TWI308869B - Chemical compounds - Google Patents

Description

A7 B7 1308869 V. DESCRIPTION OF THE INVENTION (1) The present invention relates to a compound for increasing pyruvate dehydrogenase (PDH) activity, a method for preparing the same, a pharmaceutical composition containing the same as an active ingredient, and a treatment related to reducing PDH activity Method for the disease state, use thereof as a medicament, and use thereof for the manufacture of a medicament for increasing PDH activity in a warm-blooded animal such as a human. In particular, the present invention relates to the treatment of diabetes, peripheral blood vessels in a warm-blooded animal such as a human. Compounds of disease and myocardial deficiency, and more particularly such compounds, are used in the manufacture of medicaments for the treatment of diabetes in warm-blooded animals such as humans. 'Adenosine triphosphate (ATP) provides the ability to synthesize complex molecules and contract in muscle within the tissue. ATP is produced from the cleavage of energy-rich receptors such as glucose or long-chain free fatty acids. In oxidative tissues such as muscle, most of the ATP system is produced from the acetyl group-based CoA entering the citric acid cycle. Therefore, the supply factor of acetyl-based CoA is the decisive factor for ATP production in oxidative tissues. From the β-oxidation of fatty acids or the result of glucose metabolism by the saccharification pathway. The key regulator controlling the rate of formation of E-based CoA from glucose is PDH, which catalyzes the oxidation of propylate to CoA and CO2, while reducing the nicotinic adenine dinuclear acid (NAD) to NADH. In disease states such as non-insulin dependent (type 2) and insulin dependent (type 1) diabetes, increased oxidation of lipids, while reducing the use of glucose, causes hyperglycemia. Reduced glucose utilization in Type 1 and Type 2 diabetes is associated with a decrease in PDH activity. In addition, further results in reducing PDH activity may result in increased lactate concentration as an increase in the effectiveness of lactose as a hepatic glucone. It is reasonable to expect that increased PDH activity will increase glucose oxidation rate and therefore total glucose utilization in addition to reducing hepatic glucose output. -4- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1308869 A7 _______B7 V. INSTRUCTIONS (2) Another factor contributing to diabetes is depleted insulin secretion, which has been shown to be associated with reduced PDH activity in pancreatic β-cells (in the rodent gene model of diabetes] Zhou et al. (1996) Diabetes 45: 580-586. Glucose oxidation produces more ATP/mole oxygen than fatty acid oxidation. In the state where energy demand exceeds energy supply such as myocardial ischemia, intermittent spasm, cerebral ischemia and reperfusion (Zaidan et al. , 1998; J. Neurochem. 70: 233-241), a balanced tendency for the utilization of elevated PDH activity in the grape's sugar metabolism preview will improve the ability to maintain ATP and thus its role. Can increase PDH activity The medicament may also be beneficial for the treatment of a condition in which excessive circulating lactic acid occurs, such as some sepsis. An agent that increases PDH activity after acute administration to an animal, di-acetic acid (DC) A) (Vary et al., 1988; Circ. Shock, 24: 3-18) has been shown to have the desired effect in reducing hyperglycemia (Stacpoole et al., 1978; N. Engl. J_ Med. 298: 526-530) and As a therapy for myocardial ischemia (Bersin and Stacpoole 1997; American Heart Journal, 134: 841-855) and lactateemia (Stacpoole et al., 1983; N. Engl. J. Med. 309: 390-396). PDH It is a multi-enzyme complex in the granulosa, which consists of multiple subunits including three enzyme activities El, E2 and E3, which are necessary for the completion of conversion of pyruvic acid to ethylene-based CoA (Patel and Roche 1990; FASEB) J., 4: 3224-323 3) » El catalyzes the irreversible loss of C02 from pyruvate; E2 forms acetyl group CoA and E3 reduces NAD to NADH. Two additional enzyme activities are related to complex: can be in three Specific kinases that phosphorylate E1 on serine residues, and specific esterases that are less involved in reversed acidification. Single phosphorylation of three serine residues deactivates E1. PDH is active (dephosphorization) This paper scale is suitable for the sleepy home (CNS> A4 specification (210 X 297 mm) A7 B7 1308869 V. Description of the invention (acidification) The ratio of states is determined by the balance between kinase and phosphatase activity. Kinase activity can be metabolized in vivo by substances such as NAD/NADH, CoA/ethylidene CoA and gland:y:diphosphate (ADP)/ATP The relative concentration, and the effectiveness of pyruvic acid itself. Compounds that increase PDH activity are assumed to treat diseases associated with glucose utilization disorders such as diabetes, obesity (Curt0 et al, 1997; Int. J. Obes. 21: 1 [7 7 -1 14 2) and lactic acid it value. In addition, such compounds are expected to limit the supply of energy-rich substances to tissues such as peripheral vascular disease (including intermittent sputum), heart failure and some cardiomyopathy, muscle weakness, hyperlipidemia and arteriosclerosis ( Stacpoole et al., 1978; N. Engl. J. Med. 298: 526-530) have utility. Compounds that activate PDH are also used to treat Alzheimer's disease (AD) (J Neural Transm (1998) 105, 855-870). European Patent Nos. 6 1 70 1 0 and 52478 1 describe a northern compound that can relax bladder smooth muscle and can be used to treat urgent incontinence. WO 9394618 > WO 9962508 'WO 9962S73 > WO 01/17942, WO 01/17955 and WO 0 1/17956 describe compounds which increase PDH activity. The compounds of the present invention are not specifically disclosed in any of the above applications and we have surprisingly found that such compounds possess beneficial properties in terms of one or more of their pharmacological activities, particularly compounds which increase pyruvate dehydrogenase, and / or pharmacological kinetics, effective, metabolic and toxic side-analysis maps make it particularly suitable for Zhao _ internal application to warm-blooded animals such as humans. Thus, the present invention provides a compound of formula (I): ____ -6- This paper scale applies to Chinese painter standard (CNS) A4 specification (210 X 297 mm) A7 B7 1308869 V. Description of invention (4) Ω Ο

Wherein R is methyl or methylsulfonyl; or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester. In one feature of the present discovery, R is a thiol group. In another feature of the invention, R is methylsulfonyl. Another feature of the invention is the related compound or a pharmaceutically acceptable salt thereof. Of course, the compound of the formula (I) and its pharmaceutically acceptable salt and in vivo hydrolysable ester may be a solvent. Soluble and non-solvent solvated forms such as water and form are present. Of course, the present invention encompasses all such solvent solvated forms that increase PDH activity. The compound of formula (I) and its pharmaceutically acceptable salts and in vivo hydrolysable esters can be prepared by any method known to be useful for the preparation of chemically related compounds. Such a method includes, for example, the European Patent Application No. 052478 1 , 0617010, 0625516 and the British Patent No. 227 80 54 and the International Patent Application No. WO 9323358, WO 9738 124, WO 9944618, WO 99475_08 'WO 9962506 WO 9962873, WO 01/17942, WO 01/17955 and WO 01/17956. Another feature of the present invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, the method of which is -7 - this 泜 尺度 scale applies to Chinese national standards <;CNS) Α4 Specifications (210 X 297 public) 1308869 A7 B7

This paper scale applies to Chinese National Standard (CMS) A4 specification (210 x 297 mm) 1308869 A7 B7 V. Description of invention (6

Wherein X is OH; (d) coupling an aniline of formula (IV) with an activated acid derivative of formula (V); (e) a compound of formula (VI): Ο Ο

Wherein L is a replaceable group; reacted with a 4-methanesulfonylhexahydropyrazine or a 4-methylhexahydropyrene 11 well; (f) a compound of formula (I) wherein R is a thiol group (VII) Compound methylation: Ο Ο

(g) methanesulfonylation of a compound of formula (VII) with a compound of formula (I) wherein R is methylsulfonyl; (h) gasification of a compound of formula (VIII): -9 - The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1308869 A7 B7

The paper size is based on the Chinese National Standard (CNS) A4 specification (210 x 297 mm). A7 B7 1308869 V. Description of the invention (1) Adding a compound of formula (V) wherein X is NH2 to the compound of formula (XII) : Ο 〇

Wherein L is a substitutable group; (m) a compound of formula (XIII) is reorganized by Smiles:

Or (η) separating the mixture of (R) and (S) mirror images of the compound of formula (1) to give (R)-mirror; and thereafter forming a pharmaceutically acceptable salt or hydrolyzable in vivo, if desired vinegar.

Suitable values for Pg are fluorenyl, decylalkyl (e.g., trialkyldecyl or alkyldiphenylalkyl) or acetoxy protecting groups. When formula (V) is an activated acid derivative, suitable values for X include halo (e.g., gas or bromine), anhydride, aryl fluorenyl (e.g., 4-nitro alum or pentafluorophenoxy) or sigma ° Sit -1 - base. L is a replaceable group. Suitable values for L include fluorine, gas, bromine, nitro, and ____-11 -_ This scale is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) A7 B7 1308869 V. Description of invention (9 Sulfonate and triflate.

Fg is a functional group. Suitable functional groups include amine groups which are internally converted by the reaction of azo and azoammonium salts with a vapor under a copper catalyst. The specific conditions for the above reaction are as follows: Method (a) Examples of suitable reagents for deprotecting the (Π) alcohol are: 1) When Pg is benzyl: (1) Hydrogen in the presence of palladium/carbon catalyst, ie hydrogenolysis Or (ii) hydrogen bromide or hydrogen iodide; 2) when Pg is a decyl protecting group: (1) tetrabutylammonium fluoride: or (hydrazine) hydrofluoric acid or hydrochloric acid: 3) when Pg is acetamidine Base time: i) a mild aqueous base such as a hydroxide chain; or ii) an ammonium or an amine such as dimethylamine. The reaction can be carried out in a suitable solvent such as ethanol, decyl alcohol, acetonitrile or dimethyl argon and conveniently in- Compounds of formula (II) at temperatures ranging from 40 to 1 Torr can be prepared according to the following scheme:

This paper size is suitable for home materials (CNS) M specifications (2iq χ 297 public fee) A7 B7 1308869 V. Description of invention (1〇HO Me Μ 0 OH (Ila) CF, EO Me, CF3 standard protection, base condition E-OH , H,S04 EtOAc

(Π) PCM \A.. ii) (IV), oo?s 2,6-di-tertiary butyl-to-bit, DCM, 'Figure 1 O OH (Hb)

E is a thiol protecting group. Suitable values for E include Ci.6 alkyl groups such as methyl and ethyl groups. The compound of the formula (Ila) is a commercially available compound. Method fb), suitable oxidizing agents include potassium permanganate, OXONETM, sodium periodate, peroxyacid (eg 3-oxoperoxybenzoic acid or acetic acid), hydrogen peroxide, TPAP (over hydrazine) Tetrapropylammonium acid) or oxygen. The reaction can be carried out in a suitable solvent such as diethyl ether, DCM, methanol, ethanol 'water, acetic acid or a mixture of two or more of these solvents. The reaction can conveniently be carried out at a temperature in the range of -40 to 100 ° C. The compound of the formula (III) can be prepared according to the following scheme: -13- This paper scale is applicable to the National Painter Standard (CNS) A4 specification (210 X 297) PCT 1308869 V. Description of invention (·Π) A7 B7

NH,

(V) (X=C1), 2,6-di-tert-butylpyridine, DCM

Pd/C, EtOAc, H2

NaN02, H20, H2S04, CuBr

II Me OH

4-methylhexa- or pyropyride or 4-methylsulfonylhexafluoropyrazine, Pd[0], i^, PhCH3, A

NaSCN, NaBr Br2, MeOH

Hydrolysis (III) i) EtI, alkali

II Me η^··€3 OH (nig) Figure 2 Compound of formula (Ilia) is a commercially available compound. Method (c) The reaction can be carried out in the presence of a suitable coupling reagent. This paper scale applies to Chinese National Standard (CNS) A4 specification (2l〇x 297 mm) 1308869 A7 B7 V. Inventive Note (12 guanamine coupling reagent can be used as a suitable coupling reagent, for example, these are coupling (Ilia) and ( V) or (IV) and (lid) conditions, or, for example, dicyclohexylcarbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinylpyridine, optionally in the presence of a base For example, in the presence of triethylamine, pyridine or 2,6-dialkylpyridine (such as 2,6-dimethylpyridine or 2,6-di-t-butylpyridine) or 2,6-diphenylpyridine. The solvent includes dimethylacetamide, DCM, benzene, THF and DMF. The coupling reaction can be conveniently carried out at a temperature ranging from -40 to 40 ° C. - The compound of the formula (IV) can be prepared according to the following scheme:

F F

NO, EtSH NaH, DMF NH, (IVa)

EtS

NO, NH, (IVb)

EtS F

i-BuONO, CuCl2, MeCN

No2 Cl (IVc)

Loading

NHPg oxidation reaction

Reduction reaction

I

Deprotection reaction Figure 3 -15- (IV) The degree of the fullness of the application is applicable to China@家标准(CNS) A4 specification (210 X 297 mm) A7 B7 1308869 V. Invention description (13)

Pg is an amine protecting group such as those described below. The compounds of the formulae (IVa) and (V) are commercially available compounds and are known in the literature. For example, the analytical acid of formula (V) can be prepared by any known method for preparing an optically active form (e.g., by recrystallization from palm salt {e.g., WO 9738124}, by enzymatic resolution or by separation of the palm stationary phase by chromatography). For example, the (R)_(+) analytic acid can be prepared by the method of the preparation of the (SH_) acid in the world patent application No. WO 9738 124, using the conventional analytical method described in European Patent Application No. Ep 0524781. (S)-(-) acid was also prepared, except that (SS-(-)-l-stylethylamine was used instead of (1S, 2R)-positive ephedra. For palmitic acid, it can also be prepared by the method of enzymatic analysis described in the tetrahedral asymmetry '1999, 10, 679'. [ch] This coupling reaction can be determined by, for example, triethylamine, ι» bite or 2,6 - Dicalcinyl 9 is achieved in the presence of a bite (such as 2,6-dimethylene 11 bite or 2,6-di-tert-butylpyrene bite) or 2,6-diphenylpyridine. Suitable solvents include dimethylacetamide, DCM, stupid, THF and DMF. The coupling reaction is conveniently from -40 to 40. Perform at a temperature range of 〇. Method (e) This reaction may be carried out by a sulfonylsulfonylhexafluoropyrene 11 well (U.S. Patent No. 6 1403 5 1) or a methylhexahydropyrazine (1-20 molar equivalents, preferably 2-10 equivalents) with ( VI) the reaction is carried out in a solvent such as N-methyl-2-pyrrolidone or dimethylacetamide or without a solvent, and is heated at a temperature of from 40 to 160 ° C to reach a compound of the formula (VI) wherein L is fluorine. It can be prepared by the following pattern: - 16 -__ This paper is again used in China National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 Oxidation reaction (VI) 1308869 V. Invention description (14) (V) (XC1 )

Cl “ OH...3 (Via)

2,6-di-tert-butylpyridine EtS

DCM

(IVd) - F Scheme 4 Compound (VII) can be used with hydrazine and a reducing agent such as sodium hydride or sodium triethoxy hydride hydride in a suitable solvent such as 1,2-dioxaethane 'DCM or In THF, methylation is preferably carried out at or near room temperature at temperatures ranging from 0 °C to reflux. Or the compound (VII) may be treated with a methylating agent such as methyl iodide or dimethyl sulfate in a solvent such as acetone or DMF, in the presence of a base such as sodium hydrogencarbonate, sodium carbonate or sodium hydroxide, optionally in the presence of a hydroxyl group. Lower methylation. The preparation of the compound (VII) is described in the following method 1. Process (g) Compound (VII) can be used in a suitable solvent such as methanesulfonate in the presence of a base such as triethylamine in a suitable solvent such as DC hydrazine, THF, p-bite or ethyl acetate at -40 ° C Methanesulfonylation at a temperature to the reflux range, preferably at or near room temperature. Method (h) Gasification can be carried out, for example, using N-ammonia succinimide in a solvent such as DCM, acetonitrile, isopropanol or DMF, at a temperature between 0 ° C and reflux, or at a temperature ranging from -20 ° C to 40 t in the presence of a catalyst such as tri-iron, in the presence of a suitable solvent such as acetic acid, DMF or acetonitrile Preferably, it is carried out at or near room temperature, and then separates the desired product and if it is formed. -17 - The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1308869 V. DESCRIPTION OF THE INVENTION (15) Heterogeneous impurities are desired. The compound of formula (VIII) can be prepared according to the following scheme: EtSNa, EtOH oxidation reaction EtS0 (Villa)

Γ v 'NO, (VIIIc) H;, Pd/C EtOH F v NO, (Vlllb) (VIII) (V) (X=ci)

EtSO,

>T NH, (Vide)

EtSO,

IT, N, ΝΜΡ, Δ v 'NH, (Vllld) (VIII 〇 compound (Villa) is commercially available. Method Π) The intra-functional conversion reaction uses reagents and reaction conditions well known in the chemical arts. For example, a functional intra-domain conversion reaction wherein Fg is ΝΗ2 (IX) The compound of formula (I) can be reacted by azo, for example with a third butyronitrile or the like in the presence of a catalyst such as vaporized copper in a solvent such as acetonitrile. It is carried out at a temperature of from 0 ° C to the reflux range, preferably at or near room temperature. Alternatively, the conversion reaction can be carried out by an azotization reaction with a nitrile salt in the presence of an acid such as HC hydrazine or sulfuric acid in a solvent such as water, acetic acid or a mixture of the two at a temperature ranging from -20 to 40 ° C, followed by The azo ammonium salt thus formed is reacted with the vaporized cuprous in the same solvent at a temperature from 0 ° C to reflux. The compound of formula (IX) can be prepared according to the following formula: -18 - The paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1308869 A7 B7 V. Invention description (16) (IVb) 1 ) CB0C), 0 2) KMnO;

HrPd port to, (IX) (Fg=NH,)

(IXc) Method m The reaction can be carried out by adding a suitable reagent such as CF3SiMe3 (Ruppert's reagent, tetrahedron, 2000, 56 (39), 7613), which can be contacted with a suitable catalyst such as palmitic fluoride. The medium (tetrahedral letter, 1994, 35, 3 1 37) was reached asymmetrically, and then the acid water test was continued to complete the hydrolysis of the tertiary alcohol decyl ether formed in the reaction. This reaction can be carried out in a suitable solvent such as toluene at a temperature of from -100 ° C to room temperature to reflux, preferably from -78 ° C to room temperature. The compound of the formula (X) can be produced by the method (c) by coupling the compound (IV) with pyruvic acid of the substituted (V) acid. Method ΠΟ The reaction can be carried out by adding a suitable organic reagent such as CH3MgBr or CH3CeCl2 in a suitable solvent such as diethyl ether or THF at a temperature of -120 ° C to 40 ° C in the palm catalyst TADDOL (tetraaryldifluorenyl di Oxyquinone dimethanol, for example, wherein the aryl group is a strepyl or 2-chaly group; Angew. Chem. Int. Ed. Engl., 1992, 3 1,84-6) is carried out. -19- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) A7 B7 1308869 V. Inventive Note (17) The compound of formula (XI) can be prepared by the method (c), ie Compound (IV) is coupled with a substituted (V) acid trifluoropyruvate (tetrahedral letter, 1989, 30 (39), 5243). Process (1) The reaction can be carried out by reacting a compound of the formula (XII) with a dianion having a compound of the formula (V) wherein X is NH2 and a two molar equivalent of a base such as sodium hydride in a suitable solvent such as THF or NMP. The reaction was carried out at a temperature of from 20 to 160 °C. The compound of the formula (XII) wherein L is C1 can be prepared, for example, from a compound of the formula (I) by diazotization, using the method as described in the method (1). Method (m) Small recombination can be carried out by treating a compound of formula (XIV) with a test such as sodium hydride in a solvent such as DMF. The compound of the formula (XIV) can be obtained from a compound of the formula (XII) wherein L is C1 and a compound of the formula (V) wherein L is NH2 and a molar equivalent such as sodium hydride in a solvent such as THF or NMP at 20- Prepared at a temperature of 160 °C. Process (η) A compound of formula (I) which is intended to be in an optically active form can be obtained by analysing a compound of formula (I) and its corresponding (S) mirror image isomer, using standard procedures well known to those skilled in the art, such as mirror image isomers. Crystallization, enzyme analysis and chromatographic separation. If not available, the essential materials of the procedure, such as those described above, may be made by a procedure selected from standard organic chemistry techniques, similar to known synthetic techniques of structurally similar compounds, similar to those described in the above procedures or examples. Technology. -20- This paper wave scale applies Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1308869

Materials such as the above synthetic methods are commercially available and/or widely reported in the scientific literature, or may be prepared from commercially available methods of adaptation to the scientific literature. Readers refer to Advanced Organic Chemistry, 4th Edition, published by Jerry March, John Wyni, General Guidelines for Agents. 1992 </ br> for the reaction and test to understand some of the sensitive bases of the compounds mentioned in the 1st &amp; Examples of which the protection system is necessary or desirable are known to those skilled in the art as it is a suitable method for such protection. Traditional protecting groups can be used consistently with standard implementations (see τ W. Greene, Organically Modified Protecting Groups, John Wyni, 1991). Examples of suitable protecting groups for the thiol group are, for example, fluorenyl groups, such as an alkanoyl group such as an ethyl fluorenyl 'aryl fluorenyl group such as a benzyl aryl group, a decyl group such as a trimethyl fluorenyl group or an arylmethyl group, for example, a fluorenyl group. The base deprotection condition will have to vary with the selected protecting group. Thus, for example, an anthracenyl group such as an alkanoyl group or an aryl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal argon oxide such as lithium hydroxide or sodium. Alternatively, a decyl group such as a trimethyl decyl group can be removed, for example, by a fluoride or an aqueous acid; or an arylmethyl group such as a fluorenyl group can be removed, for example, by hydrogenolysis in the presence of a catalyst such as palladium/carbon. For example, a broth, such as a ketone group, an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group or a tert-butoxycarbonyl group, an aryloxycarbonyl group such as a decyloxycarbonyl group or an aryl fluorenyl group For example, thiol. The deprotection conditions for the above protecting groups must vary with the chosen protecting group. Therefore, for example, the waking base or the fluorinated phenyl group or the aryl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium. a home standard (CNS) A4 grid (210 X 297 mm) A7 B7 1308869 V. Description of the invention (19) or awake group such as the third butoxycarbonyl group can be, for example, a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoro The acetic acid treatment to remove 'and the arylmethoxycarbonyl group such as a decyloxy group can be removed, for example, by argon argon on the catalyst/post, or by treatment with a Lewis acid such as hexafluoroacetic acid. A suitable alternative protecting group for the primary amine is, for example, a fluorenyl group which can be removed by treatment with an alkylamine such as dimethylaminopropylamine or 2-hydroxyethylamine or by hydrazine treatment. The protecting group can be removed at any convenient stage of the synthesis, using techniques well known in the art of chemistry, or it can be removed during subsequent reaction steps or experiments. The compound of formula (I) may form a stable acid or base salt, and in some cases the compound may be suitably applied as a salt, and the pharmaceutically acceptable salt may be prepared by conventional methods such as those described below. Examples of suitable pharmaceutically acceptable salts are the addition of organic acids to the formation of acids which are physiologically acceptable anions, such as formazanates, formates and alpha-glycerides. Suitable inorganic salts can also be formed, such as sulfates, acid salts, and vapors. The pharmaceutically acceptable salts can be obtained by standard procedures well known in the art, e.g., compounds of formula (I) (and esters thereof in some cases) are reacted with physiologically acceptable anion ions. It is also possible to prepare a corresponding alkali metal (for example sodium, if or by) or soil-checking metal (eg feed) salt, a compound of formula (I) (and some of its esters) and one equivalent of alkali metal hydroxide or The alkyl halide or a half equivalent of an alkaline earth metal argon halide or alkane halide (e.g., ethane or methoxide) is reacted in an aqueous medium followed by conventional purification techniques. The in vivo hydrolysable ester of a compound of formula (I) is, for example, a pharmaceutically acceptable ester which is hydrolyzed in a human or animal body to produce a parent acid or an alcohol. -22- This paper size is applicable to the National Standard (CNS) A4 specification (210X 297 mm)

Binding

Line A7 B7 1308869 V. INSTRUCTION DESCRIPTION (20) In vivo hydrolysable vinegars of a suitable compound of formula (I) formed with a thiol group include inorganic esters such as phosnates and alpha-stylosyloxyesters. Examples of the α-azeoxy oxyl ester include an ethoxylated methoxy group and a 2,2· dimethylpropoxycarbonyl group. Other groups which form an in vivo hydrolyzable ester with a hydroxyl group include an alkanoyl group, a benzindenyl group, a phenylethenyl group, a substituted benzamidine group and a phenylethyl group, an alkoxycarbonyl group (formation of an alkyl disk ester) , dioxin amine broth and fluorene-(dihydroaminoethyl)-fluorene-terminated amine mercapto (formation of carbamate), dialkylaminoethyl carbonyl and carboxyethyl fluorenyl Examples of the decanoic acid substituent include a morpholino group and a hexahydropyrazine which are bonded to the 3- or 4-position of the fluorenyl group from the ring nitrogen atom to the methyl group. The compound which raises the PDH activity is identified as the present invention. theme. Such properties can be assessed, for example, using one or more test procedures known in the literature, such as those described in WO 9962506; that is, test (a) - elevated PDH activity in vitro, test (b) - extravagant in isolated primary cells Increased PDH activity and test (c) - increased PDH activity in vivo and such assays are incorporated herein by reference. Increased PDH activity outside the sputum ^ This assay measures the ability of test compounds to increase PDH activity. The cDNA encoding PDH kinase can be obtained by polymerase chain reaction (PCR) and subsequently colonized. This can be demonstrated in a suitable expression system to obtain a polypeptide having PDH kinase activity. For example, human PDH kinase 2 (rPDHK2), which is expressed by recombinant protein in E. coli (£.co/〇), was found to exhibit PDH kinase activity. Human rPDHK2 (Genbank accession number L42451.1) was colonized and by Baker et al. Human (2000) J. Biol. Chem. 275, 1 5773-1 578 1 The method described is expressed. The protease cleavage site is incorporated into the expression protein described in the literature „ Other known PDH kinases for analysis can be used Colonization and in a similar manner Table -23 - Common Paper National Standard (CNS) A4 Specification (21〇x 297 mm) 1308869 A7 _____B7 5, Invention Description (21) Now, in order to express rPDHK2 activity, E. coli strain BL21 (DE3) cells were transformed with pET28A vector containing rPDHK2 cDNA. "This vector incorporates a 6-His tag on its end to the protein. E. coli grows in the fermenter to an optical density of 12 at 37»c. (550 nm), reduced to 22 ° C until the optical iff of 15 and the protein expression was induced by the addition of 〇.5 m]V [isopropylthio-β·galactosidase. The cells were grown for 3 hours at 221 And collected by centrifugation. The resuspended cell paste is homogenized and insoluble by high pressure. The material was removed by centrifugation at 26000 xg for 0 minutes. The 6-His-labeled protein was removed from the supernatant using a cobalt chelate resin (TALON: Clontech) matrix using a similar buffer containing 100 mM imidazole pH 8.0. Before the stage-stage dissolution of the bound protein, first in 20 mM N-[2-hydroxyethyl]hexahydropyridinium, [[2_ethanesulfonic acid] (HEPES), 500 mM NaCl, 1% (Wv) Alcohol, 〇1% (w/v) Pluronics F-68 pH 8.0. The solution containing 6-His-labeled protein is separated by 'ethylenediaminetetraacetic acid (EDTA) and dithiothreitol (DTT). The final concentration was adjusted to 1 mM and the label was cleaved by the addition of pre-shear protease (Amersham Pharmacia Biotechnology). This protease was removed using chytrimine Sepharose (Amersham Pharmacia Biotechnology). Unlabeled protein was dialyzed to 20 mM HEPES- Na, 150 mM gasification sodium, 0.5 mM EDTA '1% (w/v) Pluronics F68, I0/(v/v) glycol pH 8.0 storage buffer and stored in batch at _80 °C. Each batch of new raw material PDHK enzyme was titrated in the assay to determine the concentration of about 75% PDH inhibition in the analytical conditions. The prime (typically 2 μg/ml) is allowed to react with PDH (pig heart PDH, Sigma P7032) (0.05 U/ml) at 50 °C containing 50 mM 3-[N-?" (mops), -24- This is a standard Chinese National Standard (CNS) A4 specification (210X 297 public*&gt; A7 B7 1308869 V. Description of invention (22) 20 mM dipotassium orthophosphate, 60 mM potassium hydride 2 mM magnesium hydride, 0.4 mM diethylamine tetraacetic acid (EDTA), 0.2% Pluronics F-68, 1 mM dithiothreitol (DTT), and a pH of 7.3 in a buffer for 24 hours. For compound activity, the compounds were diluted in 5% DMS0 and 5 microliters were transferred to individual grids of 384-gram assay plates. The control panel contained 5 microliters of 5% DMSO to replace the compound. In order to determine the maximum rate of PDH reaction, the second series of control group grids consisted of 5 microliters of known inhibitors with a final concentration of 1 〇 μΜ in the warming reaction. Add 40 μl of pre-ligated enzyme solution and phosphorylation reaction by adding 5 μl of 10 μΜ ΑΤΡ in the above buffer. The residual activity of PDH after 45 minutes at room temperature was obtained by adding 40 μl volume of the substrate (2.5 mM coenzyme a, 2.5 mM guanamine pyrophosphate (carboxylated coenzyme), 2.5 mM sodium pyruvate, 6 mM NAD) and the culture plate. The incubation was carried out at room temperature for 9 minutes, and the production of reduced naD (NADH) was determined by a disk reading spectrophotometer to determine the optical density at 34 Å. The ECw of the test compound was used as a result of the concentration of 丨2 compounds in a general manner. Decide. For parenteral injection (including intravenous, subcutaneous, intramuscular, such as sterile fluids, suspensions or emulsions, liquids or for rectal administration such as suppositories. Typically, conventional excipients are applied. According to another feature of the invention, it is provided A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable, as defined in the art, in combination with a pharmaceutically acceptable excipient or carrier. The composition may be in a form suitable for sigma administration, such as a squeezing or sac, intramuscular, intravascular or perfusion), for topical application such as an ointment or a composition above the milk may be conventional U------25- This paper size is applicable to the _i(CNS) Α4 specification (2ι〇χ297^7 1308869 A7 B7. 5. Description of the invention (23) The composition of the present invention is advantageously presented in unit dosage form. The compound will often be 5-5000 mg/ The unit dose of the square body of the animal's decentralized area is (4), that is, about U, mg / hm "for example, (10): = 乂 preferably (10) mg / kg of the unit dose is expected: This usually provides treatment Effective dose Tablets or capsules will often contain, for example, from 1 to 250 mg of the active ingredient. According to another feature of the invention, it provides a compound as defined above or a pharmaceutically acceptable salt or body thereof. Hydrolyzed ester for use in the treatment of human or animal body by therapy. We have found that the compounds of the invention increase PDH activity and are therefore important for their blood glucose lowering effect. Another feature of the invention is a compound of formula (I) and It is conveniently a pharmaceutically acceptable salt or an in vivo hydrolysable ester as the agent β, which is a compound of the formula (I) and a pharmaceutically acceptable salt thereof or a hydrolyzable vinegar in the body as a warm animal An agent that produces elevated PDH activity in humans. In particular, it is a compound of formula (I) and a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as a medicament for treating diabetes in a warm-blooded animal such as a human. In particular, it is a compound of the formula (I) and its pharmaceutically acceptable salt or in vivo hydrolysable ester, as a medicament for treating diabetes, peripheral blood disease and myocardial ischemia in warm-blooded animals such as humans. So 'root Another feature of the invention provides a compound of formula (I) and its use in a pharmaceutically acceptable salt or in vivo hydrolysable ester for use in the manufacture of a -26-Benco scale using the Chinese National Standard (CNS&gt; Α4 Specification (210X297 mm) 1308869 A7 B7 V. INSTRUCTION DESCRIPTION (24) An agent that produces elevated PDH activity in a warm jk animal such as a human, and thus according to another feature of the invention, provides a compound of formula (I) The use of a pharmaceutically acceptable salt or an in vivo hydrolysable ester for the manufacture of a medicament for the treatment of diabetes in a warm-blooded animal such as a human. According to another feature of the invention, there is provided the use of a compound of formula (I) and a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for the treatment of diabetes, peripheral blood in a warm-blooded animal such as a human. Tube disease and myocardial ischemia, according to another feature of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt or in vivo hydrolyzable The ester is combined with a pharmaceutically acceptable excipient or carrier for use in a warm-blooded animal such as a human to produce elevated PDH activity. According to another feature of the invention, there is provided a pharmaceutical composition comprising as defined above The compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, is combined with a pharmaceutically acceptable excipient or carrier for the treatment of diabetes in a warm-blooded animal such as a human. According to still another feature of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, pharmaceutically acceptable An excipient or carrier for treating diabetes, peripheral vascular disease, and myocardial deficiency in a warm-blooded animal such as a human - according to another feature of the present invention, which provides a warm-blooded animal such as a human in need of such treatment A method of producing an increase in PDH activity, the method comprising administering to the animal an effective amount of a compound of formula (I) as defined above or in the pharmaceutical -27 • loading paper size applicable to the Chinese National Standard (CNS) A4 specification (210 x 297 metric) PCT)

Morning A7 B7 1308869 V. INSTRUCTIONS (25) Acceptable salts or in vivo hydrolysable esters. According to another feature of the invention, there is provided a method of treating diabetes in a warm-blooded animal, such as a human, in need of such treatment, the method comprising administering to the animal an effective amount of a compound of formula (I) as defined hereinbefore or in medicine An acceptable salt or an in vivo hydrolysable ester. According to another feature of the invention, there is provided a method of treating diabetes, peripheral ir bronchitis and myocardial deficiency in a warm-blooded animal such as human 47 in need of such treatment, the method comprising administering to the animal, the effective amount being as before Defining a compound of formula (1) or a pharmaceutically acceptable salt thereof or hydrolyzable in vivo, as described above, the amount of the dose required to treat or prevent a particular disease state must depend on the host treated, the route of administration, and the condition to be treated. Change in severity. Preferably, a daily dose in the range of 1 - 50 mg/kg is employed. However, the dose per dose must vary depending on the host treated, the route of administration, and the severity of the condition to be treated. Thus, the optimum dose can be determined by the physician treating any particular patient. As described above, 'the compounds defined by the present invention are important for their ability to increase PDH activity.' The compounds of the present invention are therefore useful in a range of disease states including diabetes, peripheral vascular disease, (including intermittent spasms), heart failure and some myocardium. Disease, myocardial ischemia, cerebral ischemia and reperfusion, muscle weakness, hyperlipidemia, Alzheimer's disease and/or arteriosclerosis. Or such a compound of the invention can be used in a range of disease states, including peripheral vascular disease, (including intermittent spasm), heart failure and some cardiomyopathy, myocardial ischemia, cerebral ischemia and reperfusion, muscle weakness, hyperlipidemia , Alzheimer's disease and / or arteriosclerosis 'particularly peripheral vascular disease and myocardial ischemia. ---- -28- This paper is the standard for the national standard of the country (CNS) A4 rule stone ^ 297 public complex]----- 1308869 V. Description of the invention (A7 B7 26 In addition to its use in therapeutic medicine, The compound of formula (1) and its pharmaceutically acceptable salt or in vivo hydrolysable ester can also be used as a pharmacological tool to develop and standardize in vitro or in vivo test systems for evaluation in laboratory animals such as cats, dogs, rabbits, monkeys. The effect of increasing the activity of sputum in rats and mice as part of the search for novel therapeutic agents. The present invention will now be illustrated by the following non-limiting examples, wherein, unless otherwise stated: (1) Temperature is Celsius (eC); operation is carried out in a chamber or at a normal temperature, that is, at a temperature in the range of 18-25 ° C and under an inert gas such as argon atmosphere; (π) the organic solution is dehydrated on anhydrous magnesium sulfate; the solvent is evaporated using rotary steaming

The hair dryer is subjected to a reduced pressure (600-4000 bar; 4.5-30 mmHg) and a bath temperature of up to 60 ° C. (iii) Chromatography refers to flash chromatography on crushed rubber: Bi 〇tage匣 means KP-SILTM vermiculite, 60 angstroms, 32-63 mm particle size, supplied by Biotage 'Dyax Division, 1500 Avon Street, Charlottesville, VA 22902, USA; _ (iv) Normal response The process followed by TLC and reaction time are for illustrative purposes only; (v) Yield is for illustrative purposes only and is not required for development by diligent methods; preparation is repeated when more material is required; (vi) when given, NMR The data is the delta value form for most diagnostic protons, measured in ppm (ppm) relative to the internal standard tetramethyl decane (TMS), at 300 MHz (unless otherwise stated), using full 氘Dimethyl hydrazine (DMS 0 - δ 6) as solvent; and peak multiplicity is shown as follows: s, single line; d 'double line: dd, double double line; t, triple line; tt, triple -29 - The paper size is based on the China National Standard (CNS) A4 specification (210 X 297 mm)

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1308869 A7 ______B7 V. Description of invention (27) Double line 'q' quadruple line; tq 'triple four line; mountain, township line, heart, wide, (10) Chemistry (4) has its general meaning: make (4) Units and symbols; (viii) solvent ratio is volume: volume (v/v) term; (iv) mass spectrum (then) is performed with electron energy of 7 〇 electron volts, direct exposure probe is used in chemical ionization (α) mode Needle; the ionization system shown therein is performed by electron impact (ΕΙ), fast atomic strike (FAB) or electric nozzle method (Esp); is the m/Z value; usually only the ion showing the parent mass is reported and unless otherwise There is a description of the value of 'reference (M-Η)·; (X) using the following abbreviations: NMP 1 -methyl-2 · ketone ketone DMF N, N-methylmethalamine THF tetrahydrofuran; DCM A gas-fired; and EtOAc ethyl acetate; (xi) when (R) or (S) stereochemistry is introduced at the beginning of the name, the stereochemistry indicated is -NH-C(0)-C*(Me) The center of (CF3) (0H) is as described in equation (1). fExample 1 (Ή·)-Ν-Γ2 - chaotic-4 -ethyl indeed brewed base - 3- (4-a 6 six fee. g this g-nutrient) policy ι_ 2-hydroxy-2-A -3.3.3-Tri-propane decylamine furfural (0.77 g) and sodium triethoxy hydride argon borohydride (loo gram) by adding (R)-N-(2·gas-4-ethyl term SS group -3- hexahydro 9 to 0 well -1-yl stupyl) · 2 · carbyl 2 - fluorenyl-3,3,3 - triterpene amide (0.467 g; method 1) at 1,2_ A stirred solution of dioxin (9 ml). Mix the reaction mixture at room temperature for 6 hours, -30 -_ This paper scale is applicable to China National Standard (CMS) A4 specification (210 X 297 mm) A7 B7 1308869 V. Invention description (28) Then add 1 M NaOH solution (20 mL), and product was extracted with DCM (3x30 mL). The combined organic extracts were crystallized eluted eluted elut elut elut elut elut elut elut elut NMR: l.ll (3H, t), 1.60 (3H, s), 2.1 (^ 2.18 (2H, m), 2.21 (3H, s), 2.70-2.82 (4H, m), 3.53 (2H, q) , 3.55-3.62 (2H, m), 7.91 (1H, d), 8.07 (1H, brs), 8.23 (1H, d), 9.94 (1H, brs); m/z: 456. f. Example 2 -. Nitro-4-ethylsulfonyl-3-f4-methylidate six i. pyridinium 2-hydroxy-3,3,3·trifluoropropionamide Γ#代贺法) 1·methyl Hexahydropyrazine (0.102 g) was added (R)-N-(4-ethylsulfonyl-3- gas-2-chlorophenyl)-2-yl-2-methyl-3,3, 3-Tris-propylamine (Example 15 of w〇01/17956; 0.096 g) was mixed in NMP (1 mL). The reaction mixture was heated at 130 ° C for 24 hours. The reaction mixture was allowed to cool, then a saturated solution of ammonium sulphate (100 mL) was added and the product was extracted with EtOAc (3×100 mL). The organic extract is dehydrated and the volatiles are removed by evaporation. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) ), 2.10-2.18 (2Η, m), 2 21 (3H, s), 2.70-2.82 (4H, m), 3.53 (2H, q), 3.55-3.62 (2H m), 7.91 (1H, d), 8.07 (1H, brs), 8.23 (1H, d), 9.94 〇H' brs); m/z: 456 of Example 3

(RVN42-gas-4-B, a certain M,

A7 B7 1308869 V. INSTRUCTIONS (29 ) 莘 莘 I-2·鼗-2-methyl-3J,3-trifluoropropenetriethylamine (0.091 g) and methylsulfonate (0.124 g) Add (r)_N_(2-gas-4-ethylsulfonyl-3-hexafluoroindole-1-ylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropane The guanamine (〇.401 g; Method 1) was stirred off in DCM (1 mL). The reaction mixture was taken up for 2 hours, then a saturated aqueous solution (20 mL) was added and the product was extracted with DCM (3×30 mL). The organic extract is dehydrated and the volatiles are removed by evaporation. The residue was purified by EtOAc EtOAc (EtOAc) :^1^11(匚〇(:13): 1.26 (3H, ΐ), 1·78 (3Η, s), 2.86 (3H, s), 3.01-3.18 (4H, m), 3.39 (2H, q ), 3.68 (1H, s), 3.75-3.87 (4H, m), 8.01 (1H, d), 8.57 (1H, d), 9.62 (1H, brs); m/z: 520. Paste Example 4 Γ2 -Ga-4-ethyl awake base-3-(~4-甲培酿签六翁.ϋΐ^ι»和_丨_某) Momo 1-2·hydroxy-2-methyl-3,3 , 3-trifluoropropionamide f for night sputum method) 1 - A succinyl hexafluoropyrene 11 well (0.370 g) by adding (r) _n-(4-ethyl fluorenyl-3-trans- 2-Phenylphenyl)-2-yl-2-methyl-3,3,3-trifluoropropanol (Example 15 of WO 01/17956; 0.213 g) was mixed in NMP (2 mL) Solution. The reaction mixture was heated at 150 ° C for 48 hours, allowed to cool, and then a saturated solution (100 mL) was added. The product was extracted with diethyl ether (3×100 mL). The organic extract was dehydrated and the volatiles were removed by evaporation. Residues were purified by chromatography on Biotage (8 g ver.) and eluted with 50-70% EtOAc / EtOAc. The product was then recrystallized from EtOAc / EtOAc (EtOAc: EtOAc: EtOAc (EtOAc: EtOAc) National Standard (CNS) A4 Specification (210 X 297 mm)

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Line 1308869 A7 B7 V. Description of invention (3〇) (3H, s), 2.86 (3H, s), 3.01-3.18 (4H, m), 3.39 (2H, q), 3.68 (1H, S), 3.75- 3.87 (4H, m), 8.01 (lH, d), 8.57 (1H, d), 9.62 (1H, brs); m/z: 520 °

It-4-L 砝 早 早 夂 夂 夂 夂 夂 砩 砩 砩 砩 砩 芣 芣 芣 砩 砩 砩 砩 砩 砩 砩 砩 砩 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲g) by adding (Han)-yi (4-ethylsulfonyl-3-fluoro-2-indolyl)-2.hydroxy-2-methyl-3,3,3-trifluoropropanamide ( Example 15 of WO 01/17956; 4.14 g) Stirred solution in NMP (15 mL). The reaction mixture was heated at 15 (TC) for 24 hours, allowed to cool, then a saturated solution (3.00 mL) was added. The product was extracted with a riddle (3 x 1 〇〇 ml). The organic extract was dehydrated and evaporated. The material was removed by evaporation. The residue was purified by chromatography on EtOAc EtOAc EtOAc (EtOAc) Then, it was stirred for 30 minutes at room temperature. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) ) is a solid NMR: 1.12 (3Η, t), 1.60 (3Η, s)' 2.74-2.86 (6Η,m), 3.48-3.59 (4H,m),7·89 (1H,d),8.22 (1H , d); m/z: 442 '. ' -33-

Claims (1)

1308869 Patent application No. 091119132 Chinese patent application scope replacement (November 1994) A8 B8 C8 D8 VI. Patent application scope 1. A compound of formula (I): Wherein R is an indenyl or sulfonyl group; or a pharmaceutically acceptable salt thereof. 2. A compound of formula (I) according to claim 1 wherein R is a thiol group or a pharmaceutically acceptable salt thereof. 3. A compound of formula (I) according to claim 1 wherein R is methylsulfonyl, or a pharmaceutically acceptable salt thereof. 4. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, wherein R is as defined by formula (I), unless otherwise Illustrated) includes: (a) Deprotection of protected compounds of formula (II): 〇, ◊〇 Where Pg is the alcohol protecting group; 79891-941102.doc This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1308869 8 8 8 8 AB c D VI. Patent application scope (b) III) Compound Oxidation: [0]a Where a is 0 or 1; (c) a compound of formula (IV): Ο 0 Coupling with the acid of formula (V): Where X is OH; 79891-941102.doc -2- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1308869 A8 B8 C8 D8 VI. Patent application scope (d) Formula (IV) Coupling of aniline with an activated acid derivative of formula (V); (e) a compound of formula (VI): Ο 〇 Wherein L is a substitutable group; reacted with a 4-sulfonylsulfonylhexahydropyridyl or 4-mercaptohexahydrop-p well; (f) a compound of formula (1) wherein R is a mercapto group, formula (VII) Compound thiolation: Ο 〇 (g) fluorinating a compound of formula (VII) with a compound of formula (I) wherein R is a methylsulfonyl group; (h) chlorinating a compound of formula (VIII): 79891-941102. Doc - 3 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1308869 8 8 8 8 A BCD VI. Patent application scope Ο 0 (i) converting a functional group of a compound of formula (IX) to chlorine: 〇 〇 Wherein Fg is a functional group; (j) an organometallic reagent is added to the compound of formula (X): Ο 0 (k) Adding an organometallic reagent to the compound of formula (XI): 79891-941102.doc -4- This paper scale applies to China National Standard (CNS) A4 specification (210 X297 mm) 1308869 A8 B8 C8 D8 Patent application scope 0...Ο (XI) (1) A compound of the formula (V) wherein X is ΝΗ2 is added to the compound of the formula (XII): 〇, ◊〇 (XII) wherein L is a substitutable group; (m) a compound of formula (XIII) is reorganized by Smiles 0...〇 (XIII) or (η) separating the (R) and (S) mirror-isomeric mixtures of the compound of formula (I) to give (R)-mirromer; 79891-941102.doc This paper scale applies to Chinese national standards ( CNS) Α4 Specifications (210X 297 metric tons) 1308869 Patent pending Fan Park 5.: η:! 'Formed in pharmaceutically acceptable salts. The pharmaceutically acceptable compound of formula (1) or the salt thereof is used as a medicament. ^ ί 11 Γί 1 ·3 ίΜ 17 ^ ^ a)^t ^ ^ Animals such as humans are used to make agents for the blood-staining of the PDH activity. 7—A pharmaceutical preparation for the treatment of diabetes in a warm-blooded animal such as a human being, which is medicinally acceptable, in the form of a pharmaceutical compound (1). ί 2 in: blood animals, such as humans, to produce elevated PDH activity, including, for example, the scope of the patent scope of the patent, item 匕, 匕 or its pharmaceutically acceptable Salt, together with medicinal; owed excipients or carriers. 9. A pharmaceutical composition for the treatment of diabetes in warm-blooded animals such as humans is included in any of the scope of patent application _3 A compound of formula (1) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient or carrier. -6 - 79891-941102.doc This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 PCT)