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-HT1 type 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 activity 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.

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 aspect to a composition comprising a combination of compounds com- prising a) one or several compounds with agonist activity to the 5-HT4 receptor, and b) one or several compounds with antagonist activity to the 5-HT3 receptor.

In another aspect, the present invention relates to a composition as defined above for use as a medicament., In still another aspect it relates to the use of said composition in the manufacture of a medicament for therapeutic or prophylactic treatment of a human or ani- mal body, wherein the medicament is intended for treat- ment of disorders involving airway constriction, such as asthma, chronic obstructive pulmonary disease, emphysema and chronic bronchitis.

In a preferred embodiment said compound with 5-HT4 receptor agonist activity included in the composition is 5-HT or a derivative thereof with agonist activity to the 5-HT4 receptor. The combination of a) one or several 5-HT4 receptor agonist (s), and b) one or several 5-HT3 receptor antagonist (s) increases airway relaxation compared to the use of either compound alone, wherein said combination has the capacity of reducing the abnormal airway con- striction by at least. 30%, preferably at least 60%, and most preferably at least 90%.

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 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

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 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- <BR> <BR> <BR> quinoxalinecarbonitrile, 4-Ph-N-Me-quipazine, 5-((dimet- hylamino) methyl)-3- (1-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, GYKl- 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 listed.

N-substituted benzamides Metoclopramide QX 222. The compound is an analogue to lidocain, 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> <BR> <BR> <BR> -kloro-o-anisamtd

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 = 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, R (+)-zacopride 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 (-)- 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 SC-52491 (Azanoradamantane) SC-53116 ((l-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- (1-methyl-2-oxopropoxy) ben- zamide). Batanopride 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 Bisindoles 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 HCl) o BRL 47204 FK 1052 ( (+)-8, 9-dihydro-10-methyl-7- [ (5-methyl-lH- imidazol-4-yl) methyl] pyrido [1, 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 Exy 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- methoxytryptamine-induced contractions of guinea pig isolated ileum. FK1052, ondansetron and granisetron concentration-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 ondan- setron (6.79) and granisetron (7.86), respectively.

FK1052, unlike ondansetron and granisetron, inhib- ited the 5-HT4-mediated component of concentration- response curve to 5-HT. Furthermore, FK1052 sup- pressed 5-methoxytryptamine, a 5-HT4 agonist-induced contraction in a concentration-dependent but insur- mountable manner.

RU 24969 (5-methoxy-3 (1, 2, 3,6-tetrahydropyridin-4- yl)-1 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=Zofran Ondansetronum INN (Ondansetron) 2,3-Dihydro-9-metyl-3-[(2-metyliI} iidazol-l-yl) metyl] karbazol 4 (1H<BR> -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 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. 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; Neurocrastroenterol 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: (2,6,8,9aß)-octahydro-3-oxo-2,6-methan- 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 sponta- neously active dopamine cells in the substantia ni- gra pars compacta (SNC or A9) and ventral tegmental area (VTA or A10). This was accomplished using the standard extracellular single unit recording tech- niques. 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 ^ Interestingly, the chronic administration of 1.0 mg/kg LY 277359 increased the number of A10, but not A9 dopamine cells. In contrast, chronic treatment with 10 mg/kg selectively decreased the number of spontaneously active A10 dopamine cells. <BR> <BR> <BR> <BR> <BR> <P> GR65630 (3-(5-methyl-lH-imidazol-4-yl)-1-(1-methyl-<BR> <BR> <BR> <BR> lH-indol-3-yl)-1-propanone) 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 10 (8) 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 +/- 0.21 fmol/mg protein). of high affinity (Kd +/- 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/l, Kd2 20.1 +/-9.7 nmol/1 ; 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)-1H-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 inhibitors of serotonin-induced bradycardia (5-HT3-mediated ac- tivation of the von Bezold Jarisch reflex). 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 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.

QICS 205-930

3-Tropanyl-indole-3-carboxylate methiodide. It is also called ICS 205-930.

Indalpine (3-[2-(4-piperidinyl) ethyl]-lH-indole) 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, A, Caldero JM, Roca J, Lasheras B, Del Rio J Psycho- pharmacology (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 pro- duce any significant effect on spontaneous motor ac- tivity 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-IH-benzimidazole-l- carboxamide hydrochloride)

2-piperazin-benzimidazole 2-piperidin-benzimidazole Cilansetron (l-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 (Droperidal)<BR> <BR> 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-3 93), (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 _ 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 ita-

setron: establishing the effective dose range for 'the prophylactic control of acute emesis in cancer patients undergoing high-dose cisplatin chemothera- py., Patoia L, Del Favero A, Giglietti A,. Malacarne P, Donati D, Indelli M, Bensi G, Palladino MA, Cigarini P, Kempe R, Voigt T; Clin Oncol (R Coll Ra- diol) 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-hydroxytryptamine3 (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/kgbody 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. <BR> <BR> <P> Lurosetxon<BR> <BR> Mirisetron =WAYS00579 Ramosetron =YM 060. [(R)-5-[(1-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) - hexahydro-lH-1, 4-diazepin-6- yl]-1H- indazole-3- carboxamide dihydrochloride). The compound is also a diazepin derivative.

# DAT582 (the compound is the R-enantimer of compound 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-1H-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-in- duced bradycardia with an ED50 value of 0.25 micro- gram/kg i. v., whereas the (S) enantiomer was without effect even at 1000 micrograms/kg i. v. In antagoniz- ing 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 micrograms/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 sug- gest 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 [3,3,1] 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 [3t3l13non-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. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> BRL 43694=Kytril =Granzsetron<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> Granisetronum tNN (Granisetron) I-Metyl-N-(endo-9-metyl-9-azabicyklo[3.3.1]non-3-yl)-1H-inda zol-3- -karbmamid

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 _ 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 SHT3 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, fluvox- amine etc.) is associated with gastrointestinal dis- comfort (particularly nausea and vomiting) as a ma- jor 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 _ 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; Bur 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-211-000- Benzofuranes, benzooxazines, benzo (di) azepines, bensothi- azepines A general structure for these classes of compounds is : # 2,3-dihydro-benzofuran-7-carboxamides. X1=C, X2=0 ; 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. Ingår i Leponex, Novartis Clozapinum INN (Klozapin) 8-Kloro-11-(4-metyl-1-piperazinyl)-5H-dibenso[b,e][1,4]diaze pin * Amitryptiline Amitriptylinum INN (AmitriptyUn) <BR> 5-(3-Dimetylaminopropyliden)-10,11-dihydro-5H-<BR> <BR> <BR> <BR> -dibens[a,d]cyklohepten

Cyproheptadine. Is the active ingredient of Periac- tin, MSD Diltiazem Is the active ingredient in Cardizem, Pharmacia Cor- poration Diltiazemum INN (Diltiazem) (rS, 3S)-3-(Acetyloxi)-5-[2-(dimetylamino)etyl-2-(4-metoxifenyl)- 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-Metyl-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-1-one) 'SEC 579 RS 56532 ( (S)-6-amino-5-chloro-2- (l-azabicyclo- [2,2,2] octan-3-yl) 2, 3-dihydro-1H-benz [de]- isoquinoline-1, 3-dione hydrochloride) <BR> <BR> 3- (l-piperazinyl)-2-quinoxalinecarbonitrile<BR> <BR> # 3-(4-allylpiperazin-1-yl)-2-quinoxalinecarbonitrile e 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)-l-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-lH-benzo [de]- isoquinoline-hydrochloride Quipazine (2- (1-piperazinyl)-Quinoline) N-metylquipazin 4-Ph-N-Me-quipazine RS-42358-197 E (S)-N- (l-azabicyclo [2.2.2] oct-3-yl)- 2,4,5,6-tetrahydro-1 H-benzo [de] isoquinolin-l-one hydrochloride] RS-056812-198 (R)-N- (quinuclidin-3-yl)-2- (l-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-1H-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)-1-azabicyclo [2.2.2] oct-3-yl]- 2,3,3a, 4,5,6-hexahydro-1-oxo-1H-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-Hydrox!cty!)-L-piperazmy!)propy!j-2- -trifluorometylfentiazin

# 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 Kacraku 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-(1-methyl-lH-indol-3- yl)-1,2,4-oxadiazole 1, 4-Benzoxazin-8-Carboxamide

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-hydroxy- phenyl)-beta-methyl-1-piperidine-ethanol tartrate) (ifenprodil tartrate) MCPP (Meta-chlorophenylpiperazine) (mCPP) MK-212 (6-chloro-2- [l-piperazinyl]-pyrazine) # Metergoline ([[(8{BETA})-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 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 stimulation, as indicated by the more pronounced ef- fect of pulses delivered at 5 Hz for 24 s instead of 72 s or 120 s. McNeil-A-343 (4-(m-chlorophenyl- carbamoyloxy)-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- (1-methyl-1H-indol-3-yl)-1, 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: _ 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), ketanserin (0.01-10 mg/kg) and sulpiride (32-320 mg/kg) dose- dependently attenuated the psychological stress le- sion formation, and the activity was arranged in the order of their in vitro binding affinities for the 5-HT3, but not 5-HT1A or 5-HT2 receptors. In con- trast, a peripherally acting 5-HT3 antagonist, M- 840 ( [ [3- (l-methyl-lH-indol-3-yl)-l, 2,4-oxadiazol-5-

yl]-methyl] trimethyl-ammonium iodide), dopamine act- ing compounds, haloperidol and FR64822 [N- (4-pyri- dylcarbamoyl) amino-ll2l3ì6-tetrahydropyridine) l and antisecretory drugs, atropine and famotidine, mini- mally affected the lesion formation.

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 aryl- piperazines at 5-HT3 receptors. Arylpiperazines, as mentioned earlier, are relatively nonselective agents ; however, many bind at 5-HT3 receptors with significantly higher affinity that phenylbiguanide.

We identified some structural similarities between the arylpiperazines and phenylbiguanide and, in col- laboration with Milt Teitler, made a series of hy- brid analogs that we hoped would bind with higher affinity 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. vou. edu/raglserotorun/-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-a] thieno [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-1- 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 NlE-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 EP0417746 (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

Rl 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 C1-6 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 O ; 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.

'ex0430190 (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 C1-6 alkoxy (optionally substituted with phenyl), lower CI-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, C3-8 cyclo- alkyl, C3-8 cycloalkyl-C1_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 CI-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, C1_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 R1 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.

# EP0711299 (May 1994, Pharmacia S. p. A) Azabicycloalkyl Derivatives Of Imidazol (1, 5-A) Indol-3-One As 5HT 3 An- tagonists (I) wherein each of R, R1 and R2, which may be the same or different, is hydrogen, halogen, hydroxy, cyano, C1- C6 alkyl, CF3, C1-C6 alkoxy, C1-C6 alkylthio, for- myl, C2-C6 alkanoyl, carboxy, C1-C6 alkoxycarbonyl, nitro,-N (R4 R5) in which each of R4 and R5 inde- pendently is hydrogen, C1-C6 alkyl, formyl or C-Cg 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, Cl--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,ishydrogen, halogen, hydroxy, cyano, C1-C6 alkyl, CF3, C1-C6 alkoxy, C1-C6 alkylthio, formyl, C2-C6 alkanoyl, carboxy, C1-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-C5 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, C1-C6 alkoxy, Cl-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, C1-6 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 R10, which. may be the same or different, is hydrogen or C1-C6 alkyl, R9 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 (1), 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, C1-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-SO2 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.

EPO581388 (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 Cul-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; R1 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.

"ex0392663 (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 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_, C1-6 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 Cl-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 C1-6 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.

RU2059023 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 Cl_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: &num &num STR2&num &num 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

wherein Rl 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 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, R1 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, C1-4 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, C1-6 alkyl or Cul-6 alkoxy, or R2 is in the 4- position and is hydrogen, halogen, CF3, C1-6 alkyl, C1-7 acyl, C1-7 acylamino, phenyl op- tionally substituted by one or two C1-6 alkyl, C1-6 alkoxy or halogen groups, or amino, amino- carbonyl or aminosulphonyl, optionally substi- tuted by oone or two C1-6 alkyl or C3-g cyclo- alkyl groups or by C4-5 polymethylene or by phenyl, CI-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, C1-6 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 0, 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 ;

X1 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.

'ex0482939 (October 1991, Ono Pharmaceuticals) Isoqui- nolinone derivative. wherein each substituent R1 is the same or different and is hydrogen, halogen, Cl_4 alkyl, C1-4 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 R1 is hydrogen, C1-4 alkyl, C1-4 alkoxy or a group of formula :-NR4R5 wherein R4 is hydrogen, halogen, Cl-4 alkyl or C2-4 alkanoyl and R5 is hydrogen, C1-4 alkyl or benzyl; R2 is hydrogen or C1-4 alkyl ; R3 is hydrogen or Cl-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-alkyla-mino 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

R1 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 (C1) =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.

W09209284 2, 6-Methano-2-H-1-benzoxacincarboxamides as 5-HT3 antagonists.

Other 5-HT3 antagonist compounds EP0611370 (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 R1 is C1-6 alkoxy, C3-8 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 R1 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.

EP0607233 (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: (I)

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-N1-Azabicyclo-Ureas As 5-HT3 Antagonists A compound of formula (I) or a pharmaceutically ac- ceptable salt thereof: (I) wherein Al, 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-0-,-CO-or -N- ;

R1 and R2 are hydrogen 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-HT 3 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-6alkyi or Cl-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- <BR> <BR> 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, C1-6 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, CONR7R8 or SO2NR7R8 wherein R7 and Rg are independently hydrogen or C1-6 alkyl or together are C4-6 polymethylene, NO2, (CE2) mORg wherein m is' 1 or 2 and Rg is C1-6 alkyl or S (O) nR1o wherein n is 0,1 or 2 and Rio is C1-6 alkyl ; L is NH or 0 ; 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); &num &num STR2&num &num 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.

Several known substances are able to stimulate the relaxing 5-HT4 receptor, without significantly activating the constricting 5-HT3 receptor, thereby causing airway relaxation. Such agonist compounds are exemplified below.

Most of the different 5-HT4 agonists can be referred to specific groups, where each group contains a common structural element. The largest group, and also the basis for several others, are the benzamides. They all contain the structural element 4-amino-5-chloro-2-methoxy benz- amide and are further developments of the first 5-HT4 agonist, metoclopramide, with the structural formula:

Another common feature is a basic nitrogen in a side chain from the amide nitrogen. This basic nitrogen is of- ten a part of a sterically locked system. Examples of substances from this group are: BRL 20627, BRL 24682, BRL 24924, Cisapride, Metoclopramide, ML-1035, Mosapride, R076186, Renzapride, RS 67506 (N- [2- [4- [3- (4-amino-5- chloro-2-methoxyphenyl)-3-oxopropyl]-1-piperidinyl]- ethyl]-methanesulfonamide monohydrochloride), Cinita- pride, SB 205149, SC-49518, SC-52491, SC-53116 (4-amino- <BR> <BR> <BR> <BR> 5-chloro-N- [ [lS, 7aS)-hexahydro-lH-pyrrolizin-1-yl] methyl]- 2-methoxybenzamide), SDZ 216,454, TKS 159, Y-34959, YM-09151, YM-47813, Zacopride, Zelmac (SDZ HTF919; tegaserod).

Thus, a structure-activity relation study performed indicates that a benzene ring and a basic nitrogen in the same plane as the ring and at a distance of 81 A from the center of the benzene ring is required. The nitrogen should be locked in that position with a view to obtain- ing selectivity. for the 5-HT4 receptor. A lipophilic group on the basic nitrogen also seems to be important for the agonistic action. Further, a heteroatom with a free electron pair close to the indole nitrogen in trypt- amine seems to give a positive effect. Benzoic acid esters are modifications of the benzamide theme:

The only difference is that the amide group has been replaced with an ester group. Examples are ML 10302 (4- amino-5-chloro-2-methoxy-benzoic acid-2- (1-piperidinyl)- ethylester), RS 57639, and SR 59768.

Another variant of the basic theme is to introduce the methoxy group into a ring, thereby arriving at a 2,3- -dihydro-bensofuran-7-carboxamide group. Examples are ADR 932, Prucalopride (=R 093877); and SK-951. Benzofuranes and benzotiophenes are also contempla- ted, as well as the benzodioxan

SB 204070 Still another variant is based on the discovery that the benzoic acid antagonist RS 23597 (an ester) was transformed to an agonist if it was converted to a ketone e. g. RS 67333 and RS 17017.

The basic concept also applies for naphtalimides, e. g. RS 56532.

Benzindolones are also contemplated.

The amide function may also be replaced with an oxa- diazol ring. e. g. YM-53389 Benzimidazolone-l-carboxamides e. g.'BIMU 1, BIMU 8 (2,3-dihydro-N- [ (3-endo)-8-methyl-8- azabicyclo [3.2.1) oct-3-yl)-3- (1-methylethyl)-2-oxo-lH- benzimidazole-1-carboxamide monohydrochloride)., DAU 6215, and DAU 6236, are also contemplated.

The carboamides

are also contemplated.

Some indols are also useful as 5-HT4 agonists, e. g.

5-methoxytryptamine, 2-methylserotonine, and 5-hydroxy- -N, N-di-methyltryptamine.

It should be noted that many of these substances may be quaternized on the nitrogen in the side chain without losing the activity.

Benzokinolinones According to the present invention, the tollowing compounds can also be used as agonists to the 5-HT4 recep- tor: 5-carboxamidotryptamine (5-CT), with the structural formula: 5-HT, 3-Me-8-OH-DPAT, 8-OH-DPAT (8-hydroxy-2-dipropyl- aminotetralin), RS 23597-190, RS 67532, RU 28253, SB 204070, Bufotenine, 5-MeO-N, N, DMT, GR 113,808, a-me- tyl-5-HT, arylcarbamate derivatives of 1-piperidineetha- nol, 4-amino-5-chloro-2-methoxybenzoic acid esters, <BR> <BR> 4-amino-5-chloro-2-methoxy-N-((2S, 4S)-1-ethyl-2-hydroxy- methyl-4-pyrrolidinyl) benzamide (e. g. TKS 159), thiophene

carboxamide derivatives 3 (a-j), 5. azabicyclo (x. y. z) derivatives, 2-piperazinylbenzoxazole derivatives, 2-piperazinyl-benzothiazole derivatives (e. g. VB20B7), Sandoz compound lb, clebopride, 2-piperidinmethylethers of benzimidazole, zelmac, 2-[1-(4-piperonyl)piperazinyl]- benzothiazole, benzpyranes, substituted dihydrobenzofuran derivatives with the following structure (see EP 0 766 680) wherein R1, R2 and R3 are, each independently, hydrogen, C1-C6 alkyl, halogen, hydroxy, C1-C4 alkoxy, amino, C1-C4 alkylamino or Cl-C4 di-alkylamino; X is O, NH or CH2 ; Z is a group (a), (b), (c) or (d) (b)

(c) (d) wherein n is 1,2,3 or 4; m is zero or 1; q is zero, 1 or 2; R4 is hydrogen, C1-C6 alkyl, benzyl, cyclohexyl- methyl or-CH2-CH2-SO2NH-R6 in which R6 is C1-C6 al- kyl or benzyl; R5 is C1-C6 alkyl ; and T is halogen; provided that, when Z is defined under (c), then X is 0 or CH2 ; or a pharmaceutically acceptable salt thereof, for use as a 5-HT4 receptor agonist..

Compounds with the following indazole structure: (see JP O N % % Me Ct NH ,. fl°I (I) I n Me

This 5-HT4 receptor agonist contains a new diazabi- cyclo derivative of formula I (R is a 4-6C cycloalkyl) or its pharmaceutically permissible salt as an active compo- nent. The compound of formula I is especially preferably N- (endo-3, 9-dimethyl-3,9-diazabicyclo [3,3,1] non-7-yl)-1- cyclobutylindazol-3-carboxamide. The 5-HT4 receptor ago- nist is especially an agent for the yl)-1-cyclobutyl- indazol-3-carboxamide. The 5-HT4 receptor agonist is especially an agent for the oxidiazole derivatives (see W095/32965) (a) An oxadiazole derivative represented by general for- mula (I) and useful as a 5-HT4 receptor agonist, a phar- maceutically acceptable salt thereof, or a medicinal com-

position thereof wherein one of R1 and R2 represents (a) and the other represents-A-Het; A represents a mere bond or lower alkylene; Het represents a monocyclic, fused or cross-linked heterocyclic group containing at least one nitrogen atom and bonded to A at the ring carbon atom; and R3 represents lower alkyl, lower alkenyl or lower al- kynyl.

4-amino-5-chloro-2-methoxybenzoic esters (see W095/25100) wherein n is 1 or 2, R. represents a hydrogen or halogen atom or a cyano, hydroxy, (Cl-C4) alkyl, (C1-C4)- alkoxy, carboxy, (Cl-C4) alkoxycarbonyl, aminocarbonyl, mono (Cl-C4) alkylaminocarbonyl, di (Cl-C4) alkylamino- carbonyl, mono (Cl-C4) alkylamino, di (Cl-C4) alkylamino, (Cl-C5) alcanoylamino or (Cl-C5) alcanoyl group, and when R is a hydrogen atom the dashed liine may represent a dou- ble bond, as well as pharmaceutically acceptable salts or solvates and quaternary ammonium salts for the prepara- tion of medicaments having 5-HT4 agonistic Oxazabicyclo derivatives (see EP 0 623 621)

wherein R is a hydrogen atom, a halogen atom, a halo (C1-C6) alkyl group, a (Cl-C6) alkoxy group, a ni- tro group, a hydroxyl group or an amino group, n is 1 or 2, the R groups being the same or different when n is 2, and Ar represents a radical of formula (II), (III), (IV), (V), (VI), (VII) or (VIII)

wherein Ra to Re are independently a hydrogen atom, a halo- gen atom, a hydroxyl group, a (C1-C6) alkoxy group or a (C1-C8) alkyl group; R1 is a hydrogen atom, a (C1-C8) alkylgroup, a (C3-C8) alkenyl group, a (C3-C8) alkynyl group, a (C3-C6) cycloalkyl group, a (C3-C6) cycloalkyl (C1-C6)- alkylgroup, a (C1-C6) alkoxy (C2-C5) alkyl group, a (C3-C6) oxoalkyl group, a (Cl-C6) alkoxycarbonyl- (C1-C6) alkyl group, a (Ci-Cg). alkoxycarbonyl group, a (C1-C6) alkanoyl group,. a di (C1-C6) alkylamino (C2-C6)- alkyl group, a hydroxy (C2-C6) alkyl group, a halo (C1-C6) alkyl group, a cyano (C1-C6) alkyl group, 4,6- diamino-2-triazinylmethyl group or a benzyl group optionally substituted by one or two substituents selected from the group consisting of halogen, (C1-C6) alkoxy, nitro, hydroxyl and amino; Z is CH or N; R2, R3, R5, R6, Rg, Rlo and Ril are independently a hydrogen. atom or a (C1-C6) alkyl group; R4 is a (C1-C6) alkyl group, a pyridyl group or a phenyl group optionally substituted by halogen, C1- C6 alkyl, Cl-C6 alkoxy or trifluoromethyl; Q is N, S or 0 ; X is a halogen atom; Y is NH2 or a phthalimido group ; R7 is a hydrogen atom; R8 is a hydrogen atom or a (C1-C4) alkyl group; or R7 and R8 together form a single bond.

Compounds having the following structure (see EP 0 908 459)

wherein A-D is C=N or N-C=O ; n is 1,2,3,4 or 5; R is hydrogen, halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, cyano, trifluoromethyl, carboxamido, mono or di (C1-C4 alkyl) carboxamido; RI is hydrogen, C1-C6 alkyl, C3-C6 cykloalkyl, or substituted C3-C6 cycloalkyl. ; R2 and R3 are each hydrogen or taken together form a bridge of 1 to 4 methylene units ; X is OR4 or NR4R5 ; R4 is hydrogen, Cl-C6 alkyl, C3-C6 cycloalkyl, sub- stituted C3-C6 cycloalkyl, phenyl, substituted phenyl, (C1-C6 alkyl) CO, benzoyl, substituted ben- zoyl, tricyclo[3, 3,1, 13.7]decan-1-oyl, or S (0) 2R6 ; R5 is hydrogen or R4 and R5 together with the nitro- gen to which they are attached form a 1-pyrrolidi- nyl, l-piperazinyl, 1, 2,3,4-tetrahydro-2-isoquinoli- nyl, 2,3-dihydro-1-indolinyl, 4-morpholiinyl, 1- piperidinyl, 1-hexamethyleneiminyl, or phthalimidyl ring ; R6 is C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, phenyl, or substituted phenyl; or a pharmaceutically acceptable salt thereof. Benzamide derivatives having the following structu- res

having the substituents specified in WO 97/10207 having the substituents specified in W095/18104. and (see JP11001472) (II)

(III) This novel compound is represented by formula I [R1 is a halogen; R2 is H, a lower alkyl ; R3 is H, a lower alkyl, a lower alkanoyl; R4 is a lower alkoxy; a is 1 or 2; b is 2 or 3; i is 1 or 2; j is 2 or 3; k is 0,1,2; X is- (CH2) m- (m is 1 or 2); A is a group of formula II or formula III (p is 1,2,3; q is 0,1,2,3; r is 0,1,2; R5a is H, a lower alkyl ; R5b is H, a lower alkyl)], typi- cally 4-amino-N- [l- [1- (3-aminopropyl)-4-piperidinyl- methyl]-5-chloro-2-methoxybenzamide.

Indazolecarboxamides (see WO 96/33713) wherein: R is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl ; R1 is hydrogen, halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy or alkylthio, cyano, trifluoromethyl, carbox- amido, mono-or di (C1-C4 alkyl) carboxamido;

m, n and o are independently 0-5, provided that the sum of m, n and o is 2-5; R2 is hydrogen or C-Calkyi ; R3 and R4 combine with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-pipera- zinyl, 1,2,3,4-tetrahydro--isoquinolinyl, 2,3-di- hydro-1-indolinyl, 4-morpholinyl, 1-piperidinyl or 1-hexamethyleneiminyl, substituted with phenyl, naphthyl, (phenyl or naphthyl) (C1-C3 alkyl), (phenyl or naphthyl) (C1-C3 alkanoyl), amino, mono-or di (C4-C4 alkyl) amino, or a group of the formula -NH-Y-R5; provided that a piperazinyl or morpholinyl group may not be substituted with amino, mono-or di (Ci-C4 alkyl) amino, or-NH-Y-R5 ; wherein a phenyl or naphthyl group is unsubstituted or substituted with 1-3 halo, Cl-C3 alkyl or Cl-C3 alkoxy groups; Y. is carbonyl, sulfonyl, aminocarbonyl or oxycarbo- nyl; (+)-norcisapride of formula (I) and compounds (V), and its pharmaceutically acceptable acid additions salts; compounds of formula (V), wherein the piperidine ring has the absolute configuration (3S, 4R) and PG is methyloxy- carbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl or phenylmethyl. (see WO 99/02496) (I)

Thiophene carboxamide, 5-HT4 agonist Synthesis of thiophene caboxamide derivatives as seroto- nin 5-HT4 receptor agonists. Monge A, Palop J, Pérez S, Oset C, Lasheras B; Farmaco 1997 Feb, 52: 2: 89-92.

New thiophene carboxamide derivatives 3 (a-j) were synthesized as serotonin 5-HT4 receptor agonists.

Preliminary results showed that the compounds 3a, 3d, 3e and 3f caused concentration dependent relaxa- tion of carbachol-induced contraction in tunica mus- cularis mucosae in rat oesophagus.

(I) EP 0 957 099 A2 or the pharmaceutically acceptable salt thereof, wherein Z is oxygen, S (0) m wherein m is 0,1 or 2; or NQ wherein Q is hydrogen, (C1-C6) alkyl or phenyl; X is hydrogen, chloro, fluoro, bromo, iodo, hydroxy, nitro, cyano, (C1-C6) alkyl, trifluoromethyl, (C1-C6) alkoxy, (C1-C6) alkyl S (O) a wherein a is 0,1 or 2; or phenyl wherein the phenyl group is option- ally substituted by hydrogen, halo, hydroxy, nitro, cyano, (Cl-C6) alkyl, trifluoromethyl, (C1-C8) alkoxy, or (Cl-C6) alkyl S (O) b wherein b is 0,1 or 2;

Y is wherein M is oxygen or sulfur ; X2 is hydrogen fluoro, chloro, trifluoromethyl, (C1-C6) alkyl, (Ci-C6) alkoxy or (C1-C6) alkyl S (O) c wherein c is 0,1 or 2; R1 is a group of formulas

wherein the broken line represents an optional dou- ble bond; p is 1,2 or 3; E is ocygen or S (O) d wherein d is 0,1 or 2; R8 is selected from the group consisting of hydro- gen, (C1-C6) alkyl optionally substituted with (C1-C6) alkoxy or one to three fluorine atoms, or [(C1-C4) alkyl] aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl (CH2) q-, wherein the hetero- aryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C1-C6) alkyl, (C1-C6) alkoxy, trifluoromethyl, cyano and (Ci-Cg) alkyl S (O) e wherein e is 0,1 or 2; R7 is selected from the group consisting of hydro- gen, (C1-C6) alkyl, [(C1-C4) alkyl] aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl- (CH2) r-, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzothiazolyl and r is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more sub- stituents independently selected from the group con- sisting of chloro, fluoro, bromo, iodo, (Cl_C6)- alkyl, (C1-C6) alkoxy, trifluoromethyl,-C (=O)-(C1- C6) alkyl, cyano and (C1-C6) alkyl S (O) f, wherein f is 0,1 or 2: or R6 and R7 taken together form a 2 to 4 carbon chain; R8 is hydrogen or (C1-C3) alkyl;

R9 is hydrogen or (Cl-C6) alkyl; or R8 and R9, together with the nitrogen atom to which they are attached, form a 5 to 7 membered het- eroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxy-' gen; R10 is hydrogen or (Cl-C6) alkyl; R2 is hydrogen, (Cl-C4) alkyl, phenyl or naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independ- ently selected from chloro, fluoro, bromo, iodo, (Cl-C6) alkyl, (Cl-C6) alkoxy, trifluoromethyl, cyano and (C1-C6) alkyl S (O) g wherein g is 0,1 or 2; and R3 is- (CH2) tB, wherein t is zero, one, two or three and B is hydrogen, phenyl, naphthyl or a 5 or 6 mem- bered heteroaryl group containing from one to four heteroatoms in the ring, and wherein each of the foregoing phenyl, naphthyl and heteroaryl groups may optionally be substituted with one or more substitu- ents independently selected from chloro, fluoro, bromo, iodo, (C1-C6) alkyl, (Cl-C6) alkoxy, (C1-C6)- alkoxy-(C1-C6) alkyl, trifluoromethyl, trifluorometh- oxy, cyano, hydroxy, COOH and (C1-Cg) alkyl S (0) h wherein h is 0,1 or 2.

Piperazinyl benzothiazole, 5-HT4 agonist VB20B7, a novel 5-HT-ergic agent with gastrokinetic ac- tivity. I. Interaction with 5-HT3 and 5-HT4 receptors.

Ramirez MJ, Garcia-Garayoa E, Romero G, Monge A, Roca J, Del Rio J, Lasheras B J Pharm Pharmacol 1997 Jan, 49: 1: 58-65.

This study describes the in-vitro interaction of the gastrokinetic agent 2 [1- (4-piperonyl) piperazinyl]- benzothiazole (VB20B7) with the 5-hydroxytryptamine 5-HT3 and 5-HT4 receptor subtypes, using functional as well as radioligand binding studies. The benzami- de derivative cisapride was used as a comparison. In radioligand binding assays VB20B7 showed, like cisa- pride, a weak affinity at 5-HT3 receptors from rat cerebral cortex. The new compound lacked any affini- ty at other 5-HT receptors or at dopaminergic D2 re- ceptors, whereas cisapride showed-high affinity for the 5-HT4 receptors from guinea-pig hippocampus and moderate affinity at dopaminergic D2 receptors. In the non-stimulated guinea-pig ileum, the concentra- tion-response curves to the specific 5-HT3 agonist 2-Me-5-HT and to 5-HT were shifted to the right by VB20B7. In the rat oesophagus tunica muscularis mu- cosae preparation (TMM), VB20B7 was evaluated for its activity at 5-HT4 receptors. VB20B7 behaved as a 5-HT4 receptor agonist, inducing a concentration- dependent relaxation of the preparation precontrac- ted with carbachol. In this preparation, VB20B7 and cisapride were able to stimulate adenylate cyclase activity, an effect probably mediated through acti- vation of 5-HT4 receptors, as can be inferred from the blockade by the 5-HT4 antagonist, tropisetron, of the enhanced cAMP formation. However, consistent with the lack of affinity at central 5-HT4 recep-

tors, VB20B7 did not stimulate cAMP formation in guinea-pig hippocampal slices. VB20B7 also caused an increase in the twitch response of the transmurally stimulated guinea-pig ileum, although at a concen- tration higher than cisapride. This effect was blocked by desensitisation of the 5-HT4 receptor with 5-MeOT and also by the 5-HT4 receptor antago- nist tropisetron. Both VB20B7 and cisapride increa- sed the K (+) evoked acetylcholine release in this preparation. The results show that VB20B7 possesses affinity for 5-HT4 receptors located in the rat TMM and guinea-pig ileum preparations, but is devoid of affinity at central 5-HT4 receptors. In addition, VB20B7 shows low to mederate affinity at both cen- tral and peripheral (enteric) 5-HT3 receptors. The interaction of VB20B7 with the peripheral 5-HT4 and 5-HT3 receptors may be relevant for the gastrokine- tic effects of the new compound.

VA21B7 (3- [2- (4'-piperonylpiperazinyl) indolyl]- caboxaldehyde). The pharmacology of VA21B7 : an atypi- cal 5-HT3 receptor antagonist with anxiolytic-like properties in animal models. Artaiz I, Romero G, Zazpe A, Monge A, Caldero J'ill, Roca J, Lasheras B, Del Rio J Psychopharmacolocr (Berl) 1995 Jan, 117 : 2: 137-48.

WO 95/32965 2-[4-[3-(4-aryl/heteroaryl-1-piperazineyl)propoxy]phenyl]- 2H-benzotriazoles and their N-oxides as ligands for sero- toning and dopamine receptors., Sparatore A, Goegan M, Cagnotto A, Sparatore F; Farmaco 1999 Jun 30, 54: 6: 402-10.- A small set of 2-4- [3- (4-aryl/heteroaryl-pipera- zinyl) propoxy] phenyl-2H-benzo tri azoles and cores-

ponding N-oxides were prepared. The synthesized com- pounds were able to bind on some serotonin (5-HT1A, 5-HT2A) and dopamine (D2, D3) receptors, while disp- laying poor or no affinity for 5-HT1B, 5-HT2C, 5-HT3 and 5-HT4 subtypes. The strong contribution of the N-oxide function for the binding on 5-HT1A, D2 and D3 receptors is noteworthy. For 2-4- [3- [4- (2-methoxy- phenyl)-l-piperazinyl] propoxy] phenyl-2H-benzotria- zole-1-oxide (4b), the binding constants (Ki) were 11.9 (5-HT1A) and 10.5 nM (D3). In a general pharma- cological screening, the 2-4- [3- (4-phenyl-l-pipera- zinyl) propoxy] phenyl-2H-benzotriazole (3a) exhibited only very weak activities, with the exception of protecting mice from cyanide-induced hypoxia.

Arylcarbamates Arylcarbamate derivatives of l-piperidineethanol as po- tent ligands for 5-HT4 receptors. Soulier JL, Yang D, Brémont B, Croci T, Guzzi U, Langlois M; J Med Chem 1997 May 23,40: 11 : 1755-61.

A series of carbamate derivatives (7) of 2- (1- piperidinyl) ethyl 4-amino-5-chloro-2-methoxybenzo- ates, which have been described as potent agonists and antagonists of 5-HT4 receptors, were synthe- sized. They were evaluated using radioligand binding assays with [3H] GR 113808, a 5-HT4 receptor selective ligand, in the rat striatum and the electrically stimulated myenteric plexus longitudinal muscle of the guinea pig. In contrast to the previously desc- ribed ester derivatives, a drop in the affinity for 5-HT4 receptors was observed and the compounds were inactive as agonists in the guinea pig ileum prepa- ration. Unexpectedly, the ortho-substituted carbama- tes 8b, c (R'=H, RO=MeO or EtO, R"=H) had nanomolar affinity for 5-HT4 receptors (Ki = 8.9 +/-0.5 and

2.6 +/-0.4 nM, respectively). As reported previous- ly, the cis-or trans-3,5-dimethyl substitution of piperidine (8n, o) was particularly favorable (Ki = 1.1 +/-0.6 nM for both isomers). 8c is an antago- nist equipotent to the 5-HT4 receptor antagonist SDZ 205-557 (1).

The most interesting 5-HT4 receptor agonists for the present indications are VB20B7, RS67333, BIMU 1, BIMU 8, 5-methoxytryptamine, Zacopride, RS56532, Mosapride, Pan- copride, Itasetron, BRL 24924, and SC 53116.

Further 5-HT4 agonist structures useful according to the present invention X R, pa-ìcuß 0 P 1.-'. \.'--. 2-piperidinmethylethers of bensimida ? ol N OX XNR1 ? 0 N-Ri N Erz oxadiazalon based substance vs N Y""SO W. /.. \-\ O N-\ o ! x , g2 : iicul2.. rly , y H N kinolines 1 R O M/, I N . N p^-iicul2rly _N N '. N 3 N u o nez .'N . i. . ¢4H t N R2 G/ R. fY--C8 R3 NH2 cri ROI , \ \ N N t--. I/N. o R2 3 Ci r R 1 N . Pa-'iuI2tly O"p N- U bensopyranes. O. Q N . --' zu D [. zu i RR3 NHSQCH, Roi m/ '

The present invention relates to a composition comprising a combination of compounds comprising a) at least one compound with agonist activity to the 5-HT4 re- ceptor, and b) at least one compound with antagonist activity to the 5-HT3 receptor, e. g. for use as a medica- ment. The present invention also relates to the use of said composition for the manufacture of a medicament in- tended for treatment of disorders involving airway con- striction, as defined above, whereby said composition has the strong bronchorelaxing effect of 5-HT but substanti- ally no constrictor effect. The administration of the composition can be simultaneous or sequential. The com- pounds with agonist activity to the 5-HT4 receptor in- cluded in said composition may also be unspecific, e. g.

5-HT.

In said combination of compounds with 5-HT4 agonist and 5-HT3 antagonist activity,. the relative amount of either compound may vary. Typically, the 5-HT4 agonist is given in a somewhat larger concentration than the 5-HT3 antagonist.

The most preferred compositions according to the present invention are the following, in each example named in the following order: 5-HT4-receptor agonist, 5-HT3-receptor antagonist, -VB20B7 and tropanyl 3,5-dimethylbenzoate VB20B7 and MDL 72222 RS67333 and tropanyl 3,5-dimethylbenzoate -RS67333 and MDL 72222 Zacopride and tropanyl 3,5-dimethylbenzoate -Zacopride and MDL 72222 -RS56532 and tropanyl 3,5-dimethylbenzoate -RS56532 and MDL 72222 -Itasetron and tropanyl 3,5-dimethylbenzoate -Itasetron and MDL 72222 -VB20B7 and SDZ 216-525 -RS67333 and SDZ 216-525

-RS67333 and 3 (1-piperazinyl)-2-quinoxalinecarbo- nitrile -VB20B7 and 3- (1-piperazinyl)-2-quinoxalinecarbonit- rile -RS67333 and tropanyl 3,5-dimetylbenzoate -RS67333 and VB20B7 -RS67333 and 5-((dimethylamino) methyl)-3-(1-methyl- lH-indol-3-yl)-1, 2,4-oxadiazole, and -VB20B7 and 5-((dimethylamino) methyl)-3-(1-methyl-lH- indol-3-yl)-1,2,4-oxadiazole The most preferred combinations are - VB20B7 and tropanyl 3,5-dimethylbenzoate -RS67333 and tropanyl 3,5-dimethylbenzoate -Zacopride and tropanyl 3,5-dimethylbenzoate -VB20B7 and 3- (l-piperazinyl)-2-quinoxalinecarbonit- rile -RS67333 and VB20B7 -VB20B7 and 5-((dimethylamino) methyl)-3-(1-methyl-lH- indol-3-yl)-1,2,4-oxadiazole The present invention also relates to a method for treatment of disorders involving airway constriction, wherein said method comprises the administration to a hu- man or animal patient of a therapeutically effective amount of a composition comprising a combination of a) a compound with agonist activity to the 5-HT4 receptor, and b) a compound with antagonist activity to. the 5-HT3 re- ceptor. Preferably, said method relates to the treatment of asthma, chronic bronchitis, emphysema and chronic ob- structive pulmonary disease.

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 unspecific 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, citalo- pram, 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 i-s serotonin (5-HT), which activiates 5-HT1, 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 jj. 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 FM 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 induce a weak bronchoconstriction rather than a relaxation in asthmatic (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). If instead, according to the present invention, a composition comprising a com- bination of compounds that stimulates the relaxing 5-HT4 receptor and blocks the contracting 5-HT3 receptor is given, the relaxing effect is persistent, and not tran- sient. The action of this combination at two different receptors causes a greater airway relaxation than an ac- tion at only one receptor. I should be noted that more

than one of the 5-HT4 receptor agonists and more than one of the 5-HT3 receptor antagonists may be included in such a composition. A reduced effect, however still satisfac- tory is attained, by the administration of only the 5-HT3 receptor antagonist.

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 in combina- tion with a 5-HT3 receptor antagonist results in a much better relaxation of the bronchi, compared to administra- tion of only one of those compounds.