JP2009137864A - Pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound having an excellent inhibitory action on dipeptidyl peptidase IV (DPPIV), a method for producing the same, and its use or the like. <P>SOLUTION: The present invention relates to a 2-cyanopyrrolidine derivative represented by formula [I] or its pharmacologically acceptable salt, a method for producing the same, a pharmaceutical composition comprising the same as its effective component, and its use or the like for inhibiting the activity of DPPIV. In the formula, R represents (1) morpholino or (2) piperazin-1-yl that may have a substituent. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a novel 2-cyanopyrrolidine derivative useful as a medicament having an excellent inhibitory action on dipeptidyl peptidase IV (DPPIV), a production method thereof, a use thereof and a pharmaceutical composition containing the same.

  Dipeptidyl peptidase IV (DPPIV) is a kind of serine protease that specifically hydrolyzes Xaa-Pro or Xaa-Ala (Xaa may be any amino acid) dipeptide from the N-terminus of the polypeptide chain. .

  There are various reports regarding the role of DPPIV (also referred to as CD26) in vivo and the relationship with diseases (Non-Patent Documents 1 to 4).

GLP-1 (glucagon-like peptide 1) is a peptide hormone having a function of amplifying insulin secretion mainly in a glucose-dependent manner, and is secreted mainly from the lower part of the small intestine after meal and acts on the pancreas. There are also reports suggesting that GLP-1 has an antifeedant action. DPPIV hydrolyzes and inactivates GLP-1 to produce a peptide that acts as an antagonist of GLP-1.
Substances that inhibit the enzyme activity of DPPIV enhance the insulin secretion response to oral glucose load and improve impaired glucose tolerance by enhancing the action of endogenous GLP-1 through its inhibitory action To do.

  For this reason, DPPIV inhibitors are considered useful for the prevention and treatment of diabetes (particularly type 2 diabetes). In addition, other diseases induced or exacerbated by impaired glucose tolerance (hyperglycemia (eg, postprandial hyperglycemia), hyperinsulinemia, diabetic complications (eg, renal disorder, neuropathy), abnormal lipid metabolism, It is expected to be effective in preventing and treating obesity. Furthermore, the effect in prevention and treatment of diseases (overeating, obesity, etc.) that are expected to be improved by enhancing the anti-feeding action of GLP-1 is also expected.

  In addition, expression of DPPIV (CD26) present on the surface of T cells and the like is induced in immune system cells as T cells are activated, and plays an important role in T cell activation and proliferation. It is known that when this DPPIV (CD26) is blocked with an antibody or an inhibitor, T cell activation is suppressed. In addition, there is an interest in the relationship between this enzyme and pathological conditions in disorders of collagen metabolism and immune disorders. For example, DPPIV (CD26) positive rate of peripheral blood T cells is increased in rheumatic patients, and high DPPIV activity is detected in urine of nephritic patients. Furthermore, DPPIV (CD26) is thought to play an important role in HIV entry into lymphocytes.

Therefore, substances that inhibit DPPIV (CD26) also prevent autoimmune diseases (eg, arthritis, rheumatoid arthritis), osteoporosis, acquired immune deficiency syndrome (AIDS), transplanted organ / tissue rejection, and the like. Or a therapeutic effect is expected.

On the other hand, as a 2-cyanopyrrolidine derivative having DPPIV inhibitory action,
The following Patent Documents 1 to 6 and the like describe N- (substituted glycyl) -2-cyanopyrrolidine derivatives.
Moreover, the following patent documents 7 to 10 describe N- (substituted glycyl) -2-cyanopyrrolidine derivatives having a bicyclooctane structure.
Holst et al., Diabetes, 47, 1663-1670, 1998 Augustyns et al., Current Medicinal Chemistry, Vol. 6, pp. 311-327, 1999 Meester et al., Immunol. Today, Vol. 20, pp. 367-375, 1999 Fleicher et al., Immunol. Today, Vol. 15, pp. 180-184, 1994 US6,011,155 WO1998 / 19998 WO2000 / 34241 WO2001 / 96295 WO2002 / 30890 WO2002 / 30891 WO2005 / 075421 WO2005 / 077900 WO2005 / 082847 WO2006 / 012395

The present invention provides a novel compound having an excellent inhibitory action on dipeptidyl peptidase IV (DPPIV), a method for producing the same, a use thereof, and a pharmaceutical composition containing the compound.

  The present inventors have found a novel 2-cyanopyrrolidine derivative having an excellent inhibitory action on DPPIV and completed the present invention. Moreover, the pharmaceutical composition which uses this as an active ingredient was created, and this invention was completed.

  That is, the present invention relates to the general formula [I]

[Wherein R is
(1) Morpholino or
(2) Represents optionally substituted piperazin-1-yl. ]
Or a pharmacologically acceptable salt thereof (hereinafter referred to as compound [I]).

The present invention also relates to a method for producing the compound [I] or a pharmacologically acceptable salt thereof.
The present invention also relates to a pharmaceutical composition containing as an active ingredient a 2-cyanopyrrolidine derivative represented by the above general formula [I] or a pharmacologically acceptable salt thereof.
The present invention also relates to a therapeutic or prophylactic method comprising administering to a patient an effective amount of the compound [I] or a pharmaceutically acceptable salt thereof. The present invention also relates to the use of the compound [I] or a pharmacologically acceptable salt thereof for the manufacture of a medicament.
The present invention also relates to the use of the above compound [I] or a pharmaceutically acceptable salt thereof for inhibiting the activity of DPPIV.

The compound [I] of the present invention or a pharmacologically acceptable salt thereof has an excellent inhibitory action on DPPIV. The pharmaceutical composition containing the target compound of the present invention as an active ingredient is useful as an active ingredient in a medicament for treating or preventing a disease or symptom (such as diabetes) that is expected to be improved by inhibiting DPPIV.

In the present invention, examples of the lower alkyl group, lower alkylsulfonyl group, and lower alkoxy group include linear or branched ones having 1 to 6 carbon atoms (C _1-6 ), especially 1 to 4 carbon atoms. (C _1-4 ).
Moreover, as a lower alkanoyl group, a C2-C7 ( _C2-7 ) thing is mentioned, Especially a C2-C5 ( _C2-5 ) thing is mentioned.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the compound [I] of the present invention, a preferable example of “optionally substituted piperazin-1-yl” represented by R is “piperazine-1- optionally substituted at the 4-position nitrogen atom”. Il ".

Examples of the substituent in “piperazin-1-yl optionally substituted at the 4-position nitrogen atom” include:
Lower alkanoyl;
Lower alkylsulfonyl;
Lower alkoxycarbonyl optionally substituted with lower alkoxy; and benzoyl optionally substituted with a halogen atom;
Etc.

Among the compounds [I] of the present invention, as a preferred compound group,
The compound whose R is morpholino is mentioned.
Alternatively, a compound group in which R is piperazin-1-yl optionally substituted at the 4-position nitrogen atom can be mentioned.

Specific examples of the compound of the present invention include a free form of each compound shown in the production examples described later or a pharmacologically acceptable salt thereof.

  The compounds of the invention may be in the free form or in the form of a pharmacologically acceptable salt. Examples of pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate or hydrobromide, acetate, fumarate, oxalate, citrate, methane Examples thereof include organic acid salts such as sulfonate, benzenesulfonate, p-toluenesulfonate, and maleate.

The compound of the present invention includes any of its internal salts and adducts, solvates or hydrates thereof.

The compound [I] of the present invention or a pharmacologically acceptable salt thereof has an excellent inhibitory action on the enzyme activity of DPPIV. The action also shows high selectivity for DPPIV.
That is, it is particularly selective for DPPIV compared to inhibition against various serine proteases other than DPPIV (eg, plasmin, thrombin, prolyl endopeptidase, trypsin, dipeptidyl peptidase II, dipeptidyl peptidase 8, etc.). Strong inhibitory activity.

In addition, the compound [I] of the present invention or a pharmacologically acceptable salt thereof exhibits excellent sustained action when administered in vivo.

In addition, the compound [I] of the present invention or a pharmacologically acceptable salt thereof exhibits various medicinal effects through its DPPIV inhibitory action, such as improving the insulin secretion response to oral glucose load.

Therefore, the compound [I] of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing this as an active ingredient can be used for the inhibition of DPPIV. In addition, the compound or the pharmaceutical composition can be used for the treatment or prevention of diseases or symptoms that are expected to be improved by inhibiting DPPIV.

  Examples of such diseases and symptoms include diabetes (for example, type 1 diabetes, type 2 diabetes), hyperglycemia (for example, postprandial hyperglycemia), hyperinsulinemia, diabetic complications (for example, renal disorders, nerves, etc.). Disorders), obesity, overeating, abnormal lipid metabolism (eg, hyperlipidemia such as hypertriglyceridemia), autoimmune diseases (eg, arthritis, rheumatoid arthritis, etc.), osteoporosis, acquired immune deficiency syndrome (AIDS) ), Rejection of transplanted organs / tissues, and the like.

The compound [I] of the present invention or a pharmacologically acceptable salt thereof, or a pharmaceutical composition containing this as an active ingredient is particularly useful for the treatment or prevention of diabetes (particularly type 2 diabetes).

A treatment or prevention method in which an effective amount of the compound [I] of the present invention or a pharmacologically acceptable salt thereof is administered to a patient or the like is also applied to the above purpose and is included in the present invention. The use of the compound [I] of the present invention or a pharmacologically acceptable salt thereof for the manufacture of a medicament is also applied to the above purpose and is included in the present invention.

The DPPIV inhibitory action of the compound of the present invention and the drug efficacy based thereon (antiglycemic effect, insulin secretion response improving effect on glucose load, etc.) are known methods or equivalent methods (WO 98/19998; WO 00/34241; Holst et al., Diabetes). 47, 1663-1670, 1998; Augustyns et al., Current Medicinal Chemistry, 6, 311-327, 1999; Meester et al., Immunol. Today, 20, 367-375. 1999; Fleicher et al., Immunol. Today, Vol. 15, pp. 180-184, 1994).

Further, the in vivo action of the DPPIV inhibitory action of the compound of the present invention is also confirmed by a known method (the method described in Pederson et al., Diabetes, 1998, Vol. 47, pages 1253-1258, etc.). be able to.

When the compound [I] of the present invention or a pharmacologically acceptable salt thereof is used as an active ingredient for a pharmaceutical use, it is used together with an inert carrier according to the administration method, and a conventional pharmaceutical preparation (tablet, granule, Capsules, powders, solutions, suspensions, emulsions, injections, drops, etc.). Examples of such carriers include binders (such as gum arabic, gelatin, sorbit, and polyvinylpyrrolidone) that are acceptable in general medicine, excipients (such as lactose, sugar, corn starch, and sorbit), and lubricants (stearic acid). Magnesium, talc, polyethylene glycol, etc.) and disintegrants (potato starch, etc.). In the case of an injection or infusion, it can be formulated using distilled water for injection, physiological saline, aqueous glucose solution, or the like.

The administration method when the compound [I] of the present invention or a pharmacologically acceptable salt thereof is used for pharmaceutical use is not particularly limited, and a general oral or parenteral method (intravenous, intramuscular) , Subcutaneous, transdermal, nasal, other transmucosal, enteral, etc.).

When the compound [I] of the present invention or a pharmacologically acceptable salt thereof is used for pharmaceutical use, the dosage is effective enough to exhibit a medicinal effect depending on the potency and characteristics of the compound as an active ingredient. What is necessary is just to set suitably in the range of quantity. The dose varies depending on the administration method, age of the administration subject (patient, etc.), body weight, and condition, but a general dose, for example, an appropriate amount in the range of 0.001 to 300 mg / kg per day is usually used. Set to

In the present invention, DPPIV includes DPPIV of human or non-human warm-blooded animals. In the present invention, the target of application of the pharmaceutical, the pharmaceutical composition, and the treatment or prevention method includes humans or warm-blooded animals other than humans (particularly preferably humans).

The target compound [I] of the present invention can be produced by the following method.
It is not limited to this.

General formula [2]
(In the formula, Z ¹ represents a reactive residue, and other symbols have the same meaning as described above.)
The compound represented by the general formula [3]
(In the formula, the symbols have the same meaning as described above.)
The desired compound [I] can be produced by reacting with a compound represented by the formula (I) or a salt thereof to produce a pharmacologically acceptable salt if desired.

As the salt of compound [3], for example, a salt with an inorganic acid such as hydrochloride or sulfate, or an organic acid salt such as methanesulfonate or p-toluenesulfonate can be used.

As the reactive residue represented by Z ¹ , a conventional reactive residue such as a halogen atom, a lower alkylsulfonyloxy group, an arylsulfonyloxy group or the like can be preferably used, and a halogen atom is particularly preferable.

  The reaction of compound [2] with compound [3] or a salt thereof can be carried out in a suitable solvent or without solvent in the presence or absence of a deoxidizing agent.

  Examples of the deoxidizer include inorganic bases (for example, alkali metal hydrides such as sodium hydride, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium methoxide, sodium hydroxide, potassium hydroxide, etc. An alkali metal hydroxide or the like) or an organic base (for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine, or the like) can be preferably used.

  This reaction suitably proceeds at 0 to 120 ° C, particularly at room temperature to 80 ° C.

The solvent may be any solvent that does not adversely influence the reaction, such as acetonitrile, ethanol, isopropyl alcohol, propyl alcohol, acetone, N, N-dimethylacetamide, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ether, dioxane, ethyl acetate. , Toluene, methylene chloride, dichloroethane, chloroform, or a mixed solvent thereof can be appropriately used.

The target compound [I] produced by the above production method can be further converted into another target compound [I] by the method described in the production examples below and / or a known method or a combination thereof.

Moreover, the raw material compound in the said method can be manufactured by the known method and / or the method as described in a postscript reference example, or those combinations.

For example, the raw material compound [2]
It can be produced according to the method described in the literature of Villhauer et al. (Villhauer et al., Journal of Medicinal Chemistry, 2003, Vol. 46, pages 2774-2789), International Patent Publications WO98 / 19998, WO00 / 34241, etc. it can.

  Further, for example, among the raw material compounds [3], the compound [3a] in which R is morpholino can be produced as follows.

General formula [11]
(In the formula, Q ¹ represents an amino group-protecting group.)
Or a salt thereof represented by the general formula [12a]
(In the formula, Z ² and Z ³ represent reactive residues.)
With a compound represented by
General formula [13]
(In the formula, the symbols have the same meaning as described above.)
Or a salt thereof is obtained.
The compound represented by the formula [3a] or a salt thereof can be produced by removing the amino-protecting group from the compound [13] or a salt thereof and optionally converting the product into a salt.

As the amino group protecting group represented by Q ¹ , any conventional amino group protecting group such as t-butoxycarbonyl group, benzyloxycarbonyl group, 2-nitrobenzenesulfonyl group can be preferably used.

As the reactive residues represented by Z ² and Z ³ , conventional reactive residues such as halogen atoms, lower alkylsulfonyloxy groups, arylsulfonyloxy groups and the like can be preferably used. preferable.

Examples of the salts of the compounds [11], [13] and [3a] include salts with inorganic acids such as hydrochloride and sulfate, or organic acid salts such as methanesulfonate and p-toluenesulfonate. Can be used.

  Each reaction can be carried out as follows.

The reaction of compound [11] or a salt thereof and compound [12a]
The reaction can be carried out in a suitable solvent or without a solvent in the presence or absence of a deoxidizer.

  Examples of the deoxidizer include inorganic bases (for example, alkali metal hydrides such as sodium hydride, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium methoxide, sodium hydroxide, potassium hydroxide, etc. An alkali metal hydroxide or the like) or an organic base (for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine, or the like) can be preferably used.

  This reaction suitably proceeds at 0 to 120 ° C, particularly at room temperature to 80 ° C.

Any solvent may be used as long as it does not adversely affect the reaction. For example, N, N-dimethylacetamide, acetonitrile, ethanol, isopropyl alcohol, propyl alcohol, acetone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ether, dioxane, acetic acid. Ethyl, toluene, methylene chloride, dichloroethane, chloroform or a mixed solvent thereof can be appropriately used.

Removal of the amino-protecting group (Q ¹ ) from the compound [13] or a salt thereof can be carried out by a conventional method, for example, acid treatment using trifluoroacetic acid, hydrochloric acid or the like in a suitable solvent or without solvent, It can be carried out by treatment with a thiol alkali metal salt or the like, or catalytic reduction.

  Further, for example, among the raw material compound [3], the compound [3b] in which R is piperazin-1-yl optionally substituted at the 4-position nitrogen atom can be produced as follows.

General formula [11]
(In the formula, Q ¹ represents an amino group-protecting group.)
Or a salt thereof represented by the general formula [12b]
(In the formula, Q ² represents an amino-protecting group, and Z ⁴ and Z ⁵ represent a reactive residue.)
With a compound represented by
General formula [14]
(In the formula, the symbols have the same meaning as described above.)
Or a salt thereof is obtained.
An amino group protecting group (Q ² ) is removed from compound [14] or a salt thereof,
General formula [15]
(In the formula, the symbols have the same meaning as described above.)
Or a salt thereof is obtained.
The compound [15] or a salt thereof, if necessary, after appropriately adding a substituent to the 4-position nitrogen atom of piperazin-1-yl, removing the amino group protecting group (Q ¹ ), and optionally converting the product into a salt. By doing so, the general formula [3b]
(In the formula, R ¹ represents piperazin-1-yl which may be substituted at the 4-position nitrogen atom.)
Or a salt thereof can be produced.

The amino group protecting group represented by Q ² is preferably different from Q ¹ .
As the amino group protecting group represented by Q ² , any conventional amino group protecting group such as 2-nitrobenzenesulfonyl group, t-butoxycarbonyl group, benzyloxycarbonyl group and the like can be suitably used.

As the reactive residues represented by Z ⁴ and Z ⁵ , conventional reactive residues such as halogen atoms, lower alkylsulfonyloxy groups, arylsulfonyloxy groups and the like can be preferably used. preferable.

Examples of the salts of the compounds [14], [15] and [3b] include salts with inorganic acids such as hydrochloride and sulfate, or organic acid salts such as methanesulfonate and p-toluenesulfonate. Can be used.

  Each reaction can be carried out as follows.

The reaction of compound [11] or a salt thereof and compound [12b]
The reaction can be carried out in the same manner as in the reaction of the compound [11] or a salt thereof and the compound [12a] or a salt thereof.
The removal of the amino protecting group (Q ¹ or Q ² ) can be carried out by a conventional method as described above.

The compound [I] of the present invention or its starting compound produced as described above is isolated and purified as it is or as a salt thereof. The salt can be produced by subjecting it to a commonly used salt formation treatment. Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, crystallization, filtration, recrystallization, and various types of chromatography.

In the compounds of the present invention, optical isomers such as racemates, optically active substances, diastereomers and the like may exist alone or as a mixture. Stereochemically pure isomers can be derived by using stereochemically pure raw material compounds or by separating optical isomers by a general racemic resolution method. A mixture of diastereomers can be separated by a conventional method such as fractional crystallization or chromatography.

  Hereinafter, although this invention is demonstrated in more detail with a manufacture example, these do not restrict | limit this invention.

  In addition, Table 1 and Reference Example Table at the end show chemical structural formulas and physical property values of the compounds of Production Examples and Reference Examples.

In the table, MS · APCI (m / z) represents a mass spectrometry value.
(APCI: atmospheric pressure chemical ionization mass spectrum)
Further, the abbreviation “Me” in this specification is a methyl group,
“Ph” is a phenyl group,
“Ns” represents a 2-nitrobenzenesulfonyl group.

Experimental Example 1 Test of DPPIV inhibitory activity Human serum or recombinant human DPPIV as an enzyme source (Biochim. Biophys. Acta, 1131, 333-336, 1992 and Biochem. J., 373, 179- 189, 2003), the inhibitory activity of the compounds of the present invention against DPPIV was measured as follows. After dissolving the test compound in dimethyl sulfoxide, the sample compound was sequentially diluted with a buffer solution (40 mM HEPES, 1% BSA, pH 7.8) to prepare a sample solution having a final concentration of 3 pM to 10 μM (final concentration of dimethyl sulfoxide: 0.1%). . 150 μl of the buffer solution and 25 μl of the sample solution were added to 25 μl of an enzyme solution containing 25 μl of human serum or recombinant human DPPIV (0.89 μg / mL), and incubated at 37 ° C. for 10 minutes. Thereafter, 50 μl of a glycyl-L-proline p-nitroanilide tosylate [Gly-Pro-pNA • Tos manufactured by Peptide Research Institute] solution was added as a substrate (final substrate concentration: 0.234 mM) to initiate the reaction. The reaction was carried out by incubating at 37 ° C. for 20 minutes, during which the DPPIV activity was measured by monitoring the change in absorbance at 405 nm. The 50% inhibitory concentration (IC ₅₀ ) was determined as the DPPIV inhibitory activity.

As a result, it was confirmed that all of the compounds of Production Examples 1.01 to 2.04 of the present invention showed an IC ₅₀ value of 10 nM or less and had excellent inhibitory activity.

  Production example 1.01

(1) 4-morpholin-4-ylbicyclo [2.2.2] octo-1-ylamine (Reference Example 2.01) 181 mg, 1-chloroacetyl- (S) -2-cyanopyrrolidine (literature (EB Villhauer et al., Journal of Medicinal Chemistry, 2003, Vol. 46, pp. 2774-2789) 149 mg), potassium carbonate 357 mg, potassium iodide 15 mg mixed solution of 50% acetonitrile / chloroform 10 mL was stirred at room temperature for 4 days. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was redissolved in chloroform. The chloroform solution was extracted with a 5% aqueous citric acid solution adjusted to pH 4.5 with potassium carbonate in advance, and the aqueous layer was washed three times with chloroform. Potassium carbonate was added to the aqueous layer to adjust the pH to 8.5, followed by extraction with chloroform three times. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was triturated in diethyl ether and filtered to give (S) -2-cyano-1- [2- (4-morpholin-4-ylbicyclo [2.2.2] octo-1-ylamino) 166 mg of acetyl] pyrrolidine was obtained as a crystalline powder.

(2) Diethyl ether, 4 mol / L hydrochloric acid 1,4-dioxane solution was added to the free form obtained in (1) above and stirred, and the precipitated solid was triturated and collected by filtration (S) -2-cyano. 166 mg of -1- [2- (4-morpholin-4-ylbicyclo [2.2.2] octo-1-ylamino) acetyl] pyrrolidine dihydrochloride (following table, production example 1.01) was obtained as a colorless powder.

  Production Example 2.01

(1) [4- (4-propionylpiperazin-1-yl) bicyclo [2.2.2] oct-1-yl] carbamic acid benzyl ester (Reference Example 4.01) 195 mg, 10% palladium carbon 50 mg, and 50% ethanol / A mixture of 20 mL of tetrahydrofuran was stirred at room temperature for 4 hours under a hydrogen atmosphere (1 atm). The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure.
129 mg of 4- (4-propanoylpiperazin-1-yl) bicyclo [2.2.2] octo-1-ylamine was obtained.

(2) A mixture of 137 mg of the compound obtained in the above (1), 137 mg of 1-chloroacetyl- (S) -2-cyanopyrrolidine, 214 mg of potassium carbonate, 10 mg of potassium iodide and 16 mL of 38% acetonitrile / chloroform at room temperature Stir for days. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was redissolved in chloroform. The chloroform solution was extracted with a 5% aqueous citric acid solution adjusted to pH 4.5 with potassium carbonate in advance, and the aqueous layer was washed three times with chloroform. Potassium carbonate was added to the aqueous layer to adjust the pH to 8.5, followed by extraction with chloroform three times. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: 10% chloroform-methanol), and diethyl ether, 4 mol / L hydrochloric acid 1,4-dioxane solution was added to the resulting free form and stirred. The precipitated solid was triturated and filtered to give (S) -2-cyano-1- {2- [4- (4-propionylpiperazin-1-yl) bicyclo [2.2.2] octo-1-ylamino] acetyl. } 43 mg of pyrrolidine dihydrochloride (table below, production example 2.01) was obtained as a colorless powder.

Production example 2.02 to 2.04
In the same manner as in Production Example 2.01, the compounds shown in Tables below and Production Examples 2.02 to 2.04 were obtained.

  Reference example 1.01

(1) Bicyclo [2.2.2] octane-1,4-dicarboxylate synthesized according to the method described in the literature (Ernest W. Della et al., Australian Journal of Chemistry, 1985, Vol. 38, pages 1705-1718) A mixed solution of 7.38 g of a 28% sodium methoxide methanol solution and 689 mg of distilled water was added dropwise to an 88 mL tetrahydrofuran solution of 8.83 g of the ester under ice cooling, and the mixture was stirred at room temperature for 15 minutes. To the reaction solution, 88 mL of n-hexane was added and stirred vigorously for 3 hours. Further, 264 mL of n-hexane was further added and stirred well. The precipitated solid was collected by filtration and washed with n-hexane to obtain a monocarboxylic acid sodium salt. Obtained. This compound was dissolved in distilled water and washed with diethyl ether. The aqueous layer was acidified with 2 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 6.67 g of bicyclo [2.2.2] octane-1,4-dicarboxylic acid monomethyl ester as a colorless powder.

(2) 6.67 g of the compound obtained in the above (1), 9.39 g of diphenylphosphoric acid azide, and 4.77 mL of triethylamine are dissolved in 130 mL of toluene, stirred at room temperature for 1 hour and at 70 ° C. for 30 minutes, and further heated to reflux for 1 hour. did. The reaction solution was allowed to cool to room temperature, 32.4 mL of benzyl alcohol was added, and the mixture was further heated to reflux for 5 hours. The reaction mixture is allowed to cool to room temperature, water is added to the reaction mixture, and the organic layer is washed successively with saturated aqueous sodium hydrogen carbonate, water, 2 mol / L hydrochloric acid, saturated brine, dried over anhydrous sodium sulfate, and the solvent is reduced in pressure. Distilled off. The obtained residue was dissolved in 100 mL of methanol, a 1 mol / L aqueous sodium hydroxide solution was added, and the mixture was heated and stirred at 50 ° C. for 2 hours. The reaction solution is allowed to cool to room temperature, methanol is distilled off under reduced pressure, the aqueous layer is washed four times with diethyl ether, the aqueous layer is acidified with concentrated hydrochloric acid under ice-cooling, and the precipitated solid is collected by filtration, washed with water, and then washed with room temperature. By air drying, 8.15 g of 4-benzyloxycarbonylaminobicyclo [2.2.2] octane-1-carboxylic acid was obtained as a colorless powder.

(3) 5.76 g of the compound obtained in the above (2), 5.65 g of diphenyl phosphate azide, and 2.85 mL of triethylamine were dissolved in 110 mL of toluene, stirred at 70 ° C. for 30 minutes, and then heated to reflux for 30 minutes. After allowing the reaction solution to cool to room temperature, toluene was distilled off under reduced pressure, and the residue was dissolved in 10 mL of dimethoxyethane. This solution was dropped into 200 mL of 2 mol / L hydrochloric acid heated and stirred at 100 ° C., and the mixture was heated and stirred at the same temperature for 2 hours. The reaction mixture was allowed to cool to room temperature, washed 3 times with diethyl ether, the aqueous layer was basified with 2 mol / L aqueous sodium hydroxide solution, and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2.12 g of (4-aminobicyclo [2.2.2] oct-1-yl) carbamic acid benzyl ester (table below, reference example 1.01) Obtained as a yellow oil.

  Reference example 2.01

(1) Under an argon atmosphere, (4-aminobicyclo [2.2.2] oct-1-yl) carbamic acid benzyl ester (Reference Example 1.01) 332 mg, bis (2-chloroethyl) ether 191 mg, sodium carbonate 376 mg, sodium iodide 400 mg of N, N-dimethylacetamide suspension (7 mL) was heated and stirred at 100 ° C., and 20 mg of bis (2-chloroethyl) ether was added twice every 30 minutes, for a total of 40 mg. After further stirring at 100 ° C. for 2 hours, the reaction solution was allowed to cool to room temperature, and ethyl acetate and water were added to the reaction solution and stirred to dissolve insoluble matters. After separating the aqueous layer, the organic layer was washed 4 times with water and once with saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: 0 → 2% chloroform-methanol), and the resulting solid was triturated in n-hexane and collected by filtration (4-morpholin-4-ylbicyclo [2.2 .2] Oct-1-yl) carbamic acid benzyl ester 297 mg was obtained as a crystalline powder.

(2) A mixture of the compound obtained in (1) (295 mg), 10% palladium carbon (50 mg), and ethanol (10 mL) was stirred at room temperature for 4 hours in a hydrogen atmosphere (1 atm). The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 180 mg of 4-morpholin-4-ylbicyclo [2.2.2] oct-1-ylamine (table below, Reference Example 2.01) as a colorless powder.

  Reference example 3.01

(1) Under an argon atmosphere, 1.75 g of (4-aminobicyclo [2.2.2] oct-1-yl) carbamic acid benzyl ester (Reference Example 1.01), N, N-bis (2-chloroethyl) -2-nitrobenzenesulfone A suspension of 2.29 g of amide (synthesized by the method described in Japanese Patent Publication 2006-56884, WO2004 / 64721), 2.02 g of sodium carbonate and 2.10 g of sodium iodide, 35 mL of N, N-dimethylacetamide was heated at 100 ° C. for 4 hours. Stir. The reaction solution was allowed to cool to room temperature, and ethyl acetate and water were added to the reaction solution and stirred to dissolve insoluble matters. After separating the aqueous layer, the organic layer was washed 5 times with water and once with saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: 0 → 5% chloroform-methanol), and the resulting solid was triturated in diethyl ether to give {4- [4- (2-nitrobenzenesulfonyl) piperazine- 1.77 g of 1-yl] bicyclo [2.2.2] oct-1-yl} carbamic acid benzyl ester was obtained as a crystalline powder.

(2) To a suspension of 60% sodium hydride (482 mg) in tetrahydrofuran (30 mL) was added dropwise 1-dodecanethiol (2.88 mL) in N, N-dimethylformamide (10 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The resulting creamy reaction solution was ice-cooled, and a solution of 2.77 g of the compound obtained in (1) above in 30 mL of N, N-dimethylformamide was added dropwise, followed by stirring at room temperature for 2 hours. Diethyl ether and 2 mol / L hydrochloric acid water were added to the reaction solution, the organic layer was separated, and the aqueous layer was washed with diethyl ether. The aqueous layer was basified with 2 mol / L aqueous sodium hydroxide and extracted three times with chloroform. The combined extracts were washed with saturated brine and concentrated under reduced pressure. The obtained residue was diluted again with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate and anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Diethyl ether, 4 mol / L hydrochloric acid 1,4-dioxane solution (3.9 mL) was added to the residue and stirred, and the precipitated solid was triturated and collected by filtration (4-piperazin-1-ylbicyclo [2.2.2] oct-1 -Yl) 2.04 g of carbamic acid benzyl ester dihydrochloride (table below, reference example 3.01) was obtained as a pale yellow powder.

  Reference Example 4.01

(4-Piperazin-1-ylbicyclo [2.2.2] oct-1-yl) carbamic acid benzyl ester dihydrochloride (Reference Example 3.01) 250 mg, propionyl chloride 78 μL, triethylamine 416 μL in 10 mL of methylene chloride was stirred at room temperature for 3 hours. After adding saturated sodium bicarbonate water, the aqueous layer was separated. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: 0 → 7% chloroform-methanol), and the resulting solid was triturated in diethyl ether and collected by filtration to give [4- (4-propionylpiperazine-1- Yl) 198 mg of bicyclo [2.2.2] oct-1-yl] carbamic acid benzyl ester (table below, reference example 4.01) was obtained as a crystalline powder.

Reference examples 4.02 to 4.04
In the same manner as in Reference Example 4.01, the compounds shown in the following table and Reference Examples 4.02 to 4.04 were obtained.

Claims (7)

Formula [I]

[Wherein R is
(1) Morpholino or
(2) Represents optionally substituted piperazin-1-yl. ]
A pharmaceutical composition comprising as an active ingredient a 2-cyanopyrrolidine derivative represented by the formula or a pharmacologically acceptable salt thereof.   The pharmaceutical composition according to claim 1, wherein R is morpholino.   The pharmaceutical composition according to claim 1, wherein R is piperazin-1-yl optionally substituted at the 4-position nitrogen atom. A pharmaceutical composition comprising, as an active ingredient, a free form of each compound or a pharmacologically acceptable salt thereof shown in Production Examples below. The pharmaceutical composition according to any one of claims 1 to 4, which is a pharmaceutical composition for inhibiting DPPIV, or a pharmaceutical composition for treating or preventing a disease or condition that is expected to be improved by inhibiting DPPIV. object. The pharmaceutical composition according to any one of claims 1 to 4, which is for the treatment or prevention of diabetes. The pharmaceutical composition according to any one of claims 1 to 4, which is for the treatment or prevention of type 2 diabetes.