WO2015106717A1

WO2015106717A1 - Pyridazinone derivatives, preparation method and use therefor

Info

Publication number: WO2015106717A1
Application number: PCT/CN2015/070944
Authority: WO
Inventors: 吴勇; 朱义; 王一茜; 海俐; 李�杰; 余永国; 刘威加
Original assignee: 四川百利药业有限责任公司
Priority date: 2014-01-16
Filing date: 2015-01-16
Publication date: 2015-07-23
Also published as: CN103772352B; CN103772352A

Abstract

Disclosed are pyridazinone derivatives as represented by formula (I) or pharmaceutically acceptable salts thereof or hydrates thereof. The present invention provides a series of pyridazinone derivatives that are easily synthesized and have excellent anti-tumor effects. The invention further provides a preparation method and use for said pyridazinone derivatives.

Description

Pyridazinone derivatives, preparation method and use thereof

Technical field

The invention relates to a compound, a preparation method and use thereof, in particular to a pyridazinone derivative, a preparation method thereof and use thereof.

Background technique

Pyridazinone compounds exhibit a wide range of biological activities, such as antidepressants, vasodilators, cardiotonics, analgesics/anti-inflammatory drugs, antihypertensives, and as acaricides, herbicides in agriculture, and As an inhibitor of acetylcholinesterase, aldose reductase, monoamine oxidase, CDKs, COX-2, P38 MAP kinase, and the like.

Some pyridazinone compounds show some antitumor activity. The patent document US 2007/0072866 A1 reports a class of pyridazinone compounds having the structural formula

As a GSK-3β inhibitor, it is used to treat metabolic diseases or neurodegenerative diseases and related diseases.

The patents WO 03/059891 and WO 2005/007632 disclose pyridazinone compounds for the treatment of diseases or conditions caused or aggravated by P38 MAP kinase activity and/or TNF activity dysregulation. The pyridazinone compound in the above patent document has a structural formula of

It can be used to treat inflammatory diseases, diabetes, Alzheimer's disease or cancer, in which R _{4 is} mainly aryl substituted, R ₁ is mainly halogen, R ₂ is a more type of substitution, and R ₃ is H substitution. Halogen and other substituents, but aryl containing compounds are not directly attached to the pyridazine ring.

Aventis applied for a pyridazinone derivative as a CDK2 inhibitor with a structure of

Wherein X is C(O)NHR, NHC(O)R and a nitrogen-containing heterocycle, R ₂ is H, and R ₃ is an aromatic ring and a heterocyclic ring.

The pyridazinone compounds disclosed in the patent documents CN101538245 and CN101537006 are mainly used for anti-hepatocarcinoma drugs, and the structure thereof is

A class of compounds with 6-(3-(trifluoromethyl)phenyl)pyridazin-3(2H)-one as the core.

Summary of the invention

It is an object of the present invention to provide a new class of pyridazinone derivatives. At the same time, the present invention also provides a preparation method and use of a pyridazinone derivative.

In order to achieve the above object, the technical solution adopted by the present invention is:

a pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof having the following structure:

Wherein R _{1 is} selected from halogen, H, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Ring base

R _{2 is} selected from halogen, H, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl a substituted or unsubstituted heterocyclic group;

A and B are independent of N or C respectively;

R ₃ is halogen, -OH, -SH, substituted or unsubstituted C ₆ -C ₁₂ aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C ₁ -C ₁₀ hydrocarbyl, substituted or unsubstituted a C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted heterocyclic group, -ORa, -NHRa, -NRaRb or -SRa;

R ₄ is an electron withdrawing group.

Preferably, the substituent substituted in R ₁ is selected from H, halogen, nitro or hydroxy.

Preferably, the aryl group in R ₁ is a 5- to 10-membered aromatic mono- or bicyclic ring system; the heterocyclic group is a 3- to 10-membered non-aromatic mono- or bicyclic heterocyclic ring including one or more selected from one or more selected from the group consisting of A hetero atom of N, O or S.

Preferably, the substituent substituted in R ₂ is selected from H, halogen, nitro or hydroxy.

Preferably, the aryl group in R ₂ is a 5- to 10-membered aromatic mono- or bicyclic ring system; the heteroaryl group is a 5- to 10-membered aromatic heterocyclic ring, including one or more selected from N, O or S. a hetero atom; a heterocyclic group is a 3 to 10 membered non-aromatic mono- or bicyclic heterocyclic ring including one or more heteroatoms selected from N, O or S.

In a preferred embodiment, in the R ₃ , Ra and Rb are each independently a substituted or unsubstituted C ₁ -C ₁₀ alkyl group, a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl group, a substituted or unsubstituted aryl group. A heteroaryl group, a substituted or unsubstituted, or a substituted or unsubstituted heterocyclic group.

Further preferably, in the Ra and Rb, the substituted substituent is selected from the group consisting of halogen, -OH, nitro, C ₁ -C ₆ alkyl, carboxyl, C ₁ -C ₆ alkoxycarbonyl, phenyl, -NH ₂ a C ₁ -C ₆ alkyl-substituted amino group, a hydroxy-substituted C ₁ -C ₆ alkyl group, a hydroxy-substituted C ₁ -C ₆ alkoxy group, a heterocyclic group, a C ₁ -C ₄ alkyl-substituted heterocyclic ring Base or trifluoromethyl.

Further preferably, in the Ra and Rb, the aryl group is a 5- to 10-membered aromatic mono- or bicyclic ring system; the heteroaryl group is a 5- to 10-membered aromatic heterocyclic ring, including one or more selected from N, O or S Hetero atom; a heterocyclic group is a 3 to 10 membered non-aromatic mono- or bicyclic heterocyclic ring including one or more heteroatoms selected from N, O or S.

Preferably, in the R ₃ , the aryl group is a 5- to 10-membered aromatic mono- or bicyclic ring system; the heteroaryl group is a 5- to 10-membered aromatic heterocyclic ring, including one or more selected from N, O or S. A hetero atom; a heterocyclic group of a 3 to 10 membered non-aromatic mono- or bicyclic heterocyclic ring comprising one or more heteroatoms selected from N, O or S.

Preferably, in the R ₄ , the electron withdrawing group is selected from the group consisting of a trifluoromethyl group, a trichloromethyl group, a difluoromethyl group, a nitro group or a cyano group.

A method for producing a pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt or hydrate thereof, Method 1:

Wherein Z is a halogen, and A, B, R ₁ , R ₂ , R ₃ and R _{4 are} as defined above.

Method 2:

Wherein A, B, R ₁ , R ₂ , R ₃ and R _{4 are} as defined above.

Method 3:

Wherein A, B, R ₁ , R ₂ , R ₃ and R _{4 are} as defined above.

Method 4:

Wherein A, B, R ₁ , R ₂ , R ₃ and R _{4 are} as defined above.

A pharmaceutical composition comprising the above pyridazinone derivative or a pharmaceutically acceptable salt, hydrate, pharmaceutically acceptable N-oxide, pharmaceutically acceptable prodrug thereof.

Use of the above pyridazinone derivative or a pharmaceutically acceptable salt, hydrate thereof, pharmaceutically acceptable N-oxide, pharmaceutically acceptable prodrug for the preparation of an antitumor drug.

Preferably, the antitumor drug is an anti-hepatocarcinoma drug or an anti-cancer drug.

The pharmaceutically acceptable salts in the present invention include: mineral acids such as hydrochloride, hydrobromide, sulfate, phosphate, and the like, malate, fumarate, maleate, methanesulfonic acid, p-toluene Organic acid salts such as sulfonic acid, formate, phthalate, acetate, oxalate, succinate, tartaric acid, malonic acid, lactate, mandelate, and sodium and potassium salts , barium salts, calcium salts, etc.

The beneficial effects of the present invention are that the present invention provides a series of new compounds, and the synthesis method is simple. Its anti-tumor effect is obvious.

detailed description

All of the features disclosed in this specification, or steps in all methods or processes disclosed, may be combined in any manner other than mutually exclusive features and/or steps.

Example 1 Synthesis of Intermediate 5a

Compound (4a) (200 mg, 0.7245 mmol) and 5 ml of AcOH were mixed and refluxed at an external temperature of 120 ° C for 2 h. TLC detection (PE: EA = 5:1), the starting material was completely reacted and the reaction was stopped. The reaction solution was poured into water, adjusted to neutral pH aqueous ammonia, the reaction mixture was extracted with EA, the organic layers were combined, washed with brine, dried over anhydrous Na ₂ SO ₄ to give a light yellow solid 160 mg, namely 5a, yield 85%. M.p241-243 °C. ¹ H NMR {400 MHz, DMSO-d6 (TMS), δ (ppm)}: 13.507 (s, 1H), 9.164 (d, 1H, J = 2.0), 8.649 (d, 1H, J = 2.4), 8.231 (d) , 1H, J = 10.0), 7.090 (d, 1H, J = 10.0).

Synthesis of Compound 7a of Example 2

Compound (4a) (100 mg, 0.362 mmol) and 5 ml of AcOH were mixed and refluxed at an external temperature of 120 ° C for 20 h. TLC detection (PE: EA = 3:1), the starting material was completely reacted, and the reaction was stopped. The reaction solution was poured into water, adjusted to neutral pH aqueous ammonia, the reaction mixture was extracted with EA, the organic layers were combined, washed with brine, dried over anhydrous Na ₂ SO ₄ to give a light yellow solid 60mg, namely 7a, a yield of 68.6%.

Synthesis of Compound 7b of Example 3

The compound (5a) (50 mg, 0.194 mmol) and piperidine (2 ml) were refluxed at an external temperature of 80 ° C for 1 hour, and the reaction of the starting material by TLC (PE: Acetone = 1:1) was completed. The piperidine was spin-dried, the reaction solution was dissolved in EA, dried, and then purified by column chromatography (PA _: Acetone = 10:1) to give a dark yellow solid. That is 7b. Yield: 85%. Mp: 168-170 ° C. ¹ H NMR {400 MHz, CDCl ₃ (TMS), δ (ppm)}: 10.916 (s, 1H); 8.656 (s, 1H); 8.249 (s, 1H); 7.6855 (d, 1H) , J = 10.0); 7.062 (d, 1H, J = 9.6); 3.662 (s, 4H); 1.985 (s, 4H): 1.597 (s, 2H).

Synthesis of Compound 7c and Compound 7d of Example 4

1 g (3.6 mmol) of compound 1a, 0.42 g (0.36 mmol) of tetrakis(triphenylphosphine)palladium, 1.8 g (5.4 mmol) of 3,6-diiodopyridazine, 7.2 ml (14.4 mmol) of sodium carbonate solution (2 mol) /L), 20ml of dioxane was added to a 50ml round bottom flask, after argon replacement for 3 times, and refluxed at an external temperature of 110 ° C for 5 h, after the reaction was completed, the solvent was removed, and then dry-loaded column chromatography (PE: Acetone = 8:1) gave a brown solid 2a, 1.16 g, yield: 74.2%.

2a was dissolved in 10 ml of acetic acid, and stirred at an external temperature of 100 ° C for 3 h. The reaction of the starting material was completed, the solvent was evaporated under reduced pressure, dried and applied to a column chromatography (PE: Acetone = 8:1) to obtain compound 7c. White solid 747 mg, yield: 86%. ¹ H NMR {400 MHz, CDCl ₃ (TMS), δ (ppm)}: 8.879 (d, 1H, J = 2.0); 8.29 (d, 1H, J = 2.0); 7.727 (d, 1H, J = 10.0); 7.108 (d, 1H, J = 10.0); 5.304 (s, 1H); 3.452 (t, 4H, J = 4.8); 3.049 (t, 4H, J = 4.0).

7c (300 mg) was dissolved in 1 ml of hydrogen chloride methanol (2 mol/L), and 10 ml of acetone was added thereto with stirring at room temperature, and the mixture was washed with a white solid, and dried by filtration to give a yield of 95%. M.p: >250 °C.

Synthesis of Compound 7e of Example 5

The compound (5a) (50 mg, 0,194 mmol) and morpholine (2 ml) were refluxed at an external temperature of 80 ° C for 1 hour, and the reaction of the material was confirmed by TLC (PE: Acetone = 1:1). The reaction was stopped, the reaction mixture was poured into water, the aqueous layer extracted with EA, the organic layers were combined, washed with brine, dried over anhydrous Na ₂ SO _4. Spin dry EA. Column chromatography (PA: Acetone = 8:1) gave 30 mg of beige solid. Yield: 82%. Mp: 198 to 200 °C. ¹ H NMR {400 MHz, CDCl ₃ (TMS), δ (ppm)}: 11.813 (s, 1H); 8.769 (d, 1H, J = 2.0); 8.324 (d, 1H, J = 2.4); 7.345 (d, 1H, J = 10.0); 7.118 (d, 1H, J = 10.0); 3.843 (t, 4H, J = 4.4); 3.459 (t, 4H, J = 4.8).

Synthesis of Compound 7f of Example 6

Compound (5a) (50 mg, 0.194 mmol), 4-hydroxypiperidine (58.784 mg, 0.582 mmol), THF (5 ml), DBU (3 drop) was reacted overnight at ambient temperature 60 ° C, TLC (PE: Acetone = 1) : 1), the raw material reaction is complete. The reaction was stopped, the reaction solution was washed with water, DCM, the organic layers were combined, washed with brine, dried over anhydrous Na ₂ SO _4. Spin dry DCM. Column chromatography (PE: Acetone = 40:1) gave a beige solid. Yield: 80%. Mp: 200 to 202 °C. ¹ H NMR {400 MHz, DMSO-d6 (TMS), δ (ppm)}: 13.225 (s, 1H); 8.908 (d, 1H, J = 1.6); 8.362 (d, 1H, J = 2.0); 8.116 (d) , 1H, J = 10.0); 7.012 (d, 1H, J = 10.0); 4.767 (d, 1H, J = 4.0); 3.691 (d, 1H, J = 3.6); 3.598 (t, 2H, J = 4.4 3.97 (t, 2H, J = 10.4); 1.846 (t, 2H, J = 6.0); 1.487 (m, 2H).

Synthesis of Compound 7g of Example 7

Compound (9) (80 mg, 0.31 mmol), K ₂ CO ₃ (130 mg, 0.932 mmol) and tetrahydropyrrole (2 ml) were mixed and reacted at an external temperature of 90 ° C for 10 h, and detected by TLC (PE: Acetone = 1:1) The raw material reacted completely and the reaction was stopped. The tetrahydropyrrole was spun dry, the reaction solution was dissolved in EA, dried and applied to a column chromatography (PE: Acetone = 10:1) to give a dark yellow solid. Yield: 82%. Mp: 210 to 212 °C. ¹ H NMR {400 MHz, CDCl ₃ (TMS), δ (ppm)}: 11.356 (s, 1H); 8.720 (d, 1H, J = 2.0); 8.260 (d, 1H, J = 2.4); 7.085 (d, 1H, J = 10.0); 7.091 (d, 1H, J = 9.6); 3.402 (d, 4H, J = 5.2); 1.687 (m, 4H).

Synthesis of compound 7h of Example 8

The compound (5a) (50 mg, 0.194 mmol), N-methylpiperazine (2 ml) was reacted at an external temperature of 80 ° C for 1 h, and was subjected to TLC (DCM:MeOH = 20:1). The reaction was stopped, the reaction solution was poured into water, extracted with EA, and the organic layer was combined, washed with brine and dried over anhydrous Na2SO4. Spin dry EA. Column chromatography (DCM:MeOH = 50:1) The yield was 80%. Mp: 216 to 218 °C. ¹ H NMR {400 MHz, CDCl ₃ (TMS), δ (ppm)}: 11.00 to 12.00 (br, 1H); 8.776 (d, 1H, J = 2.0); 8.289 (d, 1H, J = 2.0); d, 1H, J = 10.0); 7.097 (d, 1H, J = 10.0); 3.547 (t, 4H, J = 4.4); 2.654 (m, 4H); 2.425 (s, 3H)

Synthesis of Compound 7i of Example 9

Compound (9) (50 mg, 0,194 mmol), cyclohexylamine (2 ml) was refluxed at 80 ° C for 20 h, TLC detection

Claims

a pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof having the following structure:

Wherein R 1 is selected from halogen, H, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Ring base

R 2 is selected from halogen, H, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl a substituted or unsubstituted heterocyclic group;

A and B are independent of N or C respectively;

R 3 is halogen, -OH, -SH, substituted or unsubstituted C 5 -C 10 aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 10 hydrocarbyl, substituted or unsubstituted a C 3 -C 10 cycloalkyl, substituted or unsubstituted heterocyclic group, -ORa, -NHRa, -NRaRb or -SRa;

R 4 is an electron withdrawing group.
A pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof according to claim 1, wherein the R 1 is Substituted substituents are selected from H, halogen, nitro or hydroxy.
A pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof according to claim 1, wherein the R 1 is The aryl group is a 5- to 10-membered aromatic mono- or bicyclic ring system; the heterocyclic group is a 3- to 10-membered non-aromatic mono- or bicyclic heterocyclic ring including one or more heteroatoms selected from N, O or S.
A pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof according to claim 1, wherein the R 2 is Substituted substituents are selected from H, halogen, nitro or hydroxy.
A pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof according to claim 1, wherein the R 2 is The aryl group is a 5- to 10-membered aromatic mono- or bicyclic ring system; the heteroaryl group is a 5- to 10-membered aromatic heterocyclic ring including one or more heteroatoms selected from N, O or S; the heterocyclic group is 3 to A 10-membered non-aromatic mono- or bicyclic heterocyclic ring comprising one or more heteroatoms selected from N, O or S.
A pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof according to claim 1, wherein the R 3 is , Ra and Rb are each independently substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl a heterocyclic group, or a substituted or unsubstituted heterocyclic group.
A pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof according to claim 6, wherein the Ra and Rb are The substituted substituent is selected from the group consisting of halogen, OH, nitro, C 1 -C 6 alkyl, carboxyl, C 1 -C 6 alkoxycarbonyl, aryl, -NH 2 , C 1 -C 6 alkyl An amino group, a hydroxy-substituted C 1 -C 6 alkyl group, a hydroxy-substituted C 1 -C 6 alkoxy group, a heterocyclic group, a C 1 -C 4 alkyl-substituted heterocyclic group or a trifluoromethyl group.
A pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof according to claim 6, wherein the Ra and Rb are Wherein the aryl group is a 5- to 10-membered aromatic mono- or bicyclic ring system; the heteroaryl group is a 5- to 10-membered aromatic heterocyclic ring comprising one or more heteroatoms selected from N, O or S; A 3 to 10 membered non-aromatic mono- or bicyclic heterocyclic ring comprising one or more heteroatoms selected from N, O or S.
A pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof according to claim 1, wherein the R 3 is The aryl group is a 5- to 10-membered aromatic mono- or bicyclic ring system; the heteroaryl group is a 5- to 10-membered aromatic heterocyclic ring including one or more hetero atoms selected from N, O or S; A 3 to 10 membered non-aromatic mono- or bicyclic heterocyclic ring comprising one or more heteroatoms selected from N, O or S.
The pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof according to claim 1, wherein in the R4, The electron withdrawing group is selected from the group consisting of trifluoromethyl, trichloromethyl, difluoromethyl, nitro or cyano.
A pyridazinone derivative of the formula (I), or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof, according to any one of claims 1 to 10, characterized in that the compound is selected from:
The method for producing a pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt or hydrate thereof according to any one of claims 1 to 10, which comprises the steps of:

Wherein Z is a halogen, and A, B, R 1 , R 2 , R 3 and R 4 are as defined in any one of claims 1 to 10.
The method for producing a pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt or hydrate thereof according to any one of claims 1 to 10, which comprises the steps of:

Wherein A, B, R 1 , R 2 , R 3 and R 4 are as defined in any one of claims 1-10.
A method for producing a pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof according to any one of claims 1 to 8, which comprises the following step:

Wherein A, B, R 1 , R 2 , R 3 and R 4 are as defined in any one of claims 1-10.
The method for producing a pyridazinone derivative of the formula (I) or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof according to any one of claims 1 to 10, which comprises the following Steps:

Wherein A, B, R 1 , R 2 , R 3 and R 4 are as defined in any one of claims 1-10.
A pharmaceutical composition comprising the pyridazinone derivative according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof.
Use of a pyridazinone derivative or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof according to any one of claims 1 to 11 for the preparation of an antitumor drug.
The use of a pyridazinone derivative or a pharmaceutically acceptable salt, hydrate, N-oxide or prodrug thereof according to claim 17, wherein the antitumor drug is an anti-hepatocarcinoma drug or an antibiotic Gastric cancer drugs.