GB1562825A - N-(2-(5-methoxa-6-halo-indol-3-yl)-ethyl)-amides methods for their preparation and their use - Google Patents

Description

(54) N- E 2-(5-METHOXY-6-HALO-INDOL-3-YL)ETHYL1 AMIDES, METHODS FOR THEIR PREPARATION AND THEIR USE (71) We, ELI LILLY AND COMPANY, a corporation of the State of Indiana, United States of America, having a principal place of business at 307 East McCarty Street, City of Indianapolis, State of Indiana, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to novel N - [2 - (5 - methoxy - 6 - haloindol - 3 yl)ethylj amides which are valuble, orally active, ovulation inhibitors.

Melatonin (N - acetyl - 5 - methoxytryptamine) is a natural product isolated from the pineal glands of beef cattle. It is reported by Ying and Greep, Endocrinology, 92 (1), 333-5 (1973), that melatonin has an inhibitory effect on ovulation in cyclic rodents. This inhibitory effect is realized when melatonin is administered intracardially in relatively large doses during the critical period of proestrus. However, when melatonin is administered orally, its inhibitory effect on ovulation is substantially diminished over that available by intracardial administration. It now has been discovered that a particular class of tryptamines, N - acyl - 5 - methoxy - 6 - halotryptamines, exhibits a high level of activity as ovulation inhibitor even when administered orally.

The presem invention provides novel compounds of the formula

in which R is hydrogen, C1-C4 alkyl, phenyl, or phenyl substituted with halo, C14 alkyl or Cl*CS alkoxy; Rl is hydrogen or C1-C4 alkyl; R2 is hydrogen or Ra, and R3 is haloacetyl, C1-C6 alkanoyl, benzoyl, or benzoyl substituted with halo or methyl (as hereinafter defined); and X is halogen.

The present invention also provides a process for preparing novel 5-methoxy-6halotryptamine compounds of formula I wherein R, R1, R2, R, and X are as defined above, which comprises reacting a 5-methoxy-6-halotryptamine compound of the formula

wherein R and X are as defined above, with an active derivative of a carboxylic acid of the formula

wherein R1 is as defined above; and if desired reacting the compound so obtained wherein R2 is hydrogen with an acylating agent of the formula R3---Cl ASt IIIa wherein Ra is as defined above, in the presence of a strong base.

Compounds of formula I are orally active as inhibitors of ovulation in mammals.

Preferred compounds of formula I are those in which R2 is hydrogen.

Another preferred class of compounds of formula I are those in which R2 is haloacetyl, C1C5 alkanoyl, benzoyl, or benzoyl substituted with halo or methyl.

In the definition of the compounds of this invention, the term "CI--C, alkyl" is employed. By this term is meant any of the following groups: methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, and t-butyl.

The term "C14 alkoxy" also is employed herein and means methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and t-butoxy.

The terms "halo" and "halogen" where used herein means chloro, bromo, iodo, and fluoro, and, preferably, chloro.

When, in the above definition, the term R represents a substituted phenyl group, examples of such a group include 4 - chlorophenyl, 2 - fluorophenyl, 3 - iodophenyl, 4 - bromophenyl, 3,4 - dibromophenyl, 4 - methylphenyl, 2 - ethylphenyl, 3 propylphenyl, 4 - isopropylphenyl, 4 - n - butylphenyl, 3 - t - butylphenyl, 4 - secbutylphenyl, 3,4 - dimethylphenyl, 4 - methoxyphenyl, 3 - ethoxyphenyl, 2 propylphenyl, 4 - isopropoxyphenyl, 3 - isobutoxyphenyl, 4 - t - butoxyphenyl or 3 ethoxy -4 - methoxyphenyl. - The term "haloacetyl" as used herein in definition of the group R2 refers to chloroacetyl, bromoacetyl, fluoroacetyl, and iodoacetyl.

The term "C1----C5 alkanoyl" as used herein with reference to the group R2 includes formyl, acetyl, propionyl, butyryl, a-methylpropionyl, valeryl, a-methylbutyryl, ss-methylbutyryl, and pivaloyl. Preferred C1-C5 alkanoyl groups are acetyl and pivaloyl, and most preferably, acetyl.

The term "benzoyl substituted with halo" used in definition of the group R2 defines mono- and dihalobenzoyl groups. Specific monohalobenzoyl groups are chlorobenzoyl, bromobenzoyl, fluorobenzoyl, and iodobenzoyl. Preferably, the monohalobenzoyl group is a 4-halobenzoyl, and the preferred halo substituent is chloro.

The dihalobenzoyl groups defined by R2 generally are those in which both of the halo substituents are the same, and, preferably, are those in which the halo substituents are located in the 2- and 4-positions. Typical dihalobenzoyl groups include 2,4-dichlorobenzoyl, 2,4-dibromobenzoyl, 2,4-difiuorobenzoyl, and 2,4-diiodobenozyl.

The preferred group is 2,4-dichlorobeuzoyl.

The term "benzoyl substituted with methyl" contemplates "methylbenzoyl", "dimethylbenzoyl", and "trimethylbenzoyl". Preferred groups include 2-methylbenzoyl, 2,6-dimethylbenzoyl, or 2,4,6-trimethylbenzoyl.

Examples of the compounds of formula I include the following: N - [2 - (3 - methoxy - 6 chloroindol - 3 - yl)ethyl]acetamide; N - [2 - (3 - methoxy - 6 - fluoroindol - 3 - yl)ethyl]acetamide; N - [2 - (5 - methoxy - 6 - bromoindol - 3 - yl)ethyl]formamide; N - [2 - (5 - methoxy - 6 - iodoindol - 3 - yl)ethyl]propionamide; N - [2 - (5 - methoxy - 6 - chloroindol - 3 - yl)ethyl] - n - butyramide; N - [2 - (2 - methyl - 5 - methoxy - 6 - bromoindol - 3 - yl)ethyl] acetamide; N - [2 - (2 - ethyl - 5 - methoxy - 6 - chloroindol - 3 - yl)ethyl]acetamide; N - [2 - (2 - n - propyl - 5 - methoxy - 6 - chloroindol - 3 - yl)ethyl]formamide; N - [2 - (2 - n - butyl - S - methoxy - 6 - chloroindol - 3 - yl)ethyl]formamide; N - [2 - (2 - ethyl - 5 - methoxy - 6 - iodoindol - 3 - yl)ethyl]propionamide; N - [2 - (2 - isopropyl - 5 - methoxy - 6 - fluoroindol - 3 - yl)ethyl] methylpropionamide; N - [2 - (2 - phenyl - 5 - methoxy - 6 - chloroindol - 3 - yl)ethyl]formamide; N - [2 - (2 - phenyl - 5 - methoxy - 6 - bromoindol - 3 - yl)ethyl]acetamide; N - [2 - (2 - phenyl - 5 - methoxy - 6 - iodoindol - 3 - yl)ethyl]propionamide; N - [2 - ((2 - (4 - chlorophenyl) - 5 - methoxy - 6 - chloroindol - 3 - yl))ethyl]- formamide; N - [2 - ((2 - 3 - fluorophenyl) - 5 - methoxy - 6 - bromoindol - 3 - yl))ethyl]acetamide; N - [2 - ((2 - (2 - fluorophenyl) - 5 - methoxy - 6 - chloroindol - 3 - yl))ethyl]propionamide; N - [2 - ((2 - (4 - methylphenyl) - 5 - methoxy - 6 - bromoindol - 3 ethyl] formamide; N - [2 - ((2 - (3 - ethylphenyl) - 5 - methoxy - 6 - fluoroindol - 3 - yl))ethyl]butyramide; N - [2 - ((2 - (4 - n - propylphenyl) - 5 - methoxy - 6 - chloroindol - 3 ethyl] formamide; N - [2 - ((2 - (3 - isopropylphenyl) - 5 - methoxy - 6 - fluoroindol - 3 ethyl] acetamide; N - [2 - ((2 - (4 - methoxyphenyl) - 5 - methoxy - 6 - chloroindol - 3 ethyl] propionamide; N - [2 - ((2 - (3 - ethoxyphenyl) - 5 - methoxy - 6 - bromoindol - 3 ethyl]acetamide; N - [2 - ((2 - (3 - n - propoxyphenyl) - 5 - methoxy - 6 - fluoroindol - 3 ethyl] acetamide; N - [2 - ((2 - (4 - t - butoxyphenyl) - 5 - methoxy - 6 - chloroindol - 3 ethyl] fonnamide; N - [2 - ((2 - (3 - n - butoxyphenyl) - 5 - methoxy - 6 - chloroindol - 3 ethyl] acetamide; N - [2 - (1 - acetyl - 5 - methoxy - 6 - chloroindol - 3 - yl)ethyl] acetamide; N - [2 - (1 - propionyl - 5 - methoxy - 6 - fluoroindol - 3 - yl)ethyl] acetamide; N - [2 - (1 - pivaloyl -5- methoxy - 6 - bromoindol - 3 - yl)ethyl]formamide; N - [2 - (1 - chloroacetyl - 5 - methoxy - 6 - iodoindol - 3 - yl)ethyl]propionamide.

N - [2 - (1 - bromoacetyl - 5 - methoxy - 6 - chloroindol - 3 - yl)ethylJ butyramide; N - [2 - (1 - valeryl - 2 - methyl - 5 - methoxy - 6 - bromoindol - 3 - yl)ethyl]acetamide; N - [2 - (1 - butyryl - 2 - ethyl - 5 - methoxy - 6 - chloroindol - 3 - yl)ethyl]acetamide; N - [2 - (1 - benzoyl - 2 - n - propyl - 5 - methoxy - 6 - chloroindol - 3 - yl)ethyl] formamide; N - [[2 - [1 - (4 - chlorobenzoyl) - 2 - n - butyl - 5 - methoxy - 6 - chloroindol 3 - yl]ethyl]]formamide; N - [[2 - [1 - (4 - bromobenzoyl) - 2 - ethyl - 5 - methoxy - 6 - iodoindol - 3yl] ethyl] ] propionamide; N - [[2 - [1 - (2,4 - dichlorobenzoyl) - 2 - isopropyl - 5 - methoxy - 6 - fluoro indol - 3 - yl]ethyl] ] - a - methylpropionamide; N - [[2 - [1 - (2,4 - difluorobenzoyl) - 2 - phenyl - 5 - methoxy - 6 - chloro- indol - 3 -yl]ethyl]] formamide; N - [[2 - 1 - (4 - iodobenzoyl) - 2 - phenyl - 5 - methoxy - 6 - bromoindol - 3 yljethyl] ] acetamide; N - [[2 - [1 - (2 - methylbenzoyl) - 2 - phenyl - 5 - methoxy - 6 - iodoindol 3 - yl] ethyl] ] propionamide; N - [[2 - [1 - (2,6 - dimethylbenzoyl) - 2 - (4 - chlorophenyl) - 5 - methoxy- 6 - chloroindol - 3 - yl]ethyl] ]formamide; N - [[2 - [1 - (2,4,6 - trimethylbenzoyl) - 2 - (3 - fluorophenyl) - 5 - methoxy6 - bromoindol - 3 - yl] ethyl] acetamide; N - [2 - (1 - pivaloyl - 5 - methoxy - 6 - chloroindol - 3 - yl)-ethyl]acetamide; N - [2 - (1 - chioroacetyl - 5 - methoxy - 6 - chloroindol - 3 - yl)ethyl]acetamide; N - [[2 - [1 - (4 - chlorobenzoyl) - 5 - methoxy - 6 - chloroindol - 3 - yl] ethylj ] acetamide; N - [[2 - [1 - (2,4 - dichlorobenzoyl) - 5 - methoxy - 6 - chloroindol - 3 - yl]ethyl] ] acetamide; N - [[2 - [1 - (2 - methylbenzoyl) - 5 - methoxy - 6 - chloroindol - 3 yl]ethyl]]- acetamide; N - [[2 - [1 - (2,6 - dimethylbenzoyl) - 5 - methoxy - 6 - chloroindol - 3 - yl]ethyl] ] acetamide; and N - [[2 - [1 - (2,4,6 - trimethylbenzoyl) - 5 - methoxy - 6 - chloroindol - 3 yl] ethyl] j acetamide.

The compounds of formula I are prepared by acylating a substituted tryptamine of the formula

in which X and R are as aforedescribed. The acylation is accomplished by employment of conventional procedures. For example, the substituted tryptamine can be reacted with an activated form of a carboxylic acid of the formula

in which R1 is as defined hereinabove. Suitable such activated forms include, for example, the anhydride or mixed anhydride of the carboxylic acid. Acylation also can be carried out by reacting the carboxylic acid in the form of its acid halide with the tryptamine in the presence of a hydrogen halide acceptor. Hydrogen halide acceptors which can be used include a tertiary amine, such as pyridine, or triethylamine; alkylene oxides, such as propylene oxide; urea and substituted ureas, such as Nmethylurea; and inorganic bases, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, or sodium bisulfite.

The substituted tryptamines used as starting materials in the aforedescribed acylation are prepared by a variety of known procedures. A preparation of 5-methoxy6-halotryptamines is illustrated by the following generalized reaction scheme:

As shown in the above generalized reaction scheme, the 5-methoxy-6-halotryptamines are prepared by first halogenating 3-methoxy-4-aminotoluene (IV) to give 3-methoxy-4-halotoluene (V). The halogenated compound then is reacted with pyridine hydrochloride at an elevated temperature of from 180 C. to 2400 C. to provide a 2-halo-5-methylphenol (VI). The phenol is reacted with sodium nitrite in acid solution at a temperature from OOC. to 20"C. to give an intermediate nitroso compound (VII). Reaction of the nitroso compound with aqueous nitric acid at a temperature of from 300C. to 600C. provides a 2-halo-4-nitro-5-methylphenol (VIII).

In those cases in which X is chloro, the 2-chlorophenol intermediate compound is commercially available and thus may itself be used as the initial starting material.

The halonitrophenol then is alkylated, for example, by refiuxing it with dimethyl sulfate and potassium carbonate in methanol or ethanol, or by heating it with methyl iodide and potassium carbonate in N,N-dimethylformamide, to provide 2-nitro-4halo-5-methoxytoluene (IX). The nitrotoluene compound is reacted with N,N-di-' methylformamide dimethylacetal in N,N-dimethylformamide at a temperature of from 100"C. to 1300C. to give an N,N-dimethyl-2-(2'-nitro-4'-halo-5'-methoxy- phenyl)ethyleneamine intermediate (X), which, upon hydrogenation over Raney nickel, cyclizes to give a 5-methoxy-6-haloindole (XI).

The haloindole then is treated with diethylamine and formalin in aqueous acetic acid solution. The resulting mixture is added to aqueous base, and the total is extracted. The solvents are evaporated, and the recovered intermediate product is dissolved in a mixture of water, methanol and N,N-dimethylformamide and is reacted with sodium cyanide. Methyl iodide then is added dropwise to the solution to give a 3-cyanomethyl-5-methoxy-6-haloindole (XII). The cyano compound is reduced with a metal hydride, for example, lithium aluminum hydride, to provide the desired 5 methoxy-6-halotryptamine (XIII).

Tryptamines having a substituent at the 2-position of the indole moiety are prepared by a modification of the aforedescribed sequence. Compound (X), prepared as described above, is treated with a compound of the formula

in which Y is halo and R' is C144 alkyl, phenyl or substituted phenyl as aforedescribed. This reaction is carried out in the presence of triethylamine or pyridine and at room temperature to produce the corresponding 2-acyl substituted ethyleneamine (XIV). The ethyleneamine then is treated with hydrochloric acid in aqueous dioxane at a temperature of about 100"C. to produce the corresponding 2-nitro-4halo-5-methoxybenzyl ketone (XV). The latter is ring-closed by treatment with hydrogen over Raney nickel at a temperature of 25 C. to 40"C. to the desired 2substituted indole (XVI). This sequence is illustrated by the following generalized reaction scheme:

HJCO(CHJ)Z Rl COl-Y R-C-Y c112c4 X)~02 pgridine or (I) iriethylamine HCI H3CO c'=cHN(c)2 82COI 20 dioxane (nv) 112 fCH-RI Raneu Nickel NO2 enzene (nor) H3CO X > R H (:flr) Compound (XVI) then is treated in the manner aforedescribed with reference to compound (XI) to produce the desired tryptamine.

Alternatively, the indole, whether unsubstituted at the 2-position (compound XI) or substituted at the 2-position (compound XVI), can be treated by the following generalized scheme to produce the desired tryptamine intermediate:

As shown by the above generalized scheme, the indole is treated with phosphorus oxychloride and DMF to produce the corresponding 3-formyl indole (XVII). The latter is treated with nitromethane and ammonium acetate to obtain the corresponding 3-(2'-nitroethenyl)indole (XVIII), which then is reduced to the desired tryptamine (XIX).

Compounds of formula I in which R2 is other than hydrogen are prepared from the N-unacylated compounds. They are prepared by treating the latter with an appropriate acylating agent. Typically, the N-unacylated compound is reacted with at least an equimolar amount of an acyl halide of the formula R3C1 in which R3 represents any of the groups defined above. The reaction is carried out in the presence of a moderate molar excess (about 10%) of a strong base such as sodium hydride at room temperature in an inert solvent and for a time sufficient to accomplish conversion.

The compounds of formula I exhibit an inhibitory effect on ovulation when administered orally. This inhibitory effect is markedly superior to the effect achieved by oral administration of melatonin. Thus, the compounds of formula I are especially useful as orally active inhibitors of ovulation in birds and mammals. As a result, therefore, the compounds of formula I are useful in controlling the animal population and as contraceptives in living beings. The compounds of formula I also are valuable for animal pest control. For example, the compounds of formula I can be formulated in combination with baits and/or attractants and placed in feeding stations accessible to undesirable rodents and other small animals including Canidae such as coyotes, foxes, wolves, jackals, and wild dogs; and birds, such as starting, gulls, redwing blackbirds, or pigeons, to greatly reduce the population thereof. By reason of the activity of the compounds of formula I, they can be used to reduce hazards to aviation by lessening the presence of birds and animals on runways and in the vicinity of air fields. The compounds also can be used to reduce the population of undesirable birds and animals so as to aid in the prevention and the spread of disease, and to reduce the destruction of property in both rural and urban areas.

The compounds of formula I can be administered as such, or they can be com pounded and formulated into pharmaceutical preparations in unit dosage form for oral or parenteral administration. In the compounding or formulation, organic or in organic solids and/or liquids which are pharmaceutically acceptable carriers can be employed. Suitable such carriers will be well recognized by those of ordinary skill in the art. The compositions may take the form of tablets, powder granules, capsules, suspensions, or solution.

The compounds of formula I when administered in an effective amount, will produce the inhibition of pregnancy in birds and mammals. The usual daily dose is from 0.02 milligrams to 20 milligrams per kilogram body weight of the recipient.

The preferred daily dose is from 1 milligram to 8 milligrams per kilogram body weight of the recipient.

The following examples are provided to further illustrate this invention. They are not intended to be limiting upon the scope thereof.

Example 1.

N- [2- (5-Methoxy-6-chloroindol-3-yl)ethyl] acetamide A mixture of 142 g. (1.10 mole) of 2-chloro-5-methylphenol in 300 ml. of acetic acid and 40 ml of sulfuric acid was prepared. The mixture was stirred and a solution of 70 g of sodium nitrite in 200 ml. of water was added dropwise over a period of about 100 minutes. During the sodium nitrite addition the temperature of the mixture was maintained at 8--120C. with an ice-salt bath. After the addition was completed, the mixture was stirred for another 30 minutes and then was poured into a large volume of ice water. The crude 2-chloro-4-nitroso-5-methylphenol was collected by filtration and used without further purification.

The crude nitroso compound was added in portions to a stirred solution of 100 ml.

of 70% nitric acid and 300 ml. of water maintained at a temperature of 40--50"C.

Heating and stirring were continued until the evolution of brown fumes ceased. The mixture was then poured into water, and the product was collected by filtration. The product was recrystallized from ethanol-water. After collecting the first crop, the mother liquor was concentrated and chilled to yield a second crop of product. Total yield was 155 g. (83%) of 2-chloro-4-nitro-5-methylphenol, m.p. 142--4"C.

A mixture of 25 g. (0.133 mole) of the 2-chloro-4-nitro-5-methylphenol, 20 g.

(0.145 mole) of potassium carbonate, and 14 ml. (18.6 g.; 0.148 mole) of dimethyl sulfate in 500 ml. of absolute ethanol was reflexed for two hours. An additional 19 g.

of potassium carbonate and 5 ml. of dimethyl sulfate were added to the mixture, and refluxing was continued for two hours. After cooling, the mixture was poured into one liter of cold water and extracted with several portions of ether. The ether extracts were combined, mixed with methylene chloride, and washed with water. The extracts then were dried over sodium sulfate, and the solvents were removed in vacuo. The residue was washed with petroleum ether and dried to yield 26.4 g. (94 percent) of 2-nitro-4-cloro-5-methoxytoluene.

A solution of 15.1 g. (0.075 mole) of the 2-nitro-4-chloro-5-methoxytoluene, 10.7 g. (0.09 mole) of N,N-dimethylformamide-dimethylacetal, and 1.0 g. of tri- ethylenediamine in 100 ml. of N,N-dimethylformamide was heated overnight at about 1200C. in a distillation apparatus under a gentle nitrogen sweep to yield N,N dimethyl-2-( 2'-nitro-4'-chloro-5'-methoxyphenyl) ethyleneamine. The intermediate was not isolated. Instead, it was hydrogenated in situ over 0.4 g. of Raney nickel at 15 psi during which time the temperature rose to 40--50"C. The hydrogenated solution was filtered, and the filtrate was poured into 500 ml. of ice water containing 10 ml. of acetic acid. The resulting mixture was extracted with several portions of methylene chloride. The combined organic extracts were washed with sodium chloride solution and dried over sodium sulfate. The solvent was removed, and the crude product was sublimed at 4 mm. pressure and 1300 C. The colorless sublimate was recrystallized from methanol-water to yield 6.1 g. (45 percent) of 5-methoxy-6-chloroindole, m.p.

12 & 280C.

A solution of 14 ml. of 60 percent acetic acid and 4.8 g. of diethylamine was prepared and cooled to about 50C. To this solution were added 5.1 ml. of formalin.

After stirring for ten minutes, the cold solution was added to a cold solution of 10 g.

(55 mmole) of 5-methoxy-6-chloroindole in 20 ml. of absolute ethanol. The solution was allowed to warm to room temperature and was stirred for one hour. The solution then was poured into 200 ml. of cold 1N sodium hydroxide, and the mixture was extracted several times with ether. The combined ether extracts were washed with sodium chloride solution, dried over sodium sulfate, and the solvent removed in vacuo.

The residue was taken up in a solution of 200 ml. of methanol, 10 ml. of N,Ndimethylformamide, 10 ml. of water and 13.3 g. (0.27 mole) of sodium cyanide. To this solution were added dropwise over a period of about one hour 21 ml. (48 g., 0.34 mole) of methyl iodide. After the addition of methyl iodide was complete, the solution was stirred for about one hour and then was poured into ice water. The aqueous mixture then was extracted with methylene chloride. The extract was dried over sodium sulfate, and the solvent was removed in vacuo. The residue was recrystallized from an ether-pentane mixture to yield 6.1 g. (50 percent) of 3-cyanomethyl-5 methoxy-6-chloroindole, m.p. 133-1370C.

A solution 7.6 g. (0.2 mole) of lithium aluminum hydride in 200 ml. of tetrahydrofuran was stirred under nitrogen while a solution of 5.2 ml. (9.8 g., 0.1 mole) of 100 percent sulfuric acid in 40 ml. of tetrahydrofuran was added. A solution of 6.0 g. (27 mmoles) of 3-cyanornethyl-5-methoxy-6-chloroindole in 40 ml. of tetrahydrofuran then was added over a 30-minute period. The reaction was allowed to proceed for another hour with stirring. The mixture then was poured into ice followed by 20 percent sodium hydroxide solution. The resulting mixture was extracted with several portions of chloroform. The extracts were washed with sodium chloride solution, dried over sodium sulfate, and the solvent was removed in acuo. The residue was boiled in ether, and a small amount of pentane was added. The mixture was cooled, and the crystalline product collected by filtration. After drying, 5.04 g. (83 percent) of 5-methoxy-6-chlorotryptamine were obtained.

To a solution of 0.5 g. (2.23 mmoles) of the tryptamine in 5 ml of pyridine was added 0.5 ml. of acetic anhydride. The mixture was allowed to stand overnight The solvent was removed in vacuo, and the residue was taken up in a mixture of chloroform and ethyl acetate. The solution was washed with sodium bicarbonate solution and dried over sodium sulfate. The solvent was removed in vacuo. The residue was boiled in benzene. After cooling the product was collected and the benzene treatment was repeated. The product then was dried to yield 0.52 g. (87 percent) of N- [2- (5-methoxy-6-chloroindol-3-yl)ethyl] acetamide, m.p. 149.5-1500C.

Example 2.

N- [2- ( 5-Methoxy-6-chloroindol-3-yl )ethyl] propionamide A solution of 0.5 g. (2.23 mmole) of 5-methoxy-6-chlorotryptamine, prepared as described in Example 1, in 4 ml. of benzene and 1 ml. of pyridine was acylated with propionic anhydride following the procedure described in Example 1. N-[2-(5- Methoxy - 6 - chlorindo] - 3 - yl)ethyl]propionamide 0.56 g. m.p. 10e101bC.. was obtained.

Example 3.

N- [2-( 5-Methoxy-6-chloroindol-3-yl)ethyl]butyramide A solution of 0.5 g. (2.23 mmole) of 5-rnethoxy-6-chlorotryptarnine, prepared as described in Example 1, in 5 ml of pyridine was acylated with butyryl chloride following the procedure described in Example 1. N- [2-(5-Methoxy-6-chloroindol-3- yl)ethyl]butyramide, 0.41 g. (62 percent), m.p. 98-98.50C., was obtained.

Example 4.

N- [2-(5-Methoxy-6-fluoroindol-3-yl)ethyl] acetamide To 68.5 grams (0.5 mole) of 2-methoxy-4-methylaniline in a 2 liter flask was added a solution of 136 ml. of concentrated hydrochloric acid in 930 ml. of water.

The solution was cooled and stirred at about --5"C., and a solution of 42 grams (0.61 mole) of sodium nitrite in 110 ml. of water was slowly added. The mixture was maintained at about --50C. for about 20 minutes after which 75 ml. (0.60 mole) of 65 percent aqueous hexafluorophosphoric acid were rapidly added. The resulting mixture was stirred and maintained cold for about 30 minutes, and the resulting product then was collected by filtration. The product was washed with 400 ml. of cold water followed by a solution of 120 ml. of methanol and 460 ml. of ether. The resulting diazonium hexafluorophosphate salt was collected on a filter and dried in vacuo overnight. The resulting dried salt weighed 155 grams (96 percent).

A 1 liter flask containing 500 ml. of mineral oil was fitted with a reflux con denser, a magnetic stirrrer, a thermometer, and a connecting tube leading to a 300 ml.

Erlenmeyer flask. To the Erlenmeyer flask was added the entire quantity of the diazonium salt. The oil was heated to 16500. by means of an oil bath. The diazonium salt then was added in portions over a 45 minute period. There was a slightly exothermic reaction. Upon completion of the reaction, the flask was rapidly cooled and 400 ml. of 10 percent aqueous sodium carbonate solution were cautiously added.

The mixture was subjected to steam distillation. The resulting oily layer was collected.

The aqueous layer was extracted with 350 ml

A mixture of 25 grams (0.15 mole) of the fluoronitrophenol, 22 grams of potassium carbonate, 15.4 ml. of dimethyl sulfate, and 550 ml. of ethanol was refluxed overnight Analysis of the reaction mixture indicated that no alkylation had taken place. The mixture then was diluted with 300 ml. of N,N-dimethylformamide and about 50 ml. of water. Two equivalents of methyl iodide then were added. The mixture was heated at 1000C. overnight. The mixture then was cooled and added to a large volume of ice water. The product separated, was collected by filtration, and dried. The collected product was recrystallized from methanol-water to obtain 22.2 grams of 2-nitro4-fluoro-5-methoxytoluene, m.p. 95--95.5"C.

A mixture of 10 grams (0.054 mole) of the fluoronitrotoluene, 7.7 grams (0.065 mole) of N,N-dimethylformamide dimethylacetal, and 1.0 grams of triethylenediamine in 75 ml. of N,N-dimethylformamide was heated at 1250C. under a gentile nitrogen sweep ovemight. The solvent then was removed in vacuo with gentle application of heat. The resulting residue was taken up in methanol and filtered to give a deep red green iridescent product, m.p. lld117"C. A total of 8.35 grams (64 percent) of N,N-dimethyl-2-(2'-nitro-4'-fluoro-5'-methoxyphenyl)ethyleneamine was obtained.

The ethyleneamine was hydrogenated in benzene over Raney nickel. The resulting reaction mixture was washed with 500 mL of water containing 4 ml. of phosphoric acid.

The resulting aqueous phase then was extracted with methylene chloride, and all the organic portions were combined. The combined organic solutions were then washed with aqueous sodium chloride solution and dried over sodium sulfate. The solvent then was removed in vacuo, and the resulting crude product was sublimed from a fused state at 0.2 mm. pressure. The resulting sublimate was recrystallized from methanol-water to obtain a first and second crop totalling 3.02 grams (54 percent) of 5-medhoy-6-fluoroindole, m.p. 73--740C.

To a mixture of 2.8 ml. of 60 percent acetic acid and 0.96 grams of diethylamine maintained at about 5 C. was added 1.0 ml. of formalin. The resulting solution was added to a mixture of 2.0 grams (12.1 mmole) of the fluoroindole in 4 ml. of absolute ethanol. The solution was allowed to warm to room temperature and was stirred for about one hour. The solution then was poured into 40 ml. of 1N sodium hydroxide.

The resulting mixture was extracted several times with ether. The ether extracts were combined and washed with aqueous sodium chloride solution, dried over sodium sulfate, and evaporated. The resulting residue was added to a solution of 40 ml. of methanol, 2 ml. of N,N-dimethylfonnamide, 2 ml. of water, and 2.66 grams of sodium cyanide. To the resulting mixture then were added dropwise 4.2 ml. (9.6 grams; 0.068 mole) of methyl iodide over a period of about one hour. The resulting mixture was maintained for about another hour. The mixture then was poured into ice water, and the aqueous mixture was extracted with methylene chloride. The extract was dried over sodium sulfate, and the solvent was removed in vacuo. The residual product then was washed with a cold mixture of ether and petroleum ether. The product was recrystallized from benzene-hexane to obtain 1.11 grams (45 percent) of 3-cyano methyl-5-methoy-6-fluoroindole, m.p. 97--980C.

A solution of 1.9 grams (0.05 mole) of lithium aluminum hydride in 50 ml. of tetrahydrofuran was prepared and stirred under nitrogen. A solution of 1.3 ml. (2.45 grams; 0.025 mole) of 100 percent sulfuric acid in 10 ml. of tetrahydrofuran was prepared and then was added to the lithium aluminum hydride solution. The resulting mixture contained lithium sulfate as a suspension. A solution of 1.0 grams (4.9 mmole) of the cyanomethylindole in 10 ml. of tetrahydrofuran then was added to the mixture over a period of about 15 minutes. Stirring was continued for an additional one hour.

The reaction mixture then was poured into ice followed by 20 percent sodium hydroxide solution. The resulting mixture was extracted with several portions of chloroform. The extracts were washed with sodium chloride solution, dried over sodium sulfate, and the solvent was removed in vacuo. The resulting residual oil crystallized upon addition of ether. The tan product was washed three times with small amounts of a 1:1 mixture of ether and petroleum ether. Upon drying, 0.83 grams (81 percent) of 5-methoxy-6-fluorotryptamine was obtained. m.p. 114--117"C.

Recrystallized from benzene-hexane, m.p. 12210C.

A mixture of 0.75 grams (3.6 mmole) of the tryptamine, 2.0 ml. of pyridine, and 8.0 ml. of benzene was prepared. Acetic anhydride (1.0 ml.) was slowly added.

The mixture was stirred at room temperature for four hours, and the solvents then were removed in vacuo with moderate heating. The resulting crystalline residue was dissolved in a 1:1 mixture of warm ethyl acetate and chloroform. The solution was washed with water, then with sodium chloride solution, and then dried over sodium sulfate. The solvents were removed in vacuo. The crystalline residue was boiled in benzene for a few minutes. The mixture was allowed to stand at room temperature for several hours, and the resulting product was collected by filtration and dried to obtain 0.81 grams (90 percent) of N-[2-(5-methoxy-6-fluoroindol-3-yl)ethyl]acetamide, m.p. 1S8-1590C.

Example 5.

N- [2- ( 6-Chloro-5-methoxy-2-methylindol-3 -yl) ethyl] acetamide To a solution of 20 g. (0.078 mole) of N,N-dimethyl-2-(2'-m.troA'-chloro-5'- methoxyphenyl)ethyleneamine and 19.8 ml. (19.4 g., 0.25 mole) of pyridine in 200 ml. of methylene chloride was added dropwise a solution of 11 ml. (12.2 g., 0.156 mole) of acetyl chloride in 200 ml. of methylene chloride. The addition was carried out over a period of about three hours. The mixture was stirred overnight and then was poured into a large volume of cold NaHCO, solution. The aqueous phase was extracted with fresh methylene chloride. The combined organic solutions were washed with water and dried over sodium sulfate. Removal of the solvent in vacuo gave a residue which was dissolved in 450 ml. of dioxane. To the resulting solution were added 150 ml. of 1M HCI solution. After stirring overnight at room temperature, the solution was reflexed for three days. After cooling, 80 ml. of 1M NaOH were added, and the bulk of the dioxane was removed under reduced pressure. The product was then extracted into chloroform. The extract was evaporated, and the residue was chromatographed over 200 g. of Flurosil (Registered Trade Mark), eluting with benzene. Crystallization from benzene-hexane gave 6.49 g. (34% yield) of 4-chloro 5-methoxy-2-nitrophenylacetone, m.p. 114--115"C.

Using 2 g. of Raney nickel, 6.49 g. (0.026 mole) of the arylacetone in 90 ml. of benzene were hydrogenated under 50 psi of hydrogen for 1 hour. The exothermic reduction caused the temperature to rise to 400C. After removal of the benzene, the residue was crystallized from methanol-water affording 1.5 g. of 6-chloro-5-methoxy 2-methylindole, m.p. 115-1160C. Evaporation of the mother liquor followed by sublimation and recrystallization from methanol-water provided another 0.62 g. of product, m.p. 11P-115"C. Total yield: 2.12 g., 41%.

A mixture of 3.6 ml. (3.42 g. 0.047 mole) of DMF and 1.04 ml. (1.74 g., 0.0114 mole) of phosphorus oxychloride was prepared at 1(200C. After 1S minutes, 2.05 g. (0.0105 mole) of the indole in 1 ml. of DMF was added, and the temperature was raised to 35 C. After one hour the mixture was poured onto crushed ice. This mixture was treated gradually with 2 g. of NaOH in 10 ml. of water, maintaining an acidic pH through the first three-fourths of the addition. Following addition of the base, the mixture was boiled for one hour. After the mixture was cooled and allowed to stand overnight, the product was collected. Boiling the product in methanol afforded 2.13 g. (91% yield) of pure 6-chloro-5-methoxy-2-methylindole-3-carbox- aldehyde, m.p. 256 dec.

A mixture of 0.5 g. (0.002 mole) of the indole-carboxaldehyde, 40 ml. of nitromethane, 10 drops of acetic acid, and 0.4 g. of ammonium acetate was reflexed overnight. Another 0.4 g. of ammonium acetate was added, and the mixture was reflexed for an additional day. The nitromethane was removed in vacuo, and the residue was washed with water. Recrystallization from ethanol gave 0.35 g. (59% yield) of pure 1 ;(6'-chloro-5'-methoxy-2'-methylindol-3'-yl ) -2-nitroethene, m.p. 238 Odec.

A solution of 1.47 g. (0.039 mole) of lithium aluminum hydride in 90 ml. of ThF was stirred under nitrogen. A solution of 1.02 ml. of sulfuric acid (100%) in 15 ml. of THF was added to the mixture followed by addition over a one hour period of a solution of 0.35 g. (0.0013 mole) of the nitrovinylindole in 15 ml. of THF. The mixture was stirred overnight, and the excess hydride then was destroyed by addition of ice chips. The mixture then was poured into a 20% NaOH solution, and the total was extracted with several portions of chloroform. After drying over sodium sulfate, the solvent was removed from the extracts, and the residue was recrystallized from benzene-hexane. The yield of 6-chloro-5-methoxy-2-methyltryptamine, m.p. 152--153; was 0.50 g. (79%).

A solution of 0.11 g. of the tryptamine in 5 ml. of benzene and 0.37 ml. of pyridine was stirred in an ice bath. To the stirred mixture was added 0.05 ml. of acetic anhydride. After stirring for one hour at room temperature, the mixture was poured into ice water and extracted with benzene. The benzene extract was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed over 10 g. of silica gel eluting with ethyl acetate. The pure N- [2-(6-chloro-5-methoxy-2-methylindol-3- yl)ethyl]acetamide, m.p. 119-121; weighing 0.11 g. (85% yield) was recovered.

Example 6.

N-[2-( 1-Acetyl-5-methoxy-6-chloroindol-3 -yl) ethyl] acetamide To 30 ml. of N,N-dimethylformamide were added 210.7 mg. (0.79 mole) of N-[2-(5-methoxy-6-chloroindol-3-yl)ethyl]acetamide (prepared as in Example 1) followed by 20.8 mg. of sodium hydride. The resulting mixture was stirred at room temperature for about one hour, and 68.2 mg. (0.06 ml.) of acetyl chloride were added. The mixture was stirred for an additional hour and then was poured into ice water containing a small amount of acetic acid. The resulting mixture was extracted with chloroform, and the extract was washed twice with saturated aqueous sodium chloride solution. The chloroform extract was dried over sodium sulfate and was concentrated in a rotary evaporator. The residue was recrystallized from benzene-ether and was vacuum-dried to obtain 108 mg. (40.8%) of the title compound, m.p. 1781810C.

Analysis, Calc'd for C15H1,N2O,Cl: C, 58.35 ; H, 5.55 ; N, 9.07 Found: C, 58.02*; H, 5.82*; N, 9.07*.

*Result is an average of two analyses.

IR (KBr) 1646 (C=O), 1703 cm-1 (C=O).

UV 4 (MeOH) 256 (e 17,200), 274 sh nm (e 10,300).

NMR (DMSO-d6) 8 1.81 (s, 3H, amide Ac); 2.29 (t, J=7 Hz., 2H, a-CH2); 2.58 (s, 3H, 1-Ac); 3.37 (q, J=7 Hz, 2H, B--CH,); 3.90 (s, 3H, OCH,); 7.33 (s, 1H, 4--H); 7.67 (s, 1H, 2-H); 7.99 (broad t, 1H, N-H); and 8.31 (s, 1H, 7-H).

The following Table is provided to show ovulation inhibitory activity of the compounds of formula I. Adult female rats with regular estrus cycles of four days each are employed. The estrus cycle consists of two days of diestrus followed by a day of proestrus and then a day of estrus. On the afternodn of proestrus, luteinizing hormone (LH) is released into the blood by the pituitary gland The LH travels to the ovary where it induces ovulation, resulting in the presence of eggs in the oviduct on the day of estrus.

The test compound is administered orally at noon on the day of proestrus. The rat is sacrificed on the following day (estrus) and the oviduct is removed and examined microscopically for the presence of ova. The absence of ova indicates that the compound is active in blocking ovulation.

TABLE Inhibition of Ovulation

Inhibition R R1 X Min. Eff. Dose, mg.

H CH3 Ha 8 H CH3 Cl 1 H C2H, Cl 1 H C,H7 Cl 4 H CH3 F 1 CH3 CH, Cl 1 aMelatonin.

Claims (26)

WHAT WE CLAIM IS:

1. A 5-methoxy-6-halotryptamine compound of the formula

in which R is hydrogen, C1 Cs alkyl, phenyl, or phenyl substituted with halo, C,-C4 alkyl, or C1~C4 alkoxy; R1 is hydrogen or C1C, alkyl; R2 is hydrogen or Ra, and R3 is haloacetyl, C1C" alkanoyl, benzoyl, or benzoyl substituted with halo or methyl (as hereinbefore defined); and X is halogen.

2. Compound of Claim 1, in which R2 is hydrogen.

3. Compound of Claim 1, in which R2 is haloacetyl, Ct alkanoyl, benzoyl, or benzoyl substituted with halo or methyl.

4. Compound of any of Claims 1 to 3, in which R is methyl.

5. Compound of any of Claims 1 to 3, in which R is hydrogen.

6. Compound of any of Claims 1 to 5, in which R1 is hydrogen.

7. Compound of any of Claims 1 to 5, in which R1 is C19 alkyl.

8. Compound of Claim 7, in which R1 is methyl.

9. Compound of Claim 7, in which R1 is ethyl.

10. Compound of any of Claims 1 to 9, in which X is chloro.

11. Compound of any of Claims 1 to 9, in which X is fluoro.

12. Compound of any Claims 1 or 3 to 11, in which R2 is acetyl.

13. Compound of any Claims 1 or 3 to 11, in which R2 is pivaloyl.

14. Compound of any of Claims 1 or 3 to 11, in which Rn is benzoyl, 4-chlorobenzoyl, 2-methylbenzoyl, 2,6-dimethylbenzoyl or 2,4,6-trimethylbenzoyl.

15. N- [2- (S-Methoxy-6-chloroindol-3-yl)ethyl] acetamide.

16. N- [2- (5-Methoxy-6chloroindol-3-yl) ethyl] propionamide.

17. N- [2- (5-Methoxy-6-chloroindol-3-yl)ethyl] butyramide.

18. N- [2-(5-Methoxy-6-fluoroindol-3-yl) ethyl] acetamide.

19. N- [2-(5-Methoxy-6-chloro-2-methylindol-3-yl)ethyl] acetamide.

20. N- [2-( 1-Acetyl-5-methoxy-6-chloroindol-3 -yl ) ethyl] acetamide.

21. A process for preparing 5-methoxy-6-halo-tryptamine compounds of formula I as claimed in Claim 1 which comprises a 5-methoxy-6-halotryptamine compound of the formula:

wherein R and X are as defined in Claim 1, with an active derivative of a carboxylic acid of the formula

wherein R1 is as defined in Claim 1; and if desired reacting the compound so obtained wherein R2 is hydrogen with an acylating agent of the formula R,Cl IIIa wherein R3 is as defined in Claim 1, in the presence of a strong base.

22. A process according to claim 21 for preparing a 5-methoxy-6-halo-tryptamine compound of formula I substantially as hereinbefore described with particular reference to any one of the Examples.

23. A 5-Methoxy-6-halotryptamine compound of formula I as defined in Claim 1, substantially as hereinbefore described with particular reference to the Examples.

24. A compound of formula I whenever prepared by a process according to claim 21 or 22.

25. A pharmaceutical formulation which comprises a compound of formula I as claimed in any one of claims 1 to 20, 23 or 24 associated with a pharmaceutically acceptable carrier therefor.

26. A method of inhibiting ovulation in a mammal which comprises orally administering a compound of formula I as claimed in any one of claims 1 to 20, 23 or 24 to said mammal.