Sulfonamide compounds and application of same to preparation of drugs used for treating metabolic diseases

Abstract

The invention relates to novel high-selectivity FABP4 inhibitors prepared from sulfonamide compounds or pharmaceutically acceptable salts, stereisomers or prodrug molecules thereof. The novel high-selectivity FABP4 inhibitors can be used for treating or preventing related metabolic diseases, mainly including insulin resistance, type 2 diabetes, atherosclerosis, hyperlipidemia, non-alcoholic fattyliver, etc. The sulfonamide compounds or the pharmaceutically acceptable salts, stereisomers or prodrug molecules thereof are as shown in a formula which is described in the specification. In the formula, R0 is optionally selected from a group consisting of C1-C5 straight-chain or branched-chain alkyl groups, C3-C6 cycloalkyl groups and C1-C5 straight-chain and branched-chain alkoxy groups; R1 isoptionally selected from a group consisting of H, C1-C5 straight-chain or branched-chain alkyl groups, C3- C6 cycloalkyl groups and substituted benzyl groups; n is 0, 1 or 2; and A is a substituted and saturated / unsaturated aromatic ring.

Description

technical field

[0001] The invention belongs to the field of medicinal chemistry, and relates to a fatty acid binding protein 4 (FABP4) inhibitor, in particular to a novel high-efficiency and selective FABP4 inhibitor of sulfonamide compounds or pharmaceutically acceptable salts or stereoisomers or prodrug molecules thereof , which can be used to treat or prevent some metabolic related diseases, mainly including insulin resistance, type 2 diabetes, atherosclerosis, hyperlipidemia, non-alcoholic fatty liver, etc. Background technique

[0002] According to reports, with the change of people's diet structure and living habits, the incidence of diabetes has been increasing year by year, and it has become one of the three major chronic non-communicable diseases that threaten human health, of which type 2 diabetes accounts for more than 90%. The etiology of diabetes is complex and individual differences are large, which seriously threatens human health, increases social burden, an...

Examples

Embodiment 1

[0052] 4-Chloro-3-((4-methoxynaphthalene)-1sulfonamide)benzoic acid (GDD-5-1)

[0053] 4-Chloro-3-((4-methoxynaphthalene)-1-sulfonamido)benzoic acid

[0054]

[0055] Step 1: 4-Methoxynaphthalene-1-sulfonyl chloride (GDD-5-4)

[0056] 4-Methoxynaphthalene-1-sulfonyl chloride

[0057]

[0058] 4-Methoxynaphthalene (3 mL) was dissolved in chloroform (30 mL), chlorosulfonic acid (2.75 mL) was slowly added dropwise under ice-cooling and the reaction was continued at 0°C for 2 h. The reaction solution was slowly poured into ice water (50 mL), the chloroform layer was separated first, then the aqueous layer was extracted with ethyl acetate (50 mL×3), the organic phases were combined, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, an off-white solid GDD-5-4 (2.73 g) was obtained, which was directly used in the next reaction without isolation;

[0059] Step 2: 4-Chloro-3-((4-methoxynaphthalene)-1sulfonamide)benzoic acid (GDD-5-1)

[0060...

Embodiment 2

[0065] 4-methyl-3-((4-methoxynaphthalene)-1sulfonamide)benzoic acid (GDD-5-2)

[0066] 4-Methyl-3-((4-methoxynaphthalene)-1-sulfonamido)benzoic acid

[0067]

[0068] The synthetic method is as embodiment 1,

[0069] 189.3mg of white solid was obtained, the yield was 51.01%. 1 H NMR (400MHz, DMSO-d6) δ12.81(s, 1H), 9.91(s, 1H), 8.65(d, J=8.5Hz, 1H), 8.26(d, J=8.2Hz, 1H), 7.94 (d,J=8.4Hz,1H),7.69(t,J=7.4Hz,1H),7.66–7.59(m,2H),7.55(d,J=7.8Hz,1H),7.12(d,J= 7.9Hz, 1H), 6.99(d, J=8.4Hz, 1H), 4.02(s, 3H). 13 C NMR(100MHz,DMSO-d6)δ166.65,158.92,145.78,138.70,135.20,131.40,130.82,129.00,128.66,128.27,126.69,126.64,126.37,125.15,124.62,122.46,102.76,56.24,17.78.ESI-MS :calcd for[M-H] - m / z 370.1, found: 370.1.

Embodiment 3

[0071] 4-Fluoro-3-((4-methoxynaphthalene)-1sulfonamide)benzoic acid (GDD-5-3)

[0072] 4-Fluoro-3-((4-methoxynaphthalene)-1-sulfonamido)benzoic acid

[0073]

[0074] The synthetic method is as embodiment 1,

[0075] 234.6mg of white solid was obtained, the yield was 62.51%. 1 H NMR (400MHz, DMSO-d6) δ13.11(s, 1H), 10.57(s, 1H), 8.65(d, J=8.6Hz, 1H), 8.25(d, J=8.3Hz, 1H), 8.02 (d,J=8.4Hz,1H),7.84(d,J=7.7Hz,1H),7.71(t,J=7.8Hz,1H),7.67–7.59(m,2H),7.20–7.11(m, 1H), 7.02(d, J=8.5Hz, 1H), 4.01(s, 3H). 13 C NMR(151MHz,DMSO-d6)δ165.72,159.05,158.36,156.67,131.42,128.52,128.24,127.84,127.22,126.27,125.77,125.02,124.76,124.30,122.22,116.17,102.58,56.15.ESI-MS:calcd for[M-H] - m / z 374.1, found: 374.1..

technical field

[0001] The invention belongs to the field of medicinal chemistry, and relates to a fatty acid binding protein 4 (FABP4) inhibitor, in particular to a novel high-efficiency and selective FABP4 inhibitor of sulfonamide compounds or pharmaceutically acceptable salts or stereoisomers or prodrug molecules thereof , which can be used to treat or prevent some metabolic related diseases, mainly including insulin resistance, type 2 diabetes, atherosclerosis, hyperlipidemia, non-alcoholic fatty liver, etc. Background technique

[0002] According to reports, with the change of people's diet structure and living habits, the incidence of diabetes has been increasing year by year, and it has become one of the three major chronic non-communicable diseases that threaten human health, of which type 2 diabetes accounts for more than 90%. The etiology of diabetes is complex and individual differences are large, which seriously threatens human health, increases social burden, an...

Examples

Embodiment 1

[0052] 4-Chloro-3-((4-methoxynaphthalene)-1sulfonamide)benzoic acid (GDD-5-1)

[0053] 4-Chloro-3-((4-methoxynaphthalene)-1-sulfonamido)benzoic acid

[0054]

[0055] Step 1: 4-Methoxynaphthalene-1-sulfonyl chloride (GDD-5-4)

[0056] 4-Methoxynaphthalene-1-sulfonyl chloride

[0057]

[0058] 4-Methoxynaphthalene (3 mL) was dissolved in chloroform (30 mL), chlorosulfonic acid (2.75 mL) was slowly added dropwise under ice-cooling and the reaction was continued at 0°C for 2 h. The reaction solution was slowly poured into ice water (50 mL), the chloroform layer was separated first, then the aqueous layer was extracted with ethyl acetate (50 mL×3), the organic phases were combined, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, an off-white solid GDD-5-4 (2.73 g) was obtained, which was directly used in the next reaction without isolation;

[0059] Step 2: 4-Chloro-3-((4-methoxynaphthalene)-1sulfonamide)benzoic acid (GDD-5-1)

[0060...

Embodiment 2

[0065] 4-methyl-3-((4-methoxynaphthalene)-1sulfonamide)benzoic acid (GDD-5-2)

[0066] 4-Methyl-3-((4-methoxynaphthalene)-1-sulfonamido)benzoic acid

[0067]

[0068] The synthetic method is as embodiment 1,

[0069] 189.3mg of white solid was obtained, the yield was 51.01%. 1 H NMR (400MHz, DMSO-d6) δ12.81(s, 1H), 9.91(s, 1H), 8.65(d, J=8.5Hz, 1H), 8.26(d, J=8.2Hz, 1H), 7.94 (d,J=8.4Hz,1H),7.69(t,J=7.4Hz,1H),7.66–7.59(m,2H),7.55(d,J=7.8Hz,1H),7.12(d,J= 7.9Hz, 1H), 6.99(d, J=8.4Hz, 1H), 4.02(s, 3H). 13 C NMR(100MHz,DMSO-d6)δ166.65,158.92,145.78,138.70,135.20,131.40,130.82,129.00,128.66,128.27,126.69,126.64,126.37,125.15,124.62,122.46,102.76,56.24,17.78.ESI-MS :calcd for[M-H] - m / z 370.1, found: 370.1.

Embodiment 3

[0071] 4-Fluoro-3-((4-methoxynaphthalene)-1sulfonamide)benzoic acid (GDD-5-3)

[0072] 4-Fluoro-3-((4-methoxynaphthalene)-1-sulfonamido)benzoic acid

[0073]

[0074] The synthetic method is as embodiment 1,

[0075] 234.6mg of white solid was obtained, the yield was 62.51%. 1 H NMR (400MHz, DMSO-d6) δ13.11(s, 1H), 10.57(s, 1H), 8.65(d, J=8.6Hz, 1H), 8.25(d, J=8.3Hz, 1H), 8.02 (d,J=8.4Hz,1H),7.84(d,J=7.7Hz,1H),7.71(t,J=7.8Hz,1H),7.67–7.59(m,2H),7.20–7.11(m, 1H), 7.02(d, J=8.5Hz, 1H), 4.01(s, 3H). 13 C NMR(151MHz,DMSO-d6)δ165.72,159.05,158.36,156.67,131.42,128.52,128.24,127.84,127.22,126.27,125.77,125.02,124.76,124.30,122.22,116.17,102.58,56.15.ESI-MS:calcd for[M-H] - m / z 374.1, found: 374.1..

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