AU616907B2 - Melatonin analogues - Google Patents

Description

s:~-7 r~-i I-;I a AU-AI-23097/88 616907

PCT

WORLD INTELLECTUAL PROPERTY ORGANIZATION International Bureau 0 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 (11) International Publication Number: WO 89/ 01472 CO7D 209/14, 209/16, 487/04 Al C07D 471209/14, A6K 316, 487/0 (43) International Publication Date: 23 February 1989 (23.02.89) C07D 471/04, A61K 31/40 (21) International Application Number: (22) International Filing Date: (31) Priority Application Numbers: PCT/US88/01859 20 May 1988 (20.05.88) 086,062 086,290 17 August 1987 (17.08.87) 17 August 1987 (17.08.87) (32) Priority Dates: (33) Priority Country: (72) Inventors; and Inventors/Applicants (for US only) :DUBOCOVICH, Margarita, L. [AR/US]; 3930 N. Pinegrove, Suite 2815, Chicago, IL 60613 PECK, James, V. [US/US]; 2524 Bowdoin Place, Costa Mesa, CA 92626 HELMY, Atef, A. [US/ US]; 627 South Velare, 37, Anaheim, CA 92804 RA- JADHYAKSHA, Vithal, J. [US/US]; 27436 Esquina, Mission Viejo, CA 92691 (US).

(74) Agent: BOSTICH, June, Nelson Research Development Co., 1001 Health Sciences Road West, Irvine, CA 92715

(US).

(81) Designated States: AT (European patent), AU, BE (European patent), CH (European patent), DE (European patent), DK, FI, FR (European patent), GB (European patent), IT (European patent), JP, KR, LU (European patent), NL (European patent), NO, SE (European patent), US, US.

Published With international search report.

Parent Applications or Grants (63) Related by Continuation

US

Filed on

US

Filed on 086,062 (CIP) 17 August 1987 (17.08.87) 086,290 (CIP) 17 August 1987 (17.08.87) -t ITn

I

y E 1

JC.-

(71) Applicant (for all designated States except US): NCLSON-R-E- S-EA-R--&-EDEVEe-PME-N-T-e0-[US/US]; 1001 Health Sciences Road West, Irvine, CA 92715 (US).

S.D.J.P. 27 APR 1989 j

I

AUSTRALIAN

(54) Title: MELATONIN ANALOGUES PATENT OFFICE

(I)

it -(CR2)nNH -C-[A]x(R 2 )y

/R

1 (CR2)m (57) Abstract Compounds kepresented by general formula wherein RI is an aryl radical having from 4 to 14 carbon atoms; R 2 is selected from the group consisting of hydrogen, lower alkyl and phenyl radicals; A is O, S or N; m is 1 to 3; n is 1 to 3; x is 0 (r I and y is I when A is O or S and y is 2 when A is N, their use as melatonin antagonists, and preparation.

WO89/01472 PCT/US88/01859 -1- MELATONIN ANALOGUES Background of the Invention 1. Field of the Invention This invention relates to novel 2-aryl substituted N-acetyltryptamines having pharmacological activity, e.g., melatonin antagonist activity and methods for the synthesis thereof.

2. Background of the Art Melatonin, 5-methoxy-N-acetyltryptamine, is a major hormone of the pineal gland. The synthesis and secretion of Smelatonin exhibit a circadian rhythm that changes with the seasons and with age, pubescence and senesence. The rhythm appears to be the result of both endogenous mechanisms and environmental cues, most notably, the exposure of mammals to light which inhibits melatonin synthesis and secretion.

Melatonin is thought to be the hormonal mediator of photoj' periodic changes. Evidence suggests that melatonin is involved in the regulation of circadian rhythms and a variety of neural and endocrine functions. Melatonin has been Simplicated in a number of human disorders, particularly F those relating to chronobiologic abnormalities. Researchers have suggested administering melatonin to alleviate or prevent disturbances in circadian rhythms caused by the rapid crossing of time zones, jet lag, or changes in work shifts from night to day. See European Patent Application 0 126 630, by Short et al.

It has been proposed that melatonin mediates the effects of shortening days on the winter depressive symptoms of seasonal affective disorder (SAD) and that the symptoms of SAD result from secretion of melatonin, either in WO 89/01472 PCT/US88/01859 -2some abnormal way or in a population who is abnormally sensitive to its effects. See Rosenthal et al., J. Neural Transm. (1986) [suppl] 21:257-267. Thus, Lewy, in Science, Vol. 235 at pp. 352-354, uses bright light to suppress night-time melatonin production in humans and has shown that this treatment reverses the depressive symptoms of patients with SAD.

Melatonin analogues have been studied for their effects on the reproductive system, specifically antigonadal activity and inhibition of release of luteinizing hormone see Flaugh et al. Journal of Medicinal Chemistry, (1979) 22:63-69.

Frohn et al., Life Sciences, Vol. 27, pp. 2043-2046, Pergamon Press and Clemens et al., J. Neural Transm. (1986) [suppl] 21:451-459, disclose melatonin analogues wherein the activity of such analogues is related to structure.

Analogues with improved metabolic stability, e.g.

2-methyl-6,7 dichloromelatonin, are disclosed.

Heward and Hadley, (1975) Life Sci. 17:1167-1168, reported an in-vitro method for measuring the melatonin response of various indoleamines, including melatonin and by frog skin lightening. Of the compounds disclosed in this article, only N-acetyltryptamine and N-acetylserotonin were reported to have "melatonin blocking activity." Dubocovich, Evr. J. Pharmacol. 105:193-194, 1984, also reported that N-acetyltryptamine competitively antagonized the inhibitory effect of melatonin in the chicken retina, thus demonstrating melatonin blocking activity by a more sensitive in-vitro method than utilized by Heward and Hadley.

Thus, it is clear that there is a continuing interest in developing melatonin analogues and using such melatonin analoaues for treatina chronobioloaical. neural and endocrine WO 89/01472 PCT/US88/01859 -3- Description of the Drawing Figures Figure 1 shows the spatial orientation of the compounds of the instant invention wherein the longi-tudinal axis of the indole moiety and the 2-aryl substituent is polyplanar as described herein and have melatonin antagonist activity; and Figure 2 shows a closely related analogue wherein such longitudinal axis is uniplanar as described herein and is hypothesized as not showing melatonin antagonist activity.

Figure 3a is a concentration-response plot and 3b is a Schild Plot showing the melatonin antagonist activity of one of the preferred compounds of the present invention.

-4- Summary of Invention The present invention provides novel compounds which may have melatonin antagonist activity or agonist activity and are represented by the formula:

O

II 2)y

(CR

2 )nNH C[A]x(R 2

R

1 CR2)m r o

R

6

H

t. wherein each R is independently selected from the group consisting of hydrogen, halogen, e.g. fluoro and chloro, 15 and lower alkyl radicals, C l to C 4 alkyl radicals, methyl, ethyl, n-propyl and isopropyl; R 1 is an aryl radical (including heteroaryl radicals) having from to 14 carbon atoms, e.g. a phenyl, thienyl, furanyl, pyridyl or a naphthyl radical; R 2 is selected from the group of hydrogen, lower alkyl, C 1 to C 4 alkyl radicals and phenyl radicals; R 3 is selected from the group consisting of hydrogen, halogen, e.g. fluoro and chloro, hydroxy, lower alkyl, C 1 to C 4 alkyl radicals, lower alkoxy, C 1 to C 4 alkoxy and phenoxy radicals; R 4 is selected from the group consisting of hydrogen, halogen, fluoro and chloro, hydroxy, lower alkyl, C 1 to C 4 alkyl radicals, lower alkoxy,

C

1 and C 4 alkoxy and phenoxy radicals; R 5 is selected from the group consisting of hydrogen, halogen, fluoro and chloro, hydroxy, lower alkyl, C 1 to C 4 alkyl, lower alkoxy, i.e. C l to C 4 alkoxy and phenoxy; R 6 is selected from the group consisting of hydrogen, halogen, fluoro and chloro, hydroxy, lower alkyl, C 1 to C 4 alkyl, lower alkoxy, C 1 to C 4 alkoxy and phenoxy and A is O, S or N; m is an integer of 910809,dbdat.74,23097.res,4 ,l WO 89/01472 PCT/US88/01859 from 1 to 3; n is an integer of from 1 to 3, x is 0 or 1 and y is 1 when A is 0 or S and y is 2 when A is N.

Preferably each R is a hydrogen radical, R2 is a lower alkyl radical, m is 1, n is 2 and x is 0. More preferably Rl is selected from the group consisting of hydrocarbyl radicals such as phenyl and naphthyl, e.g.

phenyl.

These compounds have melatonin agonist or antagonist activity and are useful in the treatment of jet lag, depression and other abnormalities which may be associated with circadian or seasonal rhythms and/or the amount of melatonin in the body and/or functions regulated by the hormone melatonin.

ii

I'"'J

1 WO 89/01472 PCT/US88/01859 -6- Detailed Description of Invention In the compounds of the present invention the longitu-dinal axis of the indole ring and the 2-aryl substituent are preferably polyplanar. That is, the longitudinal axis of the indole moiety (See A of Figure 1) is preferably oriented to lie in a different plane than R1 (See B of Figure To achieve this orientation R1 must be connected to the indole moiety by a methylene or polymethylene bridge, m is an integer of 1 to 3 but not 0.

It is also noted that since R1 is a "bulky" group such polyplanar orientation of the compounds of the present invention is energy-favored.

While not wishing to be bound by theory, it is believed that in compounds that are similar in structure to the present compounds, 2-phenyl N-acetyltryp-tamine, as illustrated in Figure 2, wherein the longitudinal axis of the indole moiety and the 2-phenyl substituent (See C of Figure 2) is uniplanar, melatonin antagonist activity is not observed.

In particular, R 1 may be selected from the group consisting of phenyl, thienyl, furanyl, pyridyl, pyrrolyl and other aromatic and heteroaromatic radicals comprising single rings of five or six members.

The above radicals may also be substituted with various functional groups. In particular, such substituents may be selected from the group consisting of hydroxy, nitro, azido, sulfonamido, halogen, hydrocarbyl and hetero atom-substituted hydrocarbyl radicals, wherein said hetero-atoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms. R 1 may also represent polyphenyl radicals such WO89/01472 PCT/US88/01859 WO 89/01472 i -7asbiphenyl and similar polyaromatic and poly heteroaromatic radicals.

R1 may also be selected from the group consisting of organic radials having fused aromatic rings, that is, radicals comprising at least two rings that share a pair of carbon atoms or a carbon and nitrogen atom.

Preferably, R1 comprises no more than 3 fused aromatic rings, and more preferably R1 comprises 2 fused aromatic rings. Examples of radicals suitable for R1 include naphthyl, anthracyl, phenanthryl, benzofuranyl, benzothienyl, indolyl, indazolyl, benzotriazolyl, triazolopyridinyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl, benzopy-ranyl, quinolyl, phthalazinyl, purinyl, naphthothienyl, indolizinyl, quinlizinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, etc.

The above radicals may also be substituted with various functional groups. In particular, such substituents may be selected from the group consisting of hyroxy, nitro, azido, sulfonamido, halogen, hydrocarbyl and hetero atom-substituted hydrocarbyl radicals, wherein said hetero-atoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms.

The above compounds may be made as described in the examples below.

Specific preferred compounds which are within the scope of this invention include: 2-benzyl-N-acetyltryptamine 2-(2-chlorobenzyl)-N-acetyltryptamine 2-(2-methylbenzyl)-N-acetyltryptamine WO 89/01472 PCT/US88/01859 -8- 2-(2-nitrobenzyl)-N-acetyltryptamine 2-(l-naphthyl)methyl-N-acetyltryptamine 2-(2-thienylmethyl)-N-acetyltryptamine A preferred embodiment of the present invention comprises a method of treating any disorder in which it is therapeutic to mimic or inhibit melatonin function or influence circadian rhythms by administering a therapeutically effective amount of one or more of the compounds of the present invention to a patient suffering from such disorder.

Another preferred embodiment of the present invention comprises a method of treating chronobiological disorders, Se.g., seasonal affective disorders (SAD), sleep disorders, and symptoms such as drowsiness and fatigue that are associated with disturbances in sleep/wake cycles jet lag, workers on night shifts, etc.) by administering a therapeutically-effective amount of one or more of the compounds of the present invention to a patient suffering from one or more of such chrono-biological disorders.

Another preferred embodiment of the present invention comprises a method of treating various psychiatric disorders related to altered melatonin function or influenced by melatonin and circadian rhythms, affective disorders (mania and depression), alcoholism, and stress by administering a therapeutically-effective amount of one or more of the compounds of the present invention to a patient suffering from one or more of such psychiatric disorders.

Another preferred embodiment of the present invention comprises a method of treating or inducing various endocrinerelated conditions attributed to altered melatonin function or influenced by melatonin and biological rhythms, particularly relating to regulation of reproductive WO 89/01472 PCT/US88/01859 -9maturation and function, idiopathic delayed puberty, premature labor, and antifertility, by administering a therapeutically-effective amount of one or more of the compounds of the present invention to a patient suffering from or desiring to induce one or more of such endocrine related conditions. In addition, it is thought that the melatonin agonist compounds of the invention can be used to treat or prevent glaucoma by lowering the intraoccular pressure and to manipulate body weight by administering an effective amount of one or more of the melatonin agonist compounds herein.

Finally, a preferred embodiment of the present invention uses the melatonin agonists herein to manipulate the breeding cycles in animals by administering to such animal an effective amount of one or more of the compounds of the present invention.

In general, a pharmacologically effective daily dose can be from 0.01 mg/kg to 100 mg/kg per day, and preferably from 0.1 mg/kg to 25 mg/kg per day, bearing in mind, of course, that in selecting the appropriate dosage in any specific case, consideration must be given to the r patient's weight, general health, metabolism, age and other factors which influence response to the drug. A Iparticularly preferred dose is 1.0 mg/kg per day.

Another embodiment of this invention is the provision of pharmaceutical compositions in dosage unit form which comprise from about 2 mg. to 500 mg. of a compound of the above formula.

The pharmaceutical composition may be in a form suitable for oral use, for example, as tablets, aqueous oroily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

WO 89/01472 PCT/US88/01859 Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide a pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets.

These excipients may be, for example, inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and Sdisintegrating agents, for example maize starch, or alginic acid; binding agent, for example starch, gelatine, or acacia; and lubricating agents, for example magnesium stearate, stearic acids, or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract. Thereby a sustained action over a longer period can be provided.

Formulations for oral use can also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate, or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with an oil medkiu, for example arachis oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active compound in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents can be a naturally- 1 I WO 89/01472 PCT/US88/01859 -11occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example of polyoxethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxy-cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example, polyoxyethylene sorbitol monooleate, or condensation product of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The said aqueous suspensions can also contain one or more preservatives, for example ethyl, n-propyl, or p-hydroxy benzoate, one or more coloring agents, one or more Sflavoring agents, and one or more sweetening agents, such Sas sucrose, saccharin, or sodium or calcium cyclamate.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring, and coloring agents, can also be present.

I Syrups and elixirs can be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.

WO89/01472 PCT/US88/01859 -12- The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol.

The pharmaceutical compositions of the present invention also include compositions for transdermal and/or intranasal administration. Thus, the compounds of the present invention can be compounded with a penetrationenhancing agent such as l-n-dodecylazacyclopentan-2-one or the other penetration-enhancing agents disclosed in U.S.

Patent Nos. 3,991,203 and 4,122,170 which are hereby incorporated by reference to describe penetrationenhancing agents which can be included in the transdermal Sor intranasal compositions of this invention.

The pharmaceutical compositions can be tableted or otherwise formulated so that for every 100 parts by weight of the composition there are present between 5 and 95 parts by weight of the active ingredient. The dosage unit form will generally contain between about 1 mg. and about 100 mg. of the active ingredient of the formula stated above.

From the foregoing formulation discussion it is apparent that the compositions of this invention can be administered orally or parenterally. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, or intrasternal injection or fusion techniques.

To illustrate the manner in which the invention can be carried cut, the following examples are given. It is understood, however, that the examples are for the purpose of illustration and the invention is not to be regarded as limited to any of the specific materials or conditions therein.

WO 89/01472 PCT/US88/01859 -13- EXAMPLE 1 Preparation of 2-benzyl-N-acetyl tryptamine.

gm (0.05M) tryptamine, 5.8 gm (0.055M) benzaldehyde and 440 ml 0.125N sulfuric acid were mixed together and heated in a stirred one liter round bottomed flask to 70-75 C for 24 hours. The resultant precipitate was filtered off and recrystallized from a solution of ethanol made basic with ammonium hydroxide. The resultant free amine had a melting point of 168-174"C.

4.10 gm (0.026m) of the above product (l-benzyltetra-hydrocarboline hydrochloride) was combined with 600 mg palladium on carbon, 30 ml glacial acetic acid and 180 ml deionized water. This mixture was placed in a bomb under approximately 100 lbs/in 2 hydrogen heated to 35'C. The reaction was continued for 6 hours and then let cool to room temperature overnight. This mixture was filtered and the filtrate extracted with dichloromethane. The aqueous solution was then treated with ammonium hydroxide, and the resultant precipitate filtered off, washed with water and dried. The melting point was 159-163"C. Yield: 2.2 gm 0.3 gm (0.0012M) of the above product (2-benzyl tryptamine) was dissolved in ethyl acetate and made basic with several drops of ammonium hydroxide. 50 mg potassium carbonate was added, with 0.3 ml (0.01M) acetic anhydride.

This mixture was stirred for 15 minutes at room temperature under nitrogen. Water was added and the organic phase separated. This was washed with brine and dried with magnesium sulfate. Concentration gave a residue which was purified by column chromatography (C-18 column, methanol/water gradient) to give 0.075 gm of 2-benzyl-n-acetyl tryptamine. Elemental analysis: C 77.94%, H 6.89%, N 9.39%, Theoretical: C 78.05%, H 6.89%, N 9.58%.

3- r_ WO 89/01472 PCT/US88/0185 9 -14- EXAMPLE 2 Preparation of tryptamine.

tryptamine was employed in place of tryptamine (EXAMPLE 1) to provide the above compound.

EXAMPLE 3 Preparation of 2-(4-methoxy)benzyl-N-acetyl tryptamine.

p-Methoxybenzaldehyde was employed in place of benzaldehyde (EXAMPLE 1) to provide the above compound.

EXAMPLE 4 Preparation of 2-(4-methyl)benzyl-N-acetyl tryptamine.

p-Tolualdehyde was employed in place of benzaldehyde (EXAMPLE 1) to provide the above compound.

EXAMPLE Preparation of 2-(l-naphthyl)methyl-N-acetyl tryptamine.

l-Naphthaldehyde was employed in place of benzaldehyde (EXAMPLE 1) to provide the above compound.

WO 89/01472 PCT/US88/01859 Melatonin Receptor Assay Melatonin has been shown to inhibit dopamine release from rabbit retina via a specific receptor mechanism (Dubocovich, 1983, Nature, 306:782-784 and 1985, J.

Pharmacol. Exp. Ther. 234:395-401). Competitive antagonists are expected to prevent the decrease in dopamine release by melatonin and shift the melatonin concentration-response curve to higher concentrations.

Method: The method of Dubocovich, 1985, was used to demonstrate melatonin receptor antagonist activity.

Briefly, dopamine release was elicited in vitro by electrical field stimulation (3 Hz, 2 min. 20 mA, 2 msec.) of rabbit retinal pieces which had been prelabeled with 3H-dopamine. Release was determined as the percentage of total tissue radioactivity that was released during stimulation minus the spontaneous release level determined before and after stimulation. Two periods of stimulation (S 1 and S 2 were applied 40 minutes apart in each experiment. Results are expressed as the ratio of release in S 2 to release in S1.

In the control experiments, melatonin, at various concentrations, was present during S 2 and release was depressed relative to that seen in Sl. To test for antagonist activity, a compound was added 40 min. prior to S 1 and as present throughout the remainder of the experiment which involved adding melatonin during the S 2 period.

Preliminary experiments were run with the compound alone in S2 to test for any direct effects of the compounds on dopamine release.

WO 89/01472 PCT/US88/01859 -16- EXAMPLE 6 The compound of Example 1 had no significant direct effects on either spontaneous or stimulated dopamine release when tested at concentrations of 0.1-10 gM. (As shown in the figure, the compound by itself did not modify the control ratio S 2

/S

1 The presence of increasing concentrations of melatonin (lpM-100nM) in S 2 did progressively decrease the S2/S 1 ratio. The concentration of melatonin which inhibited release by 50% (IC 50 was 0.04 nM. As shown in Figure 3a, the effectiveness of any given melatonin concentrations was decreased by increasing concentrations of this compound, and the melatonin concentration-response curves were shifted in parallel to the right (increasing the IC 50 values). As shown in Figure 3a, melatonin was either absent (open symbols) or present at various concentrations (filled symbols) during

S

2 The compound of Example 1 (N-0774) was present during both S 1 and S 2 at a concentration of 0.1 gM A 1gM or 10 gM The affinity constant (KB) for antagonists can be estimated from the Schild plot shown in SFigure 3b (Arunlakshana and Shild, 1959, Br. J. Pharmacol.

14:48-58); and in the case of this compound, the estimated KB was found to be 20 nM.

Conclusion: The compound of example 1,2-benzyl-Nacetyl tryptamine, is a potent, competitive antagonist at melatonin receptors.

EXAMPLE 7 The melatonin receptor assay described above was used to test compounds 1-5 for activity. The compounds did not inhibit 3 H-dopamine release from rabbit retina when present alone during the S 2 period of electrical stimulation.

However, all of the compounds significantly antagonized the ability of 0.1 nM melatonin to inhibit 3 H-dopamine release as shown in the following Table: PCT/US88/0185 9 WO 89/01472 -17- Table 3 H-Dopamine Release S 2/SI(n)* Control 0.98 0.05 (14) Melatonin (0.lnM) 0.48 0.004 (26) Melatonin compound of Example 1: 1-M0.65 0.07 (4) 6 M 0.91 0.09 1O- 5 M 0.94 0.09 (3) Melatonin compound of Example 2: 10 M 0.56 0.2 9 m 0.92 0.04 (3) 8 m 0.87 0.02 (2) 10-7M4 1.07 0.04 Melatonin compound of Example 3: 7 M 0.69 0.04 (3) 8 m 0.92 0.05 (3) Melatonin compound of Example 4: 10-6M4 0.86 0.10 (3) Melatonin compound of Example 6 M 0.75 0.10 (4) the number of experimental observations

Claims (20)

1. Compounds represented by the formula: R3 R 3 (CR 2 )nNH C-[A](R 2 R4 (CR2 m H wherein each R is independently selected from the group consisting of hydrogen, halogen and lower alkyl radicals; R 1 is an aryl radical having from 5 to 14 carbon atoms; R is selected from the group consisting of hydrogen, 15 lower alkyl and phenyl radicals; R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy and phenoxy radicals; R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy and "20 phenoxy radicals; !o R 5 is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy and phenoxy radicals; R is selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy and phenoxy radicals; A is O, S or N; m is an integer of from 1 to 3; n is an integer of from 1 to 3; x is 0 or 1 and y is 1 when A is 0 or S and y is 2 when A is N.

2. The compound of Claim 1 wherein each R is a hydrogen radical, R 2 is a lower alkyl radical, m is 1, n is 2 and x is 0.

3. The compound of Claim 1 or Claim 2 wherein R 1 is a hydrocarbyl radical. 910809,dbdat074,23097.res,18 1*Y; l -19-

4. The compound of Claim 3 wherein R 3 R 4 R 5 and R 6 are hydrogen radicals. The compound from phenyl, naphthyl, phenyl radicals.

6. The compound radical and R 4 R 5 and of Claim 4 wherein R 2 is selected p-methyl phenyl and p-methoxy of Claim 3 wherein R 3 is a methoxy R 6 are hydrogen radicals. 6

7. The compound of Claim 6 wherein R 1 is a phenyl radical.

8. The compound of Claim 5 wherein R 1 is a phenyl radical.

9. The compound naphthyl radical. The compound methyl phenyl radical. of Claim 5 wherein R1 is a of Claim 5 wherein R 1 is a p-

11. The compound methoxy phenyl radical. of Claim 5 wherein R 1 is a p-

12. A method of treating psychiatric disorders related to melatonin function or influenced by melatonin and circadian rhythms by administering a therapeutically effective amount of one or more of the compounds of any one of Claims 1, 2, 5, 6, 8 and 10 to a patient suffering from such disorder.

13. The method of Claim 12 wherein the disorder is a chronobiological disorder. 910809,dbdatO74,23097.res,19 r C i r r I ~1

14. The method of Claim 12 wherein the disorder is an endocrine disorder.

15. A method of treating or inducing a condition in which it is therapeutic to inhibit melatonin function or influence circadian rhythms by administering to a human or animal a therapeutically effective amount of one or more of the compounds of any one of Claims 1, 2, 5, 6, 8 and

16. The method of Claim 15 wherein the breeding cycles in anilals is manipulated by administering said compounds.

17. A process for preparing 2-aryl substituted N- acetyltryptamines which comprises the steps of: reacting a tryptamine compound having the formula: CR 2 )nNH 2 wherein each R is independently selected from hydrogen, halogen and lower alkyl radicals and wherein R 3 R 4 R and R 6 are independently selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl and lower alkyoxy radicals; with an aldehyde represented by the formula: R 1 CHO wherein R 1 is an aryl radical in the presence of an acid to yield a l-benzyltetrahydrocarboline compound having 91o8o9,dbdLO74,23097.res,20 -21 the formula: R 3 CR2) n 4 R 6 H R 1 reducing said carboline of step to yield a compound having the formula: R R3 (CR 2 nNH2 SR4 R6 H R 1 15 and,

21.(c) acetylating the compound of step to obtain a 2-aryl substituted N-acetyltryptamine having the formula: methoxybenzyl.. R S R 3 (CR2)nN-C-CH3 6 11 2 18. The process of Claim 17 wherein each R is H. 19. The process of Claim 18 wherein R3, is methoxy a n d R 4 R 5 a n d R 6 a r e H >u The process of Claim 18 wherein R 3 R 4 R 5 and R 6 are H. 21. The process of Claim 20 wherein R 1 is p- methoxybenzyl. A 'g i 910809,dbdat074,23097.res,21 i 'r I -22-

22. The process of Claim 20 wherein R 1 is p- methylbenzyl.

23. The process of Claim 20 wherein R 1 is naphthyl.

24. The process of Claim 20 wherein R 1 is benzyl. The process of Claim 19 wherein R 1 is benzyl.

26. Compounds of Claim 1, processes for their preparation or methods of treatment involving them substantially as hereinbefore described with reference to the Examples and/or drawings. n r DATED this 9th day of August, 1991 Whitby Research, Inc. By Its Patent Attorneys DAVIES COLLISON i. 910809,dbdat-074,23097res,22