GB2023590A - 3-amino-2-(5-fluoro and 5- methoxy-1H-indol-3-yl) Propanoic Acid Derivatives and Their Preparation and Use - Google Patents

3-amino-2-(5-fluoro and 5- methoxy-1H-indol-3-yl) Propanoic Acid Derivatives and Their Preparation and Use Download PDF

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GB2023590A
GB2023590A GB7919449A GB7919449A GB2023590A GB 2023590 A GB2023590 A GB 2023590A GB 7919449 A GB7919449 A GB 7919449A GB 7919449 A GB7919449 A GB 7919449A GB 2023590 A GB2023590 A GB 2023590A
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/10Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/10Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/10Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane

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Abstract

The compounds of the formula <IMAGE> wherein X is fluorine or methoxy, and R is a hydrogen or methyl group, such that R is hydrogen only when X is fluorine, and their acid addition salts, which are novel, are useful in the treatment of hypertension. They may be prepared from the corresponding 5-substituted indole-3-acetonitriles.

Description

SPECIFICATION 3-Amino-2-(5-Fluoro and 5-Methoxy-1 H-lndol-3-yl) Propanoic Acid Derivatives and their Preparation and Use Tryptophan, an essential amino acid nutrient having the formula:
is converted in part by the body into serotonin and melatonin. This later named compound possesses central nervous system activity. Another metabolite of tryptophan, 5-hydroxytryptophan, has been reported by Antonaccio and Robson (J. Pharm. Pharmacol. 25, 495 [1973]) to cause a decrease in blood pressure in monoamine oxidase-inhibited dogs. Another tryptophan derivative, .w-methyl-5- hydroxytryptophan, has been reported to lower blood pressure in spontaneously hypertensive rats when given at the extremely large dose of 200 mg/kg (Tabei et a/., Eur. J.Pharmacol., 7, 39 [1969]). 5 Fluorotryptophcn has been reported to interfere with the synthesis of indole from anthranilic acid and inhibit the growth of E. Coli (Bergmann, Proc. Konig, Ned. Akad. Wetenschap, Series C, 57 108 [1954]).
Rozhkov et (Zh. Org. Khim. 12 [5], 1076 [1976]) have synthesized the structural isomer of tryptophan having the structure:
Rozhkov eft at state no utility for this compound.
Johnson eft at have reported that the corresponding cr,-dehydro compound:
is useful as a chromophore intermediate (Biolumin. Progr. Proc. Kanagawa-Ken, Jap. 1965, 67; Chem.
Abst. 67; 53994K [1967]).
The present invention provides the compounds of the formula:
wherein R is hydrogen or methyl and X is fluorine or methoxy such that R is hydrogen only when X is fluorine, and their acid addition salts. These compounds are useful in treating hypertension.
According to a feature of the invention the compounds of formula I wherein R is a hydrogen atom are prepared by a) reacting a compound having the formula:
wherein X is fluorine or methoxy, with an alkali metal base and an acyloxylating agent to produce a compound having the formula:
wherein X is as defined above and R, is a lower alkyl or aryl group; b) hydrogenating the compound of formula Ill in the presence of a catalyst to produce a compound having the formula:
wherein R1 and X are as defined above; c) hydrolysing the compound of formula IV with an aqueous alkali metal hydroxide to produce a compound having the formula:
wherein M+ is an alkali metal cation and X is as defined above; and d) decarboxylating the compound of formula V with an aqueous acid and isolating the desired product of formula I.
The compounds of formula I wherein R is a methyl group may be made by esterifying the corresponding acid with methanol in the presence of an acid catalyst. 3-Amino-2-(5-methoxy-1 Hindol-3-yl) propanoic acid is a useful intermediate in the preparation of compounds of formula I.
Suitable pharmacologically acceptable acid addition salts of the compounds of formula I are salts prepared from suitable acids, such as hydrochloric, hydrobromic, maleic, orfumaric acid. The acid addition salts are prepared by reacting compounds of formula I with at least one equivalent of acid in a water-polar organic solvent mixture, such as water and ethanol.
The compounds and salts of this invention possess unexpected pharmacological properties that render them useful as therapeutic agents for the treatment of hypertension in an individual for whom such therapy is indicated. In the process of lowering blood pressure the instant compounds produce no tachycardia. The term "individual" means a human being or an experimental animal that is used as a model for a human being. The effective dose may vary from individual to individual, but it is easily determined by one skilled in the art without undue experimentation. Dose forms for the administration of compounds having Formula I may be prepared by recognized methods in the pharmaceutical sciences. Various dose forms of compounds having Formula I may be administered by conventional known methods of therapeutic administration such as oral, intravenous, parenteral, or the like.
The process for preparing compounds having Formula I begins by reacting a compound having Formula li
with an alkali metal base and an acyloxylating agent to produce a compound having Formula Ill,
In Formulas II and Ill, X is a fluorine atom or a methoxy group. The compound having Formula II where Xis fluorine is novel, but can be prepared as described in Example 2A below. In Formula Ill, R1 is a lower alkyl, aryl group or the like. Lower alkyl groups have from 1 to 3 carbon atoms and aryl groups include benzyl, phenyl and the like.
The alkali metal base used in this reaction may be sodium metal, lithium hydride, sodium ethoxide, potassium t-butoxide, or the like. This reaction may be performed in a suitable solvent, such as benzene, dimethylformamide, dimethoxyethane, or the like; or the solvent may be an acyloxylating agent, such as diethyl carbonate, dimethyl carbonate, dibenzyl carbonate or the like. The acyloxylating agent may be one of the carbonates indicated in the previous sentence, or ethyl chloroformate, methyl chloroformate, or the like.
The molar ratios of the compound having Formula II to alkali metal base to acyloxylating agent preferably range from about 1:2:2 to 1:2:10, respectively, with the latter ratio preferred. The preferred reagents are sodium metal and diethyl carbonate, wherein the latter acts as both solvent and acyloxylating agent. The reaction takes place in the temperature range of about OOC to 1 00C, but it is preferred to have the temperature near 1 00C in order to drive the reaction to completion by distilling off a by-product of the reaction, e.g. ethanol.
The compound having Formula Ill is hydrogenated to convert the cyano group into an aminomethyl group and produce a compound having the Formula IV
wherein X and R, are as above. This reduction is performed under pressure in the presence of a catalyst, such as Raney nickel, Palladium on charcoal, Rhodium on charcoal, or the like. Raney nickel is preferred. The reduction is preferably carried out in a suitable solvent such as methanol, ether, dimethylformamide, or the like at a temperature from about 1 5"C to 600C. Certain acylating agents may act as solvents also, as further described below.
It should be noted that certain undesirable side reactions may occur during the hydrogenation step above. These side reactions can be preferably avoided by protection of the amine group with an acylating agent. The hydrogenated compound above reacts with an acylating agent to produce the Nacylated compound having the Formula,
wherein X and R1 are as above, and R2 is a lower alkyl or aryl group. The acylation is performed by reacting a compound having Formula IV with an acylating agent, such as acetyl chloride, acetic anhydride, propionyl chloride, benzoyl chloride, or the like, in a solvent such as ether, dimethylformamide, acetic anhydride, or the like, at a temperature from about 0 to about 600C.
It should be recognized by those skilled in the art that if acylation is required for protection then the separate reactions of hydrogenation and acylation can also be accomplished in one step. For example, our preferred mode combines the hydrogenation and acylation reactions and most preferably utilizes acetic anhydride as both the solvent for hydrogenation and the acylating agent.
The compound having Formula IV is then hydrolyzed to produce an alkali salt having the Formula V,
wherein M is an alkali metal cation, with an aqueous solution of an alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide, barium hydroxide, or the like, at a concentration from about 3 N to 10 N for about 1 to 1 5 hours, at a temperature from about 500C to 1 000C. The salt is not isolated, but is then promptly decarboxylated to the free acid having Formula I wherein R is hydrogen by addition of an aqueous acid, such as hydrochloric acid, sulfuric acid, or the like. The compound having Formula I wherein R is hydrogen is isolated, after the acidic solution is neutralized, filtered and concentrated.
The compound having Formula I, wherein R is hydrogen, is then esterified by reacting it with methanol in the presence of an acid catalyst, such as hydrochloric acid, sulfuric acid, sulfonyl chloride or the like, and the product, having Formula I, wherein R is methyl, is isolated by convenient means such as preferably crystallization.
Example 1 This Example illustrates the preparation of methyl 3-amino-2-(5-methoxy-1 H-indol-3yl) propanoate and also describes the preparation of intermediates.
A. Ethyl 2-cyano-2-(1 -ethoxycarbonyl-5-methoxy-l H-indol-3-yl) acetate (Compound 1 A) A vigorously stirred solution of 5-methoxyindole-3-acetonitrile (22.7 g, 0.13 mole; prepared as described by Juby and Hudyma, J. Med. Chem. 12, 396 (1969)) in 200 ml of diethylcarbonate was heated at 110C and sodium (6.0 g, 0.26 mole) was added in small pieces over a 30 minute period, during which time ethanol distilled off. The mixture was kept at 11 00C for an additional 60 minutes, and the excess solvent removed in vacuo. The remaining mixture was cooled to about 200C and a dilute solution of acetic acid (1 8 ml glacial acetic acid in 100 ml of water) was added thereto.Then 200 ml of ethyl acetate was added, and the mixture stirred until ail solids had dissolved. The organic portion of this mixture was separated, washed with brine, dried over MgS04, and the solvent evaporated in vacuo to leave a dark residue. This residue was chromatographed on Silica Gel 60 with benzene:ethyl acetate (9:1 v:v) solvent and the solvent evaporated in vacuo to isolate compound 1A above as a light yellow syrup. The product was crystallized from methanol; yield 20 g (47%), mp 81830C.
Anal.
Calcd.forC17H18N205: C, 61.81; H, 5.49; N, 8.48 Found: C, 62.37; H, 5.58; N, 8.55.
B. Ethyl 3-acetylamino-2-(1-ethoxywarbonyl-5-methoxy-1 H-indol-3-yl)propanoate (TR-3328) A solution of Compound 1 A, prepared above, (7.4 g, 0.022 mole) in 1 50 ml of acetic anhydride was hydrogenated for 20 hours at 50 psi, using about 10 g of Raney nickel as a catalyst. The catalyst was then removed by filtration, and the solvent was evaporated in vacuo to leave a thick syrup. This syrup was dissolved in 200 ml of ethyl acetate which was then washed five times with 6% aqueous potassium carbonate solution and dried over MgS04. The solvent was then evaporated in vacuo, and the syrup which remained was crystallized from ethyl acetate:petroleum ether. One recrystallization from the same solvent pair yielded 4.6 g (56%) of product, mp. 88-900C.
Anal.
Calcd. for C19H24N206: C, 60.62; H, 6.43; N, 7.44 Found: C, 60.93; H, 6.70; N, 7.87 C. 3-Amino-2-(5-methoxy-1 H-indol-3yl)propanoic acid (TR-3361) A mixture of TR-3328 (5.3 g, 0.014 mole; prepared in Part 1 B above) and 18 ml of 10 N NaOH was heated at reflux temperature for 8 hours. The mixture was diluted with 100 ml of water, powdered charcoal was added, and the resulting mixture stirred and filtered to produce a clear filtrate. The filtrate was acidified to pH 6.0 with acetic acid, diluted to 200 ml with water, heated to boiling, treated with powdered charcoal, filtered, concentrated in vacuo until solid material was seen, and cooled at about 40C for 1 6 hours.The solid was then removed by filtration, recrystallized from water, and dried over P20,: yield 2.1 g (64%), mp. 205-2070C dec.
Anal.
Caícd. for C12H14N203: C,61.52; H,6.02; N,11.96 Found: C, 60.58; H, 6.27: N, 11.82 D. Methyl 3-Amino-2-(5-methoxy-1 H-indol-3-yl)propanoate Hydrochloride (TR-3369) A stirred suspension of TR-3361 (1 g, 0.0043 mole, prepared in Part 1 C, above) in 8 ml of methanol was cooled to --100C and SOCI2 (0.4 ml, 0.0056 mole) was added dropwise to generate a clear yellow solution. This solution was stirred for 18 hours at 1 80C, and the solvent was then removed in vacuo to leave a gummy residue which turned into a solid upon trituration with ethyl acetate. The residue was partitioned between ethyl acetate and 6% K2CO3 solution.The organic phase was washed once with brine, dried over MgSO4, and 1.1 ml of 4 N HCI (in dioxane) was added to produce a precipitate. The solid was removed by filtration and dried over P205 to yield 0.8 g product (67%), mp.
Anal.
Calcd. for C13H'7N203CI: C, 54.83; H, 6.02; N, 9.84; Cl, 12.45 Found: C, 54.36; H, 6.23; N,9.54 Cm,12.21 Example 2 This example describes the preparation of 3-amino-2-(5-fluoroindol-3-yl)propanoic acid and its intermediates.
A. 5-Fluoroindole-3-acetonitrile A mixture of 38 g of 3-dimethylaminomethyl-5-fluoroindole (0.198 mole; cf. Hoffman etna!. J.
Heteorocyclic Chem. 2, 298 (1965); of the 5-fluorogramine therein) in 500 ml of methanol was prepared. Then a solution of 25.7 g of KCN (0.396 mole) in 50 ml of water was added, with stirring.
The stirred mixture was cooled to 200C and 34.6 ml of methyl iodide (0.556 mole) was added over a 20 minute period. The mixture was then stirred at about 200C for 1 6 hours. The solvent was removed by evaporation and the residue was partitioned between ether and water. The ether portion was washed with water, 5% HCI, saturated NaHCO3 solution, water, and brine, dried over MgS04 and evaporated to leave a liquid residue. This residue was distilled at reduced pressure in a Kugelrohr apparatus. The fraction distilling at 134--1400C and 0.3 and 0.1 Torr was collected and crystallized from ethyl acetate-petroleum ether, mp 58--590, yield 5.3 g (44%).
B. Ethyl 2-cyano-2-(1-ethoxywarbonyl-5-fluoroindol-3-yl)acetate (Compound 2B) A stirred solution of 5-fluoroindole-3-acetonitrile (15.3 g; 0.88 mole; prepared in Part 2A above) in250 ml of diethylcarbonate was heated at 11000 and sodium (4.0 g; 0.17 mole) was added in small pieces. The mixture was then kept at 1 100C for an additional 30 minutes, during which time ethanol distilled off. The excess solvent and ethanol was then removed in vacuo. The residue that remained was cooled and to it was added a dilute solution of acetic acid (25 ml of glacial acetic acid in 100 ml of water). This aqueous mixture was extracted with two 100 ml portions of ether, which were combined, dried over MgSO4 and evaporated to leave a syrup. This syrup crystallized when triturated with methanol.The yield of product was 1 7 g (61%).
C. Ethyl 3-acetylamino-2-(1-ethoxycarbonyl-5-fluoroindol-3-yl)propanoate (Compound 2C).
A solution of Compound 2B, (17 g, 0.054 mole; prepared in Part 28 above) in 250 ml of acetic anhydride was hydrogenated as in Example 1 B, and the crystalline product isolated following the procedure therein. The product melted at 12O1210C; the yield was 99 (46%).
Anal.
Calcd. for C18H21FN205: C, 59.32; N, 7.69; H, 5.81.
Found: C, 59.05; N, 7.54; H, 5.82.
D. 3-Amino-2-( 5-fluoro-1 H-indol-3-yl)propanoic acid (TR-3913).
A 4.5 g (0.017 mole) sample of the Compound 2C, prepared in Part 2C above, was hydrolyzed as described in Example 1C above. Isolation of the crystalline product (29 (72%), mp 244--2450C) was accomplished by the procedure therein.
Anal.
Calcd. for C"H"FNO2: C, 59.46% H, 4.99; N,12.61 Found: C, 58.67; H, 4.96; N, 12.89 Example 3 Methyl 3-amino-2-(-5-fluoro-1 H-indol-3-yl)propanoate hydrochloride TR-391 5) The methyl ester of TR-3913 was prepared as described in Example 1 D, except TR-3913 (1.6 g, 0.007 mole) was utilized in place of TR-3361 and 0.74 ml of thionyl chloride (0.010 mole) was used.
TR-39 15, mp 18618700, was isolated in 63% yield (1.2 g).
Anal.
Calcd. for C,2H,4FN202CI: C, 52.85; H, 5.17; N, 10.27 Found: C, 52.71; H, 5.16; N, 10.04 Example 4 This example describes the results obtained when the compounds of this invention and reference compounds were tested for their ability to lower blood pressure in hypertensive rats.
Rats were made hypertensive by applying a figure-of-eight ligature to one kidney and removing the other kidney two weeks later. At least four weeks elapsed, after the second operation, before experimental studies were performed. Indirect systolic blood pressure measurements were made with an occluding cuff and pulse sensor system fitted to the rats' tails. Control blood pressure measurements were made before any compounds were administered. Blood pressure measurements were then made 1, 2, 4, 6 and 8 hours after the oral administration of the test compounds at the dose level of 10 mg/kg. Compounds 1 D, 2D and 3 were tested in 10 rats and reference compounds A and B were tested in 5 rats. Statistical significance of differences between control and post-treatment values was determined by Wilcoxon's signed rank test (F. Wilcoxon and R. A.Wilcox, Some Rapid Approximate Statistical Procedures, Lederle Laboratories, Pearl River, 1964).
The results of the tests are given in the table below.
Changes in rat blood pressure (mm Hg) upon oral administration of test compound Example Compound mg/kg 1 hr 2 hr 4 hr 6 hr 8 hr 1D TR-3369 3 43* 36* 18* 0 -3 1D TR-3369 10 85* 71* 38* -10 +2 2D TR-3913 10 19* 26* 27* -15 0 3 TR-3915 10 28* 18* 9 -9 -4 -1 References Compound A 10 -9 -6 0 +6 -1 References Compound B 10 -2 -7 + 14 +22* +6 * Statistically significant (p < 0.05) Reference Compound A refers to 5-hydroxy tryptophan Reference Compound B refers to r-methyl, 5-hydroxytryptophan ethyl ester The data above clearly shows that the claimed compounds are useful for lowering blood pressure in a hypertensive animal and have an especially long duration of action. By comparison with Reference Compounds A and B, reported to lower blood pressure, the claimed compounds are dramatically more active and especially over a longer period of time.

Claims (14)

Claims
1. A compound having the structural formula:
wherein R is hydrogen or methyl, and X is fluorine or methoxy such that R is hydrogen only when X is fluorine, and its acid addition salts.
2. Methyl 3-amino-2-(5-methoxy-1 H-indol-3yl)propanoate hydrochloride.
3. 3-Amino-2-(5-fluoro-1 H-indol-3-yl)propanoic acid.
4. Methyl 3-amino-2-(5-fluoro-1 H-indol-3-yl)propanoate hydrochloride.
5. A compound as claimed in any one of claims 1 to 4 for use in therapy for treating hypertension.
6. A process for preparing a compound as claimed in claim 1 wherein R is a hydrogen atom, which comprises: a) reacting a compound having the formula:
wherein X is fluorine or methoxy, with an alkali metal base and an acyloxylating agent to produce a compound having the formula:
wherein X is as defined above and R, is a lower alkyl or aryl group; b) hydrogenating the compound of formula Ill in the presence of a catalyst to produce a compound of the formula:
wherein R1 and X are as defined above; c) hydrolysing the compound of formula IV with an aqueous alkali metal hydroxide to produce a compound of the formula:
wherein M+ is an alkali metal cation and X is as defined above; and d) decarboxylating the compound of formula V with an aqueous acid and isolating the desired product of formula I.
7. The process according to claim 6 wherein the compound of formula Ill is hydrogenated in the presence of an acylating agent.
8. The process according to claim 7 wherein the acyloxylating agent is diethylcarbonate, dimethylcarbonate, dibenzyl carbonate, ethyl chloroformate, or methyl chloroformate, and the acylating agent is acetyl chloride, acetic anhydride, proponyl chloride, or benzoyl chloride.
9. The process according to claim 6, 7 or 8 wherein the catalyst is Raney nickel, palladium on charcoal or rhodium on charcoal.
10. The process according to any of claims 6 to 9 wherein the ratio of the compound of formula II to the alkali metal base to the acyloxylating agent in step (a) on a molar basis is from about 1:2:2 to 1:2:10 respectively.
11. A process for preparing a compound of the formula:
wherein Xis fluorine or methoxy which comprises esterifying a compound of the formula:
wherein X is fluorine or methoxy, with methanol in the presence of an acid catalyst.
12. 3-Amino-2-(5-methoxy-1 H-indol-3-yl)propanoic acid.
1 3. A process according to claim 6 substantially as described in Example 1 or 2.
14. A process according to claim 11 substantially as described in Example 1 D or 3.
1 5. A compound as claimed in claim 1 when prepared by a process as claimed in any of claims 6 to 11, 1 2 or 14.
GB7919449A 1978-06-15 1979-06-04 3 - amino - 2 - 5 fluoro and 5-methoxy-1h-indol - 3 - yl propanoic acid derivatives and their preparation and use Expired GB2023590B (en)

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US9663529B2 (en) 2013-07-02 2017-05-30 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors
US9914740B2 (en) 2013-07-02 2018-03-13 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9663529B2 (en) 2013-07-02 2017-05-30 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors
US9914740B2 (en) 2013-07-02 2018-03-13 Bristol-Myers Squibb Company Tricyclic pyrido-carboxamide derivatives as rock inhibitors

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