JPS604184A - Pyrazoloindazole derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 is H or methyl; R2 is H, methyl or phenyl). EXAMPLE:2-Bromo-7-methyl-9-phenyl-2, 3-dihydro-1H-pyrazolo[ 1,2-a ]-indazolium bromide. USE:A bronchodilator. PREPARATION:The compound of formula I is obtained by the thermal cyclization of the compound of formula II. The starting compound of formula II can be prepared easily by reacting the compound of formula III with alkyl bromide, and adding bromine to the reaction product. The compound of formula I can be converted to the compound of formula IV by reacting with NaHCO3 in an aqueous solution. A compound of formula IV wherein R3 is CH3 is prepared directly by reacting the compound of formula III with 3-chloro-2-methyl-1-propene, adding bromine to the reaction product, and thermally cyclizing the addition product.

Description

Detailed Description of the Invention The present invention is based on the following general formulas (,1) and (II) (where R1 is a hydrogen atom or a methyl group, R2 is a hydrogen atom, a methyl group, or a phenyl group, and R3 is a hydrogen atom) or methyl group).

The compound of the present invention of formula (1) is produced, for example, by the following method. That is, the following general formula Cu1l)CH,CH-C
It is produced by heating and ring-closing a compound represented by H, Br 8" (wherein R1 and R2 have the above-mentioned meanings). Compound (II) is represented by general formula (IV) ( In the formula R
1y R2 has the above-mentioned meaning) by reacting with allyl bromide and then adding bromine.

The compound of formula (If) is obtained by preparing the compound of formula [I] in an aqueous solution.
Obtained by reacting sodium hydrogen carbonate.

In addition, in formula (II), the one where R3=OH3 is represented by the formula CI
The compound of V) was reacted with 3-chloro-2-methyl-1-prepene, bromine was added thereto, and the ring was closed by heating. Add 3f of butylammonium butymite to 200d of benzene and 120d of 25% aqueous sodium hydroxide solution and stir at 60°C for 30 minutes. After separating the benzene layer, it is washed with water, dried and concentrated under reduced pressure. Dissolve the residue in 300 g of carbon tetrachloride, cool with ice and cool with 501 g of carbon chloride.
25f of bromine dissolved in 1 L is added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 10 minutes, and 11-form was added to dissolve the oily substance that had sunk to the bottom. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue was dissolved in 200 m of methyl ethyl kentone, heated under reflux for 15 hours, and the precipitate was filtered off to give 2-bromo-7-methyl-9-phenyl-2,3-dihydro-IH-pyrazolo(1,2-a ) indazolium bromide 34.9 f
can get. When this is recrystallized from water, the decomposition point is 183℃
shows.

Elemental analysis 017)! CHN as ts N2 Br5t Calculated value (to) 50.03 3.95 6.86 Actual value (to) 50.04 3.97 6.85 Example 2゜According to the method of Example 1, 2- from indazole Bromo-2,3-dihydro-IH-pyrazolo[1,2-a) indazolium tetramite was obtained. Recrystallization from ethanol-ether shows a decomposition point of 181-2°C.

Elemental analysis OHN calculated value as 010H1ON2Br2) 37.77 3.17 8.81 Actual value (
2) 37J0 3.14 8.65 Example 3゜According to the method of Example 1, 2-busymo-9-methyl-2,3-dihydro-IH-pyrazolo(1,2-a)in was prepared from 3-methylindazole. Dazolium bromide was obtained. Recrystallization from water-acetone showed a decomposition point of 202°C.

Elemental analysis 011H12N2Br2 ・-! -H20 as 0 HN Calculated value (to) 38,74 3.84 8.21 Actual value (to) 38,47 3.59 8.02 Example 4゜2-Brom-7- obtained in Example 1 Methyl-9-phenyl-2,3-dihydro-IH-pyrazo p(1,2-a
) Add indazolium bromide LOP to 250 m of water, add 2°52 of sodium bicarbonate, and heat at 60°C.
, heat and stir for 4 hours. Concentrate the solvent to 100%,
Subjected to HP-20 (300WLl) column chromatography,
The target product was collected and concentrated, and the residue was suspended in acetone and filtered to obtain 7-methyl-9-phenyl-9H-virazot' (1,
2-a) Obtain indazolium bromide 5.1f. When recrystallized from water, it shows a decomposition point of 238°C.

Elemental analysis OHN as 017H15N2Br Calculated value (total) 62.40 4.62 8.56 Actual value (total) 62.31 4.64 8.60 Example 5゜2~Brom-2 obtained in Example 2 ,3-dihydro-
From IH-pyrazolo[:1,2-a]indazolium bromide, 9H-pyrazolo(
1,2-a) Indazolium bromide was obtained. When recrystallized from water-acetone, it shows a melting point of 222-3°C.

Elemental analysis 010 R9N2 OHN as Br Calculated value (1) 50.66 3.83 11.82 Actual value % 50.54 3.79 11.60 Example 6° 2-brome-9 obtained in Example 3 -methyl-2,3
9-Methyl-9H-pyrazolo CI, 2-a:1 indazolium bromide was obtained from -dihydro-IH-pyrazolo(1,2-a) indazolium bromide according to the method of Example 4. Recrystallization from ethanol-ether shows m p of 205-6°C.

Elemental analysis 011 I (OHN as 11N2 Br Calculated value (to) 52,61 4.42 11.16 Actual value (to) 52.71 4.39 11.01 Example 7
5-Methyl-3-phenylindazole 32.61, tetrabutylammonium bromide 32.3-di-2-methyl-Apetaben 16F were added to 250 grams of benzene and 70 grams of a 25% aqueous sodium hydroxide solution and heated under reflux for 3 hours. , wash the benzene layer with water, dry and concentrate. The residue was dissolved in 250 d of carbon tetrachloride, and 251 d of bromine was added under water cooling. After stirring at room temperature for 30 minutes, the residue was washed with water, dried, and concentrated.
Do time. The precipitate was filtered to obtain 8.11 of sufu-dimethyl-9-phenyl-9H-virazot'(1,2-a) indazolium bromide. Decomposition point 2 when recrystallized from water
Indicates 70°C.

Elemental analysis 018H17N2 0 as Br, HN Calculated value (1) 63.35 5.02 8.21 Actual value (A 63.14 5.04 8.11 Applicant Chugai Pharmaceutical Co., Ltd.

Claims (1)

[Scope of Claims] A pyrazoloindazole derivative represented by the general formula (wherein B1 represents a hydrogen atom or a methyl group, and R2 represents a hydrogen atom, a methyl group, or a phenyl group). 2. A pyrazoloindazole derivative represented by the general formula (wherein R1 means a hydrogen atom or a methyl group, R2 means a hydrogen atom, methyl group or phenyl group, and R3 means a hydrogen atom or a methyl group).