Field of the Invention The present invention relates to a compound having antagonist activity to the 5-HT3 receptor for use as a medicament and to the use of said compound in the manu- facture of a medicament for therapeutic or prophylactic treatment of disorders involving airway constriction of a human or animal body, as well as methods of treatment, wherein said compound is administered.

Background of the Invention The seven main receptors of the 5-HT (serotonin; 3- (P-aminoethyl)-5-hydroxyindole) type are well known and occur throughout the body, e. g. in the airways, and their relevance has mainly been reported to be of significance in conjunction with treatment of CNS, muscle and gastric disorders, as disclosed in e. g. WO 98/18458 and US 5 246 935. In such treatments, compounds having ago- nist activity to a 5-HT1type receptor are often used. As examples of other 5-HT receptors, mention can be made of receptors of the 5-HT2,5-HT3,5-HT4,5-HT5,5-HT6 and 5- HT7 type. For a recent review of 5-HT receptors, see Ger- hardt, C. C., van Heerikhuizen, H., Eur. J. Pharm., 334, 1-23 (1997), which is incorporated herein by reference.

A review of typical agonists and antagonists of various 5-HT receptors is disclosed in R. A. Glennon, Neu- roscience and Biobehavioral Reviews, 14,35-47 (1990), : the whole content of which is incorporated herein by-'ref- erence.

SU 1 701 320 Al discloses the use of serotonin for treatment of acute asthma attacks. This reference does not suggest any receptor mechanism for serotonin, which is a compound with both a contracting and a relaxing ef- fect on the airways, as is further discussed herein be- low.

In the RBI Handbook or Receptor Classification and Signal Transduction, 3rd Edition, 1998, RBI, One

Strathmore Road, Natick, MA 01760-2447, USA, Editor :- Keith J. Watling are also 5-HT receptor compounds having agonist or antagonist activìty to various receptors dis- closed.

Disclosure of the Invention The present invention is based on the novel finding that certain 5-HT receptors are of utmost importance in regulating bronchocontraction, that is determining the level of airway constriction. In summary, it is disclosed herein that compounds having antagonist activity to the 5-HT3 receptor are suitable agents in the treatment of disorders involving airway constriction. Methods for- treatment of disorders involving airway constriction are also disclosed.

As used herein, the expression"disorders involving airway constriction", equivalent to the expression"bron- chocontraction disorder", refers to an abnormal increase of the force development of the smooth muscle in human or animal airways, resulting in a reduced diameter in some or all of the airways of the lungs and/or the extrapulmo- nary airways, such as occurring in asthma, chronic ob- structive pulmonary disease, emphysema and chronic bron- chitis. Said expression also refers, in a wider sense, to reduction of airflow, more precisely airway diameter, caused by swelling, oedema, plasma extravasation or mu- cous secretion caused by e. g. asthma or any other disor- der related thereto.

The expression"has the capacity of reducing the ab- normal airway constriction by at least.... used through- out the present patent application means that the com- pound in question or the composition of compounds in com- bination as well as the derivatives and pharmaceutically acceptable salts thereof, persistently reduces, in a cer- tain degree, airway constriction caused either by (1) the underlying disease (asthma etc) or (2) the administration of 5-HT or other substances capable of activating con- stricting 5-HT receptors, e. g. 5-HT3 receptors. The level

of constriction in the airways can, for instance, be-de- termined by spirometric measurements of the Forced Expi- ratory Volume (FEV1), compared to the normal value for healthy people. Alternatively, the expiratory capacity for a patient can be compared to his own FEV1 during pe- riods of relatively little obstructive problems.

The present invention relates, in one of its aspect, to a compound having antagonist activity to the 5-HT3 re- ceptor for use as a medicament. In another aspect it re- lates to use of said compound in the manufacture of a me- dicament for therapeutic or prophylactic treatment of a human or animal body, wherein the medicament is intended for treatment of disorders involving airway constriction, such as asthma.

In a preferred embodiment, the invention relates to the use of a compound having antagonist activity to a 5-HT3 receptor in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders in- volving airway constriction, wherein said antagonist has the capacity of reducing the pathological airway con- striction by at least 30%, preferably at least 60%, and most preferably at least 90%.

Said airway constriction may occur in conjunction with such disorders as e. g. asthma, emphysema, chronic bronchitis, and chronic obstructive pulmonary disease.

According to the present invention, several known 5-HT3 antagonist compounds are, unexpectedly, able to en- hance a 5-HT-induced airway relaxation. The 5-HT3 recep- tor is a ligand modulated ion channel. Several potent and specific 5-HT3 antagonists exist today, of which ondan- setron, tropisetron, granisetron, and dolasetron are com- mercial pharmaceuticals, but not against disorders in- volving airway constriction.

Some of the 5-HT3 receptor antagonists are at the same time 5-HT4 receptor agonists. However, for a sub- stance to be active as a 5-HT3 receptor antagonist, the distance from the aromatic center to the basic nitrogen

should be about 7,5 A and no large substituents are to- lerated on the basic nitrogen. In contrast, for 5-HT4 re- ceptor agonists the corresponding distance is about 8 A, and a large lipophilic group may be bound to the basic nitrogen, thereby obtaining a better binding to 5-HT4.

The 5-HT3 antagonists may be divided into certain classes on the basis of chemical structure. Some are un- specific, e. g. benzazepines, e. g. mirtazapine benztiazephines, e. g. diltiazem

and fentiazines e. g. perphenazine, chlorpromazine, stemetil.

Some are at the same time 5-HT4 agonists, e. g. ben- zamides (cisapride, zacopride, mosapride, metoclo- pramide, pancopride, BRL 24924, BMY 33462) WAY 100289 2,3-dihydro-benzofuran-7-carboxamides

(e. g. zatosetron=LY 277359, ADR 851); 1, 4-bensoxazin-8-carboxamides e. g. azasetron (=Y25130) benzimidazolones

e. g. itasetron (=DAU 6215); indazol-3-carboxamides e. g. N 3389, LY 278584, DAT 582 (= (R) AS-5370) The latter group reminds most of the specific 5-HT3 antagonists, which contains the group in different forms, such as

N<BR> #<BR> ''N<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 0 ondansetron (=GR 38032 F) alosetron cilansetron (=KC 9946) In one group of substances the structure has been inverted and the carbonyl group has been placed on the indoline nitrogen FK 1052 This substance is unique by being an antagonist against both 5-HT3 and 5-HT4 receptors.

BRL 46470 A BRL 46470A binds to two different positions of the receptor.

A further development is the so-called bisindoles YM 114 Another group is the isoquinoline-1-ones palonosetron (=RS 25259-197) RS 42358-197 and the quinoline-3-carboxamides WAY-SEC 579 Mirisetron (=WAY 100579) Also the quinoline-4-carboxylates are active anta- gonists

e. g. KF 17643 e. g. KF 18259 Other compounds are benzimidazolones e. g. droperidol (neurolidol, etc.), itasetron (DAU6215), and the naphtimides RS 56532 e. g. RS 56532 A unique single structure is MDL 72222, which also is a specific 5-HT3 antagonist

Other specific structures are GK 128 Talipexole iodophenpropit

thioperamide, and 2-piperidin-and 2-piperazin- benzimidazoles.

According to the present invention, the following compounds can also be used as antagonists to the 5-HT3 receptor: (R)-zacopride, 2-methyl-5HT, 3- (1-piperazinyl)- 2-quinoxalinecarbonitrile, 3- (4-allylpiperazin-1-yl)-2- quinoxalinecarbonitrile, 4-Ph-N-Me-quipazine, 5- ( (dimet- hylamino) methyl)-3- (l-methyl-lH-indol-3-yl)-1, 2,4-oxa- dizole, 5,7-DHT, 5-[(dimethylamino) methyl]-3-(1-methyl- 1H-indol-3-yl)-1, 2,4-oxadizole, ADR-882, Amitriptyline, Anpirtoline, AS-5370, Batanopride, BIMU 1, BRL 24682, BRL 43694, BRL 46470 (=Ricasetron), BRL 47204, Bufoten- ine, CF 109203 (=BIM), Cizapride, Clozapine, CP-93318, Cyameazine, Cyproheptadine, Dolasetron mesilat (=MDL 73147 EF), Fluphenazone, Galdansetron, GR 38032 F, GR 67330, Granisetron (=Kytril=BRL 43694), GR-H, GYK1- 48903, ICS 205-930, Imipramine, Indalpine, KAE-393/YM- 114, KB-6922, KB-6933, KB-R 6933, KF-20170, Lerisetron, Lurosetron, LY 258-458, LY 278-989, LY-211-000, McNeil-A- 343, MCPP, MDL 72699, Mepyramine, Metergoline, Methyser- gide, Mianserin, MK 212, N-3256, NAN-190, N-metylquipa- zin, 3- (l-piperazinyl)-2-quinoxalinecarbonitrile, ONO- 3051, Pancopride, Phenylbiguanide, Pitozifen, Prochlor- perazine (Stemetil), QICS 205-930, R (+) zacopride, Renzapride, RG 12915, Ritanserin, RP 62203, RS-25259-197, RS-056812-198, RS-25259, RU 24969, S (-) Zacopride, S-

apomorfin, SC-52491, SC-53116, SDZ 206-792, SDZ 206--830, SDZ 210-204, SDZ 210-205, SDZ 214-322, SDZ 322, SN-307, TFMPP, TMB 8, trifluoperzine, tropanyl-3,5-di- methylbenzoate, 3-tropanyl-indole-3-carboxylate methio- dide, VA 21 B 7, Y 2513, SEC 579, BRL 46470 A, Pizotifen, Dolasetron (=MDL 74156), Galanolactone, GR 65 630, Ifen- prodil, L-683877, Litoxetine, Quipazine, QX 222, Ramose- tron (=YM 060), RS 56812, SDZ 216-525, Trimebutine, GR 65630, Tropisetron (=ICS 205-930=Rifenserin), Bemese- tron, L-683,877, LY-278,584 maleate and pharmaceutically acceptable salts thereof with the same or essentially the same relaxation enhancing effect and capability of reduc- ing abnormal airway constriction as specified above.

In the following, an alternative presentation of useful compounds according to the present invention and references thereto is presented.

N-substi tuted benzamides Metoclopramide * QX 222. The compound is an analogue to lidocaino, which is a N-substituted benzamide derivative.

Cisapride (Cizapride) cis-4-Amino-N- [l- [3- (p- fluorophenoxy)propyl]-3-methoxy-4-piperidyl]-5- chloro-o-anisamide. The compound is also a known 5- HT4 agonist. cis-4-Amino-N-[1-[3-(p-fluorofenoxi)propyl]-3-metoxi-4-piper idyl]-5-<BR> -kloro-o-anisamid

Pancopride (((+-) N-(l-azabicyclo-[2,2,2]-oct-3-yl)- 2-cyclopropylmethoxy-4-amino-5-chlorobenzamide) Pancopride, a potent and long-acting 5-HT3 receptor antagonist, is orally effective against anticancer drug-evoked emesis., Fernández AG, Puig J, Beleta J, Doménech T, Bou J, Berga P, Gristwood RW, Roberts DJ; Eur J Pharmacol 1992 Nov 10,222: 2-3: 257-64 Pancopride ( (+-) N- (l-azabicyclo- [2, 2,2]-oct-3-yl)-2- cyclopropylmethoxy-4-ami no-5-chlorobenzamide) is a new potent and selective 5-HT3 receptor antagonist, orally and parenterally effective against cytotoxic drug-induced emesis. In vitro, pancopride displayed high affinity (Ki = 0.40 nM) for [3H] GR65630- labelled 5-HT3 recognition sites in membranes from the cortex of rat brains. In vivo, pancopride an- tagonized 5-HT-induced bradycardia in anaesthetized rats when administered i. v. 5 min (ID50 = 0. 56 mi- crogram/kg) or p. o. 60 min (ID50 = 8. 7 micro- grams/kg) before 5-HT challenge. A single oral dose (10 micrograms/kg) of pancopride produced a signifi-

cant inhibition of the bradycardic reflex over-an 8-h period. Pancopride dose dependently inhibited the number of vomiting episodes and delayed the on- set of vomiting induced by cisplatin in dogs (ID50 = 3.6 micrograms/kg i. v. and 7.1 micrograms/kg p. o.).

Pancopride was also effective in blocking mechlor- ethamine-and dacarbazine-induced emesis. Unlike metoclopramide, pancopride was shown to lack any measurable antidopaminergic activity both in vitro and in vivo. These results support clinical data, indicating that pancopride will be a useful drug for treating cytostatic-induced emesis in humans.

(R)-zacopride (R+ zacopride, zacopride) IUPAC name: 4-amino-N- (l-azabicyclo [2.2.2] oct-3yl)-5-chloro-2- methoxy-benzamide.

The differential activities of R (+)-and S (-)-zaco- pride as 5-HT3 receptor antagonists.

Barnes JM, Barnes NM, Costall B, Domeney AM, Johnson DN, Kelly ME, Munson HR, Naylor RJ, Young R; Pharma- col Biochem Behav 1990 Dec, 37: 4: 717-27 R (+)- and S (-)-zacopride were assessed as potential 5-HT3 receptor antagonists in behavioural and bio- chemical tests. The S (-) isomer was more potent than the R (+) isomer to antagonise the hyperactivity in- duced by the injection of amphetamine or the infu- sion of dopamine into the nucleus accumbens in the rat. In contrast, the R (+) isomer was more potent to reduce the aversive behaviour of mice to a brightly illuminated environment and in a marmoset human threat test, to facilitate social interaction in rats, to increase performance in a mouse habituation test and prevent a scopolamine-induced impairment, and to antagonise the inhibitory effect of 2-methyl- 5-hydroxytryptamine to reduce [3H] acetylcholine re-

lease in slices of the rat entorhinal cortex. In binding assays, [3H] S (-)-zacopride and [3H] R (+)- zacopride labelled homogenous populations of high- affinity binding sites in the rat entorhinal cortex, compete for a further 10 to 20% of the binding of [3H] R (+)/S (-)-zacopride-or [3H] R (+)- zacopride in excess of that competed for by (S) (-)- zacopride. It is concluded that both isomers of za- copride have potent but different pharmacological activities, with the possibility of different recog- nition sites to mediate their effects.

BRL 24682 The compound is also a known 5-HT4 agonist.

* BRL 24924 [ (+/-)- (endo)])-4-amino-5-chloro-2-methoxy-N- (l- azabicyclo- [3. 3.1]-non- 4-yl) benzamide hydrochlori- de. The compound is also a known 5-HT4 agonist.

# Mosapride ((4-amino-5-chloro-2-ethoxy-N-[[4- (4- fluorobenzyl)-2-morpholinyl] methyl] benzamide cit- rate.

* Renzapride= BRL 24924; see above <BR> <BR> <BR> <BR> <BR> SC-52491 (Azanoradamantane)<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> SC-53116 ((1-S, 8-S)-4-amino-5-chloro-N-[(hexahydro- 1H-pyrrolizin-1-yl) methyl]-2-methoxy-benzamide hyd- rochloride) * Batanopride (4-amino-5-chloro-N- [2- (diethylamino)- ethyl] 2- (l-methyl-2-oxopropoxy) benzamide). Batano- pride is also known by the name BMY-25801.

'WAY 100289

Indoles, Indole-1-carboxamides and Imidazole derivatives 2-methyl-5-HT 5, 7-DHT= 5,7-dihydroxy-tryptamine Disindoles Bufotenine = (5-hydroxy-N, N-dimethyltryptamine) BRL 46470A (endo-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) 2,3-dihydro-3,3 dimethyl-indole-1- carboxamide, hydrochloride) BRL 46470 (endo-N- (8-methyl-8-azabicyclo [3.2.1] oct- 3yl)-2,3-dihydro-3,3- dimethyl-indole-1-carboxamide HC1) BRL 47204 FK 1052 ( (+)-8, 9-dihydro-10-methyl-7- [ (5-methyl-lH- imidazol-4-yl) methyl] pyrido [l, 2-a] indol-6 (7H)-one hydrochloride) Pharmacological characterization of FK1052, a dihy- dropyridoindole derivative, as a new serotonin 3 and 4 dual receptor antagonist., Nagakura Y, Kadowaki M, Tokoro K, Tomoi M, Mori J, Kohsaka M; J Pharmacol Exp Ther 1993 May, 265: 2: 752-8 (+)-8,9-Dihydro-10-dihydro-10-methyl-7- [ (5-methyl-4- imidazolyl) methyl] pyrido- [1, 2-a] indol-6 (7H)-one hy- drochloride (FK1052) is a newly designed and synthe- sized 5-hydroxytryptamine (5-HT) 3 receptor antago- nist with 5-HT4 receptor antagonistic activity. This compound, as well as ondansetron and granisetron,

dose-dependently inhibited the von Bezold-Jarish re- flex, a 5-HT3 receptor-mediated response, after in- travenous (i. v.) and intraduodenal (i. d.) dosing to rats. The ID50 values showed FK1052 (0.28 micro- gram/kg, i. v., 5.23 micrograms/kg, i. d.) to be more potent than ondansetron (5.23 micrograms/kg, i. v., 170 micrograms/kg, i. d.) and granisetron (0.70 mi- crograms/kg, i. v., 66 micrograms/kg, i. d.). Further- more, bioavailabilities of the test drugs by ID50 ratio (i. d./i. v.) showed that FK1052 (17) was better absorbed than ondansetron (33) and granisetron (94) and possessed a similar duration of action to that of ondansetron and granisetron. We also examined the effects on 2-methyl-5-HT-, 5-HT-and 5-methoxytryp- tamine-induced contractions of guinea pig isolated ileum. FK1052, ondansetron and granisetron concen- tration-dependently inhibited 2-methyl-5-HT, a 5-HT3 agonist-induced contraction. The pA2 values for the 5-HT3 receptor indicated that FK1052 (8.36) was 40 times and three times more potent than ondansetron (6.79) and granisetron (7.86), respectively. FK1052, unlike ondansetron and granisetron, inhibited the 5- HT4-mediated component of concentration-response curve to 5-HT. Furthermore, FK1052 suppressed 5- methoxytryptamine, a 5-HT4 agonist-induced contrac- tion in a concentration-dependent but insurmountable manner.

RU 24969 (5-methoxy-3 (1,2,3,6-tetrahydropyridin-4- yl)-l H-indole) SDZ 206-792 Characterisation of 5-HT3 recognition sites in mem- branes of NG 108-15 neuroblastoma-glioma cells with [3H] ICS 205-930. Neijt HC, Karpf A, Schoeffter P,

Engel G, Hoyer D Naunyn Schmiedebergs Arch Pharmacol 1988 May, 337: 5: 493-9 1. The binding characteristics of [3H] ICS 205-930, a potent and selective 5-hydroxytryptamine 5-HT3 re- ceptor antagonist, were investigated in membranes prepared from murine neuroblastoma-glioma NG 108-15 cells. 2. [3H] ICS 205-930 bound rapidly, reversibly and stereoselectively to a homogeneous population of high affinity recognition sites: Bmax = 58 +/-3 fmol/mg protein, pKD = 9.01 +/-0.08 (n = 11). Non linear regression and Scatchard analysis of satura- tion data suggested the existence of a single class of [3H] ICS 205-930 recognition sites on NG 108-15 cells. The binding was rapid, stable and reversible.

The affinity of [3H] ICS 205-930 determined in ki- netic studies was in agreement with that obtained under equilibrium conditions. 3. Competition studies performed with a variety of agonists and antagonists also suggested the presence of a homogeneous popula- tion of [3H] ICS 205-930 recognition sites. All com- petition curves were steep and monophasic and were best fit by a 1 receptor site model. [3H] ICS 205-930 binding sites displayed the pharmacological profile of a 5-HT3 receptor. Potent 5-HT3 receptor antago- nists showed nanomolar affinities for [3H] ICS 205- 930 binding sites with the following rank order of potency: SDZ 206-830 greater than ICS 205-930 greater than SDZ 206-792 greater than BRL 43694 greater than quipazine greater than BRL 24924 greater than SDZ 210-204 greater than MDL 72222 greater than SDZ 210-205. Metoclopramide, mCP and mianserin showed submicromolar affinity.

Ondansetron=GR 38032F=SN-307=Zofrans Ondansetronum INN (Ondansetron) <BR> 2,3-D1hydro-9-metyl-3-[(2-metylimidazol-1-yl) metyl] karbaZol-4 (1H -on

The compound is both an indole derivative and an imidazole. Other imidazole derivatives are listed below.

GR 38032 F Comparison of the 5-HT3 receptor antagonist proper- ties of ICS 2. 05-930, GR38032F and zacopride., Cohen ML, Bloomquist W, Gidda JS, Lacefield W; J Pharmacol Exp The 1989 Jan, 248: 1: 197-201 The well-documented 5-HT3 receptor antagonists, ICS 205-930 and GR38032F, have been compared with regard to their inhibitory activity at 5-HT3 receptors to another gastrokinetic agent, zacopride. Zacopride and ICS 205-930 showed similar affinity (-log kB ap- proximately 8.0), whereas GR38032F showed lower af- finity (-log ka approximately 7.0) at 5-HT3 recep- tors in the guinea pig ileum. After i. v. administra- tion to anesthetized rats, zacopride was approxi- mately 10-fold more potent than either ICS 205-930 or GR38032F, which were equipotent as inhibitors of serotonin-induced bradycardia (5-HT3-mediated acti- vation of the von Bezold Jarisch reflex). After oral administration to anesthetized rats, zacopride re- mained approximately 10-fold more potent than ICS 205-903, which was approximately 2-fold more potent

than GR38032F as an inhibitor of serotonin-induced bradycardia. Furthermore, the inhibitory effective- ness of GR38032F persisted for less than 3 hr after oral administration and for less than 15 min after intravenous administration. ICS 205-930 produced maximal inhibition of serotonin-induced bradycardia for over 3 hr with heart rate returning to control values 6 hr after oral administration. Zacopride possessed the longest duration of inhibitory effec- tiveness in urethane-anesthetized rats with maximal inhibition still apparent 6 hr after oral admini- stration. All three agents inhibited cisplatin-- induced emesis after i. v. administration in dogs with zacopride being 10-fold more potent than ICS 205-930 or GR38032F, which were equipotent. These comparative data with three 5-HT3 receptor antago- nists indicate that in animals, zacopride was more potent and longer acting than either ICS 205-930 or GR38032F. Furthermore, after oral administration to rats, GR38032F was slightly less potent than ICS 205-930 and possessed the shortest duration of ac- tion.

Alosetron=Lotronex (Glaxo)

The compound is both an indole derivative and an imi- dazole. Other imidazole derivatives are listed below.

The pharmacological properties of the novel selective 5-HT3 receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat., Clayton NM, Sargent R, Butler A, Gale J, Maxwell MP, Hunt AA, Barrett VJ, Cambridge D, Boun- tra C, Humphrey PP; Neurovastroenterol Motil 1999 Jun, 11: 3: 207-17 The purpose of this study was to investigate the phar- macological properties of the novel, selective 5-HT3 receptor antagonist, alosetron, and its effects on transit time in both the normal and perturbed small intestine of the rat. Alosetron concentration- dependently inhibited radioligand binding in membranes containing rat and human 5-HT3 receptors with esti- mated pKi values of 9.8 (n = 3) and 9.4 (n = 6), re- spectively. In selectivity studies alosetron had lit- tle or no significant affinity for any of the many other receptors and ion channels studied. Alosetron potently antagonized the depolarization produced by 5- HT in the rat vagus nerve (estimated pKB value of 9.8, n = 25). In anaesthetized rats, i. v. administration of alosetron inhibited 2-methyl-5-HT induced bradycar- dia (Bezold Jarisch index) at 1 and 3 microg kg-1, with an agonist dose ratio of approximately 3.0 at 1.0 microg kg-1, = 3-5). Alosetron administered via the duodenum also inhibited this reflex, with duration of action that was significantly longer than that seen with ondansetron (120-60 min, respectively, n = 6).

Alosetron had no significant effect on normal small intestinal propulsion in the rat, but fully reversed the increase in intestinal propulsion (96%, n = 3) produced by egg albumin challenge. Alosetron is a highly selective 5-HT3 antagonist which normalizes

perturbed small intestinal propulsion. Previous clini- cal data in IBS patients together with the transit data provide a good rationale for further studies with alosetron in IBS patients.

# Bemesetron * Galdansetron Dolasetron mesilat =MDL73147 EF= Anzemet.

IUPAC name: (2,6,8,9aS)-octahydro-3-oxo-2,6-methano- 2H-quinolizin-8-yl-lH-indole-3-carboxylate monomethanesulfonate, monohydrate.

# Dolasetron=MDL74156 * Tropisetron =Navoban ~ IUPAC name: laH, 5aH-Tropane-3a-yl-3-indole- carboxylate

Zatosetron =LY 277359. The compound is also called LY 19617.

The effect of acute and chronic LY 277359, a selec- tive 5-HT3 receptor antagonist, on the number of spontaneously active midbrain dopamine neurons., Mi- nabe Y, Ashby CR Jr, Wang RY ; Eur J Pharmacol 1991 Dec 17,209: 3: 151-6 In this study, we have examined the effect of acute and chronic administration of LY 277359, a putative 5-HT3 receptor antagonist, on the number of spontan- eously active dopamine cells in the substantia nigra pars compacta (SNC or A9) and ventral tegmental area (VTA or A10). This was accomplished using the stand- ard extracellular single unit recording techniques.

The acute administration of LY 277359 (0.1 or 1.0 mg/kg i. p.) produced a significant increase in the number of spontaneously active A10, but not A9, dopamine cells compared to saline controls. The acute administration of 10 mg/kg of LY 277359 did not significantly alter the number of spontaneously active dopamine cells in either area. In contrast to

its acute effects, the administration of 0.1 mg/kg per day of LY 277359 for 21 days decreased the num- ber of spontaneously active A9 and A10 dopamine cells. However, the i. v. administration of (+/-)- apomorphine (50 micrograms/kg) did not reverse LY 277359's action, suggesting that the chronic LY 277359-induced reduction of dopamine cells was not the result of depolarization block. To test whether chronic administration of LY 277359 at a high dose would induce depolarization block of dopamine cells, rats were treated with 1.0 or 10 mg/kg LY 277359.

Interestingly, the chronic administration of 1.0 mg/kg LY 277359 increased the number of A10, but not A9 dopamine cells. In contrast, chronic treat- ment with 10 mg/kg selectively decreased the number of spontaneously active A10 dopamine cells. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>'GR65630 (3- (5-methyl-lH-imidazol-4-yl)-l- (l-methyl-<BR> <BR> <BR> <BR> <BR> lH-indol-3-yl)-1-propanone)<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> GR67330 [3H] GR67330, a very high affinity ligand for 5-HT3 receptors.

Kilpatrick GJ, Butler A, Hagan RM, Jones BJ, Tyers MB Naunyn Schmiedebergs Arch Pharmacol 1990 Jul, 342: 1: 22-30 GR67330 potently inhibited 5-hydroxytryptamine (5- HT)-induced depolarizations of the rat isolated va- gus nerve. At the higher concentrations used (0.3 nmol/1-1 nmol/1) this was accompanied by a marked ~reduction in the maximum response to 5-HT. The cal- culated pKB value was 10.2. The binding of the tri- tiated derivative of GR67330 to homogenates of rat entorhinal cortex was examined. Kinetic analysis re- vealed that specific [3H] GR67330 (0.1 nmol/1) bind- ing was rapid and reversible. Association and disso-

ciation rate constants were 1.48 +/-0. 36 x 1OC8) mol/1-1 s-1 and 7.85 +/-0.41 x 10 (-3) s-1 respec- tively. Equilibrium saturation analysis revealed specific binding was to a single site. (Bmax 22.6 +/- 0.21 fmol/mg protein) of high affinity (Kd 0.038 +/- 0.003 nmol/1). At low ligand concentrations, spe- cific binding was up to 90% of total binding. If un- labelled GR67330 was used to define non-specific binding two sites were evident (Kdl 0.066 +/-0.007 nmol/1, Kd2 20.1 +/-9.7 nmol/l ; Bmaxl 31.5 +/-3.2 fmol/mg protein, Bmax2 1110 +/-420 fmol/mg pro- tein). [3H] GR67330 binding was inhibited potently by 5-HT3 antagonists and agonists. Ligands for other 5-HT receptors and other neurotransmitter receptors were either only weakly active or inactive at inhib- iting binding. Hill numbers for antagonist inhibi- tion of binding were close to unity, except for quipazine which was significantly greater than one.

In common with other 5-HT3 binding studies, all 5-H- agonist tested had Hill numbers greater than one (1.51-1.71). GR38032 and GR65630 inhibited a greater proportion of binding than other 5-HT3 antagonists, this additional binding was interpreted as inhibi- tion from a second saturable site unrelated to the 5-HT3 receptor.

ICS 205-930 ( (3 Alpha-Tropanyl)-lH-Indole-3-carboxy- lic acid ester) Comparison of the 5-HT3 receptor antagonist proper- ties of ICS 205-930, GR38032F and zacopride., Cohen ML, Bloomquist W, Gidda JS, Lacefield W J Pharmacol Exp Ther 1989 Jan, 248: 1: 197-201 The well-documented 5-HT3 receptor antagonists, ICS 205-930 and GR38032F, have been compared with regard to their inhibitory activity at 5-HT3 receptors to another gastrokinetic agent, zacopride. Zacopride

and ICS 205-930 showed similar affinity (-log kB ap- proximately 8.0), whereas GR38032F showed lower af- finity (-log ka approximately 7.0) at 5-HT3 recep- tors in the guinea pig ileum. After i. v. admini- stration to anesthetized rats, zacopride was ap- proximately 10-fold more potent than either ICS 205-930 or GR38032F, which were equipotent as in- hibitors of serotonin-induced bradycardia (5-HT3- mediated activation of the von Bezold Jarisch re- flex). After oral administration to anesthetized rats, zacopride remained approximately 10-fold more potent than ICS 205-903, which was approximately 2-fold more potent than GR38032F as an inhibitor of serotonin-induced bradycardia. Furthermore, the in- hibitory effectiveness of GR38032F persisted for less than 3 hr after oral administration and for less than 15 min after intravenous administration.

ICS 205-930 produced maximal inhibition of seroto- nin-induced bradycardia for over 3 hr with heart rate returning to control values 6 hr after oral ad- ministration. Zacopride possessed the longest dura- tion of inhibitory effectiveness in urethane- anesthetized rats with maximal inhibition still ap- parent 6 hr after oral administration. All three agents inhibited cisplatin-induced emesis after i. v. administration in dogs with zacopride being 10-fold more. potent than ICS 205-930 or GR38032F, which were equipotent. These comparative data with three 5-HT3 receptor antagonists indicate that in animals, zaco- pride was more potent and longer acting than either ICS 205-930 or GR38032F. Furthermore, after oral ad- ministration to rats, GR38032F was slightly less po- tent than ICS 205-930 and possessed the shortest du- ration of action.

QICS 205-930

3-Tropanyl-indole-3-carboxylate methiodide. It-is also called ICS 205-930. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Indalpine (3-[2-(4-piperidinyl) ethyl]-lH-indole)<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> t * VA21B7 (3-[2-(4'-piperonylpiperazinyl)-indolyl] car- boxaldehyde) The pharmacology of VA21B7 : an atypical 5-HT3 recep- tor antagonist with anxiolytic-like properties in animal models. Artaiz I, Romero G, Zazpe A, Monge A, Caldero JM, Roca J, Lasheras B, Del Rio J Psycho- pharmacolocrv (Berl) 1995 Jan, 117: 2: 137-48 VA21B7 (3- [2- (4'-piperonylpiperazinyl) indolyl] car- boxaldehyde) was synthesized as a potential 5-HT3 receptor antagonist. Even though VA21B7 showed a higher affinity towards 5-HT3 receptors as compared to other receptors studied, it was not a potent 5- HT3 receptor antagonist either in the periphery or in the brain. In a simple animal model of anxiety such as the two-compartment box in mice, a remark- able anxiolytic-like effect was found at doses of 2-500 micrograms/kg IP and also at low oral doses, in the microgram range. These drug doses did not produce any significant effect on spontaneous motor activity of mice. The anxiolytic profile of VA21B7 was further explored using other models of anxiety in rats such as the elevated plus-maze and punished- drinking. VA21B7 was compared with standard 5-HT3 receptor antagonists such as ondansetron, tropise- tron and granisetron, with the 5-HT1A agent buspi- rone and with diazepam. In the plus-maze, VA21B7 showed an anxiolytic-like profile after doses of 0.25-0.5 mg/kg IP or 2-4 mg/kg PO which did not mod- ify the number of total entries into the open and closed arms of the maze. Diazepam, granisetron and

tropisetron were also effective in this test but not ondansetron and buspirone. VA21B7 was also able to release suppressed behaviour in the punished-drink- ing test. The dose-response curve was bell-shaped with a peak at 2-4 mg/kg. At variance with other studies, 5-HT3 receptor antagonists also increased the number of shocks taken in this test and the dose-response curve was also bell-shaped. VA21B7 was not anticonvulsant like diazepam, its anxiolytic ac- tion in the light/dark test was not flumazenil- sensitive and there was no rebound anxiogenic effect on withdrawal from chronic VA21B7 treatment for--15 consecutive days. Moreover, VA21B7 was not amnesic like the benzodiazepines but low doses of 2-4 mg/kg reduced the memory deficits induced in rats by sco- polamine. Much higher doses were necessary to de- crease spontaneous motor activity in rats. Since VA21B7 appears to be well tolerated in rodents at high doses, we think that it is of potential inter- est as an anxiolytic in humans.

Benzimidazolones, benzimidazoles and other imidazoles The common chemical structure of a benzimidazolone is : Iodophenpropit (4-(lH-imidazol-4-yl-methyl)- piperidine) BIMU 1 (endo-N- (8-methyl-8-azabicyclo [3.2. 1.] oct-3- yl)-2,3-dihydro-3-ethyl-2-oxo-lH-benzimidazole-l- carboxamide hydrochloride)

* 2-piperazin-benzimidazole- * 2-piperidin-benzimidazole * Cilansetron (1-10-[(2-methyl-lH-imidazol-l- yl) methyl-5, 6,8,9,10,11-hexahydro-4H-pyrido [3,2,1- jk] carbazol-11-one hydrochloride) * GK 128 (2-[(2-methylimidazol-1-yl) methyl] benzo [i]- thiochromen-1-one monohydrochloride hemihydrate Effect of a novel 5-hydroxytryptamine3 (5-HT3) re- ceptor antagonist, GK-128, on 5-HT3 receptors medi- ating contractions and relaxations in guinea-pig distal colon.

Ito C, Kawamura R, Isobe Y, Tsuchida K, Muramatsu M, Higuchi S; Gen Pharmacol 1997 Sep, 29: 3: 353-9 We investigated 5-hydroxytryptamine3 (5-HT3) recep- tor-mediating contractions and relaxations in the guinea-pig isolated distal colon using various 5-HT3 receptor agonists and antagonists, including GK-128 (2-[(2-methylimidazol-1-yl) methyl] benzo [f] thio- chromen-1-one monohydrochloride hemihydrate).

2. Selective 5-HT3 receptor agonists, 2-methyl-5-HT and m-chlorophenylbiguanide, produced spantide- insensitive contraction and atropine-insensitive contraction and the relaxation. These agonists showed a small, but significant, difference of po- tency between contraction and relaxation. 3. GK-128 competitively blocked both 2-methyl-5-HT-and m- chlorophenylbiguanide-induced responses with similar potency. The affinities of GK-128 for spantide- insensitive contraction and atropine-insensitive contraction were ten-fold higher than for relaxa- tion. 4. Other selective 5-HT3 receptor antagonists, azasetron and tropisetron, also exhibited higher af-

finity in contraction than in relaxation, but the extent of their affinity differences was smaller than that observed in GK-128. In contrast, grani- setron, ramosetron and ondansetron exhibited no. sig- nificant differences in their affinity values among the three responses. 5. These results suggest that the 5-HT3 receptors which mediate contraction and relaxation in the guinea-pig distal colon may not be the same, and that GK-128 is a 5-HT3 receptor an- tagonist with a stronger potency for contraction.

Droperidol. Ingår i Dridol, Janssen-Cilag Droperidolum INN (Droperidol) 1-[1-(3-(4-Fluorobensoyl)propyl)-1,2,3,6-tetrahydro-4-pyridy l]-1,3-<BR> -dihydro-2H-bensimidazol-2-on KAE-393/YM-114 ((R)-5-[(2, 3-dihydro-1-indolyl)carbonyl]-4,5,6,7- tetrahydro-lH-benzimidazole Comparison of the effects of trimebutine and YM114 (KAE-393), a novel 5-HT3 receptor antagonist, on stress-induced defecation. Miyata K, Ito H, Yamano M, Hidaka K, Kamato T, Nishida A, Yuki H; Eur J Pharmacol 1993 Dec 7,250: 2: 303-10 YM114 (KAE-393), (R) -5- [(2,3-dihydro-1-indolyl) - carbonyl]-4, 5,6,7-tetrahydro-lH-benzimidazole hy- drochloride, is a derivative of YM060, a potent 5-

HT3 receptor antagonist. We investigated the effects of YM114 on 5-HT3 receptors, both in vitro and in vivo, and on bowel dysfunction induced by restraint stress, 5-HT and thyrotropin-releasing hormone (TRH), and compared them with the effect of trime- butine. YM114 dose dependently inhibited the reduc- tion in heart rate induced by 5-HT (30 micrograms/kg i. v.) in rats (ED50 = 0.31 micrograms/kg i. v.), and the potency of YM114 was almost the same as that of the racemate. The S-form of YM114 also inhibited 5- HT-induced bradycardia, but 1350 times less potent than the R-form. YM114 and its S-form inhibited-- [3H] GR65630 binding to NlE-115 cell membranes in a concentration-dependent manner with Ki values of 0.341 and 616 nM, respectively, showing the isomeric activity ratio (R-/S-form) of YM114 to be much greater (1800). YM114 antagonized 5-HT-induced depo- larization of the nodose ganglion (EC50 = 1.39 nM).

Trimebutine (1 mg/kg i. v.) failed to inhibit 5-HT- induced bradycardia, implying that it does not pos- sess 5-HT3 receptor antagonistic activity. YM114 significantly and dose dependently prevented re- straint stress-, 5-HT-and TRH-induced increases in fecal pellet output, and restraint stress-and 5-HT- induced diarrhea in rats and mice (ED50 = 6.9,72.5, 154.6,9.7 and 52.4 micrograms/kg p. o., respecti- vely). Trimebutine significantly prevented stress- and 5-HT-induced diarrhea (ED50 = 29.4 and 87.3 mg/kg p. o., respectively), but only partially af- fected stress-, 5-HT-and TRH-induced increases in fecal pellet output. Thus, YM114 is a potent and stereoselective 5-HT3 receptor antagonist with much greater protective effects against stress-induced defecation than trimebutine. hydrochloride).

Itasetron=DAU6215 ((3-alpha-tropanyl) lH-benzimida- zolone-3-carboxamide chloride)

Intravenous itasetron: establishing the effective dose range for the prophylactic control of acute emesis in cancer patients undergoing high-dose cis- platin chemotherapy., Patoia L, Del Favero A, Gigli- etti A, Malacarne P, Donati D, Indelli M, Bensi G, Palladino MA, Cigarini P, Kempe R, Voigt T; Clin On- col (R Coll Radiol) 1999,11: 2: 99-104 Nausea and vomiting induced by chemotherapy are a major cause of distress to patients and reduce com- pliance with potentially beneficial treatment. Ita- setron hydrochloride is a new 5-hydroxytryptami-ne3 (5-HT3) antagonist with potent antiemetic proper- ties. It is more potent than ondansetron in animal models and in early clinical studies it demonstrates a long half-life and does not undergo hepatic bio- transformation before elimination. The aim of this open, uncontrolled study was to establish the effec- tive dose range of itasetron hydrochloride given in- travenously (i. v.) to patients due to receive high- dose cisplatin chemotherapy (50-120 mg/m2) for the first time. Thirty-nine patients were enrolled in the trial and received a single i. v. infusion of itasetron hydrochloride at a dose of 17-280 mi- crog/kg body weight before commencing the cisplatin infusion (median dose 90-110 mg/m2). Antiemetic pro- tection was demonstrated by doses in the range of 35-280 microg/kg. The 17 microg/kg dose was not ef- fective. Treatment failure (>5 emetic episodes/24 hours) was reported in only six (16%) of the 38 evaluable patients over all treatment groups. Ad- verse events were generally mild or moderate and of a similar type and incidence to those of current 5-HT3 antagonists. Physicians'and patients'assess- ments of efficacy and tolerability of itasetron hy- drochloride were similar, the majority rating the treatment as'good'or'very good'. In conclusion,

itasetron hydrochloride is effective in the dose range 35-280 microg/kg in preventing cisplatin- induced emesis. Taken together with results from a larger dose-finding study, a dose corresponding to 35 microg/kg (equivalent to 2.5 mg itasetron, calcu- lated as free base) has been pursued in Phase III studies with the i. v. formulation.

Lerisetron New 2-piperazinylbenzimidazole derivatives as 5-HT3 antagonists. Synthesis and pharmacological evalua- tion. Orjales A, Mosquera R, Labeaga L, Rodes R J Med Chem 1997 Feb 14,40: 4: 586-93 A series of 2-piperazinylbenzimidazole derivatives were prepared and evaluated as 5-HT3 receptor an- tagonists. Their 5-HT3 receptor affinities were evaluated by radioligand binding assays, and their abilities to inhibit the 5-HT-induced Bezold-Jarisch reflex in anesthetized rats were determined. Com- pound 7e (lerisetron, pKi = 9.2) exhibited higher affinity for the 5-HT3 receptor than did tropisetron and granisetron, while compound 7q (pKi = 7.5) had very low affinity for this receptor, showing that substitution on the N1 atom of the benzimidazole ring is essential for affinity and activity. The ef- fect of substitution on the aromatic ring of benzim- idazole by several substituents in different posi- tions is also discussed. A strong correlation be- tween the 5-HT3 antagonistic activity of the studied compounds and the position of substitution on the aromatic ring was established. Thus, while the 4-methoxy derivative 7m showed weak affinity for the 5-HT3 receptor (pKi = 6.7), the 7-methoxy derivative 7n exhibited the highest affinity (pKi = 9.4). Com- pounds 7e and 7n are now under further investigation

as drugs for the treatment of nausea and emesis evoked by cancer chemotherapy and radiation.

# Lurosetron * Mirisetron =WAY100579 Ramosetron =YM 060. [ (R)-5- [ (l-methyl-3-indolyl)- carbonyl]-4, 5,6,7-tetrahydro-lH-benzimidazole hydro- chloride Indazole carboxamide derivatives The compounds have the general structure.

AS5370 ( (+/-)-N- [1-methyl-4- (3-methyl-benzyl)-<BR> hexahydro-lH-1,4-diazepin-6-yl]-lH-indazole-3- carboxamide dihydrochloride). The compound is also a diazepin derivative.

# DAT582 (the compound is the R-enantimer of com- pound AS5370) 5-HT3 receptor antagonist effects of DAT-582, (R) enantiomer of AS-5370.

Yoshida N, Omoya H, Kato S, Ito T, Eur J Pharmacol 1992 Jun 17,216: 3: 435-40 The serotonin 5-HT3 receptor antagonist effects of DAT-582, the (R) enantiomer of AS-5370 ( (+/-)-N- [1- methyl-4-(3-methyl-benzyl) hexahydro-lH-1,4-diazepin-

6-yl]-lH-indazole-3-carboxamide dihydrochloride), and its antipode were compared with those of AS-5370 and existing 5-HT3 receptor antagonists. In anesthe- tized rats, DAT-582 antagonized 2-methyl-5-HT- induced bradycardia with an ED50 value of 0.25 mi- crogram/kg i. v., whereas the (S) enantiomer was without effect even at 1000 micrograms/kg i. v. In antagonizing the bradycardia, DAT-582 was as potent as granisetron, slightly more potent than AS-5370, and 2,5 and 18 times more potent than ondansetron, ICS 205-903 and renzapride, respectively, although it was less potent than zacopride. DAT-582 inhibited cisplatin (10 mg/kg i. v.)-induced emesis in ferrets with an ED50 value of 3.2 micrograms/kg i. v. twice. The antiemetic activity of DAT-582 was more potent than that of the existing 5-HT3 receptor antagonists examined, except zacopride. In contrast, the (S) enantiomer had little effect at 1000 micro- grams/kg i. v. twice. In isolated guinea-pig ileum, DAT-582 inhibited 5-HT-induced contractions with an IC50 value of 91 nM, whereas the (S) enantiomer hardly inhibited them even at 1000 nM. These results suggest that DAT-582, the (R) enantiomer of AS-5370, potently and selectively blocks 5-HT3 receptors.

N-3389 (N-3389 (endo-3,9-dimethyl-3,9- diazabicy- clo [3,3, l] non-7-yl lH-indazole-3-carboxamide dihy- drochloride) Antagonistic activities of N-3389, a newly synthe- sized diazabicyclo derivative, at 5-HT3 and 5-HT4 receptors., Hagihara K, Hayakawa T, Arai T, Eguchi H, Mino S, Kawase S, Eur J Pharmacol 1994 Dec 12, 271: 1: 159-66 The antagonistic activities of compound N-3389 (endo-3,9-dimethyl-3,9- diazabicyclo [3,3,1] non-7-yl

lH-indazole-3-carboxamide dihydrochloride) at 5=HT3 and 5-HT4 receptors were examined using in vitro and in vivo assays. N-3389 showed potent 5-HT3 receptor antagonistic activities in a radioligand binding as- say (pKi = 8.77), against 2-methyl-5-HT (2-Me-5--HT)- induced bradycardia in rats (ED50 = 0.73 micro- grams/kg i. v., 38 micrograms/kg p. o.) and against 2- Me-5-HT-induced contraction in longitudinal muscle myenteric plexus preparations of guinea-pig ileum (IC50 = 3.2 x 10 (-8) M). As a preliminary to inves- tigating the effect of N-3389 on 5-HT4 receptors, we examined the contraction induced by 5-HT in guinea- pig ileum preparations. We confirmed that 5-HT (10 (- 8)-10 (-5) M) induced biphasic contractions in the preparations. Furthermore, 5-HT3 receptor antagonism inhibited the late phase of the contraction induced by high concentrations of 5-HT (3 x 10 (-6)-10 (-5) M), whereas 5-HT4 receptor antagonism inhibited the early phase of the contraction induced by low con- centrations of 5-HT (10 (-8)-10 (-6) M). N-3389 (10 (- 7)-10 (-5) M) inhibited both phases of contraction induced by 5-HT. In addition, N-3389 (3 x 10 (-7)-3 x 10 (-6) M) was found to inhibit the increase of elec- trically stimulated twitch responses induced by 5-HT (10 (-8) M) longitudinal muscle myenteric plexus preparation of the guinea-pig ileum. These results suggest that N-3389 acts as a 5-HT3 and 5-HT4 recep- tor antagonist.

BRL 43694=Kytril =Granisetron ~<BR> <BR> <BR> <BR> <BR> Granisetronnm LNN (Oramsetron) 1-Metyl-N-(endo-9-metyl-9-azabicyklot3. 3. 1]non-3-yl)-1H-indazol-3- -karberxamid

Selective and functional 5-hydroxytryptamine3 recep- tor antagonism by BRL 43694 (granisetron).; Sanger GJ, Nelson DR Eur J Pharmacol 1989 Jan 10, 159: 2: 113-24 The activity of BRL 43694 (granisetron) was investi- gated using established models of 5-HT3 receptor ac- tivity. In guinea-pig isolated ileum, BRL 43694 an- tagonised the contractions evoked by relatively high concentrations of 5-HT (pA2 = 8. 1 +/-0.2). However, except in high concentrations, BRL 43694 did not af- fect the contractions of similar preparations of il- eum, evoked by electrical field stimulation (cholin- ergically mediated), the nicotinic agonist dimethyl- phenyl piperazinium (DMPP) or by cholecystokinin oc- tapeptide. Similarly, BRL 43694 did not affect elec- trically evoked, cholinergically mediated contrac- tions of rat or human isolated stomach. In other models of 5-HT3 receptor activity (rabbit isolated heart, Bezold-Jarisch reflex in anaesthetised rats), potent antagonism by BRL 43694 was demonstrated. In radioligand binding studies on rat brain membranes, BRL 43694 had little or no affinity for 5-HT1A, 5-HT1B, 5-HT2 or for many other binding sites. BRL

43694 may therefore be a potent and selective 5-HT3 receptor antagonist.

Litoxetine=SL81. 0385 Litoxetine: a selective 5-HT uptake inhibitor with concomitant 5-HT3 receptor antagonist and antiemetic properties. Angel I, Schoemaker H, Prouteau M, Gar- reau M, Langer SZ.; Eur J Pharmacol 1993 Mar 2, 232: 2-3: 139-45 The selective 5HT uptake inhibitor, litoxetine- (SL 81.0385), currently under development as an antide- pressant was shown to have antiemetic properties in the ferret. Litoxetine (at 1 and 10 mg/kg i. v.) dose dependently reduced the number of retches and vomit- ing as well as the number of emetic episodes induced by cisplatin (10 mg/kg i. v.) and delayed the onset of emesis. Fluoxetine (at 1 or 10 mg/kg i. v.) failed to inhibit cisplatin-induced emetic responses and, in contrast, significantly increased the number of retches and vomiting and accelerated the onset of emesis. The possibility that the antiemetic effects of litoxetine may be mediated through an interaction with 5HT3 receptors was studied using [3H] quipazine or [3H] BRL 43694 to label the 5HT3 receptor. Li- toxetine has moderate affinity for cerebral 5HT3 re- ceptors (Ki = 85 nM), while fluoxetine, similar to other 5HT uptake inhibitors, has only negligible af- finity for this receptor (Ki = 6.5 microM). It is proposed that litoxetine inhibits cisplatin-induced emetic responses due to its moderate 5HT3 antagonist properties. The clinical use of the majority of se- rotonergic antidepressants (e. g. fluoxetine, flu- voxamine etc.) is associated with gastrointestinal discomfort (particularly nausea and vomiting) as a major side-effect. If nausea and vomiting associated

with the use of 5 HT uptake inhibitors are due-to stimulation of 5HT3 receptors, the concomitant 5HT3 antagonism of litoxetine may limit the gastrointes- tinal side-effects of this novel, antidepressant and thus. offer an important advantage.

LY 278584 ( (l-methyl-N- (8-methyl-8-azabicyclo- [3.2.1.]oct-3-yl)-lH-indazole-3-carboxamide) Specific [3H] LY278584 binding to 5-HT3 recognition sites in rat cerebral cortex.

Wong DT, Robertson DW, Reid LR; Eur J Pharmacol--1989 Jul 4,166: 1: 107-10 Binding of [3H] LY278584 a 1-methyl-indazole-carbox- amide, to putative 5-HT3 recognition sites in mem- branes isolated from cerebral cortex of rat brain, is examined. Specific binding of [3H] LY278584 ac- counts for 83-93% of total binding. The unlabelled LY278584 has 500 times greater affinity for [3H] LY278584 recognition sites than its 2-methyl analogue (LY278989), and their potencies parallel their antagonism of the peripheral 5-HT3 receptors.

Moreover, the order of potencies of other known an- tagonists of 5-HT3 receptors supports the conclusion that 3H] LY278584 binds to putative 5-HT3 receptors in cortical membranes.

* LY-278,584 maleate, see above.

* LY258-458 LY 278989 Specific [3H] LY278584 binding to 5-HT3 recognition sites in rat cerebral cortex.

Wong DT, Robertson DW, Reid LR; Eur J Pharmacol 1989 Jul 4,166: 1: 107-10

Binding of [3H] LY278584 a 1-methyl-indazole-carbox- amide, to putative 5-HT3 recognition sites in mem- branes isolated from cerebral cortex of rat brain, is examined. Specific binding of [3H] LY278584 ac- counts for 83-93% of total binding. The unlabelled LY278584 has 500 times greater affinity for [3H] LY278584 recognition sites than its 2-methyl analogue (LY278989), and their potencies parallel their antagonism of the peripheral 5-HT3 receptors.

Moreover, the order of potencies of other known an- tagonists of 5-HT3 receptors supports the conclusion that [3H] LY278584 binds to putative 5-HT3 receptors in cortical membranes. <BR> <BR> <P> LY-211-000<BR> <BR> Benzofuranes, r benzooxazines, benzo (diJazepines, benso- thiazepines A general structure for these classes of compounds is :

* 2,3-dihydro-benzofuran-7-carboxamides. X1=C, X2-=O; five-membered ring system.

RG 12915 ( [4- [N- (l-azabicyclo [2.2.2.] octan-3- (S)- yl)] 2-chloro-cis 5a- (S)-9a- (S)-5a, 6,7,8,9,9a- hexahydrobenzofurancarboxamide hydrochloride]) * ADR 851 [4-amino-5-chloro-2,3-dihydro-N- (pyrrolidin- 2-ylmethyl) benzofuran-7-carboxamide ADR-882 Analgesic effects of S and R isomers of the novel 5- HT3 receptor antagonists ADR-851 and ADR-882 in rats.; Sufka KJ, Giordano J, Eur J Pharmacol 1991 Oct 29,204: 1: 117-9 The present study examined analgesia produced by S and R isomers of the novel 5-HT3 receptor antago- nists, ADR-851 and ADR-882 (0.1-10 mg/kg s. c.) against acute thermal, mechanical and formalin- induced inflammatory pain in rats. Neither isomer of ADR-851 or ADR-882 was analgesic in the thermal or mechanical test. Similarly, neither S or R forms of ADR-882 produced significant anti-nociception in the formalin test. In contrast, ADR-851R produced sig- nificant analgesia at 3 and 10 mg/kg doses in this test, while ADR-851S produced significant analgesia only at 1 mg/kg.

RP 62203 (2- [3- (4- (4-fluorophenyl)-piperazinyl)- propyl] naphto [1, 8-ca] isothiazole-1, 1-dioxide) # Clozapine. Ingar i Leponex, Novartis Clozapinum INN (Klozapin) 8-Kloro-11-(4-methyl-1-piperazinyl)-5H-dibenso[b,e][1,4]diaz epin

Amitryptiline Amitriptylinum INN (Amitriptylin) 5-(3-Dimetylaminopropyliden)-10,11-dihydro-5H-<BR> -dibensta, dlcyklohepten

Cyproheptadine. Is the active ingredient of Periac- tin, MSD * Diltiazem Is the active ingredient in Cardizem, Pharmacia Cor- poration Diltiazemum INN (Diltiazem) (2S,3S)-3-(Acetyloxi)-5-[2-(dimethylamino)ethyl]-2-(4-metoxi fenyl)-2, 3-<BR> <BR> -dihydro-1,5-bensotiazepin-4(5H)-on * Imipramin 5-(3-Dimetylaminopropyl)-10,11-dihydro-5H-dibenso[b,f]azepin

* Mianserin

Mirtazapine (1,2,3,4,10,14b-hexahydro-2-methyl-. pyrazino [2,1-a] pyrido [2,3-c] benzazepine) Pizotifen Pizotifenum INN (Pizotifen) 4-(1-Methyl-4-piperidyliden)-9,10-dihydro-4H-benso- -[4,5]cyklohepta[1,2-b]tiofen

Quinolines, quinolicines and isoquinolines The common structure of quinoline is:

Isoquinoline and quinolizine are isomers of quinoline.

# Quinoline-3-carboxamides

# Quinoline-4-carboxylates # Isoquinoline-1-one (isomer till quinolin-l-one) # SEC 579 RS 56532 ( (S)-6-amino-5-chloro-2- (l-azabicyclo- [2,2,2] octan-3-yl) 2,3-dihydro-lH-benz [de]- isoquinoline-1, 3-dione hydrochloride) <BR> <BR> # 3- (1-piperazinyl)-2-quinoxalinecarbonitrile<BR> <BR> # 3- (4-allylpiperazin-1-yl) -2-quinoxalinecarbonitrile KF 17643 (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl- 2- (n-propyloxy)-4-quinolinecarboxylate) # KF 18259 ( (endo- (8-methyl-8-aza- bicyclo [3.2.1] oct- 3-yl) -1-isobutyl-2-oxo-1, 2-dihydro-4-quinoline- carboxylate hydrochloride) KF 20170 (endo-N- (8-methyl-8-aza-bicyclo [3.2.1] oct- 3-yl)-4-hydroxy-3-quinolinecarboxamide # Palonosetron=RS 25259-197 (3aS) -2- [(S) -1-azabicyclo[2. 2.2] oct-3-yl]- 2,3,3a, 4,5, 6-hexahydro- 1- oxo-1H-benzo [de] - isoquinoline-hydrochloride # Quipazine (2- (1-piperazinyl)-Quinoline) # N-metylquipazin 4-Ph-N-Me-quipazine

RS-42358-197 [(S)-N-(1-azabicyclo [2.2.2] oct-3-yl)- 2,4,5,6-tetrahydro-1 H-benzo [de] isoquinolin-l-one hydrochloride] <BR> <BR> <BR> <BR> <BR> RS-056812-198 (R)-N-(quinuclidin-3-yl)-2-(1-methyl- 1 H-indol-3-yl)-2-oxo-acetamide RS-25259-197 [(3aS)-2-[(S)-1-azabicyclo[2.2.2] oct-3- yl]-2, 3,3a, 4,5,6-hexahydro-1-oxo-lH-benzo [de]- isoquinoline-hydrochloride) The interaction of RS 25259-197, a potent and selec- tive antagonist, with 5-HT3 receptors, in vitro.

Wong EH, Clark R, Leung E, Loury D, Bonhaus DW, Jakeman L, Parnes H, Whiting RL, Eglen RM, Br J Pharmacol 1995 Feb, 114: 4: 851-9 A series of isoquinolines have been identified as 5- HT3 receptor antagonists. One of these, RS 25259-197 [ (3aS)-2- [ (S)-l-azabicyclo [2.2.2] oct-3-yl]- 2,3,3a, 4,5,6-hexahydro-1-oxo-lH-benzo [de] iso- quinoline-hydrochloride], has two chiral centres.

The remaining three enantiomers are denoted as RS 25259-198 (R, R), RS 25233-197 (S, R) and RS 25233- 198 (R, S). 2. At 5-HT3 receptors mediating contrac- tion of guinea-pig isolated ileum, RS 25259-197 an- tagonized contractile responses to 5-HT in an unsur- mountable fashion and the apparent affinity (pKB), estimated at 10 nM, was 8.8 +/-0.2. In this tissue, the-log KB values for the other three enantiomers were 6.7 +/-0.3 (R, R), 6.7 +/-0.1 (S, R) and 7.4 +/-0. 1 (R, S), respectively. The apparent affinities of RS 25259-197 and RS 25259-198, RS 25233-197 and RS 25233-198 at 5-HT3 receptors in membranes from NG-108-15 cells were evaluated by a [3H]-quipazine binding assay. The-log Ki values were 10.5 +/-0.2, 8.4 +/-0.1,8.6 +/-0.1 and 9.5 +/-0.1, respec-

tively, with Hill coefficients not significantly different from unity. Thus, at these 5-HT3 recep- tors, the rank order of apparent affinities was (S, S) > (R, S) > (S, R) = (R, R). 3. RS 25259-197 dis- placed the binding of the selective 5-HT3 receptor ligand, [3H]-RS 42358-197, in membranes from NG-108- 15 cells, rat cerebral cortex, rabbit ileal myen- teric plexus and guinea-pig ileal myenteric plexus, with affinity (pKi) values of 10.1 +/-0.1,10.2 +/- 0.1,10.1 +/-0. 1 and 8.3 +/-0.2, respectively.

Phenthiazines and Benzoxazines Chlorpromazine Chlorpromazinum INN (Klorpromazin) 10- (3-Dimetylaminopropyl)-2-klorofentiazin

Cyamemazine (10- (3-Dimethylamino-2- methylpropyl) phenothiazine-2-carbonitrile) Fluphenazin Fluphenazinum INN (Flufenazin) 10-[3-(4-(2-Hydroxietyl)-1-piperazinyl)propyl]-2 -trifl uorometyltentiazln Prochlorperazine=Stemetil

KB-6933 (6-amino-5-chloro-1-isopropyl-2-(4-methyl-1- piperazinyl) benzimidazole dimaleate) Perfenazine. Invar i Trilafon. Cl istallet for CF3 i formeln for Flufenazine Trifluoperazine Azasetron=Y25130 (+/-)-N-(1-azabicyclo [2.2.2] oct-3- yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4- benzoxazine-8-carboxamide monohydrochloride Pharmacokinetics of azasetron (Serotone), a selec- tive 5-HT3 receptor antagonist.

Tsukagoshi S Gan To Kavaku Ryoho 1999 Jun, 26: 7: 1001-8

5-HT3 receptor antagonists have been established in a number of clinical trials as effective agents in the management of nausea and vomiting induced by cancer chemotherapy including cisplatin. Azasetron (Serotone) is a potent and selective 5-HT3 receptor antagonist, and classified as benzamide derivative.

It has a different chemical structure from indole- type 5-HT3 receptor antagonists such as granisetron, ondansetron, ramosetron and tropisetron. The major difference is found in the pharmacokinetic profiles.

Approximately 60-70% of azasetron administered i. v. and orally is excreted in urine as the unmetabolized form. Also, orally-administered azasetron has shown to be absorbed and/or secreted by the saturable transport mechanism in the small intestine, result- ing in good bioavailability as approximately 90%. In this report, the relationship between the structure of 5-HT3 receptor antagonists (especially azasetron) and their pharmacokinetics were described.

* 5- ( (Dimethylamino) methyl)-3- (l-methyl-lH-indol-3- yl)-1, 2,4-oxadiazole * 1, 4-Benzoxazin-8-Carboxamide <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> Other compounds, including piperidines, piperazines, al- kaloides, benzoates and ureas * Anpirtoline (6-Chloro-2- [piperidinyl-4-thio]- pyridine) Ritanserin NAN-190 (1- (2-methoxyphenyl)-4- [4- (2-phthalimido)- butyl] piperazine) * Naphtimides.

* TFMPP (1- (3-trifluoromethylphenyl) piperazine)

* Ifenprodil (dl-erythro-4-benzyl-alpha- (4-hydro- phenyl)-beta-methyl-l-piperidine-ethanol tartrate) (ifenprodil tartrate) # MCPP (Meta-chlorophenylpiperazine) (mCPP) # MK-212 (6-chloro-2- [1-piperazinyl]-pyrazine) # Metergoline ( [ [ (8 (BETAI)-1, 6-dimethylergolin-8- yl] methyl]-Carbamic acid phenylmethyl ester) # Methysergide (1-methyl-D-lysergic acid butanolamide) # S-apomorfin Tropanyl-3, 5-dimethylbensoate # Trimebutine, ett 3,4,5-trimetoxybensoate derivat.

# TMB-8 (8- (N, N-diethylamino) octyl 3,4,5-trimethoxy- benzoate) Phenylbiguanide Functional characterization of a 5-HT3 receptor which modulates the release of 5-HT in the guinea- pig brain., Blier P, Bouchard C Br J Pharmacol 1993 Jan, 108: 1: 13-22

1. The aims of the present study were to confirm the modulation by 5-HT3 receptors of the electrically evoked release of tritium from slices preloaded with [3H]-5-HT of guinea-pig frontal cortex, hippocampus and'hypothalamus, and to assess their functional role in 5-HT release. 2. The selective 5-HT3 ago- nist, 2-methyl-5-HT, introduced 8 min before the electrical stimulation, enhanced in a concentration- dependent manner the evoked release of [3H]-5-HT in the three brain regions studied. The 5-HT3 agonists, phenylbiguanide and m-chlorophenyl-biguanide, did not enhance the release of tritium in frontal cortex and hypothalamus slices. 3. In hypothalamus slices, this response was lost when 2-methyl-5-HT was intro- duced 20 min before the stimulation, thus indicating that these 5-HT3 receptors desensitize rapidly. When 2-methyl-5-HT was added 20-min before the first stimulation period to desensitize the 5-HT3 recep- tors, removed for 24 min, and then re-introduced 8 min before the second stimulation period, the en- hancing effect of 2-methyl-5-HT was restored, thus indicating that these 5-HT3 receptors can rapidly regain normal sensitivity. 4. The enhancing effect of 2-methyl-5-HT was attenuated by the 5-HT3 recep- tor antagonists m-chloro-phenylpiperazine = quip- azine = ondansetron > or = ICS 205-930 = BRL 24924 > MDL 72222 =. zacopride. 5. The 5-HT reuptake blocker, paroxetine, enhanced the electrically evoked release of tritium when introduced 8 min before stimulation; this effect of paroxetine was blocked by ICS 205- 930, thus indicating that these 5-HT3 receptors can be activated by endogenous 5-HT. 6. In the absence of electrical stimulation, 2-methyl-5-HT (10 microM) produced a marked enhancement of the basal release of [3H]-5-HT which was calcium-dependent and blocked by S-zacopride but not by paroxetine. 7. The enhanc- ing effect of 2-methyl-5-HT was dependent both on

the frequency of stimulation, as indicated by the attenuated effect of 120 stimulations delivered at 1 Hz instead of 5 Hz, and on the duration of the sti- mulation, as indicated by the more pronounced effect of pulses delivered at 5 Hz for 24 s instead of 72 s or 120 s. McNeil-A-343 (4- (m-chlorophenylcarbamoyl- oxy)-2-butynyl-trimethylammonium chloride).

MDL 72222 (1 alpha H, 3 alpha, 5 alpha H-tropan-3- yl-3,5-dichlorobenzoate) MDL 72222: a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors., Fozard JR Naunyn Schmiedebergs Arch Pharmacol 1984 May, 326: 1: 36-44 The properties of MDL 72222 (1 alpha. H, 3 alpha, 5 alpha H-tropan-3-yl-3,5-dichlorobenzoate), a novel compound with potent and selective blocking actions at certain excitatory 5-hydroxytryptamine (5-HT) re- ceptors on mammalian peripheral neurones, are de- scribed. On the rabbit isolated heart, MDL 72222 was a potent antagonist of responses mediated through the receptors for 5-HT present on the terminal sym- pathetic fibres. The threshold for antagonism was approximately 0.1 nM and the negative logarithm of the molar concentration of MDL 72222 which reduced the chronotropic response of the isolated rabbit heart to twice an ED50 of 5-HT to that of the ED50 was 9.27. MDL 72222 was also highly selective since responses to the nicotine receptor agonist, dimeth- ylphenylpiperazinum iodine (DMPP), were inhibited only at concentrations more than 1000 times those necessary to inhibit 5-HT. In the anaesthetized rat, MDL 72222 produced marked blockade of the Bezold- Jarisch effect of 5-HT. Again, inhibition was selec- tive since much higher doses of MDL 72222 failed to

alter the response to electrical stimulation of the efferent vagus nerves. In contrast, MDL 72222 proved only a weak and essentially non-selective antagonist of responses mediated by the 5-HT M-receptor present on the cholinergic nerves of the guinea-pig ileum.

MDL 72222 does not block smooth muscle contractile responses elicited by oxytocin or mediated through 5-HT D-receptors, muscarinic or nicotinic cholino- ceptors or histamine H1-receptors except at rela- tively high concentrations.

* MDL 72699 MDL 72699 ar kvartenara saltet av MDL 72222.

* Mepyramine (N, N-dimethyl N'- (methoxy-4 benzyl)-N'- (pyridyl-2) ethylenediamine).

* Galanolactone= Gingerol The irregularly shaped roots (rhizomes) of ginger (zingiber officinale) are used extensively in Chi- nese, Indian, and Japanese cultures where they are believed to have anti-inflammatory, analgesic, cho- lesterol-lowering, and antithrombotic properties.

Al-though ginger has been evaluated for the treat- ment of nausea and vomiting associated with hyper- emesis gravidarum, anesthesia, and chemotherapy, this review will focus on ginger for motion sick- ness.

Talipexole Additional compounds

* YM 26103-2 * YM 26308-2 * M-840 ( [ [3- (l-methyl-lH-indol-3-yl)-l, 2, 4-oxadiazol- 5-yl]-methyl] trimethyl-ammonium iodide) Ref. A mechanism of 5-HT3 receptor mediation is in- volved etiologically in the psychological stress le- sion the stomach of the mouse., J Pharmacol Exp Ther, 1994 Oct, 271: 1,100-6 The role of brain amines, possibly involved in psy- chological stress, was evaluated and we postulate that the 5-hydroxytryptamine 5-HT3 receptors in the central nervous system are involved in the gastric lesion formation by psychological stress. The stress was in a communication box paradigm, in which each nonshocked mouse (responder) was placed in a Plexi- glas compartment adjacent to mice receiving electri- cal shocks (sender). The responder mice revealed rather depressed gastric secretion, but developed gastric lesions which are significantly attenuated by pretreatment of dl-p-chlorophenylalanine methyl ester: HCl (PCPA; 200-400 mg/kg p. o.), but not 6- hydroxydopamine (6-OH-DA; 60 micrograms/body i. c. v. or 80 mg/kg i. p. 1 hr after a 20-mg/kg i. p. dose of desipramine). Oral treatment with GR38032F (0. 01- 1 mg/kg), ICS205-930 (0.01-20 mg/kg), MDL72222 (0.01-1 mg/kg), metoclopramide (0.1-100 mg/kg), ke- tanserin (0.01-10 mg/kg) and sulpiride (32-320 mg/kg) dose-dependently attenuated the psychological stress lesion formation, and the activity was ar- ranged in the order of their in vitro binding af- finities for the 5-HT3, but not 5-HT1A or 5-HT2 re- ceptors. In contrast, a peripherally acting 5-HT3 antagonist, M-840 ( [ [3- (l-methyl-lH-indol-3-yD- 1, 2,4-oxadiazol-5- yl]-methyl] trimethyl-ammonium io-

dide), dopamine acting compounds, haloperidol and FR64822 [N- (4-pyridylcarbamoyl) amino-1, 2,3,6-tetra- hydropyridine), and antisecretory drugs, atropine and famotidine,. minimally affected the lesion forma- tion.

SDZ ICT 322, an indole-3-carboxylic acid scopine es- ter MD-354 MD-354. We were intrigued by the novel 5-HT3 agonist phenylbiguanide. It seemed quite selective for 5-HT3 receptors, but displayed rather low affinity (Ki >1, 000 nM). In a prior study with Dr. S. Peroutka, we had investigated the SAFIR of various arylpipera- zines at 5-HT3 receptors. Arylpiperazines, as men- tioned earlier, are relatively nonselective agents; however, many bind at 5-HT3 receptors with signifi- cantly higher affinity that phenylbiguanide. We identified some structural similarities between the arylpiperazines and phenylbiguanide and, in collabo- ration with Milt Teitler, made a series of hybrid analogs that we hoped would bind with higher affin- ity than phenylbiguanide. Two such analogs were meta-chlorophenylbiguanide (mCPBG) and 2-naphthyl- biguanide (Ki = 10-20 nM); both displayed signifi- cantly higher affinity than phenylbiguanide. Al- though we reported these compounds in abstract form, a full paper http ://www. phc. vcu. edu/rag/serotonin/-seven on mCPBG independently appeared by another group of in- vestigators at the same time. It was not until a few years later that we finally published a full paper on these agents. However, in the course of our stud- ies, we identified a novel class of 5-HT3 agonists: the arylguanides. MD-354, for example, was found to bind at 5-HT3 receptors with high affinity (Ki ca. 35 nM) and to display agonist actions in several as- say systems.

MD-354 S 21007 (21007 [5- (4-benzyl piperazin-1-yl) 4H pyr- rolo [1, 2-aathieno [3,2-e] pyrazine]).

Interaction of S 21007 with 5-HT3 receptors. In vi- tro and in vivo characterization.

. Delagrange P, Emerit MB, Merahi N, Abraham C, Morain P, Rault S, Renard P, Pfeiffer B, Guardiola-Lemaitre B, Hamon M; Eur J Pharmacol 1996 Dec 5,316: 2-3: 195- 203.

The interaction of S 21007 [5- (4-benzyl piperazin-l- yl) 4H pyrrolo [1, 2-a] thieno [3,2-e] pyrazine] with se- rotonin 5-HT3 receptors was investigated using bio- chemical, electrophysiological and functional as- says. Binding studies using membranes from N1E-115 neuroblastoma cells showed that S 21007 is a selec- tive high affinity (IC50 = 2. 8 nM) 5-HT3 receptor ligand. As expected of an agonist, S 21007 stimu- lated the uptake of [14C] guanidinium (EC50 approxi- mately 10 nM) in NG 108-15 cells exposed to sub- stance P, and this effect could be prevented by the potent 5-HT3 receptor antagonist ondansetron. In ad- dition, like 5-HT and other 5-HT3 receptor agonists (phenylbiguanide and 3-chloro-phenylbiguanide), S 21007 (EC50 = 27 microM) produced a rapid inward current in N1E-115 cells. The 5-HT3 receptor agonist

action of S 21007 was also demonstrated in urethane- anaesthetized rats as this drug (120 micrograms/kg i. v.) triggered the Bezold-Jarisch reflex (rapid fall in heart rate), and this action could be pre- vented by pretreatment with the potent 5-HT3 recep- tor antagonist zacopride. Finally, in line with its 5-HT3 receptor agonist properties, S 21007 also triggered emesis in the ferret. Evidence for 5-HT3 receptor antagonist-like properties of S 21007 was also obtained in some of these experiments since previous exposure to this compound prevented both the 5-HT-induced current in N1E-115 cells and the Bezold-Jarisch reflex elicited by an i. v. bolus of 5-HT (30 micrograms/kg) in urethane-anaesthetized rats. These data suggest that S 21007 is a selective 5-HT3 receptor agonist which can exhibit antagonist- like properties either by triggering a long lasting receptor desensitization or by a partial agonist ac- tivity at 5-HT3 receptors in some tissues.

Further, in the following patent publications more compounds useful according to the present invention are presented.

N-substituted benzamides 'ex0417746 (September 1990, G. D. Searle & Co) N-Aza- bicyclo/3. 3.0/octane amides of aromatic acids. See also US5126343.

or a pharmaceutically acceptable salt thereof wherein n is 0 or 1; Ar can be benzamide

R1 is alkoxy of 1 to 6 carbon atoms; and R2 and R3 are the same or different and are hydro- gen, halogen, CF3, hydroxy, C1_6 alkoxy, C2_7 acryl, amino, amino substituted by. one or two Ci_6 alkyl groups, C2_7 acylamino, aminocarbonyl or aminosul- fone, optionally substituted by one or two C1_6 al- kyl groups, C1_6 alkyl sulfone or nitro groups; wherein X can be NR, S, or 0 ; Y can be CH or N; R is H, alkyl or aryl; and m is 1 or 2.

The structure is a benzamide with Ar=Ph-CONH-.

A compound of the formula or a pharmaceutically ac- ceptable salt thereof wherein n is = or 1; and Ar is an aromatic amide moiety, which compound exhibits prokinetic activity and is a 5-HT3 antagonist.

EP0430190 (November 1990, Syntex, Inc) New tricyclic compounds in which the dashed line denotes an optional double bond; n is 1, 2 or 3; p is 0,1,2 or 3 ; q is 0,1 or 2; each R1 is independently selected from halogen, hy- droxy, lower Cl_6 alkoxy (optionally substituted with phenyl), lower C1_6 alkyl, nitro, amino. amino- carbonyl, (lower C1_6 alkyl) amino, di (lower C1_6 al- kyl) amino, and (lower C1_6 alkanoyl) amino; each R2 is lower C1_6 alkyl ; and R3 is selected from

in which u, x, y and z are all independently an integer from 1 to 3; and R4 and R5 are independently C1_7 alkyl, C3_g cyclo- alkyl, C3-8 cycloalkyl-Cl_2 alkyl, or a group (CH2) tR6 where t is 1 or 2 ant R6 i thienyl, pyr- rolyl or furyl optionally further substituted by one or two substituents selected from C1_6 alkyl, C1-6 alkoxy, trifluoromethyl or halogen, or is phenyl op- tionally substituted by one or two substituents se- lected from C1_4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C1_4 alkyl (optionally substituted by hydroxy, Cl_4 alkoxy, carboxy, esterified carboxy or in vivo hydrolyzable acyloxy); or a pharmaceutically acceptable salt thereof or an N- oxide thereof; or an individual isomer or mixture of isomers thereof.

The present invention is directed to new pharmaceu- tically active compounds with 5-HT3 receptor anta- gonist activity of Formula I: in which the dashed line denoted an optional double bond; n is 1,2 or 3; p is 0,1,2 or 3; q is 0,1 or 2; each Rl is halogen, hydroxy, alkoxy (optionally substituted with phenyl), alkyl, nitro, amino, amino carbonyl, (alkyl) amino, di (alkyl) amino, and (alkanoyl) amino; each R2 is alkyl ; and R3 is in which u, x, y and z are all independently an integer from 1 to 3; and R4 and R5 are independently alkyl, cycloalkyl, cycloal- kylalkyl, or a group (CH2) tR6 where t is 1 or 2 and R6 is thienyl, pyrrolyl or furyl optionally further substituted by one or two substituents selected from alkyl, alkoxy, trifouoromehtyl or halogen, or is phenyl optionally substituted by alkoxy, trifluo- romethyl, halogen, nitro, carboxy, esterified car- boxy, and alkyl (optionally substituted).

Indoles, Indole-1-carboxamides and Imidazole deriva- tives EP0721949 (September 1993, Tokyo Tanabe Coompany Lim- ited) Indoline compound and 5-HT3 receptor antagonist containing the same as active ingredient. wherein R1 represents the group

R2 represents a phenyl group which may be substi- tuted or an aromatic heterocyclic group, and R3 rep- resents hydrogen, a halogen, or a lower alkyl group, hydroxyl group, lower alkoxy group, carbamoyl group or lower alkoxycarbonyl group, or a physiologically acceptable salt thereof, or its solvate.

An indoline compound represented by general formula (I); a physiologically acceptable salt thereof; sol- vates of these compounds; and a 5-HT3 receptor anta- gonist containing the same as the active ingredient.

In formula (I) R1 represents the group (a) or (b), R2 represents optionally substituted phenyl or het- eroaryl; and R3 represents hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy, carbamoyl or lower alkoxycarbonyl. The compound has a potent antagonism against 5-HT3 receptors in the intestinal tract as compared with the known 5-HT3 receptor antagonists and is excellent in the persistence of the activity.

Hence it is useful for preventing or treating vomit- ing or nausea induced by chemotherapy or radiation, irritable bowel syndrome and diarrhea.

'ex0711299 (May 1994, Pharmacia S. p. A) Azabicycloalkyl Derivatives Of Imidazol (1, 5-A) Indol-3-One As 5HT 3 An- tagonists

wherein each of R, R1 and R2, which may be the same or different, is hydrogen, halogen, hydroxy, cyano, C1- C6 alkyl, CF3, Cl-C6 alkoxy, C1-C6 alkylthio, for- myl, C2-C6 alkanoyl, carboxy, Cl-C6 alkoxycarbonyl, nitro,-N (R4 Rs) in which each of R4 and R5 inde- pendently is hydrogen, Cl-C6 alkyl, formyl or C2-C6 alkanoyl; or a (R6 R7) N-SO2 group, in which each of R4 and R7 independently is hydrogen or C1-C6 alkyl ; R3 is a group a) or b) wherein n is an integer of 1 or 2 and R8 is hydrogen, C1-C6 alkyl unsubstituted or substituted by phenyl, C2-C4

alkenyl, C2-C4 alkynyl, formyl or C2-C6 alkanoyl; and the pharmaceutically acceptable salts thereof.

Novel 5-HT3 receptor antagonist compounds having general formula (I) wherein each of R, R1 and R2, which may be the same or different, is'hydrogen, halogen, hydroxy, cyano, C1-C6 alkyl, CF3, Cl-C6 alkoxy, C1-C6 alkylthio, formyl, C2-C6 alkanoyl, carboxy, Cl-C6 alkyl-carbonyl, nitro,-N (R4 R5) in which each of R4 and R5 independently is hydrogen, C1-C6 alkyl, formyl or C2-C6 alkanoyl; or a (R6 R7) N-S02 group, in which each of R6 and R7 independ- ently is hydrogen or C1-C6 alkyl ; R3 is a group (a) or (b) wherein n is an integer of 1 or 2 and R8 is hydrogen, C1-C6 alkyl unsubstituted or substituted by phenyl, C2-C4 alkenyl, C2-C4 alkynyl, formyl or C2-C6 alkanoyl; and the pharmaceutically acceptable salts thereof, are provided.

EP0711293 (May 1994, Pharmacia S. p. A) Imidaxolylalkyl Derivatives Of Imidazol (1, 5-A) Indol-3-One And Their Use As Therapeutic Agents.

(I) wherein n, 1,2 or 3 is; each of R, R1 and R2, which may be the same or dif- ferent, is hydrogen, halogen, hydroxy, cyano C1-C6 alkyl, CF3, Cl-C6 alkoxy, C1-C6 alkylthio, formyl, C2-C6 alkanoyl, carboxy, C1-C6 alkoxycarbonyl, ni- tro,-N (R4) R5 in which each of R4 and R5 independ-

ently is hydrogen, C1-C6 alkyl, formyl or C2-C6 al- kanoyl; or a R6. (R7) N-SO2 group, in which each of R6 and R7 independently is hydrogen or C1-C6 alkyl ; R3 is an imidazolyl group having the formula a) or b) wherein each of R6 and Rlo, which may be the same or different, is hydrogen or Cl-C6 alkyl, Rg is hydro- gen, C1-C6 alkyl or a nitrogen protection group cho- sen from triphenylmethyl, t-butyloxycarbonyl, benzy- loxycarbonyl, acetyl, formyl, di (p-methoxyphenyl)- methyl and (p-methoxyphenyl) diphenylmethyl; and the pharmaceutically acceptable salts thereof.

Novel 5-HT3 receptor antagonist compounds having formula (I), wherein n is 1,2 or 3; each of R, R1 and R2, which may be the same or different, is hy- drogen, halogen, hydroxy, cyano, C1-C6 alkyl, CF3, C1-C6 alkoxy, C1-C6 alkylthio, formyl, C2-C6 alka- noyl, carboxy, Cl-C6 alkoxy-carbonyl, nitro, -N (R4 R5), in which each of R4 and R5 independently is hydrogen, C1-C6 alkyl, formyl or C2-C6 alkanoyl; or a (R6 R7) N-S02 group, in which each of R6 and R7 independently is hydrogen or C1-C6 alkyl ; R3 is an

imidazolyl group of formula (a) or (b), wherein each of R8 and R10 which may be the same or different is hydrogen or C1-C6 alkyl, R9 is hydrogen, C1-C6 alkyl or a nitrogen protecting group; and the pharmaceuti- cally acceptable salts thereof, are disclosed.

EP0581388 (July 1993, Glaxo Group Ltd) Pyridoindolone Methansulphonate as 5HT and 5HT3 receptor antagonists.

This invention relates to the novel salt 6-fluoro- 2,3,4,5-tetrahydro-5-methyl-2- [ (5-methyl-lH-imidazol- 4-yl) methyl]-lH-pyrido [4,3-b] indol-1-one methane sul- phonate, to solvates of this salt, to pharmaceutical compositions containing it and to its use in medici- ne as 5-HT3 receptor antagonists.

EP0364274 (October 1989, Glaxo Group Ltd) Imidazole derivatives.

(I) wherein Im represents an imidazolyl group of the formula:

and one of the groups represented by R3, R4 and R5 is a hydrogen atom, or a C1_6 alkyl, C3_7 cycloal- kyl, C3-6 alkenyl, phenyl or phenyl C1_3 alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1_6 alkyl group; Rland R2 each represent a hydrogen atom, or together with the carbon atoms to which they are attached form a phenyl ring; X represents an oxygen or a sulphur atom, or a group NR6, wherein R6 represents a C1_6 alkyl group; Z-Y represents the group CH-CH2 or C=CH; and physiologically acceptable salts and solvates thereof, which comprises: (A) for the production of a compound of formula (I) in which Z-Y represents the group CH-CH2, hydrogen- ating a compound of formula (II):

or a protected derivative thereof, followed if nec- essary by removal of any protecting groups present; or (B) for the production of a compound of formula (I) in which Z-Y represents the group C=CH, reacting a compound of formula (II), or a protected derivative thereof, with an organic acid or a mineral acid, followed if necessary by removal of any protecting groups present; or (C) converting a compound of general formula (I) into another compound of formula (I) using conven- tional techniques ; or (D) removing protecting group (s) from a protected form of a compound of formula (I); and when the compound of formula (I) is obtained as a mixture of enantiomers, optionally resolving the mixture to obtain the desired enantiomer; and/or where the compound of formula (I) is in the form of a free base, optionally converting the free base into a salt.

The invention provides imidazole derivatives of the general formula (I) wherein Im represents an imi- dazolyl group of the formula: and one of the groups represented by R3, R4 and R5 is a hydrogen atom, or a C1-C6 alkyl, C3-7 cycloalkyl, C3-6 alkenyl, phenyl or phenyl C1-3 alkyl group, and each of the other two groups, which may be the same or different, rep- resents a hydrogen atom or a C1-6 alkyl group; Rl and R2 each represent a hydrogen atom, or together with the carbon atoms to which they are attached form a phenyl ring; X represents an oxygen or a sul- phur atom, or a group NR6, wherein R6 represents a C1-6 alkyl group; Z-Y represents the group CH-CH2 or C=CH ; and physiologically acceptable salts and sol- vates thereof. The compounds of formula (I) are po- tent and selective antagonists of 5-hydroxytrypta-

mine at 5-HT3 receptors and are useful, for example, in the treatment of psychotic disorders, anxiety and nausea and vomiting.

EP0392663 (March 1989, One Pharmaceutical Co Ltd) Car- boline derivative as a 5-HT3 receptor antagonist.

A y-carboline of the formula I I or pharmaceutically acceptable acid addition salt and/or hydrate thereof for use in a method of treat- ment or prophylaxis of diseases or conditions in- duced by the action of 5-hydroxytryptamine on 5- hydroxytryptamine 3-receptors in a mammal, including man.

The present invention provides y-carbolines of the formula: or non-toxic acid additional salts thereof and/or hydrates thereof, for use as 5-HT3 receptor antagonists. The present invention also provides pharmaceutical compositions comprising compounds of the formula I.

'ex0357417 (August 1989, Glaxo Group Ltd) Lactam de- rivatives.

Compounds of the general formula (I)

(I) wherein n represents 2 or 3; Im represents an imidazolyl group of the formula: wherein one of the groups represented by RI, R2 and R3 is a hydrogen atom or a C1_6 alkyl, C3_7 cycloal- kyl, C3-6 alkenyl, phenyl or phenyl C1_3 alkyl- group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1_6 alkyl group; Y represents a group- (CH2) m-, wherein m represents 2,3 or 4; or Y represents a group-X (CH2) p_, Cul-6 alkyl group, and X is attached to the benzene ring moiety of the molecule; and physiologically acceptable salts and solvates thereof.

The invention provides lactam derivatives of the general formula (I) wherein n represents 2 or 3; Im

represents an imidazolyl group of the formula: wherein one of the groups represented by R1, R2 and R3 is a hydrogen atom or a C1-6 alkyl, C3-7 cycloal- kyl, C3-6 alkenyl, phenyl or phenyl C1-3 alkyl- group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1-6 alkyl group; Y represents a group- (CH2) m- , wherein m represents 2,3 or 4; or Y represents a group-X (CH2) p-, wherein p represents 2 or 3, X rep- resents an oxygen or a sulphur atom or a group NR4, where R4 is a Cl-6 alkyl group, and X is attached to the benzene ring moiety of the molecule; and physio- logically acceptable salts and solvates thereof. The compounds of formula (I) are potent and selective antagonists of 5-hydroxytryptamine at 5-HT3 recep- tors and are useful, for example in the treatment of psychotic disorders, anxiety and nausea and vomit- ing.

RU2059623 Tetrahydrobenzimidazole derivatives or its pharmaceutically acceptable salt. tetrahydrobenzimidazole derivative of the formula and a pharmaceutical composition containing an effective amount of com- pound and a pharmaceutically

acceptable carrier showing activity of a 5-HT3 re- ceptor antagonist.

US5, 045,545 (May 1989, Glaxo Group Limited) [(Imidazol- 4 (and 5)-yl) methyl] tetracyclic ketones having 5-HT3 antagonist activity.

The invention relates to tetracyclic ketones of the general formula (I) wherein n represents 1,2 or 3; Im represents an imidazolyl group of the formula: wherein one of the groups represented by R1, R2 and R3 is a hydrogen atom or a C1_6 alkyl, C3_7 cycloal- kyl, C3-6 alkenyl, phenyl or phenyl C1_3 alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1_6 alkyl group; Y represents a group- (CH2) m-, wherein m represents 2,3 or 4; or a group-X (CH2) p_, where p represents 2 or 3, X represents an oxygen or a sulphur atom or a group NR4, where R4 is a C1_6 alkyl group, and X is attached to the benzene ring moiety of the mole- cule;

and physiologically acceptable salts and solvates thereof.

The compounds are potent and selective antagonists of the effect of 5-HT3 receptors and are useful, for example, in the treatment of psychotic disorders, anxiety, and nausea and vomiting.

The invention relates to tetracyclic ketones of the general formula (I) ##STR1## wherein n represents 1, 2 or 3; Im represents an imidazolyl group of the formula: ##STR2## wherein one of the groups repre- sented. by R. sup. 1, R. sup. 2 and R. sup. 3 is a hydrogen atom or a C. sub. 1-6 alkyl, C. sub. 3-7 cycloalkyl, C. sub. 3-6 alkenyl, phenyl or phenyl C. sub. 1-3 alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C. sub. 1-6 alkyl group; Y represents a group -- (CH. sub. 2) m--, where m represents 2,3 or 4, or a group-X (CH. sub. 2). sub. p--, where p represents 2 or 3, X represents an oxygen or a sulphur atom or a group NR. sup. 4, where R. sup. 4 is a C. sub. 1-6 alkyl group, and X is attached to the benzene ring moiety of the molecule; and physiologically acceptable salts and solvates thereof. The compounds are potent and selective antagonists of the effect of 5-HT at 5-HT. sub. 3 receptors and are useful, for example, in the treatment of psychotic disorders, anxiety, and nausea and vomiting.

Indazole carboxamide derivatives EP0630893 (March 1992, Kyorin Pharmaceutical Co., Ltd.) N, N'-Disubstituted Amide Derivative.

A 5-HT3 antagonist containing a novel N, N'-disub- stituted amide derivative having a potent and selec- tive 5-HT3 receptor antagonism, represented by gene- ral formula (I), a hydrate thereof, or an acid addi- tion salt thereof, wherein R1 represents hydrogen or lower alkyl ; R2 and R3 may be the same or different from each other and each represents hydrogen, lower alkyl, lower alkenyl, aryl-substituted lower alkyl which may be substituted, acyl or lower alkoxy- carbonyl; R4 represents hydrogen, lower alkyl or lower alkoxy; A represents CH or N; and n represents 1, 2 or 3.

EP0558923 (January 1992, Nisshin Flour Milling Co., Ltd.) Diazabicyclo derivatives as 5-HT3 antagonists (I) wherein R1 is alkyl, 3-methyl-2-butenyl, cyclopropylmethyl, 2-propynyl, cyanomethyl, 2-oxopropyl, 2-hydroxypro- pyl, 2-pyridylmethyl, methoxycarbonylmethyl, 2- ethoxyethyl, isobutoxycarbonyl, or 4,6-diamino-2- triazinylmethyl; R2 is hydrogen; and R3 and R4 are methyl.

Diazabicyclo derivatives of formula (I) and pharma- ceutically acceptable salts thereof: wherein R1 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cy- cloalkylalkyl, alkoxyalkyl, oxoalkyl, alkoxy- cabonylalkyl, alkoxycarbonyl, acyl, dialkylaminoal- kyl, hydroxyalkyl, haloalkyl, cyanoalkyl, heterocy- cloalkyl, aryl, heteroarylalkyl or arylalkyl, the aryl group and the aryl moiety being optionally sub- stituted by alkoxy, nitro, alkyl, amino or halo; R2 is hydrogen or alkyl ; R3 and R4 may be the same or different and each is hydrogen, alkyl, alkenyl, acyl, alkoxyalkyl or arylalkyl wherein the aryl moi- ety is optionally substituted by alkoxy, nitro, al- kyl, amino or halo; with the proviso that when R2 is hydrogen and both R3 and R4 are methyl, Rl does not represent hydrogen, alkyl, unsubstituted benzyl or dimethylaminoethyl ; having 5-HT3 receptor antagonist activity.

Quinolines and Isoquinolines W09964421 (June 1999, Arena Pharmaceuticals, Inc) Ace- tylcholine enhancers.

An acetylcholine enhancer selected from the group consisting of the chemical compounds represented by the following structures:

Disclosed herein are quinoline derivatives having dual mechanistic properties, referred to in this patent documents as"acetylcholine enhancers", i. e., compounds which evidence acetylcholinesterase (AChE) inhibition activity, and 5-HT3 receptor antagonist activity. A particularly preferred compound is 2- [2- (1-benzylpiperizin-4-yl) ethyl]-2,3-dihydro-9-methoxy- lH-pyrrolo [3,4-b] quinolin-1-one hemifumarate, refer- red to herein as Compound A ("Cm. A").

EP0526545 (April 1991, Beecham Group p. l. c.) Isoquin- oline Amides And Esters As 5-HT3 Receptor Antagonists.

A compound of formula (I), or a pharmaceutically ac- ceptable salt thereof:

(I) wherein E is NH or O, R1 is hydrogen, halogen, Cl_4 alkyl, C1_4 alkoxy, hydroxy or nitro; Z is an azacyclic or azabicyclic side chain; and i) the group CO-E-Z is in the 1-position and ei- ther R2 is in the 3-position and is hydrogen, Cl_6 alkyl or Cl_6 alkoxy, or R2 is in the 4- position and is hydrogen, halogen, CF3, Cl-6 alkyl, C1_7 acyl, C1-7 acylamino, phenyl op- tionally substituted by one or two C1_6 alkyl, Cl-6 alkoxy or halogen groups, or amino, amino- carbonyl or aminosulphonyl, optionally substi- tuted by oone or two Cl_6 alkyl or C3_g cyclo- alkyl groups or by C4_5 polymethylene or by phenyl, C1_6 alkylsulphonyl, C1_6 alkylsulphi- nyl, C1_6 alkoxy, C1_6 alkylthio, hydroxy or nitro; or ii) the group CO-E-Z is in the 3-position and ei- ther R2 is in the 1-position and is hydrogen, Cl-6 alkyl or C1_6 alkoxy, or R2 is in the 4- position and is hydrogen or C1_6 alkoxy; having 5-HT3 receptor antagonist activity.

Isoquinoline derivatives (I) having 5-HT3 receptor antagonist activity, a process for their preparation and their use as pharmaceuticals. In formula (I) E

is NH or O, R1 is hydrogen, halogen, alkyl, alkoxy, hydroxy or nitro; Z is an azacyclic or azabicyclic side chain, such as a group of formula (a), (b) or (c) wherein; p is 1 or 2; q is 1 to 3; r is 1 to 3; R3 or R4 is hydrogen or alkyl, and Y is a group -CH2-X-CH2-wherein X is-CH2-, oxygen ; sulphur or X is a bond; and (I) when the group CO-E-Z is in the 1-position and either R2 is in the 3-position and is hydrogen, alkyl, or alkoxy, or R2 is in the 4-position and is hydrogen CF3, alkyl, acyl, acyla- mino (substituted) phenyl or (substituted) amino, (substituted) aminocarbonyl or (substituted) amino- sulphonyl; (II) the group CO-E-Z is in the 3- position and either R2 is in the 1-position and is hydrogen, alkyl or alkoxy or R2 is in the 4-position and is hydrogen or alkoxy.

EP0628043 (February 1992, Merrell Dow Pharmaceutical Inc) 2,6-Methano-2H-Quinolizin As 5-HT3-Receptor An- tagonist A compound of the formula: where R is hydrogen or alkyl ; R1 is hydrogen, amino, mono-and di-alkylamino, acylamino, halo or haloalkyl ; R2 is hydrogen, halo, sulfamyl, mono-and di- alkylsulfamyl or haloalkyl ;

R'and R"are independently hydrogen or alkyl ; vicinal R'and/or R"groups may form a C=C double bond; geminal R and R'and R and R"groups may be- (CH2) n- where n is 2 to 6; Z is where m is 0-2, n is 1-2 and X is N or S; or pharma- ceutically acceptable salts thereof.

This invention relates to 5-chloro-2,3-dihydro-2,2- dimethylbenzofuran-7-carboxylic acid-octahydro-3- hydroxy-2,6-methano-2H-quinolizin-8-yl ester (I), a novel 5-HT3-receptor angatonist, its method of preparation, and to its end-use application in the treatment of radio-and chemo-therapeutically- induced nausea and vomiting, in the treatment of pain associated with migraine, in the treatment of cognitive disorders, in treating hallucinatory en-

dogenous psychoses of the type manifested in pa- tients suffering from schizophrenia and mania, for irritable bowel syndrome, and to combat drug abuse.

EP0482939 (October 1991, Ono Pharmaceuticals) Isoqui- nolinone derivative. wherein each substituent R1 is the same or different and is hydrogen, halogen, C1_4 alkyl, Cl-4 alkoxy or a group of formula: -NR4R5 wherein R4 is hydrogen, C1_4 alkyl or C2_4 alkanoyl and R5 is hydrogen, C1_4 alkyl or benzyl; each substituent R2 is the same or different and is hydrogen or C1_4 alkyl ; each substitutent R3 is the same or different and is hydrogen or C1_4 alkyl ; 1 is 1,2,3 or 4; m is 1 or 2; n is 1 or 2 and ---is a single bond or double bond; or a non-toxic acid addition salt thereof or a hydrate thereof.

Isoquinolinone derivatives of the formula: wherein Rl is hydrogen, Cl-4 alkyl, Cl-4 alkoxy or a group of formula:-NR4R5 wherein R4 is hydrogen, halogen, Cl-4 alkyl or C2-4 alkanoyl and R5 is hydrogen, Cl-4 alkyl or benzyl; R2 is hydrogen or C1-4 alkyl ; R3 is hydrogen or C1-4 alkyl ; 1 is 1,2,3 or 4; m is 1 or 2; n is 1 or 2 and---is a single bond or double bond an non-toxic acid addition salts thereof and are useful for the prevention and/or treatment of diseases induced when 5-HT acts on 5-HT3 receptors (especially vomiting induced by the administration of an anti-cancer agent).

Benzofuranes, Benzooxazines and Benzo (di) azepines US4935511 (September 1989, Rorer Pharmaceutical Corpo- ration) Benzoxazine benzooxazipine carboxamide 5-HT3 antagonists. where X is hydrogen, halo, sulfamyl, alkylsulfamyl or al- kylsulfonyl; Y is hydrogen, amino, mono-or di-alkylamino or halo ; Z is

3-quinuclidine, 4-quinuclidine, 4- (1-azabicyclo- [3. 3.1] nonane), 3- (9-methylazabicyclo [3.3.1] nonane) or 4- [3-methoxy-1- (3 (- [4-fluorophenoxy] propyl) piperi- dine]; R, R1, R2, R3 and R4 are independently : hydrogen or alkyl ; x is 2 or 3; y is 1 to 4; and pharmaceutically acceptable salts thereof.

This invention relates to benzoxazine and benzoxaze- pine carboxamide compounds which exhibit 5-HT. sub. 3 antagonist properties including CNS, anti-emetic and gastric prokinetic activity and which are void of any significant D. sub. 2 receptor binding affinity.

This invention also relates to pharmaceutical compo- sitions and methods for the treatment of gastroin- testinal and mental disorders using said compounds.

IL 107654 Use of substituted N-3,4-dihydro-4-oxo-2-2- pyrimidyl) amino alkyl-4-piperidinyl 2,2-dimethyl-7- benzofuran and benzopyrancarboxamide.

A pharmaceutically acceptable acid addition salt form or a stereochemically isomeric form thereof, wherein R1 and R2 represent hydrogen, or Rl and R2 taken together from a bivalent radical of formula -CH=CH-CH=CH- (a) -CH=C (Cl)-CH=CH- (b) or -CH=CH-C (Cl) =CH- (c) ; n represents 2,3 or 4; R3 represents hydrogen or methoxy ; m represents 1 or 2;

R4 represents hydrogen, amino or Cl. 3alkylcarbonyl- amino; and R5 represents hydrogen or halo, for the manufacture of a medicament for treating 5- HT3-mediated disorders.

US5288731 (August 1992, Rhone-Poulenc Rorer Pharmaceu- ticals Inc) 2,6-Methano-2H-1-Benzoxacincarboxylic acids, esters and amides. and its steroisomers, enantiomers, diasteroisomers and racemic mixtures with an amine of the formula H2N-Z; where R1 is hydrogen, an amino or alkylamino option- ally substituted with a protecting group halo or ha- loalkyl ; R2 is hydrogen, halo, sulfamyl, mono-and di-alkyl- sulfamyl or haloalkyl ; R'and R"are hydrogen or alkyl ; and Z is: and its racemic mixtures and stereospecific isomers.

Novel compounds which are 2,6-methano-2H-1-benzoxo- cincaboxamides having 5-HT. sub. 3-antagonist proper- ties including unique CNS, antiemetic and gastric prokinetic activities and which are void of any sig- nificant D. sub. 2 receptor binding affinity, thera- peutic compositions and methods of treatment of dis- orders which result from 5-HT. sub. 3 activity using said compounds. Processes for their preparation and the preparation of their intermediates are also dis- closed.

# WO9209284 2,6-Methano-2-H-1-benzoxacincarboxamides as 5-HT3 antagonists.

Other 5-HT3 antagonist compounds 'ex0611370 (October 1992, Smithkline Beecham Plc) Pyri- dine-3-Carboxylic Acid Esters Or Amides Useful As 5-HT3 Antagonists.

A compound of formula (I), or a pharmaceutically ac- ceptable salt thereof: (I) wherein RI is C1-6 alkoxy, C3_g cycloalkoxy or C3-8 cyclo- alkyl C1_4 alkoxy; R2 is hydrogen, halo, C1_6 alkyl, C1_6 alkoxy or amino optionally substituted by one or two C1_6 alkyl groups;

R3 is hydrogen, halo or C1_6 alkyl ; L is O or NH; and Z is a di-azacyclic or azabicyclic side chain; having 5-HT3 receptor antagonist activity.

Compounds of formula (I) and pharmaceutically accep- table salts thereof wherein Rl is C1-6 alkoxy, C3-8 cycloalkoxy or C3-8 cycloalkyl C1-4 alkoxy; R2 is hydrogen, halo, C1-6 alkyl, C1-6 alkoxy or amino op- tionally substituted by one or two C1-6 alkyl groups; R3 is hydrogen, halo or C1-6 alkyl ; L is O or NH; and Z is a di-azacyclic or azabicyclic side chain; having 5-HT3 receptor antagonist activity.

'ex0607233 (October 1991, Smithkline Beecham Plc) 3,9- Diazabicyclo (3.3.1) Nonane Derivatives With 5-HT3 Re- ceptor Antagonist Activity A compound of formula (I), or a pharmaceutically ac- ceptable salt thereof: wherein X is a phenyl group or a monocyclic 5 or 6 membered heteroaryl group, either of which group is optional- ly fused to a saturated or unsaturated 5-7 membered carbocyclic or heterocyclic ring; A is a linking moiety; Z is a carboxylic acyl group; and R is hydrogen or methyl; having 5-HT3 receptor antagonist activity.

Compounds of formula (I), and pharmaceutically ac- ceptable salts thereof, wherein X is a phenyl group or a monocyclic 5 or 6 membered heteroaryl group, either of which group is optionally fused to a satu- rated or unsaturated 5-7 membered carbocyclic or he- terocyclic ring; A is a linking moiety ; Z is a car- boxylic acyl group; and R is hydrogen or methyl; ha- ving 5-HT3 receptor antagonist activity.

W09308185 (January 1991, Smithkline Beecham Plc) N- Aryl-Nl-Azabicyclo-Ureas As 5-HT3 Antagonists A compound of formula (I) or a pharmaceutically ac- ceptable salt thereof: (I) wherein A1, A2, A3 and the carbon atoms to which they are attached form a 5-or 6-membered non-aromatic hete- rocyclic ring containing at least one-O-,-CO-or -N- ; R1 and R2 are hydrogen or C1_6 alkyl ; Y is hydrogen, halo, C1_6 alkyl or C1_6 alkoxy; L is O or NH; Z is an azabicyclic side chain; having 5-HT3 receptor antagonist activity.

Compounds of formula (I) and pharmaceutically accep- table salts thereof, wherein Al, A2, A3 and the carbon atoms to which they are attached form a 5-or 6-membered non-aromatic heterocyclic ring containing

at least one-0-,-CO-or-N- ; Rl and R2 are hydro- gen or C1-6 alkyl ; Y is hydrogen, halo, Cl-6 alkyl or C1-6 alkoxy; L is O or NH; Z is an azabicyclic side chain; having 5-HT3 receptor antagonist activi- ty.

# US4808588 (July 1987, Beecham Group) Heterocyclic ure- as and carbonates useful as pharmaceuticals. wherein Het is monocyclic heteroaryl having two adjacent carbon atoms, a and b, depicted in formula (I) se- lected from the group consisting of pyridine, pyri- midine, pyrazine, pyrrole, imidazole, thiophene, fu- ran, oxazole and thiazole; R1 and R2 are independently selected from hydrogen, halogen, CF3, C1_6 alkyl and C1_6 alkoxy; R3 is hydrozy, Cl_6 alkoxy, C3-7 alkenyl-methoxy, phenoxy or phenyl C1_4 alkoxy in which either phenyl moiety may be substituted by one or two C1-6 alkyl, C1_6 alkoxy or halo; CO2R6 wherein R6 is hydrogen or C1_6 alkyl, CONR7Rg or SO2NR7R8 wherein R7 and R8 are independently hydrogen or C1_6 alkyl or together are C4-6 polymethylene, NO2, (CH2) mOR9 wherein m is 1 or 2 and Rg is C1_6 alkyl or S (O) nR10 wherein n is 0,1 or 2 and R1o is C1_6 alkyl ; L is NH or O ; Z is a group of formula (a), (b) or (c):

(a) (b) (c) wherein n is 2 or 3; p is 1 or 2; q is 1 to 3; r is 1 to 3; and R4 or R5 is C1_4 alkyl.

Compounds of formula (I), or a pharmaceutically ac- ceptable salt thereof: ##STR1## wherein: Het is mo- nocyclic heteroaryl having two adjacent carbons atoms, a and b, depicted in formula (I) ; pl R. sub. 1 and R. sub. 2 are independently selected from hydro- gen, halogen, CF. sub. 3, C. sub. 1-6 alkyl and C. sub. 1- 6 Alkoxy; R. sub. 3 is hydroxy, C. sub. 1-6 alkoxy, C. sub. 3-7 alkenyl-methoxy, phenoxy or phenyl C. sub. 1-4 alkoxy in which either phenyl moiety may be substituted by one or two C. sub. 1-6 alkyl, C. sub. 1-6 alkoxy or halo; Co. sub. 2 R. sub. 6 wherein R. sub. 6 is hydrogen or C. sub. 1-6 alkyl, CONR. sub. 7 R. sub. 8 or SO. sub. 2 NR. sub. 7 R. sub. 8 wherein R. sub. 7 and R. sub. 8 are independently hydrogen or C. sub. 1-6 alkyl or together are C. sub. 4-6 polymethylene, NO. sub. 2, (CH. sub. 2). sub. m OR. sub. 9 wherein m is 1

or 2 and R. sub. 9 is C. sub. 1-6 alkyl or S (O). sub. n R. sub. 10 wherein n is 0,1 or 2 and R. sub. 10 is C. sub. 1-6 alkyl ; L is NH or O ; Z is a group of for- mula (a), (b) or (c); ##STR2## wherein n is 2 or 3; p is 1 or 2; q is 1 to 3; r is 1 to 3; and R. sub. 4. or R. sub. 5 is C. sub 1-4 alkyl ; having 5-HT. sub. 3 an- tagonist activity, a process for their preparation and their use as pharmaceuticals.

The most preferred 5-HT3 receptor antagonists for the present indications are tropanyl 3,5-dimethylbenzo- ate, MDL 72222, SDZ 216-525, ICI 169369, Zacopride, Tro- pisetron, Ramosetron, Ondansetron, Granisetron, Azase- tron, Dolasetron, and Cilansetron.

Brief Description of the Drawing Fig. 1 depicts the effects of 5-HT and the selective 5-HT4 agonist RS 67333 on the spontaneous tone in a human airway preparation in vitro. Note that 5-HT only gives a transient relaxation, while the selective 5-HT4 agonist causes a strong sustained relaxation effect.

Detailed Description of the Invention As appears from Fig. 1, the contractile component often manifests itself as a reduction or a complete eli- mination of the 5-HT induced relaxation, rather than in an increase of force from the control (pre-exposure) level. In the case of"specific"agonists to the 5-HT4 receptor, this sustained relaxing effect is achieved be- cause the contractile 5-HT3 receptor is not affected; only the relaxing 5-HT4 receptor is activated. In the case of antagonists to the 5-HT3 receptor, this effect is achieved due to direct blocking of the 5-HT3 receptor, whereby the specific agonists to the 5-HT4 receptor, such as 5-HT, can act without also causing contraction by the 5-HT3 receptor.

It should be noted that the medicament prepared ac- cording to present invention in each embodiment may op-

tionally include two or more of the above outlined com- pounds.

Further, in the embodiment when the compound having 5-HT3 antagonist activity is administered, optionally to- gether with complementary serotonin or derivatives there- of, a serotonin uptake inhibitor can be added with a view to amplifying the relaxing effect, e. g. fluoxetin, cita- lopram, paroxetine, sertralin, and fluvoxamine.

The typical daily dose of the medicament prepared according to the invention varies within a wide range and will depend on various factors such as the individual re- quirement of each patient and the route of administra- tion.

Said medicament may be prepared as a composition adapted either for administration via the respiratory tract or for oral, intravenous, intramuscular, intrathe- cal, topical, intraperitoneal or subcutaneous administra- tion, in association with one or more pharmaceutically acceptable carriers, diluents or adjuvants that are well known in the art.

Moreover, said medicament is preferably administered via the respiratory tract in the form of e. g. an aerosol or an air-suspended fine powder. However, in some cases useful alternative administration forms are tablets, cap- sules, powders, microparticles, granules, syrups, suspen- sions, solutions, transdermal patches or suppositories.

The subject-matter of the present invention was in- ter alia deduced from animal experiments, where a spe- cific behavior of the airway smooth muscle called "spontaneous tone"was examined. The spontaneous tone, which involves a spontaneous continuous contraction in the airway smooth muscle, was studied due to a suspicion that defective regulation of the spontaneous tone could be an important cause of the bronchoconstriction observed in asthmatic patients.

The examinations of the spontaneous tone were per- formed in accordance with the methods disclosed in the

thesis"Regulation of spontaneous tone in guinea pig tra- chea"by S. Skogvall, Department of Physiological Sci- ences, Lund University, 1999, which is incorporated here- in by reference. As evidenced by these examinations, the airways normally display a highly regular type of oscil- lating tone if exposed to physiological conditions, and this oscillating tone can be reversibly affected by ad- ministration of various substances. When the epithelium is removed, the preparations instead displays a strong, smooth type of tone.

In short, the animal experiments in said thesis showed that the spontaneous tone to a large degree is controlled by powerful regulating factors released from a specific type of airway epithelium cells, so called neu- roepithelial endocrine (NEE) cells.

Later experiments, not included in the thesis, have revealed that one of the regulating factors is serotonin (5-HT), which activiates 5-HTl, 5-HT3, 5-HT4,5-HT5, 5-HT6 and 5-HT7 as well as 5-HT2 receptors, in particular 5-HT2, 5-HT3, and 5-HT4 receptors.

Additional experiments have shown that when a small dose (1 pM) serotonin (5-HT) was added to denuded guinea- pig airway smooth muscle preparations displaying a strong, smooth spontaneous tone, the average force level was increased significantly, i. e. a transient contraction was observed. A contractile effect of serotonin (5-HT) on airways (smooth muscle) has previously been reported, see e. g. Skogvall, S., Korsgren, M., Grampp, W., J. Appl.

Phys., 86: 789-798,1999. However, when a large dose (100 M) of 5-HT was used, the spontaneous tone was, af- ter a transient contraction, significantly suppressed to a level of about half the force observed in control (drug-free) conditions. The spontaneous tone returned to approximately its normal pre-treatment level when the preparations were again exposed to control, drug-free conditions. Thus, it has now surprisingly been shown that serotonin causes a contraction of guinea-pig airways at

low concentrations and relaxation at high concentrations, i. e. a dual effect.

Similar experiments have also been performed on hu- man airway preparations from patients undergoing lobec- tomy or pulmectomy due to lung cancer. In humans, 5-HT was even more potent in relaxing the airway-smooth muscle than in guinea pig: even as low a concentration as 1 pM 5-HT induced a significant relaxation in preparations displaying a spontaneous tone.

Human airways are generally considered to display only a weak contraction when exposed to 5-HT. Neverthe- less, examinations on spontaneous tone on human in vitro preparations have shown that 5-HT indeed causes a con- traction also in this tissue. However, this contraction takes a longer time to develop than in guinea pig and the contractile effect is seen as a termination of the re- laxation, rather than an increase of tone from the base- line (pre-treatment). The relaxation, which has a maximum after 10-15 min, disappears gradually during the follow- ing 30-45 min (see Fig 1). In guinea pig trachea, the first 5-HT-induced effect is a contraction which reaches a maximum after approximately 10 min, and this is fol- lowed, within approximately 30 min, by a considerable re- duction of tone, i. e. a relaxation below the pre-treat- ment level. The transient nature of the 5-HT relaxation in human airways is most likely caused by a simultaneous activation of the fast relaxing 5-HT4 receptor, and an activation of the slower contracting receptor, which in human airways surprisingly has been found to be the 5-HT3 receptor. This is clear, because activation of the relax- ing 5-HT4 receptor by a substance that lacks 5-HT3 recep- tor activating properties (such as RS 67333), results in a relaxation that is persistent and not transient (see Fig. 1).

It has previously been suggested that 5-HT may be useful in the treatment of bronchoobstructive diseases.

In SU 1 701 320 it is suggested that the 5-HT, i. e. sero-

tonin, may be of use as an addition to standard beta2 re- ceptor stimulation for the treatment of acute asthma at- tacks. However, from the presently described experiments it seems clear that 5-HT alone is unsuitable, i. e. not effective or useful, for the treatment of said diseases, e. g. asthmatic disorders, because of the only transient relaxing effect by 5-HT (see Fig. 1). Also, reports from other groups indicate that 5-HT if anything tends to in- duce a weak bronchoconstriction rather than a relaxation in asthmatics (see e. g. Dupont et al. 1999, Eur Resp J 14: 642-649 and Takahashi et al. 1995, Am J Respir Crit Care Med 152: 377-380, which are incorporated herein by reference).

In summary, it has now been discovered that agonist action on the 5-HT4 receptor results in a relaxing ef- fect, whereas agonist action on 5-HT3 receptors results in a contractile effect. In conclusion, the dual effect of 5-HT is most likely a result of its agonist action on the relaxing 5-HT4 receptor as well as on the contracting 5-HT3 receptor.

It was also deduced from these experiments that com- pounds having agonist activity to the 5-HT4 receptor, while having only low or no agonist activity to a 5-HT3 receptor, therefore are useful as agents for treatment of disorders involving airway constriction, as defined above.

In the above mentioned experiments it has been shown that compounds having antagonist activity to a 5-HT3 re- ceptor are useful as agents for treatment of disorders involving airway constriction, since they are capable of blocking the contractile effect of a compound having ago- nist activity to a 5-HT3 receptor. Administration of se- rotonin, a serotonin reuptake inhibitor or any other sub- stance having 5-HT4 receptor agonist activity results in increased relaxation of the bronchi.