WO2002036114A1 - Composition comprising serotonin receptor antagonists, 5 ht-2 and 5 ht-3 - Google Patents

Abstract

A composition comprising a combination of compounds comprising: a) at least one compound with antagonist activity to the 5-HT3 receptor; and b) at least one compound with antagonist activity to the 5-HT2 receptor is described.

Description

COMPOSITION COMPRISING SEROTONIN RECEPTOR ANTAGONISTS, 5 HT-2 and 5 HT-3.

Field of the Invention

The present invention relates to a composition comprising a combination of a) at least one compound with antagonist activity to the 5-HT₃ receptor and b) at least one compound with antagonist activity to the 5-HT₂ receptor, to a composition as defined above for use as a medicament, to the use of said composition in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders involving airway constriction in humans or animals, and to a method of treatment of such disorders, wherein said compound is administered. Background of the Invention

There are seven main types of 5-HT (serotonin; 3- (β- aminoethyl) -5-hydroxyindole) receptors, (5-HT_x_₇) . These receptors occur throughout the body, e.g. in the airways, and have mainly been reported to be of significance in conjunction with treatment of CNS, muscle and gastric disorders. In such treatments, compounds with agonist activity to a 5-HTχ type receptor are often used. For a recent review of 5-HT receptors, see Gerhardt , C.C. & van Heerikhuizen, H. , Eur. J. Pharm., 334, 1-23 (1997), which is incorporated herein by reference. For a review of typical agonists and antagonists of various 5-HT recep- " tors, see R.A. Glennon, Neuroscience and Biobehavioral

Reviews, 14, 35-47 (1990), the whole content of which is incorporated herein by reference. Further information regarding 5-HT receptors and their agonists and antagonists can be found in the RBI Handbook of Receptor Classification and Signal Transduction, 3^rd Edition, 1998,

RBI, One Strathmore Road, Natick, MA 01760-2447, USA, Editor: Keith J. Watling, which is also incorporated herein by reference. SU 1 701 320 Al discloses the use of the unspecific 5-HT receptor agonist for treatment of acute asthma attacks. However, the -present application do not refer to the use of 5-HT receptor agonists (such as 5-HT) , but rather 5-HT receptor antagonists. Disclosure of the Invention

The present invention is based on the novel finding that certain 5-HT receptors are of the utmost importance in determining the level of airway constriction. In summary, it is disclosed herein that the administration of a composition comprising a combination of compounds comprising a) at least one compound with antagonist activity to the 5-HT₃ receptor and b) at least one compound with antagonist activity to the 5-HT₂ receptor, causes a distinct airway relaxation, and is therefore suitable as an agent for treatment of disorders involving airway constriction. A method for treatment of disorders involving- ■ airway constriction is also disclosed.

As used herein, the expression "airway constriction" refers to an abnormal increase of force development of the smooth muscle in human or animal airways, resulting in a reduced diameter in some or all of the airways, such as occurring in asthma, chronic obstructive pulmonary disease, emphysema and chronic bronchitis. Said expres- sion also refers, in a wider sense, to a reduction of the airway diameter caused by swelling, oedema, plasma extra- vasation or mucous secretion caused by e.g. asthma or any other disorder related thereto.

The expression "has the capacity of reducing the ab- normal airway constriction by at least ....%" used in the present patent application means that the combination of compounds in question reduces, to a certain 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 constricting 5-HT receptors. The level of constriction in the airways can e.g. be determined by spiro etric measurements of the Forced Expiratory Volume in 1 second (FEV1) , compared to the normal value for healthy people. Alternatively, the expiratory capacity for a patient can be compared to his own FEV1 during periods of relatively little obstructive problems.

The present invention relates, in one of its aspects, to a composition comprising a combination of compounds comprising a) at least one compound with antagonist activity to the 5-HT₃ receptor and b) at least one compound with antagonist activity to the 5-HT₂ 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 animal body, wherein the medicament is intended for treatment of disorders involving airway constriction, such as- asthma, chronic obstructive pulmonary disease, emphysema and chronic bronchitis. The combination of a) at least one 5-HT₃ receptor antagonist and b) at least one 5-HT₂ receptor antagonist increases airway relaxation compared to the use of either compound alone, wherein said combination has the capacity of reducing the abnormal airway constriction by at least 30%, preferably at least 60%, and most preferably at least 90%.

According to the present invention, several known 5-HT₃ antagonist and 5-HT₂ antagonist compounds are, unexpectedly, able to induce airway relaxation. The 5-HT₃ receptor is a ligand modulated ion channel. Several potent and specific 5-HT₃ antagonists exist today, of which ondansetron, tropisetron, grani- setron, and dolasetron are commercial pharmaceuticals, but not against disorders involving airway constriction. The following 5-HT₃ receptor antagonists are contemplated according to the present invention: a) 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 5-HT₄ agonists, e.g. benzamides

, -

and

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

The latter group reminds most of the specific 5-HT₃ antagonists, which contains the group

in different forms, such as

ondansetron

alosetron cilansetron

In one group of substances the structure has been inverted and the carbonyl group has been placed on the indoline nitrogen

This substance is unique by being an antagonist against both 5-HT₃ and 5-HT₄ receptors.

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

A further development is- he so-called bisindoles

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 antagonists

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

Talipexole

iodophenpropit

thiopera ide, and

2-piperidin- and 2 -piperazinbenzimidazoles .

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-l-yl) -2- quinoxalinecarbonitrile, 4-Ph-N-Me-quipazine, 5- ( (dimethylamino) methyl) -3- (1 -methyl-lH-indol-3 -yl) -1,2, 4-oxa- dizole, 5,7-DHT, 5- [ (dimethylamino) methyl] -3- (1-methyl- lH-indol-3-yl) -1, 2 , 4-oxadizole, ADR-882, Amitriptyline, AS-5370, Batanopride, BIMU 1, BRL 24682, BRL 43694, BRL 46470 (=Ricasetron) , BRL 47204, Bufotenine, CF 109203 (=BIM) , Cizapride, Clozapine, CP-93318, Cyameazine, Cy- proheptadine, Dolasetron, 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, Luro- setron, LY 258-458, LY 278-989, LY-211-000, McNeil-A-343 , MCPP, MDL 72699, Mepyramine, Metergoline, Methysergide, Mianserin, MK 212, N-3256, NAN-190, N-metylquipazin, - . 3- (1-piperazinyl) -2-quinoxalinecarbohitrile, ONO-3051, Pancopride, Phenylbiguanide., Pitozifen, Prochlorperazine, QICS 205-930, R (+) zacopride, Renzapride, RG 12915, Ritan- serin, RP 62203, 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, trifluoper- zine, tropanyl-3 , 5-dimethylbenzoate, 3-tropanyl-indole-3- carboxylate methiodide, tropisetron, VA 21 B 7, Y 2513,- zelmac, SEC 579, BRL 46470 A, Pizotifen, Dolasetron (=MDL

74156) , Galanolactone, GR 65 630, Ifenprodil, L-683877,

Litoxetine, Quipazine, QX 222, Ramo^'setron (=YM 060) , RS 56812, SDZ 216-525, Trimebutine, GR 65630, Tropisetron, Bemesetron, L-683,877, LY-278-, 584 maleate and pharmaceutically acceptable salts thereof with the same or essentially the same relaxation enhancing effect.

In the following, an alternative presentation of useful compounds according to the present invention and references thereto is listed. N-substi tuted benzamides

Metoclopramide

H,

• QX 222. The compound is an analogue to lidocain^®, which is a N-substituted benzamide derivative.

Cisapride (Cizapride) cis-4-Amino-N- [1- [3- (p- fluorophenoxy)propyl] -3-methoxy-4-piperidyl] -5- chloro-o-anisamide . The compound is. also a known 5- HT4 agonist.

cis-4-Amino-⁽V-[L-[3-( -Ωuorofenoxi)proρvl]-3-metoxi-4-piρeri yl]-5- - loro-σ-anisaπud

Pancopride ( ( (+-)N- (1-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., Fernandez AG_/ Puig J, Beleta ^'j, Domenech T, Bou J, Berga P, Gristwood RW, Roberts DJ; Eur J Pharmacol 1992 Nov 10, 222:2-3:257-64

Pancopride ( (+-)N- (1-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 antagonized 5-HT-induced bradycardia in anaesthetized rats when administered i.v. 5 min (ID50 = 0.56 microgram/kg) or p.o. 60 min ^' (ID50 ^■= 8.7 micrograms/kg) before 5-HT challenge. A single oral dose (10 micrograms/kg) of pancopride produced a significant inhibition of the bradycardic reflex over an 8-h period. Pancopride dose dependently inhibited the number of vomiting episodes and delayed the onset of vomiting induced by cisplatin in dogs (ID50 = 3.6 micrograms/kg i.v. and 7.1 micrograms/kg p.o.). Pancopride was also effective in blocking mechlorethamine- 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- (1-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; Pharmacol Biochem Behav 1990 Dec, 37:4:717-27

R(+)- and S (-) -zacopride were assessed as potential 5-HT3 receptor antagonists in behavioural and biochemical tests. The S(-) isomer was more potent than the R(+) isomer to antagonise the hyperactivity induced by the injection of amphetamine or the . infusion 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 scopola ine-induced impairment, and to antagonise the inhibitory effect of 2-methyl-5-hydroxytryptamine to reduce [3H] acetylcholine release 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 (S) (-) -zacopride . It is concluded that both isomers of zacopride have potent but different pharmacological activities, with the possibility of different recognition 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- (1- azabicyclo- [3.3.1] -non- 4-yl) benzamide hydrochloride. The compound is also a known 5-HT4 agonist .

• Mosapride ( (4-amino-5-chloro-2-ethoxy-N- [ [4- (4- fluorobenzyl) -2-morpholinyl] methyl] benzamide citrate.

Renzapride= BRL 24924; see above

SC-52491 (Azanoradamantane)

• SC-53116 ( (1-S, 8-S) -4-amino-5-chloro-N- [ (hexahydro- lH-pyrrolizin-1-yl) methyl]"-2-methoxy-benzamide hydrochloride)

• Batanopride (4-amino-5-chloro-N- [2-

(diethylamino) ethyl] 2- (1-methyl-2 -oxopropoxy ) benzamide) . 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. l]oct-3-yl) 2 , 3-dihydro-3 , 3 dimethyl-indole-1- carboxamide, hydrochloride)

BRL 46470 (endo-N- (8-methyl-8-azabicyclo [3.2.1] oct-

3yl) -2,3-dihydro-3,3- dimethyl-indole-1-carboxamide HC1)

BRL 47204

-FK 1052 ( (+) -8,9-dihydro-10-methyl-7- [ (5 -methyl-1H- imidazol-4- yl) methyl] pyrido [1, 2 -a] indol-6 (7H) -one hydrochloride)

Pharmacological characterization of FK1052, a dihydropyridoindole derivative, as a new serotonin 3 and 4 dual receptor antagonist . , Nagakura Y, Kadowaki M, Tokoro K, To oi M, Mori J, Kohsaka M; J Pharmacol Exp Ther 1993 May, 265:2:752-8

(+) -8, 9-Dihydro-10-dihydro-10-methyl-7- [ (5-methyl-4- imidazolyl) methyl] yrido- [1, 2-a] indol-6 (7H) -one hydrochloride (FK1052) is a newly designed and synthesized 5-hydroxytryptamine (5-HT) 3 receptor antagonist with 5-HT4 receptor antagonistic activity. This compound, as well as ondansetron and granisetron, dose-dependently inhibited the von Bezold-Jarish reflex, a 5-HT3 receptor-mediated response, after intravenous (i.v.) and intraduodenal (i.d.) dosing to rats. The ID50 values showed FK1052 (0.28 microgram/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 micrograms/kg, i.v., 66 micrograms/kg, i.d.). Furthermore, 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 ondansetron J 6 . 79) and granisetron (7.86), respectively. FK1052, unlike ondansetron and granisetron, inhibited the 5- HT4 -mediated component of concentration-response curve to 5-HT. Furthermore, FK1052 suppressed 5- methoxytryptamine, a 5-HT4 agonist-induced contraction in a concentration-dependent but - ■ insurmountable 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 membranes 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-hydrox tryptamine 5-HT3 receptor 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 saturation 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 kinetic 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 population of [3H] ICS 205-930 recognition sites. All ■competition 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 antagonists 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 -206-7.92 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.

• 38032F=SN-307=Zofran^®

Ondansetronum INN (Ondansetron)

2 -Dihydro-9-metyl-3-[(2-metylimidazol-l-yl)metyl]karbazol-4(lH ^'

-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 properties 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 approximately 8.0), whereas GR380.32F showed lower^*'- - affinity (-log ka approximately 7.0) at 5-HT3 . receptors in the guinea pig ileu . After i.v. administration to anesthetized rats, zacopride was approximately 10-fold more potent than either ICS 205-930 or GR38032F, which were equipotent as inhibitors of serotonin-induced bradycardia (5-HT3- mediated activation 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 effectiveness of GR38032F persisted for less than 3 hr after oral administration and for less than 15 min after intravenous administration."^' ICS 205-930 produced maximal inhibition of 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 effectiveness in urethane- anesthetized rats with maximal inhibition still apparent 6 hr after oral administration. All three agents inhibited- cisplatin-induced emesis after i.v. administration in dogs with zacopride being 10-fold more potent than ICS 205-930 or GR38032F, which were equipotent . These comparative data with three 5-HT3 receptor antagonists indicate that in animals, 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 action.

Alosetron=Lotronex (Glaxo)

The compound is both an indole derivative and an imidazole. 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, Bountra C, Humphrey PP; Neurogastroenterol Motil 1999 Jun, 11:3:207-17 The purpose of this study was to investigate the pharmacological 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 estimated pKi values of 9.8 (n = 3) and 9.4 (n = 6), respectively. In selectivity studies alosetron had little 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 bradycardia (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 clinical 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= Anze et IUPAC name: (2 , 6, 8 , 9aβ) -octahydro-3-oxo-2 , 6-methaήo-

2H-quinolizin-8-yl-lH-indole-3-carboxylate monome thane sulf onate , 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 selective 5-HT3 receptor antagonist, on the number of spontaneously -active midbrain dopamine neurons., Minabe 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 spontaneously active dopamine cells in the substantia nigra pars compacta (SNC or A9) and ventral tegmental area (VTA or AlO) . This was accomplished using the standard extracellular single unit recording techniques. The acute administration of LY 277359 (0.1 or 1.0 mg/kg i.p.) produced a significant increase in the number of spontaneously active AlO, but not A9, dopamine cells compared to - saline controls. The acute administration of 10 mg/ g 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 number of spontaneously active A9 and AlO dopamine cells. However, the i.v. administration of (+/-) -apomorphine (50 micrograms/kg) did not reverse LY 277359 's action, - suggesting that the chronic LY 277359-induced reduction of dopamine cells was not the result of depolarization block. To test whether chronic administration of LY 277359 at a high dose would induce depolarization block of dopamine cells, rats were treated with 1.0 or 10 mg/kg LY 277359. Interestingly, the chronic administration of 1.0 mg/kg LY 277359 increased the number of AlO, but not A9 dopamine cells. In contrast, chronic treatment ,. with 10 mg/kg selectively decreased the number of spontaneously active AlO dopamine cells. • GR65630 (3- (5-methyl-lH-imidazol-4-yl) -1- (1-methyl- 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 vagus 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 calculated pKB value was 10.2. The binding of the tritiated derivative of GR67330 to homogenates of rat entorhinal cortex was examined. Kinetic analysis revealed that specific [3H] GR67330 (0.1 nmoly'l) binding was rapid and reversible. Association and dissociation 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 respectively. Equilibrium saturation analysis revealed specific binding was to a single site ^"(Bmax 22.6 +/- 0.21 fmol/mg protein) of high affinity (Kd 0.038 +/- 0.003 nmol/1). At low ligand concentrations, specific binding was up to 90% of total binding. If unlabelled GR67330 was used to define non-specific binding two sites were evident (Kdl 0.066 +/- 0.007 nmol/1, Kd2 20.1 +/- 9.7 nmol/1; Bmaxl 31.5 +/- 3.2 fmol/mg protein,- Bmax2 1110 +/- 420 fmol/mg protein) . [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 inhibiting binding. Hill numbers for antagonist inhibition 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 inhibition from a second saturable site unrelated to the 5-HT3 receptor.

ICS 205-930 ((3 Alpha-Tropany1) -1H-Indole-3 -carboxylic acid ester)

Comparison of the 5-HT3 receptor antagonist properties 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 approximately 8.0), whereas GR38032F showed lower affinity (-log ka approximately 7.0) at 5-HT3 receptors in the guinea pig ileum. After i.v. administration to anesthetized rats, zacopride was approximately 10-fold more potent than either ICS 205-930 or GR38032F, which were equipotent as inhibitors of serotonin-induced bradycardia (5-HT3- mediated activation 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 effectiveness of GR38032F persisted for less than 3 hr after oral administration and for less than 15 min after intravenous administration. ICS 205-930 produced maximal inhibition of 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 effectiveness in urethane- anesthetized rats with maximal inhibition still apparent 6 hr after oral administration. All three agents inhibited cisplatin-induced emesis after i.v. administration in dogs with zacopride being 10-fold ■more potent than ICS 205-930 or GR38032F, which were equipotent . These comparative data with three 5-HT3 receptor antagonists indicate that in animals, zaco- pride was more potent and longer acting than either ICS 205-930 or GR38032F. Furthermore, after oral administration to rats, GR38032F was slightly less - - potent than ICS 205-930 and possessed the shortest duration of action.

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] carboxaldehyde)

The pharmacology of VA21B7: an atypical 5-HT3 receptor antagonist with anxiolytic-like properties in animal models. Artaiz I, Romero G, Zazpe A, Monge A, Calderό JM, Roca J, Lasheras B, Del Rio J Psychopharma col ogy (Berl) 1995 Jan, 117:2:137-48 VA21B7 (3- [2- (4 ' -piperonylpiperazinyl) indolyl] carboxaldehyde) 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 remarkable anxiolytic-like effect was found at doses of 2-500 micrograms/kg IP. and also at low oral doses, in the microgram range. These drug doses did -not produce any significant effect on spontaneous motor activity of mice. The anxiolytic profile of VA21B7 was further explored using other models f anxiety in rats such as the elevated plus-maze and punished-drinking. VA21B7 was compared with standard 5-HT3 receptor antagonists such as ondansetron, - - tropisetron and granisetron, with the 5-HT1A agent buspirone 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 modify the number of total entries into the open and closed arms of the maze. Diazepam, granisetron an 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 action 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 scopolamine . Much higher doses were necessary to decrease spontaneous motor activity in rats. Since VA21B7 appears to be well tolerated in rodents at • high doses, we think that it is of potential interest as an anxiolytic in humans.

Benzimidazolones , benzimidazoles and other imidazoles

The common chemical structure of a benzimidazolone is :

Iodophenpropit (4- (lH-i idazol-4-yl-methyl) - piperidine)

BIMU 1 (endo-N- (8-methyl-8-azabicyclo [3.2.1. ]oct-3- yl) - 2 , 3-dihydro-3-ethyl-2-oxo-lH-benzimidazole-l- carboxamide hydrochloride)

• 2-piperazin-benzimidazole

• 2-piperidin-benzimidazole

• Cilansetron (1-10- [ (2-methyl-lH-imidazol-1- ■ ' yl) methyl] -5, 6,8, 9, 10,11-hexahydro-4H-pyrido [3,2,1- jk] carbazol-11-one hydrochloride)

• GK 128 (2- [ (2-methylimidazol-l-yl) methyl] benzo [i] - thiochromen-1-one monohydrochloride hemihydrate Effect of a novel 5-hydroxytryptamine3 (5-HT3) receptor antagonist, GK-128, on 5-HT3 receptors mediating 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) receptor-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-l-yl) methyl] benzo [f] thiochromen-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 potency 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 relaxation. 4. Other selective 5-HT3 receptor antagonists, azasetron and tropisetron, also exhibited higher affinity in contraction than in relaxation, but the extent of their affinity differences was smaller than that observed in GK- 128. In contrast, granisetron, ramosetron and ondansetron exhibited no significant 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 antagonist with a stronger potency for contraction. • Droperidol. Ingar i Dridol, Janssen-Cilag

Droperidolum INN (Droperidol) y^⁽J^"^r^U-^orob.^enso>'^,)p^roPy^|)- ^.6-tetrahydro-4-pyridyl].l,3- -αι ydro-2/ -bensιπudazol-2-oα

• 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-indμced defecation. Miyata K, Ito H, Yamano M, Hidaka K, Ka ato T, Nishida A, Yuki H; Eur J Pharmacol 1993 Dec 7, 250:2:303-10

YM114 (KAE-393), (R) -5- [ (2 , 3 -dihydro-1-indolyl). - carbonyl] -4,5,6,7- tetrahydro-lH-benzimidazole hydrochloride, 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 trimebutine. YM114 dose dependently inhibited the reduction in heart rate induced by 5-HT (30 micrograms/kg i.v.) in rats (ED50 = 0.31 micrograms/kg i.v.), and the potency of YM114 was almost the same as that of the racemate. The S-form of YM114 also inhibited 5-HT-induced bradycardia, but 1350 times less potent than the R-form. YM114 and its S-form inhibited [3H]GR65630 binding to N1E- 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 depolarization 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 possess 5-HT3 -receptor antagonistic activity. YM114 significantly and dose dependently prevented restraint 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., respectively). - - Trimebutine significantly prevented stress- and 5- HT-induced diarrhea (ED50 = 29.4 and 87.3 mg/kg p . o . , respectively), but only partially affected stress-, 5-HT- and TRH-induced increases in fecal pellet output. Thus, YM114 is a potent and stereoselective 5-HT3 receptor antagonist with much greater protective effects against stress-induced defecation than trimebutine .hydrochloride) .

• Itasetron=DAU6215 ( (3-alpha-tropanyl) lH-benzimida- zolone-3-carboxamide chloride) Intravenous itasetron: establishing the effective dose range for the prophylactic control of acute emesis in cancer patients undergoing high-dose cisplatin chemotherapy., 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 Radiol) 1999, 11:2:99-104 Nausea and vomiting induced by chemotherapy are a ,. major cause of distress to patients and reduce compliance with potentially beneficial treatment. Itasetron hydrochloride is a new 5- hydroxytryptamine3 (5-HT3) antagonist with potent antiemetic properties. 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 biotransformation before elimination. The aim of this open, uncontrolled study was to establish the effective dose range of itasetron hydrochloride given intravenously (i.v.)_ι 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 microg/kg body weight before commencing the cisplatin infusion (median dose 90-110 mg/m2) . Antiemetic protection was demonstrated by doses in the range of 35-280 microg/kg. The 17 microg/kg dose was not effective. Treatment failure (>5 emetic episodes/24 hours) was reported in only six (16%) of the 38 evaluable patients over all treatment groups. Adverse events were generally mild or moderate and of a similar type and incidence to those of current 5-HT3 antagonists. Physicians' and patients' assessments of efficacy and tolerability of itasetron hydrochloride 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, calculated 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 evaluation. Orj ales 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 antagonists. 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.

Compound 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 NI atom of the benzimidazole ring is essential for affinity and activity. The effect of substitution on the aromatic ring of benzimidazole by several substituents in different positions is also discussed. A strong correlation between 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) . Compounds 7e and 7n are now under further investigation as drugs for the treatment of nausea and emesis evoked by cancer chemotherapy and radiation.

Lurosetron • Mirisetron =WAY100579

• Ramosetron =YM 060. [ (R) -5- [ (1 -methyl -3 -indolyl) - carbonyl] -4,5,6, 7-tetrahydro-lH-benzimidazole hydrochloride]

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, O oya H, Kato S, Ito T, Eur J Pharmacol 1992 Jun 17, 216:3:435-40

The serotonin 5-HT3 receptor antagonist effects of DAT-582, the (R) enantiomer of AS-5370 ((+/-) -N- [1- methyl-4- (3 -methyl-benzyl) hexahydro-lH-1, 4-diazepin- 6- yl] -1H- indazole-3 -carboxamide dihydrochloride), and its antipode were compared with those of AS-5370 and existing 5-HT3 receptor antagonists. In anesthetized rats, DAT-582 antagonized 2 -methyl-5- HT-induced bradycardia with an ED50 value of 0.25 microgram/kg i.v., whereas the (S) enantiomer was without effect even at 1000 micrograms/kg i.v. In antagonizing the bradycardia, DAT-582 was as potent as granisetron, slightly more potent than AS-5370, and 2, 5 and 18 times more potent than ondansetron, ICS 205-903 and renzapride, respectively, although it was less potent than zacopride. DAT-582 inhibited cisplatin (10 mg/kg i .v. ) -induced emesis in ferrets with an ED50 value of 3.2 micrograms/kg i.v. twice. The antiemetic activity of DAT-582 was more potent than that of the existing 5-HT3 receptor antagonists examined, except zacopride. In contrast, the (S) enantiomer had little effect at 1000 micrograms/kg i.v. twice. In isolated guinea-pig ileu , DAT-582 inhibited 5-HT-induced contractions with an IC50 value of 91 nM, whereas the (S) enantiomer hardly inhibited them even at 1000 nM. These results suggest that DAT-582, the (R) enantiomer of AS-5370, potently and selectively blocks 5-HT3 receptors. - .

N-3389 (N-3389 (endo-3 , 9-dimethyl-3 , 9- diazabicyclo [3 , 3 , 1] non-7-yl lH-indazole-3- carboxamide dihydrochloride)

Antagonistic activities of N-3389, a newly synthesized diazabicyclo derivative, at 5-HT3 and 5- HT4 receptors., Hagihara K, Hayakawa T, Arai T,^"

Eguchi H, Mino S, Kawase S, Eur J Pharmacol 1994 Dec 12, 271:1:159-66

The antagonistic activities of compound N-3389 (endo-3, 9-dimethyl-3 , 9- diazabicyclo [3 , 3 , 1] non-7 -yl lH-indazole-3 -carboxamide dihydrochloride) at 5-HT3 and 5-HT4 receptors were examined using in vitro and in vivo assays. N-3389 showed potent 5-HT3 receptor antagonistic activities in a radioligand binding assay (pKi = 8.77), against 2-methyl-5-HT (2-Me-5- HT) -induced bradycardia in rats (ED50 = 0.73 micrograms/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 investigating 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 concentrations 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 electrically 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 receptor antagonist.

• BRL 43694=Kytril^® =Granisetron

Graπisetronum E N (Granisetron) l-Metyl-N-(en o-9-metyl-9-azafaicyklo[3.3.1]non-3-yl)-lH-indazol-3- -karboxamid

Selective and functional 5-hydroxytryptamine3 receptor 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 investigated using established models of 5-HT3 receptor activity. In guinea-pig isolated ileum, BRL 43694 antagonised the contractions evoked by *' relatively high concentrations of 5-HT (pA2 = 8.1 +/- 0.2) . However, except in high concentrations, BRL 43694 did not affect the contractions of similar preparations of ileum, evoked by electrical field stimulation (cholinergically mediated) , the nicotinic agonist dimethylphenyl piperazinium (DMPP) or by cholecystokinin octapeptide. Similarly, BRL 43694 did not affect electrically evoked, cholinergically mediated contractions 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, Garreau 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 antidepressant 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 vomiting as well as the number of emetic episodes induced by cisplatin (10 mg/kg i.v.) and delayed the onset of emesis. Fluoxetine (at 1 or 10 mg/kg i.v.) failed to inhibit cisplatin-induced emetic responses and, in contrast, significantly increased the number of retches and vomiting and accelerated the onset of emesis. The possibility that the antiemetic effects of litoxetine may be mediated through an interaction with 5HT3 receptors was studied using [3H] quipazine or [3H]BRL 43694 to label the 5HT3 receptor. Litoxetine has moderate affinity for cerebral 5HT3 receptors (Ki = 85 nM) , - . while ' fluoxetine, similar to other 5HT uptake inhibitors, has only negligible affinity 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 serotonergic antidepressants (e.g. fluoxetine, fluvoxamine etc.) is associated with gastrointestinal discomfort (particularly nausea and vomiting) as a major side-effect. If nausea and vomiting associated with the use of 5 HT uptake inhibitors are due to stimulation of 5HT3 receptors, the concomitant 5HT3 antagonism of litoxetine may limit the gastrointestinal side-effects of this novel antidepressant and thus offer an important advantage .

LY 278584 ( (1-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 19-89 Jul 4, 166:1:107-10 ^{■ •} .

Binding of [3H]LY278584 a 1-methyl-indazole-carbox- amide, to putative 5-HT3 recognition sites in membranes isolated from cerebral cortex of rat brain, is examined. Specific binding of [3H]LY278584 accounts 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 antagonists of 5-HT3 receptors supports the conclusion that 3H]LY278584 binds to putative 5-HT3. receptors- in cortical membranes.

• LY-278,584 maleate, see above.

• LY258-458

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

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

Binding of [3H]LY278584 a 1-methyl-indazole-carbox- amide, to putative 5-HT3. recognition sites in membranes isolated from cerebral cortex of rat brain, is examined. Specific binding of [3H]LY278584 accounts 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 antagonists 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, Jbensot iazepines

-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- (1-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 antagonists, 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 significant 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- ( -fluorophenyl) -piperazinyl) propyl] naphto [1,8- ca] isothiazole-1, 1-dioxide)

• Clozapine. Ingar i Leponex, Novartis

Clozapinum INN (Klozapin)

8-Kloro-l l-(4-metyl-l-piperazinyl)-5H-dibensof , e][l,4]diazepin

• Amitryptiline

Amitriptylinum INN (Amitriptylin) 5-(3-Dimetylaminoproρyliden)-10,ll-dihydro-5H- -dibens[a, djcyklohepten

Cyproheptadine . Is the active ingredient of Periactin, MSD

Diltiazem

Is the active ingredient in Cardizem, Pharmacia

Corporation

Diltiazemui-α INN (Diltiazem)

(2S,3S)-3-(Acetyloxi)-5-[2-(di etylamino)etyl]-2-(4-metoxifenyl)-2,3-

-di ydro-r,5-bensotiazepin-4(5H)-on

Imipramin

5-(3-Dimetylaminoρroρyl)-10,π-di ydro-5 -dibenso[6, azepin

• Mirtazapine (1, 2, 3 , 4, 10, 14b-hexahydro-2-methyl- pyrazino [2, 1-a] pyrido [2,3-c] benzazepine)

• Pizotifen

Pizotifenum INN (Pizotifen)

4-(l-Metyl-4-piperidyliden)-9,10-dihydro-4H-benso-

-[4,5]cykloheρta[l,2-b]tiofen

Quinoline , 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 - (1-azabicyclo- [2, 2, 2] octan-3-yl) 2 , 3-dihydro-lH-benz [de] - isoquinoline-1, 3-dione hydrochloride)

• 3- (1-piperazinyl) -2-quinoxalinecarbonitrile

• 3- (4-allylpiperazin-l-yl) -2-quinoxalinecarbonitrile

• KF 17643 (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl- 2- (n-propyloxy) -4-quinolinecarboxylate)

• KF 18259 ( (endo- (8-methyl-8-aza- bicyclo [3.2.1] oct- 3-yl) -1 -isobutyl -2 -oxo-1, 2 -dihydro-4-quinolinecarboxylate 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 [ (S) -N- (1-azabicyclo [2.2.2] oct-3-yl) - 2 , 4 , 5, 6-tetrahydro-l H-benzo [de] isoquinolin-1-one hydrochloride]

• RS-056812-198 (R) -N- (quinuclidin-3-yl) -2- (1-methyl- 1 H-indol-3-yl) -2-oxo-acetamide

• RS-25259-197 [ (3aS) -2- [ (S) -1-azabicyclo [2.2.2] oct-3 - yl] -2 , 3 , 3a, 4, 5, 6-hexahydro- 1- oxo-lH-benzo [de] - isoquinoline-hydrochloride)

The interaction of RS 25259-197, a potent and selective 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-lH-benzo [de] iso- quinoline-hydrochloride] , has two chiral centres. The remaining three enantiomers are denoted as

RS 25259-198 (R,R), RS 25233-197 (S,R) and RS 25233- 198 (R,S). 2. At 5-HT3 receptors mediating contraction of guinea-pig isolated ileum, RS 25259- 197 antagonized contractile responses to 5-HT in an unsurmountable 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, respectively, with Hill coefficients not significantly different from unity. Thus, at these 5-HT3 receptors, the rank order of apparent affinities was (S,S) > (R,S) > (S,R) = (R,R) . 3. RS 25259-197 displaced 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 myenteric plexus and guinea-p^'ig 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

Chlorprόmazimu-n INN (Klorpromazin) 10-(3-Dimetylaminoρroρyl)-2-klorofentiazin

• Cyamemazine (10- (3 -Dimethylamino-2- methylpropyl)phenothiazine-2-carbonitrile)

• Fluphenazin

Fϊuphenazinum INN (Flufcnazin) lO-[3-(4-(2-Hydroxictyl)-L-piperazinyl)ρroρyl]-2- -tri luorometylt'entiazin

• Prochlorperazine=Stemetil

KB-6933 (6-amino-5-chloro-l-isopropyl-2- (4-methyl-l- piperazinyl) benzimidazole dimaleate)

Perfenazine. Ingar 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 selective 5-HT3 receptor antagonist. Tsukagoshi S Gan To Kagaku 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, resulting 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-1H-indol-3- yl) -1,2, 4 -oxadiazole

• 1, 4 -Benzoxazin-8-Carboxamide Other compounds , including piperidines, piperazines, alkaloides, 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 -trif luoromethylphenyl) 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- [lrpiperazinyl] -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 agonist, 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 cort-ex and hypothalamus slices. 3. In hypothalamus slices, this response was lost when 2-methyl-5-HT was introduced 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 receptors, removed for 24 min, and then re- introduced 8 min before the second stimulation period, the enhancing 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 receptor antagonists m-chloro- phenylpiperazine = quipazine = 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 icroM) 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 enhancing 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 effect 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) receptors on mammalian peripheral neurones, are described. On the rabbit isolated heart, MDL 72222 was a potent antagonist of responses mediated through the receptors for 5-HT present on the terminal sympathetic 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, dimethylphenylpiperazinum 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 selective 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 cholinoceptors or histamine HI-receptors except at relatively 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 Chinese, Indian, and Japanese cultures where they are believed to have anti-inflammatory, analgesic, cholesterol -lowering, and antithrombotic properties. Al-though ginger has been evaluated for the treatment of nausea and vomiting associated with hyperemesis gravidarum, anesthesia, and chemotherapy, this review will focus on ginger for motion sickness. 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 involved etiologically in the psychological stress lesion the stomach of the mouse. , J Pharmacol Exp Ther, 1994 Oct, 271:1, 100-6

The role of brain amines, possibly involved in psychological 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 electrical 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; 200-4Q-0 mg/kg p.o.), but not 6-hydroxydo amine (6-OH-DA; 60 micrograms/body i.e.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 lesion 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 contrast, a peripherally acting 5-HT3 antagonist, M-840 ( [ [3- (l-methyl-lH-indol-3- yl) -1,2, 4-oxadiazol-5- yl] -methyl] trimethyl-ammonium iodide) , dopamine^' acting compounds, haloperidol and FR64822 [N- (4-pyridylcarbamoyl) amino-1,2,3, 6- tetrahydropyridine) , and antisecretory drugs, atropine and famotidine, minimally affected the lesion formation.

• SDZ ICT 322, an indole-3-carboxylic acid scopine ester

• 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, a's 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 collaboration with Milt Teitler, made a series of hybrid 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 significantly higher affinity than phenylbiguanide. Although we reported these compounds in abstract form, a full paper http://www.phc.vcu.edu/ra.--/serotonin/ - seven on mCPBG independently appeared by another group of investigators 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 studies, 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 assay systems.

S 21007 (21007 [5-(4-benzyl piperazin-1-yl) 4H pyrrolo [1, 2 -a] thieno [3 , 2-e] pyrazine] ) .

Interaction of S 21007 with 5-HT3 receptors. In vitro 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] yrazine] with serotonin 5-HT3 receptors was investigated using biochemical, electrophysiological and functional assays. Binding studies using membranes from N1E-115 neuroblastoma cells showed that S 21007 is a selective high affinity (IC50 = 2.8 nM) 5-HT3 receptor ligand. As expected of an agonist, S 21007 stimulated the uptake of [14C] guanidinium (EC50 approximately 10 nM) in NG 108-15 cells exposed to substance P, and this effect could be prevented by the potent 5-HT3 receptor antagonist ondansetron. In addition, 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 prevented by pretreatment with the potent 5-HT3 receptor 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 NlE-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 activity at 5-HT3 receptors in some tissues.

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

N-substi tuted 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

Ri is alkoxy of 1 to 6 carbon atoms; and R² and R³ are the same or different and are hydrogen, halogen, CF3 , hydroxy, C]__g alkoxy, C2-7 acryl, amino, amino substituted by one or two C^-g alkyl groups, C2-7 acylamino, aminocarbonyl or a inosulfone, optionally substituted by one or two ^_g alkyl groups, C_]__g alkyl sulfone or nitro groups; wherein X can be NR, S, or 0; Y can be CH or N; R is H, alkyl or aryl; and m is 1 or 2.

The structure is a benzamide with Ar=Ph-C0NH- .

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

EP0430190 (November 1990, Syntex, Inc) New tricyclic compounds in which the dashed line denotes an optional double bond; n is 1, 2 or 3; p is 0, 1, 2 or 3; q is 0, 1 or 2 ; each R¹ is independently selected from halogen, hydroxy, lower Cτ_._g alkoxy (optionally substituted with phenyl), lower C__ alkyl, nitro, amino. aminq- carbonyl, (lower Ci- alkyl)amino, di (lower C__g alkyl) amino, and (lower Cχ_ alkanoyl ) amino ,- . each R² is lower C^.g 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 C;L_-7 alkyl, C3.-8 cycloalkyl, C3-.8 cycloalkyl-C]__2 alkyl, or a group (CH2)t^R6 where t is 1 or 2 ant Rg i thienyl, pyrrolyl or furyl optionally further substituted by one or two substituents selected from C^_g alkyl, C;[__g alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from C]__4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and C1--4 alkyl (optionally substituted by hydroxy, C± - 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 pharmaceutically active compounds with 5-HT3 receptor antagonist 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 RI 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, cycloalkylalkyl, 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, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and alkyl (optionally substituted) .

Indoles, Indole -1 -carboxamides and Imidazole derivatives • EP0721949 (September 1993, Tokyo Tanabe Coompany Limited) Indoline compound and 5-HT3 receptor antagonist containing the same as active ingredient.

wherein R^ represents the group

R² represents a phenyl group which may be substituted or an aromatic heterocyclic group, and R3 represents 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 antagonist containing the same as the active ingredient. In formula (I) RI represents the group (a) or (b) , R2 represents optionally substituted phenyl or heteroaryl; 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 vomiting or nausea induced by chemotherapy or radiation, irritable bowel syndrome and diarrhea.

EPΘ711299 (May 1994, Pharmacia S.p.A) Azabicycloalkyl Derivatives Of I idazol (1, 5-A) Indol-3-One As 5HT 3 Antagonists

wherein each of R, R]_ and R2 , which may be the same or different, is hydrogen, halogen, hydroxy, cyano, C]_- Cg alkyl, CF3 , C^-Cg alkoxy, C^-Cg alkylthio, formyl, C2~C alkanoyl, carboxy, C^-Cg alkoxycarbonyl, nitro, -N(R4 R5) in which each of R4 and R5 independently is hydrogen, C^-Cg alkyl, formyl or C2~C alkanoyl; or a (Rg R7)N-S02 group, in which each of R4 and R7 independently is hydrogen or C]_-Cg alkyl; R3 is a group a)

or b)

wherein n is an integer of 1 or 2 and R_Q is hydrogen, C^-Cg "alkyl unsubstituted or substituted by phenyl, C2-C4 alkenyl, C2-C4 alkynyl, formyl or C2~Cg alkanoyl; and the pharmaceutically acceptable salts thereof.'

Novel 5-HT3 receptor antagonist compounds having general formula (I) wherein each of R, RI and R2 , which may be the same or different, is hydrogen, 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 independently is hydrogen or C1-C6 alkyl; R3 is a group (a) or (b) wherein n is an integer of 1 or 2 and R8 is hydrogen, C1-C6 alkyl unsubstituted or substituted by phenyl, C2-C4 alkenyl, C2-C4 alkynyl, formyl or C2-C6 alkanoyl; and the- pharmaceutically _. acceptable salts thereof, 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 .

wherein n, 1, 2 or 3 is; each of R, Rι_ and R2 , which may be the same or different, is hydrogen, halogen, hydroxy, cyano C]_-

C₆ alkyl, CF₃ , C_-Cg alkoxy, C -Cg alkylthio,

^■formyl, C2~Cg alkanoyl, carboxy, C^-Cg alkoxycarbonyl, nitro, -N(R4)R5 in which each of R4 and R5 independently is hydrogen, Cι~Cg alkyl, formyl or C2~C alkanoyl; or a Rg(R7)N-S02 group, in which each of Rg and R7 independently is hydrogen or

Cx-Cg alkyl; - -

R3 is an imidazolyl group having the formula a)

R.

or b) 0

wherein each of Rg and R _Q, which may be the same or different, is hydrogen or Cχ-Cg alkyl, R₉ is hydrogen, C^-Cg alkyl or a nitrogen protection group chosen from triphenylmethyl, t-butyloxycarbonyl, benzyloxycarbonyl, acetyl, formyl, di (p-methoxy- phenyl ) methyl and (p-methoxyphenyl ) diphenylmethyl ; and the pharmaceutically acceptable salts thereof.

Novel 5-HT3 receptor antagonist compounds having formula (I), wherein n is 1, 2 or 3; each of R, RI and R2 , which may be the same or different, is hydrogen, halogen, hydroxy, cyano, C1-C6 alkyl, CF3 , C1-C6 alkoxy, C1-C6 alkylthio, formyl, C2-C6 alkanoyl, carboxy, C1-C6 alkoxy-carbonyl , nitro, -N(R4 R5) , in which each of R4 and R5 independently s hydrogen, C1-C6 alkyl, formyl or C2-C6 alkanoyl; or a (R6 R7)N-S02 group, in which each of R6 and R7 independently is hydrogen or C1-C6 alkyl; R3 is an imidazolyl group of formula (a) or (b) , wherein each of R8 and RIO 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 pharmaceutically acceptable salts thereof, are disclosed.

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

This invention relates to the novel salt 6-fluoro- 2,3,4,5 -1etrahydro-5-methyl-2 -[ (5-methyl-1H-imidazol- 4-yl) methyl]-lH-pyrido[4, 3 -b]indol-l-one methane sul- phonate, to solvates of this salt, to pharmaceutical compositions containing it and to its use in medicine as 5-HT3 receptor antagonists. EP0364274 (October 1989, Glaxo Group Ltd) Imidazole derivatives.

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 Cι_g alkyl, 03.7 cycloalkyl, C3_ alkenyl, phenyl or phenyl Cχ_3 alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C]__ alkyl group;

R!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 sulphur atom, or a group NR⁶, wherein R⁶ represents a C;L_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, hydrogenating a compound of formula (II) :

or a protected derivative thereof, followed if necessary 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 conventional 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 imidazolyl 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 Cl-3 alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a Cl-6 alkyl group; RI 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 sulphur atom, or a group NR6 , wherein R6 represents a Cl-6 alkyl group; Z-Y represents the group CH-CH2 or C=CH; and physiologically acceptable salts and solvates thereof. The compounds of formula (I) are potent and selective antagonists of 5-hydroxytrypt,a- mine at 5-HT3 receptors and are useful, for example, in the treatment of psychotic disorders, anxiety and nausea and vomiting.

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

A γ-carboline of the formula I

or pharmaceutically acceptable acid addition salt and/or hydrate thereof for use in a method of treatment or prophylaxis of diseases or conditions induced by the action of 5-hydroxytryptamine on 5- hydroxytrypt mine 3 -receptors in a mammal, including man.

The present invention provides γ-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 .

• EP0357417 (August 1989, Glaxo Group Ltd) Lactam derivatives .

Compounds 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 C^.g alkyl, C3_7 cycloalkyl, C₃_g 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 C_]__g alkyl group; Y represents a group -(CH2)_m- wherein m represents 2, 3 or 4; or Y represents a group -X(CH2)p-, C]__g 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 RI, R² and "R3 is a hydrogen atom or a Cl-6 alkyl, C3-7 cycloalkyl, 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 Cl-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 represents an oxygen or a sulphur atom or a group NR4 , where R4 is a Cl-6 alkyl group, and X is attached to the benzene ring moiety of the molecule; and physiologically acceptable salts and solvates thereof. The compounds of formula (I) are potent and selective antagonists of 5-hydroxytryptamine at 5- HT3 receptors and are useful, for example in the treatment of psychotic disorders, anxiety .and nausea and vomiting.

RU2059623 Tetrahydrobenzimidazole derivatives or its pharmaceutically acceptable salt.

tetrahydrobenzimidazole derivative of the formula

and a pharmaceutical

K composition containing an effective amount of compound

and a pharmaceutically

H acceptable carrier showing activity of a 5-HT3 receptor antagonist .

US5, 045,545 (May 1989, Glaxo Group Limited) [(Imidazol- 4 (and 5) -yl) ethyl] 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 :

R^J

wherein one of the groups represented by R^, R² and R³ is a hydrogen atom or a C_]__g alkyl, 03.7 cycloalkyl, C3_g^" 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 C^-. alkyl group;

Y represents a group - { R2 ) _m- , wherein m represents 2, 3 or 4; or a group -X(CH2) _, where p represents 2 or 3 , X represents an oxygen or a sulphur atom or -a group NR⁴ , where R⁴ is a Cι_g 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-HT3 receptors and are useful, for- example, in the treatment of psychotic disorders-, anxiety, and nausea and vomiting.

The invention relates to tetracyclic ketones of the general formula (I)##STR1## wherein n represents 1, 2 or 3 ; Im represents an imidazolyl group of the formula: ##STR2## wherein one of the groups repre- sented by R.sup.l, R.sup.2 and R.sup.3 is a hydrocfen 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' -disubstituted amide derivative having a potent and selective 5-HT3 receptor antagonism, represented by general formula (I), a hydrate thereof ,^' or an acid addition salt thereof, wherein RI 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 alkoxycarbonyl; 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

R¹ is alkyl, 3-methyl-2-butenyl , cyclopropylmethyl , 2-propynyl, cyanomethyl , 2-oxopropyl, 2-hydroxypro- pyl, 2-pyridylmethyl, methoxycarbonylmethyl , 2- ethoxyethyl, isobutoxycarbonyl, or 4 , 6-diamino-2- triazinylmethyl ; R² is hydrogen; and R³ and R⁴ are methyl .

Diazabicyclo derivatives of formula (I) and pharmaceutically acceptable salts thereof: wherein R¹ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl , oxoalkyl , alkoxy- cabonylalkyl, alkoxycarbonyl, acyl, dialkylamino- alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, hetero- cycloalkyl, aryl, heteroarylalkyl or arylalkyl, the aryl group and the aryl moiety being optionally substituted 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 moiety is optionally substituted by alkoxy, nitro, alkyl, amino or halo; with the proviso that when R² is hydrogen and both R3 and R4 are methyl, RI does not represent hydrogen, alkyl, unsubstituted benzyl or dimethyla inoethyl; having 5-HT3 receptor antagonist activity.

Quinolines and Isoquinolines

W09964421 (June 1999, Arena Pharmaceuticals, Inc) Acetylcholine 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 acetylcholmesterase (AChE) inhibition activity, and 5-HT3 receptor antagonist activity. A particularly preferred compound is 2-[2- (l-benzylpiperizin-4-yl) ethyl]-2 , 3-dihydro-9-methoxy- lH-pyrrolo[3 , 4-b]quinolin-l-one hemifumarate, referred to herein as Compound A ("Cm.A") .

EP0526545 (April 1991, Beecham Group p.l.c.)' Isoquinoline Amides And Esters As 5-HT3 Receptor Antagonists . A compound of formula (I) , or a pharmaceutically acceptable salt thereof:

wherein

E is NH or 0,

Rl is hydrogen, alogen, C1--4 alkyl, ^-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 either R2 is in the 3 -position and is hydrogen, C]__g alkyl or Cτ_-g alkoxy, or R2 is in the 4- position and is hydrogen, halogen, CF3 , Cτ__ alkyl, ^-η acyl, C]__7 acylamino, phenyl optionally substituted by one or two C^-g alkyl, C_]__g alkoxy or halogen groups, or amino, aminocarbonyl or aminosulphonyl , optionally substituted by oone or two C]__g alkyl or C3..8 cycloalkyl groups or by 04.5 polymethylene or by phenyl, Cι_g alkylsulphonyl, Cτ__g alkyl- suphinyl, C^-g alkoxy, C^.g alkylthio, hydroxy or nitro; or

ii) the group CO-E-Z is- in the 3 -position and either R2 is in the 1-position and is hydrogen, Cη__g alkyl or Cι__ alkoxy, or R2 is in the 4- position and is hydrogen or Cη__g 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 ^" harmaceuticals . In formula (I) E is NH or 0, RI 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, acyl- amino (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 Antagonist

A compound of the formula:

where

R is hydrogen or alkyl; Rτ_ 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 R¹ and/or R" groups may form a C=C double bond; geminal R and R¹ and R and R" groups may be ~(CH2)_n- where n is 2 to 6;

where m is 0-2, n is 1-2 and X is N or S; or pharmaceutically 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 endogenous psychoses of the type manifested in patients suffering from schizophrenia and mania, for irritable bowel syndrome, and to combat drug abuse.

• EP0482939 (October 1991, Ono Pharmaceuticals) Isoquinolinone derivative.

wherein each substituent R¹ is the same or different and is hydrogen, halogen, C]__4 alkyl, Cι_4 alkoxy or a group of formula:

-NR⁴R⁵

wherein R⁴ is hydrogen, Cχ_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 C_]__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 RI is hydrogen, Cl-4 alkyl, Cl-4 alkoxy or a group of formula: -NR4R5 wherein R4 is hydrogen, halogen, Cl-4 alkyl or C2-4 alkanoyl and R5 is hydrogen, Cl-4 alkyl or benzyl; R² is hydrogen or Cl-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) .

Benzof ranes, Benzooxazines and Benzo (di) azepines - .

US4935511 (September 1989, Rorer Pharmaceutical Corporation) Benzoxazine benzooxazipine carboxamide 5- HT3 antagonists.

where

X is hydrogen, halo, sulfamyl, alkylsulfamyl or alkylsulfonyl ;

Y is hydrogen, amino, mono- or di-alkylamino or halo; Z is

3 -quinuclidine , 4 -quinuclidine , 4 - ( 1-azabicyclo-

[3 . 3 . l]nonane) , 3 - ( 9 -methylazabicyclo[3 . 3 . l]nonane) or 4 -[3 -methoxy- 1 - ( 3 ( - [4 -fluorophenoxy]propyl ) piperi dine] ; R, Rχ _; 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 benzoxazepine carboxamide compounds which exhibit ^'5- HT.sub.3 antagonist properties including CNS, antiemetic and gastric prokinetic activity and which are void of any significant D.sub.2 receptor binding affinity. This invention also relates to pharmaceutical compositions and methods for the treatment of gastrointestinal 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 RI and R2 represent hydrogen, or RI and R2 taken together from a bivalent radical of formula

-CH=CH-CH=CH- (a) - -CH=C(C1) -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 Pharmaceuticals Inc) 2, 6-Methano-2H-l- Benzoxacincarboxylic acids, esters and amides.

and its steroisomers, enantiomers, diasteroisomers and racemic mixtures with an amine of the formula H₂N-Z; where

Rl is hydrogen, an amino or alkylamino optionally substituted with a protecting group halo or haloalkyl; 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-l-benzoxo- cincaboxamides having 5-HT . sub .3 -antagonist properties including unique CNS, antiemetic and gastric prokinetic activities and which are void of any significant D.sub.2 receptor binding affinity, therapeutic compositions and methods of treatment 'Of disorders which result from 5-HT. sub.3 activity using said compounds. Processes for their preparation and the preparation of their intermediates are also disclosed.

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

Other 5-HT3 antagonist compounds

EP0611370 (October 1992, Smithkline Beecham Pic) Pyridine-3 -Carboxylic Acid Esters Or Amides Useful As 5-HT3 Antagonists.

A compound of formula (I) , or a pharmaceutically acceptable salt thereof:

wherein

Rτ_ is C]__g alkoxy, C3.-.8 cycloalkoxy or 03.3 cyclo- ^' alkyl C]__4 alkoxy;

R2 is hydrogen, halo, C_]__^'g alkyl, C]__ alkoxy or amino optionally substituted by one or two C _g alkyl groups ;

R3 is hydrogen, halo or C_]__g 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 acceptable salts thereof wherein RI is Cl-6 alkoxy, C3-8 cycloalkoxy or C3-8 cycloalkyl Cl-4 alkoxy; R2 is hydrogen, halo, Cl-6 alkyl, Cl-6 alkoxy or amino- optionally substituted- by one or two Cl-6 alkyl .groups; R3 is hydrogen, halo or Cl-6 alkyl; L is 0 ■ or NH; and Z is a di-azacyclic or^' azabicyclic side chain; having 5-HT3 receptor antagonist activity.

• EP0607233 (October 1991, Smithkline Beecham Pic) 3,9- Diazabicyclo (3.3. l)Nonane Derivatives With 5-HT3 Receptor Antagonist Activity

A compound of formula (I) , or a pharmaceutically acceptable salt 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 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 acceptable 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 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.

WO9308185 (January 1991, Smithkline Beecham Plc)N- Aryl-Nl-Azabicyclo-Ureas As 5-HT3 Antagonists

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

A_]_, A2 , A3 and the carbon atoms to which they are attached form a 5- or 6-membered non- romatic heterocyclic ring containing at least one -0-, -C0- or -N- ; R]_ and R2 are hydrogen or C^_g alkyl; Y is hydrogen, halo, Cι--g alkyl or Cχ--g alkoxy; L is 0 or NH;

Z is an azabicyclic side chain; having 5-HT3 receptor - antagonist activity.

Compounds of formula (I) and pharmaceutically acceptable 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- ; RI and R2 are hydrogen or Cl-6 alkyl; Y is hydrogen, halo, Cl- 6 alkyl or Cl-6 alkoxy; L is 0 or NH; Z is an azabicyclic side chain; having 5-HT3 receptor antagonist activity.

US4808588 (July 1987, Beecham Group) Heterocyclic ureas and carbonates useful as pharmaceuticals.^'

wherein

Het is monocyclic heteroaryl having two adjacent carbon atoms, a and b, depicted in formula (I) selected from the group consisting of pyridine, pyrimidine, pyrazine, pyrrole, imidazole, thiophene, furan, oxazole and thiazole;

Rl and R2 are independently selected from hydrogen, halogen, CF3 , C^.g alkyl and C -6 alkoxy;

R3 is hydrozy, Cχ_g alkoxy, C3_₇ alkenyl -methoxy, phenoxy or phenyl Cχ_4 alkoxy in which either phenyl moiety may be substituted by one or two C_]__g alkyl, Cτ__g alkoxy or halo; CC^ wherein Rg is hydrogen or C!_g alkyl, CONR₇R₈ or S0₂NR₇R₈ wherein R₇ and Rβ >"^' are independently hydrogen or Cι_g alkyl or together are C4_ polymethylene , NO2 , (CH2)_m ^OR9 wherein m^' is^'. 1 or 2 and R9 is C --g alkyl or S(0)_nR;ι_o wherein n is 0, 1 or 2 and R o is ^cl - ζ alkyl; L is NH or O;

Z is a group of formula (a) , (b) or (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 C _4 alkyl. -

Compounds of formula (I) , or a pharmaceutically acceptable salt thereof: ##STR1## wherein: Het is monocyclic heteroaryl having two adjacent carbons atoms, a and b, depicted in formula (I); pi R.sub.l and R.sub.2 are independently selected from hydrogen, 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(0).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 0; Z is a group of formula (a) , (b) or (c) ; ##STR2## wherein n is 2 or 3; p is 1 or 2; q is 1 to 3; r is 1 to 3 ; and R.sub.4 or R.sub.5 is C.sub 1-4 alkyl; having 5- HT.sub.3 antagonist activity, a process for their'^' preparation and their use as pharmaceuticals.

The most preferred 5-HT₃ receptor antagonist is tropanyl-3, 5-dimethylbenzoate.

According to the present invention several known substances are, unexpectedly, able to induce airway smooth muscle relaxation by blocking the constricting 5-

HT₂ receptor. Such antagonists are selected from the following groups and substances: Ketanserin, i.e. 7- azido-3- [2- [4- (4-fluorobenzoyl) -1-piperidinyl] ethyl] -6- iodo-2,4(lH, 3H) -quinazolinedione, having the structural formula:

AMI-193, i.e. 8- [3- (4-fluorophenoxy) propyl] -1- phenyl-1, 3 , 8-triazaspi-ro [4, 5] decan-4-one, having the structural formula:

1- ( (indolyl azacycloalkyl) alkyl) -2,1, 3-benzo- thiadiazole 2, 2 -dioxides with the following structure (see WO 00/49017) .

thiopyran derivatives represented by the following formula (I) or (I'), or the salt thereof (see US 6,100,265) .

wherein A is S or -CH=CH- ; the dotted line indicates that- the bond may be either present or absent; Z and Z' are typically

0 .0-:-. -... -0-:; ";!:\Pat\ .bk\.--:--;\';000\.-:0.1 rCiO £;----_ (Pi '.:.:! -^:10 '■ . 0832 (.lied scannrit-l--? L is an ethylene -or trimethylene group; Y is CH or N; n is 2; B is a carbonyl group; m is 0 or 1; D is a phenyl group; and E^ and E2 are hydrogen atoms, pyrrolidine compounds with the following structure: (see WO 00/26186)

Pyrrolothiazine and pyrrolothiazepine compounds (see EP 0 970 089)

(a pyrrolesulfonamide compound having formula (I) wherein the ring P represented by is a pyrrole ring having structure β or ψ wherein A represents alkylene, alkenylene or alkynylene; and Y represents a group δ in which W represents CH, C= or N; m stands for 0 or 1 when W is CH or N, or m stands for 1 when W is C=; B represents a specific divalent group; Ei and E2 each independent- ly represents H or lower alkyl; and D represents an aromatic hydrocarbon group or heterocyclic group; I stands for 0 or 1; the dashed line indicates the presence or absence of a bond; and, when the bond is present, Z2 is not present and Zη_ represents H but, when the bond is absent, Z]_ represents H-and Z2 represents OH or Z]_ and Z2 are combined together to represent 0 or a group NOR5, in which R5 represents H, or alkyl, aralkyl or aryl; and R represents H, alkyl, cycloalkyl, cycloalkyl -alkyl or aralkyl .

Azabicycle-substituted phenylindole derivatives wi,.th the following formula (see WO 00/04017) .

Oxazolidines ( see EP 0 964 863 )

Pyrrolothiazine and pyrrolothiazepine compounds (see EP 0 970 088 )

(a pyrrolesulfonamide derivative having formula (I) wherein the ring P represented by α is a pyrrole ring having structure β or ψ wherein R represents alkyl, cycloalkyl, cycloalkyl-alkyl or aralkyl; the dashed .line indicates the presence or absence of a bond; and, when the bond is present, Z2 is not present and Z_ represents H but, when the bond is absent, Z]_ represents H and Z2 - - represents OH or Z]_ and Z2 are combined together to represent O or a group NOR]_, in which R_ represents H, or alkyl, aralkyl or aryl; £ stands for 0 or 1 ; A represents alkylene, alkenylene or alkynylene; and Y represents a group 1 in which W represents CH, C= or N; m stands for 0 or 1 when W is CH or N, or m stands for 1 when W is C=; B represents a specific divalent group; E]_ and E2 each independently represents H or lower alkyl; and D represents an aromatic hydrocarbon group or heterocyclic group) , indole derivatives (see WO 99/58525 and WO 00/4901J ) with the following structures (see also WO 99/47511) .

preferably 3- (piperidin-3-yl) -1 H indole compounds (see WO 98/38189) . oxazolidine compounds (indole compounds) with the following structure

pyrroloazepine compounds with the following structures (see US 5,962,448).

Piperidine derivatives (JP 11246526 )

pyrrole sulphonamide-based compounds (see JP 11193290) , substituted 1, 2 ,3 , 4-tetrahydronaphtalene derivatives (see EP 0 888 319) , preferably piperidinyl and piperazinyl substituted 1,2,3,4- tetrahydronaftalen compounds, benzothiazine derivatives (see US 5,874,429),

2-{2-[4-fluoro-2- (2 -phenylethyl) phenoxy]ethyl}-4- hydroxy-1-methylpyrrolidine (see JP 11158067)

and biphenyl derivatives (see US 5,849,912), - . and ALEPH-2, amperozide, amesergide, aryloxyalkylimid- azolines, l-aryl-4-propylpiperazines, BIMT 17, .1-3- [4- (3- chlorophenyl) -1-piperazinyl] propyl-6-fluoroindolin-2 (1 H)-one, CGS 18102A, cinanserin, clonidine, cyprohepta- dine, deramciclane, desmethyl-WAY 100635, dotarizine, DV 7028, elymoclavine, fananserin, 4- (4-fluorobenzoyl) -1- (4-phenylbutyl) -piperidine, 8- [3- (4-fluorobenzoyl) pro- ' pyl] -1-methyl-l, 3 , 8-triazaspiro [4, 5] decan-4-one, FG5893 hydrochloride, FG5974, FG5983, hexahydrocarbazoles, (3H)WAY 100635, ICI 169,369, 8- [3- (4-iodobenzoyl) propyl] - 1-methyl-l, 3, 8-triazaspiro [4,5] decan-4-one, LEK-8804, loxapine, LSD, LU 111995, LY53857, (S, S) -LY-53 , 857 , (R,S) -LY-53, 857, (S , R) -LY-53 , 857 , (R, R) -LY-53 , 857 ,

LY-53, 857 free base, LY 215840, MDL-11,939, MDL 28133A, MDL 100,151, MDL 100,907, mesulergine, Metergoline, Metergoline fenylmethyl ester, 1-3- [4- (2 -methoxyphenyl) - 1-piperazinyl] propyl indolin-2 (1H) -one, methysergide, Mianserin, NE-100, N-desmethylclozapine, Nefazodone, N- ethoxycarbonyl-2 -ethoxy-1, 2-dihydroquinoline, NRA0045, olanzapine, ondansetron, 1- (2-pyrimidinyl) piperazine derivatives, pirenpirone, pizotifen, pizotyline, pro- methazine, raclopride, roxindole, risperidone, ritan- serin, RP62203, sarpogrelate and its active metabolite (M-l) , serotonin reuptake inhibitors like fluoxetine, YM 992, medifoxamine, cericlamine, imipramine, iprindole, BIMT 17, citalopram, paroxetine, sertraline, sulpride (+)-, fluvoxamine, spiro indoles N-substituted with a 3- (dimethylamino) propyl chain, spiperone, SR 46349B, thioridazine, WAY 100635, WY-50,324, MDL 100,907, LY-53, 857 maleate, Pirenperone, Sulpiride (+-)+.

The most preferred 5-HT₂ antagonist is 4- (4-fluorobenzoyl) -1- (4-phenylbutyl) -piperidine.

The preferred combinations of 5-HT₃ and 5-HT₂ antagonists are the following: - 3- (1-piperazinyl) -2-quinoxalinecarbonitrile and 4(4- fluorobenzoyl) -1- (4-phenylbutyl) -piperidine

3- (1-piperazinyl) -2-quinoxalinecarbonitrile and - - AMI-193

3- (1-piperazinyl) -2-quinoxalinecarbonitrile and MDL 119395

Tropanyl 3 , 5-dimethylbenzoate and 4(4-fluoro- benzoyl) -1- (4-phenylbutyl) -piperidine

Tropanyl 3 , 5-dimethylbenzoate and AMI-193 Tropanyl 3 , 5-dimethylbenzoate and MDL 11939 - VB20B7 and 4 (4-fluorobenzoyl) -1- (4-phenylbutylJ - piperidine

- VB20B7 and AMI-193

- VB20B7 and MDL 11939 MDL 72222 and Cinanserin - 5- ( (dimethylamino) methyl) -3- (1-methyl-1H-indol-3- yl) -1, 2,4-oxadizole and AMI-193

5- ( (dimethylamino) methyl) -3- (l-methyl-lH-indol-3- yl) -1, 2,4-oxadizole and 4 (4-fluorobenzoyl) -1- (4-phenylbutyl) -piperidine The present invention is also intended to comprise derivatives and analogs of the 5-HT₄ receptor antagonists, 5-HT₃ receptor antagonists and 5-HT₂ receptor antagonists mentioned above having the same or essential same airway relaxation effect .

The present invention also relates to a method for treatment of disorders involving airway constriction, »^•' wherein said method comprises the administration to a human or animal patient of a therapeutically effective amount of a composition comprising a combination of a) at least one compound with antagonist activity to the 5-HT₃ receptor and b) at least one compound with antagonist activity to the 5-HT₂ receptor. Preferably, said method relates to the treatment of asthma, chronic bronchitis, emphysema and chronic obstructive pulmonary disease.

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 requirement of each patient and the route of administration. _ _ In said -combination of compounds with 5-HT₃ and 5-HT₂ -antagonist activity, • the relative amount of either com-^' pound may vary, but typically are about equal.

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

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, capsules, powders, microparticles, granules, syrups, suspensions, solutions, transdermal patches or suppositories. Detailed Description of the Invention The subject-matter of the present invention was inter alia deduced from animal experiments, where a specific behaviour of the airway smooth muscle called UI t tsJ H --¹ cπ o cπ O cπ o cπ •

it has now unexpectedly been shown that 5-HT causes a contraction of guinea pig airways at low concentrations and a relaxation at high concentrations, i.e. a dual effect. Furthermore, it was found that the 5-HT_2a receptor antagonist ketanserin almost completely abolished the contraction but did^' not affect the relaxation, demonstra-^' ting that the contraction and relaxation was caused by activation of different receptors.

Similar experiments have also been performed on human airway preparations from patients undergoing lobec- to y or pulmecto y 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 l μM 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, our examinations of spontaneous tone on human in vitro preparations have shown that 5-HT indeed causes a contraction 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 relaxation, rather than an increase of tone from the baseline (pre-treatment) level. The relaxation, which has a maximum after 10-15 min, disappears gradually during the following 30-45 min (see Fig 1) . In contrast, in guinea pig trachea, the first 5-HT-induced effect is a contraction which reaches a maximum after- approximately 10 min, and this is followed, within approximately ^' _; 30 min, by a relaxation below the pre-treatment 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 slower contracting 5-HT₃ and 5-HT₂ receptors. This is clear, because activation of the relaxing 5-HT receptor by a substance that lacks 5-HT₃ and 5-HT₂ receptor activating properties (such as^'RS 67333), results in a re- laxation that is persistent and not transient. Further, unspecific agonists, such as 5-HT, can cause a sustained relaxation if the constricting 5-HT₂ and 5-HT₃ receptors are simultaneously blocked. As mentioned above, our experiments have shown that^' there is a continuous release of 5-HT in human airways, most likely from the NEE cells, and that this endogenous 5-HT stimulates the contracting 5-HT₂ and 5-HT₃ receptors. This is clear because a blockade of 5-HT₂ and 5-HT₃ recep- tors caused a distinct smooth muscle relaxation in examined preparations, implying that the 5-HT₂- and 5-HT₃- mediated contraction is an important factor in the generation of spontaneous tone in human airways.

In SU 1 701 320 it is suggested that 5-HT may be of use as an addition to standard beta2 receptor stimulation for the treatment of acute asthma attacks . No receptor mechanism for the effect of 5-HT is disclosed in that - - patent. SU 1 701 320 is not relevant for the present_. application since we do not propose the use of- 5-HT receptor agonists (such as 5-HT) , but rather 5-HT receptor antagonists .

The action of this combination at two different receptors causes a greater airway relaxation than an action at only one receptor. Further, we have found that the most important contractile receptor in some individuals is 5-HT₂ and in others 5-HT₃, which necessitates a combi- nation of blocking substances.

In summary-, it has now been discovered that inhibition of the 5-HT₃ receptor and/or the 5-HT₂ receptor re- suits in airway relaxation. It was deduced from these experiments that compounds with antagonist activity to the 5-HT₂ receptor and compounds with antagonist activity to the 5-HT3 receptor therefore are useful as agents for treatment of disorders involving airway constriction, as defined above.

Thus, the present invention relates to a composition comprising a combination of compounds comprising a) at least one compound with antagonist activity to the 5-HT₃ receptor and b) at least one compound with antagonist activity to the 5-HT₂ -receptor as a medicament. The present invention also relates to the use of said combina- tion for the manufacture of a^' medicament intended for treatment of disorders involving airway constriction, wherein the administration of said combination can be simultaneous or sequential.

Claims

1. A composition- comprising a combination of compounds comprising a) at least one compound with antagonist, activity to the 5-HT₃ receptor, and b) at least one compound with antagonist activity to the 5-HT₂ receptor.

2. A composition according to claim 1, wherein said composition has the capacity of reducing pathological airway constriction by at least 30%, preferably at least 60%, and most preferably at least 90%, and wherein said combination is chosen from the following groups of 5-HT₃ antagonists and 5-HT₂ antagonists, or derivatives or pharmaceutically acceptable salts thereof . a) 5-HT₃ receptor antagonists

benzazepines, preferably mirtazapine

benztiazephines , preferably diltiazem

and fentiazines

preferably perphenazine, chlorpromazine, stemetil; compounds also having 5-HT₄ receptor agonist activity, preferably benzamides

, -

and

2 , 3 -dihydro-benzofuran-7-carboxamides

(preferably zatosetron=LY 277359, ADR 851) 1, 4 -bensoxazin-8-carboxamides

preferably azasetron (=Y25130) benzimidazolones

preferably itasetron (=DAU 6215) ; indazol-3 -carboxamides

preferably N 3389, LY 278584, DAT 582; wherein the latter group reminds most of the specific 5-HT₃ antagonists, which contains the group

in different forms, such as

.ondansetron

alosetron cilansetron

substances the structure of. which has been inverted^' and the carbonyl group has been placed on the indoline nitrogen

also being an antagonist against both 5-HT₃ and 5-HT₄ receptors,

bisindoles

isoquinoline-1-ones

palonosetron (=RS 25259-197) RS 42358-197

and the quinoline-3 -carboxamides

WAY-SEC 579 Mirisetron (=WAY 100579) ,

quinoline-4-carboxylates

preferably KF 17643

preferably KF 18259;

benzimidazolones

preferably droperidol (neurolidol) , itasetron (DAU6215) , and the naphtimides

preferably RS 56532;

MDL 72222, which also is a specific 5-HT₃ antagonist;

Talipexole

iodophenpropit

thioperamide, and

2-piperidin- and 2-piperazin- benzimidazoles; and also

(R) -zacopride, 2 -methyl-5HT, 3- (1-piperazinyl) -2- quinoxalinecarbonitrile, 3- (4-allylpiperazin-l-yl) -2- quinoxalinecarbonitrile, 4-Ph-N-Me-quipazine, 5- ( (dime- thylamino) methyl) -3- (1-methyl-1H-indol-3 -yl) -1, 2,4- oxadizole, 5,7-DHT, 5- [ (dimethylamino) methyl] -3- (1- methyl-lH-indol-3-yl)-l, 2,4-oxadizole, ADR-882, A i- triptyline, AS-5370, Batanopride, BIMU 1, BRL 24682, BRL 43694, -BRL 46470 (=Ricasetron) , BRL 47204, Bufo- tenine, CF 109203 (=BIM) , Cizapride, Clozapine, CP-9331-8, 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, Methysergide, Mianserin, MK 212, N-3256, N7ΛN-190, N- metylquipazin, 3- (1-piperazinyl) -2-quinoxalinecarbonitrile, ONO-3051, Pancopride, Phenylbiguanide, Pito- zifen, Prochlorperazine, QICS 205-930, R (+) zacopride, - . Renzapride, RG 12915,. Ritanserin, RP 62203, RS-056812- 198, RS-25259, RU 24969, S (^'-) Zacopride, S-apoτriorfin, 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-dimethylbenzoate, 3-tropanyl-indole-3-carboxylate methiodide, VA 21 B 7, Y 2513, zelmac, SEC 579, BRL 46470 A, Pizo- tifen, Dolasetron (=MDL 74156), Galanolactone, GR 65 630, Ifenprodil, L-683877, Litoxetine, Quipazine, QX 222, Ramosetron (=YM 060), RS 56812, SDZ 216-525, Trimebutine, GR 65630, Tropisetron, Bemesetron, L-683,877, LY-278, 584 maleate and pharmaceutically acceptable salts thereof with the same or essentially the same relaxation enhancing effect, and b) 5-HT₂ receptor antagonists: Ketanserin, i.e. 7- azido-3- [2- [4- (4-fluorobenzoyl) -1-piperidinyl] ethyl] -6- iodo-2,4(lH, 3H) -quinazolinedione, having the structural formula:

AMI-193, i.e. 8- [3- (4-fluorophenoxy) propyl] -1-phenyl- 1, 3, 8-triazaspiro [4, 5] decan-4-one, having the structural formula :

1- ( (indolyl azacycloalkyl) alkyl) -2,1, 3-benzo- thiadiazole 2, 2 -dioxides with the following structure:

thiopyran derivatives represented by the following formula (I) or (I¹), or the salt thereof:

wherein A is S or -CH=CH-; the dotted line indicates that the bond may be either present or absent; Z and Z' are typically

L is an ethylene or trimethylene group; Y is CH or N; n is 2; B is a carbonyl group; m is 0 or 1 ; D is a phenyl group; and Ei and E2 are hydrogen atoms, pyrrolidine compounds with the following structure:

pyrrolothiazine and pyrrolothiazepine compounds

^{ϊ H}^ ^El^£2

(a pyrrolesulfonamide compound having formula (I) wherein the ring P represented by α is a pyrrole ring having structure β or ψ wherein A represents alkylene, alkenylene or alkynylene; and Y represents a group δ in which represents CH, C= or N; m stands for 0 or 1 when W is CH or N, or m stands for 1 when is C=; B represents a specific divalent group; E_ and E2 each independently represents H or lower alkyl; and D represents an aromatic hydrocarbon group or heterocyclic group; £ stands for 0 or 1; the dashed line indicates the presence or absence of a bond; and, when the bond is present, Z2 is not present and Z]_ represents H but, when the bond is absent, Z- represents H and Z2 represents OH or Z]_ and Z2 are combined together to represent O or a group NOR5, in which R5 represents H, or alkyl, aralkyl or aryl; and R represents H, alkyl, cycloalkyl, cycloalkyl-alkyl or aralkyl ; azabicycle-substituted phenylindole derivatives with the following formula.

oxazolidines

pyrrolothiazine and pyrrolothiazepine compounds

^""? y-^Ja-^O rø

#

(a pyrrolesulfonamide derivative having formula (I) wherein the ring P represented by is a pyrrole ring having structure β or ψ wherein R represents alkyl, cycloalkyl, cycloalkyl-alkyl or aralkyl; the dashed line indicates the presence or absence of a bond; and, when the bond is present, Z2 is not present and Z-_ represents H but, when the bond is absent, Z]_ represents H and Z2 - - represents OH or Z _ and Z2 are combined together to represent 0 or a group NOR_]!_., in which R^ represents H, or alkyl, aralkyl or aryl; £ stands for 0 or 1; A represents alkylene, alkenylene or alkynylene; and Y represents a group 1 in which W represents CH, C= or N; m stands for 0 or 1 when W is CH or N, or m stands for 1 when W is C=; B represents a specific divalent group; Ej_ and E2 each independently represents H or lower alkyl; and D represents an aromatic hydrocarbon group or heterocyclic group) , indole derivatives with the following structures.

_R4 preferably 3- (piperidin-3-yl) -1 H indole compounds, oxazolidine compounds (indole compounds) with the following structure

pyrroloazepine compounds with the following structures :

fc a pyrrole nag Iwv-cz the following s-ruc.t-f c; -ote-- by

piperidine derivatives_.

pyrrole sulphonamide-based compounds, substituted 1,2,3, 4-tetrahydronaphtalene derivatives, piperidinyl and piperazinyl substituted 1,2,3,4- tetrahydronaftalen compounds, benzothiazine derivatives,

2-{2-[4-fluoro-2- (2-phenylethyl) phenoxy]ethyl}-4- ,- hydroxy-1-methylpyrrolidine

and biphenyl derivatives;

LY-53, 857 maleate, Pirenperone, Sulpiride (+-)+, and. ALEPH-2, amperozide, amesergide, aryloxyalkylimidazolin- es, l-aryl-4-propylpiperazines, BIMT 17, 1-3- [4- (3- chlorophenyl) -1-piperazinyl] propyl-6-fluoroindolin-

2(1 H) -one, CGS 18102A, cinanserin, clonidine, cyprohep- tadine, deramciclane, desmethyl-WAY 100635, dotarizine,,- DV 7028, elymoclavine, fananserin, 4- (4-fluorobenzoyl) -1- (4-phenylbutyl) -piperidine, 8- [3- (4-fluorobenzoyl) propyl] - 1-methyl-l, 3, 8-triazaspiro [4,5] decan-4-one, FG5893 hydrochloride, FG5974, FG5983, hexahydrocarbazoles , (3H)WAY 100635, ICI169,369, 8- [3 - (4-iodobenzoyl) propyl] -1-methyl- 1, 3 , 8-triazaspiro [4, 5] decan-4-one, LEK-8804, loxapine, LSD, LU 111995, LY53857, (S, S) -LY-53 , 857 , (R,S)-LY- 53,857, (S,R) -LY-53, 857, (R, R) -LY-53 , 857 , LY-53, 857 free base, LY 215840, MDL-11,939, MDL 28133A, MDL 100,151, MDL 100,907, mesulergine, Metergoline, Metergoline fenyl- methyl ester, 1-3- [4- (2-methoxyphenyl) -1-piperazinyl] - propyl indolin-2 (1H) -one, methysergide, Mianserin, NE-100, N-desmethylclozapine, Nefazodone, N-ethoxy- carbonyl-2-ethoxy-1, 2-dihydroquinoline, NRA0045, olanza- pine, ondansetron, 1- (2-pyrimidinyl) piperazine deriva- »- tives, pirenpirone, pizotifen, pizotyline, pro ethazine, raclopride, roxindole, risperidone, ritanserin, RP62203, sarpogrelate and its active metabolite (M-1) , serotonin reuptake inhibitors like fluoxetine, YM 992, medifox- amine, cericlamine, imipramine, iprindole, BIMT 17, citalopram, paroxetine, sertraline, sulpride (+)-, flu- voxamine, spiro indoles N-substituted with a 3- (dimethylamino) propyl chain, spiperone, SR 46349B, thioridazine, WAY 100635, WY-50,324, MDL 100,907. 3. Composition according to claim 2, wherein it comprises a combination of compounds selected from one of the following combination of 5-HT₃ receptor antagonists, and 5-HT₂ receptor antagonists;

3- (1-piperazinyl) -2-quinoxalinecarbonitrile and 4(4- fluorobenzoyl) -1- (4-phenylbutyl) -piperidine

3- (1-piperazinyl) -2-quinoxalinecarbonitrile and AMI-193

3- (1-piperazinyl) -2-quinoxalinecarbonitrile and MDL 119395 - Tropanyl 3 , 5-dimethylbenzoate and 4(4-fluoro- benzoyl) -1- (4-phenylbutyl) -piperidine

Tropanyl 3 , 5-dimethylbenzoate and AMI-193 Tropanyl 3 , 5-dimethylbenzoate and MDL 11939

- VB20B7 and 4 (4-fluorobenzoyl) -1- (4-phenylbutyl) - piperidine

- VB20B7 and AMI-193

- VB20B7 and MDL 11939 MDL 72222 and Cinanserin

5- ( (dimethylamino) methyl) -3- (l-methyl-lH-indol-3- yl) -1, 2,4-oxadizole and AMI-193

5- ( (dimethylamino) methyl) -3- (l-methyl-lH-indol-3- yl) -1, 2 , 4-oxadizole and 4 (4-fluorobenzoyl) -1- (4-phenylbutyl) -piperidine

4. Composition according to claim 2 for use as a medicament.

5. Composition according to claim 3 for use as a medicament .

6. Use of a composition comprising a combination of compounds comprising a) at least one compound with antagonist activity to the 5-HT₃ receptor, and b) at least one compound with antagonist activity to the 5-HT₂ recep- tor for the manufacture - of a medicament for therapeutic or prophylactic treatment of disorders involving airway constriction, chosen from the group consisting of asthma, emphysema, chronic bronchitis and chronic obstructive pulmonary disease.

7. Use according to claim 6 of a composition as defined in claim 2.

8. Use according to claim 7 of a composition as defined in claim 3.

9. A method for the treatment of disorders involving airway constriction chosen from the group consisting of asthma, emphysema, chronic bronchitis and chronic obstructive pulmonary disease, wherein said method com- , - . prises administration of a therapeutically effective amount of a composition according to any one of claims • 1-3.