JPS6039678B2 - Production method of new indole derivatives - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for producing novel indole derivatives.

The present invention is based on the general formula (wherein R is hydrogen or lower alkyl, RI is hydrogen or lower alkyl, R2 is hydrogen, R3 is hydrogen, R4 is hydrogen, lower alkyl, 5 carbon atoms cycloalkyl having ~7 carbon atoms, phenyl, aroyl, or cycloalkanoyl optionally substituted by one or two halogen, lower alkoxy, lower alkyl or trifluoromethyl groups, and A has 2 to 7 carbon atoms. and wherein X is oxygen or sulfur) as well as acid addition salts thereof.

The term "lower" as used herein with respect to alkyl groups means groups having 1 to 6 carbon atoms.

It is usually preferred that such radicals have 1 to 4 carbon atoms. The alkylene group A has 2 to 4 carbon atoms and may be straight chain or branched, and if A is branched then methyl to straight chain alkylene containing up to 4 carbon atoms in the chain It is preferable to have one substituent.

A is, for example, 1 CH3 day 2-, a day 2CH2CH2
-, -CDCH2CH2Cday2-, -C〇(CH2)31 or -CHOH(CH2)3, but one CQCday2 is preferred.

Examples of lower alkyl groups in R, RI or R4 include methyl, ethyl, n-propyl, isopropyl, n
-butyl and isobutyl may be mentioned.

When R4 is a substituted phenyl group, this is one selected from halogen, such as chlorine, fluorine or bromine, lower alkoxy, such as methoxy or ethoxy, lower alkyl, such as methyl or ethyl, and trifluoromethyl; It can be phenyl substituted with two substituents.

When R4 is a cycloalkyl group, for example, cycloalkyl group
Bentyl, cyclohexyl and cycloheptyl.

When R4 is an alloyl group, it can be penzoyl, and when it is a cycloalkanoyl group, it can be cyclohexanoyl.

Preferred compounds in formula 1 are R1, R2 and R3
is hydrogen, R4 is phenyl, 2-trifluoromethylphenyl and penzoyl, R is hydrogen or methyl, and A is -C ratio C
It is a compound of H2-.

Particularly preferred compounds in the present invention are 1-phenyl-3-[1-(2-[indolyl]ethyl)piveridi-4
-yl] urea; 1-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]-131[2-trifluoromethylphenyl]urea: 1-penzoyl-31[1-yl]
2-[3-indolyl]ethyl)piverizy-4-yl]
Urea; 1-phenyl-3-[1-(2-[3-indolyl]ethyl)piverid-4-yl]thiourea and 1-
[1-(2-[3-indolyl]ethyl)piveridi-4
-yl]-1-methyl-3-phenylurea and its pharmaceutically acceptable acid addition salts. Acid addition salts within the scope of the present invention of compounds of formula 1 include salts formed from inorganic and organic acids, especially salts formed at pharmaceutically acceptable acid addition temperatures, such as sulfates, hydrochlorides, hydrobromides, salts, etc. Hydrourides, nitrates, phosphates, sulfonates (e.g. methanesulfonate and p-toluenesulfonate)
, acetate, maleate, fumarate, tartrate and formate.

Compounds of formula 1 exhibit pharmacological activities such as effects on the circulatory system, in particular hypotensive and/or antihypertensive effects.

Compounds of formula 1 can be prepared in a number of ways by assembling the molecules from appropriate starting materials using known methods.

A preferred method for producing the compound of formula 1 includes formula 0 (wherein R
, R1, R2, R3 and A have the same meanings as defined for formula 1) with the formula mbR4N=C
There is a method of reacting with a compound represented by =A (mb) (in the formula, R4 has the same meaning as defined for formula 1 except that it is not hydrogen, and X is oxygen or sulfur).

When × is oxygen, compound mb is isocyanate (R4N
C○, m), and when × is sulfur, the compound mb is an isocyanate (R4NCS, ma). Typically, reactions producing compounds of Formula 1 occur at room temperature.

The starting material where R is hydrogen in the formula m is as described in British Patent No. 121.
It can be produced by the method described in No. 857.

The starting material in which R is lower alkyl is represented by the formula 0'
They can be prepared by alkylating the corresponding compounds in which R is hydrogen or by a method analogous to that described in GB 121857.

A compound in which R is hydrogen in formula 1 is a compound in which R is hydrogen in formula 1.
Corresponding compounds in which 4 is aroyl or cycloalkanoyl can be prepared by hydrolysis.

As a second method for producing the compound of formula 1, the compound of formula W (wherein R1
, R2, R3 and A are as defined for formula 1, and Y is a halogen atom or an organic sulfonyl group such as a tosyl group. There is a method of reacting with a compound represented by (X has the same meaning as defined for formula 1).

Compounds of formula W can be prepared by the method described in British Patent No. 121,857.

Compounds of formula V can be prepared by known methods. As a third method for producing the compound of formula 1, a compound represented by the formula (wherein R1, R2, R3, x and A have the same meanings as defined for formula 1) is prepared by preparing the compound of formula R4.
There is a method of reacting with an amine represented by NQ(x) (same definition as defined for formula 1, except that R4 is not hydrogen).

Compounds in which X is sulfur can be obtained by reacting an amine of formula D' where R is hydrogen with {a} thiophosgene followed by calcium oxide or 'b} carbon disulfide followed by ammonia to obtain compounds represented by formula K. This is then converted into a heavy metal salt M fat 2 (where M is a divalent heavy metal and B2 is two monovalent anions or one divalent anion; as an example of MA2, are CuS04, POC03,
FeS04 and Pb(N03)2) can also be produced.

Compounds in which X is oxygen in the formula can be prepared by reacting compounds in which R is hydrogen with phosgene according to the following formula and then treating the product with calcium oxide.

Other methods for producing the compound of formula 1 include
(wherein R, R1, R2, R3, R4 and A have the same meanings as defined for formula 1, and X, e are anions such as halogen ions) be.

A compound of formula a can be reduced with an alkali metal boron hydride such as sodium boron hydride to lead to the corresponding compound of formula.

Compounds in which X is oxygen in a or W of the formula can also be subjected to catalytic hydrogenation, for example in the presence of a Raney nickel or platinum catalyst, to give the corresponding compound of formula 1.
Even after the compound of general formula 1 is obtained, one or more substituents within the molecule can be converted to other substituents within the range specified for formula 1, if necessary.

In each of the above reactions, if necessary, the reactive pupil group can be protected during the reaction and removed in subsequent steps.

As mentioned above, compounds of formula 1 have useful pharmacological properties and can therefore be used as active ingredients in pharmaceutical compositions.

In this case, the active ingredient compound is optionally powdered. In addition to the active ingredient, the composition also includes a non-sterile carrier. Any suitable raccoon body known in the art can be used to prepare this pharmaceutical composition.
In compositions of this type, the carrier can be solid or liquid or a mixture of solid and liquid. Solid compositions include powders, tablets and capsules. The solid waste material is one or more substances which may also act as flavoring agents, brighteners, solubilizers, suspending agents, binders or disintegrants. It may also be an encapsulating agent. In the case of powders, the carrier is pulverized and mixed with the pulverized active ingredient. For tablets, the active ingredient is mixed with a carrier having the necessary binding properties in appropriate proportions and compressed into the desired shape and size. Powders and tablets: 5 None, 99%, preferably 10 None, 80%
It is preferable that the active ingredient is contained in the active ingredient. Suitable solid waste materials include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, gum tragacanth, methylcellulose, sodium hydroxymethylcellulose, low-melting waxes and cocoa butter. I can do it. The term composition includes forming the active ingredient using an encapsulating agent as a carrier;
Also included are dosage forms in which the active ingredient (alone or together with other carriers) is surrounded by a carrier. Cashew agents are also included. Suitable liquid compositions include sterile solutions, suspensions,
There are emulsifiers, syrups and elixirs.

The active ingredient is dissolved or suspended in a sterile pharmaceutically acceptable liquid medium, such as sterile water, sterile organic solvent, or a mixture of both. Preferred liquid carriers are those suitable for parenteral injection. If the active ingredient exhibits sufficient solubility, it is dissolved in normal saline as a carrier. If the active ingredient does not have sufficient solubility, it can often be dissolved in a suitable organic solvent, such as an aqueous propylene glycol or polyethylene glycol solution. Hydrous propylene glycol containing 10 to 75% by weight of glycol is generally suitable. In other cases, the composition may be prepared by suspending the powdered active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil such as peanut oil. Liquid pharmaceutical compositions of sterile solutions or suspensions can be used for intramuscular, intraperitoneal, or subcutaneous injection. In many cases, the compounds are orally active and can be administered orally as either liquid or solid compositions. Preferably, the pharmaceutical composition is in unit dosage form. In this type of dosage form, the composition is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged composition, eg, a packaged powder or vial or ampoule, containing a specified quantity of the composition. The unit dosage form can be a capsule, cashew, or tablet itself, or it can be the appropriate number thereof in any packaged form. The amount of active ingredient in a unit dosage composition can be varied and adjusted from 5 legs or less to 50 legs or more depending on the particular needs and activity of the active ingredient. The invention also encompasses the use of compounds in unit dosage form without rods. Next, the present invention will be explained in detail by way of examples. In the examples, temperatures are expressed in degrees Celsius. Example 11
-Phenyl-3-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]urea-3-[2-(4-aminopiveridyl)ethyl]indole hydrate (1.31 evening)
is dissolved in hot dry benzene (125M) and to this is added a solution of phenyl isocyanate (0.63M, 5% excess) in benzene (25M).

This mixture was incubated overnight at room temperature, and the title compound (1.74
(evening).

This was dissolved in ethanol-hydrochloric acid/ether as hydrochloride (1.3
9), melting point 214-219o. C22 day 2
6N40・HC1・1/2 ratio ○; Calculated value C64.77,
Day 6.92, N13.74 Analysis value C64.69 Day 6.9
1, N13.45% This product shows very good antihypertensive activity.

Example 21-(4-chlorophenyl)-3-[1-(21-[3-indolyl]ethyl)piveridi-4-yl]urea 3-[2-(4-aminopiveridyl)ethyl]indole hydrate ( 1.05%) and 4-chlorophenylisocyanate (0.65%, 5% excess) are condensed analogously to Example 1 to give the crude title compound (1.55%).

Treatment of this with ethanolic hydrochloric acid/ether gives the pure hydrochloride hemihydrate (1.41 min, mp 244.4°, decomposed). C2 day 25CIN40・HCI・1/
2 ratio ○; calculated value C59.72, day 6.15, N12.6
6. Analysis value C60.02, N12.36% per day 6.3 This product shows antihypertensive activity.

Example 3 1-[3,4-dichlorophenyl]-31[1-(2-
[3-indolyl]ethyl)piverid-4-yl]urea 3-[2-(4-aminopiveridyl)ethyl]indole hydrate (1.31) and 3,4-dichlorophenyliso Cyanate (0.99%, 5% excess) is condensed as in Example 1 to give the crude title compound (2.03%).

Treatment of this with ethanolic hydrochloric acid/ether gives the pure hydrochloride salt (1.70°C, mp 258.4°, decomposed). Calculated value as C22 day 24CI2N40・HCI; C56.48, day 5.39, NIl. 98, Analysis value:
C56.69, Sun 5.53, NIl. 84% of this product exhibits antihypertensive activity.

Example 4 1-[1-(2-[3-indolyl]ethyl)piverid-4-yl]-3-[4-methoxyphenyl]urea 3-[2-(4-aminopiveridyl)ethyl]indole water (1.31 t) and 4-methoxyphenylisocyanate (0.78 t, 5% excess) are condensed as in Example 1 to give the crude title product (1.86 t).

Treatment of this with ethanolic hydrochloric acid/ether gives the pure hydrochloride hydrate (1.96 min, mp 220.40, decomposed). Calculated value as C23 58N402, HC1, day 20: C61.81, day 6.99, N12.53
, Analysis value; C62.22, day 6. Hammer NI Pine, 40% This product exhibits antihypertensive activity.

Example 5 1-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]-3-[3-tolyl]urea 3-[2-(4
-aminopiveridyl)ethyl]indole hydrate (1.
31) and 3-t1' lysocyanate (0.70
5% excess) is condensed analogously to Example 1 to give the crude title compound (1.70% excess).

Treatment of this with ethanolic hydrochloric acid/ether gives the pure hydrochloride salt (1.57 min, mp 228.90, decomposed). Calculated value as C2348N40/HCI: C66
．． 93, day 7.08, N13.57, analysis value; C67.
01, day 7.21, N13.66% This product exhibits antihypertensive activity.

Example 6 1-[1-(2-[3-indolyl]ethyl)piverid-4-yl]-3-[2,6-dimethylphenyl]urea Using the method of Example 1, 4-amino-1-[2- (3-indolyl)ethyl] Piverizine Sailor 0 (1.307 evening)
and 2,6-dimethylphenylisocyanate (0.
The title compound was converted to hydrochloride (1.
110 evenings, 52%).

Melting point 329.70 (decomposed). C24th 3oN40・HC
Calculated values as I; C67.55, day 7.32, N13.
12. Analysis value: C67.55, day 7.50, N12.6
3% This product shows antihypertensive activity in standard test methods.

Example 7 1-[1-(2-[3-indolyl]ethyl)piveridi-4-yl)-13-[2-trifluoromethylphenyl]urea Using the method of Example 1, 4-amino-1-[2-(3
-indolyl)ethyl]piveridine hydrate (1.307
The title compound is obtained as the hydrochloride salt (1.835%, 82%) from 2-trifluoromethylphenylisocyanate (0.982%, 5% excess).

Melting point 233.6o (decomposed). C23 ratio 5N40・HCI
Calculated values: C59.18, day 5.61, N12.0
0, analysis value; C59.28, day 5.79, NIl. 66
%This product shows a significant hypotensive effect in standard test methods.

Example 8 1-benzoyl-3-[1-(2-[3-indolyl])
Using the method of Example 1,
From 4-amino-1-[2-(3-indolyl)ethyl]piveridine hydrate (1.307 mm) and penzoyl isocyanate (1.471 mm), the title compound was obtained as the hydrochloride (1.436 mm, 63%). obtain.

Melting point 248.0o (decomposed). C23rd 26N402・H
Calculated value as CI: C64.73, day 6.3〆N13.1
2. Analytical value C64.43 days 6.60N13.11 This product is an intermediate of the following example and also shows remarkable antihypertensive activity and good antihypertensive activity. Example 911 [11 (21 [3
-indolyl]ethyl)piveridi-4-yl]urea 1-
Penzoyl-31[11(21[3-indolyl]ethyl)piveridi-4yl]urea hydrochloride is refluxed in sodium hydroxide solution (20') for 1 hour.

The reaction mixture is cooled and the standard compound is added to the filtrate. Yield 0.
678 min., 83%, melting point 212. (decomposition). C, 6th day 2N40, calculated value C67.10, day 7.74, N
I9.57, analysis value C67.50 days 7.74 NI9.3
5% This product exhibits antihypertensive effects at low doses according to standard test methods, but the duration is short.

It also exhibits antihypertensive activity. Example 10 1-phenyl-3-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]thiourea 4-amino-1-
[2-(3-indolyl)ethyl]piveridine hydrate (
1.31 evening, 0.005 mol) was dissolved in benzene (125 [
) and dissolved in phenylysothiocyanate (0.
After 74 days, 0.0055 mol) was added dropwise.

After 2 hours, the mixture is filtered to give the title compound (free base) as a white fish crystalline solid (1.76 hours).

This is dissolved in a minimum amount of hot ethanol, saturated ethanolic hydrochloric acid is added until acidic, and the solution is then left to precipitate crystals. Upon filtration, the hydrochloride salt of the title compound is obtained as colorless prismatic crystals. Yield: 1.75 hours, melting point: 224.8〇〇 Calculated value as C22 ratio 6N4S/HCI; C Satoshi. 67, day 6.56, N13.50, analysis value: C
63.67, day 6.74, N13.32% This product exhibits antihypertensive and antihypertensive activity.

Example 111-[1-(2-[3-indolyl]ethyl)piverid-4yl]-3-cyclohexylurea 4-amino-1-[2-(3-indolyl)ethyl]piveridine hydrate (1.307 pm, 0.005 mol) benzene (
50 secretion), cyclohexyl isocyanate 0.6
88 minutes, 0.055 mol) was added and the mixture was incubated for 1 hour.

When filtered, the title compound appears as colorless prismatic crystals (1.89
3 evenings). Melting point 203-80. Calculated value as C22 day spot N40; C71.70, day 8.75, N1
5.21, analysis value; C71.74 days 9.0fuN14.9
1% This product shows antihypertensive activity.

Example 12 11[11(21[3-indolyl]ethyl)piveridi-4-yl]131(3-trifluoromethylphenyl)urea31[21(4-aminopiveridyl)ethyl]indole hydration Example 1
Reaction with m-trifluoromethylphenylisocyanate (1.03 mmol, 0.0055 mol) according to method 1 gives 0.87 mmol of the hydrochloride salt of the title compound.

Melting point 200.00C23 expansion 5F3N40・HCI, calculated value, C59.11, day 557, NIl. 99, analysis value; C59.51, day 5.84, NIl. 95% of this product exhibits antihypertensive activity.

Example 13 1-[1-(2-[3-indolyl)ethyl)piveridi-4-yl]-1-methyl-3-phenylurea 3-[2
-(4-Methylaminopiveridyl)ethyl]indole (1.28 hours, 0.005 mol) and phenyl isocyanate (0.66 hours, 0.0055 mol) are condensed by the method of Example 11 to give the title Compound hydrochloride (0.
69) and a melting point of 217.60.

C23 ratio 8N40・HC1・1/4 ratio ○, calculated value; C66.17, day 7.24, N13.42, analysis value,
C65.85, day 7.37, N13.03% This product exhibits significant hypotensive activity.

Example 14 - 1-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]-1-methyl-3-phenylthiourea 3-[2-(4-methylami/piveridyl)ethyl]indole (1.28 evening, 0.005 mol) of dry benzene (
75'), and phenylysothiocyanate (
0.74 hours, 0.0055 mol).

Incubation is continued for 2 hours and the mixture is evaporated to give the title compound. Adding hydrochloric acid in ethanol to this and precipitating with ether yields the hydrochloride. Yield 0.95mm, melting point 1
Calculated value as 93.70C23&8N4S・HCI;C
64.39, day 6.81, N13.06, analysis value; C6
4.05, day 6.99, N13.11% Example 15 1-benzoyl-31 [11 (21 [3-indolyl])
Ethyl)piverid-4-yl]thiourea ammonium thiocyanate (2.28 pm) was taken in dry acetone (20 ml), and this solution was poured into benzoyl chloride (4.22 pm). Add dry acetone (20') solution.

The mixture was heated at 450°C for 5 minutes and then 3-[2-(4-aminopiveridyl)ethyl]indole (7.8
4) Add a solution of dry acetone (30'). After refluxing for 2 minutes, the mixture is cooled, poured into ice water (250 ml) and the liberated oil is extracted into chloroform.

Drying (M$04) and evaporation of the extract yields the title compound. This is crystallized as the hydrochloride salt from ethanol-hydrochloric acid/ether. Yield 1.65 kg, melting point 212-2
Calculated value as 20 of 150C23rd 26N406・HC1・1′: 361.74, day 6.19, N12.52
, Analytical value: C61.70, day 6.4fN12.14% This product shows antihypertensive activity.

Example 16 1-[1-(2-[3-indolyl]ethyl)pibe IJ
di-4-yl]thiourea 1-benzoyl-3-[1-(
2-[3-indolyl]ethyl)piveridi-4-yl]
Thiourea (2.21 min.) is refluxed for 5 minutes in water (20 min.) containing sodium hydroxide (1.0 min.).

This mixture was cooled and filtered to give the title compound (1.59
Evening) is obtained. Crystallization from ethylhydrochloric acid/ether gives the hydrochloride salt (1.467 m). Melting point 228-
9oC,6 is 2N4S・HCI, calculated value: C56
．． 70, day 6.84, N16.53, analysis value: C56.
78, day 7.20, N16.42%. Example 17 1-Phenyl-3-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]3 in urea dichloroethane
-[2-(4-Isocyanatopiveridyl)ethyl]-
To a solution of indole (2.69 g) is added 1 equivalent of aniline in dichloromethane.

The mixture is stirred for one hour at room temperature. The product is taken off and converted into the hydrochloride salt in ethanol/CI/ether (yield: 1.43 min): mp 214-2190. Example 18 1-(4-chlorophenyl)-3-[1-(2-[3-
Indolyl]ethyl)piverid-4-yl]urea Example 17
3-[2-(4-isocyanate piberidyl)]
Ethyl]-indole (2.69 m) is condensed with 4-chloroaniline to give the crude title compound.

Treat this product with ethanolic HCI/ether,
Obtain pure hydrochloride hemihydrate (1.26 min); melting point 24
4.4o (decomposition). Example 1911 [3/4-jiku.

ruphenyl]13-[11(21[3-indolyl]ethyl)piverid-4-yl]urea By the method of Example 17, 31[21(4-isocyanatopiveridyl)ethyl]-indole (2.69) and 3,4-dichloroaniline are condensed to give the crude title compound. Treatment of this product with ethanolic HCI/ether affords the pure hydrochloride salt (0.95; mp 2.40 (decomposed)).
Example 201-[1-(2-[3-indolyl]ethyl)
Piveridi-4-yl]-3-[4-methoxyphenyl]
Using the method of Urea Example 17, 6-[2-(4-isocyanatopiveridyl)ethyl]-indole (2.69%) and 4
-Methoxyaniline to give the crude title compound.

Treatment of the product with ethanolic HCI/ether affords the pure hydrochloride hydrate (1.35 min); mp 220.4
o (decomposition). Example 211-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]-3-[3-tolyl]urea 3-[2-(4-isocyanatopiveridyl)ethyl] ] Indore (2.69 evening) and 3
-methylaniline to give the crude title compound.

The product is treated with ethanolic HCI/ether to give the pure hydrochloride salt (0.86%); mp 228.90 (decomposed). Example 22 1-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]-3-[2,6-dimethylphenyl]urea 1-[2-(3 -indolyl)ethyl]piverizine (2.69 pm)
and 2,6-dimethylaniline to obtain the title compound as a hydrochloride (yield: 0.0%): melting point 329.7 (
Disassembly).

Example 23 1-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]-131[2-trifluoro.

4-Isocyanate 1-[2-(3-indolyl)ethyl] using the method of Example 17
The title compound is obtained as the hydrochloride salt from piberidine (2.69 min) and 2-trifluoromethylaniline (yield: 0.74 min); mp 233.6° (decomposition).

Example 241-Phenyl-3-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]thiourea 4-isothiocyanate-1-[2-(3-indolyl)ethyl]piveridine (3.01 evening) Dissolve in benzene and add aniline dropwise.

After 2 hours, the mixture is heated to give the title compound as a white amorphous solid.

The product is dissolved in up to 4 volumes of hot ethanol, saturated ethanol HCI is added until acidic, and the solution is then allowed to crystallize. The hydrochloride salt of the title compound (0.64 poly) was collected as anhydrous prisms; melting point 224.800.
Example 25 11[11(21[3-indolyl]ethyl)piverid-4-yl]13-cyclohexylurea 4-isocyanate-11[21(3-indolyl)ethyl]piveridine (2.69 ) with cyclohexylamine in benzene and the mixture was heated for 18 hours.

The title compound (1.83 min.) was filtered off as colorless prisms; melting point 203. but. Example 261-[1-(2
1[3-indolyl]ethyl)piverid-4-yl]131(3-trifluoromethylphenyl)ureaBy the method of Example 24, 31[21(4-isocyanatopiveridyl)ethyl]indole ( Reaction of 2.69 ml with 3-trifluoromethylaniline gives the hydrochloride salt of the title compound (1.17 ml); mp 2000.

Example 27 1-benzoyl-3-[1-(2-[3-indolyl]
3-(2-bromoethyl)indole (22.4) in urea dimethylformamide (200) 1-penzoyl-3-(piveridi-
A solution of urea (22.6 mm) and anhydrous sodium carbonate (5.8 mm) was heated at 100° C. for 3 hours.

The solution is poured into water to precipitate the title compound, which is filtered off (35 min, 87.2%). The product is converted to the hydrochloride salt with ethanolic HCI: mp 24. Example 28 1-phenyl-3-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]urea By the method of Example 27,
3-(2-furomoethyl) and 1-phenyl-3-(piveridi-4-yl)urea are reacted to obtain the title compound.

The product is converted to the hydrochloride salt in ethanolic HCI/ether; mp 214-2190. Example 29 1-(4-chlorophenyl)-3-[1-(2-[3-
Indolyl]ethyl)piverid-4-yl]urea Example 27
3-(2-furomoethyl)indole and 1-(4-k) by the method of

(ruphenyl)-3-(piverid-4yl)urea to give the crude title compound. Treatment of the product with ethanolic HCI/ether gives the pure hydrochloride hemihydrate; mp 244.4o. Example 301-[3.4
-Dichlorophenyl]131[1-(21[3-indolyl]ethyl)piverid-4-yl]urea By the method of Example 27, 3-(2-bromoethyl)indole and 11(
Reaction with 3,4-dichlorophenyl)-3-(piverid-4-yl)urea yields the crude title compound.

Treatment of the product with ethanolic HCI/ether gives the pure hydrochloride salt: mp 258.4o (decomposed). Example 31 1-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]-3-[4-methoxyphenyl]urea Example 2
7, 3-(2-bromoethyl)indole and 1-(4-methoxyphenyl)-3-(piveridi-4)
The crude product of the title compound is obtained by reaction with urea.

Treatment of the product with ethanolic HCI/ether gives the pure hydrochloride salt: mp 220.4o (decomposed). Example 32 1-[1-(2-[3-indolyl]ethyl)piverid-4yl]-3-[3-tolyl]urea By the method of Example 27, 3-[2-bromoethyl]indole and 1-(3
-tolyl)-3-(piverid-4-yl)urea to give the crude title compound.

Treatment of the product with ethanolic HCI/ether gives the pure hydrochloride salt; mp 228.9o (decomposed). Example 1-[1-(2-[3-indolyl]ethyl)piverid-4-yl]-3-[2,6-dimethylphenyl]urea Using the method of Example 27, 3-[2-bromoethyl]indole and 1-(2,6-dimethylphenyl)-3-
The title compound is obtained as the hydrochloride salt from (biverid-4yl)urea; mp 329.70 (decomposition).

Example milk 1-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]1-3-[2-trifluoromethylphenyl]urea Using the method of Example 27, 3-[2-furomoethyl]indole and 1 The title compound is obtained as the hydrochloride salt from -(2-trifluoromethylphenyl)-13-(piveridi-4-yl)urea: mp 233.60 (decomposition).

Example 35 1-[1-(2-[3-indolyl]ethyl)piveridi-4-i]urea Using the method of Example 27, 3-[2-furomoethyl]indole and 1-amino-3-(piveridi-4- The title compound is obtained from urea: melting point 21
2. 〆(decomposition).

Example 36 1-phenyl-3-[1-(2-[3-indolyl]ethyl)piverid-4-yl]thiourea By the method of Example 27, 3-[2-furomoethyl]indole and 1-phenyl-3-( piberid-4yl)thiourea to give the title compound.

The product is dissolved in a minimum amount of hot ethanol, saturated ethanol one day CI is added until acidic, and the solution is then allowed to crystallize. The hydrochloride salt of the title compound is obtained as a colorless prism: mp 224.80. Example 37 1-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]1-3-cyclohexyl]urea Using the method of Example 27, 3-[2-furomoethyl]indole and 1-cyclohexyl The title compound is obtained from 4-yl) urea as colorless prisms; mp 203.8o.

Example 11[1-(21[3-indolyl]ethyl)piveridi-4-yl]131[3-trifluoromethylphenyl]ureaUsing the method of Example 27, 31[2-bromoethyl]indole and 1 The hydrochloride salt of the title compound is obtained from 1-(3-trifluoromethylphenyl)-3-(piveridi-4-yl) urea; melting point 20000 Example 39 1-[1-(2-[3-indolyl]ethyl) Using the method of Example 27, the title compound was prepared from 3-[2-bromoethyl]indole and 1-phenyl-3-(piverid-4-yl)1-3-methylurea. Obtain hydrochloride: melting point 21
7.60.

Example 40 1-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]-1-methyl-3-phenylthioureaExample 2
Using method 7, 3-[2-bromoethyl]indo-
and 1-phenyl-3-(piverid-4yl)-3-methylthiourea to obtain the title compound.

This is converted to the hydrochloride salt by addition of hydrogen chloride in ethanol and precipitation with ether: mp 193.70.
Example 41 1-Phenyl-3-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]urea 1-(2-[3-indolyl]ethyl)-4-(
3-phenyl-1-ureido) pyridinium bromide (
Add an excess amount of sodium boron hydride little by little to the suspension of 4.37 pm).

Continue stirring and heat the mixture to reflux for up to 1 hour. Add water and filter the product. From this product, using ethanolic HCI/ether, the hydrochloride salt of the title compound (1.82 min) is obtained: mp 214-21900
42 1-(4-chlorophenyl)-3-[1-(2-[3-
Indolyl]ethyl)piverid-4-yl]urea Example 41
By the method of 1-(2-[3-indolyl]ethyl)
Reduction of 1-4-(3,4-dichlorophenyl-1-ureido)pyridinium bromide (4.72 hours) affords the crude title compound.

Treat this product with ethanolic HCI/ether,
Obtain pure hydrochloride hemihydrate (2.31 min); melting point 24
4.4o (decomposition). Example 43 1-[3,4-dichlorophenyl]-31[1-(2-
[3-indolyl]ethyl)piverid-4-yl]urea By the method of Example 41, 1-(2-[3-indolyl]ethyl)-141(3-[3,4-dichlorophenyl]-1
-ureido) pyridinium.

Reduction of the mido (5.07 m) affords the crude title compound. Treatment of this with ethanolic HCI/ether gives the pure hydrochloride salt (1.96%); mp 2984
0 (decomposition). Example 44 1-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]-3-[4-methoxyphenyl]urea Example 4
1-(2-[3-indolyl]ethyl)-4-(3-[4-methoxyphenyl]-1-ureido)pyridinium bromide (4.67 m) was reduced by the method of 1.
The crude title compound is obtained.

Treatment of this product with ethanolic HCI/ether affords the pure hydrochloride hydrate (2.25 min);
(Disassembly). Example 45 1-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]-3-[3-tolyl]urea 1-(2-[3-indolyl]ethyl)-4-(
3-Tolyl-1-ureido)pyrinium bromide (4.
51) to give the crude title compound.

Treatment of this with ethanolic HCI/ether gives the pure hydrochloride salt (2. lactate): mp 228.9o (decomposed).
Example 461-[1-(2-[3-indolyl]ethyl)
11(2-[3-indolyl]ethyl)-41(31[3,4-dimethylphenyl]urea ]-1-ureido) pyridinium.

The title compound is obtained as the hydrochloride salt (yield: 1.61 min.) from Mido (4.65 min.): mp 329.7o (decomposition).
Example 471-[1-(2-[3-indolyl]ethyl)
piberid-4-yl]-3-[2-trifluoromethylphenyl]urea Using the method of Example 41, 1-(2-[3
-indolyl]ethyl)-4-(3-[2-trifluoromethylphenyl]-1-ureido]pyridinium bromide (5.05 min) to obtain the title compound as a hydrochloride (yield: 2.39 min); Melting point 233.60 (decomposed).

Example 48 1-benzoyl-3-[1-(2-[3-indolyl]
11(21[3-indolyl]ethyl)141(3
-benzoyl-1-ureido)pyridinium bromide (
The title compound is obtained as the hydrochloride salt (yield: 2.45 min): mp 248° (decomposition).

Example 49 1-[1-(2-[3-indolyl]ethyl)piverid-4-yl]urea In the method described in Example 41, 1-(2-[
Reduction of 3-indolyl]ethyl)-4-(1-ureido)pyridinium bromide (3.61 m) gives the title compound (1.96 m); mp 212. 〆(decomposition).

Example 501-phenyl-3-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]thiourea 1-(2-[3-indolyl]ethyl)-4-(3-phenyl-1) -Thioureido)pyridinium bromide (4.53 hours) is reduced to give the title compound (melting base).

Dissolve this in a minimum amount of hot ethanol, add saturated ethanol CI until acidic, then allow the solution to crystallize. The title compound acid salt (1.84°C) was collected as a cool colored prism: mp 24.8o. Example 5
11-[1-(2-[3-indolyl]ethyl)piverid-4-yl]-3-cyclohexylurea By the method of Example 41, 1-(2-[3-indolyl]ethyl)-41(3-cyclohexyl-urea) Treatment of pyridinium bromide (1-ureido) (4.43 m) gave the title compound (1.7
7 evening) obtained: melting point 203.8〇〇〇〇〇〇　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　-3-(3-tolylfluoromethylphenyl)urea By the method of Example 41, 1 -(2-[3-indolyl]ethyl)-4-(3-[3-trifluoromethylphenyl]-1-ureido)pyridinium bromide (5
．． 05 pm) to yield the title compound, isolated as the hydrochloride salt (yield: 2.42 pm); mp 20 ppm.

Example 11 [11 (2-[3-indolyl]ethyl)piverid-4-yl]11-methyl13-phenylurea 11 (21[3-indolyl]ethyl)141 (
Reduction of 3-phenyl-1-methylureido)pyridinium bromide (4.51 evening) to produce the title compound,
Isolated as hydrochloride salt (yield: 1.89 min); mp 21
7.60.

Example 541-[1-(2-[3-indolyl]ethyl)
Piverid-4-yl]-1-methyl-3-phenyruthiourea 1-(2-[3-indolyl]ethyl)-4-(3-phenyl-1-methylthioureido)pyridinium bromide (4.65 mol) was prepared by the method of Example 41. reduction to yield the title compound, which is converted to the hydrochloride salt by addition of hydrogen chloride in ethanol and precipitation with ether (yield:
1.03 pm); melting point 193.7.

The following compound is prepared according to the method of Example 41: Example 551
1 [11 (21 [1-methyl (indol-3-yl)]
[ethyl)piveridi-4-yl]-3-benzoylurea 3-[2-(4-aminopiveridyl)ethyl]-1-methylindole (2.75 m) and penzoyl isocyanate to produce the hydrochloride of the title compound (1 .85 m) obtained: melting point of hydrochloride; 233-2 Io.

Example 561-[1-(3-[indol-3-yl]propyl)piveridi-4-yl]-3-penzoyl urea 3
The hydrochloride of the title compound (1.68 m) is obtained from 1[3-(4-aminopiveridyl)propyl]indole (2.75 m) and penzoyl isocyanate; melting point of the hydrochloride: 268-2690.

Example 573-benzoyl-1-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]-1-methylurea 3-[2-(4-methylaminopiveridyl)ethyl]
The hydrochloride salt of the title compound (0.97 min) is obtained from indole (2.75 min) and penzoyl isocyanate; melting point of the hydrochloride: 224-2250.

Example: Preparation of the title compound from 1-butyl-31[11(21[3-indolyl]ethyl)piveridi-4yl]urea 3-[21(4-aminopiveridyl)ethyl]indole (2.61) and butyl isocyanate. Hydrochloride (2.
Obtained 43: Melting point of hydrochloride: 195-1970.

Example 59 1-cyclohexanoyl-3-[1-(2-[3-indolyl]ethyl)piveridi-4-yl]urea 3-[2-(4-aminopiveridyl)ethyl] in dry benzene (125) ] Add cyclohexanoyl isocyanate (1.47 min.) to the solution of indole (13.1 min.).

The mixture is stirred at room temperature for 24 hours, the title compound is collected, washed, dried and then converted to the hydrochloride salt (1.4 hours) in ethanolic hydrogen chloride; melting point: 236.3oo.
. Elemental analysis: C2 is 32N402, calculated value: C
60.64%; Day 7.85%: N12.30% Actual value:
C 60.55%; Day 7.59%; N 12.14% This product shows very good hypotensive activity.

Example 60 1-Fenyl-3-[1-(2-[3-indolyl]piverid-4-yl]urea isopropanol (100 units [
) in a solution of 1-phenyl-3-[1-(2-[3-indolyl]ethyl)-11,2,3,6-tetrahydropyridi-14-yl]urea (1.0 μm) with sodium boron hydride. (Add stepwise under reflux over 18 minutes and continue refluxing for 2 hours.)

Claims (1)

[Claims] 1 Formula I ▲ Numerical formulas, chemical formulas, tables, etc.▼ (In the formula, R is hydrogen or lower alkyl, R^1 is hydrogen or lower alkyl, R^2 is hydrogen, ,
R^3 is hydrogen, R^4 is hydrogen, lower alkyl, cycloalkyl having 5 to 7 carbon atoms, 1 or 2
phenyl, aroyl or cycloalkanoyl optionally substituted by halogen, lower alkoxy, lower alkyl or trifluoromethyl groups, A is an alkylene group having 2 to 4 carbon atoms, and X is oxygen or Formula II ▲ Numerical formulas, chemical formulas, tables, etc. are available for producing compounds represented by (sulfur) and their acid addition salts. (In the formula, R, R^1, R^2, R^3 and A is as defined for formula I) with the formula R^4NCX, where R^4 is as defined for formula I except for hydrogen, and X is oxygen or sulfur. ), optionally the product is isolated as its acid addition salt, and if a compound in which R^4 is hydrogen is also desired, R^4 is aroyl or cycloalkanoyl. A method for producing the above indole derivative, which comprises hydrolyzing a compound of formula I. 2 Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R is hydrogen or lower alkyl, R^1 is hydrogen or lower alkyl, R^2 is hydrogen,
R^3 is hydrogen, R^4 is hydrogen, lower alkyl, cycloalkyl having 5 to 7 carbon atoms, 1 or 2
a phenyl, aroyl or cycloalkanoyl group optionally substituted by halogen, lower alkoxy, lower alkyl or trifluoromethyl groups, A is an alkylene group having 2 to 4 carbon atoms, and X is oxygen or sulfur) and its acid addition salts, formula VII ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (wherein, R^1, R^2, R^3, A and X is as defined for formula I) with an amine of formula R^4NH_2 (wherein R^4 is as defined for formula I except for hydrogen) and optionally isolate the product as an acid addition salt, and also, if a compound where R^4 is hydrogen is desired, a compound of the formula where R^4 is aroyl or cycloalkanoyl.
A method for producing the above indole derivative, which comprises hydrolyzing the compound of I. 3 Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R is hydrogen or lower alkyl, R^1 is hydrogen or lower alkyl, R^2 is hydrogen,
R^3 is hydrogen, R^4 is hydrogen, lower alkyl, cycloalkyl having 5 to 7 carbon atoms, 1 or 2
phenyl, aroyl or cycloalkanoyl optionally substituted by halogen, lower alkoxy, lower alkyl or trifluoromethyl groups, A is an alkylene group having 2 to 4 carbon atoms, and
is oxygen or sulfur) and its acid addition salts, formula IV ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (where R^1, R^2, R^3 and A has the same meaning as defined for formula I, and Y is a halogen atom or an organic sulfonyl group).
There are mathematical formulas, chemical formulas, tables, etc. ▼ (wherein R, R^4 and A method for producing the above-mentioned indole derivative, which comprises separating the indole derivatives. 4 Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R is hydrogen or lower alkyl, R^1 is hydrogen or lower alkyl, R^2 is hydrogen, R
^3 is hydrogen and R^4 is substituted by hydrogen, lower alkyl, cycloalkyl having 5 to 7 carbon atoms, 1 or 2 halogen, lower alkoxy, lower alkyl or trifluoromethyl group; may be phenyl, aroyl, or cycloalkanoyl, A is an alkylene group having 2 to 4 carbon atoms, and
is oxygen or sulfur) and its acid addition salts, formula VI ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (where R, R^1, R^2, R^3 , R^4 and A are as defined for formula I) with an alkali metal boron hydride, optionally converting the product into its acid addition salt. Method for producing indole derivatives. 5 Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R is hydrogen or lower alkyl, R^1 is hydrogen or lower alkyl, R^2 is hydrogen,
R^3 is hydrogen, R^4 is hydrogen, lower alkyl, cycloalkyl having 5 to 7 carbon atoms, 1 or 2
phenyl, aroyl, or cycloalkanoyl optionally substituted with halogen, lower alkoxy, lower alkyl, or trifluoromethyl groups;
is an alkylene group having 2 to 4 carbon atoms, and X is oxygen or sulfur), and its acid addition salts are prepared using Formula VIa ▲Mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R, R^1, R^2, R^3, R^4 and A
is the same as defined for formula I, and X_1 is an anion) with an alkali metal boron hydride, optionally converting the product into its acid addition salt. A method for producing the above indole derivative.