Combination drug

1 . A pharmaceutical agent comprising a dipeptidyl peptidase IV inhibitor and a biguanide agent in combination.

2 . The pharmaceutical agent according to claim 1 , which enhances the effects of active circulating glucagon-like peptide-1 (GLP-1) and/or active circulating glucagon-like peptide-2 (GLP-2).

3 . A pharmaceutical agent that enhances the effects of active circulating GLP-2.

4 . A pharmaceutical agent comprising a dipeptidyl peptidase IV inhibitor and the pharmaceutical agent according to claim 3 in combination.

5 . The pharmaceutical agent according to claim 1 or 4 , wherein the dipeptidyl peptidase IV inhibitor is a compound represented by the following formula, or a salt or hydrate thereof,

(wherein,

T 1 represents a monocyclic or bicyclic 4- to 12-membered heterocyclic group containing one or two nitrogen atoms in the ring, that may have one or more substituents;

X represents a C 1-6 alkyl group which may have one or more substituents, a C 2-6 alkenyl group which may have one or more substituents, a C 2-6 alkynyl group which may have one or more substituents, a C 6-10 aryl group which may have one or more substituents, a 5 to 10-membered heteroaryl group which may have one or more substituents, a C 6-10 aryl C 1-6 alkyl group which may have one or more substituents, or a 5 to 10-membered heteroaryl C 1-6 alkyl group which may have one or more substituents;

Z 1 and Z 2 each independently represent a nitrogen atom or a group represented by the formula —CR 2 ═;

R 1 and R 2 each independently represent a group according to the formula -A 0 -A 1 -A 2 (wherein

A 0 represents a single bond or a C 1-6 alkylene group, which may have 1 to 3 substituents selected from group B consisting of the substituents described below;

A 1 represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group represented by the formula —O—CO—, a group represented by the formula —CO—O—, a group represented by the formula —NR A —, a group represented by the formula —CO—NR A —, a group represented by the formula —NR A —CO—, a group represented by the formula —SO 2 —NR A —, or a group represented by the formula —NR A —SO 2 —;

A 2 and R A each independently represent a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, C 6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic group, a 5 to 10-membered heteroaryl C 1-6 alkyl group, a C 6-10 aryl C 1-6 alkyl group, or a C 2-7 alkylcarbonyl group;

however, A 2 and R A each independently may have 1 to 3 substituents selected from the substituent group B described below:

when Z 2 is a group represented by the formula —CR 2 ═, R 1 , and R 2 may in combination form a 5 to 7-membered ring;

except in cases where: [1] R 1 is a hydrogen atom; Z 1 is a nitrogen atom; and Z 2 is —CH═;

and [2] Z 1 is a nitrogen atom; and Z 2 is —C(OH)═;

<Substituent group B>

Substituent group B represents the group consisting of: a hydroxyl group, a mercapto group, a cyano group, a nitro group, a halogen atom, a trifluoromethyl group, a C 1-6 alkyl group which may have one or more substituents, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a group represented by the formula —SO 2 —NR B1 —R B2 , a group represented by the formula —NR B1 COR B2 , a group represented by the formula —NR B1 —R B2 (where R B1 and R B2 each independently represent a hydrogen atom or a C 1-6 alkyl group), a group represented by the formula —CO—R B3 (where R B3 represents a 4 to 8-membered heterocyclic group), a group represented by the formula —CO—R B4 —R B5 and a group represented by the formula —CH 2 —CO—R B4 —R B5 (where R B4 represents a single bond, an oxygen atom, or a group represented by the formula —NR B6 —; R B5 and R B6 each independently represent a hydrogen atom, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic C 1-6 alkyl group, a C 6-10 aryl C 16 alkyl group, or a 5 to 10-membered heteroaryl C 1-6 alkyl group)).

6 . The pharmaceutical agent according to claim 5 , wherein T 1 is a piperazin-1-yl group or a 3-amino-piperidin-1-yl group.

7 . The pharmaceutical agent according to claim 5 , wherein T 1 is a piperazin-1-yl group.

8 . The pharmaceutical agent according to claim 5 , wherein X is a 3-methyl-2-buten-1-yl group, a 2-butynyl group, a benzyl group, or a 2-chlorophenyl group.

9 . The pharmaceutical agent according to claim 5 , wherein X is a 2-butynyl group.

10 . The pharmaceutical agent according to claim 5 ,

wherein,

Z 1 is a nitrogen atom; and

Z 2 is a group represented by the formula —CR 2 ═.

11 . The pharmaceutical agent according to claim 5 ,

wherein,

Z 2 is a nitrogen atom; and

Z 1 is a group represented by the formula —CR 2 ═.

12 . The pharmaceutical agent according to claim 5 , wherein R 1 is either a methyl group, a cyanobenzyl group, a fluorocyanobenzyl group, a phenethyl group, a 2-methoxyethyl group, or a 4-methoxycarbonylpridin-2-yl group.

13 . The pharmaceutical agent according to claim 5 , wherein R 1 is a methyl group, or a 2-cyanobenzyl group.

14 . The pharmaceutical agent according to claim 5 , wherein R 2 is either a hydrogen atom, a cyano group, a methoxy group, a carbamoylphenyloxy group, or a group represented by the formula:

(where,

A 27 represents an oxygen atom, a sulfur atom, or —NH—;

A 28 and A 29 each independently represent a hydrogen atom or a C 1-6 alkyl group).

15 . The pharmaceutical agent according to claim 5 , wherein R 2 is a hydrogen atom, a cyano group, or a 2-carbamoylphenyloxy group.

16 . The pharmaceutical agent according to claim 5 , wherein the compound represented by formula (I) is any one compound selected from:

(1) 7-(2-butynyl)-2-cyano-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurine-6-one;

(2) 3-(2-butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]pyridazin-4-one;

(3) 2-(3-aminopiperidin-1-yl)-3-(2-butynyl)-5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one;

(4) 2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purine-2-yloxy]benzamide;

(5) 7-(2-butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purine-2-carbonitrile; and

(6) 2-[3-(2-butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridazin-5-ylmethyl]benzonitrile; or a salt or hydrate thereof.

17 . The pharmaceutical agent according to claim 1 or 4 , wherein the dipeptidyl peptidase IV inhibitor is a compound represented by the following formula, or a salt or hydrate thereof,

(wherein

T 1 represents a monocyclic or bicyclic 4- to 12-membered heterocyclic group containing one or two nitrogen atoms in the ring, that may have one or more substituents;

X represents a C 1-6 alkyl group which may have one or more substituents, a C 2-6 alkenyl group which may have one or more substituents, a C 2-6 alkynyl group which may have one or more substituents, a C 6-10 aryl group which may have one or more substituents, a 5 to 10-membered heteroaryl group which may have one or more substituents, a C 6-10 aryl C 1-6 alkyl group which may have one or more substituents, or a 5 to 10-membered heteroaryl C 1-6 alkyl group which may have one or more substituents;

R 1 and R 2 each independently represent a group according to the formula -A 0 -A 1 -A 2

(wherein

A 0 represents a single bond or a C 1-6 alkylene group, which may have 1 to 3 substituents selected from group B consisting of the substituents described below;

A 1 represents a single bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group represented by the formula —O—CO—, a group represented by the formula —CO—O—, a group represented by the formula —NR A —, a group represented by the formula —CO—NR A —, a group represented by the formula —NR A —CO—, a group represented by the formula —SO 2 —NR A —, or a group represented by the formula —NR A SO 2 —;

A 2 and R A each independently represent a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, C 6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic group, a 5 to 10-membered heteroaryl C 1-6 alkyl group, a C 6-10 aryl C 1-6 alkyl group, or a C 2-7 alkylcarbonyl group;

however, A 2 and R A each independently may have 1 to 3 substituents selected from the substituent group B described below:

<Substituent group B>

Substituent group B represents the group consisting of: a hydroxyl group, a mercapto group, a cyano group, a nitro group, a halogen atom, a trifluoromethyl group, a C 1-6 alkyl group which may have one or more substituents, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a group represented by the formula —SO 2 —NR B1 —R B2 , a group represented by the formula —NR B1 —CO—R B2 , a group represented by the formula —NR B1 —R B2 (where R B1 and R B2 each independently represent a hydrogen atom or a C 1-6 alkyl group), a group represented by the formula —CO—R B3 (where R B3 represents a 4 to 8-membered heterocyclic group), a group represented by the formula —CO—R B4 R B5 and a group represented by the formula —CH 2 —CO—R B4 —R B5 (where R B4 represents a single bond, an oxygen atom, or a group represented by the formula —NR B6 —; R B5 and R B6 each independently represent a hydrogen atom, a C 1-6 -alkyl group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic C 1-6 alkyl group, a C 6-10 aryl C 16 alkyl group, or a 5 to 10-membered heteroaryl C 1-6 alkyl group)).

18 . The pharmaceutical agent according to claim 17 , wherein T 1 is a piperazin-1-yl group.

19 . The pharmaceutical agent according to claim 17 , wherein X is a 2-butynyl group or a 2-chlorophenyl group.

20 . The pharmaceutical agent according to claim 17 , wherein X is a 2-butynyl group.

21 . The pharmaceutical agent according to claim 17 , wherein R 1 is a hydrogen atom, a methyl group, a 2-propynyl group, a 2-butynyl group, a cyanomethyl group, a phenethyl group, a phenoxyethyl group, or a group represented by the formula:

(where R 3 represents a hydroxyl group, a C 1-6 alkoxy group, or a phenyl group).

22 . The pharmaceutical agent according to claim 17 , wherein R 2 is a hydrogen atom, a C 1-6 alkyl group, an ethoxyethyl group, a tetrahydrofuranylmethyl group, or a group represented by the formula:

(where,

R 4 and R 5 are identical to or different from each other, and independently represent a hydrogen atom, a methyl group, or a phenyl group; and

R 6 represents a hydroxyl group, a C 1-6 alkoxy group, or a phenyl group), or a group represented by the formula:

23 . The pharmaceutical agent according to claim 17 , wherein the compound represented by formula (II) is any one compound selected from:

(1) 7-(2-butynyl)-1,3-dimethyl-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione;

(2) 7-(2-butynyl)-3-methyl-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione;

(3) methyl[7-(2-butynyl)-3-methyl-2,6-dioxo-8-(piperazin-1-yl)-2,3,6,7-tetrahydropurin-1-yl]acetate;

(4) 7-(2-butynyl)-3-methyl-8-(piperazin-1-yl)-1-(2-propynyl)-3,7-dihydropurine-2,6-dione;

(5) 1,7-bis(2-butynyl)-3-methyl-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione;

(6) [7-(2-butynyl)-3-methyl-2,6-dioxo-8-(piperazin-1-yl)-2,3,6,7-tetrahydropurin-1yl]acetonitrile;

(7) 7-(2-butynyl)-3-methyl-1-[(2-oxo-2-phenyl)ethyl]-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione;

(8) 7-(2-butynyl)-3-ethyl-1-methyl-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione;

(9) methyl[7-(2-butynyl)-1-methyl-2,6-dioxo-8-(piperazin-1-yl)-1,2,6,7-tetrahydropurin-3-yl]acetate;

(10) 7-(2-butynyl)-3-(2-tetrahydrofuranyl)methyl-1-methyl-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione;

(11) methyl[7-(2-butynyl)-1-methyl-2,6-dioxo-8-(piperazin-1-yl)-1,2,6,7-tetrahydropurin-3-yl]phenylacetate;

(12) 7-(2-butynyl)-3-propyl-1-methyl-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione;

(13) 7-(2-butynyl)-3-(2-oxo-2-phenethyl)-1-methyl-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione;

(14) ethyl2-[7-(2-butynyl)-1-methyl-2,6-dioxo-8-(piperazin-1-yl)-1,2,6,7-tetrahydropurin-3-yl]propionate;

(15) 7-(2-butynyl)-3-(2-ethoxyethyl)-1-methyl-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione;

(16) 7-(2-butynyl)-3-isopropyl-1-methyl-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione;

(17) 7-(2-butynyl)-3-(3,3-dimethyl-2-oxobutyl)-1-methyl-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione;

(18) 7-(2-butynyl)-1-methyl-3-(2-oxopyrrolidin-3-yl)-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione;

(19) 7-(2-butynyl)-3-(2-ethoxyethyl)-1-(2-oxo-2-phenylethyl)-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione;

(20) methyl[7-(2-butynyl)-2,6-dioxo-1-(2-oxo-2-phenylethyl)-8-(piperazin-1-yl)-1,2,6,7-tetrahydropurin-3-yl]acetate;

(21) ethyl[7-(2-butynyl)-2,6-dioxo-1-(2-phenethyl)-8-(piperazin-1-yl)-1,2,6,7-tetrahydropurin-3-yl]acetate;

(22) [7-(2-butynyl)-2,6-dioxo-1-(2-phenethyl)-8-(piperazin-1-yl)-1,2,6,7-tetrahydropurin-3-yl]acetate;

(23) 7-(2-butynyl)-3-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1-(2-phenethyl)-8-(piperazin-1-yl)-3,7-dihydropurine-2,6-dione;

(24) 2-[7-(2-butynyl)-2,6-dioxo-1-(2-phenethyl)-8-(piperazin-1-yl)-1,2,6,7-tetrahydropurin-3-yl]-N-methylacetamide;

(25) 2-[7-(2-butynyl)-2,6-dioxo-1-(2-phenethyl)-8-(piperazin-1-yl)-1,2,6,7-tetrahydropurin-3-yl]-N-cyclopropyl acetamide;

(26) 2-[7-(2-butynyl)-2,6-dioxo-1-(2-phenethyl)-8-(piperazin-1-yl)-1,2,6,7-tetrahydropurin-3-yl]-N-phenylacetamide; and

(27) 2-[7-(2-butynyl)-2,6-dioxo-1-(2-phenethyl)-8-(piperazin-1-yl)-1,2,6,7-tetrahydropurin-3-yl]-N-(2-propynyl) acetamide; or a salt or hydrate thereof.

24 . The pharmaceutical agent according to claim 1 , wherein the biguanide agent is metformin.

25 . The pharmaceutical agent according to claim 1 or 2 , which is a preventive or therapeutic agent for a disease which is associated with active circulating GLP-1 and/or active circulating GLP-2.

26 . The pharmaceutical agent according to claim 25 , wherein the disease is at least any one selected from the group consisting of: diabetes, obesity, hyperlipidemia, and gastrointestinal diseases.

27 . The pharmaceutical agent according to claim 3 or 4 , which is a preventive or therapeutic agent for a disease which is associated with active circulating GLP-2.

28 . The pharmaceutical agent according to claim 27 , wherein the disease is a gastrointestinal disease.

29 . A method for preventing or treating a disease which is associated with active circulating GLP-1 and/or active circulating GLP-2, which comprises administering the pharmaceutical agent according to claim 1 or 2 at an effective amount.

30 . The use of the pharmaceutical agent according to claim 1 or 2 for producing a preventive or therapeutic agent for a disease which is associated with active circulating GLP-1 and/or active circulating GLP-2.

31 . A method for preventing or treating a disease which is associated with active circulating GLP-2, which comprises administering the pharmaceutical agent according to claim 3 or 4 at an effective amount.

32 . The use of the pharmaceutical agent according to claim 3 or 4 for producing a preventive or therapeutic agent for a disease which is associated with active circulating GLP-2.

33 . A method for enhancing the effects of active circulating GLP-1 and/or active circulating GLP-2, which comprises using the pharmaceutical agent according to claim 1 or 2 .

34 . A method for enhancing the effects of active circulating GLP-2, which comprises using the pharmaceutical agent according to claim 3 or 4 .