patent update: central & peripheral nervous system: agents for the treatment of sleep disorders:...
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Patent Update
Central & Peripheral Nervous System
Agents for the treatment of sleep disorders: patent activity July 1992 to June 1994
Katherine S Talc& and Brett T Watson
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA
Exp. Opin Ther. Patents (1994) 4(10): 1243-1252
This update includes basic patents and patent applications published between July 1992 and June 1994 which may have utility for the treatment of three major groups of sleep disorders, namely, simple insomnia, sleep disorders secondary to anxiety or mood disorders, and sleep disorders stemming from circadian rhythm disruptions. Accordingly, the patents are grouped by their presumed mode of action as non-psychotropic agents, psychotropic agents, and chronobiotic agents. For the purposes of this review, only those patents and applications which specifically describe or claim sleep enhancing or sedative-hypnotic properties are included. Coverage is limited to novel small-molecule, non-peptidergic agents.
Introduction
Sleep disorders are a major, though often trivialised and underdiagnosed medical problem. It is estimated that one out of seven individuals in America and other western countries suffers from a chronic sleep problem [ll. About one-third of the patients of general practi- tioners and two-hds of psychiatric patients report difficulty sleeping 121. Although there are many differ- ent types of sleep disorders, the most common ones which appear to be amenable to pharmacological intervention include simple insomnia, sleep distur- bances secondary to mood disorders, and sleep prob- lems associated with circadian rhythm disruption [31.
By far the most common complaint relating to sleep is insomnia. A 1 9 1 Gallup survey indicated that one- third of American adults are affected by insomnia [41, which is often triggered by acute emotional or physical stress (e.g. illness) or environmental change. This type of simple insomnia often resolves itself, although occasionally short term use of a sedative-hypnotic to relieve sleeplessness and fatigue may be necessary [31.
Often, the situation is more complex than simple insomnia, because the sleep disorder is related to an underlying anxiety or mood disorder. It is thought that
as many as 80% of the cases of insomnia seen in general practice may be related to anxiety and depres- sion [I]. Among depressed patients, 90% complain of sleep problems and although most of these patients experience reduced sleep, approximately 20% sleep excessively 131. When the sleep disorder is determined to be secondary to an anxiety or mood disorder, treatment must address both issues and usually con- sists of an anxiolytic or antidepressant with sleep modulating properties [31.
The sleep/wake cycle is one of the fundamental biological rhythms in man and a number of sleep disorders are related to the desynchronisation of an individual’s activity/rest pattern and their endogenous sleep/wake cycle [5]. These disorders include difficul- ties in sleep due to rotating work-shifts, jet-lag, and delayed or advanced sleep phases. The affected popu- lations are significant in size. For example, it is esti- mated that 2-5% of Americans suffer from sleep disturbances associated with shift work [31. The elderly are another significant segment of the population which may fall into this category. Changes in sleep architecture have been observed with advancing age, including an increase in the number and duration of awakenings during the night 161. This may be related
1243 1994 8 Ashley Publications Ltd ISSN 1354-3776
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1244 Central & Peripheral Nervous System - Patent Update
to reports of a reduction of amplitude and desynchron- isation of certain circadian cycles in the elderly. At present there is no accepted pharmacotherapy for the treatment of sleep disorders arising from circadian disruption. However, there is active, ongoing research in the area and the recent patent activity indicates that interest in the development of a chronobiotic agent to resynchronise sleep/wake cycles is growing.
This update includes basic patents and patent applica- tions published between July 1992 and June 1994 which may have utility for the treatment of the three major groups of sleep disorders discussed above, namely, simple insomnia, sleep disorders secondary to anxiety or mood disorders, and sleep disorders stem- ming from circadian rhythm disruptions. Accordingly, the patents are grouped by their presumed mode of action as non-psychotropic agents, psychotropic agents, and chronobiotic agents. For the purposes of this review, only those patents and applications which specifically describe or claim sleep enhancing or seda- tive-hypnotic properties are included. Coverage is limited to novel, small-molecule, non-peptidergic agents.
Non-psvchotropic Agents
Compounds with general sedating properties can func- tion to help induce sleep by a variety of mechanisms including interaction at histamine or opiate receptors.
Ligands for histamine receptors In two separate patent applications, Schering has disclosed histaminergic ligands which, by virtue of their affinity for the H3 receptor, are claimed to be of use in treating sleep disorders. These include a series of imidazolylalkylpiperazine (e.g. 1) and diazepine derivatives [loll as well as a series of imidazolyl- or imidazolylalkylpyrrolidine (e.g. 2) or azetidine deriva- tives 11021. Binding affinities were determined in guinea-pig brain tissue using either [3Hl-R-a-methyl- histamine or [3Hl-Nmethylhistamine. In addition, a large number of imidazole derivatives have been de- scribed by Inserm in collaboration with Soci6t6 Civile Bioproject as H3 antagonists which may be useful as sedatives and sleep regulators 11031. A preferred com- pound is 3. The same groups have also described a few simple amidine, isourea (e.g. 4), and isothiourea derivatives of histamine as H3 agonists which function as efficient sedatives via their central nervous system effects [1041. No biological data are presented.
Ligands for opiate receptors DuPont Merck Pharmaceuticals has disclosed a series of nitrogen-based heterocycles (e.g. 5) which were shown to be selective opioid K agonists as measured in rat brain homogenates (Ki =1-12,400 nm) [1051.
These compounds showed potent analgesic and strong sedative effects in mice.
1 Ki=0,0047pM 2 a)n=O R=H K ~ - ~ . ~ ~ ~ ~ ~ b)n=l R=CHB) -
Schering
3 4
Societe Civile Bioproject INSERM
5
DuPont Merck
Unspecified site of action Hoffmann-La Roche has disclosed a series of tricyclic pyridone derivatives (e.g. 6) which are suggested to have muscle relaxant properties and are proposed to be useful for the treatment of sleep disorders [lob]. Data suggest that these compounds increase non-REM sleep in rats. Egis Gyogyszergyar has claimed a series of bedelindene derivatives as having “tranquillo- sedative” effects 11073. Representative compounds (e.g. 7) were shown to potentiate hexobarbital induced sleep time.
6
Hoffmann-La Roche
7
Egis Gyogyszergyar
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Agents for the treatment of sleep disorders. patent activity July 1992 to June 1994 - Takaki & Watson
Psychotropic Agents
Modulators of GABA and serotonin receptors are the major classes of compounds which are claimed for the treatment of sleep problems related to anxiety and other mood disorders.
Modulators of the GABA receptor complex GABA is an inhibitory neurotransmitter, the release of which can elicit a number of pharmacological re- sponses including muscle relaxation, reduction in anxiety, and sedation. The release of GABA is influ- enced by ligands which bind to modulatory sites on the GABA receptor complex including the ben- zodiazepine site and a site defined by the binding of t-butylbicyclophosphorothionate (TBPS).
Li$8nds for the bnzodiazepine binding site In December 1992, Sepracor, in two separate patent applications, sought protection for the (+) [lo81 and (-1 [lo91 enantiomers of the benzodiazepine agonist zopi- clone (8) for the treatment of sleep disorders. Sepracor suggests that in their pure forms, the two enantiomers have higher potency with respect to the treatment of sleep disorders than the racemic mixture. Their defini- tion of sleep disorders includes insomnia, disturbed sleep patterns, and sleep induction before surgery or during disturbed states. In January 1993, RhBne- Poulenc Rorer also applied for patent protection for the (+) isomer of zopiclone as a sedative/hypnotic agent I l l O l . Their application proposes that in the mouse, the (+) isomer is less toxic and more active than the racemic mixture and that the (-1 isomer is inactive and more toxic than the racemic mixture. The activity is based on benzodiazepine receptor binding and suggests that the (+) isomer works on diverse parameters of sleep including augmentation of the duration and quality of sleep as well as diminution of the number of nightly and early awakenings.
0 0
Sa R=COCH3 "
9b R=H Sepracor RhBne-Poulenc Rorer RhBnePoulenc Rorer
Rh6ne-Poulenc Rorer has applied for protection for novel isoindolinone derivatives (e.g. 9a) which are structurally related to zopiclone [llll . Although no specific mechanism of action is discussed, the com- pounds are suggested to be hypnotic agents and are said to reduce convulsions induced by pentetrazol. The specific compound 9b, in racemic or optically
active form, is the subject of a separate RhBne-Poulenc Rorer patent application 11121. Both enantiomers are reported to have good affinity for the benzodiazepine site and are consequently presumed to be useful as hypnotics, anxiolyws, anticonvulsants and muscle re- laxants.
Several series of polycyclic imidazole derivatives have been shown to interact with the benzodiazepine site and are consequently suggested to be sedative hyp- notic agents. Hoffmann-La Roche has disclosed a series of tetracyclic imidazodiazepines (10) which demon- strate affinity for the benzodiazepine site as measured by the displacement of [%]-flumazenil in rat cortex [1131. IC9s are in the range of 0.20-3.0 nM. Upjohn has a series of 3-substituted-imidazo(l,5-u)- and imi- dazo(l,5 -a)triazolO(l,5-~)quinoxalines and quinazo- lines (e.g. 11-13) which interact with the benzodiazepine receptor [1141. The affinity of five compounds was measured in vitro (Ki =1.67-11.50 vs. [3Hl-flumazenil). Of these, compound 13 was reported to have the highest affinity (Ki = 1.67). In another patent application, Upjohn has claimed additional 4-oxoimidazo(l,5-u)quinoxalines (14), as well as the 5-0x0 isomer and some diimidazoquinazolines [ l l f . Thirty compounds, including 14 are specifically claimed. No biological data are provided, but the compounds are claimed for the treatment of disorders associated with benzodiazepine receptors. Upjohn has also disclosed a related series of imidazdl,5-alquinox- alines I1161. Although structurally related to the ben- zodiazepine receptor ligands previously described by Upjohn, no biological data are given. A preferred compound in this series is 15.
i / c N 1 H,CI \CH,
10 Hoffmann-La Roche 11
12 13
0 - CH, 0: I
14 " H,C CH,
15 11-15 Upjohn
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1246 Central & Peripheral Nervous System - Patent Update
Another series of imidazoquinazolines (16) has been described by Novo Nordisk to possess strong affinity for the benzodiazepine receptor suggesting their utility as anxiolytic and hypnotic agents [lli'l. In particular, the oxadiazole derivative 17 displaces [3H]-fluni- trazepam binding from the benzodiazepine receptor in vim with an ED50 of 0.29 mgkg. Displacement of [3H]-flunitrazepam has also been used to determine the affinity of a series of imidazobenzoxazines claimed by Upjohn 11181. For example, compound 18 is reported to possess a Ki of 8.56.
'-0 R,
I
benzimidazole-Fcarboxyl (25b) derivatives which were determined to have affinity for the ben- zodiazepine site on GABAA receptors as evidenced by the inhibition of [3Hl-flunitrazepam binding [126]. A series of aryl-substituted pyrrolopyrazines have been patented by Neurogen on the basis of their potency in binding to the benzodiazepine site [1271. The 2-fluoro- 4-methoxy derivative (26) displaces [3Hl-flumazenil in rat cortical tissue with an IC50 of 0.029 pM. Also based upon the inhibition of [3H1-flumazenil bindmg, Syn- thelabo has described a series of imidazo[2,1-6lben- zothiazole-3-acetamide derivatives (27) which have affinity for the benzodiazepine type 1 and type 2 receptors (01 and 0 2 ) [1281. IC50 values in the range of 0.1-1,000 nM are reported for these compounds. Finally, Dainippon Pharmaceutical Co has disclosed a series of 3-oxadiazolyl-l,6-naphthyridine derivatives as agonists for the benzodiazepine binding site [1291. There are 168 specific examples described, among
X=N or CH 16 Novo Nordisk
17 lo'
18 Novo Nolrlisk Upjohn
In several different patents, Neurogen has disclosed a number of new classes of ligands for the ben- zodiazepine binding site. Compounds in four series, oxazoloquinolinones (19) [119,1201, imidazopyrimi- dines (20) 11211, imidazoquinoxalinones (21) [122], and pyrroloquinolinetriones (22) [123] were shown to bind to the benzodiazepine site in rat cortical tissue with IC50 values in the range of 0.033-0.600 ph4 (vs [3Hl-flumazenil). In another series, aryl- and cycloal- kyl-fused imidazopyrazinediones (23) are claimed [1241. Compound 23 displaces [3Hl-flumazenil from rat cortical tissue with an IC50 of 0.009 pM. Finally, Neurogen has also disclosed a series of aryl and cycloalkyl-fused imidazopyrazinols [1251. Of the com- pounds for which binding data are specifically pro- vided, the highest affinity is demonstrated by the ylohexyl fused derivative 24 (IC50=0.0054 @I vs [ HI-flumazenil). All of the Neurogen compounds are suggested to have value in the diagnosis and treatment of various CNS disorders including sleep disorders.
Benzodiazepine ligands from a variety of other struc- tural classes have also been suggested to have utility in the treatment of sleep disorders. McNeilab has disclosed a series of 3-oxo-pyrido(l ,2-u)benzimida- zole-4-carboxyl (25a) and 4-oxo-azepino(l,2-u)
0 p +N
ONj H GtN%o " H
22 21 0
23
\
CH3
H 24
19 -24 Neurogen
O-CH3
Wb n=2 McNeilab 26 Neurogen
O-CH3
Wb n=2 McNeilab 26 Neurogen
R-CH,
27 Synthelabo 28 Dainippon
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Agents for the treatmemt of sleep disorders: patent activity July 1992 to June 1994 - Takaki & Watson 1247
which derivative 28 is a preferred compound possess- ing an IC50 of 1.29 nM vs [3HJ-diazepam.
Ligands which displace pH]-TBPS Cocensys and the University of Southern California have disclosed a series of 3a-hydroxylated steroid derivatives which act at a newly identified site on the GABA receptor-chloride ionophore complex (GR com- plex) which is distinct from other known sites of interaction (i.e., barbiturate, benzodiazepine, and GABA) [130,1311. These compounds are said to have activities similar to the benzodiazepines due to their ability to modulate brain excitability by regulating the chloride ion channels associated with the GR complex. As such they may be useful for the treatment of various psychological disorders including anxiety and insom- nia. The compounds were tested for their ability to displace [35Sl-T13PS (t-butylbicyclophosphorothionate) from the GR complex; the most active was 5a-preg- nan-3a-20-one (29) with an IC50 of 38 nM. In a related application, Cocensys has disclosed a method of screening for agonists at this site [1321. A n expressed GR complex is formed in cells via co-expression of cDNA encoding the human GRC subunits. The ability of the appropriate steroids to modulate ben- zodiazepine binding to the expressed receptor com- plex is then determined. A method for treating insomnia, anxiety, or mood disorders utilising such agonists is specifically claimed.
w HO \\%W
H
29
Cocensys University of Southern California
SmithKline Beecham has disclosed a series of tetrahy- drobenzo-thienopyridines (30) which are suggested to be CNS active and useful for the treatment of a variety of disorders including sleep disorders 11331. Although no biological mechanism of action is proposed, a number of the compounds show displacement of [35S]-TBPS from rat cerebral cortices with Ic50 values less than 25 pM.
30 SrnithKline Beecham
Unspecified action on the GABA complex In two patents, researchers at Washington University have described tricyclic steroid analogues (31) which
are useful for enhancing GABA-induced chloride cur- rents at the GR complex found in the rat hippocampal cell [134,1351. These compounds exhibit reversible GABA potentiating effects at 1 pM and are proposed to be useful for treating disorders which may be ameliorated by increasing neuronal inhibition via modulation of GABA-regulated chloride channels. The compounds are proposed to be sedative-hypnotic agents.
R
=0 CN
HO 4 31 COCH3
Washington University
Modulators of serotonergic receptors Alterations of serotonergic neurotransmission have been implicated in the modulation of the sleep-wake cycle 171 and in the aetiology of anxiety 181 and depression 191.
&MIA ligands American Home Products has patented the use of the known ~ - H T ~ A modulating bridged 2-(4arylpiperaz- inylalkyl)hexahydroisoindol-1,3-diones for the treat- ment of sleep disorders based upon the presumed role of serotonin in altering the sleep-wake cycle [1361. The agent zalospirone (32) is specifically claimed. Several additional series of aryl piperazine ~ - H T ~ A antagonists have been claimed by Wyeth for the regulation of the sleep/wake cycle as well as the treatment of anxiety. In one series the aryl group of the aryl piperazine is a monocyclic aryl or heteroaryl radical 11371. Binding data and preparative procedures are provided only for compound 33 which binds to the 5-H"i~ site in rat hippocampal membranes with an IC50 of 4 nM (vs. [3Hl-8-OH-DPA?3. In another series, the aryl group is a bicyclic oxygen-containing radical and the position of the amide nitrogen is switched to the other side of the carbonyl [1381. Compound 34 is specifically claimed and exemplified by preparation. Its binding affinity for the 5-HT1.4 site in rat hippocampal mem- branes is 0.6 n M (IC5o vs. [3Hl-8-OH-DPAT>. Finally, analogues of both of the previously described series have been prepared in whch the aromatic group a to the carbonyl is a heteroaryl radical [1391. A repre- sentative structure is compound 35 which has a bind- ing affinity of 2.2 n M (Ic50 vs [3Hl-8-OH-DPAT).
A series of 4-(arylmethylaminomethy1)piperidine de- rivatives (36) has been shown by a group at Pierre Fabre Medicament to have affinity for the 5-H"i~ receptor based on their ability to displace [3H]-8-OH- DPAT from rat brain tissue [140]. Specific claims are made for their use in the treatment of anxiety, depres-
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1248 Central 8r Peripheral Ne!rvous System - Patent Update
sion, and sleep disorders. In addition, aminomethyl- substituted 2,3-dihydropyrano[2,3-blpyridines with what is described as “higher selectivity” for the 5 - m ~ receptor have been patented by Bayer 11411. Binding data for the 5-HTi receptor in calf hippocampal mem- branes (vs. [3Hl-serotonin) is provided only for com- pound 37 (Ki = 1.0 nM).
U
0 32
American Home Products
H3C - 0
33 Ar=Ph 35 Ar=Bpyridinyl
n 0 0 o$cb \
34
33-35 John Wyeth
Y X R ICm(nM)
CH2 0 3-Me 3.8
0 CH2 3-CI 2.1
36 Pierre Fabre Medicament
0 0 H 3.0
choroid plexus membranes (pKiz7.6) and antagonises 5-HT-induced contractions of the rat stomach fundus, is one of 27 compounds which are specifically claimed. Eli Lilly has patented a series of tetrahydropyridoindole derivatives as 5-HTlc ligands which might be utilised for the treatment of sleep disorders [1431. Nineteen compounds are exemplified by preparation. Of these, compound 39 possesses the highest affinity for the 5-mic site (1C50 = 6 nM vs. [3Hl-mesulergine). A few compounds also possess affinity for the 5-HT2 site.
H H
39 Eli Lilly
MZ ligands Rh6ne-Poulenc Rorer has described the use of several new series of 5 - m ~ ligands for the treatment of anxiety and sleep disorders. One patent claims benzisothia- zoline dioxide- (&), phenanthridone- (41), and benzimidazolinone- (42) phenylpiperazines which displace I3H1-ketanserin with an Ic50 C 25 nM [la]. Another patent claims 3-aminobenzisothiazole diox-
40
41
37 Bayer AG
5-HT1 c ligands The Beecham Group has claimed a series of indole ureas as 5-mlc antagonists for the treatment or pro- phylaxis of anxiety and sleep disorders [1421. Com- pound 38, which displaces [3H]-mesdergine from pig 40-42 Rhbne-Poulenc Rorer
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Agents for the treatment of sleep disorders: patent activity July 1992 to June 1994 - Takaki & Watson 1249
ide- (49, 4-oxotetrahydrobenzazasilane- (u), and tetrahydroisoquinolinone- (45) phenylpiperazines which possess IC50s for the 5-m2 site of < 50nM [1451.
0 0,ll
43
n
'.Si H,C CH,
44
0
W N '
45
43-45 RhBnePoulenc Rorer
Unspecified serotonergic interactions
Hoffmann-La Roche has described a series of pyra- noindoles (e.g. 46) for the potential treatment of sleep disorders [ 1461. The compounds demonstrate affinity for multiple serotonin receptors in the following ranges: ~-HTIA (IC50 = 407-2370 a), ~-HTIB ( ~ 5 0 =
56.10- 398 nM), 5 - m ~ (Ic50 = 57-1350 nM) and 5-HT2 (IC50 = 374-12500 nM). IRJ has filed for coverage on a series of aminodichlorobenzyl propanol esters for the treatment of various mood disorders, depression, and insomnia [1471. A number of the compounds, including 47, appear to be serotonin antagonists based on their ability to produce a reduction in the typical behaviours produced by ip administration of the serotonin precur- sor 5-hydroxytryptophan in mice. In two separate applications, BASF has disclosed N-substituted 3-az- abicycld3.2.0lheptane derivatives such as 48 11481 and 49 11491 as novel neuroleptic agents which may also possess antidepressant and sedative/hypnotic proper- ties. The compounds appear to interact at multiple receptor sites. Data for specific receptor interactions are not provided but protocols for the antagonism of both apomorphine-induced climbing in mice and the serotonin syndrome in rats are described.
Monoamine oxidase inhibitors Tanabe Seiyaku has disclosed a series of antidepres- sant naphthyloxazolidone derivatives (e.g. 50) which may also be useful for the treatment of anxiety and insomnia accompanying anxiety [l50l. Compound 50
demonstrated in vitm MAO-A inhibition of 109.2% in an assay utilising mouse brain.
46
Hoffmann-La Roche 0
H3C7 'CH, 47
lnstitut de Recherche Jouveinal
40 BASF
49
BASF
50
Tanabe Seiyaku
Chronobiotic Aaents
Melatonin (51) is a hormone which is produced and secreted by the pineal gland in a cyclical fashion with the highest levels occurring at night. It is thought to play a major role in transducing environmental infor- mation about daylength and thus synchronising cir- cadian rhythms to the dayhight cycle [lo]. As early as 1984, a patent was issued to Monash University for the use of melatonin as a chronobiotic agent in humans for treating jet lag and work-shift syndrome [151]. More recently, a method has been patented by the University of Oregon for the use of melatonin to treat circadan rhythm disorders based upon the precise administra- tion of melatonin according to a phase diagram eluci-
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1250 Central & Peripheral Nervous System - Patent Update
dated specifically for humans 11521. The use of a single, acute physiological dose of melatonin (0.1-0.3 mg, Po> has also been claimed for the induction of sleep in humans, independent of its circadian effects 11531. However, the study of melatonin analogues or mela- tonin mimetics has only recently reached the point of generating significant patent activity.
Melatonin and its simple halogenated derivatives, 2- bromo (52), 2-ido (531, and 6-chloromelatonin (54) have been claimed for the therapy of sleep disorders either alone, or in association with a benzodiazepine derivative 11541. Administration of both 2-bromo and 24odomelatonin directly into the parietal cortex of rats and rabbits significantly inhibited the spontaneous activity of both cortical and thalamic neurones. When administered to insomniacs, 2-bromomelatonin signifi- cantly increased sleep efficiency while decreasing wake after sleep onset. Other simple Nacyl-2-alkyl- tryptamines (e.g. 55) have been claimed as melatonin agonists which may improve the temporal organisation of sleep by influencing sleep macro- and microstruc- ture via an interaction with the GABA receptor com- plex 11551. A method for the transdermal delivery of melatonin and its simple indole analogues (e.g. 51-55) for the treatment of chronopathologies such as jet lag and sleep disturbances has also been claimed 11561.
also disclosed isomeric naphthalene derivatives (e.g. 61) as melatonin ligands 11601. The aromatic ring system has been modified even further as a series of benzoxazolinones, benzothiazolinones, and benz- oxazinones (62-64) which are said to bind to mela- tonin receptors in an “interesting manner” 11611. These compounds are claimed to be active in potentiating pentobarbital induced sleep in mice.
X=S,O Y=CH X=O,NH Y=N
56 H3C,
0
57
P N 2. R
58 X=O kNHCH2CH2CH3 59 X=S R=NHCH2CH2CH3 60 X=O R=CH3 0
H3C.
0 0
51 X=Y=H R=CH3 melatonin 52 X=H Y=Br R=CH3 2-bmmomelatonin 53 X=H Y=l R=CH3 2-idomelatonin 54 X=CI Y=H R=CH3 Gchlommelatonin 55 X=H Y=CH3 R ~ y ~ l ~ p t ~ p y l
IFLO
The indole nucleus of melatonin has been replaced by a number of aromatic systems to provide novel mela- tonin ligands claimed to be useful for the treatment of sleep disorders. A variety of benzannelated heterocy- clic derivatives often specifically formulated as cyclo- propane carboxamides (e.g. 56,571 have been claimed by Adir 11571, as have a series of naphthylethylurea (e.g. 58) and naphthylethylthiourea (59) derivatives 11581. The naphthylethylureas are closely related to a group of Nnaphthylethylamides (60) whch consti- tuted one of the first non-indolic series of high affinity melatonin ligands reported 111,1591. AU of these naph- thalene and benzannelated heteroaromatic derivatives are claimed to be highly specific for the melatonin binding site in sheep pars tuberalis with the best compounds demonstrating an affinity 100 times supe- rior to that of melatonin itself. More recently, Adir has
61 62 X=O,S
CH, CH3
63 x 4 , s 64
56-64 Adir
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 S A D result from secretion of melatonin, either in some abnormal way or in a population that is abnormally sensitive to its effects 1121. Bright light can suppress night-time melatonin production in humans and it has been used to effec- tively treat chronobiological sleep and mood disorders. A melatonin receptor antagonist, by blocking the
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Agents for the treatment of sleep disorders: patent activity July 1992 to June 1994 - Takaki & Watson 1251
effects of melatonin, might exert the same effects as bright light and offer a potential therapy for these types of sleep and mood disorders. A series of 2-arylalkyl-N acyltxyptamine derivatives (e.g. 65, N-0774, luzindole) have been identified as melatonin antagonists based on their ability to antagonise the melatonin-induced inhibition of stimulated dopamine release from the rabbit retina [162]. In a behavioural despair test for antidepressant activity (Porsolt swim test), either com- pound 65 or bright light reduced the immobility time of C3H/HeN mice if administered at midnight when endogenous levels of melatonin are high. Although not specifically linked to any claim for the treatment of sleep or mood disorders, a series of naphthalene derivatives (e.g. 66) have also been identified as melatonin antagonists based on their ability to block melatonin’s inhibition of forskolin stimulated CAMP accumulation in sheep pars tuberalis tissue [1631. Fi- nally, a series of indole derivatives, including some tetrahydro-P-carboline derivatives (e.g. 67), have been reported to be melatonin antagonists although infor- mation on the method used for such a classification is not provided [1641.
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