5-Hydroxyindole-3-carboxylic acid amide compounds, pharmaceutical compositions and use

Hydroxyindole-3-carboxylic acid amide compounds of the general formula: ##STR1## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are, the same or different, respectively a hydrogen atom, an alkyl group, an aryl group, an aralkyl group or a heteroaryl group, or R.sup.1 and R.sup.2 and/or R.sup.3 and R.sup.4 are respectively groups which are combined to each other taken together with the adjacent nitrogen atom to form a heterocyclic group, R.sup.5 is an alkyl group, R.sup.6 is a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group or an aralkyl group and X is a hydrogen atom, a halogen atom or a lower alkanoyl group, or their acid addition salts. These compounds are of use as diuretics or a therapeutic medicine for circulation system diseases.

TECHNICAL FIELD 
The present invention relates to 5-hydroxyindole-3-carboxylic acid amide 
compounds and their acid addition salts which are novel and of use as 
diuretics or therapeutic medicines for circulation system diseases. 
BACKGROUND ART 
With an increase in the population of aged people, various diseases of 
circulation systems, particularly cerebral and cardiac circulation system 
diseases caused by atheroclerosis, hypertension, etc. have become a 
serious social problem. As the therapeutic medicines for such diseases, 
useful medicaments are those which have hyperkinemic actions, particularly 
those which exhibit vasodilating actions on cerebral blood vessels and 
coronary blood vessels, or those which have diuretic actions. 
Also, in recent years, better use have been made of the medicaments which 
have anti-platelet aggregation actions for the treatment of thrombotic 
diseases. Furthermore, in view of the fact that leucotrienes which are 
metabolically produced by 5-lipoxygenase on arachidonic acid cascade 
possess potent coronary vasospasm, attention has been paid to the 
relationship between cardiac diseases such as angina pectoris and 
leukotrienes. Therefore it is said that the compounds which have 
5-lipoxygenase-inhibitory actions are of use for the treatment of such 
circulatory diseases. 
In U.S. Pat. No. 2852527 and Journal of Medicinal Chemistry, vol. 10, p. 
264 (1967), there are described lower alkyl esters of 2-lower 
alkyl-5-hydroxy-4-tertiary-aminoindole-3-carboxylic acids which have 
central nervous system-stimulating actions and hypoglycemic actions. 
However, the forementioned known compounds have high toxicity, and there 
has not been any suggestion about pharmacological actions against 
circulatory diseases. 
In the specification of U.S. Pat. No. 4581355, there are disclosed some 
species of indole-3-carboxamide compounds, which have 5-lipoxygenase 
actions, antihypertensive actions or cardiac actions, but these compounds 
do not exhibit any diuretic actions. 
DISCLOSURE OF THE INVENTION 
For the purpose of developing compounds which are useful as diuretics, the 
present inventors have intensively conducted studies to find that novel 
5-hydroxyindole-3-carboxylic acid amide compounds and their acid addition 
salts have antihypertensive actions, cerebral vasodilating actions, 
coronary vasodilating actions, anti-platelet aggregation actions and/or 
5-lipoxygenase-inhibiting actions besides excellent diuretic actions, and 
that thus they are useful as diuretics, antihypertensive agents and 
therapeutic agents for cerebral and cardiac circulation system diseases. 
These findings have resulted in the completion of the present invention. 
That is, the present invention relates to 5-hydroxyindole-3-carboxylic acid 
amide compounds of the general formula: 
##STR2## 
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are, the same or different, 
independently a hydrogen atom, an alkyl group, an aryl group, an aralkyl 
group or a heteroaryl group, or R.sup.1 and R.sup.2 and/or R.sup.3 and 
R.sup.4 respectively are combined to each other to form a heterocyclic 
group as taken together with the adjacent nitrogen atom, R.sup.5 is an 
alkyl group, R.sup.6 is a hydrogen atom, an alkyl group, a cycloalkyl 
group, an aryl group or an aralkyl group and X is a hydrogen atom, a 
halogen atom or a lower alkanoyl group, or their acid addition salts. 
With reference to the above-mentioned substituents, the halogen atom 
represents chlorine, bromine, fluorine or iodine atom, the alkyl group 
represents a straight- or branched-chain alkyl having 1 to 8 carbon atoms 
such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 
pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, 2-ethylhexyl or 
1,1,3,3-tetramethylbutyl, the lower alkanoyl group represents an alkanoyl 
having 2 to 5 carbon atoms such as acetyl, propionyl, butyryl, pivaloyl or 
valeryl, the cycloalkyl group represents a cycloalkyl having 3 to 7 carbon 
atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 
cycloheptyl, the aryl group represents phenyl, naphthyl or so on, the 
aralkyl group represents benzyl, phenylethyl, phenylpropyl, phenylbutyl or 
so on, the heteroaryl group represents pyrazolyl, imidazolyl, pyridyl, 
furyl, thienyl, pyrimidinyl, quinolyl, benzofuryl, benzothienyl, 
benzimidazolyl or the like, and said aromatic (hetero) cyclic groups may 
have on the ring at least one substitutent selected from among halogen 
atoms (as exemplified by the above-mentioned), alkyl groups (as 
exemplified by the above-mentioned), alkoxy groups (straight- or 
branched-chain alkoxy having 1 to 8 carbon atoms such as methoxy, ethoxy, 
propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, 
heptyloxy and octyloxy), trifluoromethyl group, nitro group and amino 
group. The heterocyclic group formed combinedly as taken together with the 
adjacent nitrogen atom represents 1-pyrrolidinyl, piperidino, 
1-piperazinyl, 4-methyl-1-piperazinyl, 4-(2-hydroxyethyl)-1-piperazinyl, 
4-phenyl-1-piperazinyl, 4-diphenylmethyl- 1-piperazinyl, morpholino or so 
on. 
As the acid addition salts of the compounds of formula (I), there are 
mentioned inorganic acid salts such as hydrochloride, hydrobromide, 
phosphate and sulfate and organic acid salts such as fumarate, maleate, 
succinate, tartrate, methanesulfonate and pamoate. As such acid addition 
salts, those which are pharmaceutically acceptable in view of the object 
of the present invention to provide drugs for human beings are preferred. 
As the compounds of formula (I), preferred are the compounds wherein 
R.sup.1 and R.sup.2 represents groups which are combined to each other 
with the adjacent nitrogen atom to form piperidine and among them, more 
preferable compounds include 
4-(5-hydroxy-2-methyl-4-piperidinomethylindol-3-ylcarbonyl)morpholine, 
4-(6-bromo-5-hydroxy-2-methyl-4-piperidinomethylindol-3-ylcarbonyl)morphol 
ine, 
N,N-dibutyl-5-hydroxy-2-methyl-1-(2-phenylethyl)-4-piperidinomethylindole- 
3-carboxyamide, 
N,N-dibutyl-5-hydroxy-2-methyl-1-(2-phenylethyl)-4-piperidinomethyl-6-prop 
ionylindole-3-carboxamide, 
N,N-dibutyl-1-hexyl-5-hydroxy-2-methyl-4-piperidinomethyl-6-propionylindol 
e-3-carboxamide, 
1,N-dibutyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3-carboxamide, 
6-bromo-1,N-dibutyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3-carboxam 
ide, 
6-bromo-N-butyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3-carboxamide, 
4-[6-bromo-5-hydroxy-2-methyl-1-(2-phenylethyl)-4-piperidinomethylindol-3- 
ylcarbonyl]morpholine, 
4-(6-bromo-1-butyl-5-hydroxy-2-methyl-4-piperidinomethylindol-3-ylcarbonyl 
)morpholine, 
N,N-dibutyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3-carboxamide, 
6-bromo-N,N-dibutyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3-carboxam 
ide, 1-(6 
-bromo-5-hydroxy-2-methyl-4-piperidindomethylindol-3-ylcarbonyl)piperidine 
, and 
N,N-dibutyl-5-hydroxy-2-methyl-1-phenyl-4-piperidinomethyl-6-propionylindo 
le-3-carboxamide and their acid addition salts. 
The compounds of formula (I) of the present invention can be produced by, 
for example, the following methods. 
Method 1 
The compounds of formula (I) wherein X is a hydrogen atom can be produced 
by subjecting the compounds of formula 
##STR3## 
wherein each of the symbols is as defined above, to the Mannich reaction 
(reviewed in Organic Reactions, vol. 1, p. 303 (1942) or so on). 
The reaction proceeds preferably in a solvent inert to the reaction such as 
methanol, acetic acid or dioxane at room temperature to reflux. 
Method 2 
The compounds of formula (I) wherein X is a lower alkanoyl group can be 
produced by subjecting the corresponding compounds of formula (I) wherein 
X is a hydrogen atom to the Friedel-Crafts reaction. 
The reaction can proceed by allowing to react a lower alkanoyl halide with 
the compound of formula (I) in the presence of a Lewis acid such as 
aluminum chloride, tin tetrachloride or ferric chloride in a solvent inert 
to the reaction such as dichloromethane, dichloroethane or nitrobenzene. 
Method 3 
The compounds of formula (I) wherein X is a halogen atom can be produced by 
subjecting the corresponding compounds of formula (I) wherein X is a 
hydrogen atom to halogenation reaction. 
The reaction can be conducted with the use of a halogenation agent such as 
bromine, sulfuryl chloride, perchloryl fluoride and iodine monochloride in 
a solvent inert to the reaction such as acetic acid, chloroform and carbon 
tetrachloride. 
Also, the compounds of formula (I) wherein X is a halogen atom can be 
produced by subjecting the corresponding compounds of formula 
##STR4## 
wherein X' is a halogen atom and other symbols are as defined above to the 
Mannich reaction in the same manner as Method 1 mentioned above. 
Method 4 
The compounds of formula (I) wherein either R.sup.1 or R.sup.2 is a 
hydrogen atom or both R.sup.1 and R.sup.2 are hydrogen atoms can be 
produced by respectively synthesizing the compounds of formula (I) wherein 
either R.sup.1 or R.sup.2 is benzyl or both R.sup.1 and R.sup.2 are 
benzyl, followed by subjecting the synthesized compounds to a conventional 
debenzylation reaction such as catalytic hydrogenation reaction. 
The compounds of formula (I) thus obtained can be converted to the 
above-described corresponding acid addition salts by the conventional 
treatment with an inorganic acid such as hydrochloric acid, hydrobromic 
acid, phosphoric acid or, sulfuric acid or an organic acid such as fumaric 
acid, maleic acid, succinic acid, citric acid, tartaric acid, 
methanesulfonic acid or pamoic acid.

The diuretic actions and the actions on circulation systems of the 
compounds of this invention are described by illustrating the following 
Pharmacological Experimental Examples. 
PHARMACOLOGICAL EXPERIMENTAL EXAMPLE 1 
Diuretic action 
Male Wistar strain rats (each weighing 180 to 220 g, six animals per group) 
were subjected to the experiment after they had been fasted for 18 hours 
and further deprived of food and water for 3 hours. 
After the rats were orally administered with test compounds suspended in a 
0.9% saline solution at the dose of 25 ml/kg, each of them was put in a 
metabolic cage. The urine excreted within 6 hours after the administration 
was collected, and the urine volume and sodium (Na), potassium (K) and 
chlorine (Cl) ions were assayed. The urine sodium and potassium ions were 
measured by the flame spectrophotometry and the chlorine ions were 
measured by the chloride counter. The results are shown in Table 1. 
The test compounds were the compounds described below in Examples and the 
following (as applies to the following Pharmacological Experimental 
Examples), and the compounds numbers respectively correspond to the 
compound numbers described at the end of the compound names recited in 
Examples and the following. In the table, each of the numerals represents 
average value.+-.average error and the mark * designates that the value is 
statistically significant as compared with the control by P&lt;0.05 and mark 
** designates that the value is statistically signficant by P&lt;0.01. 
TABLE 1 
__________________________________________________________________________ 
Dose Urine Volume 
Excretion of Electrolyte 
(mg/kg, 
(ml/100 g body 
(.mu.eq/100 g body weight/ 6 hrs.) 
Test Compound 
p.o.) 
weight/ 6 hrs.) 
Na K Cl Na/K 
__________________________________________________________________________ 
Compound (2) 
0 0.8 .+-. 0.1 
134 .+-. 19 
70 .+-. 7 
170 .+-. 19 
2.0 .+-. 0.3 
3.0 2.0 .+-. 0.2** 
284 .+-. 30** 
95 .+-. 7* 
349 .+-. 27** 
3.1 .+-. 0.3* 
Compound (10) 
0 1.0 .+-. 0.3 
148 .+-. 30 
51 .+-. 8 
169 .+-. 23 
2.8 .+-. 0.2 
10.0 2.6 .+-. 0.3** 
402 .+-. 43** 
73 .+-. 8* 
379 .+-. 35** 
5.8 .+-. 0.7** 
Compound (17) 
0 1.5 .+-. 0.2 
212 .+-. 21 
75 .+-. 7 
256 .+-. 20 
2.9 .+-. 0.4 
10.0 2.4 .+-. 0.2** 
346 .+-. 28** 
64 .+-. 4 
358 .+-. 25** 
5.7 .+-. 0.9** 
__________________________________________________________________________ 
PHARAMACOLOGICAL EXPERIMENTAL EXAMPLE 2 
Action on coronary blood flow 
A mongrel adult dog was anesthetized by intravenous administration with 
sodium pentobarbital at the dose of 30 mg/kg body weight. In accordance 
with the method by Yago et al [Folia pharmacologica japonica, vol. 57, p. 
380 (1961)], the left coronary artery was perfused and the volume of blood 
flow was measured. The test compounds were administered in the coronary 
artery at a dosage of 10 to 30 .mu.l. The effects of the test compounds on 
the coronary blood flow were represented by ED.sub.50 (.mu.g) which was 
determined as the dose required for increasing the coronary blood flow to 
the level of 50% of the effect which was attained by administering the 
coronary artery 3 .mu.g of Nifedipine [dimethyl 
2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate]. The 
results are tabulated in Table 2. 
PHARMACOLOGICAL EXPERIMENTAL EXAMPLE 3 
Action on vertebrarterial blood flow 
After mongrel adult dog was anesthetized by intravenous administration of 
sodium pentobarbital at the dose of 25 mg/kg body weight, the right 
vertebrartery was perfused and the volume of blood flow was measured. The 
test compounds were administered in the vertebral artery. 
With the maximum increase rate in the blood flow being taken as 100% when 
100 .mu.g of papaverine hydrochloride 
(1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinoline hydrochloride) 
was administered in the vertebral artery, the effects of the test 
compounds were represented by ED.sub.100 (.mu.g) which denotes the dose 
required for attaining an increased rate of the blood flow of 100%. The 
results are indicated in Table 2. 
TABLE 2 
______________________________________ 
Vertebrarterial 
vasodilating 
Coronary vasodilating 
action, 
Test Compound 
action, ED.sub.50 (.mu.g) 
ED.sub.100 (.mu.g) 
______________________________________ 
Compound (4) 
12 63 
Compound (6) 
10 48 
Compound (8) 
63 58 
Compound (25) 
22 76 
______________________________________ 
PHARMACOLOGICAL EXPERIMENTAL EXAMPLE 4 
5-Lipoxygenase-inhibitory action 
In accordance with the method of Ochi et al (J. Biol. Chem., vol. 258, pp. 
5754-5758 (1983)), the 105,000.times.g supernatant fraction of 
intraperitoneal polymorph leukocyte of guinea pigs was prepared, and the 
capability of producing 5-hydroxyeicosatetraenoic acid (5-HETE) from 
arachidonic acid was assayed. 
Male guinea pigs weighing about 500 g were intraperitoneally administered 
with 1/10 volume (at the dose of 10 ml/100 g body weight) of a 2% casein 
solution and operated in the abdomen 16-18 hours after the administration. 
The intraperitoneal effusion was taken and the insdie of the abdomen was 
washed with a saline solution containing 10 mM phosphate buffer solution 
(pH 7.4) twice. The obtained effusion and the washing solution were 
collected and centrifuged at 150.times.g for five minutes. A 0.2% saline 
solution was added to the sediment, followed by hypotonic treatment to 
subject the mixed erythrocyte to hemolysis. After a 1.6% saline solution 
was added thereto to make the mixture isotonic, it was centrifuged in the 
same manner and suspended in 50 mM Hepes buffer solution (pH 8.0). The 
suspension was treated with supersonic waves (by Branson sonifier, model 
185) and centrifuged at 10,000.times.g for 10 minutes. The supernatant was 
further centrifuged at 105,000.times.g for 60 minutes. The supernatant 
thus obtained was taken as the 5-lipoxygenase fraction which was freezed 
to -70.degree. C. to be preserved. 
The reaction mixture was prepared in the total amount of 0.2 ml from 
5-lipoxygenase fraction (0.5 mg protein), 3.4 .mu.M [1-.sup.14 C] 
arachidonic acid (40 nCi, Amersham International), 1 mM potassium 
chloride, 2 mM ATP and 1 mM glutathion in 50 mM Tris-hydrochloride buffer 
solution (pH 7.3). The test compound dissolved in dimethylsulfoxide and 
the supernatant fraction were pre-incubated at 30.degree. C. for 2 
minutes. Afer .sup.14 C-arachidonic acid was added thereto, the mixture 
was incubated at 30.degree. C. for 3 minutes. The reaction was terminated 
by adding 20 .mu.l of 0.4M citric acid solution. The reaction mixture was 
extracted with 1 ml of ethyl ether, wherewith 0.5 g of anhydrous sodium 
sulfate was admixed. The mixture was lightly centrifuged. The supernatant 
(0.6 ml) was put in another test tube, which was evaporated to dryness. 
The residue was dissloved in 50 .mu.l of chloroform-methanol (2:1), and 
the solution was spotted on the silica gel plate (Whatman, LK.sub.5 DF) 
where standard arachidonic acid, prostaglandin B.sub.2, 5- and 12-HETE had 
in advance been spotted as the markers. The thin-layer chormatography was 
conducted by the use of ethyl ether-petroleum ether-acetic acid 
(85:15:0.1) as the developing solvent. The amount of the produced 5-HETE 
was assayed by means of the Linear analyzer (Berthold, model LB282). 
As a result, the 50% inhibitory concentration of Compound (4) and Compound 
(25) against the production of 5-HETE ws respectively 20 .mu.M and 19 
.mu.M. 
Though ddY strain mice were intraperitoneally or orally administered with 
Compound (2) at the dose of 300 mg/kg, none of them was observed to die. 
As shown in the foregoing Experimental Examples, the compounds of this 
invention are useful as diuretics and therapeutic medicines for chronic 
edema, hypertension, ischemic diseases in the brain and heart, thrombotic 
diseases, congestive heart diseases, cerebral and coronary-vasospasms and 
so on. 
When the compounds of the present invention are used as the above-mentioned 
medicines, a therapeutically effective amount of the compounds of the 
present invention are, if suitable, in an admixture with a 
pharmacologically acceptable pharmaceutical additives (carriers, 
excipients, diluents and so on), formed into powders, granules, tablets, 
capsules and injectable preparations, which can be administered orally or 
parenterally. While the dose varies depending upon target diseases to be 
treated, symptoms, compounds to be adminstered, when orally administered, 
the dose is generally about 1 mg to 500 mg daily per adult. 
PHARMACEUTICAL FORMULATION EXAMPLE 
The tablet containing 5 mg of the compound of the present invention can be 
prepared by the following formulation. 
______________________________________ 
Compound (2) 5.0 mg 
Corn starch 15.0 mg 
Lactose 60.0 mg 
Fine crystalline cellulose 
16.0 mg 
Talc 3.0 mg 
Magnesium stearate 1.0 mg 
100.0 mg 
______________________________________ 
The tablet can be, if desired, made sugar-coated or film-coated tablet. 
EXAMPLE 
The present invention is concretely described below by illustrating Working 
Examples, which are not to be construed as limitative. 
EXAMPLE 1 
4-(5-Hydroxy-2-methyl-4-piperidinomethyl-1H-indol-3-ylcarbonyl)morphopine 
[Compound (1)] 
Piperidine (2 g) and 1.9 g of a 37% formalin were added to a solution of 5 
g of 4-(5-hydroxy-2-methyl-1H-indol-3-ylcarbonyl)morpholine in 100 ml of 
acetic acid, and after the mixture was stirred at 60.degree. C. for 4 
hours, the acetic acid was distilled off under reduced pressure. Ethyl 
acetate and water were added to the residue, which was made alkaline with 
potassium carbonate to separate crystals. The crystals were collected by 
filtration and recrystallized from ethyl acetate-methanol to give 2.3 g of 
the titled compound in the form of white crystals, m.p. 
232.degree.-238.degree. C. (decomposition). 
EXAMPLE 2 
4-(6-Bromo-5-hydroxy-2-methyl-4-piperidinomethyl-1H-indol-3-ylcarbonyl)morp 
holine [Compound (2)] 
Bromine (2.3 g) was dropwise added to a solution of 5 g of Compound (1) in 
50 ml of acetic acid at the temperature of 15.degree. C. After the mixture 
was stirred at room temperature for two hours, isopropyl ether was added. 
Water was added to the separated oily substance, which was made alkaline 
with potassium carbonate, followed by extraction with chloroform. After 
the organic layer was washed with water and dried, the solvent was 
distilled off. Ethyl acetate was added to the residue to separate 
crystals. The crystals were collected by filration and recrystallized from 
methanol to give 2.8 g of the titled compound as white crystals, m.p. 
216.degree.-218.degree. C. (decomposition). 
EXAMPLE 3 
N,N-Dibutyl-5-hydroxy-2-methyl-1-(2-phenylethyl)-4-piperidinomethylindole-3 
-carboxamide [Compound (3)] 
Piperidine (11 g) and 11 g of 37% formalin were added to a solution of 44 g 
of N,N-dibutyl-5-hydroxy-2-methyl-1-(2-phenylethyl)indole-3-carboxamide in 
20 m of acetic acid, and the mixture was stirred at 60.degree. C. for 2 
hours. The acetic acid was distilled off under reduced pressure. Water was 
added to the residue, which was made alkaline with potassium carbonate, 
followed by extraction with ethyl acetate. After the organic layer was 
washed with water and dried, the solvent was distilled off. Hexane was 
added to the residue to separate crystals. The crystals were collected by 
filtration and recrystallized from isopropyl ether to give 31 g of the 
titled compound as white crystals, m.p. 105.degree.-107.degree. C. 
EXAMPLE 4 
N,N-Dibutyl-5-hydroxy-2-methyl-1-(2-phenylethyl)-4-piperidinomethyl-6-propi 
onylindole-3-carboxamide [Compound (4)] 
Anhydrous aluminum chloride (8.6 g), 6 g of propionyl chloride and 13 g of 
Compound (3) were added to 100 ml of dichloroethane, and the mixture was 
heated under reflux for 5 hours. The reaction mixture was added to ice 
water, which was extracted with chloroform. Potassium carbonate was added 
to the extracted layer and the mixture was stirred for 30 minutes. After 
the organic layer was washed with water and dried, the solvent was 
distilled off. Petroleum ether was added to the residue to separate 
crystals. The crystals were collected by filtration and recrystallized 
twice from hexane to give 7.7 g of the titled compound as yellow crystals, 
m.p. 111.degree.-112.degree. C. 
EXAMPLE 5 
N,N-Dibutyl-1-hexyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3-carboxami 
de hydrochloride [Compound (5)] 
Piperidine (10.6 g) and 10.4 g of 37% formalin were added to a solution of 
43.7 g of N,N-dibutyl-1-hexyl-5-hydroxy-2-methylindole-3-carboxamide in 
200 ml of acetic acid, and the mixtue was stirred at 60.degree. C. for 2 
hours. The acetic acid was distilled off under reduced pressure. Water was 
added tothe residue, which was made alkaline with potassium carbonate, 
followed by extraction with ethyl acetate. After the organic layer was 
washed with water and dried, the solvent was distilled off. The residue 
was converted to the hydrochloride with the use of ethanolhydrochloric 
acid, followed by recrystallization from acetone to give 22 g of the 
titled compound as white crystals, m.p. 170.degree.-171.degree. C. 
(decomposition). 
EXAMPLE 6 
N,N-dibutyl-1-hexyl-5-hydroxy-2-methyl-4-piperidinomethyl-6-propionylindole 
-3-carboxamide [Compound (6)] 
Anhydrous aluminum chloride (6.4 g), 4.4 g of propionyl chloride and 10 g 
of Compound (5) were added to 100 ml of dichloroethane, and the mixture 
was heated under reflux for 5 hours. The reaction mixture was poured into 
ice-water, followed by extraction with chloroform. An aqueous solution of 
potassium carbonate was added to the extracted layer, and the mixture was 
stirred for 30 minutes. After the organic layer was washed wtih water and 
dried, the solvent was distilled off. Hexane was added to the residue to 
separate crystals. The crystals were collected by filtration and 
recrystallized from isopropyl ether to give 7.9 g of the titled compound 
as yellow crystals, m.p. 124.degree.-125.degree. C. 
By the same manner as the above-mentioned Example 1 to 6, for example, the 
following compounds can be produced. 
(7) 
4-(6-Acetyl-5-hydroxy-2-methyl-4-piperidinomethyl-1H-indol-3-ylcarbonyl)mo 
rpholine [Compound (7)], m.p. 226.degree.-228.degree. C. (decomposition) 
(8) 1,N-Dibutyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3-carboxamide 
[Compound (8)], m.p. 108.degree.-110.degree. C. 
(9) 
6-Bromo-1,N-dibutyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3-carboxam 
ide [Compound (9)], m.p. 135.degree.-137.degree. C. 
(10) 
6-Bromo-N-butyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3-carboxamide 
[Compound (10)], m.p. 202.degree.-203.degree. C. (decomposition) 
(11) 
4-[6-Bromo-5-hydroxy-2-methyl-1-(2-phenylethyl)-4-piperidinomethylindol-3- 
ylcarbonyl]morpholine [Compound (11)], m.p. 215.degree.-217.degree. C. 
(decomposition) 
(12) 
4-[5-Hydroxy-2-methyl-1-(2-phenylethyl)-4-piperidinomethylindol-3-ylcarbon 
yl]morpholine [Compound (12)], m.p. 167.degree.-169.degree. C. 
(13) 
4-[6-Acetyl-5-hydroxy-2-methyl-1-(2-phenylethyl)-4-piperidinomethylindol-3 
-ylcarbonyl]morpholine [Compound (13)], m.p. 174.degree.-175.degree. C. 
(14) 
4-(1-Butyl-5-hydroxy-2-methyl-4-piperidinomethylindol-3-ylcarbonyl)morphol 
ine [Compound (14)], m.p. 150.degree.-152.degree. C. 
(15) 
4-(6-Bromo-1-butyl-5-hydroxy-2-methyl-4-piperidinomethylindol-3-ylcarbonyl 
)morpholine [Compound (15)], m.p. 156.degree.-158.degree. C. 
(16) 
5-Hydroxy-2-methyl-N-octyl-1-(2-phenylethyl)-4-piperidinomethylindole-3-ca 
rboxamide [Compound (16)], m.p. 109.degree.-111.degree. C. 
(17) N,N-Dibutyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3-carboxamide 
[Compound (17)], m.p. 157.degree.-159.degree. C. 
(18) 
6-Bromo-N,N-dibutyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3-carboxam 
ide [Compound (18)], m.p. 213.degree.-215.degree. C. (decomposition) 
(19) 
1-(6-Bromo-5-hydroxy-2-methyl-4-piperidinomethyl-1H-indol-3-ylcarbonyl)pip 
eridine [Compound (19)], m.p. 174.degree.-176.degree. C. (decomposition) 
(20) 
N,N-Dibutyl-5-hydroxy-2-methyl-1-phenyl-4-piperidinomethylindole-3-carboxa 
mide [Compound (20)], m.p. 143.degree.-144.degree. C. 
(21) 
6-Acetyl-N,N-dibutyl-5-hydroxy-2-methyl-1-phenyl-4-piperidinomethylindole- 
3-carboxamide [Compound (21)], m.p. 136.degree.-138.degree. C. 
(22) 
6-Bromo-N,N-dibutyl-5-hydroxy-2-methyl-1-phenyl-4-piperidinomethylindole-3 
-carboxamide [Compound (22)], m.p. 183.degree.-184.degree. C. 
(23) 
6-Acetyl-5-hydroxy-2-methyl-N-octyl-1-phenyl-4-piperidinomethylindole-3-ca 
rboxamide [Compound (23)], m.p. 143.degree.-145.degree. C. 
(24) 
6-Bromo-N,N-dibutyl-5-hydroxy-2-methyl-1-(2-phenylethyl)-4-piperidinomethy 
lindole-3-carboxamide [Compound (24)], m.p. 115.degree.-116.degree. C. 
(25) 
N,N-Dibutyl-5-hydroxy-2-methyl-1-phenyl-4-piperidinomethyl-6-propionylindo 
le-3-carboxamide [Compound (25)], m.p. 115.degree.-116.degree. C. 
(26) 
6-Bromo-5-hydroxy-2-methyl-N-octyl-1-phenyl-4-piperidinomethylindole-3-car 
boxamide [Compound (26)], m.p. 204.degree.-206.degree. C. (decomposition) 
(27) 
5-Hydroxy-2-methyl-N-octyl-1-phenyl-4-piperidinomethylindole-3-carboxamide 
hydrochloride [Compound (27)], m.p. 198.degree.-199.degree. C. 
(28) 
6-Bromo-N,N-dibutyl-1-hexyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3- 
carboxamide [Compound (28)], m.p. 92.degree.-93.degree. C. 
(29) 
1,N-Dibutyl-5-hydroxy-2-methyl-4-piperidinomethyl-6-propionylindole-3-carb 
oxamide [Compound (29)], m.p. 135.degree.-136.degree. C. 
(30) 
N-Butyl-1-hexyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3-carboxamide 
[Compound (30)], m.p. 120.degree.-121.degree. C. 
(31) 
N-Butyl-1-hexyl-5-hydroxy-2-methyl-4-piperidinomethyl-6-propionylindole-3- 
carboxamide [Compound (31)], m.p. 174.degree.-175.degree. C. 
(32) 
1-Benzyl-5-hydroxy-2-methyl-N-octyl-4-piperidinomethylindole-3-carboxamide 
[Compound (32)], m.p. 144.degree.-146.degree. C. 
(33) 
1-Benzyl-5-hydroxy-2-methyl-N-octyl-4-piperidinomethyl-6-propionylindole-3 
-carboxamide hydrochloride monohydrate [Compound (33)], m.p. 
199.degree.-200.degree. C. (decomposition) 
(34) 
N-Pentyl-5-hydroxy-2-methyl-1-phenyl-4-piperidinomethylindole-3-carboxamid 
e hydrochloride [Compound (34)], m.p. 226.degree.-228.degree. C. 
(decomposition) 
(35) 
N-Butyl-5-hydroxy-2-methyl-1-phenyl-4-piperidinomethylindole-3-carboxamide 
[Compound (35)], m.p. 158.degree.-160.degree. C. 
(36) 
1-Hexyl-5-hydroxy-2-methyl-4-piperidinomethyl-N-(4-pyridyl)indole-3-carbox 
amide [Compound (36)], m.p. 193.degree.-194.degree. C. (decomposition) 
(37) 
5-Hydroxy-2-methyl-N-pentyl-1-phenyl-4-piperidinomethyl-6-propionylindole- 
3-carboxamide hydrochloride [Compound (37)], m.p. 224.degree.-226.degree. 
C. (decomposition) 
(38) 
5-Hydroxy-2-methyl-1-phenyl-4-piperidinomethyl-N-(4-pyridyl)indole-3-carbo 
xamide [Compound (38)], m.p. 178.degree.-180.degree. C. 
(39) 
6-Bromo-5-hydroxy-2-methyl-1-phenyl-4-piperidinomethyl-N-(4-pyridyl)indole 
-3-carboxamide [Compound (39)], m.p. 209.degree.-211.degree. C. 
(decomposition) 
(40) 1-Hexyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3-carboxamide 
[Compound (40)], m.p. 174.degree.-175.degree. C. 
(41) 
N-Hexyl-5-hydroxy-2-methyl-1-phenyl-4-piperidinomethylindole-3-carboxamide 
[Compound (41)], m.p. 152.degree.-154.degree. C. 
(42) 1,N-Diphenyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3-carboxamide 
[Compound (42)], m.p. 157.degree.-159.degree. C. 
(43) 
5-Hydroxy-2-methyl-1-phenyl-N-(2-phenylethyl)-4-piperidinomethylindole-3-c 
arboxamide [Compound (43)], m.p. 180.degree.-182.degree. C. 
(44) 
6-Bromo-1-hexyl-5-hydroxy-2-methyl-4-piperidinomethylindole-3-carboxamide 
[Compound (44)], m.p. 157.degree.-158.degree. C. 
(45) 
1-Hexyl-5-hydroxy-2-methyl-N-pentyl-4-piperidinomethylindole-3-carboxamide 
[Compound (45)], m.p. 140.degree.-141.degree. C. 
(46) 
1-Hexyl-5-hydroxy-2-methyl-N-phenyl-4-piperidinomethylindole-3-carboxamide 
[Compound (46)], m.p. 138.degree.-140.degree. C. 
(47) 
1-Hexyl-5-hydroxy-2-methyl-N-(2-phenylethyl)-4-piperidinomethylindole-3-ca 
rboxamide [Compound (47)], m.p. 98.degree.-100.degree. C. 
(48) 
1,N-Diphenyl-5-hydroxy-2-methyl-4-piperidinomethyl-6-propionylindole-3-car 
boxamide hydrochloride [Compound (48)], m.p. 237.degree.-239.degree. C. 
(decomposition) 
(49) 
2,N-Dimethyl-N-benzyl-5-hydroxy-1-phenyl-4-piperidinomethylindole-3-carbox 
amide [Compound (49)], m.p. 162.degree.-164.degree. C. 
(50) 
5-Hydroxy-2-methyl-1-phenyl-N-(2-phenylethyl)-4-piperidinomethyl-6-propion 
ylindole-3-carboxamide hydrochloride [Compound (50)], m.p. 
209.degree.-211.degree. C. (decomposition) 
(51) 
1-Hexyl-5-hydroxy-2-methyl-N-phenyl-4-piperidinomethyl-6-propionylindole-3 
-carboxamide [Compound (51)], m.p. 203.degree.-204.degree. C. 
(52) 
2,N-Dimethyl-1-hexyl-5-hydroxy-N-octyl-4-piperidinomethylindole-3-carboxam 
ide hydrochloride [Compound (52)], m.p. 177.degree.-178.degree. C. 
(decomposition) 
(53) 
2,N-Dimethyl-1-hexyl-5-hydroxy-N-octyl-4-piperidinomethyl-6-propionylindol 
e-3-carboxamide [Compound (53)], m.p. 119.degree.-120.degree. C. 
(54) 
N,N-Diethyl-1-hexyl-5-hydroxy-2-methyl-4-piperidinomethyl-6-propionylindol 
e-3-carboxamide [Compound (54)], m.p. 154.degree.-155.degree. C. 
(55) 
N-Benzyl-2,N-dimethyl-1-hexyl-5-hydroxy-4-piperidinomethyl-6-propionylindo 
le-3-carboxamide [Compound (55)], m.p. 116.degree.-117.degree. C. 
(56) 
5-Hydroxy-2-methyl-1-(4-methylphenyl)-N-octyl-4-piperidinomethyl-6-propion 
ylindole-3-carboxamide [Compound (56)], m.p. 127.degree.-128.degree. C. 
The present invention has been described in detail in the foregoing 
specification including Working Examples, which can be modified and varied 
to such an extent as not to conflict with the concept and the scope of the 
present invention.