HK1125922B - N-substituted thiomorphoine derivatives and their pharmaceutical compositions as inhibitors of dipeptidyl peptidase iv (dpp-iv) - Google Patents

Description

N-substituted thiomorpholine derivatives as dipeptide peptide kinase-IV inhibitors and their medical use

Technical Field

The present invention relates to N-substituted thiomorpholine compounds as inhibitors of dipeptide peptide kinase IV (DPP-IV), all possible isomers thereof, pharmaceutically acceptable salts thereof, solvates or hydrates thereof or prodrugs thereof; as well as a preparation method of the compound shown in the formula I, a pharmaceutical composition containing the compound shown in the formula I and application of the compound in the medical field, in particular application in preparing medicines for treating and preventing diabetes (especially type II diabetes), hyperglycemia, syndrome X, hyperinsulinemia, obesity, atherosclerosis and various immunomodulatory diseases.

Background

Dipeptide peptide kinase IV (DPP-IV) is a widely expressed multifunctional type II transmembrane glycosylated protein in a variety of mammalian tissues, a T cell activation antigen CD26, and an Adenosine Deaminase (ADA) -binding protein. The single chain of human DPP-IV (hDPP-IV) is composed of 766 amino acids, and is divided into 5 structural regions: cytoplasmic (1-6), transmembrane (7-28), hyperglycosylation (29-323), cysteine-rich (324-551) and catalytic (552-766) regions, which differ slightly in length from species to species. Soluble DPP-IV is a homodimer of about 210-290 kDa and can also be polymerized into complexes of up to 900 kDa. DPP-IV binds to the membrane via a hydrophobic helix at the amino terminus formed by a hyperglycosylation domain and a cysteine-rich domain, and the serine protease domain at the carboxy terminus is homologous to the α/δ hydrolase. The dimeric form is a prerequisite for its activity (heterodimers are the fibroblast activity protein FAP α).

DPP-IV is widely recognized to play an important role in neuropeptide metabolism, T cell activation, cancer cell attachment to the endothelium, and HIV entry into lymphocytes. DPP-IV is capable of specifically cleaving dipeptides from peptides in which the penultimate amino acid is predominantly proline, alanine or hydroxyprolineThe N-terminus is cleaved off. Its action substrate is included in T₂Two incretins that play important roles in the DM immune response signaling process: fragments of glucagon-like peptide 1 (GLP-1)_7-36) And Gastric Inhibitory Peptide (GIP)_1-42). GLP-1 and GIP are incretins secreted from L cells and K cells of the gastric mucosa in response to ingested carbohydrates and fats, respectively, and play a critical role in stabilizing postprandial blood glucose concentrations. After meals, the gastric mucosa stresses to secrete GLP-1 and GIP, both of which act on the pancreas to enhance glucose-induced insulin secretion, regulating blood glucose concentration. In vivo DPP-IV can hydrolyze the amino-acid to generate corresponding amino-terminal cleaved form of GIP_3-42And GLP-1_9-36Losing its insulin-inducing activity. It can be seen that inhibition of DPP-IV enhances the activity of GIP and GLP-1, and glucose tolerance levels will be improved accordingly.

The results of experiments on DPP-IV deficient mice by Marguet et al and Conarello et al show that the mice deficient in DPP-IV are completely viable and have normal phenotype, and that the mice deficient in DPP-IV have higher glucose tolerance and higher blood insulin and GLP-1 concentrations than wild-type mice.

In conclusion, the inhibition of plasma DPP-IV activity has the function of reducing blood sugar, and the action mechanism is at least three as follows: the activity of insulin is protected, the half-life period of complete GLP-1 in circulating blood is less than 1min under physiological conditions, inactive metabolites after GLP-1 is degraded by DPP-IV can be combined with GLP-1 receptors to antagonize active GLP-1, the effect of independently injecting GLP-1 is short, and endogenous or even exogenous GLP-1 can be completely protected by a DPP-IV inhibitor from being inactivated by the DPP-IV. GLP-1 is known to have various physiological activities, including promoting the expression of insulin gene, promoting the growth of beta cells, inhibiting the secretion of glucagon, increasing satiety, reducing food intake, inhibiting gastric emptying, normalizing blood glucose levels, and increasing GLP-1 levels and reducing GLP-1 metabolite antagonism by DPP-IV inhibitors. In addition, the GIP secreted from the upper k cells of the small intestine acts on a G protein-coupled receptor to cause the increase of adenylate cyclase activity, activate enzyme A2. to increase the level of intracellular calcium ions, and promote the release of insulin. GIP also promotes transcription and translation of the preproinsulin gene, up-regulates plasma membrane glucose transport and increases β -cell hexokinase activity, and thus GIP has a therapeutic effect on type II diabetes (T2 DM). However, similarly to GLP-1, endogenous GIP is also rapidly inactivated by DPP-IV. After intravenous injection of GIP in pigs by Deacon et al, the radioimmunoassay showed only 14.5% intact GIP immunoreactivity. When the immune activity of GIP was increased to 49% by using DPP-IV inhibitor, it was revealed that DPP-IV, though not the only GIP-degrading enzyme in vivo, plays an important role in its inactivation. DPP-IV inhibitors are shown to protect active incretins and to exert their effect.

Two of the two stimulation islet beta cell regeneration, Pospisilik and the like give P32/98 (a DPP-IV inhibitor) to streptozotocin induced DM male mice, 2 times/d, and after 7 weeks, the immunohistochemistry analysis shows that the islet number is increased by 35 percent compared with a control group, the total beta cell number is increased by 120 percent, the islet beta cell fraction is increased by 12 percent of a product variety, and the plasma insulin level is close to normal. The effect of the DPP-IV inhibitor on stimulating insulin regeneration and improving beta cell survival is probably to improve the combination of GLP-1 and GLP-1 receptors on the surface of islet-derived precursor cells (NIPs) positive to islet nestin so as to promote the differentiation of the NIP cells into islet cells.

And the research shows that the DPP-IV inhibitor not only has a treatment effect on DM, but also has a prevention effect on delaying the generation and development of DM. Sudre et al treated obese mice with FE999011, a long acting DPP-IV inhibitor, demonstrated that FE999011 slows glucose release dose-dependently, and that FE999011 increased glucose tolerance at 10mg/kg, 2 times/d. The long-term treatment with the same dosage can delay the hyperglycemia of the obese mice for 21 days, simultaneously improve the symptoms of polydipsia, polyphagia and the like, reduce the occurrence of hypertriglyceridemia, prevent the free fatty acid in blood from rising, improve the GLP-1 level of basic blood plasma after treatment, and obviously up-regulate the GLP-1 receptor gene expression of pancreas. Therefore, researchers believe that DPP-IV inhibitors can delay the progression to type II diabetes due to impaired glucose tolerance. Another study suggests that application of DPP-IV inhibitor can improve impaired glucose tolerance, increase insulin sensitivity, and improve the response of beta cells to glucose.

Thus, inhibition of DPP-IV may provide a treatment for type II diabetes and other DPP-IV mediated diseases.

Disclosure of Invention

The invention aims to provide a dipeptide peptide kinase IV (DPP-IV) inhibitor with a novel structure type, which can protect intestinal insulin from being degraded, improve abnormal glucose tolerance and increase insulin sensitivity by inhibiting the activity of the dipeptide peptide kinase IV so as to achieve the purpose of reducing blood sugar, thereby effectively treating diabetes and other DPP-IV regulated diseases.

The present invention provides novel compounds of general formula I as defined in the claims, or all possible isomers thereof, pharmaceutically acceptable salts thereof, solvates or hydrates thereof, or prodrugs thereof,

formula I

Wherein:

r1 is selected from hydrogen, cyano, halogen or trifluoromethyl;

a is an amino acid having at least one functional group in its side chain;

b is a compound connected with the A side chain functional group by a covalent bond and is selected from polypeptide consisting of 0-5 amino acids.

In one embodiment of the invention, A in formula I is an alpha-amino acid.

In another embodiment of the invention, A in formula I is a natural alpha-amino acid.

In another embodiment of the invention, A in formula I is an unnatural amino acid.

In another embodiment of the present invention, a in formula I is selected from leucine, valine, glycine, alanine, valine, isoleucine, phenylalanine, proline, tryptophan, serine, tyrosine, cysteine, preferably valine.

The most preferred compounds of the invention are:

compound 1: (R) -3-cyano-4- (2-amino-3-methyl-butyryl) thiomorpholine hydrochloride; or

Compound 2: (R) -3-cyano-4- (2-amino-4-methyl-pentanoyl) thiomorpholine hydrochloride; or all possible isomers, pharmaceutically acceptable salts, solvates or hydrates thereof, or prodrugs thereof.

Another aspect of the present invention relates to a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof.

The compounds of formula I of the present invention can be prepared by the following reaction scheme, reacting BOC-protected A with (R) -3-amidothiomorpholine according to the following formula:

wherein A is an amino acid having at least one functional group in its side chain, preferably valine and leucine.

Specifically, after BOC protection of amino acid, (R) -3-amidothiomorpholine) was dissolved in dry THF in equimolar amounts, 1.5 times of EDCI and 1.5 times of HOBT were added, 2 times of diisopropylethylamine was added dropwise, and the mixture was stirred at room temperature for 12 to 16 hours. Concentrating under reduced pressure after reaction, diluting with water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate for 4 hr, removing solvent under reduced pressure, dissolving the residue in dry THF, adding 2 times of trifluoroacetic anhydride, stirring for 1 hr, and adding saturated NaHCO₃Washing with water until no air bubbles appear, extracting with ethyl acetate, and drying with anhydrous sodium sulfate 4And h, separating by silica gel column chromatography (ethyl acetate: cyclohexane is 1:4) to obtain colorless oily substance, dissolving the colorless oily substance in 3N ethyl acetate hydrochloride, and stirring for 5h to obtain the compound. If desired, the compounds of formula (I) are converted into their pharmaceutically acceptable salts or solvates or hydrates or prodrugs thereof according to methods conventional in the art.

The invention also relates to a preparation method of the compound of the formula III, wherein the compound of the formula III is a key intermediate for synthesizing the compound of the formula I, the invention provides a novel, simple and feasible stereospecific cyclization reaction which is suitable for large-scale synthesis, the stereospecific compound of the formula III can be obtained, the compound of the formula III is converted into the compound of the formula II through ammoniation, and the compound of the formula II can further react with A to obtain the compound of the formula I.

Formula IIIFormula II

The compounds of formula III according to the invention can be prepared by the following reaction scheme:

formula IV formula III

Specifically, the compound of the formula IV is subjected to stereoselective ring closure in water under the action of an acid-binding agent and alkali to obtain the compound of the formula III. The acid-binding agent base includes, but is not limited to, sodium hydroxide, potassium hydroxide, triethylamine, sodium bicarbonate, sodium carbonate, etc., preferably sodium bicarbonate.

The preparation of the specific compound of formula III, (R) -3-carboxylic acid methyl ester thiomorpholine hydrochloride can be seen in example 1.

The invention also relates to pharmaceutical compositions containing a compound of formula (I) or all its possible isomers, pharmaceutically acceptable salts, solvates or hydrates or prodrugs thereof, together with one or more pharmaceutically acceptable carriers or excipients.

"pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients that make up a carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of these ingredients, or from decomposition of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Thus, the pharmaceutical compositions of the present invention include any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention may also comprise one or more other compounds as active ingredients, for example one or more other DPP-IV inhibitors, said other active ingredients being selected from insulin sensitizers, PPAR agonists, biguanides or PTP-1B inhibitors and the like.

Another aspect of the present invention relates to the use of a compound of formula (I) of the present invention or all its possible isomers, a pharmaceutically acceptable salt, solvate or hydrate thereof or a prodrug thereof, for the manufacture of a medicament for the treatment of dipeptide peptide kinase IV related diseases including, but not limited to, diabetes (especially type II diabetes), hyperglycemia, syndrome X, hyperinsulinemia, obesity, atherosclerosis and various immunomodulatory diseases.

Another aspect of the present invention relates to a method for the treatment of diseases associated with dipeptide peptide kinase IV, including but not limited to diabetes (especially type II diabetes), hyperglycemia, syndrome X, hyperinsulinemia, obesity, atherosclerosis and various immunomodulatory diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) of the present invention or all its possible isomers, a pharmaceutically acceptable salt, solvate or hydrate thereof, or a prodrug thereof.

Detailed Description

The following specific examples are illustrative of the preferred embodiments of the present invention, but are not intended to limit the invention in any way.

The melting point of the compound was determined by a RY-1 melting point apparatus, with no correction by thermometer. Mass spectra were determined by a Micromass ZabSpec high resolution mass spectrometer;¹H-NMR was measured by JNM-ECA-400 superconducting NMR instrument, operating frequency¹H-NMR400MHz。

Example 1

Preparation of (R) -3-amidothiomorpholine

Step 1Preparation of 2-hydroxyethylcysteine

109.5g (0.9mol) of L-cysteine was taken, placed in a 2000ml flask and dissolved in 1000ml of water. Then 24ml of 1mol/l NaOH solution is added, the mixture is placed in an ice bath, 96ml (1.8mol) of ethylene oxide is taken, the mixture is slowly dropped into the cysteine solution under the ice bath, the mixture is stirred for one hour, the ice bath is removed, the temperature is returned to the room temperature, and the reaction is carried out for one hour. The mixture was extracted with 1000ml of dehydrated ether in four times, and the water layer was retained. The aqueous layer was evaporated to dryness to give yellow crystals, washed with water: ethanol 85 ml: 350ml of recrystallization is carried out, after filtration, 2000ml of 95 percent ethanol is used for washing, and 121.8g of white crystal is obtained after drying, and the yield is 74.3 percent.¹H-NMR(400MHz，D₂O)δ：2.80(t，2H，J＝6.036Hz)，3.08(dd，1H，J₁＝7.48Hz，J₂＝14.80Hz)，3.18(dd，1H，J₁＝4.27Hz，J₂＝14.81Hz)，3.77-3.81(m，2H)3.96(dd，1H，J₁＝4.272Hz，J₂＝7.816Hz)

Step 2Preparation of 2-chloroethylcysteine

40g (0.24mol) of 2-hydroxyethylcysteine was taken out and placed in a 1000ml flask, 550ml of concentrated hydrochloric acid was added thereto, and the mixture was refluxed for 7 hours, and then allowed to stand at room temperature to precipitate white crystals. Filtering and drying to obtain 41.6g of white crystals, and the yield is 93.8%.¹H-NMR(400MHz，D₂O)δ：，3.01-3.04(m，2H)，3.12(dd，1H，J₁＝7.35Hz，J₂＝15.07Hz)，3.26(dd，1H，J₁＝4.444Hz，J₂＝14.984Hz)，3.78-3.84(m，2H)4.27-4.30(m，1H)

Step 3Preparation of methyl 2-chloroethyl-caspase hydrochloride

39g (0.21mol) of 2-chloroethylcysteine was dissolved in 500ml of anhydrous methanol and cooled in an ice bath. 80ml (1.1mol) of thionyl chloride was slowly dropped under ice bath conditions, and after the addition, the temperature was raised to room temperature and the reaction was carried out at room temperature for 24 hours. The solvent was distilled off under reduced pressure, dissolved in anhydrous methanol (200 ml. times.2) and then evaporated to dryness to remove excess thionyl chloride. The obtained solid was recrystallized from 50ml of anhydrous methanol and 160ml of anhydrous ether to obtain 37.5g of white crystals, with a yield of 76.1%. .¹H-NMR(400MHz，D₂O)δ：2.99-3.049(m，2H)3.20(dd，1H，J₁＝7.50Hz，J₂＝14.00Hz)3.34(dd，1H，J₁＝4.480Hz，J₂＝15.034Hz)，，3.78-3.82(m，2H)，3.90(s，3H)4.45(dd，1H，J₁＝4.50Hz，J₂＝7.48Hz)

Step 4Preparation of (R) -3-carboxylic acid methyl ester thiomorpholine hydrochloride

Dissolving 20g (0.085mol) of 2-chloroethylcysteine methyl ester hydrochloride in 200ml of water, dropwise adding a solution of 7.2g (0.085mol) of sodium bicarbonate in 120ml of water under ice bath, reacting for 1 hour at constant temperature under ice bath, stopping the reaction, extracting with ethyl acetate (100ml multiplied by 3) for three times, combining ester layers, drying for 4 hours by using anhydrous sodium sulfate, evaporating the solvent under reduced pressure, dissolving the residue in 400ml of anhydrous methanol, stirring and reacting for 5 days at normal temperature, evaporating the solvent under reduced pressure, and recrystallizing the residue with anhydrous methanol/ethyl acetate to obtain 8.9g of white crystals with the yield of 49.2％。¹H-NMR(400M Hz，DMSO-d₆)δ：2.86-2.88(m，1H)，2.96-2.99(m，1H)3.06-3.22(m，3H)3.48-3.50(m，1H)，，3.78(s，3H)4.42(dd，1H，J₁＝3.52Hz，J₂＝8.56Hz)10.1(brs，2H)

Step 5Preparation of (R) -3-amidothiomorpholine

Taking 8.9g (0.042mol) of (R) -3-carboxylic acid methyl ester thiomorpholine hydrochloride to dissolve in 200ml of anhydrous methanol, introducing ammonia gas to react for 48 hours, evaporating the solvent, dissolving the residue with anhydrous ethanol, filtering out insoluble substances, evaporating the solvent to dryness, and recrystallizing the residue with anhydrous methanol/anhydrous ether to obtain 5.44g of white crystals, wherein the yield is 89.2%.¹H-NMR(400M Hz，CDCl₃)δ：¹H-NMR(400HMZ，CDCl₃)δppm：2.45～2.47(d，1HJ＝8.4Hz)2.50～2.55(m，2H)2.56～2.58(m，1H)3.21～3.28(m，2H)5.33(s，1H)7.08(s，1H)7.26(s，1H)

Example 2

Compound 1: preparation of (R) -3-cyano-4- (2-amino-3-methyl-butyryl) thiomorpholine hydrochloride

Boc-VaL0.217g (0.001mol) and 0.147g (0.001mol) of (R) -3-amidothiomorpholine prepared in example 1 were dissolved in 20ml of dry THF, 0.29g (0.0015mol) of EDCI and 0.18g of HOBT (0.0015mol) were added dropwise, and 0.35ml (0.002mol) of diisopropylethylamine was added dropwise and stirred at room temperature for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, diluted with 20ml of water, extracted with ethyl acetate 50 ml. times.3, the organic phase was dried over anhydrous sodium sulfate for 4 hours, the solvent was removed under reduced pressure, the residue was dissolved in 20ml of dry THF, 2.8ml (0.002mol) of trifluoroacetic anhydride was added, stirred for 1 hour, and then saturated NaHCO was used₃Washing with aqueous solution until no air bubble appears, extracting with ethyl acetate (50 ml. times.3), drying over anhydrous sodium sulfate for 4h, separating by silica gel column chromatography (AcOEt: Cyclohexane ═ 1:4) to obtain colorless oil,dissolved in 30ml of 3N ethyl acetate hydrochloride and stirred for 5h, a white precipitate appeared, which was filtered off and the filter cake was washed with ethyl acetate to give the title compound as a white solid 0.072g with a yield of 27.2%.¹H-NMR(400HMZ，DMSO)δppm：0.90～0.95(m，6H)2.01～2.06(m，1H)2.50(s，1H)2.85～3.01(m，3H)3.39～3.44(m，1H)4.33～4.44(m，2H)6.15(s，1H)8.43(brs，3H)FAB-MS m/e:228[M+1]⁺。

Example 3

Compound 2: preparation of (R) -3-cyano-4- (2-amino-4-methyl-pentanoyl) thiomorpholine hydrochloride

Boc-Leu0.231g (0.001m0l) and (R) -3-amidothiomorpholine prepared in example 1 0.147g (0.001mol) were dissolved in 20ml of dry THF, 0.29g (0.0015mol) EDCI and 0.18g HOBT (0.0015mol) were added dropwise, and diisopropylethylamine 0.35ml (0.002mol) was added dropwise and stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with 20ml of water, extracted with ethyl acetate (50 ml. times.3), the organic phase was dried over anhydrous sodium sulfate for 4 hours, the solvent was removed under reduced pressure, the residue was dissolved in 20ml of dry THF, 2.8ml (0.002mol) of trifluoroacetic anhydride was added thereto, stirred for 1 hour, and then saturated NaHCO was used₃The aqueous solution was washed until no air bubbles appeared, ethyl acetate (50ml × 3) was extracted, dried over anhydrous sodium sulfate for 4 hours, and subjected to silica gel column chromatography (ethyl acetate: cyclohexane ═ 1:4) to obtain a colorless oil, which was dissolved in 30ml of 3N ethyl acetate hydrochloride and stirred for 5 hours to cause white precipitates, and after filtration, the cake was washed with ethyl acetate to obtain 0.096g of the objective compound as a white solid in 34.8% yield.¹H-NMR(400HMZ，D₂O)δppm：0.77～0.81(m，6H)1.41～1.61(m，1H)2.48～2.52(d，1HJ＝7.6Hz)2.68～2.28(m，2H)2.90～2.95(m，1H)3.51～3.57(t，2H J＝12.4Hz)3.88～3.93(d，1HJ＝14.4Hz)3.35～3.70(m，1H)5.97(s，1H)EI-MS m/e:241[M⁺]。

Examples4Determination of the inhibition Rate and IC of DPP-IV peptidase Activity of Compounds 1 and 2₅₀

Step 1DPP-IV preparation

Human colon cancer cell line cells (Caco-2) culture: caco-2 cells were cultured in DMEM (high-sugar, containing 10% fetal bovine serum, 1% NAA) medium, the cells were passaged at a ratio of 1:1 or 1:2 to make the cells grow close to confluency, the culture was continued for 2-3 weeks with liquid change every 2-3 days, the cells were observed to show brush border protrusions indicating that the cells had differentiated, and the cells were collected. DPP-IV preparation: washing cells with precooled PBS for 2-3 times, adding 0.5-1ml of ice-cold 10mM Tris-HCl (containing 0.15M NaCl, 0.04t.i.u aprotinin, 0.5% nonionic detergent P40, PH8) into each culture flask, dissolving the cells, collecting the cells into a centrifuge tube, centrifuging at 4 ℃ and 35000g for 30min, taking supernatant, measuring protein content, and storing in a low-temperature refrigerator.

Step 2:DPP-IV activity assay and Compound screening

The experiment is divided into: enzyme control group, substrate control group, enzyme reaction control group, compound group were performed in 96-well plate, reaction system 150. mu.l. Diluted test compound was added to the compound group in 96 well plates at 30 μ l/well; adding 20 μ l of DPP-IV enzyme solution into an enzyme control group, and adding 20 μ l of DPP-IV enzyme solution into a compound group; adding analysis buffer (25Mm Tris-HclPH7.4 containing 140mM NaCl, 10Mm KCl, 1% bovine serum albumin), 130 μ l enzyme control group, 125 μ l substrate control group, 105 μ l enzyme reaction control group, and 75 μ l compound group; the reaction was started by adding 25. mu.l of substrate (1mM) and the reaction time was 10min at room temperature. No substrate was added to the enzyme control; after reacting for 10min, adding 19 mul/hole 25% glacial acetic acid to terminate the reaction; absorbance was measured by a microplate reader at 405nM wavelength, and calculated inhibition was shown in the following table.

Claims (7)

1. A compound selected from:

(R) -3-cyano-4- (2-amino-3-methyl-butyryl) thiomorpholine hydrochloride;

(R) -3-cyano-4- (2-amino-4-methyl-pentanoyl) thiomorpholine hydrochloride;

or a pharmaceutically acceptable salt thereof.

2. A process for the preparation of a compound according to claim 1, which process comprises reacting BOC-protected a with (R) -3-amidothiomorpholine according to the formula:

wherein A is leucine or valine.

3. The process of claim 2, wherein the key intermediate (R) -3-amidothiomorpholine in the process is prepared as follows: in water and under the action of acid-binding agent alkali, carrying out stereoselective ring closure on the compound shown in the formula IV to obtain a compound shown in the formula III:

the compound of formula III is then converted to (R) -3-amidothiomorpholine by amination.

4. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

5. Use of a compound of claim 1 for the preparation of a dipeptide peptide kinase iv inhibitor.

6. Use of a compound of claim 1 for the manufacture of a medicament for the treatment and/or prevention of a dipeptide peptide kinase iv related disease selected from the group consisting of diabetes, hyperglycemia, syndrome X, hyperinsulinemia, obesity, atherosclerosis.

7. The use of claim 6, wherein the diabetes is type II diabetes.