JP2008501617A - Imidazotriazinone derivatives having PDE7 inhibitory action - Google Patents

Abstract

で示されるイミダゾトリアジノン誘導体であって、特に式中、Ｒ^１がシクロヘキシル基であり、Ｒ^２がメチル基であり、Ｒ^３が水素原子、ニトロ基、シアノ基、ハロゲン原子、基：−ＮＲ^５Ｒ^６、−Ｃ(＝Ｏ)Ｒ^７、−ＳＯ_２Ｒ^７、−ＯＲ^８、−ＮＲ^８ＣＯＲ^７、−ＮＲ^８ＳＯ_２Ｒ^７、ヘテロアリール基、置換若しくは非置換のＣ_１〜６のアルキル基、置換若しくは非置換のＣ_１〜６のアルケニル基、または置換若しくは非置換の飽和または不飽和のヘテロシクロアルキル基であり、ＡがＣＲ^４であり、ＢがＣＨであるイミダゾトリアジノン誘導体。
It has an action of selectively inhibiting PDE7, thereby increasing intracellular cAMP level, and further inhibiting T cell activation, which is useful for the prevention and treatment of various allergic diseases, inflammation and immune diseases. Provided is a compound of formula (IA) or (IB):

In particular, in the formula, R ¹ is a cyclohexyl group, R ² is a methyl group, and R ³ is a hydrogen atom, a nitro group, a cyano group, a halogen atom, a group: —NR ^{5 R 6, -C (= O} ) R 7, -SO 2 R 7, -OR 8, -NR 8 COR 7, -NR 8 SO 2 R 7, heteroaryl groups, substituted or unsubstituted _{C 1 to 6} An alkyl group, a substituted or unsubstituted C _1-6 alkenyl group, or a substituted or unsubstituted saturated or unsaturated heterocycloalkyl group, wherein A is CR ⁴ and B is CH Derivative.

Description

  The present invention relates to an imidazotriazinone derivative having a selective PDE7 (type VII phosphodiesterase) inhibitory action, a pharmacologically acceptable salt thereof or a solvate thereof. These compounds are effective compounds against diseases in various therapeutic fields including allergic diseases and inflammation / immune diseases.

  Intracellular second messengers cAMP or cGMP are degraded and inactivated by phosphodiesterases (PDE 1 to 11). Among them, PDE7 selectively degrades cAMP and is characterized as an enzyme that is not inhibited by rolipram, which is a selective inhibitor of PDE4 that also degrades cAMP.

  PDE7 has been suggested to play an important role in T cell activation (Beavo et al .; Science, 283 (1999) 848), and T cell activation is associated with various allergic diseases, inflammation and immunity. Diseases such as bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory Involved in exacerbation of pathology in diseases such as enteritis, hepatitis, pancreatitis, encephalomyelitis, sepsis, Crohn's disease, transplant rejection, graft-versus-host disease (GVH disease), restenosis after angioplasty It is known (J. Allergy Clin. Immunol., 2000 Nov; 106 (5 Suppl): S221-6; Am. J. Respir. Crit. Care Med., 1996 Feb; 153 (2): 629- 32; Am. J. Respir. Crit. Care Med., 1999 Nov; 160 (5 Pt 2): S33-7; Clin. Exp. Allergy, 2000 Feb; 3 0 (2): 242-54; Hosp. Med., 1998 Jul; 59 (7): 530-3; Int. Arch. Allergy Immunol., 1998 Mar; 115 (3): 179-90; J. Immunol. , 1991 Feb 15; 146 (4): 1169-74; Osteoarthritis Cartilage, 1999 Jul; 7 (4): 401-2; Rheum. Dis. Clin. North Am., 2001 May; 27 (2): 317-34 J. Autoimmun., 2001 May; 16 (3): 187-92; Curr. Rheumatol. Rep., 2000 Feb; 2 (1): 24-31; Trends Immunol., 2001 Jan; 22 (1): 21 -6: Curr. Opin. Immunol., 2000 Aug; 12 (4): 403-8; Diabetes Care, 2001 Sep; 24 (9): 1661-7; J. Neuroimmunol., 2000 Nov 1; 111 (1- 2): 224-8; Curr. Opin. Immunol., 1997 Dec; 9 (6): 793-9; JAMA, 1999 Sep 15; 282 (11): 1076-82; Semin. Cancer Biol., 1996 Apr; 7 (2): 57-64; J. Interferon Cytokine Res., 2001 Apr; 21 (4): 219-21). Therefore, a compound having PDE7 inhibitory activity is considered to be useful for various allergic diseases and inflammation / immune diseases involving T cells.

  So far, compounds that selectively inhibit PDE7 include imidazopyridine derivatives (patent international publication WO 01/34601), dihydropurine derivatives (patent international publication WO 00/68203), pyrrole derivatives (patent international publication WO 01 / 32618), benzothiopyranoimidazolone derivatives (German Patent No. 19950647), heterocyclic compounds (patent international publication WO 02/88080, patent international publication WO 02/87513), quinazolines and pyridopyrimidine derivatives (patent) International publication WO 02/102315), spiro tricyclic derivatives (patent international publication WO 02/74754), thiazole and oxadiazole derivatives (patent international publication WO 02/28847), sulfonamide derivatives (patent international publication WO 01 / 98274 ), Heterobiallylsulfonamide derivatives (patent international publication WO 01/74786), dihydroisoquinoline derivatives (patent international publication WO 02/40450), guanine derivatives (Bioorg. Med. Chem. Lett., 11 (2001) 1081 ), Benzothiadiazine (J. Med. Chem., 43 (2000) 683), and benzothienothiadiazine derivatives (Eur. J. Med. Chem., 36 (2001) 333) are provided. However, no therapeutic drug has been developed that uses the enzyme's inhibitory action as the main medicinal mechanism.

On the other hand, compounds having an imidazotriazinone skeleton (patent international publication WO 01/47928, patent international publication WO 02/98880, patent international publication WO 02/98879, patent international publication WO 02/98873, patent international publication WO 02/79203, patent international publication WO 02/74774, patent international publication WO 02/68423, patent international publication WO 02/64593, patent international publication WO 02/50078, patent international publication WO 01/64677, European Patent Publication No. 1092719, Patent International Publication No. WO 99/67244, and Patent International Publication No. WO 99/24433) are known, and R ¹ in the general formula in this specification is a cycloalkyl group, or tert- There is no compound showing a butyl group, and there is any suggestion about PDE7 inhibitory activity That is not.

  An object of this invention is to provide the new compound which has PDE7 inhibitory activity, and the PDE7 inhibitor which uses the said compound as an active ingredient.

  The compound provided by the present invention increases intracellular cAMP levels by selectively inhibiting PDE7, and further inhibits T cell activation, thereby preventing various allergic diseases, inflammation and immune diseases. And useful compounds.

  Specifically, bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammation It is useful as a preventive or therapeutic agent for diseases such as enterocolitis, hepatitis, pancreatitis, encephalomyelitis, sepsis, Crohn's disease, transplant rejection, GVH disease, restenosis after angioplasty.

  As a result of diligent research to develop a compound having an excellent PDE7 inhibitory action, the present inventors have demonstrated that a compound having an imidazotriazinone skeleton represented by the following general formula (IA) or (IB) The present inventors have newly found that there is an excellent PDE7 inhibitory action and excellent PDE7 inhibition selectivity, and have completed the present invention.

  That is, according to the present invention, the following general formula (IA) or (IB):

(Where
A represents N or CR ⁴ ;
B represents N or CH;
R ¹ represents a substituted or unsubstituted C _3-7 cycloalkyl group, or a tert-butyl group;
R ² represents a hydrogen atom, a C _1-6 alkyl group,
R ³ represents a hydrogen atom, a nitro group, a cyano group, a halogen atom, a heteroaryl group, a substituted or unsubstituted C _1-6 alkyl group, a substituted or unsubstituted C _2-6 alkenyl group, or a substituted or non-substituted group. Substituted saturated or unsaturated heterocycloalkyl groups, groups: —NR ⁵ R ⁶ , —C (O) R ⁷ , —SO ₂ R ⁷ , —OR ⁸ , —NR ⁸ COR ⁷ , —NR ⁸ SO ₂ R ⁷
R ⁴ represents a hydrogen atom or a C _1-3 alkoxy group optionally substituted with one or more fluorine atoms,
R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted C _1-6 alkyl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted heterocycloalkyl group,
R ⁷ represents a hydrogen atom, a substituted or unsubstituted C _1-6 alkyl group, a substituted or unsubstituted heterocycloalkyl group, OH, —OR ⁸ or —NR ⁵ R ⁶ ,
R ⁸ represents a hydrogen atom, a substituted or unsubstituted C _1-6 alkyl group, or a substituted or unsubstituted heterocycloalkyl group. )
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

  The present invention also provides a PDE7 inhibitor comprising the imidazotriazinone derivative provided above, a pharmacologically acceptable salt thereof, or a solvate thereof as an active ingredient.

  The present invention will be described in detail below.

In the present specification, the “C _1-6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms. The “C _2-6 alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms. The “cycloalkyl group” is a cycloalkyl group having 3 to 8 carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. “Heterocycloalkyl group” is a 3- to 7-membered ring containing 1 to 4 heteroatoms consisting of oxygen, nitrogen or sulfur atoms. Specific examples include piperidinyl, pyrrolidinyl, piperazinyl, tetrahydrofuryl. , Tetrahydropyranyl, morpholinyl, azetidinyl group, homopiperazinyl group and the like.

  Further, the “heteroaryl group” is a monocyclic ring having 5 to 7 members having 2 to 8 carbon atoms and containing 1 to 4 heteroatoms composed of oxygen atom, nitrogen atom or sulfur atom. A polycyclic heteroaryl group in which two or more of the same or different monocycles are fused, such as pyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyrazinyl, indolyl, quinolyl, isoquinolyl, tetrazolyl, pyridinyl, pyrazolyl, pyridazinyl, pyrimidinyl group, etc. Can give. Furthermore, the “halogen atom” is a chlorine, fluorine, bromine or iodine atom.

In the present invention, “substituted or unsubstituted C _1-6 alkyl group”, “substituted or unsubstituted C _3-8 cycloalkyl group”, “substituted or unsubstituted alkenyl group”, “substituted or unsubstituted” Specific examples of the substituent represented by “heterocycloalkyl group” and “substituted or unsubstituted acyl group” include substituted or unsubstituted such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and the like. Linear, branched or cyclic alkyl groups, substituted or unsubstituted cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; hydroxyl groups; cyano groups; optionally substituted such as methoxy, ethoxy, etc. Alkoxy group; substituted or non-substituted amino, methylamino, ethylamino, dimethylamino, etc. Substituted or unsubstituted acyl groups such as acetyl and propionyl; optionally substituted aryl groups; substituted or unsubstituted heteroaryl groups; substituted or unsubstituted saturated or unsaturated heterocycloalkyl groups; substituted Or a substituted or unsubstituted amide group; a halogen atom; a nitro group; a substituted or unsubstituted sulfone group; an oxo group; a urea group; a substituted or unsubstituted straight chain such as ethenyl, propenyl, cyclohexenyl, etc. , Branched, or cyclic alkenyl groups.

In the compounds of the general formulas (IA) and (IB) provided by the present invention, a preferred group of compounds is that R ¹ is a cyclopentyl group, a cyclohexyl group or a cycloheptyl group, R ² is a methyl group, and R ³ is A hydrogen atom, a halogen atom, a heteroaryl group, a substituted or unsubstituted C _1-6 alkyl group, a substituted or unsubstituted C _2-6 alkenyl group, or an optionally substituted saturated or unsaturated heterocycloalkyl Group, group: —NR ⁵ R ⁶ , R ⁵ R ⁶ is a substituted or unsubstituted heterocycloalkyl group, A is CR ⁴ , R ⁴ is a methoxy group, an ethoxy group, and B is CH It is a compound which is.

  The compounds of the general formulas (IA) and (IB) may exist in the form of tautomers, or may exist as individual tautomers and a mixture of individual tautomers. . Furthermore, radiolabeled derivatives of the compounds of general formulas (IA) and (IB) are also included in the present invention.

  Further, the compounds provided by the present invention include those having one or more asymmetric carbon atoms, and based on this, (R) isomers, (S) optical isomers, racemates, diastereomers, etc. Exists. Moreover, since it has a double bond depending on the kind of substituent, geometric isomers such as (Z) isomer and (E) isomer also exist. The compound provided by the present invention includes any case where these isomers are separated or a mixture of isomers.

  Some of the compounds provided by the present invention can form salts with various acids. Such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid. Acid addition salts with organic acids such as lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, picric acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, trichloroacetic acid, trifluoroacetic acid, aspartic acid, glutamic acid I can give you.

  Further, the compound provided by the present invention can further form a pharmacologically acceptable metal salt with a metal, particularly an alkali metal or an alkaline earth metal. Examples of such salts include sodium salts, potassium salts, calcium salts and the like. Furthermore, the compounds of the present invention can also include hydrates, solvates such as ethanol and isopropanol, and polymorphic substances.

  Among the imidazotriazinone derivatives represented by the general formula (IA) or (IB) provided by the present invention, the following can be exemplified as particularly preferred specific examples.

6-cyclohexyl-2- (2-methoxyphenyl) -8-methylimidazo [1,5-a] [1,3,5] triazin-4 (3H) -one;
6-cyclohexyl-2- [2-methoxy-4- (1-piperazinyl) phenyl] -8-methylimidazo [1,5-a] [1,3,5] triazin-4 (3H) -one;
6-cyclohexyl-2- [2-methoxy-4- (4-methyl-1-piperazinyl) phenyl] -8-methylimidazo [1,5-a] [1,3,5] triazine-4 (3H -On;
2- [4- (4-Amino-1-piperidinyl) -2-methoxyphenyl] -6-cyclohexyl-8-methylimidazo [1,5-a] [1,3,5] triazine-4 (3H)- on;
6-cyclohexyl-2- {2-methoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -8-methylimidazo [1,5-a] [1,3,5] triazine-4 ( 3H) -on;
6-Cyclohexyl-2- {4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl} -8-methylimidazo [1,5-a] [1,3,5] triazine-4 ( 3H) -on;
6-cyclohexyl-2- [4- (1,4-diazepan-1-yl) -2-methoxyphenyl] -8-methylimidazo [1,5-a] [1,3,5] triazine-4 (3H -On;
6-Cyclocyclohexyl-2- [2-methoxy-4- (4-methyl-1,4-diazepan-1-yl) phenyl] -8-methylimidazo [1,5-a] [1,3,5] triazine -4 (3H) -one;
6-Cyclohexyl-2- [4- (4-hydroxy-1-piperidinyl) -2-methoxyphenyl] -8-methylimidazo [1,5-a] [1,3,5] triazine-4 (3H)- on;
6-cyclohexyl-2- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] -2-methoxyphenyl} -8-methylimidazo [1,5-a] [1,3,5] triazine-4 ( 3H) -on;

6-cyclohexyl-2- [2-methoxy-4- (1-piperazinylsulfonyl) phenyl] -8-methylimidazo [1,5-a] [1,3,5] triazin-4 (3H) -one ;
6-cyclohexyl-2- {2-methoxy-4-[(4-methyl-1-piperazinyl) sulfonyl] phenyl} -8-methylimidazo [1,5-a] [1,3,5] triazine-4 ( 3H) -on;
6-Cyclohexyl-2- [4- (1,4-diazepan-1-ylsulfonyl) -2-methoxyphenyl] -8-methylimidazo [1,5-a] [1,3,5] triazine-4 ( 3H) -on;
6-cyclohexyl-2- {2-methoxy-4-[(4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -8-methylimidazo [1,5-a] [1,3, 5] triazine-4 (3H) -one;
5-cyclohexyl-2- (2-methoxyphenyl) -7-methylimidazo [5,1-f] [1,2,4] triazin-4 (3H) -one;
5-cyclohexyl-2- [2-methoxy-4- (4-methyl-1-piperazinyl) phenyl] -7-methylimidazo [5,1-f] [1,2,4] triazine-4 (3H)- on;
5-cyclohexyl-2- [2-methoxy-4- (1-piperazinyl) phenyl] -7-methylimidazo [5,1-f] [1,2,4] triazin-4 (3H) -one;
2- [4- (4-Amino-1-piperidinyl) -2-methoxyphenyl] -5-cyclohexyl-7-methylimidazo [5,1-f] [1,2,4] triazine-4 (3H)- on;
5-cyclohexyl-2- {2-methoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -7-methylimidazo [5,1-f] [1,2,4] triazine-4 ( 3H) -on;
5-cyclohexyl-2- {4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl} -7-methylimidazo [5,1-f] [1,2,4] triazine-4 ( 3H) -on;

5-cyclohexyl-2- [4- (1,4-diazepan-1-yl) -2-methoxyphenyl] -7-methylimidazo [5,1-f] [1,2,4] triazine-4 (3H -On;
5-cyclohexyl-2- [2-methoxy-4- (4-methyl-1,4-diazepan-1-yl) phenyl] -7-methylimidazo [5,1-f] [1,2,4] triazine -4 (3H) -one;
5-cyclohexyl-2- [4- (4-hydroxy-1-piperidinyl) -2-methoxyphenyl] -7-methylimidazo [5,1-f] [1,2,4] triazine-4 (3H)- on;
5-cyclohexyl-2- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] -2-methoxyphenyl} -7-methylimidazo [5,1-f] [1,2,4] triazine-4 ( 3H) -on;
5-cyclohexyl-2- [2-methoxy-4- (1-piperazinylsulfonyl) phenyl] -7-methylimidazo [5,1-f] [1,2,4] triazin-4 (3H) -one ;
5-cyclohexyl-2- {2-methoxy-4-[(4-methyl-1-piperazinyl) sulfonyl] phenyl} -7-methylimidazo [5,1-f] [1,2,4] triazine-4 ( 3H) -on;
5-cyclohexyl-2- [4- (1,4-diazepan-1-ylsulfonyl) -2-methoxyphenyl] -7-methylimidazo [5,1-f] [1,2,4] triazine-4 ( 3H) -on;
5-cyclohexyl-2- {2-methoxy-4-[(4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -7-methylimidazo [5,1-f] [1,2, 4] triazine-4 (3H) -one;
6-cyclohexyl-2- (2-ethoxyphenyl) -8-methylimidazo [1,5-a] [1,3,5] triazin-4 (3H) -one;
6-cyclohexyl-2- [2-ethoxy-4- (1-piperazinyl) phenyl] -8-methylimidazo [1,5-a] [1,3,5] triazin-4 (3H) -one;

6-Cyclohexyl-2- [2-ethoxy-4- (4-methyl-1-piperazinyl) phenyl] -8-methylimidazo [1,5-a] [1,3,5] triazin-4 (3H) -one ;
2- [4- (4-Amino-1-piperidinyl) -2-ethoxyphenyl] -6-cyclohexyl-8-methylimidazo [1,5-a] [1,3,5] triazine-4 (3H)- on;
6-Cyclohexyl-2- {2-ethoxy 4- [4- (methylamino) -1-piperidinyl] phenyl} -8-methylimidazo [1,5-a] [1,3,5] triazine-4 (3H -On;
6-Cyclohexyl-2- {4- [4- (dimethylamino) -1-piperidinyl] -2-ethoxyphenyl} -8-methylimidazo [1,5-a] [1,3,5] triazine-4 ( 3H) -on;
6-Cyclohexyl-2- [4- (1,4-diazepan-1-yl) -2-ethoxyphenyl] -8-methylimidazo [1,5-a] [1,3,5] triazine-4 (3H -On;
6-Cyclohexyl-2- [2-ethoxy-4- (4-methyl-1,4-diazepan-1-yl) phenyl] -8-methylimidazo [1,5-a] [1,3,5] triazine- 4 (3H) -one;
6-Cyclohexyl-2- [4- (4-hydroxy-1-piperidinyl) -2-ethoxyphenyl] -8-methylimidazo [1,5-a] [1,3,5] triazine-4 (3H)- on;
6-cyclohexyl-2- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] -2-ethoxyphenyl} -8-methylimidazo [1,5-a] [1,3,5] triazine-4 ( 3H) -on;
6-cyclohexyl-2- [2-ethoxy-4- (1-piperazinylsulfonyl) phenyl] -8-methylimidazo [1,5-a] [1,3,5] triazin-4 (3H) -one;

6-cyclohexyl-2- {2-ethoxy 4-[(4-methyl-1-piperazinyl) sulfonyl] phenyl} -8-methylimidazo [1,5-a] [1,3,5] triazine-4 (3H -On;
6-Cyclohexyl-2- [4- (1,4-diazepan-1-ylsulfonyl) -2-ethoxyphenyl] -8-methylimidazo [1,5-a] [1,3,5] triazine-4 ( 3H) -on;
6-cyclohexyl-2- {2-ethoxy 4-[(4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -8-methylimidazo [1,5-a] [1,3,5 ] Triazine-4 (3H) -one;
5-cyclohexyl-2- (2-ethoxyphenyl) -7-methylimidazo [5,1-f] [1,2,4] triazin-4 (3H) -one;
5-cyclohexyl-2- [2-ethoxy-4- (4-methyl-1-piperazinyl) phenyl] -7-methylimidazo [5,1-f] [1,2,4] triazin-4 (3H) -one ;
5-cyclohexyl-2- [2-ethoxy-4- (1-piperazinyl) phenyl] -7-methylimidazo [5,1-f] [1,2,4] triazin-4 (3H) -one;
2- [4- (4-Amino-1-piperidinyl) -2-ethoxyphenyl] -5-cyclohexyl-7-methylimidazo [5,1-f] [1,2,4] triazine-4 (3H)- on;
5-cyclohexyl-2- {2-ethoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -7-methylimidazo [5,1-f] [1,2,4] triazine-4 (3H -On;
5-cyclohexyl-2- {4- [4- (dimethylamino) -1-piperidinyl] -2-ethoxyphenyl} -7-methylimidazo [5,1-f] [1,2,4] triazine-4 ( 3H) -on;
5-cyclohexyl-2- [4- (1,4-diazepan-1-yl) -2-ethoxyphenyl] -7-methylimidazo [5,1-f] [1,2,4] triazine-4 (3H -On;

5-cyclohexyl-2- [2-ethoxy-4- (4-methyl-1,4-diazepan-1-yl) phenyl] -7-methylimidazo [5,1-f] [1,2,4] triazine- 4 (3H) -one;
5-cyclohexyl-2- [4- (4-hydroxy-1-piperidinyl) -2-ethoxyphenyl] -7-methylimidazo [5,1-f] [1,2,4] triazine-4 (3H)- on;
5-cyclohexyl-2- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] -2-ethoxyphenyl} -7-methylimidazo [5,1-f] [1,2,4] triazine-4 ( 3H) -on;
5-cyclohexyl-2- [2-ethoxy-4- (1-piperazinylsulfonyl) phenyl] -7-methylimidazo [5,1-f] [1,2,4] triazin-4 (3H) -one;
5-cyclohexyl-2- {2-ethoxy-4-[(4-methyl-1-piperazinyl) sulfonyl] phenyl} -7-methylimidazo [5,1-f] [1,2,4] triazine-4 (3H -On;
5-cyclohexyl-2- [4- (1,4-diazepan-1-ylsulfonyl) -2-ethoxyphenyl] -7-methylimidazo [5,1-f] [1,2,4] triazine-4 ( 3H) -on;
5-cyclohexyl-2- {2-ethoxy-4-[(4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -7-methylimidazo [5,1-f] [1,2,4 ] Triazin-4 (3H) -one.

  The compound of formula (IA) according to the present invention can be synthesized, for example, by the method shown below.

Wherein A, B, R ¹ , R ² and R ³ are as defined above, L is a C _1-3 alkyl group, Y is a hydroxyl group or a halogen atom, preferably a chlorine atom, Z is a halogen atom, preferably an iodine atom.)

  In order to carry out this method, according to a known method, first, compound (V) is obtained from compound (VII). This reaction is a method of synthesizing the acid amide compound (V) from the amine compound (VII) and the carboxylic acid component (VIII), and can be carried out in many ways. For example, when Y is a halogen atom (preferably a chlorine atom), it is 1 to 5 equivalents, preferably 1.5 equivalents, relative to compound (VII) in an inert solvent such as dichloromethane at 0 ° C. to room temperature. In the presence of a tertiary amine such as triethylamine, 1 to 1.5 equivalents, preferably 1.2 equivalents, of compound (VIII) are used relative to compound (VII), optionally in the presence of a catalyst such as 4-dimethylaminopyridine. Below can be implemented.

  When Y is a hydroxyl group, 1 to 1.5 equivalents, preferably 1.2 equivalents of a condensing agent, for example, 1 equivalent to compound (VII) in an inert solvent such as dichloromethane at 0 ° C. to room temperature. 1-1.5 equivalents, preferably 1.2 equivalents of compound (VIII) relative to compound (VII) in the presence of -ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, optionally a catalyst, For example, the reaction can be carried out in the presence of 4-dimethylaminopyridine. After completion of the reaction, the product is diluted with an organic solvent immiscible with water, washed successively with water and saturated brine, and the solvent is distilled off to obtain the target compound (V). If necessary, it can be purified by column chromatography or the like.

  As the starting material compound (VII), a commercially available or known compound can be used. Further, even in the compound (VIII) used in this reaction, a commercially available compound or a known compound can be used.

  Next, compound (III) can be obtained from compound (V) obtained above according to a known method. The reaction is carried out in an alcohol solvent such as ethanol or methanol at 0 ° C. to reflux temperature with respect to compound (V), preferably 1 to 1.5 equivalents, preferably 1 equivalent of a metal such as sodium ethoxide or sodium methoxide. The reaction can be carried out by reacting compound (VI) in the presence of an alkoxide. After completion of the reaction, it is acidified with an inorganic acid such as hydrochloric acid, extracted with an organic solvent immiscible with water, the extracted organic solvent is washed successively with water and saturated brine, and the solvent is distilled off to distill off the target compound (III). Can be obtained. If necessary, it can be purified by column chromatography or the like.

  Compound (II) is obtained from the obtained compound (III) according to a known method. This reaction is carried out by allowing 0.3 to 2 equivalents, preferably 0.5 equivalents, of compound (IV) to act on compound (III) in an alcohol solvent such as methanol and ethanol at room temperature to reflux temperature. can do. After completion of the reaction, water is added, extraction is performed with an organic solvent immiscible with water, the extracted organic solvent is washed successively with water and saturated brine, and the solvent is distilled off to obtain the target compound (II). . If necessary, it can be purified by column chromatography or the like.

  Subsequently, imidazotriazinone ring formation is performed on the obtained compound (II) to obtain the target compound (IA) of the present invention. This reaction can be carried out using a known cyclization method (for example, J. Org. Chem., 1981, 46, 3681-3685). Specifically, compound (II) is added with 1 to 5 equivalents, preferably 3 equivalents of chlorotrimethylsilane in pyridine and stirred, and then 1 to 5 equivalents, preferably 3 equivalents of hexamethyldisilazane is used. The reaction can be carried out at room temperature to reflux temperature.

  After completion of the reaction, the reaction solution is distilled off, and an alcohol solvent such as methanol or ethanol is added to the residue and stirred. The target organic compound (IA) can be obtained by sequentially washing the extracted organic solvent with water and saturated brine, and distilling off the solvent. If necessary, it can be purified by column chromatography or the like.

  The above reactions are all general and appropriate reagents and conditions for their implementation can be readily established by reference to standard textbooks and the examples described below. Accordingly, other methods and variations that can prepare the compounds defined in compound (IA) will also be apparent to those skilled in the art.

  The compound of formula (IB) according to the present invention can be synthesized, for example, by the method shown below.

Wherein A, B, R ¹ , R ² and R ³ are as defined above, L is a C _1-3 lower alkyl group, and Z ′ is a halogen atom, preferably a chlorine atom. )

  In order to carry out this method, the target compound (IB) can be obtained according to a known method (for example, JP-T-2001-522851). Specifically, compound (XI) is compound (XIV) in an ether solvent such as tetrahydrofuran in the presence of an organic base such as pyridine and triethylamine and a catalyst such as 4-dimethylaminopyridine at 0 ° C. to reflux temperature. To give compound (X). Further, compound (XII) is obtained by allowing hydrazine hydrate to act at 0 ° C. to reflux temperature in an alcohol solvent such as ethanol of compound (XIII). Subsequently, compound (IX) is obtained by reacting compound (X) and compound (XII) at room temperature to reflux temperature in an alcohol solvent such as ethanol. Compound (IX) can be carried out in a reaction using phosphorus oxychloride in a halogenated hydrocarbon solvent such as 1,2-dichloroethane or chloroform.

  After completion of the reaction, neutralize with an aqueous solution of an inorganic base such as sodium bicarbonate, extract with an organic solvent immiscible with water, wash the extracted organic solvent sequentially with water and saturated brine, and evaporate the solvent. The target compound (IB) can be obtained. In addition, a commercially available or well-known compound can be used for the compound (XI), the compound (XIV), and the compound (XIII) which are starting materials. Compound (XIII) can also be synthesized according to a known method (for example, JP-T-2001-522851).

  All of the above reactions are quite general and appropriate reagents and conditions for their implementation can be readily established by reference to standard textbooks and the examples described below. Alternative methods and variations by which all compounds defined in compound (IB) can be prepared will also be apparent to those skilled in the art.

  The present invention will be described in more detail with reference to the following test examples and examples, but it goes without saying that the scope of the present invention is not limited by these test examples and examples.

  The synthesis of the compounds of the present invention and intermediates for use therein will be described in detail in the examples described below.

  The chemical structures of the compounds of the present invention and intermediates produced in the examples and the identification data thereof are collectively shown in the table below. In addition, each compound in an Example respond | corresponds with the corresponding Example number in the table | surface mentioned later.

  The PDE7 (VII type phosphodiesterase) inhibitory activity of the compounds of the present invention produced in the examples described later was confirmed by the following test examples.

Test Example 1 In order to evaluate the ability of the compounds of the present invention to inhibit PDE7 (type VII phosphodiesterase), the method of Biochemical. Pharmacol., 48 (6), 1219-1223 (1994) was partially modified. The following assay was used.

1) PDE7 (VII type phosphodiesterase) active fraction was obtained. That is, human acute lymphoblastoid lymphoma T cell line MOLT-4 (which can be purchased from ATCC as ATCC number CRL-1582) is cultured in RPMI 1640 medium containing 10% fetal bovine serum and 5 × 10 ⁸ cells. Of MOLT4 was obtained. Cells were collected by centrifugation and 10 mL of buffer A (25 mM Tris-HCl, 5 mM 2-mercaptoethanol, 2 mM benzamidine, 2 mM EDTA, 0.1 mM 4- (2-aminoethyl) benzenesulfonyl hydrochloride, pH = 7 5). It is obtained by homogenizing cells with a Polytron (registered trademark) homogenizer and further centrifuging (4 ° C., 100,000 G, 60 minutes) after centrifugation (4 ° C., 25,000 G, 10 minutes). The supernatant was filtered through a 0.2 μm filter to obtain a soluble fraction.

2) The HiTrapQ column (5 mL × 2) equilibrated with buffer A was packed with the obtained soluble fraction. Phosphodiesterase was eluted using 300 mL of buffer A containing a linear gradient of 0-0.8 M sodium chloride, and 60 5 mL fractions were collected. Each fraction was examined for cAMP metabolic phosphodiesterase activity. Among the fractions that have metabolic activity of cAMP in each fraction and do not lose metabolic activity by 10 μM rolipram (a type IV phosphodiesterase selective inhibitor) and 10 μM milrinone (a type III phosphodiesterase selective inhibitor), 350 mM sodium chloride Fractions eluted as an activity peak centered around were collected and used as a stock solution for examining PDE7 inhibitory activity.

3) The test compound has a desired concentration of 20 mM Tris-HCl (pH 7.5), 1 mM MgCl ₂ , 100 μM EDTA, 330 μg / mL bovine serum albumin, 4 μg / mL 5′-nucleotidase, 0.1 μCi ³ H- The reaction was carried out at 25 ° C. for 2 hours in a reaction mixture containing cAMP (0.064 μM cAMP), 10 μM rolipram and type VII phosphodiesterase stock solution. After adding QAE-Sephadex suspended in 10 mM Hepes-Na (pH = 7.0) to the reaction solution and allowing to stand for 5 minutes, a supernatant was obtained, and further QAE-Sephadex was added and left to stand for 5 minutes. The radioactivity in the resulting supernatant was measured.

4) IC ₅₀ was calculated for each compound as the concentration of the test compound that inhibits the metabolic activity of PDE7 by 50%.

Measured by PDE7 inhibitory activity in the above-described measurement method of each compound denotes a compound of example number an IC ₅₀ value of phosphodiesterase inhibitory activity showed the following 1 [mu] M.
Compound 8: IC ₅₀ = 0.34 μM,
Compound 11: IC ₅₀ = 0.055 μM,
Compound 12: IC ₅₀ = 0.49 μM

  As a result of the phosphodiesterase inhibitory activity test, it was confirmed that the imidazotriazinone derivative according to the present invention exhibits a very good PDE7 inhibitory effect.

  Since the compound of the present invention is a selective inhibitor for PDE7 and has a selectivity of 10 times or more for PDE4 (type IV phosphodiesterase) having high similarity to PDE7, side effects caused by PDE4 are Expected to be less.

  That is, the selectivity of the inhibitory activity of the compound of the present invention for PDE4 (type IV phosphodiesterase) was confirmed by the following test.

Test Example 2 PDE4 Inhibitory Activity Measurement Method In order to evaluate PDE4 inhibition of the compound of the present invention that inhibits PDE7, the following assay was performed by partially modifying the method of Biochemical. Pharmacol., 48 (6), 1219-1223 (1994). Using.

1) A PDE4 active fraction was obtained. That is, 30 mL of buffer B (20 mM Bis-Tris, 5 mM 2-mercaptoethanol, 2 mM benzamidine, 2 mM) was obtained from 3 Balb / c mice (female, 12 weeks old) (available from CLEA Japan). EDTA, 0.1 mM 4- (2-aminoethyl) benzenesulfonyl hydrochloride, 50 mM sodium acetate, pH = 6.5). Obtained by homogenizing the liver with a Polytron (registered trademark) homogenizer and further centrifuging (4 ° C., 100,000 G, 60 minutes) the supernatant after centrifugation (4 ° C., 25,000 G, 10 minutes) The supernatant was filtered through a 0.2 μm filter to obtain a soluble fraction.

2) A 1 × 10 cm DEAE Sepharose column equilibrated with buffer B was packed with the obtained soluble fraction. Phosphodiesterase was eluted using 120 mL of buffer B containing a linear gradient of 0.05-1 M sodium acetate and 24 5 mL fractions were collected. Each fraction was examined for cAMP metabolic phosphodiesterase activity. Among the fractions having cAMP metabolic activity in each fraction and the metabolic activity being lost by 30 μM rolipram (PDE4 selective inhibitor), the fraction eluted as an activity peak centered around 620 mM sodium acetate Collected and used as a stock solution to test for PDE4 inhibitory activity.

3) The test compound has a desired concentration of 20 mM Tris-HCl (pH 7.5), 1 mM MgCl ₂ , 100 μM EDTA, 330 μg / mL bovine serum albumin, 4 μg / mL 5′-nucleotidase, 0.1 μCi ³ H- The reaction was carried out at 25 ° C. for 2 hours in a reaction mixture containing cAMP (0.064 μM cAMP) and PDE4 stock solution. After adding QAE-Sephadex suspended in 10 mM Hepes-Na (pH = 7.0) to the reaction solution and allowing to stand for 5 minutes, a supernatant was obtained, and further QAE-Sephadex was added and left to stand for 5 minutes. The radioactivity in the resulting supernatant was measured.

4) IC ₅₀ was calculated for each compound as the test compound concentration that inhibits the metabolic activity of PDE4 by 50%.
As a result of the above test, the IC ₅₀ against PDE4 of the compound of the present invention was 10 times or more weak inhibitory activity compared to the PDE7 inhibitory action of the same compound.

  The compound provided by the present invention increases intracellular cAMP level by selectively inhibiting PDE7, and further, is useful for various allergic diseases, inflammatory / immune diseases by inhibiting T cell activation. . Bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, It is useful as a prophylactic or therapeutic agent for diseases such as hepatitis, pancreatitis, encephalomyelitis, sepsis, Crohn's disease, transplant rejection, GVH disease, restenosis after angioplasty.

  In order to use the active ingredient of the present invention as a pharmaceutical composition or a PDE7 inhibitor, one or more of the compounds of the present invention are formulated and formulated into a dosage form according to the administration method according to a conventional method. Use it. For example, dosage forms such as capsules, agents, granules, fine granules, syrups, and dry syrups are exemplified for oral administration, and suppositories such as suppositories and vaginal suppositories are available for parenteral administration. Examples thereof include nasal administration agents such as an agent, a spray, and a transdermal absorbent such as an ointment and a transdermal absorbable tape.

  The clinical dose of the compound of the present invention varies depending on the symptoms, severity, age, presence of complications, etc. of the patient to be administered, and also varies depending on the preparation. 0.1 to 1000 mg, preferably 0.1 to 500 mg, more preferably 1 to 100 mg. In the case of parenteral administration, a dose of 1/10 to 1/2 of that for oral administration may be administered. These doses can be appropriately increased or decreased depending on the age and symptoms of the patient.

  Furthermore, the toxicity of the compounds of the present invention is low, and the safety of these compounds is expected to be high.

[Production Examples and Examples]
The synthesis of the compounds of the invention and intermediates for use therein are illustrated by the following preparation examples and examples.

  The chemical structures and identification data of the compounds in the following production examples and examples are collectively shown in the following tables. The compounds of Production Examples and Examples correspond to the compound numbers in the table.

Production Example 1 (Compound 1)
4-Bromo-2-methoxybenzamide To a suspension of 12.59 g (54.5 mmol) of 4-bromo-2-methoxybenzamide in 70 mL of 1,2-dichloroethane was added 11.9 mL (163.5 mmol) of thionyl chloride. The mixture was heated under reflux for an hour, and the solvent was distilled off under reduced pressure to obtain acid chloride. Next, a solution of acid chloride in 80 mL of acetone was added dropwise to 125 mL of 28% aqueous ammonia at 0 ° C., and the precipitated solid was collected by filtration to obtain 9.22 g (74%) of the title compound.

Production Example 2 (Compound 2)
4-Bromo-2-methoxybenzonitrile To a solution of 9.22 g (40.1 mmol) of the compound obtained in Example 1 in 200 mL of anhydrous dichloromethane was added at 0 ° C. with 11.17 mL (80.2 mmol) of triethylamine, anhydrous trifluoromethanesulfonic acid 8 0.09 mL (48.1 mmol) was added, and the mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 1 hour. Next, water was added to the reaction solution, extracted with dichloromethane, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to obtain 7.84 g (92%) of the title compound.

Production Example 3 (Compound 3)
To a suspension of 4-bromo-2-methoxybenzamidine hydrochloride ammonium chloride 5.349 g (100 mmol) in toluene 200 mL was added dropwise 1 M trimethylaluminum hexane solution 100 mL (100 mmol) at 0 ° C., and 1.5 mL at room temperature. Stir for hours. Next, 8.48 g (40 mmol) of the compound obtained in Example 2 was added to the reaction solution, and the mixture was heated and stirred at 80 ° C. for 24 hours. Next, the reaction solution was ice-cooled, 30 g of silica gel and 300 mL of chloroform were added, the mixture was stirred at room temperature for 30 minutes, filtered through celite, and the residue was washed with 400 mL of methanol. The mother liquor was concentrated, 200 mL of a chloroform / methanol = 9/1 solution was added to the residue, filtered, and the mother liquor was concentrated. The residue was washed with ether to give 3.47 g (33%) of the title compound.

Production Example 4 (Compound 4)
(R)-(Acetylamino) (cyclohexyl) acetic acid (R)-(acetylamino) (1,4-cyclohexadien-1-yl) acetic acid (15 g) in methanol (500 mL) was added with platinum oxide (500 mg). Stir at room temperature for 4 hours. Next, the reaction solution was filtered, and the mother liquor was concentrated. The residue was recrystallized from ethanol to obtain 11.4 g (75%) of the title compound.

Production Example 5 (Compound 5)
Ethyl cyano [(cyclohexylcarbonyl) amino] acetate To a solution of 18.3 g (143 mmol) of ethyl aminoacetate in 500 mL of anhydrous dichloromethane was added 30 mL (214 mmol) of triethylamine and 23 mL (171 mmol) of cyclohexanecarbonyl chloride, and the mixture was stirred at 0 ° C. for 3 hours. Next, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the solid was collected by filtration. The filtrate was evaporated under reduced pressure, ethyl acetate was added to the residue, and the solid was collected by filtration. This operation was further repeated, and the filtrate was purified by silica gel column chromatography (dichloromethane / methanol = 50: 1). The resulting crude crystals were washed with ether, and all the above solids were combined to give 24.3 g (71%) of the title compound. )

Production Example 6 (Compound 6)
Ethyl 2-cyano-2-[(cyclohexylcarbonyl) amino] propanoate To 150 mL of ethanol was added 2.3 g (102 mmol) of sodium to prepare sodium ethoxide. This solution was brought to 0 ° C., a suspension of 24.2 g (102 mmol) of the compound obtained in Example 5 in 150 mL of ethanol was added, and the mixture was stirred until the reaction solution was completely dissolved. Next, 6.32 mL (102 mmol) of methyl iodide was added, and the mixture was stirred at room temperature for 4 hours. Next, 1M hydrochloric acid aqueous solution was added to the reaction solution to make it acidic, and the reaction solution was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. A mixture of ethyl acetate / hexane = 1/1 was added to the residue, and the solid was collected by filtration. The filtrate was evaporated under reduced pressure, and a mixed solution of ethyl acetate / hexane = 1/1 was further added, and the solid was collected by filtration. The filtrate was evaporated, and the residue was purified by silica gel column chromatography (hexa / ethyl acetate = 2/1) and combined with the solid to obtain 22.8 g (88%) of the title compound.

Production Example 7 (Compound 7)
117 mg (5.10 mmol) of sodium was added to 16 mL of N- [6-amino-2- (2-methoxyphenyl) -5-methyl-4-oxo-4,5-dihydro-5-pyrimidinyl] cyclohexanecarboxamide ethanol and sodium ethoxy was added. Adjusted. To this solution, 865 mg (4.64 mmol) of 2-methoxybenzamidine was added and stirred at room temperature for 45 minutes. Next, insoluble matters were removed by filtration, and a solution of the compound 2.34 g (9.27 mmol) obtained in Example 6 in 25 mL of ethanol was added to the filtrate, and the mixture was heated to reflux for 20 hours. Next, the reaction solution was brought to room temperature, and the precipitated solid was collected by filtration. The filtrate was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue and the solid collected by filtration were combined, recrystallized from ethanol, and the mother liquor was further purified by silica gel column chromatography (dichloromethane / methanol = 20/1 to 10/1) to obtain 343 mg (21%) of the title compound. Got.

Example 1 (Compound 8)
6-Cyclohexyl-2- (2-methoxyphenyl) -8-methylimidazo [1,5-a] [1,3,5] triazin-4 (3H) -one 320 mg (0. 90 mmol) of pyridine (15 mL) was added with chlorotrimethylsilane (0.34 mL, 2.7 mmol) and stirred at room temperature for 30 minutes. Next, 0.57 mL (2.7 mmol) of hexamethyldisilazane was added to the reaction solution, and the mixture was heated to reflux for 5 hours. The reaction solution was brought to room temperature, and the solvent was distilled off under reduced pressure. Methanol was added to the residue and stirred for 1 hour. Next, the reaction solution was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain 20 mg (7%) of the title compound.

Production Example 8 (Compound 9)
N- [6-Amino-2- (4-bromo-2-methoxyphenyl) -5-methyl-4-oxo-4,5-dihydro-5-pyrimidinyl] cyclohexanecarboxamide In Preparation Example 7 of 2-methoxybenzamidine Instead, the reaction was carried out in the same manner except that the compound obtained in Production Example 3 was used to obtain 439 mg (9%) of the title compound.

Example 2 (Compound 10)
2- (4-Bromo-2-methoxyphenyl) -6-cyclohexyl-8-methylimidazo [1,5-a] [1,3,5] triazin-4 (3H) -one In Example 1, the Preparation Example The reaction was conducted in the same manner except that the compound obtained in Production Example 9 was used instead of the compound obtained in 7, and 14 mg (3%) of the title compound was obtained.

Example 3 (Compound 11)
6-cyclohexyl-2- [2-methoxy-4- (4-methyl-1-piperazinyl) phenyl] -8-methylimidazo [1,5-a] [1,3,5] triazine-4 (3H)- Under a stream of on- argon, a solution of 12 mg (0.029 mmol) of the compound obtained in Example 2 in 2 mL of toluene was added 10 μL (0.086 mmol) of N-methylpiperazine, 5.5 mg (0.058 mmol) of tert-butoxy sodium, and tri-tert. -0.6 mg (0.0029 mmol) of butylphosphine and 0.3 mg (0.0014 mmol) of palladium (II) acetate were added and stirred at 110 ° C. for 4 hours. Next, the reaction solution was brought to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30/1 to 10/1) to obtain 3 mg (24%) of the title compound.

Example 4 (Compound 12)
5-cyclohexyl-2- (2-methoxyphenyl) -7-methylimidazo [5,1-f] [1,2,4] triazin-4 (3H) -one 1.5 g of the compound obtained in Preparation Example 4 About 5 mg of DMAP is added to a solution of 7.52 mmol) in pyridine and heated to reflux. Ethyl oxalyl chloride 1.68mL (15.06mmol) is dripped and it heat-refluxes for 3 hours. The reaction solution was poured into ice-water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Dissolve the residue in 5 mL of ethanol, reflux with sodium bicarbonate for 2.5 hours, return to room temperature and filter. To a suspension of 1.41 g (7.52 mmol) of 2-methoxybenzamidine hydrochloride in 8 mL of ethanol, 365 μL (7.52 mmol) of hydrazine monohydrate is added dropwise and stirred at room temperature for 10 minutes. The above ethanol solution is added to the reaction solution and stirred at 70 ° C. for 4 hours. After filtration, the solution was diluted with methylene chloride, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 10 mL of 1,2-dichloroethane, 1.25 mL of phosphorus oxychloride was added, and the mixture was heated to reflux for 2 hours. Next, the reaction solution was brought to room temperature, diluted with methylene chloride, neutralized with saturated aqueous sodium bicarbonate and solid sodium bicarbonate, and extracted. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5 mg (0.2%) of the title compound.

  The chemical structures and identification data of the compounds produced in the above examples are summarized in the following table.

The imidazotriazinone derivative of the present invention has an action of selectively inhibiting PDE7, thereby increasing intracellular cAMP levels and further inhibiting various T cell activation by inhibiting T cell activation. Useful for the prevention and treatment of inflammatory and immune diseases.
Moreover, since PDE7 is selectively inhibited, it has little influence on other PDEs, and a reduction in side effects when used as a pharmaceutical is expected.

Claims (11)

General formula (IA) or (IB):

(Where
A represents N or CR ⁴ ;
B represents N or CH;
R ¹ represents a substituted or unsubstituted cycloalkyl group or a tert-butyl group;
R ² represents a hydrogen atom, a C _1-6 alkyl group,
R ³ represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a heteroaryl group, a substituted or unsubstituted C _1-6 alkyl group, a substituted or unsubstituted C _2-6 alkenyl group, or a substituted or non-substituted group. Substituted saturated or unsaturated heterocycloalkyl group, groups: —NR ⁵ R ⁶ , —C (O) R ⁷ , —SO ₂ R ⁷ , —OR ⁸ , —NR ⁸ COR ⁷ , —NR ⁸ SO ₂ R ⁷
R ⁴ represents a hydrogen atom or a C _1-3 alkoxy group optionally substituted with one or more fluorine atoms,
R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted C _1-6 alkyl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted heterocycloalkyl group,
R ⁷ represents a hydrogen atom, a substituted or unsubstituted C _1-6 alkyl group, a substituted or unsubstituted heterocycloalkyl group, OH, —OR ⁸ or —NR ⁵ R ⁶ ,
R ⁸ represents a hydrogen atom, a substituted or unsubstituted C _1-6 alkyl group, or a substituted or unsubstituted heterocycloalkyl group. )
Or an imidazolate derivative thereof, a salt thereof, or a solvate thereof. The compound of Claim 1 represented by general formula (IA). The compound of Claim 1 represented by general formula (IB). The compound according to claim 1, wherein R ¹ is a substituted or unsubstituted C _3-8 cycloalkyl group. The compound according to claim 4, wherein R ¹ is selected from the group consisting of a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. The compound according to any one of claims 1 to 5, wherein A is CR ⁴ and R ⁴ is a methoxy group or an ethoxy group. The compound according to any one of claims 1 to 6, wherein B is CH. The compound according to any one of claims 1 to 7, wherein R ² is a methyl group. R ³ is a hydrogen atom, a halogen atom, a saturated or unsaturated heterocycloalkyl group, a group selected from the group consisting of: —NR ⁵ R ⁶ , —C (═O) R ⁷ , —SO ₂ R ⁷ The compound according to claim 1, wherein R ⁷ is OH, —OR ⁸ , —NR ⁵ R ^6, or a substituted or unsubstituted heterocycloalkyl group. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, a pharmacologically acceptable salt thereof, or a solvate thereof as an active ingredient. A PDE7 inhibitor comprising the compound according to any one of claims 1 to 9, a pharmacologically acceptable salt thereof, or a solvate thereof as an active ingredient.