JP2004244412A - 2-cyanopyrrolidine derivative having substituent at 4-position, method for producing the same, and medicament containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a 2-cyanopyrrolidine derivative having a substituent at the 4-position or its salt, having excellent dipeptidylpeptidase (DPP-IV) inhibitory activity and high stability, and useful for preventing/treating diabetes, obesity, HIV infection, metastasis of cancer, dermatitis, prostatomegaly, periodontitis or autoimmune diseases. <P>SOLUTION: The 2-cyanopyrrolidine derivative expressed by formula (I) [A is F, monofluoromethyl, difluoromethyl or trifluoromethyl; B is C-(CH<SB>3</SB>)<SB>2</SB>CH<SB>2</SB>-NH-D or expressed by formula (2) (a bond expressed by a full line together with a dotted line is a single bond or a double bond; and D is a heterocyclic ring which may be substituted); and C is H or a 1-8C lower alkyl] and having the substituent at the 4-position, or its pharmaceutically acceptable salt, is provided in the specification. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

  The present invention has a dipeptidyl peptidase IV (DPP-IV) inhibitory activity and prevents or treats diabetes, obesity, HIV infection, cancer metastasis, skin disease, prostatic hyperplasia, periodontitis or autoimmune disease. A 2-cyanopyrrolidine derivative having a substituent at the 4-position or a salt thereof, which is useful for the above.

Dipeptidyl peptidase (DPP-IV) is a serine protease that recognizes the amino acid sequence having proline second from the N-terminus and produces a dipeptide. DPP-IV is widely distributed in mammalian tissues and has been reported to be particularly present in blood, kidney, intestinal epithelium and placenta. Although the physiochemical role of DPP-IV in mammals has not been completely elucidated, neuropeptide degradation (FEBS Letters, 91 , 360-364, 1978), activation of T cells (Biomedica Biochimica Acta, 44 , K9-K15, 1985), Adhesion of metastatic tumor cells to endothelium (Journal of Cell Biology, 121 , 1423-1432, 1993), Invasion of HIV virus into lymphocytes (Science, 262 , 2045-2050, 1993) It is being clarified to be involved in a wide range of physiological functions such as.

In particular, the role of DPP-IV as an enzyme that inactivates the glucagon-like peptide (GLP-1), a substance in the body that has a strong insulin secretion capacity and regulates postprandial blood glucose levels, has attracted attention (Journal of Clinical). Endocrinology and Metabolism, 80 , 952-957, 1995). GLP-1 is metabolized in vivo in a short time. In particular, metabolism by DPP-IV is important, and GLP-1 is rapidly cleaved to produce inactive GLP-1. Furthermore, since this inactive GLP-1 exhibits an antagonistic action on the GLP-1 receptor, it is considered that the physiological action of GLP-1 is further attenuated (European Journal of Pharmacology, 318 , 429-435, 1996). ). From the above, the method of suppressing the degradation of GLP-1 by inhibiting DPP-IV is considered to be the best approach for enhancing GLP-1 activity. That is, the DPP-IV inhibitor is expected to be an excellent therapy for improving postprandial hyperglycemia without side effects such as prolonged hypoglycemia for non-insulin-dependent diabetes (type 2 diabetes) patients.

  Against this background, studies on DPP-IV inhibitors have been actively conducted recently, and many DPP-IV inhibitors have been reported. For example, Patent Document 1 proposes a compound represented by the following general formula (A). Patent Document 2 proposes a compound exemplified by the following general formula (B). Further, Patent Document 3 proposes a compound represented by the following general formula (C).

It has been reported that the compound represented by the general formula (A) has a short-lasting effect due to low chemical stability (Biochemistry, 38 , 11597-11603, 1999). The compound represented by the general formula (B) having a dimethyl substituent in the ethylenediamino part of the compound represented by the general formula (A) and the general formula (C) in which a fluorine atom is introduced on a pyrrolidine ring are chemically synthesized. It has been reported that the effect of sustaining action was improved by improving the stability (22nd Medicinal Chemistry Symposium, Abstracts of Lectures, 2P-6, 2002). However, these compounds have insufficient DPP-IV inhibitory activity and are not satisfactory as pharmaceuticals. Accordingly, development of a compound that has a therapeutic effect and high chemical stability due to DPP-IV activity and is satisfactory as a pharmaceutical has been desired.

US Patent No. 6,011,155 WO 02/051836 pamphlet WO 03/002553 pamphlet

  The present inventor has excellent dipeptidyl peptidase (DPP-IV) inhibitory activity and high stability, and is useful for diabetes, obesity, HIV infection, cancer metastasis, dermatitis, prostatic hypertrophy, periodontitis or autoimmune disease. An object of the present invention is to provide a 2-cyanopyrrolidine derivative having a substituent at the 4-position or a salt thereof, which is useful for prevention / treatment, and a therapeutic agent containing the derivative.

As a result of intensive studies, the present inventors have found that a fluorine atom, a monofluoromethyl group, a difluoromethyl group or a trifluoromethyl group is attached to the 4-position of a 2-cyanopyrrolidine ring represented by the general formula (I), The inventors have found that a compound having a sulfonamide group-substituted heterocycle in the chain has excellent DPP-IV inhibitory activity and high stability, and have completed the present invention.
That is, the present invention provides the following general formula (I):

[In the formula, A is a fluorine atom, a monofluoromethyl group, a difluoromethyl group or a trifluoromethyl group, B is -C (CH ₃ ) ₂ CH ₂ -NH-D or

(In the formula, a bond indicated by both a solid line and a dotted line represents a single bond or a double bond. D represents a heterocyclic ring which may have a substituent.), C represents a hydrogen atom or a lower alkyl group (C1- C8). ]
Is a 2-cyanopyrrolidine derivative having a substituent at the 4-position or a pharmaceutically acceptable salt thereof.
In the above general formula (I), C is a hydrogen atom, and B is a group represented by the following formula:
-C (CH ₃ ) ₂ CH ₂ -NH-D or

[In the formula, a bond indicated by both a solid line and a dotted line indicates a single bond or a double bond. D is the following general formula (II) or general formula (III):

(Wherein, a, b, c, d, and e are one or two nitrogen atoms and the remainder is a carbon atom. E and F may be the same or different, and each independently represents a hydrogen atom, a halogen atom A lower alkoxy group (C1-C8), a lower alkyl group (C1-C8), a lower haloalkyl group (C1-C8), a benzene ring which may have a substituent, a heterocyclic ring which may have a substituent, amino group, carboxyl group, lower alkoxycarbonyl group (C1-C8), a carbamoyl group, a lower alkanoyl group (C1-C8), a cyano group, .G showing a nitro group or a hydroxyl group represents a -SO ^₂ NR ¹ R _2, H represents -NR ¹ SO ₂ R ^2. R ¹ and R ² may be the same or different and each independently represents a hydrogen atom, a lower alkyl group (C1-C8) which may form a ring, a lower haloalkyl. Group (C1-C8), benzene ring optionally having substituent (s), heterocycle optionally having substituent (s) or lower A 2-cyanopyrrolidine derivative having a substituent at the 4-position or a pharmaceutically acceptable salt thereof is preferable.

  Furthermore, the present invention relates to a medicament comprising a 2-cyanopyrrolidine derivative having a substituent at the 4-position represented by the above general formula (I) or a pharmaceutically acceptable salt thereof and a pharmacologically acceptable carrier. A composition. Further, the present invention is a dipeptidyl peptidase IV inhibitor containing a 2-cyanopyrrolidine derivative having a substituent at the 4-position represented by the general formula (I) or a pharmaceutically acceptable salt thereof. Further, the present invention is a therapeutic agent for a disease involving dipeptidyl peptidase IV, which comprises a 2-cyanopyrrolidine derivative having a substituent at the 4-position represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. The disease can be due to diabetes, obesity, HIV infection, cancer metastasis, skin disease, benign prostatic hyperplasia, periodontitis or autoimmune disease.

  The novel 2-cyanopyrrolidine derivative having a substituent at the 4-position of the present invention has dipeptidyl peptidase IV (DPP-IV) inhibitory activity and high stability, and has diabetes, obesity, HIV infection, cancer metastasis, dermatitis, It is useful for preventing or treating benign prostatic hyperplasia, periodontitis or autoimmune diseases.

  The compound represented by formula (I) will be described in detail. In the definition of the general formula in this specification, the term “lower” means carbons 1 to 8 which may have a branch, unless otherwise specified. A in the general formula (I) includes a fluorine atom, a monofluoromethyl group, a difluoromethyl group, and a trifluoromethyl group. B is a group represented by the aforementioned general formula. C is a hydrogen atom or a lower alkyl group having 1 to 8 carbon atoms (methyl group, ethyl group, propyl group, isopropyl group, butyl group, pentyl group, cyclopentyl group, hexyl group, cyclohexyl group, heptyl group, cycloheptyl group, octyl Group).

  D is an optionally substituted heterocycle (pyridine, pyrimidine, pyrazine, pyridazine) and the like, and the substituent is a hydrogen atom, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom). , Lower alkoxy groups (methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, cyclopentyloxy, hexyloxy, cyclohexyloxy, heptyloxy, cycloheptyloxy, octyloxy) , Lower alkyl groups (methyl, ethyl, propyl, isopropyl, butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl), lower haloalkyl groups (monofluoromethyl Group, difluoromethyl group, trifluoromethyl Group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, monochloromethyl group, dichloromethyl group, trichloromethyl group, 2,2,2-trichloroethyl group), benzene ring, heterocycle (pyridine, Pyrimidine, pyrazine, pyridazine), amino group, carboxyl group, lower alkoxycarbonyl group (methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, pentyloxycarbonyl group, cyclopentyloxycarbonyl group, hexyl Oxycarbonyl, cyclohexyloxycarbonyl, heptyloxycarbonyl, cycloheptyloxycarbonyl, octyloxycarbonyl), carbamoyl, lower alkanoyl (acetyl, propionyl, butyro) Le group), a cyano group, a nitro group, and a hydroxyl group.

G is include -SO ^₂ NR ¹ R _2, H can be mentioned -NR ¹ SO ^₂ R _2. Here, R ¹ and R ² may be the same or different and each independently represents a hydrogen atom or a lower alkyl group which may form a ring (methyl group, ethyl group, propyl group, isopropyl group, butyl group, pentyl group) Group, cyclopentyl group, hexyl group, cyclohexyl group, heptyl group, cycloheptyl group, octyl group), lower haloalkyl group (monofluoromethyl group, difluoromethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group , Pentafluoroethyl group, monochloromethyl group, dichloromethyl group, trichloromethyl group, 2,2,2-trichloroethyl group), benzene ring, heterocycle (pyrrole, furan, thiophene, pyridine, pyrimidine, pyrazine, pyridazine) or And lower alkanoyl groups (acetyl group, propionyl group, butyroyl group) and the like.

  Further, the compounds of the present invention include any stereoisomers, optical isomers, tautomers, and arbitrary mixtures thereof. The pharmaceutically acceptable salts of compound (I) include inorganic acid addition salts (salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acid addition salts (methanesulfone Acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, apple Acids, pantothenic acid, etc.), amino acids (salts with glutamic acid, aspartic acid, etc.) and the like.

The compound represented by the above general formula (I) is specifically exemplified below.
(1) (2S, 4S) -1- {1- [5- (dimethylaminosulfonylpyridin-2-yl) piperidin-4-yl] amino} acetyl-4-fluoro-2-cyanopyrrolidine (2) (2S , 4S) -1- {1- [5- (Methylaminosulfonylpyridin-2-yl) piperidin-4-yl] amino} acetyl-4-fluoro-2-cyanopyrrolidine (3) (2S, 4S) -1 -{1- [5- (Diethylaminosulfonylpyridin-2-yl) piperidin-4-yl] amino} acetyl-4-fluoro-2-cyanopyrrolidine (4) (2S, 4S) -1- {1- [5 -(Ethylaminosulfonylpyridin-2-yl) piperidin-4-yl] amino {acetyl-4-fluoro-2-cyanopyrrolidine (5) (2S, 4S) -1- {1- [5- (pyrrolidine-1) -Yl) aminosulfonylpyridin-2-yl] piperidin-4-yl] amino {acetyl-4-fluoro-2-cyanopyrrolidine (6) (2S, 4S) -1- {1- [5-[(piperidin- 1-yl)] amino Sulfonylpyridin-2-yl] piperidin-4-yl] amino} acetyl-4-fluoro-2-cyanopyrrolidine

(7) (2S, 4S) -1- {3-[(5-dimethylaminosulfonylpyridin-2-yl) amino] -2-methylpropylamino} acetyl-4-fluoro-2-cyanopyrrolidine (8) ( 2S, 4S) -1- {3-[(5-methylaminosulfonylpyridin-2-yl) amino] -2-methylpropylamino} acetyl-4-fluoro-2-cyanopyrrolidine (9) (2S, 4S) -1- {3-[(5-Diethylaminosulfonylpyridin-2-yl) amino] -2-methylpropylamino} acetyl-4-fluoro-2-cyanopyrrolidine (10) (2S, 4S) -1- {3 -[(5-ethylaminosulfonylpyridin-2-yl) amino] -2-methylpropylamino {acetyl-4-fluoro-2-cyanopyrrolidine (11) (2S, 4S) -1- {3-[[( 5- (pyrrolidin-1-yl) aminosulfonylpyridin-2-yl] amino] -2-methylpropylamino} acetyl-4-fluoro-2-cyanopyrrolidine (12) (2S , 4S) -1- {3-[[(5- (Piperidin-1-yl) aminosulfonylpyridin-2-yl] amino] -2-methylpropylamino} acetyl-4-fluoro-2-cyanopyrrolidine

(13) (2S, 4S) -1- {1-[(5-methylsulfonylaminopyridin-2-yl) piperidin-4-yl] amino} acetyl-4-fluoro-2-cyanopyrrolidine (14) (2S , 4S) -1- {1-[[5-[(2,2,2-trifluoroethyl) sulfonylamino] pyridin-2-yl] piperidin-4-yl] amino} acetyl-4-fluoro-2- Cyanopyrrolidine (15) (2S, 4S) -1- {1-[[5-[(2,4-difluorophenyl) sulfonylamino] pyridin-2-yl] piperidin-4-yl] amino} acetyl-4- Fluoro-2-cyanopyrrolidine (16) (2S, 4S) -1- {3-[(5-methylsulfonylaminopyridin-2-yl) amino] -2-methylpropylamino} acetyl-4-fluoro-2- Cyanopyrrolidine (17) (2S, 4S) -1- {1- [5-[(2,2,2-trifluoroethyl) sulfonylamino] pyridin-2-yl] -2-methylpropylamino} acetyl-4 -Fluoro-2-cyanopyrroli Gin (18) (2S, 4S) -1- {1- [5-[(2,4-difluorophenyl) sulfonylamino] pyridin-2-yl] -2-methylpropylamino} acetyl-4-fluoro-2 -Cyanopyrrolidine (19) (2S, 2S) -1- {2- [2- [5- (2-azabicyclo [2.2.2] octane-2-sulfonyl) pyridin-2-yl] aminomethylpropylamino} acetyl -4-Fluoro-2-cyanopyridine Compounds (1), (2),... (19) are hereinafter referred to as Compound 1, Compound 2,.

  The 2-cyanopyrrolidine of the present invention can be produced by the following method. A scheme of a method for producing a compound in which C in Formula (I) is a hydrogen atom is shown below.

(In the formula, each symbol is as defined above.)
In the above scheme, the compound represented by the general formula (IV) is prepared by a method described in the literature (Joural of Organic Chemistry, 67 , 7162-7164, 2002. Bioorganic and Medicinal Chemistry, 8 , 1365-1377, 1996. Journal of American Chemical Society , 103 , 5390-5398, 1983.) or can be prepared by conventional techniques based on these documents.

  Step 1: a step of obtaining an amide compound (V) by an acylation reaction of the compound (IV). The reaction is usually carried out in an inert solvent in the presence of a base such as potassium carbonate, triethylamine, N, N-diisopropylethylamine and the like, and the solvent used may be any aprotic solvent, preferably acetonitrile. , Tetrahydrofuran (THF), dichloromethane, chloroform, N, N-dimethylformamide (DMF) and the like. The reaction is usually carried out at a temperature of -20 ° C to 80 ° C, preferably at 0 ° C to 25 ° C.

  Step 2: a step of obtaining the cyano compound (III) by dehydrating the compound (V). The reaction uses diphosphorus pentoxide, phosphorus oxychloride-imidazole, trifluoroacetic anhydride, p-toluenesulfonyl chloride-pyridine, etc. as a dehydrating agent in an inert solvent such as dichloromethane, pyridine, etc., from 0 ° C. to near the solvent boiling point. At a temperature of

  Step 3: In this step, compound (III) is obtained by reacting compound (III) with amino compound (VI). The reaction is usually performed in the presence of a base such as potassium carbonate, triethylamine, N, N-diisopropylethylamine and the like in an inert solvent, and preferable examples include acetonitrile, THF, dichloromethane, chloroform, DMF, methanol and the like. The reaction is usually carried out at a temperature of 0 to 80 ° C, preferably at 25 to 60 ° C.

  The 2-cyanopyrrolidine of the general formula (I) of the present invention thus produced can be obtained by a known separation and purification means such as extraction, concentration, distillation, crystallization, filtration, recrystallization, various kinds of chromatography and the like. It can be isolated as having any purity by appropriately attaching it. Further, 2-cyanopyrrolidine of the general formula (I) may be an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, if necessary. , Formic, acetic, trifluoroacetic, oxalic, citric, malonic, fumaric, glutaric, adipic, maleic, tartaric, succinic, mandelic, malic, pantothenic, etc.), amino acids (It can be an acid addition salt with an organic acid such as glutamic acid or aspartic acid. It also exists as a solvate such as a hydrate.

  The compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof has excellent DPP-IV inhibitory activity against mammals. Therefore, the compound of the present invention or a pharmacologically acceptable salt thereof is useful as an inhibitor of DPP-IV, and is useful for prevention and treatment of a disease in which GLP-1 is considered to be involved. Further, the compound of the present invention can be administered to the same control simultaneously with other therapeutic agents for diabetes, therapeutic agents for diabetic complications, antihyperlipidemic agents or antihypertensive agents, or can be administered at a time interval. it can. Examples of the therapeutic agent for diabetes include an insulin sensitivity enhancer, an α-glycosidase inhibitor, a sodium-glucose cotransport carrier inhibitor, and a biguanide. Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors. Examples of the antihyperlipidemic agent include a statin compound which is a cholesterol synthase inhibitor, a squalene synthase inhibitor or a fibrate compound having a triglyceride lowering effect, and a cholesterol absorption inhibitor. Examples of antihypertensives include calcium antagonists and angiotensin II antagonists. When the compound of the present invention is used in combination with another drug, the compounding ratio is appropriately selected depending on the administration subject, age and weight of the administration subject, symptoms, administration time, dosage form administration method, combination, and the like.

  When the 2-cyanopyrrolidine of the general formula (I) of the present invention is used as the above-mentioned drug, a suitable pharmacologically acceptable carrier and excipient (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.) Binders (eg, starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, alginic acid, gelatin, polyvinyl pyridone, etc.), lubricants (eg, stearic acid, magnesium stearate, calcium stearate, talc, etc.), It is mixed with a disintegrant (eg, carboxymethylcellulose, talc, etc.), a diluent (eg, physiological saline, etc.) and the like, and in the form of powders, fine granules, capsules, tablets, external preparations or injections, etc. by a conventional method. It can be administered orally or parenterally.

  The dose of the composition of the present invention varies depending on the administration route, target disease, patient condition, body weight or age, and compound used, and can be appropriately set according to the purpose of administration. Usually, when administered orally to an adult, it is preferable to administer 0.01 to 1000 mg / kg body weight / day, preferably 0.05 to 500 mg / kg body weight / day, once or several times a day, Of course, these are only examples and are not limited to these.

  The compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof has excellent DPP-IV inhibitory activity against mammals. Therefore, the compounds of the present invention represented by the general formula (I) or pharmacologically acceptable salts thereof are useful as DPP-IV inhibitors, and diseases in which GLP-1 is considered to be involved, For example, it is useful for prevention and treatment of various diseases caused by DPP-IV such as prevention and treatment of diabetes and obesity.

[DPP-IV inhibition test]
The DPP-IV activity was measured using an extract of an established cell line (Caco-2) derived from human colonic fibroid cells as an enzyme, and a DPP-IV-specific artificial substrate H-Ala-Pro-p-nitroaniline (BACHEM) It was measured by the absorbance method using The inhibitory rate in the presence of the test substance at each concentration with respect to the solvent-added group was calculated, and the concentration of the test substance that inhibits the enzyme activity by 50% (IC ₅₀ value) was calculated.
Caco-2 extract 100μl / well
Artificial substrate (80μM) 50μl / well
Test substance 20μl / well
Buffer 30μl / well
Total volume 200μl / well
Table 1 shows the DPP-IV inhibitory activity of the compound of the present invention.

As is clear from Table 1, the compounds of the present invention have stronger DPP-IV inhibitory activity than Comparative Examples (A), (B) and (C).
[Stability test]
The stability of compounds 1 and 7 of the present invention in phosphate buffer at pH 7.0 was compared with compound (A) described in US Pat. No. 6,011,155. Each compound was dissolved in a 1/15 M phosphate buffer (pH 7.0) to prepare a solution having a concentration of 1 × 10 ⁻⁵ M. After 2 hours, 24 hours, and 48 hours of incubation at 25 ° C., the concentration of each compound was measured by HPLC. The measurement by the HPLC method uses Inertsil ODS-2 for the column and a mixture of water and acetonitrile at a ratio of 4: 1 (w / w) (containing 0.5% sodium 1-octanesulfonate) as the eluent. The measurement was performed at 270 nm at a flow rate of 1 mL / min. Table 2 shows the results.

  Table 2 shows that compounds 1 and 7 of the present invention are more stable than the comparative examples.

Next, the production method of the compound of the present invention will be described with reference to examples, but the present invention is not limited thereto. Nuclear magnetic resonance spectra were measured at 400 MHz. For chemical shift, tetramethylsilane (TMS) was used as an internal standard, and relative delta (δ) values were expressed in parts per million (ppm). s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), bs (broad singlet) and the like.
Example 1

Production of (2S, 4S) -1- {1- [5- (dimethylaminosulfonylpyridin-2-yl) piperidin-4-yl] amino} acetyl-4-fluoro-2-cyanopyrrolidine (Compound 1)
(1) Production of (2S, 4S) -1-chloroacetyl-4-fluoro-2-cyanopyrrolidine.
A suspension of 2.4 g of (2S, 4S) -4-fluoropyrrolidine-2-carboxamide trifluoroacetate in 24 mL of dichloromethane was added with 3.0 mL of triethylamine, 0.24 g of DMAP and 0.85 mL of chloroacetyl chloride under ice-cooling. And stir at room temperature for 1 hour. Ethyl acetate is added to the reaction solution, and the precipitate is removed by filtration. The filtrate is evaporated, and the obtained residue is dissolved in 43 mL of dichloromethane. Under ice cooling, add 5.8 mL of trifluoroacetic anhydride and stir at room temperature for 0.5 hour. The reaction solution is poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with dichloromethane. The dichloromethane extract is washed with water and saturated saline and then dried over anhydrous sodium sulfate. After filtration, the filtrate is distilled off, and the obtained residue is purified by silica gel column chromatography to obtain 0.53 g of the title compound. Melting point 143-145 ℃
1H-NMR (CDCl3) δ = 2.52 (2H, m), 4.09 (4H, m), 4.93 (1H, m), 5.32 (1H, m).

(2) Production of (2S, 4S) -1- {1- [5- (dimethylaminosulfonylpyridin-2-yl) piperidin-4-yl] amino} acetyl-4-fluoro-2-cyanopyrrolidine (Compound 1 )
4-amino-1- (dimethylaminosulfonylpyridin-2-yl) piperidine at room temperature in a solution of (2S, 4S) -1-chloroacetyl-4-fluoro-2-cyanopyrrolidine 0.17 g in acetonitrile 10 mL-methanol 2 mL at room temperature Add 0.78 g and stir for 16 hours. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is evaporated, and the obtained residue is purified by silica gel column chromatography to obtain the title compound (0.09 g). 187-189 ° C
1H-NMR (CDCl3) δ = 1.45 (2H, m), 1.78 (1H, m), 1.95 (2H, m), 2.45 (2H, m), 2.69 (6H, s), 2.82 (1H, m), 3.12 (2H, m), 3.74 (4H, m), 4.34 (2H, m), 4.95 (1H, m), 5.38 (1H, m), 6.64 (1H, d, J = 9Hz), 7.71 (1H, d, J = 9Hz), 8.49 (1H, s).
Example 2

Production of (2S, 4S) -1- {1- [5- (methylaminosulfonylpyridin-2-yl) piperidin-4-yl] amino} acetyl-4-fluoro-2-cyanopyrrolidine (Compound 2)
4-amino-1- (methylaminosulfonylpyridin-2-yl) piperidine in a solution of (2S, 4S) -1-chloroacetyl-4-fluoro-2-cyanopyrrolidine 0.47 g in acetonitrile 18 mL-methanol 3 mL at room temperature Add 2.0 g and stir for 16 hours. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is evaporated, and the obtained residue is purified by silica gel column chromatography to obtain 0.18 g of the title compound. 114-116 ° C
1H-NMR (CD3OD) δ = 1.36 (2H, m), 2.01 (2H, m), 2.54 (5H, s + m), 2.96 (3H, m), 3.71 (4H, m), 4.44 (2H, m ), 4.97 (1H, m), 5.38 (1H, m), 6.87 (1H, d, J = 9Hz), 7.78 (1H, d, J = 9Hz), 8.44 (1H, s).
Example 3

Production of (2S, 4S) -1- {1- [5- (diethylaminosulfonylpyridin-2-yl) piperidin-4-yl] amino} acetyl-4-fluoro-2-cyanopyrrolidine (Compound 3)
(2S, 4S) -1-Chloroacetyl-4-fluoro-2-cyanopyrrolidine A solution of 0.52 g of acetonitrile in 15 mL of methanol in 3 mL of 4-amino-1- (diethylaminosulfonylpyridin-2-yl) piperidine 3.2 at room temperature g and stir for 21 hours. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is distilled off, and the obtained residue is purified by silica gel column chromatography to obtain 0.53 g of the title compound. Melting point 156-158 ℃
1H-NMR (CDCl3) δ = 1.14 (6H, t, J = 7Hz), 1.46 (2H, m), 1.64 (1H, bs), 1.95 (2H, m), 2.51 (2H, m), 3.08 (2H , m), 3.19 (4H, q, J = 7Hz), 3.75 (4H, m), 4.33 (2H, m), 4.96 (1H, m), 5.39 (1H, m), 6.62 (1H, d, J = 9Hz), 7.74 (1H, d, J = 9Hz), 8.53 (1H, s).
Example 4

Production of (2S, 4S) -1- {1- [5- (ethylaminosulfonylpyridin-2-yl) piperidin-4-yl] amino} acetyl-4-fluoro-2-cyanopyrrolidine (Compound 4)
(2S, 4S) -1-Chloroacetyl-4-fluoro-2-cyanopyrrolidine 0.48 g of acetonitrile 18 mL-methanol 3 mL solution at room temperature with 4-amino-1- (ethylaminosulfonylpyridin-2-yl) piperidine Add 2.7 g and stir for 21 hours. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is distilled off, and the obtained residue is purified by silica gel column chromatography to obtain 0.17 g of the title compound. Melting point 90-92 ℃
1H-NMR (CD3OD) δ = 1.05 (3H, t, J = 7Hz), 1.38 (2H, m), 2.02 (2H, m), 2.38 (2H, m), 2.96 (5H, m), 3.56 (4H , m), 4.43 (2H, m), 4.97 (1H, m), 5.38 (1H, m), 6.86 (1H, d, J = 9Hz), 7.79 (1H, d, J = 9Hz), 8.44 (1H , s).
Example 5

Production of (2S, 4S) -1- {1- [5- (pyrrolidin-1-yl) aminosulfonylpyridin-2-yl] piperidin-4-yl] amino} acetyl-4-fluoro-2-cyanopyrrolidine ( Compound 5) To a solution of (2S, 4S) -1-chloroacetyl-4-fluoro-2-cyanopyrrolidine 0.35 g in acetonitrile 15 mL-methanol 3 mL at room temperature was added 4-amino-1- [5- (pyrrolidine-1- 2.10 g of yl) sulfonylpyridin-2-yl] piperidine and stir for 20 hours. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is distilled off, and the obtained residue is purified by silica gel column chromatography to obtain 0.32 g of the title compound. Melting point 181-183 ℃
1H-NMR (CDCl3) δ = 1.42 (2H, m), 1.77 (4H, t, J = 7Hz), 1.95 (2H, m), 2.51 (3H, m), 3.08 (2H, m), 3.20 (4H , t, J = 7Hz), 3.74 (4H, m), 4.34 (2H, m), 4.95 (1H, m), 5.38 (1H, m), 6.63 (1H, d, J = 9Hz), 7.77 (1H , d, J = 9Hz), 8.55 (1H, s).
Example 6

(2S, 4S) -1- {1- [5-[(piperidin-1-yl)] aminosulfonylpyridin-2-yl] piperidin-4-yl] amino} acetyl-4-fluoro-2-cyanopyrrolidine Production (Compound 6)
4-amino-1- [5- (piperidin-1-yl) sulfonyl in a solution of (2S, 4S) -1-chloroacetyl-4-fluoro-2-cyanopyrrolidine 0.20 g in acetonitrile 15 mL-methanol 3 mL at room temperature Add 1.30 g of [pyridin-2-yl] piperidine and stir for 16 hours. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is distilled off, and the obtained residue is purified by silica gel column chromatography to obtain the title compound (0.04 g). Melting point 118-120 ℃
1H-NMR (CDCl3) δ = 1.54 (7H, m), 1.96 (2H, m), 2.65 (7H, m), 3.75 (6H, m), 4.06 (6H, m), 4.35 (2H, m), 4.96 (1H, m), 5.38 (1H, m), 6.62 (1H, d, J = 9Hz), 7.70 (1H, d, J = 9Hz), 8.48 (1H, s).
Example 7

Production of (2S, 4S) -1- {3-[(5-dimethylaminosulfonylpyridin-2-yl) amino] -2-methylpropylamino} acetyl-4-fluoro-2-cyanopyrrolidine (Compound 7)
(1) Production of (2S, 4S) -1-bromoacetyl-4-fluoro-2-cyanopyrrolidine.
To a suspension of 4.8 g of (2S, 4S) -4-fluoropyrrolidine-2-carboxamide trifluoroacetate in 36 mL of dichloromethane was added 6.0 mL of triethylamine, 0.24 g of DMAP, and 2.1 mL of bromoacetyl bromide under ice-cooling. Then, stir at room temperature for 2 hours. Ethyl acetate is added to the reaction solution, and the precipitate is removed by filtration. The filtrate is distilled off, and the obtained residue is dissolved in dichloromethane (53 mL). Add 11.6 mL of trifluoroacetic anhydride under ice-cooling, and stir at room temperature for 0.5 hour. The reaction solution is poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with dichloromethane. The dichloromethane extract is washed with water and saturated saline and then dried over anhydrous sodium sulfate. After filtration, the filtrate is evaporated, and the obtained residue is purified by silica gel column chromatography to obtain 1.25 g of the title compound. 125-127 ° C
1H-NMR (CDCl3) δ = 2.47 (2H, m), 3.95 (4H, m), 4.93 (1H, m), 5.40 (1H, m).

(2) Production of (2S, 4S) -1- {3-[(5-dimethylaminosulfonylpyridin-2-yl) amino] -2-methylpropylamino} acetyl-4-fluoro-2-cyanopyrrolidine (compound 7) 2- (5-Dimethylaminosulfonylpyridin-2-yl) amino-2 was added to a solution of 0.30 g of (2S, 4S) -1-bromoacetyl-4-fluoro-2-cyanopyrrolidine in 10 mL of THF and 2 mL of methanol. -Add 1.0 g of methylpropylamine and 0.18 g of potassium carbonate and heat to reflux for 2.5 hours. Water is added to the reaction solution, and extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is distilled off, and the obtained residue is purified by silica gel column chromatography to obtain 0.12 g of the title compound. 155-157 ℃
1H-NMR (CDCl3) δ = 1.17 (6H, s), 1.94 (1H, m), 2.69 (6H, s), 3.66 (6H, m), 4.92 (1H, m), 5.37 (1H, m), 5.89 (1H, bs), 6.48 (1H, d, J = 9Hz), 7.63 (1H, d, J = 9Hz), 8.42 (1H, s).
Example 8

Production of (2S, 4S) -1- {3-[(5-methylaminosulfonylpyridin-2-yl) amino] -2-methylpropylamino} acetyl-4-fluoro-2-cyanopyrrolidine (Compound 8)
2- (5-Methylaminosulfonylpyridin-2-yl) amino-2-methyl was added to a solution of (2S, 4S) -1-bromoacetyl-4-fluoro-2-cyanopyrrolidine 0.50 g in THF 18 mL-methanol 3 mL. Add 1.6 g of propylamine and 0.30 g of potassium carbonate and heat to reflux for 5 hours. Water is added to the reaction solution, and extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is distilled off, and the obtained residue is purified by silica gel column chromatography to obtain 0.50 g of the title compound. Melting point 93-95 ℃
1H-NMR (CD3OD) δ = 1.16 (6H, s), 2.50 (5H, s + m), 3.73 (6H, m), 4.90 (1H, m), 5.38 (1H, m), 6.62 (1H, d , J = 8Hz), 7.66 (1H, d, J = 8Hz), 8.30 (1H, s).
Example 9

Production of (2S, 4S) -1- {3-[(5-diethylaminosulfonylpyridin-2-yl) amino] -2-methylpropylamino} acetyl-4-fluoro-2-cyanopyrrolidine (Compound 9)
2- (5-diethylaminosulfonylpyridin-2-yl) amino-2-methylpropyl was added to a solution of 0.60 g of (2S, 4S) -1-bromoacetyl-4-fluoro-2-cyanopyrrolidine in 15 mL of THF-3 mL of methanol. Add 1.80 g of amine and 0.35 g of potassium carbonate, and heat to reflux for 8 hours. Water is added to the reaction solution, and extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is distilled off, and the obtained residue is purified by silica gel column chromatography to obtain 0.67 g of the title compound. Melting point 72-74 ° C 1H-NMR (CDCl3) δ = 1.15 (12H, t + m), 1.69 (1H, bs), 2.44 (2H, m), 3.59 (10H, q + m), 4.91 (1H, m ), 5.36 (1H, m), 6.43 (1H, d, J = 9Hz), 7.66 (1H, d, J = 9Hz), 8.45 (1H, s).
Example 10

Production of (2S, 4S) -1- {3-[(5-ethylaminosulfonylpyridin-2-yl) amino] -2-methylpropylamino} acetyl-4-fluoro-2-cyanopyrrolidine (Compound 10)
(2S, 4S) -1-bromoacetyl-4-fluoro-2-cyanopyrrolidine 0.40 g of THF (15 mL) -methanol (3 mL) was added to 2- (5-ethylaminosulfonylpyridin-2-yl) amino-2-methyl Add 1.4 g of propylamine and 0.24 g of potassium carbonate and heat to reflux for 8 hours. Water is added to the reaction solution, and extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is distilled off, and the obtained residue is purified by silica gel column chromatography to obtain 0.68 g of the title compound. Melting point 76-78 ℃
1H-NMR (CD3OD) δ = 1.05 (3H, t, J = 7Hz), 1.16 (6H, s), 2.40 (2H, m), 2.84 (2H, q, J = 7Hz), 3.51 (6H, m) , 4.90 (1H, m), 5.38 (1H, m), 6.61 (1H, d, J = 8Hz), 7.66 (1H, d, J = 8Hz), 8.30 (1H, s).
Example 11

(2S, 4S) -1- {3-[[(5- (pyrrolidin-1-yl) aminosulfonylpyridin-2-yl] amino] -2-methylpropylamino} acetyl-4-fluoro-2-cyanopyrrolidine Preparation of (Compound 11)
2- [5- (Pyrrolidin-1-yl) sulfonylpyridin-2-yl] was added to a solution of (2S, 4S) -1-bromoacetyl-4-fluoro-2-cyanopyrrolidine 0.42 g in THF 15 mL-methanol 3 mL. Add 1.60 g of amino-2-methylpropylamine and 0.25 g of potassium carbonate and heat to reflux for 5 hours. Water is added to the reaction solution, and extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is evaporated, and the obtained residue is purified by silica gel column chromatography to obtain 0.31 g of the title compound. 140-142 ° C
1H-NMR (CDCl3) δ = 1.18 (6H, s), 1.79 (4H, m), 2.60 (2H, m), 3.55 (10H, m), 4.92 (1H, m), 5.37 (1H, bs), 5.76 (1H, m), 6.45 (1H, d, J = 9Hz), 7.70 (1H, d, J = 9Hz), 8.48 (1H, s).
Example 12

(2S, 4S) -1- {3-[[(5- (piperidin-1-yl) aminosulfonylpyridin-2-yl] amino] -2-methylpropylamino]} acetyl-4-fluoro-2-cyano Preparation of pyrrolidine (Compound 12)
To a solution of 0.30 g of (2S, 4S) -1-bromoacetyl-4-fluoro-2-cyanopyrrolidine in 15 mL of THF-3 mL of methanol was added 2-amino-N- [5- (piperidin-1-yl) sulfonylpyridine-. Add 1.20 g of 2-yl] -2-methylpropylamine and 0.18 g of potassium carbonate and heat to reflux for 4.5 hours. Water is added to the reaction solution, and extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is evaporated, and the obtained residue is purified by silica gel column chromatography to obtain 0.29 g of the title compound. 160-162 ° C
1H-NMR (CDCl3) δ = 1.22 (6H, m), 1.43 (1H, bs), 1.62 (5H, m), 2.60 (2H, m), 2.96 (4H, t, J = 5Hz), 3.65 (6H , m), 4.92 (1H, d, J = 9Hz), 5.34 (1H, m), 5.75 (1H, m), 6.44 (1H, d, J = 9Hz), 7.62 (1H, d, J = 9Hz) , 8.40 (1H, s).
Example 13

Production of (2S, 4S) -1- {1-[(5-methylsulfonylaminopyridin-2-yl) piperidin-4-yl] amino} acetyl-4-fluoro-2-cyanopyrrolidine (Compound 13)
4-amino-1- [5- (methylsulfonylamino) pyridin-2-yl was added to a solution of 0.23 g of (2S, 4S) -1-bromoacetyl-4-fluoro-2-cyanopyrrolidine in 14 mL of THF-2 mL of methanol. ] Add 1.00 g of piperidine dihydrochloride and 0.26 g of potassium carbonate and heat to reflux for 5 hours. Water is added to the reaction solution, and extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is evaporated, and the obtained residue is purified by silica gel column chromatography to obtain 0.22 g of the title compound. Melting point 105-107 ° C 1H-NMR (CD3OD) δ = 1.43 (2H, m), 1.94 (2H, m), 2.68 (2H, m), 2.91 (6H, s + m), 3.75 (4H, m), 4.24 (2H, m), 4.98 (1H, d, J = 9Hz), 5.38 (1H, m), 6.82 (1H, d, J = 9Hz), 7.47 (1H, d, J = 9Hz), 7.94 (1H , s).
Example 14

(2S, 4S) -1- {1-[[5-[(2,2,2-trifluoroethyl) sulfonylamino] pyridin-2-yl] piperidin-4-yl] amino} acetyl-4-fluoro- Production of 2-cyanopyrrolidine (Compound 14)
4-amino-1- [5- (2,2,2-trifluoroethyl) was added to a solution of 0.34 g of (2S, 4S) -1-bromoacetyl-4-fluoro-2-cyanopyrrolidine in 15 mL of THF-3 mL of methanol. ) Sulfonylaminopyridin-2-yl] piperidine dihydrochloride (1.80 g) and potassium carbonate (0.40 g), and heat under reflux for 2 hours. Water is added to the reaction solution, and extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is distilled off, and the obtained residue is purified by silica gel column chromatography to obtain 0.05 g of the title compound. Melting point 70-72 ℃
1H-NMR (CD3OD) δ = 1.53 (2H, m), 2.07 (2H, m), 2.40 (2H, m), 3.09 (3H, m), 4.33 (6H, m), 4.37 (2H, m), 5.00 (1H, d, J = 9Hz), 5.40 (1H, m), 6.86 (1H, d, J = 9Hz), 7.49 (1H, d, J = 9Hz), 7.95 (1H, s).
Example 15

(2S, 4S) -1- {1-[[5-[(2,4-difluorophenyl) sulfonylamino] pyridin-2-yl] piperidin-4-yl] amino} acetyl-4-fluoro-2-cyano Preparation of pyrrolidine (compound 15)
4-amino-1- [5- (2,4-difluorophenyl) sulfonylamino was added to a solution of 0.30 g of (2S, 4S) -1-bromoacetyl-4-fluoro-2-cyanopyrrolidine in 15 mL of THF-3 mL of methanol. Add 1.50 g of [pyridin-2-yl] piperidine dihydrochloride and 0.30 g of potassium carbonate, and heat to reflux for 5 hours. Water is added to the reaction solution, and extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is distilled off, and the obtained residue is purified by silica gel column chromatography to obtain 0.20 g of the title compound. Melting point 147-149 ℃
1H-NMR (CD3OD) δ = 1.39 (2H, m), 2.01 (2H, m), 2.50 (2H, m), 2.82 (3H, m), 3.70 (4H, m), 4.20 (2H, m), 4.98 (1H, d, J = 9Hz), 5.38 (1H, m), 6.71 (1H, d, J = 9Hz), 7.19 (3H, m), 7.87 (2H, m).
Example 16

Production of (2S, 4S) -1- {3-[(5-methylsulfonylaminopyridin-2-yl) amino] -2-methylpropylamino} acetyl-4-fluoro-2-cyanopyrrolidine (Compound 16)
2- (5-methylsulfonylaminopyridin-2-yl) amino-2-methyl was added to a solution of (2S, 4S) -1-bromoacetyl-4-fluoro-2-cyanopyrrolidine 0.35 g in THF 15 mL-methanol 3 mL. Add 1.65 g of propylamine dihydrochloride and 0.35 g of potassium carbonate and heat to reflux for 2 hours. Water is added to the reaction solution, and extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is evaporated, and the obtained residue is purified by silica gel column chromatography to obtain 0.06 g of the title compound. Melting point 92-94 ℃
1H-NMR (CD3OD) δ = 1.18 (6H, s), 2.55 (2H, m), 2.89 (3H, s), 3.55 (6H, m), 4.92 (1H, d, J = 9Hz), 5.38 (1H , m), 6.57 (1H, d, J = 9Hz), 7.35 (1H, d, J = 9Hz), 7.84 (1H, s).
Example 17

(2S, 4S) -1- {1- [5-[(2,2,2-trifluoroethyl) sulfonylamino] pyridin-2-yl] -2-methylpropylamino} acetyl-4-fluoro-2- Production of cyanopyrrolidine (compound 17)
2- [5- (2,2,2-trifluoroethyl) sulfonylaminopyridine was added to a solution of 0.40 g of (2S, 4S) -1-bromoacetyl-4-fluoro-2-cyanopyrrolidine in 15 mL of THF-3 mL of methanol. Add 2.92 g of [-2-yl] amino-2-methylpropylamine dihydrochloride and 0.40 g of potassium carbonate and heat to reflux for 5 hours. Water is added to the reaction solution, and extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is distilled off, and the obtained residue is purified by silica gel column chromatography to obtain 0.19 g of the title compound. 111-113 ° C
1H-NMR (CD3OD) δ = 1.19 (6H, s), 2.49 (2H, m), 3.75 (8H, m), 4.93 (1H, d, J = 9Hz), 5.37 (1H, m), 6.59 (1H , d, J = 9Hz), 7.35 (1H, d, J = 9Hz), 7.86 (1H, s).
Example 18

(2S, 4S) -1- {1- [5-[(2,4-difluorophenyl) sulfonylamino] pyridin-2-yl] -2-methylpropylamino} acetyl-4-fluoro-2-cyanopyrrolidine Production (Compound 18)
2- [5- (2,4-difluorophenyl) sulfonylaminopyridin-2-yl] in a solution of 0.40 g of (2S, 4S) -1-bromoacetyl-4-fluoro-2-cyanopyrrolidine in 15 mL of THF-3 mL of methanol 1.99 g of amino-2-methylpropylamine dihydrochloride and 0.45 g of potassium carbonate are added, and the mixture is heated under reflux for 3 hours. Water is added to the reaction solution, and extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is evaporated, and the obtained residue is purified by silica gel column chromatography to obtain 0.20 g of the title compound. 86-88 ° C
1H-NMR (CD3OD) δ = 1.11 (6H, s), 2.38 (2H, m), 3.20 (1H, m), 3.68 (5H, m), 4.90 (1H, d, J = 9Hz), 5.37 (1H , m), 6.43 (1H, d, J = 9Hz), 7.12 (3H, m), 7.60 (1H, s), 7.72 (1H, s).
Example 19

(2S, 4S) -1- {2- [2- [5- (2-azabicyclo [2.2.2] octane-2-sulfonyl) pyridin-2-yl] amino] -2-methylpropylamino} acetyl-4 Preparation of -Fluoro-2-cyanopyrrolidine (Compound 19) A solution of (2S, 4S) -1-bromoacetyl-4-fluoro-2-cyanopyrrolidine 0.30 g in THF 12 mL-methanol 2 mL was treated with 2- [5- (2- 1.30 g of azabicyclo [2.2.2] octane-2-sulfonyl) pyridin-2-yl] amino-2-methylpropylamine and 0.18 g of potassium carbonate are added, and the mixture is heated under reflux for 5 hours. Water is added to the reaction solution, and extracted with ethyl acetate. After washing the ethyl acetate extract with saturated saline, it is dried over anhydrous sodium sulfate. After filtration, the filtrate is distilled off, and the obtained residue is purified by silica gel column chromatography to obtain 0.18 g of the title compound. 149-151 ° C
1H-NMR (CDCl3) δ = 1.19 (6H, s), 1.71 (10H, m), 2.45 (2H, m), 3.59 (8H, m), 4.91 (1H, m), 5.36 (1H, m), 5.69 (1H, bs), 6.43 (1H, d, J = 9Hz), 7.69 (1H, d, J = 9Hz), 8.47 (1H, s).
Table 3 summarizes the structural formulas, melting points and [α] ²⁴ _D of the compounds obtained in the above Examples.

Claims (10)

General formula (I) of the following formula:

Wherein A is a fluorine atom, a monofluoromethyl group, a difluoromethyl group or a trifluoromethyl group, B is -C (CH ₃ ) ₂ CH ₂ -NH-D or

(In the formula, a bond indicated by both a solid line and a dotted line represents a single bond or a double bond. D represents a heterocyclic ring which may have a substituent.), C is a hydrogen atom, a lower alkyl group (C1- C8). ]
A 2-cyanopyrrolidine derivative having a substituent at the 4-position represented by or a pharmaceutically acceptable salt thereof. Formula according to claim 1, wherein in (I), A is a fluorine atom, C is a hydrogen atom, B is _{-C (CH 3) 2 CH 2} -NH-D
[Wherein D is the following general formula (II):

(Wherein, a, b, c, d, and e are one or two nitrogen atoms and the remainder is a carbon atom. E and F may be the same or different, and each independently represents a hydrogen atom, a halogen atom A lower alkoxy group (C1-C8), a lower alkyl group (C1-C8), a lower haloalkyl group (C1-C8), a benzene ring which may have a substituent, a heterocyclic ring which may have a substituent, amino group, carboxyl group, lower alkoxycarbonyl group (C1-C8), a carbamoyl group, a lower alkanoyl group (C1-C8), a cyano group, .G showing a nitro group or a hydroxyl group denotes the -SO ^₂ NR ¹ R _2. R ¹ and R ² may be the same or different and each independently has a hydrogen atom, a lower alkyl group (C 1 -C 8) which may form a ring, a lower haloalkyl group (C 1 -C 8), or a substituent. A benzene ring, an optionally substituted heterocycle or a lower alkanoyl group (C1-C8) .)], Or a 2-cyanopyrrolidine derivative having a substituent at the 4-position or a pharmaceutically acceptable salt thereof. In the general formula (I) according to claim 1, A is a fluorine atom, C is a hydrogen atom, and B is a group represented by the following formula:

[In the formula, a bond indicated by both a solid line and a dotted line indicates a single bond or a double bond. D is the following general formula (II):

(Wherein, a, b, c, d, and e are one or two nitrogen atoms and the remainder is a carbon atom. E and F may be the same or different, and each independently represents a hydrogen atom, a halogen atom A lower alkoxy group (C1-C8), a lower alkyl group (C1-C8), a lower haloalkyl group (C1-C8), a benzene ring which may have a substituent, a heterocyclic ring which may have a substituent, amino group, carboxyl group, lower alkoxycarbonyl group (C1-C8), a carbamoyl group, a lower alkanoyl group (C1-C8), a cyano group, .G showing a nitro group or a hydroxyl group denotes the -SO ^₂ NR ¹ R _2. R ¹ and R ² may be the same or different and each independently has a hydrogen atom, a lower alkyl group (C 1 -C 8) which may form a ring, a lower haloalkyl group (C 1 -C 8), or a substituent. A benzene ring, an optionally substituted heterocycle or a lower alkanoyl group (C1-C8) And a pharmaceutically acceptable salt thereof, which has a substituent at the 4-position. In the general formula of claim 1 wherein (I), A is a fluorine atom, C is a hydrogen atom, B is _{-C (CH 3) 2 CH 2} -NH-D
[Wherein D is the following general formula (III):

(Wherein, a, b, c, d, and e are one or two nitrogen atoms and the remainder is a carbon atom. E and F may be the same or different, and each independently represents a hydrogen atom, a halogen atom A lower alkoxy group (C1-C8), a lower alkyl group (C1-C8), a lower haloalkyl group (C1-C8), a benzene ring which may have a substituent, a heterocyclic ring which may have a substituent, amino group, carboxyl group, lower alkoxycarbonyl group (C1-C8), a carbamoyl group, a lower alkanoyl group (C1-C8), a cyano group, .H showing a nitro group or a hydroxyl group denotes the -NR ¹ SO ^₂ R _2. R ¹ and R ² may be the same or different and each independently has a hydrogen atom, a lower alkyl group (C 1 -C 8) which may form a ring, a lower haloalkyl group (C 1 -C 8), or a substituent. A benzene ring, an optionally substituted heterocycle or a lower alkanoyl group (C1-C8) And a pharmaceutically acceptable salt thereof, which has a substituent at the 4-position. In the general formula (I) according to claim 1, A is a fluorine atom, C is a hydrogen atom, and B is a group represented by the following formula:

[In the formula, a bond indicated by both a solid line and a dotted line indicates a single bond or a double bond. D is the following general formula (III):

(Wherein, a, b, c, d, and e are one or two nitrogen atoms and the remainder is a carbon atom. E and F may be the same or different, and each independently represents a hydrogen atom, a halogen atom A lower alkoxy group (C1-C8), a lower alkyl group (C1-C8), a lower haloalkyl group (C1-C8), a benzene ring which may have a substituent, a heterocyclic ring which may have a substituent, amino group, carboxyl group, lower alkoxycarbonyl group (C1-C8), a carbamoyl group, a lower alkanoyl group (C1-C8), a cyano group, .H showing a nitro group or a hydroxyl group denotes the -NR ¹ SO ^₂ R _2. R ¹ and R ² may be the same or different and each independently represents a hydrogen atom, a lower alkyl group (C1-C8), a lower haloalkyl group (C1-C8), a benzene ring which may have a substituent, A heterocyclic group or a lower alkanoyl group (C1-C8) which may have a group.)] A characteristic 2-cyanopyrrolidine derivative having a substituent at the 4-position or a pharmaceutically acceptable salt thereof. General formula (VI) of the following formula:

(Wherein, A has the same meaning as described above, and X represents a halogen atom, a methanesulfonyl group, a toluenesulfonyl group or a trifluoromethanesulfonyl group.) And a compound represented by the general formula B-NH ₂ (B is The method for producing a 2-cyanopyrrolidine derivative having a substituent at the 4-position or a pharmaceutically acceptable salt thereof according to claim 1, wherein the amino compound is represented by the following formula: A pharmaceutical composition comprising a 2-cyanopyrrolidine derivative having a substituent at the 4-position according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmacologically acceptable carrier. A dipeptidyl peptidase IV inhibitor comprising a 2-cyanopyrrolidine derivative having a substituent at the 4-position according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. A therapeutic agent for a disease involving dipeptidyl peptidase IV, comprising a 2-cyanopyrrolidine derivative having a substituent at the 4-position according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient. 10. The therapeutic agent according to claim 9, wherein the disease is caused by diabetes, obesity, HIV infection, cancer metastasis, skin disease, benign prostatic hyperplasia, periodontitis or autoimmune disease.