JPH03188064A - 2-phenylindole derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 is H or lower alkyl; R2 to R4 are H, halogen, lower alkyl, lower alkoxy, lower alkanoyloxy, aralkyloxy, lower alkylthio, CN, NO2 or -NR6R7 (R6 and R7 are H, lower alkyl, acyl, etc.); R5 is H or lower alkyl) and its salt. EXAMPLE:5-Acetylamino-2-(3-t-butyl-4-hydroxy-5-methylphenyl)-3-methyli ndole. USE:An anti-allergic agent, antirheumatic agent, antithrombogenic agent, remedy for arteriosclerosis, cerebral circulation improver, immuno-regulator, remedy for dermatic psoriasis, etc. PREPARATION:The objective compound can be produced by reacting a phenylhydrazine compound of formula II (R12 is lower alkyl or phenylthio) with a compound of formula III, cyclizing the resultant compound of formula IV by treating with polyphosphoric acid, etc., to obtain a compound of formula V and, if R12 is phenylthio, removing the group from the product.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 2-phenylindole derivatives,
More specifically, in the formula, R represents a hydrogen atom or a lower alkyl group; R3, R
1 and R6 are the same or different, and each is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group, an aralkyloxy group, a lower alkylthio group, a lower haloalkyl group, a cyano group, and R
7 are the same or different and each represents a hydrogen atom, a lower alkyl group, an aralkyl group, or an acyl group, or R
, R, and R4 together represent a lower alkylenedioxy group; and R represents a hydrogen atom or a lower alkyl group, and salts thereof.

As a 2-phenylindole derivative, for example, 2-(3,5-dimethyl-4-hydroxyphenyl)indole is useful as a stabilizer for vinyl chloride polymers, as disclosed in JP-A-51-11762. It has been disclosed that Y. Isomu et al.
ra et al., Chem.

Pharm, Bull, ), Volume 31, 3168-317
8 (1983), the species 2-(3,5-Gt)
It has been disclosed that ert -phthyl-4-hydroxyphenyl) intole derivatives have anti-inflammatory effects.

On the other hand, as an indole derivative having 5-lipoxygenase inhibitory activity, the present inventors previously discovered that the 1st position is Cs C
12 alkyl group or alkenyl group, moly 2
disclosed a type of indole derivative having a p-substituted phenyl group bonded to the - position (Japanese Patent Application Laid-Open No. 162573/1983).

Furthermore, the present inventors have disclosed that a 2-phenylindole derivative in which the 3-position is substituted with an n-butylthio, phenylthio, or pyridylthio group simultaneously has the same action of inhibiting lipoxygenase and inhibiting cyclooxygenase. (Japanese Unexamined Patent Publication No. 130567/1983).

Furthermore, the present inventors previously determined that the 2-position is 3.5-G-C1
It has been discovered and disclosed that an indole derivative substituted with ~C,alkyl-4-hydroxyphenyl group has a specific boxygenase inhibitory effect (Japanese Patent Application Laid-Open No. 1983-1993).
60648 and JP-A-62-53962)
.

This time, the present inventors have discovered that the 2-phenylindole derivative represented by the above formula CI) is a novel compound that has not been described in conventional literature, and that the selectivity of the polyunsaturated fatty acid glue poxygenase inhibitory effect is further improved. This discovery led to the completion of the present invention.

Polyunsaturated fatty acids, especially arachidonic acid, are constituents of phospholipids present in biological membranes, and are removed from biological membranes into cells by various stimuli (e.g., inflammatory stimuli, antigen-antibody reactions (immune stimulation), etc.). is released. The liberated arachidonic acid is
Slow reacting substances of anaphylaxis [510W reactin], which are normally metabolized by cyclooxygenase and lipoxygenase, are metabolized by 5-lipoxygenase.
g 5ubstance of anaphylaxis
s (S RS -A)] is considered to be one of the causative substances of allergic symptoms involved in allergic reactions. In addition, fatty acid peroxide, which is a polyunsaturated fatty acid polyboxygenase metabolite, has negative effects on living organisms, such as by inhibiting the production of prostacyclin, which plays an important role in the defense of living tissues.

Conventionally, 3-amino-
1-(3-1-lifluoromethylphenyl)=2-pyrazoline [BW755CF and 5.8.11.14-eicosatetraic acid are known, but both lack specificity and are effective against not only lipoxygenase but also cyclooxygenase. It also inhibited the

However, the compound of formula (I) provided by the present invention is useful for polyunsaturated fatty acid glue boxygenases, especially 5-
It has the unique action of specifically inhibiting lipoxygenase, being resistant to glucuronidation and exhibiting an excellent inhibitory effect, especially when administered orally.
Effectively suppresses allergic reactions such as asthma, allergic dermatitis, allergic rhinitis, food allergies, and/or
Alternatively, it is extremely useful for inhibiting the production of fatty acid peroxides and protecting living tissues from these peroxides.

As used herein, the term "lower" means that the group or compound to which this term is attached has no more than 6 carbon atoms, preferably no more than 4 carbon atoms.

In the formula (1), examples of the "lower alkyl group" include methyl, ethyl, n-propyl, 1so-propyl, n-butyl, 5ea-butyl, ter L-butyl,
Examples of lower alkoxy groups include n-pentyl and n-hexyl groups, such as methoxy, ethoxy, n-hexyl, etc.
-propoxy, 1so-propoxy, n-butoxy, t
Included are ert-butoxy, n-hexyloxy, and the like. Examples of the [lower alkanoyloxy group] include acetyloxy and propionyloxy groups, and examples of the "aralkyl group" include benzyl and 7enethyl groups. Further, examples of the "lower alkylthio group" include methylthio and ethylthio groups, and examples of the "lower haloalkyl group" include trifluoromethyl groups.

"Acyl group" is a residue moiety obtained by removing at least one ○H from an organic acid such as a mono- or polycarboxylic acid or an organic sulfonic acid, specifically, the formula -COR, -5○
Groups such as ffRI or let COR+oCO- are included. Here, Rs is a hydrogen atom; it may be substituted with a halogen atom, an amino group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkanoyloxy group, a lower alkyl group optionally substituted with a carbamoyl group, or an aryl group. Lower alkenyl group; means lower cycloalkyl group: or aryl group, R9 means lower alkyl group or aryl group optionally substituted with lower alkyl group, R1° means lower alkylene group or lower alkenylene group are doing.

Examples of "acyl groups" include formyl, acetyl, propionyl, butyryl, trifluoroacetyl, glycyl, alanyl, β-alanyl, leucyl, inleucyl, valyl, lysyl, aspartyl, glutamyl, asparaginyl, glutaminyl, 3- Carboxypropyl, 4-carboxybutanoyl, 3-ethoxycarbonylpropionyl, 4-ethoxycarbonylbutanoyl, acetoxyacetyl, acetoxypropionyl, 3-
Rubamoylprobionyl, phenylacetyl, phenylpropionyl, acryloyl, methacryloyl, cinnamoyl, cyclohexanecarbonyl, benzoyl, naphthoyl, methanesulfonyl, benzenesulfonyl, p
-Toluenesulfonyl, malonyl, succinyl, kurtaryl or maleoyl groups, etc. can be mentioned.

These include:

Amino, methylamino, diethylamino, inroylamino, benzylamino, N-methyl-N-benzylamino, formylamino, acetylamino, N-methyl-N
- acetylamino, trifluoroacetylamino, glycylamino, alanylamino, lysylamino, glutamylamino, asparaginylamino, 3-carboxypropionylamino, 3-ethoxycarbonylpropionylamino, acetoxyacetylamino, 3-carbamoylpropionylamino, phenylacetylamine, Acryloylamino, cinnamoylamino, cyclohexanecarbonylamino, benzoylamino, methanesulfonylamino, p-toluenesulfonylamino, scunnimide, glutarimide or maleimide groups, etc.

On the other hand, "halogen atom" includes fluorine, chlorine, and bromine atoms.

Furthermore, examples of two adjacent groups of R2, R1 and R6 together representing a "lower alkylenedioxy group" include methylenedioxy, ethylenedioxy and propylenedioxy groups.

Representative examples of the compound of formula (I) provided by the present invention are as follows.

combination 0 1 2 N111° CH.

R2, R3, R6 5-NH.

5-NHCOCH3 5-NHCOCHJHz 5-NHCOCF3 5-NHCOCH,CH,C00H 5-NHCOCJOCOCHs 5-NHCOCsHi 5-NH5OzCHs O\ H5-F H5-OCO3 H5,6-0-CH,-0- 5-Nl2,6-CI 5-NH.

4~CI -Br -F -F -CH3 5-i-C3H a 7'-CH3 -0CH3 6-OCR.

-0CR3 5-0-+-C3Hy 5-OCOCR.

7-OCO (1:H.

5-OCR,C,)+5 -3CH3 -CF3 -CN 6 7 8 5-No.

5-NH.

6-NH.

7-NH.

5-NHCH.

CHs 7-NHCHzCaHs 5-NHCHO 5-Nl(COCH3 7-NHCOC2H.

5-NHCOCF3 5-NHCOCH, NH.

5-NHCOCHCH.

NH1 5-NHCOCRCH(CHs)* NH3 CH.

! rNHcOcHcH2COOH Gi N.H.

CH.

5-NHCOCHCH2CHICONHINH.

7-NHCOCH2CHICHICOOH 5-NHCOCH2CHICHICOOC! H65-N
HCOCH,0COCH3 5-NHCOCHzCsHs 5-NHCOCH=CHz 5-NHCOC,H.

7-NHSOiCHs 5-NHCOCH3 Enter 0 game 4-C1,5-NH.

5-NH*, 6-F 5-NH2, 6-0CH3 4-OCH, 5-NH.

5-OCH, 6-OCR.

CH.

CH.

CH.

CH.

CH.

CH.

C.I.

CH.

CH.

CH3 CH.

CH.

C,H.

C,H.

C,H.

C,H.

C,H.

5-OCH,,6-OCH3, 5-O-CH2-0-6 5-0-CHiCHz-0-6 4-0-CH, -0-5 5-OCH.

5-NH.

5-NHCOCH.

5-NH.

-F 5-CH.

5-OCH, 6-OCH.

5-NH,,6-OCH.

5-CH.

5-OCR.

5-NH.

5-NHCOCH3 5-NH,,6-C1 7-OCH3H CH3 n-C4■.

n-C, R13 n-CsH+5 n-C,H.

n-C,H.

n-C,H.

n-C4H@■ In these compounds of formula (I), R1 is a hydrogen atom,
A methyl group or an ethyl group is preferred, and a hydrogen atom is preferred as R6.

Further, among the compounds of formula (I), preferred compounds include those in which R11 represents a hydrogen atom, a methyl group, or an ethyl group, and one or two of R2, R31, and R and l are hydrogen atoms. , a halogen atom, a lower alkyl group, a divalent acyl group when lowered, and the remainder represents a hydrogen atom, or two adjacent ones of R2+, R31 and R41 are taken together to form a lower alkylene dioxy The following compounds are mentioned, in which the remainder represents a hydrogen atom.

Further, the compound of formula (I) can exist as a salt, and examples of such salts include metal salts such as sodium and potassium salts, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, etc. and salts with organic acids, among which pharmaceutically acceptable salts are preferred.

The compound of the formula (1) can be produced according to the Fischer indole synthesis method which is known per se. Specifically, for example, in the formula, Ro represents a hydrogen atom, and R71 represents a hydrogen atom, a lower alkyl group, an aralkyl group. or acyl group, or Ra+ and R? + is the same as R.

In the formula, R,, R3, R1 and R5 have the above-mentioned meanings.
□ represents a lower alkyl group or a phenylthio group, and in the formula obtained, R1□, R2, R3, R1 and R6 have the above-mentioned meanings.By cyclizing the compound of the following, in the formula, RI2, R2, R1, R4 and R1 have the above meanings, and then the phenylthio group is removed from the compound of formula (V) when R1□ is a phenylthio group and converted into a hydrogen atom. , and, if necessary, can be produced by introducing a lower alkyl group to the 1-position of the indole ring of the compound of formula (V) when R6 is a hydrogen atom.

In the above reaction, the reaction between the compound of formula (II) or a salt thereof and the compound of formula (II[) is usually carried out in an appropriate solvent,
For example, the reaction can be carried out in alcohols such as methanol, ethanol and propatool; ethers such as tetrahydro7rane and dioxane; or a mixed solvent of two or more of these solvents. The reaction temperature is not critical and can be varied over a wide range depending on the type of starting materials and solvent used, but is generally between room temperature and the reflux temperature of the reaction mixture, preferably between 50°C and the reflux temperature of the reaction mixture. It is desirable to carry out the reaction at a temperature within this range.

Furthermore, the above reaction can be carried out in the presence of an appropriate acid catalyst. Examples of acid catalysts that can be used include organic acids such as trifluoroacetic acid and glacial acetic acid; inorganic acids such as hydrochloric acid and sulfuric acid, and these catalysts are generally used for compound 1 of formula (n).
1/1000 to 10 per mole. Preferably l/10-1
It can be used in molar amounts. In addition, the above formula (I
When using the compound [) in the form of hydrochloride or sulfate,
The above acid catalyst is not particularly necessary.

The amount of the compound of formula (I[r) to be used with respect to the compound of formula (n) or its salt is also not particularly limited.
It is advantageous to use the compound of formula (In) in a proportion of usually 1 to 2 mol, particularly 1 to 1.1 mol, per mol of the compound or salt thereof.

Most of the compounds of formula (n) used as starting materials in the above reactions are known. Compounds of formula (I[r) with which said compounds are reacted are also at least partially known [see, for example, Bulltin de Société Simique de France (Bull, Sac;
Chim, France), 1966, p. 640], and novel ones can also be produced using known methods, such as Fries rearrangement or Friedel-Crafts reaction.

The above reaction produces the compound of formula (IV), which can be subjected to the cyclization reaction as it is or after being separated from the reaction mixture according to a conventional method.

Cyclization of compounds of formula (IT) can be carried out in the absence of a solvent or in a suitable solvent such as halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, tetrachloroethane, etc. The compound may be a polyphosphoric acid (including a mixture of phosphorus pentoxide and phosphoric acid in any proportion) or an organic ester thereof (for example, a lower alkyl ester of polyphosphoric acid such as polyphosphoric acid ethyl ester, or a polyphosphoric acid such as trimethylsilyl ester of polyphosphoric acid). trialkylsilyl esters of acids), or Lewis acids such as tin tetrachloride, 4
This can be carried out by treating with titanium chloride or the like, or by treating the compound of formula (■) with an acidic alcohol solvent. The former treatment with polyphosphoric acid or its organic ester or Lewis acid can generally be carried out at a temperature of 40 to 150°C, preferably 60 to 120°C, and the latter treatment with an acidic alcoholic solvent (e.g. methanol, ethanol, propatool, The treatment with Impropatol, saturated anhydrous hydrogen chloride in an alcohol such as ethylene glycol, etc.) can generally be carried out at room temperature to the reflux temperature of the reaction mixture, preferably at 50°C to the reflux temperature of the reaction mixture. .

The amount of the polyphosphoric acid or its organic ester or Lewis acid used is not critical, but is usually at least approximately equal weight to the compound of formula (IV), preferably 5 to 50
It is advantageous to use a double weight excess. The acidic alcohol solvent can be used in an amount of at least about 1 equivalent, preferably in large excess, per 1 mole of the compound of formula (■), as the equivalent of the acid in the alcohol solvent.

The compound of the formula (V) can be obtained in good yield by the cyclization reaction.

In the compound of formula (V) thus obtained, R1,
When represents a phenylthio group, the compound of formula (I) of the present invention can be obtained by subjecting it to a hydrogenolysis reaction to remove the phenylthio group. The elimination reaction of the phenylthio group can be carried out by a method known per se, for example, the formula (V)
This can be carried out by reacting the compound with hydrogen in a solvent such as methanol, alcohol or ethanol in the presence of a catalyst such as Raney nickel.

Furthermore, when R6 represents a hydrogen atom in the compound of formula (V), the hydrogen atom can be replaced with a lower alkyl group, if necessary.

The conversion can be carried out, for example, by first treating the compound of formula (V) with sodium hydride to replace the hydrogen atom at position 1 of the indole ring with a sodium atom, and then reacting it with a lower alkyl halide. I can do it.

The compound of formula (1) thus obtained can be separated from the reaction mixture and/or purified by methods known per se, such as extraction, filtration, distillation, recrystallization, column chromatography, thin layer chromatography, etc. I can do it.

In the compound of formula (1) obtained as described above, R
, Rx and qR1 is a hydrogen atom, the hydrogen atom can be converted according to a conventional aromatic ring nitration method [for example, Journal of Organic Chemistry (J, Org.

Chem, ), Vol. 31, pp. 65-69 (1966)], for example, by reaction with potassium nitrate in concentrated sulfuric acid, and R2,
When R8 or R4 is a nitro group, according to the usual method [
For example, Organic Synthesis Collective Porium I (Org, 5ynth.

Co11. I), pp. 240-241 (1948)
Reference] The nitro group can be converted into an amino group by catalytic reduction, and if R, R, or R6 is a bromine atom, the bromine atom can be converted into an amino group using a reaction known per se [e.g. Tetrahedron
n), Vol. 23, pp. 3823-3827 (1967)
], it can be converted to a cyano group by treatment with copper(I) cyanide.

Furthermore, the amino group on the indole ring of formula (I) is
Conventional alkylation methods for amino groups [e.g. annarene,
Ann, Vol. 598, pp. 174-185 (1956)], the amino group can be changed to a 7- or di-(lower alkyl or aralkyl) amino group, The amino group can be converted into an acylamino group by an acylation method [see, for example, Ber, Vol. 71, pp. 1480-1481 (1938)]. In this reaction, if the acyl group contains a free amino group, the amino group is protected in advance with a known protecting group, such as a benzyloxycarbonyl group, t-butoxycarbonyl group, etc.
It is desirable to remove the protecting group after performing the acylation reaction.

In addition, when R2, R1 or R4 is an acylamino group, according to a conventional method [for example, organic synthesis,
Collective Polium I (Org.

5ynth, Co11. Vol, I), 1
11-113 (1932) Reference 1 The acylamino group can also be converted into a free amino group by hydrolysis.

The compound of formula (I) produced by the method described above can be converted into a salt thereof, if necessary. The conversion of the compound of formula (I) into a salt is carried out by methods known per se, for example by treatment with an acid or an inorganic base in the absence of a solvent or in a suitable inert solvent according to conventional methods. I can do it.

The compound of formula (I) provided by the present invention as described above selectively inhibits polyunsaturated fatty acid lipoxygenase, particularly 5-lipoxygenase, present in biological membranes, thereby inhibiting lipoking. It has the effect of inhibiting only the production of enzyme-based metabolites. Therefore, the compound of formula (I) of the present invention is useful for controlling various physiological effects that are undesirable for living organisms and are caused by the involvement of lipoxygenase metabolites.

In particular, the compounds of the present invention have the remarkable characteristics of being well absorbed when administered orally and being difficult to form glucuronide conjugates (therefore, being difficult to be inactivated in vivo), making them extremely useful.

Furthermore, the compound of formula (I) of the present invention has the unique feature of also having the effect of scavenging active oxygen in the living body.

Therefore, the compounds of formula (I) provided by the present invention are:
Anti-asthmatic agents, anti-allergic agents (prevention and treatment of allergic dermatitis, allergic rhinitis, hives diagnosis, gastrointestinal tract allergies, food allergies, etc.), anti-rheumatic agents, anti-thrombotic agents,
Arteriosclerosis treatment, late stage during subarachnoid hemorrhage! shrinkage treatment agent,
It can be used as a cerebral circulation improving agent, a coronary artery improving agent, a therapeutic agent for ischemic myocardial infarction, a therapeutic agent for ischemic cerebral infarction, an immunomodulator, a therapeutic agent for ulcerative colitis, a therapeutic agent for skin psoriasis, and the like.

That the compound of formula (I) of the present invention has a selective polyunsaturated fatty acid glue poxygenase inhibitory effect can be demonstrated by the following animal experiments.

(1) The inhibitory effects of the compounds of the present invention on lipoxygenase and cyclooxytana-5-lipoxygenase and cyclooxygenase activities were determined by the method of Siegel et al. [Pr.
ostaglandins, vol. 21, p. 123 (19
1981)].

That is, leukocytes (more than 90% are polymorphonuclear leukocytes and contain a large amount of 5-lipoxygenase) in the exudate collected from the pleural cavity of a rat with carrageenan pleurisy induced.
was added to 50IIIM Tris-HCl buffer (pH 7,
4). Add test drug, 11C arachidonic acid and calcium ionophore CA to a certain amount of this leukocyte suspension.
xsrat) was added and incubated for 2 minutes, and the 11C arachidonic metabolite produced at that time was fractionated by thin layer chromatography (silica gel, plastic plate, developing solvent: hexane: diethyl ether: acetic acid - 40:60:2). After exposing the thin laminate to X-ray film,
Each arachidonic acid metabolite fraction was identified by comparison with a standard product, and each corresponding fraction and other radioactive fractions were collected. The radioactivity of each fraction was then measured using a liquid scintillation counter, and the percentage of radioactivity in each fraction relative to the total radioactivity was determined (production rate). Using this production rate as an index, the inhibition rate of the test drug against the synthetic ability of each fraction was determined.

Lipoxygenase activity is 5S-hydroxy-6,8,
11,14-eicosatetraenoic acid (5-HETE) and 5S,12R-dihydroxy-6°8.10.14-
The production of eicosatetraenoic acid (5,12-diHETE) is used as an indicator, and cyclooxygenase activity indicates the production of 12-hydroxyhebutadecatrienoic acid (HHT).
It became a mark.

All test drugs were dissolved in a 10% dimethyl sulfoxide solution. Well, the final concentration of dimethyl sulfoxide in the assay system is 265%.

The results are shown in the table below.

Thus, the compound of formula (I) of the present invention can be administered orally or parenterally (e.g. It can be administered intramuscularly, intravenously, subcutaneously, rectally, etc.) or locally.

When the compound of formula (I) of the present invention is used as a medicament,
They can be formulated into a variety of forms suitable for oral, parenteral or topical administration. For example, the compounds of the invention may be added to non-toxic excipients, binders, lubricants, disintegrants, preservatives, tonicity agents, stabilizers, dispersants, antioxidants, etc. commonly used in such drugs. It can be formulated using additives such as agents, colorants, flavoring agents, buffering agents, propellants, and surfactants.

Such drugs may be prepared in tablets, capsules, or tablets depending on their use.
It can be prepared in any formulation form such as granules, powders, fine granules, pills, troches, suppositories, ointments, patches, injections, syrups, and aerosols. Therefore, examples of the above-mentioned non-toxic additives that can be used include starch,
Gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or its salts, gum arabic, polyethylene glycol, p-hydroxybenzoic acid alkyl ester, syrup, ethanol, clopylene glycol, Vaseline, carpowax, glycerin, sodium chloride, sodium nitrite, sodium phosphate, citric acid, dichlorodifluoromethane, l
, 2-dichlorotetrafluoroethane, sorbitan trioleate, and the like. The medicament may also contain other therapeutically useful agents.

The dosage of the compound of formula (I) of the present invention is determined based on the type of warm-blooded animal including humans, the route of administration, the severity of the symptoms,
Although it can vary widely depending on the doctor's diagnosis, it is generally 1 to 100 mg/kg, preferably 2 mg/kg per day.
~50 mg/kg. However, as mentioned above, depending on the severity of the patient's symptoms and the doctor's diagnosis, it is of course possible to administer an amount smaller than the lower limit or larger than the upper limit of the above range. The above dosage can be administered once a day or in divided doses.

The present invention will be further explained below with reference to Examples.

Example 1 60 g of 3-t-butyl-4-hydroxy-5-methyl clobiophenone and 55 g of 4-acetylaminophenylhydrazine hydrochloride are heated under reflux for 6 hours in an Impropateur 1i. After the reaction, the reaction mixture was poured into ice water and the precipitated crystals were collected by filtration and recrystallized from methanol-water to give 5-acetylamino-2-(3-t-butyl-4-hydroxy-5-methylphenyl)- 3-methylindole 78g
I got it.

Melting point: 176.8-178.7°C 1472.1432.1368.1324.1218.
12002-27 (3H, s), 2.32 (38, s)
, 7.10-7.80 (5H.

m), 8.22 (IH, s), 9.65 (18, s),
10.78 (18°8) Example 2 5-acetylamino-2(3-t-butyl-4-hydroxy-5-methylphenyl)-3-methylindole 7
4.8g concentrated hydrochloric acid 200a+1 and ethanol 300m
Add to the solution of j2 and heat under reflux for 2 hours. After the reaction, the reaction mixture was poured into ice water, the precipitated crystals were collected by filtration, and ethanol-
Recrystallized from ether to give 5-amino-2-(3-t-
Butyl-4-hydroxy-5-methylphenyl)-3-
62 gmm of methyl indole salt was obtained.

l534.1492.1470. 1252.1196
pm NMR, δ (CD3), So: 1.44 (9Ls)
, 2.28 (3H, s), 2.36 (3H, s), 6.
85-7.55 (5H, m), 8.35 (IH, s),
10.13 (2H, s), 11.24 (lH, s) Example 3 4-Butanoyl-2-t-butyl-6-methylphenol and 4-acetylaminophenylhydrazine hydrochloride were added in the same manner as in Example 1. 5-acetylamino-2-
(3-t-butyl-4-hydroxy-5-methylphenyl)-3-ethylindole was obtained.

Melting point: 224.0-225.5°C (recrystallized from ethanol-hexane) 1470.1328.1216.806.560 (3H
, s), 2.32 (3H, s), 2.86 (2H, q)
, 4.87 (IH, s), 6.90-7.95 (7H,
m) Example 4 5-acetylamino-2-(3-t-butyl-4-hydroxy-5-methylphenyl)-3-ethylindole was treated in the same manner as in Example 2 to give 5-amino-2- (3-
t-dityl-4-human axy-5-methylphenyl)-
3-ethylindole hydrochloride was obtained.

1458.1432.1196 (3B, s), 2.81 (2H, q), 6.9-7.5
5 (5H, m), 8.35 (IH, s), 10.13 (
2H,s), ll-21(IH,s) Example 5 4 g of 2-t-butyl-6-methyl-4-phenylthioacetylphenol and 2.9 g of 4-acetylaminophenylhydrazine hydrochloride were mixed with Example 1. 5-acetylamino-2-(3-t-butyl-4-
3.4 g of hydroxy-5-methylphenyl)-3-phenylthioindole was added to 40 mA of Raney nickel (1 part of water).
00mji 2 times, acetone loo+J 2 times and methanol 100mj 22 times to inactivate) and methanol 200-, after absorbing hydrogen 500-2
Heat to reflux for an hour. Afterwards, the catalyst was filtered off, recrystallized from isopropyl ether, and 5-acetylamino-2-(3
-t-Butyl-4-hydroxy-5-methylphenyl Melting point: 135.7-137.7°C co+-'IR, νKBr: 3304, 2972, 16
54, 1470, 1432, 1324, 1190 99m NIJI? , δ: 1.47 (9H, s)
, 2.18 (3H.s), 2.29DC13 (3H.s), 4.95 (IH.s), 6.60 (IN
, s), 7. QO-7-45 (7H, m), 7.71 (
IH,s), 8.25(1!(,broad)Example 6 5-acetylamino-2-(3-t-butyl-4-hydroxy-5-methylphenyl)indole was treated in the same manner as in Example 2. and 5-amino-2-(3-t-butyl-
4-hydroxy-5-methylphenyl)indole hydrochloride was obtained.

cm-'IR, v KBr: 3432, 2912, 15
64, 1482, 1190pm NMR, δ (CD,), So: 1.44 (9H, s
), 2.27 (3H, s), 6.74 (IH, s), 6
．． 90-7.60 (6H, +a), 10.12 (2) 1
.

Broad), 11-61 (IH, s) Example 7 3-t-Butyl-4-hydroxy-5-methylpropiophenone and 4-acetylamino-3-methoxyphenylhydrazine hydrochloride as in Example 1 5.
-Acetylamino-2-(3-1-butyl-4-hydroxy-5-methyl-7-methyl) 6-medoxy 3-methylindole was obtained.

Melting point: 246.1-247.4°C (recrystallized from methanol-ethyl acetate) I252.1198.1154 22m NMR, δ(.,,),. : 1.43 (9H, s)
, 2.06 (3H, s), 2.26 (3H, s), 2.
29 (3H, s), 3.83 (3H, s), 6.81-
7.90 (4H, m), 8.16 (IH, s), 8.7
9-8.91 (IH, s) Example 8 5-acetylamino-2-(3-t-butyl-4-hydroxy-5-methylphenyl)-6-medoxy 3-methylindole was prepared in the same manner as in Example 2. Upon treatment, 5-amino-2-(3-t-butyl-4-hydroxy-5-methylphenyl)-6-medoxy 3-methylindole hydrochloride was obtained.

Melting point: 233.2-235.2°C (decomposition)ell
″″′ IR,y KBr: 3520.3420.295
2.1480.1346.1306.1254.120
4.1156pm NMR, δ(CD, ), 30' 1.43(9H,s
), 2.27 (3H, s), 2.32 (3H, s), 3
．． 92 (3H, s), 6.98-7.56 (4H, m)
, 846-8.35 (IH, broad), 9.6-1
0.1 (2H, broad) Example 9 3-t-butyl-4-hydroxy-5-methylpropiophenone and 4-acetylamino-3-chlorophenylhydrazine hydrochloride were treated in the same manner as in Example 1, 5-acetylamino-2-(3-(-butyl-4-hydroxy-5-methylphenyl)-5-ria-3-methylindole and 5-acetylamino-2-(3-t-butyl-4 -hydroxy-5-methylphenyl)-4-'1
A mixture of 3-methylindoles was obtained as crystals.

Example IO The crystals of the mixture obtained in Example 9 were treated in the same manner as in Example 2, separated by silica gel column chromatography (elution solvent: chloroform:methanol (20 wl)),
The first eluate was converted into the hydrochloride salt in methanol and
Recrystallized from ethyl acetate to give 5-amino-2-(3-t
-butyl-4-hydroxy-5-methylphenyl)-6
-chloro-3-methylindole hydrochloride was obtained.

Melting point: 223.6-225.5°0 (decomposition) 1238
．． 1184.1162.1082pm NMR, δ(.,,),. : 1.43 (9H, s)
, 2.28 (3H, s), 2.35 (3H, s), 7.
16-7.75 (4H, m), 8.1-8.7 (IH.

The second eluate was then treated as above to give 5-amino-2-(3-t-butyl-4-hydroxy-5-methylphenyl)-4-chloro-3-methylindole hydrochloride. I got it.

Melting point: 183.6-186.8°C (decomposed) 1198.
115g 22m NMR, δ(.Ds)ts. : 1.43 (9H, s)
, 2.27 (3H, s), 2.57 (3H, s), 7.
11-7.43 (4H, m), 7.9-8.6 (IH.

Broad) Implementation flll1 3-t-Butyl-4-hydroxy-5-methylpropiophenone and phenylhydrazine hydrochloride were treated in the same manner as in Example 1 to give 2-(3-t-butyl-4-hydroxy-5 -methylphenyl)-3-methylindole was obtained.

Melting point: 133.0-133.6°C (recrystallized from ether-petroleum ether) 1318.1232.1190.1182.744pm NMR, δ: 1.47 (9H, s), 2.
32 (3H, s), 2.43 CDCI.

(3H, s), 4.85 (II, s), 7.05-7.
65 (68, 11+), 7.90 (1B, broa
d) Example 12 3-t-Butyl-4-hydroxy-5-methylpropiophenone and 4-methoxyphenylhydrazine hydrochloride were treated in the same manner as in Example 1 to give 2-(3-t-butyl-4
-hydroxy-5-methylphenyl)-5-methoxy-
3-methylindole was obtained.

Melting point: 141.4-143.0°C (ethyl ether-
Recrystallized from n-hexane) 1210.1076.826.792 pm NIJR, δ: 1.47 (9H, s), 2.
32 (3B, s), 2,40DCI3 (3H, s), 3.88 (3H, s), 6.73-7.
40 (5H, m), 7.7-7.9 (IH, broad
) Example 13 3-t-Butyl-4-hydroxy-5-methylpropiophenone and 3,4-methylenedioxyphenylhydrazine hydrochloride were treated in the same manner as in Example 1 to obtain 2-(3-t
-butyl-4-hydroxy-5-methylphenyl)-3
-Methyl-5,6-methylene dioxindole was obtained.

Melting point: 153.5-155.7℃ (ethyl ether n-
recrystallized from hexane) 1234.1186.1102.836 (3H, s),
5.92 (2H, s), 6.73-7.36 (4H, m
), 7.65-7.85 (IH, broad) Example 1
4 3-t-Butyl-4-hydroxy-5-methylpropiophenone and 4-fluorophenylhydrazine hydrochloride were treated in the same manner as in Example 1 to obtain 2(3-t-butyl-4-
Hydroxy-5-methylphenyl)-5-fluoro-3
-Methyl intole was obtained.

Melting point: 8:L7-85.5°C (recrystallized from ethyl ether-petroleum ethyl) 1450.1428.1228.1184.1066.
946.794pplTl: 1.47 (9H, s),
2.32 (3H, s), 2.37 NMR゛8 CDCl
.

(3H, s), 6.7 low 7-40 (5H, m), 7.
74-7.98 (IH.

Broad) Example 15 3-t-Butyl-4-hydroxy-5-methylpropiophenone and 4-methylphenylhydrazine hydrochloride were treated in the same manner as in Example 1 to produce 2-(3-t-butyl-4 −
Hydroxy-5-methylphenyl)-3,5-dimethylindole was obtained.

Melting point: 65.1-68.2°C (recrystallized from petroleum ether) cm-' IR, ν: 3436.2960.1456.14
30.1232, Br 1196.796 NMR1δppl″l: 1.47 (9H, s), 2.
32 (3H, s), 2.40 CDCI.

(3H, s), 2.47 (3H, s), 6.88-7.
40 (5H, m), 7.73-7.87 (lH, bro
ad) Example 16 5-amino-2-(3-t-butyl-4-hydroxy-
5-methylphenyl)-3-methylindole 600a
+g, 320o1g of formic acid, and 20mβ of toluene are heated under reflux for 3 hours. After the reaction, the solvent is distilled off, ethyl acetate is added, the mixture is washed with a saturated aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was recrystallized from ethyl ether-n-hexane.
2-(3-t-phthyl-4-hydroxy-5-methyl7enyl)-5-formylamino-3-methylindole 570+ag was obtained.

Melting point: 127.2-129.7℃ cm"-' IRly KBr: 3368.1678.147
2.1196 (3H, s), 6.77-8.70 (9H
, m) Example 17 5-amino-2-(3-t-butyl-4-hydroxy-
5-methylphenyl)-3-methylindole 700m
g was dissolved in pyridine 5+J, 300 mg of methanesulfonyl chloride was added thereto, and the mixture was stirred at room temperature for 7 hours. After the reaction, the reaction mixture is poured into ice water, extracted with ethyl acetate, washed with 10% hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography [elution solvent: chloroform:methanol (20:1)] and recrystallized from ethyl ether-hexane to give 2-(3-t-butyl -4-
770 mg of hydroxy-5-methylphenyl)-5-methanesulfonylamino-3-methylindole was obtained.

Melting point: 125.2-127.5°C 1152 ppm NMR, δCDCl: 1.47 (9H, s), 2
．． 32 (3H, s), 2.40 (3H, s), 2.97
(3H, s), 6.38 (LH, broad), 6.9
6-7.50 (6H, m), 8.03 (IH, broa
d) Example 18 5-amino-2-(3-t-butyl-4-hydroxy-
5-methylphenyl)indole was treated in the same manner as in Example 17 to give 2-(3-t-butyl 4-hydroxy-5-
Methylphenyl)-5-methanesulfonylaminoindole was obtained.

Melting point: 161.0-162.0°C (ethyl ether-
(recrystallized from petroleum ether) 148 29m NMR, δ: 1.47 (9H, s), 2.3
2 (3H, s), 2.96 CDCI.

(3H, s), 4.92 (IH, s), 6.29 (IH
, s), 6.60-7.50 (6H, m), 8.35 (
LH, broad) Example 19 5-amino-2-(3-t-butyl-4-hydroxy-
5-methylphenyl)-3-methylindole 500m
Dissolve g in 50 aoj2 of methanol, add 2 drops of acetic acid, 2 drops of acetone and 500 g of sodium cyanoborohydride.
and stirred at room temperature for 3 hours. After the reaction, the solvent is distilled off, ethyl acetate is added, and the mixture is washed with 10% hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate.

The solvent was distilled off, the residue was converted into a hydrochloride, and then recrystallized from ethyl ether to give 2-(3-t-butyl-4-hydroxy-
5-methylphenyl)-5-isopropylamino-3-
430 reports on methylindole hydrochloride were obtained.

Melting point: 231.2-235.0°C (decomposition) 29m NMR, δ: 1.30 (6H, d, J-6
Hz), 1.44 (9H, s), (a+1)zs.

2.29 (3H, s), 2.37 (3H, s), 3.4
0-3.90 (IH.

m), 7.07-7.67 (5H, m), 8.36 (I
H, broad), 10.89 (IH, broad),
11.32 (IH, broad) Example 20 5-amino-2-(3-t-butyl-4-hydroxy-
5-methylphenyl)-3-methylindole1. Og
was dissolved in 10 ml of pyridine, and 7 ml of trifluoroacetic anhydride was added.
Add 50 mg and stir at room temperature for 2 hours. After the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate.
Wash with 0% hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, and dry over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography [elution solvent: chloroform:methanol (40:l)]
] After purification, recrystallize from ethyl ether-n-hexane,
830 mg of 2-(3-t-butyl-4-hydroxy-5-methylphenyl)-5-)lifluoroacetylamino-3-methylindole was obtained.

Melting point: 197.8-198.4°C 152 29m NMR, δ: l-47 (9H, s), 2.32
(3H, s), 2.39CDCIm (3H, S), 7.10-7.40 (5H, m), 7.
80 (IH, broad), 7.70-8.13 (2H
, broad) Example 21 5-amino-2-(3-t-butyl-4-hydroxy-
5-methylphenyl)-3-methylindole 500+
Dissolve ag in 5 Tml of pyridine and add 180 ml of succinic anhydride.
mg and heated under reflux for 2 hours. After the reaction, the reaction mixture is poured into ice water, extracted with ethyl acetate, washed with 10% hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was recrystallized from ether to give 2-(3-t-butyl-4-hydroxy-5-methylphenyl)-3-methyl-5-succil
474.1432 (3H, s), 2.10-2.80 (4H, m), 7.
06-7.37 (4H.

m), 7.78 (IH, broad), 9.85 (lH
, broad), 10.75 (IH, broad) Example 22 5-amino-2-(3-t-butyl-4-human oki'y
-5-methylphenyl)-3-methylindole l,
Dissolve Og in 30mj2 of methyl ethyl ketone, add 610+eg of benzyl bromide and 360m of triethylamine.
g and heated under reflux for 1.5 hours.

After the reaction, the solvent is distilled off, ethyl acetate is added to the residue, washed with a saturated aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography [elution solvent: chloroform], converted into a hydrochloride, and recrystallized from ethyl ether-n-hexane to give 5-benzylamino-2C3° j4.
A 4-hydroxy-5-methylphenyl)-3-methylindole salt diverticulate salt was obtained.

Melting point: 193.0-196.3°C (decomposed) em-' IR, ν: 3436.1468.1432.1
196Br NMR1δ-), So'l-43(9',S)
, 2.27 (38, s), 2.34 (3H, S), 4.
53 (2H, s), 6.86-7.70 (lOH, m)
, 8.31 (1B, broad), 11.32 (2H,
broad) Example 23 (a) L-N-benzyloxycarbonylalanine 44
6mg of methylene chloride 20m! After adding 420+ og of dicyclohexylcarbodiimide to the solution and stirring at room temperature for 30 minutes, 5-amino-2-(3-t-7'thyl-4
A solution of 616 mg of -hydroxy-5-methylphenyl), -3-methylindole in 30 tal of methylene chloride is added dropwise, and the mixture is stirred overnight at room temperature. After the reaction, insoluble matters are removed by filtration, and the filtrate is washed with saturated sodium bicarbonate 10% hydrochloric acid and water, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography [elution solvent: chloroform:methanol (20:1)] for 11 hours.
4'lk, (s)-5-(2-benzyloxycarbonylaminoprobionylamino)-2-(3-t-
Butyl-4-hydroxy-5-methylphenyl)-3-
Methylindole was obtained quantitatively.

(b) (s)-5-(2 obtained in step (a) above
-benzyloxycarbonylaminoprobionylamino)-2-(3-t-butyl-4-hydroxy-5-methylphenyl)-3-methylindole1. Add 300 mg of 5% palladium-carbon to a 30-methanol solution of Og, and stir for 8 hours under a hydrogen stream. After the reaction, remove the catalyst by filtration,
It was purified by silica gel column chromatography [elution solvent: chloroform:methanol (9:1)], converted into a hydrochloride, and then recrystallized from ethyl ether to obtain (s)-5-
(2-aminoprobionylamino) -2-(3-t-
Butyl-4-hydroxy-5-methylphenyl)-3-
520 mg of methylindole hydrochloride was obtained.

Cm″″1 1R,v KBr: 3432.1674.148
011196NMR1δ(.Da)xs.・1.44 (
9H, ·), 1.51 (3H, d, J・7H'), 2.
27 (3H, s), 2.34 (3H, s), 3.87-
4.30 (IH.

m), 7.10-7.37 (4H, m), 7.78 (L
H, s), 8.34 (3H, broad), 10.46
(LH, broad), 10.89 (IH.

broad) Example 24 (a) N-t-butoxycarbonylglycine 35Q
420 mg of dicyclohexylcarbodiimide was added to a solution of 20 mg of methylene chloride, and after stirring at room temperature for 30 minutes, 5-amino-2-(3-t-butyl-4-hydroxy-5-methylphenyl)-3-methylindole was added. 61
Add dropwise 6 mg of methylene chloride, 30-solution and stir at room temperature for 5 hours.

After the reaction, insoluble materials are removed by filtration, and the filtrate is washed with saturated sodium bicarbonate, 10% hydrochloric acid and water, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography [elution solvent: chloroform:methanol (20:l)] to give 5-t-butoxycarbonylaminoacetylamino-2-(3-1-butyl-4
-Hydroxy-5-methylphenyl)-3-methylindole (520 mg) was obtained.

(b) 520 mg of 5-t-butoxycarbonylaminoacetylamino-2-(3-t-butyl-4-hydroxy-5-methylphenyl)-3-methylindole obtained in step (a) above was added to trifluoroacetic acid. Dissolve in lO- and stir at room temperature for 1 hour. After the reaction, the reaction mixture was poured into ice water, made slightly alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography [elution solvent: chloroform:
The product was purified with methanol (9:1)], converted into a hydrochloride, and then recrystallized with ethyl ether to give 5-aminoacetylamino-2-(3-t-butyl-4-hydroxy-5-methylphenyl)-3- Wash with methyl N-hydrochloric acid and water in this order,
Dry with anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography [elution solvent: chloroform:methanol (95:5)] to obtain 2
2.2 g of -(3-t-butyl-4-hydroxy-5-methylphenyl)-5-(3-ethoxycarbonylglopionylamino)-3-methylindole was obtained.

99m NMR, δ: 1.43 (9H, s), 2
．． 27 (3H, s), 2.33 (CDs)zs.

(3H, s), 3.77 (2H, s), 7.10-7.
40 (4H, m), 7.78 (IH, s), 8-28 (
38, broad), 10.44 (LH.

Broad), 10.91 (IH, broad) Example 25 5-amino-2-(3-t-butyl-4-hydroxy-
2 g of 5-methylphenyl)-3-methylindole was dissolved in 20 ml of dry pyridine, and 1.2 g of ethylsuccinic acid chloride was added thereto under stirring while cooling with water, followed by stirring at room temperature for 1.5 hours. After reaction, pour the reaction mixture into ice water and extract with ethyl acetate, then add water, 11478.1432.1240.119
8.1162pm NMR, δ: 1.27 (3!(,t), 1.
46 (9H, s), 2.31DC13 (31,, s), 2.38 (3H, s), 2.72 (4
H, t), 4.16 (2H, q), 4.90 (IH, b
road), 7.05-7.85 (5H.

m), 7.52 (LH, s), 7.90 (IH, s) Example 26 5-amino-2-(3-t-butyl-4-hydroxy-
5-methylphenyl)-3-methylindole 500m
180 g of succinic anhydride was added to a pyridine 5-solution under ice cooling.
mg and stir for 10 minutes.

After the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate.
% hydrochloric acid and water, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was recrystallized from ether-n-hexane to give 2-(3-t-butyl-4-hydroxy-
520 mg of 5-methylphenyl)5-(3-carboxypropionylamino)3-methylindole was obtained.

NMR.

99m δ: 1.43 (9H, s), 2.27 (3H
, s), 2.32 DCIs (3H, s), 2.36-2.70 (4H, m), 7.
00-7.37C4H.

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) In the formula, R_1 represents a hydrogen atom or a lower alkyl group; R_2
, R_3 and R_4 are the same or different, and each is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group, an aralkyloxy group,
lower alkylthio group, lower haloalkyl group, cyano group,
Represents a nitro group or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, where R_6 and R_7 are the same or different and each represents a hydrogen atom, a lower alkyl group, an aralkyl group, or an acyl group,
or a compound and a salt thereof, wherein adjacent two of R_2, R_3 and R_4 together represent a lower alkylenedioxy group; R_5 represents a hydrogen atom or a lower alkyl group; and a salt thereof. 2. The compound according to claim 1, wherein R_1 represents a hydrogen atom, a methyl group, or an ethyl group. 3. The compound according to claim 1, wherein R_5 represents a hydrogen atom. 4. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I -1) In the formula, R_1_1 represents a hydrogen atom, methyl group, or ethyl group, and one or two of R_2_1, R_3_1, and R_4_1 are hydrogen atoms, Represents a halogen atom, lower alkyl group, lower alkoxy group, or ▲a mathematical formula, chemical formula, table, etc.▼, where R_6_1 represents a hydrogen atom and R_
7_1 represents a hydrogen atom, a lower alkyl group, an aralkyl group, or an acyl group, or R_6_1 and R_7_1 together represent a divalent acyl group, and the remainder represent a hydrogen atom, or R_2_1, R_3_1, and R_4_1 Claim 1 is a compound or a salt thereof, in which two adjacent ones together represent a lower alkylenedioxy group, and the rest represent a hydrogen atom.
Compounds described in Section.