JP2000063381A - Pyridopyrimidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound changing the balance of [type-1 helper T cell (Th1)/type-2 helper T cell (Th2)] by inhibiting the immune response of Th2 and by enhancing the immune response of Th1 and useful for an immunoregulator and treatment of bacterial infectious disease, malignant tumor or the like. SOLUTION: This compound is expressed by formula I [R1 is a group of formula II (ring A is a 3-10C cycloalkane or the like; R5 is a 1-10C alkyl or the like) or the like; R2 is H, a 1-6C alkoxy or the like; R3 is H, a 1-6C alkoxy or the like; R4 is H, a 1-6C alkoxy or the like] and e.g. N-(2-aminopyrido[2,3- d]pyrimidin-4-yl)-N-pentylamine. The compound of formula I is obtained by reacting a compound of formula III with phosphorus oxychloride to form a compound of formula IV and then by reacting it with a compound of formula H2NR1.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pyridopyrimidine derivative. More specifically, the present invention is a type 2 helper T
Suppresses the immune response on the cell (hereinafter abbreviated as Th2) side,
An active ingredient is a pyridopyrimidine derivative or a pharmaceutically acceptable salt thereof that enhances the immune response on the side of type 1 helper T cells (hereinafter abbreviated as Th1) and changes the Th1 / Th2 balance in the whole body. It relates to an immunomodulator. Specifically, it relates to a therapeutic agent for an allergic disease in which an immune response on the Th2 side is abnormally enhanced. More specifically, the present invention suppresses the Th2 side immune response and enhances the Th1 side immune response to thereby cause diseases caused by abnormally enhanced Th2 side immune response, that is, asthma, allergic dermatitis or allergic disease. A pyridopyrimidine derivative or a pharmaceutically acceptable salt thereof, which is effective for treating or preventing allergic diseases such as rhinitis, autoimmune diseases such as systemic lupus erythematosus, and acquired immune deficiency syndrome (AIDS). It relates to an immunomodulator as an active ingredient. Furthermore, a pyridopyrimidine derivative or a pharmaceutically acceptable salt thereof which is capable of treating or preventing viral or bacterial infections, malignant tumors and the like due to the action of enhancing the Th1 side immune response of the present invention. It relates to an immunomodulator as an active ingredient. Pyridopyrimidine for treating or preventing various diseases, for example, bacterial infections, malignant tumors, etc., which enhance treatment or prevention by enhancing Th1 immune response by selective immunomodulatory action to enhance Th1 immune response The present invention relates to an immunomodulator containing a derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0002]

2. Description of the Related Art Mosmann et al. First proposed that lymphocytes called helper T cells (hereinafter abbreviated as Th), which play a central role in the immune response, are classified into two different subsets. is there. They classify mouse helper T cells (Th) into subsets of Th1 and Th2 according to the type of cytokines produced (J. I.
mmunol. (1986) 136: 2348-2357). The Th1 type cytokines include interleukin 2 (IL-2),
Interferon γ (IFN-γ) and the like can be mentioned. T
Interleukin 4 is an h2-type cytokine
(IL-4), interleukin 5 (IL-5), interleukin 10 (IL-10), interleukin 1
3 (IL-13) and the like.

[0003] Today, the concept of the Th1 / Th2 classification is not limited to classification of helper T cell subsets, and which helper T cell subset is mainly involved in various immune responses in the living body. From the viewpoints, they are respectively referred to as “Th1 immune response” and “Th2 immune response”.
Side immune response ”. The main components of the Th1 side immune response are cytokines such as interferon γ (IFN-γ) and interleukin 2 (IL-2) produced in association with Th1 activation. These Th1-type cytokines mainly induce viruses, bacteria, etc. by inducing the activation of macrophages, natural killer cells, etc., and enhancing the activation of Th1 by IL-12 etc. produced from activated macrophages. It is known to be involved in cell-mediated immunity such as defense against infection. On the other hand, the main components of the Th2-side immune response are IL-4 and IL produced by Th2 activation.
-5 and other cytokines. It is known that these Th2-type cytokines are involved in humoral immunity such as antibody production from B cells (including IgE class).

[0004] Since Th2 produces cytokines involved in allergic reaction such as IL-4 and IL-5 as described below, Th2 is regarded as an important regulatory cell for allergic reaction. For example, IL which is a representative of Th2 type cytokines
-4 induces the production of IgE antibodies on B cells. It also induces VCAM-1 gene expression, which is an important molecule that functions when eosinophils adhere to vascular endothelial cells and infiltrate tissues (Pharmacia (1993) 29 : 1123-1128). Recently IL-
4 is also attracting attention as a differentiation and growth factor of Th2 itself. IL-5, which is a Th2-type cytokine like IL-4
Induces differentiation, proliferation, migration or activation of eosinophils. Allergic inflammation is characterized by eosinophil infiltration, activation, and degranulation, as represented by chronic airway inflammation in asthma, for example. From this, IL
-5 is considered to be the causative agent of the allergic inflammatory response.

[0005] From the characteristics of Th2 type cytokines as described above, Th2 has two allergies: an "immediate reaction" of allergy involving IgE antibodies and mast cells, and a "late reaction" involving eosinophils. Control any of the reactions,
It is recognized as the central cell in the allergic inflammatory response. Therefore, the allergic disease is considered to be a disease caused by abnormally enhanced Th2 immune response. This idea is supported by the fact that the production of Th2-type cytokines such as IL-4 and IL-5 or the presence of Th2 has been confirmed in the respiratory tract and skin which are lesions of allergic diseases. .

[0006] From the above, suppression of both immediate-type and delayed-type allergic reactions, or marked infiltration of eosinophils,
In addition, it is important to suppress the Th2 side immune response in order to suppress the allergic inflammatory reaction characterized by activation at the stage of its underlying cause and to treat and prevent allergic diseases in general. Conceivable. In other words, if a drug capable of suppressing the Th2 immune response is developed,
It is considered to be an effective therapeutic or preventive drug for allergic diseases.

[0007] Among allergic diseases, particularly in severe chronic asthma and atopic dermatitis, it is considered that the delayed-type allergic reaction plays an important role. However, currently used antiallergic agents mainly suppress only an immediate allergic reaction centering on antihistamine action and the like, and their clinical effects are not sufficient. From this point of view, it is desired to develop a drug that suppresses the Th2 side immune response, which suppresses both the delayed-type and immediate-type allergic reactions as described above and treats or prevents allergic diseases in general. -ing

[0008] Further, bronchodilators represented by xanthine derivatives or β-stimulants, which have been used for many years in the treatment of asthma, are known to have an action of suppressing the contraction of bronchial smooth muscle due to various stimuli. There is. However, it is ineffective against chronic airway inflammation, which is the underlying etiology of asthma. In addition, side effects on the circulatory system pose a problem with both xanthine derivatives and β-stimulants. In today's asthma treatment, as clearly shown in WHO guidelines, asthma is regarded as chronic inflammation of the respiratory tract, and elimination of this chronic airway inflammation should be the primary goal of treatment. Became. Chronic airway inflammation in asthma is triggered by infiltration, activation and degranulation of eosinophils, and is characterized by pathological images leading to thickening and fibrosis of airway epithelium with chronic inflammation. The guideline positions inhaled steroids, the only drug currently effective against this chronic airway inflammation, as the first-line drug for moderate to moderate asthma.

[0009] After all, for these severe asthma and atopic dermatitis, it is considered that only the steroid drug is effective, and the steroid drug is now frequently used. However, it has been a problem that various side effects (steroid dermatosis, induced infection, adrenocortical dysfunction, etc.) are caused by long-term administration of the steroid. From these viewpoints,
By selectively suppressing the immune response on the Th2 side, both immediate and delayed allergic reactions are suppressed, or allergic inflammatory reactions characterized by marked infiltration and activation of eosinophils. Is suppressed at the stage of its root cause,
It is desired to develop a drug capable of treating or preventing allergic diseases in general.

[0010] Furthermore, when the development of a therapeutic drug or a prophylactic drug with fewer side effects is taken into consideration, as long as the drug that suppresses the Th2 side immune response as described above enhances the Th1 side immune response, It seems to be more convenient as a medicine. That is, as described above, Th1 is mainly
Since it plays an important role for the organism to protect against infections against viruses and bacteria by producing IFN-γ, the drug developed for the purpose of suppressing the Th2 immune response enhances the action of Th1. If it does, it is highly desirable in terms of side effects. For example, immunosuppressant cyclosporine and FK506
Is known to strongly suppress Th2 activation. However, these cyclosporins and FK506 are
Has a non-specific immunosuppressive effect that suppresses Th1 activation as well as or even stronger than that of the above-mentioned non-specific immunosuppressive effect. Serious side effects, such as opportunistic infections caused by the above, or an increase in carcinogenicity, are a problem.
Similar problems can be considered for other non-specific immunosuppressants.

[0011] From the above, T typified by the production of IFN-γ
If a drug that enhances the immune response on the h1 side and suppresses the immune response on the Th2 side, which is represented by the production of IL-4 and IL-5, is developed, the treatment for allergic diseases as described above is effective and has few side effects. It is considered to be a drug or preventive drug. In addition, autoimmune diseases in which antibody production or humoral immunity is abnormally enhanced, such as systemic lupus erythematosus, are also presumed to be in a state in which Th2 immune response is also abnormally elevated (Medical Immunology (1988)). ) 15: 401).
Therefore, the immune response on the Th1 side as described above is enhanced, and
It is expected that the drug that suppresses the immune response on the side will also be a therapeutic drug for autoimmune diseases.

[0012] WO 93/07124 discloses pyridopyrimidine derivatives that exhibit activity as phosphodiesterase inhibitors. Also disclosed is the potential as an anti-allergic agent based on its activity as a phosphodiesterase inhibitor. However, in the case of theophylline, which is a typical antiallergic agent based on the activity as an existing phosphodiesterase inhibitor, its main antiallergic effect is bronchodilator effect in asthma. As described above, bronchodilators typified by xanthine derivatives or β-stimulants are known to have an action of suppressing the contraction of bronchial smooth muscle by various stimuli, but only the action of suppressing symptoms, It is ineffective against chronic airway inflammation, the underlying etiology of asthma. Moreover,
When considering the phosphodiesterase isoenzyme,
Isoenzyme, which is mainly involved in allergic inflammation, is cA
It is MP phosphodiesterase (PDE-III or IV), and it is considered that by inhibiting cAMP phosphodiesterase, intracellular cAMP concentration is increased and an anti-inflammatory action is expressed. On the other hand, the inhibitors disclosed in WO 93/07124 are those for cGMP phosphodiesterase (PDE-V) and those for calmodulin-dependent phosphodiesterase (PDE-I) as isoenzymes. When diesterase is inhibited, the intracellular cGMP concentration rises and vasodilatory and bronchodilatory actions are exhibited, but since it has no inhibitory action on inflammatory cells, anti-inflammatory action cannot be expected. Rather,
Many researchers today are aiming at PDE-IV specific inhibitors for the purpose of reducing side effects and enhancing antiallergic activity. WO 93/07124 does not specifically describe the pyridopyrimidine derivative of the present invention which enhances the Th1 side immune response and suppresses the Th2 side immune response. Further, the pyridopyrimidine derivative of the present invention does not exhibit phosphodiesterase inhibitory activity.

[0013]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
The present invention is to provide a compound that enhances the immune response on the 1 side and suppresses the immune response on the Th2 side, thereby changing the Th1 / Th2 balance as a whole and regulating the immune response. Specifically, interferon γ (IFN-
The present invention provides a compound that enhances the production of Th1 type cytokines such as γ) and conversely suppresses the production of Th2 type cytokines such as interleukin 4 (IL-4) and interleukin 5 (IL-5). More specifically, for example,
Allergic diseases, parasitic infections, autoimmune diseases such as systemic lupus erythematosus, viral or bacterial infections, malignant tumors or acquired immunodeficiency syndrome (AID
S) and other therapeutic or prophylactic agents.

[0014]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that pyridopyrimidine derivatives and salts thereof enhance the Th1 side immune response and the Th2 side immunity. It was found that the response was suppressed, and furthermore, the Th1 / Th2 balance was changed as a whole,
They have found that they regulate the immune response and have completed the present invention.

The present invention, 1. Formula (1)

[Chemical 6] (In the formula, R ¹ is the formula (2)

[Chemical 7] (In the formula, A ring is a cycloalkane having 3 to 10 carbon atoms,
Represents a cycloalkene having 5 to 10 carbon atoms, a substituted cycloalkane, a bicycloalkane having 7 to 10 carbon atoms, a substituted bicycloalkane, or a heterocycle containing oxygen or a sulfur atom as a hetero atom, and 1 or 2 sulfur atoms May combine with an oxygen atom of to form sulfinyl or sulfonyl. R ⁵ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, or 3 carbon atoms.
6 cycloalkyl group, cycloalkylalkyl group, or OR 9 ^{(R 9} is a straight-chain or branched lower alkyl group having 1 to 6 carbon atoms, lower alkenyl group having 3 to 6 carbon atoms having 4 to 10 carbon Represents a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a cycloalkylalkyl group having 4 to 10 carbon atoms). ), Or formula (3),

[Chemical 8] (In the formula, R ⁶ is a linear or branched lower alkyl group having 2 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, a hydroxyl group, a halogen atom, or A linear or branched lower alkyl group having 1 to 6 carbon atoms substituted with an alkoxy group having 1 to 4 carbon atoms, a phenyl group, a cycloalkyl group having 3 to 8 carbon atoms, an oxygen atom as a hetero atom from 1 to 5 to 7-membered saturated heterocycle containing two or C (= O) R ¹⁰ (wherein R is
¹⁰ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, A cycloalkylalkyl group having 4 to 10 carbon atoms or C (═O) R ¹¹ (in the formula, R ¹¹ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, a lower alkyl group having 2 to 6 carbon atoms) An alkenyl group, a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkylalkyl group having 4 to 10 carbon atoms). ), R ⁷ is a hydrogen atom, carbon number 1
To C6 linear or branched lower alkyl group, C6 to C10 aryl group, halogen atom, C1 to C4 alkoxy group, or C1 to C4 substituted alkyl group To 10 represent an aryl group, a carbamoyl group, or a hydroxymethyl group, and R ⁸ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms. ), R ² represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a halogen atom, and R ³ represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a halogen atom, R
⁴ represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a halogen atom. ) The pyridopyrimidine derivative and its salt represented by these. 2. R ¹ is the formula (2)

[Chemical 9] (In the formula, A ring is a cycloalkane having 3 to 10 carbon atoms,
Represents a cycloalkene having 5 to 10 carbon atoms, a substituted cycloalkane, a bicycloalkane having 7 to 10 carbon atoms, a substituted bicycloalkane, or a heterocycle containing oxygen or a sulfur atom as a hetero atom, and 1 or 2 sulfur atoms May combine with an oxygen atom of to form sulfinyl or sulfonyl. R ⁵ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, or 3 carbon atoms.
6 cycloalkyl group, cycloalkylalkyl group, or OR 9 ^{(R 9} is a straight-chain or branched lower alkyl group having 1 to 6 carbon atoms, lower alkenyl group having 3 to 6 carbon atoms having 4 to 10 carbon Represents a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a cycloalkylalkyl group having 4 to 10 carbon atoms). The pyridopyrimidine derivative according to claim 1 or a pharmaceutically acceptable salt thereof. 3. R ¹ is the formula (3)

[Chemical 10] (In the formula, R ⁶ is a linear or branched lower alkyl group having 2 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, a hydroxyl group, a halogen atom, or A linear or branched lower alkyl group having 1 to 6 carbon atoms substituted with an alkoxy group having 1 to 4 carbon atoms, a phenyl group, a cycloalkyl group having 3 to 8 carbon atoms, an oxygen atom as a hetero atom from 1 to 5 to 7-membered saturated heterocycle containing two or C (= O) R ¹⁰ (wherein R is
¹⁰ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, A cycloalkylalkyl group having 4 to 10 carbon atoms or C (═O) R ¹¹ (in the formula, R ¹¹ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, a lower alkyl group having 2 to 6 carbon atoms) An alkenyl group, a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkylalkyl group having 4 to 10 carbon atoms). ), R ⁷ is a hydrogen atom, carbon number 1
To C6 linear or branched lower alkyl group, C6 to C10 aryl group, halogen atom, C1 to C4 alkoxy group, or C1 to C4 substituted alkyl group To 10 represent an aryl group, a carbamoyl group, or a hydroxymethyl group, and R ⁸ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms. 4.) The pyridopyrimidine derivative according to claim 1 or a pharmaceutically acceptable salt thereof; To 3. 5. An immunomodulator, which comprises the pyridopyrimidine derivative described above or a pharmaceutically acceptable salt thereof as an active ingredient and suppresses the immune response of the type 2 helper T cell side and enhances the immune response of the type 1 helper T cell side; 1. To 3. 5. A therapeutic or prophylactic agent for a disease having an abnormally enhanced immune response on the type 2 helper T cell side, which comprises the above-mentioned pyridopyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient; 4. A disease in which an immune response on the type 2 helper T cell side is abnormally enhanced is an allergic disease. 7. The therapeutic or prophylactic agent as described above; or 7. 5. Asthma, allergic rhinitis or atopic dermatitis is the allergic disease in which the immune response on the type 2 helper T cell side is abnormally enhanced. The therapeutic or prophylactic agent as described;
Regarding

[0016]

DETAILED DESCRIPTION OF THE INVENTION

The substituents in the present invention will be specifically described below. Examples of the cycloalkane having 3 to 10 carbon atoms in the ring A include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0018] Examples of the cycloalkene having 5 to 10 carbon atoms in the A ring include cyclopentenyl and cyclohexenyl.

[0019] Examples of the bicycloalkane having 7 to 10 carbon atoms in the A ring include bicyclo [2.2.1] heptane, bicyclo [2.2.1] hept-5-ene and bicyclo [2.
2.2] octane, bicyclo [2.2.2] octa-5
-En and the like.

[0020] Oxygen as a hetero atom in the ring A or a hetero ring containing a sulfur atom includes, for example, oxetane, thietane (trimethylene sulfide), thietan-1-oxide (trimethylene sulfoxide), thietane-1,
1-dioxide (trimethylene sulfone), tetrahydrofuran, tetrahydrothiophene, tetrahydrothiophene-1-oxide, tetrahydrothiophene-1,
1-dioxide, tetrahydro-4H-pyran, thian (pentamethylene sulfide), thian-1,1-dioxide (pentamethylene sulfone), thian-1-oxide (pentamethylene sulfoxide), oxepane (hexamethylene oxide), thiepan ( Hexamethylene sulfide), thiepan-1-oxide (hexamethylene sulfoxide), thiepan-1,1-dioxide (hexamethylene sulfone), 7-oxabicyclo [2.2.
1] heptane, 7-oxabicyclo [2.2.1] hept-5-ene and the like.

[0021] Examples of the substituent of the substituted cycloalkane and the substituted bicycloalkane in the A ring include an alkyl group having 1 to 3 carbon atoms, a carbonyl group, a hydroxy group, an alkoxycarbonyl group, a hydroxycarbonyl group, a carbamoyl group, and the like. , Or substituents of adjacent carbon atoms may be combined to form a tetramethylene group, or carbon atoms on the ring may be replaced by carbonyl groups. The substituent is one, or a plurality of the same or different. Examples of the alkyl group having 1 to 3 carbon atoms include methyl, ethyl, propyl and 2-propyl.

[0023] Examples of the linear or branched alkyl group having 1 to 6 carbon atoms in R ⁵ include, for example, methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 3-methylpropyl, 1,1- Dimethylethyl, pentyl, hexyl and the like can be mentioned.

[0023] Examples of the alkenyl group having 2 to 6 carbon atoms in R ⁵ include vinyl, allyl, butenyl, pentenyl, hexenyl and the like.

[0024] Examples of the alkynyl group having 3 to 6 carbon atoms in R ⁵ include propargyl, butynyl, pentynyl and the like.

[0025] Examples of the cycloalkyl group having 3 to 6 carbon atoms in R ⁵ include cyclopropyl, cyclobutyl,
Examples include cyclopentyl and cyclohexyl.

[0026] Examples of the cycloalkylalkyl group having 4 to 10 carbon atoms in R ⁵ include cyclopropylmethyl, cyclobutylmethyl group, cyclopentylethyl, cyclohexylmethyl, cyclohexylpropyl and the like.

[0027] Examples of the linear or branched alkyl group having 1 to 6 carbon atoms in R ⁹ include, for example, methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 3-methylpropyl, 1,1- Dimethylethyl, pentyl, hexyl and the like can be mentioned.

[0028] Examples of the alkenyl group having 3 to 6 carbon atoms in R ⁹ include allyl, butenyl, pentenyl, hexenyl and the like.

[0029] Examples of the alkynyl group having 3 to 6 carbon atoms in R ⁹ include propargyl, butynyl, pentynyl and the like.

[0030] Examples of the cycloalkyl group having 3 to 6 carbon atoms in R ⁹ include cyclopropyl, cyclobutyl,
Examples include cyclopentyl and cyclohexyl.

[0031] Examples of the cycloalkylalkyl group having 4 to 10 carbon atoms in R ⁹ include cyclopropylmethyl, cyclobutylmethyl group, cyclopentylethyl, cyclohexylmethyl, cyclohexylpropyl and the like.

[0032] Examples of the linear or branched alkyl group having 2 to 6 carbon atoms in R ⁶ include, for example, ethyl, propyl,
2-propyl, butyl, 2-butyl, 3-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl and the like can be mentioned.

[0033] Examples of the alkenyl group having 2 to 6 carbon atoms in R ⁶ include allyl, butenyl, pentenyl, hexenyl and the like.

[0034] Examples of the alkynyl group having 3 to 6 carbon atoms in R ⁶ include propargyl, butynyl, pentynyl and the like.

[0035] Examples of the halogen atom of the substituent of the linear or branched lower alkyl group having 1 to 6 carbon atoms in R ⁶ include fluorine, chlorine, bromine, iodine and the like. Examples of the alkoxy group having 1 to 4 carbon atoms as the substituent of the linear or branched lower alkyl group having 1 to 6 carbon atoms in R ⁶ include methoxy, ethoxy, propyloxy, butoxy and the like. 1 carbon atom in R ⁶
When the substituent of the linear or branched lower alkyl group of 1 to 6 is a hydroxyl group, the substitution position is preferably not the terminal of the alkyl group. The number of substituents in the straight-chain or branched lower alkyl group having 1 to 6 carbon atoms in R ⁶ is 1 or 2 or more. Preferred examples of the substituent of the linear or branched lower alkyl group having 1 to 6 carbon atoms in R ⁶ include a hydroxyl group and a hydroxymethyl group, and the substitution position is 1 or 2
The position (position 2 or 3 as viewed from the amino group at the 4-position of the pyridopyrimidine ring) is preferred.

[0036] Examples of the cycloalkyl group having 3 to 8 carbon atoms in R ⁶ include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Examples of the 5- to 7-membered saturated heterocycle containing 1 to 2 oxygen atoms as the hetero atom in R ⁶ include tetrahydrofuran, oxane,
1,4-dioxane, oxepane, etc. are mentioned.

[0037] Examples of the aryl group having 6 to 10 carbon atoms in R ⁷ include phenyl and naphthyl. R
Examples of the halogen atom of the substituent in the substituted aryl group having 6 to 10 carbon atoms in ⁷ include fluorine,
Examples thereof include chlorine, bromine and iodine. Examples of the alkoxy group having 1 to 4 carbon atoms as the substituent of the substituted aryl group having 6 to 10 carbon atoms in R ⁷ include, for example, methoxy, ethoxy, propyloxy, 2-propyloxy,
Butoxy and the like can be mentioned.

[0038] Examples of the linear or branched alkyl group having 1 to 6 carbon atoms in R ⁷ and R ⁸ include, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, and 2-methylpropyl. , Pentyl group, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-
Examples thereof include ethylpropyl, 2-ethylpropyl, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1-ethylbutyl, 2-ethylbutyl and 1-propylpropyl.

[0039] Examples of the linear or branched lower alkyl group having 1 to 6 carbon atoms in R ¹⁰ include, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, pentyl. Group, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-
Examples include ethylpropyl, 2-ethylpropyl, hexyl and the like. A preferred range of the linear or branched lower alkyl group having 2 to 6 carbon atoms in R ¹⁰ is a linear or branched lower alkyl group having 2 to 4 carbon atoms, and specific examples include: Ethyl, propyl,
1-Methylethyl, butyl, etc. are mentioned.

[0040] Examples of the alkenyl group having 2 to 6 carbon atoms in R ¹⁰ include allyl, butenyl, pentenyl, hexenyl and the like.

[0041] Examples of the alkynyl group having 3 to 6 carbon atoms in R ¹⁰ include propargyl, butynyl, pentynyl and the like.

[0042] Examples of the cycloalkyl group having 3 to 6 carbon atoms in R ¹⁰ include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0043] Examples of the cycloalkylalkyl group having 4 to 10 carbon atoms in R ¹⁰ include, for example, cyclopropylmethyl, cyclobutylmethyl group, cyclopentylethyl,
Examples thereof include cyclohexylmethyl and cyclohexylpropyl.

[0044] Examples of the linear or branched lower alkyl group having 1 to 6 carbon atoms in R ¹¹ include, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, pentyl. Group, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-
Examples include ethylpropyl, 2-ethylpropyl, hexyl and the like.

[0045] Examples of the alkenyl group having 2 to 6 carbon atoms in R ¹¹ include allyl, butenyl, pentenyl, hexenyl and the like.

[0046] Examples of the alkynyl group having 3 to 6 carbon atoms in R ¹¹ include propargyl, butynyl, pentynyl and the like.

[0047] Examples of the cycloalkyl group having 3 to 6 carbon atoms in R ¹¹ include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0048] Examples of the cycloalkylalkyl group having 4 to 10 carbon atoms in R ¹¹ include, for example, cyclopropylmethyl, cyclobutylmethyl group, cyclopentylethyl,
Examples thereof include cyclohexylmethyl and cyclohexylpropyl.

[0049] Examples of the alkoxy group having 1 to 6 carbon atoms in R ² , R ³ and R ⁴ include methoxy, ethoxy, propyloxy, 2-propyloxy, butoxy, 1,1.
-Dimethylethoxy, pentoxy, hexoxy and the like.

[0050] Examples of the halogen atom in R ² , R ³ and R ⁴ include fluorine, chlorine, bromine and iodine.

The pyridopyrimidine derivative, which is the active ingredient of the medicament of the present invention, can be converted into a pharmaceutically acceptable salt. Examples of the pharmaceutically acceptable salt include an acid addition salt and a base addition salt. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide and sulfate, citrates, oxalates, malates, tartrates, fumarates, maleates and other organic acids. Examples of the base addition salt include inorganic base salts such as sodium salt and calcium salt, and organic base salts such as meglumine salt and trishydroxymethylaminomethane salt. The present invention also includes solvates such as hydrates of pyridopyrimidine derivatives or pharmaceutically acceptable salts thereof.

[0052] The compound represented by the formula (1) of the present invention can be produced by the following method and methods according thereto.

[Chemical 11] (In the formula, R ¹ , R ² , R ³ , and R ⁴ have the same meanings as in formula (1).) Production method 1 Compound (21) is reacted with phosphorus oxychloride to give compound (22). Obtainable. In the reaction, a solvent may be added if necessary. As the solvent, toluene,
Examples thereof include aromatic hydrocarbon solvents such as xylene. In the reaction, a reaction aid such as N, N-dimethylaminopyridine may be optionally used. The reaction temperature may be in the range of about room temperature to the reflux temperature of the solvent.

[0053] The compound (22) can be reacted with the compound (23) to obtain the compound (1) of the present invention. Examples of the reaction solvent include aromatic hydrocarbon solvents such as toluene and xylene, tetrahydrofuran (hereinafter abbreviated as THF), ether solvents such as dioxane, alcohol solvents such as ethanol, 2-propanol and butanol, and dimethylformamide. (Hereinafter abbreviated as DMF),
An inert solvent such as acetonitrile can be used. The reaction is an organic base such as triethylamine, if necessary.
An inorganic base such as sodium carbonate or potassium carbonate may be added. The reaction temperature is selected, for example, from a room temperature to a temperature range around the boiling point of the solvent.

Production Method 2 Compound (25) can be obtained by reacting compound (24) with compound (23). As the reaction solvent, for example, an aromatic hydrocarbon solvent such as toluene or xylene,
Examples thereof include ether solvents such as THF and dioxane, alcohol solvents such as ethanol, 2-propanol and butanol, and inert solvents such as DMF and acetonitrile. In the reaction, an organic base such as triethylamine or an inorganic base such as sodium carbonate or potassium carbonate may be added, if necessary. The reaction temperature is selected, for example, from a room temperature to a temperature range around the boiling point of the solvent.

The compound (25) of the present invention can be obtained by reacting the compound (25) with ammonia in an organic solvent. Examples of the organic solvent include alcohol solvents such as methanol and ethanol, ether solvents such as dioxane and ethylene glycol dimethyl ether, and the like. The reaction is carried out in an autoclave at about room temperature to about 200 ° C.
Up to the temperature range. In addition, the compound (25) of the present invention can also be obtained by reducing the compound (25) with triphenylphosphine after the reaction with sodium azide. The reaction with sodium azide is carried out in an inert solvent such as DMF. The reaction temperature is selected from the range of about room temperature to around the boiling point of the solvent. The reduction with triphenylphosphine is performed in an ether solvent such as THF. The reaction temperature is selected from a temperature range from about room temperature to around the boiling point of the solvent.

[0056] The compound of the present invention represented by the formula (1) or an intermediate for producing the same can be purified by a conventional method. For example, it can be purified by column chromatography, recrystallization and the like. As a recrystallization solvent,
For example, alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene, ketone solvents such as acetone, hexane and the like. Examples thereof include hydrocarbon solvents and the like, or mixed solvents thereof.

[0057] When carrying out the above reaction, if necessary, techniques of protection and deprotection can be used. For protection and deprotection technologies, see (TW Greene and PGM Wut
s, "Protecting Groups in Organic Synthesis", 1991,
JOHN WILEY & SONS, INC.).

[0058] The pyridopyrimidine derivative of the present invention or a pharmaceutically acceptable salt thereof may form a solvate such as a hydrate, and the present invention also includes these.

The compounds included in the present invention may have asymmetry or have a substituent having an asymmetric carbon, and such compounds have optical isomers. The compound of the present invention includes a mixture of each of these isomers and an isolated one. Examples of a method for obtaining such optical isomers purely include optical resolution.

[0060] As the optical resolution method, the compound of the present invention or an intermediate thereof is used in an inert solvent (for example, an alcohol solvent such as methanol, ethanol and 2-propanol, an ether solvent such as diethyl ether, an ester solvent such as ethyl acetate). Solvents, aromatic hydrocarbon solvents such as toluene, acetonitrile and the like and mixed solvents thereof, optically active acids (for example, mandelic acid, N-benzyloxyalanine, monocarboxylic acids such as lactic acid, tartaric acid, o-diisopropylpropionate). It is also possible to form a salt with a dicarboxylic acid such as lidene tartaric acid or malic acid, or a sulfonic acid such as camphorsulfonic acid or bromocamphorsulfonic acid). When the compound of the present invention or an intermediate thereof has an acidic substituent such as a carboxyl group, an optically active amine (for example, α-
Phenethylamine, quinine, quinidine, cinchonidine,
It is also possible to form salts with cinchonine, organic amines such as strychnine).

[0061] Examples of the temperature for forming the salt include a range of room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to once raise the temperature to around the boiling point of the solvent. The precipitated salt can be cooled, if necessary, before being collected by filtration to improve the yield. The amount of the optically active acid or amine used is appropriately in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent, relative to the substrate.
Crystals in an inert solvent as required (eg, methanol, ethanol, alcohol solvent such as 2-propanol, ether solvent such as diethyl ether, ester solvent such as ethyl acetate, aromatic hydrocarbon solvent such as toluene, Recrystallized with acetonitrile etc. and their mixed solvent),
It is also possible to obtain a highly pure optically active salt. If necessary, the obtained salt can be treated with an acid or a base by a usual method to give a free form.

[0062] The pyridopyrimidine derivative of the present invention can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. Parenterally, it can be administered in the form of a topical agent, injection, transdermal agent, nasal agent and the like. Examples of the oral agent or the rectal agent include capsules, tablets, pills, powders,
Examples include cachets, suppositories, solutions and the like. Examples of the injection include a sterile solution or suspension. Examples of the topical agent include creams, ointments, lotions, transdermal agents (ordinary patch agents, matrix agents) and the like. The above-mentioned dosage forms are prepared by a conventional method together with pharmaceutically acceptable excipients and additives. Examples of pharmaceutically acceptable excipients and additives include carriers, binders, perfumes, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives and the like. To be Examples of the pharmaceutically acceptable carrier include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter and the like. To be Capsules can be prepared by incorporating a compound of the invention with a pharmaceutically acceptable carrier. The compounds of the present invention can be mixed with pharmaceutically acceptable excipients or encapsulated without excipients. The cachet can be manufactured in the same manner. Injection solutions include solutions, suspensions,
Emulsion etc. are mentioned. Examples thereof include an aqueous solution and a water-propylene glycol solution. The solution may also be prepared in the form of a solution of polyethylene glycol or / and propylene glycol, which may contain water. Suitable solutions for oral administration include the compound of the present invention added to water, a coloring agent,
If necessary, flavors, stabilizers, sweeteners, solubilizers, thickeners and the like can be added for production. A liquid suitable for oral administration can also be produced by adding the compound of the present invention together with a dispersant to water and making the mixture viscous. Examples of the thickener include pharmaceutically acceptable natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, known suspending agents, and the like. Examples of the topical administration agent include the above liquid agents, creams, aerosols, sprays, powders, lotions, ointments and the like. The above-mentioned topical preparation can be produced by mixing the compound of the present invention with a pharmaceutically acceptable diluent and carrier which are usually used. Ointments and creams are obtained, for example, by formulating an aqueous or oily base with a thickening agent and / or a gelling agent. Examples of the base include water, liquid paraffin, vegetable oil (peanut oil, castor oil, etc.) and the like. Examples of the thickener include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycol, lanolin, hydrogenated lanolin and beeswax. Lotions may contain one or more pharmaceutically acceptable stabilizers, suspending agents, emulsifying agents, diffusing agents, thickening agents, coloring agents, perfumes and the like in an aqueous or oily base. . The powder is formulated with a pharmaceutically acceptable powder base. Examples of the base include talc, lactose, starch and the like. Drops can be formulated with an aqueous or non-aqueous base and one or more pharmaceutically acceptable diffusing agents, suspending agents, solubilizing agents and the like. The topical agent may optionally contain a preservative such as methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, and benzalkonium chloride, and a bacterial growth inhibitor. A liquid spray, powder or drop preparation containing the compound of the present invention as an active ingredient can be administered intranasally. The dose and frequency of administration vary depending on symptoms, age, body weight, dosage form, etc., but when administered orally, it is usually in the range of about 1 to about 500 mg, preferably about 5 to about 100 per day for an adult.
The mg range can be administered once or in several divided doses. About 0.1 to about 300 when administered as an injection
The range of mg, preferably the range of about 1 to about 100 mg can be administered once or in several divided doses.

[0063] The pyridopyrimidine derivative of the present invention produces IL-4 and IL from mouse lymph node cells by antigen-specific stimulation.
-5 production is suppressed and conversely IFN-γ production is enhanced. The cytokine production regulatory activity test used for this evaluation is carried out by the following method.

[0064] Cytokine production regulatory activity test Keyhole Lympet Hemocyanin (hereinafter referred to as KLH) 0.2
mg to aluminum hydroxide adjuvant (Alu-Gel-S; Se
rva Feinbiochemica GmbH & Co., Code No. 12261) or Freund's complete adjuvant (Difco Lab., Detroi
, Michigan, Code No. 3113-60-5) and subcutaneously injected into the footpad of a mouse (0.1 ml). After 8 to 10 days, popliteal lymph nodes are removed and a cell suspension is prepared using an animal cell culture medium. Lymph node cell suspension (1 to 5 x10 ⁶ cells / ml)
KLH (1-100 μg / ml) and drug were added, 37 ° C
Cultured in the presence of% CO ₂ for 4 days (Corning 25850, 0.15 ml / we
ll), the cytokine produced in the supernatant
Quantify by ISA method. Interleukin 4 (IL-4) and interleukin 5 (IL-5) are quantified as representative Th2 type cytokines, and interferon γ (IFN-γ) is quantified as a representative Th1 type cytokine.

【Example】

Reference Example 1 N- (2-chloropyrido [2,3-d] pyrimidin-4-yl) -N-
Pentylamine

[Chemical 12] 1-1) Pyrido [2,3-d] pyrimidine-2,4-diol

[Chemical 13] 2-Aminonicotinic acid (5.0 g, 36.2 mmol) and urea (9.0
The mixture (g, 0.15 mol) was heated to 190 ° C. Then, after slowly raising the temperature to 210 ° C., the reaction mixture was cooled to room temperature. A 2N aqueous sodium hydroxide solution (50 ml) was added to the reaction mixture. The reaction mixture is heated to dissolve,
Carbon dioxide was passed through the reaction solution to lower the pH of the reaction solution to 7.
The precipitated crystals were collected by filtration. The filter cake was washed with water and then with methanol. The obtained crystals were dried under reduced pressure to give the title compound (6.2 g). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ; 8.60 (dd, 1H, J = 4.
7, 1.8 Hz), 8.27 (dd, 1H, J = 7.7, 1.8 Hz), 7.25 (d
d, 1H, J = 7.7, 4.7 Hz).

1-2) 2,4-dichloropyrido [2,3-d] pyrimidine

[Chemical 14] Pyrido [2,3-d] pyrimidine-2,4-diol (1.0 g,
A mixture of 6.13 mmol) and phosphoryl chloride (20 ml) was heated and refluxed for 3 hours. The reaction solution was concentrated under reduced pressure and the solvent was distilled off. The residue was poured into saturated saline and extracted with chloroform. The organic layer was washed with saturated brine and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (3% MeOH / CHCl ₃ ) and the title compound (65 mg, 5.
3%). ¹ H NMR (300 MHz, CDCl ₃ : CD ₃ OD = 1: 1) δ; 8.60
(dd, 1H, J = 5.0, 1.9 Hz), 8.41 (dd, 1H, J = 7.9,
1.9 Hz), 7.25 (dd, 1H, J = 7.9, 5.0 Hz).

1-3) N- (2-chloropyrido [2,3-d] pyrimidin-4-yl) -N-pentylamine

[Chemical 15] 2,4-Dichloropyrido [2,3-d] pyrimidine (53 mg, 0.2
Pentylamine (0.1 ml) was added to a solution of 64 mmol) in tetrahydrofuran (3 ml), and the mixture was stirred at room temperature for 5 minutes. The reaction solution was poured into aqueous ammonium chloride and extracted with chloroform. The organic layer was washed with saturated brine and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (3% MeOH / CHCl ₃ ) and the title compound (23 mg, 34.7%)
Got ¹ H NMR (300 MHz, CDCl ₃ ) δ; 8.93 (dd, 1H, J = 4.4,
1.8 Hz), 8.64 (brd, 1H, J = 8.0 Hz), 7.62 (brs, 1
H), 7.38 (dd, 1H, J = 8.0, 4.4 Hz), 3.75-7.68 (m,
2H), 1.77-1.65 (m, 2H), 1.43-1.25 (m, 4H), 0.87
(t, 3H, J = 7.1 Hz). ¹³ C NMR (75MHz, CDCl ₃ ) δ; 161.9, 161.6, 159.3, 15
5.8, 132.5, 121.3, 108.7, 42.0, 29.0, 28.5, 22.3,
13.9.

Example 1 N- (2-aminopyrido [2,3-d] pyrimidin-4-yl) -N-
Pentylamine

[Chemical 16] N- (2-chloropyrido [2,3-d] pyrimidin-4-yl) -N-
A mixture of pentylamine (20 mg) and 5M NH ₃ / MeOH (60 ml) was kept in an autoclave at 150 ° C for 16 hours. Purification by preparative TLC (15% MeOH / CHCl ₃ ) gave the title compound (10.2 mg, 55%). ¹ H NMR (300 MHz, CDCl ₃ ) δ; 8.69 (brd, 1H, J = 4.6
Hz), 8.08 (brd, 1H, J = 7.9 Hz), 7.04 (dd, 1H, J =
7.9, 4.6 Hz), 6.46 (brs, 1H), 5.90 (brs, 2H), 3.5
8-3.48 (m, 2H), 1.75-1.65 (m, 2H9, 1.47-1.35 (m, 4
H), 0.98-0.87 (m, 3H).

Example 2 Effect of Compound of Example 1 on Cytokine Production from Mouse Lymph Node Cells Experimental Method 1. Animal BALB / c mice were purchased from Japan Charles River (Yokohama), and 8-week-old females were used. . 2. Medium D-MEM (High Glucose) medium (Nikken Institute of Biomedical Research (Kyoto), Code No. CM4402) inactivated fetal bovine serum (Fetal Bovine Serum, Characterized, Cod) at 56 ° C for 30 minutes
e No.A-1115-L, HyClone Lab., Logan, Utah) 20%,
2-Mercaptoethanol (Sigma, St Louis, MO, Code
No.M-6250) 50 μM, Penicillin 100 units / m
l, streptomycin 100 μg / ml (Penicilin-Strept
omycin; Gibco-BRL, Code No. 15140-122). 3. The drug compound was dissolved in dimethyl sulfoxide (Nacalai Tesque (Kyoto) Code No. 11J) to 100 mM,
Diluted to final concentration with medium. 4. Sensitization and preparation of lymph node cells 0.2 mg of KLH was added to Freund's complete adjuvant (Difco La
b., Detroit, Michigan, Code No. 3113-60-5) and subcutaneously injected into the footpad of a mouse (0.1 ml). Eight days later, popliteal lymph nodes were removed to prepare a cell suspension. 5. Cytokine-producing lymph node cell suspension (2.5 x 10 ⁶ cells / ml) by antigen stimulation
g / ml) and chemicals were added and 4 at 37 ° C in the presence of 5% CO _2.
After day culture (Corning 25850, 0.15 ml / well), the cytokine produced in the supernatant was quantified by a specific ELISA method. Interleukin 4 (IL-4) and interleukin 5 (IL-5) as typical Th2 type cytokines
Was quantified for interferon γ (IFN-γ) as a typical Th1 type cytokine.

[0070] 6. ELISA method Quantification of IL-4 was performed by the following ELISA method. Rat anti-mouse IL-4 antibody (Pharmingen, San
Diego, CA, Code No.18031D, 0.5 mg / ml) is diluted 250 times with carbonate buffer, and 50 μl / well is added to each 96-well plate (Falcon 3912, Becton Dickinson and company, F
ranklin Lakes, NJ) and coated overnight at 4 ° C. After that, the plate was PBS (-) containing 3% BSA (Phosphate-containing no calcium chloride and magnesium chloride).
Blocked with buffered saline) (200 μl / wel
l). PBS containing 0.05% polyoxyethylene sorbitan monolaurate (Tween 20 (registered trademark) Nacalai Tesque (Kyoto) Code No. 281-51)
Wash with (-) (PBST) three times, and culture supernatant to 50μ
L / well was seeded and incubated at room temperature for 4 hours.
Recombinant mouse IL-4 (Pharmi
ngen, Code No.19231W) was used. PBST plate
Was washed 3 times with a biotin-labeled rat anti-mouse IL-4 antibody (Pharmingen, Code No. 18042D, 0.
5 mg / ml) was diluted 500-fold with PBS (-) containing 0.1% BSA (100 μl / well), and the mixture was incubated at room temperature for 1 hour. The bound secondary antibody is streptavidin alkaline phosphatase (Kirkegaard & Perry Lab., G
aithersburg, MD, Code No.15-30-00) (0.25 μg / ml, 1
00 μl / well). Incubate at 37 ° C. for 1 hour, wash the plate 3 times with PBST, and add PNPP substrate (p-nitrophenyl phosphate disodium Nacalai Tesque) (1 mg / ml, 100 μl / well) to develop color. Microplate reader (MTP-120 Microplate for measurement)
reader, Corona Electric) was used (wavelength 415 nm). IF
For the quantification of N-γ, rat anti-mouse IFN-γ was used as the primary antibody.
Antibodies (Pharmingen, San Diego, CA, Code No. 18181D, 0.
5mg / ml), biotin-labeled rat anti-mouse as secondary antibody
IFN-γ antibody (Pharmingen, Code No.18112D, 0.5mg / ml)
Was carried out in the same manner as above. Recombinant mouse IFN-γ (Pharmingen, Code No.19301
U) was used. Rat-5 anti-mouse IL-5 antibody (Pharmingen, SanDiego, CA, Code
No.18051D, 0.5mg / ml), biotin-labeled rat anti-mouse IL-5 antibody as secondary antibody (Pharmingen, Code No.18062)
D, 0.5 mg / ml) in the same manner. Recombinant mouse IL-5 (Pharmingen, Co.
deNo.19241W) was used. The experiment was performed in triplicate, and the average value was calculated. 7. Results It was confirmed that the compound of Example 1 suppresses IL-4 and IL-5 production from mouse lymph node cells to antigen-specific stimulation and enhances INF-γ production.

Example 3 Effect of Example Compound on Cytokine Production from Mouse Lymph Node Cells Experimental Method 1. Drug As in Example 2, various analog compounds were dimethyl sulfoxide (Nacalai Tesque (Kyoto) Code No. 11J). ), Dissolve to 10 to 100 mM, and dilute to the final concentration with the medium. 2. The antigen-sensitized lymph node cell preparation method, the cytokine production method by antigen stimulation, and the cytokine quantification method are performed as described in Example 2. IL-4 is quantified as a representative Th2 type cytokine. For each analog compound, calculate the IL-4 production inhibition rate at various concentrations,
From the graph of compound concentration and inhibition rate, 50 of each analog compound
Determine the% inhibitory concentration (IC ₅₀ ) value.

Example 4 Effect of the compound of Example 1 on IgE production in vivo in mouse Experimental method 1) Animal BALB / c was purchased from Japanese Mouse Charles River (Yokohama) as an 8-week-old female mouse for 9 days. Used after preliminary breeding. 2) Ovalbumin-sensitized ovalbumin (Sigma Chemical Co., St. Louis, M
O) saline solution (4 μg / ml) and aluminum hydroxide
Adjuvant (Alu-Gel-S; Serva Feinbiochemica GmbH
& Co., Code No. 12261) are mixed in equal amounts and 0.5 ml is intraperitoneally administered to a mouse. 3) Method of drug administration The test compound (the compound of Example 1) was suspended in methylcellulose, 1 hour before and 1 hour after sensitization with ovalbumin.
Orally administered once daily every day from the day to the 12th. Methylcellulose alone is administered to the control group. 4) Blood collection and plasma preparation On day 13 after sensitization, blood is collected from the orbital venous plexus by heparinized capillary tube under anesthesia and centrifuged to prepare plasma. 5) Measurement of blood IgE amount Blood IgE amount is measured by the ELISA method. Rat anti-mouse IgE monoclonal antibody (code number 7
627, Yamasa Shoyu Co., Ltd., Chiba). Using a biotin-labeled rat anti-mouse IgE monoclonal antibody (Code No. 7617, Yamasa Shoyu Co., Ltd., Chiba) as a secondary antibody, measurement is performed in the same manner as in Example 2. Plasma is diluted 500 times and measured, and the amount of IgE in blood is calculated from a standard curve using mouse IgE (product number 7626 Yamasa soy sauce, Chiba). 6) Statistical processing method The results are statistically processed by t-test or Welch's test.

Example 5 Effect on TNCB-induced contact dermatitis Experimental method 1) Animal BALB / c was purchased from Japan Charles River Co., Ltd., female mice of 6-8 weeks old were used after preliminarily breeding for 1 week. 2) Sensitization The abdomen of the mouse is shaved and sensitized by applying an acetone solution of 7% 2,4,6-trinitrochlorobenzene (TNCB) at a dose of 0.1 ml / head. 3) Method for measuring auricular thickening After 6 days of sensitization, 1% TNCB acetone solution is applied to both surfaces of the left ear of the mouse to induce auricular thickening, and the auricular thickening after 24 hours is measured. The ear thickness is expressed by (thickness of left ear applied)-(thickness of right ear not applied). 4) Drug administration method 0.4 mg of the compound of Example 1 is dissolved in 20 μl of acetone and applied to the left ear of a mouse 1-2 hours before sensitization.

Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/505 ADA A61K 31/505 ADA AED AED (72) Inventor Fujio Anto 3-1, Kasugadaka, Konohana-ku, Osaka No. 98 Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Norio Fujiwara 3-1-1 Kasugade, Konohana-ku, Osaka City No. 98 Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Kiyotaka Iwai 3-chome, Kasugade, Konohana-ku, Osaka No. 1-98 Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Hiroshi Tanaka 3-98 Kasugade, Konohana-ku, Osaka City Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Hajime Kawakami Kasuga, Kasuga, Konohana-ku, Osaka 3-Chome 1-98 Sumitomo Pharmaceutical Co., Ltd. F term (reference) 4C065 AA04 BB10 CC01 DD03 EE02 HH01 JJ01 KK01 LL07 PP01 4C086 AA01 AA02 AA03 CB10 MA01 MA04 NA14 ZA34 ZA89 ZB07 ZB13 ZB26 ZB32 ZB33 ZB33 ZB33 ZB33 ZB33 ZB33

Claims (7)

[Claims] 1. Formula (1): (In the formula, R ¹ is represented by the formula (2): (In the formula, A ring is a cycloalkane having 3 to 10 carbon atoms,
Represents a cycloalkene having 5 to 10 carbon atoms, a substituted cycloalkane, a bicycloalkane having 7 to 10 carbon atoms, a substituted bicycloalkane, or a heterocycle containing oxygen or a sulfur atom as a hetero atom, and 1 or 2 sulfur atoms May combine with an oxygen atom of to form sulfinyl or sulfonyl. R ⁵ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, or 3 carbon atoms.
6 cycloalkyl group, cycloalkylalkyl group, or OR 9 ^{(R 9} is a straight-chain or branched lower alkyl group having 1 to 6 carbon atoms, lower alkenyl group having 3 to 6 carbon atoms having 4 to 10 carbon Represents a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a cycloalkylalkyl group having 4 to 10 carbon atoms). ), Or formula (3), (In the formula, R ⁶ is a linear or branched lower alkyl group having 2 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, a hydroxyl group, a halogen atom, or A linear or branched lower alkyl group having 1 to 6 carbon atoms substituted with an alkoxy group having 1 to 4 carbon atoms, a phenyl group, a cycloalkyl group having 3 to 8 carbon atoms, an oxygen atom as a hetero atom from 1 to 5 to 7-membered saturated heterocycle containing two or C (= O) R ¹⁰ (wherein R is
¹⁰ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, A cycloalkylalkyl group having 4 to 10 carbon atoms or C (═O) R ¹¹ (in the formula, R ¹¹ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, a lower alkyl group having 2 to 6 carbon atoms) An alkenyl group, a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkylalkyl group having 4 to 10 carbon atoms). ), R ⁷ is a hydrogen atom, carbon number 1
To C6 linear or branched lower alkyl group, C6 to C10 aryl group, halogen atom, C1 to C4 alkoxy group, or C1 to C4 substituted alkyl group To 10 represent an aryl group, a carbamoyl group, or a hydroxymethyl group, and R ⁸ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms. ), R ² represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a halogen atom, and R ³ represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a halogen atom, R
⁴ represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a halogen atom. ) The pyridopyrimidine derivative and its salt represented by these. 2. R ¹ is represented by the formula (2): (In the formula, A ring is a cycloalkane having 3 to 10 carbon atoms,
Represents a cycloalkene having 5 to 10 carbon atoms, a substituted cycloalkane, a bicycloalkane having 7 to 10 carbon atoms, a substituted bicycloalkane, or a heterocycle containing oxygen or a sulfur atom as a hetero atom, and 1 or 2 sulfur atoms May combine with an oxygen atom of to form sulfinyl or sulfonyl. R ⁵ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, or 3 carbon atoms.
6 cycloalkyl group, cycloalkylalkyl group, or OR 9 ^{(R 9} is a straight-chain or branched lower alkyl group having 1 to 6 carbon atoms, lower alkenyl group having 3 to 6 carbon atoms having 4 to 10 carbon Represents a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a cycloalkylalkyl group having 4 to 10 carbon atoms). The pyridopyrimidine derivative according to claim 1 or a pharmaceutically acceptable salt thereof. 3. R ¹ is represented by the formula (3): (In the formula, R ⁶ is a linear or branched lower alkyl group having 2 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, a hydroxyl group, a halogen atom, or A linear or branched lower alkyl group having 1 to 6 carbon atoms substituted with an alkoxy group having 1 to 4 carbon atoms, a phenyl group, a cycloalkyl group having 3 to 8 carbon atoms, an oxygen atom as a hetero atom from 1 to 5 to 7-membered saturated heterocycle containing two or C (= O) R ¹⁰ (wherein R is
¹⁰ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, A cycloalkylalkyl group having 4 to 10 carbon atoms or C (═O) R ¹¹ (in the formula, R ¹¹ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, a lower alkyl group having 2 to 6 carbon atoms) An alkenyl group, a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkylalkyl group having 4 to 10 carbon atoms). ), R ⁷ is a hydrogen atom, carbon number 1
To C6 linear or branched lower alkyl group, C6 to C10 aryl group, halogen atom, C1 to C4 alkoxy group, or C1 to C4 substituted alkyl group To 10 represent an aryl group, a carbamoyl group, or a hydroxymethyl group, and R ⁸ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms. The pyridopyrimidine derivative according to claim 1 or a pharmaceutically acceptable salt thereof. 4. A type 2 helper T cell side immune response which suppresses an immune response of a type 2 helper T cell side comprising the pyridopyrimidine derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. An immunomodulator that enhances the immune response. 5. A therapeutic or prophylactic agent for a disease in which the type 2 helper T cell side immune response is abnormally elevated, comprising the pyridopyrimidine derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient. . 6. The therapeutic or prophylactic agent according to claim 5, wherein the disease in which the immune response on the type 2 helper T cell side is abnormally enhanced is an allergic disease. 7. The therapeutic or prophylactic agent according to claim 6, wherein the allergic disease in which the immune response on the type 2 helper T cell side is abnormally enhanced is asthma, allergic rhinitis or atopic dermatitis.