阅读说明：本技术 双取代的α、β不饱和酮及其制备方法和应用 (Disubstituted alpha, beta unsaturated ketone, preparation method and application thereof ) 是由 吴林韬 王志军 韩春 武曦 苏峰 李梦瑶 苏静 于 2019-09-30 设计创作，主要内容包括：本申请公开了一种具有式I的结构的双取代α、β不饱和酮及其制备方法,其中X、R<Sub>1</Sub>、R<Sub>2</Sub>、R<Sub>3</Sub>、R<Sub>4</Sub>、R<Sub>5</Sub>、R<Sub>6</Sub>、R<Sub>7</Sub>、R<Sub>8</Sub>和R<Sub>9</Sub>的定义详见说明书。本申请还提供了含有式I的结构的化合物作为活性成分的药物组合物。体外活性测试显示,本申请化合物表现出了对肿瘤细胞明显的抑制作用。<Image he="419" wi="700" file="DDA0002223606950000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The application discloses disubstituted alpha, beta unsaturated ketones having the structure of formula I and a process for their preparation, wherein X, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 And R 9 The definition of the compound is shown in the specification in detail. The present application also provides pharmaceutical compositions containing a compound of the structure of formula I as an active ingredient. In vitro activity tests show that the compound shows obvious inhibition effect on tumor cells.)

1. A disubstituted alpha, beta unsaturated ketone having the structure of formula I or a pharmaceutically acceptable salt thereof,

wherein X represents O or S or NH or N-R or CH₂R is unsubstituted alkyl or substituted alkyl;

R₁to R₈Each independently represents the following group: H. hydroxy, alkoxy, unsubstituted mercapto, substituted mercapto, halogen, saturated alkyl, unsaturated alkyl, nitro or cyano;

R₉represents the following groups: H. alkyl, phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolinyl, indolyl, and purinyl, said phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolinyl, indolyl, and purinyl being optionally substituted with alkyl, halo, or alkoxy.

2. The disubstituted α, β unsaturated ketone of claim 1, wherein X is NH and R is a pharmaceutically acceptable salt thereof₁To R₈Is hydrogen, R₉Represents the following groups: H. alkyl, phenyl, pyridyl, furyl, thienyl and pyrrolyl, said phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolinyl, indolyl and purinyl being optionally substituted with alkyl, halogen or alkoxy.

3. The disubstituted α, β unsaturated ketone of claim 1, wherein X is NH and R is a pharmaceutically acceptable salt thereof₁To R₃Is hydrogen, R₄Is methyl or chlorine, R₅To R₈Is hydrogen, R₉Represents the following groups: H. alkyl, phenyl, pyridyl, furyl, thienyl and pyrrolyl, said phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolinyl, indolyl and purinyl being optionally substituted by alkyl, halogen or alkoxyAnd (4) substitution.

4. The disubstituted α, β unsaturated ketone of claim 1, wherein X is NH and R is a pharmaceutically acceptable salt thereof₁、R₂、R₄Is hydrogen, R₃Is methyl, R₅To R₈Is hydrogen, R₉Represents the following groups: H. alkyl, phenyl, pyridyl, furyl, thienyl and pyrrolyl, said phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolinyl, indolyl and purinyl being optionally substituted with alkyl, halogen or alkoxy.

5. The disubstituted α, β unsaturated ketone of claim 1, wherein X is NH and R is a pharmaceutically acceptable salt thereof₁To R₄Is hydrogen, R₅Is isopropyl, R₆To R₈Is hydrogen, R₉Represents the following groups: H. alkyl, phenyl, pyridyl, furyl, thienyl and pyrrolyl, said phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolinyl, indolyl and purinyl being optionally substituted with alkyl, halogen or alkoxy.

6. The disubstituted α, β unsaturated ketone, or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, wherein R₉Represents the following groups: h; an alkyl group; a phenyl group; phenyl substituted with alkyl, halogen or alkoxy; a pyridyl group; a furyl group; and a pyrrolyl group.

7. The disubstituted α, β unsaturated ketone of claim 1, or a pharmaceutically acceptable salt thereof, wherein said disubstituted α, β unsaturated ketone is selected from the group consisting of:

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N-phenylbenzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-methylphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-methylphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-methylphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-ethylphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-ethylphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-isopropylphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-isopropylphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-isopropylphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-chlorophenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-chlorophenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-chlorophenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-bromophenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-bromophenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-bromophenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N-methylbenzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N-isopropylbenzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-methoxyphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-methoxyphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-ethoxyphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-ethoxyphenyl) benzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) benzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N-phenylbenzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-methylphenyl) benzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-methylphenyl) benzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-ethylphenyl) benzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-chlorophenyl) benzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-bromophenyl) benzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-bromophenyl) benzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-methoxyphenyl) benzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-ethoxyphenyl) benzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-ethoxyphenyl) benzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-isopropoxyphenyl) benzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-isopropoxyphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-pyridinyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-pyrrolyl) benzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-pyridinyl) benzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-pyridinyl) benzamide;

4- (3- (7-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-pyrrolyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N-phenylbenzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-methylphenyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-ethylphenyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-ethylphenyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-ethylphenyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-isopropylphenyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-isopropylphenyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-isopropylphenyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-chlorophenyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-bromophenyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N-methylbenzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N-ethylbenzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N-isopropylbenzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-methoxyphenyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-ethoxyphenyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-ethoxyphenyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-isopropoxyphenyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-pyridinyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-furanyl) benzamide;

4- (3- (6-methyl-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-pyrrolyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N-phenylbenzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N- (3-methylphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N- (4-methylphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N- (2-ethylphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N- (3-ethylphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N- (2-isopropylphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N- (3-chlorophenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N- (3-bromophenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N-methylbenzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N-ethylbenzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N- (2-methoxyphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N- (2-isopropoxyphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N- (3-isopropoxyphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N- (4-isopropoxyphenyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N- (3-pyridinyl) benzamide;

4- (3- (1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -3-isopropyl-N- (3-furanyl) benzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N-phenylbenzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-methylphenyl) benzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-methylphenyl) benzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-ethylphenyl) benzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-chlorophenyl) benzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-chlorophenyl) benzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-chlorophenyl) benzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-bromophenyl) benzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-methoxyphenyl) benzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-methoxyphenyl) benzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-ethoxyphenyl) benzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (4-ethoxyphenyl) benzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-isopropylphenyl) benzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-furanyl) benzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (3-furanyl) benzamide;

4- (3- (7-chloro-1H-benzoimidazol-2-yl) -3-oxoprop-1-enyl) -N- (2-pyrrolyl) benzamide.

8. A method of synthesizing the disubstituted α, β unsaturated ketones of formula I or pharmaceutically acceptable salts thereof of any one of claims 1 to 7, said method of synthesizing comprising:

and (3) acylating the intermediate V by thionyl chloride, and then aminolyzing to synthesize a target compound:

in formula I, X represents O or S or NH or N-R or CH₂R is unsubstituted alkyl or substituted alkyl; r₁To R₈Each independently represents the following group: H. hydroxy, alkoxy, unsubstituted mercapto, substituted mercapto, halogen, saturated alkyl, unsaturated alkyl, nitro or cyano; r₉Represents the following groups: H. alkyl, phenyl, pyridyl, furyl, thienyl and pyrrolyl, said phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolinyl, indolyl and purinyl being optionally substituted with alkyl, halogen or alkoxy.

9. A pharmaceutical composition comprising a disubstituted α, β unsaturated ketone having the structure of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7.

10. Use of a disubstituted α, β unsaturated ketone of formula I as defined in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 9 in the preparation of an anti-tumor medicament.

Technical Field

The application relates to the field of pharmaceutical chemistry, in particular to disubstituted alpha and beta unsaturated ketone and salt thereof, a pharmaceutical composition containing the same, and a preparation method and application of the disubstituted alpha and beta unsaturated ketone and the salt thereof.

Background

1,3-diaryl-2-propen-1-one (1,3-diaryl-2-propen-1-one), commonly known as chalcone (chalcone), is an important class of secondary metabolites in plants and a natural precursor for the synthesis of brass and isoflavones. Chalcones consist of A, B two aromatic rings, and an α, β -unsaturated carbonyl system linking the two rings. The aromatic ring attached to the carbonyl group is commonly referred to in the literature as the a ring, and the ring attached to a carbon-carbon double bond is commonly referred to as the B ring. At present, chalcone compounds are synthesized mainly by introducing different substituent groups such as hydroxyl, methoxy, heterocycle and the like on two aromatic rings, or reducing (or replacing) double bonds and carbonyl groups on a carbon chain to enable the carbon chain to be cyclized and the like. The research shows that the chalcone structure is closely related to the antitumor activity of the chalcone, and for example, when a ring A replaces a large hydrophobic group, the chalcone structure is favorable for the antitumor effect; the substitution of the B ring has little influence on the conjugated system of the parent nucleus, but the substitution with the oxygen-containing function is favorable for the activity. In addition, after the substitution of alpha is introduced, the cis-form between the alpha and beta double bonds of the parent nucleus is changed into the trans-form, so that the anticancer activity of the compound is changed.

Martel-Frachet et al synthesized methoxy-substituted chalcone compound 1, which achieved half inhibition on low-differentiation tumor cell lines and high-differentiation tumor cell lines when the concentration of compound 1 was 5. mu. mol/L and 50. mu. mol/L, respectively; xu et al examined and analyzed the cytotoxicity of chalcone compounds such as compounds 2,3,4 in various colon cancer cell lines; wang et al performed a biological activity evaluation of novel chalcone 5 and the results showed: has obvious inhibiting effect on HIF-1 and also reduces the migration and infiltration of VEGF-induced Hepg3B cells and HUVEC cells.

Disclosure of Invention

The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.

Specifically, the application provides disubstituted alpha and beta unsaturated ketones with a general formula I and salts thereof, and the compounds have antitumor cell proliferation activity and can be used for treating cancers.

The application also provides a synthetic method of the disubstituted alpha and beta unsaturated ketone.

The application also provides the application of the disubstituted alpha and beta unsaturated ketone in treating cancer and related diseases caused by the cancer.

The present application also provides a pharmaceutical composition for treating cancer comprising the disubstituted alpha, beta unsaturated ketones or salts thereof.

Disubstituted alpha, beta unsaturated ketones having the structure of formula I are designed and synthesized. The disubstituted alpha, beta unsaturated ketones comprise benzo five-membered heterocyclic units, such as benzimidazole units, benzothiazole units or benzoxazole units; alpha, beta unsaturated ketone units; and an amide unit. The benzo five-membered heterocyclic unit can comprise substituents such as alkyl, halogen, alkoxy, hydroxyl, sulfydryl and the like. Discussion is made on the influence of the benzo penta-hetero element with different substituents such as alkyl, halogen, alkoxy, hydroxyl and the like, and the introduction of alpha, beta unsaturated ketone units and amide units with different substituents at the 2-position on the antitumor activity of the compound.

The application provides disubstituted alpha, beta unsaturated ketone with a structure shown as a general formula I or medicinal salt thereof,

in formula I, X represents O or S or NH or N-R or CH₂R is unsubstituted alkyl or substituted alkyl; r₁To R₈Each independently represents the following group: H. hydroxy, alkoxy, unsubstituted mercapto, substituted mercapto, halogen, saturated alkyl, unsaturated alkyl, nitro or cyano; r₉Represents the following groups: H. alkyl, phenyl, pyridyl, furyl, thienyl and pyrrolyl, said phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolinyl, indolyl and purinyl being optionally substituted with halogen, alkyl or alkoxy.

In formula I, the benzo five-membered heterocycle may be a benzopyrrole, benzimidazole, benzothiazole or benzoxazole, preferably benzimidazole.

In the formula I, the benzo five-membered heterocycle may have a substituent R₁、R₂、R₃And R₄Preferably with a substituent R₃Or R₄. The substituent R₁To R₄May each independently be H, hydroxy, alkoxy, unsubstituted mercapto, substituted mercapto, halogen, saturated alkyl, unsaturated alkyl, nitro or cyano, preferably saturated alkyl, unsaturated alkyl and halogen, further preferably methyl and chlorine.

In the formula I, the alpha, beta unsaturated ketone unit may have a substituent R₅、R₆、R₇And R₈One or more of the above.

In formula I, preferably the alpha, beta unsaturated ketone unit has a substituent R₅。R₅Can be H, hydroxy, alkoxy, unsubstituted mercapto, substituted mercapto, halogen, saturated alkyl, unsaturated alkyl, nitro or cyano, preferably saturated or unsaturated alkyl andhalogen, further preferably isopropyl.

In the formula I, R₉Represents the following groups: H. alkyl, phenyl, pyridyl, furyl, thienyl and pyrrolyl, said phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolinyl, indolyl and purinyl being optionally substituted with halogen, alkyl or alkoxy, preferably H, alkyl, phenyl or substituted phenyl, pyridyl, furyl, pyrrolyl.

In formula I, X is NH, R₁To R₈Is hydrogen, R₉Represents the following groups: H. alkyl, phenyl, pyridyl, furyl, thienyl and pyrrolyl, said phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolinyl, indolyl and purinyl being optionally substituted with halogen, alkyl or alkoxy.

In formula I, X is NH, R₁To R₃Is hydrogen, R₄Is methyl, R₅To R₈Is hydrogen, R₉Represents the following groups: H. alkyl, phenyl, pyridyl, furyl, thienyl and pyrrolyl, said phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolinyl, indolyl and purinyl being optionally substituted with halogen, alkyl or alkoxy.

In formula I, X is NH, R₁、R₂、R₄Is hydrogen, R₃Is methyl, R₅To R₈Is hydrogen, R₉Represents the following groups: H. alkyl, phenyl, pyridyl, furyl, thienyl and pyrrolyl, said phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolinyl, indolyl and purinyl being optionally substituted with halogen, alkyl or alkoxy.

In formula I, X is NH, R₁To R₄Is hydrogen, R₅Is isopropyl, R₆To R₈Is hydrogen, R₉Represents the following groups: H. alkyl, phenyl, pyridyl, furyl, thienyl and pyrrolyl, said phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolinyl, indolyl and purinyl being optionally substituted by halogen, alkyl orAlkoxy substitution.

In formula I, X is NH, R₁To R₃Is hydrogen, R₄Is chlorine, R₅To R₈Is hydrogen, R₉Represents the following groups: H. alkyl, phenyl, pyridyl, furyl, thienyl and pyrrolyl, said phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolinyl, indolyl and purinyl being optionally substituted with halogen, alkyl or alkoxy.

In formula I, the term "saturated or unsaturated hydrocarbon group" refers to a saturated or unsaturated, linear or branched hydrocarbon group having 18 or less carbon atoms.

In the present application, the term "alkyl" refers to a linear or branched alkyl or cycloalkyl group having 6 or less carbon atoms.

In the present application, the term "substituted phenyl" refers to phenyl substituted with alkoxy, halogen, or alkyl.

In this application, the term "substituted pyridyl" refers to pyridyl substituted with alkoxy, halogen, or alkyl.

In the present application, the term "substituted furyl" refers to furyl substituted with alkoxy, halogen, or alkyl.

In the present application, the term "substituted thienyl" refers to a thienyl group substituted with an alkoxy, halogen or alkyl group.

In the present application, the term "substituted pyrrolyl" refers to pyrrolyl substituted with alkoxy, halogen or alkyl.

In the present application, the term "halogen" refers to chlorine, bromine and iodine.

In the application, the compound is not subjected to chiral resolution in the synthesis process, and the obtained final products are all racemized products.

According to the disubstituted alpha and beta unsaturated ketone and the medicinal salt thereof provided by the application, the research result of the antitumor effect in a nude mouse shows that the compound has obvious effect of inhibiting human HCT116 cells, MCF7 cells or HepG2 cells.

As a non-limiting example, the disubstituted α, β unsaturated ketones described herein may be selected from the specific compounds listed in table 1 below.

The present application also provides methods of synthesizing the compounds of formula I. The synthesis method comprises the following steps:

firstly, cyclizing an initial raw material II and lactic acid to synthesize an intermediate III under an acidic condition;

then, the intermediate III is oxidized into an intermediate IV;

condensing the intermediate IV with substituted aldehyde to generate an intermediate V;

and finally, acylating and aminolyzing the intermediate V to synthesize the target compound.

In the synthesis method of the present application, intermediate V is acylated with thionyl chloride and then aminolyzed to obtain target compound I:

in formula I, X represents O or S or NH or N-R or CH₂R is unsubstituted alkyl or substituted alkyl; r₁To R₈Represents the following groups: H. hydroxy, alkoxy, unsubstituted mercapto, substituted mercapto, halogen, saturated alkyl, unsaturated alkyl, nitro or cyano; r₉Represents the following groups: H. alkyl, phenyl, pyridyl, furyl, thienyl and pyrrolyl, said phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolinyl, indolyl and purinyl being optionally substituted with halogen, alkyl or alkoxy.

In the synthesis method of the present application, the intermediate IV is subjected to an aldehyde-ketone condensation with a substituted aldehyde to give a compound V:

in formula V, X represents O or S or NH or N-R or CH₂R is unsubstituted alkyl or substituted alkyl; r₁To R₈Represents the following groups: H. hydroxy, alkoxy, unsubstituted mercapto, substituted mercapto, halogen, saturated hydrocarbon, unsaturatedAnd hydrocarbyl, nitro or cyano groups.

In the synthesis method of the application, when X represents O or S or NH or CH₂When the intermediate IV is obtained by the following method: the intermediate III is oxidized to form the intermediate IV, for example, CrO is added dropwise under acidic conditions₃To obtain intermediate IV:

when X represents N-R, R being unsubstituted alkyl or substituted alkyl, intermediate III' is prepared by oxidation, e.g. by dropwise addition of CrO under acidic conditions₃Then, with an alkylating agent under conditions well known to those skilled in the art, to obtain intermediate IV':

in the synthesis method of the present application, the intermediate III is obtained by the following method: substituted aniline II is used as a starting material and reacts with lactic acid under acidity to obtain an intermediate III:

in formula III, X represents O or S or NH or N-R or CH₂R is unsubstituted alkyl or substituted alkyl; r₁To R₄Represents the following groups: H. hydroxyl, alkoxy, unsubstituted mercapto, substituted mercapto, halogen, saturated hydrocarbyl, unsaturated hydrocarbyl, nitro or cyano.

The present application also provides a pharmaceutical composition comprising the compound of formula I.

In the present application, the pharmaceutical composition may further comprise pharmaceutically acceptable excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, diluents and solvents for injection.

The pharmaceutical compositions provided herein may be in various dosage forms for administration prepared according to conventional manufacturing methods in the pharmaceutical arts, e.g., by mixing the active ingredient with one or more carriers and then formulating into the desired dosage form. For example, the compound itself or a mixture thereof with a pharmaceutically acceptable excipient, diluent or the like can be administered orally in the form of tablets, capsules, granules, powders or syrups, or non-orally in the form of injections. The pharmaceutical compositions herein preferably contain 0.1% to 99.5% by weight of the active ingredient, most preferably 0.5% to 99.5% by weight of the active ingredient. The above preparation can be prepared by conventional pharmaceutical method. Examples of pharmaceutically acceptable adjuvants which may be used include excipients (e.g. saccharide derivatives such as lactose, sucrose, glucose, mannitol and sorbitol, starch derivatives such as corn starch, potato starch, dextrin and carboxymethyl starch, cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, acacia, dextran, silicate derivatives such as magnesium aluminium metasilicate, phosphate derivatives such as calcium phosphate, carbonate derivatives such as calcium carbonate, sulphate derivatives such as calcium sulphate and the like), binders (e.g. gelatin, polyvinylpyrrolidone and polyethylene glycol), disintegrants (e.g. cellulose derivatives such as sodium carboxymethyl cellulose, polyvinylpyrrolidone), lubricants (e.g. talc, calcium stearate, magnesium stearate, spermaceti, boric acid, sodium benzoate, leucine), Stabilizers (methyl paraben, propyl paraben, etc.), flavoring agents (e.g., commonly used sweeteners, acidulants, flavors, etc.), diluents, and solvents for injection (e.g., water, ethanol, glycerin, etc.).

The application also provides application of the disubstituted alpha and beta unsaturated ketone with the formula I or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing antitumor drugs. The compounds of the present application may be used to treat one or more of colon cancer, breast cancer, liver cancer, lung cancer, stomach cancer, prostate cancer, ovarian cancer, cervical cancer, breast cancer, and leukemia.

The compound has obvious inhibition effect on one or more of human lung adenocarcinoma cells, human colon cancer cells, human breast cancer cells, human liver cancer cells, glioma cells, bone marrow cells, lymphocytes or prostate cancer cells, for example, the compound has obvious inhibition effect on one or more of human lung adenocarcinoma cells A549, human colon cancer cells HCT116, human breast cancer cells MCF7, human liver cancer cells HepG2, human brain glioma cells U87, human acute T lymphocyte leukemia cell line Jurkat or human prostate cancer cells PC-3. Furthermore, the compound has obvious inhibition effect on human colon cancer cells HCT116, human breast cancer cells MCF7 and human liver cancer cells HepG 2.

The compounds of the present application or pharmaceutical compositions comprising the active compounds may be administered to a subject by any convenient route of administration, whether systemically/peripherally or locally. Routes of administration include, but are not limited to: orally (e.g., by ingestion); taking orally; under the tongue; transdermal (including, for example, via a patch, plaster, etc.); transmucosal (including, for example, through patches, plasters, etc.); intranasally (e.g., by nasal spray); ophthalmic (e.g., via eye drops); lung (e.g., by using inhalation or insufflation therapy, e.g., via aerosol, e.g., through the mouth or nose); rectally (e.g., by suppository or enema); the vagina (e.g., through a pessary); parenterally, for example, by injection, including subcutaneous injection, intradermal injection, intramuscular injection, intravenous injection, intraarterial injection, intracardiac injection, intrathecal injection, intraspinal injection, intracapsular injection, subcapsular injection, intraorbital injection, intraperitoneal injection, intratracheal injection, subcuticular injection, intraarticular injection, subarachnoid injection, and intrasternal injection.

The size of the dose of the compound of formula I for treatment will naturally vary according to the nature and severity of the condition, the age and sex of the animal or patient and the route of administration, according to well-known medical principles. In using the compounds of the present application for therapeutic purposes, they are typically administered at daily doses ranging, for example, from 0.1mg/kg body weight to 75mg/kg body weight. Lower doses will be administered when the parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, dosages in the range of, for example, 0.1mg/kg body weight to 30mg/kg body weight will generally be used. For administration by inhalation, a dose in the range of, for example, 0.05mg/kg body weight to 25mg/kg body weight will be used. Oral administration will contain about 0.5mg to 0.5g of a compound of the invention, particularly in tablet form, unit dosage form.

The compounds described herein may be formed into and/or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) an acid addition salt formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid: such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; (2) salts are formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), alkaline earth metal ion (e.g., magnesium, or calcium), or aluminum ion, or is coordinated with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

Additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the application. The objectives and other advantages of the application may be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.

Drawings

The accompanying drawings are included to provide a further understanding of the claimed subject matter and are incorporated in and constitute a part of this specification, illustrate embodiments of the subject matter and together with the description serve to explain the principles of the subject matter and not to limit the subject matter.

FIG. 1 is a graph of the effect of Compound 1 and Compound 10 at different concentrations on the G2/M, S and G1 phases of the cell cycle.

Detailed Description

To make the objects, technical solutions and advantages of the present application more apparent, embodiments of the present application will be described in detail below with reference to the accompanying drawings. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.