CN106146361A - Indenes-1-subunit sulfonyl benzoyl hydrazine derivant and its production and use - Google Patents

Indenes-1-subunit sulfonyl benzoyl hydrazine derivant and its production and use Download PDF

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CN106146361A
CN106146361A CN201510160256.3A CN201510160256A CN106146361A CN 106146361 A CN106146361 A CN 106146361A CN 201510160256 A CN201510160256 A CN 201510160256A CN 106146361 A CN106146361 A CN 106146361A
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independently
alkyl
halogen
yuan
cycloalkyl
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赵瀛兰
杨胜勇
魏于全
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Sichuan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The invention belongs to chemical medicine, be specifically related to indenes-1-subunit sulfonyl benzoyl hydrazine derivant and its production and use.The invention provides a kind of indenes-1-subunit sulfonyl benzoyl hydrazine derivant, its structure is as shown in formula I.Present invention also offers preparation method and the purposes of the indenes-1-subunit sulfonyl benzoyl hydrazine derivant shown in above-mentioned formula I.Indenes-1-subunit sulfonyl benzoyl hydrazine the derivant that the present invention provides has good inhibiting effect to the propagation of tumor cell, provides a kind of new selection for antitumor drug preparation field.

Description

Indenes-1-subunit sulfonyl benzoyl hydrazine derivant and its production and use
Technical field
The invention belongs to chemical medicine, be specifically related to indenes-1-subunit sulfonyl benzoyl hydrazine derivant and preparation method thereof and use On the way.
Background technology
Malignant tumor is one of the major disease threatening human life healthy, has the most become the mankind being only second to cardiovascular disease The second largest cause of the death.Further, up-to-date statistical data shows, in world wide, and particularly developing country, sending out of malignant tumor The trend that sick rate and mortality rate rise the most year by year.Chemotherapy is most important treating malignant tumor means in addition to operation and radiotherapy.Pass The chemotherapeutics of system mainly acts on the common constituents relevant to all cells life and death such as DNA, RNA and tubulin, causes Its selectivity is low, toxicity is big.And target therapeutic agent, i.e. act on the regulation and control having greatest differences in tumor cell with normal cell The key molecule of growth and proliferation of cell and signal transduction pathway thereof, have the height of the selectivity to tumor cell, the poison of normal tissue Property the advantage such as low, the most become the focus of antitumor drug research.
In numerous intracellular signal transduction pathway regulation and control, important regulating and controlling effect is played in the histone methylated transduction to signal, Research shows, the generation of many tumors is all relevant with histone methylated exception with development, therefore, regulates and controls histone methylated water Heisei is important antineoplaston research direction.
Found that lysine specificity demethylase 1 (LSD1) can regulate 4 first of histone H 3 lysine in the last few years Base and di-methylation level (H3K4me1/2) and 9 monomethyls of histone H 3 lysine and di-methylation level (H3K9me1/2) thus develop closely related with the generation of tumor.Research be further illustrated in a lot of cancer as carcinoma of prostate, Breast carcinoma all detects that LSD1 high expressed, downward LSD1 expression can make H3K4 methylation level promote thus suppress The increment of cancerous cell.Therefore LSD1 is a promising important target of tool.
Summary of the invention
The invention provides a kind of indenes-1-subunit sulfonyl benzoyl hydrazine derivant, its structure is as shown in formula I:
Wherein, R1、R2Independently be-H, C1～C8Alkyl, C3～C8Cycloalkyl,-OH、C1～C8Alcoxyl Base or halogen；Or, R1And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～3 N, O Or S atom；The substituent group of described replacement 5～8 yuan of saturated heterocyclics is-H, C1～C8Alkyl, C3～C8Cycloalkyl, C1～C8 Alkoxy or halogen；
R3～R8Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C8Alkyl ,-OH, C3～C8Cycloalkyl or C1～C8Alkoxyl；
R9～R12Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C8Alkyl ,-OH or C1～C8Alkoxyl；
R13～R17Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C8Alkyl or C1～C8Alkoxyl.
As preferred embodiments of the present invention, R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl, -OH、C1～C4Alkoxy or halogen；Or, R1And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, described saturated heterocyclic Containing 1～3 N, O or S atom；The substituent group of described replacement 5～8 yuan of saturated heterocyclics is-H, C1～C4Alkyl, C3~ C6Cycloalkyl, C1～C4Alkoxy or halogen；
R3～R8Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C4Alkyl ,-OH, C3～C6Cycloalkyl or C1～C4Alkoxyl；R9～R12Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C4Alkyl ,-OH or C1~ C4Alkoxyl；R13～R17Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C4Alkyl or C1～C4Alcoxyl Base.
Preferably, R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl,Or halogen；Or, R1 And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～3 N, O or S atom；Described take The generation substituent group of 5～8 yuan of saturated heterocyclics is-H, C1～C4Alkyl, C3～C6Cycloalkyl or halogen；
R3～R8Independently be-H, halogen, C1～C4Alkyl or C3～C6Cycloalkyl；R9～R12Independently be-H, halogen, C1～C4Alkyl ,-OH or C1～C4Alkoxyl；R13～R17Independently be-H, halogen, C1～C4Alkyl or C1～C4 Alkoxyl.
It is further preferred that R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl orOr, R1 And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～3 N, O or S atom；Described take The generation substituent group of 5～8 yuan of saturated heterocyclics is-H or C1～C4Alkyl；
R3～R8Independently be-H, halogen, C1～C4Alkyl or C3～C6Cycloalkyl；R9～R12Independently be-H, halogen, C1～C4Alkyl ,-OH or C1～C4Alkoxyl；R13～R17Independently be-H, halogen, C1～C4Alkyl or C1～C4 Alkoxyl.
Further preferred, R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl orOr, R1 And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～2 N or O atom；Described replacement 5～ The substituent group of 8 yuan of saturated heterocyclics is-H or C1～C4Alkyl；
R3～R8Independently be-H, halogen, C1～C4Alkyl or C3～C6Cycloalkyl；R9～R12Independently be-H, halogen, C1～C4Alkyl ,-OH or C1～C4Alkoxyl；R13～R17Independently be-H, halogen, C1～C4Alkyl or C1～C4 Alkoxyl.
Preferably, R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl orOr, R1And R2Ring Being combined into substituted 5～8 yuan of saturated heterocyclics, described saturated heterocyclic contains 1～2 N or O atom；Described replacement 5～8 yuan The substituent group of saturated heterocyclic is-H or C1～C4Alkyl；
R3～R8Independently be-H, C1～C4Alkyl or C3～C6Cycloalkyl；R9～R12Independently be-H, halogen, C1～C4 Alkyl or-OH；R13～R17Independently be-H, halogen or C1～C4Alkoxyl.
It is further preferred that R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl orOr, R1 And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～2 N or O atom；Described replacement 5～ The substituent group of 8 yuan of saturated heterocyclics is-H or C1～C4Alkyl；
R3～R8Independently be-H；R9～R12Independently be-H, halogen, C1～C4Alkyl or-OH；R13～R17Independently be -H, halogen or C1～C4Alkoxyl.
Further preferred, R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl orOr, R1 And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～2 N or O atom；Described replacement 5～ The substituent group of 8 yuan of saturated heterocyclics is-H or C1～C4Alkyl；
R3～R8Independently be-H；R9～R12Independently be-H, halogen or-OH；R13～R17Independently be-H, halogen or C1～C4Alkoxyl.
Further preferred, R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl orOr, R1 And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～2 N or O atom；Described replacement 5～ The substituent group of 8 yuan of saturated heterocyclics is-H or C1～C4Alkyl；
R3～R8Independently be-H；R9～R12Independently be-H, halogen or-OH；R13～R17Independently be-H or C1～C4 Alkoxyl.
Optimum, R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl orOr, R1And R2Ring Being combined into substituted 5～8 yuan of saturated heterocyclics, described saturated heterocyclic contains 1～2 N or O atom；Described replacement 5～8 yuan The substituent group of saturated heterocyclic is-H or C1～C4Alkyl；
R3～R8Independently be-H；R9～R12Independently be-H ,-Cl or-OH；R13～R17Independently be-H or methoxyl group.
Indenes-1-subunit sulfonyl benzoyl hydrazine derivant shown in above-mentioned formula I, its structural formula is as follows:
Present invention also offers the preparation method of the indenes-1-subunit sulfonyl benzoyl hydrazine derivant shown in above-mentioned formula I, it synthesizes road Line is:
The preparation method of the indenes-1-subunit sulfonyl benzoyl hydrazine derivant shown in above-mentioned formula I, its synthesis step is:
1) existTHF (oxolane) in, drip m-chloro sulfonyl benzoic acid in 0 DEG C, then normal-temperature reaction 8-12h, Obtain intermediate 2；
2) by carboxylic acid in methanol, the concentrated sulphuric acid of dropping catalytic amount, reacts with intermediate 2, obtains intermediate 3；
3) intermediate 3 is dissolved in methanol, adds the hydrazine hydrate of 2～5eq, react 12h in 65～70 DEG C, obtain intermediate 4；
4) intermediate 4 again withReaction, obtains type I compound.
Wherein, in the preparation method of above-mentioned indenes-1-subunit sulfonyl benzoyl hydrazine derivant, step 1) described between chlorosulfonyl benzene Formic acid withMol ratio be 13.
Wherein, in the preparation method of above-mentioned indenes-1-subunit sulfonyl benzoyl hydrazine derivant, step 2) temperature of described reaction is 65 DEG C, the time of reaction is 12h.
Wherein, in the preparation method of above-mentioned indenes-1-subunit sulfonyl benzoyl hydrazine derivant, step 4) described intermediate 4 withMol ratio be 1 1.5.
Wherein, in the preparation method of above-mentioned indenes-1-subunit sulfonyl benzoyl hydrazine derivant, step 4) solvent of described reaction is Ethanol.
Wherein, in the preparation method of above-mentioned indenes-1-subunit sulfonyl benzoyl hydrazine derivant, step 4) described reaction to drip The glacial acetic acid of catalytic amount.
Wherein, in the preparation method of above-mentioned indenes-1-subunit sulfonyl benzoyl hydrazine derivant, step 4) temperature of described reaction is 80 DEG C, the time of reaction is 8～12h.
Wherein, R1、R2Independently be-H, C1～C8Alkyl, C3～C8Cycloalkyl,-OH、C1～C8Alcoxyl Base or halogen；Or, R1And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～3 N, O Or S atom；The substituent group of described replacement 5～8 yuan of saturated heterocyclics is-H, C1～C8Alkyl, C3～C8Cycloalkyl, C1～C8 Alkoxy or halogen；R3～R8Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C8Alkyl ,-OH, C3～C8 Cycloalkyl or C1～C8Alkoxyl；R9～R12Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C8Alkyl ,-OH Or C1～C8Alkoxyl；R13～R17Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C8Alkyl or C1~ C8Alkoxyl.
Above-mentioned indenes-1-subunit sulfonyl benzoyl hydrazine derivant includes their isotopic compound, racemic modification, optically active Isomer, polymorphic forms or its mixture.
Present invention also offers the indenes-1-subunit sulfonyl benzoyl hydrazine derivant pharmaceutically acceptable salt shown in above-mentioned formula I or Hydrate.
Present invention also offers the prodrug of the indenes-1-subunit sulfonyl benzoyl hydrazine derivant shown in above-mentioned formula I, according to the present invention, Prodrug is the derivant of above-claimed cpd, and their own is likely to be of more weak activity or even without activity, but upon administration, In physiological conditions (such as by metabolism, solvolysis or other by the way of) be converted to corresponding biologically active form.
A kind of pharmaceutical composition, is to be added by the indenes-1-subunit sulfonyl benzoyl hydrazine derivant shown in formula I and salt thereof or hydrate Add what the complementary composition of pharmaceutically acceptable was prepared from.
Present invention also offers the indenes-1-subunit sulfonyl benzoyl hydrazine derivant shown in above-mentioned formula I and salt thereof or hydrate in system Purposes in standby LSD1 inhibitor.
Present invention also offers the indenes-1-subunit sulfonyl benzoyl hydrazine derivant shown in above-mentioned formula I and salt thereof or hydrate in system Purposes in standby antitumor drug.
Described tumor is LSD1 high expressed tumor, such as: breast carcinoma, colon cancer, carcinoma of prostate, pulmonary carcinoma, gastric cancer etc..
The beneficial effects of the present invention is: creatively synthesis sulfonyl benzoyl hydrazine derivant, and confirm that it is targeting LSD1, And the propagation of tumor cell is had good inhibiting effect.Provide a kind of new selection for antitumor drug preparation field, have Well market prospect.
Detailed description of the invention
The preparation method of the indenes-1-subunit sulfonyl benzoyl hydrazine derivant shown in formula I, its synthetic route is:
The preparation method of the indenes-1-subunit sulfonyl benzoyl hydrazine derivant shown in above-mentioned formula I, its synthesis step is:
1) existTHF (oxolane) in, drip m-chloro sulfonyl benzoic acid in 0 DEG C, then normal-temperature reaction 8-12h, Obtain intermediate 2；
2) by carboxylic acid in methanol, the concentrated sulphuric acid of dropping catalytic amount, reacts with intermediate 2, obtains intermediate 3；
3) intermediate 3 is dissolved in methanol, adds the hydrazine hydrate of 2～5eq, react 12h in 65～70 DEG C, obtain intermediate 4；
4) intermediate 4 again withReaction, obtains type I compound.
Wherein, in the preparation method of above-mentioned indenes-1-subunit sulfonyl benzoyl hydrazine derivant, step 1) described between chlorosulfonyl benzene Formic acid withMol ratio be 13.
Wherein, in the preparation method of above-mentioned indenes-1-subunit sulfonyl benzoyl hydrazine derivant, step 2) temperature of described reaction is 65 DEG C, the time of reaction is 12h.
Wherein, in the preparation method of above-mentioned indenes-1-subunit sulfonyl benzoyl hydrazine derivant, step 4) described intermediate 4 withMol ratio be 1 1.5.
Wherein, in the preparation method of above-mentioned indenes-1-subunit sulfonyl benzoyl hydrazine derivant, step 4) solvent of described reaction is Ethanol.
Wherein, in the preparation method of above-mentioned indenes-1-subunit sulfonyl benzoyl hydrazine derivant, step 4) described reaction to drip The glacial acetic acid of catalytic amount.
Wherein, in the preparation method of above-mentioned indenes-1-subunit sulfonyl benzoyl hydrazine derivant, step 4) temperature of described reaction is 80 DEG C, the time of reaction is 8～12h.
The preparation of embodiment 1 3-(morpholine sulfonyl) benzoic acid (intermediate 2-1)
Morpholine (300mg) is dissolved in 5mL oxolane, when 0 DEG C, instills the tetrahydrochysene of m-chloro sulfonyl benzoic acid (250mg) Furan (3mL) solution, after dripping, room temperature reaction 12h, column chromatography purification obtains white solid 160mg, productivity 52%.
1H NMR(400MHz,CDCl3): δ 11.46 (s, 1H), δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 3.64 (brs, 4H), δ 3.11 (brs, 4H) ppm.
The preparation of embodiment 2 3-(N methyl piperazine sulfonyl) benzoic acid (intermediate 2-2)
N methyl piperazine (340mg) is dissolved in 5mL oxolane, when 0 DEG C, instills m-chloro sulfonyl benzoic acid (250mg) Oxolane (3mL) solution, after dripping, room temperature reaction 12h, column chromatography purification obtains white solid 166mg, productivity 53%.
1H NMR(400MHz,CDCl3): δ 11.46 (s, 1H), δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 3.64 (brs, 4H), δ 3.11 (brs, 4H), δ 2.26 (s, 3H) ppm.
The preparation of embodiment 3 3-(diethylamine sulfonyl) benzoic acid (intermediate 2-3)
Diethylamine (249mg) is dissolved in 5mL oxolane, when 0 DEG C, instills the four of m-chloro sulfonyl benzoic acid (250mg) Hydrogen furan (3mL) solution, after dripping, room temperature reaction 12h, column chromatography purification obtains white solid 147mg, productivity 52%.
1H NMR(400MHz,CDCl3): δ 11.46 (s, 1H), δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 3.29 (m, 4H), δ 1.02 (m, 6H) ppm.
The preparation of 4 carboxyl benzene sulfonyl methylamines (intermediate 2-4) of embodiment
Methylamine (106mg) is dissolved in 5mL oxolane, when 0 DEG C, instills the tetrahydrochysene of m-chloro sulfonyl benzoic acid (250mg) Furan (3mL) solution, after dripping, room temperature reaction 12h, column chromatography purification obtains white solid 123mg, productivity 52%.
1H NMR(400MHz,CDCl3): δ 11.46 (s, 1H), δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 2.47 (s, 3H) ppm.
The preparation of embodiment 5 3-(N-methylhomopiperazin sulfonyl) benzoic acid (intermediate 2-5)
N-methylhomopiperazin (388mg) is dissolved in 5mL oxolane, when 0 DEG C, instills m-chloro sulfonyl benzoic acid (250mg) Oxolane (3mL) solution, after dripping, room temperature reaction 12h, column chromatography purification obtains white solid 118mg, productivity 36%.
1H NMR(400MHz,CDCl3): δ 11.46 (s, 1H), δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 3.26 (brs, 2H), δ 3.16～3.10 (m, 4H), δ 2.26 (s, 3H), δ 2.48 (brs, 2H), δ 2.26 (s, 3H), δ 1.50 (m, 2H) ppm.
The preparation of embodiment 6 N, N-dimethyl-3-carboxybenzenesulfonamide (intermediate 2-6)
Dimethylamine (153mg) is dissolved in 5mL oxolane, when 0 DEG C, instills the four of m-chloro sulfonyl benzoic acid (250mg) Hydrogen furan (3mL) solution, after dripping, room temperature reaction 12h, column chromatography purification obtains white solid 131mg, productivity 52%.
1H NMR(400MHz,CDCl3): δ 11.46 (s, 1H), δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 2.47 (s, 6H) ppm.
The preparation of embodiment 7 3-(N-cyclo-hexylamine sulfonyl) benzoic acid (intermediate 2-7)
Cyclohexylamine (337mg) is dissolved in 5mL oxolane, when 0 DEG C, instills the four of m-chloro sulfonyl benzoic acid (250mg) Hydrogen furan (3mL) solution, after dripping, room temperature reaction 12h, column chromatography purification obtains white solid 165mg, productivity 53%.
1H NMR(400MHz,CDCl3): δ 11.46 (s, 1H), δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 3.0 (m, 1H), δ 1.60 (brs, 4H), δ 1.48 (m, 2H), δ 1.15 (brs, 4H) ppm.
The preparation of 8 carboxyl benzene sulfonyl n-butylamines (intermediate 2-8) of embodiment
N-butylamine (249mg) is dissolved in 5mL oxolane, when 0 DEG C, instills the four of m-chloro sulfonyl benzoic acid (250mg) Hydrogen furan (3mL) solution, after dripping, room temperature reaction 12h, column chromatography purification obtains white solid 147mg, productivity 52%.
1H NMR(400MHz,CDCl3): δ 11.46 (s, 1H), δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 3.40 (t, J=7.6Hz, 2H), δ 1.5～1.3 (m, 4H), δ 0.9 (t, J=7.7Hz, 3H) ppm.
The preparation of embodiment 9 3-(N-cyclopenta sulfamic) benzoic acid (intermediate 2-9)
Aminocyclopentane (290mg) is dissolved in 5mL oxolane, when 0 DEG C, instills the four of m-chloro sulfonyl benzoic acid (250mg) Hydrogen furan (3mL) solution, after dripping, room temperature reaction 12h, column chromatography purification obtains white solid 157mg, productivity 53%.
1H NMR(400MHz,CDCl3): δ 11.46 (s, 1H), δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 2.65 (m, 1H), δ 1.73 (m, 4H), δ 1.50 (m, 4H)ppm。
The preparation of embodiment 10 3-(N-cyclopropylamine sulfonyl) benzoic acid (intermediate 2-10)
Cyclopropylamine (194mg) is dissolved in 5mL oxolane, when 0 DEG C, instills the four of m-chloro sulfonyl benzoic acid (250mg) Hydrogen furan (3mL) solution, after dripping, room temperature reaction 12h, column chromatography purification obtains white solid 146mg, productivity 55%.
1H NMR(400MHz,CDCl3): δ 11.46 (s, 1H), δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 1.35 (t, J=7.6Hz, 1H), δ 0.70 (d, J=7.7Hz, 2H)ppm。
The preparation of embodiment 11 3-(N-phenyl amine sulfonyl) benzoic acid (intermediate 2-11)
Aniline (317mg) is dissolved in 5mL oxolane, when 0 DEG C, instills the tetrahydrochysene of m-chloro sulfonyl benzoic acid (250mg) Furan (3mL) solution, after dripping, room temperature reaction 12h, column chromatography purification obtains white solid 122mg, productivity 40%.
1H NMR(400MHz,CDCl3): δ 11.46 (s, 1H), δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 7.20 (d, J=7.6Hz, 2H), δ 6.81 (d, J=7.6Hz, 1H), δ 6.63 (d, J=7.6Hz, 2H) ppm.
The preparation of embodiment 12 3-(N-Methyl-N-phenyl sulfamic) benzoic acid (intermediate 2-12)
Methylphenylamine (364mg) is dissolved in 5mL oxolane, when 0 DEG C, instills m-chloro sulfonyl benzoic acid (250mg) Oxolane (3mL) solution, after dripping, room temperature reaction 12h, column chromatography purification obtains white solid 128mg, productivity 40%.
1H NMR(400MHz,CDCl3): δ 11.46 (s, 1H), δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 7.20 (d, J=7.6Hz, 2H), δ 6.81 (d, J=7.6Hz, 1H), δ 6.63 (d, J=7.6Hz, 2H), δ 3.20 (s, 3H) ppm.
The preparation of embodiment 13 3-(N-(2,5-Dimethoxyphenyl) sulfamic) benzoic acid (intermediate 2-13)
By 2,5-dimethoxyaniline (520mg) is dissolved in 5mL oxolane, instills m-chloro sulfonyl benzoic acid when 0 DEG C (250mg) oxolane (3mL) solution, after dripping, room temperature reaction 12h, column chromatography purification obtains white solid 166mg, Productivity 40%.
1H NMR(400MHz,CDCl3): δ 11.46 (s, 1H), δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 6.80 (d, J=7.6Hz, 1H), δ 6.24 (d, J=7.6Hz, 1H), δ 6.07 (s, 1H), δ 3.9 (s, 3H), δ 3.7 (s, 3H) ppm.
The preparation of embodiment 14 3-(morpholine sulfonyl) essence of Niobe (intermediate 3-1)
Being dissolved in 4mL methanol by 3-(morpholine sulfonyl) benzoic acid (100mg), add the concentrated sulphuric acid of catalytic amount, 65 DEG C anti- 12h, column chromatography purification is answered to obtain white solid 60mg, productivity 54%.
1H NMR(400MHz,CDCl3): δ 8.38 (t, J=1.6Hz, 1H), δ 8.27 (m, 1H), δ 7.92 (m, 1H), δ 7.64 (t, J=8.0Hz, 1H), δ 3.95 (s, 3H), δ 3.73 (m, 4H), δ 3.00 (m, 4H) ppm.
The preparation of embodiment 15 3-(N methyl piperazine sulfonyl) essence of Niobe (intermediate 3-2)
3-(N methyl piperazine sulfonyl) benzoic acid (100mg) is dissolved in 4mL methanol, adds the concentrated sulphuric acid of catalytic amount, 65 DEG C of reaction 12h, column chromatography purification obtains white solid 57mg, productivity 54%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 3.95 (s, 3H), δ 3.64 (brs, 4H), δ 3.11 (brs, 4H), δ 2.26 (s, 3H) ppm.
Execute the preparation of example 16 3-(diethylamine sulfonyl) essence of Niobe (intermediate 3-3)
3-(diethylamine sulfonyl) benzoic acid (100mg) is dissolved in 4mL methanol, the concentrated sulphuric acid of addition catalytic amount, 65 DEG C Reaction 12h, column chromatography purification obtains white solid 57mg, productivity 54%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 3.95 (s, 3H), δ 3.29 (m, 4H), δ 1.02 (m, 6H) ppm.
The preparation of embodiment 17 3-(N-methyl amine sulfonyl) essence of Niobe (intermediate 3-4)
Between Jiang, carboxyl benzene sulfonyl methylamine (100mg) be dissolved in 4mL methanol, adds the concentrated sulphuric acid of catalytic amount, and 65 DEG C are reacted 12h, Column chromatography purification obtains white solid 57mg, productivity 53%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 3.95 (s, 3H), δ 2.47 (s, 3H) ppm.
The preparation of embodiment 18 3-(N-methylhomopiperazin sulfonyl) essence of Niobe (intermediate 3-5)
3-(N-methylhomopiperazin sulfonyl) benzoic acid (100mg) is dissolved in 4mL methanol, adds the concentrated sulphuric acid of catalytic amount, 65 DEG C of reaction 12h, column chromatography purification obtains white solid 55mg, productivity 53%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 3.95 (s, 3H), δ 3.26 (brs, 2H), δ 3.16～3.10 (m, 4H), δ 2.26 (s, 3H), δ 2.48 (brs, 2H), δ 2.26 (s, 3H), δ 1.50 (m, 2H) ppm.
The preparation of embodiment 19 3-(N, N-dimethyl amine sulfonyl) benzoate (intermediate 3-6)
N, N-dimethyl-3-carboxybenzenesulfonamide (100mg) are dissolved in 4mL methanol, the concentrated sulphuric acid of addition catalytic amount, 65 DEG C Reaction 12h, column chromatography purification obtains white solid 57mg, productivity 54%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 3.95 (s, 3H), δ 2.47 (s, 6H) ppm.
The preparation of embodiment 20 3-(N-cyclo-hexylamine sulfonyl) essence of Niobe (intermediate 3-7)
3-(N-cyclo-hexylamine sulfonyl) benzoic acid (100mg) is dissolved in 4mL methanol, adds the concentrated sulphuric acid of catalytic amount, 65 DEG C of reaction 12h, column chromatography purification obtains white solid 56mg, productivity 54%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 3.95 (s, 3H), δ 3.0 (m, 1H), δ 1.60 (brs, 4H), δ 1.48 (m, 2H), δ 1.15 (brs, 4H) ppm.
The preparation of embodiment 21 3-(N-n-butylamine sulfonyl) essence of Niobe (intermediate 3-8)
Between Jiang, carboxyl benzene sulfonyl n-butylamine (100mg) be dissolved in 4mL methanol, adds the concentrated sulphuric acid of catalytic amount, and 65 DEG C are reacted 12h, Column chromatography purification obtains white solid 56mg, productivity 53%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 3.95 (s, 3H), δ 3.40 (t, J=7.6Hz, 2H), δ 1.5～1.3 (m, 4H), δ 0.9 (t, J=7.7Hz, 3H) ppm.
The preparation of embodiment 22 3-(N-cyclopenta sulfamic) essence of Niobe (intermediate 3-9)
3-(N-cyclopenta sulfamic) benzoic acid (100mg) is dissolved in 4mL methanol, adds the concentrated sulphuric acid of catalytic amount, 65 DEG C of reaction 12h, column chromatography purification obtains white solid 57mg, productivity 54%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 3.95 (s, 3H), δ 2.65 (m, 1H), δ 1.73 (m, 4H), δ 1.50 (m, 4H)ppm。
The preparation of embodiment 23 3-(N-cyclopropylamine sulfonyl) essence of Niobe (intermediate 3-10)
3-(N-cyclopropylamine sulfonyl) benzoic acid (100mg) is dissolved in 4mL methanol, adds the concentrated sulphuric acid of catalytic amount, 65 DEG C of reaction 12h, column chromatography purification obtains white solid 57mg, productivity 54%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 3.95 (s, 3H), δ 1.35 (t, J=7.6Hz, 1H), δ 0.70 (d, J=7.7Hz, 2H)ppm。
The preparation of embodiment 24 3-(N-phenyl amine sulfonyl) essence of Niobe (intermediate 3-11)
3-(N-phenyl amine sulfonyl) benzoic acid (100mg) is dissolved in 4mL methanol, the concentrated sulphuric acid of addition catalytic amount, 65 DEG C Reaction 12h, column chromatography purification obtains white solid 57mg, productivity 54%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 7.20 (d, J=7.6Hz, 2H), δ 6.81 (d, J=7.6Hz, 1H), δ 6.63 (d, J=7.6Hz, 2H), δ 3.95 (s, 3H) ppm.
The preparation of embodiment 25 3-(N-Methyl-N-phenyl sulfamic) essence of Niobe (intermediate 3-12)
3-(N-Methyl-N-phenyl sulfamic) benzoic acid (100mg) is dissolved in 4mL methanol, adds the dense of catalytic amount Sulphuric acid, 65 DEG C of reaction 12h, column chromatography purification obtains white solid 58mg, productivity 54%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 7.20 (d, J=7.6Hz, 2H), δ 6.81 (d, J=7.6Hz, 1H), δ 6.63 (d, J=7.6Hz, 2H), δ 3.95 (s, 3H), δ 3.20 (s, 3H) ppm.
The preparation of embodiment 26 3-(N-(2,5-Dimethoxyphenyl) sulfamic) essence of Niobe (intermediate 3-13)
Being dissolved in 4mL methanol by 3-(N-(2,5-Dimethoxyphenyl) sulfamic) benzoic acid (100mg), addition is urged The concentrated sulphuric acid of change amount, 65 DEG C of reaction 12h, column chromatography purification obtains white solid 55mg, productivity 53%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 6.80 (d, J=7.6Hz, 1H), δ 6.24 (d, J=7.6Hz, 1H), δ 6.07 (s, 1H), δ 3.9 (brs, 6H), δ 3.7 (s, 3H) ppm.
The preparation of embodiment 27 3-(morpholine sulfonyl) benzoyl hydrazine (intermediate 4-1)
3-(morpholine sulfonyl) essence of Niobe (120mg) is dissolved in 5mL methanol, addition hydrazine hydrate (67mg), 130 DEG C Microwave reaction 30min, column chromatography purification obtains white solid 90mg, productivity 75%.
1H NMR(400MHz,CDCl3): δ 8.16 (m, 1H), δ 8.12 (m, 1H), δ 8.04 (m, 1H), δ 7.85 (m, 1H), δ 7.63 (t, J=8.0Hz, 1H), δ 4.19 (m, 2H), δ 3.71 (m, 4H), δ 2.97 (m, 4H) ppm.
The preparation of embodiment 28 3-(N methyl piperazine sulfonyl) benzoyl hydrazine (intermediate 4-2)
3-(N methyl piperazine sulfonyl) essence of Niobe (120mg) is dissolved in 5mL methanol, adds hydrazine hydrate (64mg), 130 DEG C of microwave reaction 30min, column chromatography purification obtains white solid 79mg, productivity 75%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 8.04 (m, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 4.19 (m, 2H), δ 3.64 (brs, 4H), δ 3.11 (brs, 4H), δ 2.26(s,3H)ppm。
The preparation of embodiment 29 3-(diethylamine sulfonyl) benzoyl hydrazine (intermediate 4-3)
3-(N methyl piperazine sulfonyl) essence of Niobe (120mg) is dissolved in 5mL methanol, adds hydrazine hydrate (70mg), 130 DEG C of microwave reaction 30min, column chromatography purification obtains white solid 79mg, productivity 75%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 8.04 (m, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 4.19 (m, 2H), δ 3.29 (m, 4H), δ 1.02 (m, 6H) ppm.
The preparation of embodiment 30 3-(N-methyl amine sulfonyl) benzoyl hydrazine (intermediate 4-4)
3-(N-methyl amine sulfonyl) essence of Niobe (120mg) is dissolved in 5mL methanol, adds hydrazine hydrate (84mg), 130 DEG C of microwave reaction 30min, column chromatography purification obtains white solid 80mg, productivity 75%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 8.04 (m, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 4.19 (m, 2H), δ 2.47 (s, 3H) ppm.
The preparation of embodiment 31 3-(N-methylhomopiperazin sulfonyl) benzoyl hydrazine (intermediate 4-5)
3-(N-methylhomopiperazin sulfonyl) essence of Niobe (120mg) is dissolved in 5mL methanol, adds hydrazine hydrate (61mg), 130 DEG C of microwave reaction 30min, column chromatography purification obtains white solid 78mg, productivity 75%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 8.04 (m, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 4.19 (m, 2H), δ 3.26 (brs, 2H), δ 3.16～3.10 (m, 4H), δ 2.26 (s, 3H), δ 2.48 (brs, 2H), δ 2.26 (s, 3H), δ 1.50 (m, 2H) ppm.
The preparation of embodiment 32 3-(N, N-dimethyl amine sulfonyl) benzoyl hydrazine (intermediate 4-6)
3-(N, N-dimethyl amine sulfonyl) essence of Niobe (120mg) is dissolved in 5mL methanol, adds hydrazine hydrate (79mg), 130 DEG C of microwave reaction 30min, column chromatography purification obtains white solid 80mg, productivity 75%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 8.04 (m, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 4.30 (m, 2H), δ 2.47 (s, 6H) ppm.
The preparation of embodiment 33 3-(N-cyclo-hexylamine sulfonyl) benzoyl hydrazine (intermediate 4-7)
3-(N-cyclo-hexylamine sulfonyl) essence of Niobe (120mg) is dissolved in 5mL methanol, adds hydrazine hydrate (65mg), 130 DEG C of microwave reaction 30min, column chromatography purification obtains white solid 78mg, productivity 75%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 8.04 (m, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 4.19 (m, 2H), δ 3.0 (m, 1H), δ 1.60 (brs, 4H), δ 1.48 (m, 2H), δ 1.15 (brs, 4H) ppm.
The preparation of embodiment 34 3-(N-n-butylamine sulfonyl) benzoyl hydrazine (intermediate 4-8)
3-(N-n-butylamine sulfonyl) essence of Niobe (120mg) is dissolved in 5mL methanol, adds hydrazine hydrate (71mg), 130 DEG C of microwave reaction 30min, column chromatography purification obtains white solid 79mg, productivity 75%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 8.04 (m, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 4.19 (m, 2H), δ 3.40 (t, J=7.6Hz, 2H), δ 1.5～1.3 (m, 4H), δ 0.9 (t, J=7.7Hz, 3H) ppm.
The preparation of embodiment 35 3-(N-cyclopenta sulfamic) benzoyl hydrazine (intermediate 4-9)
3-(N-cyclopenta sulfamic) essence of Niobe (120mg) is dissolved in 5mL methanol, adds hydrazine hydrate (68mg), 130 DEG C of microwave reaction 30min, column chromatography purification obtains white solid 79mg, productivity 75%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 8.04 (m, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 4.19 (m, 2H), δ 2.65 (m, 1H), δ 1.73 (m, 4H), δ 1.50 (m, 4H) ppm.
The preparation of embodiment 36 3-(N-cyclopropylamine sulfonyl) benzoyl hydrazine (intermediate 4-10)
3-(N-cyclopropylamine sulfonyl) essence of Niobe (120mg) is dissolved in 5mL methanol, adds hydrazine hydrate (75mg), 130 DEG C of microwave reaction 30min, column chromatography purification obtains white solid 79mg, productivity 75%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 8.04 (m, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 4.19 (m, 2H), δ 1.35 (t, J=7.6Hz, 1H), δ 0.70 (d, J=7.7Hz, 2H) ppm.
The preparation of embodiment 37 3-(N-phenyl amine sulfonyl) benzoyl hydrazine (intermediate 4-11)
3-(N-phenyl amine sulfonyl) essence of Niobe (120mg) is dissolved in 5mL methanol, adds hydrazine hydrate (66mg), 130 DEG C of microwave reaction 30min, column chromatography purification obtains white solid 79mg, productivity 75%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 8.04 (m, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 7.20 (d, J=7.6Hz, 2H), δ 6.81 (d, J=7.6Hz, 1H), δ 6.63 (d, J=7.6Hz, 2H), δ 4.20 (m, 2H) ppm.
The preparation of embodiment 38 3-(N-Methyl-N-phenyl sulfamic) benzoyl hydrazine (intermediate 4-12)
3-(N-Methyl-N-phenyl sulfamic) essence of Niobe (120mg) is dissolved in 5mL methanol, adds hydrazine hydrate (63mg), 130 DEG C of microwave reaction 30min, column chromatography purification obtains white solid 81mg, productivity 75%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 8.04 (m, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 7.20 (d, J=7.6Hz, 2H), δ 6.81 (d, J=7.6Hz, 1H), δ 6.63 (d, J=7.6Hz, 2H), δ 4.19 (m, 2H), δ 3.20 (s, 3H) ppm.
The preparation of embodiment 39 3-(N-(2,5-Dimethoxyphenyl) sulfamic) benzoyl hydrazine (intermediate 4-13)
3-(N-(2,5-Dimethoxyphenyl) sulfamic) essence of Niobe (120mg) is dissolved in 5mL methanol, adds Entering hydrazine hydrate (55mg), 130 DEG C of microwave reaction 30min, column chromatography purification obtains white solid 78mg, productivity 75%.
1H NMR(400MHz,CDCl3): δ 8.15 (s, 1H), δ 8.04 (m, 1H), δ 7.96 (d, J=7.6Hz, 1H), δ 7.84 (t, J=7.7Hz, 1H), δ 7.74 (s, 1H), δ 7.35 (d, J=7.6Hz, 1H), δ 6.80 (d, J=7.6Hz, 1H), δ 6.24 (d, J=7.6Hz, 1H), δ 6.07 (s, 1H), δ 4.19 (m, 2H), δ 3.9 (s, 3H), δ 3.7 (s, 3H) ppm.
Embodiment 40 N'-(7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(morpholine sulfonyl) benzoyl hydrazine (compound 5-1) Preparation
3-(morpholine sulfonyl) benzoyl hydrazine (100mg) is dissolved in 2mL ethanol with 7-hydroxide radical-1-indenone (42mg), 80 DEG C Backflow 8h, column chromatography purification obtains white solid 59mg, productivity 50%.
1H NMR (400MHz, DMSO) δ 11.36 (s, 1H), δ 10.20 (s, 1H), δ 8.23 (d, J=7.6Hz, 1H), δ 8.16 (s, 1H), 7.96 (d, J=7.7Hz, 1H), δ 7.87 7.81 (m, 1H), δ 7.32 (t, J=7.7Hz, 1H), δ 6.92 (d, J=7.3 Hz, 1H), δ 6.77 (d, J=8.1Hz, 1H), δ 3.64 (brs, 4H), δ 3.10 (m, 4H), δ 2.92 (brs, 4H) ppm.
Embodiment 41 N'-(4-chloro-7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(morpholine sulfonyl) benzoyl hydrazine (compound Preparation 5-2)
3-(morpholine sulfonyl) benzoyl hydrazine (100mg) and 4-chloro-7-hydroxy group 1-Indanone (52mg) is dissolved in 2mL In ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 63mg, productivity 50%.
1H NMR (400MHz, DMSO) δ 11.46 (s, 1H), δ 10.28 (s, 1H), δ 8.23 (d, J=7.6Hz, 1H), δ 8.15 (s, 1H), δ 7.96 (d, J=7.7Hz, 1H), δ 7.84 (t, J=7.8Hz, 1H), δ 7.35 (d, J=8.6Hz, 1H), δ 6.84 (d, J =8.5Hz, 1H), δ 3.64 (brs, 4H), δ 3.11 (brs, 4H), δ 2.92 (brs, 4H) ppm.
Embodiment 42 N'-(7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N methyl piperazine sulfonyl) benzoyl hydrazine (compound Preparation 5-3)
3-(N methyl piperazine sulfonyl) benzoyl hydrazine (100mg) is dissolved in 2mL ethanol with 7-hydroxide radical-1-indenone (40mg) In, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 57mg, productivity 50%.
1H NMR (400MHz, DMSO) δ 11.48 (s, 1H), δ 10.23 (s, 1H), δ 8.28 (d, J=7.7Hz, 1H), δ 8.21 (s, 1H), δ 8.01 (d, J=7.7Hz, 1H), δ 7.87 (t, J=7.8Hz, 1H), δ 7.33 (t, J=7.8Hz, 1H), δ 6.92 (d, J =7.4Hz, 1H), δ 6.77 (d, J=8.1Hz, 1H), δ 3.39 (m, 8H), δ 3.10 (m, 4H), δ 2.78 (s, 3H) ppm.
Embodiment 43 N'-(4-chloro-7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N methyl piperazine sulfonyl) benzoyl hydrazine (is changed Compound 5-4) preparation
3-(N methyl piperazine sulfonyl) benzoyl hydrazine (100mg) 7-chloro-with 4-hydroxy group 1-Indanone (49mg) is dissolved in In 2mL ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 62mg, productivity 50%.
1H NMR (400MHz, DMSO) δ 11.53 (s, 1H), δ 10.30 (s, 1H), δ 8.24 (d, J=7.4Hz, 1H), δ 8.16 (s, 1H), δ 7.97 (d, J=7.8Hz, 1H), δ 7.85 (t, J=7.8Hz, 1H), δ 7.36 (d, J=8.6Hz, 1H), δ 6.84 (d, J =8.6Hz, 1H), δ 3.39 (m, 8H), δ 3.11 (s, 3H), δ 2.78 (s, 3H) ppm.
Embodiment 44 N'-(7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(diethylamine sulfonyl) benzoyl hydrazine (compound 5-5) Preparation
3-(diethylamine sulfonyl) benzoyl hydrazine (100mg) is dissolved in 2mL ethanol with 7-hydroxide radical-1-indenone (44mg), 80 DEG C of backflow 8h, column chromatography purification obtains white solid 59mg, productivity 50%.
1H NMR (400MHz, DMSO) δ 11.36 (s, 1H), δ 10.21 (s, 1H), δ 8.22 (s, 1H), δ 8.16 (d, J=7.7 Hz, 1H), δ 8.01 (d, J=7.8Hz, 1H), δ 7.77 (t, J=7.8Hz, 1H), δ 7.32 (t, J=7.7Hz, 1H), δ 6.92 (d, J =7.4Hz, 1H), δ 6.77 (d, J=8.0Hz, 1H), δ 3.21 (q, J=7.0Hz, 4H), δ 3.10 (brs, 4H), δ 1.07 (t, J= 7.0Hz,6H)ppm。
Embodiment 45 N'-(4-chloro-7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(diethylamine sulfonyl) benzoyl hydrazine (chemical combination Thing 5-6) preparation
3-(diethylamine sulfonyl) benzoyl hydrazine (100mg) and 4-chloro-7-hydroxy group 1-Indanone (54mg) is dissolved in 2mL In ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 64mg, productivity 50%.
1H NMR (400MHz, DMSO) δ 11.46 (s, 1H), δ 10.30 (s, 1H), δ 8.22 (s, 1H), δ 8.16 (d, J=7.6 Hz, 1H), δ 8.02 (d, J=7.7Hz, 1H), δ 7.77 (t, J=7.7Hz, 1H), δ 7.35 (d, J=8.6Hz, 1H), δ 6.84 (d, J =8.5Hz, 1H), δ 3.21 (q, J=7.0Hz, 4H), δ 3.11 (brs, 4H), δ 1.06 (t, J=7.0Hz, 6H) ppm.
Embodiment 46 N'-(7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-methyl amine sulfonyl) benzoyl hydrazine (compound Preparation 5-7)
3-(N-methyl amine sulfonyl) benzoyl hydrazine (100mg) and 7-hydroxide radical-1-indenone (52mg) are dissolved in 2mL ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 63mg, productivity 50%.
1H NMR (400MHz, DMSO) δ 11.35 (s, 1H), δ 10.22 (s, 1H), δ 8.24 (s, 1H), δ 8.15 (d, J=7.6 Hz, 1H), δ 7.99 (d, J=7.6Hz, 1H), δ 7.78 (t, J=7.7Hz, 1H), δ 7.64 (d, J=4.8Hz, 1H), δ 7.32 (t, J =7.7Hz, 1H), δ 6.91 (d, J=7.4Hz, 1H), δ 6.77 (d, J=8.0Hz, 1H), δ 3.10 (m, 4H), δ 2.45 (d, J= 4.8Hz,3H)ppm。
Embodiment 47 N'-(4-chloro-7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-methyl amine sulfonyl) benzoyl hydrazine (is changed Compound 5-8) preparation
3-(N-methyl amine sulfonyl) benzoyl hydrazine (100mg) is dissolved in 2mL with 4-chloro-7-hydroxy group 1-Indanone (64mg) In ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 69mg, productivity 50%.
1H NMR (400MHz, DMSO) δ 11.46 (s, 1H), δ 10.30 (s, 1H), δ 8.24 (s, 1H), δ 8.15 (d, J=7.6 Hz, 1H), δ 7.99 (d, J=7.7Hz, 1H), δ 7.79 (t, J=7.7Hz, 1H), δ 7.65 (d, J=4.8Hz, 1H), δ 7.35 (d, J=8.6Hz, 1H), δ 6.83 (d, J=8.6Hz, 1H), δ 3.11 (brs, 4H), δ 2.45 (d, J=4.8Hz, 3H) ppm.
Embodiment 48 N'-(7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-methylhomopiperazin sulfonyl) benzoyl hydrazine (chemical combination Thing 5-9) preparation
3-(N-methylhomopiperazin sulfonyl) benzoyl hydrazine (100mg) and 7-hydroxide radical-1-indenone (38mg) are dissolved in 2mL second In alcohol, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 57mg, productivity 50%.
1H NMR(400MHz,DMSO)δ11.38(s,1H),δ10.22(s,1H),δ8.25–8.14(m,2H),δ8.00(d, J=7.5Hz, 1H), δ 7.79 (t, J=7.7Hz, 1H), δ 7.32 (t, J=7.7Hz, 1H), δ 6.92 (d, J=7.3Hz, 1H), δ 6.77 (d, J=8.0Hz, 1H), δ 3.26 (brs, 2H), δ 3.16～3.10 (m, 4H), δ 2.26 (s, 3H), δ 2.48 (brs, 2H), δ 2.26 (s, 3H), δ 1.50 (m, 2H) ppm.
Embodiment 49 N'-(4-chloro-7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-methylhomopiperazin sulfonyl) benzoyl hydrazine The preparation of (compound 5-10)
By molten for 3-(N-methylhomopiperazin sulfonyl) benzoyl hydrazine (100mg) 7-chloro-with 4-hydroxy group 1-Indanone (47mg) In 2mL ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 61mg, productivity 50%.
1H NMR(400MHz,DMSO)δ11.48(s,1H),δ10.32(s,1H),δ8.23–8.14(m,2H),δ8.00(d, J=7.8Hz, 1H), δ 7.79 (t, J=7.8Hz, 1H), δ 7.35 (d, J=8.6Hz, 1H), δ 6.84 (d, J=8.6Hz, 1H), δ 3.26 (brs, 2H), δ 3.16～3.10 (m, 4H), δ 2.26 (s, 3H), δ 2.48 (brs, 2H), δ 2.26 (s, 3H), δ 1.50 (m, 2H)ppm。
Embodiment 50 N'-(7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N, N-dimethyl amine sulfonyl) benzoyl hydrazine (chemical combination Thing 5-11) preparation
3-(N, N-dimethyl amine sulfonyl) benzoyl hydrazine (100mg) and 7-hydroxide radical-1-indenone (49mg) are dissolved in 2mL second In alcohol, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 61mg, productivity 50%.
1H NMR (400MHz, DMSO) δ 11.37 (s, 1H), δ 10.21 (s, 1H), δ 8.21 (d, J=7.6Hz, 1H), δ 8.17 (s, 1H), δ 7.97 (d, J=7.7Hz, 1H), δ 7.83 (t, J=7.7Hz, 1H), δ 7.32 (t, J=7.7Hz, 1H), δ 6.92 (d, J =7.4Hz, 1H), δ 6.77 (d, J=8.0Hz, 1H), δ 3.10 (m, 4H), δ 2.66 (s, 6H) ppm.
Embodiment 51 N'-(4-chloro-7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N, N-dimethyl amine sulfonyl) benzoyl hydrazine The preparation of (compound 5-12)
By molten for 3-(N, N-dimethyl amine sulfonyl) benzoyl hydrazine (100mg) 7-chloro-with 4-hydroxy group 1-Indanone (60mg) In 2mL ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 67mg, productivity 50%.
1H NMR (400MHz, DMSO) δ 11.47 (s, 1H), δ 10.29 (s, 1H), δ 8.21 (d, J=7.7Hz, 1H), δ 8.17 (s, 1H), δ 7.97 (d, J=7.8Hz, 1H), δ 7.83 (t, J=7.7Hz, 1H), δ 7.35 (d, J=8.6Hz, 1H), δ 6.84 (d, J =8.6Hz, 1H), δ 3.11 (brs, 4H), δ 2.66 (s, 6H) ppm.
Embodiment 52 N'-(7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-cyclo-hexylamine sulfonyl) benzoyl hydrazine (compound Preparation 5-13)
3-(N-cyclo-hexylamine sulfonyl) benzoyl hydrazine (100mg) and 7-hydroxide radical-1-indenone (40mg) are dissolved in 2mL ethanol In, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 58mg, productivity 50%.
1H NMR (400MHz, DMSO) δ 11.35 (s, 1H), δ 10.22 (s, 1H), δ 8.29 (s, 1H), δ 8.12 (d, J=7.6 Hz, 1H), δ 8.02 (d, J=7.7Hz, 1H), δ 7.85 (d, J=7.3Hz, 1H), δ 7.75 (t, J=7.7Hz, 1H), δ 7.31 (t, J =7.8Hz, 1H), δ 6.91 (d, J=7.4Hz, 1H), δ 6.77 (d, J=8.0Hz, 1H), δ 3.10 (m, 4H), δ 2.97 (brs, 1H),δ1.57(m,4H),δ1.13(m,4H),δ1.09–0.96(m,2H)ppm。
Embodiment 53 N'-(4-chloro-7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-cyclo-hexylamine sulfonyl) benzoyl hydrazine (is changed Compound 5-14) preparation
3-(N-cyclo-hexylamine sulfonyl) benzoyl hydrazine (100mg) 7-chloro-with 4-hydroxy group 1-Indanone (49mg) is dissolved in In 2mL ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 62mg, productivity 50%.
1H NMR (400MHz, DMSO) δ 11.45 (s, 1H), δ 10.30 (s, 1H), δ 8.29 (s, 1H), δ 8.12 (d, J=7.6 Hz, 1H), δ 8.03 (d, J=7.7Hz, 1H), δ 7.85 (d, J=7.2Hz, 1H), δ 7.76 (t, J=7.7Hz, 1H), δ 7.34 (d, J =8.6Hz, 1H), δ 6.83 (d, J=8.6Hz, 1H), δ 3.11 (brs, 4H), δ 2.98 (m, 1H), δ 1.58 (m, 3H), δ 1.13 (m, 4H), δ 1.06 (t, J=7.0Hz, 4H) ppm.
Embodiment 54 N'-(7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-n-butylamine sulfonyl) benzoyl hydrazine (compound Preparation 5-15)
3-(N-n-butylamine sulfonyl) benzoyl hydrazine (100mg) and 7-hydroxide radical-1-indenone (44mg) are dissolved in 2mL ethanol In, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 62mg, productivity 51%.
1H NMR (400MHz, DMSO) δ 11.35 (s, 1H), δ 10.22 (s, 1H), δ 8.25 (s, 1H), δ 8.14 (d, J=7.6 Hz, 1H), δ 7.99 (d, J=7.7Hz, 1H), δ 7.80 7.72 (m, 2H), δ 7.32 (t, J=7.7Hz, 1H), δ 6.91 (d, J= 7.4Hz, 1H), δ 6.77 (d, J=8.1Hz, 1H), δ 3.10 (m, 4H), δ 2.76 (m, 2H), δ 1.35 (m, 2H), δ 1.24 (m, 2H), δ 0.80 (t, J=7.2Hz, 3H) ppm.
Embodiment 55 N'-(4-chloro-7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-n-butylamine sulfonyl) benzoyl hydrazine (is changed Compound 5-16) preparation
3-(N-n-butylamine sulfonyl) benzoyl hydrazine (100mg) 7-chloro-with 4-hydroxy group 1-Indanone (54mg) is dissolved in In 2mL ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 64mg, productivity 50%.
1H NMR (400MHz, DMSO) δ 11.45 (s, 1H), δ 10.30 (s, 1H), δ 8.26 (s, 1H), δ 8.14 (d, J=7.6 Hz, 1H), δ 8.00 (d, J=7.6Hz, 1H), δ 7.81 7.72 (m, 2H), δ 7.35 (d, J=8.6Hz, 1H), δ 6.83 (d, J= 8.5Hz, 1H), δ 3.11 (brs, 4H), δ 1.40 1.31 (m, 2H), δ 1.24 (m, 2H), δ 1.06 (m, 2H), δ 0.80 (t, J= 7.2Hz,3H)ppm。
Embodiment 56 N'-(7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-cyclopenta sulfamic) benzoyl hydrazine (compound Preparation 5-17)
3-(N-cyclopenta sulfamic) benzoyl hydrazine (100mg) and 7-hydroxide radical-1-indenone (42mg) are dissolved in 2mL ethanol In, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 58mg, productivity 51%.
1H NMR (400MHz, DMSO) δ 11.35 (s, 1H), δ 10.22 (s, 1H), δ 8.28 (s, 1H), δ 8.13 (d, J=7.6 Hz, 1H), δ 8.01 (d, J=7.8Hz, 1H), δ 7.83 (d, J=7.0Hz, 1H), δ 7.76 (t, J=7.8Hz, 1H), δ 7.31 (t, J =7.7Hz, 1H), δ 6.91 (d, J=7.4Hz, 1H), δ 6.77 (d, J=8.1Hz, 1H), δ 3.45 (m, 1H), δ 3.10 (m, 4H), δ1.65–1.51(m,4H),δ1.35(m,4H)ppm。
Embodiment 57 N'-(4-chloro-7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-cyclopenta sulfamic) benzoyl hydrazine (is changed Compound 5-18) preparation
3-(N-cyclopenta sulfamic) benzoyl hydrazine (100mg) 7-chloro-with 4-hydroxy group 1-Indanone (52mg) is dissolved in In 2mL ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 63mg, productivity 51%.
1H NMR (400MHz, DMSO) δ 11.46 (s, 1H), δ 10.30 (s, 1H), δ 8.28 (s, 1H), δ 8.13 (d, J=7.6 Hz, 1H), δ 8.02 (d, J=7.6Hz, 1H), δ 7.84 (d, J=7.0Hz, 1H), δ 7.76 (t, J=7.7Hz, 1H), δ 7.35 (d, J =8.6Hz, 1H), δ 6.83 (d, J=8.6Hz, 1H), δ 3.44 (m, 1H), δ 3.11 (brs, 4H), δ 1.62 1.50 (m, 4H), δ 1.41–1.27(m,4H)ppm。
Embodiment 58 N'-(7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-cyclopropylamine sulfonyl) benzoyl hydrazine (compound Preparation 5-19)
3-(N-cyclopropylamine sulfonyl) benzoyl hydrazine (100mg) and 7-hydroxide radical-1-indenone (47mg) are dissolved in 2mL ethanol In, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 60mg, productivity 51%.
1H NMR (400MHz, DMSO) δ 11.37 (s, 1H), δ 10.22 (s, 1H), δ 8.29 (s, 1H), δ 8.17 (d, J=7.6 Hz, 1H), δ 8.09 (s, 1H), δ 8.02 (d, J=7.6Hz, 1H), δ 7.79 (t, J=7.7Hz, 1H), δ 7.31 (t, J=7.7Hz, 1H), δ 6.91 (d, J=7.4Hz, 1H), δ 6.77 (d, J=8.1Hz, 1H), δ 3.10 (m, 4H), δ 2.14 (brs, 1H), δ 0.51 (d, J=5.5Hz, 2H), δ 0.40 (brs, 2H) ppm.
Embodiment 59 N'-(4-chloro-7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-cyclopropylamine sulfonyl) benzoyl hydrazine (is changed Compound 5-20) preparation
3-(N-cyclopropylamine sulfonyl) benzoyl hydrazine (100mg) 7-chloro-with 4-hydroxy group 1-Indanone (57mg) is dissolved in In 2mL ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains white solid 68mg, productivity 51%.
1H NMR (400MHz, DMSO) δ 11.47 (s, 1H), δ 10.30 (s, 1H), δ 8.28 (s, 1H), δ 8.17 (d, J=7.4 Hz, 1H), δ 8.09 (s, 1H), δ 8.03 (d, J=7.4Hz, 1H), δ 7.80 (t, J=7.6Hz, 1H), δ 7.35 (d, J=8.5Hz, 1H), δ 6.84 (d, J=8.5Hz, 1H), δ 3.11 (m, 4H), δ 2.51 (m, 1H), δ 0.50 (d, J=5.1Hz, 2H), δ 0.39 (brs,2H)ppm。
Embodiment 60 N'-(7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-phenyl amine sulfonyl) benzoyl hydrazine (compound Preparation 5-21)
3-(N-phenyl amine sulfonyl) benzoyl hydrazine (100mg) and 7-hydroxide radical-1-indenone (41mg) are dissolved in 2mL ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains yellow solid 58mg, productivity 50%.
1H NMR(400MHz,DMSO)δ11.32(s,1H),δ10.46(s,1H),δ10.18(s,1H),δ8.25(s,1H),δ 8.10 (d, J=7.6Hz, 1H), δ 7.94 (d, J=7.7Hz, 1H), δ 7.71 (t, J=7.7Hz, 1H), δ 7.31 (t, J=7.7Hz, 1H), δ 7.24 (t, J=7.6Hz, 2H), δ 7.11 (d, J=7.9Hz, 2H), δ 7.04 (t, J=7.2Hz, 1H), δ 6.91 (d, J= 7.4Hz, 1H), δ 6.76 (d, J=8.1Hz, 1H), δ 3.11 (t, J=6.2Hz, 2H), δ 3.05 (t, J=6.4Hz, 2H) ppm.
Embodiment 61 N'-(4-chloro-7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-phenyl amine sulfonyl) benzoyl hydrazine (is changed Compound 5-22) preparation
3-(N-phenyl amine sulfonyl) benzoyl hydrazine (100mg) is dissolved in 2mL with 4-chloro-7-hydroxy group 1-Indanone (50mg) In ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains yellow solid 63mg, productivity 50%.
1H NMR(400MHz,DMSO)δ11.42(s,1H),δ10.46(s,1H),δ10.26(s,1H),δ8.25(s,1H),δ 8.09 (d, J=7.6Hz, 1H), δ 7.95 (d, J=7.7Hz, 1H), δ 7.71 (t, J=7.7Hz, 1H), δ 7.34 (d, J=8.6Hz, 1H), δ 7.24 (t, J=7.7Hz, 2H), δ 7.11 (d, J=7.9Hz, 2H), δ 7.04 (t, J=7.3Hz, 1H), δ 6.83 (d, J= 8.5Hz,1H),δ3.09(brs,4H)ppm。
Embodiment 62 N'-(7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-Methyl-N-phenyl sulfamic) benzoyl hydrazine (is changed Compound 5-23) preparation
3-(N-Methyl-N-phenyl sulfamic) benzoyl hydrazine (100mg) and 7-hydroxide radical-1-indenone (39mg) are dissolved in 2mL In ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains yellow solid 57mg, productivity 50%.
1H NMR (400MHz, DMSO) δ 11.33 (s, 1H), δ 10.19 (s, 1H), δ 8.20 (d, J=7.5Hz, 1H), δ 8.01 (s, 1H), δ 7.74 (t, J=7.7Hz, 1H), δ 7.67 (d, J=7.7Hz, 1H), δ 7.34 (m 4H), δ 7.13 (d, J=7.6Hz, 2H), δ 6.91 (d, J=7.4Hz, 1H), δ 6.76 (d, J=8.0Hz, 1H), δ 3.19 (s, 3H), δ 3.12 (m, 2H), δ 3.05 (m, 2H)ppm。
Embodiment 63 N'-(4-chloro-7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-Methyl-N-phenyl sulfamic) benzoyl The preparation of hydrazine (compound 5-24)
By 3-(N-Methyl-N-phenyl sulfamic) benzoyl hydrazine (100mg) and 4-chloro-7-hydroxy group 1-Indanone (48mg) Being dissolved in 2mL ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains yellow solid 62mg, productivity 50%.
1H NMR (400MHz, DMSO) δ 8.20 (d, J=7.5Hz, 1H), δ 8.00 (s, 1H), δ 7.74 (t, J=7.7Hz, 1H), δ 7.67 (d, J=7.7Hz, 1H), δ 7.38 7.29 (m, 4H), δ 7.13 (d, J=7.6Hz, 2H), δ 6.83 (d, J=8.6 Hz,1H),δ3.19(s,3H),δ3.09(brs,4H)ppm。
Embodiment 64 N'-(7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-(2,5-Dimethoxyphenyl) sulfamic) benzene The preparation of formylhydrazine (compound 5-25)
By 3-(N-(2,5-Dimethoxyphenyl) sulfamic) benzoyl hydrazine (100mg) and 7-hydroxide radical-1-indenone (34mg) Being dissolved in 2mL ethanol, 80 DEG C of backflow 8h, column chromatography purification obtains yellow solid 55mg, productivity 50%.
1H NMR(400MHz,DMSO)δ11.31(s,1H),δ10.20(s,1H),δ9.77(s,1H),δ8.25(s,1H),δ 8.11 (d, J=7.5Hz, 1H), δ 7.92 (d, J=7.7Hz, 1H), δ 7.70 (t, J=7.7Hz, 1H), δ 7.31 (t, J=7.7Hz, 1H), δ 6.91 (d, J=7.3Hz, 1H), δ 6.86 6.80 (m, 2H), δ 6.76 (d, J=8.1Hz, 1H), δ 6.68 (dd, J=8.9, 2.8Hz, 1H), δ 3.66 (s, 3H), δ 3.44 (s, 3H), δ 3.11 (t, J=5.7Hz, 2H), δ 3.05 (t, J=5.7Hz, 2H) ppm.
Embodiment 65 N'-(4-chloro-7-hydroxyl-2,3-dihydro-1H-indenes-1-subunit)-3-(N-(2,5-Dimethoxyphenyl) sulfamic) The preparation of benzoyl hydrazine (compound 5-26)
By 3-(N-(2,5-Dimethoxyphenyl) sulfamic) benzoyl hydrazine (100mg) and 4-chloro-7-hydroxy group indenes-1- Ketone (42mg) is dissolved in 2mL ethanol, and 80 DEG C of backflow 8h, column chromatography purification obtains yellow solid 59mg, productivity 50%.
1H NMR(400MHz,DMSO)δ11.42(s,1H),δ10.28(s,1H),δ9.77(s,1H),δ8.24(s,1H),δ 8.11 (d, J=7.5Hz, 1H), δ 7.92 (d, J=7.7Hz, 1H), δ 7.70 (t, J=7.7Hz, 1H), δ 7.34 (d, J=8.5Hz, 1H), δ 6.87 6.78 (m, 3H), δ 6.68 (dd, J=8.9,2.7Hz, 1H), δ 3.66 (s, 3H), δ 3.43 (s, 3H), δ 3.09 (brs,4H)ppm。
The horizontal Inhibition test of embodiment 66 vitro enzyme
1, main agents:
LSD1 test kit is purchased from Cayman Chemical company, catalog number: 50100；
384 orifice plates are bought in Perkin Elmer company, catalog number: 6007299；
Horseradish peroxidase, H3K4me2 and 10-acetyl-3,7-dihydroxyphenoxazine (10-acetyl group-3,7- Dihydroxy phenothiazine) it is purchased from Cayman Chemical company.
2, experimental technique:
Testing compound 100%DMSO (dimethyl sulfoxide) is dissolved, and be diluted to make detectable concentration be respectively 100 μMs, 30 μMs, 10 μMs, 3 μMs, 1 μM, 300nM, 100nM, 30nM, 10nM, 3nM, 1nM and 0.3nM.Respectively Draw the testing compound solution after the 2.5 above-mentioned dilutions of μ L to join in 384 orifice plates.By LSD1 enzyme with analyzing assay buffer dilution Take 40 μ L after 17 times to be added sequentially in 384 orifice plates, the most respectively by the substrate in test kit, horseradish peroxidase, H3K4me2 and 10-acetyl-3,7-dihydroxyphenoxazine (10-acetyl group-3,7-dihydroxy phenothiazine) is sequentially added into 384 In orifice plate, regulate fluorescence microplate reader excitation wavelength 530nm, launch wavelength 595nm and detect.
Table 1 is the vitro enzyme level suppression result of the compounds of this invention.
The vitro enzyme level suppression result of table 1 the compounds of this invention
" N.I. " in table 1 represents do not have inhibitory action." RC " represents control compound, and described control compound is document (V. Sorna,E.R.Theisen,B.Stephens,S.L.Warner,D.J.Bearss,H.Vankayalapati,S.Sharma, High-throughput virtual screening identifies novel N'-(1-phenylethylidene)-benzohydrazides as Potent, specific, and reversible LSD1inhibitors, J.Med.Chem.2013,56,9496-9508.) disclosed in chemical combination Thing, its structural formula is:
As it can be seen from table 1 the compound that the present invention has cyclic amino substituent group shows preferable LSD1 activity inhibition (compound 5-1,5-2,5-3,5-4,5-9 and 5-10).Particularly compound 5-1 has potent LSD1 inhibitory activity, Its IC50 value is only 1.4nM, is about 10 times of control compound.Compound 5-2,5-3,5-4,5-9 and 5-10 are the brightest Show and be better than control compound.
Embodiment 67 tumor cell in vitro proliferation inhibition test
The purpose of this experiment is detection invention Compounds in vitro tumor cell proliferation inhibition activity, and the method for employing is MTT (four Methyl-azoles salt) colorimetry.
1 experiment material
1.1 main agents
RPMI-1640, DMEM high glucose medium, hyclone, pancreatin etc. are purchased from Gibco BRL company (Invitrogen Corporation, USA).Tetramethyl azo azoles salt (MTT), dimethyl sulfoxide (DMSO) are Sigma company (USA) Product.It is configured to 50mM with 100%DMSO during experiment in vitro and stores liquid, put-20 DEG C of refrigerators and keep in Dark Place standby, face the used time It is diluted to desired concn with complete culture solution.
1.2 cell lines and cultivation
This experiment breast cancer cell line mcf-7 used, Prostatic cancer cell lines DU145 are all purchased from ATCC company of the U.S., by This laboratory preserves.All above cell strain is all with containing 10% hyclone, 100U/mL penicillin, 100 μ g/mL streptomycins RPMI-1640 complete medium or DMEM complete medium at 5%CO2, cultivate under the conditions of 37 DEG C.
2 experimental techniques
With complete cell culture fluid, cell concentration is adjusted to 1 × 104Individual/mL (cell concentration of 96h) and 2 × 104Individual/ml (72h Cell concentration) cell suspension, be inoculated in 96 orifice plates, every hole 100 μ L cell suspension, after having inoculated cell, with completely Culture medium is supplied and made its volume is 200 μ L, overnight incubation.Next day, inhale and abandon supernatant, the most respectively by testedization of gradient concentration Compound processes cell.Setting the negative control group of not drug containing and isopyknic solvent control group, DMSO concentration is 0.1% simultaneously, Each dosage group sets 3 multiple holes, at 37 DEG C, 5%CO2Under the conditions of cultivate.Respectively after 72h and 96h, every hole adds dense Degree is the MTT reagent 20 μ L of 5mg/mL, after being further cultured for 2～4h, abandons supernatant, and every hole adds DMSO 150 μ L, Vibration mixing 15min, measures absorbance (A) value (A value is directly proportional) to viable count by microplate reader (λ=570nm), Take its meansigma methods.Relative cell proliferation suppression ratio=(control group A 570-experimental group A570)/control group A 570 × 100%.Real Testing data mean to represent, following compound on intracellular inhibited proliferation all represents with IC50 or suppression ratio.
3 experimental results
Using above method, to breast cancer cell line mcf-7, Prostatic cancer cell lines DU145 has carried out proliferation inhibition activity survey Examination, the results are shown in Table 2.
Table 2 the compounds of this invention proliferation inhibition activity (IC50) to human tumor cell line MCF-7, DU145.
Above cell strain is the LSD1 overexpression cell line of document report, and result shows, the compounds of this invention is to above-mentioned tumor The propagation of cell has the strongest inhibitory action.

Claims (10)

1. indenes-1-subunit sulfonyl benzoyl hydrazine derivant, its structure is as shown in formula I:
Wherein, R1、R2Independently be-H, C1～C8Alkyl, C3～C8Cycloalkyl,-OH、C1～C8Alcoxyl Base or halogen；Or, R1And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～3 N, O Or S atom；The substituent group of described replacement 5～8 yuan of saturated heterocyclics is-H, C1～C8Alkyl, C3～C8Cycloalkyl, C1～C8 Alkoxy or halogen；
R3～R8Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C8Alkyl ,-OH, C3～C8Cycloalkyl or C1～C8Alkoxyl；
R9～R12Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C8Alkyl ,-OH or C1～C8Alkoxyl；
R13～R17Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C8Alkyl or C1～C8Alkoxyl.
Indenes-1-subunit sulfonyl benzoyl hydrazine derivant the most according to claim 1, it is characterised in that:
R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl,-OH、C1～C4Alkoxyl or halogen Element；Or, R1And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～3 N, O or S Atom；The substituent group of described replacement 5～8 yuan of saturated heterocyclics is-H, C1～C4Alkyl, C3～C6Cycloalkyl, C1～C4Alcoxyl Base or halogen；
R3～R8Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C4Alkyl ,-OH, C3～C6Cycloalkyl or C1～C4Alkoxyl；R9～R12Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C4Alkyl ,-OH or C1~ C4Alkoxyl；R13～R17Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C4Alkyl or C1～C4Alcoxyl Base；
Preferably, R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl,Or halogen；Or, R1 And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～3 N, O or S atom；Described take The generation substituent group of 5～8 yuan of saturated heterocyclics is-H, C1～C4Alkyl, C3～C6Cycloalkyl or halogen；
R3～R8Independently be-H, halogen, C1～C4Alkyl or C3～C6Cycloalkyl；R9～R12Independently be-H, halogen, C1～C4Alkyl ,-OH or C1～C4Alkoxyl；R13～R17Independently be-H, halogen, C1～C4Alkyl or C1～C4 Alkoxyl；
It is further preferred that R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl orOr, R1 And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～3 N, O or S atom；Described take The generation substituent group of 5～8 yuan of saturated heterocyclics is-H or C1～C4Alkyl；
R3～R8Independently be-H, halogen, C1～C4Alkyl or C3～C6Cycloalkyl；R9～R12Independently be-H, halogen, C1～C4Alkyl ,-OH or C1～C4Alkoxyl；R13～R17Independently be-H, halogen, C1～C4Alkyl or C1～C4 Alkoxyl；
Further preferred, R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl orOr, R1 And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～2 N or O atom；Described replacement 5～ The substituent group of 8 yuan of saturated heterocyclics is-H or C1～C4Alkyl；
R3～R8Independently be-H, halogen, C1～C4Alkyl or C3～C6Cycloalkyl；R9～R12Independently be-H, halogen, C1～C4Alkyl ,-OH or C1～C4Alkoxyl；R13～R17Independently be-H, halogen, C1～C4Alkyl or C1～C4 Alkoxyl.
Indenes-1-subunit sulfonyl benzoyl hydrazine derivant the most according to claim 2, it is characterised in that:
R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl orOr, R1And R2Cyclization is for replacing 5～8 yuan of saturated heterocyclics, described saturated heterocyclic contains 1～2 N or O atom；Described replacement 5～8 yuan of saturated heterocyclics Substituent group be-H or C1～C4Alkyl；
R3～R8Independently be-H, C1～C4Alkyl or C3～C6Cycloalkyl；R9～R12Independently be-H, halogen, C1～C4 Alkyl or-OH；R13～R17Independently be-H, halogen or C1～C4Alkoxyl；
It is further preferred that R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl orOr, R1 And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～2 N or O atom；Described replacement 5～ The substituent group of 8 yuan of saturated heterocyclics is-H or C1～C4Alkyl；
R3～R8Independently be-H；R9～R12Independently be-H, halogen, C1～C4Alkyl or-OH；R13～R17Independently be -H, halogen or C1～C4Alkoxyl；
Further preferred, R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl orOr, R1 And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～2 N or O atom；Described replacement 5～ The substituent group of 8 yuan of saturated heterocyclics is-H or C1～C4Alkyl；
R3～R8Independently be-H；R9～R12Independently be-H, halogen or-OH；R13～R17Independently be-H, halogen or C1～C4Alkoxyl；
Further preferred, R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl orOr, R1 And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～2 N or O atom；Described replacement 5～ The substituent group of 8 yuan of saturated heterocyclics is-H or C1～C4Alkyl；
R3～R8Independently be-H；R9～R12Independently be-H, halogen or-OH；R13～R17Independently be-H or C1～C4 Alkoxyl.
Indenes-1-subunit sulfonyl benzoyl hydrazine derivant the most according to claim 3, it is characterised in that:
R1、R2Independently be-H, C1～C4Alkyl, C3～C6Cycloalkyl orOr, R1And R2Cyclization is for replacing 5～8 yuan of saturated heterocyclics, described saturated heterocyclic contains 1～2 N or O atom；Described replacement 5～8 yuan of saturated heterocyclics Substituent group be-H or C1～C4Alkyl；
R3～R8Independently be-H；R9～R12Independently be-H ,-Cl or-OH；R13～R17Independently be-H or methoxyl group.
Indenes-1-subunit sulfonyl benzoyl hydrazine derivant the most according to claim 1, it is characterised in that: structural formula is as follows Shown in:
6. the preparation method of the indenes-1-subunit sulfonyl benzoyl hydrazine derivant described in Claims 1 to 5, it is characterised in that: close One-tenth route is:
The preparation method of the indenes-1-subunit sulfonyl benzoyl hydrazine derivant shown in above-mentioned formula I, its synthesis step is:
1) existTHF (oxolane) in, drip m-chloro sulfonyl benzoic acid in 0 DEG C, then normal-temperature reaction 8-12h, Obtain intermediate 2；
2) by carboxylic acid in methanol, the concentrated sulphuric acid of dropping catalytic amount, reacts with intermediate 2, obtains intermediate 3；
3) intermediate 3 is dissolved in methanol, adds the hydrazine hydrate of 2～5eq, react 12h in 65～70 DEG C, obtain intermediate 4；
4) intermediate 4 again withReaction, obtains type I compound；
Wherein, step 1) described m-chloro sulfonyl benzoic acid withMol ratio be 13；
Wherein, step 2) temperature of described reaction is 65 DEG C, the time of reaction is 12h；
Wherein, step 4) described intermediate 4 withMol ratio be 1 1.5；The solvent of described reaction is ethanol； The glacial acetic acid of catalytic amount to be dripped in described reaction；The temperature of described reaction is 80 DEG C, and the time of reaction is 8～12h；
Wherein, R1、R2Independently be-H, C1～C8Alkyl, C3～C8Cycloalkyl,-OH、C1～C8Alcoxyl Base or halogen；Or, R1And R2Cyclization is substituted 5～8 yuan of saturated heterocyclics, and described saturated heterocyclic contains 1～3 N, O Or S atom；The substituent group of described replacement 5～8 yuan of saturated heterocyclics is-H, C1～C8Alkyl, C3～C8Cycloalkyl, C1～C8 Alkoxy or halogen；R3～R8Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C8Alkyl ,-OH, C3～C8 Cycloalkyl or C1～C8Alkoxyl；R9～R12Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C8Alkyl ,-OH Or C1～C8Alkoxyl；R13～R17Independently be-H, halogen ,-CF3、-OCF3、-CN、C1～C8Alkyl or C1~ C8Alkoxyl.
7. indenes-1-subunit sulfonyl benzoyl hydrazine derivant the pharmaceutically acceptable salt described in Claims 1 to 5 or hydrate.
8. a pharmaceutical composition, be by the indenes-1-subunit sulfonyl benzoyl hydrazine derivant described in any one of Claims 1 to 5, Salt or hydrate described in claim 7 add what the complementary composition of pharmaceutically acceptable was prepared from.
9. indenes-1-subunit sulfonyl benzoyl hydrazine the derivant described in Claims 1 to 5, the salt described in claim 7 or hydration Thing purposes in preparing LSD1 inhibitor.
10. indenes-1-subunit sulfonyl benzoyl hydrazine the derivant described in Claims 1 to 5, the salt described in claim 7 or hydration Thing purposes in preparing antitumor drug.
CN201510160256.3A 2015-03-16 2015-04-07 Indenes-1-subunit sulfonyl benzoyl hydrazine derivant and its production and use Pending CN106146361A (en)

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