CN1380279A - (4-alkynyl), aromatic keto-acid compound, synthesis method and its application - Google Patents

Abstract

The invention relates to a (4-alkynyl)-aromatic keto acid compound, a synthesis method and an application thereof. The compound has the structural formula I: wherein R is H or C _1-10 hydrocarbon group; R ¹ is H, C _1-10 hydrocarbon group or CH ₂ OR ⁵ ; R ² is H, C _1-6 straight chain or with branched alkyl; R ³ or/and R ⁴ are H, OH, OR ⁵ , NHCOOR ⁵ ; R ⁵ is a C _1-10 hydrocarbon group; the hydrocarbon group is a straight chain alkyl, branched or aromatic Alkyl, aryl or substituted aryl groups. It can be used as an inhibitor of matrix protease, so it may be used to treat cancer, arthritis, body ulcers, emphysema, atherosclerosis and other diseases.

Description

(4-alkynyl)-aryl keto acid compound, synthesis method and application

technical field

The invention relates to (4-alkynyl)-aromatic keto acid compounds, a synthesis method and applications thereof. The compound can be used as an inhibitor of matrix protease, and thus may be used to treat diseases such as cancer, arthritis, body ulcer, emphysema, and vascular atherosclerosis.

Background technique

Matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that can degrade all major components of the extracellular matrix and thus participate in the renewal of connective tissue (Ryoichi Hirayama, Minoru Yamamota.Bioorg.Med.Chem.1997 , 5, 765). Studies have shown that some subtypes of MMP are necessary for normal physiological activities of the human body, while other subtypes play an extremely important role in certain pathological processes, such as osteoarthritis, tumor metastasis and spread, multiple Arteriosclerosis, etc. (Schwartz, M.A.; Van Eart, H.E. Prog. Med. Chem. 1992, 29, 271). Overexpression of these enzymes can lead to a large number of diseases such as cancer, arthritis, body ulcers, emphysema, atherosclerosis and so on. Therefore, using MMPs as target enzymes to develop matrix metalloproteinase inhibitors (MMPIs) to treat these diseases has been one of the hot topics of medicinal chemists for more than ten years. According to the structure and mechanism of action, these inhibitors can be divided into succinyl hydroxy acids, sulfonamide hydroxamic acids, carboxylic acids, etc.

Among them, carboxylic acid matrix metalloproteinase inhibitors have been paid more and more attention by medicinal chemists in various countries due to their high selectivity to various types of matrix metalloproteinases.

Contents of the invention

The object of the present invention is to provide a (4-alkynyl)-aryl keto acid compound.

The purpose of the present invention is also to provide a method for synthesizing the above-mentioned (4-alkynyl)-aryl keto acids.

Another object of the present invention is to provide an application of the above-mentioned (4-alkynyl)-aryl keto acid compound.

The (4-alkynyl)-aryl ketoacids carboxylic acid matrix protease inhibitors involved in the present invention have a novel structure, and activity measurements show that some of them have potent and selective inhibition of matrix metalloproteinases. subunit capabilities. It may be used to treat cancer, arthritis, body ulcers, emphysema, atherosclerosis and other diseases.

(4-alkynyl)-aryl ketoacid compound of the present invention has following structural formula: Wherein R is H or C _1-10 hydrocarbon group; R ¹ is H, C _1-10 hydrocarbon group or CH ₂ OR ⁵ ; R ² is H, C _1-6 straight chain or branched alkyl; R ³ or/and R ⁴ are H, OH, OR ⁵ , NHCOOR ⁵ ; R ⁵ is a C _1-10 hydrocarbon group; the hydrocarbon group is a straight-chain alkyl, an alkyl with a branched or aryl group, an aromatic base or substituted aryl. Take the following compounds as examples:

The synthetic method of compound of the present invention can be classified and described as follows:

为原料，路易斯酸为催化剂，室温下，有机溶剂中反应16-24小时，生成分子式为

卤代苯基酮，其中卤代苯、 和路易斯酸的摩尔比为1∶1-2∶1-3；在-78℃-室温和C_1-8的烷基锂作用下，4-卤代苯基酮与α-卤代酸酯发生烷基化反应，反应5-20小时，得到R²和/或R³取代的4-(4-卤代苯基)-4-氧化-丁酸，其中4-卤代苯基酮、α-卤代酸酯和C_1-8的烷基锂的摩尔比依次为1∶1.00-1.5∶1.0-2.0。该反应最好在无水无氧条件下和四氢呋喃溶液中进行。R ² and/or R ³ are the synthesis of chirally substituted compounds: using R ² and/or R ³ chirally substituted succinate lactone as the starting material, in a polar organic solvent and under the action of a Lewis acid, Chiral substituted R ² and/or R ³ succinate lactone, halobenzene and Lewis acid in a molar ratio of 1:1-1.5:3-7, refluxed for 16-36 hours, Friedel-Crafts acylation to generate R ² and/or R ³ chiral substituted 4-(4-halophenyl)-4-oxo-butanoic acid; or re-esterification to the corresponding R ² and/or R ³ chiral substituted 4-(4- Halophenyl)-4-oxo-butyrate. The reaction formula is as follows: For ^R2 and/or ^R3 substituted mesogenic compounds, there are two methods: one is to use halobenzene and

As a raw material, Lewis acid is a catalyst, and at room temperature, reacted in an organic solvent for 16-24 hours to generate a molecular formula of

Halogenated phenyl ketones, wherein halogenated benzene, The molar ratio with Lewis acid is 1:1-2:1-3; under the action of -78°C-room temperature and C _1-8 alkyllithium, 4-halogenated phenyl ketone and α-halogenated ester will generate Alkylation reaction, reaction for 5-20 hours, to obtain R ² and/or R substituted 4-( ⁴ -halophenyl)-4-oxo-butyric acid, wherein 4-halophenyl ketone, α- The molar ratio of haloester and C _1-8 alkyllithium is 1:1.00-1.5:1.0-2.0 in sequence. The reaction is best carried out in tetrahydrofuran solution under anhydrous and oxygen-free conditions.

R ² and/or R substituted 4-(4- ^halophenyl )-4-oxo-butanoic acid re-esterification to the corresponding R ² and/or R substituted ^4- (4-halophenyl )-4-Oxo-butyrate.

The C _1-8 alkyllithium can be butyllithium, dibutyllithium, diisopropyllithium (LDA), octyllithium and the like.

The second is Friedel _- Crafts acylation of halobenzene and haloacetyl halide _under the same conditions as above to generate haloacetyl halophenyl ketone; ) COOR under anhydrous and oxygen-free conditions, the alkylation reaction occurs as above, that is, under the action of C _1-8 alkyllithium at -78°C-room temperature, react for 5-20 hours to obtain R ² and/or R ³ substituted 4-(4-Halophenyl)-4-oxo-butanoic acid. Wherein the molar ratio of haloacetyl halophenyl ketone, disubstituted acetate and C _1-8 alkyllithium is 1:1.00-1.5:1.0-2.0 in sequence. The reaction is best carried out in tetrahydrofuran solution under anhydrous and oxygen-free conditions. Or re-esterification to the corresponding R ² and/or ^R substituted 4-(4-halophenyl)-4-oxo-butyrate. The reaction formula is as follows:

Esterification of 4-(4-halophenyl)-4-oxo-butyric acid substituted by R ² and/or R ³ above, 4-(4-halobenzene substituted by R ² and/or R ³ Base)-4-oxo-butanoic acid reacts with saturated alcohol ROH/hydrochloric acid at room temperature for 1-10 hours to become the corresponding ^R2 and/or ^R3 substituted 4-(4-halophenyl)-4-oxo - Butyrate.

In organic polar solvents, 4-(4-halophenyl)-4-oxo-butyrate substituted by R ² and/or R ³ , the corresponding alkyne CH≡CR ¹ , a lone pair of electrons on the nitrogen Organic compound acid-binding agent and catalyst, react at 50-100°C for 16-36 hours, introduce 4-alkynyl group to obtain γ-carbonylbenzenebutyrate compound substituted by 4-alkynyl group wherein the molar ratio of 4-(4-halophenyl)-4-oxo-butyrate substituted by ^R2 and/or ^R3 , alkyne ^CH≡CR1 and acid-binding agent is 1:1-3:0.01- 0.15, the weight ratio of 4-(4-halophenyl)-4-oxidation-butyrate and catalyst is 1:0.001-0.010, and the catalyst is dichloroditriphenylphosphorous palladium, cuprous iodide , tetrabutylammonium iodide or mixtures thereof. The organic compound acid-binding agent containing a lone pair of electrons on the nitrogen is pyridine, trimethylamine, triethylamine, trioctylamine, 4-dimethylaminopyridine, N, N-diisopropylethylamine or bis pyridine.

The above R ² and/or R substituted 4-(4-halophenyl)-4-oxo-butyrate is hydrolyzed with aqueous solution of sodium hydroxide or potassium, and acidified to obtain the corresponding ^{R 2 and} /or R ³ Substituted 4-(4-halophenyl)-4-oxo-butanoic acids.

In the above method, R, R ¹ , R ² , R ³ , R ⁴ or R ⁵ are as described above.

The (4-alkynyl)-aromatic ketoacid compounds of the present invention are not only easy to synthesize, but also have tested their inhibitory activity against three matrix proteases, showing that the compound can be used as an inhibitor of matrix proteases, and thus can be used to treat Drugs for cancer, arthritis, body ulcers, emphysema, atherosclerosis and other diseases.

Detailed ways

The following examples will help to understand the present invention, but do not limit the content of the present invention.

Synthesis of Example 14-(4-phenylethynyl)-phenyl-4-oxidation-1-butyric acid (1) 1. Aluminum trichloride (10mmol) and bromobenzene (2mmol) were mixed in 50mL dichloromethane , cooled to 0°C in an ice bath, and then slowly added a dichloromethane solution of succinolactone (1.8mmol/10ml) dropwise. Naturally raised to room temperature, and then heated to reflux for 24 hours. After the reaction was complete, the reaction mixture was poured into a mixture of 30 g of ice and 50 mL of 3M hydrochloric acid, and stirred for 1 hour. The organic phase was separated and the aqueous phase was extracted three times with chloroform. The organic phases were combined, washed with saturated brine, and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography to obtain the product 4-(4-bromophenyl)-4-oxo-1-butyric acid. Yield 79%;

¹ HNMR (300MHz, CDCl ₃ ): δ7.86(d, J=8.6Hz, 2H), 7.63(d, J=8.6Hz,

2H), 3.28(t, J=6.6Hz, 2H), 2.81(t, J=6.5Hz, 2H); EIMS(m/z): 256

(M ⁺ ), 183, 155. 2. The compound 4-(4-bromophenyl)-4-oxygen-1-butanoic acid (25.4mmol) was dissolved in 100mL saturated

MeOH/HCl, stirred at room temperature for 12 hours. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was distilled with acetic acid

The ethyl ester was dissolved, washed with saturated brine, and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure, and the residue was

The product 4-(4-bromophenyl)-4-oxo-butyric acid methyl ester was obtained by column chromatography. Yield 84.4%. ¹ HNMR (300MHz,

CDCl ₃ ): δ7.85(d, J=8.0Hz, 2H), 7.63(d, J=7.8Hz, 2H), 3.72(s, 3H),

3.29(t, J=6.5Hz, 2H), 2.78(t, J=6.3Hz, 2H); EIMS(m/z): 270(M ⁺ ),

272 (M ⁺ +2), 183. 3. Under the protection of argon, 1-phenylacetylene (20mmol) and the compound 4-(4-bromophenyl)-4-oxo-butyric acid

Methyl ester was mixed in 50mL DMF and 5mL triethylamine, then added dichloroditriphenylphosphopalladium (20mg),

Cuprous iodide (20mg) and tetrabutylammonium iodide (20mg). Then, heated to 75°C and stirred for 24 hours

hour. After the reaction was complete, 15 mL of methanol was added to quench the reaction. The solvent was evaporated under reduced pressure, and the residue was distilled with acetic acid

dissolved in ethyl ester, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was passed through the column

Chromatography gave the product 4-(4-phenylethynyl)-phenyl-4-oxy-1-butyric acid methyl ester. Yield 96%; ¹ HNMR

(300MHz, CDCl ₃ ): δ7.98(d, J=10.0Hz, 2H), 7.62(d, J=10.8Hz, 2H),

7.56(m, 2H), 7.39(m, 3H), 3.72(s, 3H), 3.33(t, J=6.7Hz, 2H), 2.79

(t, J=6.7Hz, 2H); EIMS (m/z): 292 (M ⁺ ), 205, 176; HRMS (m/z) found

292.11014 C ₁₉ H ₁₆ O ₃ required 292.10995.4. Dissolve the substrate 4-(4-phenylethynyl)-phenyl-4-oxy-1-butyric acid methyl ester in methanol and add 20%

aqueous sodium hydroxide solution, stirred at room temperature. After the reaction is complete, adjust the pH to 1 with 2M hydrochloric acid, and then use chlorine to

Imitation extraction three times. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column layer

The product 4-(4-phenylethynyl)-phenyl-4-oxy-1-butyric acid was isolated. Yield 52%. ¹ HNMR (300MHz,

CDCl ₃ ): δ7.96 (d, J=8.5Hz, 2H), 7.61 (d, J=8.5Hz, 2H), 7.53 (m 2H),

7.36(m, 3H), 3.30(t, J=6.5Hz, 2H), 2.81(t, J=6.5Hz, 2H); EIMS

(m/z): 278 (M ⁺ ), 205, 176; HRMS (m/z) found 278.09179 C ₁₈ H ₁₆ O ₃ required

278.09430.

Example 2 (S) Synthesis of 4-(4-3-methoxyl-1-propynyl)-phenyl-4-oxidation-2-methoxycarbonylamino-1-butyric acid tert-butyl ester (7) 1. Mix aluminum trichloride (10mmol) and bromobenzene (2mmol) in 50mL dichloromethane, cool in an ice bath

Cool to 0°C, then slowly dropwise add the dichloromethane solution of compound (R)-3-methoxycarbonylaminosuccinate

solution (1.8mmol/10ml). Naturally raised to room temperature, and then heated to reflux for 24 hours. After the reaction is complete,

The reaction mixture was poured into a mixture of 30 g of ice and 50 mL of 3M hydrochloric acid, and stirred for 1 hour.

The organic phase was separated and the aqueous phase was extracted three times with chloroform. Combine the organic phases and wash with saturated brine

washed and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography to obtain the product (S)-2-(methoxycarbonyl

base) amino-4-(4-bromophenyl)-4-oxo-butanoic acid, yield 67%; [α] ²⁰ _D 75.6 (c 3.8, CHCl ₃ );

¹ HNMR (300MHz, CDCl ₃ ): δ7.79(d, J=8.2Hz, 2H), 7.61(d, J=8.3Hz,

2H), 5.91(br, 1H), 4.73(m, 1H), 3.75(m, 1H), 3.67(s, 3H), 3.56(m,

1H); EIMS(m/z): 329(M ⁺ ), 284, 183; HRMS(m/z): found 328.99471,

C ₁₂ H ₁₂ BrNO ₅ requires 328.98088.2. Compound (s)-2-(methoxycarbonyl)amino-4-(4-bromophenyl)-4-oxo-butanoic acid (5.0g, 15.2

mmol) was dissolved in 70 mL of tert-butanol, then Boc ₂ O (3.82 g, 7.5 mmol) and DMAP were added

(100mg). Stirring at room temperature for 3 hours, after the reaction was over, the solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate

The ester was dissolved, washed with water and saturated brine successively, and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure, and the residual

The residue was subjected to column chromatography to obtain (s)-2-(methoxycarbonyl)amino-4-(4-bromophenyl)-4-oxo-butyric acid tert-butyl ester,

5.58 g, yield 95.3%. [α] ²⁶ _D 26.6 (c 1.20, CHCl ₃ ); ¹ HNMR (300 MHz, CDCl ₃ ):

δ7.81(d, J=8.6Hz, 2H), 7.632(d, J=8.4Hz, 2H), 5.74(br, 1H), 4.64

(m, 1H), 3.67(s, 3H), 3.61(dd, J=17.6, 4.0Hz, 1H), 3.43(dd, J=

17.6, 4.3Hz, 1H), 1.43(s, 9H); EIMS (m/z): 286 (M ⁺ -COOt-Bu), 185. 3. 3-Methoxy-1- Propyne (20mmol) and compound (s)-2-(methoxycarbonyl)ammonia

Base-4-(4-bromophenyl)-4-oxidation-butyric acid tert-butyl ester was mixed in 50mL DMF and 5mL triethylamine, and then

Dichlorobistriphenylphosphopalladium (20 mg), cuprous iodide (20 mg) and tetrabutylammonium iodide (20 mg) were added.

Then, it was heated to 75° C. and stirred for 24 hours. After the reaction was complete, 15 mL of methanol was added to quench the reaction.

The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate.

The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography to obtain the product (S) 4-(4-3-methoxy-1-propynyl)-phenyl

-4-Oxo-2-methoxycarbonylamino-1-butyric acid tert-butyl ester, yield 93%; [α] ²⁶ _D 16.7 (c 0.66,

CHCl ₃ ); ¹ HNMR (300MHz, CDCl ₃ ): δ7.89(d, J=8.3Hz, 2H), 7.54(d, J=

8.3Hz, 2H), 5.55(br, 1H), 4.60(t, J=4.2Hz, 1H), 4.34(s, 2H), 3.67

(, m, 1H), 3.64(s, 3H), 3.46(s, 3H), 3.43(m, 1H), 1.42(s, 9H);

EIMS (m/z): 376 (M ⁺ +1), 320, 302; HRMS (m/z) found 302.10371

(C ₂₀ H ₂₅ NO ₅ -OC ₄ H ₉ ) required 302.10284.

Example 3 Synthesis of (+/-) 4-(4-3-hydroxyl-1-propynyl)-phenyl-4-oxidation-2-ethyl-2-phenyl-1-butyric acid (19) 1. Mix aluminum trichloride (20mmol) and bromobenzene (10mmol) in 50mL dichloromethane, ice bath

After cooling to 0°C, a dichloromethane solution of bromoacetyl bromide (10mmol/10ml) was slowly added dropwise. natural rise

to room temperature and stirring was continued for 24 hours. After the reaction was complete, the reaction mixture was poured into 30 g of ice and 50

mL of 3M hydrochloric acid and stirred for 1 hour. The organic phase was separated and washed with saturated brine

washed and dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography to obtain the product 4-bromophenyl-methyl bromide

Base ketone, the yield is about 75%. ¹ HNMR (300MHz, CDCl ₃ ): δ7.79 (d, J=10.9Hz, 2H),

7.57 (d, J=10.8Hz, 2H), 4.33 (s, 2H); EIMS (m/z): 274 (M ⁺ ), 276, 278. 2. Compound (+/-) α-ethylphenylacetic acid Methyl ester (2.50g, 14.0mmol) was dissolved in 100mL THF

Muttering. The solution was cooled to -78°C under the protection of argon, and then slowly added LDA (1.0M, 15mL, 15.0

mmol). Continue stirring at this temperature for 1 hour, then slowly add compound 4-bromophenyl-bromomethyl ketone

Tetrahydrofuran solution (4.1g, 15.0mmol in 40mL THF). The reaction mixture was continued at -78°C

Stirring was continued for 1 hour, then warmed to room temperature, and stirring was continued for 8 hours. After the reaction is complete, the reaction mixture

Add 150 mL of saturated ammonium chloride aqueous solution to quench the reaction. Then add 150mL saturated NaCl water solution

solution, extracted with ethyl acetate (250 mL). The organic phase was dried over _{anhydrous Na2SO4} . The solvent was evaporated under reduced pressure, and the residual

The residue was subjected to column chromatography to obtain 4.5 g (85.7%) of the alkylated product (+/-) 2-ethyl-2-phenyl-4-(4-bromobenzene

base)-4-oxo-butyric acid methyl ester. ¹ HNMR (300MHz, CDCl ₃ ): δ7.85 (d, J=8.5Hz, 2H),

7.61(d, J=8.5Hz, 2H), 7.36'7.25(m, 5H), 3.77(s, 2H), 3.30(s,

3H), 2.39~2.22(m, 2H), 0.67(t, J=7.5Hz, 3H); EIMS(m/z): 375(M ⁺ +1),

377,314,316,185,187. 3. Under argon protection, 3-hydroxy-1-propyne (20mmol) and compound (+/-) 2-ethyl-2-phenyl

-4-(4-bromophenyl)-4-oxo-butyric acid methyl ester is mixed in 50mL DMF and 5mL triethylamine, then add

Dichloroditriphenylphosphopalladium (20mg), cuprous iodide (20mg) and tetrabutylammonium iodide (20mg) were added.

Then, it was heated to 75° C. and stirred for 24 hours. After the reaction was complete, 15 mL of methanol was added to quench the reaction.

The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate.

The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography to obtain the product (+/-) 4-(4-3-hydroxy-1-propynyl)-phenyl

- 4-Oxo-2-ethyl-2-phenyl-1-butyric acid methyl ester, yield 46%. ¹ HNMR (300MHz, CDCl ₃ ): δ7.92

(d, J=7.8Hz, 2H), 7.51(d, J=8.1Hz, 2H), 7.38~7.25(m, 5H), 4.57

(d, J=5.5Hz, 2H), 3.79(s, 2H), 3.66(s, 3H), 2.37~2.29(m, 2H),

0.69(t, J=7, 5Hz, 3H); EIMS(m/z): 351(M ⁺ +1), 290, 159; HRMS(m/z)

found 350.15214 C ₂₂ H ₂₂ O ₄ required 350.14984. 4. Substrate (+/-) 4-(4-3-hydroxy-1-propynyl)-phenyl-4-oxygen-2-ethyl-2 -Phenyl-1-butyric acid

Dissolve the methyl ester in methanol, then add 20% aqueous sodium hydroxide solution, and stir at room temperature. After the reaction is complete,

Adjust the pH to 1 with 2M hydrochloric acid, and extract three times with chloroform. The organic phases were combined and dried over anhydrous sodium sulfate.

The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography to obtain the product (+/-) 4-(4-3-hydroxy-1-propynyl)-phenyl

-4-Oxo-2-ethyl-2-phenyl-1-butyric acid, yield 83%. ¹ HNMR (300MHz, CDCl ₃ ): δ7.92

(d, J=7.5Hz, 2H), 7.50(d, J=7.6Hz, 2H), 7.42~7.25(m, 5H), 4.52

(s, 2H), 3.80(m, 2H), 2.34~2.25(m, 2H), 0.72(t, J=7.0Hz, 3H);

EIMS (m/z): 337 (M ⁺ +1), 319, 263, 174, 159; HRMS (m/z) found 318.12426

(C ₂₁ H ₂₀ O ₄ -H ₂ O)required 318.12559.

Synthesis of Example 3 (+/-) 4-(4-1-n-decynyl)-phenyl-4-oxidation-3-ethyl-1-butyric acid methyl ester (16) 1. The trichloride Aluminum (20mmol) and bromobenzene (10mmol) were mixed in 50mL dichloromethane, ice bath

After cooling to 0°C, a dichloromethane solution of n-butyryl chloride (10mmol in 10ml) was slowly added dropwise. nature

Warm to room temperature and continue stirring for 24 hours. After the reaction was complete, the reaction mixture was poured into a mixture of 30 g of ice and

50mL of 3M hydrochloric acid in a mixture, stirred for 1 hour. Separate the organic phase, saturated with table salt

Washed with water, dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography to obtain the product 4-bromophenyl-

n-Propyl ketone, yield about 75% ¹ HNMR (300MHz, CDCl ₃ ): δ7.83 (d, J=10.7Hz,

2H), 7.60(d, J=10.6Hz, 2H), 2.91(t, J=7.3Hz, 2H), 1.80~1.67

(m, 2H), 1.00 (t, J=7.4Hz, 3H); EIMS (m/z): 220 (M ⁺ ), 222, 185,

183.2. The compound 4-bromophenyl-n-propyl ketone (3.00 g, 13.6 mmol) was dissolved in 100 mL of tetrahydrofuran.

The solution was cooled to -78°C under the protection of argon, and LDA (1.0 M, 15 mL, 15.0 mmol) was added slowly.

Stirring was continued at this temperature for 1 hour, and a tetrahydrofuran solution of methyl bromoacetate (2.1 g,

14.0mmol in 12mL THF). The reaction mixture was stirred at -78°C for 1 hour, then raised to room temperature

temperature and continued to stir for 8 hours. After the reaction is complete, add 50 mL of saturated ammonium chloride to the reaction mixture

Aqueous solution quenched the reaction. Then add 50mL of saturated NaCl aqueous solution, ethyl acetate (250mL)

Pick. The organic phase was dried over _{anhydrous Na2SO4} . The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain 3.3 g (81.5%)

Alkylation product (+/-) 3-ethyl-4-(4-bromophenyl)-4-oxy-butyric acid methyl ester. ¹ HNMR (300MHz,

CDCl ₃ ): δ7.78(d, J=10.8Hz, 2H), 7.55(d, J=10.6Hz, 2H), 3.72(M,

1H), 3.40(S, 3H), 2.88(DD, J=17.0, 9.5Hz, 1H), 2.44(, dd, J=17.0,

4.7Hz, 1H), 1.71~1.42(m, 2H), 0.81(t, J=7.3Hz, 3H); EIMS(m/z):

298(M ⁺ ), 299.3. Under the protection of argon, n-decyne (20mmol) and compound (+/-) 3-ethyl-4-(4-bromophenyl)-4-

Oxidation-Methyl butyrate was mixed in 50mL DMF and 5mL triethylamine, then dichloroditriphenylphosphine was added

Palladium (20 mg), cuprous iodide (20 mg) and tetrabutylammonium iodide (20 mg). Then, heated to 75°C

Stir for 24 hours. After the reaction was complete, 15 mL of methanol was added to quench the reaction. The solvent was evaporated under reduced pressure, leaving

The residue was dissolved in ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure,

The residue was subjected to column chromatography to obtain the product (+/-) 4-(4-1-n-decynyl)-phenyl-4-oxygen-3-ethyl-1-butane

Acid methyl ester, yield 76.6%. ¹ HNMR (300MHz, CDCl ₃ ): δ7.82 (d, J=10.8Hz, 2H),

7.41(d, 10.6Hz, 2H), 3.73(m, 1H), 3.43(s, 3H), 2.98(dd, J=17.0,

4.7Hz, 1H), 2.61~2.47(m, 3H), 1.78~0.86(m, 17H); EIMS(m/z): 356

(M ⁺ ), 241; _HRMS (m/z) found _{356.23524 C23H32O3} required 356.23514.

Example 4

The compounds of the present invention have been tested by Ye Qizhuang, a researcher at the National Drug Screening Center of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, for their inhibitory activity on matrix proteases. These compounds were tested against MMP-1 (collagenase-1), MMP-3 (matrix hydrolase-1), MMP-9 (gelatinase-B), MMP-12 (macrophage elastase), MMP-13 (Collagenase-3), MMP-15 (membrane type 2-MMPs), MMP-16 (membrane type 3-MMPs), the results are shown in the table below.

Table 1 Inhibitory activity of 4-substituted γ-carbonylbenzenebutyrates on matrix metalloproteinases compound IC50(μM) MMP-1 MMP-3 MMP-9 MMP-12 MMP-13 MMP-15 MMP-16 2345101112131415171819202122 >83.25>83.25>83.25>83.25>83.25>83.25>6.25>83.25>83.25>83.2572.557>83.25>83.25>83.25>83.25>83.25 54.33152.1465.5305.32350.00617.6721.653.8576.0993.753>83.25>83.25>83.25>83.25>83.25>83.25 ＞83.25＞83.2510.99017.884＞83.2515.023＞6.25＞83.2582.27921.6810.762＞83.25＞83.2536.25531.15646.348 40.44033.2113.1886.09626.3325.5370.1674.3404.8123.37187.715＞83.25＞83.25＞83.2515.330＞83.25 >83.25>83.2568.776>83.25>83.25>83.25>6.25>83.2537.659>83.25>83.25>83.25>83.25>83.2531.382>83.25 >83.25>83.2547.150>83.25>83.25>83.25>6.25>83.25>83.25>83.25>83.25>83.25>83.25>83.25>83.25>83.25 >83.25>83.25>83.25>83.25>83.25>83.25>6.25>83.25>83.25>83.25>83.25>83.25>83.25>83.25>83.25>83.25

It can be seen from the table that the synthesized 4-alkynyl substituted γ-carbonylbenzenebutyric acid compounds have good inhibitory activity on matrix metalloproteinases. They can selectively inhibit MMP-3, MMP-9, MMP-12, but have little effect on MMP-1, MMP-13, MMP-15 and MMP-16. The 4-position alkynyl substituent of this type of compound is an essential group with inhibitory effects on MMP-3, MMP-9 and MMP-12. And with the increase in volume and lipophilicity of the 4-alkyne substituent, its inhibitory activity on MMP-3 and MMP-12 is also significantly enhanced, while the lipophilicity is weakened, and its inhibitory activity on MMP-9 is obviously enhanced. The introduction of substituents at the β-position of the ester group can improve their inhibitory activity on MMP-3 and MMP-12, while the introduction of substituents at the α-position of the ester group will cause the reduction or even disappearance of the inhibitory activity. Introducing an alkoxycarbonyl amino group at the alpha position of the ester group can improve the inhibitory activity on MMP-3 and MMP-12.

Claims (8)

1. one kind (4-alkynyl)-aryl ketones acid compounds, it has following structural formula:

Wherein R is H or C _1-10Alkyl; R ¹Be H, C _1-10Alkyl or CH ₂OR ⁵R ²Be H, C _1-6Straight chain or have the alkyl of side chain; R ³Or/and R ⁴Be H, OH, OR ⁵, NHCOOR ⁵R ⁵Be C _1-10Alkyl; Described alkyl is straight chained alkyl, have the alkyl of side chain or aryl, aryl or substituted aryl.

2. a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 1 is characterized in that having following structural formula:

3. the synthetic method of a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 1 is characterized in that synthetic respectively by the following method:

1) in polar organic solvent, the R that chirality replaces ²And/or R ³Succinic Acid lactone, halogeno-benzene and lewis acidic mol ratio are 1: 1-1.5: during 3-7, under the Lewis acid effect, backflow 16-36 hour, the Fu Ke acidylate takes place generate R ²And/or R ³4-(4-halogenophenyl)-4-oxidation-butyric acid that chirality replaces

Perhaps R ²And/or R ³4-(4-halogenophenyl)-4-oxidation-butyric acid that chirality replaces is with the aqueous hydrolysis of sodium hydroxide or potassium, and the mineral acid acidifying gets R ²And/or R ³4-(4-halogenophenyl)-4-oxidation-butyric ester that chirality replaces;

2) in the organic solvent and Louis acid catalysis under, halogeno-benzene and

Room temperature reaction 16-24 hour, the generation molecular formula was Halogenophenyl ketone, wherein halogeno-benzene,

With lewis acidic mol ratio be 1: 1-2: 1-3;

At-78 ℃-room temperature and C _1-8The lithium alkylide effect under, 4-halogenophenyl ketone and alpha-halogen acid esters XCH ₂Alkylated reaction takes place in COOR, reacts 5-20 hour, obtains R ²And/or R ³4-(4-the halogenophenyl)-4-oxidation-butyric acid meso compound that replaces Wherein 4-halogenophenyl ketone, alpha-halogen acid esters and C _1-8The mol ratio of lithium alkylide be followed successively by 1: 1.00-1.5: 1.0-2.0;

R ²And/or R ³4-(4-the halogenophenyl)-4-oxidation-butyric acid that replaces is with the aqueous hydrolysis of sodium hydroxide or potassium, and the mineral acid acidifying gets R ²And/or R ³4-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces;

3) under Lewis acid effect in polar organic solvent, halogeno-benzene and halo acetyl halide

With lewis acidic mol ratio be 1: 1-1.5: during 3-7, the Fu Ke acidylate took place generate halo ethanoyl halogenophenyl ketone in backflow 16-36 hour;

At-78 ℃-room temperature and C _1-8The lithium alkylide effect under, halo ethanoyl halogenophenyl ketone and two substituted acetic acid ester PhCH (C ₂H ₅) alkylated reaction takes place COOR, react to obtain R in 5-20 hour ²And/or R ³4-(4-the halogenophenyl)-4-oxidation-butyric acid that replaces

Wherein, halo ethanoyl halogenophenyl ketone and two substituted acetic acid ester and C _1-8The mol ratio of lithium alkylide be followed successively by 1: 1.00-1.5: 1.0-2.0;

Perhaps by R ²And/or R ³4-(4-halogenophenyl)-4-oxidation-butyric acid that replaces and saturated alcohol roh/hydrochloric acid room temperature reaction 1-10 hour can become corresponding R ²And/or R ³4-(4-the halogenophenyl)-4-oxidation-butyric ester that replaces.

4) 4-of Qu Daiing (4-halogenophenyl)-4-oxidation-butyric acid with saturated alcohol roh/hydrochloric acid room temperature reaction 10-1 hour, becomes 4-(4-halogenophenyl)-4-oxidation-butyric ester

In organic polar solvent, 4-(4-halogenophenyl)-4-oxidation-butyric ester, corresponding alkynes CH ≡ CR ¹, contain the organic compound acid binding agent and the catalyzer of lone-pair electron on the nitrogen, 4 alkynyls are introduced in 50-100 ℃ of reaction 16-36 hour, gamma-carbonyl group benzenebutanoic acid compounds that must the 4-alkynyl substituted Wherein 4-(4-halogenophenyl)-4-oxidation-butyric ester, alkynes CH ≡ CR ¹With the mol ratio of acid binding agent be 1: 1-3: 0.01-0.15, the weight ratio of 4-(4-halogenophenyl)-4-oxidation-butyric ester and catalyzer is 1: 0.001-0.010, described catalyzer is dichloro two triphenyl phosphorus palladiums, cuprous iodide, tetrabutylammonium iodide or their mixture

5) above-mentioned R ²And/or R ³4-(4-halogenophenyl)-4-oxidation-butyric acid that chirality or achirality replace is with the aqueous hydrolysis of sodium hydroxide or potassium, and the mineral acid acidifying gets esterification and gets R ²And/or R ³4-(4-halogenophenyl)-4-oxidation-butyric ester that chirality or achirality replace.

4. the synthetic method of described a kind of (4-the alkynyl)-aryl ketones acid compounds of claim 3 is characterized in that wherein 2) and 3) reaction be under the anhydrous and oxygen-free condition He in the tetrahydrofuran solution, to carry out.

5. the synthetic method of a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 3, the organic compound acid binding agent that it is characterized in that containing on the described nitrogen lone-pair electron is pyridine, Trimethylamine 99, triethylamine, trioctylamine, 4-Dimethylamino pyridine, N, N-diisopropyl ethyl amine or bipyridine.

6. the synthetic method of a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 3 is characterized in that described C _1-8Lithium alkylide be butyllithium, di-isopropyl lithium, octyl group lithium.

7. the purposes of a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 1 is characterized in that the inhibitor of stromatin enzyme.

8. the purposes of a kind of (4-alkynyl)-aryl ketones acid compounds as claimed in claim 7 is characterized in that a kind of treatment cancer,, the medicine of sacroiliitis, body ulcer, pulmonary emphysema or blood vessel scleratheroma disease.