JPS6040420B2 - 3-Amino-2-(5-fluoro- and 5-methoxy-1H-indol-3-yl)propanoic acid derivatives, their preparation and use - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has the following features: '1) Structural formula 1 [wherein R is hydrogen or a methyl group, and X is a fluorine or methoxy group, provided that when x is fluorine, R is only hydrogen. and acid addition salts thereof: [2] A method for the therapeutic treatment of hypertension in an individual in need of such treatment, comprising administering to the individual a therapeutically effective amount of a compound of formula 1. :3) a) A compound having the formula D [wherein X is fluorine or a methoxy group] is combined with an alkali metal base and acetic acid.

Reacted with a xylating agent to form m [wherein x is as defined above, and R is a lower alkyl or aryl group]
Producing a compound having the formula: [b} Hydrogenating a compound having the formula m in the presence of a catalyst to produce a compound having the formula W [wherein R and X are as defined above]: {c ) Hydrolyzing a compound of formula W with an aqueous alkali metal hydroxide to produce a compound of formula V, where M is an alkali metal cation and X is as defined above. ; and {d} A process for the preparation of a compound of formula 1, in which R is a hydrogen atom, by degalboxylating a compound of formula V with aqueous acid and separating the expected product;■ prepared in 3'd} above A process for preparing a compound of formula 1, wherein R is a methyl group, comprising esterifying the compound with methanol in the presence of an acid catalyst: and '5} An intermediate 3-amino intermediate useful in the preparation of a compound having formula 1 2-[5-methoxy-IH-indol-3-yl]propanoic acid.

Tryptophan, an essential amino acid nutrient with the formula
Part of it is converted into serotonin and melatonin in the body.

This latter named compound has central nervous system activity. Other metabolites of tryptophan are inhibited by monoamine oxidase, which can lower blood pressure.
to female ccjo and ro 戊ON [J. Phann. Ph
Anncol, 25, 495 (1973)]. Another tryptophan derivative, Q-methyl-5-hydroxytryptophan, contains 200 9'kg
It has been reported that when administered in very large doses, it lowers blood pressure in momentarily hypertensive rats.
Taoietal. , Eur. J. Pharmacol
7, 39 (1969)]. 5-fluorotryptophan interferes with the synthesis of indole from anthranilic acid and inhibits E. It has been reported that the growth of coli is inhibited [Bergmann, ProC. Konig
, Ned, Akad, Wete Ship Chap, Serie
s C, 57, 108 (1954)].

R.

zhk. v et al [Zh. 〇rg-Khim. 12(5),
1076 (1976)] synthesized a structural isomer of tryptophan having the structural formula, but did not mention the usefulness of this compound.

Johnson et al. reported that the corresponding Q.8-tehydro compounds are useful as chromophore intermediates] Bjolum;n,
Progr. ProC. KanagaW. ken, J.
ap. 1965/67: Chem. Abst. 67:5
3994K (1967)].

Novel compounds having formula 1 are the subject of the present invention. In the compound having formula 1, R is hydrogen or a methyl group, and X is a fluorine or methoxy group, provided that when x is fluorine, then R is the only group.

The present invention further includes pharmaceutically acceptable acid addition salts of compounds having formula 1.

Such salts are prepared from suitable acids such as hydrochloric acid, hydrobromic acid, maleic acid, fumaric acid, and the like. Acid addition salts are
It can be prepared by reacting a compound of formula 1 with at least one equivalent of acid in a water-based organic solvent compound, such as water and ethanol. The compounds and salts of the present invention have unexpected pharmacological properties that make them useful as therapeutic agents for treating hypertension in individuals in need of treatment. This compound does not induce jaw pulse in the process of lowering blood pressure. "Individual" means a human being or an experimental animal used as a human model. Effective dosages will vary from individual to individual and can be readily determined by one of ordinary skill in the art without undue experimentation. Dosage forms for administration of compounds having formula 1 can be manufactured by recognized methods of pharmaceutical chemistry. The various dosage forms of compounds having Formula 1 can be administered by conventional known administration methods such as orally, intravenously, parenterally, and the like. A process for making a compound having formula 1 begins by reacting a compound having formula 0 with an alkali metal base and an acyloxylating agent to produce a compound having formula m.

In formulas 0 and m, X is fluorine or a methoxy group.
Compounds of formula 2, where X is fluorine, are new but can be prepared as described in the Examples section below. In formula m, R
, is a lower alkyl group, an aryl group, etc. This lower alkyl group has 1 to 3 carbon atoms, and includes aryl groups such as pendyl and phenyl. The alkali metal bases used in this reaction include sodium metal, lithium hydride,
Sodium ethoxide, potassium ten-butoxide, etc. may also be used.

The reaction may be carried out in a suitable solvent such as benzene, dimethylformamide, dimethoxyethane, etc., or the solvent may be an acyloxylating agent such as diethyl carbonate, dimethyl carbonate, dibenzyl carbonate, etc. The acyloxylating agent may be one of the carbonates mentioned above, or ethyl chloroformate, methyl chloroformate, and the like. The molar ratio of compound of formula D:alka IJ metal base:acyloxylating agent is preferably about 1:2.
:2 to 1:2:10, with the latter ratio being preferred.

Preferred reagents are sodium metal and diethyl carbonate. In this case the latter acts both as a solvent and as an acyloxylating agent. The reaction takes place at a temperature range of about 0 to 110 dC, although it is preferred to use temperatures close to 110 DEG C. in order to distill off reaction by-products such as ethanol and complete the reaction. A compound having the formula m is hydrogenated to convert the cyano group into an aminomethyl group to give a compound having the formula W, where x and R are as defined above.

This reduction is carried out using catalysts such as Raney nickel, palladium
It is carried out under pressure in the presence of carbon, rhodium carbon, etc. The reduction is preferably carried out in a suitable solvent such as methanol, ether,
It is carried out in dimethylformamide, etc. Certain acylating agents also act as solvents, as further discussed below.
It must be mentioned that during the above hydrogenation undesired side reactions may occur.

These side reactions can preferably be avoided by protecting the amine group with an acylating agent. The above hydrogenated compound reacts with an acylating agent to give an N-acyl compound having the formula: where X and R are as defined above and R2 is a lower alkyl or aryl group.

Acylation is carried out by combining a compound of formula W with an acylating agent such as acetyl chloride, acetic anhydride, propionyl chloride, benzyl chloride, etc. This is done by reacting with It should be appreciated that if acylation is required for protection, separate reactions of hydrogenation and acylation may be performed in one step.

For example, a suitable method combines hydrogenation and acylation reactions,
Most preferably acetic anhydride is utilized as the solvent for both the hydrogenating and acylating agents. The compound of formula N is then:
Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide at a concentration of about 1 to 1 liter and about 5
It is hydrolyzed to give an alkali metal salt having formula V, where Mx is an alkali metal cation, by using a temperature of 0 to 10,000° C. for about 1 to 1 hour.

This salt is not separated but is immediately decarboxylated by addition of an aqueous acid such as hydrochloric acid, sulfuric acid, etc. to the free acid of formula 1 where R is hydrogen. Compounds of formula 1, where R is hydrogen,
The acidic solution is separated after being pricked, filtered and concentrated.
Compounds of formula 1 in which R is hydrogen are esterified by reaction with methanol in the presence of acid catalysts such as hydrochloric acid, sulfuric acid, sulfonyl chloride, etc., and products of formula 1 in which R is methyl are conveniently esterified. Separation by means such as preferably crystallization.

Example 1 This example describes methyl 3-amino-2-[5-methoxy-I
The method for producing H-indol-3-yl]propanoate and further its intermediates is illustrated.

A Ethyl 2-cyano-2[1-ethoxycarbonyl-
5-Methoxy-IH-indol-3-yl]acetate [Compound IA] Diethyl carbonate 200 underground 5-
Methoxyindole-3-acetonitrile [22.7 evenings, 0.13 mol: JUBY and HUDYMA, J
．． Med. Chem. 12, 396 (1969)] was heated to 11,000 ℃, and sodium [6.0 μm, 0.26 mol] was added in small pieces to 30
It was added over a period of minutes.

Ethanol was distilled off during this period. The mixture was kept at 110C0 for an additional 60 minutes and excess solvent was removed under vacuum.
The remaining mixture was cooled to about 2000 ml and diluted with a dilute solution of acetic acid [
100 parts water and 18 parts underground glacial acetic acid] was added to this. Then 200 g of ethyl acetate was added and the mixture was stirred until all solids were dissolved. The organic portion of the mixture was separated, washed with brine, dried over M 04, and the solvent was evaporated under vacuum to leave a dark colored residue. The residue was chromatographed on silica gel (SilicaQI) 60 drop benzene:ethyl acetate [9:lv:v] and the solvent was evaporated under vacuum to isolate the compound as a light yellow syrup. The product was crystallized from methanol; yield 20 ml (47%), mp 81-83 qo. analysis. C,
Calculated values for 7 days, 8N205: C, 61.81; days, 5.49; N, 8.48 experimental values: C, 62.37; days, 5.58; N, 8.55.

B Ethyl 3-acetylamino-2-[1-ethoxycarbonyl-5-methoxyIH-indol-3-yl]propanoate [TR-3328] Compound IA prepared above [7.4 evening, 0.022 mol]
A 150% solution of acetic anhydride was hydrogenated for 20 hours at 5 ml using Raney nickel as a catalyst.

The catalyst was then filtered off and the solvent was evaporated under vacuum to obtain a viscous syrup. Add this syrup to 200' of ethyl acetate.
and then washed five times with 6% aqueous potassium carbonate solution and dried over MgSO4.

The solvent was then evaporated under vacuum and the remaining syrup was crystallized from ethyl acetate:petroleum ether. By recrystallizing once from the same solvate, the melting point was 88-90.
4.6 hours (56%) of product was obtained. analysis.

Calculated value for C, 9 days 24N205: C, 60.62
: Sun, 6.43: N, 7.44 Experimental value: C, 60.93
; Sun, 6.70; N, 7.87C 3-amino-2-[
5-MethoxyIH-indol-3-yl]propanoic acid [TR-3361] TR-3328 [5.3 evening, 0.014 mol; above IB
A mixture of 18M of ION NaOH and 18M of ION NaOH was heated under reflux for 8 hours.

This mixture was diluted with 100 ml of water, powdered activated carbon was added, and the resulting mixture was stirred and filtered to obtain a clear filtrate. The furnace liquor was acidified to pH 6.0 with acetic acid, diluted to above 200 with water, heated to boiling, treated with powdered activated carbon, oven-treated, concentrated under vacuum until solid material was observed, It was cooled to about 4°C. The solid is then separated into a furnace,
It was recrystallized from water and dried over P205. Yield 2.1 more [
64%], melting point 205-2070 (decomposition). analysis. C,
Calculated value for 2 days, 4N203: C, 61.52: Day, 6.02: N, 11.96 Experimental value: C, 60.58:
Sun, 6.27; Sun, 11.82D Methyl 3-amino-
2-[5-methoxy-IH-indol-3-yl]propanoate hydrochloride [TR-3369] Methanol 8M
Medium TR-3361 [1 night, 0.0043 mol; above IC
The suspended suspension of [manufactured in
OC12 [0.4 Desk, 0.0056 mol] was added dropwise to give a clear yellow solution.

The solution was stirred at 18q0 for 1 hour, then the solvent was removed under vacuum to yield a rubbery residue. This turned into a solid when treated with ethyl acetate. The residue was partitioned between ethyl acetate and 6% K2C03 solution. The organic phase was washed once with brine, dried over MgSO4 and precipitated by addition of 1.1M 4N HCl (in dioxane).

This solid was separated by furnace and dried with P205, yielding 0.8% product.
[67%] was obtained. analysis. Calculated values for C, 3 days, 7N203CI: C, 54.83; days, 6.02; N, 9
．． 84; CI, 12.45 Experimental value: C, 54.36: Days, 6.23; N, 9.54; CI, 12.21 Melting point 2
070 IR (KC1) 1730 skin-1 NMR (CD30D) 63.3-3.6 (m, 2, CH
C93NH), 3.73 (s, 3, C03CH3), 3
．． 83 (s, 3, 5-OCH3), 4.42 (t, 1,
CHCH2NH), 6.7-7.4 (m, 4, aromatic ring +
2-CH); MSm/e248 (M+ free base) Example 2 This example describes a method for producing 3-amino-2-[5-fluorindol-3-yl]propanoic acid and its intermediates. do.

A 5-fluorindole-3-acetonitrinolemethanol 500 underground 3-dimethylaminomethyl-5-fluorindole 38 [0.198 mol: Reference, Ho
ffman etal. , J. Hete de ocycli
c Chem. , 2, 298 (1965); 5 of them
- for fluorogramin] was prepared.

A solution of 25.7 ml (0.396 mol) of KCN in 50 ml of water was then added with stirring. The cooled mixture was cooled to 20:00, and 34.6% of methyl iodide [0.
556 mol] was added in 20 minutes. The mixture was then incubated at approximately 2,000 ml for one hour. The solvent was removed by evaporation and the residue was partitioned between ether and water. The ether portion was washed with water, 5% HCl, saturated NaHCQ solution, water and brine, dried over MgSO4 and evaporated to give a liquid residue. This residual liquid was dissolved in Kugerrohr (Ku
Distillation was carried out under reduced pressure using a 100-degree LROHR apparatus.

Fractions distilling at 134-140 CO and 0.3-0.1 Ton were collected and crystallized from ethyl acetate/petroleum ether.

Melting point 58-59o, yield 5.3 [44%]. B Ethyl 2-cyano-2-[1-ethoxycarbonyl-5-fluorindol-3-yl]acetate [the compound is]
A diluted solution of 5-fluorindole-3-acetonitrile [15.8 mol, 0.88 mol; manufactured by the above-mentioned company] of 250 dimethyl carbonate was heated to 110 oo, and a solution of sodium chloride [4.0 mol; 0.17 mol] was added in small pieces.

The mixture was then held at 11,000 for an additional 30 minutes, during which time the ethanol was distilled off. Excess solvent and ethanol were removed under vacuum. The residue was cooled and a dilute solution of acetic acid (25 parts of glacial acetic acid in 100 parts of water) was added to it. The aqueous mixture was extracted with two 100' portions of ether, combined, dried over MgSO4 and evaporated to give a syrup. This syrup crystallized when soothed with methanol. Product yield was 17 min (61%). C Ethyl 3-acetylamino-2-[1-ethoxycarbonyl-5-fluorindole-3-yl]propanoate [Compound book] Acetic anhydride 250 Secretion compound plaque [17th night, 0.054 mol; The solution of Preparation] was hydrogenated as in Example IB and the crystallized product was isolated.

The product melts at 120-121°C and the yield is 9 min [46
%〕Met. analysis.

C, 8th 2, Calculated value for FN203: C, 59.3
2; N, 7.69: Day, 5.81 Experimental value: C, 59.0
5:N, 7.54:Day, 5.820 3-Ami/-2-[5-fluoro-IH-indol-3-yl]propanoic acid [TR-3913] Sample 4 of the compound book prepared in the above manner. 5th evening [0.017
mol] was hydrolyzed as in Example IC.

Then, in the same manner, a crystalline product [2 hours (72%), melting point 2
44-245 qo] were separated. analysis. C,. Day,. F
Calculated value for N02: C, 59.46: day, 4.99
:N, 12.61 Experimental value: C, 58.67; Day, 4.9
6:N, 12.89 Reference example methyl 3-amino-2-[5
-Fluor-IH-Indole-3-yl] Bropanoate Hydrochloride [TR-3915] TR-3913 [1.6
The methyl ester of TR-3913 was prepared as described in Example ID except that thionyl chloride (0.007 mole) was substituted for TR--3361 and 0.74 mole of thionyl chloride was used (0.010 mole).

TR-3915, melting point 186-18700, was isolated in 63% yield (1.2 min). analysis.

C, 2 days, calculated value for 4FN202CI: C, 52
．． 85; Sun, 5.17: N, 10.27 Experimental value: C, 5
2.71: Day, 5.16: N, 10.04 Example 3 This example demonstrates the results obtained when compounds of the invention and a reference compound were tested for their ability to lower blood pressure in hypertensive rats. show.

Rats were made hypertensive by applying a figure-eight knot to one kidney and removing the other kidney two weeks later.

Experimental studies were performed at least 4 weeks after the second surgery. i.e. an occlusion cuff (cMf) suitable for the rat tail.
and indirect cardiac systolic blood pressure was measured using a pulse sensor system. Baseline blood pressure was measured before administering each compound. The test compound was then added to 10 pairs of 9′k9
Blood pressure measurements were taken 1, 2, 4, 6, and 8 hours after oral administration at a dosage of . Compound ID, fox and 3 to 1
Reference compounds A and B were tested in 0 rats and reference compounds A and B in 5 rats. The statistical significance of the difference between the baseline and post-processed values is determined by the ordination test described by Wilcoxon [F. Wilxon and
R. A. Wilcox, Some Rapid Ap
pr. Ximate Statistica I Pro
cedures, Lederle Laborahori
es, Pearl River, 1964]. The trial results are shown in the table below. Change in blood pressure of rats upon oral administration of test compound × Statistically significant (p<0.05)
×husband mean systolic pressure
(ressure) Reference compound A relates to 5-hydroxytryptophan.

Reference compound B relates to Q-methyl, 5-hydroxytryptophan ethyl ester.

The above data show that the compounds of the invention are useful in lowering blood pressure in hypertensive animals and have a particularly long duration of action.

When compared to reference compounds that have been reported to lower blood pressure, the compounds of the invention exhibit dramatic effects and are particularly active over long periods of time. As shown by the results of the above tests, the active compounds of the present invention are effective in rats at doses of about 3 to about 10 9/k9 when administered orally. For humans, a dose of about 1 9/kg is effective when administered orally; for humans, a dose of about 0.17 to about 0.34 9/kg is effective when administered orally. be.

Claims (1)

[Claims] 1 Structural formula I ▲ Includes mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R is hydrogen or a methyl group, and X is a fluorine or methoxy group, provided that when X is fluorine R is only hydrogen] and oxidized salts thereof. 2. The compound according to claim 1, which is methyl 3-amino-2-[5-methoxy-1H-indol-3-yl]propanoate hydrochloride. 3. The compound according to claim 1, which is 3-amino-2-[5-methoxy-1H-indol-3-yl]propanoic acid. 4 The following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R is hydrogen or a methyl group, and X is a fluorine or methoxy group, provided that when X is fluorine, only the hydrogen of R is] 1. A therapeutic agent for hypertension, comprising a compound having the following and a pharmaceutically acceptable acid addition salt thereof as active ingredients. 5. The therapeutic agent according to claim 4, wherein the compound of the formula is methyl 3-amino-2-[5-methoxy-1H-indol-3-yl]propanoate hydrochloride. 6 The compound of the formula is 3-amino-2-[5-fluoro-
The therapeutic agent according to claim 4, which is 1H-indol-3-yl]propanoic acid. 7 (a) Formula II ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ A compound having [In the formula, X is fluorine or a methoxy group] is reacted with an alkali metal base and an acyloxylating agent to form Formula III ▲ Mathematical formula, chemical formula , tables, etc. ▼ Producing a compound having the formula [wherein X is the same as above and R_1 is a lower alkyl or aryl group]; (b) producing a compound having the formula III in the presence of a catalyst; (c) Hydrogenating the compound having the formula IV ▲ mathematical formula, chemical formula, table, etc. ▼ [wherein R_1 and X have the same meanings as above]; By hydrolyzing hydroxide, the formula V▲ has mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, M^+ is an alkali metal cation, and
is the same as defined above];
and (d) Formula I consisting of decarboxylating a compound having formula V with aqueous acid and isolating the desired product ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [wherein R is a hydrogen atom] ] A method for producing a compound having the following. 8. The method of claim 7, wherein the compound of formula III is hydrogenated in the presence of an acylating agent. 9. The acyloxylating agent is selected from the group consisting of diethyl carbonate, dimethyl carbonate, dibenzyl carbonate, ethyl chloroformate and methyl chloroformate, and the acylating agent is selected from the group consisting of acetyl chloride, acetic anhydride, propionyl chloride and benzoyl chloride. 9. A method according to claim 8, selected from: 10 Claim 9 in which the acylating agent is acetic anhydride
The method described in section. 11. The method of claim 7, wherein the catalyst is selected from the group consisting of Raney nickel, palladium, carbon and rhodium-carbon. 12 Claim 1 in which the catalyst is Raney nickel
The method described in Section 1. 13 The molar ratio of the compound of formula II, the alkali metal base and the acyloxylating agent in step (a) is 1 each, unless the acyloxylating agent is used in excess as a solvent.
8. The method according to claim 7, wherein the ratio is 2:2 to 1:2:10. 14 Structural formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, X is a methoxy group] A formula that involves esterifying a compound with methanol in the presence of an acid catalyst There are tables etc. ▼ [In the formula, X has the same meaning as above] A method for producing a compound having the following. 15 Claim 1 which is 3-amino-2-[5-methoxy-1H-indol-3-yl]propanoic acid
Compounds described in Section.