TW200938200A - Methyl-substituted piperidine derivative - Google Patents

Abstract

Disclosed is 2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]- 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile having high DPP-IV inhibitory activity and improved safety and toxicity, or a pharmaceutically acceptable salt thereof.

Description

200938200 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to 2-({6-[(3R)-3-amino-3-methylpiperidin-yl]-indole, 3-dimethyl -2,4-di-oxyl-1,2,3,4-tetrahydro-5H.pyrrole[3,2-d]pyrimidinyl-yl}fluorenyl-4-fluorobenzonitrile (hereinafter, as needed It is sometimes abbreviated as Compound A) or a pharmaceutically acceptable salt thereof (hereinafter, Compound a or a pharmaceutically acceptable salt thereof may be simply referred to as a compound of the present invention as needed). The compound of the present invention can be used as a medicine, and more specifically, can be effectively used as a dipeptidyl peptidase IV (DPP-IV) inhibitor. The present invention further relates to a therapeutic agent for diabetes containing the compound of the present invention as an active ingredient. [Prior Art] Various DPP-IV inhibitors have been reported so far, for example, as disclosed in Patent Documents 1 and 2, a compound having a pyrrole [3,2-d]pyrimidine ring can be effectively used as a DPP-IV inhibitor. . However, the compounds of the present invention are not specifically described in these documents. [Patent Document 1] International Publication No. 2006/068163 Handbook [Patent Document 2] International Publication No. 2007/07 1738 Manual [Disclosure] [Problems to be Solved by the Invention] An object of the present invention is to provide an excellent DPP_IV. A new compound that inhibits activity. [Means for Solving the Problem] The inventors of the present invention conducted intensive studies to achieve the above problems, and as a result, found that the compound of the present invention has an excellent DPP-IV inhibitory action. Further, 136433.doc 200938200 is now: The following experimental examples show that the metabolic reaction inhibiting structurally similar compounds have a dependence-dependent-inhibition (MBI 'mechanical inhibition, thorn), and The compounds of the present invention can avoid MBI, thereby completing the present invention. That is, the present invention relates to the following: Π] 2-({6-[(3R)_3-amino-3'methylpiperidin+yl]_13_dimethyl-2,4_di-oxy-1 , 2,3,4-tetrahydro-5H_n piroxime [3,2_d]-nose-5-yl}methyl-4-fluorobenzonitrile or a pharmaceutically acceptable salt thereof;

[2] 2-({6-[(3R)-3-Aminomethyl(tetra))yl]13 dimethyl_24_di- oxy-^4.tetrahydro- 5H" than slightly 幷[3,2_d (4) _5_ yl} methyl) _ 4-fluorobenzonitrile; [3] a peptidyl peptidase iv inhibitor comprising the compound of (1) or a pharmaceutically acceptable salt thereof, or as in [2] And a compound for the treatment of diabetes, which comprises the compound of (1) or a pharmaceutically acceptable salt thereof, or a compound according to [2] as an active ingredient. [Effects of the Invention] The compound of the present invention is excellent £) 乂 乂 乂 乂 乂 乂 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 "Glucosin-like peptide-丨)" has the effects of promoting insulin secretion depending on blood sugar levels, improving pancreatic function, improving postprandial hyperglycemia, improving glucose intolerance, and improving insulin resistance, thereby being useful as type 2 diabetes Therapeutic drugs (non-insulin dependent diabetes) (RA Pederson et al, I36433.doc 200938200

Diabetes Vol. 47, pp. 1253-1258, 1998). On the other hand, the irreversible inhibition of metabolic enzymes is called Mechanism-based-inhibitic^MBI). It is characterized in that it is temporarily suppressed after the administration of the drug is stopped. The mechanism is known to be that a metabolite produced by a metabolic enzyme forms a stable complex with the metabolic enzyme or is covalently bonded to the metabolic enzyme. The agent having the function of the drug and the agent metabolized by the enzyme of (4) are used together with the blood concentration of the drug after the promotion, thereby causing the drug interaction. Here, the drug having the function of MBI is a drug which is not easily used, such as limited use. For example, there are reports: the metabolites of Clarionin (4) 3 secrets (4) have the effect of MBI, and when combined with terfenadine "pool", the blood concentration of terfenadine will rise, and the heart rate will not rise. In the development of a drug with a high therapeutic effect and a high degree of safety, it is important to avoid the important issues of the MBI system. For example, the Medical Review of the Ministry of Health, Labour and Welfare In Q5 of Q&A in the "Method of Action", "When the inhibition mechanism of cytochrome is irreversible, ... whether it is necessary to carry out a clinical test" is described as ".··If you are worried In the case of a clinically harmful interaction, it is desirable to stop development. However, in predicting the development of a drug, if it is more useful than its risk, ... can be clinically tested." On the website of the Α 于, in "Guidance foi Project III (http.//www.fda.gov/cber/gdlns/metabol.htm#iii: contrast, when positive findings arise in ir 136433.doc 200938200 vitro metabolic and/or Drue-drue s lnteracti〇n studies, clinical studies are recommended·.. (phase μ* *, m pc· < lower, if positive results increase in in vitro metabolism and/or drug interaction studies, A clinical study is recommended.) BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. Compound A is a compound represented by the following formula: [Chemical Formula 1]

Examples of the "pharmaceutically acceptable salt" include inorganic acid salts such as hydrochloride, hydrogen hydrochloride, sulfate, phosphate, or nitrate, or acetate, propionate, oxalate, and amber. Acid salt, lactate, malate,

= tartrate, citrate, maleate, fumarate, methylate, benzoate, p-toluene; 5^ salt, or an acid salt such as ascorbate. Further, the present invention also includes a solvate such as a hydrate or an ethanol solvent of the compound of the present invention. Furthermore, the invention also includes all tautomers of the compounds of the invention, all stereoisomers present, and all crystal forms. Hereinafter, the method for producing the compound of the present invention will be exemplified, but the present invention is of course not limited thereto. Furthermore, in the present specification, the simplification of the description is used, and the following symbols are sometimes used. Me: methyl, Et: ethyl,: tertylene 136433.doc 200938200, Boc: tert-butoxycarbonyl The compound of the present invention can be synthesized from a well-known compound by a combination of well-known synthesis methods. For example, it can be synthesized according to the method described in International Publication No. 2006/068163. An example of this is shown below: [Chemical 2]

Step 4

136433.doc -10- 200938200

The compound (5) can be produced by reacting a compound (indicated with a chemical person) in an inert solvent. Examples of the inert solvent include an aromatic hydrocarbon solvent such as methyl, benzo or dimethyl benzene. The temperature can be selected from the range of about 3 〇 to about 100. 2) Step 2: The substance (1·7) can be compounded in an inert solvent in the presence of an organic test ( 1-5) It is produced by reacting with the compound 〇_6). Examples of the inert solvent include a nitrile solvent such as acetonitrile or propionitrile, etc. As an organic test, fluorene-diazabicyclo[54〇] Monocarbene (deletion), Μ·diazabis([4'3'〇]壬_5_female, or υ-diazabicyclo[5 4 〇]undecyl _7_ rarity. The temperature, usually can be selected within the range of about 赃~about (10), and can also be carried out under reflux. 3) Step 3 The s (1 9) can be obtained by using the solvent + in the presence of the test. The compound (1·7) is produced by reacting the compound (1·7) with the compound 〇·8). As the base, for example, carbonic acid-sodium carbonate, cesium carbonate, hydrogencarbonate #, or hydrogencarbonate can be listed. Such as carbonic acid test, Jinhuang sleeping room ± α ·, brother 'better is exemplified by potassium carbonate, etc. As an inert solvent, a non-philanthropy: u open table thousand solvents (N, N-dimethylformamidine) An amine or a dimethyl group, etc.) is a stagnation/treat agent (ether, tetrahydrofuran or ι, 4-dioxane, etc.), a ketone (C 136433.doc 200938200 - etc.) or a mixed solvent thereof, etc., preferably N-dimercaptoamine, etc. may be mentioned. The reaction temperature 'usually can be selected from the range of about 1 G ° C to about 6 (rc). 4) Step 4 The compound (M0) can be obtained by using an inert solvent towel. The compound 〇_9) is produced by reacting with an inspection lamp, and examples thereof include a metal amide such as a chloramine or a chloramine, or a hydrogenated alkali metal such as sodium hydride or potassium hydride. Examples thereof include an aromatic hydrocarbon such as toluene, benzene or xylene, a hydrocarbon solvent such as hexane or heptane, a third butanol, an acetonitrile, and an n,n-dimethylguanamine solvent.趟, tetrahydroanthracene 0, or I, heart 2, number ^, etc.) 'or these mixed solvents, etc. ◎ Regarding the conditions, as the base, lithium guanamine is preferred. As the solvent, a mixed solvent of a third butanol and acetonitrile or a mixed solvent of a third butanol, acetonitrile, heptane, and toluene is preferred. The reaction temperature is usually in the range of about 10 C to about 100 ° C. 5) Step 5 Compound (1-11) can be produced by reacting compound (1_1〇) with an inert acid in an inert solvent. Examples of the inert solvent include water, acetic acid, or propionic acid. The organic acid or an aromatic hydrocarbon solvent such as toluene, benzene or xylene is usually subjected to the reaction in a mixed solvent of water, acetic acid and toluene. The reaction temperature is usually from about 20 ° C to about 80 °. Choose within the scope of C. 6) Step 6 The compound (1-12) can be produced by reacting the compound (l-ii) with an inorganic base in an inert solvent. The inorganic base may, for example, be potassium carbonate or carbon 136433.doc • 12- 200938200 acid or sodium carbonate. As an inert solvent (N,N-di-f-carbamamine or a second list of aprotic solvents NN_-methyl-methyl, etc.), etc., it is preferred to use N,N-methylcartoamine 0 as the reaction temperature. The selection of β β in the range of 8 〇 t: is about 2 (TC to about 7). Step 7 The compound (M4) can be produced by reacting the compound (IV) with a methane in an inert solvent. As an inert solvent, aprotic dissolution is exemplified.

„Or dimethyl (tetra), etc.), it is preferred to use hydrazine, Ν·^-f-based amide, as a reaction to /5 deer, electricity, usually in the range of about 2〇〇c~ about 5CTC In the range of the selection, it is also possible to add methyl iodide to the reaction solution in the step 6 to react. 8) Step 8 Compound (1_15) can be present in an inert solvent, zinc and pd catalyst And in the presence or absence of a phosphine, the compound (ι_ΐ4) is produced by subjecting the compound to an inert solvent, and examples thereof include N-methyl-2-pyrrolidone or N,N-dimethylformamide. The pd catalyst may, for example, be a tris(dibenzylideneacetone)dipalladium complex Pd2(dba)3.CHC13, bis[tris(t-butyl)phosphine]palladium complex PdUtert-Bu)#]2 Tetrakis(triphenylphosphine)palladium complex

Pd(PPh3)4, bis(dioxaethyloxy)pound complex pd(〇c〇CF3)2; as phosphine', triphenylphosphine [PhsP], tri(tert-butyl)phosphine [(tert_BuhP], tri-o-phthalylphosphine [(〇_τ〇ι) 3ρ], diphenylphosphinoferrocene [DPPf], diphenylphosphinobutane [DpPb], etc. When pd2(dba)2 is used as the Pd catalyst, it is preferable to use (〇_τ〇1) 3Ρ. As the reaction temperature, it is usually selected in the range of about 80 ° C to about 13 CTC. Step 136433.doc 13 200938200 'Also can be documented (eg, Synth. Commun. 24, 887 (1994),

The manufacturing method described in Organic Letters 9, 1711 (2007), Tetrahedron Lett. 40, 8193 (1999), Tetrahedron Lett. 45, 1441 (2004), etc. is incorporated by reference. 9) Step 9 As the step 9, the following production method (A) and production method (B) can be used. Production method (A): Compound A can be produced by reacting compound (1-15) with benzenesulfonic acid or its monohydrate in an inert solvent, and then neutralizing with an inorganic base after completion of the reaction. The inorganic base may, for example, be sodium hydroxide or potassium hydroxide, and is usually used as an aqueous solution. The inert solvent may, for example, be an alcohol solvent (such as ethanol, decyl alcohol or 2-propanol) or a nitrile solvent (such as acetonitrile or propionitrile). A mixture/mixture of an alcohol solvent and a nitrile solvent is usually used. The reaction temperature is usually from about 5 Torr to about 1 Torr. Choose within the range of 匸. Process U (Β). The compound oxime can be produced by reacting the compound (1-15) with a mineral acid in an inert solvent. The inert solvent may, for example, be mono-methane, 1,2-diethane or a hydrocarbon-based solvent such as gas. As a mineral acid, hydrochloric acid etc. are mentioned. The reaction temperature is usually from about -10 ° C to about 30. Choose within the range of 〇. The raw materials, reagents and the like used above are commercially available compounds unless otherwise specified, or may be prepared by well-known methods using well-known methods. For example, the compounds may be described in accordance with the literature Letters 7, 55_58 (2〇〇5) ) method to synthesize. Further, the compound of the present invention can also be synthesized as a racemate (racemie 136433.doc 200938200 body)' and fractionated by column chromatography using a filler to which an optically active ligand is bonded. The compound of the present invention can be mixed with a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol or propylene to form a salt. Examples of the pharmaceutically acceptable acid include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, a mineral acid, or acetic acid, propionic acid, oxalic acid, saprotic acid, lactic acid, acid-like acid, tartaric acid, citric acid, and horse. Organic acids such as acid, fumaric acid, sulfonic acid, benzoic acid, p-toluenesulfonic acid, ascorbic acid.

It is considered that the compound of the present invention can be applied to the treatment of various diseases by its inhibition of DPP-IV. The compounds described in the present specification can be used for: postprandial hyperglycemia for inhibiting pre-diabetes symptoms, treatment of non-insulin-dependent diabetes mellitus, treatment of autoimmune diseases such as arthritis or rheumatoid arthritis, and treatment of intestinal mucosal diseases. Promote growth, inhibit rejection of transplanted organs, treat obesity, treat eating disorders, treat HIV infection, inhibit cancer metastasis, treat prostatic hypertrophy, treat periodontitis, and treat osteoporosis. When used in therapy, the compounds of the present invention can be formulated into pharmaceutical compositions for oral or parenteral (for example, intravenous, subcutaneous, or intramuscular injection, topical, 'rectal, transdermal, or nasal) administration. Give. Examples of the composition for oral administration include a tablet, a capsule, a pill, a granule, a powder, a liquid, a suspension, and the like; as a composition for parenteral administration, for example, : water for injection, oily agent, #paste, emulsion, lotion, aerosol (aer〇s〇I), suppository, or patch. Such formulations may be prepared using previously well known techniques' which may contain non-toxic and inert carriers or excipients which are generally employed in the field of formulation 136433.doc 15 200938200. The dosage varies depending on various compounds, as well as the patient's disease, age, weight, sex, symptoms, route of administration, etc., usually for adults (body weight 5 〇 kg) ' is 0.1 to 1000 mg / day, preferably called / The amount of the day is administered to the compound of the present invention once a day or two to three times a day. Also, it can be administered once in a few days to several weeks. In order to enhance the effect of the compound of the present invention, it may be combined with a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an anti-hyperlipidemic agent, a hypotensive agent, an anti-obesity agent, a diuretic or the like (hereinafter, simply referred to as a co-agent) Used in combination. The administration period of the compound of the present invention and the concomitant drug is not limited, and δHai or the like can be administered to the subject at the same time, and the subject can be administered to the subject at regular intervals. Further, the compound of the present invention and a concomitant agent may be used as a mixture. The dosage of the pharmaceutical agent can be selected according to the amount of the clinical use. Further, the ratio of the compound of the present invention to the concomitant agent can be appropriately selected depending on the subject to be administered, the route of administration, the disease, the symptom, the combination, and the like of the subject. For example, when the administration target is a human, it is possible to use 〇〇1 to 1 〇〇 by weight of the compound of the present invention, which is a weight-damaged compound, and the drug can be used as a therapeutic agent for diabetes. (for example, animal insulin preparations extracted from the pancreas of cattle and pigs; human insulin preparations synthesized by genetic engineering using Escherichia coli, yeast, etc.), insulin resistance improving agents (for example, pioglitazone (pi〇gUtaz〇) Ne) or its hydrochloride, troglhazone, rosiglitazone Oosigkitazone or its maleate, GI 26257〇, JTT 5〇i, 136433.doc 200938200 MCC-555, ΥΜ-440, KRP-297, CS_011, etc.), α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate) Etc.), biguanid (eg, metformin, etc.), insulin secretion promoter (eg, tolbutamide, glibenclamide, gliclazide) Gliclazide), Gas chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, etc.; Repaglinide, senaglinide, nateglinide, mitiglinide, etc., GLP-1, GLP-1 analogue (exenatide, benefit) Liraglutide, SUN-E7001, AVE010, BIM-51077, CJC1131, etc., protein tyrosine phosphatase inhibitors (eg, acid, etc.), β3 agonists (eg, GW-427353B, Ν-5984, etc.). As a therapeutic agent for diabetic complications, there may be mentioned aldose reductase inhibitors (for example, tolrestat, epalrestat, zenarestat, sputum posite ( Zopolrestat), minalrestat, fidarestat, ranirestat, SK-860, CT-112, etc., neurotrophic factors (eg, NGF, NT-3, BDNF) Etc.), PKC inhibitors (eg, LY-33353 1 et al), AGE inhibitors (eg, ALT946, pimagedine, piratoxatine, N-benzimidazole) Barium bromide (ALT766), etc., active oxygen removal drug (eg, lipoic acid, etc.), 136433.doc -17· 200938200 brain jk tube dilator (eg 'tiapride, mexiletine, etc.) ). As the anti-hyperlipidemic agent, HMG-CoA reductase inhibitors (for example, pravastatin, simvastatin, lovastatin, l〇vastatin, atorvastatin) may be mentioned. Atorvastatin), fluvastatin, itatartan, itavastatin, or the like, sodium squalene (SqUalene) synthetase inhibitor, AC AT inhibitor, and the like. As the antihypertensive agent, an angiotensin converting enzyme inhibitor (for example, capt〇prii, enalapril, alapril, and delapril) can be mentioned. , lisinopril, imidapril, benazepril, ciazapriri, temocapril, trandlapril, etc. Angiotensin-antimony antagonists (eg, olmesartan vinegar (〇lmesartan medoxomil), candesartan cilexetil, losartan, eprosarta, salbuta Valsartan), telmisartan, irbesartan, tasosartan, etc., sputum antagonists (eg 'nicardipine hydrochloride, manidipine hydrochloride (man) i dipine hydrochloride), nisoldipine, nitrendipine, nilvadipine, ainl〇dipine, etc., renin inhibitors (aliskiren, etc.) Wait. As the anti-obesity agent, for example, a neutral anti-obesity agent (for example, phentermine, sibutramine, amfepramone, dexamfetamine, horse 0 bow)丨嗓 136433.doc 200938200 (mazindol), SR-141716A, etc.), pancreatic lipase inhibitor (eg, orlistat, etc.), peptide anorexia (eg, leptin eptin), CNTF ( Ciliary neurotrophic factor), cholecystokinin agonist (for example, lintitript, FPL-15849, etc.). Examples of the diuretic include a xanthine derivative (for example, salicylate salicylate, salicylate cocoa, etc.), and a quinone-based preparation (for example, acetaminophen, cyclopentanene p, and second gas). Tillage, hydrogen sulphide, hydrofluorothiazepine, benzylhydrochlorothiazide, penfiutizide, / white teeth, polythiazide, methychlothiazide, a 33⁄4 antagonist (eg, 'Spir〇n〇lact〇ne, triamterene, etc.), a carbonic acid liver enzyme inhibitor (eg, acetazolamide, etc.), A gas benzene sulfonamide-based preparation (for example, chlorthalidone, mefruside, indapamide, etc.), azose sernide, isosorbic vinegar ( Isosorbide), ethacrynic acid, "piretanide", bumetanide, furosemide, and the like. The drug to be used is preferably GLP-1, a GLP-1 analogue, an α-glucosidase inhibitor, a biguanide, an insulin secretion promoter, an insulin resistance improving agent, and the like. The above-mentioned concomitant agents may be used in combination of two or more kinds in an appropriate ratio. When the compound of the present invention is used in combination with a concomitant agent, the amount of the agent can be reduced within a safe range in consideration of the side effects of the agent. In particular, the biguanide can also be reduced below the usual dosage. Therefore, 136433.doc 200938200 can safely prevent side effects caused by such agents. Further, the administration amount of the diabetic complication agent, the anti-hyperlipidemic agent, the antihypertensive agent, and the like can be reduced, and as a result, the side effects caused by the agents can be effectively prevented. EXAMPLES Hereinafter, the present invention will be specifically described by way of Reference Examples, Examples and Test Examples, but the present invention is of course not limited to these Examples. Further, the names of the compounds shown in the following Reference Examples and Examples are not necessarily based on Bellows. Named by the naming method. [Example 1] Reference Example 1 3-{(3R)-3-[(Tertibutoxycarbonyl)amino]_3_methylpiperidin-indenyl}_2cyano-3-(methylthio) Tert-butyl acrylate [Chemical 3]

Add (3R)_3_[(Tertibutoxycarbonyl)amino group to a solution of 2_cyano-3,3·bis(decylthio)acrylic acid tert-butyl ester (48.43 g) in toluene (25 ml) _3_Methylpiperidine (40.23 g) was used as a solution (7 mL) and stirred at 80 °C. After 4 hours, heptane (3 〇〇 ml) was added at 8 ° C and returned to room temperature. Thereafter, after stirring for 1 hour in an ice bath, the precipitated white solid was recovered by filtration. The title compound (64.50 g) was obtained as white solid. 136433.doc -20- 200938200 MS (ESI+) 412 (M++1, 60%) Reference Example 2 3-[(2-Bromo-5-succinyl)amino]-3-{(311)-3 -[(Tertibutoxycarbonyl)amino]-3-methyl benzyl-1-yl}-2-cyanoacrylate tert-butyl ester [Chemical 4]

化合物 The compound of Reference Example 1 (70.7 g) was dissolved in acetonitrile (7 mL), and DBU (52.35 g), 2-s--5-fluorof-amine (36.22 g) was added at 5 Torr.授 Under the mixing. After 5 hours, it was diluted with hydrazine (200 ml) and washed with water. The organic layer obtained by washing with water, 10% sulfur·hydrogen potassium water, 9%, 1% by gas, and an aqueous solution of sodium oxide is dried, dried with sulfuric acid (iv), and concentrated under reduced pressure to obtain a yellow amorphous body. Title Compound (10).3 g) e MS (ESI+) 567 (M++1, 60%) Reference Example 3 3-K2 5-Anodyl) (2-ethoxyethoxyethyl)amine 3- [(Tertidinoxymethyl)amino]-based brigade bite base to the third alkyl butyl propionate [Chemical 5]

r\

136433.doc -21 - 200938200 The compound of Reference Example 2 (1〇8·3 g) was dissolved in dimethylformamide (170 ml), potassium carbonate (104.8 g) was added and mixed at room temperature. . Ethyl bromoacetate (50.63 g) was added dropwise and stirred at 401 for 1 hour. Adding a scorpion, filtering the diatomaceous earth, washing the obtained organic layer with water and drying it with sodium sulfate, filtering, and concentrating under reduced pressure, thereby obtaining the title compound as a dark red amorphous substance (124.10 g) ). ' MS (ESI+) 653 (M++1, 60%) Reference Example 4 3-Amino-1-(2-an _5-a-benzyl)-5-{(3R)-3-[(third Butoxy olylamine amine yl]-3- fluorenyl 0 bottom -1-yl}-11^-〇 略 -2-2,4-dicarboxylic acid -2-B S-4 - third 6]

Heptane (丨 46 ml) was added to lithium amide (9.6 g), and a mixed solution of second butanol (268 g) and heptane (3 〇mi) was added dropwise at 8 (TC). After hours, it was cooled. To the mixture was added acetonitrile (340 ml), and a mixture of the compound of Example 3 (124.10 g) was added to the mixture, and the mixture was stirred. After 2 hours, the solvent was distilled off under reduced pressure and then added. Toluene (7 〇〇ml) and water (370 ml). Adjust the pH to about 5 以 with concentrated hydrochloric acid, then pass the diatomaceous earth filter knives to dry the organic layer with sodium sulphate, filter, and then Concentrated under reduced pressure to obtain the title as a dark red oily substance

136433.doc -22- 200938200 Compound (100 g). MS (ESI+) 653 (Μ++1, ι〇〇〇/〇) Reference Example 5

3-[(Aminomethyl)amino] small (2_Mo.5. fluoro- benzyl)-5_{(3r)3 士二氧的基基) Amino] Winter Methyl Bite Bit 4Mhw4_; Ethyl-4-tert-butyl ester-T

[Chemistry 7]

于In Russia, a mixture of the compound of Reference Example 4 (i〇〇g) dissolved in acetic acid (tip ml) was added dropwise to the mixture of 25 cyanide (20 g dissolved in water (40 g)). Solution, and _. After 2 hours, return to room temperature, dilute with toluene (700 ml), and then wash with water (10) _ 3 times.

After washing the organic layer with brine, the sodium salt was subjected to (iv), and then decompressed to reduce the pressure, whereby the title compound (110 g) was obtained as a dark red amorphous material. MS (ESI+) 696 (M++1, EtOAc) Methylpiperidin-1-yl b 1,3_dimethyl 'heart di-oxy 2,3,4,5-tetrahydro-exo_pyrrole[3,2-d]pyrimidine_7-曱Acid tert-butyl ester [Chemical 8] 136433.doc •23· 200938200

The compound of Reference Example 5 (110 g) was dissolved in dimethyl decylamine (29 〇 ml). Potassium carbonate (66 g), water (2.9 ml) was added and transferred at 50X:. After 5 hours, it was cooled to 3 ° C, and methyl iodide (51 g) was added dropwise and stirred. After 2 hours, water (400 ml) was added, and the precipitated solid was recovered by filtration. The solid obtained was subjected to slurry washing in isopropyl alcohol (700 ml) at 60 t and returned to room temperature. The solid was recovered by filtration and again in isopropanol © (400 ml), 60. The slurry is washed under the armpit. The obtained solid was dried under reduced pressure to give the title compound (54.7 g). MS (ESI+) 678 (M++1,1 〇〇〇/0) Reference Example 7 5-(2-Cyano-5-arsonyl)_6_{(3R)_3_[(T-butoxy) Amino]_3_mercaptopiperidin-1yl}-1,3-dimethyl-2,4-dioxy 2,3,4,5-tetrahydro-1 Η-° ratio 幷[3 , 2-d] pyridine bite 7-carboxylic acid third butyl vinegar © [Chemical 9]

In the compound of Reference Example 6 (27.14 g), fluorenyl-mercaptopyrrolidone 136433.doc -24- 200938200 (100 ml), tris(dibenzylideneacetone)dipalladium (1.83 g), tris(o-tolyl) were added. Phosphine (4.99 g), zinc cyanide (Zn(CN)2) (2.90 g)' and subjected to 5 times of degassing under reduced pressure and nitrogen substitution. This mixture was taken at 120. (: mixing was carried out. After 2 hours, it was cooled to room temperature, and then filtered with diatomaceous earth. The obtained organic layer was added to a mixture of ammonia water, saturated aqueous ammonium chloride solution and water at 4:4:1. 'In the solution' and vigorously stirred. The yellow solid formed was recovered by filtration, and the slurry was washed in acetonitrile (20 ml) at 8 (TC for 2 hours).

After stirring for an hour in an ice bath, it was recovered by filtration. The obtained solid was dried under reduced pressure to give the title compound (18.30 g) as a white solid. . MS (ESI+) 625 (M++1, 90%) Example 1 2-({6-[(3R)-3-amino-3-methylpiperidine· , 4-tertiary benzonitrile [10] oxy-1,2,3,4-tetrahydro-5H-oxime [3,2-d], $ _5_yl} f))

CN

-CN

Whb. To 5-(2-cyano-5-fluoroylidene, c-mercapto) '6-{(3R)-3_[(tatabutoxy)amino]-3- at 40 °C曱基旅bit-1_基^ > 1'3-dimethyl-2,4_diyl-2,3,4,5-tetrahydro-IK-»Biloxi [3,2_d] After a solution of 苯-7-carboxylic acid tert-butyl ester (18.3 g) in acetonitrile (30 ml), a solution of benzenesulfonic acid monohydrate 136433.doc -25-200938200 (10.85 g) in ethanol (15 ml) was added dropwise. Stir at 8 °c for 2 hours. After returning to room temperature and diluting it with ethyl acetate (50 ml), a solution obtained by dissolving Na〇H (2·49 g) in water (50 ml) was added and neutralized. The organic layer was washed with brine, dried over sodium sulfate sulfate ]H NMR (400 MHz, DMSO-d6) δ 7.97-8.00 (m, iH)>7>3〇_ · 7.35 (m, 1H), 6.36-6.39 (m, 1H), 5.99 (s, 1H) , 5.65 (s, 2H), 3.37 (s, 3H), 3.14 (s, 3H), 2.73-2.82 (m, 2H), 2.55-2.63 (m, 2H), 1.62-1.68 (m, 1H), 1.47 -1.59 (m, 1H), 1.40 (brs, 2H), © 1.28-1.38 (m, 2H), 0.89 (s, 3H) MS (ESI+) 425 (M++1, 100%) Example 2 2- ({6-[(3R)-3-Amino-3·methylpiperidinyl dimethyl-2,4-di-oxyl-1,2,3,4-tetrahydro-5H-pyrrole[3 , 2-d]pyrimidin-5-yl}fluorenyl)-4-fluorobenzonitrile hydrochloride [Chemical 11]

The compound (14 〇 mg) obtained in the same manner as in Example i was dissolved in a gas (3·ml), and the hydrochloride salt of 丨N (2 〇mi) was added and concentrated to give the title compound. (150 mg). 136433.doc • 26, 200938200 'H NMR (400 MHz, DMSO-d6) δ 8.17 (brs, 3H), 7.97-8.00 (m, 1H), 7.30-7.35 (m, 1H), 6.25-6.28 (m, (H, 2H) , 2.69-2.73 (m, 1H), 1.78-1.90 (m, 2H), 1.56-1.61 (m, 2H), 1.24 (s, 3H) MS (ESI+) 425 (M++1, 100%) Reference 8 2-({6-[(311)-3-Aminopiperidin-1-yl]-1,3-dimethyl-2,4-di-oxyl_ 1, 1,2,3,4- Tetrahydro-5H-pyrrole[3,2_d]pyrimidin-5-yl}indenyl)-4-fluorobenzonitrile (hereinafter referred to as compound B) hydrochloride [Chemical 12]

The synthesis was carried out by the method described in Example 13 of the International Publication No. 2006/068163. NMR (300 MHz, CDC13) δ 8.50 (brs, 3H), 7·71_7·65 (Π1, 1Η), 7.07-7.00 (m, 1H), 6.57-6.53 (m, 1H), 5.84 (d, J = 16.7 Hz, 1H), 5.73 (s, 1H), 5.64 (d, J = 16.7 Hz, 1H), 3.59-3.57 (m, 1H), 3.45 (s, 3H), 3.39-3.37 (m, 1H), 3.33 (s, 3H), 3.16-3.09 (m, 1H), 2.70-2.68 (m, 2H), 2.08-2.06 (m, 1H), 1.80-1.78 (m, 2H), 1.60-1.58 (m, 1H) MS (ESI+) 411 (M++1, 100%) 136433.doc -27· 200938200 Reference Example 9 2-({6-[(3R)-3-Amino-Based Ethyl Ethylene) Methyl sulphate-i'2'3'4-tetrahydro _5H. bite 幷 [3, 2, bite _5_ yl} methyl) ice gas section guess (hereinafter referred to as compound C) [ 13]

Ch3 5-(2-cyano_5_) synthesized from 3 [(t-butoxycarbonyl)amino]-3-ethylpiperidine of the racemate in the same manner as in Reference Examples 1 to 7 Fluorobenzyl) 6-{3-[(t-butoxycarbonyl)amino]_3-ethylbine-1-yl}-1,3-dimethyl-2,4-di-oxy- 2,3,4,5-tetrahydro-11^-deuterium oxime [3,2-(1] pulverized-7-carboxylic acid tert-butyl ester (1.0 g) 'synthesized in the same manner as in Example 1. The title compound racemic (630 mg). Then, using CHIRALPAK (registered trademark) AD-H (Daicel Chemical Industries, Ltd.), palmitic stationary phase: amylose three (3, (amylose tris (3,5-dimethylphenyl carbamate)), in hexane / isopropanol / diethylamine = 70 / 30 / 0. l (v / The racemate was isolated under the conditions of v), whereby the title compound (220 mg) was obtained..H NMR (400 MHz, DMSO-d6) δ 7.97-8.01 (m, 1H), 7.31-7.36 (m , 1H), 6.39-6.42 (m, 1H), 6.00 (s, 1H), 5.59-5.70 (m, 2H), 3.37 (s, 3H), 3.14 (s, 3H), 2.76-2.84 (m, 2H ), 2.57 136433.doc 28· 200938200 (s, 2H), 1.65-1.70 (m,1H), 1.49-1.53 (m,1H),1.10-1.40 (m, 6H), 0.64 (t, J = 7.5 Hz, 3H) MS (ESI+) 439 (M++l, 1〇〇〇) /〇) Reference Example 10 (3R)-3-methyl-pyridinium carboxylic acid ethyl ester. 1/2 di-p-tolyl-yl-D-tartrate [Chemical 14]

To a solution of ethyl piperidinecarboxylate (20_0 g) in toluene (100 ml) at a temperature of -20 to -30 ° C, sodium hexahydrodiazane sodium tetrahydrofuran (1 .〇Μ ' 152) was slowly added dropwise. Ml) solution. After stirring for 30 minutes, iodonane (19.4 g) was slowly added dropwise at a temperature of -20 to -30 ° C, and then slowly returned to room temperature. Water (20.8 ml) was added, liquid separation, concentration, and the residue obtained was diluted with toluene, and then washed with water (20 ml). After drying with sodium sulfate, the mixture was subjected to concentration under reduced pressure, and ethyl acetate (125 ml) was added to the obtained oily component. To the solution was added a solution of di-p-tolyl-7-tartaric acid in ethyl acetate (60 ml) at 50 ° C and stirred. After aging, the mixture was returned to room temperature, and the resulting white solid was recovered by filtration, and then dried under reduced pressure, whereby the title compound (13.87 §) was obtained. MS (ESI+) 171 (M++1, 100%) (md.)

The compound of Reference Example 10 (13.87 g) was dissolved in water (55 ml), and a 10% aqueous potassium carbonate solution (55 ml) and ether (50 mi) were added and stirred. After 30 minutes, the title compound (4 23 g) was obtained as a yellow oily component, which was dried over sodium sulfate and filtered, and then concentrated under reduced pressure. MS (ESI+) 171 (M++1,1%) Reference Example 12 (3R)-3-indenylbene-bend-1,3-dicarboxylic acid-1-benzyl ester_3_ethyl ester [Chem. 16]

The compound of Reference Example 11 (4.23 g) was dissolved in tetrahydrofuran (2 〇mi), and triethylamine (3.76 ml) was added and cooled in an ice bath. Slowly add benzyl formate (3.55 ml) to return to room temperature and stir overnight. After filtration through diatomaceous earth, the solvent was distilled off and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and then evaporated to dryness to give the title compound (7.32 MS (ESI+) 306 (M++l, 100%) Reference Example 13 (3R)-1-[(Benzyloxy)carbonyl]_3-mercaptopiperidin-3-indole acid [Chem. 17] I36433.doc -30- 200938200

〇r〇x To the compound of Reference Example 12 (7.32 g), decyl alcohol (10 ml) and 3 N aqueous sodium hydroxide (10 ml) were added at 50. (3: After stirring for 3 hours, the methanol was distilled off, and the pH was adjusted to 5 or less with concentrated hydrochloric acid. After extraction with ether, the organic layer was washed with water and saturated brine, dried over sodium sulfate and filtered. The title compound (5.45 g) was obtained as a yellow oily component. MS (ESI+) 278 (M+-H, 100%) Reference Example 14 (3R)-3-[(T-butoxy) Carbonyl)amino]-3-methylpiperidine oxime-formic acid benzyl ester [Chemical 18]

0 l^l^o Human [^NHBoc ❹ The compound of Reference Example 13 (5.45 g) was dissolved in toluene (3 mL), and triethylamine (2.09 g) was added. While confirming the generation of nitrogen gas at 90 ° C, a toluene solution of diphenyl azide phosphate (5.47 g) was slowly added dropwise (2 Torr. After the dropwise addition was completed, the mixture was stirred at 90 ° C for 1 hour. After warming, it was washed twice with water (27 ml), dried with sodium sulfate, and dried under reduced pressure until the volume reached about 1/3. To the obtained solution was added tert-butanol (3.7) 1111) and potassium butoxide (1.0 §), at 3 〇. (: stirring is carried out. After 2 hours, it is washed with water, saturated aqueous ammonium chloride solution and saturated brine, dried and filtered with sodium sulfate. The title compound (3.62 g) was obtained as a white solid. MS (ESI+) 349 (M++1, 20%) 15 (3R)-3-[(Tertibutoxycarbonyl)amino]_3•methylpiperidine [Chem. 19]

The compound of Reference Example 14 (34.8 g) was dissolved in ethyl acetate (5 〇(6)) hydrazine, 1 N hydrochloric acid (0.5 mi) and 10% pd/c (2 〇g) were added, and pressurized under hydrogen (2_2.5 atm) for stirring. After 2 hours, it was filtered through celite, washed with 3 N aqueous sodium hydroxide solution, water and saturated brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The title compound (2〇4 g). MS (ESI+) 215 (M++1, 60%) Reference Example 16 3-[(T-butoxycarbonyl)amine-based [Methylethyl]

^-^vL-NHBoc

NHBoc was used in the same manner as in Reference Example 10 (in which the salt was formed without using di-p-bromo-D-tartaric acid), 12, 13, and 14, 3-[(second The title compound (4.20 g) was obtained as a colorless oily component. m.p. MS (ESI+) 229 (M++1, 60%) Test Example Test Example 1 In vitro DPP-IV inhibition test The test was carried out in such a manner that the final concentration of human plasma containing DPP-IV enzyme reached 10%* The test substance solution was added to the microanalysis plate. Further, the substrate was added at a final concentration of 50 μM (Glycyl® 醯-L-proline 4-Glycolyl-7-decylamine (Glycyl-L-Proline 4-Methylcoum aryl-7) -Amide), PEPTIDE INSTITUTE) The activity of the enzyme was determined by continuously measuring the intensity of the fluorescence (excitation wavelength 380 nm, measuring wavelength 460 nm) using a fluorescence analyzer at room temperature. The concentration of the test substance (IC50 value) when the enzyme activity was suppressed to 50% was calculated. [Table 1] Test compound Human DPPIV inhibitory activity IC5〇(nM) Compound A 1.6 Compound B hydrochloride 0.34 Compound C 26 Test Example 2 Evaluation of mechanism-based inhibition (MBI) of CYP3A4

Various concentrations of the test compound are added to human liver microsomes in the presence or absence of NADPH (ni cot inamide adenine dinucleotide phosphate) at 37 ° C 136433.doc - Pre-trained for 15 minutes under 33-200938200. Thereafter, the reaction solution was diluted 20-fold with a mixture of midazolam and NADPH as a substance of CYP3A4, and further reacted at 37 °C for 5 minutes. The reaction was stopped by adding 3 times the amount of methanol, and the production amount of midazolam metabolite (1-Hydroxy midazolam) was measured by LC/MS/MS, whereby the CYP3A4 activity was evaluated. The activity at the time of pre-culture in the absence of NADPH was used as a control, and the amount of activity reduction in the pre-culture in the presence of NADPH was divided by the time (15 minutes), and the obtained value was set as the inactivation rate constant. (kobs). At this time, the relationship between the concentration (I) of the test compound and kobs can be expressed by kobs = kinactxI / (K'app + I). The regression analysis was performed by the nonlinear least squares method to calculate the maximum inactivation velocity constant (kinact) and the apparent dissociation constant (K'app), and the intensity of MBI was determined based on the value of kinact/K'app. The results obtained are shown in Fig. 1, Fig. 2 and Table 2. Compound B (Reference Example 8) showed inactivation of concentration-dependent CYP3A4. The 3-ethyl substitution of Compound B, Compound C (Reference Example 9), also showed inactivation of CYP3A4, but its strength was lower than that of Compound B. On the other hand, the 3-mercapto substituent, Compound A (Example 1), was not inactivated, and regression analysis of kobs = kinactxI / (K'app + I) could not be performed. [Table 2] Test compound kinact (min'1) K'app (μΜ) kinact/K'app (min'VnM) Compound A NA Ν.Α. Ν·Α. Compound B hydrochloride 0.0391 26.0 1.50 Compound C 0.0227 22.0 1.03 136433.doc -34- 200938200 NA: not applicable (not applicable) According to Test Examples 1 and 2, 'the difference between Compound B, Compound A and Compound C is only the substitution on 3-aminopiperidine. The groups are respectively a hydrogen atom, a methyl group, and an ethyl group. However, the DPP-IV inhibitory activity IC5〇(nM) of the compound B having a hydrogen atom (〇.34 nM) and the compound A (1.6 nM) having a methyl group is two, compared with the compound C having an ethyl group. The activity is very low (26 nM). On the other hand, in the case of mb I which is very important in the safety of pharmaceuticals, the compound B (0.34 nM) having a hydrogen atom detects MBI, whereas the compound having a methyl group (1·6 nM) is not detected. Out of MBI. However, the compound C having an ethyl group which is further extended by the carbon chain detects MBI again. Based on these results, it was found that the compound A having a methyl group is a compound which is particularly excellent in both DPP-IV inhibitory activity and MBI. The reason for this is considered to be that the difference in substituents in the overall structure of the compound of the present invention affects the respective interactions of Dpp_iv and CYP3A4. However, in terms of the interaction with Dpp_IV, a compound having a hydrogen atom and a compound having a methyl group are stronger, and in contrast to the interaction with CYP3A4, a compound having a hydrogen atom and having an ethyl group The compound is stronger, and the compound having a sulfhydryl group is not expected to interact with 〇γρ3Α4 based on previous knowledge. [Industrial Applicability] According to the present invention, a compound having DPP-iv inhibitory activity and improved safety, toxicity and the like can be provided. The compound of the present invention can be used for: postprandial hyperglycemia for inhibiting pre-diabetes symptoms, treatment of non-insulin-dependent diabetes, treatment of arthritis or rheumatoid 136433.doc -35- 200938200 autoimmune diseases such as arthritis, treatment of intestinal mucosal diseases Promote growth, inhibit transplant rejection, treat obesity, treat diet disorders, treat mv sensation, inhibit cancer metastasis, treat prostatic hypertrophy, treat inflammatory disease, and treat osteoporosis. BRIEF DESCRIPTION OF THE DRAWINGS In Fig. 1, A shows the metabolic activity of a substance (midaz〇iam) after pre-incubation of compound VIII with human liver microsomes in the presence of NADPH. The result of pre-culture effects on metabolic activity. B represents the result obtained by performing the same test using Compound B.匸 The results obtained by the same test using Compound C are not shown. In the respective figures, the vertical axis indicates metabolic activity (%). The horizontal axis represents time (minutes). 〇 indicates the value at 0 μΜ, • indicates the value at 1 μΜ, □ indicates that the value at 5 μΜ indicates the value at 1〇μΜ, △ indicates the value at 2〇μΜ, and ▲ indicates at 50. The value under μΜ, ◊ represents the value at 10〇μΜ. In Fig. 2, Α represents the deactivation rate constant of the compound at each concentration. B represents the deactivation rate constant of Compound B at each concentration. C represents the deactivation rate constant of Compound C at each concentration. In each of the figures, the vertical axis represents the deactivation rate constant (min·1). The horizontal axis indicates the concentration (μΜ) of each compound. 136433.doc -36-

Claims (1)

200938200 X. Patent application scope·· 2. 2-({6-[(3R)_3_Amino_3_ hydrazinopiperidinyl] yl) diyloxy W·tetrahydro·5Η_material 幷[3,2_句喷1 } f)-4-fluorobenzonitrile or a pharmaceutically acceptable salt thereof. 5 to azidine-5- a 2-({6-[(3R)_3_amino-3-methylpiperidine small group w^yl 2〆·di-oxy-^3,4-tetrahydro _5H-pyrrole [3,2_dJ〇^yl}methyl)-4-fluorobenzonitrile. A dipeptidyl peptidase IV inhibitor comprising as an active ingredient an octapeptide as claimed in the claims or a pharmaceutically acceptable salt thereof, or a compound according to claim 2. A therapeutic agent for diabetes which comprises a compound as claimed or a pharmaceutically acceptable salt thereof, or a compound of claim 2 as an active ingredient. 136433.doc