CN115340526B - Phthalimide compound, pharmaceutical composition, preparation method and application thereof - Google Patents

Phthalimide compound, pharmaceutical composition, preparation method and application thereof Download PDF

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CN115340526B
CN115340526B CN202110517928.7A CN202110517928A CN115340526B CN 115340526 B CN115340526 B CN 115340526B CN 202110517928 A CN202110517928 A CN 202110517928A CN 115340526 B CN115340526 B CN 115340526B
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hydrogen
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oxygen
different substituents
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CN115340526A (en
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李波
施菊妹
徐志建
余丹丹
董三峰
冯麒麟
张勇
王英聪
贾琦
陈凯先
朱维良
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Shanghai Institute of Materia Medica of CAS
Shanghai Tenth Peoples Hospital
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

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Abstract

The invention relates to a phthalimide compound shown as a formula I, a pharmaceutical composition, a preparation method and application thereof, wherein the definition of each substituent group in the formula I is described in the specification. The phthalimide compound has broad-spectrum or selective inhibition activity on various tumor cells, and has potential application in treating tumor or cancer diseases, in particular myeloma and lymphoma.

Description

Phthalimide compound, pharmaceutical composition, preparation method and application thereof
Technical Field
The invention relates to the fields of pharmaceutical chemistry and pharmacotherapeutics, in particular to a phthalimide compound, a pharmaceutical composition thereof, a preparation method thereof and medical application thereof in treating tumors or cancers.
Background
Multiple Myeloma (MM) has a incidence rate of 4-5/10 ten thousand, and a ratio of men to women of 1.6:1, and is the second most common hematological cancer worldwide. Currently, the MM patients in China have about 2 thousands of new cases each year, and the patients mainly comprise middle-aged and elderly people with ages of more than 40 years. With the aggravation of the aging society, the incidence of the disease tends to rise year by year. MM is currently incurable, and the survival rate in 5 years is only 47% [ Chen Weiqiong, mo Zuyan, wang Shanshan, huang Bo, wang Xiaotao ] new developments in the treatment of multiple myeloma with curative and refractory treatment [ J ]. Medical review, 2020, (06): 1097-1103].
The clinical therapeutic drugs for MM mainly include: glucocorticoids (dexamethasone, prednisone), chemotherapeutics (marflange, doxorubicin, vincristine and cyclophosphamide), proteasome inhibitors (bortezomib, carfilzomib), immunomodulators (thalidomide, lenalidomide or pomalidomide), histone Deacetylase (HDAC) inhibitors (panobinostat) [ Bazarbachi AH, al Hamed R, malard F, harassauu JL, mohty M.Relapsed refractory multiple myeloma: a computable overview. Leukemia.2019,33 (10): 2343-2357).]. MM has unknown etiology, strong heterogeneity, and complex clinical characteristics of patients, and thus has a different response to drug treatment. As bortezomib and lenalidomide used in the current clinical line, patients still relapse after monotherapy or combination therapy with glucocorticoid, chemotherapeutic or HDAC inhibitors, after relapseIs the main cause of failure in therapy [ Pinto V, bergantim R, caires HR, seca H,JE,Vasconcelos MH.Multiple Myeloma:Available Therapies and Causes of Drug Resistance.Cancers.2020,12(2):E407；Ito S.Proteasome Inhibitors for the Treatment of Multiple Myeloma.Cancers.2020,12(2):E265.]。
therefore, there is a great need to develop drugs with new mechanisms of action to overcome the widely existing drug resistance problem, thereby providing an alternative solution for the cure of MM patients.
Disclosure of Invention
The phthalimide compound, the stereoisomer or the medicinal salt thereof disclosed by the invention can inhibit the growth of various tumor cells, so that the phthalimide compound can be developed into a novel medicament for treating various tumors or cancers.
According to an object of the present invention, there is provided a phthalimide compound of formula I:
wherein,
represents a double bond or a single bond;
A. b, E, G, W, U independently represent carbon or nitrogen, respectively;
x is oxygen, nitrogen, sulfur, carbonyl, C2-C6 alkylene or C1-C6 alkylene, preferably oxygen, C2-C4 alkylene or C1-C3 alkylene, for example X may be oxygen, ethylene, methylene or ethylene;
R 1 absent or oxygen, NH, R 11 N-, carbonyl or C1-C6 alkylene, R 11 Is C1-C6 alkyl, preferably R 1 Absent or oxygen, NH, R 11 N-or C1-C3 alkylene, R 11 C1-C3 alkyl, e.g. R 1 Absent or can be oxygen, NH, CH 3 N-, methylene or ethylene;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, hydroxy, amino, mercapto, C1-C6 alkyl, C6-C12 aryl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio, C6-C12 aryloxy, C6-C12 arylamino, C6-C12 arylthio and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C6 alkyl-substituted saturated or unsaturated 4-7 membered aliphatic ring or a 4-7 membered heterocyclic ring, said 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur; preferably, R 2 Represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C6 alkyl or halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C6 alkyl-substituted saturated 5-7 membered aliphatic ring; more preferably, R 2 Represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C3 alkyl and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C3 alkyl-substituted cyclohexane ring;
R 3 is absent or represents 1 to 4 identical or different substituents, and each R 3 Independently selected from hydrogen, hydroxy, amino, mercapto, C1-C6 alkyl, C6-C12 aryl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio, C6-C12 aryloxy, C6-C12 arylamino, C6-C12 arylthio and halogen, or two adjacent R 3 And the carbon atoms to which they are attached together form an unsubstituted or C1-C6 alkyl-substituted saturated or unsaturated 4-7 membered aliphatic ring or a 4-7 membered heterocyclic ring, said 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur;
R 4 to represent 1 to 4 identical or different substituents, and each R 4 Independently selected from hydrogen, hydroxy, amino, mercapto, C1-C6 alkyl, C6-C12 aryl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio, C6-C12 aryloxy, C6-C12 arylamino, C6-C12 arylthio and halogen, or two adjacent R 4 And carbon attached theretoThe atoms together form an unsubstituted or C1-C6 alkyl-substituted saturated or unsaturated 4-7 membered aliphatic ring or a 4-7 membered heterocyclic ring, said 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur.
In one embodiment, the phthalimide compound of formula I according to the present invention is represented by formula I' below
Wherein the method comprises the steps ofR 1 、R 2 X is defined as above, respectively.
In one embodiment, in the phthalimide compound of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof according to the present invention,
represents a double bond or a single bond;
A. b, E, G, W, U independently represent carbon or nitrogen, respectively;
x is oxygen, nitrogen, sulfur, carbonyl, C2-C6 alkenylene or C1-C6 alkylene;
R 1 absent or oxygen, NH, R 11 N-, carbonyl or C1-C6 alkylene, R 11 Is C1-C6 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, hydroxy, amino, mercapto, C1-C6 alkyl, C6-C12 aryl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio, C6-C12 aryloxy, C6-C12 arylamino, C6-C12 arylthio and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C6 alkyl-substituted saturated or unsaturated 4-7 membered aliphatic ring or a 4-7 membered heterocyclic ring, said 4-7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur;
R 3 absence or representation of 1-4Identical or different substituents, and each R 3 Independently selected from the group consisting of hydrogen, hydroxy, amino, mercapto, C1-C6 alkyl, C6-C12 aryl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio, C6-C12 aryloxy, C6-C12 arylamino, C6-C12 arylthio, and halogen;
R 4 to represent 1 to 4 identical or different substituents, and each R 4 Independently selected from the group consisting of hydrogen, hydroxy, amino, mercapto, C1-C6 alkyl, C6-C12 aryl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio, C6-C12 aryloxy, C6-C12 arylamino, C6-C12 arylthio, and halogen.
In one embodiment, in the phthalimide compound of formula I, stereoisomers or pharmaceutically acceptable salts thereof according to the invention,
represents a double bond or a single bond;
A. b, E, G, W, U independently represent carbon or nitrogen, respectively;
x is oxygen, C2-C4 alkenylene or C1-C3 alkylene;
R 1 absent or oxygen, NH, R 11 N-or C1-C3 alkylene, R 11 Is C1-C3 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C6 alkyl or halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C6 alkyl-substituted saturated 4-7 membered aliphatic ring;
R 3 is absent or represents 1 to 4 identical or different substituents, and each R 3 Independently selected from the group consisting of hydrogen, hydroxy, amino, mercapto, C1-C6 alkyl, C6-C12 aryl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkylthio, C6-C12 aryloxy, C6-C12 arylamino, C6-C12 arylthio, and halogen;
R 4 to represent 1 to 4 identical or different substituents, and each R 4 Independently selected from hydrogen, hydroxy, amino, mercapto, C1-C6 alkyl, C6-C12 aryl, C1-C6 alkoxy, C1-C6 alkylAmino, C1-C6 alkylthio, C6-C12 aryloxy, C6-C12 arylamino, C6-C12 arylthio and halogen.
In one embodiment, in the phthalimide compound of formula I, stereoisomers or pharmaceutically acceptable salts thereof according to the invention,
represents a double bond or a single bond;
A. b, E, G, W, U each independently represents carbon;
x is oxygen, C2-C4 alkenylene or C1-C3 alkylene;
R 1 absent or oxygen, NH, R 11 N-or C1-C3 alkylene, R 11 Is C1-C3 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C6 alkyl and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C6 alkyl-substituted saturated 5-7 membered aliphatic ring;
R 3 is hydrogen;
R 4 is hydrogen.
In one embodiment, in the phthalimide compound of formula I, stereoisomers or pharmaceutically acceptable salts thereof according to the invention,
represents a double bond or a single bond;
A. b, E, G, W, U each independently represents carbon;
x is methylene;
R 1 absent or oxygen, NH, R 11 N-, carbonyl or C1-C6 alkylene, R 11 Is C1-C6 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C3 alkyl and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an undetachedA substituted or C1-C3 alkyl-substituted cyclohexane ring;
R 3 is hydrogen;
R 4 is hydrogen.
In one embodiment, in the phthalimide compound of formula I, stereoisomers or pharmaceutically acceptable salts thereof according to the invention,
represents a double bond or a single bond;
A. b, E, G, W, U each independently represents carbon;
x is oxygen;
R 1 absent or oxygen, NH, R 11 N-, carbonyl or C1-C6 alkylene, R 11 Is C1-C6 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C3 alkyl and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C3 alkyl-substituted cyclohexane ring;
R 3 is hydrogen;
R 4 is hydrogen.
In one embodiment, in the phthalimide compound of formula I, stereoisomers or pharmaceutically acceptable salts thereof according to the invention,
represents a double bond or a single bond;
A. b, E, G, W, U each independently represents carbon;
x is vinylidene;
R 1 absent or oxygen, NH, R 11 N-, carbonyl or C1-C6 alkylene, R 11 Is C1-C6 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C3 alkyl and halogen, or two adjacent R 2 And connected with itThe attached carbon atoms together form an unsubstituted or C1-C3 alkyl-substituted cyclohexane ring;
R 3 is hydrogen;
R 4 is hydrogen.
In one embodiment, in the phthalimide compound of formula I, stereoisomers or pharmaceutically acceptable salts thereof according to the invention,
represents a double bond or a single bond;
A. b, E, G, W, U each independently represents carbon;
x is oxygen, ethylene, methylene or ethylene;
R 1 absent or oxygen, NH, CH 3 N-, methylene or ethylene;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C3 alkyl and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C3 alkyl-substituted cyclohexane ring;
R 3 is hydrogen;
R 4 is hydrogen.
Specifically, the phthalimide compound shown in the formula I is selected from the following compounds:
。
according to another object of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of phthalimides of formula I as described above, stereoisomers and pharmaceutically acceptable salts thereof, and optionally pharmaceutically acceptable excipients.
According to a further object of the present invention, there is provided the use of a phthalimide compound of formula I, a stereoisomer or a pharmaceutically acceptable salt thereof as described above, for the preparation of a medicament for the treatment of tumors or cancers.
According to the present invention, the tumor or cancer is one or more selected from lung cancer, colorectal cancer, breast cancer, liver cancer, stomach cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, myeloma, lymphoma and leukemia.
According to another object of the present invention, there is provided a method for preparing a phthalimide compound represented by formula I as described above, the method comprising:
the compound 5 and the compound 6 are subjected to ammonolysis reaction to generate a compound 7, the compound 7 is subjected to ring closure in the presence of alkalinity and condensing agent to generate a compound 8,
wherein R is 1 、R 2 、R 3 、R 4 X, A, B, E, G, W, U are defined as described above.
In the method of the invention, the alkali can be selected from one or more of organic alkali and inorganic alkali, the organic alkali can be selected from one or more of triethylamine, pyridine, diisopropylethylamine and dimethylaminopyridine, and the inorganic alkali can be selected from one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide and potassium tert-butoxide; the condensing agent can be one or two selected from EDCI (1-ethyl-3 (3-dimethylpropylamine) carbodiimide) and HOBT (1-hydroxybenzotriazole).
In the process according to the invention, the ring closure is preferably carried out in the presence of the condensing agents EDCI (1-ethyl-3 (3-dimethylpropylamine) carbodiimide), HOBT (1-hydroxybenzotriazole) and triethylamine.
When compound 8When representing a double bond, compound 9 can also be produced by hydrogenation reduction or addition reaction of the double bond;
wherein R is 1 、R 2 、R 3 、R 4 X, A, B, E, G, W, U are defined as described above.
Compound 5 and compound 6 can be produced by the following reactions, respectively:
the compound 1 and the compound 2 undergo cycloaddition reaction under the condition of presence or absence of acid to generate a compound 5; the compound 3 and the compound 4 undergo a coupling reaction under alkaline conditions to generate a compound 6.
R 1 、R 2 、R 3 、R 4 X, A, B, E, G, W, U one of Ra, rb is halogen, hydroxy, amino, mercapto or acyl halide and the other is boric acid, boric acid ester, C2-C6 alkenyl or C1-C6 haloalkyl as defined above.
In the above reaction, the acid may be selected from one or more of a lewis acid or a protic acid. Lewis acids such as aluminum trichloride; protic acids such as p-toluene sulfonic acid;
in the above reaction, the base may be selected from one or more of an organic base or an inorganic base. The organic base can be selected from one or more of triethylamine, pyridine, diisopropylethylamine and dimethylaminopyridine, and the inorganic base can be selected from one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide and potassium tert-butoxide.
In the present invention, the "C1-C6 alkyl" means a straight-chain or branched alkyl group having 1 to 6 (1, 2,3, 4, 5, 6) carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl and the like. In one embodiment, the C1-6 alkyl is preferably C1-C3 alkyl. "C1-C3 alkyl" as used herein refers to the above examples containing 1 to 3 carbon atoms.
As used herein, "C1-C6 alkoxy" refers to a "C1-C6 alkyl-O-" group such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, and the like. In one embodiment, the C1-6 alkoxy group is preferably a C1-C4 alkoxy group. The term "C1-C4 alkoxy" refers to a specific example of the above examples containing 1 to 4 carbon atoms.
The "halogen" refers to fluorine, chlorine, bromine, iodine and the like.
The term "C1-C6 alkylthio" as used herein refers to a "C1-C6 alkyl-S-" group wherein C1-C6 alkyl is as described above.
The term "C1-C6 alkylamino" as used herein refers to a "C1-C6 alkyl-NH-" group wherein C1-C6 alkyl is as described above.
The term "C1-C6 alkylene" as used herein means a straight or branched chain divalent alkyl radical containing 1 to 6 (1, 2,3, 4, 5, 6) carbon atoms, such as methylene (-CH) 2 (-), ethylene (-CH) 2 CH 2 -or-CH (CH) 3 ) (-), propylene (-CH) 2 CH 2 CH 2 (-), etc.
"C2-C6 alkenylene" as used herein refers to a straight or branched chain divalent alkenyl group containing 2 to 6 (2, 3, 4, 5, 6) carbon atoms, such as vinylidene (-ch=ch-or=c=ch) 2 ) Etc.
"C6-C12 aryl" as used herein refers to a monocyclic or bicyclic aromatic ring radical containing 6 to 12 ring atoms, but no heteroatoms in the ring atoms, such as phenyl, naphthyl.
C6-C12 aryloxy refers to a "C6-C12 aryl-O-" group, wherein C6-C12 aryl is as described above.
C6-C12 arylamino refers to a "C6-C12 aryl-NH-" group, where C6-C12 aryl is as described above.
C6-C12 arylthio refers to a "C6-C12 aryl-S-" group, wherein C6-C12 aryl is as described above.
The term "saturated or unsaturated 4-7 membered aliphatic ring" as used herein means a saturated or unsaturated carbocyclic ring having 4, 5, 6 or 7 ring atoms, and includes cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclobutene ring, cyclopentene ring and the like.
The "saturated or unsaturated 4-7 membered heterocyclic ring" as used herein means a saturated or unsaturated 4-7 membered heterocyclic ring having 4, 5, 6 or 7 ring atoms and containing 1,2, 3 or 4 hetero atoms selected from nitrogen, oxygen and sulfur, and includes pyrrole, imidazole, triazole, tetrazole, thiophene, thiazole, furan, oxazole, pyridine, pyrimidine, triazine, aza Zhuo Huan and the like.
Advantageous effects
The invention designs and synthesizes phthalimide compounds, and discovers that the compounds have broad-spectrum or selective tumor cell inhibition activity through activity tests on various tumor cells, which shows that the compounds have potential application in treating tumor or cancer diseases, in particular myeloma and lymphoma.
Drawings
FIG. 1 is a graph showing experimental results of compound I-2 anti-multiple myeloma animals, wherein A shows photographs showing changes in tumor size of a control group and an experimental group to which compound I-2 is administered, B shows tumor weights of the control group and the experimental group to which compound I-2 is administered, C shows changes in tumor volumes of the control group and the experimental group to which compound I-2 is administered, and D shows changes in average body weights of nude mice of the control group and the experimental group to which compound I-2 is administered;
FIG. 2 is a graph showing experimental results of compound I-3 against multiple myeloma animals, wherein A shows photographs of tumor size changes of a control group and an experimental group to which compound I-3 is administered, B shows tumor weights of the control group and the experimental group to which compound I-3 is administered, C shows tumor volume changes of the control group and the experimental group to which compound I-3 is administered, and D shows average weight changes of nude mice of the control group and the experimental group to which compound I-3 is administered.
Detailed Description
The invention is further illustrated, but is not limited, by the following examples. Unless specifically indicated, methods, materials, equipment, and the like employed in the present application are those commonly used in the art.
Preparation example
EXAMPLE 1 preparation of Compound I-1
Cis-2, 3-norbornanedicarboxylic anhydride (83 mg,0.5 mmol) and 4- (4-picolyl) aniline (92 mg,0.5 mmol) were dissolved in 20ml of tetrahydrofuran, and after stirring at room temperature for 12 hours the precipitated solid precipitate was filtered, followed by redissolving the filter cake using 20ml of DMF and adding EDCI (1-ethyl-3 (3-dimethylpropylamine) carbodiimide) (191 mg,1 mmol), HOBT (1-hydroxybenzotriazole) (135 mg,1 mmol) and triethylamine (142. Mu.l, 1 mmol) in sequence. Stirring at room temperature for 12 hours, after TLC monitors the generation of a target product, evaporating the reaction liquid under reduced pressure, adding 50ml of ethyl acetate for redissolution, washing once with water, washing once with saturated sodium chloride, drying with anhydrous sodium sulfate, evaporating the organic phase under reduced pressure again, and separating by thin layer chromatography to obtain 76.7mg of white powder with the yield of 46.2%. 1 H NMR(600MHz,Chloroform-d)δ8.56–8.51(m,2H),7.30(d,J＝2.0Hz,2H),7.25–7.22(m,2H),7.17–7.11(m,2H),4.02(s,2H),2.85(dq,J＝3.4,1.7Hz,2H),2.81(s,2H),1.75(dt,J＝8.0,2.5Hz,2H),1.47–1.42(m,2H),1.38–1.34(m,2H). 13 C NMR(150MHz,Chloroform-d)δ178.08,149.91,149.19,139.39,130.50,129.76,126.63,124.24,48.71,40.83,40.34,33.40,28.06.HRMS(ESI)：C 21 H 21 N 2 O 2 [M+H] + Calculated values: 333.1598, found: 333.1597.
EXAMPLE 2 preparation of Compound I-2
Bicyclo [2.2.2]Octyl-5-ene-2, 3-dicarboxylic anhydride (89 mg,0.5 mmol) and 4- (4-picolyl) aniline (92 mg,0.5 mmol) as compound I-1The synthesis method gave 74.3mg of white powder in 43.2% yield. 1 H NMR(500MHz,Chloroform-d)δ8.54–8.49(m,2H),7.25(d,J＝8.4Hz,2H),7.18–7.09(m,4H),6.29(dd,J＝4.5,3.1Hz,2H),3.99(s,2H),3.27(ddt,J＝4.8,3.2,1.5Hz,2H),3.02(t,J＝1.6Hz,2H),1.71–1.65(m,2H),1.49–1.42(m,2H). 13 C NMR(125MHz,Chloroform-d)δ178.05,149.90,149.21,139.28,132.44,130.53,129.65,126.72,124.22,44.22,40.83,32.04,23.68.HRMS(ESI)：C 22 H 21 N 2 O 2 [M+H] + Calculated values: 345.1598, found: 345.1597.
EXAMPLE 3 preparation of Compound I-3
Cantharidin (93 mg,0.5 mmol) and 4- (4-picolyl) aniline (92 mg,0.5 mmol) were dissolved in 10ml toluene, then triethylamine (140 μl,1 mmol) was added, the reaction was stopped after heating to 200 ℃ after sealing with a tube, the reaction was cooled to room temperature, then 20ml of water was added to quench the reaction, then extracted 3 times with 20ml of ethyl acetate, the organic phases were combined and washed once with water, saturated sodium chloride and dried over anhydrous sodium sulfate, and then 63.5mg of yellow powder was isolated using thin layer chromatography, yield 35%. 1 H NMR(600MHz,Chloroform-d)δ8.53–8.43(m,2H),7.26(s,4H),7.13–7.09(m,2H),4.69(dd,J＝3.4,2.1Hz,2H),3.99(s,2H),1.91–1.80(m,2H),1.75(d,J＝3.6Hz,2H),1.25(s,6H). 13 C NMR(150MHz,Chloroform-d)δ180.25,149.45,148.82,138.85,130.17,129.21,126.28,123.79,83.64,53.62,40.39,23.37,12.45.HRMS(ESI)：C 22 H 23 N 2 O 3 [M+H] + Calculated values: 363.1703, found: 363.1698.
EXAMPLE 4 preparation of Compound I-4
Norcantharidin (84 mg, 0.5)mmol) and 4- (4-picolyl) aniline (92 mg,0.5 mmol) were dissolved in 20ml tetrahydrofuran and after stirring at room temperature for 12 hours the precipitated solid precipitate was filtered, then the filter cake was redissolved with 20ml DMF and EDCI (191 mg,1 mmol), HOBT (135 mg,1 mmol) and triethylamine (142 μl,1 mmol) were added sequentially. After stirring at room temperature for 12 hours, the reaction solution is evaporated to dryness under reduced pressure after TLC monitors the generation of a target product, 50ml of ethyl acetate is added for redissolution, water is washed once, saturated sodium chloride is washed once, anhydrous sodium sulfate is dried, then the organic phase is evaporated to dryness under reduced pressure again, and the yellow powder is obtained by thin layer chromatography separation, and the yield is 21 percent. 1 H NMR(600MHz,Chloroform-d)δ8.58–8.45(m,2H),7.29(d,J＝8.5Hz,2H),7.26–7.24(m,2H),7.17–7.12(m,2H),5.02(dd,J＝3.3,2.1Hz,2H),4.02(s,2H),3.07(s,2H),1.94(dq,J＝10.4,2.8Hz,2H),1.69(dd,J＝17.2,3.1Hz,2H). 13 C NMR(150MHz,Chloroform-d)δ176.37,149.85,149.41,139.46,130.36,129.75,126.74,124.32,79.55,50.03,40.84,28.64.HRMS(ESI)：C 20 H 19 N 2 O 3 [M+H] + Calculated values: 335.1390, found: 335.1393.
EXAMPLE 5 preparation of Compound I-5
Maleic anhydride (4.9 g,50 mmol) was dissolved in excess furan (34 g,300 mmol), after stirring at room temperature for 48 hours, a large amount of white solid was precipitated from the reaction solution, and 8.26g of nordehydrocantharidin was obtained by filtration, followed by synthesis of nordehydrocantharidin (82 mg,0.5 mmol) and 4- (4-picolyl) aniline (92 mg,0.5 mmol) according to the synthesis method described for compound I-1 to give 45.2mg of pink powder in 27% yield. 1 H NMR(600MHz,Chloroform-d)δ8.56–8.52(m,2H),7.30(d,J＝8.7Hz,2H),7.27(d,J＝2.3Hz,2H),7.18–7.12(m,2H),6.60(t,J＝1.0Hz,2H),5.42(d,J＝1.1Hz,2H),4.02(s,2H),3.04(s,2H). 13 C NMR(150MHz,Chloroform-d)δ175.39,149.94,149.13,139.61,136.71,130.21,129.76,126.80,124.24,81.42,47.55,40.84.HRMS(ESI)：C 20 H 17 N 2 O 3 [M+H] + Calculated values: 333.1234, actual measurement: 333.1226.
EXAMPLE 6 preparation of Compound I-6
Nordehydrocantharidin (83 mg,0.5 mmol) and 4- (4-aminophenoxy) pyridine (93 mg,0.5 mmol) were synthesized as described for compound I-1 to yield 86.1mg of brown powder in 51% yield. 1 H NMR(400MHz,Chloroform-d)δ8.51(d,J＝5.5Hz,2H),7.41–7.34(m,2H),7.24–7.18(m,2H),6.94–6.89(m,2H),6.61(d,J＝1.1Hz,2H),5.43(d,J＝1.0Hz,2H),3.06(s,2H). 13 C NMR(125MHz,Chloroform-d)δ175.26,164.15,154.12,151.55,136.73,128.58,128.43,121.15,112.57,81.48,47.57。HRMS(ESI)：C 19 H 15 N 2 O 4 [M+H] + Calculated values: 335.1026, found: 337.1030.
EXAMPLE 7 preparation of Compound I-7
Maleic anhydride (98 mg,1 mmol) was dissolved in bromofuran (292 mg,2 mmol), a large amount of white solid was precipitated from the reaction solution after stirring at room temperature for 48 hours, bromonordehydrocantharidin was obtained by filtration, and bromonordehydrocantharidin (121 mg,0.5 mmol) and 4- (4-picolyl) aniline (92 mg,0.5 mmol) were synthesized as described for compound I-1 to give 66.2mg of white powder in 32% yield. 1 H NMR(400MHz,Chloroform-d)δ8.57–8.50(m,2H),7.30(d,J＝8.5Hz,2H),7.27–7.23(m,2H),7.14–7.09(m,2H),6.61(d,J＝1.9Hz,1H),5.40(dd,J＝1.9,0.9Hz,1H),5.24(d,J＝0.8Hz,1H),4.02(s,2H),3.25–3.16(m,2H). 13 C NMR(125MHz,Chloroform-d)δ174.31,149.99,149.03,139.80,135.07,129.80,126.75,124.21,85.67,83.34,48.61,46.81,40.85.HRMS(ESI)：C 20 H 16 BrN 2 O 3 [M+H] + Calculated values: 411.0339, found: 411.0349.
EXAMPLE 8 preparation of Compound I-8
Bromonordehydrocantharidin (121 mg,0.5 mmol) and 4- (4-aminophenoxy) pyridine (93 mg,0.5 mmol) were synthesized as described for compound I-1 to yield 79.6mg as a white powder in 39% yield. 1 H NMR(500MHz,Chloroform-d)δ8.58–8.45(m,2H),7.39–7.35(m,1H),7.28(s,1H),7.24–7.17(m,2H),6.92(dt,J＝4.9,1.3Hz,2H),6.64(dd,J＝14.9,1.9Hz,1H),5.47–5.19(m,2H),3.88–3.79(m,1H),3.26–3.19(m,1H). 13 C NMR(125MHz,Chloroform-d)δ174.23,164.09,154.38,154.28,151.59,135.06,133.97,128.39,127.45,121.17,112.58,85.71,83.89,83.38,81.75,48.62,47.51,46.82,45.80.HRMS(ESI)：C 19 H 14 BrN 2 O 4 [M+H] + Calculated values: 413.0131, found: 413.0145.
EXAMPLE 9 preparation of Compound I-9
Maleic anhydride (49 mg,0.5 mmol) and menthofuran (150 mg,1 mmol) were dissolved in 2ml of acetone, the reaction solution was stirred at room temperature for one week, and then evaporated to dryness under reduced pressure, followed by rinsing with diethyl ether three times to obtain the acid anhydride required for the reaction. The anhydride (121 mg,0.5 mmol) and 4- (4-picolyl) aniline (92 mg,0.5 mmol) were then synthesized as described for compound I-1 to give 103.2mg as a white powder in 49% yield. 1 H NMR(400MHz,Chloroform-d)δ8.53(d,J＝5.1Hz,2H),7.30(s,1H),7.28–7.24(m,3H),7.16–7.09(m,2H),5.02(s,1H),4.01(d,J＝5.3Hz,2H),3.09(d,J＝6.5Hz,1H),2.89(d,J＝6.5Hz,1H),2.62–2.44(m,2H),1.90(dd,J＝37.4,16.3Hz,7H),1.52(t,J＝12.9Hz,1H),1.22–1.13(m,1H),1.07(dd,J＝14.6,6.5Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ175.66,149.81,149.21,140.45,139.26,136.07,129.60,126.74,124.18,90.55,83.80,51.35,48.24,40.77,34.88,32.82,29.20,22.26,22.18,10.00.HRMS(ESI)：C 26 H 27 N 2 O 3 [M+H] + Calculated values: 415.2016, found: 415.2014.
EXAMPLE 10 preparation of Compound I-10
The acid anhydride (121 mg,0.5 mmol) prepared in the preparation of Compound I-9 and 4- (4-aminophenoxy) pyridine (93 mg,0.5 mmol) were synthesized as described for Compound I-1 to give 91.6mg as a yellow oil in 44% yield. 1 H NMR(500MHz,Chloroform-d)δ8.56–8.46(m,2H),7.44–7.37(m,2H),7.22–7.17(m,2H),6.95–6.87(m,2H),5.31(s,1H),5.02(s,1H),3.10(d,J＝6.5Hz,1H),2.90(d,J＝6.3Hz,1H),2.64–2.45(m,2H),1.95–1.75(m,7H),1.13–1.05(m,3H). 13 C NMR(125MHz,Chloroform-d)δ175.63,164.28,151.50,140.55,136.18,128.81,128.44,121.12,112.51,90.70,83.93,53.41,51.44,48.34,34.98,32.90,29.30,22.34,22.26,10.07.HRMS(ESI)：C 25 H 25 N 2 O 4 [M+H] + Calculated values: 417.1809, found: 417.1807.
EXAMPLE 11 preparation of Compound I-11
Maleic anhydride (9.8 g,100 mmol) and 2, 3-dimethyl-1, 3-butadiene (8.2 g,100 mmol) were dissolved in 200ml acetone, and after stirring at room temperature for 3 days, the reaction mixture was stirred with silica gel, and 16.2g of the objective anhydride was obtained by silica gel column chromatography. The anhydride (90 mg,0.5 mmol) and 4- (4-picolyl) aniline (92 mg,0.5 mmol) were then synthesized as described for compound I-1 to give 86.3mg as a pink powder in 50% yield. 1 H NMR(400MHz,Chloroform-d)δ8.55–8.48(m,2H),7.27(d,J＝8.2Hz,2H),7.19–7.15(m,2H),7.15–7.11(m,2H),4.01(s,2H),3.29–3.18(m,2H),2.56(d,J＝14.8Hz,2H),2.33(d,J＝14.4Hz,2H),1.75–1.72(m,6H). 13 C NMR(125MHz,Chloroform-d)δ179.32,149.49,139.09,130.76,129.69,127.05,126.67,124.48,124.36,40.87,40.10,30.97,19.23.HRMS(ESI)：C 21 H 23 N 2 O 2 [M+H] + Calculated values: 337.1754, found: 337.1756.
EXAMPLE 12 preparation of Compound I-12
The acid anhydride (90 mg,0.5 mmol) produced in the preparation of Compound I-11 and 4- (4-aminophenoxy) pyridine (93 mg,0.5 mmol) were synthesized as described for Compound I-1 to give 84.2mg of a white powder in 48% yield. 1 H NMR(500MHz,Chloroform-d)δ8.58–8.45(m,2H),7.30(d,J＝6.7Hz,2H),7.26–7.14(m,2H),6.95–6.85(m,2H),3.25(tt,J＝2.6,1.3Hz,2H),2.58(dt,J＝14.7,1.4Hz,2H),2.41–2.28(m,2H),1.76(d,J＝1.1Hz,6H). 13 C NMR(125MHz,Chloroform-d)δ179.25,164.23,153.86,151.54,129.06,128.22,127.08,121.14,112.51,40.11,30.97,19.26.HRMS(ESI)：C 21 H 21 N 2 O 3 [M+H] + Calculated values: 349.1547, found: 349.1541.
EXAMPLE 13 preparation of Compound I-13
4-Methylhexahydrophthalic anhydride (84 mg,0.5 mmol) and 4- (4-picolyl) aniline (92 mg,0.5 mmol) were synthesized as described for compound I-1 to give 23.2mg as a yellow oil in 14% yield. 1 H NMR(400MHz,DMSO-d 6 )δ8.52–8.46(m,2H),7.40–7.33(m,2H),7.21–7.17(m,2H),6.92–6.86(m,1H),6.52–6.48(m,1H),4.02(s,2H),2.97(ddt,J＝21.9,10.3,7.3Hz,2H),2.18–1.96(m,3H),1.59(ddd,J＝12.9,7.4,4.2Hz,2H),1.49–1.35(m,2H),0.90(dd,J＝10.4,6.4Hz,3H)。HRMS(ESI)：C 21 H 22 N 2 O 2 [M+H] + Calculated values: 334.1754, found: 334.1758.
EXAMPLE 14 preparation of Compound I-14
N-methylpyrrole (81 mg,1 mmol) and maleic anhydride (98 mg,1 mmol) were dissolved in methylene chloride, aluminum trichloride (13 mg,0.1 mmol) was added to react for 1 day, the reaction solution was washed three times with water, and then evaporated to dryness under reduced pressure to obtain the objective acid anhydride, which was then synthesized (89 mg,0.5 mmol) and 4- (4-pyridylmethyl) aniline (92 mg,0.5 mmol) according to the synthetic method described for Compound I-1 to give 17.2mg of the product as a yellow oil in 10% yield. 1 H NMR(400MHz,Chloroform-d)δ8.53(d,J＝5.2Hz,2H),7.31(d,J＝4.1Hz,2H),7.26(d,J＝8.7Hz,2H),7.13(d,J＝5.5Hz,2H),6.71–6.68(m,1H),6.14(dd,J＝3.7,2.9Hz,1H),4.02(d,J＝3.8Hz,3H),3.80(s,3H),3.37(dd,J＝18.4,9.5Hz,1H),3.13(dd,J＝18.4,4.9Hz,1H).HRMS(ESI)：C 21 H 20 N 3 O 2 [M+H] + Calculated values: 346.1550, found: 346.1556.
experimental examples of Activity test
Test example 1 the effect of the compounds of the invention on the activity of blood tumor cells.
1. Experimental materials:
(1) Cell lines: human multiple myeloma cells (ARP-1, OCI-MY 5) cells were purchased from the American ATCC and NCI-H929R cells were passaged for this laboratory.
(2) The main reagent comprises: 1640 medium (Gibco Co., USA), fetal bovine serum (Gibco Co., USA), cell Counting Kit-8 kit (CCK 8, japan Co., ltd.).
(3) The main instrument is as follows: carbon dioxide incubator (Thermo Forma company of U.S.), full-automatic enzyme-labeled instrument (Bio-TEK, elx 800).
2. The experimental method comprises the following steps:
(1) Cell culture
Culturing cells in 1640 culture medium (containing 10% fetal bovine serum and pH 7.2), adding 2mmol/L glutamine, placing in cell incubator at 37℃、5％CO 2 Culturing in the environment.
(2) Determination of the inhibition of the individual cells by the drugs using CCK8 kit
Single cell suspensions of human multiple myeloma cells (ARP-1, OCI-MY5, NCI-H929R cells) were taken, and the cell concentration was adjusted to 2X 10≡5/mL after counting. The 96-well plates were taken and 95. Mu.L of the above cell suspension was added to each well, followed by 5. Mu.L of the drug prepared in the medium-formulated examples at the concentrations shown in Table 1, and the control group was added with the corresponding volume of medium, with 3 parallel wells per group. Continuously culturing for 48h, adding 10 μl of CCK8 reagent into each well 2h before culturing, adding CO 2 Culturing is continued in the incubator. After 2h, the OD value of each hole at 450nm is detected by an automatic enzyme-labeling instrument. Cell viability and inhibition were calculated:
cell viability (%) = (experimental well OD mean/control well OD mean) ×100%. Cell inhibition (%) =100% -cell survival (%). Each set of experiments was repeated three times.
3. Experimental results
TABLE 1 results of anti-multiple myeloma cell Activity
The result of inhibiting the activity of the tumor cells shows that the compound has the activity of inhibiting the proliferation of the tumor cells in vitro, has a certain inhibiting effect on bortezomib drug-resistant multiple myeloma cells NCI-H929R, and overcomes the problem of the drug resistance of the bortezomib to a certain extent.
Test example 2 animal experiments on multiple myeloma.
1. Experimental materials
(1) Cell lines: human multiple myeloma cells (NCI-H929 cells) (American ATCC, preserved by passage in this laboratory) were cultured in 1640 medium (containing 10% fetal bovine serum).
(2) Experimental animals: male BALB/C nude mice (6-8 weeks, purchased from Shanghai Sipuler-BiKai laboratory animals Co., ltd.) were kept in an SPF-class environment (Shanghai, tenth people hospital center laboratory animal house).
2. Experimental method
(1) Cell culture is described in particular in test example 1.
(2) Animal experiment and results thereof
PBS buffer containing 2.5X10-H929 cells was injected under the left proximal armpit of nude mice, and when tumors grew to be measurable, the nude mice were randomly divided into 2 groups, the first group of nude mice were daily intraperitoneally injected with the compound prepared in the example, the second group was a blank control group, and the second group of nude mice were daily intraperitoneally injected with the same volume of solvent (100. Mu.L, solvent=15. Mu.L of LDMSO+85. Mu.L of physiological saline). Tumor size (tumor length and width, tumor volume=1/2×length× (width)/(2)) and nude mice body weight were measured every two days, mice were sacrificed 16 days after administration and tumors were photographed.
(3) Experimental results
FIG. 1 shows the experimental results of the compound I-2 anti-multiple myeloma animals, FIG. 2 shows the experimental results of the compound I-3 anti-multiple myeloma animals, and the results show that the compound has in vivo anti-tumor activity and can obviously inhibit the growth of tumors in vivo.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (12)

1. A phthalimide compound of formula I, stereoisomers or pharmaceutically acceptable salts thereof:
wherein,
represents a double bond or a single bond;
when (when)When a double bond is represented, it is,
A. e independently represents carbon, B, G, W, U independently represents carbon or nitrogen, respectively;
x is oxygen, nitrogen, sulfur, C2-C6 alkenylene or C1-C6 alkylene;
R 1 absent or oxygen, NH, R 11 N-or C1-C6-alkylene, R 11 Is C1-C6 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C6 alkyl and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C6 alkyl-substituted saturated or unsaturated 4-7 membered aliphatic ring;
R 3 represents 1 to 4 identical or different substituents, and each R 3 Independently hydrogen or C1-C6 alkyl;
R 4 represents 1 to 4 identical or different substituents, and each R 4 Independently hydrogen or C1-C6 alkyl;
when (when)When the compound represents a single bond,
A. e independently represents carbon, B, G, W, U independently represents carbon or nitrogen, respectively;
x is oxygen, nitrogen, sulfur, C2-C6 alkenylene or C1-C6 alkylene;
R 1 is oxygen, NH or R 11 N-，R 11 Is C1-C6 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C6 alkyl and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C6 alkyl-substituted saturated or unsaturated 4-7 membered ringAn aliphatic ring;
R 3 represents 1 to 4 identical or different substituents, and each R 3 Independently hydrogen or C1-C6 alkyl;
R 4 represents 1 to 4 identical or different substituents, and each R 4 Independently hydrogen or C1-C6 alkyl.
2. The phthalimide compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein,
when (when)When a double bond is represented, it is,
x is oxygen, C2-C4 alkenylene or C1-C3 alkylene;
R 1 absent or oxygen, NH, R 11 N-or C1-C3 alkylene, R 11 Is C1-C3 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C6 alkyl or halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C6 alkyl-substituted saturated 4-7 membered aliphatic ring;
R 3 represents 1 to 4 identical or different substituents, and each R 3 Independently hydrogen or C1-C6 alkyl;
R 4 represents 1 to 4 identical or different substituents, and each R 4 Independently hydrogen or C1-C6 alkyl;
when (when)When the compound represents a single bond,
x is oxygen, C2-C4 alkenylene or C1-C3 alkylene;
R 1 is oxygen, NH or R 11 N-，R 11 Is C1-C3 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C6 alkyl and halogen, or two adjacent R 2 And connected with itThe attached carbon atoms together form an unsubstituted or C1-C6 alkyl-substituted saturated 4-7 membered aliphatic ring;
R 3 represents 1 to 4 identical or different substituents, and each R 3 Independently hydrogen or C1-C6 alkyl;
R 4 represents 1 to 4 identical or different substituents, and each R 4 Independently hydrogen or C1-C6 alkyl.
3. The phthalimide compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein,
when (when)When a double bond is represented, it is,
x is oxygen, C2-C4 alkenylene or C1-C3 alkylene;
R 1 absent or oxygen, NH, R 11 N-or C1-C3 alkylene, R 11 Is C1-C3 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C6 alkyl and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C6 alkyl-substituted saturated 5-7 membered aliphatic ring;
R 3 is hydrogen;
R 4 is hydrogen;
when (when)When the compound represents a single bond,
x is oxygen, C2-C4 alkenylene or C1-C3 alkylene;
R 1 is oxygen, NH or R 11 N-，R 11 Is C1-C3 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C6 alkyl and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C6 alkyl-substituted saturated 5-7 membered aliphatic ring;
R 3 is hydrogen;
R 4 is hydrogen.
4. The phthalimide compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein,
when (when)When a double bond is represented, it is,
x is methylene;
R 1 absent or oxygen, NH, R 11 N-or C1-C6-alkylene, R 11 Is C1-C6 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C3 alkyl and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C3 alkyl-substituted cyclohexane ring;
R 3 is hydrogen;
R 4 is hydrogen;
when (when)When the compound represents a single bond,
x is methylene;
R 1 is oxygen, NH or R 11 N-，R 11 Is C1-C6 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C3 alkyl and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C3 alkyl-substituted cyclohexane ring;
R 3 is hydrogen;
R 4 is hydrogen.
5. The phthalimide compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein,
when (when)When a double bond is represented, it is,
x is oxygen;
R 1 absent or oxygen, NH, R 11 N-or C1-C6-alkylene, R 11 Is C1-C6 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C3 alkyl and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C3 alkyl-substituted cyclohexane ring;
R 3 is hydrogen;
R 4 is hydrogen;
when (when)When the compound represents a single bond,
x is oxygen;
R 1 is oxygen, NH or R 11 N-，R 11 Is C1-C6 alkyl;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C3 alkyl and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C3 alkyl-substituted cyclohexane ring;
R 3 is hydrogen;
R 4 is hydrogen.
6. The phthalimide compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein,
when (when)When a double bond is represented, it is,
x is oxygen, ethylene, methylene or ethylene;
R 1 absent or oxygen, NH, CH 3 N-, methylene or ethylene;
R 2 represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C3 alkyl and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C3 alkyl-substituted cyclohexane ring;
R 3 is hydrogen;
R 4 is hydrogen;
when (when)When the compound represents a single bond,
x is oxygen, ethylene, methylene or ethylene;
R 1 is oxygen, NH or CH 3 N-；
R 2 Represents 1 to 3 identical or different substituents, and each R 2 Independently selected from hydrogen, C1-C3 alkyl and halogen, or two adjacent R 2 And the carbon atoms to which they are attached together form an unsubstituted or C1-C3 alkyl-substituted cyclohexane ring;
R 3 is hydrogen;
R 4 is hydrogen.
7. The phthalimide compound of claim 1, stereoisomers or pharmaceutically acceptable salts thereof, wherein the phthalimide compound is selected from the group consisting of:
。
8. a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the phthalimides of any of claims 1-7, stereoisomers or pharmaceutically acceptable salts thereof and optionally a pharmaceutically acceptable adjuvant.
9. Use of a phthalimide compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of a tumor or cancer.
10. The use according to claim 9, wherein the tumor or cancer is selected from one or more of lung cancer, colorectal cancer, breast cancer, liver cancer, stomach cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, myeloma, lymphoma and leukemia.
11. The method for producing a phthalimide compound described in claim 1, which comprises:
the compound 5 and the compound 6 are subjected to ammonolysis reaction to generate a compound 7, the compound 7 is subjected to ring closure in the presence of alkalinity and condensing agent to generate a compound 8,
wherein R is 1 、R 2 、R 3 、R 4 X, A, B, E, G, W, U are defined as in claim 1.
12. The method of claim 11, wherein,
when (when)When representing double bond, the compound 8 generates double bond hydrogenation reduction or addition reaction to generate a compound 9;
and/or
Compound 5 and compound 6 were each produced by the following reaction:
the compound 1 and the compound 2 undergo cycloaddition reaction under the condition of presence or absence of acid to generate a compound 5; the compound 3 and the compound 4 undergo a coupling reaction under alkaline conditions to generate a compound 6;
wherein R is 1 、R 2 、R 3 、R 4 X, A, B, E, G, W, U one of Ra and Rb is halogen, hydroxy, amino, mercapto or acyl halide and the other is boric acid, boric acid ester, C2-C6 alkenyl or C1-C6 haloalkyl as defined in claim 11.
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EP1927594A1 (en) * 2003-01-14 2008-06-04 Arena Pharmaceuticals, Inc. 1,2,3-Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
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