JPH04211651A - Bone-resorption inhibiting agent and indole derivative - Google Patents

Abstract

PURPOSE:To provide an indole derivative directly acting to the bone to exhibit excellent bone-resorption suppressing action and useful as a therapeutic agent for osteoporosis. CONSTITUTION:A bone-resorption suppressing agent containing the compound of formula I (ring A and ring B may have substituents; R is H, lower alkyl or acyl; A is hydroxymethyl or carboxyl which may be esterified or amidated) or its salt as an active component. Among the compounds of formula I, the compound of formula II [n and m are 2-4; R<1> and R<2> are (substituted) OH or (substituted) alkyl; each two of R<1> and R<2> may form a ring together with a benzene ring and a bivalent hydrocarbon residue or alkylene dioxy bonded with the group] or its salt [e.g. 2-hydroxymethyl-5,6-dimethoxy-3-(4- methoxyphenyl)indole] is a new compound.

Description

Detailed Description of the Invention [0001] [Industrial Application Field] The present invention relates to a novel bone resorption inhibitor comprising an indole derivative as an active ingredient, which is useful as a therapeutic agent for osteoporosis and has bone resorption inhibitory activity. Concerning indole derivatives. BACKGROUND OF THE INVENTION Osteoporosis is a pathological condition or disease in which the quantitative loss of bone exceeds a certain level, causing certain symptoms or dangers. The main symptoms are kyphosis of the spine, fractures of the lumbar spine, vertebral bodies, femoral neck, lower end of radius, ribs, upper end of humerus, etc. The causes are diverse, including endocrine and nutritional disorders. Conventionally, therapeutic agents such as estrogen agents, calcitonin, vitamin D, and calcium agents have been administered. [0003] However, when administering the above-mentioned therapeutic agents, sufficient effects are not obtained because the subjects to be administered are limited or the effects are uncertain. [Means for Solving the Problem] As a result of intensive research aimed at developing a more general drug that acts directly on bones to suppress bone resorption, the present inventors found that the following general formula The present invention was completed by discovering that the indole derivative represented by (I) acts directly on bones and exhibits an excellent bone resorption inhibitory effect. That is, the present invention provides (1) general formula 000
6] [Formula, A ring and B ring may be substituted, R is a hydrogen atom, a lower alkyl group or an acyl group, and A is a hydroxymethyl group or an esterified or amidated group] A bone resorption inhibitor comprising an indole derivative or a salt thereof as an active ingredient, and (2) the general formula: [Formula 4] [where n and m are 2] represents an integer of ~4, R1 and R
2 is the same or different and represents an optionally substituted hydroxyl group or an optionally substituted alkyl group, or two of R1 or R2 are a divalent hydrocarbon residue or an alkylene dioxy group; Each may form a ring with the benzene ring to which it is bonded, R represents a hydrogen atom, a lower alkyl group, or an acyl group, and A represents a hydroxymethyl group or a carboxyl group that may be esterified or amidated. ] It relates to an indole derivative or a salt thereof. In the above general formula (I), ring A and/or
When ring B is substituted, examples of the substituent include a halogen atom, an optionally substituted alkyl group, an aryl group, an alkenyl group, and a hydroxyl group. The number of substitutions is 1 to 4, respectively. Next, each of the above substituents will be explained. [0009] Examples of halogen atoms include fluorine, chlorine,
Mention may be made of bromine and iodine, with fluorine or chlorine being preferred. The alkyl group in the optionally substituted alkyl group may be linear, branched, or cyclic having 1 to 10 carbon atoms, such as methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Among these, those having 1 to 6 carbon atoms are preferred. Examples of substituents that the alkyl group may have include halogen, nitro, amino (acyl, alkyl, iminomethyl, imino (aryl substituted) methyl, amidino, and amino). ), phosphoryl, alkoxyphosphoryl, sulfo, cyano, hydroxy, carboxy, hydrazino, imino, amidino, carbamoyl, aryl (halogen, alkyl, alkoxy, alkylamino, amino, carbamoyl, sulfo, alkylsulfonyl, cyano, hydroxy, carboxy , nitro, acyloxy,
It may have aralkyloxy, phosphoryl, alkoxyphosphoryl, or sulfooxy as a substituent. ), heterocycle (nitro, oxo, aryl, alkenylene, halogenoalkyl, alkylsulfonyl, alkyl, alkoxy, alkylamino,
Amino, halogen, carbamoyl, hydroxy,
It may have cyano, carboxy, phosphoryl, alkoxyphosphoryl, or sulfo as a substituent. ), etc. Examples of the aryl group in the optionally substituted aryl group include phenyl, naphthyl,
Examples include biphenyl, anthryl, and indenyl. Examples of the substituents that the aryl group may have include halogen, nitro, cyano, amino (
It may have alkyl, alkenyl, cycloalkyl, or aryl as a substituent. ), phosphoryl, sulfo, hydroxy, sulfooxy, sulfamoyl, alkyl (may have amino, halogen, hydroxy, cyano, alkoxyphosphoryl as a substituent), alkoxy, aralkyloxy, alkylsulfonamide, methylenedioxy, alkoxyphosphoryl, alkylsulfonyl,
Examples include alkylsulfonylamino. Aryl groups can also be cycloalkyl and fused rings (e.g., tetrahydronaphthyl, indanyl, acenaphthynyl, etc.)
may be formed. The alkenyl group in the optionally substituted alkenyl group may be linear, branched, or cyclic having 2 to 10 carbon atoms, such as allyl.
), vinyl, crotyl, 2-penten-1-yl,
3-penten-1-yl, 2-hexen-1-yl, 3-hexen-1-yl, 2-cyclohexenyl, 2-cyclopentenyl, 2-methyl-2-propen-1-yl, 3-methyl- Examples include 2-buten-1-yl, and among these, those having 2 to 6 carbon atoms are preferred. Examples of the substituents that the alkenyl may have include alkyl having 1 to 6 carbon atoms (which may have the same substituents as the above-mentioned alkyl groups); ), halogen, nitro, amino (may have acyl, iminomethyl, amidino, alkyl, aryl as a substituent), phosphoryl, sulfo, cyano, hydroxy, carboxy,
Alkyloxycarbonyl, carbamoyl, alkylthio, arylthio, alkylsulfinyl,
Examples include groups such as arylsulfinyl, alkoxyphosphoryl, alkylsulfonyl, arylsulfonyl, sulfamoyl, aryl, and acyl. The above alkenyl or alkenylene includes isomers (E, Z forms) regarding the double bond. Examples of halogen in the above substituent include chlorine, bromine, fluorine, and iodine. The alkyl in the above description of the substituent has preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and particularly 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl. ，
tert-butyl, sec-butyl, n-pentyl,
Examples include isopentyl, n-hexyl, isohexyl, heptyl, octyl, nonyl, and decyl. The cycloalkyl used as the above substituent preferably has 3 to 6 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl,
Examples include cyclohexyl. The alkoxy as the above-mentioned substituent preferably has 1 to 4 carbon atoms, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy. [0016] As the aryl as the above substituent,
Examples include phenyl and naphthyl. Examples of the heterocycle as the above-mentioned substituent include pyridine, pyridazine, thiazole, oxazole, and morpholine. The above-mentioned acyl as a substituent has preferably 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and the like. Examples of aralkyl as the above-mentioned substituent include benzyl, phenethyl, and phenylpropyl. Examples of the alkenyl or alkenylene as the above-mentioned substituent include those similar to the above-mentioned alkenyl or methylene. Specific examples of substituted alkyl include trifluoromethyl,
2,2,2-trifluoroethyl, difluoromethyl, trichloromethyl, hydroxymethyl, 1-
Hydroxyethyl, 2-hydroxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, 1-methoxyethyl, 2-methoxyethyl, 2,2-dimethoxyethyl, 2,2-diethoxyethyl, 2-diethoxyphosphorylethyl, etc. can be mentioned. Specific examples of substituted aryl groups include:
For example, 4-chlorophenyl, 4-fluorophenyl,
Examples include 2,4-dichlorophenyl, p-tolyl, 4-methoxyphenyl, 4-(N,N-dimethylamino)phenyl, 4-diethoxyphosphorylphenyl, and the like. Specific examples of substituted alkenyl include 2,2-dichlorovinyl, 3-hydroxy-2-propen-1-yl, 2-methoxyvinyl, and the like. Examples of the optionally substituted hydroxyl group include a hydroxyl group and a suitable substituent for the hydroxyl group, in particular a group used as a protecting group for the hydroxyl group, such as alkoxy, alkenyloxy, aralkyloxy, acyloxy, etc. Examples include aryloxy. As the alkoxy, alkoxy having 1 to 10 carbon atoms (
Examples, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy,
(heptyloxy, nonyloxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc.)
is preferred. The alkenyloxy includes allyl (
Examples of the aralkyloxy include those having 1 to 10 carbon atoms, such as oxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, and 2-cyclohexenylmethoxy; examples of the aralkyloxy include phenyl-C1-4 alkyl; Oxy (
Examples include benzyloxy, phenethyloxy, etc.). The acyloxy is preferably an alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, n-butyryloxy, isobutyryloxy, etc.). Examples of the aryloxy include phenoxy and 4-chlorophenoxy. [0020] Furthermore, each of the alkyl, alkenyl, acyl, and aryl groups in the above alkoxy, alkenyloxy, aralkyloxy, acyloxy, and aryloxy may have a substituent,
The substituent includes, for example, halogen (e.g., fluorine,
chlorine, bromine, iodine, etc.), hydroxyl group, 1 or more carbon atoms
6 alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-
pentyloxy, n-hexyloxy, etc.), and the number of substituents is preferably 1 to 3. Specific examples include trifluoromethoxy, 2,2,2-trifluoroethoxy,
Difluoromethoxy, 2-methoxyethoxy, 4-
Examples include chlorobenzyloxy, 2-(3,4-dimethoxyphenyl)ethoxy, and the like. Substituents when ring A and/or ring B are substituted include:
Among the above-mentioned substituents, an optionally substituted hydroxyl group is preferred. Furthermore, in any of the above cases, when there are two or more substituents, these may form a ring with the benzene ring to which they are bonded via divalent hydrocarbon residues or alkylene dioxy groups. As a specific example of such a case, two substituents are linked to form -(CH2)l
−, −(CH=CH)k− or −O(CH2)p
O- (l, k and p each represent an integer.)
Examples include cases in which such a ring forms a 5-, 6-, and 7-membered ring together with two adjacent carbon atoms of the benzene ring. The lower alkyl group represented by R in the above general formula (I) is a linear group having 1 to 6 carbon atoms,
It may be branched or cyclic, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, n-
Examples include pentyl, isopentyl, neopentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the lower acyl group include those in which the above-mentioned lower alkyl group and carbonyl group are bonded. Preferred groups for R include hydrogen or a lower alkyl group having 1 to 3 carbon atoms. The above general formula (
In I) and (I'), the ester residue in the esterified carboxyl group represented by A is a lower alkyl group in the above description of R and a carbon number of 7 to 15 such as benzyl, phenethyl, phenylpropyl, benzhydryl, etc. These include halogen, alkoxy groups having 1 to 4 carbon atoms, and 1 to 3 aralkyl groups.
may be replaced. [0025] Examples of amidated carboxyl groups include those in which an amino group, which may be substituted with an optionally substituted hydrocarbon residue, and a carbonyl group are bonded. Examples of the optionally substituted hydrocarbon residues include an alkyl group, an aryl group, an alkenyl group, and a heterocyclic group, each of which may be substituted. , the alkenyl group is explained by the general formula (I
) is the same as the explanation in the case of ring A and/or ring B. Furthermore, the heterocycle in the optionally substituted heterocyclic group includes, for example, a 5- to 7-membered heterocycle containing one sulfur atom, nitrogen atom, or oxygen atom, and a 5- to 7-membered heterocycle containing 2 to 4 nitrogen atoms. 5- to 6-membered heterocycles, 5- to 6-membered heterocycles containing 1 to 2 nitrogen atoms and 1 sulfur or oxygen atom; It may be fused with a ring, a benzene ring or a 5-membered ring containing one sulfur atom. Specific examples of the above heterocyclic groups include 2-pyridyl, 3-pyridyl, 4-pyridyl,
Pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrido[
2,3-d]pyrimidyl, benzopyranyl, 1
, 8-naphthyridyl, 1,5-naphthyridyl,
1, 6-naphthyridyl, 1, 7-naphthyridyl,
Quinolyl, Thieno[2,3-b]pyridyl, Tetrazolyl, Thiadiazolyl, Oxadiazolyl,
Examples include triazinyl, triazolyl, thienyl, pyrrolyl, pyrrolinyl, furyl, pyrrolidinyl, benzothienyl, indolyl, imidazolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl, and morpholino. As the substituent which the nuclear heterocycle may have, for example, amino(acyl, halogen, acyl, phenyl, alkyl) may be included as a substituent.
), halogen, nitro, sulfo, cyano, hydroxy, carboxy, oxo, thioxo, alkyl having 1 to 10 carbon atoms (having aryl, halogen, amino, hydroxy, carboxy, alkoxy, alkylsulfonyl, dialkylamino as a substituent) ), cycloalkyl, alkoxy (which may have halogen or hydroxy as a substituent), acyl having 1 to 4 carbon atoms, aryl (
It may have halogen, nitro, alkyl, alkoxy, amino, sulfo, hydroxy, or cyano as a substituent. ), oxo, etc. Specific examples of substituted heterocyclic groups include:
For example, 5-chloro-2-pyridyl, 3-methoxy-
2-pyridyl, 5-methyl-2-benzothiazolyl, 5
-Methyl-4-phenyl-2-thiazolyl, 3-phenyl-5-isoxazolyl, 4-(4-chlorophenyl)-5-methyl-2-oxazolyl, 3-phenyl-1,2,4-thiadiazol-5-yl , 5-methyl-1,3,4-thiadiazol-2-yl, 5
-acetylamino-2-pyrimidyl, 3-methyl-2-
Examples include thienyl, 4,5-dimethyl-2-furanyl, 4-methyl-2-morpholinyl, and the like. In the above general formula (I'), R1
The optionally substituted hydroxyl group or alkyl group represented by R2 and R2 include the optionally substituted hydroxyl group or alkyl group listed as A ring and B ring in general formula (I). The explanation of each substituent is the same as that for general formula (I) above.
Furthermore, in any of the above cases, when there are two or more substituents, these may mutually form a ring with a divalent hydrocarbon residue or an alkylene dioxy group. As a specific example of such a case, two substituents are linked and -(
CH2)l-, -(CH=CH)k- or -O(C
H2) forms a ring represented by pO- (l, k and p each represent an integer), which together with two adjacent carbon atoms of the benzene ring form a 5-, 6- and 7-membered ring There are cases. The substituents represented by R and A in the above general formula (I') are explained in the same manner as in the above general formula (I). The target compounds of the present invention are:
For example, it is manufactured by any of the following methods. Method A [Chemical formula 5] [In the above formula, E has the same meaning as the ester residue in the description of the substituent represented by A, and ring A and ring B have the same meaning as above] Method B [ [In the above formula, ring A, ring B, R and E have the same meanings as above] Method C [Formula 7] [In the above formula, ring A, ring B and R have the same meanings as above] have the same meanings] Method D [Chemical formula 8] [In the above formula, ring A, ring B and R have the same meanings as defined above] Method E [Chemical formula 9] [In the formula above, E' is the same as defined above] In the description of the substituent represented by A, ring A, ring B, and R have the same meanings as described above.] Method F [Formula 10] [In the above formula, C is the same as the above A The same meaning as the amidated carboxyl group in the explanation of the substituent represented by A ring, B
Ring and R have the same meanings as above] Method G When ring A and/or ring B in compound (I) is substituted with a substituted hydroxyl group, the substituent of the hydroxyl group is removed to produce a phenol derivative. Method H When ring A and/or ring B in compound (I) is substituted with a hydroxyl group, an alkyl, aralkyl or acyl substituted product of the hydroxyl group is produced using this compound as a raw material. Each manufacturing method will be explained in detail below. Method A In this method, compound (I-1) is synthesized by heating the compound represented by general formula (II) in the presence of a suitable acid in a suitable solvent or without a solvent. (I) of this Act
The cyclization reaction from I) to (I-1) is carried out using the usual Fisher indole synthesis method.
Synthesis). Said synthetic means may follow any known method, for example as described in W. Su
mpter, F. Miller, The Chemistry of Heterocyclic Compounds (Th
e Chemistry of Heterocycle
ic Compounds), Volume 8, Heterocyclic Compounds with Indole and Carbazole Systems (Heterocyclic
Compounds with Indole and
Carbazole Systems) [Interscience Publishers]
ce Publishers, Inc. New Y
ork), 1954] and W. Houlihan
Author, Volume 25, Page 232 [Wiley-Inter-science 1
972]; New Experimental Chemistry Course 14, Synthesis and Reactions of Organic Compounds (IV) (edited by the Chemical Society of Japan, Maruzen, 1978)
; The method described in Large Organic Chemistry 14, Heterocyclic Compounds I, p. 342 (Asakura Shoten, 1959) is used. For example, the reaction is carried out in an alcohol such as ethanol, methanol, propanol or isopropanol as a solvent in the presence of hydrogen chloride, sulfuric acid, acetic acid, formic acid, phosphoric anhydride, etc., or a Lewis acid such as zinc chloride. The amount of acid used is 0.00% per 1 mole of compound (II). It is preferably about 5 to 10 moles. The reaction temperature is about 10°C to about 20°C in either case.
The temperature is 0°C, preferably about 30°C to about 150°C, and the reaction time is usually 0.5 to 100 hours, preferably 1 to 30 hours. When acetic acid is used as an acid catalyst, acetic acid can also be used as a solvent. Starting compound of this production method (
II), for example W. Sumpter, F. M
Iller, The Chemistry of Heterocyclic Compounds
of Heterocyclic Compounds
), Volume 8, Heterocyclic Compounds with Indole and Carbazole Systems (
Heterocyclic Compoundswit
h Indole and Carbazole Sys
tems) [Interscience Publishers (
Interscience Publishers, I
nc. , New York), 1954] by the known Japp-Klingemann reaction. Method B In this method, (I-1) is substituted with a base (eg, sodium hydride, potassium hydride, sodium amide, triethylamine, N-methylmorpholine, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.). ) in the presence of the formula R-X [wherein X represents a leaving group such as halogen (e.g., chlorine, bromine, iodine) or sulfonyloxy (e.g., mesyloxy, tosyloxy, benzenesulfonyloxy), and R is (I-2) is produced by reacting with a compound represented by [having the same meaning as]. This reaction can be carried out using an appropriate solvent (e.g., tetrahydrofuran, dioxane, ether, toluene, xylene, benzene,
2-dichloroethane, 1, 1, 2, 2-tetrachloroethane, N, N-dimethylformamide,
(dimethyl sulfoxide, etc.) Medium, -20℃~100
It is carried out at a temperature of preferably -10°C to 50°C. (R-
The amount of X) used is preferably in excess of (I-1). Method C This method is carried out according to a known reduction reaction. For example, methods described in New Experimental Chemistry Course 15, Oxidation and Reduction [II] (Maruzen, 1977), such as reduction with metals and metal salts, reduction with metal hydrides, reduction with metal hydrogen complexes, hydrogen transfer. Reduction by reaction, reduction by catalytic hydrogenation, etc. are used. Method D In this method, compound (I-1) or (I-2) produced by method A or method B is subjected to a hydrolysis reaction to form compound (I-4).
Manufacture. This hydrolysis reaction is carried out in a solvent in the presence of an acid or a base according to a conventional method. Examples of solvents include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, N,
N-dimethylformamide, dimethyl sulfoxide,
A mixed solvent of acetone or the like and water can be used as appropriate. Examples of bases that can be used include potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, and lithium hydroxide. Examples of acids include hydrochloric acid, sulfuric acid, acetic acid,
Hydrobromic acid etc. are used. An acid or base is a compound (
I-1) or (I-2) in excess (base:
(1.2 to 6 equivalents, acid: 2 to 50 equivalents). This reaction is usually carried out at about -20°C to about 150°C, preferably at about -10°C to about 100°C. Method E In this method, the carboxylic acid derivative (I-4) is esterified to produce the compound (I-5). This esterification reaction can be carried out by a method known per se, for example (I-4
) and an alkyl halide in the presence of a base for esterification, or reactive derivatives of (I-4), such as acid anhydrides, acid halides (acid chlorides, acid chlorides,
A method of appropriately reacting an acid bromide (acid bromide), imidazolide, or a mixed acid anhydride (eg, anhydride with methyl carbonate, anhydride with ethyl carbonate, anhydride with isobutyl carbonate, etc.) with alcohol is used. Method F In this method, the carboxylic acid derivative (I-4) is amidated to produce the compound (I-6). Carboxylic acid (I-4)
The reaction between (I-4) and the amine derivative can be carried out by a method known per se, for example, by directly condensing (I-4) and the amine derivative with dicyclohexylcarbodiimide, or by using a reactive derivative of (I-4), such as an acid anhydride. thing,
A method of appropriately reacting acid halides (acid chlorides, acid bromides), imidazolides, or mixed acid anhydrides (e.g., anhydrides with methyl carbonate, anhydrides with ethyl carbonate, anhydrides with isobutyl carbonate, etc.) with amine derivatives. etc. are used. The simplest method among these is (
I-4) is a method using an acid halide or mixed acid anhydride. When using an acid halide, the reaction is carried out in a base (e.g. triethylamine, N
-methylmorpholine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, etc.)
It is carried out at -10°C to 50°C in the presence of (I-4), and the amount of amine derivative used is 1 to 1. It is 2 moles. When using a mixed acid anhydride, first (I-4)
and chlorocarbonate (e.g., methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate, etc.) in the presence of a base (e.g., triethylamine, N-methylmorpholine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, etc.) The reaction is preferably carried out at -10°C to 30°C in an appropriate solvent (e.g., chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, water, or a mixture thereof), and the amount of the amine derivative used is (I-4) 1 mol. The amount is 1 to 1.2 mol. Method G In this method, a phenol derivative is produced from a compound (I) in which the substituents of ring A and/or ring B are substituted hydroxyl groups by removing the substituents of the hydroxyl groups. For the conversion of alkyloxy or aralkyloxy derivatives to phenol derivatives, boron tribromide or boron trichloride is preferably used. This reaction is carried out at -50°C to 40°C, preferably -20°C to
Performed at 30°C. The amount of boron tribromide or boron trichloride used is preferably in excess of (I). Conversion of the acyloxy derivative to the phenol derivative is carried out in the same manner as in Method D. Method H In this method, an alkyl, aralkyl or acyl substituted product of the hydroxyl group is produced from a compound (I) in which the substituent on the A ring and/or the B ring is a hydroxyl group. The alkyl or aralkylation of the hydroxyl group is carried out by a method similar to or similar to the above-mentioned method B. Acylation is carried out by a method known per se, but generally compound (I) and a carboxylic acid capable of introducing the acyl group, such as an acid halide, an acid anhydride, or an active ester, are used in an anhydrous organic solvent. This is done by reacting with a suitable acylating agent. The reaction may be carried out in the presence of a suitable organic or inorganic base if desired, and the reaction temperature is between 0°C and 7°C.
A temperature of 0°C and a reaction time of 0.5 to 48 hours are suitable, but a temperature of 20°C to 50°C and a reaction time of 1 to 20 hours are particularly good. [0047] Also, pharmacologically acceptable substances such as hydrochloric acid,
Compounds (I ) can be easily produced. Furthermore, the compound (
When I) has an acidic group such as carboxylic acid in its molecule, a pharmacologically acceptable salt with an alkali metal such as potassium or sodium can be produced by a conventional method. Next, the method for producing compound (I) will be specifically explained with reference to Reference Examples and Examples, but the scope of the present invention is not limited by these. Reference Example Reference Example 1 3,4-xylidine (0.61g), concentrated hydrochloric acid (1.
5ml) Sodium nitrite (0.414g) in the solution
A solution of water (2.0 ml) was added dropwise at 0°C. The mixture was further stirred at 0°C for 30 minutes, then added with sodium acetate (1.23g) and 2-(3,4-dimethoxybenzyl)acetoacetic acid methyl ester (1.33g).
added. The reaction mixture was stirred at room temperature for 1 hour, then poured into water and extracted with ether. The ether layer was washed with a saturated aqueous sodium bicarbonate solution and water in that order, and then dried (MgSO4).
and concentrated under reduced pressure. The residue was methanol (20 ml
) and 1N KOH (5 ml, methanol solution)
was added dropwise at 0°C. After stirring for another hour at 0°C, it was neutralized with acetic acid, poured into water, and the precipitated crystals were collected by filtration and recrystallized from acetone-methanol to give 3-(3,4-dimethoxyphenyl)-2-(3, 4-dimethylphenylhydrazino) methyl propionate (1.25g, 70%)
A pale red prismatic crystal of was obtained. Melting point: 148-150°C. Reference Examples 2 to 41 The compounds shown in Table 1 were obtained in the same manner as in Reference Example 1. 00
49] [Table 1] [Table 2] [0051] [Table 3] [Table 4] [Table 5] [Table 5] [Example] Example 1 2-( 3, 4 -dimethoxyphenylhydrazino)
A mixture of methyl -3-(3,4-dimethylphenyl) propionate (0.8 g), concentrated sulfuric acid (1 ml) and methanol (25 ml) was heated under reflux for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated.
The precipitated crystals were collected by filtration and recrystallized from ether, 5.
6-dimethoxy-3-(3,4-dimethylphenyl) methyl indole-2-carboxylate (0.45
7 g (60%) of colorless prismatic crystals were obtained. Melting point: 185-186°C. Examples 2 to 41 The compounds shown in Table 2 were obtained in the same manner as in Example 1. 00
55] [Table 6] [Table 7] [Table 7] [Table 8] [Table 9] [Table 10] [0060] Example 42 5,6-dimethoxy-3-(3 , 4-dimethoxyphenyl) methyl indole-2-carboxylate ( 7
．． 5g) of N,N-dimethylformamide (1
00ml) solution with oily sodium hydride (60%,
1. After adding 6g) and stirring at room temperature for 30 minutes,
Ethyl iodide (4.8 ml) was added dropwise. The reaction mixture was further stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (
After concentrating (MgSO4), the precipitated crystals were collected by filtration and recrystallized from ether to give methyl 1-ethyl-5,6-dimethoxy-3-(3,4-dimethoxyphenyl) indole-2-carboxylate (6.38 g, 77%)
A pale red prismatic crystal of was obtained. Melting point: 191-192°C. Examples 43-75 The compounds shown in Table 3 were obtained in the same manner as in Example 42. 0
[Table 11] [Table 12] [Table 12] [Table 13] [Table 14] Example 76 5,6-dimethoxy-3-(4-methoxyphenyl) indole-2-carboxylic acid Methyl (0.25g
) in tetrahydrofuran (10 ml) and lithium aluminum hydride (LiAlH4) (56 mg)
The mixture was added dropwise to a suspension of 10% in tetrahydrofuran (10ml) at room temperature. After further stirring at room temperature for 2 hours, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (
After concentration (MgSO4), the precipitated crystals were collected by filtration and recrystallized from acetone to give 2-hydroxymethyl-5,6.
Colorless prism crystals of -dimethoxy-3-(4-methoxyphenyl)indole (0.145 g, 63%) were obtained. Melting point: 169-170°C. Examples 77-80 The compounds shown in Table 4 were obtained in the same manner as in Example 76. 0
[Table 15] Example 81 Methyl 5,6-dimethoxy-3-(3,4-dimethoxyphenyl) indole-2-carboxylate (0
．． A mixture of 54g), 2N-NaOH (10ml) and methanol (25ml) was stirred under reflux for 3 hours. The reaction mixture was poured into water, acidified with 6N-HCl, and extracted with chloroform. The chloroform layer was washed with water, dried (MgSO4), concentrated, the precipitated crystals were collected by filtration, and recrystallized from methanol to give 5,6-dimethoxy-3-(3,
Pale red prismatic crystals of (4-dimethoxyphenyl) indole-2-carboxylic acid (0.443 g, 85%) were obtained. Melting point: 198-200°C. Examples 82 to 85 The compounds shown in Table 5 were obtained in the same manner as in Example 81. 0
[Table 16] Example 86 5,6-dimethoxy-3-(3,4-dimethoxyphenyl) indole-2-carboxylic acid (0.35
Oxalyl chloride (0.1 ml) was added to a solution of N,N-dimethylformamide (7 g) and N,N-dimethylformamide (1 drop) in tetrahydrofuran (10 ml), stirred at room temperature for 30 minutes, and then concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 ml). Meanwhile, a solution of diethylaminophosphonate (0.92 g) in tetrahydrofuran (5 ml) was added with oily sodium hydride (60%
, 0.133 g) was added under ice cooling and stirred at the same temperature for 15 minutes. The aforementioned tetrahydrofuran solution was added to this mixture under ice cooling. The reaction mixture was stirred for an additional 30 minutes under ice cooling, then poured into water and extracted with ethyl acetate. The ethyl acetate layer was prepared using saturated aqueous sodium hydrogen carbonate solution, 2N HCl
and water, dried (MgSO4), concentrated, collected the precipitated crystals by filtration, and recrystallized from ethyl acetate to give N-diethoxyphosphoryl-5,6-dimethoxy-3-(3,
Pale yellow prismatic crystals of (4-dimethoxyphenyl) indole-2-carboxamide (0.056 g, 11%) were obtained. Melting point: 217-219°C. Example 87 5,6-dimethoxy-3-(3,4-dimethoxyphenyl) indole-2-carboxylic acid (0.2
g) and N,N-dimethylformamide (one drop)
Oxalyl chloride (0.06 ml) was added to a tetrahydrofuran (10 ml) solution, stirred at room temperature for 30 minutes, and then concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 ml). This tetrahydrofuran solution was mixed with diethyl 4-aminobenzylphosphonate (
0.204g) and triethylamine (0.09g)
ml) in tetrahydrofuran (10 ml). The reaction mixture was further stirred at room temperature for 2 hours, then poured into water and extracted with chloroform. The chloroform layer consists of water, saturated aqueous sodium bicarbonate solution, water, 2NHC
After washing with N-[4
-(diethoxyphosphorylmethyl) phenyl]-5
, 6-dimethoxy-3-(3,4-dimethoxyphenyl) indole-2-carboxamide (0.2
83 g (87%) of pale yellow prismatic crystals were obtained. Melting point: 213-215°C. Examples 88-90 The compounds shown in Table 6 were obtained in the same manner as in Example 87. 0
[Table 17] Example 91 Methyl 3-(4-methoxyphenyl)-5,6-dimethylindole-2-carboxylate (0.3 g)
of boron tribromide in dichloromethane (10 ml) solution.
(0.18 ml) of dichloromethane (0.36
ml) solution was added dropwise at 0°C and stirred at the same temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), concentrated, and the precipitated crystals were collected by filtration and recrystallized from acetone to give methyl 3-(4-hydroxyphenyl)-5,6-dimethylindole-2-carboxylate (0. 127g, 44%)
Colorless needle crystals were obtained. Melting point 247-248°C. Examples 92 to 98 The compounds shown in Table 7 were obtained in the same manner as in Example 91. 0
[Table 18] Example 99 5,6-dihydroxy-3-(3,4-dihydroxyphenyl) Methyl indole-2-carboxylate (
0.2 g) of N,N-dimethylformamide (
Potassium carbonate (0.701 g) and ethyl iodide (0.42 ml) were added to the solution (10 ml) and stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography using ethyl acetate-hexane (1:4, v/v).
5,6-diethoxy-3-(
Methyl indole-2-carboxylate (3,4-diethoxyphenyl) was obtained. Recrystallized from ether-isopropyl ether to give colorless prismatic crystals (0.131 g,
48%) was obtained. Melting point: 134-135°C. Examples 100 to 104 The compounds shown in Table 8 were obtained in the same manner as in Example 99. [Table 19] Example 105 N,N of 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylic acid (0.3 g)
- Potassium carbonate (0.139 g) and ethyl iodide (0.13 ml) were added to a dimethylformamide (5 ml) solution, and after stirring at room temperature for 3 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), concentrated, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 5,6-dimethoxy-3-(3,4
Pale red prismatic crystals of ethyl -dimethoxyphenyl)indole-2-carboxylate (0.272 g, 84%) were obtained. Melting point: 171-172°C. Examples 106 to 110 The compounds shown in Table 9 were obtained in the same manner as in Example 105. [Table 20] Example 111 N,N was added to a solution of 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylic acid (2.0 g) in tetrahydrofuran (50 ml). -dimethylformamide (3 drops) and oxalyl chloride (0.59 m
1) was added, stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The residue was dissolved in benzene (20ml). This benzene solution was mixed with tert-butanol (0.79 ml).
) and N,N-dimethylaniline (0.85 ml) in benzene (30 ml). The reaction mixture was stirred overnight at room temperature and then mixed with water, saturated aqueous sodium bicarbonate solution,
Washed with water in sequence, dried (MgSO4), concentrated, collected the precipitated crystals by filtration, and recrystallized from acetone to obtain 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2.
-tert-butyl carboxylate (1.61g, 70%
) colorless prism crystals were obtained. Melting point: 185-186°C. Next, the method and results for measuring the bone resorption inhibitory effect of compound (I) will be shown. [Bone resorption inhibitory effect] The bone resorption inhibitory effect was measured using Royce's method [Journal of Clinical Investigation (J. Cl.
in. Invest. )44, 103-116 (
1965)]. That is, Sprague-Dawle on the 19th day of pregnancy.
45Ca (calcium isotope, C
50 μCi of aCl2 solution was injected subcutaneously, the abdomen was opened the next day, the fetal rat was removed aseptically, and the left and right forearm bones (radius, ulna) of the fetal rat were separated from the trunk under a dissecting microscope, and connective tissue and cartilage were removed as much as possible. This was used as a bone culture sample. 0.6ml of BGJb for each piece of bone
Medium (Fitton-Jackson mod
cation, [GIBCO Laborator
ies (USA)] with bovine serum albumin, 2 mg/ml
After culturing at 37°C for 24 hours in the above medium containing the compound at 10 μg/ml and 1 μg/ml, the culture was continued for another 2 days, and the radioactivity of 45Ca in the medium and The radioactivity of 45Ca in the bone was measured, and the ratio (%) of 45Ca released from the bone into the medium was determined according to the following formula. ##EQU00001## Bones obtained from fetuses from the same litter were similarly cultured for 2 days without addition of the compound, and this was used as a control group. The mean value ± standard deviation of the values obtained from five bones in each group was determined, and the ratio (%) of this value to the value of the control group was determined and shown in Table 10. [Table 21] As is clear from Table 10, compound (I) has an excellent bone resorption inhibitory effect. Therefore, the compound (
I) can be administered to mammals (eg, mice, rats, rabbits, dogs, cats, cows, pigs, humans, etc.) and used as a bone resorption inhibitor. [0078] When administering the present compound to humans, the administration method may be either oral or parenteral routes. Compositions for oral administration include solid or liquid dosage forms;
Specifically, tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, and capsules (
(including soft capsules), syrups, emulsions, and suspensions. Such compositions are produced by methods known per se and contain carriers or excipients commonly used in the pharmaceutical field. For example, carriers and excipients for tablets include lactose, starch, sucrose,
Examples include magnesium stearate. Compositions for parenteral administration include, for example, injections and suppositories, and injections include dosage forms such as subcutaneous injections, intradermal injections, and intramuscular injections. Such an injection can be prepared by a method known per se, that is, compound (I
) in a sterile aqueous or oily liquid commonly used for injections. Examples of aqueous solutions for injection include physiological saline and isotonic solutions, which may be used in combination with appropriate suspending agents such as sodium carboxymethyl cellulose, nonionic surfactants, etc., if necessary. Examples of oily liquids include sesame oil and soybean oil, and solubilizing agents such as benzyl benzoate and benzyl alcohol may be used in combination. The prepared injection solution is usually filled into suitable ampoules. When compound (I) or a salt thereof is used as a bone resorption inhibitor, the daily dose for adults is:
1-500 mg for oral administration, preferably 10-15
Estimated to be 0 mg. Formulation Example 1 Composition of one tablet Among the above compositions, (1), (2), (3) and (4) were mixed, water was added thereto, and kneaded.
The mixture was vacuum dried at 40° C. for 16 hours, crushed in a mortar, and passed through a 16-mesh sieve to form granules. (6) was added to the granules and mixed, and tablets of 200 mg each were manufactured using a rotary tablet press (manufactured by Kikusui Seisakusho). Formulation Example 2 Among the above compositions, (1), (2), (3),
Tablets were produced in the same manner as in Formulation Example 1 using (4), (5) and (6). Apply the acetone solution of (7) to this tablet using a bar coater (
(manufactured by Freund, West Germany), and
Enteric-coated tablets were manufactured with 210 mg per tablet. Formulation Example 3 Composition in Capsule Among the above compositions, (1), (2), (3) and (4) were mixed, water was added thereto, kneaded, and then 4
The mixture was vacuum dried at 0° C. for 16 hours, ground in a mortar, and passed through a 16-mesh sieve to form granules. The granules were filled into gelatin No. 3 capsules using a capsule filling machine (manufactured by Xanaci, Italy) to produce capsules. Formulation Example 4 Among the above compositions, (2), (3), (4)
, (5) and (6) are dissolved in about half the amount of distilled water above at 80°C while stirring. The resulting solution was heated to 40°C.
(1) is dissolved in the solution. The solution was then adjusted to the final volume by adding distilled water for injection.
The injectable solution is prepared by sterilization by sterile filtration using a suitable filter paper. Effects of the Invention The drug of the present invention has a strong bone resorption inhibitory effect and acts directly on bones to improve bone metabolism, so it can be expected to be used as a preventive and therapeutic drug for osteoporosis.

Claims (2)

[Claims] Claim 1: General formula [Formula 1] [wherein A ring and B ring may be substituted, R is a hydrogen atom, a lower alkyl group or an acyl group, and A is a hydroxymethyl group or an esterified or A bone resorption inhibitor containing an indole derivative or a salt thereof as an active ingredient. [Claim 2] General formula [Formula 2] [wherein n and m represent integers of 2 to 4, R1 and R
2 is the same or different and represents an optionally substituted hydroxyl group or an optionally substituted alkyl group, or two of R1 or R2 are a divalent hydrocarbon residue or an alkylene dioxy group; Each may form a ring with the benzene ring to which it is bonded, R represents a hydrogen atom, a lower alkyl group, or an acyl group, and A represents a hydroxymethyl group or a carboxyl group that may be esterified or amidated. ] An indole derivative or a salt thereof.