JP2002308774A - Iv-type phosphodiesterase selective inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new usage of a pharmaceutical agent of 7- aminopyrido[2.3-d]pyrimidine derivative. SOLUTION: A lithecbole accelerator, a colon-stomach cramp treating agent, an antiinflammatory agent, an agent for treating allergic-atopic disease (excluding dermatitis), a cerebral function improving agent, an antidepressant, an anxiolytic, a liver function failure treating agent and a platelet aggregation suppressor containing a compound expressed by the general formula (I) (wherein, R1 is H, a lower alkenyl, a phenyl or the following group, that is, a lower alkyl which is optionally substituted with a substituent selected from oxo, an alkoxy, and phenyl, naphthyl and furyl each substituted with an alkoxy, a carboxyl, an alkoxycarbonyl, a mercapto, a halogen, trifluoromethyl and/or nitro, and an isoxazolyl, a pyridyl, a thienyl and a 1,3-dioxolanyl; R2 , R3 and R4 are each independently H, a halogen, a lower alkoxy, a benzyloxy, a carboxyl or a lower alkoxycarbonyl) as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 7-aminopyrido [2,3-
It relates to a novel pharmaceutical use of d] pyrimidine derivatives.

[0002]

BACKGROUND OF THE INVENTION In 1960, EW Sutherland et al. Revealed that cyclic adenosine-3 ', 5'-monophosphate (cAMP) was a second intracellular messenger, and cA
Intracellular levels of MP were found to be involved in the regulation of tissue function. Intracellular levels of cAMP are determined by the balance between the rate of cAMP production controlled by adenylate cyclase and the rate of cAMP degradation controlled by a group of phosphodiesterase (PDE) isoenzymes. Activation of adenylate cyclase or inhibition of PDE increases intracellular cAMP levels, which induces cellular responses such as relaxation of smooth muscle such as bronchi, suppression of inflammatory cell activation, and enhancement of neurotransmission. As for PDE,
To date, seven types of isoenzymes (PDEs I to VII) have been found, and it has also been revealed that their distribution states are different in each tissue. Among these isoenzymes, cAMP-specific isoenzymes
Type IV phosphodiesterase (PDE IV)
Since inhibitors against the IV isoenzyme show an effect of increasing intracellular cAMP, various pharmacological actions based on this are recognized.

[0003] The pharmacological action of PDE IV inhibitors is firstly a relaxation action of smooth muscle. Airway smooth muscle contraction
Because of the suppression of PDE IV inhibitors, it has been developed as a therapeutic agent for bronchial asthma and chronic obstructive pulmonary disease. In addition, PDE IV inhibitors are useful as ureteral stones and kidney stones as excretion enhancers due to relaxation of smooth muscle tissues such as the ureter, and PDE IV inhibitors are also used for the treatment of irritative disorders of the colon or gastric spasm. Is disclosed in Japanese Patent Publication No. 8-501538.

[0004] PDE IV inhibitors suppress the release of inflammatory and allergic mediators such as histamine and have an inhibitory effect on eosinophil infiltration by antigens and platelet activating factors.
It inhibits the release of damaging proteins (MBP, ECP) from eosinophils and is therefore useful as an anti-inflammatory or anti-allergic agent. In fact, in addition to arthritis and rheumatoid arthritis, inflammatory bowel diseases including ulcerative colitis and Crohn's disease, inflammatory diseases such as psoriasis (refractory inflammatory keratosis), and allergies such as atopic dermatitis It is being developed as a treatment for diseases. In addition, JP-T-2000-503678 discloses that PDE IV inhibitors include cheilitis, conjunctivitis, contact dermatitis, eczema, psoriasis, irritable bowel disease, urticaria, vasculitis, vulvitis,
It is disclosed that it is useful for treating inflammatory, allergic or atopic diseases such as dermatitis, irritability, asthma and allergic rhinitis, and has a platelet aggregation inhibitory action.

[0005] Furthermore, PDE IV inhibitors selectively inhibit the degradation of cAMP, thereby enhancing the neuronal transmission of noradrenaline to the postsynaptic synapse, and increasing the mental activity (emotional, behavioral, memory, memory). Improvement effects have been observed, and it has been developed as a cerebral function improving agent (sequence after cerebral infarction, anti-dementia, anti-Parkinson's disease, anti-dyskinesia), antidepressant, anxiolytic, and the like. In addition, by specifically inhibiting PDE IV in the liver, it has an inhibitory effect on liver fibrosis and TNF-α production, and is being developed as an indication for liver dysfunction
There are also PDE IV inhibitors. Also in the patent gazettes, for example, JP-T-2000-510105 discloses that PDE IV inhibitors include dementia, Parkinson's disease, neurodegenerative diseases such as depression,
Arthritis, shock symptoms, sepsis, lung disease, bone resorption disorders,
It is disclosed that it is useful for inflammatory diseases such as HIV infection, cerebral malaria, multiple sclerosis, and inflammatory skin disease.

As described above, it has been shown that PDE IV inhibitors are useful for various diseases. Therefore, PDE IV inhibitors are bronchodilators by smooth muscle relaxing action, calculus excretion enhancers, therapeutic agents for colon and gastric spasm, anti-inflammatory agents by anti-inflammatory cell activation, antiallergic agents, therapeutic agents for atopic diseases, It is useful as a drug such as a brain function improving agent by a transmission enhancing action, an antidepressant, an anxiolytic, a liver dysfunction therapeutic by a liver fibrosis suppressing action, or a platelet aggregation inhibitor.

By the way, PD is used for treating the above-mentioned diseases.
In using E IV inhibitors, this inhibitor is
Simultaneously inhibiting the isoenzyme also leads to undesirable side effects. For example, inhibition of PDE III present in the myocardium induces cardiotonic effects. As a specific example, theophylline, which is a non-selective PDE inhibitor, inhibits both PDE III and PDE IV, and is known to exhibit myocardial stimulating action as an undesired side effect along with the intended anti-asthmatic action. I have. Therefore, when developing PDE IV inhibitors, other PDEs such as type III
There is a need in medical practice for more selective PDE IV inhibitors that do not affect DE isoenzyme.

The compound used in the medicament of the present invention has already been applied for a patent (JP-A-2000-119272) as a novel compound having a bronchodilator effect.
Further, a compound having a pyrido [2,3-d] pyrimidine skeleton having a similar structure has an antiallergic effect (JP-A-63-45279).
A compound having a [2,3-d] pyrimidine skeleton has a bronchodilator effect (JP-A-8-3046, JP-A-8-3)
164 and JP-A-8-3165). However, the compounds used in the medicament of the present invention
No report has been made on having a type IV selective PDE inhibitory activity.

[0009]

An object of the present invention is to provide a novel pharmaceutical use of a 7-aminopyrido [2,3-d] pyrimidine derivative which is a highly safe compound.

[0010]

The present inventors have conducted intensive studies on 7-aminopyrido [2,3-d] pyrimidine derivatives and found that 7-amino-1-phenylpyrido [2,3-d] pyrimidine.
The present inventors have found that a -2,4-dione derivative has a type IV selective PDE inhibitory activity, and completed the present invention. Therefore, the compound of the present invention is a therapeutic agent for diseases associated with PDE IV, that is, a calculus excretion enhancer, a therapeutic agent for colon and gastric spasm, an anti-inflammatory agent, a therapeutic agent for allergic and atopic diseases, a brain function improving agent, an antidepressant, It is very useful as a drug for anxiolytics, therapeutic agents for liver dysfunction, platelet aggregation inhibitors and the like.

[0011]

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 7-amino-1-phenylpyrido [2,3-d] pyrimidine-2,4 represented by the following general formula (I).
A pharmaceutical containing a dione derivative as an active ingredient.

Embedded image [Wherein, R ₁ represents hydrogen, lower alkenyl, phenyl or lower alkyl which may be substituted by a substituent selected from the following (a) to (i): (a) oxo (b) lower alkoxy ( c) phenyl (d) naphthyl (e) furyl (f) 1 optionally substituted by one or more lower alkyl, lower alkoxy, carboxyl, lower alkoxycarbonyl, mercapto, halogen, trifluoromethyl and / or nitro Or isoxazolyl optionally substituted by lower alkyl or (g) pyridyl optionally substituted by one or more lower alkyl and / or halogen; (h) thienyl optionally substituted by halogen (i ) 1,3-Dioxolanyl R ₂ , R ₃ and R ₄ are each independently hydrogen, halogen , Lower alkoxy, benzyloxy, carboxyl or lower alkoxycarbonyl. ]

In the above substituents of the formula (I), lower alkyl is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, Represents a linear or branched alkyl group having 1 to 6 carbon atoms, such as hexyl, isohexyl, and dimethylbutyl. Lower alkoxy is preferably methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, t-butyloxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, isohexyl Represents a linear or branched alkoxy group having 1 to 6 carbon atoms such as oxy and dimethylbutyloxy. Halogen preferably represents fluorine, chlorine, bromine, iodine and the like. The lower alkenyl preferably represents a linear or branched alkenyl group having 2 to 6 carbon atoms such as ethylenyl, propylenyl, butenyl, pentenyl, hexenyl and the like.

The medicament of the present invention is a therapeutic agent for diseases involving PDE IV, ie, a calculus excretion enhancer, a therapeutic agent for colon and gastric convulsions, an anti-inflammatory agent, a therapeutic agent for allergic and atopic diseases, a brain function improving agent, an antidepressant. It is useful as an agent, an anxiolytic, a therapeutic agent for hepatic dysfunction, a platelet aggregation inhibitor, and the like, and can be used, for example, for the treatment of various diseases mentioned in the above section of the prior art.

Hereinafter, preferred embodiments of the present invention will be described. (1) At least a 7-amino-1-phenylpyrido [2,3-d] pyrimidine-2,4-dione derivative represented by the following general formula (I) or a pharmaceutically acceptable salt or hydrate thereof Calcium excretion enhancer containing one kind as an active ingredient, therapeutic agent for colon and gastric spasm, anti-inflammatory agent, therapeutic agent for allergic and atopic diseases (excluding dermatitis), brain function improver, antidepressant,
Anxiolytics, therapeutic agents for liver dysfunction, platelet aggregation inhibitors.

Embedded image [Wherein, R ₁ represents hydrogen, lower alkenyl, phenyl or lower alkyl which may be substituted by a substituent selected from the following (a) to (i): (a) oxo (b) lower alkoxy ( c) phenyl (d) naphthyl (e) furyl (f) 1 optionally substituted by one or more lower alkyl, lower alkoxy, carboxyl, lower alkoxycarbonyl, mercapto, halogen, trifluoromethyl and / or nitro Or isoxazolyl optionally substituted by lower alkyl or (g) pyridyl optionally substituted by one or more lower alkyl and / or halogen; (h) thienyl optionally substituted by halogen (i ) 1,3-Dioxolanyl R ₂ , R ₃ and R ₄ are each independently hydrogen, halogen , Lower alkoxy, benzyloxy, carboxyl or lower alkoxycarbonyl. (2) 7-amino-1-phenylpyrido wherein R ₂ is hydrogen [2,3
(1) containing a -d] pyrimidine-2,4-dione derivative
The medicament according to claim. (3) R ₃ is hydrogen 7-amino-1-phenylpyrido [2,3
(2) containing a -d] pyrimidine-2,4-dione derivative
The medicament according to claim. (4) 7-amino-1-phenylpyrido [2,3] wherein R ₄ is hydrogen
(3) containing the [-d] pyrimidine-2,4-dione derivative
The medicament according to claim. (5) 7-amino-1-phenylpyrido [2,3-d] pyrimidine wherein R ₁ is a benzyl group optionally substituted with halogen
The medicament according to the above (1) to (4), comprising a -2,4-dione derivative. (6) The medicament according to the above (5), comprising a 7-amino-1-phenylpyrido [2,3-d] pyrimidine-2,4-dione derivative wherein R ₁ is a benzyl group. (7) At least a 7-amino-1-phenylpyrido [2,3-d] pyrimidine-2,4-dione derivative represented by the following general formula (I) or a pharmaceutically acceptable salt or hydrate thereof: A therapeutic agent for dermatitis containing one kind as an active ingredient.

Embedded image [Wherein, R ₁ represents hydrogen, lower alkenyl, phenyl or lower alkyl which may be substituted by a substituent selected from the following (a) to (i): (a) oxo (b) lower alkoxy ( c) phenyl (d) naphthyl (e) furyl (f) 1 optionally substituted by one or more lower alkyl, lower alkoxy, carboxyl, lower alkoxycarbonyl, mercapto, halogen, trifluoromethyl and / or nitro Or isoxazolyl optionally substituted by lower alkyl or (g) pyridyl optionally substituted by one or more lower alkyl and / or halogen; (h) thienyl optionally substituted by halogen (i ) 1,3-Dioxolanyl R ₂ , R ₃ and R ₄ are each independently hydrogen, halogen , Lower alkoxy, benzyloxy, carboxyl or lower alkoxycarbonyl. Provided that R ₁ is benzyl optionally substituted with halogen and R ₂ ,
Except when R ₃ and R ₄ are hydrogen. (8) The therapeutic agent for dermatitis according to (7), which is a therapeutic agent for atopic dermatitis.

Among the compounds of the present invention, particularly preferred compounds are as follows. 7-amino-1,2,3,4-tetrahydro-1,3-diphenylpyrido
[2,3-d] pyrimidine-2,4-dione [Compound 1] 7-amino-3-ethyl-1,2,3,4-tetrahydro-1-phenylpyrido [2,3-d] pyrimidine-2, 4-dione [compound 2] 7-amino-1,2,3,4-tetrahydro-1-phenyl-3-propylpyrido [2,3-d] pyrimidine-2,4-dione [compound 3] 7-amino- 3-butyl-1,2,3,4-tetrahydro-1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 4] 7-amino-3-ethyl-1- (3,5- Dimethoxyphenyl) -1,2,
3,4-tetrahydropyrido [2,3-d] pyrimidine-2,4-dione [compound 5] 7-amino-1- (3,5-dimethoxyphenyl) -1,2,3,4-tetrahydro- 3-propylpyrido [2,3-d] pyrimidine-2,4-dione [compound 6] 7-amino-3-butyl-1- (3,5-dimethoxyphenyl) -1,2,
3,4-tetrahydropyrido [2,3-d] pyrimidine-2,4-dione [compound 7] 7-amino-3-benzyl-1- (3,5-dimethoxyphenyl) -1,
2,3,4-tetrahydropyrido [2,3-d] pyrimidine-2,4-dione [compound 8] 7-amino-1,2,3,4-tetrahydro-1- (4-methoxyphenyl)- 3-propylpyrido [2,3-d] pyrimidine-2,4-dione [compound 9] 7-amino-3-butyl-1,2,3,4-tetrahydro-1- (4-methoxyphenyl) pyrido [2 , 3-d] Pyrimidine-2,4-dione [compound 10] 7-amino-3-benzyl-1,2,3,4-tetrahydro-1- (4-methoxyphenyl) pyrido [2,3-d] Pyrimidine-2,4-dione [Compound 11] 7-amino-1,2,3,4-tetrahydro-1- (4-methoxyphenyl) -3- (4-picolyl) pyrido [2,3-d] pyrimidine -2,4-dione [compound 12] 7-amino-1- (3,4-dimethoxyphenyl) -1,2,3,4-tetrahydro-3-propylpyrido [2,3-d] pyrimidine-2,4 -Dione [Compound 13] 7-amino-1- (2,5-dimethoxyphenyl) -1,2,3,4-tetrahydro-3-propylpyrido [2,3-d] pyrimidine-2,4-dione [Compound 14 7-amino-1- (3,5-dimethoxyphenyl) -1,2,3,4-tetrahydro-3-isobutylpyrido [2,3-d] pyrimidine-2,4-dione [compound 15] Amino-3-benzyl-1,2,3,4-tetrahydro-1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 16] 7-amino-1,2,3,4-tetrahydro 1-phenyl-3- (4-picolyl) pyrido [2,3-d] pyrimidine-2,4-dione [Compound 1
7] 7-amino-1- (3,5-dimethoxyphenyl) -1,2,3,4-tetrahydro-3- (4-picolyl) pyrido [2,3-d] pyrimidine-2,4-
Dione (compound 18) 7-amino-3-benzyl-1- (2,4-dimethoxyphenyl) -1,
2,3,4-tetrahydropyrido [2,3-d] pyrimidine-2,4-dione [compound 19] 7-amino-1- (3,5-dimethoxyphenyl) -3- (2-ethoxyethyl) -1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-2,4-dione [compound 20]

7-amino-3- (3-butenyl) -1- (3,5-dimethoxyphenyl) -1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-2,4- Dione [Compound 21] Methyl [7-amino-1,2,3,4-tetrahydro-3- (4-picolyl) -2,4-dioxopyrido [2,3-d] pyrimidin-1-yl] -3-
Benzoate [Compound 22] 7-amino-3- (4-chlorobenzyl) -1,2,3,4-tetrahydro
1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 23] 7-amino-1,2,3,4-tetrahydro-3- (2-methylpicolyl)
1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 24] 7-amino-1,2,3,4-tetrahydro-1-phenyl-3- (2-picolyl) pyrido [2 , 3-d] pyrimidine-2,4-dione [compound 2
5] 7-amino-1,2,3,4-tetrahydro-1-phenyl-3- (3-picolyl) pyrido [2,3-d] pyrimidine-2,4-dione [compound 2
6] 7-amino-3- (3-chlorobenzyl) -1,2,3,4-tetrahydro
1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 27] 7-amino-1,2,3,4-tetrahydro-3- (4-methoxybenzyl) -1-phenylpyrido [2 , 3-d] Pyrimidine-2,4-dione [compound 28] 7-amino-3- (4-fluorobenzyl) -1,2,3,4-tetrahydro-1-phenylpyrido [2,3-d] pyrimidine -2,4-dione [compound 29] 7-amino-1,2,3,4-tetrahydro-3- (4-methylbenzyl)
1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 30] 7-amino-1,2,3,4-tetrahydro-3- (3-nitrobenzyl)
1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 31] 7-amino-3- (2-chlorobenzyl) -1,2,3,4-tetrahydro
1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 32] 7-amino-1,2,3,4-tetrahydro-3- (3-methylbenzyl)
1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 33] 7-amino-3- (3,4-dichlorobenzyl) -1,2,3,4-tetrahydro-1- Phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 34] 7-amino-1,2,3,4-tetrahydro-3- (3-methoxybenzyl) -1-phenylpyrido [2,3- d] pyrimidine-2,4-dione [compound 35] 7-amino-1,2,3,4-tetrahydro-1-phenyl-3- (4-trifluoromethylbenzyl) pyrido [2,3-d] pyrimidine -2,4
-Dione [compound 36] 7-amino-1,2,3,4-tetrahydro-1-phenyl-3- (thienylmethyl) pyrido [2,3-d] pyrimidine-2,4-dione [compound 37] 7 -Amino-3- (2-furfuryl) -1,2,3,4-tetrahydro-1-
Phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 38] 7-amino-1,2,3,4-tetrahydro-1-phenyl-3- (3-thienylmethyl) pyrido [2,3 -d] pyrimidine-2,4-dione [compound 39] 7-amino-3- (2-chloro-6-methylpicolyl) -1,2,3,4-tetrahydro-1-phenylpyrido [2,3-d] Pyrimidine-2,4-
Dione [compound 40]

Methyl 4- [7-amino-1,2,3,4-tetrahydro-1-phenyl-2,4-dioxopyrido [2,3-d] pyrimidine-
3-ylmethyl] benzoate [compound 41] 7-amino-3- (2-dioxolanylmethyl) -1,2,3,4-tetrahydro-1-phenylpyrido [2,3-d] pyrimidine-2,4- Dione [compound 42] 4- [7-amino-1,2,3,4-tetrahydro-1-phenyl-2,4-dioxopyrido [2,3-d] pyrimidin-3-ylmethyl] benzoic acid [compound 43] 7-amino-3-benzyl-1- (3-chlorophenyl) -1,2,3,4-
Tetrahydropyrido [2,3-d] pyrimidine-2,4-dione [compound 44] 7-amino-1,2,3,4-tetrahydro-3- (4-nitrobenzyl)
1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 45] 7-amino-1,2,3,4-tetrahydro-3- (2-methoxybenzyl) -1-phenylpyrido [2 , 3-d] Pyrimidine-2,4-dione [compound 46] 7-amino-3- (3,5-dimethoxybenzyl) -1,2,3,4-tetrahydro-1-phenylpyrido [2,3-d ] Pyrimidine-2,4-dione [compound 47] 7-amino-3- (5-chlorothienylmethyl) -1,2,3,4-tetrahydro-1-phenylpyrido [2,3-d] pyrimidine-2, 4-dione (compound 48) 7-amino-3-benzyl-1- (3,5-difluorophenyl) -1,
2,3,4-tetrahydropyrido [2,3-d] pyrimidine-2,4-dione [compound 49] 7-amino-1,2,3,4-tetrahydro-3- (1-naphthylmethyl)
1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 50] 7-amino-1,2,3,4-tetrahydro-3- (3,4-dimethylbenzyl) -1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 51] 7-amino-3-benzyl-1,2,3,4-tetrahydro-1- (3-methoxyphenyl) pyrido [2,3- d] pyrimidine-2,4-dione [compound 52] 7-amino-3- (4-bromobenzyl) -1,2,3,4-tetrahydro
1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 53] 7-amino-3- (2-chloropicolyl) -1,2,3,4-tetrahydro
1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 54] 7-amino-3-benzyl-1- (3-benzyloxyphenyl)-
1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-2,4-dione [compound 55] 7-amino-1,2,3,4-tetrahydro-3- (3-methyliso Xazol-5-ylmethyl) -1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 56] 7-amino-3- (3,5-dimethylisoxazol-4-ylmethyl)- 1,2,3,4-tetrahydro-1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 57] 7-amino-1,2,3,4-tetrahydro-1-phenyl-3 -(5-phenylpentyl) pyrido [2,3-d] pyrimidine-2,4-dione [compound 58]

Among the above compounds of the present invention, the most preferred compound is 7-amino-3-benzyl-1,2,3,4-tetrahydro-1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [ Compound 1
6].

The general formula (I) used in the medicament of the present invention
Are represented by JP-A-63-45279, JP-A-8-3046, JP-A-8-3164, and JP-A-8-164.
It can be produced according to or according to the method described in No. 3165 or JP-A-2000-119272, and the production method will be described in detail in Examples below.

The compound represented by the above general formula (I) includes various kinds of pharmaceutically acceptable salts, if any, such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, and the like.
Phosphoric acid, perchloric acid, thiocyanic acid, boric acid, formic acid, acetic acid, haloacetic acid, propionic acid, glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid,
Fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, p-
An addition salt with an acid such as toluenesulfonic acid, naphthalenesulfonic acid, and sulfanilic acid can be given. These salts can be produced from the respective free compounds or can be mutually converted by known methods. In addition, cis-trans isomers, optical isomers, stereoisomers such as conformers, or when present in the form of hydrates or metal complex compounds,
The present invention includes all stereoisomers, hydrates and complex compounds.

The compound of the present invention can be made into a medicament in combination with a suitable medicament carrier or diluent, can be formulated by any conventional method, and can be used as a solid or semi-solid for oral or parenteral administration. It can be formulated in liquid or gaseous dosage forms. For example, as a therapeutic agent for dermatitis, the formulation of the compound of the present invention is optimally formulated into an external preparation such as a liquid, suspension / emulsion, plaster, ointment, cataplasm, liniment, lotion, etc. May be used in the form of its pharmaceutically acceptable salt, or as a combination with other pharmaceutically active ingredients. The preparation method of the external preparation is described in detail in, for example, the General Rules for Preparations in the Japanese Pharmacopoeia Manual, 13th Revision (published by Hirokawa Shoten, 1996).

The preparation for oral administration may be used as it is or together with appropriate additives, for example, conventional excipients such as lactose, mannitol, corn starch, potato starch and the like.
Binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch, gelatin, disintegrants such as corn starch, potato starch, potassium carboxymethylcellulose, lubricants such as talc, magnesium stearate, other bulking agents, wetting agents , A buffer, a preservative, a fragrance and the like can be appropriately combined to form tablets, powders, granules or capsules.

The compound of the present invention can also be used as a suppository by mixing with various bases, for example, an oily base such as cocoa butter, an emulsion base or a water-soluble base such as macrogol, or a hydrophilic base. Good.

As an injection, an aqueous solvent or a non-aqueous solvent,
For example, a solution or suspension of distilled water for injection, physiological saline, Ringer's solution, vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester, propylene glycol, or the like can be used.

Ointments are prepared according to the type of base used.
It can be broadly classified into oily ointments, emulsion ointments, water-soluble ointments, and suspension ointments. The production of these ointments, for example,
Fatty, fatty oils, lanolin, petrolatum, paraffin, wax, resins, plastics, glycols, higher alcohols, glycerin, water, emulsifiers, suspending agents, or other suitable additives As a base,
It can be carried out by adding the compound of the present invention and mixing to make the whole quality uniform.

In order to formulate a poultice, a powder of the compound represented by the above general formula (I) and an essential oil component may be mixed to produce a slurry. Depending on the type and condition of the disease, it can be formulated into a dosage form other than the above that is optimal for the treatment.

For use as an inhalant or aerosol, the compound of the present invention may be in the form of a solution, suspension or fine powder,
The aerosol container is filled with a gas or liquid propellant and, if desired, with conventional adjuvants such as wetting or dispersing agents. The compound of the present invention may be in a non-pressurized dosage form such as a nebulizer or an atomizer. Depending on the type of the disease, it can be formulated into a dosage form other than the above, such as eye drops, which is optimal for the treatment.

The desired dose of the compound of the present invention varies depending on the administration subject, dosage form, administration method, administration period and the like. To obtain the desired effect, generally 0.001 to 50 mg of the compound of the present invention is used for an adult. / Kg once or several times a day, preferably 0.05 to 25 mg / kg once a day.
Oral administration can be performed in several divided doses. In the case of parenteral administration (for example, injection), the daily dose is preferably at a dose level of 3 to 1/10 of each of the above doses. For example, in the case of an ointment, an ointment containing the compound of the present invention in an amount of 0.1% to 15% may be applied to the affected area once to several times a day as appropriate in order to obtain a desired effect on an adult.

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.

[0030]

[Examples] Starting materials can be purchased from Aldrich Chemical Company, Inc., Fluka Chemical, Inc., Lancaster Synthesis, Inc., Maybridge Chemical Company Limited, or Tokyo Chemical Industry Co., Ltd. Or J. Org. Chem., 16, p. 1879 (1951), J. Org.
The starting compound can be produced according to a known method described in the literature such as Am. Chem. Soc., 75, p.114 (1953).

Embodiment 1 (1) Production of 6-amino-5-formyl-1,3-diphenyluracil 6-amino-1,3-diphenyluracil (10.0 g, 35.8 mmo
l) in dimethylformamide (100 mL) was cooled in an ice bath, and phosphorus oxychloride (3.7 mL, 39.4 mm) was added using a dropping funnel.
ol) was added dropwise. After the reaction mixture was stirred at room temperature for 2 hours, 50 mL of water was added to stop the reaction. After adjusting the pH to 10 with a 1 N potassium hydroxide solution, the mixture was further stirred at room temperature for 1 hour. The precipitated crude crystals were filtered and washed with 100 mL of water, and then the crude crystals were collected by filtration. The crude crystals collected by filtration were further recrystallized from hexane and ethyl acetate to give 6-amino-5-formyl-1,3-
Diphenyluracil (2.2 g) was obtained in 40% yield. Mp 141 -142 ° C ¹ H-NMR (DMSO-d ₆ ) d: 7.29-7.61 (m, 10H), 9.80
(s, 1H), 9.98 (s, 1H) IR (KBr): 3309, 1730, 1662, 1647, 1616, 1516, 149
1, 1365, 770, 692 cm ^-1 Anal.Calcd for C ₁₇ H ₁₃ N ₃ O ₃ :
C, 66.44; H, 4.26; N, 13.67, Found: C, 66.59; H,
4.24; N, 13.77 MS (EI) m / z: 307 [M ⁺ ], 279, 160, 132, 77

(2) 7-amino-1,2,3,4-tetrahydro-1,
Preparation of 3-diphenylpyrido [2,3-d] pyrimidine-2,4-dione (compound 1) 6-amino-5-formyl-1,3-diphenyluracil (5.0 g,
16.3 mmol) and 2- (triphenylphosphoranylidene)
A solution of acetonitrile (5.9 g, 19.6 mmol) in anhydrous acetonitrile (100 mL) was heated to reflux for 24 hours under a stream of argon. The reaction mixture was allowed to cool, and the solvent was distilled off under reduced pressure. The precipitated crude crystals were recrystallized from benzene to give 7-amino
-1,2,3,4-tetrahydro-1,3-diphenylpyrido [2,3-d]
Pyrimidine-2,4-dione (2.4 g) was obtained in 45% yield. Mp 162 -163 ° C ¹ H-NMR (DMSO-d ₆ ) d: 6.33 (d, 1H, J = 9 Hz), 6.89
(br, 2H), 7.31-7.93 (m, 10H), 7.93 (d, 1H, J = 9
Hz) IR (KBr): 3358, 1709, 1660, 1624, 1427, 1398, 694
cm ^-1 Anal.Calcd for C ₁₉ H ₁₄ N ₄ O ₂ : C, 69.08; H, 4.27; N,
16.96, Found: C, 68.99; H, 4.37; N, 16.97 MS (EI) m / z: 330 [M ⁺ ], 211

The starting material, 6-amino, used in Example 1
Compounds 2 to 58 represented by the following general formula (II) were produced in the same manner as in Example 1, except that appropriate starting materials were used instead of -1,3-diphenyluracil. Details of the compounds are described in Tables 1 and 2.

Embedded image

[0034]

[Table 1]

[0035]

[Table 2]

Embodiment 2 FIG. Phosphodiesterase inhibitory activity The inhibitory activity of the compounds of the present invention on phosphodiesterase (PDE) isozymes was examined according to a conventional method. (1) PDE II inhibitory activity Hidaka, H. et al. (Biochem. Biophys Acta, 429: 485-497)
(1976)) and Nicholsen, CD et al. (Trends Pharmacol.
i., 12: 19-27 (1991)), the following experiment was performed. That is, PDE II purified from human platelets,
Incubation was performed at 30 ° C. for 20 minutes in the presence of 25 μM cAMP containing 0.05 μM [ ³ H] cAMP and 100 μM test substance. cA
The action of PDE, which converts MP to AMP, was stopped by boiling for 2 minutes. Next, snake venom nucleotidase was added and incubated at 30 ° C. for 10 minutes to convert AMP to adenosine. The unhydrolyzed cAMP was bound to the AGI-X2 resin, and [ ³ H] adenosine in the remaining aqueous layer was counted with a scintillation counter.

(2) PDE III inhibitory activity Hidaka, H. et al. (Biochem. Biophys Acta, 429: 485-497)
(1976)) and Nicholsen, CD et al. (Trends Pharmacol.
i., 12: 19-27 (1991)), the following experiment was performed. That is, PDE III purified from human platelets
With 1.0 μM cAMP containing 0.01 μM [ ³ H] cAMP and 100 μM
Was incubated at 30 ° C. for 20 minutes in the presence of the test substance. The action of PDE, which converts cAMP to AMP, was stopped by boiling for 2 minutes. Next, add the snake venom nucleotidase and at 30 ° C
After incubation for 10 minutes, AMP was converted to adenosine.
The unhydrolyzed cAMP was bound to the AGI-X2 resin, and [ ³ H] adenosine in the remaining aqueous layer was counted with a scintillation counter.

(3) PDE IV inhibitory action Cortijo, J. et al. (Br. J. Pharmacol., 108: 562-568 (199)
3)) and Nicholsen, CD et al. (Trends Pharmacol. Sci., 1
2: 19-27 (1991)), and the following experiment was performed. That is, PD purified from human U937 premonocyte leukemia cells
EIV was performed using 1.0 μM cAMP containing 0.01 μM [ ³ H] cAMP and 100 μM.
Incubation was performed at 30 ° C. for 20 minutes in the presence of μM test substance. The action of PDE, which converts cAMP to AMP, was stopped by boiling for 2 minutes. Next, add snake venom nucleotidase and add 30
AMP was converted to adenosine by incubating at 10 ° C for 10 minutes. The unhydrolyzed cAMP was bound to the AGI-X2 resin, and [ ³ H] adenosine in the remaining aqueous layer was counted with a scintillation counter. The inhibitory effect of the compound of the present invention on PDE IV derived from the present invention was examined.

(4) PDE V inhibitory activity Hidaka, H. et al. (Biochem. Biophys Acta, 429: 485-497)
(1976)) and Nicholsen, CD et al. (Trends Pharmacol.
i., 12: 19-27 (1991)), the following experiment was performed. That is, PDE V purified from human platelets,
Incubation was carried out at 30 ° C. for 20 minutes in the presence of 1.0 μM cAMP containing 0.01 μM [ ³ H] cAMP and 100 μM test substance.
The action of PDE, which converts cAMP to AMP, was stopped by boiling for 2 minutes. Next, snake venom nucleotidase was added and incubated at 30 ° C. for 10 minutes to convert AMP to adenosine. The unhydrolyzed cAMP was bound to the AGI-X2 resin, and [ ³ H] adenosine in the remaining aqueous layer was counted with a scintillation counter. One example of the results is shown in the table below. In addition, the PDE IV inhibitory effect of Compound 16 was dose-dependent.

[0040]

[Table 3]

[0041]

As shown in Table 3, the 7-amino-1-phenylpyrido [2,3-d] pyrimidine-2,4-dione derivative of the present invention exhibits PDE IV-selective inhibitory activity. Was. It is known that this selective PDEIV inhibitory activity not only suppresses the occurrence of undesirable side effects induced by other types of PDE inhibitory activity, but also that the compound of the present invention has extremely high safety. It has desirable properties as a pharmaceutical. Therefore, the compound of the present invention can be used as a calculus excretion enhancer, a therapeutic agent for colon and gastric convulsions, an anti-inflammatory agent, a therapeutic agent for allergic and atopic diseases, a brain function improving agent, an antidepressant, an anxiolytic agent, a therapeutic agent for hepatic dysfunction, platelets It is useful as a medicine such as an aggregation inhibitor.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 13/04 A61P 13/04 25/22 25/22 25/24 25/24 25/28 25/28 29 / 00 29/00 37/08 37/08 43/00 111 43/00 111 // C07D 471/04 C07D 471/04 118 118Z F-term (reference) 4C065 AA04 BB11 CC01 DD03 EE02 HH01 JJ06 KK09 LL04 PP03 PP06 PP07 PP12 PP16 4C086 AA01 AA02 AA03 CB09 MA01 MA04 NA14 ZA05 ZA12 ZA15 ZA54 ZA66 ZA75 ZA81 ZB11 ZB13 ZC20

Claims (2)

[Claims] 1. A 7-amino-1 represented by the following general formula (I)
-Phenylpyrido [2,3-d] pyrimidine-2,4-dione derivative or at least one pharmaceutically acceptable salt or hydrate thereof as an active ingredient, a stone discharge enhancer,
Gastrospasm remedies, anti-inflammatory drugs, remedies for allergic and atopic diseases (excluding dermatitis), brain function improvers, antidepressants, anxiolytics, hepatic dysfunction drugs, platelet aggregation inhibitors. Embedded image [Wherein, R ₁ represents hydrogen, lower alkenyl, phenyl or lower alkyl which may be substituted by a substituent selected from the following (a) to (i): (a) oxo (b) lower alkoxy ( c) phenyl (d) naphthyl (e) furyl (f) 1 optionally substituted by one or more lower alkyl, lower alkoxy, carboxyl, lower alkoxycarbonyl, mercapto, halogen, trifluoromethyl and / or nitro Or isoxazolyl optionally substituted by lower alkyl or (g) pyridyl optionally substituted by one or more lower alkyl and / or halogen; (h) thienyl optionally substituted by halogen (i ) 1,3-Dioxolanyl R ₂ , R ₃ and R ₄ are each independently hydrogen, halogen , Lower alkoxy, benzyloxy, carboxyl or lower alkoxycarbonyl. ] 2. 7-amino-1 represented by the following general formula (I)
-A therapeutic agent for dermatitis comprising as an active ingredient at least one of a phenylpyrido [2,3-d] pyrimidine-2,4-dione derivative or a pharmaceutically acceptable salt or hydrate thereof. Embedded image [Wherein, R ₁ represents hydrogen, lower alkenyl, phenyl or lower alkyl which may be substituted by a substituent selected from the following (a) to (i): (a) oxo (b) lower alkoxy ( c) phenyl (d) naphthyl (e) furyl (f) 1 optionally substituted by one or more lower alkyl, lower alkoxy, carboxyl, lower alkoxycarbonyl, mercapto, halogen, trifluoromethyl and / or nitro Or isoxazolyl optionally substituted by lower alkyl or (g) pyridyl optionally substituted by one or more lower alkyl and / or halogen; (h) thienyl optionally substituted by halogen (i ) 1,3-Dioxolanyl R ₂ , R ₃ and R ₄ are each independently hydrogen, halogen , Lower alkoxy, benzyloxy, carboxyl or lower alkoxycarbonyl. Provided that R ₁ is benzyl optionally substituted with halogen and R ₂ ,
Except when R ₃ and R ₄ are hydrogen. ]