WO2009084497A1 - Methyl-substituted piperidine derivative - Google Patents

Methyl-substituted piperidine derivative Download PDF

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WO2009084497A1
WO2009084497A1 PCT/JP2008/073275 JP2008073275W WO2009084497A1 WO 2009084497 A1 WO2009084497 A1 WO 2009084497A1 JP 2008073275 W JP2008073275 W JP 2008073275W WO 2009084497 A1 WO2009084497 A1 WO 2009084497A1
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compound
methyl
ml
yl
acid
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PCT/JP2008/073275
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French (fr)
Japanese (ja)
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Hiroyuki Nakahira
Yukihiro Nishio
Hidenori Kimura
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Dainippon Sumitomo Pharma Co., Ltd.
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Publication of WO2009084497A1 publication Critical patent/WO2009084497A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems

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

Methyl-substituted piperidine derivatives

The present invention, 2 - ({6 - [(3R) -3- amino-3-methylpiperidin-1-yl] -1,3-dimethyl-2,4-dioxo-1,2,3,4 Hydro -5H- pyrrolo [3,2-d] pyrimidin-5-yl} methyl) -4-fluorobenzonitrile (hereinafter, sometimes abbreviated as compound a necessary) or a pharmaceutically acceptable salt thereof ( hereinafter sometimes abbreviated as compound a or compound of the present invention optionally a pharmaceutically acceptable salt thereof) it relates. The present invention compounds are useful as pharmaceuticals, more particularly, it is effective as a dipeptidyl peptidase -IV (DPP-IV) inhibitor. The present invention further relates to antidiabetic agent containing the present compound as an active ingredient.

Various DPP-IV inhibitors have been reported, for example, a compound having a pyrrolo [3,2-d] pyrimidine ring in Patent Documents 1 and 2 have been reported to be effective as DPP-IV inhibitors. However, the compounds of the invention in these documents are not specifically described.
WO 2006/068163 pamphlet WO 2007/071738 pamphlet

An object of the present invention is to provide a novel compound having an excellent DPP-IV inhibitory activity.

The present inventors have made intensive studies to achieve the above object and found to have a DPP-IV inhibitory activity the compounds of the invention were excellent. Furthermore, as is clear in the test example described below, enhancement of metabolic reactions inhibition compound of structural similarity was time dependent, i.e. to have a Mechanism-based-inhibition (MBI), the compounds of the present invention is avoidance of MBI It found to be possible, which resulted in the completion of the present invention.

That is, the present invention is:
[1] 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 or a pharmaceutically acceptable salt thereof,
[2] 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,
[3] [1] compound or dipeptidyl peptidase -IV inhibitor containing a pharmaceutically acceptable salt or [2] The compound according, as an active ingredient according, and [4] [1] The compound according or antidiabetic agents containing a pharmaceutically acceptable salt or [2] the compound according to, as an active ingredient, related.

The present invention compound has an excellent DPP-IV inhibitory activity. Compounds having a DPP-IV inhibitory activity, for example by acting on the blood GLP-1 as described in WO 2006/068163 pamphlet, promotion of insulin secretion dependent on blood sugar level, the pancreatic function improvement, improvement of postprandial hyperglycemia, improvement of impaired glucose tolerance, has the effect of and improving insulin resistance is useful as a treatment for type 2 diabetes (non-insulin dependent diabetes mellitus) (RAPederson et al, diabetes Vol. 47, p1253-1258, 1998).

On the other hand, an irreversible inhibitory effect on metabolic enzymes Mechanism-based-inhibition of (MBI). After treatment discontinuation of the drug is also characterized to sustain inhibition while. Metabolites produced by metabolic enzymes in mechanistic is, it is known that the form or covalent bonds metabolic enzymes and stable complexes.
Combination with drugs that undergo metabolic and its related enzymes drug having an action of MBI raises blood levels of the latter agent may cause drug interactions. Thus, agents having the action of MBI becomes less useful, such as the use is limited. For example, a metabolite of clarithromycin has the effect of MBI, when combined with terfenadine, and increased blood levels of terfenadine have been reported to induce arrhythmia.
Therapeutic effect is high, and also in the development of highly safe drug, avoiding the MBI has become a very important issue. For example, if the Ministry of Health, Labor and Welfare and Drug Administration examination management section chief notification pharmaceutical trial onset # 813 Patent "drug for the study method of interaction" medium Q & A of the Q5 in the "cytochrome P450 inhibition mechanism is non-reversible, ... a sure clinical trials as long as the "... clinically adverse interaction is feared to question and that if" that should be carried out, discontinued development principle is desired. However, the expected utility of the development chemicals If over the risk ... it is described as performing clinical trials. ". In addition, the item III (http://www.fda.gov/cber/gdlns/metabol.htm#iii) in the website of the FDA "Guidance for Industry", "In contrast, when positive findings arise in in vitro metabolic and / or drug-drug interaction studies, has been described as clinical studies are recommended ... ".

A shows the result of Compound A and human liver microsomes was measured the metabolic activity of the substrate material (midazolam) after preincubation in the presence NADPH, was studied the effect on metabolic activity by preincubation. B shows the results obtained in a similar test with Compound B. C shows the results obtained in a similar test with Compound C. In each figure, the vertical axis represents the metabolic activity (%). The horizontal axis shows the time in minutes. ○ is 0μM, ● is 1μM, □ is 5μM, ■ is 10μM, △ is 20μM, ▲ shows 50μM, ◇ is the value at 100μM, respectively.

A represents an inactivation rate constant at each concentration of compound A. B shows the inactivation rate constant at each concentration of compound B. C shows the inactivation rate constant at each concentration of compound C. In each figure, the ordinate represents inactivation rate constants (min -1). The horizontal axis indicates the concentration ([mu] M) of each compound.

Hereinafter, more detailed description of the present invention.

Compound A is a compound represented by the following formula.

Figure JPOXMLDOC01-appb-C000001

Examples of the "pharmaceutically acceptable salts", such as the hydrochloride, hydrobromide, sulfate, inorganic salts such as phosphates or nitrates or acetates, propionates, oxalates, succinates , lactate, malate, tartaric acid, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, organic acid salts such as p- toluenesulfonic acid salt or ascorbic acid salt It is.

Further, the present invention provides solvates of hydrates or ethanol solvates, etc. of the present invention compound is also included. Furthermore, the present invention is intended to encompass all tautomers of the present compounds, are also encompass all stereoisomers present, and of the crystalline forms of any embodiment ones.

Hereinafter, the production method of the present invention compounds will be described by way of example, the present invention is not limited to this as well. In the present specification, also possible to use the following abbreviations in order to simplify the description. Me: methyl group, Et: ethyl group, t Bu: tert-butyl group, Boc: tert-butoxycarbonyl group

The present invention compounds can be synthesized by combining known synthetic methods from known compounds. For example, it can be synthesized according to the method of WO 2006/068163 pamphlet described. An example is shown below.

Figure JPOXMLDOC01-appb-C000002

1) Step 1
Compound (1-5), compound (1-1), the compound (1-2) can be prepared by reacting in an inert solvent. The inert solvent, such as toluene, benzene, or an aromatic hydrocarbon solvent such as such as xylene. The reaction temperature can usually be selected from the range of about 30 ° C. ~ about 100 ° C..

2) Step 2
Compound (1-7), the compound (1-5) with the compound (1-6), an organic base presence, in an inert solvent, is prepared by reacting. As the inert solvent include a nitrile solvent such as acetonitrile or propionitrile. The organic base, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene or 1,4-diazabicyclo, [5.4.0] undec-7-ene, and the like. The reaction temperature usually selected from the range of about 30 ° C. ~ about 80 ° C., the reaction may be carried out under reflux.

3) Step 3
Compound (1-9) in an inert solvent in the presence of a base, can be produced by reacting the compound (1-7) with the compound (1-8). As the base, for example potassium carbonate, sodium carbonate, cesium carbonate, alkali carbonates such as potassium hydrogen carbonate or sodium hydrogen carbonate and the like, preferably, potassium carbonate, and the like. As the inert solvent, aprotic solvents (N, N-dimethylformamide or dimethyl sulfoxide, etc.), ethers (diethyl ether, tetrahydrofuran or 1,4-dioxane), ketones (acetone, etc.), or a mixture thereof the solvent and the like, preferably, N, N-dimethylformamide and the like. The reaction temperature can usually be selected from the range of about 10 ° C. ~ about 60 ° C..

4) Step 4
Compound (1-10) in an inert solvent, can be produced by reacting the compound (1-9) with a base. The bases include hydrogenated alkali such as an alkali amide or potassium hydride or sodium hydride, such as lithium amide or sodium amide. As the inert solvent, toluene, benzene or an aromatic hydrocarbon solvent such as xylene, hexane or a hydrocarbon solvent such as heptane,, tert-butyl alcohol, acetonitrile, N, N- dimethylformamide, ethereal solvents (diethyl ether, tetrahydrofuran or 1,4-dioxane), or a mixed solvent thereof. The conditions, as the base, lithium amide are preferred. Mixed solvent as the solvent ter- butyl alcohol and acetonitrile or ter- butyl alcohol, acetonitrile, heptane, and mixed solvents of toluene preferred. The reaction temperature can usually be selected from the range of about 10 ° C. ~ about 100 ° C..

5) Step 5
Compound (1-11) in an inert solvent, is prepared by reacting the compound (1-10) of potassium cyanate. The inert solvent, water, acetic acid or organic acids such as acetic acid and propionic acid, or toluene, benzene, or an aromatic hydrocarbon solvent and the like, such as xylene, performed usually water, in a mixed solvent of acetic acid and toluene It is. The reaction temperature is generally selected from the range of about 20 ° C. ~ about 80 ° C..

6) Step 6
Compound (1-12) in an inert solvent, is prepared by reacting an inorganic base with the compound (1-11). The inorganic base includes potassium carbonate, cesium carbonate or sodium carbonate, is. As the inert solvent, aprotic solvents (N, N- dimethylformamide or dimethyl sulfoxide) and the like, N, using N- dimethylformamide is preferred. The reaction temperature is generally selected from the range of about 20 ° C. ~ about 80 ° C..

7) Step 7
Compound (1-14) in an inert solvent, is prepared by reacting methyl iodide with the compound (1-12). As the inert solvent, aprotic solvents (N, N- dimethylformamide or dimethyl sulfoxide) and the like, N, using N- dimethylformamide is preferred. The reaction temperature is generally selected from the range of about 20 ° C. ~ about 50 ° C.. It is also possible to react with methyl iodide was added to the reaction solution in step 6.

8) Step 8
Compound (1-15) in an inert solvent, zinc cyanide and Pd catalyst presence, in the presence of a phosphine or absence, the compound (1-14) is produced by cyanation. As the inert solvent, N- methyl-2-pyrrolidone or N, N- dimethylformamide, and the like. The Pd catalyst, tris (dibenzylideneacetone) dipalladium complex Pd 2 (dba) 3 · CHCl 3, bis [tri (tert- butyl) phosphine] palladium complex Pd [(tert-Bu) 3 P] 2, tetrakis ( triphenylphosphine) palladium complex Pd (PPh 3) 4, bis (trifluoroacetoxy) palladium complex Pd (OCOCF 3) 2. Examples of the phosphine, triphenylphosphine [Ph 3 P], tri (tert- butyl) phosphine [(tert-Bu) 3 P ], tri -o- tolyl phosphine [(o-Tol) 3 P ], diphenylphosphino ferrocene [dppf], diphenylphosphino butane [dppb], and the like. The Pd 2 (dba) 2 when used as a Pd catalyst is preferably used a (o-Tol) 3 P. The reaction temperature is generally selected from the range of about 80 ° C. ~ about 130 ° C.. In the present process, the literature (for example Synth. Commun. 24, 887 (1994), Organic Letters 9, 1711 (2007), Tetrahedron Lett. 40, 8193 (1999), Tetrahedron Lett. 45, 1441 (2004), etc. has been manufacturing method can also be used as a reference described in).

9) Step 9
As a step 9, it is possible to use the following manufacturing method (A) and Process (B).
Process (A): Compound A, Compound (1-15), in an inert solvent, it is reacted with benzenesulphonic acid or its monohydrate, after completion of the reaction by neutralizing with an inorganic base, production can do. Examples of the inorganic base, sodium hydroxide or potassium hydroxide and the like, usually used as an aqueous solution. The inert solvent includes alcohol solvents (ethanol, methanol or 2-propanol, etc.), or nitrile solvents (acetonitrile or propionitrile, etc.) and the like, usually, a mixed solvent of alcohol solvent and a nitrile-based solvent used It is. The reaction temperature can usually be selected from the range of about 50 ° C. ~ about 100 ° C..
Process (B): Compound A, Compound (1-15), in an inert solvent, by reacting with an inorganic acid, it can be produced. As the inert solvent, dichloromethane, 1,2-dichloroethane, or a halogenated hydrocarbon solvent such as chloroform and the like. Examples of the inorganic acids include hydrochloric and the like. The reaction temperature can usually be selected from the range of about -10 ℃ ~ about 30 ° C..

Such as raw materials and reagents used in the above, unless otherwise specified, it may be prepared using methods known from are commercially available compounds, or known compounds. For example, compound (1-2) can be synthesized according to a method described in the literatures (Organic Letters 7, 55-58 (2005)).

The compounds of the present invention were synthesized as racemates can be fractionated by column chromatography using a filler bound an optically active ligand.

The compounds of the present invention are, for example, water, methanol, ethanol, in a solvent such as acetone, by mixing with an acid that is pharmaceutically acceptable, may be salified. The acid is pharmaceutically acceptable, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, inorganic acids such as nitric acid or acetic acid, propionic acid, oxalic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, and organic acids such as ascorbic acid.

The compounds of the invention, its application to the treatment of various diseases more inhibitory effect on DPP-IV is considered. Compounds described herein may be processed, before postprandial hyperglycemia suppression of the diabetic condition, the treatment of non-insulin dependent diabetes mellitus, the treatment of autoimmune diseases such as arthritis and rheumatoid arthritis, the treatment of intestinal mucosa diseases, growth promotion, transplanted organ rejection suppression piece, obesity, treatment of eating disorders, the treatment of HIV infection, the suppression of cancer metastasis, the treatment of benign prostatic hyperplasia, treatment of periodontitis, and the treatment of osteoporosis.

The compounds of the present invention, when used in therapy as a pharmaceutical composition, orally or parenterally (e.g., intravenous, subcutaneous, or intramuscular injection, topically, rectally, transdermally or nasally, it can be administered in manner). The compositions for oral administration, e.g., tablets, capsules, pills, granules, powders, solutions, suspending agents and the like. Examples of compositions for parenteral administration are, for example, for injection aqueous agent, or oily, ointments, creams, lotions, aerosols, suppositories, and the like patches. These formulations are prepared using conventional techniques and may contain non-toxic and inert carrier or excipient usually used in the pharmaceutical field.

Doses, the individual compounds, also the patient's disease, the age, weight, sex, symptoms, change the route of administration, etc., for the normal adult (body weight 50 kg), the compound of the present invention, 0.1 ~ 1000 mg / day, preferably administered in one portion or two to three times a day 1 ~ 300 mg / day. In addition, it can also be administered once in a few days to a few weeks.

The compounds of the present invention, for the purpose of enhancement of its effect, an agent for treating diabetes, therapeutic agents for diabetic complications, antihyperlipidemic agents, antihypertensive agents, antiobesity agents, drugs such as diuretics (hereinafter, abbreviated as concomitant drug can be used in combination with that). Administration time of the compound of the present invention and the concomitant drug is not limited, to these administration subject, may be administered simultaneously, or may be administered in a staggered manner. Further, it may be mixture of the present invention and the combination drug compound. The dose of the concomitant drug can be appropriately selected on the clinically employed dose as a reference. The compounding ratio of the compound of the present invention and combination drug, the administration subject, can be appropriately selected depending on such administration route, target disease, condition, combination. For example, when the administration subject is a human, the compound of the present invention 1 part by weight of the concomitant drug may be used 0.01 to 100 parts by weight.

As the therapeutic agent for diabetes, insulin preparations (e.g., bovine, animal insulin preparations extracted from pancreas of swine; Escherichia coli, using a yeast, such as genetically engineered human insulin preparations synthesized by), insulin sensitizers ( examples, pioglitazone or a hydrochloride salt thereof, troglitazone, rosiglitazone or its maleate, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011 etc.), alpha-glucosidase inhibitor ( examples, voglibose, acarbose, miglitol, emiglitate etc.), biguanides (e.g., metformin), insulin secretagogues (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride etc. Sulfonylureas; repaglinide, senaglinide, nateglinide, mitiglinide, etc.), GLP-1, GLP-1 analogue (Ekisenataido, Riragurutaido, SUN-E7001, AVE010, BIM-51077, CJC1131 etc.), protein tyrosine phosphatase inhibitors (e.g., vanadic acid etc.), .beta.3 agonists (e.g., GW-427353B, like N-5984) and the like.

Therapeutic agent for diabetic complications include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat, Zoporesutatto, Minaresutatto, fidarestat, ranirestat, SK-860, CT-112 etc.), neurotrophic factors (e.g., NGF , NT-3, BDNF etc.), PKC inhibitors (e.g., such as LY-333531), AGE inhibitors (e.g., ALT946, pimagedine, pyratoxathine, N- phenacylthiazolium Lucia tetrazolium bromide (ALT766), etc.), active oxygen scavenging drugs (e.g., thioctic acid etc.), cerebral vasodilators (e.g., tiapride, mexiletine etc.). The antihyperlipidemic, HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or sodium salt thereof, etc.), squalene synthetase inhibitors, ACAT inhibitors and the like and the like. Examples of the antihypertensive agent include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, alacepril, delapril, lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, etc.), angiotensin II antagonists (e.g., olmesartan, medoxomil, candesartan, cilexetil, losartan, eprosartan, Barusantan, telmisartan, irbesartan, tasosartan etc.), calcium antagonists (e.g., nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, amlodipine, etc.), renin inhibitors (aliskiren like) .

Anti-obesity agents, for example, central antiobesity drugs (e.g., phentermine, sibutramine, amfepramone, dexamphetamine, mazindol, and the like SR-141716A), a pancreatic lipase inhibitor (e.g., orlistat, etc.), peptidic anorectics (eg, leptin, CNTF (ciliary neurotrophic factor) etc.), cholecystokinin agonists (eg, lintitript, FPL-15849 etc.) and the like can be mentioned. Examples of the diuretic agent include xanthine derivatives (e.g., theobromine sodium salicylate, and the like calcium salicylate and theobromine), thiazide preparations (e.g., Echiajido, cyclopenthiazide thiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide , methyclothiazide etc.), anti-aldosterone preparations (e.g., spironolactone, triamterene etc.), carbonic anhydrase inhibitors (e.g., acetazolamide, etc.), chlorbenzenesulfonamide preparations (e.g., chlorthalidone, mefruside, indapamide etc.), azosemide, isosorbide , ethacrynic acid, piretanide, bumetanide, furosemide and the like.

Concomitant drug is preferably GLP-1, GLP-1 analogs, alpha-glucosidase inhibitors, biguanide agents, insulin secretion accelerators, insulin sensitizers such. The above-mentioned combination drugs may be used in combination of two or more kinds thereof at an appropriate ratio.

The present invention compounds, when used in combination with a combination drug, the amount of these drugs can be reduced within a safe range in consideration of adverse effects of the drug. In particular, a biguanide can be reduced as compared with the normal dose. Thus, side effects that may be caused by these agents can be safely prevented. In addition, diabetic complications, anti-hyperlipidemia agent, can reduce the dose, such as antihypertensive agents, the side effects that would result caused by these agents can be effectively prevented.

Example
The present invention will now reference examples, examples and test examples, will be more specifically described, the present invention is not limited to this as well. The compound names shown in the following Reference Examples and Examples are not necessarily subject to IUPAC nomenclature.

Reference Example 1
tert- butyl 3 - {(3R) -3 - [(tert- butoxycarbonyl) amino] -3-methyl-piperidin-1-yl} -2-cyano-3- (methylthio) acrylate

Figure JPOXMLDOC01-appb-C000003
tert- butyl 2-cyano-3,3-bis (methylthio) acrylate in toluene (25 ml) solution of (48.43 g) (3R) -3 - [(tert- butoxycarbonyl) amino] -3-methylpiperidine (40.23 added a toluene solution (70 ml) of g) was stirred at 80 ° C.. After 4 hours, allowed to return to room temperature heptane (300 ml) was added at 80 ° C.. Then, after stirring for one hour in an ice bath, the precipitated white solid was collected by filtration. And dried under reduced pressure to obtain the title compound (64.50g) as a white solid.
MS (ESI +) 412 (M + +1, 60%)

Reference Example 2
tert- butyl 3 - [(2-bromo-5-fluorobenzyl) amino] -3 - {(3R) -3 - [(tert- butoxycarbonyl) amino] -3-methyl-piperidin-1-yl} -2- cyanoacrylate

Figure JPOXMLDOC01-appb-C000004
Compound of Reference Example 1 (70.7 g) was dissolved in acetonitrile (70 ml), DBU (52.35g), was stirred at 50 ° C. was added 2-bromo-5-fluoro-benzylamine (36.22g). After five hours, diluted with toluene (200 ml), and washed with water. The resulting organic layer was washed with water, 10% aqueous potassium hydrogen sulfate solution, washed with 10% sodium hydroxide solution, dried over sodium sulfate, filtered, as an amorphous title compound (108.3 g) of a yellow concentrated under reduced pressure to Obtained.
MS (ESI +) 567 (M + +1, 60%)

Reference Example 3
tert- butyl 3 - [(2-bromo-5-fluorobenzyl) (2-ethoxy-2-oxoethyl) amino] -3 - {(3R) -3 - [(tert- butoxycarbonyl) amino] -3-methyl piperidin-1-yl} -2-cyanoacrylate

Figure JPOXMLDOC01-appb-C000005

Dissolved compound of Reference Example 2 (108.3 g) in dimethylformamide (170 ml), stirred at room temperature was added potassium carbonate (104.8 g). After dropwise ethyl bromoacetate (50.63 g), and stirred for one hour at 40 ° C.. Toluene was filtered through celite added, and the resulting organic layer was washed with water, dried over sodium sulfate, filtered to give the title compound (124.10 g) as a dark red amorphous concentrated under reduced pressure.
MS (ESI +) 653 (M + +1, 60%)

Reference Example 4
4-tert-butyl 2-ethyl 3-amino-1- (2-bromo-5-fluorobenzyl) -5 - {(3R) -3 - [(tert- butoxycarbonyl) amino] -3-methyl-piperidine -1 - yl}-1H-pyrrole-2,4-dicarboxylate

Figure JPOXMLDOC01-appb-C000006
Heptane (146 ml) was added to the lithium amide (9.6 g), was added dropwise at 80 ° C. tert-butyl alcohol (268 g) a mixture of heptane (30 ml). Cooled to 30 ° C. After one hour, acetonitrile was added (340 ml). To the mixture was stirred with toluene (350 ml) solution of the compound of Reference Example 3 (124.10 g). After two hours, the solvent was distilled off under reduced pressure, toluene was added (700 ml) and water (370 ml). Adjusted to about pH 5.0 with concentrated hydrochloric acid, filtered through Celite, the layers were separated. The obtained organic layer was dried over sodium sulfate, filtered to give the title compound (100 g) as a dark red oil by concentration under reduced pressure.
MS (ESI +) 653 (M + +1, 100%)

Reference Example 5
4-tert-butyl 2-ethyl 3 - [(aminocarbonyl) amino] -1- (2-bromo-5-fluorobenzyl) -5 - {(3R) -3 - [(tert-butoxycarbonyl) amino] - 3-methyl-piperidin-1-yl}-1H-pyrrole-2,4-dicarboxylate

Figure JPOXMLDOC01-appb-C000007
To a mixture of the compound of Reference Example 4 (100 g) was dissolved in acetic acid (490 ml), potassium cyanate (25 g) was added dropwise a solution 40 ° C. The dissolved in water (40 g), and stirred. After two hours, returned to room temperature, diluted with toluene (700 ml), and washed three times with water (300 ml). The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to give the title compound (110 g) as a dark red amorphous concentrated under reduced pressure.
MS (ESI +) 696 (M + +1, 100%)

Reference Example 6
tert- butyl 5- (2-bromo-5-fluorobenzyl) -6 - {(3R) -3 - [(tert- butoxycarbonyl) amino] -3-methyl-piperidin-1-yl} -1,3-dimethyl 2,4-dioxo-2,3,4,5-tetrahydro -1H- pyrrolo [3,2-d] pyrimidine-7-carboxylate

Figure JPOXMLDOC01-appb-C000008
Dissolved compound of Reference Example 5 (110 g) in dimethylformamide (290 ml), potassium carbonate (66 g), and stirred at 50 ° C. was added water (2.9 ml). After five hours, cooled to 30 ° C., added dropwise methyl iodide (51 g), and stirred. After two hours, water (400 ml) was added, the precipitated solid was collected by filtration. The resulting solid was slurry washed with 60 ° C. in isopropanol (700 ml), it was returned to room temperature. The solid was collected by filtration, was slurried washed with 60 ° C. in again isopropanol (400 ml). To give the title compound (54.7 g) as a white solid by the solid obtained is dried under reduced pressure.
MS (ESI +) 678 (M + +1, 100%)

Reference Example 7
tert- butyl 5- (2-cyano-5-fluoro-benzyl) -6 - {(3R) -3 - [(tert- butoxycarbonyl) amino] -3-methyl-piperidin-1-yl} -1,3-dimethyl 2,4-dioxo-2,3,4,5-tetrahydro -1H- pyrrolo [3,2-d] pyrimidine-7-carboxylate

Figure JPOXMLDOC01-appb-C000009
Compound of Reference Example 6 (27.14 g) in N- methylpyrrolidone (100 ml), tris (dibenzylideneacetone) dipalladium (1.83 g), tris (o-tolyl) phosphine (4.99 g), zinc cyanide (Zn ( CN) 2) (2.90 g) and the mixture degassed under reduced pressure was performed five times the nitrogen replacement. The mixture was stirred at 120 ° C.. After two hours, cooled to room temperature and filtered through Celite. The obtained organic layer was aqueous ammonia, saturated aqueous ammonium chloride, water 4: 4: vigorous stirring was added to the mixed solution at 1. The resulting yellow solid was collected by filtration, acetonitrile (20 ml), washed two hours the slurry at 80 ° C., was recovered by filtration after stirring for one hour in an ice bath. To give the title compound (18.30 g) as a white solid by the solid obtained is dried under reduced pressure.
MS (ESI +) 625 (M + +1, 90%).

Example 1
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

Figure JPOXMLDOC01-appb-C000010
tert- butyl 5- (2-cyano-5-fluoro-benzyl) -6 - {(3R) -3 - [(tert- butoxycarbonyl) amino] -3-methyl-piperidin-1-yl} -1,3-dimethyl 2,4-dioxo-2,3,4,5-tetrahydro -1H- pyrrolo [3,2-d] benzenesulfonic acid to a mixture of acetonitrile (30 ml) pyrimidine-7-carboxylate (18.3 g) after the dropwise addition of ethanol (15 ml) solution of the monohydrate (10.85 g) at 40 ° C., and stirred for two hours at 80 ° C.. Returning to room temperature, the NaOH (2.49 g) after diluted with ethyl acetate (50 ml) and neutralized by adding a solution of water (50 ml). The organic layer was washed with saturated saline water to obtain dried over sodium sulfate, filtered, the title compound by concentrated under reduced pressure (11.86 g).
1 H NMR (400 MHz, DMSO -d 6) δ 7.97-8.00 (m, 1H), 7.30-7.35 (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-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 hydrochloride

Figure JPOXMLDOC01-appb-C000011
Compounds obtained in the same manner as in Example 1 (140 mg) was dissolved in chloroform (3.0 ml), and concentrated by addition of 1N hydrochloric acid ether (2.0 ml), was synthesized the title compound (150 mg).
1 H NMR (400 MHz, DMSO -d 6) δ 8.17 (brs, 3H), 7.97-8.00 (m, 1H), 7.30-7.35 (m, 1H), 6.25-6.28 (m, 1H), 6.12 (s , 1H), 5.57-5.68 (m, 2H), 3.38 (s, 3H), 3.09 (s, 3H), 3.04-3.07 (m, 1H), 2.88-2.94 (m, 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 Example 8
2 - ({6 - [(3R) -3- amino-piperidin-1-yl] -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro -5H- pyrrolo [3, 2-d] pyrimidin-5-yl} methyl) -4-fluorobenzonitrile (hereinafter compound B substantially) hydrochloride

Figure JPOXMLDOC01-appb-C000012
It was synthesized by the method of WO 2006/068163 pamphlet described in Example 13.
1 H NMR (300 MHz, CDCl 3) δ 8.50 (brs, 3H), 7.71-7.65 (m, 1H), 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%).

Reference Example 9
2 - ({6 - [(3R) -3- amino-3-ethyl-piperidin-1-yl] -1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro -5H- pyrrolo [3,2-d] pyrimidin-5-yl} methyl) -4-fluorobenzonitrile (hereinafter compound C approximately)

Figure JPOXMLDOC01-appb-C000013
3 racemic - [(tert- butoxycarbonyl) amino] -3-ethylpiperidine was synthesized in the same manner as in Reference Example 1 ~ 7 tert-butyl 5- (2-cyano-5-fluorobenzyl) -6- { 3 - [(tert-butoxycarbonyl) amino] -3-ethylpiperidine-1-yl} -1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro -1H- pyrrolo [3 , using 2-d] pyrimidine-7-carboxylate (1.0 g), was synthesized racemate (630 mg) of the title compound in the same manner as in example 1. Then, this racemate CHIRALPAK (TM) AD-H (manufactured by Daicel Chemical Industries, Ltd.; chiral stationary phase: amylose using tris (3,5-dimethylphenyl carbamate) hexane / isopropanol / diethylamine = 70/30 / to give 0.1 (v / v) the title compound by breaking the conditions of (220 mg).
1 H NMR (400 MHz, DMSO -d 6) 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 (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 + +1, 100%).

Reference Example 10
(3R)-3-methyl - ethyl nipecotate 1/2 di -p- toluoyl -D- tartrate

Figure JPOXMLDOC01-appb-C000014
Toluene solution (100 ml) in sodium hexamethyldisilazane in tetrahydrofuran (1.0M, 152 ml) of ethyl nipecotate (20.0 g) was added dropwise a solution slowly at a temperature of -20 ~ -30 ° C.. After stirring for 30 minutes, methyl iodide (19.4 g) was slowly added dropwise at a temperature of -20 ~ -30 ° C., was slowly returned to room temperature. Water (20.8 ml) was added, separated, concentrated and the resulting residue was washed after dilution with toluene with water (20 ml). Dried over sodium sulfate, filtered, and concentrated under reduced pressure, the obtained oily component was added ethyl acetate (125 ml). To the solution, and the ethyl acetate (60 ml) solution of di -p- toluoyl -D- tartaric acid added and stirred at 50 ° C.. After one hour, collected by filtration as a white solid resulting returned to room temperature to obtain the title compound (13.87 g) by drying under reduced pressure.
MS (ESI +) 171 (M + +1, 100%)

Reference Example 11
(3R)-3-methyl - ethyl nipecotate

Figure JPOXMLDOC01-appb-C000015
Compound of Reference Example 10 (13.87 g) dissolved in water (55 ml), was added and stirred 10% potassium carbonate aqueous solution (55 ml) and ether (50 ml). After 30 minutes, the organic layer was separated, dried over sodium sulfate to give after filtration, the title compound by concentrated under reduced pressure (4.23 g) as an oily component yellow.
MS (ESI +) 171 (M + +1, 100%)

Reference Example 12
1-benzyl 3-ethyl (3R)-3-methyl-piperidine-1,3-dicarboxylate

Figure JPOXMLDOC01-appb-C000016
Dissolved compound of Reference Example 11 (4.23 g) in tetrahydrofuran (20 ml), and cooled in an ice bath was added triethylamine (3.76 ml). Slowly added dropwise benzyl chloroformate (3.55 ml), and stirred overnight returned to room temperature. After celite filtration, the solvent was distilled off, and diluted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered to give the title compound (7.32 g) as an oily component yellow concentrated under reduced pressure.
MS (ESI +) 306 (M + +1, 100%)

Reference Example 13
(3R) -1 - [(benzyloxy) carbonyl] -3-methyl-3-carboxylic acid

Figure JPOXMLDOC01-appb-C000017
The compound of Reference Example 12 (7.32 g) in methanol (10 ml) and 3N sodium hydroxide solution (10 ml) was added and stirred at 50 ° C.. After three hours, the methanol was distilled off, 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, filtered to give the title compound (5.45 g) as an oily component yellow concentrated under reduced pressure.
MS (ESI +) 278 (M + +1, 100%)

Reference Example 14
Benzyl (3R) -3 - [(tert- butoxycarbonyl) amino] -3-methyl-piperidine-1-carboxylate

Figure JPOXMLDOC01-appb-C000018
Compound of Reference Example 13 (5.45 g) was dissolved in toluene (30 ml), was added triethylamine (2.09 g). Diphenylphosphoryl toluene solution of the azide (5.47 g) of (20 ml) at 90 ° C., while confirming the generation of nitrogen, was slowly added dropwise. After the addition, the mixture was stirred for one hour at 90 ° C.. Returning to room temperature, twice washed with water (27 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to a volume of about 1/3. The resulting solution tert- butanol added (3.7 ml) and tert- butoxy potassium (1.0 g), and stirred at 30 ° C.. After two hours, washed with water, saturated aqueous ammonium chloride and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (3.62 g) as a white solid by column chromatography purification.
MS (ESI +) 349 (M + +1, 20%)

Reference Example 15
(3R) -3 - [(tert- butoxycarbonyl) amino] -3-methylpiperidine

Figure JPOXMLDOC01-appb-C000019
Compound of Reference Example 14 (34.8 g) was dissolved in ethyl acetate (50 ml), was stirred with 1N hydrochloric acid (0.5 ml) and 10% Pd / C (2.0 g) was added under hydrogen pressure (2-2.5 atm). After two hours, filtered through celite, washed aqueous 3N sodium hydroxide, water and saturated brine, resulting dried over sodium sulfate, filtered, concentrated under reduced pressure to give the title compound (20.4 g) as an oily component of colorless It was.
MS (ESI +) 215 (M + +1, 60%)

Reference Example 16
3 - [(tert-butoxycarbonyl) amino] -3-ethylpiperidine

Figure JPOXMLDOC01-appb-C000020
Ethyl nipecotate from Reference Example 10 (except salt formation by di -p- toluoyl -D- tartaric acid was not performed), 12, 13, and 14 benzyl obtained in the same manner as 3 - [(tert-butoxycarbonyl) from amino] -3-ethyl-1-carboxylate (6.60 g), in the same manner as in reference example 15 to give the title compound (4.20 g) as an oily component colorless.
MS (ESI +) 229 (M + +1, 60%)

Test Example
Test Example 1 an In vitro final concentration of human plasma containing DPP-IV inhibitory activity Measurement Test DPP IV enzyme was prepared a test substance solution at various concentrations such that 10% was added to microassay plates. Further substrate (Glycyl-L-Proline 4-Methylcoumaryl-7-Amide, Peptide Institute) was added to a final concentration of 50 [mu] M, using a fluorescence plate reader at room temperature, the fluorescence intensity (excitation wavelength 380 nm, measurement wavelength the 460 nm) continuously measured to determine the enzyme activity. The enzyme activity was calculated test substance concentration (IC 50 value) which inhibited by 50%.

Figure JPOXMLDOC01-appb-T000021

Mechanism-based inhibition of symptoms for Test Example 2 CYP3A4 (MBI) Evaluation Test
It was added a test compound at various concentrations in human liver microsomes in the presence NADPH or absence, preincubated for 15 minutes at 37 ° C.. Thereafter, the reaction solution was diluted 20-fold with a mixture of NADPH midazolam (midazolam) a CYP3A4 substrate, it was further reacted for 5 minutes at 37 ° C.. 3-fold amount of methanol was added to stop the reaction, the production amount of metabolite of midazolam (1-Hydroxy midazolam) was assessed CYP3A4 activity by measuring using LC / MS / MS. And control the activity at the time of NADPH absence preincubation, the decrease in activity during NADPH presence preincubation time divided by (15 min) was inactivated rate constant (kobs). At this time, the relationship between the kobs a test compound concentration (I) is represented by kobs = kinact × I / (K'app + I). Maximum inactivation rate constant by regression analysis by non-linear least squares method (kinact), to calculate the apparent dissociation constant (K'app), was determined the intensity of MBI the value of kinact / K'app.
Figure 1 The results obtained are shown in Figure 2 and Table 2. Compound B (Reference Example 8) inactivation of concentration-dependent CYP3A4 was observed. Although compounds which are 3-ethyl substituted product B Compound C inactivation (Reference Example 9) even CYP3A4 is observed, it was low and its intensity is compared with the compound B. On the other hand, compounds which are 3-methyl-substituted product A (Example 1) is inactivated is not observed, kobs = kinact × I / (K'app + I) regression analysis to was impossible.

Figure JPOXMLDOC01-appb-T000022
NA: not applicable

From Test Example 1 and 2, Compound B, Compound A, Compound C has a substituent is a hydrogen atom on each aminopiperidine differ only in a methyl group, an ethyl group. However, the DPP-IV inhibitory activity IC 50 (nM) of the compound A (1.6 nM) is high with a compound B (0.34 nM) and methyl group having a hydrogen atom, a compound having an ethyl group as compared with those C It is low Oita activity (26nM). Meanwhile, in a very important MBI in terms of drug safety, while being detected in compound B (0.34 nM) having a hydrogen atom, are detected in a compound having a methyl group A (1.6 nM) There was no. However the compound C has an additional ethyl group extending the carbon chain also MBI is detected. These results were found to be compound A having a methyl group is a compound also particularly excellent in terms of MBI in terms of DPP-IV inhibitory activity. The reason is considered that the difference in substituents in the entire structure of the present invention compound is affecting the interaction with each of DPP-IV and CYP3A4. However, while strong compound with a compound having a methyl group having a hydrogen atom in terms of interaction with the DPP-IV, strong compound with a compound having a ethyl group having a hydrogen atom in the interaction with CYP3A4, methyl not be detected with a compound having a group is that it does not stick the completely unexpected from the conventional knowledge.

Have DPP-IV inhibitory activity according to the present invention, it is possible to provide safety was improved by toxicity compounds.
The compounds of the present invention, prior to postprandial hyperglycemia suppression of the diabetic condition, the treatment of non-insulin dependent diabetes mellitus, the treatment of autoimmune diseases such as arthritis and rheumatoid arthritis, the treatment of intestinal mucosa diseases, growth promotion, rejection of transplanted organs piece suppression, obesity, treatment of eating disorders, the treatment of HIV infection, the suppression of cancer metastasis, of prostate hypertrophy treatment, treatment of periodontitis, and the treatment of osteoporosis.

Claims (4)

  1. 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 or a pharmaceutically acceptable salt thereof.
  2. 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.
  3. The compound of claim 1, wherein or dipeptidylpeptidase -IV inhibitors containing salt thereof that is pharmaceutically acceptable or compound of claim 2 and, as an active ingredient.
  4. Antidiabetic agents containing compound according to claim 1 or a pharmaceutically acceptable salt thereof as claimed or compound of claim 2, as an active ingredient.
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WO2010086411A1 (en) 2009-01-29 2010-08-05 Boehringer Ingelheim International Gmbh Dpp-iv inhibitors for treatment of diabetes in paediatric patients
WO2010092163A2 (en) 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Antidiabetic medications
WO2011005929A1 (en) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Piperidine derivative and its use for the treatment of diabets and obesity
WO2011064352A1 (en) 2009-11-27 2011-06-03 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
WO2011113947A1 (en) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions
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WO2010079197A1 (en) 2009-01-07 2010-07-15 Boehringer Ingelheim International Gmbh Treatment of diabetes in patients with inadequate glycemic control despite metformin therapy comprising a dpp-iv inhibitor
WO2010086411A1 (en) 2009-01-29 2010-08-05 Boehringer Ingelheim International Gmbh Dpp-iv inhibitors for treatment of diabetes in paediatric patients
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