JPH0186A - Tricyclic triazolopyrimidines - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention <Industrial Application Field> The present invention relates to a compound of the formula R means an alkyl group, a halogenoalkyl group, an alkenyl group, a halogenoalkenyl group, a cycloalkyl group, or a cycloalkenyl group, and the cycloalkyl group and cycloalkenyl group include a hydroxyl group, an alkyl group, an alkoxy group, and a halogen group. It may have one or more substituents selected from atoms, amino groups, and halogenoalkyl groups, and x means a single bond, an alkylene group, or an alkenylene group.

The alkylene group and the alkenylene group may have one or more substituents selected from alkoxy groups and halogen atoms, and salts thereof.

The compound of formula (RI) has excellent antiallergic effects and is useful as a medicine.

<Conventional technology> In recent years, it has been produced by various stimuli such as immune reactions.

Leukotriene D4 (hereinafter referred to as LTD4) is gaining importance as one of the chemical mediators that cause allergic reactions, and antagonism to the two LTD4s is increasingly important as an indicator of antiallergic activity. It has been thought that

In addition, as a compound similar to the compound of the present invention, JP-A-60-
The compounds disclosed in Japanese Patent No. 226887 include histamine and slow reacti.
ng 5ubstance of anaphylax
, is release inhibitory effect and allogeneic passively sensitized rat cutaneous anaphylaxis (hereinafter referred to as PCA) have been disclosed.

There is no disclosure of the LTD4 antagonism.

<Problems to be Solved by the Invention> The present inventors have completed the present invention as a result of intensive studies to find a compound having an excellent LTD4 antagonistic effect.

<Structure of the invention> The present invention relates to compounds of formula (1) and salts thereof.

In formula (1), the alkyl group is methyl.

Examples include ethyl, propyl, isopropyl, butyl, and tertiary butyl. Examples of the alkoxy group include methoxy-6-ethoxy, propoxy, butoxy, and the like. Halogen atoms include fluorine, chlorine, bromine,
I can give you iodine. Halogenoalkyl group means one in which one or more of the above halogen atoms is substituted with an alkyl group, examples of which include halogenomethyl, halogenoethyl, halogenobutyl, dihalogenomethyl, dihalogenobutyl, trihalogenomethyl, etc. Can be done.

Examples of the alkenyl group include vinyl, propenyl, butenyl, and the like. Halogenoalkenyl means one or more of the above alkenyl groups substituted with one or more of the above halogen atoms, examples of which include halogenopropenyl, halogenobutenyl and the like. Cycloalkyl groups include cyclobutyl, cyclopentyl, cyclohexyl, cyclohebutyl, cyclooctyl, cyclononyl,
Examples include cyclodecyl, cycloundecyl, and cyclododecyl. Cycloalkenyl groups include cyclohebutenyl, cyclohexenyl, cyclooctenyl,
Cyclodecenyl.

Examples include cyclododecenyl. Alkylene group means methylene or polymethylene which may be substituted with an alkyl group, examples of which include methylene, ethylene,
trimethylene, propylene.

Examples include ethyl ethylene and tetramethylene. As alkenylene, vinylene, propenylene, l
-butenylene, 2-butenylene, 2-pentenylene, 2
-Methyl-1-butenylene, 2-methyl-2-butenylene, 4-propyl-2-pentenylene, and the like.

Salts of the compound of formula (I) include salts with alkali metals such as sodium octapotassium, alkaline earth metals such as calcium, or amines such as ammonia, tris(hydroxymethyl)aminomethane, and N-methylglucamine. I can give an example.

Although the compound of formula (I) is conveniently expressed as an I-9-oxo form, the following tautomers of the nine compounds are also included in the present invention.

Furthermore, the compound of formula (I) may exist in various isomers such as optically active forms derived from its partial structures R and X, and these various isomers and mixtures thereof are also included in the present invention.

In the compound of formula (1), X is an alkylene group or an alkenylene group, and R is a cycloalkyl group optionally substituted with one or more alkyl groups. and A is CH or N as more preferred.

The compound of formula (1) can be produced according to the reaction formula below.

(In the formula, A, R and X are the same as above.) That is, 9
A compound of formula (II) or a salt thereof is added to an appropriate amount of an acidic solvent to form an acidic solution or an acidic suspension.

The reaction for producing the compound of formula (I) by reacting with nitrite is usually carried out at water cooling to room temperature for 30 minutes to 1 day. Acidic solvents that can be used include hydrochloric acid,
Mention may be made of inorganic acids such as hydrobromic acid, organic acids such as acetic acid, propionic acid, and mixtures thereof. Examples of nitrites include sodium nitrite and potassium nitrite. The salt is usually used in an amount equal to or more than the same mole relative to the compound of formula (I).

Furthermore, the compound of formula (1) can also be obtained by treating the compound of formula (II) or a salt thereof under diazotization conditions other than those mentioned above (1), for example, with an appropriate amount of a nitrite ester such as isoamyl nitrite in the above acidic solvent. I can do it. The ester is usually used in an amount equal to or more than the same mole relative to the compound of formula (II).

The raw material compound of the above formula (Natsuri) is a new compound and can be produced by the method described below.

(In the formula, A, R'EL and X are the same as above.)
Among the compounds of Formula 1 (III), the new substance is based on the known method for producing thiadiazole derivatives (Japanese Patent Application Laid-Open No. 58-17799).
7) or the production method of thiazole derivatives (Ya, G
, Ba1on, M.D., Shulman, N.V., niu
xnetsov ; Zh.

0 "g, nihim,, 15-% No. 11 2351
(see page 1979).

The above reaction step will be explained.

The compound of formula (III) and the malonic acid ester, preferably malonic acid 2.4.6-)lichlorophenyl ester, are mixed in a solvent 1 which does not participate in the reaction, such as xylene, Dowsum A.
By reacting in the presence or absence of etc., the formula (rV
) can be produced. The reaction is usually 100
It is carried out for 30 minutes to 10 hours at ~250°C.

The compound of formula (V) can be produced by reacting the compound of formula (rV) with fuming nitric acid in the presence or absence of a solvent 1 that does not participate in the reaction, such as acetic acid or ether. The 0 reaction is usually -10 ~80℃ for 30 minutes ~15
Time is done.

A compound of formula (Vl) can be produced by reacting the compound of formula (V) with phosphorus oxychloride in the presence of a deoxidizing agent in a solvent that does not participate in the reaction or in the absence of a solvent. As the deoxidizing agent, an organic base such as dimethylaniline, diethylaniline, or tripropylamine is preferably used. The reaction is usually carried out at room temperature to 100° C. for 30 minutes to 5 hours.

The compound of formula (■) can be produced by reacting the compound of formula (Vl) with ammonia in the presence or absence of a solvent that does not participate in the reaction, such as alcohols, dioxane, etc. The reaction is usually carried out by water cooling. It is carried out at 80° C. for 30 minutes to 5 hours.

By subjecting the compound of formula (■) to a conventional reduction reaction 9 such as catalytic reduction method or reduction method using metal and acid, formula
) can be produced.

<Effects of the Invention> The compounds of the present invention have excellent LTD and antagonistic effects, and also significantly suppress PCA when administered orally.

Therefore, a compound of the present invention is effective in curing or preventing bronchial asthma, allergic gastrointestinal disorders, allergic conjunctivitis, allergic rhinitis, hay fever, measles, inflammatory diseases, and the like.

Example 1 7-Amino-2-(2-cyclohexylethyl)-6-
Nitrow 58-[1,3,4] Thiadiazoro [3,2
-a] 6.46 g of pyrimidin-5-one and 1 powdered tin
Suspend 1.9 g in dioxane and gently heat to reflux.

14.4 ml of concentrated hydrochloric acid was added dropwise. After heating under reflux for 1 hour, insoluble matter was filtered off. The filtrate was concentrated under reduced pressure, isopropanol was added, and the precipitate was collected by filtration. This was suspended in 200 ml of concentrated hydrochloric acid and 200 a+1 of water, cooled to -5 to θ°C, and 40 ml of an aqueous solution of 5.0 g of sodium nitrate was added dropwise to the suspension while stirring. After stirring for 5.5 hours under water cooling, the precipitate was collected by filtration and recrystallized from 95% ethanol to give the title compound 2. as mono yellow crystals.
Obtained 0g. Melting point: 265-270°C (decomposed) In the same manner as in Example 1, the compounds of Examples 2-16 represented by formula (I) were synthesized.

The elemental analysis values, nuclear magnetic resonance spectra, and infrared absorption spectra of the compounds described in Examples are shown in the table below.

1 C13H16N60S51,30 5.30
27.61S1. Ol 5.41 27.54 2 Cl2H,4N60S 49.64 4
．． 86 28.9549.74 4.90 29.
Ko13 C, 3H16tJ60S 51.
30 5.3G 27.6151.53 5.26
27.77 4 C1211,4N601 49.64
4.86 2+1.9549.40 4.92 28.
72 5 C14H18N605 52.81 g
, 7o 2g, 4052.76 S, Fu 2
6.306 C14H18116O552,81
5,7026,4052,865,69'26.5a 7C14H18N60S52・815・7026・40
52.81 5.68 26.58 -・1 し (t, jli J, LIJ Im, AHn15 C,, H281f6O55B, 74
7.26 21.6358.58 7.1G
21.69 16 C15H,, N50S 5g, 76
6.03 22.0?56.70 6.18 21.9
3 17 C13H14tJ60S 51.6
4 4.6? 21.8051.45 4. B5
2F, 2318C, 4H, 8N605! 52
41 5.70 26.4052.58 5.81 2
6. '22 19 C15+12ON6051 54.20
6.06 25.2854.21 6.30 25.
19 Formulas (rV), (V), (Vl) used in Examples
The synthesis method of the raw material compounds of and (■) will be described below as a reference example.

In addition, A and RX- of the compound of the reference example correspond to A and RX- of the compound of the example having the same number as the reference example, respectively.

Reference example 1 -5-one 1) 2-amino-5-(2-cyclohexylethyl)-
9.50 g of [1,3,4]thiadiazole and 21.8 g of malonic acid 2,4°6-drichlorophenyl ester were stirred in 70 ml of xylene at a bath temperature of 140 to 150° C. for 2 hours. After cooling, the precipitate was collected by filtration, washed sequentially with ethanol and ether to give 2-(2-cyclohexylethyl)-7-hydroxy-58-[1,3,
4] 10.3 g of colorless plate-like crystals of thiadiazolo[3,2-a]pyrimidin-5-one were obtained.

Elemental analysis Calculated value as Cl38I7N, 02S C5
5,89,H6,13,N 15. Q4 actual measurement value C56
,04,H6,17,N 15.222) 2-(2
-cyclohexylethyl)-7-hydroxy-5)1-
Suspend 9.77 g of [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one in 125 ml of acetic acid,
While stirring and cooling with water, 3.5 ml of fuming nitric acid was added dropwise. 2. At room temperature.
After stirring for 5 hours, the precipitate was collected by filtration, and water, isopropanol,
Washed sequentially with ether, 2-(2
-cyclohexylethyl)-7-hydroxy6-nitro[1,3,4]thiadiazolo[3,2-a]
10.3 g of pale yellow crystals of pyrimidin-5-one were obtained.

Elemental analysis C13) Calculated value as 116N404s C
48, 14, H4, 97, N 17.27 Actual value C4
7,87,H4,89,N 17.413) 2-(
2-cyclohexylethyl)-7-hydroxy-a-nitro-5H-[1,3,4]thiadiazolo[3,2-
a] Oxychloride f of 10.2 g of pyrimidin-5-one
The suspension was suspended in 30 ml of water, and 4+nl of tripropylamine was added dropwise while stirring at room temperature, and the mixture was stirred at 80 to 85°C for 3 hours. After cooling the reaction solution, the precipitate was added to ice water, collected by filtration, and washed with water to give 7-chloro-2-(2-cyclohexylethyl)-6-nitro-58-[1,3,4] having a melting point of 136-137°C.
10.4 g of crystalline powder of thiadiazolo[3,2-alpyrimidin-5-one was obtained.

Elemental analysis C+3H+5CIN403S34) Calculated value as 120 C44,96,H4,50,N 16.1
3 actual measurements C44, 92, H4, 38, N 1B, 24
4) 7-chloro-2-(2-cyclohexylethyl)-
6-Nitro 58-[1,3,4] Thiadiazoro [3
, 2-a] 9.59 g of pyrimidin-5-one was suspended in 100 ml of ethanol.

While stirring at room temperature, 7 ml of concentrated ammonia water was added and stirred for 5.5 hours. The precipitate was collected by filtration and washed sequentially with ethanol and ether to give 7-amino-2-(2
-cyclohexylethyl)-6-nitro-58-[1,
3゜4]thiadiazolo[3,2-a]pyrimidine-5
-On flame yellow crystal7. QSg was obtained.

Elemental analysis Calculated value as C15H1yNsOsS C4
B, 28. H5, 30, N 21.6B actual value C4
B, 31. H5,32,N 21.66 Compounds of Reference Examples 2 to 16 represented by formula (■) were obtained in the same manner as in Reference Example 1.

The melting points of new substances among the raw material compounds of formula (Ill) are shown below.

In addition, the number of each raw material compound is A, R-X- of the raw material compound.
The numbers were made to match the numbers of the compounds of Examples having A and R-X- corresponding to .

The excellent LTD and antagonistic effects of the compounds of the present invention are due to LTD4
This was confirmed by the inhibitory effect on the contraction of isolated guinea pig ileum.

body! A male guinea pig weighing 300 to 600 g was exsanguinated to death, and the ileum was removed to prepare a specimen approximately 2 cm in length. This ileum specimen was suspended in a Magnus bath filled with Tyrode's solution 5ai1 (30 ± 1°C) through which a mixed gas of 54 GO2 was aerated.The contraction of the ileum was 0.
．． It was recorded on a recorder by an isointense transducer under a load of 5 g.

After confirming that a stable contractile response occurs.

LTD4 (3.0 ng/ml) was added to induce a contraction reaction. The pretreatment time for the drug was 1 minute, and the degree of contraction that occurred at that time was compared with the contraction when no test drug was added, and the 5-point inhibitory dose (IC, value) was calculated from the inhibition rate.

As a control compound, 6-(2-phenylethyl l-[1°3.4]thiadiazolo[3,2-al[1,2,3]
Triazolo[4,5-d] Hirimiji: / -9(I
H)-one (see JP-A-80-221i887)
selected. ICs of this compound. The specific activity of the IC5o value of the compound of the present invention with respect to the value was calculated. The results are shown in the table below.

As is clear from the above table, the compounds of the present invention exhibited superior LTD4 antagonistic activity compared to the control compound.

Test 2 PCA test 1) Preparation of antiserum Female Sbrag Dawley rats weighing 170-250 g (CRJ-CD (50) strain 1 Charles River Japan)
To.

Each rat received 5 doses of ovalbumin dissolved in saline.
gg/kg of body weight was intramuscularly injected, and 2 x 10" of dead bacteria were suspended in iml physiological saline and injected intraperitoneally. Ten days later, 3000 N per rat was injected intramuscularly.
ippostrongylus brasiliens
is was injected subcutaneously. After 14 days, blood was collected to obtain antiserum. This antiserum was measured by 48-hour PCA using rats. Antibody titer was 1:128-1:25B.

2) PC^ Test The above-mentioned antiserum was diluted with physiological saline so that the blue-stained spot in the control group shown below had a diameter of about 10 g+a.

One Svragdawley male rat weighing around 180 g
Groups of 5 animals were injected with 0.05 ml of diluted antiserum intradermally on the back. After 48 hours, a PCA reaction was induced by intravenously administering 1 ml of 0.5 Vance Blue physiological saline solution containing 1 g of ovalbumin Sl.

30 minutes after challenge, the rats were decapitated and exsanguinated, the back skin was peeled off, and the amount of pigment in the blue spots (dye leakage spots) was determined by K.
The method of Atayama et al. (Microbiol, 1 m
mun-ol, vol. 22, pp. 89-101 1978
Measured according to the year).

The test compound (lomg) was suspended in 51 ml of 0.50 MC solution, and 10 mg/kg body weight was orally administered to each rat 30 minutes before the challenge injection. On the other hand, the control group had O, Sk CM
Only solution C was administered. The inhibition rate of PCA was determined by the following formula.

Inhibition of PCA weight) = U-vomit - x 100 a: Average value of the amount of dye in the blue-stained spots of the control group b: Average value of the amount of dye in the blue-stained spots of the drug administration group p of the compound of the present invention
The inhibition rate of c^ is shown in the table below.

As is clear from the above table, the two compounds of the present invention have excellent PCA.
It showed an inhibitory effect.

Claims (1)

[Claims] General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲
There are mathematical formulas, chemical formulas, tables, etc.▼, A' means a hydrogen atom, a lower alkyl group, or a halogeno-lower alkyl group, and R means an alkyl group, a halogenoalkyl group, an alkenyl group, a halogenoalkenyl group, a cycloalkyl group. or a cycloalkenyl group, and the cycloalkyl group and cycloalkenyl group may have one or more substituents selected from a hydroxyl group, an alkyl group, an alkoxy group, a halogen atom, an amino group, and a halogenoalkyl group, is a single bond,
It means an alkylene group or an alkenylene group, and the alkylene group and alkenylene group may have one or more substituents selected from an alkoxy group and a halogen atom. ) and its salts