WO2003097064A1

WO2003097064A1 - Therapeutic agent for diabetes

Info

Publication number: WO2003097064A1
Application number: PCT/JP2003/006136
Authority: WO
Inventors: Satoshi Nakanishi; Hiroshi Yano; Kiyotoshi Mori; Fumiko Ogino; Hideaki Kusaka; Kimihisa Ueno; Yuji Nomoto; Yuzuru Matsuda
Original assignee: Kyowa Hakko Kogyo Co., Ltd.
Priority date: 2002-05-17
Filing date: 2003-05-16
Publication date: 2003-11-27
Also published as: AU2003234929A1; JPWO2003097064A1

Abstract

A therapeutic agent for diabetes, characterized by containing at least one member selected among sulfonylurea antidiabetic agents and sulfonylurea-free K+ ATP channel blocker antidiabetic agents and at least one member selected among a fused purine derivative represented by the formula (I), a fused purine derivative represented by the formula (II), (I) (II) and pharmacologically acceptable salts of these.

Description

Specification

Diabetes treatment

Technical field

The present invention relates to a therapeutic agent for diabetes containing a condensed purine derivative.

Background technology

Diabetes is a major feature of hyperglycemia caused by metabolic abnormalities centering on glucose metabolism based on insulin secretion deficiency and decreased sensitivity of target cells. If hyperglycemia persists for a long time, serious complications occur in various organs and nerves, such as retinopathy, nephropathy, and neuropathy, mainly due to vascular disorders. Therefore, in the treatment of diabetes, it is extremely important to control and maintain a normal blood glucose level, and the means for that have been studied for a long time.

For diabetes, a type of diabetes whose onset is slow and does not necessarily require insulin treatment for life support (type 2 diabetes), treatment to control blood sugar levels by combining exercise therapy, dietary therapy, and drugs is used. As a drug, a sulfonylurea insulin secretagogue, a type of oral hypoglycemic agent, is widely used in clinical practice. Recently, insulin secretagogues such as nateglinide peripaglinide, which are non-sulfonylurea K + ATP channel blockers, are also commercially available. However, all of the currently available insulin secretagogues promote insulin secretion independent of blood glucose levels, so incorrect doses can cause severe hypoglycemia or There is a problem that it cannot be controlled, and it is not always satisfactory.

On the other hand, it has been reported that a condensed purine derivative having a structure different from that of a sulfonylurea insulin secretion enhancer can be a hypoglycemic agent capable of promoting insulin secretion in accordance with a blood glucose level (WO 00/01388, International Publication W001 / 47931). Combining multiple conventional hypoglycemic agents involves using short-acting insulin secretagogues with long-lasting hypoglycemic agents to enhance meal-related insulin secretion and treat postprandial hyperglycemia (WO 098/56378). Short-acting insulin secretagogues include sulphonylurine insulin secretagogue darikidone and non-sulfonylurea K ⁺ ATP Yanenel blockers repaglinide and nateglinide are not limited to insulin secretagogues as long-acting hypoglycemic agents, but compounds containing sulfonylurea insulin secretagogues such as dalibenclamide and daliclazide have been shown. I have. Also, a combination of repaglinide and metformin, which is not an insulin secretagogue, is known.

Disclosure of the invention

An object of the present invention is to provide a therapeutic agent for diabetes, which comprises one or more selected from a sulfonylurea antidiabetic agent and a non-sulfonylurea K + ATP channel blocker antidiabetic agent, and a condensed purine derivative.

The present invention relates to the following (1) to (18).

(1) at least one selected from a sulfolurea antidiabetic agent and a non-sulfonylurea K + ATP channel blocker antidiabetic agent, and formula (I)

(In the formula, R ^la represents a hydrogen atom, lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aromatic heterocyclic group, and R ^2a represents a hydrogen atom, lower alkyl, substituted or unsubstituted aralkyl, Represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group, R ^3a represents a hydrogen atom, lower alkyl or substituted or unsubstituted aralkyl, and X ¹ and X ² are each independently Represents a hydrogen atom, a lower alkyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted aryl, and na represents an integer of 0 to 3.) A condensed purine derivative represented by the formula (II):

\ Ν, ¹¹ ) (π)

, Ν 'nb

^R2b people

Ν χ '' ^Υ , Ζ

{Where Χ · '' Υ—Ζ is R ^lb N— C = 0 (where R ^lb is a hydrogen atom, substituted or unsubstituted Represents a substituted alkyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group) or N = C—W wherein W is a halogen, a substituted or unsubstituted aromatic Group heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, _NR ⁵ (wherein R ⁴ and R ⁵ are the same or different and are hydrogen atoms, substituted or unsubstituted lower alkyl, substituted or unsubstituted R and R ⁵ together with an adjacent nitrogen atom form a heterocyclic group, which represents an aryl or substituted or unsubstituted aralkyl of the formula: -OR ⁶ , wherein R ⁶ is substituted or unsubstituted lower alkyl, also the properly substituted represents the unsubstituted Ariru or substituted or unsubstituted Ararukiru) of, - SR ^6a (wherein, R ^6a has the same meaning as the R ^6), a substituted or unsubstituted lower alkyl or Siano Represents represents], R ^2b is a hydrogen atom, a substituted or unsubstituted lower alkyl, substitution or unsubstituted Ararukiru, substituted or unsubstituted Ariru, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted Alicyclic heterocyclic group, halogen, lower alkylthio, _NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ have the same meanings as above and R ⁵ ), -C0 ₂ H, lower alkoxyl carbonyl, R represents -COHal (wherein Hal represents halogen),-° ⁹ ° (wherein R ⁹ and R ^1C have the same meanings as R ⁴ and R ⁵ , respectively), or -CH0. ^3b is a hydrogen atom, a lower alkyl, represents Araruki Le or lower alkoxyalkyl substituted or unsubstituted, nb represents an integer of 0 to 3, V ¹ represents hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted Aralkyl of substitution, substitution or Represents an unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group, V ² represents a substituted lower alkyl or a substituted or unsubstituted aromatic heterocyclic group, and V ¹ represents a hydrogen atom, a lower alkyl, a substituted or Represents an unsubstituted aralkyl or a substituted or unsubstituted aryl, and (a) Χ ′ ·· Υ—Ζ is R ^lba N—C = 0 (where R ^lba is a substituted lower alkyl in the definition of R ^lb above. R represents a substituted lower alkyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted alicyclic heterocyclic group, a halogen, a lower alkylthio, -NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ Ru each as defined above der), - C0 ₂ H, lower alkoxy Kano repo sulfonyl, -COHal (in the formula, Hal is Ru as defined above der), -C0NR ⁹ R ¹⁰ (wherein, and R ^1G is the same meanings as defined above, respectively) or - represents a CH0 , (B) (wherein, R ^lb has the same meaning as defined above) Χ · · · Υ~Ζ is R ^lb N- C == 0 represents either R ^3b represents lower alkoxyalkyl, (c) chi · · · Υ ～ Ζ is R ^lbb N— C = 0 (where R ^lbb is Or (d) Χ · Υ-Υ represents N = C—W (where W is as defined above), and R ^2b is substituted or unsubstituted Lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, halogen, lower alkylthio, -N ⁷ R ⁸ (in the formula, R ⁷ and R ⁸ each have the same meanings as defined above), _C0 ₂ H, lower Anorekoki aryloxycarbonyl, -COHal (in the formula, Hal has the same meaning as defined above), -C0NR ⁹ R ¹⁰ (wherein Wherein, and R ^1C are the same as defined above, respectively, or -CH0, or (e) Χ to Υ · Ζ is N = C-W (wherein W is as defined above) It represents, when R ^3b represents lower alkyl, substituted or unsubstituted Ararukiru or lower alkoxyalkyl, V ² is lower alk Or a substituted or unsubstituted aralkyl or a substituted or unsubstituted aryl), and at least one selected from pharmacologically acceptable salts thereof. A therapeutic agent for diabetes.

(2) Sulfonylurea antidiabetic drugs are dalibenclamide, glipizide, daliclazide, dalimepiride, tolazamide, tolptamide, acetohexamide, carpamide, kokulpropamide, glibornuride, gliquidone, glicentolide, dalisoxamide The therapeutic agent for diabetes according to the above (1), which is one or more antidiabetic agents selected from the group consisting of glicloviramide, glyccyclamide and glibusol.

(3) The method according to (1) or (2) above, wherein the non-sulfonylurea K + ATP channel propellant—the antidiabetic agent is one or more antidiabetic agents selected from lipaglid, nateglinide and migulinide. Diabetes treatment.

(4) condensation purine derivative force (7?) - ⁸ - benzyl - ² - cyclopentyl - ^7, ⁸ _ dihydric mud - ⁴ - propyl - 1 Imidazo [2, 1] purine - 5 (4 ^) - one, ( 7?)-2-Cyclopentyl-7,8-dihydro-8- (4-picolyl) -4-propyl-1 imidazo [2,1-i] purine-5 (4> -one or (7? )-2 -Chain mouth petit / le-7,8-dihydro-8- (4-picolinole) -4- 4-propyl-1 ^ imidazo [2,1-i] purine-5 (4 ^)-one The therapeutic agent for diabetes according to any one of the above (1) to (3).

(5) at least one selected from a sulfonylurea antidiabetic agent and a non-sulfonylurea K + ATP channel blocker antidiabetic agent, and formula (I)

{Wherein, Χ to · are R ^lb N— C = 0 (where R ^lb is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted Aryl or a substituted or unsubstituted aromatic heterocyclic group) or N = C_W wherein W is a halogen, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, -NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted aralkyl; , And R ⁵ together with the adjacent nitrogen atom form a heterocyclic group), -OR ⁶ (where R ⁶ is a substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl or substituted Or unsubstituted aralkyl), -SR ^6a

(Wherein, R ^6a has the same meaning as R ⁶ above), represents a substituted or unsubstituted lower alkyl or cyano], and R ^2b represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted Aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, halogen, low Lower alkylthio, -NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ have the same meanings as R ⁴ and R ⁵ , respectively), -CO ₂ H, lower alkoxyl propylonyl, -COHal (where Hal is halogen Represents —C0NR ⁹ R ¹⁰ (wherein R ⁹ and R ^1D have the same meanings as above and R ⁵ ), or —CH 0, and R ^3b represents a hydrogen atom, lower alkyl, substituted or unsubstituted. Represents a substituted aralkyl or a lower alkoxyalkyl, nb represents an integer of 0 to 3, V ¹ represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted aryl. Or represents a substituted or unsubstituted aromatic heterocyclic group, V ² represents a substituted lower alkyl or a substituted or unsubstituted aromatic heterocyclic group, and V ¹ represents a hydrogen atom, a lower alkyl, a substituted or unsubstituted aralkyl or Replacement or Represents Ariru substitutions, and represent (a) Χ ·· 'Υ~Ζ is R ^lba N-C = 0 (wherein, R ^lba represents definitions in, substituted lower alkyl groups other than the R ^lb) Wherein R ^2b is substituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alicyclic heterocyclic group, halogen, lower alkylthio, -NR¾ ⁸ (wherein R ⁷ and R ⁸ are as defined above, respectively) der Ru), - C0 ₂ H, lower alkoxycarbonyl, -COHal (in the formula, Hal is Ru as defined above der), in -C0NR ⁹ R ¹⁰ (wherein, R ⁹ and R ^1Q are respectively as defined above Or ^-CH0 , or (b) Χ ·· Υ '·· Ζ represents R ^lbb N— C = 0 (where R ^lbb is as defined above), and R ^3b is lower alkoxy or represents alkyl, or represents (c) Χ ··· Υ~Ζ is R ^lb N- C = 0 (wherein, R ^lb represents a location換低loweralkyl), (d) Χ ·· ' Υ Ζ Is N == C—W (where W is Wherein R ^2b is substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted An alicyclic heterocyclic group, halogen, lower alkylthio, -NR ⁷ R ⁸ (wherein, R ⁷ and R are the same as defined above), -CO ₂ H, lower alkoxycarbonyl, -COHal (wherein Hal is as defined above), -C0NR ⁹ R ¹⁰ (wherein, and R ^1Q are as defined above), or -CH0, or (e) Χ—Υ ′ ·· is N = When R ^3b represents lower alkyl, substituted or unsubstituted aralkyl or lower alkoxyalkyl, V ² represents lower alkyl, substituted or unsubstituted aralkyl or Substituted or unsubstituted aryl And at least one of the condensed purine derivatives represented by the formula (I) and pharmacologically acceptable salts thereof, for preventing and / or preventing diabetic complications. Or therapeutic agent.

(6) When the sulfonylurea antidiabetic agent is glibenclamide, glibizide, daliclazide, glimepiride, tolazamide, tolptamide, acetohexamide, carpamide, kokunorepropamide, glipornulide, glicidone, glicentamide, glisoramide. The preventive and / or therapeutic agent for diabetic complications according to the above (5), which is one or more antidiabetic agents selected from glyoxepide, glicloviramide, glyciclamide and glybusol.

(7) The prevention of diabetic complications according to the above (5) or (6), wherein the non-sulfoelurea K + ATP channel blocker antidiabetic agent is one or more antidiabetic agents selected from lipaglinide, nateglinide and miglinide. And / or therapeutic agents.

(8) When the condensed purine derivative is (y?)-8_benzyl-2-cyclopentyl-7,8-dihydro-4-propyl-1-imidazo [2,1-i] purine-5 (4 / -one, ( /?)-2-Cyclopentyl-7,8-dihydro-8- (4-picolyl) -4-propyl-I imidazo [2,1-i] purine-5 (4-on or?)-2 Any of the above (5) to (7), which is -cyclobutyl-7, 8-dihydro-8_ (4-picolyl) -4-propyl-1 imidazo [2,1-i] purine- ⁵ (4-one) Or a preventive and / or therapeutic agent for diabetic complications as described in

Equation (9) (I)

(In the formula, R ^la represents a hydrogen atom, lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aromatic heterocyclic group, and R ^2a represents a hydrogen atom, lower alkyl, substituted or unsubstituted aralkyl, Substituted or substituted represents an unsubstituted aryl or substituted or unsubstituted aromatic heterocyclic group, R ^3a represents a hydrogen atom, lower alkyl or substituted or unsubstituted aralkyl, and X ¹ and X ² represent Each independently represents a hydrogen atom, a lower alkyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted aryl, and na represents an integer of 0 to 3), a condensed purine derivative represented by the formula (II): (II)

Where R is R ^lb N_C = 0 (where R ^lb is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aromatic Represents a heterocyclic group) or N = C—W wherein W is a halogen, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, -NR ⁴ R ⁵ (formula Wherein R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl or a force representing a substituted or unsubstituted aralkyl, and R ⁵ is adjacent Together with the nitrogen atom to form a heterocyclic group), -OR ⁶ , wherein R ⁶ represents a substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl ), -SR ^6a

(Wherein, R ^6a has the same meaning as R ⁶ above), represents a substituted or unsubstituted lower alkyl or cyano], and R ^2b represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted Aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, halogen, lower alkylthio, _NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ is as defined above for R ⁴ and R ⁵ ), -CO ₂ H, lower alkoxycarbonyl, -COHal (where Hal represents a halogen), -C0NR ⁹ R ¹⁰ (wherein R ⁹ And R ^ie have the same meanings as R ⁴ and, respectively, or -CH0, R ^3b represents a hydrogen atom, lower alkyl, substituted or unsubstituted aralkyl or lower alkoxyalkyl, and nb represents 0 to 3 represents an integer, V ¹ is hydrogen atoms , Substituted or unsubstituted lower alkyl, substituted or unsubstituted Ararukiru represents substitution or unsubstituted Ariru or substituted or unsubstituted aromatic heterocyclic group, V ² is a substituted lower alkyl or substituted or unsubstituted aromatic V ¹ represents a hydrogen atom, lower alkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted arylene, and ( _a ) Χ · '· Υ to Ζ are R ^lba N— C = 0 (wherein, R ^lba represents a group other than substituted lower alkyl in the definition of R ^lb ), and R ^2b represents substituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alicyclic heterocyclic. Ring group, halo Gen, lower alkylthio, - NR ⁷ R ⁸ (wherein, R ⁷ and the Ru each as defined above der), - C0 ₂ H, lower alkoxycarbonyl, - COHal (wherein, Hal is Ru as defined above der ), -CONR ⁹ ! ^ (Wherein, R ^{9 and} R ^1G have the same meanings as described above), or -CH0, or (b) Χ to Υ · 'Ζ is R ^lb N— C = 0 (wherein R ^lb is as defined above), R ^3b represents lower alkoxyalkyl, or (c) Χ · ΥΥ is R ^lbb N—C = 0 (where R ^lbb represents substituted lower alkyl) or (d) Χ · Χ to Ζ represents N = C—W (where W is as defined above), and R ^2b is substituted or Unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, halogen, lower alkylthio E, -NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ are as defined above), -CO ₂ H, lower alkoxycarbonyl, -COHal (where Hal is as defined above), -C0NR ⁹ R ¹⁰ (wherein, and R ^{1 ()} are as defined above) or -CH0, or (e) Χ ... Υ is N = CW (where W is Wherein R ^3b represents lower alkyl, substituted or unsubstituted aralkyl or lower alkoxyalkyl, and V ² may be lower alkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl. Sulfur-urea antidiabetic or non-sulfonylurea K + ATP channel containing as active ingredient at least one selected from condensed purine derivatives represented by the formula: Blocker An anti-diabetic agent effect enhancer.

(10) Sulfonylurea antidiabetic agents are dalibenclamide, glipizide, daliclazide, glimepiride, tolazamide, tolptamide, acetohexamide, carbbutamide, chlorpronomide, glibornuride, glicidone, glicentamide, griseolamide Enhanced effect of the anti-diabetic agent for sulfonylurea or non-sulfonylurea K + ATP channel blocker according to the above (9), which is one or more antidiabetic agents selected from glyoxepide, glicloviramide, and glycicamide glibusol. Agent.

(11) The above (9) or (10) according to the above (9) or (10), wherein the non-sulfonylurea K + ATP channel blocker antidiabetic agent is one or more antidiabetic agents selected from lipaglid, nateglinide and miglidide. For enhancing the effect of a sulfonylurea antidiabetic agent or a non-sulfonylurea K + ATP channel blocker antidiabetic agent. (1 2) Condensed purine derivative is (i?)-8-benzyl-2-cyclopentyl-7, 8-dihydro-4-propyl-1 ^ imidazo [2, purine-5 (4 / force-one, 0? ) - ² - consequent opening pentyl - 7, 8 - dihydric mud - 8 - (4-picolyl) - 4 - propyl - 1 ^ Imidazo [2, 1] purine - 5 (4 - or clear 2-cyclobutyl - 7,8-Dihydro-8- (4-picolyl) -4-propyl-1-imidazo [2, purine-5 (4-one according to any one of the above (9) to (11) Ruphonylurea anti-diabetic agent or non-sulfonylurea K + ATP channel blocker.

(13) Equation (I)

{Wherein, Υ'Υ · Υ is R ^lb N— C = 0 (where R ^lb is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted Aryl or a substituted or unsubstituted aromatic heterocyclic group) or N = C—W wherein W is a halogen, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic ring A group, -NR ⁴ R ⁵ (wherein and R ⁵ are the same or different and are a hydrogen atom, Or unsubstituted lower alkyl, the ability to represent a substituted or unsubstituted aryl or a substituted or unsubstituted aralkyl, and R ⁵ together with the adjacent nitrogen atom to form a heterocyclic group), -OR ⁶ (wherein, represents a substituted or unsubstituted lower alkyl, substituted or is unsubstituted Ariru or substituted or unsubstituted Ararukiru), - in S ^a (wherein, R ^6a has the same meaning as the R ⁶ ), Represents substituted or unsubstituted lower alkyl or cyano], and R ^2b represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted An aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, halogen, lower alkylthio, -NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ have the same meanings as R ⁴ and R ⁵ , respectively. Ah That), - C0 ₂ H, lower alkoxy force Ruponiru, - COHal (wherein, Hal is to display the halogen), in -C0NR ⁹ R ¹⁰ (wherein and R ^1Q are respectively the same meanings as defined above R ⁴ and R ⁵ there) or - represents CH0, R ^3b is a hydrogen atom, a lower alkyl, represents Araruki Le or lower alkoxyalkyl substituted or unsubstituted, nb represents an integer of 0 3, V ¹ represents hydrogen atom, a substituted Or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted aromatic heterocyclic group, and V ² represents substituted lower alkyl or substituted or unsubstituted aromatic heterocyclic group. Represents a ring group, V ¹ represents a hydrogen atom, lower alkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl, and (a) Χ '·' Υ · · Ζ represents R ^lba N—C = 0 (wherein, R ^lba is the R ^lb Represents the definition, a represents) a group other than substituted lower alkyl, R ^2b is substituted lower alkyl, substituted or unsubstituted Ararukiru, substituted or unsubstituted alicyclic heterocyclic group, a halo gen, lower alkylthio, - NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ Ru each as defined above der), - C0 ₂ H, lower alkoxycarbonyl - le, -COHal (in the formula, Hal is Ru as defined above der), -C0NR ⁹ R ¹⁰ (wherein, R ⁹ and R ^ie have the same ^{meanings as} described above) or -CH0, or (b) Χ—Υ ·· Ζ is R ^lb N— C = 0 (wherein, R ^lb represents the same as defined above), and R ^3b represents lower alkoxyalkyl, or (c) ^·· Υ—Υ represents R ^lbb N—C = 0 (where R ^lbb represents a substituted lower alkyl) Or (d) Χ · · Υ Ζ represents NC-W (W is as defined above), and R ^2b is a substituted or unsubstituted lower alkyl, Or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, halogen, lower alkylthio, -NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ are as defined above), -CO ₂ H, lower alkoxycarbonyl, -COHal (where Hal is as defined above), -C0NR ⁹ R ^w (wherein, and R ^ie are as defined above) or -CH0, or (e) Χ—Υ · Ζ is N == C-ff (where W is And R ^3b represents lower alkyl, substituted or unsubstituted aralkyl or lower alkoxyalkyl, and V ² may be lower alkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl. } A sulfonylurea antidiabetic or non-sulfonylurea K + ATP channel, characterized by containing, as an active ingredient, at least one selected from a condensed purine derivative represented by the formula: and a pharmacologically acceptable salt thereof. Reduction of side effects of blocker antidiabetic agent Agent.

(14) When the sulfourea antidiabetic agent is dalibenclamide, glipizide, daliclazide, glimepiride, tolazamide, tolptamide, acetohexamide, carbutamid, chlorpropamide, glipornulide, glicidone, glicentide, glisoramidide, glisoramidide The sulfonylurea antidiabetic agent or the non-sulfonylurea K + ATP channel blocker antidiabetic agent according to the above (13), which is one or more antidiabetic agents selected from glicloviramide, glyccyclamide and glybuzol.

(15) The above (13) or (), wherein the non-sulfonylurea K + ATP channel blocker antidiabetic agent is one or more antidiabetic agents selected from lipag, linid, nateglinide and migulinide. 14) The agent for reducing side effects of the sulfolurea antidiabetic agent or the non-sulfonylurea K + ATP channel blocker antidiabetic agent according to the above.

(16) Condensed purine derivative power SO?) -8-Benzyl-2-cyclopentyl-7,8-dihydro-4-propyl-1 imidazo [2,1-i] purine-5 (4-one, G0-2 -Cyclopentynole-7,8-Dihydro-8- (4-picolinole) -4 -Pupyl pill-1H-imidazo [2, purine-5 (4U) -one or 0?) -2-cyclobutyl -7,8-Dihydro-8- (4-picolyl) -4-propyl-1 imidazo [2, Purine-5 (4 ^)-one, which is one of the above (1 3) to (15) The agent for reducing the side effect of the sulfonylurea anti-diabetic agent or the non-sulfonylurea K + ATP channel blocker anti-diabetic agent described.

(17) Sulfonylurea antidiabetic and non-sulfonylurea K + ATP channel And at least one selected from the group consisting of a condensed purine derivative represented by the formula (I), a condensed purine derivative represented by the formula (II), and a pharmacologically acceptable salt thereof. The therapeutic agent for diabetes according to any one of the above (1) to (4), wherein at least one selected from the group is present in a separate preparation form.

(18) a sulfonylurea antidiabetic agent, one or more selected from non-sulfonylurea K + ATP channel blocker antidiabetic agents, and a condensed purine derivative represented by the formula (I); The diabetic complication according to any one of the above (5) to (8), wherein one or more selected from the condensed purine derivatives represented and their pharmacologically acceptable salts are present in separate pharmaceutical forms. Prophylactic and / or therapeutic agents.

Hereinafter, the compound represented by the formula (I) is referred to as compound (I). The same applies to compounds of other formula numbers.

In the definition of each group of the formula (I), the lower alkyl includes, for example, an alkyl having 1 to 10 carbon atoms which is linear, branched, cyclic or a combination thereof. Examples of the straight-chain or branched lower alkyl include, for example, methyl, ethyl, 1-pinopenole, isopropyl,? "Butinole, isobutinole, butynole, tert-butylinole, pentinole, neopentinole, /?- Hexyl, heptinol, / τ-otatinole, -nonyl, 77 "decyl and the like. The cyclic lower alkyl may have one or more rings, and more specifically, cyclopropyl, cyclobutyl, cyclopentinole, cyclohexinole, cycloheptinole, cyclopentinole, nonoleda 'Mantyl, Ryo Damantinole and the like. Of these, tert-butyl / le or pentyls are preferred. Examples of the lower alkyl represented by R ^la include a linear or branched lower alkyl or a cyclic lower alkyl having 1 to 3 rings (for example, cyclopropynole, cyclopentinole, cyclopentinole, cyclohexinole, 3- And a lower alkyl represented by R ^2a is preferably a linear or branched lower alkyl or a monocyclic lower alkyl.

Examples of aryl include monoaryl or two or more fused rings having 6 to 14 carbon atoms, more specifically, phenyl, naphthyl, indul, anthraenole and the like.

Aralkyl includes, for example, a monocyclic or two or more fused rings And aralkyl having 7 to 15 carbon atoms, more specifically, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like.

Examples of the aromatic heterocyclic group include a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring. A condensed aromatic heterocyclic group containing at least one atom selected from the group consisting of a fused bicyclic or tricyclic nitrogen atom, an oxygen atom and a sulfur atom, and the like. 14 aromatic heterocyclic groups are preferred, and more specifically, furyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolinole, tetrazolyl, oxazolyl, thiazoli / re, pyridyl, pyrazyl, pyrimidinyl, pyridazi-nore, Triadinole, indolinole, indazolinole, benzimidazolinole, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, phthalazini , Nafuchiri Jiniru, quinoxalinyl, quinazolinyl, Shin'norieru and purinyl is like et be.

Substituents of substituted aryl, substituted aralkyl and substituted aromatic heterocyclic groups may be the same or different, and may be substituted or unsubstituted lower alkyl having 1 to 3 substituents, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkyl, Unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aralkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted Arylo, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted lower alkylthio, substituted or unsubstituted lower alkylsulfur, carboxy, substituted or unsubstituted rubamoyl, substituted or unsubstituted Lower alkanol, halogen, nit , Amino, mono- or di-lower alkyl-substituted amino, such as Shiano is like et be. .

In the above functional groups, the lower alkyl portion of lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkylthio, lower alkylsulfonyl, lower alkanol, and mono- or di-lower alkyl-substituted amino has the same meaning as the above lower alkyl. In a di-lower alkyl-substituted amino, the ^two lower alkyls may be the same or different. Lower alkenyl includes, for example, linear or branched Examples thereof include chain-like alkenyl having 2 to 6 carbon atoms, more specifically, butyl, aryl, topropropenyl, methacryl, butenyl, crotyl, pentenyl, hexenyl and the like. The lower alkynyl includes, for example, linear or branched alkynyl having 2 to 6 carbon atoms, and more specifically, ethynyl, propynyl, petinole, pentynyl, hexyl and the like. The number of unsaturated bonds in lower alkenyl and lower alkynyl is not particularly limited, but is preferably one. The aralkyl part of the aralkyl is the same as the above-mentioned aralkyl, and the aryl part of the aralkyl and the aralkyl is the same as the above. Examples of the halogen include fluorine, chlorine, bromine, and iodine atoms.

In the above functional groups, substituted lower alkyl, substituted lower alkyl, substituted lower alkyl, substituted aralkyl, substituted aryl, substituted lower alkoxy, substituted aralkyloxy, substituted aryloxy, substituted aryloyl, substituted lower alkoxy carboxy- Examples of the substituents of the substituted lower alkylthio, the substituted lower alkylsulfonyl, the substituents rubamoyl and the substituted lower alkanoyl include, for example, the same or different, hydroxy, halogen, canolepoxy, snorejo, phosphono having 1 to 3 substituents. And ester groups derived from acidic groups (lower alkyl esters, aralkyl esters, aryl esters, etc.). Here, halogen is as defined above, the lower alkyl portion of the lower alkyl ester is the same as the lower alkyl, and the aryl portion of the ester is the same as the aryl. More specifically, examples of the alkyl having a substituent include hydroxyxetil, trifluoromethyi / re, and the like.

In formula (I), the substitution position of X ¹ or X ² is not particularly limited, and each can be substituted at any position on the ring. When X ¹ or X ² is a substituent other than a hydrogen atom, the configuration of the carbon atom to which they are bonded may be either 5 or;?. na is preferably 0.

In the definition of each group of the formula (II), the alkyl portion of lower alkyl, lower alkylthio, lower alkoxycarbyl and lower alkoxyalkyl includes, for example, a straight-chain, branched-chain, From the combination of these Alkyl. Examples of the linear or branched lower alkyl include, for example, methinole, ethinole, propinole, isopropinole, Λ "putinole, isoptinole, sec-petitinole, ieri-putinole, pentinole, neopentinole, 7T" hexinole,? ~ Heptinole, η ~ octyl, noel, decyl and the like. The cyclic lower alkyl may have one or more rings, e.g., cyclopropyl propyl, cyclobutyl, cyclopentinole, cyclohexinole, cycloheptinole, cyclooctinole, nonoleada mantyl, Adamanchinole, bicyclo [2.2.1] heptinole, bicyclo [2.2.2] octynole, bisik [3. 3.0] octyl, bisik [3.3.1] nonyl, and the like.

The aryl and the aryl moiety of the aralkyl include, for example, aryl having 6 to 14 carbon atoms, which is monocyclic or has 2 or more fused rings, and more specifically, phenyl, naphthyl, indul, anthranyl and the like.

The aralkyl includes, for example, aralkyl having 7 to 15 carbon atoms, the aralkyl part of which is a monocyclic or two or more fused rings, more specifically, benzyl, phenethylenol, benzhydryl, naphthylmethyl and the like.

As the aromatic heterocyclic group, for example, a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a 3- to 8-membered ring is fused. And a condensed aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and the like, and having 5 to 14 ring atoms. Group is preferred, and more specifically, furyl, chelyl, pyrrolyl, imidazolyl, vilazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, indazolyl, benzimidyl, benzimidyl Benzoxazolyl, Benzothiazolyl, Quinolinole, Isoquinolinole, Phthalazur, Naph Tilidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, purinyl and the like.

Examples of the alicyclic heterocyclic group include a 5- or 6-membered monocyclic alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring A condensed alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is condensed with Specifically, pyrrolidinyl, 2,5-dioxopyrrolidinyl, thiazolidinyl, oxosazolidinyl, 2-oxooxazolidinyl, piperidinyl, piperazel, homopiperazinyl, morpholinyl, thiomorpholininole, Tetrahydroviranyl, tetrahydrofurothiopyral, tetrahydrofuryl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroquinoxalinyl, octahydroquinolyl, dihydroindolinolinole, 1,3-dioxoisoindolinolinole, 1,3-dioxolanil, 1 , 3-Dioxolan-2-spirocyclopentyl and the like.

As a heterocyclic group formed together with an adjacent nitrogen atom, for example, a 5- or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group is A condensed heterocyclic group containing at least one nitrogen atom, which is a bicyclic or tricyclic condensed 3- to 8-membered ring, which may contain another nitrogen atom, an oxygen atom or a sulfur atom; The condensed heterocyclic group may contain another nitrogen atom, oxygen atom or sulfur atom). More specifically, pyrrolidinyl, thiazolidinyl, oxosazolidinyl, piperidino, homopiperidino, piperazi- , Homopyrazinole, Morpholino, Thiomorpholino, Tetrahydroquinolyl, Tetrahydroisoquinolyl, Octahi Droquinolinole, Benzimidazolinole, Indazolinole, India Linole, isoindolyl, purinyl, dihydroindolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl and the like.

Examples of the halogen include fluorine, chlorine, bromine, and iodine atoms.

Examples of the substituent of the substituted aryl, the substituted aralkyl, the substituted aromatic heterocyclic group and the substituted alicyclic heterocyclic group may be the same or different, and may be a substituted or unsubstituted lower alkyl having 1 to 3 substituents, substituted or unsubstituted. Aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylo, substituted or unsubstituted aralkyl, substituted or unsubstituted aralkyloxy, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, Substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted lower alkylthio, substituted or unsubstituted lower alkylsulfol, substituted or unsubstituted lower alcohol, mono Or di-lower alkyl-substituted rubamoyl, mono Shikuwaji lower alkyl-substituted amino, halogen, carboxy, hydroxy, Examples thereof include nitro, amino, and cyano. Here, the lower alkenyl includes, for example, a linear or branched alkenyl having 2 to 6 carbon atoms, more specifically, butyl, aryl, 1-propenyl, methacryl, butenyl, crotinol, Examples of the lower alkynyl include a linear or branched alkynyl having 2 to 6 carbon atoms, more specifically, ethynyl, propynyl, butyr, pentul, and the like. Hexinyl and the like. The number of unsaturated bonds in lower alkenyl and lower alkynyl is not particularly limited, but is preferably one. The lower alkyl portion of lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkylthio, lower alkylsulfonyl, lower alkanoyl, mono- or di-lower alkyl-substituent rubamoyl and mono- or di-lower alkyl-substituted amino is as defined for the lower alkyl. . The aralkyl portion of aralkyl and aralkyl is the same as the above-mentioned aralkyl. Aryl, atrox and the aryl part of Aroil are synonymous with the above-mentioned aryl. Halogen has the same meaning as the above-mentioned halogen. Substituted lower alkyl, substituted aryl, substituted aryloxy, substituted aryloyl, substituted aralkyl, substituted aralkyloxy, substituted lower alkenyl, substituted lower alkynyl, substituted lower alkoxy, substituted lower alkoxycarbonyl, substituted lower alkylthio, substituted lower alkylsulfonyl and substituted lower Examples of the substituent of the alkanoyl include the same or different hydroxy having 1 to 3 substituents, halogen, carboxy, sulfo, phosphono as defined above, and esters derived from these acidic groups (lower alkyl esters, a Aralkyl esters, aryl esters and the like; the lower alkyl portion, the aralkyl portion and the aryl portion of these esters are as defined above), and the like. In di-lower alkyl-substituted rubamoyl and di-lower alkyl-substituted amino, the two lower alkyls bonded to carbamoyl and amino, respectively, may be the same or different. Examples of the substituent of the substituted lower alkyl include the same or different and substituted with 1 to 3 lower alkoxy, hydroxy, cyano, azide, carboxy, phosphono, or esters derived from these acidic groups (lower alkyl esters, aralkyls). Esters, aryl esters, etc .; the lower alkyl, aralkyl and aryl portions of these esters are as defined above), lower alkylthio, Lower alkylaminocarbonyl, lower alkoxycarbonyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group,-NRUR ¹² (wherein R ¹¹ and R ¹² are the same or different Represents a hydrogen atom, lower alkyl, lower alkanol, aryl, aralkyl or aralkyloxy, or R ¹¹ and R ¹² together with the adjacent nitrogen atom form a heterocyclic group), halogen, lower alkyl Arylsulfonyloxy, lower alkylsulfonyl, lower alkynolesulfonyloxy, trifluoromethanesulfonyloxy and the like which may be used. Here, lower alkyl, lower alkoxy, lower alkylthio, lower alkylaminocarboer, lower alkoxycarbonyl, lower alkanol, arylsulfonyloxy optionally substituted with lower alkyl, lower alkylsulfonyl and lower alkylsulfonyloxy The lower alkyl moiety has the same meaning as the lower alkyl. The aryl part of the aryl and arylsulfonyloxy has the same meaning as the above aryl. The aralkyl portion of aralkyl and aralkyloxy has the same meaning as the above-mentioned aralkyl. The halogen, the aromatic heterocyclic group, the alicyclic heterocyclic group, and the heterocyclic group formed together with the adjacent nitrogen atom are as defined above. The substituents of the substituted aromatic heterocyclic group and the substituted alicyclic heterocyclic group are as defined above.

In formula (II), the substitution position of V ¹ or V ² is not particularly limited, and each can be substituted at any position on the ring. When V ¹ or V ² is a substituent other than a hydrogen atom, the configuration of the carbon atom to which they are bonded may be either s or scale. nb is preferably 0.

The sulfonylurea antidiabetic agent means an insulin secretagogue having a sulfolurea structure or a sulfonamide structure. Specifically, dalibenclamide, glibizide, gliclazide, glimepiride, tolazamide, tolptamide, acetohexamide, carptamide, chlorpropamide, glipolnullide, glyquidone, glicentide, glisoramide, glisoxiclamide And daribuzole. Preferably, dalibenclamide, gliclazide or glimepiride is mentioned, and particularly preferably, glipenclamide is mentioned. 6 Non-sulfonylurea K + ATP channel blocker Anti-diabetic agent does not have sulfonyl urea structure or sulfonamide structure, but is known to inhibit K + ATP channel like sulfonylurea anti-diabetic agent It means an insulin secretagogue. Specific examples include lipaglinide, nateglinide, and migulinide.

The compound (I) and pharmacologically acceptable salts of the compound (II) include base addition salts such as acid addition salts, metal salts, ammonium salts and organic amine addition salts, and amino acid addition salts. Pharmaceutically acceptable acid addition salts include, for example, inorganic acid salts such as hydrochloride, sulfate, phosphate, etc., drunkate, maleate, fumarate, tartrate, citrate, etc. Organic acid salts can be mentioned. Examples of pharmacologically acceptable metal salts include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, as well as aluminum salts and zinc salts. The pharmacologically acceptable organic amine addition salts include, for example, organic amine addition salts such as morpholine and piperidine. Examples of pharmacologically acceptable amino acid addition salts include addition salts such as lysine, glycine, and phenylalanine.

Sulfonylurea anti-diabetic agents and non-sulfonyl urea K + ATP channel blocking agents-anti-diabetic agents can also be used in the form of their pharmacologically acceptable salts. The salt is defined as the pharmacologically acceptable salt of compound (I).

Compound (1), compound (11), a sulfonylurea antidiabetic agent and a non-sulfonylurea K + ATP channel pro-diabetic agent, and a pharmaceutically acceptable salt thereof are hydrates or solvates. In some cases, these adducts can be used in the present invention. The type of the solvent that forms the solvate is not particularly limited as long as it is pharmacologically acceptable, and includes, for example, ethanol and acetone. Some of compound (1), compound (11), sulfonylurea antidiabetic agent and non-sulfonylurea K ⁺ ATP channel blocker antidiabetic agent have one or more asymmetric carbon atoms. , Pure optical isomers or diastereoisomers, any mixture of these isomers, or racemic These can also be used in the present invention. When compound (1), compound (1 1), a sulfolurea antidiabetic agent or a non-sulfonylurea K + ATP channel blocker antidiabetic agent contains a double bond, the arrangement is either or ^ In the case where a tautomer may be present in the compound (1), the compound (11), the sulfonylurea antidiabetic agent or the non-sulfonylurea K + ATP channel blocker antidiabetic agent, any of them may be used. And all possible isomers, or mixtures thereof, can be used in the present invention.

The method for producing compound (I) is described in International Publication WO098 / 15555, Japanese Patent Laid-Open Publication No. 3-204880, International Publication WO00 / 01388, Journal of Medicinal 'Chemistry, Vol. 35, p. 3578 (1992 Years), Giannole's 'Medicinal' Chemistry, Vol. 1, 36, 2508 (1993), and Journal of Chemistry, Vol. 30, Vol. 30, 241 (1993), etc. ing. The method for producing the compound (II) is described in International Publication WO01 / 47931. Therefore, those skilled in the art can obtain the compound (I) by following the methods disclosed in these documents, or by appropriately changing the reagents or the reaction raw materials and, if necessary, making appropriate modifications or alterations to those methods. And compound (II).

The intermediate compound and the target compound obtained in these production methods are purified by a purification method commonly used in organic synthetic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc. Isolation can be purified. Further, the intermediate compound can be subjected to the next reaction without purification. When producing a pharmacologically acceptable salt of the compound (I) or the compound (II), when the salt of the compound (I) or the compound (II) is obtained, it may be purified as it is, When it is obtained in the form of, it may be dissolved or suspended in an appropriate solvent, and an acid or a base may be added to form a salt. It is also possible to convert the target substance obtained in the form of a salt to a free form and then to the desired salt.

As the compound (I), preferably, in the formula (I), R ^2a is lower alkyl or a substituted or unsubstituted aralkyl, R ^3a is a hydrogen atom or a substituted or unsubstituted aralkyl, and X ² is Compounds which are a hydrogen atom and na is 0 are preferable. As the compound (II), preferably, in the formula (II), Χ to Υ · Ζ ′ are R ^lb N— C = Wherein R ^lb is as defined above, and R ^2b is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted aryl. Compounds which are unsubstituted aromatic heterocyclic groups, wherein R ^3b is a hydrogen atom or lower alkyl, V ¹ is a hydrogen atom, V ² is substituted lower alkyl, and nb is 0. More preferably, in formula (I), R ^la is hydrogen, propyl, cyclopentyl or iar-butyl and R ^2a is? Propyl, ethyl or benzyl, R ^3a is hydrogen, methyl or benzyl, X ¹ is hydrogen, lower alkyl or substituted or unsubstituted aralkyl, X ² is hydrogen, na In the compound (1) wherein _R is 0, in the formula (II), Χ is _R lbo _N _ _{C = 0} (where Rlbc represents ethyl, propyl, cyclopropylmethyl or benzyl A compound wherein R ^2b is ^ propyl, cyclobutyl or cyclopentyl, R ^3b is a hydrogen atom, V ¹ is a hydrogen atom, V ² is picolyl, and nb power S 0 (II) Is mentioned.

More specifically, the following can be exemplified as the preferred compound (1), compound (II) or a pharmaceutically acceptable salt thereof. Of these, compound 16, compound 18-20, compound 23, compound 31, compound 35, compound 37, compound 43, compound 55, compound 98, compound 104, compound 106, compound 1 10 and compound 1 12 is particularly preferred. Also preferred are compounds in free form or other pharmacologically acceptable salts of these compounds. It should be noted that compound (1), compound (II) or a pharmacologically acceptable salt thereof is not limited to these compounds. In addition to these, the compounds specifically described in JP-A-3-204880 or WO098 / 15555 or pharmacologically acceptable salts thereof may also be used as the compound (1), the compound (II) or a compound thereof. Preferred as a pharmacologically acceptable salt.

Hereinafter, specific examples of compound (1), compound (II) or a pharmaceutically acceptable salt thereof will be shown.

Compound 1: (7?)-8-ethyl-7,8-dihydro-2- (3-noradamantyl) -4-propyl-1 / imidazo [2,1-i] purine-5 (4-one L- Tartrate

Compound 2: (5) -8-ethyl-7,8-dihydro-2- (3-noradamantyl) -4-propyl-H JP03 / 06136 Imidazo [2, purine-5 U) -one D-tartrate

Compound 3: (7?)-7,8-dihydro-8-isopropyl-2- (3-noradamantyl) -4-propyl-1 ^ imidazo [2,1-] purine-5 (4-one hydrochloride

Compound 4: (S) -7,8-Dihydro-8-isopropyl-2- (3-noradamantyl) -4-propyl-1 imidazo [2,1-] purine-5 (4 ^ -one hydrochloride

Compound 5: 7,8-dihydro-2- (3-noradamantyl) -4-propynolehymidazo [2,1-i] purine-5 (4 / -one hydrochloride

Compound 6: (7?)-2-cyclopentyl-7,8-dihydro-8-methyl-4-propyl-1-imidazo [2,1-i] purine-5 (4 ^)-one hydrochloride

Compound 7: R) -2-cyclopentyl-8-ethyl_7,8-dihydro_4-propyl-lv ^ imidazo [2,1-] purine-5 (4-one-L-tartrate

Compound 8: 2- (cyclopentyl) -8-ethyl-7,8-dihydro-4-propyl-1 ^ imidazo [2,1-i] purine-5 (4 / -one D-tartrate)

Compound 9: 2-cyclopentyl-7,8-dihydro-8-isopropyl-4-propynole-1-imidazo [2,1-i] purine- ⁵ (4-one hydrochloride

Compound 10: (5) -2-cyclohexyl pentinole -7,8-dihydro-8-isopropyl-4-propyl-1 ^ imidazo [2,1-i] purine-5 (4-one hydrochloride

Compound 11 1: (-2-cyclopentyl-7,8-dihydro-8-isobutyl-4-propyl-1-imidazo [2,1-] purine-5 (4-one L-tartrate

Compound 12: (-8-e_r-butyl-2-cyclopentyl-7,8-dihydro-4-propyl-imidazo [2,1-] purine- ⁵ (4-one hydrochloride

Compound 13 3: 8-butyl-2-cyclopentyl-7,8-dihydro-4-propyl-L ^ imidazo [2,] purine-5 (4-one hydrochloride

Compound 14: (5) -8-Cyclohexinolemethyl-2-cyclopentynole-7,8-dihydro-4-propyl_1-imidazo [2,1-i] purin-5 (4 ^)-one Hydrochloride salt

Compound 15: () -2-cyclopentyl-7,8-dihydro-8-phenyl-4-propyl-1 imidazo [2,1-i] purine-5 (4-one hydrochloride

Compound 16: 0?)-8-Benzyl-2-cyclopentyl-7,8-dihydro-4-propyl-1-imidazo [2, purine- ⁵ (4τ¾) -one hydrochloride Compound 17: (6) -8-benzyl-2-cyclopentyl-7,8-dihydro-4-propyl-1-imidazo [2, l-] purin-5-one hydrochloride

Compound 18: 2-cyclopentyl-8- (4-fluorobenzyl) -7,8-dihydro-4-propyl-1 ^ · imidazo [2,1-i] purine-5 (4 ^)-one hydrochloride

Compound 19: 2-cyclopentyl-8- (3-fluorobenzyl) -7,8-dihydro-4-propyl-1 ^ imidazo [2,1-i] purine-5 (4-one hydrochloride

Compound 20: 8- (4-Chlorobenzyl) -2-cyclopentinole-7, 8-dihydro-4-propyl-1 ^ imidazo [2, 1-i] purine-5 (4-one hydrochloride

Compound 21: 8— (3-chlorobenzinole) -2-pentyl pentinole-7,8-dihydro-4-1-propynole-1 ^ imidazo [2, l-i] purine-5 (4-one hydrochloride

Compound 22: 8- (2,6-dicyclopentadiene) -2-cyclopentino-7,8-dihydro-4-propylimidazo [2,1-i] purine-5 (4-one hydrochloride salt

Compound 23: 8- (4-bromobenzyl) -2-cyclopentyl-7,8-dihydro-4-propyl-1 ^ imidazo [2, tri] purine-5 (4-one hydrochloride

Compound 24: 8- (3-bromobenzinole) -2-cyclopentyl-7,8-dihydro-4-propyl-1 imidazo [2,1-i] purine-5 (4-one hydrochloride

Compound 25: 2-cyclopentyl-7,8-dihydro-8- (4-methoxybenzyl) -4-propyl-1 ^ · imidazo [2,1-i] purine-5 (4-one hydrochloride salt

Compound 26: 2-cyclopentyl-7,8-dihydro-8- (4-ditrobenzyl) -4-propyl-1 imidazo [2,1-i] purine- ⁵ ( ⁴ -one hydrochloride

Compound 27: (7?)-8- (4-benzyloxybenzyl) -2-cyclopentyl-7,8-dihydroxy-4-propyl-1 ^ · imidazo [2, tri] purine-5 (4- On hydrochloride

Compound 28: (6) -8- (4-benzinoleoxybenzinole) -2-cyclopentyl-7,8-dihydro-4_propyl-1 imidazo [2, tri] purine-5 (4- On hydrochloride

Compound 29: (7?)-8-benzyl-2-cyclopentyl-7,8-dihydro-1-methyl-4-propyl-1 ^ imidazo [2, l-ί] purine-5 (4- On hydrochloride

Compound 30: 2-cyclopentyl-7,8-dihydro-8-diphenylmethyl-4-propyl-1 ^ imidazo [2,1-ί] purine-5 (AH) -one hydrochloride

Compound 3 1: 2-pentyl-7,8-dihydro-8-phenethyl-4-propyl-1 ^ "imi Dazo ^[2, 1- i] purin - ⁵ ⁽⁴ - one hydrochloride

Compound 32: () -4, 8-dibenzyl-2-cyclopentyl-7, 8-dihydro-1 imidazo [2, 1-i] purine-5 (4-one hydrochloride

Compound 33: 0?)-8-Benzyl-7,8-dihydro-4-propyl-l / imidazo [2, purin-5 (4 ^ -one hydrochloride

Compound 34: 1,8-Dibenzyl-7,8-dihydro-4-propyl-1-imidazo [2,1-i] purine-5 (4 ^)-one hydrochloride

Compound 35:?)-8-Benzyl-7,8-dihydro-2,4-dipropyl-1-imidazo [2, purine-5 (4J¾) -one hydrochloride

Compound 36: (;?)-8-benzyl-2-cyclopropyl-7,8-dihydro-4-propyl-imidazo [2,1-i] purine-5 (4-one hydrochloride

Compound 3 7: (7?) -8-benzyl-2-cyc-butyl-7,8-dihydro-4-propyl-1 ^ imidazo [2,1-i] purine-5 (4-one-hydrochloric acid salt

Compound 38: (R) -8-benzyl-2-cyclohexyl-7,8-dihydro-4-propynole-1 imidazo [2, purine-5 (4 劝 -one hydrochloride

Compound 39: () -8 -benzyl-7,8-dihydroxy-2- (3-noradamantyl) -4--propyl-1 ^ imidazo [2,1-i] purine-5 (4-one hydrochloride

Compound 40: 8-benzyl-2-cyclopentylmethyl-7,8-dihydro-4-propyl-1 ^ imidazo [2, tri] purine-5 (4-one hydrochloride

Compound 41 1: (7?)-8-benzyl-7,8-dihydro-2-isopropyl-4-propyl-1-imidazo [2,1-i] purine 5 (4-one hydrochloride

Compound 42 2: (/?)-8-benzyl-2- (3-furyl) -7,8-dihydro-4-propylimidazo [2, purine-5 (4one hydrochloride

Compound 4 3: (? /) - 8_ benzyl-2-Ieri- butyl - 7, 8 dihydric mud - 4-propyl - 1 ^ Imi Dazo ^[2, 1-i] purin - ⁵础- one hydrochloride

Compound 4 4: (7?) -8-benzyl-7,8-dihydro-4-propyl-2- (3-Chenyl) -I imidazo [2, purine-5 ih-one hydrochloride

Compound 45: 8- (4-bromobenzyl) -2-cyclohexyl-7,8-dihydro-4-propyl-1 imidazo [2, purine-5 ( ⁴ -one hydrochloride Compound 46: 8- (4-Chlorobenzyl) -7,8-dihydro-2,4-dipropyl_1-imidazo [2,1-] purine-5 (4-one hydrochloride

Compound 47: 8- (4-Chlorobenzyl) -2-cyclohexanol-4-propyl-7,8-dihydro-1 ^ imidazo [2,1-i] purine-5 (4-one hydrochloride

Compound 4 8: 8 - (4-click every mouth benzyl) -2-cyclobutyl-4 - propyl - 7, 8 - dihydric mud - 1 ^ Imidazo ^[2, 1-i] purin - 5 ⁽⁴ - one hydrochloride

Compound 49: 8- (4-Fluorobenzyl) -2,4-dipropyl-7,8-dihydro-1H-imidazo [2,1-] purin-5 (4 ^)-one hydrochloride

Compound 50: 2-cyclohexyl-8- (4-fluorobenzyl) -7,8-dihydro-4-propyl-1 ^ imidazo [2,1-i] purine-5 (4 ^) -One hydrochloride

Compound 51 1: () -2-cyclobutyl-8- (3-fluorobenzyl) -7,8-dihydro-4-propyl-1 imidazo [2, purine-5 (4τ¾> -one hydrochloride

Compound 52: 2-Butyl-8- (4-fluorobenzyl) -7,8-dihydro-4-propyl-1-imidazo [2,1-] purine-5 (4-one hydrochloride

Compound 53: 8- (4-Fluorobenzyl) -2- (2-furyl) -7,8-dihydro-4-propyl-1 ^ imidazo [2,1-i] purine-5 (4-one hydrochloride

Compound 54: 0?) -8-(4-Fluorobenzyl) -2- (3-furyl) -7,8-dihydro-4-propyl-1 imidazo [2,1-i] purine-5 ( 4-ON

Compound 55: (?) -2 -iari-butyl-8- (4-fluorobenzyl) -7,8-dihydro-4-propyl-1 ^ "imidazo [2,1-i] purine-5 (4 -One hydrochloride

Compound 5 6: 8- (3-Fluorobenzyl) -7,8-dihydro-2,4-dipropyl-1 imidazo [2,1-i] purine-5 (4¾-one hydrochloride

Compound 57: 2-cyclobutyl-8- (3-fluorobenzoyl) _7,8-dihydro-4-propyl-1 ^ imidazo [2,1-i] purine-5 (4-one hydrochloride

Compound 58: 8- (3-Fluorobenzyl) -7,8-dihydro-2-isobutylinole-4-propynole-1 ^ imidazo [2, purine-5 (4-one

Compound 5 9: 2- (4-Buromofueniru) - 8- (3-Furuorobenjiru) -7, 8-dihydrazide mud - 4-propyl - 1 ^ Imidazo ^[2, 1-i] purin - ⁵ (4 - one hydrochloride

Compound 60: 8- (2-fluorobenzyl) -7,8-dihydro-2-isobutyl-4-propyl ~ \ H- Midazo [2, 1-i] pudding-5 (4 / caron

Compound 6 1: 2-cyclopentyl -8- (3-methylbenzyl) -7,8-dihydro-4-propyl-1 ^ imidazo [2, purine-5 (4-one

Compound 62: 2-cyclopentyl-7,8-dihydro-8- (3-iodobenzyl) -4-propyl-1 imidazo [2,1-/] purine-5 (4-one hydrochloride

Compound 63: 2-cyclopentyl-8- (2,3-difluorobenzyl) -7,8-dihydro-4-propyl-1 imidazo [2,1-i] purine-5 (4-one Hydrochloride

Compound 64: 2-Cyclopentyl-8- (2,5-difluorobenzyl) -7,8-dihydro_4 -propylimidazo [2, tri] purine 5 (4-one hydrochloride

Compound 65: 8- (2,5-dichlorobenzyl) -2-cyclopentyl-7,8-dihydro-4-propyl-1 ^ · imidazo [2,1-i] purine-5 (4_one Hydrochloride

Compound 66: [2-cyclopentyl-7,8-dihydro-4-propyl-1 ^ imidazo [2,1-i] purine-5 (4 ^ -one) -8-spiro-cyclopentane Hydrochloride

Compound 67: [7,8-dihydro-2- (3-noradamantyl) -4-propyl-1 ^ imidazo [2,1-i] purine-5 (4-one) _8-spiro-cyclopentane

Compound 68: (5) -8-ier-butyl-7,8-dihydro-2--2- (3-noradamantinole) -4-propyl-1 ^ imidazo [2,1-i] purine 5 (4-one hydrochloride

Compound 69: (5) -8-eri-butyl-2- (3-furyl) -7,8-dihydro-4-propyl-1-imidazo [2,1-i] purine-5 (4 ^) -ON

Compound 70: () -8-2 ^^-butyl-7,8-dihydro-2- (3,5-dimethylisoxazol-4-yl) -4-propylimidazo [2, 1 -i] purine-5 (4 ^)-one hydrochloride Compound 71: (5) -7,8-dihydro-2,8-diisopropyl-4-propyl-1 ^ imidazo [2,1-i] purine- 5 (4-one hydrochloride

Compound 7 2: [2-cyclopentyl-7,8-dihydro-4-propyl-1 imidazo [2,1-i] purine-5 (4τ¾) _one] -8-spiro-cyclohexane Hydrochloride

Compound 7 3: 8- (3-cyanobenzyl) _2 -cyclopentyl-7,8-dihydro-4-propyl-1 / imidazo [2, purine 5 (4 劝 -one

Compound 74: (R) -8-Benzinole-2-cyclopentyl-4-ethyl-7,8-dihydro-1 ^ imidazo [2,1-i] purine-5 (4one hydrochloride Compound 75: 8-benzyl-2-cyclopentyl-4-cyclopropylmethinole-7,8-dihydro-IH-midazo [2,1-i] purine-5 (AH) -one

Compound 76: 0?) -8-Benzyl-2-cyctopropylmethyl-7,8-dihydro-4-propyl-I imidazo [2,1-i] purine-5 (4 ^ -one hydrochloride

Compound 7 7: 8- (3-carboxybenzyl) -2-cyclopentyl-7,8-dihydro-4-propyl-1 ^ imidazo [2,1-i] purine-5 {H) -one

Compound 78: 2-cyclopentene pentinole-7, 8-dihydro-8- (α, α-dimethinolebenzinole) -4-propyl-1 ^ imidazo [2, purine-5 (4 / -one

Compound 79: (7?)-8- (4-Hydroxybenzyl) -7,8-dihydro-4-propyl-2- (3-pyridyl) _1 imidazo [2, purine-5 (4- On

Compound 80: (?)-8-benzyl-7,8-dihydro-4-propyl-2- (3-pyridyl) -1 / "imidazo [2,1-i] purine_5 (4 / Force-on

Compound 81: () -8-benzyl-7, 8-dihydro-2-phenyl-4-propyl-1 ^ imidazo [2,1 _] purine-5 (4J¾-one

Compound 82: (;?)-8-benzyl-7,8-dihydro-2- (2,2,3,3-tetramethylcyclopropyl) -4-propyl-1 imidazo [2, 1- ] Pudding _5 (4-on

Compound 83: (R) -8-benzyl-7,8-dihydro-2- (3,4-methylenedioxyphenyl) -4-propynole-1 imidazo [2,1-i] purine- 5 (4 ^>-ON

Compound 84: (;?)-8-benzyl-7, 8-dihydro-4-propyl-2- (4-pyridyl) -1 ^ imidazo [2, purine-5 (4 / -one

Compound 85: 8-benzyl-7,8-dihydro-4-propynole-2- (2-virazyl) -1 imidazo [2,1-i] purine-5-one

Compound 86: 8-benzyl-7,8-dihydro-4-propyl-2- (2-phenyl) -1 imidazo [2,1-i] purine-5 (4H) -one

Compound 87: () -8-benzyl-2-cyclopentyl-7,8-dihydro_4-methyl-L ^ imidazo [2,1-i] purine-5 (4/1) -one

Compound 88: 0?)-8-Benzyl-2-cyclopentyl-7,8-dihydro-4-phenizole-1 ^ ~ imidazo [2,1-/] purine-5 (4τ¾-one

Compound 89: 8- (4-er-butylbenzyl) -2-cyclopentyl-7,8-dihydro-4-p Mouth pill-1 ^ imidazo [2, pudding-5 (4 劝 -on

Compound 90: 2-cyclopentyl-7, 8-dihydro-8_ (2-phenylbenzinole)-4-propyl-1 ^ imidazo [2, purine-5 (4Λ0-one

Compound 91: 2-cyclopentyl-7,8-dihydro-8_ (3-trifluoromethylinolevenyl) -4-propyl-1 ^ imidazo [2,1-i] purine-5 (4 ^) -ON

Compound 92: 2-cyclopentyl-8- [3- (2-fusoleophenoxy) benzyl] -7,8-dihydro-4-propyl-1 imidazo [2,1] purine-5 (4 ^)-ON

Compound 93: 2-cyclopentyl-7,8-dihydro-8- (3-phenoxybenzinole) -4-propyl-1 imidazo [2,1-ί] purine-5 (4 / force -ON

Compound 94: 2-Cyclopentyl-7, 8-dihydro-8- (3-trifluoromethoxybenzyl) -4-propyl-1 ^ imidazo [2,1-] purin-5 (4 ^)-one

Compound 95: 8-Bis (3,5-trifluoromethinolebenzinole) -2-cyclopentyl-7,8-dihydro-4-propyl_1imidazo [2,1i] purine-5 ( 4 / -on

Compound 96: 8-benzyl-2-cyclopentyl-7,8-dihydro-8-methyl_4-propylmidazo [2, to] purine-5 (4-one

Compound 9 7: (5) -2 consequent opening pentyl - 7, 8 dihydric mud - 8_ (4-picolyl) - 4- (? / ~ Prop Honoré) - 1 ^ Imidazo ^[2, 1-i] purin - ⁵ (AH)-ON

Compound 98: (/?)-2-cyclopentyl-7,8-dihydro-8- (4-picolyl) -4- (propyl) -1 1imidazo [2, purine-5 (4-one-D- Tartrate

Compound 99: 2-cyclopentyl-7,8-dihydro-8- (2-picolyl) _4- (propyl) -1 imidazo [2, purine-5 (4 ^)-one

Compound 100: 2-cyclopentyl-7,8-dihydro-8_ (3-picolyl) -4- (propyl) -1 imidazo [2,1-i] purine-5-one

Compound 101: 2-cyclopentyl-7,8-dihydro-8- (2-methylthiazole-4-ylmethyl) -4- (propyl) -1 imidazo [2,1-i] purine-5 ( 4 ^)-one hydrochloride Compound 102: 2-cyclopentyl-7,8-dihydro-4- (propyl) -8_ (2-pyrazulmethyl) -1 ^ imidazo [2,1-i] purine-5 (4 ^)-ON

Compound 103: 2-cyclopentyl-7,8-dihydro-4- (propyl) -8- (4-pyrimidinylmethyl) -1 imidazo [2, purine-5 (4 / carone Compound 104: 7,8-dihydro-8_ (4-picolyl) -2,4-dipropyl-l ^ imidazo [2, 1-i] purine-5 (4¾) -one

Compound 105: 0?) -2 -Cyclohexyl-7, 8-dihydro-8- (4-picolyl) -4- r "propyl" -1 imidazo [2, 1-i] purine-5 (4-on

Compound 106: (^)-2-cyclobutyl-7,8-dihydro-8- (4-picolinole) -4- (propyl) -1 imidazo [2, tri] purine-5 (4 on D-tartrate

Compound 107: 2- (r-butyl) -7,8-dihydro-8- (4-picolyl) -4-(Bushiropropyl) -1 / imidazo [2,1-] purine-5 (4-on

Compound 108: 7,8-Dihydro-2- (1-methylcyclohexanol)-8- (4-picolyl) -4-0? "Propyl) -Ιτ ^ imidazo [2,1-i ] Purin-5 (4 ^)-one dihydrochloride

Compound 109: 7,8-dihydro-8- (4-picolyl) -4- (propyl) -1 ^ "imidazo [2,1-i] purine-5 (4 / -one

Compound 110: 2-cyclopentyl-4-cyclopropylmethyl-7,8-dihydro_8- (4-picolyl) -1-imidazo [2,1-] purin-5 (4i¾) -one dihydrochloride

Compound 111: 2- (tributyl) -4-cyclopropylmethyl-7,8-dihydro-8- (4-picolyl) -1 ^ imidazo [2,1-i] purine-5 (4 ^- On dihydrochloride

Compound 112: 2-cyclopentyl-4-ethyl-7,8-dihydro-8- (4-picolyl) -1 imidazo [2,1-i] purine-5 {H) -one dihydrochloride

Compound 1 1 3: 1-benzyl-2-cyclopentyl-7,8-dihydro-8-methylsulfoeloxymethyl-4-0? "Propyl) -1 imidazo [2,1-] purine-5 (4 -ON

Compound 114: 2-cyclopentene, 7,8-dihydro-8-methylsnolephonyloxymethylin-1-yl-methoxymethyl-4-(/?-Propyl) -1 imidazo [2,1-i ] Purin-5 (4τ¾) -one Compound 1 15: 2-cyclopentyl-8- (1,3-dioxoisoindoline-2-ylmethinole) -7,8-dihydro-1-methoxymethyl-4 -(Propyl)-1 ^ imidazo [2, purin-5 (4 / force-on

Compound 116: 8-aminomethyl-2-cyclopentyl-7,8-dihydro-4- (propyl) -1 ^ imidazo [2,1-i] purine-5 (4-one dihydrochloride

Compound 1 17: 2-cyclopentyl / le-7,8-dihydro_4_r "propyl)-8- (1-virazolylmethyl) -1 imidazo [2,1-i] purine-5 (4-one 6 Compound 1 1 8: 2-cyclopentyl-7,8-dihydro-8- (1-dimidazolinolemethyl) -4-(/?-Propyl) -1 imidazo [2,1-i] purine-5 (4 on

Compound 119: 2-cyclopentinole-7,8-dihydro-4- (propynole) -8- (1,2,4-triazol-1-ylmethyl) -1 ^ imidazo [2,1-i ] Purin-5 (4 ^)-on

Compound 120: 2-cyclopentynole- ⁷ , 8-dihydro-4-(/? "Propinole) -8_ (1-pyrrolylmethyl) -1 imidazo [2,1-i] purine-5 (4 / -on

Compound 1 2 1: 8-(1-Benzimidazolylmethyl) -2-cyclopentyl-7,8-dihydrido-4--(/ ^ propyl) -1 ^ imidazo [2, 1-i] Purine-5 (4τ¾-one hydrochloride

Compound 122: 8-Chloromethyl-2-cyclopentyl-7,8-dihydro-4- (propyl)-1 ^ · imidazo [2, purine-5 (4 ^>-one hydrochloride

Compound 123: 2-cyclopentyl-7,8-dihydro-8-phenylaminoamino-4-(/? ~ Propyl) -1 ^ imidazo [2, l_i] purine- ⁵ ( ⁴ ^)-one Dihydrochloride

Compound 1 2 4: 2-cyclopentyl-7,8-dihydro-8-piperidinomethyl-4-(/? ~ Propyl) -1 imidazo [2,1-i] purine- ⁵ (4-one 2-hydrochloride salt

Compound 125: 2-cyclopentyl-7,8-dihydro-4- (propynole) -8- (1-pyrrolidyl-methyl) -1 imidazo [2,1-i] purine-5 (H) -one 2 Hydrochloride

Compound 1 2 6: 2-cyclopentyl-7,8-dihydro-8-morpholinomethyl-4_0τ ~ propyl)-1 ^ imidazo [2, purine-5 (4-one dihydrochloride

Compound 127: 8- (4-benzyl-1-piperazinylmethyl) -2-cyclopentyl-7,8-dihydro-4- (propyl) -1 imidazo [2,1-] purine-5 ( 4-one trihydrochloride Compound 1 2 8: 2_cyclopentyl-7,8_dihydro-8- (4-pheninoleic 1-piperazininolemethyl) -4- (propyl) -1 ^ imidazo [2,1- i] Purin-5 (4 ^)-one trihydrochloride Compound 1 229: 8- (4-benzylpiperidinomethyl) -2-cyclopentyl-7,8-dihydro Mouth-4- (propyl imidazo [2 , 1 '] purine-5 (4-one dihydrochloride

Compound 130: 8-Benzylaminomethyl-2-cyclopentyl-7, 8-dihydrogen _4_ (n-propyl) -I Imidazo [2, l_i] purine-5 (4-one dihydrochloride

Compound 13 1: (7?)-1,8-dibenzyl-2-bromo-7,8-dihydro-4-(/? ~ Propyl) -1 imidazo [2, purine-5 (4τ¾-one

Compound 132: 0?)-8-Penzinole-7,8-dihydroxy-deoxymethoxymethyl_2-methinorethio 6136

-4- (propyl) -1 / "imidazo [2,1-i] purine-5 (4 / -on

Compound 133: () _1,8-Dibenzyl-7,8-dihydro-4- (propyl) -2- (1-pyrrolidinyl) imidazo [2,1-i] purine-5 (4 / -one

Compound 134: () _8 -benzyl-7,8-dihydro-4- (propyl) -2- (1-pyrrolidinyl) -1 ^ imidazo [2,1-i] purine-5 (4 / -one Hydrochloride

Compound 1 35: (7?) -8-benzyl-7,8-dihydro-2-morpholino-4- (propinole) -1 imidazo [2, purine-5 (4-one

Compound 1336: 8-benzyl-7,8-dihydro-2- (1-hydroxycyclopentyl) -4- "propyl) -1 imidazo [2,1-i] purine-5 (4 / -ON

Compound 1337: 1,8-dibenzyl-2-formyl-7,8-dihydro-4-O "propyl) -1 ^ imidazo [2,1-i] purine- ⁵ (4 ^)-one

Compound 1 38: (;?)-1, 8-dibenzyl-2-chloromethyl-7, 8-dihydro-4-(--propyl) -1 imidazo [2, purine-5 (4 ^)-one

Compound 1 39: 0?)-8-Benzyl-2-dimethylaminomethyl-7,8-dihydro-4_ (Pupil pill) -1 ^ imidazo [ ² , purine- ⁵ {ΑΙί) -one

Compound 140: 0?)-8-benzyl-7,8-dihydro-2-piperidinomethyl-4- (propyl) -1 ^ "imidazo [2, purine-5 (4-one

Compound 141: 0?)-8-benzyl-2-ethoxymethyl-7,8-dihydro-4-(/? "Propyl) -1 imidazo [2,1-] purine-5 (4 ^) -On 0.5 fumaric acid

Compound 14 ^2: 0) - 8-benzyl - 2- [(4, 5 ^{^} - dimethyl - 1,3-O hexa cyclopentadienyl emissions - 2-I le] -7, 8-dihydrazide mud - 4- ( 3 ~ propyl) -L ^ imidazo [2, purine-5 (4-one

Compound 143: 1,8-dibenzyl-7,8-dihydroxy-2-methoxycarbonyl-4- (propyl) -1 ^ imidazo [2,1-i] purine-5 (4 ^)-one

Compound 144: (_ /?)-1,8-dibenzyl-7,8-dihydro-2- (2-hydroxypropane-2-yl) -4- (Λ "propyl) -1 imidazo [2 , 1- i] pudding -5 (4 ^)-on

Compound 145: (7?)-8-benzyl_7,8-dihydro-2-piperidinocarbon-4-yl- (1) -imidazo [2, purine-5 (4-one

Compound 146: () -8-benzyl-7,8-dihydro-2-morpholinocarbon-4-yl- Mouth pill)-imidazo [2, 1-] pudding -5 (4 ^ -on

Compound 147: 8_benzyl-7,8-dihydro-4- (propyl) -2- (tetrahydrofuran-2-yl) -1 ^ · imidazo [2,1-i] purine-5 ( 4 ^ -one D-tartrate

Compound 148: () -8-benzyl-2- (1-ethoxyshethyl) -7,8-dihydro-4- (propyl) -1 imidazo [2,1-i] purine-5 (4-one 0.5 Fumarate

Compound 149: 0?)-8-Benzyl-7,8-dihydro-4- (propynole) -2- (tetrahydropyran-4-yl) -1 ^ imidazo [2,1] purine-5 (4 ^)-one hydrochloride

Compound 150: () -8-benzyl-7,8-dihydro-2-(tran-4-hydroxyhexyl)-4-(/ 7-propyl) -1 ^ imidazo [2,1 '] Purine-5 (4 ^ -one hydrochloride

Compound 15 1: (7?)-8-benzyl-2- (1,3-dioxolan-2-spirocyclopentane

-2, -yl) -7,8-Dihydro-4-propyl) -1 imidazo [2,1-] purine-5 (4-one, compound 1552: (/?)-8-benzyl -2-Benzyloxymethyl-7,8-dihydro-4- (Λ "プ") 1 imidazo [2,1-i] purine-5 (4 ^)-one 0.5 fumarate

Compound 15 3: () -8 -benzyl-7,8-dihydro-2-(-methoxybenzyl) -4--(propyl) -1 imidazo [2, 1-i] purine-5 (4-one 0.5 fumarate

Compound 154: () -8-benzyl-7,8-dihydro-2- (2-methoxethyl) -4- (propyl) -1 imidazo [2,1] purine-5 (4 ^)- On hydrochloride

Compound 1 5 5: 8-benzyl - 2- (2-carboxy E Chill) - 7, 8 dihydric mud - 4 - (propyl) - 1 Imidazo ^[2, 1-i] purin - ⁵ (4 - one

Compound 156: (-8-(-butyl) -7,8_dihydro-2- (1-methylsulfonylpyridin-4-yl) -4-0? "Propyl) _1 ^ imidazo [2 , 1-i] purine-5 (4 ^)-one Compound 157: () -8-benzyl-2-butoxycarbonylpiperidine-4-yl) -7,8-dihydro-4- (propyl) -1 Imidazo [2, 1-i] purine-5 (4 劝 -one hydrochloride

Compound 158: () -2-[ra? 4-(Aminomethyl) cyclohexyl] -8 -benzyl-7,8-dihydro-4- (propyl) -1 ^ imidazo [2, 1- i] Purin-5 (4 ^)-one Compound 15 9: 2- [32- (acetamidomethyl) cyclohexyl] -8-benzyl-7,8-dihydro-4-((propyl)- 1 Imidazo [2, 1-] purine-5 (4-one hydrochloride salt

Compound 1 6 0:?? 0) - 8-benzyl - 2-Echiruchiomechiru - ^7, 8 dihydric mud - 4 - (/ ~ prop Le) - 1 Imidazo [2, 1] purine - 5 (4 - one 0.5 Fumarate

Compound 161: 0?)-8-benzyl-2-ethylsulfonylmethyl-7,8-dihydro-4- (propyl) -1 imidazo [2,1-i] purine- ⁵ (4-one 0.5 Fumarate

Compound 16 2: 0?)-1, 8-Dibenzyl-5-octopen-2-cyclopentyl-7,8-dihydro-1 imidazo [2,1-/] purine

Compound 16 3: 0?)-8-benzyl-2-cyclopentyl-7,8-dihydro-5-(/ ^ propylamino) -1 imidazo [2,1-i] purine

Compound 164: () -8-benzyl-2-cyclopentyl-7,8-dihydro-5- (2-pyridinoethylamino) -1 imidazo [2,1-i] purine

Compound 165: (7?)-8-benzyl-2-cyclopentyl-7,8-dihydro-5- (topyrrolidinyl) -1H-midazo [2, purine

Compound 166: (TP) -8-benzyl-2- (ier-butyl) -5-ethoxy-7,8-dihydro-1 imidazo [2,1-i] purine

Compound 1667: O) -8-benzyl-2-cyclopentyl-7,8-dihydro-5- (3-methylthiopropyloxy) -1 ^ imidazo [2,1-i] purine

Compound 168: G¾-8-benzyl-2-cyclopentyl-7,8-dihydro-5- (3-methylsulfonylpropyloxy) -1 imidazo [2,1-i] purine

Compound 169: (7?)-8-benzyl-2- (ieri-butyl) -7,8-dihydro-5-methylthio-1 imidazo [2, tri] purine

Compound 170: /?) -8-benzyl-2-cyclopentyl-5-ethyl-7,8-dihydro-1 imidazo [2,1-i] purine

Compound 17 1:?)-8-benzyl-5-cyano-2-cyclopentyl-7,8-dihydro-1 imidazo [2,1-i] purine

Compound 17 2:?) -8-benzyl-2-cyclopentyl-7,8-dihydro-5_ (1tetrazol-5-inole) -1 ^ imidazo [2,1-i] purine

Compound 1 7 3: 0?)-8-Benzyl-4-potoxymethyl-2-cyclopentyl-7,8-dihydro-1 ^ imidazo [2,1-i] purine-5 (4-one hydrochloride Compound 1 74: (() -8-benzyl-2-cyclopentyl-4,5,7,8-tetrahydro-5-oxo-1 ^ "imidazo [2,1-i] purine-4-y Le) -7 ^ propylacetamide

Compound 1 75: (7?)-8-benzyl-2-cyclopentyl-7,8-dihydro-4- [3- [2-oxazolidinone-3-inole) propyl] -1 imidazo [2,1-] Purine-5 (4-on 0.5 fumarate

Compound 176: (;?)-2-cyclopentyl-8- (4-fluorobenzyl) '-7,8-dihydro-4- (2-hydroxyxethyl) -1 ^ imidazo [2,1-i] Purine-5 (4-one hydrochloride Compound 177: (/?)-8-benzyl-2-cyclopentyl-7,8-dihydroxy-4- (2-hydroxy-2-methylpropyl) -1 ^ Imidazo [2, 1-i] purine 5 (4-one hydrochloride

Compound 178: (/?)-8-benzyl-2-cyclopentyl-7,8-dihydro-4- (3-hydroxypropyl) -1 ^ imidazo [2,1-i] purine-5 (4-one Hydrochloride

Compound 179: () -8-benzyl-2- (ier-butyl) -7,8-dihydro-4_ (3_hydroxypropyl) -1 ^ imidazo [2,1-i] purine-5 (4 ^ -One hydrochloride

Compound 180: 1- (0?)-8-benzyl-2-cyclopentyl-4,5,7,8-tetrahydro-5-oxo-1imidazo [2,1-i] purin-4-yl ) Butane-3-one ethylene acetal compound 18 1: () -8 -benzyl-2-cyclopentyl-7,8-dihydro-4--(3-hydroxy-3-methylbutyl)-1 ^ imidazo [ 2, Purine-5 (4 ^)-one hydrochloride

Compound 18 2: 0?)-8-Benzyl-2- (iar-butyl) -7,8-dihydro-4- (3-hydroxy

-3-methylbutyl) -1 imidazo [2, purine-5 (4-one hydrochloride

Compound 183:?)-9-benzyl-2-ethoxymethyl-6,7,8,9-tetrahydro-4-(/? ~ Propyl) -1 / · pyrimidino [2, purine-5 (on

Compound 184: 8-benzyl-2-ethoxymethyl-6,7,8,9-tetrahydro-4-propyl)-1 ^ · pyrimidino [2, purine-5 (M-one fumarate

Compound 185: 2-cyclopentyl-6,7,8,9-tetrahydro-4- (Λ-propyl) -8- (3-pyridyl) -1g-pyrimidino [2,1-i] purine-5 ( 4-ON

One or more selected from sulfonylurea antidiabetic agents and non-sulfonylurea K + ATP channel blocker antidiabetic agents, and selected from compound (1), compound (II) and pharmaceutically acceptable salts thereof The combination with at least one is not particularly limited, but preferable combinations include, for example, ① Glibenclamide and compound 16 ；

② Glibenclamide and compound 98;

③ Glibenclamide and compound 106;

④ Daliclazide and compound 16;

⑤. Daliclazide and compound 98;

⑥ daliclazide and compound 106;

Glimepiride and compound 16;

Glimepiride and compound 98;

⑨glimepiride and compound 106;

Of these, a combination of (1) glibenclamide and compound 16; (2) glibenclamide and compound 98; (3) glibenclamide and compound 106 is preferred.

One or more selected from sulferurea anti-diabetic agents and non-sulfonyl urea K + ATP channel blocker anti-diabetic agents, and selected from compound (1), compound (II) and pharmaceutically acceptable salts thereof In combination with one or more of the above, a synergistic insulin secretion-promoting effect in cultured cells / 3 cells and a high hypoglycemic effect in rats are indicated, so that diabetes therapeutics, diabetic complications (eg, retinopathy, renal disease) And / or neurosis) are useful as preventive and / or therapeutic agents. Further, at least one selected from the compound (1), the compound (II) and a pharmaceutically acceptable salt thereof is a sulfonylurea antidiabetic agent or a non-sulfonylurea K + ATP channel blocker antidiabetic. It is also useful as an active ingredient of a drug effect enhancer or a side effect reducing agent.

The therapeutic agent for diabetes or the prevention or treatment of diabetic complications of the present invention includes at least one selected from a sulfolurea antidiabetic agent and a non-sulfururea K + ATP channel blocker antidiabetic agent, The compound (1), the compound (II) and one or more selected from pharmacologically acceptable salts thereof are used in combination. At this time, it is possible to separately or simultaneously administer only the above two components in combination, but usually, a pharmaceutical composition comprising the above combination and one or more pharmaceutical additives is used. It is desirable to be provided in the form of an object.

Further, the sulfonylurea antidiabetic agent of the present invention or the non-sulfonylurea K + AT Compound (1), compound (II), and their pharmacological agents include those that enhance the effects of locker antidiabetic drugs or those that reduce the side effects of sulfonylurea antidiabetic drugs or nonsulfonylurea K + ATP channel blocker antidiabetic drugs. It is possible to administer only one or more selected from salts acceptable for the above, but usually, the active compounds (1), (II), and their pharmacologically acceptable It is desirable to provide in the form of a pharmaceutical composition containing one or more selected from salts and one or more pharmaceutical additives.

Anti-diabetic agent of the present invention, agent for preventing and / or treating diabetic complications, sulfonyl urea anti-diabetic agent or non-sulfonylurea K + ATP channel blocker anti-diabetic agent effect enhancer and sulfonylurea anti-diabetic agent or non-sulfonylurea anti-diabetic agent Sulfururea K + ATP channel blocker The anti-diabetic agent side-effect reducing agent can be administered to humans and other mammals.

Anti-diabetic agent of the present invention, prevention of diabetic complications Z or therapeutic agent, sulfonyl urea anti-diabetic agent or non-sulfonylurea K + ATP channel blocker anti-glycemic effect enhancer and sulfonylurea anti-diabetic agent Drug or non-sulfonylurea K + ATP channel blocker The form of the drug for reducing the side effects of antidiabetic drugs is not particularly limited, and it can be selected from oral or parenteral dosage forms that are most suitable for the purpose of treatment or prevention. It is possible to select the form. Pharmaceutical forms suitable for oral administration include, for example, tablets, capsules, powders, granules, fine granules, syrups, solutions, emulsions, suspensions, chewing agents, and the like. Formulations suitable for administration include, for example, injections (for subcutaneous injection, intramuscular injection, intravenous injection, etc.), infusions, inhalants, nebulizers, suppositories, gels or ointments Examples thereof include, but are not limited to, transdermal absorbents, transmucosal absorbents, transdermal absorbents in the form of patches, tapes and the like.

Liquid preparations suitable for oral administration, such as solutions, emulsions, or syrups, include water, sucrose, sorbitol, fructose, and other sugars, polyethylene glycol, propylene glycol, and other daricols, sesame oil, olive oil, and soybean oil. It can be produced by using oils such as oils, preservatives such as hydroxybenzoic acid esters, and flavors such as strawberry flavor and peppermint. Also capsule For the manufacture of solid preparations such as tablets, tablets, powders and granules, excipients such as lactose, glucose, sucrose and mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc Agents, binders such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin, surfactants such as fatty acid esters, and plasticizers such as glycerin.

Formulations for injection or infusion suitable for parenteral administration preferably contain the above-mentioned substances, which are the active ingredient, dissolved or suspended in a sterile aqueous medium isotonic with the blood of the recipient. For example, in the case of an injection, a solution can be prepared using a saline solution, a pudose solution, or an aqueous medium composed of a mixture of a saline solution and a glucose solution. Formulations for enteral administration can be prepared using carriers such as cocoa butter, hydrogenated fats and hydrogenated carboxylic acids, and are provided as suppositories. In the production of sprays, the above-mentioned substance as an active ingredient can be dispersed as fine particles, and it does not irritate the oral and respiratory tract mucous membranes of the recipient and facilitates absorption of the active ingredient. Can be used. Specific examples of the carrier include lactose and glycerin. Preparations in the form of an aerosol or dry powder can be prepared depending on the nature of the substance used as the active ingredient and the carrier used. These preparations for parenteral administration include one or more selected from glycols, oils, flavors, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. Alternatively, two or more auxiliary components can be added.

The form of administration of the therapeutic agent for diabetes and the prevention of diabetic complications of the present invention and the Z or therapeutic agent is not particularly limited, and at the time of administration, a sulfourea antidiabetic agent and a non-sulfonyl urea K + ATP channel blocker antidiabetic agent At least one selected from the group consisting of the compound (1), the compound (II) and a pharmacologically acceptable salt thereof. Such administration forms include, for example, (1) one or more selected from sulfonylurea antidiabetic agents and non-sulfonylurea K + ATP channel blocker antidiabetic agents, compound U), compound (II) and their pharmacology. Administration of a single preparation obtained by simultaneously formulating one or more salts selected from the group of salts that are acceptable, (2) Sulfonylurea antidiabetic agents, and (2) Nonsulfonylurea K + ATP channel blocker selected from antidiabetic agents One or more and the compound (1) Simultaneous administration by the same administration route of two formulations obtained by separately formulating one or more selected from compound (II) and one or more pharmacologically acceptable salts thereof, ③ sulfo- Lurea antidiabetic agent: one or more selected from non-sulfonylurea K + ATP channel blocker antidiabetic agents, compound (1), compound (II) and pharmaceutically acceptable salts thereof Administration of two preparations obtained by separately formulating one or more selected from the group consisting of two or more preparations at the same administration route with a time lag, ④Sulfonate / reurea antidiabetic agent and non-sulfolurea K + ATP channel blocker is obtained by separately formulating one or more selected from antidiabetic agents and one or more selected from compound (1), compound (II) and a pharmacologically acceptable salt thereof. Simultaneous administration of the two formulations via different routes of administration, ⑤ At least one selected from a rufonylurea antidiabetic agent and a non-sulfonylurea K + ATP channel blocker antidiabetic agent, and selected from compound (1), compound (II) and a pharmaceutically acceptable salt thereof 1 And two or more preparations obtained by separately preparing two or more preparations at different time points by different administration routes. Above all, the above ① and ③ are preferred.

More specifically, one or more compounds selected from a sulfonylurea antidiabetic agent and a non-sulfolurea K + ATP channel blocker antidiabetic agent are combined with a compound (1), a compound (II), and a pharmacological agent thereof. It is preferable to separately prepare one or more selected from salts acceptable in the form of an oral preparation such as a tablet, and to administer the two oral preparations simultaneously or with a time lag.

The dosage and frequency of administration of the therapeutic agent for diabetes or the preventive and / or therapeutic agent for diabetic complications of the present invention depends on the type and severity of the disease, the dosage form, conditions such as the age and weight of the patient, and the presence or absence of complications. Can be appropriately increased or decreased depending on the various factors described above.

The dose of the sulfonylurea antidiabetic agent or the non-sulfonylurea K + ATP channel blocker antidiabetic agent can also be appropriately selected based on the dose used clinically.

For example, when a sulfonylurea antidiabetic or non-sulfonylurea K ⁺ ATP channel blocker antidiabetic is administered to an adult diabetic patient (body weight 50 kg), the daily dose is usually 0.01 to 50000 mg, Preferably, the dose is 0.1 to 5000 mg, which can be administered once or several times a day. In particular, when glibenclamide is used as a sulfonylurea antidiabetic or non-sulfonylurea K + ATP channel blocker antidiabetic, when administered to an adult diabetic patient (body weight 50 kg), the dose per dose is usually 0. The dose is 1 to 100 mg, preferably 0.5 to 50 mg, and this amount can be administered in one or several divided doses.

When administering compound (1), compound (II) or a pharmacologically acceptable salt thereof to an adult patient with diabetes mellitus (body weight 50 kg), the dose is usually 0.01 to 50000 mg per day. Preferably, 0.:! It can be administered once or several times a day. ,

In the therapeutic agent for diabetes or the prevention and treatment of diabetic complications of the present invention, at least one selected from a sulfolurea antidiabetic agent and a non-sulfonylurea K + ATP channel blocker antidiabetic agent, and a compound ( 1), compound (II) and one or more selected from pharmacologically acceptable salts thereof, in a compounding ratio of patient, patient's age and weight, symptoms, administration time, dosage form, administration method It can be appropriately selected depending on the combination of drugs and drugs. For example, compound (1), compound (II) or a pharmacologically acceptable salt thereof is usually added to 1 part by weight of a sulfonylurea antidiabetic or non-sulfonylurea K + ATP channel blocker antidiabetic. It can be used in an amount of about 0.000001 to 100,000 parts by weight, preferably about 0.000001 to 10,000 parts by weight.

Effect enhancer of sulfonylurea antidiabetic agent or non-sulfolurea K ⁺ ATP channel blocker antidiabetic agent of the present invention and reduction of side effects of sulfolurea antidiabetic agent or nonsulfonylurea K ⁺ ATP channel blocker antidiabetic agent The dose and the number of administrations of the compound (1), the compound (II) or a pharmacologically acceptable salt thereof in the preparation are described in the above description of the dosage and the number of administrations of the therapeutic agent for diabetes of the present invention. The dose and frequency of compound (1), compound (II) or a pharmacologically acceptable salt thereof described in the above.

One or more selected from the sulfonylurea antidiabetic agent and the non-sulfonylurea K + ATP channel blocker antidiabetic agent used in the present invention, compound (1), compound (II) and their pharmacologically With one or more selected from acceptable salts Combinations include, for example, prophylaxis of diabetes (eg, type 2 diabetes, gestational diabetes, etc.); therapeutic agents; prevention and treatment of glucose intolerance; inhibitors of the transition from glucose intolerance to diabetes; hyperlipidemia (eg, high Prevention of triglycerideemia, hypercholesterolemia, hypo-HD Lemia, etc .; therapeutic agent; prevention of hyperinsulinemia; therapeutic agent; diabetic complications (eg, retinopathy, nephropathy, neuropathy, macrovascular disorder) Prevention and treatment of coronary artery and cerebrovascular disorders; Prevention and treatment of hyperammonemia; Treatment and treatment of obesity Prevention and treatment of obesity; Hypertension that causes syndrome X, visceral obesity, insulin resistance diabetes It can be used as an agent for preventing and treating bone metabolic disorders such as osteopenia and osteoporosis.

One or more selected from the sulfonyl urea anti-diabetic agent and the non-sulfonyl urea K ⁺ ATP channel blocker anti-diabetic agent used in the present invention, compound (1), compound (II) and their drugs The therapeutic effect of diabetes (eg, hypoglycemic effect, etc.) possessed by a combination with at least one selected from physiologically acceptable salts is, for example, glucose before and after administration of the combination, glucose in venous blood plasma of the administration subject, Alternatively, the concentration can be evaluated by measuring the concentration of insulin and comparing the obtained concentration before and after administration. The compound (1), the compound (II) and one or more compounds selected from the group consisting of a sulfolurea antidiabetic agent and a non-sulfonylurea K + ATP channel used in the present invention. Combination with one or more selected from physically acceptable salts has excellent insulin secretion promoting action and hypoglycemic action.

One or more selected from the sulfonylurea anti-diabetic agent and the non-sulfonylurea K + ATP channel blocker anti-diabetic agent used in the present invention, compound (1), compound (II) and their pharmacologically acceptable The combination with one or more salts selected from the group consisting of the following active ingredients has superior pharmaceutical properties (e.g., enhanced insulin secretion promoting action, enhanced hypoglycemic action, Reduction of the use of each active ingredient, reduction of side effects such as hypoglycemia, reduction of secondary ineffectiveness, improvement of stability, improvement of bioavailability, improvement of in vivo absorption). In particular, one or more compounds selected from the group consisting of the sulfoelurea antidiabetic agent and the non-sulfonylurea K + ATP channel blocker antidiabetic agent used in the present invention, compound (1), compound (II) and their pharmacologically Combination with one or more selected from acceptable salts The insulin secretion effect is greater than the additive insulin secretion promoting effect predicted from the effect of each active ingredient alone. In addition, this combination provides a high hypoglycemic effect. The combination of sulfonylurea antidiabetic drugs currently used in the treatment of mammals, including humans, and nonsulfonylurea K + ATP channel blocker antidiabetic drugs provides such a synergistic insulin secretion effect. Because of this, this new combination is extremely useful as an antidiabetic agent. In addition, by reducing the amount of sulfonylurea antidiabetic used, it is possible to delay the onset of secondary ineffectiveness often observed when a sulfonylurea antidiabetic is used for a long period of time, or to reduce the onset itself. Can be.

Next, one or more selected from the sulfonyl urea antidiabetic agent and the non-sulfo-urea K + ATP channel blocker antidiabetic agent used in the present invention, compound (1), compound (II) and The effect of a combination with one or more selected from pharmacologically acceptable salts will be described in Test Examples.

Test Example 1: Insulin secretion promoting action

Knee cells established by Takasaki et al. (Endocrinology I, Vol. 127, pp. 126-131, 1990) ΜΙΝ6 cells have an elevated insulin content and glucose-stimulated insulin secretion in vivo. ] It is close to 3 cells and well preserves the properties of knee cells in vivo in that insulin secretion increases in response to glucose concentration [The above literature and Diabetologia, 36, 1139-1145 (1993)] ]. In addition, ΜΙΝ6 cells promote insulin secretion in response to a sulfonylurea agent used as a therapeutic agent for diabetes, for example, dalibenclamide [Cellular 'signaling, Vol. 5, pp. 777-786 (1993)].

The cultivation of 試験 6 cells and the insulin secretion test using ΜΙΝ6 cells were performed basically according to the method described in Diabetologia, Vol. 36, pp. 1399-1145 (1993). The effect of the compound on insulin secretion activity in the presence of 14.5 ramol / l glucose was determined by measuring the amount of insulin in the cell culture supernatant collected as follows. MIN6 cells cultured in a 24-well plate were mixed with buffer A containing 2 mmol / l dalcos (119 mmol / l sodium chloride, 4.74 mmol / l lithium chloride, 2.54 mraol / l calcium chloride, 1.19 ml). O / l magnesium sulfate, 1.19 mmol / l phosphoric acid Washed twice with 10 ml / l of dihydrogen, 10 mmol / l 2- [4- (2-hydroxyxethyl) -1-piperazyl] ethanesulfonic acid, 0.1% bovine serum albumin pH 7.3) Thereafter, the cells were incubated at 37 ° C. for 45 minutes in buffer A containing 1 ml of 2raraol / l glucose. After incubation, the culture supernatant was replaced with buffer solution A (1 ml) containing various concentrations of test compound and 8.4 mmol / l glucose, and incubated at 37 ° C for 45 minutes. Collected.

Antibody-reactive insulin secreted into the culture supernatant is replaced with 1% bovine serum albumin, 0.1% Tween 20, 0.12% ethylenediaminetetraacetic acid (EDTA) '2Na, 0.1% sodium azide After dilution with an acid buffer, quantification was performed by radioimmunoassay. A standard curve was prepared using human insulin as a standard substance, and each insulin value was calculated from the curve. Furthermore, the relative amount (%) of each measured value was calculated, with the insulin value obtained when dimethyl sulfoxide as a solvent was added instead of the test compound as 100%. The results are shown in Table 1 as the average of 4-8 cases.

As shown in Table 1, compound (1), compound (II) or their pharmacologically acceptable salts (1 μπιοΙ / L) and glibenclamide (0.1 μmol / L When used in combination, a marked increase in insulin secretion is observed as compared to the insulin secretion obtained by using each of them alone. On the other hand, nateglinide has no combined effect.

Test Example 2: Blood glucose elevation inhibitory effect

Compound 98, compound 1◦6 and nateglinide synthesized in accordance with International Publication W001 / 47931, and glipenclamide purchased from Sigma were all suspended in a 0.5 w / v% aqueous methylcellulose solution, and 0.5 w / v% Methyl cellulose in aqueous solution And administered orally to 9-week-old male GK rats (CLEA Japan, Tokyo) at a volume of 5 mL / kg body weight. Glucose was prepared as a 20 w / v% aqueous solution using distilled water for injection, and orally administered in a volume of 10 mL / kg body weight. Blood glucose was collected from the tail vein using a 25G injection needle (Termo, Tokyo) and measured with a blood glucose meter Dexter Z and a Dexter Z sensor (Bayer Sankyo, Tokyo).

a. Effect when not used in combination with dalibenclamide

An oral glucose tolerance test for grouping was performed two days before the efficacy evaluation. Actually, after measuring the blood glucose level of the rats fasted for 24 hours, 2 g / kg of darcose was orally loaded, and the blood glucose levels were measured 30, 60 and 120 minutes after the darcose loading. The animals were divided into groups so that the area under the blood glucose curve (AUC) of the change in blood glucose over time and the average value of the blood glucose at each time point were equal in each group (6 animals in each group).

The drug efficacy was evaluated using rats fasted for 24 hours two days after grouping. After measuring the blood glucose level, the test compound was orally administered. Thereafter, the blood glucose level was measured immediately before glucose loading, and then 2 g / kg glucose was orally loaded. The blood glucose level was measured 60 minutes after the glucose load. The test compound was orally administered 15 minutes before the glucose load.

b. Effects when used in combination with dalibenclamide

Two days before the efficacy evaluation, an oral glucose tolerance test was performed in the same manner as in a, and the animals were divided into groups (n = 6). The drug efficacy was evaluated using rats fasted for 24 hours two days after grouping. Groups other than the glibenclamide non-administration group were orally administered glibenclamide 3 or 10 mg / kg. Six hours later, the blood glucose level was measured, and glucose was orally administered at 2 g / kg. Blood glucose was measured 60 minutes after glucose loading. The test compound was orally administered 15 minutes before the glucose load.

The results are shown in Tables 2 to 4.

Table 2

(ifil sugar value mg / dL)

Average

No compound administration 337 4

Nateglinide alone (30 mg / kg) 284 26

Compound 9 8 alone (42 mg / kg) 263 5 Table 3

As shown in Table 2, when the combined use with glibenclamide was not performed and the blood glucose elevation suppressing effects of each compound were compared, both compound 98 and nateglinide showed a favorable blood glucose elevation inhibiting effect. On the other hand, as shown in Table 3, when combined with dalibenclamide (3 mg / kg), the effect of nateglinide is rather attenuated, but the effect of compound 98 is enhanced more than when administered alone. Was. In addition, the effect of glibenclamide was enhanced as compared with the case of single administration. Table 4 shows that even at higher doses of dalibenclamide (10 rag / kg), the condensed purine derivatives are still highly effective. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described more specifically with reference to examples, but these examples do not limit the present invention.

Example 1: Tablet Prepare tablets of the following composition in the usual manner, Formulation compound 9 8 18 mg dalibenclamide 2 mg lactose 143.4 rag

30 mg hydroxypropyl / resenorelose 6 mg magnesium stearate-0.6 mg

200 mg Example 2: Capsules

Prepare a capsule consisting of the following composition by the usual method, Formulation Compound 106 18 mg Glibenkurami 2 mg Avicenole 99.5 mg Magnesium stearate—0.5 m

120 mg Example 3: Tablet

A tablet having the following composition is prepared by a conventional method.

Prescription Compound 9 8 18 mg Nateglinide 2 mg Lactose 143.4 rag Potato starch 30 mg Hydroxypropinoresenolerose 6 mg Magnesium stearate 0.6 mg

200 mg Example 4: Tablet

A tablet having the following composition is prepared by a conventional method.

Formulation Compound 1 6 20 mg Lactose 143.4 mg

30 mg Hydroxypropinoresenololose 6 rag

^ Magnesium phosphate 0.6 mg

200 mg

Industrial applicability

According to the present invention, an antidiabetic agent comprising a sulfonylurea antidiabetic agent or a non-sulfonylurea K + ATP channel blocker antidiabetic agent and a condensed purine derivative can be provided.

Claims

The scope of the claims

1. at least one selected from a sulfonylurea antidiabetic agent and a non-sulfonylurea K + ATP channel blocker antidiabetic agent, and formula (I)

{Wherein, Χ to Υ is R ^lb N— C = 0 (where R ^lb is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted Aryl or a substituted or unsubstituted aromatic heterocyclic group) or N = C—W wherein W is a halogen, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic ring group, -NR ⁴ R ⁵ (wherein, R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted Ariru or substituted or is unsubstituted Ararukiru And R ⁵ together with the adjacent nitrogen atom form a heterocyclic group), -OR ⁶ , wherein R ⁶ is a substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl. Or substituted or unsubstituted aralkyl), -SR ^6a

(Wherein R ^6a is as defined above), substituted or unsubstituted lower alkyl or R ^2b represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted substituted alicyclic heterocyclic group, halogen, lower-grade alkylthio, -NR ⁷ (wherein, R ⁷ and R ⁸ are the same meanings as the R ⁴ and ^{_{R 5), - C0 2 H}} , lower alkoxycarbonyl - Le, - COHal (wherein, Hal is to display the halogen), (wherein, R ⁹ and R ^1Q are respectively synonymous with the R ⁴ and R ⁵⁾ -C0NR ⁹ R ¹⁰ or others - represents CH0 , R ^3b is a hydrogen atom, a lower alkyl, represents Araruki Le or lower alkoxyalkyl substituted or unsubstituted, nb represents an integer of 0 to 3, V ¹ represents hydrogen atom, a substituted or unsubstituted lower alkyl, substituted Or unsubstituted aralkyl Or represents unsubstituted Ariru or substituted or unsubstituted aromatic heterocyclic group, V ² represents a substituted lower alkyl or substituted or unsubstituted aromatic heterocyclic group, V ¹ is a hydrogen atom, lower alkyl, substituted or Represents an unsubstituted aralkyl or substituted or unsubstituted aryl, and ( _a ) Χ · Υ ′ ′ · Ζ is R ^lba N— C = 0 (where R ^lba is a substitution in the definition of R ^lb above. Represents a group other than lower alkyl), wherein R ^2b is substituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alicyclic heterocyclic group, halogen, lower alkylthio, -NR ⁷ R ⁸ (formula among, R ⁷ and R ⁸ Ru each as defined above der), - C0 ₂ H, lower alkoxycarbonyl, -COHal (in the formula, Hal is Ru as defined above der), -C0NR ⁹ R ¹⁰ (wherein , And R ^ie have the same ^{meanings as} described above) ^or- Represents CH0, (b) Χ to Υ · · represents R ^lb N—C = 0 (where R ^lb is as defined above), and R ^3b represents lower alkoxyalkyl, during c) Χ~Υ '·· Ζ is R ^lbb N_C = 0 (wherein, either R ^lbb represents represents) the location換低loweralkyl, (d) Χ Υ · ·· Ζ is N = c-W (wherein Wherein W is as defined above, wherein R ^2b is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group A substituted or unsubstituted alicyclic heterocyclic group, halogen, lower alkylthio, -NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ are as defined above), -CO ₂ H, lower alkoxycarbonyl , -COHal (where Hal is as defined above), -CONR ⁹ R ¹⁰ (wherein and R ^w are as defined above), or -CH0, or (e) Χ to Υ ··· When Ζ represents N = CW (where W is as defined above), and R ^3b represents lower alkyl, substituted or unsubstituted aralkyl or lower alkoxyalkyl, V ² represents lower alkyl Or a substituted or unsubstituted aralkyl or a substituted or unsubstituted aryl), and at least one selected from pharmacologically acceptable salts thereof. A therapeutic agent for diabetes.

2. Dalibenclamide, glibizide, daliclazide, glimepiride, tolazamide, tolbutamide, acetohexamide, carpamide, and kuput noreprono. 2. The therapeutic agent for diabetes according to claim 1, which is one or more antidiabetic agents selected from mid, glibornuride, gliquidone, glicentide, glisoramide, glisoxepide, glicloviramide, glicyclamide and glibusol.

3. The diabetes treatment according to claim 1 or 2, wherein the non-sulfonylurea K + ATP channel blocker anti-diabetic agent is one or more anti-diabetic agents selected from Lipac, 'V-dide, nateglide, and migulinide. Agent.

4. The condensed purine derivative is ()-8-benzyl-2-cyclopentyl-7,8-dihydro-4- pulpyr-1 imidazo [2,1-i] purine-5 (4-one, ()- 2-cyclopentyl-7,8-dihydro-8- (4-picolyl) -4-propyl-1 imidazo [2,1-i] purine-5 (4-one or (^ -2-cyclobutyl -7, 8-Dihydro-8- (4-picolyl) -4-propynole-1 imidazo [2,1-i] purine-5 (4-one is described in any one of claims 1-3. Antidiabetic agent.

5. at least one selected from a sulfolurea antidiabetic agent and a non-sulfonylurea K + ATP channel blocker antidiabetic agent, and formula (I)

(Wherein, R ^la represents a hydrogen atom, lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aromatic heterocyclic group, and R ^2a represents a hydrogen atom, lower alkyl, substituted or unsubstituted aralkyl, Represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group, represents a hydrogen atom, lower alkyl or substituted or unsubstituted aralkyl, and X ¹ and X ² are each independently hydrogen. Atom, lower class Alkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl, and na represents an integer of 0 to 3), a condensed purine derivative represented by the formula (II):

(π)

(Where '' is a R ^lb N_C = 0 (where R ^lb is a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted aryl or Represents a substituted or unsubstituted aromatic heterocyclic group) or N = C—W wherein W is a halogen, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, -NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted aralkyl; , And R ⁵ together with the adjacent nitrogen atom form a heterocyclic group), -OR ⁶ (where R ⁶ is a substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl or substituted Or unsubstituted aralkyl),-SR ^6a

(Wherein, R ^6a has the same meaning as R ⁶ above), represents a substituted or unsubstituted lower alkyl or cyano], and R ^2b represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted Aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, halogen, lower alkylthio, -NR ⁷ R ⁸ (wherein R ⁷ And R ⁸ are as defined above for R ⁴ and R ⁵ ), -CO ₂ H, lower alkoxycarbonyl, -COHal (where Hal represents halogen), -C0NR ⁹ R ¹⁰ (wherein R ⁹ and R ^w have the same meanings as R ⁴ and R ⁵ , respectively) or —CH 0, R ^3b represents a hydrogen atom, lower alkyl, substituted or unsubstituted aralkyl or lower alkoxyalkyl, and nb represents represents an integer of 0 to 3, V ¹ is hydrogen atoms , Substituted or unsubstituted lower alkyl, substituted or unsubstituted Ararukiru represents substitution or unsubstituted Ariru or substituted or unsubstituted aromatic heterocyclic group, V ² is a substituted lower alkyl or substituted or unsubstituted aromatic Represents a hydrogen atom, a lower alkyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted aryl, and (a) Χ '· Υ to Ζ R ^lba N— C = 0 ( Wherein R ^lba is the aforementioned R ^lb Represents a group other than substituted lower alkyl in the definition of), wherein R ^2b is substituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alicyclic heterocyclic group, halogen, lower alkylthio, -NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ are as defined above), CO ₂ H, lower alkoxycarbonyl, —COHal (where Hal is as defined above), —C 0NR ⁹ R ¹⁰ (wherein R ⁹ and R ^1Q are as defined above) or ^-CH0 , or (b) Χ—Υ ··· R ^lbb N— C = 0 (where R ^lbb is represent the same meanings as defined above), or R ^3b is a lower alkoxyalkyl, a (Χ ··· Υ~Ζ is R ^lb N-C = 0 (wherein, R ^lb represents a location換低loweralkyl) or it represents, (d) Χ ··· Υ~Ζ is N = C-W (wherein, W is a is synonymous with the) represents, R ^2b is a substituted or unsubstituted lower alkyl, lay be substituted Non substitution Ararukiru, substituted or unsubstituted Ariru, substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, a halogen, in a lower alkylthio, -NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ have the same meanings as defined above, respectively; -CO ₂ H, lower alkoxycarbol, -COHal (where Hal has the same meaning as described above), -C0NR ⁹ R ¹⁰ (wherein, And R ^1Q each have the same meaning as described above) or -CH0, or (e)) to Υ · Υ represents N = CW (where W has the same meaning as described above), and R ^3b represents V ² may be lower alkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aralkyl when lower alkyl, substituted or unsubstituted aralkyl or lower alkoxyalkyl, and the fused purine derivatives represented by From pharmacologically acceptable salts A preventive and / or therapeutic agent for diabetic complications, characterized by containing one or more selected.

6.Sulfonylurea antidiabetic drugs include glibenclamide, glibizide, gliclazide, darimepiride, tolazamide, tolbutamide, acetohexamide, carpamide, chronorebronomide, glibornuride, gliquidone, dalicentid, dalisoglidomide, glisoxolidomide 6. The preventive and / or therapeutic agent for diabetic complications according to claim 5, which is one or more antidiabetic agents selected from glyciclamide and glybusol.

7. The prevention of diabetic complications according to claim 5 or 6, wherein the non-sulfonylurea K + ATP channel blocker antidiabetic agent is one or more antidiabetic agents selected from lipaglinide, nateglide and miglidide. And / or therapeutic agents.

8. When the condensed purine derivative is (?)-8-benzyl-2-cyclopentyl-7 8-dihydro-4-prop-pyr-1 ^ imidazo [2, l-ί] purine-5 (4-one, (7 ?) -2-cyclopentyl-78-dihydro-8- (4-picolyl) -4-propyl-1 imidazo [2 1 '] purine-5 (4-one or () -2-cyclopentyl -7 8-Dihydro-8- (4-picolyl) -4-propyl-1-midazo

[2. The preventive and / or therapeutic agent for diabetic complication according to any one of claims 57, which is purine-5 (4-on).

9. Formula (I)

(I)

(In the formula, R ^la represents a hydrogen atom, lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aromatic heterocyclic group, and R ^2a represents a hydrogen atom, lower alkyl, substituted or unsubstituted aralkyl, Represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group, R ^3a represents a hydrogen atom, lower alkyl or substituted or unsubstituted aralkyl, and X ¹ and X ² are each independently Represents a hydrogen atom, a lower alkyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted aryl, and na represents an integer of 0. 3) a condensed purine derivative represented by the formula (II):

Where 式 Υ is R ^lb NC = 0 (where R ^lb is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted Or represents an unsubstituted aromatic heterocyclic group) or N = C_W wherein W is a halogen, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, -NR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are the same or different and are each a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl or substituted or Is the power of unsubstituted aralkyl, and R ⁵ together with the adjacent nitrogen atom form a heterocyclic group), -OR ⁶ (where is substituted or unsubstituted lower alkyl, substituted or unsubstituted represents the unsubstituted Ariru or substituted or unsubstituted Ararukiru), - SR ^6a (wherein, R ^6a has the same meaning as the R ^6), represents] a lower alkyl or Shiano substituted or unsubstituted, R ^2b is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group , Halogen, lower alkylthio, -NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ have the same meanings as R ⁴ and R ⁵ , respectively), -CO ₂ H, lower alkoxycarbonyl, -COHal (wherein Hal represents halogen ), In -C0NR ⁹ R ¹⁰ (wherein and R ^1Q is above and R ⁵ as synonymous) or respectively - represents CH0, R ^3b is a hydrogen atom, lower alkyl, substituted or unsubstituted Araruki Le or Represents lower alkoxyalkyl, nb represents an integer of 0 to 3, V ¹ represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted V ² represents a substituted lower alkyl or a substituted or unsubstituted aromatic heterocyclic group; V ¹ represents a hydrogen atom, a lower alkyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted And (a) Χ—Υ · Ζ represents R ^lba N—C = 0 (wherein R ^lba represents a group other than substituted lower alkyl in the definition of R ^lb above); ^2b is a substituted lower alkyl, Substituted or unsubstituted Ararukiru, substituted or unsubstituted alicyclic heterocyclic group, a halo gen, lower alkylthio, - dish ⁷ R ⁸ (wherein, R ⁷ and R ⁸ Ru each as defined above der), - C0 ₂ H, lower alkoxycarbonyl, -COHal (in the formula, Hal is Ru as defined above der), -C0NR ⁹ R ¹⁰ (wherein, R ⁹ and R ^1G is the same meanings as defined above, respectively) or - CH0 Or (b) Χ to Υ · '· Ζ represents R ^lb N—C = 0 (where R ^lb is as defined above), and R ^3b represents lower alkoxyalkyl, or (c ) in · · Upsilon · · · Zeta is R ^lbb N-C = 0 (wherein, either R ^lbb represents represents a location換低loweralkyl), (d) Χ Υ · · · Ζ is N = C-W ( wherein, W is represents the and is synonymous), R ^2b is a substituted or unsubstituted lower alkyl, substituted or non-substitution Ararukiru, substituted or unsubstituted Ariru, substituted or unsubstituted Aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, halogen, lower alkylthio, -NR ⁷ R ⁸ (wherein, R ⁷ and each have the same meanings as defined above), - C0 ₂ H, lower Alkoki Or (e) a group consisting of: -carbonyl, -COHal (where Hal is as defined above), -C0NR ⁹ R ¹⁰ (wherein and R ¹ "are each as defined above), or -CH0. When Χ represents N 2 CW (where W is as defined above) and R ^3b represents lower alkyl, substituted or unsubstituted aralkyl or lower alkoxyalkyl, V ² represents lower alkyl Or a substituted or unsubstituted aralkyl or a substituted or unsubstituted aryl) may be contained as an active ingredient at least one selected from the pharmacologically acceptable salts thereof. , A sulfonylurea antidiabetic or non-sulfonylurea K + ATP channel blocker antidiabetic effect enhancer.

10. When the sulfonoreurea antidiabetic agent is glibenclamide, glibizide, gliclazide, glimepiride, tolazamide, tolptamide, acetohexamide, carpamide, kokulpropamide, glibornuride, glicidone, glicentide, glisoramide 10. The sulfonylurea antidiabetic or non-sulfonylurea K + ATP channel blocker antidiabetic agent according to claim 9, which is one or more antidiabetic agents selected from the group consisting of glyoxepide, glicloviramide, glyccyclamide and glybusol.

11. The sulfonylurea antidiabetic agent according to claim 9 or 10, wherein the non-sulfonylurea K + ATP channel blocker antidiabetic agent is one or more antidiabetic agents selected from lipaglide, nateglinide and miglinide. Non-sulfonyl urea K + AT II channel blocker An anti-diabetic drug potentiator.

12. Condensed purine derivative power 8-Benzi ^ /-2-cyclopentyl-7,8-dihydro-4-propyl-1 ^ imidazo [2,1-] purine-5 (4-one, () -2-cyclo Pentinole-7,8-dihydro-8- (4-picolyl) -4-propyl-1 ^ imidazo [2,1-i] purine-5 (4-one or (7?)-2-cyclobutyl - 7, 8 dihydric mud - 8- (4-picolyl) -4-propyl - 1 ^ Imida zone ^[2, 1] purine - 5 (4 - to a is any range 9-1 1 according oN The sulfonylurea anti-diabetic agent or the non-sulfo-urea K + ATP channel blocker described above.

13. Equation (I)

(In the formula, R ^la represents a hydrogen atom, lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aromatic heterocyclic group, and R ^2a represents a hydrogen atom, lower alkyl, substituted or unsubstituted aralkyl, Represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group, R ^3a represents a hydrogen atom, lower alkyl or substituted or unsubstituted aralkyl, and X ¹ and X ² are each independently Represents a hydrogen atom, a lower alkyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted aryl, iia represents an integer of 0 to 3), a condensed purine derivative represented by the formula (II):

{Wherein, toto is R ^lb N— C = 0 (where R ^lb is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted Or N = C—W wherein W is a halogen, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, -NR ⁴ R ⁵ (wherein, R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted Ariru or substituted or represents unsubstituted Ararukiru force, with R ⁵ Together with an adjacent nitrogen atom to form a heterocyclic group), -OR ⁶ , wherein R ⁶ is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aryl. Aral kill),-SR ^6a

(Wherein, R ^6a has the same meaning as R ⁶ above), represents a substituted or unsubstituted lower alkyl or cyano], and R ^2b represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted Aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, halogen, low Lower alkylthio, -dish ⁸ (wherein R ⁷ and R ⁸ have the same meanings as R ⁴ and R ⁵ , respectively), -CO ₂ H, lower anoreoxyl propylonyl, -COHal (where Hal represents halogen) ), -C0NR ⁹ R ¹⁰ (wherein, and R ^1G are as defined above for R ⁴ and R ⁵ ) or -CH 0, and ^b is a hydrogen atom, lower alkyl, substituted or unsubstituted aralkyl represents Le or lower alkoxyalkyl, nb represents an integer of 0 to 3, V ¹ represents hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted Ararukiru, the substitution or unsubstituted Ariru or substituted or V ² represents a substituted lower alkyl or a substituted or unsubstituted aromatic heterocyclic group; V ¹ represents a hydrogen atom, a lower alkyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted Place Represents Ariru of conversion, and represent (a) · 'Υ ·· · Ζ is R ^lba N- C = 0 (wherein, R ^lba represents definitions in, substituted lower alkyl groups other than the R ^lb) Wherein R ^2b is substituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alicyclic heterocyclic group, halogen, lower alkylthio, -NR ⁷ R ⁸ (wherein R ⁷ and R are the same as defined above. der Ru), - C0 ₂ H, lower alkoxycarbonyl, -COHal (in the formula, Hal is Ru as defined above der), - CONRSR (wherein, R ⁹ and R ^ie each have the same meanings as defined above) or - or represents CH0, (wherein, R ^lb is the i same meaning) (b) Χ~Υ '' · Ζ is R ^lb N- C = 0 represents either R ^3b represents lower alkoxyalkyl, (c) Χ · '· Υ ··· Ζ force SR ^lbb N_C = 0 (wherein, R ^lbb represents location換低loweralkyl) or represents, (d) Χ ·' is · Υ Ζ N = C- W (where W is the same as above) Wherein R ^2b is substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aliphatic. A cyclic heterocyclic group, halogen, lower alkylthio, -spirit ⁸ (wherein R ⁷ and R ⁸ are as defined above), -CO ₂ H, lower alkoxycarbonyl, -COHal (where Hal is Has the same meaning as described above), -C0NR ⁹ R ¹⁰ (in the formula, and R ^ie have the same meanings as above), or -CH0, or (Χ to Υ · Ζ is N = CW (wherein , W is as defined above), and when R ^3b represents lower alkyl, substituted or unsubstituted aralkyl or lower alkoxyalkyl, V ² represents lower alkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted May be the real reel} Characterized by containing as an active ingredient at least one selected from the condensed purine derivatives represented and their pharmacologically acceptable salts An antidiabetic or non-sulfonylurea K + ATP channel blocker.

14. Sulfonylurea antidiabetic agents include glibenclamide, dalividide, gliclazide, glimepiride, tolazamide, tolptamide, acethexamide, carpamide, kokunorepropamide, glipollnulide, gliquidone, glicentide, glisolomide, glisoximide The agent for reducing an adverse effect of a sulfonylurea antidiabetic agent or a non-sulfolurea K + ATP channel blocker antidiabetic agent according to claim 13, which is one or more antidiabetic agents selected from glyciclamide and glybusol.

15. The sulfonoleurea antidiabetic agent according to claim 13 or 14, wherein the non-sulfonylurea K + ATP channel blocker antidiabetic agent is one or more antidiabetic agents selected from lipaglinide, nateglinide and miglinide. Non-sulfonyl urea K + ATP channel blocker Reduces side effects of antidiabetic drugs.

16. Condensed purine derivative power 8-benzyl-2-cyclopentyl-7,8-dihydro-4-propyl-1-imidazo [2, trii] purine-5 (4-one, (me-2-cyclopentyl-7, 8-dihydrid -8- (4-picolyl) -4-pyridyl-1 imidazo [2, 1-i] purine-5 (4-one or (/?)-2-cyclobutyl-7, 8-dihydro-8- (4-picolinole) -4-propylimidazo [2,1-] purin-5 (4-sulfone according to any one of claims 13 to 15 which is 4-one) Ruurea anti-diabetic or non-sulfo-urea K + ATP channel blocker-A side effect reducing agent for anti-diabetic.

17. One or more selected from a sulfonylurea antidiabetic agent and a non-sulfonylurea K + ATP channel blocker antidiabetic agent, a condensed purine derivative represented by the formula (I), and a condensed purine derivative represented by the formula (II) 5. The therapeutic agent for diabetes according to any one of claims 1 to 4, wherein one or more selected from pharmacologically acceptable salts thereof are present in separate pharmaceutical forms.

18. At least one selected from a sulfonylurea antidiabetic agent and a non-sulfonylurea K + ATP channel blocker antidiabetic agent, a condensed purine derivative represented by the formula (I), and a condensed purine derivative represented by the formula (II) And at least one selected from pharmacologically acceptable salts thereof are present in separate pharmaceutical forms. A preventive and / or therapeutic agent for diabetic complication according to any of the above