JPH11292879A - Carboxamide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having an analgesic action, an inhibiting action against a synthesized enzyme of nitrogen monoxide and is useful for relaxation of postoperative pain, hemicrania, gout, etc., and curing or preventing of ichorrhemia, endotoxin shock, chronic rheumatism, etc. SOLUTION: This carboxamide derivative is a compound expressed by formula I R<1> is a lower alkyl; (n) is 2 or 3; A is a single bond or the like when (n) is 2 and a benzene ring or the like when (n) is 3}, preferably, N,N'-bis 5-(n)- butylpyrazoro[1,5-(a)]pyrimidin-7-yl}-1,4-benzene dicarboxamide or the like. The compound of formula I is obtained by reacting a compound of formula II e.g. 7-amino-5-(n)-butylpyrazoro[1,5-(a)]pyrimidine} with a compound of formula III (X is a halogen) (e.g. terephthaloyl chloride) in a solvent such as dichloromethane in the presence of a deoxidizer such as pyridine, preferably at from a room temperature to a refluxing temperature for about 0.5-20 hrs.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel carboxamide derivative having an analgesic action, a nitric oxide synthase inhibitory action and the like.

[0002]

BACKGROUND OF THE INVENTION An object of the present invention is to provide a novel compound having an analgesic action, a nitric oxide synthase inhibitory action and the like, which has not been described in the literature.

[0003]

According to the present invention, there is provided a compound represented by the following general formula (1):

Embedded image (Wherein, R ¹ represents a lower alkyl group, and n is 2 or 3
A represents a single bond, a lower alkylene group, a benzene ring or a naphthalene ring when n is 2, and A represents a benzene ring or a naphthalene ring when n is 3. The present invention provides a novel carboxamide derivative represented by the formula:
A is, when n is 2, a single bond, a lower alkylene group,
A benzene ring or a naphthalene ring, and when n is 3,
It is preferably a benzene ring. At that time, R ¹ is preferably an n-butyl group.

When n is 2, A is more preferably a lower alkylene group or a benzene ring. As a specific example, N, N′-bis (5-n-butylpyrazolo [1,5
-A] pyrimidin-7-yl) -1,4-benzenedicarboxamide and N, N'-bis (5-n-butylpyrazolo [1,5-a] pyrimidin-7-yl) hexanediamide. Such a compound (1) of the present invention has an analgesic action, a nitric oxide synthase inhibitory action, and the like. Therefore, the compound (1) of the present invention is effective as an analgesic for relieving postoperative pain, migraine, gout, chronic pain, neuropathic pain, cancer pain, etc., and is found in conventional analgesics. It does not show such side effects.

Further, since the compound (1) of the present invention has an action of selectively inhibiting inducible nitric oxide synthase, examples of inhibitors of the enzyme include sepsis, endotoxin shock, and chronic arthritis. It is effective for treatment and prevention of rheumatism and the like.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the lower alkyl group may be, for example, a linear or branched chain having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isobutyl, tert-butyl, pentyl, hexyl and the like. Lower alkyl group. Examples of the lower alkylene group include linear or branched lower alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, ethylidene, trimethylene, methylethylene, tetramethylene, pentamethylene, and hexamethylene groups. . In the compound (1) of the present invention, the case where n is 2 and A is a single bond refers to the case where the carbonyl groups in two carboxamide residues (-HNCO-) are directly bonded.

Specific examples of the carboxamide derivative (1) of the present invention are shown in Tables 1 and 2. In each table, Me is a methyl group,
Et is an ethyl group, n-Pr is an n-propyl group, n-Bu
Is an n-butyl group, n-Pe is an n-pentyl group, n-Hx
Indicates that it is an n-hexyl group.

[0008]

[Table 1]

[0009]

[Table 2]

The compound (1) of the present invention can be produced according to the following reaction scheme.

Embedded image (In the formula, R ¹ , n and A are the same as described above, and X represents a halogen atom.)

That is, the compound (1) of the present invention is a compound
(2) is reacted with an acid halide (3). This reaction is preferably performed in a suitable solvent in the presence of a deoxidizing agent. Examples of the solvent include aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene and petroleum ether; and linear or cyclic ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran (THF) and 1,4-dioxane. Ketones such as acetone, ethyl methyl ketone, and acetophenone; and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane.

Examples of the deoxidizing agent include tertiary amines such as triethylamine, N, N-diethylaniline, N-methylmorpholine, pyridine and 4-dimethylaminopyridine, and sodium hydroxide and potassium hydroxide. Alkali metal hydride and the like. The amounts of the acid halide (3) and the deoxidizing agent used for the compound (2) in the above reaction are not particularly limited, but usually, the acid halide (3) is used in an amount of 1 to slightly excess equivalent to the compound (2). And the amount of the deoxidizing agent is preferably 1 to an excess equivalent.
The reaction is carried out at a temperature of about 0.
It is preferable to carry out for about 5 to 20 hours.

The target compound obtained by the above reaction is
It can be easily isolated and purified by ordinary separation means. Such separation means include, for example, adsorption chromatography, preparative thin-layer chromatography,
Recrystallization, solvent extraction and the like. The present compound (1)
Can be pharmaceutically acceptable acid addition salts, and these salts are also included in the present invention. Examples of the acid forming the acid addition salt include inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, tartaric acid, citric acid and p-toluenesulfonic acid. Can be
The formation of the acid addition salt can be carried out according to a conventional method.

The compound of the present invention can be converted into an alkali metal salt such as a sodium salt and a potassium salt, an alkaline earth metal salt such as a calcium salt and a magnesium salt, and further a copper salt according to a conventional method. And their salts are also included in the present invention. The compound (1) of the present invention is used as a general pharmaceutical preparation form by using it together with a suitable nontoxic pharmaceutical carrier. As the formulation carrier, a filler, a bulking agent, a binder, which is generally used depending on a use form of the formulation,
Examples include diluents such as humectants, disintegrants, surfactants, and lubricants, and excipients, which are appropriately selected and used according to the dosage unit form of the resulting preparation.

As the dosage unit form of the pharmaceutical preparation to which the compound (1) of the present invention is used, various forms can be selected according to the purpose of treatment, and typical examples are tablets, pills, powders, and liquids. , Suspensions, emulsions, granules, capsules, suppositories,
Injection (solution, suspension), ointment and the like can be mentioned.

In the case of molding into a tablet form, the above-mentioned preparation carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, potassium phosphate and the like;
Binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone; sodium carboxymethylcellulose, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, dried Disintegrants such as starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate; surfactants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride; sucrose, stearin, cocoa butter; Disintegration inhibitors such as hydrogenated oil; Absorption accelerators such as quaternary ammonium bases and sodium lauryl sulfate; Glycerin, starch and the like Moisturizers; starch, lactose, kaolin, bentonite, colloidal adsorbent such as silicic acid; purified talc, stearates, boric acid powder, lubricant and the like such as polyethylene glycol can be used.

Further, tablets may be coated with a usual coating as required, such as sugar-coated tablets, gelatin-encapsulating agents, enteric-coated tablets,
It can be a film-coated tablet, a double tablet or a multilayer tablet. When formed into a pill form, as a pharmaceutical carrier, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol; Disintegrators such as laminaran and agar can be used.

For shaping in the form of suppositories, for example, polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides and the like can be used as pharmaceutical carriers. Capsules are usually prepared by mixing the compound (1) of the present invention with various pharmaceutical carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like according to a conventional method.

When prepared as injections such as solutions, emulsions and suspensions, these are preferably sterilized and isotonic with blood. In preparing an injection, for example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like can be used as diluents. In this case, a sufficient amount of salt, glucose, glycerin and the like to prepare an isotonic solution may be contained, and a usual solubilizing agent, a buffer, a soothing agent and the like may be added. Is also good. Further, in the above-mentioned pharmaceutical preparation, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetener and the like and other pharmaceuticals can be contained as necessary.

In preparing ointments such as pastes, creams and gels, white vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as diluents. The amount of the compound (1) of the present invention to be contained in the above pharmaceutical preparation is not particularly limited and is appropriately selected from a wide range. However, it is usually preferable that about 1 to 70% by weight be contained in the pharmaceutical preparation. .

The method of administration of the above pharmaceutical preparation is not particularly limited, and is appropriately determined according to the form of the preparation, the age, sex and other conditions of the patient, the degree of the disease and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are orally administered, and injections are administered intravenously, alone or as a mixture with ordinary replenishers such as glucose and amino acids. Independently, intramuscularly, intradermally, subcutaneously or intraperitoneally, suppositories are administered rectally. The dose of the pharmaceutical preparation is appropriately determined depending on the usage, age, sex and other conditions of the patient, degree of disease, etc.
Daily dose is about 0.5-20m / kg body weight
g, preferably about 1 to 10 mg. Further, the above pharmaceutical preparation can be administered in 1 to 4 times a day.

[0022]

The compounds of the present invention will be described in detail with reference to the following Examples and Test Examples. Example 1 [N, N'-bis (5-n-butylpyrazolo [1,5-
a] Production of pyrimidin-7-yl) -1,4-benzenedicarboxamide] 0.83 g of terephthalic acid was dissolved in 5 mL of chloroform, 1.43 g of thionyl chloride and 0.22 g of N, N-dimethylformamide were added, and room temperature was added. For 1 hour and then at 80 ° C. for 4 hours, and concentrated under reduced pressure to obtain terephthaloyl chloride. The obtained terephthaloyl chloride was diluted with 10 mL of dichloromethane and pyridine 1
The mixture was dissolved in 0 mL, and thereto was added 1.90 g of 7-amino-5-n-butylpyrazolo [1,5-a] pyrimidine under ice-cooling, followed by stirring at 0 ° C. for 1 hour and then at room temperature for 15 hours. The reaction solution was transferred to a separating funnel, washed sequentially with dilute hydrochloric acid, aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform: methanol = 10:
Purification in 1) and further recrystallization from chloroform-n-hexane gave 1.38 g of the target compound as crystals. Table 3 shows the structure and melting point of this compound.

Examples 2 to 6 Using the appropriate starting materials, in the same manner as in Example 1 above,
Each compound having the structure and melting point shown in Table 3 was produced. In Table 3, n-Bu represents an n-butyl group.

[0024]

[Table 3]

The results of NMR measurement of the obtained compounds are shown below. - Compound ¹ H-NMR of Example _{1 (CDCl 3) δ: 0.99} (6H, t, J = 7.4),
1.4-1.5 (4H, m), 1.7-1.9 (4H, m), 2.89 (4H, t, J =
7.9), 6.62 (2H, d, J = 2.5), 7.77 (2H, s), 8.06 (2H,
d, J = 2.5), 8.2-8.3 (4H, m), 10.14 (2H, brs) ・ Compound ^{1 of} Example 2 ¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, t, J = 7.4),
1.4-1.5 (4H, m), 1.7-1.9 (4H, m), 2.89 (4H, t, J =
7.7), 6.63 (2H, d, J = 2.5), 7.63 (2H, s), 8.10 (2H,
d, J = 2.5), 11.04 (2H, brs)

Compound ^{1 of} Example 3 H-NMR (CDCl ₃ ) δ: 0.95 (6H, t, J = 7.3),
1.3-1.5 (4H, m), 1.7-1.8 (4H, m), 1.9-2.0 (4H, m),
2.6-2.7 (4H, m), 2.81 (4H, t, J = 7.8), 6.55 (2H, d,
J = 2.2), 7.60 (2H, s), 7.99 (2H, d, J = 2.2), 9.26 (2
H, brs) Compound ^{1 of} Example 4 ¹ H-NMR (CDCl ₃ ) δ: 0.99 (6H, t, J = 7.4),
1.4-1.5 (4H, m), 1.7-1.9 (4H, m), 2.89 (4H, t, J =
7.9), 6.61 (2H, d, J = 2.5), 7.79 (2H, s), 7.81 (1H,
t, J = 7.9), 8.06 (2H, d, J = 2.5), 8.29 (2H, d, J = 7.
9), 8.73 (1H, s), 10.16 (2H, brs)

Compound ^{1 of} Example 5 H-NMR (CDCl ₃ ) δ: 0.99 (6H, t, J = 7.3),
1.4-1.6 (4H, m), 1.7-1.9 (4H, m), 2.90 (4H, t, J =
7.9), 6.62 (2H, d, J = 2.5), 7.81 (2H, s), 8.09 (2H,
d, J = 2.5), 8.1-8.3 (4H, m), 8.61 (2H, s), 10.22
(2H, brs) Compound ¹ H-NMR (CDCl ₃ ) of Example 6 δ: 0.99 (9H, t, J = 7.3),
1.4-1.5 (6H, m), 1.7-1.9 (6H, m), 2.89 (6H, t, J =
7.8), 6.60 (3H, d, J = 2.4), 7.77 (3H, s), 8.04 (3H,
d, J = 2.4), 8.94 (3H, s), 10.27 (3H, brs)

Test Example 1 [Test of analgesic activity of carboxamide derivative (1)] D. First, the pain threshold of the left hind footpad of each rat was determined using a pressure-stimulated analgesic effect measuring device (Unicom) using the Randall-Serit method (Rand).
all.LO and Sellitto, JJ, Arch. Int. Pharmcody
n., 111, 409 (1957)). The obtained value is referred to as “previous value”. One hour after the measurement of the preceding value, the experimental group was treated with a 5% gum arabic suspension of the test compound, and the control group was treated with a 5% gum arabic suspension containing no test compound, each at 10 mL / kg body weight. Ratio (active ingredient dose: 1 m
g / kg body weight).
After an hour, a physiological saline solution (25 ng / 0.1 mL) of Substance P (manufactured by Sigma) was injected subcutaneously into the left hind footpad of each rat.

Next, a predetermined time after the substance P injection, the pain threshold value of the left hind footpad of each group of rats was measured in the same manner as described above, and this was defined as "post-value". The pain threshold recovery rate (%) was calculated from the post-value and the pre-value of each group according to the following equation.

(Equation 1)

The results (maximum recovery rate) are shown in the table below.

[Table 4]

[0031]

The carboxamide derivative of the present invention has an effect of having an analgesic effect and an inhibitory effect of nitric oxide synthase.

Claims (6)

[Claims] [Claim 1] General formula (1): (Wherein, R ¹ represents a lower alkyl group, and n is 2 or 3
A represents a single bond, a lower alkylene group, a benzene ring or a naphthalene ring when n is 2, and A represents a benzene ring or a naphthalene ring when n is 3. ). A is a single bond, a lower alkylene group, a benzene ring or a naphthalene ring when n is 2, and n is 3
2. The carboxamide derivative according to claim 1, which is a benzene ring. 3. The carboxamide derivative according to claim 2, wherein R ¹ is an n-butyl group. 4. The carboxamide derivative according to claim 3, wherein n is 2. 5. The carboxamide derivative according to claim 4, wherein A is a lower alkylene group or a benzene ring. 6. N, N'-bis (5-n-butylpyrazolo [1,5-a] pyrimidin-7-yl) -1,4-benzenedicarboxamide or N, N'-bis (5-n-
Butylpyrazolo [1,5-a] pyrimidin-7-yl)
The carboxamide derivative according to claim 5, which is hexanediamide.