JPH0427236B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to therapeutically novel and useful 3-substituted indazole derivatives, more particularly for reducing inflammatory conditions and inhibiting the gastrointestinal ulcerogenic side effects of acidic non-steroidal anti-inflammatory drugs. A series of novel 3-substituted indazole derivatives that are particularly valuable in their ability to 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 various steroid hormone compounds such as corticosteroids, or acidic non-steroidal substances such as phenylbutazone, indomethacin, etc. but,
Furthermore, in the development of new, better, and improved anti-inflammatory agents, little is known about basic agent effects. However, basic nonsteroidal drugs are attractive in that, in addition to the usefulness that acidic nonsteroidal compounds usually have, they have almost no gastrointestinal disorder side effects, which are the disadvantages of acidic nonsteroidal compounds. The present inventors have demonstrated that certain novel 3-substituted indazole derivatives are of great potential as non-steroidal therapeutic agents for alleviating inflammatory conditions and further suppressing the gastrointestinal ulcerogenic side effects of acidic non-steroidal anti-inflammatory drugs. The present inventors have discovered that the present invention is useful for the following purposes, and have completed the present invention. That is, the novel compound of the present invention has the general formula () (In the formula, n is an integer from 1 to 6, and Z is -(CH ₂ -)
₃ , - (CH ₂ -) ₄ ,

【formula】

【formula】

[Formula] or -CH ₂ OCH ₂ -. When Z is -(CH ₂ -) ₃ , W and Y are methyl groups, and when Z is otherwise, W and Y are hydrogen atoms. ) and their physiologically acceptable acid addition salts. Examples of the novel 3-substituted indazole derivatives of the present invention include the following. (1) 3-(2-homopiperidinoethylamino)indazole (2) 3-(3-homopiperidinopropylamino)
Indazole (3) 3-(2-morpholinoethylamino)indazole (4) 3-(3-morpholinopropylamino)indazole (5) 3-[2-(4-hydroxypiperidino)ethylamino]indazole (6) 3-[3-(4-hydroxypiperidino)propylamino]indazole (7) 3-[2-(3-hydroxypiperidino)ethylamino]indazole (8) 3-[3-(3-hydroxypiperidino)propylamino]indazole (8) Peridino)propylamino]indazole (9) 3-[2-(2,6-dimethylpiperidino)ethylamino]indazole (10) 3-[3-(2,6-dimethylpiperidino)propylamino] Indazole(11) 3-[2-(4-chloropiperidino)ethylamino]indazole(12) 3-[3-(4-chloropiperidino)propylamino]indazole and their hydrobromic and hydrochloric acid addition salts. It is a legally acceptable acid addition salt. All of these specific compounds have high anti-inflammatory activity and suppress the gastrointestinal ulcerogenic side effects of acidic non-steroidal anti-inflammatory drugs. 3-aminoindazole is Bamberger,
First reported in Liebigs Ann., 305 , 339 (1899). U.S. Pat. No. 3,133,081 describes a 3-aminoindazole derivative in which the phenyl ring is substituted with a halogen or a trifluoromethyl group, and the 3-position is substituted with an amino group or the hydrogen of the amino group is substituted with a lower alkyl group. and discloses its use as a central nervous system active and muscle relaxant, analgesic, antipyretic, and tranquilizer. However, pharmacological data have not been disclosed. Moreover, it has not yet become a practical medicine. Silvestrini et.al., Arzneim-Forsch. 16 , 59
(1966) reported that 1-benzyl-3-(3-dimethylaminopropoxy)indazole hydrochloride is effective against early inflammation. This has become a practical medicine as benzydamine hydrochloride. U.S. Pat. No. 3,681,382 discloses an ω-aminoalkyl group (or an ω-aminoalkyl group having up to 5 carbon atoms with its nitrogen atom) in which the hydrogen on the nitrogen atom in the 1st position is substituted with an aryl group and the 3rd position is substituted. 3-, which is an ω-aminoalkylamide group substituted in the 3-position (or an ω-heterocyclicaminoalkylamide group having up to 5 carbon atoms together with its nitrogen atom);
Aminoindazole derivatives have been described and disclose their use as anti-depressants and anti-inflammatory agents. However, pharmacological data have not been disclosed.
Moreover, this has not yet become a practical medicine. As mentioned above, several 3-substituted indazole derivatives have been described in the chemical literature. but,
As disclosed in the present invention, the hydrogen atom is bonded to the nitrogen atom at the 1st position, and the 3rd position is a substituted 6
3-substituted indazole derivatives of the general formula () which are ω-heterocyclic aminoalkyl groups having up to 3 carbon atoms have not been contemplated by the prior art prior to the present invention. The compound represented by the general formula () of the present invention includes, for example, 3-aminoindazole and (In the formula, Y, Z, and W represent the same meanings as above, and x represents a halogen atom selected from Cl, Br, and I.) I was able to obtain it by doing so. Examples of reaction solvents include acetonitrile,
Aprotic polar solvents such as dimethyl sulfoxide and dimethylformamide, or alkanols such as methanol, ethanol, propanol, isopropanol, and n-butanol are used, and as acid acceptors for the generated hydrogen halide, 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 sodium hydroxide are used, and the reaction temperature ranges from room temperature to 200°C.
Particularly preferred is 80 to 120°C. Most of the starting compounds required to produce the 3-substituted indazole derivatives of the present invention are known compounds and can be easily synthesized by a person skilled in the art using commercially available chemical reagents as starting compounds using conventional methods of organic synthetic chemistry. . For example, 3-aminoindazole
CEKwartler et.al., J.Amer, Chem.Soc., 65 ,
1804 (1943) according to the method described in
It is easily produced by general synthetic methods that have been previously discussed. On the other hand, ω-halogenoalkylamine can be obtained from the corresponding dihalogenated alkyl compound by HCBrill, J.Amer, Chem.Soc., 47 , 1134
(1925) and CS Marvel et.al., J. Amer, Chem.
Soc., 49 , 2299 (1927). Further, the compound represented by the general formula () of the present invention is produced by another method, Reaction Formula (1).
That is, 3-halogenoindazole () and
It could be obtained by reacting an aminoalkylamine compound () in the presence of an acid acceptor for the hydrogen halide generated. (Y, Z, and W in the formula have the same meanings as above, and x represents a halogen atom selected from Cl, Br, and I.) Examples of reaction solvents include aprotic polar solvents such as acetonitrile, dimethylsulfoxide, and dimethylformamide, and chloroform, methylene chloride, carbon tetrachloride, 1,2
-A halogenated hydrocarbon solvent such as dichloroethane is used, and the acid acceptors for the generated hydrogen halide include, for example, tertiary amines such as pyridine and triethylamine, alkali metal carbonates such as potassium carbonate, and alkali metal carbonates such as sodium hydrogen carbonate. Metal bicarbonates, alkali metal hydroxides such as sodium hydroxide, etc. are used, and the reaction temperature is carried out in the range of 0°C to 200°C, particularly preferably 35 to 120°C. 3-halogenoindazole, which is a starting compound required for producing the compound represented by the general formula () of the present invention, is used in Org.Syntheses, Coll.vol., 475
(1955). Aminoalkylamine compound () which is the other raw material compound
from the corresponding halogenoaminoamine compound
It could be produced by applying the general synthesis method described in Org. Syntheses, Coll. Vol., 83 (1943). Furthermore, the compound represented by the general formula () of the present invention can be synthesized by another method, Reaction Formula (2). From 2-amino-1-(aminoalkyl)benzamide (), Org.Syntheses, Coll.Vol.,
It can be synthesized by applying the method described in 475 (1955). In this method, compound () is treated with sodium nitrite and hydrochloric acid in an aqueous solvent, reduced with sulfur dioxide, and after treatment with hydrochloric acid, the product is obtained. The temperature range used is -20 to 20°C, particularly preferably 0 to 10°C. Physiologically acceptable acid addition salts of the 3-substituted indazole derivatives of the present invention are prepared by treating the organic base with various mineral and organic acids that form non-toxic acid addition salts with pharmacologically appropriate anions. Manufactured by For example, the following acid salts, i.e.
hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, phosphate or acid phosphate, nitrate, formate, acetate, propionate, succinate, lactate, Maleate, fumarate, malonate, oxalate, citrate or acid citrate, tartrate or bitartrate, malate, mucolate, gluconate, benzoate, salicylurate , naphthalene-1,5-disulfonate, ascorbate, phenyl acetate, p-aminosalicylate, methanesulfonate, ethanesulfonate, hydroxyethanesulfonate, p-toluenesulfonate and succalate, etc. It is produced simply by treatment with an acid that forms. The above treatment can be carried out, for example, by acting in the salt formation step with substantially equimolar amounts of the appropriate acid in an aqueous solvent or a suitable organic solvent such as methanol or ethanol. The solid salt product is easily obtained by carefully evaporating the solvent. All 3-substituted indazole derivatives of the general formula () of the present invention can be used in therapeutic applications as specific anti-inflammatory agents and analgesics. In particular, compared to known 3-aminoindazole derivatives, it has a specific efficacy in reducing edema caused by inflammation and inhibiting the ulcerogenic side effects of acidic non-steroidal anti-inflammatory drugs in the gastrointestinal tract. In certain respects, the compounds of the invention exhibit distinct differences. In many cases,
The novel compounds according to the invention are considerably superior to the known 3-aminoindazole derivatives and therefore have a decisive therapeutic advantage in the inhibition of certain inflammations. Hereinafter, the effects of the compounds of the present invention will be explained based on various test results. Anti-inflammatory activity was determined using the standard carrageenan derivative rat paw edema test [CAWinter et.al., Proc.Soc.
Exp. Biol. Med., 111 , 544 (1962)].
Administered orally at a dose of 100 mg, significant (e.g. 30
%) was determined by whether or not the edema inhibition effect appeared in rats. The test results are shown in Table 1.

[Table] In Table 1, Comparative Example 1 is disclosed in U.S. Patent No. 3133081.
The phenyl ring of the compound disclosed in 1. is not substituted with a halogen or trifluoromethyl group, but the above-mentioned (2), (4), (6),
As is clear from the comparison with compounds (8), (10), and (12),
The inventors have found that a substituted amino group in the ω position of the compounds of the invention is absolutely necessary. Ulcerogenicity was determined using the following method:
The compound of the present invention was administered orally at a dose of 100 mg, and the frequency and intensity of gastric ulcers were investigated.
No gastric ulcers occurred. In other words, the weight of male rats
150 to 160 g was used in the experiment. All test drugs were suspended in 1% HCO-60 and administered orally at concentrations adjusted to a dose of 1 ml per 100 g of rat body weight. 24 hours after administration of the tested drug, the occurrence and severity of gastric ulcers in the rats were examined. As a result, 3-[3-(4-hydroxypiperidino)propylamino]indazole, a typical and preferred compound of the invention, was found to cause gastric ulcers when administered alone at a dosage level of 100 mg/Kg. There were no occurrences. On the other hand, as is well known, non-steroidal residual anti-inflammatory drugs cause gastrointestinal side effects such as gastric ulcers when administered alone. However, as a result of research into the combined use of the 3-substituted indazole derivative represented by the general formula () or its salt and the above nonsteroidal acidic anti-inflammatory drug, the present inventors found that the compound of the present invention It was found that the occurrence of ulcer-forming side effects in the gastrointestinal tract caused by steroidal acidic anti-inflammatory drugs was suppressed. That is, for example, indomethacin, when administered alone, at a dose level of 20 mg/Kg,
For example, 3-[3-(4-hydroxypiperidino)propylamino]indazole, a typical example of the present invention and a suitable compound for a dose of indomethacin 20 mg/Kg.
When used together at a dosage level of 100 mg/Kg, the frequency of gastric ulcers does not change, but the intensity increases to an ulcer index of 7.8 mm.
was suppressed. Furthermore, the novel 3-substituted indazole derivatives of the present invention have very low toxicity. Their acute toxicity in mice is as follows: 1 kg of animal body weight injected i.p.
Between 50mg and 700mg per dose. The present invention will be described below with reference to Examples, but the present invention is not limited to these Examples. Example 1 3-(aminoalkylamino)indazole is
It could be obtained by reacting 3-aminoindazole and a halogenoalkylamine salt in an aprotic polar solvent or alkanol in the presence of potassium carbonate. 3-Aminoindazole was described by CEKwartler et.
It was synthesized according to the method described in J. Am. Chem. Soc., 65 , 1804 (1943). Halogenoaminoamine salts are available from HCBrill, J.Am.
Chem.Soc., 47 , 1134 (1925) and CSMarvelet.
It was synthesized according to the method described in J. Am. Chem. Soc., 49 , 2299 (1927). 3-aminoindazole 4.0g, 1-(2-bromoethyl)homopiperidine hydrobromide 8.6g,
8.3 g of anhydrous potassium carbonate and 80 ml of dry dimethylformamide were mixed and stirred at 80° C. for 24 hours. After concentration under reduced pressure, 100 ml of chloroform and 50 ml of water were added to the residue to separate the layers. The chloroform layer was dried with Glauber's salt and evaporated under reduced pressure. The residue was chromatographed on alumina (200 g) (developing solvent: chloroform) to obtain 4.58 g (yield 59%) of 3-(2-homopiperidinoethylamino)indazole. IR (νmax, cm ^-1 ) 3320, 3170, 3080, 2950,
2870, NMR (δ, CDCl ₃ ) 1.52 (bs, 8H), 2.43 (bs,
4H), 2.75 (t, 2H), 4.33 (t, 2H), 5.21
(bs, 1H), 7.09 (m, 4H) Mass (m/e, vol intensity) 258 (M, 100),
2.59 (M+1, 31), 132 (M-126, 210), 116
(M-142, 290), 104 (M-154, 452) 4.0 g of 3-(2-homopiperidinoethylamino) indazole was dissolved in 50 ml of absolute ethanol,
Dry hydrogen chloride gas was blown into this under ice cooling.
Furthermore, anhydrous ether was added, and the precipitated crystals were collected and dried to obtain 3-(2-homopiperidinoethylamino)indazole hydrochloride. Elemental analysis value C ₁₅ H ₂₃ N ₄ Cl Calculated value C: 61.11 H: 7.86 N: 19.00 Cl: 12.03 Actual value C: 60.88 H: 7.79 N: 19.21 Cl: 12.12 Examples 2 to 12 Same method as Example 1 The procedure was exactly the same as for 3-(2-homopiperidinoethylamino)indazole, except that the corresponding ω-halogenoalkylamine salt was used instead of 8.6 g of 1-(2-bromoethyl)homopiperidine hydrobromide. Thus, each 3-(aminoalkylamino)indazole was obtained. The results are shown in Table 2, and the analysis results are shown in Table 3.

【table】

【table】

【table】

【table】

【table】

Claims (1)

[Claims] 1 General formula () (In the formula, n is an integer from 1 to 6, and Z is -(CH ₂ -)
₃ , -(CH ₂ -) ₄ , [Formula] [Formula] [Formula] or -CH ₂ OCH ₂ -. When Z is -(CH ₂ -) ₃ , W and Y are methyl groups, and when Z is otherwise, W and Y are hydrogen atoms. ) and physiologically acceptable acid addition salts thereof. 2. The compound according to claim 1, wherein n is 2 or 3. 3. The compound according to claim ₂ , wherein Z is _-CH2OCH2- . 4. The compound according to claim 3, wherein n is 3. 5. The compound according to claim 2, wherein Z is -( _CH2- ) ₃ . 6. The compound according to claim 5, wherein n is 3.