CN111269167A - N-acyl sulfonamide salt FBPase inhibitor, preparation method, pharmaceutical composition and application thereof - Google Patents

Abstract

The invention relates to an N-acyl sulfamide salt compound shown in a formula I as an FBPase inhibitor, a preparation method thereof, a composition containing one or more compounds, and application of the compound as a medicament for treating diseases related to FBPase and preparing, preventing and/or treating diabetes.

Description

N-acyl sulfonamide salt FBPase inhibitor, preparation method, pharmaceutical composition and application thereof

Technical Field

The invention relates to an N-acyl sulfonamide salt FBPase inhibitor shown in a formula I, a preparation method thereof, a composition containing one or more compounds, and application of the compounds in inhibiting FBPase and treating FBPase-related diseases and preparing, preventing and/or treating diabetes drugs.

Background

Diabetes mellitus is a polygenic regulated chronic metabolic disease, mainly manifested by persistent hyperglycemia and diabetes mellitus. Persistent hyperglycemia can lead to many complications, such as retinal, renal, neurological and vascular complications. The incidence of Chinese diabetes is rapidly increasing, and more than 9200 million Chinese diabetes patients are predicted, and about 1.48 million people are high-risk people with diabetes (New. Engl. J. Med.,2010,362: 1090-one 1101).

Diabetes mellitus is divided into two types, insulin-dependent (type I) and non-insulin-dependent (type II), wherein the type II diabetes mellitus patients account for 90-95% of the total number of diabetes mellitus patients. Biological studies have shown that the major pathological bases responsible for diabetes are insufficient insulin secretion, insulin resistance and increased hepatic glucose production. The currently clinically applied drugs are mainly of two types: one is to overcome insulin hyposecretion, such as: sulfonylureas and meglitinide insulinotropic agents; secondly, improving insulin resistance, such as: thiazolidinediones insulin sensitizers. To date, no antidiabetic agent that reduces endogenous glucose production has been clinically used. Metformin reduces hepatic glucose output, but the molecular targets of action are not yet clear.

It has been shown that increased endogenous glucose production is the primary cause of elevated fasting glucose levels in diabetic patients. Endogenous glucose is mainly derived from the liver. There are two pathways for glucose production by the liver, one is endogenous synthesis of glucose, gluconeogenesis (gluconeogenesis); the other is hepatic glycogenolysis (glycogenolysis). Therefore, the regulation of gluconeogenesis pathway and the reduction of endogenous glucose generation are potential new strategies for developing new mechanism-of-action antidiabetic drugs.

Gluconeogenesis is the process of converting lactic acid, glycine, glycerol and other three-carbon precursors into glucose under the catalytic action of various enzymes. In gluconeogenesis, Fructose-1,6-bisphosphatase (FBPase) catalyzes the conversion of Fructose-1, 6-diphosphate to Fructose-6-phosphate, releasing a molecule of phosphoric acid. The catalytic reaction is one of the speed control steps of endogenous glucose generation, inhibits the activity of FBPase, can reduce the generation of endogenous glucose, and reduces the blood sugar level. Therefore, the FBPase inhibitor is likely to become an antidiabetic with a new action mechanism, and has more significant meaning particularly in reducing fasting blood glucose level.

To date, many researchers have conducted studies on FBPase inhibitors, and various structural types of FBPase inhibitors have been reported. In 2003, Pfizer pharmaceutical company obtained indole carboxylic acid compounds through high-throughput screening, and FBPase inhibitory activity IC₅₀Values were at micromolar (bioorg. med. chem. lett.,2003,13: 2055-. In 2006, von Geldern et al reported that benzoxazole-2-benzenesulfonamide compounds have an inhibitory activity IC on FBPase₅₀Value of 10^-6-10^-7Molar levels (bioorg.med.chem.lett.,2006,16: 1811-. In 2010, Roche pharmaceutical company reported thiazole-substituted sulfonylurea FBPase inhibitors discovered by high-throughput screening, which inhibit the activity IC₅₀Value of 10^-7-10^-8Molar levels (bioorg.med.chem.lett.,2010,20: 594-. In 2007-2010, the pharmaceutical company of Metasis reported that AMP analogs were discovered by adopting a structure-based drug molecule design strategy, FBPase inhibitors were searched, and through continuous structure optimization, they obtained benzimidazole FBPase inhibitors (J.Am.chem.Soc.,2007,129: 15480-1)5490; med, chem.,2010,53:441-451) and thiazole FBPase inhibitors (j, am, chem, soc.,2007,129: 15491-15502; med. chem.,2011,54:153-].2007-09-27.)。

The invention designs and synthesizes the N-acyl sulfamide salt compound as the FBPase inhibitor, and lays a structural foundation for obtaining the FBPase inhibitor which has good pharmacokinetic property and can be orally taken. The sulfonamide salt compounds of the present application have higher solubility, in vivo exposure and oral bioavailability than the prototype compound. The invention aims to find a novel antidiabetic medicament which has strong antidiabetic activity, good pharmacokinetic property and oral administration effectiveness.

Disclosure of Invention

The invention aims to provide an N-acyl sulfamide salt derivative shown in a formula I, a preparation method thereof, a pharmaceutical composition, and application thereof in preparing FBPase inhibitors and potential pharmaceutical applications thereof and antidiabetic drugs.

In order to solve the technical problem, the invention provides the following technical scheme:

the first aspect of the technical scheme of the invention provides an N-acyl sulfamide salt derivative shown as a general formula I:

in the formula I, the compound is shown in the specification,

r is selected from the group consisting of the following atoms or groups, including

H、F、Cl、Br、CN、CF₃、OCH₃、NO₂；

Ar₁Selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

Ar₂Selected from the group consisting of:

(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

(2) substituted or unsubstituted aromatic condensed ring or condensed heterocyclic ring, substituted or unsubstituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocyclic ring, substituted or unsubstituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).

R is preferably selected from Cl and NO₂。

Preferred compounds of the present invention according to formula I of the present invention include, but are not limited to, compounds represented by formula (I-A):

Ar₁selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

Ar₂Selected from the group consisting of:

(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, whereinThe substituent is selected from C1-4 straight chain or branched chain alkyl, halogen substituted C1-4 straight chain or branched chain alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

(2) substituted or unsubstituted aromatic condensed ring or condensed heterocyclic ring, substituted or unsubstituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocyclic ring, substituted or unsubstituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).

Preferred compounds of the present invention according to formula I-A of the present invention include, but are not limited to, compounds represented by formula (I-A-a):

R_Acan be mono-substituted or poly-substituted;

R_Amay be independently selected from the following groups or structural fragments:

c1-4 straight chain or branched alkyl, halogen substituted C1-4 straight chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

Ar₂selected from the group consisting of:

(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

(2) substituted or unsubstituted aromatic condensed ring or condensed heterocyclic ring, substituted or unsubstituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocyclic ring, substituted or unsubstituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).

Preferred compounds of the present invention according to formula I-A of the present invention include, but are not limited to, compounds represented by formula (I-A-b):

R_Bcan be mono-substituted or poly-substituted;

R_Bmay be independently selected from the following groups or structural fragments:

c1-4 straight chain or branched alkyl, halogen substituted C1-4 straight chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

Ar₁selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

M is independently selected from different alkali metals (lithium, sodium, potassium, cesium) or alkaline earth metal salts (calcium, magnesium, barium).

For the purposes of the present invention, preferred compounds include, but are not limited to:

in a second aspect of the present invention, there is provided a process for the preparation of a compound of the first aspect, which comprises the steps of:

in an ethanol solution of sodium alkoxide, condensing 5-R-substituted o-bromobenzaldehyde and ethyl azidoacetate to obtain a compound 1, using o-dichlorobenzene as a solvent in the compound 1, performing ring closure at 180 ℃ to obtain 7-R-substituted 4-bromo-1-H-indole-2-carboxylic acid ethyl ester (a compound 2), and then performing methylation at an indole-1-position under the condition of cesium carbonate to obtain 7-R-substituted 4-bromo-1-methyl-indole-2-carboxylic acid ethyl ester (a compound 3); then the compound 3 and aryl bromide are subjected to coupling reaction under the catalysis of palladium to obtain a compound 4, and a corresponding compound 5 with 2-position as carboxyl is obtained after hydrolysis reaction. The compound 5 and aryl methanesulfonamide are subjected to condensation reaction to obtain a compound 6, and finally, the compound 6 and different bases are subjected to acid-base reaction to obtain an N-acyl sulfamide salt compound.

The reagent and the reaction condition are (a) ethyl azidoacetate, ethyl trifluoroacetate, sodium and ethanol, and the temperature is between 15 ℃ below zero and 0 ℃; (b) o-dichlorobenzene, 180 ℃; (c) methyl iodide, cesium carbonate, DMF, r.t.; (c) ar (Ar)₁-Br，Pd₂(dba)₃Xanthphos, sodium carbonate, toluene, water, 100 ℃; (d) sodium hydroxide, THF, ethanol, water, r.t.; (e) ar (Ar)₂-S(O)₂-OH，HATU，DMAP，Et₃N, r.t.; (g) alkali of alkali metal or alkaline earth metal, water, 80 ℃;

wherein said R, Ar₁、Ar₂And M is as defined for the compounds according to the first aspect of the invention.

In a third aspect of the present invention, there is provided a pharmaceutical composition comprising the compound according to the first aspect of the present invention and a pharmaceutically acceptable carrier.

The invention also provides a pharmaceutical composition which takes the compound as an active ingredient and comprises at least one compound in the invention and a pharmaceutically acceptable carrier. The medicine composition is selected from tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations or various particle delivery systems. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.

The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal, and the like.

The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.

The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.

These formulations are prepared according to methods well known to those skilled in the art. Adjuvants used for the manufacture of tablets, capsules, coatings are the customary auxiliaries, such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms, such as water, ethanol, propylene glycol, vegetable oils, such as corn oil, peanut oil, olive oil, etc. The formulations containing the compounds of the present invention may also contain other adjuvants such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, coloring agents, and the like.

For tableting the compounds of the invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.

The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.

To encapsulate the administration units, the active ingredient of the compounds of the invention can be mixed with diluents and glidants and the mixture can be placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.

In order to prepare the compound of the invention into injection, water, ethanol, isopropanol, propylene glycol or the mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field are added, wherein the solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl- β -cyclodextrin and the like, the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide and the like, the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate and the like, and the mannitol, glucose and the like can be added as a propping agent when preparing freeze-dried powder injection.

In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.

For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable dosage range per day for a compound of the invention is from 0.01 to 500mg/Kg body weight, preferably from 0.1 to 300mg/Kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.

The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.

The fourth aspect of the technical scheme of the invention provides application of the compound of the first aspect of the invention in preparing FBPase inhibitors and medicaments for preventing and/or treating diseases and symptoms related to FBPase. The use, characterized in that diseases and conditions associated with FBPase are selected from diabetes, chronic complications of diabetes and obesity. The diabetes is selected from type I diabetes and type II diabetes; the chronic complications of diabetes are selected from retinal, renal, nervous system and vascular complications, ischemic heart disease or atherosclerosis.

Detailed Description

The present invention will be further illustrated with reference to the following examples, but the scope of the present invention is not limited thereto.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or High Resolution Mass Spectrometry (HRMS). NMR was measured using a Varian marcry 300 or Varian marcry 400 solvent in CDCl₃、DMSO-d₆、acetone-d₆、CD₃OD, internal standard TMS, chemical shifts are given in ppm. Ms were determined using a Thermo active Plus type mass spectrometer. m.p. is the melting point given in ° c, the temperature is uncorrected. Silica gel column chromatography generally uses 200-300 mesh silica gel as a carrier.

The reagents used in the experiments were either chemically pure or analytically pure. The solvents used were all analytical grade, the anhydrous solvent used was obtained from the solvent purification system produced by Innovative TECHNOLOGY, USA, and the other solvents were not treated unless otherwise specified.

List of abbreviations:

TLC: thin layer chromatography DMAP: 4-dimethylaminopyridine

CDCl₃: deuterated chloroform DMSO-d₆: deuterated dimethyl sulfoxide

acetone-d₆: deuterated acetone CD₃OD: deuterated methanol

DMAP: 4-dimethylaminopyridine Et₃N: triethylamine

EA: ethyl acetate

HATU: 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate

XantPhos: 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene

Pd₃(dba)₂: tris (dibenzylideneacetone) dipalladium

min: the method comprises the following steps of (1) taking minutes; h: hour(s)

P/E: petroleum ether/ethyl acetate; D/M: methylene chloride/methanol

Preparation of intermediate 1-methyl-7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

a) Ethyl 2-azido-3- (5-chloro-2-bromophenyl) acrylate

Metallic sodium (8.35g,363.2mmol) was dissolved in absolute ethanol (200mL) and after the metallic sodium was completely dissolved, the reaction was cooled to-15 ℃. Adding 2-bromo-5-chlorobenzaldehyde (50g,227mmol), ethyl azidoacetate (44g,341mmol) and ethyl trifluoroacetate (TFAE,51.5g,363.2mmol) into the reaction solution in batches, reacting at-15 ℃ for 1h, heating to-5 ℃ for 1h, heating to 0 ℃ for 5h, heating to room temperature for overnight reaction, pouring the reaction solution into saturated NH₄To an aqueous Cl solution, EA (150mL × 3) was used for extraction, and the organic layers were combined, washed with a saturated sodium chloride solution (100mL × 2), dried over anhydrous magnesium sulfate, concentrated, passed through a reduced pressure column (DCM: PE: 1), concentrated, and recrystallized from PE: EA: 20:1 to obtain 36.5g of an off-white solid with a yield of 48.9%.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.13(s,1H),7.53(d,J＝8.4Hz,1H),7.15(s,2H),4.40(q,J＝7.2Hz,2H),1.42(t,J＝7.2Hz,3H).

b) 7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

Placing 2-azido-3- (5-chloro-2-bromophenyl) ethyl acrylate (15g) into a reaction bottle, adding into o-dichlorobenzene (15mL), heating to 180 ℃ for reaction, stopping the reaction after 1h, cooling, separating out a solid, and performing suction filtration to obtain 7.2g of a white solid with the yield of 52.7%.

¹H NMR(400MHz,CDCl₃)δ(ppm):9.11(brs,1H),7.27(d,J＝8.4Hz,2H),7.18(d,J＝8.0Hz,1H),4.44(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H).

c) 1-methyl-7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

Placing 7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester (26.2g,86.24mmol) in a reaction flask, adding DMF (300mL), adding cesium carbonate (55.9g,172.58mmol) and methyl iodide (24.7g,132.58mmol), stirring at room temperature for reaction, stopping reaction after 1H, pouring the reaction liquid into ice water, separating out a solid, and performing suction filtration to obtain an off-white solid of 26g with the yield of 94.8%.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.32(s,1H),7.19(d,J＝8.0Hz,1H),7.13(d,J＝8.0Hz,1H),4.46(s,3H),4.39(q,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H).

Example 11-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide sodium salt

a) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid ethyl ester

Dissolving 1-methyl-7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester (942mg,3mmol) in toluene (20mL), adding Pd under the protection of argon₂(dba)₃(686mg,0.75mmol), Xantphos (874mg,0.5mmol), then adding Na₂CO₃(954mg,9mmol) was dissolved in 5mL of water, the reaction mixture was added to a flask, and m-anisidine (1mL,9mmol) was added to the flask, followed by reflux reaction for 30 hours. Filtration was carried out, and ethyl acetate was added to the filtrate, followed by washing with dilute hydrochloric acid, washing with a saturated sodium bicarbonate solution, drying over anhydrous magnesium sulfate, and column chromatography (E: P ═ 1:30) was carried out to give 610mg of a pale yellow solid in a yield of 56.8%.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.30(s,1H),7.20(t,J＝8.4Hz,1H),7.15(d,J＝8.4Hz,1H),6.88(d,J＝7.2Hz,1H),6.69(m,2H),6.53(d,J＝6.8Hz,1H),4.47(s,3H),4.37(q,J＝7.2Hz,2H),3.79(s,3H),1.40(t,J＝7.2Hz,3H).

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid

Dissolving 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid ethyl ester (6.6g,18.4mmol) in a mixed solution of THF (30mL) and EtOH (30mL), dissolving NaOH (2.21g,55.3mmol) in 10mL of water, adding the solution to the reaction solution, reacting at 40 ℃ for 2H, concentrating, adding a small amount of water, extracting with diethyl ether, adjusting the pH of the water layer to 2-3 with dilute hydrochloric acid, separating out solids, filtering, washing the filter cake with water to obtain a yellow-green solid 6.0g, and obtaining the yield of 98.6%.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):13.00(s,1H),8.34(s,1H),7.61(s,1H),7.17(t,J＝8.0Hz,2H),6.84(d,J＝8.4Hz,1H),6.79(d,J＝8.0Hz,1H),6.75(s,1H),6.49(d,J＝8.0Hz,1H),4.35(s,3H),3.72(s,3H).

c) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide (compound P)

1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (13.56g,41.09mmol) was dissolved in DCM (200mL) and HATU (23.42g,61.6mmol), DMAP (2.51g,20.54mmol) and Et were added sequentially₃N (17.8mL,123.27mmol), stirring well, adding benzenesulfonamide (11.54g,61.6mmol), heating to 40 ℃ for reaction for 1h, concentrating, adding ethyl acetate, washing with dilute hydrochloric acid, washing with water, washing with saturated sodium chloride solution, drying over anhydrous magnesium sulfate, and recrystallizing with ethyl acetate to obtain yellow powdery solid 10.3g, yield 50%.

¹H NMR(500MHz,DMSO-d₆)δ(ppm):8.31(s,1H),7.99(d,J＝7.5Hz,2H),7.24(d,J＝8.5Hz,1H),7.22(d,J＝7.5Hz,1H),7.18(d,J＝7.5Hz,2H),7.06(d,J＝7.5Hz,1H),6.90(d,J＝7.5Hz,1H),6.87(s,1H),6.56(d,J＝7.0Hz,1H),4.24(s,3H),3.86(s,3H),3.75(s,3H)；HRMS(ESI):m/z,calcd.for C₂₃H₂₂N₄O₅ClS[M+H]⁺:501.0999,found 501.0985.

d) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide sodium salt (example 1)

1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide (998mg,2mmol) was added to a solution of H₂O (4mL), NaOH (100mg,2.5mmol) is dissolved in 1mL of water and added into the reaction solution, after the addition is finished, the temperature is raised to 80 ℃ for reaction for 4h, the reaction is stopped, the reaction solution is cooled to room temperature, the reaction solution is filtered, and a filter cake is washed by water to obtain 868mg of a khaki solid with the yield of 83%.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):8.20(s,1H),7.78-7.77(d,J＝8.4Hz,2H),7.76(s,1H),7.14-7.10(m,1H),7.00-6.98(d,J＝8.4Hz,1H),6.93-6.91(m,2H),6.79-6.41(m,3H),6.40-6.39(d,J＝2.0Hz,1H),4.29(s,3H),3.78(s,3H),3.71(s,3H).

Example 21 methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide potassium salt

1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide (220mg,0.441mmol) was added to a solution of H₂O (1.5mL), KOH (25.2mg, 0.4496mmol) was dissolved in a small amount of water and added to a reaction flask, and the temperature was raised to 80 ℃ for 1h, and the system became light yellow and clear. The reaction was stopped, water was removed by centrifugation to give a tan solid, which was recrystallized from ethanol to give 195mg of tan solid with a yield of 82.3%.

¹H NMR(400MHz,DMSO-d₆)δ8.21(s,1H),7.78-7.76(d,J＝8.8Hz,2H),7.24(s,1H),7.14-7.10(m,1H),6.99-6.97(d,J＝8.0Hz,1H),6.93-6.91(m,2H),6.79-6.41(m,3H),6.40-6.39(d,J＝2.0Hz,1H),4.29(s,3H),3.78(s,3H),3.71(s,3H).

Example 31-methyl-4- ((3-methoxy-4-fluorophenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide sodium salt

a) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid ethyl ester

Dissolving 1-methyl-7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester (316mg,1mmol) in toluene (10mL), adding Pd under the protection of argon₂(dba)₃(229mg,0.25mmol), Xantphos (291mg,0.5mmol), then adding Na₂CO₃(318mg,3mmol) was dissolved in 2.5mL of water, the reaction mixture was added, and m-anisidine (0.33mL,3mmol) was added to the reaction flask, followed by reflux reaction for 30 hours. Filtration and addition of ethyl acetate to the filtrate, washing with dilute HCl, saturated sodium bicarbonate solution, drying over anhydrous magnesium sulfate and crystallization of EA/ether gave 272mg, 72.1% as a pale yellow solid.

b) 1-methyl-4- ((3-methoxy-4-fluorophenyl) amino) -7-chloro-1H-indole-2-carboxylic acid

Ethyl 1-methyl-4- ((3-methoxy-4-fluorophenyl) amino) -7-chloro-1H-indole-2-carboxylate (200mg, 0.53mmol) was dissolved in THF/EtOH (1/2, v/v,9mL) and NaOH solution (105mg, 2.65mmol, 3mL H) was added₂O), reacting at room temperature overnight, stopping the reaction, evaporating the solvent, adding a small amount of water, adjusting the pH to 2 by 1M hydrochloric acid, separating out a solid, filtering and drying to obtain a light yellow-green solid 177mg, wherein the yield is 96%.

¹H NMR(400MHz,DMSO-d₆)δ13.01(s,1H),8.31(s,1H),7.61(s,1H),7.15-7.08(m,2H),6.98-6.95(dd,J＝8.0,4.0Hz,1H),6.77-6.72(m,2H),4.46(s,3H),3.84(s,3H)；

c) 1-methyl-4- ((3-methoxy-4-fluorophenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Dissolving 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (350mg,1mmol) in dry DCM, adding HATU (685mg, 1.8mmol), DMAP (65mg, 0.5mmol) and TEA (303mg,3mmol) in sequence, stirring uniformly, adding benzenesulfonamide (560mg, 3mmol), reacting at 40 ℃ for 1.0H, stopping the reaction, evaporating off the solvent, washing with dilute hydrochloric acid, water and brine in sequence, combining EA layers, recrystallizing EA to obtain 395mg of yellowish solid with a yield of 77%,

¹H NMR(400MHz,DMSO-d₆)δ12.50(s,1H),8.34(s,1H),7.95(d,J＝8.9Hz,2H),7.67(s,1H),7.22-7.08(m,4H),6.94(dd,J＝7.7,2.4Hz,1H),6.78(d,J＝8.3Hz,1H),6.75-6.67(m,1H),4.11(s,3H),3.86(s,3H),3.80(s,3H)；

d) 1-methyl-4- ((3-methoxy-4-fluorophenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide sodium salt

Adding water (5mL) and NaOH (86mg, 2.1314mmol) into 1-methyl-4- ((3-methoxy-4-fluorophenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-formamide (1.0805g, 2.0896mmol), heating to 80 ℃, reacting for 1H, changing the system to be light yellow and clear, stopping the reaction, removing water by rotation to obtain a brown yellow solid, and recrystallizing with ethanol to obtain 919mg of the brown yellow solid with the yield of 81.6%.

¹H NMR(400MHz,DMSO-d₆)δ8.17(s,1H),7.77(d,J＝8.6Hz,2H),7.69(d,J＝8.4Hz,0H),7.26(s,1H),7.10–7.02(m,1H),6.95(dd,J＝18.4,8.3Hz,4H),6.72(d,J＝8.2Hz,2H),4.29(s,3H),3.78(d,J＝2.3Hz,6H).

Pharmacological experiments:

EXAMPLE 1 antidiabetic Effect of example 1 and prototype Compound P on type 2 diabetic ZDF rats

Experimental animals and groups

1. Spontaneous type 2 diabetes mellitus ZDF rat

Idiopathic type 2 diabetes ZDF rats, male, 8 weeks old, certification number: no.11400700293700, purchased from Beijing Wittingle laboratory animals technology Limited, license number SYXK (Jing) 2014-. Quality rat feed 5008 (called purina) was given for approximately 7 weeks for pharmacodynamic evaluation studies after model formation of type 2 diabetes.

2. Normal ZDF control rats

Normal ZDF control rats, male, 8 weeks old, certification number: no.11400700293705, purchased from Beijing Wittingle laboratory animal technology, Inc., license number SYXK (Jing) 2014-. After approximately 7 weeks of normal maintenance feed feeding, the experiment was performed as a normal control group of ZDF, 4/cage, with free food.

3. Grouping animals

ZDF rats were given high fat feeding for about 7 weeks, and multiple index predictions were performed and grouped. The main observation indicators are: random blood glucose, fasting blood glucose, Insulin Tolerance Test (ITT) test percent decrease in blood glucose for 40min, blood Triglycerides (TG) and Total Cholesterol (TC) and body weight.

4. Experimental protocol

The animals were administered by gavage with a corresponding volume of 0.5% CMC-Na solution for 35 consecutive days 1 time per day as a control group.

1) Measuring random blood glucose on day 23 of dosing, and fasting blood glucose on day 20 of dosing;

2) at 20 days of dosing, ZDF rats underwent a sodium pyruvate tolerance test;

3) measurement of ZDF rat glycated hemoglobin (HbA1c) level on day 34 of dosing, subject drug dose setting and formulation

1. Dose setting and dispensing

1) Compound P (150mg/kg)

4.5g of compound P was weighed, placed in a mortar, ground, suspended in 0.5% CMC-Na distilled water, and made to a volume of 150 ml. The stomach was drenched at 0.5ml/100g body weight, i.e. the dose was 150 mg/kg.

2) Example 1(150mg/kg)

4.5g of example 1 was weighed, placed in a mortar, ground, suspended in 0.5% CMC-Na distilled water and made to a volume of 150 ml. The stomach was drenched at 0.5ml/100g body weight, i.e. the dose was 150 mg/kg.

3) Metformin (150mg/kg)

Weighing 4.5g of metformin, placing the compound in a mortar, grinding, dissolving with distilled water, and fixing the volume to 150 ml. The stomach was drenched at 0.5ml/100g body weight, i.e. the dose was 150 mg/kg.

Three, main instrument and reagent

1. Main instrument

mu-Quant microplate reader (MQX200, BIO-TEK, USA), air oscillator (HZQ-C, Harbin Toming medical instruments factory), low-temperature high-speed centrifuge (3-18K, SIGMA, Germany), water bath (DK-8D, Shanghai-constant technology Co., Ltd.), multifunctional microplate reader (Synergy2, BIO-TEK, Inc.), analytical balance (Sartorius, BSA224S-CW), digital display electronic scale (MODUS), 1ml syringe (BD, batch 302101), 5ml syringe (Shanghai medical laser instruments factory, Guaihai) and injection needle (prismatic plate, 0.5 × 20).

2. Primary reagent

Glucose (national drug group chemical reagent limited, 20141016), GOD enzyme (sigma) for blood glucose determination, glycated hemoglobin determination kit (Beijing Haomai bioengineering, Inc., A5911), sodium pyruvate (Beijing Bailingwei science, Inc., 297561) insulin (Lilisozhou pharmaceutical Co., Ltd., H0219).

Fourth, experiment method

1. Fasting and random blood glucose determination

Animals were bled from the tip under non-fasting conditions and random blood glucose was determined by the glucose oxidase method (same below). After the animals are fasted overnight, the tail tips are bled and fasting blood glucose is determined.

Measurement of HbA1c level

10 mul of blood is taken from the tail tip of the animal, added into 150 mul of hemolytic agent and mixed evenly. Then, absorbance was measured at a wavelength of 700/800nm according to the protocol of the kit for HbA1c, and the HbA1c level of glycated hemoglobin was calculated.

3. Sodium Pyruvate Tolerance Test (PTT, Pyruvate Sodium Tolerance Test)

On the day of the experiment, animals were fasted overnight and blood was taken from the tip of the tail 2h after gavage (fasted 17h), and then sodium pyruvate solution was gavage and blood was taken from the tip of the tail 30min and 60min after sodium pyruvate was given, and the blood glucose levels before and after pyruvic acid administration were measured.

Fifth, experimental results

1. Effect on ZDF rat random blood glucose and fasting blood glucose levels

The results are shown in table 1, compound P, at a dose of 150mg/kg, given for a long period of time, was able to lower the random blood glucose (P <0.05) in the ZDF rats by a percentage of 16.9%, with an effect superior to that of the positive drug metformin. Example 1 at a dose of 150mg/kg, it was able to reduce random blood glucose (P <0.01) and fasting blood glucose (P <0.001), with a percent reduction in random blood glucose of 27.0% and a percent reduction in fasting blood glucose of 62.2%. The effect is better than that of the positive drug metformin.

TABLE 1 Effect of Long-term administration of Compounds on random blood glucose and fasting plasma glucose in ZDF rats

Blood glucose data are expressed as mean ± sd, n ═ 10, vs Con,. P <0.05,. P <0.01,. P <0.001.

2. Effect on ZDF rat glycated hemoglobin (HbA1c)

Glycated hemoglobin (HbA1c) levels were measured on day 34 of dosing. As shown in Table 2, the blood HbA1c level of the model group (Con) rats was significantly increased (P <0.001) compared to the normal control group (Nor). The average value of HbA1c was significantly reduced in ZDF rats 34 days after administration of example 1 compared to the Con group.

TABLE 2 Effect of Long-term administration of the Compounds on ZDF rat glycated hemoglobin (HbA1c)

HbA1c (%) is represented as mean ± sd, n ═ 10.vs Con × P <0.05, × P <0.01, × P <0.001.

3. Effect on gluconeogenesis in ZDF rats

As shown in table 3, the results of the experiment performed 20 days after the administration of sodium pyruvate showed that example 1 had a stronger gluconeogenesis inhibitory ability with respect to the curve area under the blood glucose time than that of the Con group.

TABLE 3 Effect on gluconeogenesis in ZDF rats

Both blood glucose and AUC data were mean ± sd, n ═ 10, vs Con · P <0.05,. P <0.01,. P <0.001.

Experimental example 2 anti-diabetic Effect of example 1 and example 3 on type 2 diabetic KKAY mice

Experimental animals and groups

1. Spontaneous type 2 diabetes KKAy mice

Spontaneous type 2 diabetes KKAy mice, female, week-old 11-12w, certification No.: no.11401300055400, purchased from Beijing Huafukang Biotechnology GmbH, license number SCXK (Jing) 2014-. High fat diet was given for approximately 10 weeks and the type 2 diabetes model was developed for pharmacodynamic evaluation studies.

C57BL/6J mice

Normal C57BL/6J mice, female, 6-8 weeks old, certification number: no.11400700221894, purchased from Beijing Wittingle laboratory animals technology, Inc., license number SCXK (Jing) 2016-. After approximately 14 weeks of normal maintenance feed feeding, the mice were used as a control group of normal mice for the experiment, 5 mice/cage, with free food.

3. Grouping animals

KKAy mice were given high fat chow for about 10 weeks, multi-index prognosticated and grouped. The main observation indicators are: random blood glucose, fasting blood glucose, Insulin Tolerance Test (ITT) test percent decrease in blood glucose for 40min, blood Triglycerides (TG), total blood cholesterol (TC), and body weight.

Second, setting and preparing the dosage of the tested medicine

Dose setting and dispensing

1) Example 1

Set up 3 dose groups, weigh the compounds of examples 1150 mg, 300mg and 600mg respectively, put in a mortar, grind, suspend with 0.5% CMC-Na distilled water and make up to 30 ml. The administered volume was 0.1ml/10g, i.e., the dose was 50mg/kg, 100mg/kg and 200 mg/kg.

2) Example 3(100mg/kg)

300mg was weighed, the compound was put in a mortar, ground, suspended with 0.5% CMC-Na distilled water, and made to a volume of 30 ml. The administration volume was 0.1ml/10g, i.e. the dose was 100 mg/kg.

3) Metformin hydrochloride (150mg/kg)

450mg was weighed into distilled water to dissolve and to volume of 30 ml. The administration volume was 0.1ml/10g, i.e. the dose was 150 mg/kg.

Three, main instrument and reagent

1. Main instrument

mu-Quant microplate reader (MQX200, BIO-TEK, USA), air oscillator (HZQ-C, Harbin Toming medical instruments factory), low-temperature high-speed centrifuge (3-18K, SIGMA, Germany), water bath (DK-8D, Shanghai-constant technology, Inc.), multifunctional microplate reader (Synergy2, BIO-TEK, Inc.), analytical balance (Sartorius, BSA224S-CW), digital display electronic scale (MODUS), 1ml syringe (BD, batch 302101), 0.25ml syringe (Shanghai medical laser instruments factory, B05-19-U), syringe needle (prismatic, 0.5X 20).

2. Primary reagent

Glucose (national drug group chemical reagent limited, 20141016), GOD enzyme (sigma) for blood glucose measurement, glycated hemoglobin measurement kit (Beijing Haomai bioengineering, Inc., A5911), sodium pyruvate (Beijing Bailingwei science and technology, Inc., 297561), insulin (Lilisozhou pharmaceutical Co., Ltd., H0219).

Fourth, experiment method

Fasting and random blood glucose determination

Animals were bled from the tip under non-fasting conditions and random blood glucose was determined by the glucose oxidase method (same below). After the animals are fasted for 4 hours, the tail tips take blood and the fasting blood sugar is measured.

Fifth, experimental results

Effect on random and fasting blood glucose levels in KKAy mice

The mice were tested for random and fasting blood glucose levels on day 20 of dosing. As shown in table 4, example 1 had a lowering effect on the blood glucose levels in KKAy mice at 50, 100 and 200mg/kg doses compared to the model control group (Con), with random blood glucose drops of 13%, 21% (P <0.05), 49% (P <0.01), respectively; the reduction range of the fasting blood glucose is-3.7 percent, 10.4 percent and 35.4 percent respectively (P is less than 0.001). Example 3 random blood glucose was reduced by 18.4% in KKAy mice at a dose of 100mg/kg (P < 0.05). The effect is equivalent to that of example 1(100mg/kg) at the same dosage.

TABLE 4 Effect on random and fasting blood glucose in KKAY mice

vs model group P <0.05, P <0.01, P < 0.001; blood glucose data are expressed as mean ± sd, n ═ 10

Experimental example 3 evaluation of antidiabetic Activity in ICR mice in examples 1 and 2

1. Laboratory animals and groups

(1) Laboratory animal

Normal ICR mice, male, weighing 20-25g, were purchased from the institute of animals, national academy of medical sciences, 5 mice/cage.

(2) Grouping

Animals were randomized before the experiment by body weight and fasted overnight (12 h). Then, the groups were randomly divided into example 1, example 2, normal and metformin groups according to body weight.

(3) Design of experiments

The test compound and the positive control metformin were administered to the stomach in a single gavage, and the normal group was given an equal volume of water. After two hours, a sodium pyruvate tolerance test was performed.

2. Test drug, dose setting and formulation

(1) Testing samples and preparation:

example 1(150mg/kg)

0.060g was weighed, the compound was put in a mortar, ground, suspended in 0.5% CMC-Na distilled water, and made to a volume of 4 ml. The administration volume was 0.1ml/10g, i.e., the administration dose was 150 mg/kg.

Example 2(150mg/kg)

0.060g was weighed, the compound was put in a mortar, ground, suspended in 0.5% CMC-Na distilled water, and made to a volume of 4 ml. The administration volume was 0.1ml/10g, i.e., the administration dose was 150 mg/kg.

Metformin (150mg/kg)

0.060g was weighed, the compound was put in a mortar, ground, dissolved in distilled water and made to a volume of 4 ml. 3. Main instrument and reagent

(1) Main instrument

mu-Quant microplate reader (MQX200, BIO-TEK, USA), air oscillator (HZQ-C, Harbin Toming medical instruments factory), low-temperature high-speed centrifuge (3-18K, SIGMA, Germany), water bath (DK-8D, Shanghai-constant technology, Inc.), multifunctional microplate reader (Synergy2, BIO-TEK, Inc.), analytical balance (Sartorius, BSA224S-CW), digital display electronic scale (MODUS), 1ml syringe (BD, batch 302101), 0.25ml syringe (Shanghai medical laser instruments factory, B05-19-U), hypodermic needle (prismatic, 0.5X 20).

(2) Primary reagent

Glucose (national drug group chemical agents ltd, 20141016), glucose assay GOD enzyme (sigma), sodium pyruvate (beijing carbofuran technologies ltd, 297561).

4. Experimental methods

Sodium pyruvate tolerance test: on the day of the experiment, blood was taken from the tip of the tail (0 min). Test compound and the positive control metformin were then separately gavaged, and an equal volume of water (0.1mL/10g b.w.) was given to the normal group. Two hours later, sodium pyruvate (3.0g/kg, 0.1mL/10g b.w.) was administered intragastrically, and blood was taken from the tail tip at 40 and 90min after the sodium pyruvate load, respectively, and blood glucose was measured at each time point.

5. Results of the experiment

As shown in Table 5, in example 1, the rate of inhibition of gluconeogenesis was 73.9% (P <0.01) at 40 min. Metformin (150mg/kg) inhibited gluconeogenesis by 29.7% (P < 0.05). In example 2(150mg/kg), the rate of inhibition of gluconeogenesis was 26.2% at 40 min. Both example 1 and example 2 can significantly reduce the area of the curve under glycemic time, and example 1 has an effect superior to metformin and example 2.

TABLE 5 inhibition of gluconeogenesis and hypoglycemic Activity in ICR mice

Both blood glucose and AUC data above are mean ± sd, n is 10, vs is normal, P <0.05, P <0.01, P <0.001.

Experimental example 4. pharmacokinetic experiment:

first, test animal

Male SD rats, weighing 180-. Second, test method

1. Establishment of plasma sample Standard Curve

Example 1 was dissolved in DMSO (3mg/mL) and diluted with a gradient of acetonitrile containing an internal standard (YHP836, 200ng/mL) to 5, 10, 25, 50, 200, 400, 800, 1000ng/mL working solutions.

50 μ L of compound P working solution and 50 μ L of acetonitrile containing an internal standard (YHP836, 200ng/mL) were added to 50 μ L of blank plasma, and after centrifugation, the mixture was centrifuged twice (14000 rpm. times.5 min), and 3 μ L of supernatant was collected for LC/MS/MS analysis.

2. Oral administration of example 1 and the proto-Compound P to rats

Compound P and example 1 were formulated as a 15mg/mL suspension with 0.5% CMC (containing Tween 80) for oral administration and as a 0.15mg/mL solution with 20% HP- β -CD for intravenous injection.

SD rats 13, 5 per group, 3 per intravenous group were orally administered. Fasting was performed for 12h before administration, and water was freely available. The test was performed by continuous blood sampling. Rats were bled from the orbital venous plexus 5, 15, 30min, 1,2, 4, 6, 8, 12, 24h after oral administration of example 1 and prototype compound P (150mg/kg), 50 μ L of plasma was bled 5, 15, 30min, 1,2, 4, 6, 8, 12, 24h after intravenous injection of example 1(1.5mg/kg), 100 μ L of acetonitrile containing an internal standard (YHP836, 200ng/mL) was added, centrifuged (14000 rpm. times.5 min) twice after vortexing, and 3 μ L of supernatant was taken for LC/MS/MS analysis. The reticle samples were measured after dilution.

3. Plasma sample processing

LC/MS/MS conditions

A chromatographic column: zomax C18(50 mm. times.2.1 mm, 3.5 μm); column temperature: 30 ℃, mobile phase: a methanol/water gradient; flow rate: 0.2 mL/min; negative ion scanning, MRM mode detection m/z 498 → 108(bjb-2936), m/z 465 → 297 (internal standard YHP 836).

5. Data analysis

Plasma pharmacokinetic parameters were calculated using WinNonlin software.

Third, test results

Rats absorb the compound P (150mg/kg) and the compound P is absorbed quickly after oral administration, the blood concentration is maintained at a higher level for 1-12h, and the average blood peak concentration is 85 mug/mL and 305 mug/mL respectively. The in vivo exposure of rats orally administered example 1(150mg/kg) was about 4 times that of their prototype compound. Bioavailability of oral example 1(150mg/kg) was > 100%.

TABLE 6 plasma pharmacokinetic parameters of rats orally and intravenously injected with example 1 and prototype Compound P

Claims (12)

1. The N-acyl sulfamide salt compound shown in the general formula I,

in the formula I, the compound is shown in the specification,

r is selected from the group consisting of the following atoms or groups, including

H、F、Cl、Br、CN、CF₃、OCH₃、NO₂；

Ar₁Selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substitutedIt may also be polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

Ar₂selected from the group consisting of:

(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

(2) substituted or unsubstituted aromatic condensed ring or condensed heterocyclic ring, substituted or unsubstituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocyclic ring, substituted or unsubstituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight chain or branched alkyl, halogen substituted C1-4 straight chain or branched alkyl、F、Cl、Br、NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

m is independently selected from alkali metals or alkaline earth metals.

2. The N-acyl sulfonamide salts according to claim 1, wherein the compound is represented by the formula I-A

Ar₁Selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

Ar₂selected from the group consisting of:

(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; benzene ring, nitrogen-containing six-membered aromatic heterocycle andthe five-membered aromatic heterocyclic ring can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

(2) substituted or unsubstituted aromatic condensed ring or condensed heterocyclic ring, substituted or unsubstituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocyclic ring, substituted or unsubstituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

m is independently selected from alkali metals or alkaline earth metals.

3. The N-acyl sulfonamide salts according to claim 2, wherein the compound is represented by the formula I-a

R_ACan be mono-substituted or poly-substituted;

R_Amay be independently selected from the following groups or structural fragments:

c1-4 straight chain or branched alkyl, halogen substituted C1-4 straight chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

Ar₂selected from the group consisting of:

(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

(2) substituted or unsubstituted aromatic condensed ring or condensed heterocyclic ring, substituted or unsubstituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocyclic ring, substituted or unsubstituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein saidHalogen of (c) includes F, Cl, Br;

m is independently selected from alkali metals or alkaline earth metals.

4. The N-acyl sulfonamide salts according to claim 2, wherein the compound is represented by the formula I-a-b

R_BCan be mono-substituted or poly-substituted;

R_Bmay be independently selected from the following groups or structural fragments:

c1-4 straight chain or branched alkyl, halogen substituted C1-4 straight chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

Ar₁selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

m is independently selected from alkali metals or alkaline earth metals.

5. The N-acyl sulfonamide salt compound of any of claims 1-4, wherein M is selected from the group consisting of lithium, sodium, potassium, cesium, calcium, magnesium, and barium.

6. The N-acyl sulfonamide salt compound according to any of claims 1-5, wherein the compound is selected from the group consisting of:

7. a process for the preparation of the N-acyl sulfonamide salts according to any of claims 1-6, comprising the steps of:

in an ethanol solution of sodium alkoxide, condensing 5-R-substituted o-bromobenzaldehyde and ethyl azidoacetate to obtain a compound 1, using o-dichlorobenzene as a solvent in the compound 1, performing ring closure at 180 ℃ to obtain 7-R-substituted 4-bromo-1-H-indole-2-carboxylic acid ethyl ester (a compound 2), and then performing methylation at an indole-1-position under the condition of cesium carbonate to obtain 7-R-substituted 4-bromo-1-methyl-indole-2-carboxylic acid ethyl ester (a compound 3); then the compound 3 and aryl bromide are subjected to coupling reaction under the catalysis of palladium to obtain a compound 4, and a corresponding compound 5 with 2-position as carboxyl is obtained after hydrolysis reaction. Carrying out condensation reaction on the compound 5 and aryl methanesulfonamide to obtain a compound 6, and finally carrying out acid-base reaction on the compound 6 and different bases to obtain an N-acyl sulfamide salt compound;

the reagent and the reaction condition are (a) ethyl azidoacetate, ethyl trifluoroacetate, sodium and ethanol, and the temperature is between 15 ℃ below zero and 0 ℃; (b) o-dichlorobenzene, 180 ℃; (c) methyl iodide, cesium carbonate, DMF, r.t.; (c) ar (Ar)₁-Br，Pd₂(dba)₃Xanthphos, sodium carbonate, toluene, water, 100 ℃; (d) sodium hydroxide, THF, ethanol, water, r.t.; (e) ar (Ar)₂-S(O)₂-OH，HATU，DMAP，Et₃N, r.t.; (g) alkali of alkali metal or alkaline earth metal, water, 80 ℃;

wherein said R, Ar₁、Ar₂And M is as defined in claims 1-6.

8. A pharmaceutical composition comprising an effective amount of an N-acyl sulfonamide salt of any of claims 1-6 and a pharmaceutically acceptable carrier.

9. Use of a N-acyl sulphonamide salt of any of claims 1 to 6 in the preparation of an FBPase inhibitor.

10. Use of N-acyl sulfonamide salts according to any of claims 1 to 6 for the preparation of medicaments for the prophylaxis and/or treatment of diseases associated with FBPase.

11. Use according to claim 10, characterized in that the diseases associated with FBPase are selected from diabetes, diabetic complications and obesity.

12. The use according to claim 11, wherein said diabetes is selected from the group consisting of type I diabetes and type II diabetes; the diabetic complication is selected from retinopathy, nephropathy, nervous system diseases and vascular complications, ischemic heart disease or atherosclerosis.