JPS58159469A - Novel 1,3-disubstituted 3-aminoindazole derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The 1,3-disubstituted 3-aminoindazole derivative of formulaI W1 is group of formula II (Y is methylene chain; R1 and R2 are alkyl or together form a heterocyclic group with N or together form a heterocyclic group with N and O); W2 is group of formula III (Z is methylene chain, R3 and R4 and H, alkyl, or together with N form heterocyclic group or together with N and O form heterocyclic group) . EXAMPLE:1-(3-Diethylaminopropyl)-3-(3-diethylaminopropylamino)indazole. USE:Antiphlogistic agent. A non-steroidal remedy for suppressing the side effect to cause the ulcer in the digestive organs of acidic non-steroidal antiphlogistic agent. PROCESS:The compound of formulaIcan be prepared by reacting the compound of formula XW1 (X is Cl, Br or I) with 3-phthalimidoindazole derived from 3-aminoindazole and phthalic anhydride, reacting the resultant compound of formula IV with hydrazine hydrate to obtain the compound of formula V, and reacting the compound with the compound of formula XW2.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 3-disubstituted 3-mininoindazole derivatives which are novel and useful in the field of therapeutics;
More details 1. < is a series of novel No. 1 and No. 3 drugs that are particularly valuable for their ability to reduce inflammatory conditions, have analgesic effects, and suppress the gastrointestinal ulcerogenic side effects of acidic nonsteroidal anti-inflammatory drugs. The present invention relates to a disubstituted 3-aminoindazole derivative 2 and an intermediate for its production.

Various attempts have been made by many researchers in the field of organic synthetic chemistry to obtain new and useful anti-inflammatory agents. Most of these efforts involve the synthesis and testing of steroidal hormone compounds such as corticosteroids or acidic non-steroidal substances such as phenylbutacin, indomethacin, etc. However, while we are in the process of developing new, better, and improved anti-inflammatory agents, little is known about the effects of basic agents. However, basic nonsteroidal drugs have been attractive because, in addition to the usual usefulness of acidic nonsteroidal compounds, they have few undesirable side effects.

The inventors have demonstrated that certain novel 1,3-disubstituted 3-aminoindazole derivatives attenuate inflammatory conditions and further suppress the gastrointestinal ulcerogenic side effects of acidic nonsteroidal anti-inflammatory drugs. Very useful as a non-steroidal therapeutic agent for
The present invention was completed based on the discovery that the present invention is useful.

1- That is, the novel compound of the present invention has the general formula (I) 1 (
I) W.

is a methylene chain with a carbon number of 6'-1, and the hydrogen atom bonded to the carbon atom of the chain part may be further substituted with a lower alkyl group, and ru and/or Peng are hydrogen atoms. or a lower alkyl group having 1 to 6 carbon atoms, or a heterocycle carrying up to 6 carbon atoms together with the adjacent nitrogen atom, or a heterocycle having 4 carbon atoms together with the nitrogen atom jo and the oxygen atom form,
And the hydrogen atom bonded to one or more carbon atoms or nitrogen atoms of the heterocycle is further a lower alkyl group,
In the formula, Z is a methylene chain having up to 6 carbon atoms in the straight chain part, and the hydrogen atoms bonded to the carbon atoms in the chain part may be further substituted with a lower alkyl group, and / or Toshi is a hydrogen atom or a lower alkyl group having from 1 to 6 carbon atoms, or a heterocycle having up to 6 carbon atoms with adjacent nitrogen atoms or 2 nitrogen atoms and 4 carbon atoms with oxygen atoms form a heterocycle having atoms, and the hydrogen atoms bonded to one or more carbon or nitrogen atoms of the heterocycle may be further substituted with lower alkyl groups, hydroxy groups or) . ). ] 3-aminoindazole derivatives and physiologically acceptable acid addition salts thereof.

Examples of the novel 1,3-position disubstituted 3-aminoindazole derivatives of the present invention include the following.

(1) 1-(3-diethylaminoprobyl)-3-(3
-diethylaminopropylamino)indazole (2) 1-(3-diethylaminopropylamino)-3-(
3-piperidinoprobylamino)indazole (3)l
-(3-diethylaminepropyl)-3-(6-piperidinohexylamino)indazole (4) l-(3-diethylaminepropyl)-3-(3-di-n-butylaminopropylamino)indazole (5) 1- (3-diethylaminopropyl)-3-(3
-piperisiptylamino)indazole (6) l-(
3-piperidinopropyl)-3-(3-diethylaminopropylamino)indazole (7) l-(3-piperidinopropyl)-3-(3-piperidinopropylamino)indazole (8) ]-(]3-biperidinoglovir-3-(6-piperidinohexylamino)indazole (9) 1-(3-piperidinopropyl)-3-(3-piperisiptylamino)indazole (1 ))1-(3
-piperisiptyl)-3-(3-diethylaminopropylamino)intazole (]1) 1-(3-piperidinobutyl)-3-(3-piperidinoprobylamine)indazole (L2) l-(3-piperisiptyl)- 3
-(3-piperidino-5-methylhexylamino)indazole (13) 1-(3-piperidinobutyl)-3-(3-dimethylaminobutylrimino)indazole (14)]-
(]3-dimethylaminobutyl-3-(3-diethylaminopropylamino)indazoleμ5)1-(3-dimethylaminobutyl)-3-(3-
piperidinopropylamino)indazole (16) 1-
(3-dimethylaminobutyl)-3-(3-piperisiptylamino)indazole (17) l-(3-dimethylaminobutyl)-3=(3-diethylamine-5-methylhexylamino)indazole (18) ]-(]3-morpholinopropyl-3-(3-
diethylaminopropylamino)indazole (19)
] -(]3-morpholinopropyl-3-(3(29
6-syntylbiberidino)propylaminequindazole (20)] -(]3-morpholinonelovir-3~[3
-(4-chloropiperidino)propylaminequindazole)]-(]3-morpholinopropyl-3-(3-(4
-hydroxypiperidino)propylaminequindazole (22)] -(:(-pipyrrolidinoprobil-3-
(3-Homopiperidinopropylamino)indazole (
23) l-(3-pyrrolidinoprovir')-3-[3-
(2-Methylpiperidino)Flopylaminocoindazole (24) 1-(3-pyrrolidinoprovir)-3-[3-
(4-Methylpiperazino)propylaminequindazole and their physiologically acceptable acid addition salts such as hydrobromide dihydrochloride addition salts, all of these specific compounds have high anti-inflammatory activity and Suppresses the gastrointestinal ulcerogenic side effects of non-steroidal anti-inflammatory drugs.

3-aminoindazole is Bamberger,
LiebigsAnn, 305, 339 (1899H
C first to report Sareta.

U.S. Pat. No. 3,133,081 describes a 3-aminoindazole derivative in which phenyl moat is substituted with a halogen or trifluoromethyl group, and the nitrogen atom at the 1st position is bonded to hydrogen, methyl group, or phenyl group. Have you been? Discloses its use as a central nervous system active and muscle relaxant, analgesic, and tranquilizer. However, pharmacological cheaters do not disclose. Moreover, it has not yet become a practical medicine.

8i1vestrini et, al+, Arz mouth e
im-Forsch, 16. 59 (1966)
reported that 1-benzyl-5-(3-dimethylaminoglofoxy)indazole hydrochloride is inactive in early inflammation. This has become a practical medicine as penmine hydrochloride.

U.S. Pat. No. 3,681,382 discloses an ω-aminoalkyl group in which the hydrogen on the nitrogen atom in the 1st position is substituted with an aryl group and the 3rd position is substituted with an ω-aminoalkyl group (or with the nitrogen atom containing up to 5 carbon atoms). an ω-heteroaminoalkyl group or an ω-aminoalkylamide group substituted in the 3-position (or an ω-heteretary aminoalkylamide group having up to 5 carbon atoms) The radical 3-aminoindazole derivatives have been described and disclosed for use as anti-depressants and anti-inflammatory agents, but pharmacological cheaters have not been disclosed.

Moreover, it has not yet become a practical medicine.

As mentioned above, several indazole derivatives have been described in the chemical literature. However, as disclosed in the present invention, each hydrogen atom bonded to the nitrogen atom together with R at the 1st position and the amine group at the 3rd position is a ta ω-aminoalkyl group (or 6 atoms together with its adjacent nitrogen atom). Indazole derivatives of general formula (I) substituted with ω-heteroaminoalkyl groups having up to carbon atoms have not been contemplated by the prior art prior to the present invention. Compound # shown by 〇)! ; lA is, for example, 3-phthalimidoindazole obtained by reacting 3-aminointazole with phthalic anhydride, and with the general formula
1-(Aminoalkyl)-3-phthalimidoindazole is produced by reacting with ω-logenoalkylamine represented by (X represents a halogen atom selected from J, Br and 1). This is diluted with hydrazine hydrate.
The protective group of the amino group at the position is removed to obtain 1-aminoalkyl-3-aminoindazole.

The initial solvent for the reaction between 3-aminoindazole and phthalic anhydride includes dioyasane, ether,
A polar organic solvent such as tetranohydrofuran, ethanol, ethylene glycol, acetonitrile, dimethyl sulfoxide, or dimethyl formamide is used, and the reaction temperature is from room temperature to 200°C, preferably from 60 to 150°C.

Next, as a reaction solvent for 3-phthalimidoindazole and ω-norochenoalkylamine, an aprotic polar solvent such as acetonitrile, dimethyl sulfoxide, or dimethyl formamide is used, and the generated hydrogen halide is acid-receptive. For example, tertiary amines such as triethylamine, alkali metal carbonates such as potassium carbonate, alkali metal bicarbonates such as sodium hydrogen carbonate, and alkali metal hydroxides such as IJium hydroxide are used. The reaction temperature is from room temperature to 200°C, preferably from 80 to 120°C.

&'L as the final reaction solvent for "-(aminoalkyl)-3-phthalimidoindazole and hydrazine hydrate,
For example, alcohols such as methanol and ethanol, glycols such as ethylene glycol and propylene glycol, diglyme triethanolamine, etc. are used, and the reaction is preferably carried out under water cooling. General formula (I) could be obtained by reacting 1-aminoalkyl-3-aminoindazole and ω-710 genoalkylamine in the presence of an acid acceptor for hydrogen halide.

As the reaction solvent, for example, aprotic polar solvents such as acetonitrile, dimethyl sulfoxide, dimethylbormamide, or alkanols such as methanol, ethanol, glopanol, isoglobanol, n-butanol are used, and the generated halogen is Examples of acid acceptors for hydrogen chloride include tertiary amines such as triethylamine, alkali metal carbons such as potassium carbonate, alkali metal bicarbonates such as sodium hydrogen carbonate, alkali metal hydroxides such as sodium hydroxide, etc. is used,
The reaction temperature is room temperature to 200°C, preferably 80 to 120°C.
The starting compounds required for producing the 3-disubstituted 3-aminointazoles derivatives of the present invention are generally known compounds, and -1f1 commercially available chemical reagents are used as starting compounds. , which can be easily synthesized by those skilled in the art using conventional methods of organic synthetic chemistry. For example, 3-aminoindazole has C,
Kwartler et-al, J Jmer.

Chem, Soc, 65, 1804 (194 nee 3)
It is easily produced by the general synthetic method described below in VC@N, according to the method described in 1. On the other hand, the ω-halogenoalkylamine can be prepared from the corresponding enoxyalkyl aldehyde compound or the enoxyalkylketoalkyl halide compound by Marvelet, al.
,, J, #n, Chem, Soc,, 63 +
1894 (1941), Norris, J.
#n, Chem, Soc,, 3 B + 642
(1907), HoFranke and Lj, Pa.
rtch, J0Med, Chem. t9 + 6
4-5 (1966)% and C9S0MaC95Oet,
al,, J,Am,Chem.

Soc, 49, 2299 (1927), or from the corresponding dihalogenated alkyl compound, ki, COBY item 1. J, Ame
r, Chem, Soc,.

47.1134 (1925) and ClSoMaC15Oe
t,al,,J.

7der, Chem, Soc,, 49 +2299
(1927).

In addition, the compound represented by general 2) of the present invention can be synthesized by the reaction formula (1), which is another method.

(IV) (V) By reacting 1-aminoalkyl-3-halogenoindazole (IV) with an aminoalkylamine compound (V) in the presence of an acid acceptor for the generated hydrogen halide. Obtainable.

(W, W in the formula represent the same meanings as above,
represents a halogen atom selected from CL, Br and ■. ) As a reaction solvent, for example, an aprotic polar solvent such as acetonitrile, dimethyl sulfoxide, or dimethyl formamide? and halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, and 1,2-dichloroethane are used, and acid acceptors for the generated hydrogen halides include, for example, tertiary amines such as pyridine and triethylamine, Alkali metal carbonates such as potassium carbonate, alkali metal bicarbonates such as sodium hydrogen carbonate, alkali metal hydroxides such as sodium hydroxide, etc. are used, and the reaction temperature is in the range of 0°C to 200°C. 35-120°C is preferred.

1-aminoalkyl- which is the starting compound of reaction formula (1)
3-halogenoindazole (IV) is obtained by reacting 3-halogenoindazole with an ω-halogenoalkylamine represented by the general formula W, X (wherein W, X represent the same meanings as above). .

Further, the compound represented by the general formula (I) of the present invention can be synthesized by the reaction formula (2), which is another method.

That is, 3-(aminoalkylamino)indazole (■1) and a halogenoalkylamine compound (W, X)
Compound (I) can be obtained by reacting the above in the presence of an acid acceptor for the generated hydrogen halide.

31- As the reaction solvent, aprotic polar solvents such as acetonitrile, dimethyl sulfoxide, and dimethyl formamide, and alkanols such as methanol, ethanol, propatool, butanol, etc. are used, and acid acceptance of the generated hydrogen halide is used. For example, tertiary amines such as pyridine and triethylamine, alkali metal carbonates such as potassium carbonate, alkali metal bicarbonates such as hydrogen carbonate, and alkali metal hydroxides such as IJium. The reaction temperature is 0 to 200°C, especially 80 to 120°C.
is preferred.

Further, the compound represented by the general formula (I) of the present invention can be synthesized by the reaction formula (3), which is another method.

(■) l N0w, (I) 32-2-amino-1-(aminoalkyl)benzamide (■
) and the halogenoalkylamine compound (W,
, Kwartler et, al., , J. , Am., 0
'hem, SOC,,65.

1804 (] 943) to produce compound (Ii).

As a reaction solvent in the step of reacting compound (Vl) and compound (W2X) in the presence of an acid acceptor, acetonitrile,
Aprotic polar solvents such as dimethyl sulfoxide, dimethyl formamide or methanol, ethanol,
Alkanols such as propatool, butanol are used as acid acceptors (e.g., pyridine, tertiary amines such as triethylamine, alkali metal carbonates such as potassium carbonate, hydrogen carbonate), and alkali metals such as IJium. Alkali metal hydroxides such as 11 um (bicarbonate, hydroxide) are used, and the anti-15 temperature is 0 to 2
The temperature is preferably 80 to 120°C.

The next step is to react with sodium nitrite in an aqueous medium.
The product (I) is obtained by nitrosation with hydrochloric acid and reduction with stannous chloride and hydrochloric acid. The temperature range used is -20~
20°C, particularly preferably 0 to 10°C.

The physiologically acceptable acid addition salts of the 1,3-disubstituted 3-aminoindazole derivatives of the present invention can be prepared by combining the organic base with various mineral acids to form non-toxic acid addition salts having pharmacologically suitable anions. and by treatment with an organic acid. For example, acid salts, i.e., hydrochlorides, hydrobromides, hydroiodides, sulfates or bisulfates, phosphates or acid phosphates, nitrates, formates, acetates, propionates, succinate, lactate, maleate, fumarate, malonate, oxalate, citrate or acid citrate, tartrate or bitartrate, malate, mucolate, gluconate, Benzoate, salicylate, naphthalene-1,5-disulfonate, ascorbate, phenylacetate, p-amine salicylate, methanesulfonate, p-amine salt, hydroxyethanesulfonic acid It is prepared simply by treatment with an acid forming salt, benzenesulfonate, p-toluenesulfonate 2, and saccharide. The above treatment can be carried out, for example, during the salt formation step by reacting with substantially equimolar amounts of the appropriate acid in an aqueous or suitable organic solvent such as methanol or ethanol.

The solid salt product is easily obtained by carefully evaporating the solvent.

All 1,3-disubstituted 3-aminoindazole derivatives of general formula (I) of the present invention can be used for therapeutic applications as specific anti-inflammatory agents and analgesics. Particularly compared to known 3-aminoindazole derivatives, it has a unique efficacy in reducing swelling caused by inflammation and suppressing the ulcerogenic side effects of the gastrointestinal tract of acidic non-steroidal anti-inflammatory drugs. In this respect, the compounds of the present invention show a clear difference. In many cases, the new compounds according to the invention are based on the known 3-
Is it significantly better than aminoindazole derivatives? Therefore, they have a decisive therapeutic advantage in suppressing certain types of inflammation 4).

The effects of the compounds of the present invention will be explained below based on various test results.

Anti-inflammatory activity was determined using a standard carrageenan-induced rat paw edema test.C.J., Winter et al., Proc.
, Soc, Exp.

Biol, Med, 111.544 (1962)) using the method of
Oral administration at a dose of 0 to 100IIIF has a significant (for example, 20IIIF) anti-edema effect in rats? It was measured by whether or not it appeared even if it was present. The test results are shown in Table 1.

Table 11, 3-position di-substituted 3-amino indazole @conductor
Inhibition of carrageenan-induced edema formation by hydrochloride (100 μ/4 oral administration)
As is clear from the comparison with the compounds R and (3), as well as the comparison between Comparative Example 2 and the compound (1) presented in the present invention. The inventors have found that a substituted amine group is absolutely necessary.

Ulcer formation t+: The compound of the present invention was orally administered at a dose of 100 cm per animal body weight to examine the frequency and intensity of gastric ulcers, but no gastric ulcers occurred. .

That is, a male α) Donryu thread rat weighs 150~
1602 was used for the experiment. All test drugs are 1%
Suspended in HCO-60, 1 per 100 tons of rat body weight
Oral administration was performed with the concentration adjusted so that the dose was -. 24 hours after administration of the test drug, the occurrence and severity of gastric ulcers in the rats were examined.

As a result, 1-(3-diethylaminopropyl)-3-
(3-piperidinopropylamino)indazole, a typical and preferred compound of the present invention, is 101J
The drug was administered once alone and daily for 5 days at a dosage level of 2 Iv/ky, and no gastric ulcers occurred in either case.

10,000. As is well known, do non-steroidal acidic anti-inflammatory drugs cause gastrointestinal side effects such as gastric ulcers when administered alone? Rub.

However, the present inventors discovered that 1,3 represented by general formula (I)
As a result of research on the combined use of disubstituted 3-aminoindazole derivatives or salts thereof and the above-mentioned nonsteroidal acidic anti-inflammatory drugs, it was found that the compounds of the present invention are effective in preventing ulcer formation in the gastrointestinal tract due to nonsteroidal acidic anti-inflammatory drugs. It was found to suppress the occurrence of sexual side effects.

That is, for example, when indomethacin is administered alone, 10q
/ positive dose level, intensity 1 tumor index 10.2111 m)
For example, 1-(3-diethylaminepropyl)-3-(3-piperidinopropylamino)indazole, i.e. Typical and preferred compounds are prepared at 100 W/g for a dose of indomethacin 10/g.
When used in combination at a dosage level of 1w = 40-, the frequency of gastric ulcers did not change, but the intensity was suppressed to an ulcer index of 3.8wtm.

Moreover, the novel 3-position disubstituted aminoindazole derivatives of the present invention have very low toxicity. Their acute toxicity in mice is 5 kg/kf of animal body weight when injected i.p.
It is between 0■ and 700■.

The present invention will be described below with reference to Examples, but the present invention is not limited to these Examples.

Example 1 1-(aminoalkyl)-3-aminoindazole is 3
- 1,3-phthalimidoindazole obtained by reacting phthalimidoindazole and a halogenoalkylamine salt in an aprotic polar solvent or alkanol in the presence of potassium carbonate is 3-aminoindazole 5.01. 6.68 f of phthalic acid was stirred in 50° C. of dioxane at 120° C. for 5 hours. After concentration under reduced pressure, ether 3011+7! Add and cool with ice water 3
Stirred for 0 minutes. The crystals were subjected to FI& and dried under reduced pressure to obtain 8.62 of 3-phthalimidoindazole (yield 87%).
.

IR(crn'):3310. 1790.1735
．． 1625NMR [a, (CD3)280]”
7.57 (m, 8H), 13.35 (bs, IH) Mass (si/e): 263 (M+, 100), 23
6 (M-27°17), 2] 9 (M-44,10)
, 2a7 (M-56, 3), 192 (M-71, 5),
179(M-84,5)3-aminoindazole is C,
E, Kwartler et, ;d,.

J, Am, Chem, Soc,, 65, 1804
(1943).

Halogenoalkylamine salts can be prepared from the corresponding phenoxyalkyl aldehyde or phenoxyalkylketoalkyl halide compounds at Marvelet, at.
, J.Am.Chem.Sac., 63.1894
(1941), Norris, J., Am, Ch.
ern, 5oc-, 38, 642 (1907), H.
Franke and R, Paltch, J 1M
ed, Chem, 9, 643 (1966)
Yohi C, S6Marvel et, al,, JJm,
Chem.

8oC0, Su, 2299 (1927), or the corresponding dihalogenated alkyl compounds H, C, Br1ll, J, Am, Che
m,SOC,,47.

1134 (1925) and C6S, Marvel et.
al,,J,A+n-Chem,Soc,,49
．． 2299 (1927).

3-phthalimidoindazole 8.02.1-(3-bromopropyl)diethylamine hydrobromide 962 and anhydrous potassium carbonate 12.69 were stirred in anhydrous dimethylformide at 120-580°C for 12 hours. After cooling, water 8
0g1! was added and extracted with ether. The ether layer was extracted three times with 2N hydrochloric acid. The hydrochloric acid layer was washed with ether, adjusted to pH 14 with potassium carbonate, and extracted three times with chloroform. The chloroform layer was dried with Glauber's salt, chloroform was distilled off under reduced pressure, and 1-(3-diethylaminopropyl)-
6.639 of 3-phthalimidoindazole was obtained (yield 58%).

11(,(as1″):3040,2960, ]
780, 1 7 30°62O Nllil <a, CD('t, l:0.93(t
, 6H), 2.34 (bm.

4H), 2.46(q, 4H1,4,25(t, 2H)
, 7.1s (rn t8H), Mass (m/e): 377 (M+1, 10
0), 304 (M-72, 47), 290 (M-8
6,97), 276 (M 100+78), 262
(M-114,65) Add 3.25 f of 1-(3-diethylaminopropyl)-3-phthalimido indazole to 70 g of ethanol, and add 2.5 g of 85% hydrazine under water cooling.
and stirred for 3 hours under water cooling. Filter the reaction solution 1.
Solution F was distilled off under reduced pressure, 20-ounces of water was added, and the mixture was extracted with chloroform. The chloroform layer was extracted with 2N hydrochloric acid water.

The aqueous hydrochloric acid layer was adjusted to pH 10 with potassium carbonate, extracted with chloroborm, dried over sodium sulfate, and the P solution was distilled off under reduced pressure to obtain 1-(
1.759 of 3-diethylaminopropyl)-3-aminoindazole was obtained (yield: 81 cm).

IR (cm= ): 3320.3220.2930
．． 2860.1625.160O NMRCa, CI) C/-3): 0.97 (t, 6H)
, 2', 34 (bm.

4H), 2.47 (Q, 4H), 4.25 (t, 2H)
, 5.00 (bs.

2H), 7.11 (m, 4H) Mass (r+v'e): 246 (M+,
100), 217 (M-29°71), 188 (M-
58, 51), 174 (M-72, 113), 160 (
M-86, 92), 146 (M-100, 138)] -
(] 3-Diethylaminopropyl-3-aminoindazole 4.02.3-Bromopropyldiethylamine aqueous bromide cumulative salt 9.02 anhydrous potassium carbonate 7.9f in anhydrous dimethylformamide 607! at 80°C for 12 hours After cooling, 80 ml of water was added and extracted with ether.

The ether layer was extracted three times with 2N hydrochloric acid. The hydrochloric acid layer was washed with ether, adjusted to pH 14 with potassium carbonate, and extracted three times with chloroform. The chloroform layer was recorded with Glauber's salt, and chloroborum was distilled off under reduced pressure. Zanfu na Alumina (20
0F) (developing solvent, chloroborm) l-(3-diethylaminopropyl)
3.052 of -3-(3-diethylaminopropylamino)intasol was obtained (yield: 52 cm).

IR (I/maX, Iyn'): 3305.3200
,2980.28υO1615 NMIL (J, CDC15): 0.
9 3 (', 1 2 H), 1.97 (
m.

4H), 2.50 (m, 81-1.), 4.13 (t
, 411), 7.27 (m.

41■) Mass (m/e, rel 1ntensit
y): 359 (M+, 100), 360 (
M+1.39), 330 (M-29,37), 30
1 (M-58, 21), 260 (M-99, 104)
, 246 (M-113,185) 1-(3-diethylaminoprobyl)-3-(3-diethylaminoprobylamino)intasol 302 was dissolved in 50% of absolute ethanol, and the dried hydrogen chloride residue was cooled with water] It was blown in. Furthermore, add anhydrous ether,
Precipitating crystal 'aj? The residue was taken and dried to obtain 1-(3-diethylaminepropyl)-3-(3-diethylaminoprobylamino)indazole dihydrochloride.

Elemental quality value Ct, Use N5 C14 calculated value C:
58.32 H: 9.09 N: 16.19 c
T bar 16.40 actual measurement value C: 58.21 H2 8.9
8 N: 16.30 Ct: 16.51 Example 12
~5 By the same method as in Example 1, 1-(3-diethylaminopropyl)-3- (3-diethylaminoprobylamino)indazole,
Fd o) 1-(3-diethylaminepropyl)-3-
(Aminoalkylamino)indazole was obtained.

The results are shown in Table 2, and the final results are shown in Table 3.

Table 2 49-Example 6 1-(3-piperidinopropyl)-3-mininoindazole 4202.3-bromopropyldiethylamine hydrobromide 8.98% synthesized in the same manner as in Example 1,
Anhydrous potassium carbonate 7.89f was stirred in anhydrous dimethylformamide 60°C at 80°C for 12 hours. Water after cooling 80-
was added and extracted with ether. The ether layer was extracted three times with 2N hydrochloric acid.

The hydrochloric acid layer was washed with ether, adjusted to pH 14 with potassium carbonate, and extracted three times with chloroform. The chloroform layer is
It was dried with Glauber's salt, and chloroform was distilled off under reduced pressure. The residue was chromatographed on alumina (200r) (developing solvent: chloroform) to obtain 1-(3-piperidinopropyl)-3-(3-diethylaminoprobylamino)indazole 3.11f (yield: 53 Article).

IR (″max, tYn″): 3320.3210.2
960.2820, 615 NM ((a + CDC-1-s)” o, 97
(t, 6H), 1.49 (m, 8H), 2.3
2 (m, l 01-i ), 2.41 (Q, 4H
), 4.15 (t, 4H), 7.20 (m, 4H) Mass (m/e, rel 1ntensit
y): 372 (M+, ]O0), 343(
~1-29,6]), 314 (84-58.79), 2
58 (M-114, 13F), 174 (M-198, 1
40) 1-(3-Piperidinopropyl)-3-(3-diethylaminopropylamino)indazole was dissolved in 50% of absolute ethanol, and dry hydrogen chloride gas was blown into the solution under water cooling. Furthermore, anhydrous ether was added, and the precipitated crystals were collected and dried to obtain 1-(3-piperidinopropyl)-3-(3-diethylaminopropylamino)indazole dihydrochloride.

Original X analysis value C22H3,N, Cz2 Calculated value C: 59.45 H: 8.84 N: 15
．． 76 (?j: 15.95 actual value C: 59.61
tl: 8.95 N:] 5.42 Ct:]
6.02 Examples 7 to 9 1-(3-
SO8 paste 1-(3-piperidinopropyl)-3-(aminoalkylamino)indazole was obtained in exactly the same manner as the preparation of SO8 paste 1-(3-piperidinopropyl)-3-(aminoalkylamino)indazole. The results are shown in Table 4, and the analysis results are shown in Table 5.

Table 4 Example 10 1-(3-piperidinobutyl)-3-aminoindazole 4,402.3-bromopropyldimethylamine hydrobromide 8.07t synthesized in the same manner as in Example 1, anhydrous potassium carbonate 7. 81 with anhydrous dimethylformamide 6
The mixture was stirred at 80° C. for 12 hours. After cooling, water 80%
- was added and extracted with ether. The ether layer was extracted three times with 2N hydrochloric acid. The hydrochloric acid layer was washed with ether, adjusted to pH 14 with potassium carbonate, and extracted three times with chloroform.

The chloroform layer was dried with Glauber's salt, and the chloroform was distilled off under reduced pressure. The residue was chromatographed on alumina (20Of) (developing solvent: chloroform),
1-(3-Piperidinobutyl)-3-(3-diethylaminopropylamino)indazole 3.11f was obtained.

IR (I'max, IM-): 3330.32
00.2970.2830,610 Me (a, CDCz,): 0.89 (m,
9H), 1.40 (m, 8H), 2.30 (m, 9) (
), 2.46 (Q, 4) (), 4.19 (t, 4H),
7.25 (nl, 41-1) Mass (m/e, rel 1ntensit
y): 386 (M+, 100), 357 (
M-29, 51), 328 (M-58, 33), 27
2 (M-114, 108), 188 (M-198, 11
3) 1-(3-piperisiptyl)-3-(3-diethylaminopropylamino)indazole3. OV was dissolved in 50% of absolute ethanol, and dry hydrogen chloride gas was blown into the solution under water cooling. Furthermore, add anhydrous ether,
The precipitated crystals were harvested and dried to obtain 1-(3-piperisiptyl)-3-(3-diethylaminopropylamino)indazole dihydrochloride.

Elemental analysis value COH41N! French calculation value C: 60.25 H: 9.01 N: 15
．． 27 Ct: 15.47 Actual value C: 60. OI
H:9-37 N:15.43 C4:15.1
9 Examples 11-13 In a similar manner to Example 1O, 1-(
Each of 1-(3-piperidinobutyl)-3-(aminoalkylamino)indazole of E was obtained in exactly the same manner as for 3-(3-diethylaminopropylamino)indazole.

The results are shown in Table 6, and the analysis results are shown in Table 7.

Table 6 55- 56-- Example 14 3.75 g of 1-(3-dimethylaminobutyl)-3-aminoindazole synthesized in the same manner as in Example 1, 3
-Bromopropyldiethylamine hydrobromide 8.98?
, anhydrous potassium carbonate (7.899 g) was stirred in 60 tnl of anhydrous dimethylformamide at 80° C. for 12 hours. After cooling, 80 parts of water was added and extracted with ether. The ether layer was extracted three times with 2N hydrochloric acid. The hydrochloric acid layer was washed with ether, adjusted to pn 14 with potassium carbonate, and diluted with chloroform to pn 14.
The extracted chloroform NII was dried with Glauber's salt, and the chloroform was distilled off under reduced pressure. The residue is alumina (20 oy
) to perform chromatography (developing solvent.

chloroform), 1-(3-dimethylaminobutyl)-
3.08f of 3-(3-diethylaminopropylamino)indazole was obtained (yield 57%).

1, [(('n1aX, crn'): 3310.
3200,2950.2810,62O NM几(a, CDCt, ): 0.95 (m, 9
H), 2.30 (rn.

13H), 2.46((1,4l-(), 4.17(
t, 4H), 7.15(m, 41(), Mass (m/e, rel 1ntensit
y): 345 (M+, 100), 317
(M-29,76), 288 (M-58,49), 2
74 (M-72,110), 260 (M-96,13
0) 1-(3-dimethylaminobutyl)-3-(3-diethylaminopropylamino)indazole 3.02 to absolute ethanol 50#+7! Dry hydrogen chloride gas was blown into the solution under water cooling. Furthermore, anhydrous ether was added, the precipitated crystals were collected, dried, and 1-(3
-dimethylaminobutyl)-3-(3-diethylaminopropylamino)indazole dihydrochloride.

Elemental analysis value C7°H, 7N, fake total % value C: 57.41 H: 8.91 N:
16.74 ct: 16.94 actual value C: 57.
27) 1:9.08 N:16.77 Ct:
16.88 Examples 15-17 A method similar to Example 14 was used to prepare 1-(3
-dimethylaminobutyl) 59- -5-(3-diethylaminopropylamino)intersol, and each obtained ε-horn 1-(3-dimethylaminobutyl)-3-(aminoalkylamino)indazole. Ta.

The results are shown in Table 8, and the analysis results are shown in Table 9.

Table 8 61-60 - Example 18 Synthesized in the same manner as in Example 1 -(3-morpholinopropyl)-3-aminoindazole 4,217.3-
Bromopropyl diethylamine hydrobromide salt 8.98? ,
7.89 r of anhydrous potassium carbonate was stirred in 6 o of anhydrous dimethylformamide at 80°C for 12 hours. Water after cooling 8
0m was added and extracted with ether. The ether layer was extracted three times with 2N hydrochloric acid. The hydrochloric acid layer was washed with ether, adjusted to pH 14 with potassium carbonate, and extracted three times with chloroform. The chloroform layer was dried with Glauber's salt, and the chloroform was distilled off under reduced pressure. The residue was chromatographed using alumina (20(1')) (developing solvent: chloroform),
1-(3-morpholinopropyl)-3-(3-jethylaminopropylaminofindazole 3.5Or was obtained (yield 58%) 1, II also ('maX, c1n')
: 3400.3225.2950゜2880.163
O NhilL (δ, CL)Ct3): 0.99f t
, 6H), 1.60 (m.

2H), 2.44 (m, 14H), 3.59 (t
, 4H), 4.25(t, 4H), 7.2o(m, 4H
), M;13! l (m/e, rel 1nte
): 373 (M+, ] 00)
, 301 (M-72, 87), 287 (M-86,
116), 273 (M-100, 73), 259 (M
-114,57) l-(3-morpholinopropyl)-3
3.01 of -(3-diethylaminopropylamino)indazole was dissolved in 50 ttzl of absolute ethanol, and dry hydrogen chloride gas was blown into this under water cooling. Furthermore, anhydrous ether is added, the precipitated crystals are taken off, and after drying,
1-(3-Morpholip[I-bil)-3-(3-diethylaminopropylamino)indazole dihydrochloride was obtained, elemental analysis value C,,'rW3 N, C4 calculated value C:5
6.50 )]: 8.35 N: 15.69 (
C: 15.8 s Actual value C: 5642 I-1: 8
．． 17 N: ] 5.81 Ct: 15.93 Examples 19 to 21 By the same method as in Example 8, 3-bromopropyldiethylamine hydrobromide 8.98f (bF) was prepared by electrofiltration ω -Other than using halogenoalkylamide 7m,
In exactly the same manner as 1-(3-morpholinopropyl)-3-(3-diethylaminopropylamino)indazole, 1-(3-morpholinopropyl)-3-(
%minoalkyl-amino)indazole was obtained.

65-Example 22 1-(3-pyrrolidinoprobyl)-3-aminoindazole 4.22f,3- synthesized in the same manner as in Example 1
Promopropylhomobiberidine hydrobromide 9.94f,
Anhydrous potassium carbonate (7.89F) was stirred in anhydrous dimethylformamide (60°C) at 80°C for 12 hours. Water after cooling 8
0II+7! was added and extracted with ether. The ether layer was extracted three times with 2N hydrochloric acid. The hydrochloric acid layer was washed with ether, adjusted to pl-114 with potassium carbonate, and extracted three times with chloroform. The chloroform layer was dried with Glauber's salt, and the chloroform was distilled off under reduced pressure. Alumina residue (2009)
Chromatography was carried out using (developing medium, chloroform), 1-(3-pyrrolidinoprobyl)-3-(3
- Homopiperidinoprovir (mino) indazole 6.4
72 was obtained (yield 56%).

IR('maX, cIn-): 3310.3210
．． 2970.2860, 620 Oku (a, CD (13): 1.63 (m, 1
41-1), 2.11 (bs.

2H), 2.51 (m, 12H), 4.20 (t, 4H
), 7.11 (m.

4H), Mass (m/e): 383 (M+), 313
(M-70), 299 (M-84), 285 (M-98
), 271 (M-112) 1-(3-pyrrolidinopropyl)-3-(3-homopiperidinopropylamino)indazole 3.02 was dissolved in absolute ethanol 50-
Dry hydrogen chloride gas was blown into this under water cooling. Furthermore, anhydrous ether was added, precipitated crystalline P was collected, and after drying, 1-(3-pyrrolidinoprobyl)-3-(3-homopiperidinopropylamino)indazole dihydrochloride was obtained.

Elemental analysis value: C73. N, C4 Calculated value C: 60.52 H: 8.61 N: 15
．． 34 cz:i5.53 Actual value C:60.49
H: 8.68 N: 15.47 C/Hot 15.3
6 Example 23.24 In a similar manner to Example 22, 1 was prepared, except that instead of 3-bromopropylhomopiperidine hydrobromide 9.949, the corresponding ω-halogenoalkylamine salt was used.
-(3-pyrrolidinopropyl)-3-(3-homopiperidinopropylamino)indazole,
1-(3-pyrrolidinoprovir) -3-( for each of λ
Aminoalkylamino)indazole was obtained.

The results are shown in Table 12, and the analysis results are shown in Table 13.

Table 12 67-6 68- Continued from page 1 oInt. C1.3 Identification code Internal office reference number (C 07 D 401/12
-231100
7133-4 C211100)
7138-4C@ Inventor: Sugiura Tasuke, Asahi Kasei Kogyo Co., Ltd., 6-4100 Asahi-cho, Nobeoka-shi Inventor: Hironori Youkubo, Asahi Kasei Kogyo Co., Ltd., 6-4100 Asahi-cho, Nobeoka-shi Inventor: Takanori Sone Nobeoka Asahi-cho 6-4100 Asahi Kasei Kogyo Co., Ltd.

Claims (1)

[Claims] (1) General formula (1) is a methylene chain having up to 6 carbon atoms, and the hydrogen atoms bonded to the carbon atoms in the chain are further substituted with a lower alkyl group. RQK and/or R may be a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, or a heterocycle or nitrogen atom having up to 6 carbon atoms together with the adjacent nitrogen atom. and together with oxygen atoms form a heterocycle having 4 carbon atoms,
and the hydrogen atom bonded to one or more carbon atoms or nitrogen atoms of the heterocycle is further substituted with a lower alkyl group, hydroxy group, or halogen atom to form a methylene chain, and is bonded to the carbon atom of the chain part. The hydrogen atom may be further substituted with a lower alkyl group, and zgyopi/or toshi is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, or 6 to 6 carbon atoms together with the adjacent nitrogen atom. forms a heterocycle having up to 4 carbon atoms or a nitrogen atom Z and an oxygen atom, and hydrogen bonded to one or more carbon atoms or nitrogen atoms of the heterocycle Atoms may be further substituted with lower alkyl groups, hydroxy groups or halogen atoms. ) is a group. ] 3-aminoindazole derivative shown by ? and 7 physiologically acceptable acid addition salts. (2) -Y- or-(Cl-1,), -1(CHt
) 3-1-(CH2ru, the Gen atom in the claims is one selected from the group consisting of:) pyrrolidino, substituted pyrrolidino, homopiperidino, substituted homopiperidino,
The compound l according to claim 3, which is one selected from the group consisting of morpholino, substituted morpholino, piperazino, and substituted piperazino. (5) The compound according to claim 3, wherein the substituted piperidino is methylpiperazino. (6) Claim 5 in which methylpiperidino is 2-methylpiperidino and -Y- is -(CH2)3-
Compound wIa (7) The compound according to claim 3, wherein the t% piperidino is dimethylpiperidino. (8) The compound according to claim 7, wherein dimethylpiperidino is 2,6-dimethylpiperidino and -Y- is -(CH2)s-. (9) The compound according to claim 3, wherein the substituted piperidino is hydroxypiperidino. (10) The compound according to claim 9, wherein hydroxypiperidino is 4-hydroxypiperidino and -Y- is -((l(2), -). However, the compound is substituted piperidino or chloropiperidino. The compound according to claim 3. <12) Chloropiperidino is 4-chloropiperidino, and -4 -Y- is -(CHz)s-te, &le% Tht'
n Claim No. 3, which is No. 11 of the desired scope, 41
! v) Compounds. (The compound according to claim 3, wherein the substituted piperazino is methylpiperazino. (7) The methylpiperazino is 4-methylpiperazino,
-Y-?- (CH2)! - Claim 16. The compound according to claim 1 or 2, which is a lower alkyl group having the characteristic r+-. 09) The lower argyl group is an ethyl group, and -Y- is -(CH
2) An item selected from the group consisting of 3-1-CH, CH, and CH-. A compound according to claim 18. (20) The lower alkyl group is a butyl group, and -Y- is -(C
Hz) s-. C21) The lower alkyl group is a methyl group, and -Y- is -(C
)(2)3-. -CH2CH2CH- is one selected from the Naro group. A compound according to claim J8. 2) -Z- is -(CH2)2-1 (CHz)s-
1(CH2)6. The substituent group k) selected from the group consisting of: a lower argino L group, a hydroxy group, or a halogen atom; ), pyrrolidino, substituted pyrrolidino, homopiperidino, substituted homopiperidino, morpholino, substituted morpholino, piperazino, substituted piperazino (CHt) a-1-CH,C2H
,C)(-1-e)l, C1-L2CH-garabuko I CH3CH. 24. The compound according to claim 23, which is a selected member of the group C)-I3CH3. (25) The compound according to claim 23, which is it-substituted piperidinomethylpiperidino. C26) Methylpiperidino is 2-methylpiperidino,
Claim 25 which is -2- or -(CHz)s-
Compounds described in Section. 24. The compound according to claim 23, wherein C27) substituted piperidino is dimethylpiperidino. 28. The compound according to claim 27, wherein dimethylpiperidino is 2,6-dimethylpiperidino and -Z- is -(CHt)3-. (29) The compound according to claim 23, wherein the piperidino is human and is 1-xypiperidino. (30) The compound according to claim 29, wherein hydroxypiperidino is 4-hydroxypiperidino and -Z- is -(CHz)s-. (31) The compound according to claim 23, wherein the substituted piperidino is chloropiperidino. 02) Chloropiperidino is 4-chloropiperidinote, -
The compound according to claim 23, wherein Z- is -(CH2)s-. (36) i! 24. The compound of claim 23 which is substituted piperazinomethylpiperazino. (37) Methylpiperazino or 4-methylpiperazino,
Claim 3 in which -Z- is -(CHt)s-
6. The compound according to claim 1 or 22, which is a lower argyl group having 6. (39) The lower alkyl group is an ethyl group, -Z- or -(C
1-12) s-. 39. The compound according to claim 38, which is one of the above. (40) The lower alkyl group is a butyl group, and -Z- is '(C
39. The compound according to claim 38, which is H2) s-. (41) The lower alkyl group is a methyl group, -Z- or -(C
CH is one selected from the group consisting of H2)s-CH, C)l, CH-. and - are ethyl groups, and -Ys and -Z- are -
(CH2)3-, and -Z- is selected from the group consisting of -(CH,)3-1-(CH2)6- or -C)i2CH,CH- CM is one of the most popular commercials. is an n-butyl group, -Z- is -(C)3-, and -2- is -(CH2)! - The claim scope is -(CH2)s-1-(C)(2)a-5-CH,CM
2CH- Karana CH. The first claim is one selected from the group consisting of:
-Z- is -(cHt)3-
The compound according to claim 1, which is one selected from the group consisting of (C)3-1-CH2C1l□C1-1-,
Claims CH in which -Z- is -CH, CM, CH-
. I(, crab I-thyl group Te1>'l, -Z-car (
C)I, )3, -CI-(2CH,CH-CH. Claims which are one selected from the group consisting of) and -Z-car(ci(i)s-1-CH ,C)(2
There is a claim in which Cf (one selected from the group consisting of -3), and there is a claim in which Z- is -(C)I,)3-, and -Z- is -(CK)3-, there is a claim where -Z- is -(C)1211-, and -Z- or -(CH2)! - The compound according to claim 1, which is Claim 1 in which -Z- is -(CHt)3-
The compound according to claim 1, wherein -2 or -(CH2)s-, and -Z is -(CH2)3-. (59) 3-phthalimidoindazole obtained by the reaction of 3-aminoindazole and phthalic anhydride, the moiety is a methylene chain with up to 6 carbon atoms, and the hydrogen atom bonded to the carbon atom of the chain moiety may be further substituted with a lower alkyl group, R+ and/or R+ being a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, or containing up to 6 carbon atoms together with the adjacent nitrogen atom. or together with the nitrogen atom and the oxygen atom form a heterocycle having 4 carbon atoms, and the hydrogen atom bonded to one or more carbon atoms or nitrogen atoms of the heterocycle is further a lower alkyl group, It may be substituted with a hydroxy group or a halogen atom. ), where X represents a halogen atom selected from α, Bru, and ■. ] By inversely mixing with hydrazine hydrate, which is a compound of the general formula (1), obtained by the reaction of the general formula (m), which is a methylene chain of up to 6, and bonded to the carbon atom of the chain part. However, the hydrogen atom may be further substituted with a lower alkyl group. form a heterocycle with up to 6 carbon atoms or 4 carbon atoms with 8 nitrogen atoms and 4 oxygen atoms, and bonded to one or more carbon atoms or nitrogen atoms of the heterocycle. The hydrogen atoms present may be further substituted with lower alkyl groups, hydroxy groups, or halogen atoms.)
is a group represented by the following formula, where X represents a halogen atom selected from α, Br and ■. ] The general formula (
A method for producing the compound represented by I). (60) When producing the compound represented by the general formula (I) according to claim 1 or the general formula σl according to claim 59, a non-containing compound such as dimethylformamide is used as a reaction solvent. protic solvents or alkanols such as ethanol as acid acceptors, tertiary amines such as triethylamine or alkali bound carbonates such as potassium carbonate or alkali metal bicarbonates such as sodium bicarbonate; The reaction temperature is 0℃ to 2
Using the temperature of 00°C, the general formula (
The method according to item 59, in which the compound represented by Ill) is produced using an alkanol such as ethanol as a reaction solvent and a reaction temperature of -20°C to 20°C.