JP2007001946A - Pyrrolidine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound useful as a therapeutic and/or prophylactic agent of diabetes (type 2 diabetes or the like) and abnormality of glucose tolerance, and a prophylactic and/or improving agent of postprandial hyperglycemia, and having DPP4-inhibiting activities. <P>SOLUTION: The medicinal composition contains a compound represented by general formula (I) (wherein, R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>, R<SP>4</SP>, R<SP>5</SP>and R<SP>6</SP>are each independently a hydrogen atom or a substituent; R<SP>7</SP>is a substituent; R<SP>8</SP>is a hydrogen atom, a protective group of a nitrogen atom, or the like; n is an integer of 0-4; when n is 2 or more, R<SP>7</SP>s may be the same or different; R<SP>1</SP>and R<SP>2</SP>may form a heterocycle in combination with the nitrogen atom bonded thereto; R<SP>1</SP>and R<SP>3</SP>may form a heterocycle by being bonded to each other; and R<SP>5</SP>and R<SP>6</SP>may form a carbon ring or a heterocycle in combination with the carbon atom bonded thereto), a salt thereof, a solvate thereof, an N-oxide thereof or a prodrug thereof as an active ingredient. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

The present invention relates to pyrrolidine derivatives. For more details,
(1) General formula (I)

(Wherein all symbols have the same meaning as described below), a salt thereof, a solvate thereof, an N-oxide thereof or a prodrug thereof,
(2) It relates to a production method thereof, and (3) a pharmaceutical comprising them as an active ingredient.

  Dipeptidyl peptidase IV (also referred to as DPP4, DPP-IV, DP4, DPPIV, CD26, hereinafter abbreviated as DPP4) is dipeptide Xaa-Pro or Xaa-Ala from a peptide chain having proline or alanine second from the N-terminus. Is a serine protease that produces DPP4 is widely distributed in mammalian tissues, particularly known to be present in the kidney, liver, intestinal epithelium, placenta and plasma, and is involved in the metabolism of various bioactive peptides. Among them, a glucagon-like peptide (Glucagon-Like Peptide-1: also referred to as GLP-1; hereinafter abbreviated as GLP-1), which has a strong ability to promote insulin secretion and plays a role in postprandial blood glucose level regulation. The role of DPP4 as an enzyme that inactivates is attracting attention.

  As physiological functions of GLP-1, not only the insulin secretion promoting action from the pancreas but also the gastric emptying time extending action, feeding suppression action, and insulin resistance improving action are known. In fact, treatment of non-insulin dependent diabetes mellitus (type 2 diabetes) by continuous subcutaneous administration of GLP-1 has been attempted, and a GLP-1 agonist (Exenatide) has been approved in the United States as a therapeutic agent for diabetes. However, GLP-1 is metabolized in a few minutes in vivo. Among them, metabolism by DPP4 is particularly important, and DPP4 rapidly cleaves GLP-1 to produce inactive GLP-1. Since this inactive GLP-1 antagonizes the GLP-1 receptor, the physiological action of GLP-1 may be further attenuated. Therefore, a method for suppressing degradation of GLP-1 by inhibiting DPP4 is considered to be the best approach for enhancing GLP-1 action. That is, a compound that inhibits DPP4 can enhance the action of GLP-1, enhance insulin secretion and improve glucose metabolism, and prevent and / or treat diabetes (especially type 2 diabetes etc.) and impaired glucose tolerance. It is expected to be useful for preventing and / or improving postprandial hyperglycemia. In addition, it can be expected as an anti-obesity drug from its antifeedant action.

  As with GLP-1, as a physiologically active peptide that promotes insulin secretion from the pancreas, a gastric inhibitory polypeptide (also referred to as gastric inhibitory polypeptide or GIP), pituitary adenylate cyclase activation polypeptide (Pituitary Adenylate Cyclase Activating Polypeptide; also referred to as PACAP), Vasoactive Intestinal Polypeptide (also referred to as VIP), and the like. Since DPP4 is also involved in the degradation of these physiologically active peptides, a compound that inhibits DPP4 also suppresses the degradation of these physiologically active peptides, enhances the action, and enhances insulin secretion. It is expected to be useful for prevention and / or treatment of abnormal glucose tolerance (especially type 2 diabetes), prevention and / or improvement of postprandial hyperglycemia.

DPP4 is also involved in the metabolism of neuropeptides such as neuropeptide Y, endomorphin 1, endomorphin 2, and substance P. Therefore, a compound that inhibits DPP4 can also be expected as a therapeutic or analgesic for schizophrenia, depression, anxiety, epilepsy, and stress disorders by suppressing the degradation of these physiologically active peptides.
Furthermore, DPP4 is known to be involved in metabolism of various cytokines and chemokines, activation of T cells that are immunocompetent cells, adhesion of cancer cells to endothelium, proliferation of blood cells, and the like. . Through these actions, compounds that inhibit DPP4 are such as rheumatoid arthritis, autoimmune diseases such as type I diabetes, allergic diseases such as asthma and food allergies, cancer, cancer metastasis, HIV infection, anemia, thrombocytopenia, etc. Useful for treatment and / or prevention.

  Moreover, since high DPP4 expression is found in skin fibroblasts of patients with psoriasis, rheumatoid arthritis and lichen planus, and high DPP4 activity is found in patients with benign prostatic hyperplasia, compounds that inhibit DPP4 Is expected to be effective in the treatment and / or prevention of skin diseases and prostatic hypertrophy.

  In addition to these, compounds that inhibit DPP4 include hyperlipidemia, metabolic syndrome (syndrome X), diabetic complications, arteriosclerosis, polycystic ovary syndrome, infertility, growth disorder, arthritis, transplant rejection, enteritis, It is also considered useful for treatment and / or prevention of wounds and the like.

  In addition, DPP4 inhibitors in the clinical stage have a glycated hemoglobin (Hb1Ac) concentration-reducing action in diabetic patients (64th American Diabetes Society Annual Meeting, Orlando, June 2004 and 65th American Diabetes Society Annual Meeting, San Diego) 2005), it is known that DPP4 inhibitors are useful for controlling blood glucose levels.

  In addition, when it has an inhibitory action with respect to an enzyme similar in structure to DPP4, it may become an undesirable action, and a compound that selectively inhibits DPP4 is more preferable.

  As a compound having DPP4 inhibitory activity, a compound represented by the general formula (W)

(Wherein the definitions of all symbols are described in the specification) (see Patent Document 1), general formula (Y)

(Wherein, definitions of all symbols are described in the specification) (see Patent Document 2) and the like are known.

However, 1-prolyl-2-cyanopyrrolidine derivatives are known to be unstable (see Non-Patent Document 1), and among compounds represented by the general formula (W), a compound in which Z ^W is a cyano group Also, among the compounds represented by (Y), a compound in which R ^Y is a cyano group is also unstable, and as a result, there is a concern that DPP4 inhibitory activity does not last for a long time. Therefore, a compound that is stable and has long-lasting DPP4 inhibitory activity has been desired.

International Publication No. 02/14271 Pamphlet WO04 / 16587 pamphlet Bioorganic Medicinal Chemistry Letters, 1996, Vol. 6, No. 10, 1163-1166

  Drugs that are excellent in stability, effective over a long period of time as agents for the treatment and / or prevention of diabetes, impaired glucose tolerance, etc., and preventive and / or ameliorate postprandial hyperglycemia, and have a selective inhibitory effect on DPP4. Has been.

  As a result of intensive studies to find a DPP4 inhibitor that exhibits an effect over a long period of time, the present inventors have found that the pyrrolidine derivative represented by the general formula (I) achieves the object, and completed the present invention. .

  This compound has a characteristic of exhibiting inhibitory activity over a long period of time due to its high stability. Diabetes (particularly type 2 diabetes, etc.), prevention and / or treatment of impaired glucose tolerance, prevention of postprandial hyperglycemia and / or It can be an excellent drug useful for improvement.

That is, the present invention
[1] General formula (I)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ each independently represents a hydrogen atom or a substituent, R ⁷ represents a substituent, R ⁸ represents a hydrogen atom or a nitrogen atom) Or n represents 0 or an integer of 1 to 4, and when n is 2 or more, a plurality of R ⁷ may be the same or different, and R ¹ and R ² are bonded. Together with the nitrogen atom to represent a 4-10 membered monocyclic or polycyclic heterocycle, R ¹ and R ^{3 taken} together form a 5-10 membered monocyclic or polycyclic ^May form a heterocycle, and R ⁵ and R ⁶ together with the carbon atom to which they are attached are C3-10 monocyclic or polycyclic carbocycles or 5-10 membered monocyclic or polycyclic Or a salt thereof, a solvate thereof, an N-oxide thereof, or Their prodrugs,
[2] The compound according to item [1], wherein R ³ is a hydrogen atom or a C1-8 alkyl group which may have a substituent,
[3] The compound according to [1] above, wherein R ⁴ is a C1-8 alkyl group which may have a substituent.
[4] The compound according to [1], wherein R ⁵ and R ⁶ are each independently a hydrogen atom or a C1-4 alkyl group,
[5] R ¹ and R ² are both optionally substituted C1-8 alkyl groups, or together with the nitrogen atom to which R ¹ and R ² are bonded, a 4-10 membered monocycle The compound according to the above item [1], which represents a formula or a bicyclic heterocycle,
[6] R ³ is a hydrogen atom or a C1-8 alkyl group which may have a substituent, R ⁴ is a C1-8 alkyl group which may have a substituent, R ⁵ and R The compound according to the above item [1], wherein each ⁶ is independently a hydrogen atom or a C1-4 alkyl group,
[7] General formula (IA)

(Where symbol

Represents bonding to the front of the paper (β configuration), R ^3-A represents a hydrogen atom or a C1-8 alkyl group which may have a substituent, and R ^4-A represents a substituent. Represents a C1-8 alkyl group which may have, R5 ^-A and R6 ^-A each independently represent a hydrogen atom or a C1-4 alkyl group, and the other symbols are the same as those described in [1] above Represents meaning. The compound according to item [1], which is a compound represented by
[8] (1) (2S , 4S, 5S) -N 2 - ( cyanomethyl) -N ² - ethyl ^{-N 4,} N ^4, 5- trimethyl-2,4-Pyrrolidinedicarboxamide and (2) (2S, 4S, 5S) -N ^2- (cyanomethyl) -N ² , N ⁴ , N ⁴ , 5-tetramethyl-2,4-pyrrolidine dicarboxamide compound according to the preceding item [1],
[9] A pharmaceutical composition comprising, as an active ingredient, the compound represented by the general formula (I) described in [1], a salt, a solvate, an N-oxide thereof, or a prodrug thereof,
[10] The pharmaceutical composition according to [9] above, which is a therapeutic and / or prophylactic agent for DPP4-mediated diseases,
[11] DPP4-mediated disease is diabetes, obesity, schizophrenia, depression, anxiety, epilepsy, stress disease, pain, autoimmune disease, allergic disease, cancer, cancer metastasis, HIV infection, anemia, thrombocytopenia, skin Disease, prostate enlargement, hyperlipidemia, metabolic syndrome, diabetic complications, arteriosclerosis, impaired glucose tolerance, polycystic ovary syndrome, infertility, growth disorder, arthritis, transplant rejection, enteritis and wounds The pharmaceutical composition according to the above item [10], which is one or more of the following:
[12] The pharmaceutical composition according to [9] above, which is an agent for preventing and / or improving postprandial hyperglycemia,
[13] The pharmaceutical composition according to [10] above, which is a DPP4 inhibitor,
[14] The compound represented by the general formula (I) according to [1], its salt, its solvate, its N-oxide or prodrug thereof, sulfonylurea, biguanide, α-glucosidase inhibitors, insulin secretagogues, insulin sensitizers, insulin preparations, PPAR agonists, beta ₃ adrenergic receptor agonists, aldose reductase inhibitors, DPP4 inhibitors, AMP kinase activator, type 1 11β- hydroxy steroid A pharmaceutical comprising a combination of one or more selected from the group consisting of a dehydrogenase inhibitor, a lipase inhibitor and an appetite suppressant,
[15] A method comprising administering to a mammal an effective amount of a compound represented by the general formula (I) described in [1] above, a salt thereof, a solvate thereof, an N-oxide thereof or a prodrug thereof. A method of treating and / or preventing a DPP4-mediated disease,
[16] A method comprising administering to a mammal an effective amount of a compound represented by the general formula (I) described in [1] above, a salt thereof, a solvate thereof, an N-oxide thereof or a prodrug thereof. A method of inhibiting DPP4,
[17] A compound represented by the general formula (I), a salt thereof, a solvate thereof, an N-oxide thereof, or a compound thereof according to [1] for producing a therapeutic and / or prophylactic agent for DPP4-mediated diseases And a compound represented by the general formula (I) described in the preceding item [1], a salt, a solvate thereof, an N-oxide thereof, or a prodrug thereof, for producing a [18] DPP4 inhibitor Regarding the use of drag.

  Specific embodiments of the group in the compound represented by the general formula (I) are as follows.

The “substituent” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is not particularly limited as long as it is a substituent. For example, (1) a C1-8 hydrocarbon group optionally substituted by 1 to 5 R ¹⁰ , (2) a carbocycle optionally substituted by 1 to 5 R ¹¹ , (3) 1 A heterocyclic ring optionally substituted by ~ 5 R ¹¹ , (4) a halogen atom, (5) cyano, (6) —OR ²⁰ , (7) —NR ²¹ R ²² , (8) —SR ²⁰ , _{^{(9) -SO 2 R 23,}} (10) -COOR 20, (11) -CONR 21 R 22, (12) -COR 23, (13) -SO 2 NR 21 R 22, (14) -OCOR 23, (15) -OSO ₂ R ²³ , (16) -CONR ²¹ COR ²³ , (17) -CONR ²¹ SO ₂ R ²³ , (18) -NR ²⁴ CONR ²¹ R ²² , (19) -NR ²⁴ COOR ²⁰ , ( 20) -OCOOR ^{0, (21) -OCONR 21 R} 22, (22) -SO 2 OR 20 or (23) -SOR ^23, and the like, each of the substituents may be different even in the same.

R ¹⁰ represents (1) a halogen atom, (2) cyano, (3) oxo, (4) thioxo, (5) -OR ²⁰ , (6) -NR ²¹ R ²² , (7) -SR ²⁰ , (8 _{^{) -SO 2 R 23, (9}} ) -COOR 20, (10) -CONR 21 R 22, (11) -COR 23, (12) = N-OR 20, (13) -SO 2 NR 21 R 22, _{^{(14) -OCOR 23, (15}} ) -OSO 2 R 23, (16) -CONR 21 COR 23, (17) -CONR 21 SO 2 R 23, (18) -NR 24 CONR 21 R 22, (19) ^{-NR 24 COOR 20, (20)} -OCOOR 20, (21) -OCONR 21 R 22, (22) -SO 2 OR 20, (23) -OSO 2 OR 20, (24) -SOR 23, (25) Represents to five heterocyclic ring which may be substituted by ^{R 11} which may carbocyclic or (26) of 1-5 optionally substituted by ^{R 11,} when ^{R 10} is 2 or more, multiple R ¹⁰ may be the same or different.

R ¹¹ is (1) a halogen atom, cyano, oxo, thioxo, —OR ²⁰ , —NR ²¹ R ²² , —SR ²⁰ , —SO ₂ R ²³ , —COOR ²⁰ , —CONR ²¹ R ²² , —COR ²³ , _{^{= N-OR 20, -SO 2}} NR 21 R 22, -OCOR 23, -OSO 2 R 23, -CONR 21 COR 23, -CONR 21 SO 2 R 23, -NR 24 CONR 21 R 22, -NR 24 COOR ²⁰ , -OCOOR ²⁰ , -OCONR ²¹ R ²² , -SO ₂ OR ²⁰ , -OSO ₂ OR ²⁰ , -SOR ²³ , an optionally substituted carbocycle and an optionally substituted heterocycle A C1-8 hydrocarbon group optionally substituted by 1 to 5 groups selected from the ring, (2) a halogen atom, (3) nitro, ( ) Cyano, (5) oxo, (6) ^{thioxo, (7) -OR 20, (} 8) -NR 21 R 22, (9) -SR 20, (10) -SO 2 R 23, (11) -COOR ²⁰ , (12) -CONR ²¹ R ²² , (13) -COR ²³ , (14) = N-OR ²⁰ , (15) -SO ₂ NR ²¹ R ²² , (16) -OCOR ²³ , (17) -OSO _{^{2 R 23, (18) -CONR}} 21 COR 23, (19) -CONR 21 SO 2 R 23, (20) -NR 24 CONR 21 R 22, (21) -NR 24 COOR 20, (22) -OCOOR 20 _{^{, (23) -OCONR 21 R 22}} , (24) -SO 2 OR 20, (25) -OSO 2 OR 20, (26) -SOR 23, (27) carbocyclic ring which may have a substituent Other represents a heterocyclic ring which may have a (28) substituent, when R ¹¹ is 2 or more, plural R ¹¹ may be different even in the same.

R ²⁰ represents (1) a hydrogen atom, (2) an optionally substituted C1-8 hydrocarbon group, (3) an optionally substituted carbocycle or (4) a substituent. The heterocyclic ring which may have is represented.

R ²¹ , R ²² and R ²⁴ are each independently (1) a hydrogen atom, (2) a C1-8 hydrocarbon group which may have a substituent, and (3) a substituent. Represents a good carbocycle, (4) an optionally substituted heterocycle, (5) -COR ²³ or (6) -SO ₂ R ²³ .

R ²³ may have (1) a C1-8 hydrocarbon group which may have a substituent, (2) a carbocycle which may have a substituent, or (3) a substituent. Represents a heterocycle.

In the present specification, “C1-optionally substituted by 1 to 5 R ¹⁰ ” in the “substituent” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ "8 hydrocarbon group" and "C1-8 hydrocarbon group" in "C1-8 hydrocarbon group optionally having substituent (s)" in R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ Represents C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl.

  C1-8 alkyl represents, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.

  C1-4 alkyl represents, for example, methyl, ethyl, propyl, butyl and isomers thereof.

  C2-8 alkenyl represents, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and isomers thereof.

  C2-8 alkynyl represents, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and isomers thereof.

  In the present specification, the halogen atom represents, for example, fluorine, chlorine, bromine and iodine.

In the present specification, “in the carbocycle optionally substituted by 1 to 5 R ¹¹ ” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ¹⁰ “Carbocycle” in “carbocycle” and “carbocycle optionally having substituent (s)” in R ¹¹ , R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ is “C3-15 monocycle” Represents a formula or polycyclic carbocycle.

  “C3-15 monocyclic or polycyclic carbocycle” includes C3-15 monocyclic or polycyclic carbocyclic aryl, carbocycles partially or fully saturated, spiro-bonded polycycles. Cyclic carbocycles and bridged polycyclic carbocycles include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, cyclotetradecane , Cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, Ndan, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, heptalene, perhydroheptalene, biphenylene, as-indacene, s-indacene, acenaphthylene, acenaphthene, fluorene, phenalene, phenanthrene, anthracene, spiro [4.4] nonane , Spiro [4.5] decane, spiro [5.5] undecane, bicyclo [2.2.1] heptane, bicyclo [2.2.1] hept-2-ene, bicyclo [3.1.1] heptane , Bicyclo [3.1.1] hept-2-ene, bicyclo [2.2.2] octane, bicyclo [2.2.2] oct-2-ene, adamantane, noradamantane, norbornane ring and the like. .

In the present specification, “in the heterocyclic ring optionally substituted by 1 to 5 R ¹¹ ” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ¹⁰ The term “heterocycle” in “heterocycle” and “heterocycle optionally having substituent (s)” in R ¹¹ , R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ is “3- to 15-membered”. Represents a monocyclic or polycyclic heterocycle containing 1 to 5 heteroatoms selected from oxygen, nitrogen and sulfur atoms.

  “Monocyclic or polycyclic heterocycle containing 1 to 5 heteroatoms selected from 3 to 15 membered oxygen, nitrogen and sulfur atoms” includes 3 to 15 membered oxygen and nitrogen atoms. And mono- or polycyclic heteroaryls which contain 1 to 5 heteroatoms selected from sulfur atoms and may be partially or fully saturated.

  Examples of the monocyclic or polycyclic heterocyclic aryl containing 1 to 5 heteroatoms selected from a 3-15 membered oxygen atom, nitrogen atom and sulfur atom include pyrrole, imidazole, triazole, tetrazole, Pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, Thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzodioxole, benzofuran, isobenzofuran, benzothiophene, isobenzo Offene, dithiaphthalene, indazole, quinoline, isoquinoline, quinolidine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzoxepin, benzoxazepine, benzoxiadiazepine , Benzothiepine, benzothiazepine, benzothiazepine, benzoazepine, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, carbazole, β-carboline, acridine, phenazine, dibenzofuran, xanthene, dibenzothiophene, phenothiazine, phenoxazine, phenoxathiin , Thianthrene, phenanthridine, phenanthroline, perimidine ring, etc. The

  The partially or fully saturated 3-15 membered monocyclic or polycyclic heterocyclic aryl containing 1 to 5 heteroatoms selected from oxygen, nitrogen and sulfur atoms includes, for example, aziridines , Azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrimidine Pyridazine, Tetrahydropyridazine, Perhydropyridazine, Dihydroazepine, Tetrahydroazepine, Perhydroazepine, Dihydrodiazepine, Tetrahydrodiazepine, Per Drodiazepine, dihydroazocine, tetrahydroazocine, perhydroazocine, dihydrodiazocine, tetrahydrodiazocine, perhydrodiazocine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin, tetrahydrooxine Sepin, perhydrooxepin, thiirane, thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepin, tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydro Isoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thia Lysine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxa Diazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, Tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydro Thiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, Perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine , Perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine Perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzooxathiane, dihydrobenzoxazine, dihydrobenzothiazine, Pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzoazepine, tetrahydrobenzoazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepane, Dihydrobenzoxazepine, tetrahydrobenzoo Sazepine, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothiophene, perhydrodibenzofuran, perhydrodibenzothiophene, dioxolane, dioxane, dithiolane , Dithiane, dioxaindane (benzodioxole), benzodioxane, chroman, benzodithiolane, benzodithiane, tetrahydrotriazolopyrazine ring and the like.

R ¹¹ , R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ , the “substituent” in the “optionally substituted carbocycle” and R ¹¹ , R ²⁰ , R ²¹ , R ²² , The “substituent” in the “heterocycle optionally having substituents” in R ²³ and R ²⁴ is, for example, (1) nitro, (2) hydroxyl group, (3) oxo, (4) thioxo, ( 5) Aminocarbonyl substituted with C1-8 hydrocarbons such as cyano, (6) carbamoyl, (7) N-methylaminocarbonyl, N-butylaminocarbonyl, N-hexylaminocarbonyl, etc. "-8 hydrocarbon group" has the same meaning as the above "C1-8 hydrocarbon group".), (8) carboxy, (9) C such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc. -8 alkoxycarbonyl, (10) sulfo, (11), for example, fluorine, chlorine, bromine, iodine halogen, (12), for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy (1) C3-8 cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclohexyloxy, etc. (14) phenoxy, (15) eg o-, m- or p-chlorophenoxy Halogenophenoxy such as o-, m- or p-bromophenoxy, (16) for example C1-8 alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio, (17) phenylthio (18) for example methylsulfinyl, C1-8 alkylsulfinyl such as tilsulfinyl, (19) C1-8 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, (20) amino, (21) C1-8 acylamino such as acetylamino, propionylamino, (22) primary or secondary amino substituted with a C1-8 hydrocarbon group such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, dimethylamino, diethylamino (wherein “C1-8 hydrocarbon group” has the same meaning as the above “C1-8 hydrocarbon group” and may be substituted with oxo, amino, carbamoyl, etc.), (23) For example, formyl, acetyl , C1-8 acyl such as propionyl, butyryl, (24) benzoyl, (25) (a) A C1-8 hydrocarbon group such as methyl, ethyl, propyl, isopropyl, etc., which may be substituted with fluorine, chlorine, bromine, halogen of iodine, (b) oxo, hydroxyl group, etc. The “hydrocarbon group” has the same meaning as the above “C1-8 hydrocarbon group”. ), (C) having 1 to 4 substituents selected from, for example, o-, m- or p-chlorophenoxy, halogenophenoxy such as o-, m- or p-bromophenoxy, and (d) oxo, etc. Such as 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 4-tetrahydropyranyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 1,2,3- or 1,2,4- Carbon sources such as triazolyl, 1H or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidyl, 3- or 4-pyrididyl, quinolyl, isoquinolyl, indolyl In addition to 5- to 6-membered heterocyclic groups containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and the like, (26) C1-8 such as difluoromethyl, trifluoromethyl, trifluoroethyl, trichloroethyl, etc. Haloalkyl group, (27) hydroxyimino group, (28) C1-8 alkoxyimino group such as methoxyimino, ethoxyimino, (29) sulfamoyl group, (30) C1-8 carbonization such as methylaminosulfonyl Aminosulfonyl substituted with a hydrogen group (wherein, the “C1-8 hydrocarbon group” has the same meaning as the above-mentioned “C1-8 hydrocarbon group”), (31) For example, dimethylaminoethylaminosulfonyl Substituted by a C1-8 hydrocarbon group substituted with an amino group such as dimethylaminopropylaminosulfonyl Minosulfonyl (wherein the “C1-8 hydrocarbon group” has the same meaning as the above “C1-8 hydrocarbon group”), or (32) C1-8 hydrocarbon such as methylsulfonylamino A sulfonylamino substituted with a group (herein, this “C1-8 hydrocarbon group” has the same meaning as the above “C1-8 hydrocarbon group”), (33) a C1-8 hydrocarbon group (here The "C1-8 hydrocarbon group" has the same meaning as the above "C1-8 hydrocarbon group").

The “optionally substituted C 1-8 hydrocarbon group” in R ²⁰ , R ²¹ , R ²² , R ²³ and R ²⁴ is 1 to 5 selected from the above (1) to (32) It may have a substituent. Moreover, when the number of substituents is 2 or more, the respective substituents may be the same or different.

In the present specification, the ring represented by the nitrogen atom to which R ¹ and R ² are bonded (referred to as ring A) is a monocyclic or polycyclic ring containing at least one 4- to 10-membered nitrogen atom. Represents a heterocycle of formula

  The monocyclic or polycyclic heterocyclic ring containing at least one 4- to 10-membered nitrogen atom represented by ring A is a partially or fully saturated 4- to 10-membered nitrogen atom. A monocyclic or polycyclic heterocyclic aryl containing 1 to 4 heteroatoms, optionally selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, and further a substituent You may have. The substituent of the ring A has the same meaning as the “substituent” in the above-mentioned “carbocycle which may have a substituent”. Specific examples of the ring A include, for example, azetidine, pyrrolidine, piperidine, perhydroazepine, perhydroazocine, dihydropyrrole, dihydropyridine, tetrahydropyridine, dihydroazepine, tetrahydroazepine, piperazine, morpholine, thiomorpholine, oxazolidine, thiazolidine Dihydroindole, dihydroisoindole, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, tetrahydrothiazolopyridine, tetrahydrotriazolopyrazine ring and the like.

In the present specification, the ring formed by R ¹ and R ³ together (referred to as ring B) contains at least one 5- to 10-membered nitrogen atom and a single carbonyl group. Represents a cyclic or polycyclic heterocycle.

  A monocyclic or polycyclic heterocycle containing at least one 4-10 membered nitrogen atom represented by ring B is a partially or fully saturated 4-10 membered one nitrogen atom. A monocyclic or polycyclic heterocyclic aryl containing 1 to 4 heteroatoms, optionally selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom; You may have 5 substituents. Examples of the substituent for ring B include the same substituents as those described above for the “carbocycle which may have a substituent”. Specific examples of ring B include, for example,

(Wherein the dotted line represents a bond in the pyrrolidine ring to which ring B is condensed).

In the present specification, examples of the protecting group for the nitrogen atom represented by R ⁸ include C 1-8 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), benzyloxycarbonyl and the like.

In the present specification, examples of the C1-8 alkyl represented by R ⁸ include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and the like.

  In the present invention, all isomers are included unless otherwise specified. For example, alkyl, alkoxy, alkylthio, alkenyl, alkynyl and alkylene include straight chain and branched chain. Further, isomers (E, Z, cis, trans isomers) in double bonds, rings, condensed rings, isomers due to the presence of asymmetric carbon, etc. (R, S isomer, α, β isomer, enantiomer, diastereomer), Optical isomers having optical activity (D, L, d, l, +,-), polar bodies (high polar bodies, low polar bodies) by chromatographic separation, equilibrium compounds, compounds in any proportion of these, All racemic mixtures are included in the present invention.

  In the present invention, the symbol

As will be apparent to those skilled in the art, unless otherwise specified, this means that the bond is in front of the page (β arrangement), and the symbol

As will be apparent to those skilled in the art, unless otherwise specified, it is connected to the other side of the paper surface (α arrangement).

  symbol

Indicates that it is bonded in front of or on the other side of the page, or is a mixture of any proportion thereof.

The optically active compound in the present invention may contain not only 100% pure compound but also other optical isomers of less than 50%.
[Preferred embodiment of the present invention]
In the present invention, preferred embodiments are as follows.

Herein, preferably the ^{R 1} and ^{R 2,} each independently, a hydrogen atom, 1-3 C1-8 alkyl optionally substituted by ^{R 10,} substituted by one to three ^{R 10} which may be optionally C2-8 alkenyl, 1-3 C2-8 alkynyl optionally substituted by ^{R 10, -NR 21 R 22,} 3-8 membered substituted by one to three ^{R 11} A monocyclic carbocyclic ring, a 4-8 membered monocyclic heterocyclic ring substituted with 1 to 3 R ¹¹ , or 4- together with a nitrogen atom to which R ¹ and R ² are bonded It is a monocyclic or bicyclic heterocycle (referred to as ring A ′) containing at least one 10-membered nitrogen atom.

More preferably, R ¹ and R ² are each independently a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, Vinyl, allyl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, optionally substituted benzyl (e.g., o-, m-, methylbenzyl such as p-, methoxybenzyl, chlorobenzyl, fluorobenzyl, methylsulfone, etc.), thienylmethyl, furylmethyl, pyridylmethyl, methylamino, ethylamino, dimethylamino, phenylamino, 3-methylthiopropyl, 2- Tokishiechiru and the like, any combination thereof are preferred.

  Ring A ′ is preferably azetidine, pyrrolidine, thiazolidine, piperidine, morpholine, thiomorpholine, dihydroisoindole, oxazolidine, thiazolidine, piperazine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, tetrahydroquinoline, tetrahydroisoquinoline, Examples include dihydroindole and indoline.

  Ring A ′ is optionally C1-8 alkyl (methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, etc.), C1-8 alkoxy (methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, Heptyloxy, octyloxy, etc.), hydroxyl group, C1-4 alkylthio (methylthio, ethylthio, propylthio, butylthio, etc.), mercapto, cyano,-(C1-4 alkyl) -OH (hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl) Etc.), C1-4 alkyl substituted by carbocycle (benzyl, phenethyl, phenylpropyl, phenylbutyl etc.), C1-4 alkyl substituted by heterocycle (pyridylmethyl, piperidinylmethyl etc.), halogen atom ( F Element, chlorine, bromine, etc.), optionally substituted amino group (dimethylamino, diethylamino, ethylmethylamino, etc.), carbocycle (cyclopropane, cyclobutane, cyclopentane, cyclohexane, benzene, naphthalene, etc.), heterocycle ( Azetidine, pyrrolidine, thiazolidine, piperidine, morpholine, thiomorpholine, dihydroisoindole, oxazolidine, thiazolidine, imidazole, piperazine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, tetrahydroquinoline, tetrahydroisoquinoline, dihydroindole, indoline, 1 to 5 selected from pyridine, pyrrole, furan, thiophene, oxadiazole, thiadiazole and the like.

In the present specification, R ³ is preferably a hydrogen atom, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkyl substituted by —OR ²⁰ , or substituted by —NR ²¹ R ²² . C1-8 alkyl, more preferably a hydrogen atom, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,-(C1-4 alkyl) -OH,-(C1-4 alkyl) -O- ( C1-4 alkyl),-(C1-4 alkyl) -O- (C3-10 monocyclic or bicyclic carbocycle (cyclopropane, cyclobutane, cyclopentane, cyclohexane, benzene, naphthalene, etc.)), and Preferred are a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, hydroxymethyl, methoxymethyl, and phenoxymethyl. When R ³ has a ring, the ring is further substituted with a substituent (C 1-4 alkyl such as methyl, ethyl, propyl, butyl, etc., C 1-4 alkoxy such as methoxy, ethoxy, propoxy, butoxy, fluorine, chlorine, bromine, etc. A halogen atom, a hydroxyl group, etc.).

The ring formed by combining R ¹ and R ³ (ring B) is preferably pyrrolidin-2-one, piperidin-2-one, 3,4-dihydropyridin-2 (1H) -one, azepane- 2-one.

In the present specification, R ⁴ is preferably (i) a hydrogen atom, (ii) C 1-8 alkyl, (iii) C 2-8 alkenyl, (iv) C 2-8 alkynyl, (v) a carbocyclic ring, (vi) (Vii) C1-8 alkyl substituted by carbocycle, (viii) C1-8 alkyl substituted by heterocycle, (ix) C1-8 alkyl substituted by 1 to 3 halogen atoms More preferably a hydrogen atom, C1-4 alkyl, C2-4 alkenyl, C3-6 cycloalkyl, C1-4 alkyl substituted by 1 to 3 halogen atoms, still more preferably a hydrogen atom, methyl Ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, 2-propynyl, 2,2,2-trifluoroethyl.

In the present specification, R ⁵ and R ⁶ are preferably each independently a hydrogen atom, C 1-8 alkyl, C 2-8 alkenyl, or C 1-8 alkyl substituted by a carbocycle, and more preferably independently, a hydrogen atom, or represents a C1-4 alkyl which may have a substituent, a C3-6 carbocycle representing together with the carbon atom to which R ⁵ and R ⁶ are bonded, more preferably Are each independently a hydrogen atom, methyl, ethyl, propyl, butyl, benzyl, phenethyl, cyclopropylmethyl, cyclohexylmethyl. Further, cyclopropane, cyclobutane, cyclopentane, and cyclohexane formed together with the carbon atom to which R ⁵ and R ⁶ are bonded are also preferable.

In the present specification, R ⁷ is preferably C 1-8 alkyl or C 2-8 alkenyl.

n is preferably an integer of 0 or 1-2, and when a plurality of R ⁷ are present, they may be the same or different.

In the present specification, R ⁸ is preferably C 1-4 alkyl, C 1-4 alkoxycarbonyl, or benzyloxycarbonyl. In R ⁸ , C1-4 alkyl is preferably methyl or ethyl, and C1-4 alkoxycarbonyl is preferably t-butoxycarbonyl.

  As for the stereochemistry of the compound of the present invention represented by the general formula (I), any stereostructure is preferable, but in particular, any group bonded to the pyrrolidine ring is preferably bonded to the β configuration (the front side of the paper). That is, the following general formula (IX)

(Wherein all symbols have the same meaning as described above) is preferred.

  In the present invention, as a more preferred embodiment, the general formula (IA)

(Wherein all symbols have the same meaning as described above), a compound represented by the general formula (IB)

(In the formula, X represents — (CH ₂ ) _m —, m represents an integer of 1 to 6, and one of the carbon atoms contained in X may be —NH— group, oxygen atom or oxidized. A compound represented by the general formula (IC), which may be replaced by a sulfur atom, and the other symbols have the same meaning as described above:

(Where

Represents ring A, and the other symbols have the same meaning as described above. ), A salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof.

  The compounds described in the examples are also preferable, and the compounds shown in Tables 1 to 25 below are also preferable.

  In the following table, Me represents a methyl group, Et represents an ethyl group, n-Pr represents an n-propyl group, n-Bu represents an n-butyl group, n-Pen represents an n-pentyl group, and Ph represents a phenyl group.

[Salts, solvates, N-oxides and prodrugs]
Salts of the compounds represented by the general formula (I) include all pharmacologically acceptable salts. The pharmacologically acceptable salt is preferably water-soluble with little toxicity. As a suitable salt of the compound represented by the general formula (I), for example, a salt of an alkali metal (potassium, sodium, lithium, etc.), a salt of an alkaline earth metal (calcium, magnesium, etc.), an ammonium salt (tetramethylammonium salt, Tetrabutylammonium salts, etc.), organic amines (triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N-methyl- Salt of D-glutamine, etc., acid adduct salt (inorganic acid salt (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic acid salt (acetate, Trifluoroacetate, lactate, tartrate, oxalate, fumaric acid , Maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, isethionate, glucuronate, gluconate, etc. ) Etc.).

  As a suitable solvate of the compound represented by the general formula (I), for example, solvates such as water and alcohol solvents (ethanol etc.) can be mentioned. The solvate is preferably non-toxic and water-soluble. Solvates of the compound of the present invention also include solvates of the above compound of the present invention such as alkali (earth) metal salts, ammonium salts, organic amine salts, and acid adduct salts.

  The compound represented by the general formula (I) can be converted into the above salt and the above solvate by a known method.

Further, the salt includes a quaternary ammonium salt. The quaternary ammonium salts, nitrogen atoms of the compound represented by formula (I), R ⁰ group (R ⁰ group represents a C1-8 alkyl group substituted C1-8 alkyl group, by a phenyl group. ) Represents a quaternized product.

  The compound represented by the general formula (I) can be converted into an N-oxide by a known method. The N-oxide form represents a compound in which the nitrogen atom of the compound represented by the general formula (I) is oxidized.

The prodrug of the compound represented by the general formula (I) refers to a compound that is converted into a compound represented by the general formula (I) by a reaction with an enzyme, gastric acid or the like in a living body. As a prodrug of the compound represented by the general formula (I), for example, when the compound represented by the general formula (I) has an amino group (for example, in the compound represented by the general formula (I), R ⁸ is a hydrogen atom) In some cases, the amino group is acylated, alkylated or phosphorylated (for example, the amino group of the compound represented by the general formula (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5- Methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, acetoxymethylation, tert-butylated compounds, etc.); When the compound represented by the general formula (I) has a hydroxyl group, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated. Products (for example, compounds in which the hydroxyl group of the compound represented by the general formula (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); When the compound represented by (I) has a carboxy group, the carboxy group is esterified and amidated (for example, the carboxy group of the compound represented by the general formula (I) is ethyl esterified, phenyl esterified, Carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) Methyl esterification, cyclohexyloxycarbonylethyl ester Etherification, methylamidated compounds, etc.) and the like. These compounds can be produced by a method known per se. The prodrug of the compound represented by the general formula (I) may be a solvate. In addition, the prodrug of the compound represented by the general formula (I) has a general formula under physiological conditions as described in Yodogawa Shoten 1990, “Drug Development”, Vol. 7, “Molecular Design”, pages 163-198. It may be changed to the compound represented by (I). Furthermore, the compound represented by the general formula (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).
[Method for producing compound of the present invention]
The compounds of the present invention represented by the general formula (I) can be prepared by known methods such as Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd edition, by Richard C. Larock, John For example, the method described in Wiley & Sons Inc, 1999) can be produced by appropriately combining the methods described below or the methods described in the examples. In addition, in each manufacturing method below, you may use a raw material compound as a salt. As such salts, those described as the salts of the compound represented by the general formula (I) can be used.

  Among the compounds represented by the general formula (I), for example, the general formula (I-1)

(Wherein R ^8-1 represents a protecting group for a hydrogen atom or a nitrogen atom, and other symbols have the same meanings as described above), the compound represented by the following method (1) or (2) Can be manufactured.
(1) The compound represented by the general formula (I-1) is represented by the general formula (II)

(In the formula, R ^1-1 , R ^2-1 and R ^3-1 represent the same meaning as R ¹ , R ² and R ³ , respectively, but these contain a carboxyl group, an amino group, a hydroxyl group or a mercapto group. Represents a compound protected by a protecting group, Q represents a protecting group for a nitrogen atom), and a compound of the general formula (III)

(Wherein R ^4-1 , R ^5-1 and R ^6-1 represent the same meaning as R ⁴ , R ⁵ and R ⁶ , respectively, but these contain a carboxyl group, an amino group, a hydroxyl group or a mercapto group. Represents a compound protected by a protecting group.) Is subjected to an amidation reaction, followed by deprotection reaction of nitrogen atom protecting group (ie, Q) and / or other protection as necessary. It can be produced by subjecting the group to deprotection reaction.

  This amidation reaction is known, and examples thereof include (1) a method using an acid halide, (2) a method using a mixed acid anhydride, and (3) a method using a condensing agent.

Specifically explaining these methods,
(1) The method using an acid halide is, for example, a carboxylic acid in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, toluene, etc.) or without a solvent, and an acid halide agent (oxalyl chloride, thionyl chloride, cyanuric fluoride). Etc.) and a base in the presence or absence of pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc., at −20 ° C. to reflux temperature, and the resulting acid halide is converted into a base (pyridine, triethylamine). , Dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) in the presence of an amine derivative in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) at 0 to 80 ° C. The obtained acid halide can also be reacted with an amine at 0 to 40 ° C. in an organic solvent (dioxane, tetrahydrofuran, etc.) using an alkaline aqueous solution (sodium bicarbonate water or sodium hydroxide solution, etc.).
(2) A method using a mixed acid anhydride is, for example, using a carboxylic acid in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or without a solvent, and a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropyl). In the presence of ethylamine, etc., the mixture obtained by reacting with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate, etc.) at 0 to 40 ° C. The reaction is carried out by reacting the acid anhydride with an amine derivative at 0-80 ° C. in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.).
(3) A method using a condensing agent includes, for example, using a carboxylic acid and an amine derivative in an organic solvent (chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran, etc.) or without a solvent in a base (pyridine, triethylamine, N- In the presence or absence of methylmorpholine, dimethylaniline, dimethylaminopyridine, etc.), a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide (EDC) ), 1,1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine, 1-propylphosphonic acid cyclic anhydride (PPA), cyanuric chloride, etc. 1-hydroxybenzotriazole (HO Without using or using t), it is carried out by subjecting the reaction at 0 to 80 ° C..

  These reactions (1), (2) and (3) are all desirably carried out under anhydrous conditions in an inert gas (argon, nitrogen, etc.) atmosphere.

  Examples of the protecting group for the nitrogen atom represented by Q include benzyloxycarbonyl (Cbz or Z), tert-butoxycarbonyl (Boc), allyloxycarbonyl (Alloc), 1-methyl-1- (4-biphenyl) ethoxycarbonyl (Bpoc), trifluoroacetyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl, benzyloxymethyl (BOM), 2- (trimethylsilyl) ethoxymethyl (SEM) and the like. .

  Examples of the protecting group for the carboxyl group include methyl, ethyl, allyl, tert-butyl, trichloroethyl, benzyl (Bn), phenacyl, p-methoxybenzyl, trityl, 2-chlorotrityl, or a solid phase carrier to which those structures are bound. Etc.

  Examples of the hydroxyl protecting group include methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl ( TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc), 2,2 , 2-trichloroethoxycarbonyl (Troc) and the like.

  Examples of the amino-protecting group include the same protecting groups as those described above for the nitrogen atom.

  Examples of the mercapto-protecting group include benzyl (Bn), methoxybenzyl, methoxymethyl (MOM), 2-tetrahydropyranyl (THP), diphenylmethyl, acetyl (Ac) and the like.

  The protecting group for the carboxyl group, hydroxyl group, amino group and / or mercapto group is not particularly limited as long as it is a group that can be easily and selectively eliminated other than the above. For example, those described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999 are used.

  The deprotection reaction of the protecting group of nitrogen atom and the protecting group of carboxyl group, hydroxyl group, amino group and / or mercapto group is well known, for example, (1) deprotection reaction by alkaline hydrolysis, (2) Deprotection reaction under acidic conditions, (3) Deprotection reaction by hydrogenolysis, (4) Deprotection reaction of silyl group, (5) Deprotection reaction using metal, (6) Deprotection using metal complex Reaction etc. are mentioned.

Specifically explaining these methods,
(1) The deprotection reaction by alkali hydrolysis is carried out, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.), alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth It is carried out at 0 to 40 ° C. using a metal hydroxide (barium hydroxide, calcium hydroxide etc.) or carbonate (sodium carbonate, potassium carbonate etc.), an aqueous solution thereof or a mixture thereof.
(2) The deprotection reaction under acidic conditions can be performed by, for example, organic acids (acetic acid, trifluoroacetic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid) in organic solvents (dichloromethane, chloroform, dioxane, ethyl acetate, anisole, etc.). Etc.), or an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrogen bromide / acetic acid, etc.) at 0 to 100 ° C.
(3) Deprotection reaction by hydrogenolysis includes, for example, solvent (ether (tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol (methanol, ethanol, etc.), benzene (benzene, toluene, etc.), ketone System (acetone, methyl ethyl ketone, etc.), nitrile system (acetonitrile, etc.), amide system (dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixed solvent of two or more thereof, catalyst (palladium-carbon, palladium black, In the presence of palladium hydroxide, platinum oxide, Raney nickel, etc.) in a hydrogen atmosphere under normal pressure or under pressure, or in the presence of ammonium formate.
(4) The deprotection reaction of the silyl group is performed at 0 to 40 ° C. using tetrabutylammonium fluoride in an organic solvent miscible with water (tetrahydrofuran, acetonitrile, etc.), for example.
(5) The deprotection reaction using a metal is carried out, for example, in an acidic solvent (acetic acid, a buffer solution of pH 4.2 to 7.2 or a mixed solution thereof with an organic solvent such as tetrahydrofuran) in the presence of powdered zinc, If necessary, it is carried out at 0 to 40 ° C. while applying ultrasonic waves.
(6) The deprotection reaction using a metal complex is carried out by using, for example, a trap reagent (tributyltin hydride, Triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), organic acids (acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or organic acid salts (sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.) In the presence, in the presence or absence of a phosphine-based reagent (such as triphenylphosphine), metal complexes (tetrakistriphenylphosphine palladium (0), bis (triphenylphosphine) palladium (II) dichloride, palladium (II) acetate , Tris chloride ( With Li triphenylphosphine) rhodium (I) etc.), carried out at 0 to 40 ° C..

  As can be easily understood by those skilled in the art, the desired compound of the present invention can be easily produced by properly using these deprotection reactions.

In addition to the above, the deprotection reaction can be performed by a method described in, for example, TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.
(2) The compound represented by the general formula (I-1) is represented by the general formula (IV).

(Wherein all symbols have the same meanings as described above) are subjected to dehydration reaction, and if necessary, deprotection reaction of protecting group of nitrogen atom and / or deprotection of other protecting group is continued. It can also be produced by subjecting to a reaction.

The dehydration reaction using the compound represented by the general formula (IV) is known, for example, in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, toluene, etc.), a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine). Etc.) in the presence or absence of a dehydrating agent (trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, phosphorus oxychloride, thionyl chloride, 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [ 3- (dimethylamino) propyl] carbodiimide (EDC), tosyl chloride, cyanuric chloride, etc.).
(3) Among the compounds represented by the general formula (I), for example, the general formula (I-2)

(Wherein R ^8-2 represents C 1-8 alkyl, and other symbols have the same meanings as described above), the compound represented by the general formula (I-1) is R ^8A In which is a hydrogen atom, that is, the general formula (I-1-A)

(Wherein all symbols have the same meanings as described above) can be produced by subjecting the compound to an N-alkylation reaction.

  N-alkylation reactions are known and include, for example, alkylating agents (eg, methyl iodide, ethyl iodide, propyl iodide, etc.) and bases (eg, sodium hydride, triethylamine, dimethylaminopyridine, pyridine, etc.). The reaction is carried out at a temperature of 0 ° C. to 100 ° C. in the presence or absence.

  This reaction is preferably carried out under anhydrous conditions in the presence of an inert gas.

  The compounds represented by general formula (II) and general formula (IV) can be produced by the method shown in the following reaction process formula 1. Further, the compound represented by the general formula (III) is known, or can be produced by a known method using a known amino acid derivative as a starting material.

In Reaction Scheme 1, R ^A and R ^B represent a protecting group for a carboxyl group, and other symbols have the same meaning as described above.

Of the compounds represented by the general formula (II) or (IV), R ^3-1 is a hydrogen atom and Q is a Boc group, that is, in the general formula (II-A) or (IV-A) The compound shown can be manufactured by the method shown by the following reaction process formula 2.

  In reaction process formula 2, all symbols have the same meaning as described above.

  All reactions in each reaction process can be carried out according to known methods. In addition, other starting materials and reagents in the present invention are known per se or can be produced according to known methods. For example, the glutamic acid derivative represented by the general formula (V) is known, and for example, 1-methyl 5- (phenylmethyl) N-(((1,1-dimethylethyl) oxy) carbonyl) -L-glutamate is CAS registration number: 59279-58-2, and 1-methyl 5- (phenylmethyl) N-(((1,1-dimethylethyl) oxy) carbonyl) -D-glutamate is CAS registration number: 110473 -10-4, 5-methyl 1- (phenylmethyl) N-(((1,1-dimethylethyl) oxy) carbonyl) -L-glutamate is known as CAS Registry Number: 132245-78-4. The compound represented by the general formula (XIII) can be produced according to the method described in Journal of Medicinal Chemistry, 1991, Vol. 34, pages 717-725.

In each reaction in the present specification, the reaction product is obtained by a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography. It can be purified by a method such as lithography or washing, recrystallization. Purification may be performed for each reaction or after completion of several reactions.
[toxicity]
The toxicity of the compound represented by the general formula (I), a salt thereof, a solvate thereof, an N-oxide thereof or a prodrug thereof (hereinafter sometimes abbreviated as the compound of the present invention) is very low. Yes, it is safe enough to use as a medicine.
[Pharmacological activity]
Examples of pharmacological tests other than those described in the examples include the following methods.
(1) Single oral glucose tolerance test in rats This test can be carried out by appropriately modifying the method described in Diabetologia, 42, 1324-1331, 1999. For the test, 9-11 week old male SD rats or 10 week old male Zucker fatty rats (Nippon Charles River) are fasted from the day before the experiment. The compound of the present invention is dissolved in 0.5% methylcellulose distilled aqueous solution and orally administered at a concentration of 5 mL / kg. The control group receives the same dose of 0.5% methylcellulose distilled water solution. It is orally administered to a Japanese Pharmacopoeia aqueous solution of 1 g / kg body weight of sugar at a concentration of 5 mL / kg 30 minutes after administration of the compound of the present invention or 0.5% methylcellulose distilled aqueous solution. Immediately before oral administration of the drug and after oral sugar loading, blood is collected from the tail vein using heparinized capillaries, and the obtained blood is immediately centrifuged at 4 ° C. and 12,000 rpm for 3 minutes. Plasma is obtained and frozen with dry ice. The blood glucose level (mg / dl) is measured by taking 2.5 μL of plasma in a 96-well plate and measuring with a blood glucose level measurement kit: Diacolor GC ^™ (Ono Pharmaceutical Co., Ltd.). In addition, antibody-reactive insulin (IRI) in plasma is measured by an insulin measurement ELISA kit (manufactured by Morinaga Biochemical Research Institute).
(2) Repeated oral glucose tolerance test in rats The repeated oral glucose tolerance test in rats can be performed based on the method of single oral glucose tolerance test shown in (1) above. However, the oral glucose load was 3 times in total (the first oral glucose load was performed 30 minutes after the oral administration of the compound of the present invention, the second oral glucose load 6 hours later, and the third oral dose 12 hours later). Glucose loading is carried out) and blood sampling is performed immediately before oral administration of the compound of the present invention, after the first oral sugar loading, and immediately before the remaining two oral sugar loadings and after oral sugar loading.

By the tests of (1) and (2), the blood glucose level of the compound of the present invention represented by the general formula (I) can be measured. And / or improve.
[Application to pharmaceutical products]
The compound of the present invention inhibits DPP4, thereby causing DPP4-mediated diseases such as diabetes (especially type 2 diabetes), obesity, schizophrenia, depression, anxiety, epilepsy, stress diseases, pain (pain etc.), Autoimmune diseases (rheumatoid arthritis, type 1 diabetes, etc.), allergic diseases (asthma, food allergies, etc.), cancer, cancer metastasis, HIV infection, anemia, thrombocytopenia, skin diseases (psoriasis, lichen planus, etc.), prostatic hypertrophy , Hyperlipidemia, metabolic syndrome, diabetic complications, arteriosclerosis, impaired glucose tolerance, polycystic ovary syndrome, infertility, growth disorder, arthritis, transplant rejection, enteritis, wound treatment and / or prevention agent, It is also useful as an agent for preventing and / or improving postprandial hyperglycemia.

The compound of the present invention
1) complementation and / or enhancement of the therapeutic and / or prophylactic effect of the compound,
2) Improving the kinetics / absorption of the compound, reducing the dose,
And / or 3) may be administered as a medicament in combination with other drugs to reduce the side effects of the compound.

  A pharmaceutical comprising a combination of the compound of the present invention and another drug may be administered in the form of a combination drug in which both components are mixed in one preparation, or may be administered in separate preparations. When administered as separate formulations, simultaneous administration and administration by time lag are included. In addition, administration by time difference may be such that the compound of the present invention is administered first and the other drug may be administered later, or the other drug may be administered first and the compound of the present invention may be administered later. The administration method may be the same or different.

  The disease that exhibits the therapeutic and / or prophylactic effect by the concomitant drug is not particularly limited as long as it is a disease that complements and / or enhances the therapeutic and / or prophylactic effect of the compound of the present invention.

Other drugs for supplementing and / or enhancing the therapeutic and preventive effects on diabetes (such as type 2 diabetes), impaired glucose tolerance, obesity and the like and the preventive and / or ameliorating effects on postprandial hyperglycemia of the compounds of the present invention For example, sulfonylurea, biguanide, α-glucosidase inhibitor, insulin secretagogue, insulin sensitizer, insulin preparation, PPAR agonist (PPARα agonist, PPARγ agonist, PPARα + γ agonist, PPAR pan agonist Drugs), β ₃ adrenergic receptor agonists, aldose reductase inhibitors, DPP4 inhibitors, AMP kinase activators, type 1 11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibitors, lipase inhibitors, appetite suppressants Etc.

  Examples of the sulfonylurea drugs include acetohexamide, glibenclamide, gliclazide, glyclopyramide, chlorpropamide, tolazamide, tolbutamide, glimepiride and the like.

  Examples of biguanide drugs include buformin hydrochloride and metformin hydrochloride.

  Examples of the α-glucosidase inhibitor include acarbose, voglibose, miglitol and the like.

  Examples of the insulin secretagogue include nateglinide, repaglinide, mitiglinide and the like.

  As an insulin sensitizer, ONO-5816, YM-440, JTT-501, NN-2344 etc. are mentioned, for example.

  Examples of PPAR agonists include bezafibrate, clofibrate, fenofibrate, gemfibrate, etc. as PPARα agonists, pioglitazone, troglitazone, rosiglitazone, etc. as PPARγ agonists, and muraglitazar, tesaglitazar, ONO-5129, etc. as PPARα + γ agonists. However, examples of the PPAR pan agonist include GSK677754, PLX204, MCC-555, and the like.

The beta ₃ adrenergic receptor agonists, for example, AJ9677, L750355, CP331648, and the like.

  Examples of aldose reductase inhibitors include epalrestat, fidarestat, zenarestat and the like.

  Examples of DPP4 inhibitors include LAF-237, sitagliptin phosphate (MK-431, ONO-5435), BMS-477118, P93-01, GSK823093, GSK815541, GSK825964, TS-021, T-6666, SYR-322. , E-3024, NN-7201, PSN-9301, and the like.

  Examples of lipase inhibitors include orlistat and the like.

  Appetite suppressants include cannabinoid receptor 1 antagonists (eg, rimonabant), melanin-concentrating hormone receptor antagonists (eg, GSK856464, ATC-0065, ATC-0175, AMG-076, etc.), monoamine reuptake inhibitors (Eg, mazindol, sibutramine, etc.), serotonin 2c receptor agonist (eg, APD-356, SCA-136, etc.), histamine 3 receptor antagonist (eg, ABT-239, ABT-837, GT-2331, NNC-0038) -0000-1220 etc.), mazindol, sibutramine and the like.

  For example, other drugs for complementing and / or enhancing the therapeutic and / or prophylactic effect of the compound of the present invention on hyperlipidemia include, for example, HMG-CoA inhibitors, PPARδ agonists and the like.

  Examples of the HMG-CoA inhibitor include pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin, rosuvastatin, pitavastatin and the like.

  For example, as other drugs for complementing and / or enhancing the therapeutic and / or preventive effect of the compound of the present invention on allergic diseases, for example, antiallergic drugs can be mentioned.

  Antiallergic agents include, for example, amlexanox, azelastine hydrochloride, israpafant, ibudilast, imitrodast sodium, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, ozagrel hydrochloride, olopatadine hydrochloride, cromoglycate, cromoglycate sodium, fumarate Ketotifen acid, seratrodast, cetirizine hydrochloride, suplatast tosylate, tazanolast, terfenadine, domitroban calcium hydrate, tranilast, nedocromil, fexofenadine, fexofenadine, pemirolast potassium, mequitazine, ramatroban, repirinast, loratadine, etc. Is mentioned.

  For example, other drugs for complementing and / or enhancing the preventive and / or therapeutic effects of the compounds of the present invention on rheumatoid arthritis, arthritis, etc. include, for example, steroid drugs, elastase inhibitors, prostaglandins, prostaglandins. Gin synthase inhibitor, phosphodiesterase inhibitor, adhesion molecule inhibitor, anti-cytokine protein preparation (eg, anti-TNF-α preparation, anti-IL-1 preparation, anti-IL-6 preparation, etc.), anti-cytokine drug, immunomodulator, Disease-modifying anti-rheumatic agents, non-steroidal anti-inflammatory drugs, c-Jun N-terminal kinase inhibitors and the like can be mentioned.

For example, as other drugs for complementing and / or enhancing the preventive and / or therapeutic effect of the compound of the present invention against asthma, for example, steroid drugs, elastase inhibitors, prostaglandins, prostaglandin synthase inhibition Drug, phosphodiesterase inhibitor, metalloproteinase inhibitor, adhesion molecule inhibitor, leukotriene receptor antagonist, anticholinergic agent, thromboxane A ₂ receptor antagonist, thromboxane synthase inhibitor, β ₂ adrenergic receptor stimulant, Examples include xanthine derivatives, expectorants, antibiotics, antihistamines, anti-cytokine protein preparations, anti-cytokine drugs, forskolin preparations and mediator release inhibitors.

  Examples of steroid drugs include clobetasol propionate, diflorazone acetate, fluocinonide, mometasone furanate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difluprednate, diflucortron valerate, amsinonide, halsinonide, dexamethasone, Dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, deprodon propionate, prednisolone valerate acetate, fluocinolone acetonide, beclomethasone propionate, triamcinolone acetonide, pivalic acid flumetazone Alclomethasone acid, clobetasone butyrate, prednisolone, fludroxycol Cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, fludrocortisone acetate, prednisolone acetate, sodium prednisolone succinate, prednisolone butyl acetate, sodium prednisolone phosphate, halopredon acetate, methylprednisolone acetate, methyl prednisolone acetate Methylprednisolone sodium, triamcinolone, triamcinolone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, paramethasone acetate, betamethasone, fluticasone propionate, budesonide, flunisolide, ST-126P, ciclesonide, dexamethasone paromithonate, mometasone furanzone Teronsulfonate, Deflazaco , Methylprednisolone thread descriptor sulfonates, and the like methylprednisolone sodium succinate.

  Examples of the elastase inhibitor include sivelestat sodium hydrate, ONO-6818, MR-889, PBI-1101, EPI-HNE-4, R-665, ZD-0892, ZD-8321, GW-31616, DMP- 777, L-659286, L-658758, L-680833, L-683845, AE-3763 and the like.

  Examples of prostaglandins (hereinafter abbreviated as PG) include PG receptor agonists and PG receptor antagonists.

As PG receptors, PGE receptors (EP ₁ , EP ₂ , EP ₃ , EP ₄ ), PGD receptors (DP, CRTH ₂ ), PGF receptors (FP), PGI receptors (IP), thromboxane ( TX) receptor (TP) and the like.

  Examples of prostaglandin synthase inhibitors include salazosulfapyridine, mesalazine, osalazine, 4-aminosalicylic acid, JTE-522, auranofin, carprofen, difenpyramide, flunoxaprofen, flurbiprofen, indomethacin. , Ketoprofen, lornoxicam, loxoprofen, meloxicam, oxaprozin, persalmid, piperxene, piroxicam, piroxicam betadex, piroxicam cinnamate, tropine indomethacinate, zaltoprofen, pranoprofen and the like.

  Examples of phosphodiesterase inhibitors include PDE4 inhibitors rolipram, silomilast (trade name Ariflo), Bay19-8004, NIK-616, roflumilast (BY-217), cypamfilin (BRL-61063), atizolam (CP-80633), SCH-351591, YM-976, V-11294A, PD-168787, D-4396, IC-485, ONO-6126, etc., or PDE5 inhibitor sildenafil citrate, vardenafil hydrochloride and the like.

The adhesion molecule inhibitor, for example alpha ₄ integrin antagonists such as and the like.

  Anti-TNF-α preparations include antibodies to TNF-α, soluble TNF-α receptors, antibodies to TNF-α receptors, soluble TNF-α binding proteins and the like, and examples include infliximab and etanercept.

  Anti-IL-1 preparations include antibodies to IL-1, soluble IL-1 receptor, IL-1Ra, antibodies to IL-1 receptor, and the like, such as anakinra.

  Examples of the anti-IL-6 preparation include antibodies to IL-6, soluble IL-6 receptor, antibodies to IL-6 receptor, and the like, for example, MRA.

  Examples of immunomodulators include methotrexate, cyclosporine, ascomycin, leflunomide, bucillamine, salazosulfapyridine, azathioprine, tacrolimus, cyclophosphamide, FTY-720 and the like.

  Examples of the disease-modifying antirheumatic drug include gold thioglucose, gold sodium thiomalate, auranofin, chloroquine, actarit, D-penicillamine preparation, lobenzalit disodium, bucillamine, hydroxychloroquine, salazosulfapyridine and the like.

  Non-steroidal anti-inflammatory drugs include, for example, Sazapyrine, sodium salicylate, aspirin, aspirin dialuminate, diflunisal, indomethacin, suprofen, ufenamate, dimethylisopropylazulene, bufexamac, felbinac, diclofenac, tolmetin sodium, clinolyl, fenbufen, napmetone , Progouritacin, Indomethacin Farnesyl, Acemetacin, Progouritacin Maleate, Ampenac Sodium, Mofezolac, Etodolac, Ibuprofen, Ibuprofen Piconol, Naproxen, Flurbiprofen, Flurbiprofen Axetil, Ketoprofen, Calcium Fenoprofen , Thiaprofen, oxaprozin, pranoprofen, loxoprof Sodium, aluminoprofen, zaltoprofen, mefenamic acid, aluminum mefenamic acid, tolfenamic acid, fructaphenine, ketophenylbutazone, oxyphenbutazone, piroxicam, tenoxicam, ampiroxicam, napageln ointment, epilysole, thiaramide hydrochloride, tinolidine hydrochloride, emorphazone , Sulpyrine, migrenin, salidone, cedes G, amypiro-N, sorbone, pilin cold remedy, acetaminophen, phenacetin, dimethothiazine mesylate, cimetride combination drug, non-pyrine cold remedy and the like.

  Examples of leukotriene receptor antagonists include pranlukast hydrate, montelukast sodium, zafirlukast, seratrodast, MCC-847, KCA-757, CS-615, YM-158, L-740515, CP-195494, LM-1484. RS-635, A-93178, S-36496, BIIL-284, ONO-4057, and the like.

  Examples of the anticholinergic agent include ipratropium bromide, oxitropium bromide, flutropium bromide, cimetropium bromide, temiverine, tiotropium bromide, levatrope (UK-112166) and the like.

Examples of the thromboxane A ₂ receptor antagonist include seratrodast, ramatroban, domitroban calcium hydrate, KT-2-962, and the like.

  Examples of thromboxane synthase inhibitors include ozagrel hydrochloride and imitrodast sodium.

Examples of β ₂ adrenergic receptor stimulants include fenoterol hydrobromide, salbutamol sulfate, terbutaline sulfate, formoterol fumarate, salmeterol xinafoate, isoproterenol sulfate, orciprenaline sulfate, chlorprenalin sulfate, epinephrine, trimethoxy hydrochloride. Nord, hexoprenaline mesyl sulfate, procaterol hydrochloride, tulobuterol hydrochloride, tulobuterol hydrochloride, pyrbuterol hydrochloride, clenbuterol hydrochloride, mabuterol hydrochloride, ritodrine hydrochloride, bambuterol, dopexamine hydrochloride, meladrin tartrate, AR-C68397, levosalbutamol, R, R-formoterol , KUR-1246, KUL-7221, AR-C89855, S-1319, and the like.

  Examples of xanthine derivatives include aminophylline, theophylline, doxophilin, cypamphylline, diprofylline and the like.

  Examples of expectorants include ammonia fennel, sodium bicarbonate, bromhexine hydrochloride, carbocysteine, ambroxol hydrochloride, ambroxol hydrochloride sustained release agent, methylcysteine hydrochloride, acetylcysteine, L-ethylcysteine hydrochloride, tyloxapol and the like. Can be mentioned.

  Antibiotics include, for example, cefuroxime sodium, meropenem trihydrate, netilmicyl sulfate, sisomicin sulfate, ceftibbutene, PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, astromycin sulfate, cefetamethoboxil hydrochloride, etc. Is mentioned. Examples of antibiotics for inhalation include PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, astromycin sulfate, and cefetamethopivoxil hydrochloride.

  Antihistamines include, for example, ketotifen fumarate, mequitazine, azelastine hydrochloride, oxatomide, terfenadine, emedastine fumarate, epinastine hydrochloride, astemizole, ebastine, cetirizine hydrochloride, bepotastine, fexofenadine, loratadine, desloratadine, olopatadine hydrochloride TA 427, ZCR-2060, NIP-530, mometasone furoate, mizolastine, BP-294, andlast, auranofin, acribastine and the like.

  Anti-cytokine drugs include all non-protein preparations that block the action of cytokines, such as MAP kinase inhibitors, gene regulators, cytokine production inhibitors, TNF-α converting enzyme inhibitors, IL- 1β converting enzyme inhibitors, IL-6 antagonists, IL-8 antagonists, chemokine antagonists, gene therapy agents, antisense compounds and the like can be mentioned. Examples of the MAP kinase inhibitor include PD-98059. Examples of gene regulators include inhibitors of molecules related to signal transduction such as NF-κB, IKK-1, IKK-2, AP-1. Examples of the cytokine production inhibitor include suplatast tosylate (trade name IPD), T-614, SR-31747, sonatimod and the like. Examples of chemokine antagonists include ONO-4128. Examples of gene therapy drugs include gene therapy drugs aimed at enhancing the expression of genes having anti-inflammatory activity such as interleukin 4, interleukin 10, soluble IL-1 receptor, soluble TNF-α receptor, and the like. Can be mentioned.

  Examples of the mediator release inhibitor include tranilast, sodium cromoglycate, amlexanox, repirinast, ibudilast, dazanolast, pemirolast potassium and the like.

  Examples of c-Jun N-terminal kinase inhibitors include compounds described in WO00 / 35906, WO00 / 35909, WO00 / 35921, WO00 / 64872, or WO00 / 75118 pamphlets.

  In order to use a pharmaceutical composition containing the compound of the present invention or a combination agent of the compound of the present invention and another drug as an active ingredient for the above-mentioned purpose, it is usually systemically or locally, orally or parenterally. Be administered.

  The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually orally administered once to several times a day in the range of 1 ng to 1000 mg per adult per dose. Or administered parenterally once or several times a day in the range of 0.1 ng to 100 mg per adult or continuously intravenously in the range of 1 to 24 hours per day. The

  Of course, as described above, since the dosage varies depending on various conditions, an amount smaller than the above-mentioned dosage may be sufficient, or administration may be required beyond the range.

  In order to use the compound of the present invention or a combination agent of the compound of the present invention and another drug for the above-mentioned purpose, it is usually administered systemically or locally in an oral or parenteral form, and is most effective in treatment. It is desirable to select a suitable route of administration.

  When administering a pharmaceutical composition containing the compound of the present invention or a combination of the compound of the present invention and another drug as an active ingredient, a solid preparation for internal use for oral administration, a liquid for internal use, and a parenteral administration For injection, external preparation, suppository and the like.

  Examples of the solid preparation for internal use for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules.

  In such solid preparations for internal use, one or more active substances are left as they are, or excipients (lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (hydroxypropylcellulose, polyvinylpyrrolidone, metasilicate) Mixed with acid disinfectant (magnesium aluminate, etc.), disintegrating agents (calcium glycol glycolate, etc.), lubricants (magnesium stearate, etc.), stabilizers, solubilizing agents (glutamic acid, aspartic acid, etc.), etc. Used. If necessary, it may be coated with a coating agent (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers. Also included are capsules of absorbable substances such as gelatin.

  Liquid preparations for internal use for oral administration include pharmaceutically acceptable solutions, suspensions / emulsions, syrups, elixirs and the like. In such a solution, one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (purified water, ethanol or a mixture thereof). Furthermore, this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.

  Examples of the injection for parenteral administration include solutions, suspensions, emulsions, and solid injections used by dissolving or suspending in a solvent at the time of use. An injection is used by dissolving, suspending or emulsifying one or more active substances in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used. Further, this injection may contain a stabilizer, a solubilizing agent (such as glutamic acid, aspartic acid, polysorbate 80 (registered trademark)), a suspending agent, an emulsifier, a soothing agent, a buffering agent, a preservative and the like. . These are sterilized in the final process or manufactured and prepared by aseptic manipulation. In addition, a sterile solid preparation, for example, a lyophilized product, can be produced and used by dissolving it in sterilized or sterile distilled water for injection or other solvent before use.

  External dosage forms for parenteral administration include, for example, ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, eye drops and nasal drops Is included. These contain one or more active substances and are produced and prepared by known methods or commonly used formulations.

  The ointment is produced by a known or commonly used formulation. For example, it is produced and prepared by grinding or melting one or more active substances in a base. The ointment base is selected from known or commonly used ones. For example, higher fatty acid or higher fatty acid ester (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (honey beeswax) , Whale wax, ceresin, etc.), surfactants (polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (dimethylpolysiloxane, etc.), hydrocarbons ( Hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol etc.), vegetable oil (castor oil, olives) , Sesame oil, turpentine oil, etc.), animal oils (mink oil, yolk oil, squalane, squalene, etc.), water, absorption accelerator, used by mixing one or more selected from the irritation inhibitor. Furthermore, a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like may be included.

  The gel is produced by a known or commonly used formulation. For example, it is produced and prepared by melting one or more active substances in a base. The gel base is selected from known or commonly used ones. For example, lower alcohols (ethanol, isopropyl alcohol, etc.), gelling agents (carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, etc.), neutralizing agents (triethanolamine, diisopropanolamine, etc.), surfactants (monostearin) Acid polyethylene glycol, etc.), gums, water, absorption accelerators, anti-rash agents, and a mixture of one or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The cream is produced by a known or commonly used formulation. For example, it is produced and prepared by melting or emulsifying one or more active substances in a base. The cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, etc.), emulsifiers (polyoxyethylene alkyl ethers, fatty acids) Ester etc.), water, an absorption accelerator, and one or more types selected from a rash prevention agent are mixed and used. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The poultice is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base material and spreading and applying the kneaded material on a support. The poultice base is selected from known or commonly used ones. For example, thickeners (polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (urea, glycerin, propylene glycol, etc.), fillers (kaolin, zinc oxide, talc, calcium, magnesium, etc.) ), Water, a solubilizer, a tackifier, and an anti-rash agent. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The patch is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base and spreading and coating them on a support. The base for patch is selected from known or commonly used ones. For example, one or more selected from polymer bases, fats and oils, higher fatty acids, tackifiers, and rash prevention agents are mixed and used. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The liniment is produced by a known or commonly used formulation. For example, it is produced by dissolving, suspending or emulsifying one or more active substances in one or more selected from water, alcohol (ethanol, polyethylene glycol, etc.), higher fatty acids, glycerin, soap, emulsifier, suspending agent and the like. Prepared. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  Sprays, inhalants, sprays and nasal sprays are commonly used diluents such as sodium bicarbonate, sodium citrate or other buffering agents such as sodium citrate or An isotonic agent such as citric acid may be included. The production method of the spray is described in detail in, for example, US Pat. Nos. 2,868,691 and 3,095,355. Moreover, it does not matter as an aerosol agent.

  When nasal drops are administered, they are usually sprayed quantitatively into the nasal cavity using a dedicated nasal drop or sprayer, which is generally a solution and powder containing the drug.

  Eye drops for parenteral administration include ophthalmic solutions, suspension type ophthalmic solutions, emulsion type ophthalmic solutions, pre-dissolving type ophthalmic solutions, and eye ointments.

  These eye drops are produced and prepared according to known methods. For example, it is used by dissolving, suspending or emulsifying one or more active substances in a solvent. As a solvent for eye drops, for example, sterilized purified water, physiological saline, other aqueous solvents or non-aqueous preparations for injection (for example, vegetable oils), and combinations thereof are used. Eye drops include isotonic agents (sodium chloride, concentrated glycerin, etc.), buffering agents (sodium phosphate, sodium acetate, etc.), surfactants (polysorbate 80 (trade name), polyoxyl 40 stearate, polyoxyethylene (Hardened castor oil, etc.), stabilizers (sodium citrate, sodium edetate, etc.), preservatives (benzalkonium chloride, paraben, etc.) and the like may be appropriately selected as necessary. These are sterilized in the final process or manufactured and prepared by aseptic operation. In addition, an aseptic solid preparation, for example, a freeze-dried product, can be produced and dissolved before use in a sterilized or aseptically sterilized purified water or other solvent.

  Inhalants for parenteral administration include aerosols, inhalable powders or inhalable solutions, which are used by dissolving or suspending them in water or other suitable media at the time of use. It may be.

  These inhalants are produced according to known methods.

  For example, in the case of inhalation solutions, preservatives (benzalkonium chloride, parabens, etc.), coloring agents, buffering agents (sodium phosphate, sodium acetate, etc.), isotonic agents (sodium chloride, concentrated glycerin, etc.) , Thickeners (such as carboxyvinyl polymer), absorption accelerators and the like are appropriately selected as necessary.

  In the case of powders for inhalation, lubricants (stearic acid and its salts, etc.), binders (starch, dextrin, etc.), excipients (lactose, cellulose, etc.), coloring agents, preservatives (benzalkonium chloride) , Parabens, etc.), absorption promoters and the like are appropriately selected as necessary.

  A nebulizer (atomizer or nebulizer) is usually used when administering an inhalation solution, and an inhalation administration device for powder medicine is usually used when administering an inhalable powder.

  Other compositions for parenteral administration include suppositories for rectal administration and pessaries for intravaginal administration, which contain one or more active substances and are prescribed by conventional methods.

  Since the compound of the present invention has DPP4 inhibitory activity, DPP4-mediated diseases such as diabetes (especially type 2 diabetes), obesity, schizophrenia, depression, anxiety, epilepsy, stress diseases, pain (pain etc.) , Autoimmune diseases (rheumatoid arthritis, etc.), allergic diseases (asthma, food allergies, etc.), cancer, cancer metastasis, HIV infection, anemia, thrombocytopenia, skin disease, enlarged prostate, hyperlipidemia, metabolic syndrome, diabetes As an agent for the treatment and / or prevention of hypertension, arteriosclerosis, impaired glucose tolerance, polycystic ovary syndrome, infertility, growth disorder, arthritis, transplant rejection, enteritis, wounds, etc. Useful. In particular, the compound of the present invention has a characteristic of exhibiting inhibitory activity over a long period of time due to its high stability, and prevents and / or treats diabetes (particularly type 2 diabetes, etc.), impaired glucose tolerance, and prevents postprandial hyperglycemia and It can be an excellent drug useful for improvement.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these. The point of separation by chromatography and the solvent in parentheses shown in TLC indicate the elution solvent or developing solvent used, and the ratio indicates the volume ratio.

The solvent in parentheses shown in the ¹ H NMR portion indicates the solvent used in the measurement.

The compound name used in this specification is generally a computer program for naming according to IUPAC rules, ACD / Name batch (registered trademark, manufactured by Advanced Chemistry Development Inc.), or IUPAC naming. Named according to the law. In the following compound names, * represents the relative configuration of asymmetric carbon atoms.
Example 1: 1- (1,1-Dimethylethyl) 2-methyl 4- (phenylmethyl) (2S) -5-hydroxy-5-methylpyrrolidine-1,2,4-tricarboxylate under argon atmosphere -78 1-methyl 5- (phenylmethyl) N-(((1,1-dimethylethyl) oxy) carbonyl) -L-glutamate for lithium hexamethyldisilazane (1.75 L, 1.0 M tetrahydrofuran solution) at ° C (CAS registration number: 59279-58-2) (300 g) in tetrahydrofuran (850 mL) was added dropwise over 30 minutes, and the mixture was stirred for 30 minutes. Further, acetic anhydride (89 mL) was added dropwise at −78 ° C. over 15 minutes, followed by stirring for 1 hour. To the reaction mixture was added 2N hydrochloric acid (510 mL) in a water bath, and the mixture was further stirred for 20 minutes. To the reaction mixture, 2N hydrochloric acid (1.28 L), water (1.3 L) and hexane / ethyl acetate (1/1, 3 L) were added and extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give a crude product (369 g) of the title compound.
TLC: Rf 0.49 (n-hexane: ethyl acetate = 2: 1).
Example 2: 1- (1,1-dimethylethyl) 2-methyl 4- (phenylmethyl) (2S) -5-methyl-2,3-dihydro-1H-pyrrole-1,2,4-tricarboxylate To a solution of the compound prepared in Example 1 (369 g) in dichloromethane (1.05 L) was added trifluoroacetic acid (66 mL), and the mixture was stirred at room temperature for 1 hour. Water and dichloromethane were added to the reaction mixture and extracted. The organic layer was dried over anhydrous magnesium sulfate and concentrated. Hexane / t-butyl methyl ether (1/1, 1 L) and 1M aqueous sodium hydroxide solution (300 mL) were added to the residue for extraction. The organic layer was washed twice with 1N aqueous sodium hydroxide solution (300 mL), dried over anhydrous magnesium sulfate and concentrated to give a crude product of the title compound (309 g).
TLC: Rf 0.58 (n-hexane: ethyl acetate = 2: 1).
Example 3: (5S) -1-(((1,1-dimethylethyl) oxy) carbonyl) -2-methyl-5-((methyloxy) carbonyl) -4,5-dihydro-1H-pyrrole-3 - under acid argon, methanol (1.0 L) solution of the compound prepared in example 2 (309 g), 10% palladium - carbon (hydrous) (31 g) was added, under an atmosphere of hydrogen, stirred at room temperature for 5 hours did. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was recrystallized from diisopropyl ether-hexane to obtain the title compound (177 g).
TLC: Rf 0.29 (n-hexane: ethyl acetate = 2: 1);
¹ H-NMR (CDCl ₃ ): δ 4.69 (dd, 1H), 3.77 (s, 3H), 2.99-3.17 (m, 1H), 2.67-2.78 (m, 1H), 2.65 (s, 3H), 1.66 -1.68 (m, 1H), 1.46 (s, 9H).
Example 4: (2S, 3S, 5S) -1-(((1,1-dimethylethyl) oxy) carbonyl) -2-methyl-5-((methyloxy) carbonyl) pyrrolidine-3-carboxylic acid Platinum oxide (2.7 g) was added to a solution of the compound prepared in 3 (13.5 g) in acetic acid (100 mL), and the mixture was stirred at room temperature for 21 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was azeotroped with toluene to obtain a crude product of the title compound (14.6 g).
TLC: Rf 0.80 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.21-1.30 (m, 3H), 1.34-1.53 (m, 9H), 2.24-2.51 (m, 2H), 3.11-3.28 (m, 1H), 3.66-3.83 ( m, 3H), 4.15-4.47 (m, 2H), 4.97-6.29 (m, 1H).
Example 5: 1- (1,1-dimethylethyl) 2-methyl (2S, 4S, 5S) -4-((dimethylamino) carbonyl) -5-methylpyrrolidine-1,2-dicarboxylate Example 4 Dimethylamine hydrochloride (2.70 g), 1-hydroxybenzotriazole monohydrate (4.63 g), N-methylmorpholine (7.90 g) in dichloromethane (55 mL) 0 mL) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (5.80 g) were added sequentially and the mixture was stirred at room temperature for 16 hours. Water and dichloromethane were added to the reaction mixture and extracted. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 95: 5-80: 20) to give the title compound (7.25 g) having the following physical data.
Example 6: (4S, 5S) -4-((Dimethylamino) carbonyl) -1-(((1,1-dimethylethyl) oxy) carbonyl) -5-methyl-L-proline Prepared in Example 5. To a solution of the compound (7.25 g) in methanol (100 mL) was added 2M aqueous sodium hydroxide (50 mL), and the mixture was stirred at room temperature for 16 hours. Methanol was distilled off, and t-butyl methyl ether was added to the residue for extraction. Hydrochloric acid was added to the aqueous layer to adjust the pH to 3, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (6.39 g) having the following physical data.
TLC: Rf 0.41 (dichloromethane: methanol = 9: 1);
^{1 H-NMR (DMSO-d} 6): δ 0.81-0.97 (m, 3H), 1.25-1.45 (m, 9H), 2.05-2.20 (m, 1H), 2.19-2.39 (m, 1H), 2.81 ( s, 3H), 3.00 (s, 3H), 3.36-3.57 (m, 1H), 3.88-4.04 (m, 1H), 4.04-4.25 (m, 1H).
Example 7: 1,1-dimethylethyl (2S, 3S, 5S) -5-(((cyanomethyl) (ethyl) amino) carbonyl) -3-((dimethylamino) carbonyl) -2-methylpyrrolidine-1- Carboxylate

Pyridine (0.25 mL) was added to a solution of the compound prepared in Example 6 (300 mg) in dichloromethane (4 mL), cyanuric fluoride (0.085 mL) was slowly added dropwise at −10 ° C., and the mixture was mixed with 1. Stir for 5 hours. Water and dichloromethane were added to the reaction mixture, and the precipitate was filtered through celite. The filtrate was dried over anhydrous sodium sulfate and concentrated. Dichloroethane was added to the residue, (ethylamino) acetonitrile (126 mg) and pyridine (0.16 mL) were added to the mixture, and the mixture was stirred at 60 ° C. for 2.5 hours. 10% citric acid and dichloromethane were added to the reaction mixture and extracted. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 to 70:30) to give the compound of the present invention (273 mg) having the following physical data.
TLC: Rf 0.23 (ethyl acetate);
¹ H-NMR (CDCl ₃ ): δ 1.15 (d, 3H), 1.34 (t, 3H), 1.39-1.49 (m, 9H), 2.17-2.37 (m, 1H), 2.53-2.71 (m, 1H) , 2.96 (s, 3H), 3.05-3.13 (m, 3H), 3.23-3.39 (m, 1H), 3.47-3.71 (m, 2H), 3.98-4.70 (m, 4H).
Example 8: (2S, 4S, 5S ) -N 2 - ( cyanomethyl) -N ² - ethyl ^{-N 4,} N ^4, 5- trimethyl-2,4-Pyrrolidinedicarboxamide 4- methylbenzenesulfonate

Toluenesulfonic acid hydrate (170 mg) was added to a solution of the compound prepared in Example 7 (273 mg) in 2-propanol (1 mL), and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated, the residue was washed with hexane, and the residue was dried to give the title compound (322 mg) having the following physical data.
TLC: Rf 0.29 (methylene chloride: methanol = 8: 2);
¹ H-NMR (DMSO-d ₆ ): δ 1.11-1.21 (m, 6H), 2.02-2.18 (m, 1H), 2.28 (s, 3H), 2.53-2.75 (m, 1H), 2.83 (s, 3H), 3.00 (s, 3H), 3.32-3.53 (m, 2H), 3.57-3.74 (m, 1H), 3.80-4.03 (m, 1H), 4.32-4.80 (m, 3H), 7.11 (d, 2H), 7.48 (d, 2H), 8.03-8.25 (m, 1H), 9.53-9.69 (m, 1H).
Example 8 (1) to Example 8 (14)
Using the corresponding compound instead of (ethylamino) acetonitrile, the following compounds of the present invention were obtained in the same manner as in the method shown in Example 7 → Example 8.
Example 8 (1) :( 2S, 4S , 5S) -N 2 - ( ^{cyanomethyl) -N 2, N 4, N} 4, 5- tetramethyl-2,4-Pyrrolidinedicarboxamide 4- methylbenzenesulfonate
TLC: Rf 0.50 (methylene chloride: methanol = 5: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.15 (d, 3H), 2.02-2.17 (m, 1H), 2.28 (s, 3H), 2.56-2.71 (m, 1H), 2.83 (s, 3H) , 3.00 (s, 3H), 3.06 (s, 3H), 3.56-3.68 (m, 1H), 3.81-3.95 (m, 1H), 4.39 (d, 1H), 4.56 (d, 1H), 4.63-4.76 (m, 1H), 7.11 (d, 2H), 7.47 (d, 2H), 8.04-8.22 (m, 1H), 9.57-9.71 (m, 1H).
Same methanesulfonate
TLC: Rf 0.29 (dichloromethane: methanol = 5: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.15 (d, 3H), 2.03-2.18 (m, 1H), 2.32 (s, 3H), 2.56-2.73 (m, 1H), 2.83 (s, 3H) , 2.96-3.10 (m, 3H), 3.01 (s, 3H), 3.54-3.73 (m, 1H), 3.82-3.97 (m, 1H), 4.39 (d, 1H), 4.56 (d, 1H), 4.60 -4.78 (m, 1H), 8.00-8.21 (m, 1H), 9.59-9.75 (m, 1H).
Example 8 (2) :( 2S, 4S , 5S) -N 2 - ( cyanomethyl) -N ² - isopropyl ^{-N 4,} N ^4, 5- trimethyl-2,4-Pyrrolidinedicarboxamide 4- methylbenzenesulfonate
TLC: Rf 0.58 (methylene chloride: methanol = 5: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.11-1.27 (m, 9H), 2.02-2.15 (m, 1H), 2.28 (s, 3H), 2.53-2.67 (m, 1H), 2.84 (s, 3H), 3.00 (s, 3H), 3.57-3.69 (m, 1H), 3.82-4.13 (m, 2H), 4.37 (s, 2H), 4.69-4.81 (m, 1H), 7.11 (d, 2H) , 7.47 (d, 2H), 8.10-8.24 (m, 1H), 9.49-9.64 (m, 1H).
Example 8 (3) :( 2S, 4S , 5S) -N 2 - ( cyanomethyl) ^-N 2 - (2- ^{methoxyethyl)} -N ^4, N ^4, 5- trimethyl-2,4-Pyrrolidinedicarboxamide 4 -Methylbenzenesulfonate
TLC: Rf 0.25 (chloroform: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 9.65 (m, 1H), 8.15 (m, 1H), 7.46 (m, 2H), 7.10 (brd, 2H), 4.65 (m, 1H), 4.48 (d , 1H), 4.37 (d, 1H), 3.90 (m, 1H), 3.69-3.55 (m, 5H), 3.28 (s, 3H), 3.00 (s, 3H), 2.84 (s, 3H), 2.62 ( m, 1H), 2.28 (s, 3H), 2.10 (m, 1H), 1.16 (d, 3H).
Example 8 (4) :( 2S, 4S , 5S) -N 2 - butyl -N ² - ^{(cyanomethyl)} -N ^4, N ^4, 5- trimethyl-2,4-Pyrrolidinedicarboxamide 4- methylbenzenesulfonate
TLC: Rf 0.43 (methylene chloride: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 0.91 (t, 3H), 1.16 (d, 3H), 1.23-1.39 (m, 2H), 1.39-1.74 (m, 2H), 1.94-2.20 (m, 1H), 2.28 (s, 3H), 2.52-2.73 (m, 1H), 2.84 (s, 3H), 3.01 (s, 3H), 3.24-3.73 (m, 3H), 3.82-4.01 (m, 1H) 4.27-4.81 (m, 3H), 7.11 (d, 2H), 7.47 (d, 2H), 7.98-8.38 (m, 1H), 9.48-9.78 (m, 1H).
Example 8 (5) :( 2S, 4S , 5S) -N 2, N 2 - bis ^{(cyanomethyl)} -N ^4, N ^4, 5- trimethyl-2,4-Pyrrolidinedicarboxamide 4- methylbenzenesulfonate
TLC: Rf 0.32 (methylene chloride: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.15 (d, 3H), 2.06-2.24 (m, 1H), 2.28 (s, 3H), 2.55-2.76 (m, 1H), 2.84 (s, 3H) , 3.01 (s, 3H), 3.55-3.68 (m, 1H), 3.80-4.01 (m, 1H), 4.38-4.93 (m, 5H), 7.10 (d, 2H), 7.47 (d, 2H), 8.13 -8.48 (m, 1H), 9.57-9.82 (m, 1H).
Example 8 (6) :( 2S, 4S , 5S) -N 2 - ( ^cyanomethyl) -N ^4, N ^4, 5- trimethyl-2,4-Pyrrolidinedicarboxamide 4- methylbenzenesulfonate
TLC: Rf 0.33 (methylene chloride: methanol = 8: 2);
¹ H-NMR (DMSO-d ₆ ): δ 1.11 (d, 3H), 2.13-2.27 (m, 1H), 2.28 (s, 3H), 2.39-2.48 (m, 1H), 2.83 (s, 3H) , 2.99 (s, 3H), 3.57-3.68 (m, 1H), 3.86-4.00 (m, 1H), 4.18-4.35 (m, 3H) 7.11 (d, 2H), 7.47 (d, 2H), 8.23- 8.39 (m, 1H), 9.16 (t, 1H), 9.59 (s, 1H).
Example 8 (7) :( 2S, 4S , 5S) -N 2 - ( cyanomethyl) -N ² - cyclopropyl ^{-N 4,} N ^4, 5- tri-methylpyrrolidine-2,4-dicarboxamide 4-methylbenzenesulfonate Naruto
TLC: Rf 0.42 (methylene chloride: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 0.83-1.06 (m, 4H), 1.15 (d, 3H), 2.18-2.34 (m, 1H), 2.28 (s, 3H), 2.58-2.73 (m, 1H), 2.81-2.94 (m, 1H), 2.84 (s, 3H), 3.01 (s, 3H), 3.59-3.74 (m, 1H), 3.90-4.05 (m, 1H), 4.35-4.54 (m, 2H), 4.72-4.84 (m, 1H), 7.11 (d, 2H), 7.47 (d, 2H), 8.07-8.31 (m, 1H), 9.33-9.64 (m, 1H).
Example 8 (8) :( 2S, 4S , 5S) -N 2 - ( ^cyanomethyl) -N ^4, N ^4, 5- trimethyl -N ² - prop-2-yn-1-ylpyrrolidin-2,4 Dicarboxamide 4-methylbenzenesulfonate
TLC: Rf 0.44 (methylene chloride: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.15 (d, 3H), 2.04-2.26 (m, 1H), 2.28 (s, 3H), 2.57-2.77 (m, 1H), 2.84 (s, 3H) , 3.01 (s, 3H), 3.36-3.71 (m, 2H), 3.83-3.97 (m, 1H), 4.21-4.84 (m, 5H), 7.11 (d, 2H), 7.47 (d, 2H), 8.10 -8.35 (m, 1H), 9.58-9.79 (m, 1H).
Example 8 (9) :( 2S, 4S , 5S) -N 2 - ( ^cyanomethyl) -N ^4, N ^4, 5- trimethyl -N ² - (phenylmethyl) pyrrolidine-2,4-dicarboxamide 4-methyl Benzenesulfonate
TLC: Rf 0.51 (methylene chloride: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.18 (d, 3H), 2.07-2.23 (m, 1H), 2.28 (s, 3H), 2.51-2.77 (m, 1H), 2.80-2.88 (m, 3H), 2.96-3.04 (m, 3H), 3.55-3.73 (m, 1H), 3.85-4.03 (m, 1H), 4.26 (d, 1H), 4.45 (d, 1H), 4.50-4.87 (m, 3H), 7.10 (d, 2H), 7.27-7.45 (m, 5H), 7.47 (d, 2H), 8.19-8.36 (m, 1H), 9.54-9.77 (m, 1H).
Example 8 (10) :( 2S, 4S ) -N 2 - ( ^{cyanomethyl) -N 2, N 4, N} 4 - trimethyl-2,4-Pyrrolidinedicarboxamide 4- methylbenzenesulfonate
TLC: Rf 0.24 (methylene chloride; methanol = 8: 2);
¹ H-NMR (DMSO-d ₆ ): δ 1.70-1.85 (m, 1H), 2.28 (s, 3H), 2.69-2.79 (m, 1H), 2.82 (s, 3H), 3.00 (s, 3H) , 3.09 (s, 3H), 3.28-3.61 (m, 3H), 4.39 (d, 1H), 4.55 (d, 1H), 4.63-4.78 (m, 1H), 7.10 (d, 2H), 7.47 (d , 2H), 8.65-8.88 (m, 1H), 9.26-9.57 (m, 1H).
Example 8 (11) :( 2S, 4S ) -N 2 - ( cyanomethyl) -N ² - ethyl ^{-N 4, N} 4 - dimethyl-2,4-Pyrrolidinedicarboxamide 4- methylbenzenesulfonate
TLC: Rf 0.40 (methylene chloride: methanol = 8: 2);
¹ H-NMR (DMSO-d ₆ ): δ 1.18 (t, 3H), 1.69-1.84 (m, 1H), 2.28 (s, 3H), 2.64-2.80 (m, 1H), 2.82 (s, 3H) , 3.00 (s, 3H), 3.30-3.61 (m, 5H), 4.39 (d, 1H), 4.49 (d, 1H), 4.58-4.75 (m, 1H), 7.10 (d, 2H), 7.47 (d , 2H), 8.66-8.89 (m, 1H), 9.21-9.47 (m, 1H).
Example 8 (12) :( 2S, 4S , 5S) -N 2 - ( ^cyanomethyl) -N ^4, N ^4, 5- trimethyl -N ² - propyl-2,4-Pyrrolidinedicarboxamide 4- methylbenzenesulfonate
TLC: Rf: 0.53 (chloroform: methanol = 4: 1);
¹ H-NMR (DMSO-d ₆ ): δ 9.57-9.74 (m, 1H), 8.08-8.23 (m, 1H), 7.48 (d, 2H), 7.11 (d, 2H), 4.59-4.78 (m, 1H), 4.31-4.63 (m, 2H), 3.85-3.97 (m, 1H), 3.59-3.72 (m, 1H), 3.32 (t, 2H), 3.00 (s, 3H), 2.83 (s, 3H) , 2.55-2.72 (m, 1H), 2.28 (s, 3H), 2.01-2.17 (m, 1H), 1.46-1.77 (m, 2H), 1.16 (d, 3H), 0.83-0.93 (m, 3H) .
Example 8 (13) :( 2S, 4S , 5S) -N 2 - allyl -N ² - ^{(cyanomethyl)} -N ^4, N ^4, 5- trimethyl-2,4-Pyrrolidinedicarboxamide 4- methylbenzenesulfonate
TLC: Rf 0.57 (chloroform: methanol = 4: 1);
¹ H-NMR (DMSO-d ₆ ): δ 9.58-9.76 (m, 1H), 8.12-8.26 (m, 1H), 7.47 (d, 2H), 7.11 (d, 2H), 5.73-5.96 (m, 1H), 5.22-5.39 (m, 2H), 4.59-4.76 (m, 1H), 4.21-4.53 (m, 2H), 3.96-4.17 (m, 2H), 3.84-3.95 (m, 1H), 3.56- 3.70 (m, 1H), 3.00 (s, 3H), 2.83 (s, 3H), 2.53-2.69 (m, 1H), 2.28 (s, 3H), 1.99-2.19 (m, 1H), 1.16 (d, 3H).
Example 8 (14) :( 2S, 4S , 5S) -N 2 - ( ^cyanomethyl) -N ^4, N ^4, 5- trimethyl ^-N 2 - (2,2,2-trifluoroethyl) 2,4 -Pyrrolidine dicarboxamide 4-methylbenzenesulfonate
TLC: Rf 0.53 (chloroform: methanol = 4: 1);
¹ H-NMR (DMSO-d ₆ ): δ 9.65-9.81 (m, 1H), 8.26-8.39 (m, 1H), 7.46 (d, 2H), 7.10 (d, 2H), 4.25-4.96 (m, 5H), 3.87-4.00 (m, 1H), 3.54-3.70 (m, 1H), 3.01 (s, 3H), 2.84 (s, 3H), 2.57-2.77 (m, 1H), 2.28 (s, 3H) , 2.07-2.22 (m, 1H), 1.08-1.30 (m, 3H).
Example 9: 1- (1,1-dimethylethyl) 2-methyl (2S ^* , 4S ^* , 5S ^* )-4-((dimethylamino) carbonyl) -5-ethylpyrrolidine-1,2-dicarboxylate Tetrahydrofuran (150 mL) and triethylamine (4.2 mL) were added to glycine methyl ester / hydrochloride (3.77 g), propanal (1.74 g) and magnesium sulfate (30 g), and the mixture was stirred at room temperature for 1.5 hours. . Further, N, N-dimethylacrylamide (5.95 g), lithium bromide (2.61 g) and triethylamine (4.2 mL) were added, and after stirring at room temperature for 17 hours, bis (1,1-dimethylethyl) dicarbonate (6 .54 g) was added and stirred for 2 hours. The reaction mixture was extracted with ethyl acetate and ice water. The organic layer was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 50-0: 100) to give the title compound (612 mg) having the following physical data.
TLC: Rf 0.51 (ethyl acetate);
¹ H-NMR (CDCl ₃ ): δ 0.86-0.98 (m, 3H), 1.33-1.72 (m, 11H), 2.24-2.40 (m, 1H), 2.51-2.74 (m, 1H), 2.95 (s, 3H), 3.05-3.27 (m, 4H), 3.46-3.77 (m, 3H), 3.63-4.09 (m, 1H), 4.13-4.32 (m, 1H).
Example 10 (1) to Example 10 (7)
Using the compound produced in Example 9 or the compound produced by the same methodology, the present invention was subjected to the same operation as the method shown in Example 6 → Example 7 → Example 8 and had the following physical property values. A compound was obtained.
Example ^{10 (1) :( 2S *,} 4S *, 5S *) -N 2 - ( cyanomethyl) -5-ethyl ^{-N 2, N 4, N 4} - trimethyl-2,4-Pyrrolidinedicarboxamide 4-methyl Benzenesulfonate
TLC: Rf 0.38 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 0.91 (t, 3H), 1.45-1.77 (m, 2H), 1.94-2.08 (m, 1H), 2.28 (s, 3H), 2.61-2.78 (m, 1H), 2.82 (s, 3H), 2.95-3.10 (m, 6H), 3.51-3.62 (m, 1H), 3.64-3.75 (m, 1H), 4.29-4.84 (m, 3H), 7.10 (d, 2H), 7.47 (d, 2H), 7.78-8.18 (m, 1H), 9.61-9.88 (m, 1H).
Example ^{10 (2) :( 2S *,} 4S *, 5S *) -N 2 - ( cyanomethyl) ^-N 2, 5-diethyl ^{-N 4, N} 4 - dimethyl-2,4-Pyrrolidinedicarboxamide 4-methyl Benzenesulfonate
TLC: Rf 0.44 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 0.91 (t, 3H), 1.17 (t, 3H), 1.44-1.78 (m, 2H), 1.91-2.06 (m, 1H), 2.24-2.31 (m, 3H), 2.59-2.77 (m, 1H), 2.83 (s, 3H), 3.02 (s, 3H), 3.34-3.50 (m, 2H), 3.52-3.65 (m, 1H), 3.66-3.80 (m, 1H), 4.31-4.77 (m, 3H), 7.11 (d, 2H), 7.47 (d, 2H), 7.93-8.18 (m, 1H), 9.63-9.80 (m, 1H).
Example ^{10 (3) :( 2S *,} 4S *, 5R *) -N 2 - ( cyanomethyl) -N ² - ethyl ^-N 4, ^{N 4} - dimethyl-5 - ((methyloxy) methyl) -2, 4-Pyrrolidinedicarboxamide 4-Methylbenzenesulfonate
TLC: Rf 0.43 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.18 (t, 3H), 2.01-2.17 (m, 1H), 2.28 (s, 3H), 2.56-2.70 (m, 1H), 2.83 (s, 3H) , 3.00 (s, 3H), 3.27 (s, 3H), 3.32-3.61 (m, 4H), 3.64-3.78 (m, 1H), 3.82-4.03 (m, 1H), 4.28-4.58 (m, 2H) , 4.58-4.77 (m, 1H), 7.10 (d, 2H), 7.46 (d, 2H), 8.07-8.50 (m, 1H), 9.61-10.11 (m, 1H).
Example ^{10 (4) :( 2S *,} 4S *, 5R *) -N 2 - ( ^{cyanomethyl) -N 2, N 4, N} 4 - trimethyl -5 - ((phenyl) methyl) -2,4 Pyrrolidine dicarboxamide 4-methylbenzenesulfonate
TLC: Rf 0.24 (chloroform: methanol = 10: 1);
¹ H-NMR (DMSO-d ₆ ): δ 10.09 (s, 1H), 8.57 (s, 1H), 7.47 (d, 2H), 7.32 (dd, 2H), 7.10 (d, 2H), 6.98 (t , 1H), 6.89 (d, 2H), 4.75-4.81 (m, 1H), 4.57 (d, 1H), 4.41 (d, 1H), 4.23-4.30 (m, 1H), 4.14-4.20 (m, 1H ), 4.05-4.12 (m, 1H), 3.78-3.85 (m, 1H), 3.09 (s, 3H), 3.04 (s, 3H), 2.80 (s, 3H), 2.67-2.78 (m, 1H), 2.28 (s, 3H), 2.09-2.22 (m, 1H).
Example ^{10 (5) :( 2S *,} 4S *, 5R *) -N 2 - ( cyanomethyl) -N ² - ethyl ^-N 4, ^{N 4} - dimethyl-5 - ((phenyl) methyl) -2, 4-Pyrrolidinedicarboxamide 4-Methylbenzenesulfonate
TLC: Rf 0.24 (chloroform: methanol = 10: 1);
¹ H-NMR (DMSO-d ₆ ): δ 10.04 (s, 1H), 8.63 (s, 1H), 7.46 (d, 2H), 7.32 (dd, 2H), 7.10 (d, 2H), 6.98 ( t, 1H), 6.90 (d, 2H), 4.71-4.77 (m, 1H), 4.52 (d, 1H), 4.40 (d, 1H), 4.26-4.32 (m, 1H), 4.15-4.20 (m, 1H), 4.09 (dd, 1H), 3.78-3.87 (m, 1H), 3.45-3.50 (m, 2H), 3.04 (s, 3H), 2.81 (s, 3H), 2.65-2.75 (m, 1H) , 2.28 (s, 3H), 2.09-2.19 (m, 1H), 1.20 (t, 3H).
Example ^{10 (6) :( 2S *,} 4S *, 5S *) -N 2 - ( cyanomethyl) -5-cyclopropyl ^{-N 2, N 4, N 4} - trimethyl-2,4-Pyrrolidinedicarboxamide 4- Methylbenzenesulfonate
TLC: Rf 0.40 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 0.30-0.46 (m, 2H), 0.47-0.66 (m, 2H), 0.87-1.01 (m, 1H), 2.10-2.24 (m, 1H), 2.28 ( s, 3H), 2.56-2.71 (m, 1H), 2.84 (s, 3H), 2.93-3.01 (m, 1H), 3.03 (s, 3H), 3.07 (s, 3H), 3.63-3.82 (m, 1H), 4.27-4.81 (m, 3H), 7.11 (d, 2H), 7.47 (d, 2H), 8.19-8.42 (m, 1H), 9.67-9.97 (m, 1H).
Example ^{10 (7) :( 2S *,} 4S *, 5S *) -N 2 - ( cyanomethyl) -5-cyclopropyl--N ² - ethyl ^{-N 4, N} 4 - dimethyl-2,4-Pyrrolidinedicarboxamide 4-methylbenzenesulfonate
TLC: Rf 0.45 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 0.30-0.45 (m, 2H), 0.48-0.64 (m, 2H), 0.88-1.04 (m, 1H), 1.17 (t, 3H), 2.08-2.24 ( m, 1H), 2.28 (s, 3H), 2.57-2.73 (m, 1H), 2.85 (s, 3H), 2.94-3.07 (m, 1H), 3.03 (s, 3H), 3.36-3.52 (m, 2H), 3.66-3.78 (m, 1H), 4.34-4.75 (m, 3H), 7.11 (d, 2H), 7.47 (d, 2H), 8.25-8.48 (m, 1H), 9.69-9.92 (m, 1H).
Biological examples
Experimental Example 1 DPP4 Activity Inhibition Experiment A DPP4 activity inhibition experiment was performed according to the following method. DPP4 was roughly purified from human plasma by ammonium sulfate fractionation, weak anion exchange chromatography, strong cation exchange chromatography, and gel filtration chromatography. A substrate 60 μM Gly-Pro-MC (glycylprolyl-7-amido-4-methylcoumarin) aqueous solution (50 μL), the compound of the present invention (10 μL) and distilled water (20 μL) were mixed, and then 0.5 M Tris-HCl buffer (PH 7.4; 10 μL) and enzyme solution (10 μL) were added to start the enzyme reaction. Using a fluorescent plate reader (Fmax; manufactured by Molecular Devices), the change in fluorescence intensity at 460 nm when excited at 355 nm was measured for 15 minutes, the initial velocity was calculated, and DPP4 activity was obtained. The compound of the present invention was dissolved in DMSO to 10 mM, diluted to 1 mM with distilled water, and further diluted with a 10% DMSO solution (final concentration: compound: 10 μM, DMSO 1%). From the reaction rate V _{c in the} presence of the solvent and the reaction rate V in the presence of the compound of the present invention, the DPP4 activity inhibition rate (%) was determined by the following formula.
Inhibition rate (%) = (1−V / V _c ) × 100
V: Reaction rate in the presence of the compound of the present invention (RFU / min)
V _c : reaction rate in the presence of 1% DMSO solution (RFU / min)
The IC ₅₀ value was calculated according to the following formula after determining the slope (a) and intercept (b) of the regression line from the concentration and inhibition rate of the compound of the present invention at two points across the inhibition rate of 50%.
y = a × ln (x) + b
(X: concentration of the compound of the present invention (μM), y: inhibition rate (%))
IC ₅₀ = e ^{[(50−b) / a]}
As a result, the compound of the present invention showed DPP4 inhibitory activity. For example, the IC ₅₀ value of the compound of Example 8 was 24.6 nM. Therefore, the compound of the present invention is useful as a therapeutic agent for type 2 diabetes.
Experimental Example 2 Plasma DPP4-like activity inhibition experiment Plasma containing DPP4 was prepared by centrifuging blood of healthy volunteers or rats. The enzyme reaction was started by mixing 120 μM Gly-Pro-MC aqueous solution (25 μL) serving as a substrate, the compound of the present invention (10 μL) and distilled water (15 μL), and then adding plasma (50 μL). Using a fluorescence plate reader (Fmax; manufactured by Molecular Devices), the change in fluorescence intensity at 460 nm when excited at 355 nm was measured for 15 minutes, the initial velocity was calculated, and this was defined as plasma DPP4-like activity. The compound of the present invention was made into a 10 mM DMSO solution, diluted to 1 mM with distilled water, and further diluted with a 10% DMSO solution (final concentration: compound -100 μM, DMSO 1%). From the reaction rate V _{c in the} presence of the solvent and the reaction rate V in the presence of the compound of the present invention, the inhibition rate (%) of plasma DPP4-like activity was determined by the following formula.
Inhibition rate (%) = (1−V / V _c ) × 100
V: Reaction rate in the presence of the compound of the present invention (RFU / min)
V _c : reaction rate in the presence of solvent (RFU / min)
The IC ₅₀ value was calculated according to the following formula after determining the slope (a) and intercept (b) of the regression line from the concentration and inhibition rate of the compound of the present invention at two points across the inhibition rate of 50%.
y = a × ln (x) + b
(X: concentration of the present compound (μmol / L), y: inhibition rate (%))
IC ₅₀ = e ^{[(50−b) / a]}
As a result, the compound of the present invention inhibited plasma DPP4-like activity. For example, the IC ₅₀ value of the compound of Example 8 was 77.4 nM in human plasma and 67.6 nM in rat plasma. Therefore, the compound of the present invention is useful as a therapeutic agent for type 2 diabetes.
Experimental Example 3 SD rat (male, 6 to 10 weeks old) fasted from the day before the experimental test for inhibition of DPP4-like activity in plasma when orally administered to rats, and 0.5% methylcellulose distilled aqueous solution of the present compound was used. And was orally administered at a dose of 1 mg / kg.

Using a heparin-treated syringe, blood was collected from, for example, the subclavian vein before and after administration of the compound of the present invention, and plasma after centrifugation was prepared. Plasma (50 μL) and 60 μmol / L Gly-Pro-MC (50 μL) serving as a substrate were mixed to start an enzyme reaction. Using a fluorescence plate reader (Fmax; manufactured by Molecular Devices), the change in fluorescence intensity at 460 nm when excited at 355 nm was measured for 15 minutes, the initial velocity was calculated, and this was defined as DPP4-like activity. In addition, the DPP4-like activity inhibition rate (%) was determined from the following equation from the plasma reaction rate V _pre before administration of the compound of the present invention and the plasma reaction rate V _t after administration of the compound of the present invention.
Inhibition rate (%) = (1−V _t / V _pre ) × 100
V _pre : plasma reaction rate before administration of the compound of the present invention (RFU / min)
V _t : Plasma reaction rate after administration of the compound of the present invention (RFU / min)
As a result, it was revealed that the compound of the present invention inhibits plasma DPP4-like activity over a long period of time. For example, the compound of Example 8 showed 82% inhibition 6 hours after compound administration. Therefore, the compound of the present invention is useful as a long-lasting therapeutic drug for diabetes.
Experimental Example 4 Compound stability test compound (1 mg) was dissolved in Pharmacopeia 2 solution (pH 6.8) (1 mL) and heated to 40 ° C. 30 μL was collected from the solution over time and diluted with 20 mM phosphate buffer (270 μL). The obtained liquid was subjected to HPLC under the following conditions, the residual ratio of the compound was determined from the area ratio with respect to the initial value, and the half-life (T _1/2 ) was calculated.
HPLC conditions:
Equipment used: Agilent HPLC 1100
Column: YMC-Pack AM-303 (250 mm x 4.6 mm ID)
Solvent: 20 mM KH ₂ PO ₄ (pH 3.0) / CH ₃ CN = 95/5 → 50/50 (20 min)
Flow rate: 1.0 mL / min
Detection wavelength: UV 210nm
Temperature: 25 ° C
Injection volume: 10 μL
For example, the half life of the compound of Example 8 was 11 hours.

[Formulation example]
Formulation examples that can be used in the practice of the present invention are shown below.
Formulation Example 1
The following components were mixed by a conventional method and then tableted to obtain 10,000 tablets each containing 10 mg of active ingredient.
· (2S, 4S, 5S) -N 2 - ( cyanomethyl) -N ² - ethyl ^{-N 4,} N ^4, 5- trimethyl-2,4-Pyrrolidinedicarboxamide 4- methylbenzenesulfonate (100 g);
Carboxymethylcellulose calcium (disintegrant) (20 g);
Magnesium stearate (lubricant) (10 g);
-Microcrystalline cellulose (870 g).
Formulation Example 2
The following components were mixed by a conventional method, filtered through a dust filter, filled in 5 ml aliquots, and heat sterilized in an autoclave to obtain 10,000 ampoules containing 20 mg of active ingredient in one ampule.
· (2S, 4S, 5S) -N 2 - ( cyanomethyl) -N ² - ethyl ^{-N 4,} N ^4, 5- trimethyl-2,4-Pyrrolidinedicarboxamide 4- methylbenzenesulfonate (200 g);
・ Mannitol (2 kg);
-Distilled water for injection (50 L).

  The present invention can be applied to the following pharmaceutical products.

Since the compound of the present invention has DPP4 inhibitory activity, for example, diabetes (especially type 2 diabetes etc.), obesity, schizophrenia, depression, anxiety, epilepsy, stress disease, pain (pain etc.), autoimmune disease (Rheumatoid arthritis, type 1 diabetes, etc.), allergic diseases (asthma, food allergy, etc.), cancer, cancer metastasis, HIV infection, anemia, thrombocytopenia, skin diseases (psoriasis, lichen planus, etc.), prostatic hypertrophy, high fat Treatment and / or prophylaxis of blood pressure, metabolic syndrome, diabetic complications, arteriosclerosis, impaired glucose tolerance, polycystic ovary syndrome, infertility, growth disorder, arthritis, transplant rejection, enteritis, wounds, etc. It is useful as an agent for preventing and / or improving blood glucose.

Claims (18)

Formula (I)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ each independently represents a hydrogen atom or a substituent, R ⁷ represents a substituent, R ⁸ represents a hydrogen atom or a nitrogen atom) Or n represents 0 or an integer of 1 to 4, and when n is 2 or more, a plurality of R ⁷ may be the same or different, and R ¹ and R ² are bonded. Together with the nitrogen atom to represent a 4-10 membered monocyclic or polycyclic heterocycle, R ¹ and R ^{3 taken} together form a 5-10 membered monocyclic or polycyclic ^May form a heterocycle, and R ⁵ and R ⁶ together with the carbon atom to which they are attached are C3-10 monocyclic or polycyclic carbocycles or 5-10 membered monocyclic or polycyclic Or a salt thereof, a solvate thereof, an N-oxide thereof, or Their prodrugs. The compound according to claim 1, wherein R ³ is a hydrogen atom or a C1-8 alkyl group which may have a substituent. The compound according to claim 1, wherein R ⁴ is a C1-8 alkyl group which may have a substituent. The compound according to claim 1, wherein R ⁵ and R ⁶ are each independently a hydrogen atom or a C 1-4 alkyl group. R ¹ and R ² are both optionally substituted C1-8 alkyl groups, or together with the nitrogen atom to which R ¹ and R ² are bonded, a 4-10 membered monocyclic or dicyclic The compound of claim 1 which represents a cyclic heterocycle. R ³ is a hydrogen atom or a C1-8 alkyl group which may have a substituent, R ⁴ is a C1-8 alkyl group which may have a substituent, and R ⁵ and R ⁶ are each The compound according to claim 1, which is independently a hydrogen atom or a C1-4 alkyl group. Formula (IA)

(Where symbol

Represents bonding to the front of the paper (β configuration), R ^3-A represents a hydrogen atom or a C1-8 alkyl group which may have a substituent, and R ^4-A represents a substituent. Represents an optionally substituted C1-8 alkyl group, R5 ^-A and R6 ^-A each independently represent a hydrogen atom or a C1-4 alkyl group, and the other symbols have the same meanings as defined in claim 1. Represents. The compound of Claim 1 which is a compound shown by this. (1) (2S, 4S, 5S) -N 2 - ( cyanomethyl) -N ² - ethyl ^{-N 4,} N ^4, 5- trimethyl-2,4-Pyrrolidinedicarboxamide and (2) (2S, 4S, 5S ) -N ² - ^{(cyanomethyl) -N 2, N 4, N} 4, compound of claim 1 wherein is selected from 5-tetramethyl-2,4-Pyrrolidinedicarboxamide. A pharmaceutical composition comprising the compound represented by formula (I) according to claim 1, a salt thereof, a solvate thereof, an N-oxide thereof or a prodrug thereof as an active ingredient. The pharmaceutical composition according to claim 9, which is a therapeutic and / or prophylactic agent for DPP4-mediated diseases. DPP4-mediated diseases are diabetes, obesity, schizophrenia, depression, anxiety, epilepsy, stress disease, pain, autoimmune disease, allergic disease, cancer, cancer metastasis, HIV infection, anemia, thrombocytopenia, skin disease, prostate 1 selected from the group consisting of hypertrophy, hyperlipidemia, metabolic syndrome, diabetic complications, arteriosclerosis, impaired glucose tolerance, polycystic ovary syndrome, infertility, growth disorders, arthritis, transplant rejection, enteritis and wounds The pharmaceutical composition according to claim 10, which is a species or more. The pharmaceutical composition according to claim 9, which is an agent for preventing and / or improving postprandial hyperglycemia. The pharmaceutical composition according to claim 10, which is a DPP4 inhibitor. A compound represented by the general formula (I) according to claim 1, a salt thereof, a solvate thereof, an N-oxide thereof or a prodrug thereof, a sulfonylurea, a biguanide, an α-glucosidase inhibitor, an insulin secretagogues, insulin sensitizers, insulin preparations, PPAR agonists, beta ₃ adrenergic receptor agonists, aldose reductase inhibitors, DPP4 inhibitors, AMP kinase activator, type 1 11β- hydroxysteroid dehydrogenase inhibitors, A medicament comprising a combination of one or more selected from the group consisting of lipase inhibitors and appetite suppressants. A DPP4-mediated method comprising administering to a mammal an effective amount of a compound represented by the general formula (I) according to claim 1, a salt thereof, a solvate thereof, an N-oxide thereof or a prodrug thereof. For the treatment and / or prevention of sexually transmitted diseases. A method for inhibiting DPP4, comprising administering an effective amount of a compound represented by the general formula (I) according to claim 1, a salt thereof, a solvate thereof, an N-oxide thereof or a prodrug thereof to a mammal. . A compound of the general formula (I) according to claim 1, a salt thereof, a solvate thereof, an N-oxide thereof or a prodrug thereof for producing a therapeutic and / or prophylactic agent for DPP4-mediated diseases use. Use of the compound represented by formula (I) according to claim 1, a salt thereof, a solvate thereof, an N-oxide thereof or a prodrug thereof for producing a DPP4 inhibitor.