA-N CC1(C)c(cc(cc2)C#Cc3ccc(C(O)=O)c(F)c3)c2SCC1 Chemical compound CC1(C)c(cc(cc2)C#Cc3ccc(C(O)=O)c(F)c3)c2SCC1 GBXMWWXATCVPPW-UHFFFAOYSA-N 0.000 description 1
- LKWSCGYFHLJKIN-UHFFFAOYSA-N CCOC(c(c(F)c1)ccc1C#Cc(cc1)cc2c1SCCC2(C)C)=O Chemical compound CCOC(c(c(F)c1)ccc1C#Cc(cc1)cc2c1SCCC2(C)C)=O LKWSCGYFHLJKIN-UHFFFAOYSA-N 0.000 description 1
- YKLQREFLOXXOCG-UHFFFAOYSA-N CCOC(c(cc1F)ccc1I)=O Chemical compound CCOC(c(cc1F)ccc1I)=O YKLQREFLOXXOCG-UHFFFAOYSA-N 0.000 description 1
- IEMKQRSOAOPKRJ-UHFFFAOYSA-N CCOC(c(cn1)cnc1Cl)=O Chemical compound CCOC(c(cn1)cnc1Cl)=O IEMKQRSOAOPKRJ-UHFFFAOYSA-N 0.000 description 1
- DAQAQWHVVAGNDF-UHFFFAOYSA-N CCOC(c(nc1)ccc1C#Cc1ccc(C(C)(C)CCC2(C)C)c2c1)=O Chemical compound CCOC(c(nc1)ccc1C#Cc1ccc(C(C)(C)CCC2(C)C)c2c1)=O DAQAQWHVVAGNDF-UHFFFAOYSA-N 0.000 description 1
- BSPGLCYCJNUDAK-UHFFFAOYSA-N CCOC(c1cnc(C#Cc2ccc(C(C)(C)CCC3(C)C)c3c2)nc1)=O Chemical compound CCOC(c1cnc(C#Cc2ccc(C(C)(C)CCC3(C)C)c3c2)nc1)=O BSPGLCYCJNUDAK-UHFFFAOYSA-N 0.000 description 1
- KWIIUIVETQQQHX-UHFFFAOYSA-N Nc(cc(cc1)I)c1C(O)=O Chemical compound Nc(cc(cc1)I)c1C(O)=O KWIIUIVETQQQHX-UHFFFAOYSA-N 0.000 description 1
- KPMBAMKKTJSICO-UHFFFAOYSA-N OC(c(cc1F)ccc1I)=O Chemical compound OC(c(cc1F)ccc1I)=O KPMBAMKKTJSICO-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
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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
- A61K31/495—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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
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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
- C07D409/06—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 linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- the invention relates to a retinoic acid compound, a preparation method thereof, an intermediate and an application thereof.
- Tazarotene is a retinol drug with RAR subtype selectivity (J Am Acad Dermatol. 1997, 37, S12.), mainly used for local epithelial hyperplasia of the skin (psoriasis, psoriasis, Treatment of acne, etc.).
- Tazarotene is present as a prodrug of ethyl ester. The drug enters the body and is metabolized by enzyme to obtain the carboxyl-type active metabolite Tazarotenic acid, which can selectively interact with RAR ⁇ and RAR ⁇ receptors, and also has a certain effect on RAR ⁇ , but has a weak effect on RXR.
- the problem to be solved by the present invention is to provide a retinoic acid compound, a preparation method thereof, an intermediate and application thereof for the purpose of overcoming defects such as poor inhibition rate of tumor cells by tazarotene, and the compound inhibits tumor cells.
- the rate is better.
- the present invention provides a compound, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, of formula I,
- R 9a , R 9b , R 9c and R 9d are each independently hydrogen, hydroxy, nitro, cyano, halogen (for example fluorine, chlorine, bromine or iodine), C 1- C 6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl), halogen-substituted C 1 -C 6 Alkyl (the halogen may be fluorine, chlorine, bromine or iodine; the C 1 -C 6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl a "halo-substituted C 1 -C 6 alkyl group" such as a trifluoromethyl group, a C 1 -C
- the R 10 , R 11 , R 12 , R 13 and R 14 are independently hydrogen or a C 1 -C 6 alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, pentyl or hexyl);
- R 2 , R 3 , R 4 and R 5 are independently hydrogen, hydroxy, halogen (for example fluorine, chlorine, bromine or iodine), C 1 -C 6 alkyl (for example methyl, ethyl, positive) Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or yl), C 2 -C 6 alkenyl (eg vinyl or propenyl), halogen substituted C 1 -C 6 Alkyl (the halogen may be fluorine, chlorine, bromine or iodine; the C 1 -C 6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, pentyl or hexyl; said "halogen-substituted C 1 -C 6 alkyl" such as trifluoro
- n 0, 1, 2 or 3;
- R 1 is hydrogen, hydroxy, nitro, cyano, halogen (e.g., fluorine, chlorine, bromine or iodine), C 1 -C 6 alkyl (e.g.
- the R 6 , R 7 and R 8 are independently hydrogen or a C 1 -C 6 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl) Base, pentyl or hexyl);
- Y is -CN, -COOR 15 or -CO 2 NHR 16 ;
- R 15 and R 16 are independently hydrogen, C 1 -C 6 alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl) Or a hexyl group, a C 2 -C 6 alkenyl group (for example, a vinyl or propenyl group) or a C 1 -C 6 acyl group (for example, a formyl group or an acetyl group);
- said A, E, G and Z are connectable to a ring as shown below:
- the definitions of R 2 , R 3 and R 5 are as described above.
- At least one of the U, V, X and W (for example, 1, 2, 3 or 4) is N.
- the compound I when two of the U, V, X and W are N, the compound I may be any of the following compounds:
- A, E, G, Z, R 1 , m, Y, R 9a , R 9b , R 9c and R 9d are as defined above.
- the R 15 is hydrogen or ethyl.
- the definitions of R 2 and R 3 are as described above.
- the Z is -S-.
- the R 15 is a methyl group or an ethyl group.
- R 2 and R 3 are as described above.
- the Z is -(CR 2 R 3 )-, and R 2 and R 3 are as defined above.
- the Z is -(CR 2 R 3 )- or -S-, and R 2 and R 3 are as defined above.
- the definition of 3 is as described above.
- the R 15 is hydrogen or ethyl.
- R 2 and R 3 are as described above.
- the Z is -S-.
- the compound I when one of the U, V, X and W is N, the compound I may be any of the following compounds:
- A, E, G, Z, R 1 , m, Y, R 9a , R 9b , R 9c and R 9d are as defined above.
- the R 15 is hydrogen or ethyl.
- the Z is -(CR 2 R 3 )-; more preferably, the A, E, G and Z are linked to a ring as shown below:
- R 2 and R 3 are as described above.
- the Y is CN.
- the Z is -(CR 2 R 3 )-; more preferably, the A, E, G and Z are linked to a ring as shown below:
- R 2 and R 3 are as described above.
- A, E, G, Z, R 1 , m, Y, R 9a , R 9b , R 9c and R 9d are as defined above.
- At least one of the R 9a , R 9b , R 9c and R 9d (for example, 1, 2, 3 or 4) is not hydrogen.
- the R 15 is hydrogen, methyl or ethyl.
- the definitions of R 2 , R 3 and R 5 are as described above.
- the compound I is any one of the following compounds:
- the present invention also provides a process for the preparation of a compound of formula I, which comprises the steps of: coupling a compound II and III to obtain a compound I;
- X 1 is halogen (e.g., fluorine, chlorine, bromine or iodine).
- the conditions of the coupling reaction may be conventional conditions of the coupling reaction in the art, and the present invention particularly preferably has the following conditions: protection of a protective gas (for example, argon).
- a protective gas for example, argon
- an organic solvent such as DMF
- a catalyst such as Pd / Cu catalyst; said "Pd / Cu catalyst” such as Pd (PPh 3 ) 2 Cl 2 and CuI
- a base such as diisopropylamine
- the compound I can be further subjected to flexible functional group conversion and adjustment (including but not limited to chemical operations such as esterification, ester hydrolysis, reduction, acylation, oxidation, etc.) to obtain a compound I having a different functional group.
- flexible functional group conversion and adjustment including but not limited to chemical operations such as esterification, ester hydrolysis, reduction, acylation, oxidation, etc.
- the method for preparing the compound I may further comprise the steps of: deprotecting the compound IV to obtain the compound III;
- the conditions of the deprotection reaction may be conventional conditions for the deprotection reaction in the art, and the present invention particularly preferably has the following conditions: in an organic solvent (for example, tetrahydrofuran), Compound IV may be subjected to a deprotection reaction in the presence of a base (for example, tetra-n-butylammonium fluoride) to obtain a compound III.
- an organic solvent for example, tetrahydrofuran
- Compound IV may be subjected to a deprotection reaction in the presence of a base (for example, tetra-n-butylammonium fluoride) to obtain a compound III.
- a base for example, tetra-n-butylammonium fluoride
- the preparation method of the compound I may further comprise the steps of: coupling the compound V and the trimethylethynyl silane to obtain the compound IV;
- X 2 is a halogen (e.g., bromine or iodine).
- the conditions of the coupling reaction may be conventional conditions of the coupling reaction in the art, and the present invention particularly preferably has the following conditions: protection of a protective gas (for example, argon).
- a protective gas for example, argon
- an organic solvent such as DMF
- a catalyst such as Pd / Cu catalyst; said "Pd / Cu catalyst” such as Pd (PPh 3 ) 2 Cl 2 and CuI
- a base such as diisopropylamine
- the invention also provides a compound as shown in formula II, III, IV or V,
- the invention also provides the use of a compound of formula I, an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a primary tumor .
- tumors include, but are not limited to, melanoma, esophageal cancer, gastric cancer, lung cancer, liver cancer, ovarian cancer, colon cancer, renal cancer, cholangiocarcinoma, breast cancer or prostate cancer.
- the invention also provides the use of a compound of formula I, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis and/or Treatment of metastatic tumors.
- the tumor includes, but is not limited to, melanoma, esophageal cancer, gastric cancer, lung cancer, liver cancer, ovarian cancer, colon cancer, renal cancer, cholangiocarcinoma, breast cancer, prostate cancer.
- the invention also provides the use of a compound of formula I, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis and/or Treatment, leukemia and/or lymphoma.
- the invention also provides the use of a compound of formula I, an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in animal fetal development, One or more of internal environment stability, vision, morphogenesis, skin aging, and control of cell differentiation.
- the invention also provides the use of a compound of formula I, an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of psoriasis .
- the invention also provides the use of a compound, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, of formula I, for the manufacture of a medicament for the treatment of acne.
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula I, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- the pharmaceutical composition can be administered orally, by injection, or topically.
- the pharmaceutical composition is administered by the oral route, and the composition may be, but is not limited to, the following forms: tablets, capsules, suspensions, solutions, emulsions, microspheres or nanosphere suspensions, or controlled release. Lipid vesicles or polymer vesicles.
- the composition may be a solution or suspension for infusion or injection.
- the compounds of the invention are administered at a daily dose of from about 0.01 mg/kg to 100 mg/kg body weight in divided doses of 1-3.
- the concentration of the compounds of the invention used systemically is generally from 0.01% to 10% by weight, preferably from 0.01% to 1% by weight, based on the weight of the composition.
- the pharmaceutical composition is particularly useful for treating skin and mucosal diseases by topical administration, and may be in the form of a liquid, a paste or a solid, especially an ointment, a cream, In the form of a solution, a gel, a spray, a suspension, or a patch. It may also be a microsphere or nanosphere suspension, or a controlled release lipid vesicle or polymer vesicle or a gelled or polymeric patch.
- the concentration of the topically applied compound is usually from 0.001% to 10% by weight, preferably from 0.01% to 1% by weight, based on the total weight of the composition.
- compositions may also contain inert additives, or a pharmaceutically active ingredient that is positively associated with the pharmaceutical composition, or a mixture of such ingredients.
- inert additives or a pharmaceutically active ingredient that is positively associated with the pharmaceutical composition, or a mixture of such ingredients.
- a "C 1 -C 6 acyl” refers to an alkyl group containing 1 to 6 carbon atoms, such as an acyl group containing one carbon atom refers to HC (O) - (i.e. formyl),
- the acyl group having 2 carbon atoms is CH 3 C(O)- (i.e., acetyl); and may also include propionyl, butyryl or valeryl.
- alkyl refers to a saturated straight or branched monovalent hydrocarbon radical having from one to twenty carbon atoms.
- alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-butyl, 2-methyl-2 -propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2 -methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl , 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-g Base, 1-octyl.
- alkenyl refers to a straight, branched or cyclic non-aromatic hydrocarbon radical containing the specified number of carbon atoms and at least one carbon to carbon double bond. Preferably there is one carbon-carbon double bond and up to four non-aromatic carbon-carbon double bonds may be present.
- C 2 -C 12 alkenyl means an alkenyl group having 2 to 12 carbon atoms.
- the "C 2 -C 6 alkenyl group” means an alkenyl group having 2 to 6 carbon atoms, and includes a vinyl group, a propenyl group, a butenyl group, a 2-methylbutenyl group, and a cyclohexenyl group.
- aryl refers to any stable monocyclic or bicyclic carbon ring which may be up to 7 atoms in each ring, at least one of which is an aromatic ring.
- aryl unit include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. It will be understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the linkage is carried out through an aromatic ring.
- arylhetero or “heteroaryl” (including when used alone and in other groups) denotes a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is an aromatic ring and Containing from 1 to 4 heteroatoms selected from O, N, and S.
- Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, oxazolyl, porphyrin, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl , benzothienyl, benzofuranyl, quinolyl, isoquinolinyl, oxazolyl, isoxazolyl, fluorenyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, Pyrrolyl, tetrahydroquinoline.
- Heteroaryl is also understood to include any nitrogen-containing heteroaryl N-oxide derivative.
- heteroaryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or does not contain a hetero atom
- linkage is carried out by an aromatic ring or by a hetero atom on the ring, respectively.
- halogen includes F, Cl, Br, I.
- pharmaceutically acceptable salt refers to a conventional acid addition or base addition salt which retains the biological effectiveness and properties of Compound I, which is formed from a suitable non-toxic organic or inorganic acid, or an organic or inorganic base.
- acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphorous acid, sulfuric acid, phosphoric acid, and those derived from organic acids.
- nitric acid such as formic acid, acetic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, lactic acid, tartaric acid, succinic acid, Fumar Acid, mandelic acid, malic acid, camphorsulfonic acid, etc.
- base addition salts include salts derived from ammonium, potassium, sodium, calcium, and quaternary ammonium hydroxides such as tetramethylammonium hydroxide.
- Chemical modification of a pharmaceutical compound (i.e., a drug) to a salt is a technique well known to pharmacists to achieve improved physical and chemical stability, hygroscopicity, flowability, and solubility of the compound.
- “Pharmaceutically acceptable” in the term “pharmaceutically acceptable carrier” means that the subject to whom the particular compound is administered is pharmaceutically acceptable and substantially non-toxic.
- the reagents and starting materials used in the present invention are commercially available.
- the positive progress of the present invention is that the compound of the present application has a better inhibition rate against tumor cells.
- FIG. 1 WYC-103 induces differentiation and apoptosis of melanoma B16-F1TRC cells
- Figure 3 Inhibition of WYC-209 against lung cancer A549 tumor regenerative cells, wherein Figure 3a shows inhibition of lung cancer A549 treated with WYC-209 on day 0; Figure 3b shows treatment of lung cancer A549 with WYC-209 on day 3 Inhibition.
- Figure 4 Inhibition of WYC-209 against breast cancer MCF-7 tumor regenerative cells, wherein Figure 4a shows inhibition of breast cancer MCF-7 treated with WYC-209 on day 0; Figure 4b shows use on day 3 WYC-209 treatment of breast cancer MCF-7 inhibition.
- Figure 5 Inhibition of WYC-209 against melanoma MDA-MB-435S tumor regenerative cells, wherein Figure 5a shows the inhibition of treatment of melanoma MDA-MB-435S with WYC-209 on day 0; Figure 5b shows On day 3, WYC-209 was used to treat the inhibition of melanoma MDA-MB-435S.
- Figure 6 Inhibition of WYC-209 against ovarian cancer A2780 tumor regenerative cells, wherein Figure 6a shows the inhibition of ovarian cancer A2780 treated with WYC-209 on day 0; Figure 6b shows treatment with WYC-209 on day 3 Inhibition of ovarian cancer A2780.
- Fig. 7 Study on the inhibitory effect of WYC-209 on tumor regenerative cells of gastric cancer Hs-746T, wherein Fig. 7a shows the inhibition of treatment of gastric cancer Hs-746T with WYC-209 on day 0; Fig. 7b shows the use of WYC- on day 3 209 treatment of gastric cancer Hs-746T inhibition.
- Figure 8 Inhibition of WYC-209 against breast cancer MDA-MB-231 tumor regenerative cells, wherein Figure 8a shows the inhibition of treatment of breast cancer MDA-MB-231 with WYC-209 on day 0; Figure 8b shows On day 3, WYC-209 was used to treat the inhibition of breast cancer MDA-MB-231.
- Figure 9 WYC-331 against ovarian cancer A2780 and breast cancer MDA-MB-231 tumor regenerative cell inhibitory activity, wherein Figure 9a shows the inhibition of ovarian cancer A2780 treated with WYC-331 on day 3; Figure 9b shows On day 3, WYC-331 was used to treat the inhibition of breast cancer MDA-MB-231.
- Figure 10 WYC-209 cytotoxicity study (WYC-209 inhibits B16 growth but has no significant effect on 3T3 cells); wherein, Figure 10a shows treatment of 3T3 cells with 10 ⁇ M WYC-209 for 18 hours; Figure 10b shows no WYC-209, B16 cells were treated with 10 ⁇ M WYC-209 for 48 hours.
- Figure 11 WYC-331 cytotoxicity study; wherein, Figure 11a shows that 3T3 cells were treated with 1 ⁇ M, 10 ⁇ M WYC-331 for 24 hours; Figure 11b shows that B16 cells were treated with 1 ⁇ M, 10 ⁇ M WYC331 for 24 hours, respectively.
- Figure 12 Inhibition of subcutaneous melanoma by WYC-103, tumor volume on day 19 of the experiment.
- Figure 13 Study on the inhibitory effect and in vivo toxicity of WYC-103 on subcutaneous melanoma.
- Figure 14 Inhibition of subcutaneous melanoma by WYC-103, tumor volume on day 26 of the experiment.
- Figure 15 Inhibition of lung metastatic melanoma by WYC-103; wherein, Figure 15a shows the injection of 3000 melanoma regenerative cells, administration of WYC103, lung tissue on day 29 of the experiment; Figure 15b shows the injection of 3000 melanoma regenerative cells DMSO was administered to the lung tissue on the 29th day of the experiment; Fig. 15c shows the injection of 3000 melanoma regenerative cells, WYC103, lung tissue on the 35th day of the experiment; Fig.
- FIG. 15d shows the injection of 3000 melanoma regenerative cells, given DMSO, the 35th day of the experiment Lung tissue;
- Figure 15e shows lung tissue administered to WYC103 on day 37 of the experiment;
- Figure 15f shows lung tissue on day 37 of the experiment given DMSO.
- Figure 16 Inhibition of lung metastatic melanoma by WYC-209, wherein Figure 16a shows lung tissue administered to DMSO; Figure 16b shows lung tissue administered with 1.0 ⁇ M WYC-209; Figure 16c shows administration of 10 ⁇ M WYC-209 Lung tissue.
- Figure 17 Single crystal structure diagram of WYC-209A.
- Figure 18 Single crystal structure diagram of WYC-209B.
- WYC-202 (30 mg, 0.098 mmol) was added to the flask, 2 mL of dry dichloromethane was added, and the mixture was cooled to 0 °C in an ice water bath, then mCPBA (24 mg, 0.098 mmol) was added, and the reaction was carried out for 1 hour in an ice water bath and then moved to room temperature for 2 h. , TLC tracking. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate.
- WYC-205 (70 mg, 0.2 mmol) was added to the flask, 3 mL of dry dichloromethane was added, and the mixture was cooled to 0 °C in an ice water bath, then mCPBA (49 mg, 0.2 mmol) was added, and the reaction was carried out for 1 hour in an ice water bath and then moved to room temperature for 2 h. , TLC tracking. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate.
- WYC-209A 2-((4,4-Dimethyl-1S-oxodithiothiopyran-6-)ethynyl)pyrimidine-5-carboxylic acid ethyl ester
- Diethyl D-tartrate (82.7 mg, 0.4 mmol) was dissolved in anhydrous CH 2 Cl 2 (1 mL), and Ti(iso-PrO) 4 (0.2 mmol, 58 uL) was quickly added at 16 °C and stirred for 3 minutes. Water (3.6 uL, 0.2 mmol) was added dropwise and stirring was continued for 20 minutes. It was then cooled to -20 degrees, and WYC-203 (69 mg, 0.2 mmol) and cumene hydroperoxide (74 uL, 0.4 mmol) were quickly added, and the reaction was stopped after 3 hours.
- the reaction liquid was poured into 10 mL of a mixed solution of ferrous sulfate (0.2 g), citric acid (67 mg), dioxane and diethyl ether (2:1:2), and stirred for 15 minutes.
- WYC-209B 2-((4,4-Dimethyl-1R-oxodithiothiopyran-6-)ethynyl)pyrimidine-5-carboxylic acid ethyl ester
- Diethyl L-tartrate (82.7 mg, 0.4 mmol) was dissolved in anhydrous CH 2 Cl 2 (1 mL), and Ti(iso-PrO) 4 (0.2 mmol, 58 uL) was quickly added at 16 °C and stirred for 3 minutes, slowly. Water (3.6 uL, 0.2 mmol) was added dropwise and stirring was continued for 20 minutes. It was then cooled to -20 degrees, and WYC-203 (69 mg, 0.2 mmol) and cumene hydroperoxide (74 uL, 0.4 mmol) were quickly added, and the reaction was stopped after 3 hours.
- the reaction liquid was poured into 10 mL of a mixed solution of ferrous sulfate (0.2 g), citric acid (67 mg), dioxane and diethyl ether (2:1:2), and stirred for 15 minutes.
- the aqueous layer was extracted with EtOAc.
- ESI (+)-MS 369.4 [M+1] + .
- the single crystal structure diagrams of WYC-209A and WYC-209B are shown in Fig. 17 and Fig. 18, respectively.
- 6-ethynyl-4,4-dimethylbenzothiopyran (2.03 g, 10 mmol) was added to the flask, and 27 mL of dry dichloromethane was added thereto, and the mixture was cooled to 0 ° C in ice water, and then mCPBA (1.73 g, 10 mmol) was added. After reacting for 10 min in an ice water bath, the reaction was carried out to room temperature for 1 h, and then moved to room temperature for 2 h, followed by TLC.
- WYC-216 (80 mg, 0.22 mmol) was added to the flask, 6 mg of DMAP was added, 2 mL of dry pyridine was added under argon atmosphere, cooled to 0 °C in an ice water bath, and acetyl chloride (31 ⁇ l, 0.44 mmol) was added dropwise, ice After reacting for 10 min in a water bath, it was moved to room temperature for 9 h, and was followed by TLC. After the reaction is completed, it is quenched with methanol, diluted with ethyl acetate, diluted with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc.
- WYC-214 (152 mg, 0.42 mmol) was added to the flask, 10 mg of DMAP was added, 5 mL of dry dichloromethane, 0.212 mL of triethylamine was added under argon atmosphere, and the mixture was cooled to 0 degree in ice water bath, and added dropwise.
- the acid chloride (67 ⁇ l, 0.84 mmol) was reacted in an ice water bath for 10 min, then transferred to room temperature for 12 h, followed by TLC. After the reaction is completed, it is quenched with methanol, diluted with ethyl acetate, diluted with EtOAc EtOAc EtOAc EtOAc.
- Ethyl 4-(3-bromophenyl)-2-butenoate (1.05 g, 3.92 mmol) was added to a flask, and (10% wt) dry Pd/C (220 mg, 0.194 mmol) was added and protected under argon 20 mL of ethyl acetate was added thereto, and hydrogen gas was introduced and replaced with 3 times of gas, and reacted at normal temperature and normal pressure for 24 hours, followed by TLC.
- 2-Fluoro-4-iodobenzoic acid (1.0 g, 3.76 mmol) was added to the flask, and 10 mL of absolute ethanol was added under argon atmosphere, and the mixture was heated to 0 ° with ice water, and 0.5 mL of concentrated sulfuric acid was added dropwise. The temperature was refluxed for 4 h, and TLC was followed. After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L sodium hydroxide to neutrality, washed with saturated sodium hydrogencarbonate, washed with saturated sodium chloride, and then dried over anhydrous sodium sulfate.
- 2,3-Difluoro-4-iodobenzoic acid (0.5 g, 1.76 mmol) was added to the flask, 4 mL of absolute ethanol was added under argon, ice water was added to 0 °, and 0.3 mL of concentrated sulfuric acid was added dropwise. After the addition was completed, the temperature was refluxed for 6 h, and TLC was followed. After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L sodium hydroxide to neutrality, washed with saturated sodium hydrogencarbonate, washed with saturated sodium chloride, and then dried over anhydrous sodium sulfate.
- the compound 3-amino-4-iodobenzoic acid methyl ester (1.5 g, 5.43 mmol) was added to the flask, 20 mL of dry dichloromethane, 4.5 mL of dry triethylamine was added, and 0.77 mL of acetyl chloride was added dropwise in an ice water bath. The reaction was allowed to proceed overnight at room temperature and was followed by TLC. After the reaction was completed, it was quenched with EtOAc EtOAc (EtOAc)EtOAc.EtOAc. :1) The product was obtained as methyl 3-acetamido-4-iodobenzoate (1.34 g , 77.5%).
- 5-bromopyridazine-2-carboxylic acid (1.0 g, 5 mmol) was added to the flask, 5 mL of absolute ethanol was added under argon atmosphere, and the mixture was cooled to 0 ° with ice water, 0.3 mL of concentrated sulfuric acid was added dropwise, and the temperature was raised after the addition was completed.
- the reflux reaction was carried out for 6 h, followed by TLC. After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L sodium hydroxide to neutrality, washed with saturated sodium hydrogencarbonate, washed with saturated sodium chloride, and then dried over anhydrous sodium sulfate.
- WYC-209 (1.1 g, 3 mmol) was added to the flask, 20 mL of dry dichloromethane was added, and the mixture was cooled to 0 °C in an ice water bath, then mCPBA (0.663 g, 3.6 mmol) was added, and the reaction was carried out for 10 min in an ice water bath and then transferred to room temperature for 3 h. After moving to room temperature for 4 h, TLC was followed. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate.
- WYC-316 (107 mg, 0.272 mmol) was added to the flask, and 3.5 mL of dry dichloromethane was added thereto. After cooling to 0 °C in an ice water bath, m-CPBA (67.3 mg, 0.272 mmol) was added, and the reaction was carried out for 1 hour in an ice water bath. The reaction was carried out for 2 h at room temperature and followed by TLC. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate.
- WYC-322 (100 mg, 0.284 mmol) was added to the flask, 3.5 mL of dry dichloromethane was added, and the mixture was cooled to 0 °C in an ice water bath, then m-CPBA (49 mg, 0.284 mmol) was added, and the mixture was reacted for 1 hour in an ice water bath and then transferred to room temperature. The next reaction was 2 h, and TLC was followed. After the reaction was completed, it was quenched with sodium thiosulfate solution, diluted with ethyl acetate, washed with saturated sodium hydrogen sulfate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate.
- 6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene 50 mg, 0.235 mmol
- ethyl 2-chloropyrimidine-4-carboxylate 50.3 mg, 0.27 mmol
- Pd(PPh 3 ) 2 Cl 2 14 mg, 0.02 mmol
- CuI 5.6 mg, 0.03 mmol
- DMF 0.14 mL of dry Et 3 N, heated to 70 ° C for 8 h, TLC tracking.
- 6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene 60 mg, 0.283 mmol
- 2-chloro-5-cyanopyridine 59.5 mg, 0.325
- Pd(PPh3)2Cl2 16.8 mg, 0.024 mmol
- CuI 6.8 mg, 0.036 mmol
- protecting with argon gas and replacing the gas three times to remove oxygen adding 2 mL of dry DMF with a syringe, 0.17 mL of dry Et3N was reacted at 70 ° C for 8 h, followed by TLC.
- Example 78 Ethyl 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)pyrimidine-2-carboxylate
- 6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene 50 mg, 0.205 mmol
- compound c 75.3 mg, 0.271 mmol
- Pd(PPh 3 ) 2 Cl 2 14 mg, 0.02 mmol
- CuI 5.6 mg, 0.03 mmol
- protected with argon and replaced with 3 times of gas to remove oxygen and 2 mL of dry DMF, 0.14 mL of dried Et. 3 N, heated to 70 ° for 8 h, TLC tracking.
- Example 80 2-Hydroxy-4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)benzoic acid
- Example 84 Ethyl methyl ester 5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-)ethynyl)pyrimidine-2-carboxylate
- the product (25 mg, 0.072 mmol) was placed in a flask, 1.5 mL of absolute ethanol was added under argon atmosphere, and the mixture was heated to 0 ° with ice water, and 5 ⁇ L of concentrated sulfuric acid was added dropwise thereto. After the completion of the dropwise addition, the mixture was heated to reflux for 4 hours, and was subjected to TLC. After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L of sodium hydroxide to neutrality, washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and the organic phase is dried over anhydrous sodium sulfate, filtered, and dried.
- WYC-337 (25mg, 0.075mmol) was added to the flask, 1.5mL absolute ethanol was added under argon protection, ice water bath was added to 0 degree, 5 ⁇ l concentrated sulfuric acid was added dropwise, and the reaction was heated and refluxed for 4 hours after TTG tracking. TLC tracking . After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L of sodium hydroxide to neutrality, washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and the organic phase is dried over anhydrous sodium sulfate, filtered, and dried.
- the product (25 mg, 0.075 mmol) was placed in a flask, 1.5 mL of absolute ethanol was added under argon atmosphere, and the mixture was cooled to 0 ° with ice water, and 5 ⁇ l of concentrated sulfuric acid was added dropwise. After the addition was completed, the mixture was heated to reflux for 4 hours, and was subjected to TLC. After the reaction is completed, it is cooled to room temperature, and the sulfuric acid is neutralized with 1 mol/L of sodium hydroxide to neutrality, washed with a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and the organic phase is dried over anhydrous sodium sulfate, filtered, and dried.
- TRCs melanoma-derived cells
- Melanoma B16-F1 cells were incubated with 3D fibrin glue medium (90-Pa) for 5 days, and the desired melanoma tumor regenerative cells were screened (Nat. Mater. 2012, 11, 734). Subsequently, the culture medium was separately treated with collagenase and neutral protease II to release melanoma tumor regenerative cells, and the resulting regenerated cells were transferred to a fresh preparation medium and resuspended, and maintained in a single cell state. Melanoma B16-F1 regenerative cells were inoculated in 3D fibrin glue medium (90-Pa) for 5 days, with 0.1% DMSO as a negative control group, Tazarotene and Bexarotene.
- the drugs were added at a concentration of 10 ⁇ M, incubated for 5 days, and the tumor clone size was observed and measured, and the inhibition rate of each drug for melanoma B16-F1 tumor regenerative cells was calculated.
- the results of the test for inhibiting cell activity of the compound comprising the compound against melanoma B16-F1 are shown in Table 2 below.
- Table 2 Test results of melanoma B16-F1 regenerative cell inhibitory activity
- the inhibition rate of the regenerative cells of melanoma tumor B16-F1 showed that most of the compounds showed significant tumor growth inhibitory activity at a concentration of 10 ⁇ M, such as compound WYC-103 (86.8%), WYC-207 (92.5%), WYC-209 (98.8%), WYC-209A (98.9%), WYC-209B (98.7%), WYC-212 (93.2%), WYC-217 (90.3%), WYC-218 (90.4%), WYC- 329 (94.5%), WYC-331 (96.0%), etc., the corresponding tumor clones were basically not used for growth or growth very slowly. The results were not only in sharp contrast with the negative control group, but also met or exceeded the inhibitory activity of the positive drug Tazarotene (67.6%) and Bexarotene (63.3%) on tumor clone growth.
- a dose-effect curve study of tumor growth inhibition was then performed on compounds exhibiting significant tumor clonal growth inhibitory activity in the primary screening.
- Tumor clones administered by equivalence gradient were fixed, DAPI nuclear staining and volume measurement, inhibition rate calculation and dose-response curve regression were performed to determine the compounds with better activity WYC-103, WYC-209, WYC-320, WYC-
- the IC 50 of 329 and WYC-331 is shown in Table 3 below.
- the compounds WYC-103 and WYC-209 for the inhibition and differentiation of melanoma tumor B16-F1 regenerative cells are shown in the electron micrograph (Fig. 1, Fig. 2).
- Fig. 1 and Fig. 2 cell survival was observed by DAPI staining.
- the above human tumor cells were separately incubated with 3D fibrin glue medium (90-Pa) for 5 days, and the desired tumor regenerative cells were selected. Subsequently, the medium was separately treated with collagenase and neutral protease II to release the tumor-regenerating cells, and then the resulting regenerated cells were transferred to a fresh preparation medium and resuspended, and maintained in a single cell state.
- Single tumor regenerative cells were inoculated in 3D fibrin glue medium (90-Pa) for 5 days, and 0.1% DMSO was used as a negative control group (DMSO group in Fig. 3 to Fig. 8), with no drug added as a blank group ( In Fig. 3 to Fig. 8, the None group) was studied by administration from 0 days and administration from 3 days, respectively, and the tumor clone volume was calculated and measured.
- the compound WYC-209 can effectively inhibit the proliferation of various tumor regenerative cells at 1.0 ⁇ M, which greatly blocked the volume growth of tumor clones.
- the volume of tumor clones was only blank group. 25-30% (Fig. 3-8, Fig. 3-8 refers to drug9# for WYC-209).
- the concentration of WYC-209 was increased to 10 ⁇ M, the proliferation of the above six tumor regenerative cells was inhibited at a higher level, and the volume of the tumor clone was even less than 10% of the volume of the blank group.
- the use of compound WYC-209 can even reverse the growth trend of tumor clones.
- Compound WYC-331 showed good inhibitory activity against melanoma B16-F1 tumor regenerative cell proliferation, and then we investigated the inhibitory activity of this compound against ovarian cancer A2780 and breast cancer MDA-MB-231 tumor regenerative cells.
- the above human tumor cells were separately incubated with 3D fibrin glue medium (90-Pa) for 5 days, and the desired tumor regenerative cells were selected. Subsequently, the medium was separately treated with collagenase and neutral protease II to release the tumor-regenerating cells, and then the resulting regenerated cells were transferred to a fresh preparation medium and resuspended, and maintained in a single cell state.
- Single tumor regenerative cells were inoculated in 3D fibrin glue medium (90-Pa) for 5 days, 0.1% DMSO as a negative control group (DMSO group in Fig. 9), and no drug addition as a blank group (Fig. 9) In the middle group, the drug was administered at a concentration of 0.1 ⁇ M, 1.0 ⁇ M, and 10 ⁇ M from the third day, and the tumor clone volume was observed and measured.
- the compound WYC-331 could completely inhibit the proliferation of ovarian cancer A2780 tumor regenerative cells and breast cancer MDA-MB-231 tumor regenerative cells at 10 ⁇ M, which greatly blocked the tumor.
- the volume of the clones increased, and the volume of the tumor clones was only 10-15% of the blank group.
- the use of compound WYC-331 even reversed the growth trend of tumor clones (Fig. 9, where #31 indicates WYC-331).
- cell staining studies found that tumor clones inhibited by WYC-331 remained viable, and only a few cells showed apoptosis.
- mice embryonic fibroblast 3T3 cell line and melanoma cell B16-F1 were used as models to study the in vitro toxicity of compounds WYC-209 and WYC-331, respectively.
- the effects of compounds WYC-209 and WYC-331 on the proliferation of mouse embryonic fibroblasts 3T3 and melanoma cells B16-F1 were compared at 10 ⁇ M.
- the results showed that the compound WYC-209 did not affect the proliferation of mouse embryonic fibroblasts 3T3, nor induced apoptosis of this type of cells; at the same time, compound WYC-209 could significantly block the growth of melanoma cell clones, and at 6- 48 hours showed significant apoptosis.
- This experiment shows that the compound WYC-209 has a certain specificity for melanoma tumor-regeneration cells, has a weak effect on ordinary cells, and has less cytotoxicity (Fig. 10).
- the compound WYC-331 strongly inhibited the proliferation of melanoma cells B16-F1, but at the same time did not show significant apoptosis-inducing effects on mouse embryonic fibroblasts 3T3 and melanoma cells B16-F1. This shows that the compound WYC-331 also has some selectivity for melanoma-regenerating cells, and no obvious is observed. Cytotoxicity, but the mechanism of action may be different from the compound WYC-209 ( Figure 11).
- B16-F1 cells were incubated with 3D fibrin glue medium (90-Pa) for 5 days, and the desired tumor regenerative cells were screened. Subsequently, the medium was treated with collagenase and neutral protease II to release tumor regenerative cells. The resulting regenerated cells are then pipetted into the new preparation medium and maintained in a single cell resuspended state.
- 3D fibrin glue medium 90-Pa
- mice Six immunocompetent mice were randomly divided into two groups: the drug-administered group and the DMSO-negative control group.
- the melanoma model was subcutaneously implanted by subcutaneous injection of 30,000 melanoma-derived cells. Subsequently, it was administered by tail vein injection according to the body weight of the mouse and the blood volume. From day 0, the drug-administered group was treated with WYC-103 once every 2 days according to the blood concentration of 10 ⁇ M. The survival of the mice was observed by normal feeding, and the results were as follows. After 19 days of experimentation, the subcutaneous melanoma volume of the drug-administered group was significantly smaller than that of the DMSO control group. According to statistical analysis, the tumor volume of the drug-administered group was only 50% of the control group (Fig. 12).
- the drug-administered group was injected with WYC-103 once every 2 days according to the blood concentration of 10 ⁇ M; the positive control group was administered in the same manner with BMS-453 (WYC-114) as the positive drug; 0.1% DMSO was injected once in the same manner.
- mice in the positive drug control group died.
- 50% of the mice in the drug-administered group and the negative control group died.
- the tumor volume of the mice in the drug-administered group was only 50% of the negative control group, and the growth of the subcutaneous transplanted tumors of the mice in the drug-administered group was significantly inhibited.
- the mouse body weight study showed that the body weight of the mice in the administration group was stable and balanced, and no obvious side effects were observed (Fig. 13, wherein drug3# indicates WYC-103, drug14# indicates BMS-453).
- mice with normal immune function C57BL/6, female, 6-8 weeks were randomly selected as the matrix, and 3000 melanoma regenerative cells were injected into the mice via the tail vein to establish a lung cancer metastasis model.
- the model mice were randomly divided into two groups: the drug-administered group and the negative control group.
- the compounds WYC-103 (to the drug) and DMSO (negative control group) were subjected to 10 ⁇ M blood according to the tail vein injection method. The drug concentration and 0.1% of the dose were injected every two days.
- the first control group died in the negative control group.
- the mice in one administration group were killed at the same time.
- the negative control group showed obvious melanoma lung metastasis tumor tissue.
- the lung tissue of the mice in the administration group was all normal.
- the second control group died in the negative control group, and a large number of melanoma lung metastasis tumor tissues appeared in the negative control group, while the lung tissues in the corresponding administration group were all normal.
- 3 mice died in the negative control group, and only 1 mouse remained in the negative control group, so all the mice in both groups were sacrificed and anatomically compared.
- 3 negative control mice showed severe melanoma lung metastasis, while the lung tissues of the mice in the administration group were all normal.
- the experiment showed that the compound WYC-103 could effectively prevent melanoma-derived cells from metastasizing to the lungs to form secondary lung tumors at a blood concentration of 10 ⁇ M, and WYC-103 showed no obvious side effects during the whole experiment. It is hopeful that it will be further used for the prevention and treatment of human metastatic cancer.
- B16-F1 cells were incubated with 3D fibrin glue medium (90-Pa) for 5 days, and the desired tumor regenerative cells were screened. Subsequently, the medium was treated with collagenase and neutral protease II to release tumor regenerative cells. The resulting regenerated cells were pipetted into a fresh preparation medium and maintained in a single cell resuspended state. Subsequently, 24 immunocompetent mice were randomly selected from immunocompetent mice (C57BL/6, female, 6-8 weeks), divided into low-dose group (1.0 ⁇ M) and high-dose group (10 ⁇ M).
- DMSO negative control group Three study groups were in the DMSO negative control group, with 8 mice in each group.
- the 30,000 melanoma regenerative cells (ten times the animal model used in the compound WYC-103) were injected into the mice via the tail vein to establish a model of melanoma B16-F1 to lung metastasis. Subsequently, it was administered by tail vein injection according to the body weight of the mouse and the blood volume. From the 5th day, the drug-administered group was intravenously injected with WYC-209 every 2 days according to the plasma concentrations of 1.0 ⁇ M and 10 ⁇ M, respectively, and the DMSO group was administered 0.1% in the same manner. DMSO was used as a negative control, and there was no significant difference in body weight between the groups. Observe the statistical results of normal feeding.
- Figures 1 to 7 are lung tissue maps of the experiment for 30 days). In the same period, only one of the 8 mice in the 10 ⁇ M administration group developed melanoma metastasis in the lungs, and no abnormalities were found in the liver and stomach. By the 30th day, 6 mice (75%) in the DMSO group had pulmonary metastasis melanoma, 4 mice (50%) in the 1.0 ⁇ M administration group had pulmonary metastatic melanoma, and only 10 in the 10 ⁇ M administration group. Only mice (12.5%) suffered from metastatic melanoma in the lungs (see Figure 16c for details). Figures 1 to 5 show the lung tissue map for 30 days, and Figures 6-8 show experiments 29, 24, and 20 respectively. Lung tissue map). The lung tissue weight of each group also showed statistically significant differences.
- WYC-103, WYC-209 and WYC-331 had strong inhibitory effects on melanoma-regenerating cells, and the inhibitory activity of melanin-regenerating cells reached 0.45, respectively.
- WYC-209 has strong anti-tumor cells such as lung cancer cell A549, breast cancer cell MCF-7, melanoma cell MDA-MB-435S, ovarian cancer cell A2780, gastric cancer cell Hs-746T, breast cancer cell MDA-MB-231 Inhibition.
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Abstract
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Claims (14)
- 一种如式I所示的化合物、其对映异构体、非对映异构体或药学上可接受的盐,其中,U为CR9a或N;V为CR9b或N;X为CR9c或N;W为CR9d或N;所述的R10、R11、R12、R13和R14独立地为氢或C1-C6的烷基;AE、EG和GZ之间独立地为单键或双键;当A、E、G或Z与两个单键连接时,相应的A、E、G和Z独立地为:-(CR2R3)-、-C(=O)-、-(NR4)-、-(N→O)-、-O-、-S-、-S(=O)-或-SO2-;当A、E、G或Z与一个单键和一个双键连接时,相应的A、E、G或Z独立地为:-(CR5)=或-N=;所述的R2、R3、R4和R5独立地为氢、羟基、卤素、C1-C6的烷基、C2-C6的烯基、卤素取代的C1-C6的烷基、C1-C6的烷氧基、C1-C6的酰基、C6-C10的芳基或“杂原子为氧、硫或氮原子,杂原子数为1~2个的C3-C6的杂芳基”;m为0、1、2或3;当有多个R1取代时,取代基相同或者不同;R1为氢、羟基、硝基、氰基、卤素、C1-C6的烷基、卤素取代的C1-C6的烷基、C1-C6烷氧基、-NR6R7或-COOR8;所述的R6、R7和R8独立地为氢或C1-C6的烷基;Y为-CN、-COOR15或-CO2NHR16;所述的R15和R16独立地为氢、C1-C6的烷基、C2-C6的烯基或C1-C6烷基酰基;
- 如权利要求1所述的如式I所示的化合物,其特征在于,所述的R2、R3、R4和R5独立地为卤素时,所述的“卤素”为氟、氯、溴或碘;和/或,所述的R2、R3、R4和R5独立地为“C1-C6的烷基”时,所述的“C1-C6的烷基”为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基或己基;和/或,所述的R2、R3、R4和R5独立地为“C2-C6的烯基”时,所述的“C2-C6的烯基”为乙烯基或丙烯基;和/或,所述的R2、R3、R4和R5独立地为“卤素取代的C1-C6的烷基”时,所述的“卤素取代的C1-C6的烷基”为三氟甲基;和/或,所述的R2、R3、R4和R5独立地为“C1-C6的烷氧基”时,所述的“C1-C6的烷氧基”为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基或己氧基;和/或,所述的R2、R3、R4和R5独立地为“C1-C6的酰基”时,所述的“C1-C6的酰基”为乙酰基或甲酰基;和/或,所述的R2、R3、R4和R5独立地为“C6-C10的芳基”时,所述的“C6-C10的芳基”为苯基;和/或,所述的R2、R3、R4和R5独立地为“杂原子为氧、硫或氮原子,杂原子数为1~2个的C3-C6的杂芳基”时,所述的“杂原子为氧、硫或氮原子,杂原子数为1~2个的C3-C6的杂芳基”为吡啶基或嘧啶基;和/或,所述的R1为“卤素”时,所述的“卤素”为氟、氯、溴或碘;和/或,所述的R1为“C1-C6的烷基”时,所述的“C1-C6的烷基”为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基或己基;和/或,所述的R1为“卤素取代的C1-C6的烷基”时,所述的“卤素取代的C1-C6的烷基”为三氟甲基;和/或,所述的R1为“C1-C6烷氧基”时,所述的“C1-C6烷氧基”为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基或己氧基;和/或,所述的R6、R7和R8独立地为“C1-C6的烷基”时,所述的“C1-C6的烷基”为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基或己基;和/或,所述的R9a、R9b、R9c和R9d独立地为“卤素”时,所述的“卤素”为氟、氯、溴或碘;和/或,所述的R9a、R9b、R9c和R9d独立地为“C1-C6的烷基”时,所述的“C1-C6的烷基”为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基或己基;和/或,所述的R9a、R9b、R9c和R9d独立地为“卤素取代的C1-C6的烷基”时,所述的“卤素取代的C1-C6的烷基”为三氟甲基;和/或,所述的R9a、R9b、R9c和R9d独立地为“C1-C6烷氧基”时,所述的“C1-C6烷氧基”为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基或己氧基;和/或,所述的R10、R11、R12、R13和R14独立地为“C1-C6的烷基”时,所述的“C1-C6的烷基”为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基或己基;和/或,所述的R15和R16独立地为“C1-C6的烷基”时,所述的“C1-C6的烷基”为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基或己基;和/或,所述的R15和R16独立地为“C2-C6的烯基”时,所述的“C2-C6的烯基”为乙烯基或丙烯基;和/或,所述的R15和R16独立地为“C1-C6的酰基”时,所述的“C1-C6的酰基”为甲酰基或乙酰基。
- 如权利要求4所述的如式I所示的化合物,其特征在于,所述的化合物A中,当Y为-COOR15时,所述的R15为氢或乙基;和/或,所述的化合物B中,当所述的Y为-COOR15时,所述的R15为甲基或乙基;和/或,所述的化合物C中,当所述的Y为-COOR15时,所述的R15为氢或乙基;和/或,所述的化合物D中,当所述的Y为-COOR15时,所述的R15为氢或乙基;和/或,所述的化合物E中,所述的Y为CN;和/或,所述的化合物F中,当所述的Y为-COOR15时,所述的R15为氢、甲基或乙基;
- 如权利要求5所述的如式I所示的化合物,其特征在于,所述的化合物A中,当所述的Y为COOH时,所述的Z为-S-;和/或,所述的化合物A中,当所述的Y为COOEt时,所述的Z为-(CR2R3)-、-S(=O)-或-SO2-;和/或,所述的化合物B中,当所述的Y为COOMe时,所述的Z为-(CR2R3)-;和/或,所述的化合物B中,当所述的Y为COOEt时,所述的Z为-(CR2R3)-或-S-;和/或,所述的化合物B中,当所述的Y为COOEt时,所述的Z为-(CR2R3)-或-S-;和/或,所述的化合物B中,当所述的Y为CN时,所述的Z为-(CR2R3)-、-S-或-S(=O)-;和/或,所述的化合物C中,当所述的Y为COOH时,所述的Z为-S-;和/或,所述的化合物C中,当所述的Y为COOEt时,所述的Z为-(CR2R3)-、-S-或-S(=O)-。
- 如权利要求1~7中任一项所述的如式I所示的化合物、其对映异构体、非对映异构体或药学上可接受的盐在制备药物中的应用,所述的药物用于治疗原发肿瘤。
- 如权利要求1~7中任一项所述的如式I所示的化合物、其对映异构体、非对映异构体或药学上可接受的盐在制备药物中的应用,所述的药物用于预防和/或治疗转移肿瘤。
- 如权利要求1~7中任一项所述的如式I所示的化合物、其对映异构体、非对映异构体或药学上可接受的盐在制备药物中的应用,所述的药物用于预防和/或治疗、白血病和/或淋巴癌。
- 如权利要求1~7中任一项所述的如式I所示的化合物、其对映异构体、非对映异构体或药学上可接受的盐在制备药物中的应用,所述的药物用于动物胎儿发育、内环境稳定、视觉、形态发生、皮肤老化和控制细胞分化中的一种或多种。
- 一种药物组合物,其包含如权利要求1~7中任一项所述的如式I所示的化合物、其对映异构体、非对映异构体或药学上可接受的盐,及可药用载体。
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