JPH0232059A - Indazole derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R is H, lower alkyl, etc.; Ar is group of formula II (Q<1>-Q<3> are H, halogen, lower alkyl, etc.), etc.; X is H, lower alkyl, halogen, etc.] and its salt. EXAMPLE:1-(2-Dimethylaminoethyl)-3-(2-phenylethenyl)-1H-indazole. USE:A drug expected to be useful as an antitumor agent. It has excellent cytotoxic activity. PREPARATION:The objective compound of formula I-2 can be produced according to the reaction formula by reacting a compound of formula II-1 with 1-5 equivalent of a compound of formula III and its acid addition salt in the presence of equivelent or excess base (e.g., NaH or Na2CO3) in an inert solvent (e.g., DMF, DMSO or THF) usually at room temperature - 70 deg.C and reacting the resultant compound of formula II-2 with a compound of formula IV in the presence of equivalent amount of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel indazole derivatives having anti-cellular activity.

Prior Art Compounds in which the 3-position of indazole is carboxyl, acetyl, benzoyl, etc. via vinylene (-[H=CH-) are known from Khim, Geterosikl, 5oedi
n,, 7゜957 (+978) C Chemical Abstracts (c, A, )89゜163493q (1
978)].

Problems to be Solved by the Invention The object of the present invention is to provide novel indazole derivatives based on the new finding that the compounds according to the present invention have anticellular activity.

Means for Solving the Problems The present invention provides a compound of formula (1) (wherein R is hydrogen, substituted or unsubstituted lower alkyl, -(C)+2). NR'R' (wherein R1 and R2 are the same or different and selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl, lower alkanoyl, and a group forming a heterocycle together with the adjacent nitrogen atom, and n is represents an integer from 1 to 6), -(CH2),, N(
CH2), NR'R'C In the formula, R3 is selected from the group consisting of hydrogen, lower alkyl and lower alkanoyl, m represents an integer of 1 to 6, and R1, R2 and n are as defined above. ) and trityl, each of which is the same or different as hydrogen, halogen, lower alkyl, hydroxyl, lower alkoxyl, nitro, nitroso, carboxyl, lower alkoxy group,
-NR1R" (wherein RIM and R2a are the above-mentioned R
' and synonymous with the definition of R2), 0([:Hz)n
'NR' In the R2 expression, 口2 has the same meaning as the definition of n above, RIM and R2a have the same meanings as above) and Q'
, pyridyl and and lower alkoxyl), and X represents a group selected from the group consisting of hydrogen, lower alkyl, halogen, hydroxyl, lower alkoxyl, nitro, nitroso, -NR1bR2b
(wherein Rlb and 1t2b have the same meanings as the definitions of R1 and R2 above) and -0(C1lz)n5NR1
bR2b (where nb has the same meaning as the definition of n above, [
llb and R2b have the same meanings as above)) An indazole derivative represented by [hereinafter referred to as compound (1)]. The same applies to compounds of other formula numbers] and pharmacologically acceptable salts thereof.

Lower alkyl in the definition of 6 groups in formula (I) refers to straight chain or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, 1-propyl, n-butyl, 1-butyl. , S-butyl, t-butyl, pentyl, hexyl, etc., and substituents in substituted lower alkyl include hydroxyl and halogen.

Lower alkanoyl is a linear or branched alkanoyl group having 1 to 6 carbon atoms, such as formyl, acetyl, n-propionyl, l-propionyl, lobetyryl, 1-butyryl, t-butyryl, n-pentanoyl, etc., and trifluoroacetyl, etc. includes.

Alkoxyl in lower alkoxyl and lower alkoxycarbonyl is a linear or branched chain having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, butoxy, S-butoxy, t
-butoxy, n-hexyloxy, and the like.

In addition, halogen includes fluorine, chlorine, bromine, and iodine atoms, and examples of heterocycles formed with adjacent nitrogen atoms include 5- to 7-membered alicyclic heterocycles, such as pyrrolidine, piperidine, and N-substituted heterocycles. or unsubstituted piperazine, morpholine, thiomorpholine, N-substituted or unsubstituted homopiperazine, etc., and examples of the substituent include lower alkyl or lower alkanoyl as defined above.

The pharmacologically acceptable salts of compound (1) include pharmacologically acceptable acid addition salts, such as hydrochloride, hydrobromide,
Examples include inorganic acid salts such as sulfates and phosphates, and organic acid salts such as oxalates, acetates, malonates, succinates, fumarates, maleates, tartrates, and citrates. .

The method for producing compound (1) will be explained below. However, the method for producing compound (1) is not limited thereto.

In compound (1), a compound (1) in which R is hydrogen and a compound (1-2> in which R is a group other than hydrogen) can be produced according to the following reaction steps.

(■Ct■0□ (i, H=CHΔr (wherein, R' represents a group other than hydrogen according to the above definition of R, 11a1 represents a halogen, R4 represents lower alkyl or benzyl, and 81 , X and R are as defined above) Here, the halogen represented by Hal is chlorine, bromine and iodine, and the lower alkyl represented by R4 is methyl,
Examples include ethyl and n-propyl.

Compound (II-2) can be prepared by a known method [for example, J, 8m, Chem, Soc, 74. 2009 (
1952); C, 8, 87°18451
0 (1977) etc.] or compound (II-1) synthesized according to it and 1 to 5 equivalents of compound (I) or an acid addition salt thereof (the same salts as above are exemplified; in the following description ) in the presence of equivalent to excess base in an inert solvent, usually at room temperature to 70°C,
It can be obtained by reacting for 10 hours. Suitable bases include inorganic bases such as sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, and silver oxide, and organic bases such as sodium methoxide, sodium ethoxide, potassium t-butoxide, triethylamine, and pyridine. However, suitable inert solvents include dimethylformamide, dimethylsulfoxide, tetrahydrofuran, chloroform, dichloromethane, and lower alcohols such as methanol, ethanol, l-propanol, and t-butanol (step 1).

Compound (1-1) or (1-2) can be obtained from the corresponding compound (I[-1) or (II-2), respectively. The reaction is carried out with compound (n-1) or (II-2)
) and known methods [eg J, Org.

Che+n, 26.5243 (1961), etc.] or 1 to 2 equivalents of a compound (■) synthesized in accordance therewith is usually cooled in an inert solvent in the presence of an equivalent amount of base to the compound (TV). It is carried out at room temperature, preferably -40 to 25°C, and completed in 0.5 to 10 hours. A suitable base is
Sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, botium 1-butoxide,
Suitable inert solvents include n-butyllithium, S-butyllithium, lithium diisopropylamide, etc.
Dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dimethoxyethane, methanol, ethanol, 1-propanol, t-butanol, etc. are used (steps 2 and 3), respectively.

Compound (1-2) can also be produced from compound (I-1) and compound (III) according to the same method as step 1 (step 4).

Compounds obtained by these production methods (in H,
If the defined groups change under the conditions of the process or are unsuitable for carrying out the process, the methods commonly used in organic chemistry, such as protection of functional groups, deprotection [e.g.
active Groups in OrganicS
ynthesis, by T. Green, John
Willey & 5ons Inc. (1981)).

Moreover, among the compounds (1) obtained here, further novel compounds (1) can also be obtained by using these as synthetic intermediates.

For example, in the definition of formula (1), the compound Na) in which at least one of O', Q2 and 03 (sometimes collectively referred to as Q) and/or X is amino (NL) is , a compound in which the corresponding group is nitro (1b
) can also be obtained by reducing.

In the reaction, compound (I b) is mixed with 5 to 1
It is usually completed in 1 to 10 hours at room temperature to 90° C. in the presence of 5% palladium/carbon and 4 to 20 equivalents of hydrazine hydrate. Examples of lower alcohols used as solvents include methanol, ethanol, n-propanol, 1-
Examples include propatool and ethylene glycol.

In another method, compound (I a) is converted into compound N b
) in lower alcohol/hydrochloric acid in the presence of 1 to 3 times the weight of iron powder at room temperature to 90°C for 5 minutes to 2 hours. The hydrochloric acid used is 2 to 1
The amount used is 4 to 20 times that of compound (Ib) at 2N. Examples of lower alcohols include methanol, ethanol, n-
Proper Tools, 1-Proper Tools, etc. can be used.

Q and [/4ta l;! l(,-NHR”lbarN(R5
)2 [wherein R5 is synonymous with lower alkyl or lower alkanoyl defined in formula (1)]
c) is the corresponding amino compound (Ia) or its acid addition salt and 1 to 10 equivalents of the compound (V) R'-Hal (V) represented by the following formula (wherein R5 and Hat are as defined above) ) and
0-60°C in an inert solvent in the presence of an equivalent to excess of base
It can also be obtained by reacting for usually 1 to 20 hours. Examples of the base include sodium carbonate, potassium carbonate, triethylamine, pyridine, 4-dimethylaminopyridine, silver oxide, etc., and examples of the inert solvent include dimethylformamide, dimethylsulfoxide, tetrahydro7rane,
Chloroform, dichloromethane, etc. are used.

Q and/or X are 0(Cl12)nNR'R2
(In the formula, R', R' and n are as defined above) Compound (Id) is a compound (Ie) in which the corresponding group is hydroxyl and a compound represented by the following formula of 1 to 2 equivalents M. (VT) or its acid addition salt Hal ([:)lx)nNR'R' (Vl)
(wherein R1, R2, Hal and n are as defined above) in an inert solvent in the presence of an equivalent to an excess of base,
It can also be obtained by reacting at room temperature to 70°C for 15 to 10 hours. As a base, sodium hydride, n
-Butyllithium, S-butyllithium, t-butyllithium, potassium carbonate, tricarbonate! , etc. are used, and as inert solvents, dimethylformamide, dimethyl sulfoxide, dichlorofuran, dichloromethane, ether, etc. are used.

A compound (I f) in which Q is carboquinyl can also be obtained by hydrolyzing a compound (Ig) in which the corresponding group is lower alkoxycarbonyl. The reaction is
Compound (Ig) is hydroxylated in a 1 to 10 N hydroxide solution, or potassium hydroxide, or in a mixed solvent of an aqueous alkali solution of these and methanol or ethanol, usually at room temperature to 70°C. It should be completed in 0.5 to 10 hours.

The intermediates and target compounds in the above-mentioned 1-d production method are:
Purification methods commonly used in organic synthetic chemistry, such as filtration, extraction,
It can be isolated and purified by drying, concentration, recrystallization, various chromatography, etc.

Further, the intermediate can also be subjected to the next reaction without being particularly purified.

When you want to obtain the salt of compound (1), if compound (+) can be obtained in the form of a salt, you can simply purify it as it is, or if you can obtain it in the free form, you can obtain the salt by the usual method. Just let it form.

Compound (1) and its pharmacologically acceptable salts may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.

In the compound (I) obtained by the above production method, the vinylene group (-F''H=[:H-) has Y0 and 2 forms.
Geometric isomers exist, and the above-mentioned production method usually provides a mixture of them.

In some cases, such mixtures can be separated by methods commonly used in organic synthetic chemistry, such as various chromatographic recrystallizations.

In addition, the present invention provides compound (1) with E/
Not only the Zl-mer, but also all possible stereoisomers and mixtures thereof are included.

Specific examples of compounds (+>) obtained by each manufacturing method are listed below.
Shown in the table.

No. table CI-13 (CII3) 2NCIl□0112 (CL)　2NCLCII2 (CL) 2NCII□C112 To I -Ku○sweat OCH.

Be o, 7 Be○, , -CO, l:H.

1'9. ＞ (CI+3>2NCI(, C1+.

(○, ″N (CI+,) 2N (:112CI+2I] -0CI+ to C.

(CL)JCH,CH2 1:○゛゛辷N02 (CH3), NC11, CI+.

1'○ゝ-N mouth ＼－－／ (C11,), NCII, CH2 (C113>211CII, CH.

to( JC Masu [1 \-) 0, C1(.

izu<o×c++.

\OCI+.

CR3 X0CH.

CI+.

(CsHs) 3C DC1+3 OCI+.

ゝOCH.

’　QC)13 (ΣN Be, Q,’+ OCII 3 ゝOCI+.

(C113) 2NCH2CH2 -CL CH3 12″○n One... [:L ゝOCR.

C) 13 One”;-NO3 (CL) 2NCII2CH2 (CII+>2NCH2CI□ To I (CII3) 2NCH2C11□ Ze C Re OH CI(.

(C)13) JCH, CH.

i0”;-o++ Lee Kano BeΩ/-OH ()io+2c++.

(CL), NC112cH.

(Il’ll, ), N[l+21”+12CH.

(CI, l) 2MCII□[112 1■ 1" I( ■( “OCH3 O to 1qn ゝOCI+.

-Temata-0C1liCIIJ (C113) zbe○>
-0CtlzCIItCIIaN (CH3) 2-〇 and 0CI(-CtlJ (C1l-) 2i0.-co
□11 +011 Dun[1CLC)I,N (CH,) 2+11J Next, the anti-cellular activity of compound (1) against cancer cells will be shown in a test example.

Test Example (1) 1.11': RPMI in each formula of F 7 cell 96-well microtiter plate 1.
-IG40 medium (manufactured by Gibcn Sf), 10% tallow serum, lojAg/ml insulin and 10-'
A medium consisting of M estradiol (hereinafter referred to as medium A):
) prepared to 4.5 x 10' pieces/ml
CF7 cells were dispensed in 0.1...1 portions. After culturing the plate in a carbon dioxide gas incubator at 37°C for 20 hours,
Add 0.05 mj of the specimen (test compound) suitably diluted to the medium and incubate in a carbon dioxide incubator for 3
The cells were cultured at 7°C for 72 hours. After removing the cultured soil, 0.1 ml each of medium A and 0.02% neutral red were added to the residue, and the cells were cultured at 37° C. for 1 hour in a carbon dioxide incubator to stain the cells.

After removing the 1st culture fluid, the residue was washed once with physiological saline. Next, after extracting the pigment with 0.001 N hydrochloric acid/30% ethanol, the dye was extracted at 550 nm using a microplate league.
The absorbance was measured. By comparing the absorbance of untreated cells and cells treated with a known concentration of the specimen, the concentration of the specimen that inhibits cell proliferation by 50% (IC3°) was calculated. The results are shown in Table 2.

(2) MEM medium (
3 in a medium consisting of Hinaga Pharmaceutical Co., Ltd.) and 2mM glutamine.
HeLa5. 0.1 cells
Dispense 1 ml. Below is the above! Ins as in the case of JCF7 cells. was calculated. The results are shown in Table 2.

Table 2 *: Not tested As shown in Table 2, Compound (I) exhibits excellent anti-cell activity and is expected to be used as an anti-tumor agent.

Examples are shown below, and the physicochemical properties of the obtained compounds are shown in Tables 4-1 and 4-2.

In addition, the example number corresponds to the compound number.

Example 1 1-(2-dimethylaminoethyl)-3-(2-phenylethynyl)-LH-indazole 3-formyl-1
-(2-dimethylaminoethyl)-18-indazole 1.60 g and benzyl phosphite diethyl ester 1.
Dissolve 85 g in 30 ml of dimethylformamide and add 0.34 g of sodium hydride (60% oil) with stirring.
g was added little by little, and the mixture was further stirred at room temperature for 1.5 hours. After the reaction is complete, add a small amount of saturated sodium sulfate aqueous solution,
The reaction solution was concentrated under reduced pressure. Water was added to the obtained oil, extracted with ethyl acetate, and dried over anhydrous sulfuric acid. The resulting residue was purified by silica gel column chromatography using chloroform-methanol (30:1 v/v) as an eluent to obtain 1.56 g (72.7%) of the title compound. Ta. This was dissolved in 160 ml of ethyl acetate and 7.5 ml of a 1.15N hydrogen chloride-ether solution was added to give a hydrochloride.

The compounds obtained in the same manner as in Example 1 and their yields are shown in Table 3-1.

Table 3 1 Example 45゜5-amino-3-[2-,(4-ethoxy-2-oxo-28-1-benzopyran-7-yl)ethynyl] -
370.70 g of 1-(2-dimethylaminoethyl)IH-indazole compound and 0.0 g of 10% palladium/carbon
45 g was suspended in 15 n1 of ethanol, and 0.45 ml of hydrazine monohydrate was added at 50°C. After further heating to 70° C. and stirring for 3 hours, the insoluble matter when heated was removed from door to door. After cooling, the precipitate precipitated was counted, and further purified by silica gel column taromadography using chloroform-methanol (9: IV/V) as the elution solvent.
0.54 g (82.8%) of the title compound was obtained. This was made into a hydrochloride by a conventional method.

The compounds obtained by the same method as Example 45 and their yields are shown in Table 3-2.

Table 3-2 Example 48゜3-(2-(4-aminophenyl)ethynyl)-1-
31.22 g of (2-dimethylaminoethyl)-1H-indazole compound and 1.22 g of iron powder were mixed with 2 ml of ethanol.
While stirring, 6 ml of 4N hydrochloric acid was added. This solution was stirred at 80°C for 15 minutes, and after cooling, 6ml of 10N sodium hydroxide and 50ml of dichloromethane were added.
After adding 1 and removing insoluble matter, water was added for extraction. The dichloromethane layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was dissolved in chloroform-methanol (
15: IV/V) was used as an elution solvent to obtain 0.83 g (74.7%) of the title compound. This was made into a hydrochloride by a conventional method.

Example 49゜3-C2-(2-aminophenyl)ethynyl]1-(
2-dimethylaminoethyl)-1H-indazole The title compound was obtained in a yield of 51.8% in the same manner as in Example 48.

Example 50゜3-C2-(4-hydroxyphenyl)ethynyl]-
1-(2-dimethylaminoethyl)-18 indazole ethanethiol 0.29 ml dimethylformamide 7
ml solution) IJium (60% oil) 0,
16 g was added and stirred for 5 minutes. There compound 20,5
Add 8 ml of 0 g dimethylformamide solution and
Stirred at ℃ for 7.5 hours. After the reaction, a small amount of saturated aqueous sodium sulfate solution was added and the mixture was concentrated under reduced pressure.

Water was added to the obtained oil, extracted with chloroform, washed with an aqueous ammonium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using chloroform-methanol (15: IV/V) as an eluent to obtain 0.34 g (77.3%) of the title compound. This was converted into a hydrochloride using a conventional method.

Example 51゜3-C2-(4-1:)'roxyphenyl)ethynyl)-1-methyl-IH-indazole The title compound was obtained in a yield of 80.5% in the same manner as in Example 50.

Example 52゜60.50 g of 3-[:2-(3,4-dihydroxyphenyl)ethynyl]-1-(2-dimethylaminoethyl)IH-indazole compound was added to 5 ml of tetrahydrofuran and 2 ml of water.
．． 0 ml and 4.5 ml of concentrated hydrochloric acid,
Stirred at ℃ for 2.5 hours. The reaction solution was poured into water, adjusted to pH 9 with 2N sodium hydroxide, and extracted with chloroform. The chloroform layer was washed with an aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, and then -Cj reduced pressure a.
Contraction 1. 1. The obtained residue was purified by silica gel column chromatography using chloroporum methanol (9: IV/V) as an eluent to obtain the title compound 0.
．． 31 g (69.6%) were obtained.

,, 17 is converted into hydrochloride using a conventional method.

Example 1) 3゜3-[2-(2-Hydroxy-5-methoteschiffSnil)
Ethynyl:] -1-(2-dimethylaminoethyl)-
111-indazoleethanethiol 1.27 ml dimethylformamide 2
(Sodium hydride <60% oil in 1 ml solution) [
), and stirred for 5 minutes (7 ml.) Then, a 7 ml solution of compound 81 and OOg in dimethylformamide was added and stirred at 100°C for 9.5 hours. After the reaction, a small amount of saturated ammonium chloride aqueous solution was added, It was condensed under reduced pressure. Water was added to the obtained oil, extracted with chloroform, washed with an aqueous ammonium chloride solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure.(!) The resulting residue was diluted with chloroform-methanol ( 0.65 g (67.7%) of the title compound was obtained by purification by silica gel column chromatography using 9:1V/v) as an eluent.3 This was converted into a hydrochloride by a conventional method.

The compounds obtained by the same method as Example 53 and their yields are shown in Table 3-3.

Table 3-3 Example 57゜1-(2-8[1-(2-dimethylamino)ethquinphenyl]ethynyl)-1-(2-dimethylaminoethyl l-11(-,-indazole compound) 500. 30g
and 0.21 g of 2-dimethylaminoethyl chloride were suspended in 10 ml of dimethylformamide, and while stirring, 0.098 g of sodium hydride (6f% oil) was added, stirred at 70° C. for 7 hours, and then passed through once. The P solution was concentrated under reduced pressure, water was added to the obtained oil, and the mixture was extracted with chloroform.

The 1v1 form layer was dried with anhydrous sulfuric acid. After drying with IJum, the resulting residue was purified by licage gel column chromatography using 12% form-methanol (6: IV/V) as the elution solvent. 0.16 g (43.2%) of the title compound was obtained by Sukokichi.This was mixed with the hydrochloride [7t, 2.

Table 3-4 shows the compounds converted to (-) by the same method as in Example 57 and their yields.

Table 3-4 Example 60゜3-[2-(4-carboxyphenyl)ether]-
111.7 g of 1-,12-dimethylaminoethyl)-1H indazole compound was dissolved in a mixed solution of 35 ml of methanol and 35 ml of 4N sodium hydroxide (stirred at -150°C for 1 hour. The reaction solution was cooled and dissolved in 6N hydrochloric acid. at pH 5
, 5, and concentrated under reduced pressure. After methanol was added to the residue and precipitated common salt was separated by ρ, water was added and crystallized to obtain 1.04 g (63.7%) of the title compound IM. This was converted into a hydrochloride using a conventional method.

Example 61゜5-acetylamino-3-[1-(4-ethoxy-2-
oxo-28-1-benzobilane-fil)ethynyl)
450.15 g of -1-(2-dimethylaminoethyl)-1H-indazole compound was dissolved in 8 ml of taloloforno, 0.25 ml of triethylamine was added, and 0.13 ml of acetyl chloride was added while stirring under water cooling. ,
Stirred for 5 hours. After the reaction, chloroform and water were added, and the pH was adjusted to 8 with an aqueous sodium hydrogen carbonate solution. The separated chloroform layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform-methanol<9
:IV/V) was purified by silica gel column chromatography using as elution solvent to obtain 0.12% of the title compound.
g (72.2%) was obtained. This was made into a hydrochloride by a conventional method.

Example 62゜3-[1-(4-hydroxyphenyl)ethynyl]
-18-indazole '3 from 431.22 g of compound in the same manner as in Example 53
-C2-(4-hydroxyphenyl)ethynylyo1-
Trityl-IH-Indazole 0.85g (71.7%
) was obtained.

0.15 g of the above compound, 6 ml of methanol and 0 concentrated hydrochloric acid
．． 6 ml was added and stirred for 3.5 hours. Add chloroform and water to the reaction solution, and adjust the pH to 7 with an aqueous sodium hydrogen carbonate solution.
Adjusted to 5. The separated chloroform layer was dried over anhydrous sodium carbonate and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography using chloroform-methanol (6:1V/V) as a developing solvent to obtain 0.068 g (91.7%) of the title compound. This was recrystallized from chloroform-methanol-ethyl acetate.

Example 63゜3-(2-C4-(2-dimethylamino)ethoxyphenyl]ethynyl)-18-indazole3-C2-(4-hydroxyphenyl)ethynyl]-1-)rityl-IH obtained in Example 62 3-(1-[4-(2-
dimethylamino)ethoxyphenyl]ethynyl) -1
-) Rif-Roux IH Indazole 0.49g (95,0
%) was obtained.

To the above compound were added 18 ml of methanol, 10 ml of water and 2.2 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature overnight. Chloroform and water were added to the reaction solution, and the pH was adjusted to 7.5 with a 10% aqueous sodium hydroxide solution. The separated chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using chloroform-methanol (9+ IV/V) as an eluent to obtain 0.15 g (53.1%) of the title compound.
I got it. This was converted into a hydrochloride using a conventional method.

Example 64 80.35 g of 3-[2-(2,5-dihydroxyphenyl)ethynyl]-1-(2-dimethylaminoethyl)-IH-indazole compound was dissolved in 20 ml of dichloromethane and cooled to -40°C under a nitrogen stream. did. While stirring, 6 ml of 1N boron tribromide-hexane solution was added, the temperature was gradually returned to room temperature, and the mixture was stirred overnight. The reaction solution was poured into ice water and subjected to 2N hydroxide. After adjusting the pH to 8 with an aqueous IJ solution, the mixture was extracted with chloroform and anhydrous sulfuric acid. The reaction mixture was dried with U ram and concentrated under reduced pressure. The obtained residue was diluted with taloloformomethanol (6:I
V/V) was used as an eluent to obtain 0.03 g of the title compound (
9.3%). This was made into a hydrochloride by a conventional method.

Table 4-1 56.37 10.27 Effects of the Invention According to the present invention, compound (1) and its pharmacologically acceptable salts have excellent anti-cellular activity and are expected as anti-tumor agents. Ru.

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ {In the formula, R is hydrogen, substituted or unsubstituted lower alkyl, -(CH_2)_nNR^1R^2 (In the formula, R^1
and R^2 are the same or different and selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl, lower alkanoyl, and a group that forms a heterocycle with the adjacent nitrogen atom, and n represents an integer of 1 to 6. ), ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^3 is selected from the group consisting of hydrogen, lower alkyl, and lower alkanoyl, m represents an integer from 1 to 6, ^2O and n have the same meanings as above) and represent a group selected from the group consisting of trityl, and Ar has a numerical formula, a chemical formula, a table, etc.
^1, Q^2 and Q^3 are each the same or different and represent hydrogen, halogen, lower alkyl, hydroxyl,
lower alkoxyl, nitro, nitroso, carboxyl,
Lower alkoxycarbonyl, -NR^1^aR^2^a
(In the formula, R^1^a and R^2^a have the same meanings as the definitions of R^1 and R^2 above), -O(CH_2)n
^aNR^1^aR^2^a (in the formula, n^a has the same meaning as the definition of n above, and R^1^a and R^2^a have the same meanings as above) and Q^1, Any two of the ortho positions of Q^2 and Q^3 together ▲There is a mathematical formula, chemical formula, table, etc.▼ (In the formula, R^4 and R^5 are the same or different and hydrogen, lower alkyl and pyridyl and ▲mathematical formulas, chemical formulas, tables, etc.▼(wherein Y is hydrogen, lower alkyl, represents a group selected from the group consisting of (selected from the group consisting of lower alkoxyl), where X is hydrogen,
Lower alkyl, halogen, hydroxyl, lower alkoxyl, nitro, nitroso, -NR^1^bR^2^b(
In the formula, R^1^b and R^2^b are synonymous with the definitions of R^1 and R^2 above) and -O(CH_2)n
Selected from the group consisting of ^bNR^1^bR^2^b (where n^b has the same meaning as the definition of n above, and R^1^b and R^2^b have the same meanings as above) An indazole derivative represented by the following formula and a pharmacologically acceptable salt thereof.