WO2001095903A1 - 5-ht3 receptor antagonists for treatment of disorders involving airway constriction - Google Patents

5-ht3 receptor antagonists for treatment of disorders involving airway constriction Download PDF

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WO2001095903A1
WO2001095903A1 PCT/SE2000/002613 SE0002613W WO0195903A1 WO 2001095903 A1 WO2001095903 A1 WO 2001095903A1 SE 0002613 W SE0002613 W SE 0002613W WO 0195903 A1 WO0195903 A1 WO 0195903A1
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receptor
alkyl
methyl
group
hydrogen
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French (fr)
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Staffan Skogvall
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Respiratorius Ab
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Publication of WO2001095903A1 publication Critical patent/WO2001095903A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404Indoles, e.g. pindolol
    • A61K31/4045Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/08Bronchodilators

Definitions

  • the present invention relates to a compound having antagonist activity to the 5-HT 3 receptor for use as a medicament and to the use of said compound in the manu- 5 facture of a medicament for therapeutic or prophylactic treatment of disorders involving airway constriction of a human or animal body, as well as methods of treatment, wherein said compound is administered.
  • the seven main receptors of the 5-HT (serotonin; 3- ( ⁇ -aminoethyl) -5-hydrox indole) type are well known and occur throughout the body, e.g. in the airways, and their relevance has mainly been reported to be of significance in conjunction with treatment of CNS, muscle and gastric
  • SU 1 701 320 Al discloses the use of serotonin for treatment of acute asthma attacks. This reference does
  • the present invention is based on the novel finding that certain 5-HT receptors are of utmost importance in regulating bronchocontraction, that is determining the level of airway constriction.
  • compounds having antagonist activity to the 5-HT 3 receptor are suitable agents in the treatment of disorders involving airway constriction.
  • Methods for treatment of disorders involving airway constriction are also disclosed.
  • the expression “disorders involving airway constriction”, equivalent to the expression “bronchocontraction disorder”, refers to an abnormal increase of the force development of the smooth muscle in human or animal airways, resulting in a reduced diameter in some or all of the airways of the lungs and/or the extrapulmo- nary airways, such as occurring in asthma, chronic obstructive pulmonary disease, emphysema and chronic bronchitis. Said expression also refers, in a wider sense, to reduction of airflow, more precisely airway diameter, caused by swelling, oedema, plasma extravasation or mucous secretion caused by e . g. asthma or any other disorder related thereto.
  • the expression "has the capacity of reducing the abnormal airway constriction by at least ....%" used through- out the present patent application means that the compound in question or the composition of compounds in combination as well as the derivatives and pharmaceutically acceptable salts thereof, persistently reduces, in 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, e.g. 5-HT 3 receptors.
  • the level of constriction in the airways can, for instance, be " determined by spirometric measurements of the Forced Expiratory Volume (FEVl) , compared to the normal value for healthy people. Alternatively, the expiratory capacity for a patient can be compared to his own FEVl during periods of relatively little obstructive problems.
  • FEVl Forced Expiratory Volume
  • the present invention relates, in one of its aspect, to a compound having antagonist activity to the 5-HT 3 receptor for use as a medicament. In another aspect it re- lates to use of said compound 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.
  • the invention relates to the use of a compound having antagonist activity to a 5-HT 3 receptor in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders involving airway constriction, wherein said antagonist has the capacity of reducing the pathological airway constriction by at least 30%, preferably at least 60%, and most preferably at least 90%.
  • Said airway constriction may occur in conjunction with such disorders as e. g. asthma, emphysema, chronic bronchitis, and chronic obstructive pulmonary disease.
  • 5-HT 3 antagonist compounds are, unexpectedly, able to enhance a 5-HT-induced airway relaxation.
  • the 5-HT 3 receptor is a ligand modulated ion channel .
  • 5-HT 3 receptor antagonists are at the same time 5-HT 4 receptor agonists.
  • the distance from the aromatic center to the basic nitrogen should be about 7,5 A and no large substituents are tolerated on the basic nitrogen.
  • the corresponding distance is about 8 A, and a large lipophilic group may be bound to the basic nitrogen, thereby obtaining a better binding to 5-HT .
  • the 5-HT 3 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
  • 5-HT 4 agonists e.g. ben- zamides
  • zatosetron LY 277359, ADR 851
  • This substance is unique by being an antagonist against both 5-HT 3 and 5-HT receptors.
  • BRL 46470A binds to two different positions of the receptor.
  • Another group is the isoquinoline-1-ones
  • MDL 72222 which also is a specific 5-HT 3 antagonist
  • Renzapride, RG 12915, Ritanserin, RP 62203, RS-25259-197 , RS-056812-198, RS-25259, RU 24969, S (-) Zacopride, S- apo orfin, SC-52491, SC-53116, SDZ 206-792, SDZ 206- " 830, SDZ 210-204, SDZ 210-205, SDZ 214-322, SDZ 322, SN-307, TFMPP, TMB 8, trifluoperzine, tropanyl-3 , 5-di- methylbenzoate, 3-tropanyl-indole-3-carboxylate methio- dide, VA ' 21 B 7, Y 2513, SEC 579, BRL 46470 A, Pizotifen, Dolasetron ( MDL 74156), Galanolactone, GR 65 630, Ifen- prodil, L-683877, Litoxetine, Quipazine, QX 222, Ramo
  • 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 .
  • ci 5 -4-Amino- j V- l-[3- ( p-.fluoro enoxi)propvl]-3-rnetoxi-4-piperi yl]-5- -kloro-o-anisa id
  • Pancopride ( (+-) N- (1-azabicyclo- [2,2,2] -oct-3-yl) - 2-eye1opropylmethoxy-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
  • pancopride antagonized 5-HT-induced bradycardia in anaesthetized rats when administered i.v.
  • a single oral dose (10 micrograms/kg) of pancopride produced a signifi- cant inhibition of the bradycardic reflex over " an 8-h period.
  • Pancopride dose dependently inhibited the number of vomiting episodes and delayed the 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 mechlor- ethamine- and dacarbazine-induced emesis.
  • pancopride 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(+)- 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.
  • the R(+) isomer was more potent to reduce the aversive behaviour of mice to a brightly illuminated environment and in a marmoset human threat test, to facilitate social interaction in rats, to increase performance in a mouse habituation test and prevent a scopolamine-induced impairment, and to antagonise the inhibitory effect of 2 -methyl- 5-hydroxytryptamine to reduce [3H] acetylcholine re- lease in slices of the rat entorhinal cortex.
  • [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.
  • the compound is also a known 5-HT4 agonist.
  • Batanopride (4-amino-5-chloro-N- [2- (diethylamino) - ethyl] 2- (1-methyl-2 -oxopropoxy ) benzamide). Batano- pride is also known by the name BMY-25801.
  • (+) -8, 9-Dihydro-10-dihydro-10 -methyl -7- [ (5-methyl-4- imidazolyl) methyl] pyrido- [1, 2-a] indol-6 (7H) -one hydrochloride (FK1052) is a newly designed and synthe- sized 5-hydroxytryptamine (5-HT) 3 receptor antagonist with 5-HT4 receptor antagonistic activity.
  • FK1052 unlike ondansetron and granisetron, inhibited the 5- HT4 -mediated component of concentration-response curve to 5-HT. Furthermore, FK1052 suppressed 5- methoxytrypta ine, a 5-HT4 agonist-induced contraction in a concentration-dependent but insurmountable manner .
  • [3H] ICS 205-930 a potent and selective 5-hydroxytryptamine 5-HT3 receptor antagonist, were investigated in membranes prepared from murine neuroblastoma-glioma NG 108-15 cells.
  • 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.
  • 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 206-792 greater than BRL 43694 greater than quipazine greater than BRL 24924 greater than SDZ 210-204 greater than MDL 72222 greater than SDZ 210-205.
  • Metoclopramide, mCP and mianserin showed submicromolar affinity.
  • the compound is both an indole derivative and ah imidazole.
  • Other imidazole derivatives are listed below.
  • 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 acti- vation of the von Bezold Jarisch reflex) .
  • ICS 205-930 or GR38032F which were equipotent as inhibitors of serotonin-induced bradycardia
  • 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.
  • 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.
  • GR38032F was slightly less potent than ICS 205-930 and possessed the shortest duration of action.
  • the compound is both an indole derivative and an imidazole.
  • Other imidazole derivatives are listed below.
  • Alosetron is a highly selective 5-HT3 antagonist which normalizes perturbed small intestinal propulsion.
  • IUPAC name (2 , 6, 8 , 9a ⁇ ) -octahydro-3-oxo-2 , 6-methano- 2H-quinolizin-8-yl-lH-indole-3-carboxylate monomethanesulfonate, monohydrate .
  • Zatosetron LY 277359.
  • the compound is also called LY 19617.
  • LY 277359 a putative 5-HT3 receptor antagonist
  • SNC or A9 substantia nigra pars compacta
  • VTA or A10 ventral tegmental area
  • GR67330 potently inhibited 5-hydroxytryptamine (5- HT) -induced depolarizations of the rat isolated va- gus nerve. At the higher concentrations used (0.3 nmol/1-1 nmol/1) this was accompanied by a marked reduction in the maximum response to 5-HT. The calculated pKB value was 10.2. The binding of the tri- tiated derivative of GR67330 to homogenates of rat entorhinal cortex was examined. Kinetic analysis revealed that specific [3H] GR67330 (0.1 nmol/1) binding was rapid and reversible.
  • 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.
  • zacopride was ap- • proximately 10-fold more potent than either ICS 205-930 or GR38032F, which were equipotent as inhibitors of serotonin-induced bradycardia (5-HT3- mediated activation of the von Bezold Jarisch re- flex) .
  • ICS 205-930 or GR38032F which were equipotent as inhibitors of serotonin-induced bradycardia
  • 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.
  • 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.
  • ICS 205-930 or GR38032F were 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.
  • VA21B7 (3- [2- (4 ' -piperonylpiperazinyl) • indolyl] car- boxaldehyde)
  • VA21B7 an atypical 5-HT3 recep- tor antagonist with anxiolytic-like properties in animal models.
  • VA21B7 (3- [2- (4 ' -piperonylpiperazinyl) indolyl] car- boxaldehyde) was synthesized as a potential 5-HT3 receptor antagonist. Even though VA21B7 showed a higher affinity towards 5-HT3 receptors as compared to other receptors studied, it was not a potent 5- HT3 receptor antagonist either in the periphery or in the brain. In a simple animal model of anxiety such as the two-compartment box in mice, a 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.
  • VA21B7 The anxiolytic profile of VA21B7 was further explored using other models of anxiety in rats such as the elevated plus-maze and punished- drinking.
  • VA21B7 was compared with standard 5-HT3 receptor antagonists such as ondansetron, tropise- tron and granisetron, with the 5-HT1A agent buspi- rone and with diazepam.
  • 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 and tropisetron were also effective in this test but not ondansetron and buspirone.
  • VA21B7 was also able to release suppressed behaviour in the punished-drink- ing test.
  • the dose-response curve was bell-shaped with a peak at 2-4 mg/kg.
  • 5-HT3 receptor antagonists also increased the number of shocks taken in this test and the dose-response curve was also bell-shaped.
  • VA21B7 was not anticonvulsant like diazepam, its anxiolytic ac- tion in the light/dark test was not flumazenil- sensitive and there was no rebound anxiogenic effect on withdrawal from chronic VA21B7 treatment for- 15 consecutive days.
  • VA21B7 was not amnesic like the benzodiazepines but low doses of 2-4 mg/kg reduced the memory deficits induced in rats by sco- polamine. Much higher doses were necessary to 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 inter- est as an anxiolytic in humans.
  • 5-hydroxytryptamine3 (5-HT3) recep- tor-mediating contractions and relaxations in the guinea-pig isolated distal colon using various 5-HT3 receptor agonists and antagonists, including GK-128 (2- [ (2-methylimidazol-l-yl) methyl] benzo [f] thio- chromen-1-one monohydrochloride hemihydrate) .
  • GK-128 (2- [ (2-methylimidazol-l-yl) methyl] benzo [f] thio- chromen-1-one monohydrochloride hemihydrate
  • Selective 5-HT3 receptor agonists, 2-methyl-5-HT and m-chlorophenylbiguanide produced spantide- insensitive contraction and atropine-insensitive contraction and the relaxation. These agonists showed a small, but significant, difference of po- tency between contraction and relaxation. 3.
  • GK-128 competitively blocked both 2 -methyl-5-HT- and - 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 af- finity in contraction than in relaxation, but the extent of their affinity differences was smaller than that observed in GK-128.
  • granisetron, ramosetron and ondansetron exhibited no. sig- nificant differences in their affinity values among- the three responses. 5.
  • trimebutine and YM114 (KAE-393) , a novel 5-HT3 receptor antagonist, on stress-induced defecation.
  • YM114 (KAE-393), (R) -5- [ (2 , 3-dihydro-1-indolyl) - carbonyl] -4, 5, 6, 7- tetrahydro-lH-benzimidazole hy- drochloride, is a derivative of YM060, a potent 5- HT3 receptor antagonist.
  • YM114 was investigated the effects of YM114 on 5-HT3 receptors, both in vitro and in vivo, and on bowel dysfunction induced by restraint stress, 5-HT and thyrotropin-releasing hormone (TRH) , and compared them with the effect of trime- butine.
  • 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) .
  • 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 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
  • Gigli- etti A Malacarne P
  • Donati D Indelli M
  • Bensi G
  • Itasetron hydrochloride is a new 5-hydroxytryptamlne3 (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 bio- transformation before elimination.
  • the aim of this open, uncontrolled study was to establish the effective dose range of itasetron hydrochloride given in- travenously (i.v.) to patients due to receive high- dose cisplatin chemotherapy (50-120 mg/m2) for the first time.
  • the compounds have the general structure .
  • DAT-582 In anesthetized rats, DAT-582 antagonized 2 -methyl-5-HT- induced bradycardia with an ED50 value of 0.25 mi- crogram/kg i.v., whereas the (S) enantiomer was without effect even at 1000 micrograms/kg i.v.
  • DAT-582 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.
  • DAT-582 -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.
  • the (S) enantiomer had little effect at 1000 micrograms/kg i.v. twice.
  • 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.
  • N-3389 (N-3389 (endo-3 , 9-dimethyl-3 , 9- diazabicy- clo [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.
  • IC50 3.2 x 10 (-8) M
  • 5-HT (10 (- 8) -10 (-5) M) induced biphasic contractions in the preparations. Furthermore, 5-HT3 receptor antagonism inhibited the late phase of the contraction induced by high concentrations of 5-HT (3 x 10 ( -6) -10 (-5) M) , whereas 5-HT4 receptor antagonism inhibited the early phase of the contraction induced by low con- centrations of 5-HT (10 (-8) -10 (-6) M) .
  • N-3389 (10 (- 7) -10 (-5) M) inhibited both phases of contraction induced by 5-HT.
  • 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.
  • Granisetronu ⁇ i INN Granisetron
  • BRL 43694 (granisetron) wasomme- gated using established models of 5-HT3 receptor activity.
  • BRL 43694 did not af- feet the contractions of similar preparations of ileum, evoked by electrical field stimulation (cholin- ergically mediated) , the nicotinic agonist dimethyl- phenyl piperazinium (DMPP) or by cholecystokinin oc- tapeptide.
  • electrical field stimulation cholin- ergically mediated
  • DMPP dimethyl- phenyl piperazinium
  • DMPP cholecystokinin oc- tapeptide
  • BRL 43694 did not affect elec- trically evoked, cholinergically mediated contractions of rat or human isolated stomach.
  • BRL 43694 did not affect elec- trically evoked, cholinergically mediated contractions of rat or human isolated stomach.
  • 5-HT3 receptor activity rabbit isolated heart, Bezold-Jarisch reflex in anaesthetised rats
  • potent antagonism by BRL 43694 was demonstrated.
  • 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 a selective 5-HT uptake inhibitor with concomitant 5-HT3 receptor antagonist and antiemetic properties. Angel I, Schoemaker H, Prouteau M, Gar- reau M, Langer SZ.; Eur J Pharmacol 1993 Mar 2, 232:2-3:139-45
  • the selective 5HT uptake inhibitor, litoxetine (SL 81.0385), currently under development as an antide- pressant was shown to have antiemetic properties in the ferret.
  • 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.
  • litoxetine inhibits cisplatin-induced emetic responses due to its moderate 5HT3 antagonist properties.
  • the clinical use of the majority of se- rotonergic antidepressants e.g.
  • fluoxetine, flu- voxamine etc. is associated with gastrointestinal discomfort (particularly nausea and vomiting) as a major side-effect. If nausea and vomiting associated with the use of 5 HT uptake inhibitors are due " to stimulation of 5HT3 receptors, the concomitant 5HT3 antagonism of litoxetine may limit the gastrointestinal side-effects of this novel, antidepressant and thus -.offer an important advantage.
  • [3H]LY278584 a 1-methyl-indazole-carboxamide, 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.
  • the order of potencies of other known an- tagonists of 5-HT3 receptors supports the conclusion that 3H]LY278584 binds to putative 5-HT3 receptors in cortical membranes.
  • ADR 851 [4-amino-5-chloro-2, 3-dihydro-N- (pyrrolidin- 2-ylmethyl) benzofuran-7-carboxamide
  • 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 .
  • neither S or R forms of ADR-882 produced significant anti-nociception in the formalin test.
  • 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.
  • Amitriptylinum INN ( Amitriptylin) 5-(3-Di etylarainopropyliden)-l0,ll-dihydro-5H- -dibens[ , djcyklohepten
  • Diltiazem Is the active ingredient in Cardizem, Pharmacia " Corporation
  • Isoquinoline and quinolizine are isomers of quinoline
  • the -log KB values for the other three enantiomers were 6.7 +/- 0.3 (R,R), 6.7 +/- 0.1 (S,R) and 7.4 +/- 0.1 (R,S), respectively.
  • the apparent affinities of RS 25259-197 and RS 25259-198, RS 25233-197 and RS 25233-198 at 5-HT3 receptors in membranes from NG-108-15 cells were evaluated by a [3H] -quipazine binding assay.
  • the -log Ki values were 10.5 +/- 0.2, 8.4 +/- 0.1, 8.6 +/- 0.1 and 9.5 +/- 0.1, respec- tively, with Hill coefficients not significantly- different from ⁇ nity.
  • Chlorpromazinum INN Korean (Klorpromazm) 10-(3-Dimetylaminopropyl)-2 ⁇ klorofentiazin
  • azasetron (Serotone)
  • Serotone a selective 5-HT3 receptor antagonist.
  • Tsukagoshi S Gan To Ka ⁇ aku Rvoho 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.
  • 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.
  • MCPP Metal-chlorophenylpiperazine
  • Methysergide (1-methyl-D-lysergic acid butanolamide)
  • TMB-8 (8- (N,N-diethylamino) octyl 3 , 4 , 5-trimethoxy - benzoate)
  • 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-
  • 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.
  • 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.
  • 5-HT 5-hydroxytryptamine
  • MDL 72222 was a potent antagonist of responses mediated through the receptors for 5-HT present on the terminal sym- pathetic fibres.
  • the threshold for antagonism was approximately 0.1 nM and the negative logarithm of the molar concentration of MDL 72222 which reduced the chronotropic response of the isolated rabbit heart to twice an ED50 of 5-HT to that of the ED50 was 9.27.
  • MDL 72222 was also highly selective since responses to the nicotine receptor agonist, dimeth- ylphenylpiperazinum iodine (DMPP) , were inhibited only at concentrations more than 1000 times those necessary to inhibit 5-HT. In the anaesthetized rat, MDL 72222 produced marked blockade of the Bezold-
  • DMPP dimeth- ylphenylpiperazinum iodine
  • MDL 72222 did not block smooth muscle contractile responses elicited by oxytocin or mediated through 5-HT D-receptors, muscarinic or nicotinic cholino- ceptors or histamine Hl-receptors except at rela- tively high concentrations.
  • the irregularly shaped roots (rhizomes) of ginger 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 treat- ment of nausea and vomiting associated with hyper- emesis gravidarum, anesthesia, and chemotherapy, this review will focus on ginger for motion sickness .
  • the stress was in a communication box paradigm, in which each nonshocked mouse (responder) was placed in a Plexi- glas compartment adjacent to mice receiving electri- cal shocks (sender) .
  • the responder mice revealed rather depressed gastric secretion, but developed gastric lesions which are significantly attenuated by pretreatment of dl-p-chlorophenylalanine methyl ester :HC1 (PCPA; 200-400 mg/kg p.o.), but not 6- hydroxydopamine (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) .
  • PCPA dl-p-chlorophenylalanine methyl ester :HC1
  • 6-OH-DA 6- hydroxydopamine
  • GR38032F (0.01- 1 mg/kg), ICS205-930 (0.01-20 mg/kg), MDL72222 (0.01-1 mg/kg), metoclopramide (0.1-100 mg/kg), ke- tanserin (0.01-10 mg/kg) and sulpiride (32-320 mg/kg) dose-dependently attenuated the psychological stress lesion formation, and the activity was ar- ranged in the order of their in vitro binding affinities for the 5-HT3, but not 5-HT1A or 5-HT2 re- ceptors .
  • a peripherally acting 5-HT3 antagonist M-840 ([ [3- (1-methyl-lH-indol-3 -yl) - 1, 2 ,4-oxadiazol-5- yl] -methyl] trimethyl-ammonium io- dide)
  • dopamine acting compounds haloperidol and FR64822 [N- (4-pyridylcarbamoyl) amino-1,2, 3, 6-tetra- hydropyridine)
  • antisecretory drugs atropine and famotidine
  • S 21007 As expected of an agonist, S 21007 stimu- lated 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.
  • the 5-HT3 receptor agonist action of S 21007 was also demonstrated in urethane- anaesthetized rats as this drug (120 micrograms/kg i.v.) triggered the Bezold-Jarisch reflex (rapid fall in heart rate) , and this action could be pre- vented by pretreatment with the potent 5-HT3 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.
  • 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.
  • R 1 is alkoxy of 1 to 6 carbon atoms; and R 2 and R 3 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 aminosul- fone, optionally substituted by one or two Cj__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.
  • 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 R 1 is independently selected from halogen, hydroxy, lower C ] __g alkoxy (optionally substituted with phenyl), lower C ⁇ _ alkyl, nitro, amino. aminocarbonyl, (lower C ⁇ _ alkyl) amino, di (lower C ] __g al- kyl) amino, and (lower C ⁇ _g alkanoyl) amino,- each R 2 is lower C _ alkyl; and R 3 is selected from
  • u, x, y and z are all independently an integer from 1 to 3 ;
  • R 4 and R 5 are independently ⁇ - ⁇ alkyl, C3.-8 cycloalkyl, C3_8 cycloalkyl-C ⁇ _2 alkyl, or a group
  • 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 Rl' is halogen, hydroxy, alkoxy (optionally substituted with phenyl) , alkyl, nitro, amino, amino carbonyl, (alkyl) amino, di (alkyl) amino, and (alkanoyl) amino; each R 2 is alkyl; and R3 is in which u, x, y and z are all independently an integer from 1 to 3; and R4 and R5 are independently alkyl, cycloalkyl, cycloal- kylalkyl, or a group (CH2)tR6 where t is 1 or 2 and R6 is thienyl, pyrrolyl or furyl optionally further substituted by one or two substituents selected from alkyl, alk
  • R ⁇ represents the group
  • R 2 represents a phenyl group which may be substituted or an aromatic heterocyclic group
  • R 3 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.
  • Rl represents the group (a) or (b)
  • R2 represents optionally substituted phenyl or het- eroaryl
  • 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.
  • each of R, R ] _ and R2 which may be the same or different, is hydrogen, halogen, hydroxy, cyano, C3.- Cg alkyl, CF3 , C ⁇ -Cg alkoxy, C ⁇ -Cg alkylthio, formyl, C.2-Cg alkanoyl, carboxy, C ⁇ -Cg alkoxycarbonyl, nitro, -N(R4 R5) in which each of R4 and R5 inde- pendently is hydrogen, C ⁇ -Cg alkyl, formyl or C2 ⁇ Cg alkanoyl; or a (Rg R7)N-S ⁇ 2 group, in which each of R4 and R7 independently is hydrogen or C ⁇ Cg alkyl; R3 is a group a)
  • n is an integer of 1 or 2 and Rs is hydrogen, C;L-Cg alkyl unsubstituted or substituted by phenyl, C2-C4 alkenyl, C2-C4 alkynyl, formyl or C2 ⁇ C alkanoyl; and the pharmaceutically acceptable salts thereof.
  • Novel 5-HT3 receptor antagonist compounds having general formula (I) wherein each of R, Rl 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
  • EP0711293 (May 1994, Pharmacia S.p.A) Imidaxolylalkyl Derivatives Of Imidazol (1, 5-A) Indol-3 -One And Their Use As Therapeutic Agents.
  • each of R, R ⁇ _ and R2 which may be the same or different, is hydrogen, halogen, hydroxy, cyano C ] _-Cg alkyl, CF 3 , Ci-C alkoxy, C ⁇ -Cg alkylthio, formyl, C2-C 6 alkanoyl, carboxy, C ⁇ Cg alkoxycarbonyl, nitro, -N(R4)R 5 in which each of R4 and R 5 independ- ently is hydrogen, C ⁇ C alkyl, formyl or C2 ⁇ Cg alkanoyl; or a Rg.(R 7 )N-S0 2 group, in which each of Rg and R 7 independently is hydrogen or C ⁇ -C alkyl; R 3 is an imidazolyl group having the formula
  • each of Rg and Rio which may be the same or different, is hydrogen or C ⁇ -Cg alkyl
  • R 9 is hydrogen, C ⁇ -Cg alkyl or a nitrogen protection group chosen from triphenylmethyl, t-butyloxycarbonyl, benzy- loxycarbonyl, acetyl, formyl, di (p-methoxyphenyl) - methyl and (p-methoxyphenyl) diphenylmethyl; and the pharmaceutically acceptable salts thereof.
  • Novel 5-HT3 receptor antagonist compounds having formula (I), wherein n is 1, 2 or 3; each of R, Rl 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 is hydrogen, C1-C6 alkyl, formyl or C2-C6 alkanoyl; or a (R6 R7)N-S02 group, in which each of R6 and R7 independently is hydrogen or C1-C6 alkyl; R3 is an imidazolyl group of formula (a) or (b) , wherei each of R8 and RIO which may be the same or different is hydrogen or C1-C6 alkyl, R
  • This invention relates to the novel salt 6-fluoro- 2,3,4, 5-tetrahydro-5-methyl-2-[ (5-methyl -IH-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.
  • Im represents an imidazolyl group of the formula:
  • R 3 , R 4 and R 5 is a hydrogen atom, or a C _g alkyl, C3-.7 cycloalkyl, C3--g alkenyl, phenyl or phenyl C --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;
  • R 1 and R 2 each represent a hydrogen atom, or together with the carbon atoms to which they are attached form a phenyl ring;
  • the compounds of formula (I) are potent and selective antagonists of 5-hydroxytrypt
  • EP0392663 (March 1989, One Pharmaceutical Co Ltd) Car- boline derivative as a 5-HT3 receptor antagonist.
  • the present invention provides ⁇ -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 .
  • n 2 or 3
  • Im represents an imidazolyl group of the formula
  • R 1 , R 2 and R 3 is a hydrogen atom or a C ⁇ _g alkyl, C 3 _ 7 cycloalkyl, C 3 _ alkenyl, phenyl or phenyl 0 3 .- 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(CH 2 )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 Rl, R 2 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 rep- resents an oxygen or a sulphur atom or a group NR4, where R4 is a Cl-6 alkyl group, and X is attached to the benzene ring moiety of the molecule; and physiologically acceptable salts and
  • H acceptable carrier showing activity of a 5-HT3 receptor antagonist.
  • the invention relates to tetracyclic ketones of the general formula (I)
  • n 1, 2 or 3 ;
  • Im represents an imidazolyl group of the formula:
  • R 1 , R 2 and R 3 are a hydrogen atom or a C ⁇ .g alkyl, C3-.7 cycloalkyl, C3_ 6 alkenyl, phenyl or phenyl C]__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 a group -X(CH2) -/ where p represents 2 or 3 , X represents an oxygen or a sulphur atom or a group NR 4 , where R 4 is a C _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 represented, by R.sup.l, R.sup.2 and R.sup.3 is a hydrogen atom or a C. sub.1-6 alkyl, C. sub.3-7 cycloalkyl, C. sub.3-6 alkenyl, phenyl or phenyl C. sub.1-3 alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C. sub.1-6 alkyl group; Y represents a group -- (CH.
  • 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.
  • EP0630893 (March 1992 , Kyorin Pharmaceutical Co . Ltd . ) N, N ' -Disubstituted Amide Derivative .
  • a 5-HT3 antagonist containing a novel N,N'-disub- stituted amide derivative having a potent and selective 5-HT3 receptor antagonism represented by general formula (I) , a hydrate thereof, or an acid addition salt thereof, wherein Rl 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.
  • Rl 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
  • R 1 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 ;
  • R 2 is hydrogen; and R 3 and R 4 are methyl .
  • An acetylcholine enhancer selected from the group consisting of the chemical compounds represented by the following structures :
  • acetylcholine enhancers i.e., compounds which evidence acetylcholinesterase (AChE) inhibition activity, and 5-HT3 receptor antagonist activity.
  • a particularly preferred compound is 2-[2- (1-benzylpiperizin-4-yl) ethyl]-2 , 3 -dihydro-9-methoxy- lH-pyrrolo[3 ,4-b]quinolin-l-one hemifumarate, referred to herein as Compound A (“Cm.A”) .
  • EP0526545 (April 1991, Beecham Group p. I.e.) Isoquin- oline Amides And Esters As 5-HT3 Receptor Antagonists
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • E is NH or O
  • Rl is hydrogen, halogen, C ] _schreib4 alkyl, C ⁇ _4 alkoxy, hydroxy or nitro;
  • Z is an azacyclic or azabicyclic side chain
  • 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 C ⁇ _g alkoxy, or R2 is in the 4- position and is hydrogen, halogen, CF3 , C]__ alkyl, C -.7 acyl, C ⁇ _ acylamino, phenyl optionally substituted by one or two C ] __g alkyl, C ⁇ --g alkoxy or halogen groups, or amino, amino- carbonyl or aminosulphonyl , optionally substituted by oone or two C ] __g alkyl or C3-.3 cycloalkyl groups or by C4-.5 polymethylene or by phenyl, C ⁇ _g alkylsulphonyl , C ] __g alkylsulphi- nyl, C]___g alkoxy, C _g alkylthio, hydroxy or nitro;
  • the group CO-E-Z is in the 3-position and either R2 is in the 1-position and is hydrogen, C]__g alkyl or C ⁇ _g alkoxy, or R 2 is in the 4- position and is hydrogen or C _g alkoxy;
  • Isoquinoline derivatives (I) having 5-HT3 receptor antagonist activity a process for their preparation and their use as pharmaceuticals.
  • E is NH or O
  • Rl 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
  • R is hydrogen or alkyl
  • R is hydrogen, amino, mono- and di-alkylamino, acylamino, halo or haloalkyl
  • 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 en- dogenous 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) Isoqui- nolinone derivative.
  • each substituent R 1 is the same or different and is hydrogen, halogen, C -.4 alkyl, C ⁇ _4 alkoxy or a group of formula:
  • R 4 is hydrogen, C ⁇ _4 alkyl or C2-.4 alkanoyl and R ⁇ is hydrogen, C --4 alkyl or benzyl; each substituent R 2 is the same or different and is hydrogen or C ] __4 alkyl; each substitutent R 3 is the same or different and is hydrogen or C -.4 alkyl;
  • 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) .
  • X is hydrogen, halo, sulfamyl, alkylsulfamyl or alkylsulfonyl; Y is hydrogen, amino, mono- or di-alkylamino or halo; Z is
  • R, R]_, R2 , R3 and R4 are independently: hydrogen or alkyl ; x is 2 or 3 ; y is 1 to 4; and pharmaceutically acceptable salts thereof.
  • This invention relates to benzoxazine and benzoxaze- pine carboxamide compounds which exhibit 5-HT. sub.3 antagonist properties including CNS, anti-emetic and gastric prokinetic activity and which are void of any significant D.sub.2 receptor binding affinity.
  • This invention also relates to pharmaceutical compositions and methods for the treatment of gastrointestinal and mental disorders using said compounds.
  • Rl and R2 represent hydrogen, or
  • R5 represents hydrogen or halo, for the manufacture of a medicament for treating 5-
  • R 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:
  • 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.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • R is C _ alkoxy, C 3 _g cycloalkoxy or C 3 _g cycloalkyl C ⁇ _ 4 alkoxy;
  • R 2 is hydrogen, halo, C ⁇ _g alkyl, C ⁇ _g alkoxy or amino optionally substituted by one or two C ⁇ _ alkyl groups;
  • R 3 is hydrogen, halo or C _g alkyl;
  • L is O or NH
  • Z is a di-azacyclic or azabicyclic side chain; having 5-HT 3 receptor antagonist activity. .
  • Rl 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 op- tionally substituted by one or two Cl-6 alkyl groups
  • R3 is hydrogen, halo or Cl-6 alkyl
  • L is O or NH
  • Z is a di-azacyclic or azabicyclic side chain; having 5-HT3 receptor antagonist activity.
  • a compound of formula (I) or a pharmaceutically ac- ceptable salt thereof:
  • 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-HT 3 receptor antagonist activity.
  • Ai, 2 , 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
  • Rl and R2 are hydrogen or C ⁇ _g alkyl
  • Y is hydrogen, halo, C ⁇ _g alkyl or C ⁇ _g alkoxy; L is 0 or NH;
  • Z is an azabicyclic side chain; having 5-HT3 receptor antagonist activity.
  • Het is monocyclic heteroaryl having two adjacent carbon atoms, a and b, depicted in formula (I) selected from the group consisting of pyridine, pyri- midine, pyrazine, pyrrole, imidazole, thiophene, fu- ran, oxazole and thiazole;
  • R l and R 2 are independently selected from hydrogen, halogen, CF 3 , C ⁇ _g alkyl and C ⁇ _g alkoxy;
  • R 3 is hydrozy, C ⁇ _g alkoxy, 0 3 .7 alkenyl-methoxy, phenoxy or phenyl C 1 -- 4 alkoxy in which either phenyl moiety may be substituted by one or two C ⁇ _g alkyl, C ⁇ _g alkoxy or halo; CC ⁇ Rg wherein Rg is hydrogen or ⁇ _g alkyl, CONR 7 R 8 or S0 2 NR 7 R 8 wherein R 7 and R ⁇ are independently hydrogen or C ⁇ _ alkyl or together are C 4 _g polymethylene, NO 2 , (CH 2 ) m OR 9 wherein m is 1 or 2 and R 9 is C ⁇ _g alkyl or S(0) n R ⁇ o wherein n is 0, 1 or 2 and RIQ is C ⁇ _ alkyl; L is NH or 0;
  • Z is a group of formula (a) , (b) or (c) :
  • 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.l- 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.
  • 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-HT 3 receptor antagonists for the present indications are tropanyl 3 , 5-dimethylbenzo- ate, MDL 72222, SDZ 216-525, ICI 169369, Zacopride, Tropisetron, Ramosetron, Ondansetron, Granisetron, Azasetron, Dolasetron, and Cilansetron. Brief Description of the Drawing
  • Fig. 1 depicts the effects of 5-HT and the selective 5-HT 4 agonist RS 67333 on the spontaneous tone in a human airway preparation in vitro. Note that 5-HT only gives a transient relaxation, while the selective 5-HT 4 agonist causes a strong sustained relaxation effect.
  • the contractile component often manifests itself as a reduction or a complete elimination of the 5-HT induced relaxation, rather than in an increase of force from the control (pre-exposure) level.
  • this sustained relaxing effect is achieved because the contractile 5-HT 3 receptor is not affected; only the relaxing 5-HT 4 receptor is activated.
  • antagonists to the 5-HT 3 receptor this effect is achieved due to direct blocking of the 5-HT 3 receptor, whereby the unspecific agonists to the 5-HT 4 receptor, such as 5-HT, can act without also causing contraction by the 5-HT 3 receptor.
  • the medicament prepared according to present invention in each embodiment may op- tionally include two or more of the above outlined compounds .
  • a serotonin uptake inhibitor can be added with a view to amplifying the relaxing effect, e.g. fluoxetin, cita- lopram, paroxetine, sertralin, and fluvoxamine.
  • the typical daily dose of the medicament prepared according to the invention varies within a wide range and will depend on various factors such as the individual requirement of each patient and the route of administration.
  • Said medicament may be prepared as a composition adapted either for administration via the respiratory tract or for oral, intravenous, intramuscular, intrathe- cal, topical, intraperitoneal or subcutaneous administration, 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.
  • useful alternative administration forms are tablets, cap- sules, powders, microparticles, granules, syrups, suspensions, solutions, transdermal patches or suppositories.
  • the subject-matter of the present invention was inter alia deduced from animal experiments, where a specific behavior of the airway smooth muscle called "spontaneous tone" was examined.
  • the spontaneous tone which involves a spontaneous continuous contraction in the airway smooth muscle, was studied due to a suspicion that defective regulation of the spontaneous tone could be an important cause of the bronchoconstriction observed in asthmatic patients.
  • 5-HT serotonin
  • 5-HT 3/ 5-HT 4 activiates 5-HT ⁇ , 5-HT 3/ 5-HT 4 , 5-HT 5 , 5-HT 6 and 5-HT 7 as well as 5-HT 2 receptors, in particular 5-HT 2 , 5-HT 3 , and 5-HT 4 receptors.
  • the relaxation which has a maximum after 10-15 min, disappears gradually during the follow- ing 30-45 min (see Fig 1) .
  • 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 considerable reduction of tone, i.e. a relaxation below the pre-treat- ment level.
  • the transient nature of the 5-HT relaxation in human airways is most likely caused by a simultaneous activation of the fast relaxing 5-HT 4 receptor, and an activation of the slower contracting receptor, which in human airways surprisingly has been found to be the 5-HT 3 receptor.

Abstract

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

Description

5-HT3 RECEPTOR ANTAGONISTS FOR TREATMENT OF DISORDERS INNOLVING AIRWAY CONSTRICTION
Field of the Invention
The present invention relates to a compound having antagonist activity to the 5-HT3 receptor for use as a medicament and to the use of said compound in the manu- 5 facture of a medicament for therapeutic or prophylactic treatment of disorders involving airway constriction of a human or animal body, as well as methods of treatment, wherein said compound is administered. Background of the Invention
10 The seven main receptors of the 5-HT (serotonin; 3- (β-aminoethyl) -5-hydrox indole) type are well known and occur throughout the body, e.g. in the airways, and their relevance has mainly been reported to be of significance in conjunction with treatment of CNS, muscle and gastric
15 disorders, as disclosed in e. g. WO 98/18458 and
US 5 246 935. In such treatments, compounds having agonist activity to a 5-HTχ type receptor are often used. As examples of other 5-HT receptors, mention can be made of receptors of the 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HTs and 5-
20 HT7 type. For a recent review of 5-HT receptors, see Ger- hardt, C.C., van Heerikhuizen, H., Eur. J. Pharm. , 334, 1-23 (1997), which is incorporated herein by reference.
A review of typical agonists and antagonists of various 5-HT receptors is disclosed in R.A. Glennon, Neu-
25 roscience and Biobehavioral Reviews, 14, 35-47 (1990) , the whole content of which is incorporated herein by reference .
SU 1 701 320 Al discloses the use of serotonin for treatment of acute asthma attacks. This reference does
30 not suggest any receptor mechanism for serotonin, which is a compound with both a contracting and a relaxing effect on the airways, as is further discussed herein below.
In the RBI Handbook or Receptor Classification and
35 Signal Transduction, 3rd Edition, 1998, RBI, One Strathmore Road, Natick, MA 01760-2447, USA, Editor:' Keith J. Watling are also 5-HT receptor compounds having agonist or antagonist activity to various receptors disclosed. Disclosure of the Invention
The present invention is based on the novel finding that certain 5-HT receptors are of utmost importance in regulating bronchocontraction, that is determining the level of airway constriction. In summary, it is disclosed herein that compounds having antagonist activity to the 5-HT3 receptor are suitable agents in the treatment of disorders involving airway constriction. Methods for treatment of disorders involving airway constriction are also disclosed. As used herein, the expression "disorders involving airway constriction", equivalent to the expression "bronchocontraction disorder", refers to an abnormal increase of the force development of the smooth muscle in human or animal airways, resulting in a reduced diameter in some or all of the airways of the lungs and/or the extrapulmo- nary airways, such as occurring in asthma, chronic obstructive pulmonary disease, emphysema and chronic bronchitis. Said expression also refers, in a wider sense, to reduction of airflow, more precisely airway diameter, caused by swelling, oedema, plasma extravasation or mucous secretion caused by e . g. asthma or any other disorder related thereto.
The expression "has the capacity of reducing the abnormal airway constriction by at least ....%" used through- out the present patent application means that the compound in question or the composition of compounds in combination as well as the derivatives and pharmaceutically acceptable salts thereof, persistently reduces, in 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, e.g. 5-HT3 receptors. The level of constriction in the airways can, for instance, be" determined by spirometric measurements of the Forced Expiratory Volume (FEVl) , compared to the normal value for healthy people. Alternatively, the expiratory capacity for a patient can be compared to his own FEVl during periods of relatively little obstructive problems.
The present invention relates, in one of its aspect, to a compound having antagonist activity to the 5-HT3 receptor for use as a medicament. In another aspect it re- lates to use of said compound 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. In a preferred embodiment, the invention relates to the use of a compound having antagonist activity to a 5-HT3 receptor in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders involving airway constriction, wherein said antagonist has the capacity of reducing the pathological airway constriction by at least 30%, preferably at least 60%, and most preferably at least 90%.
Said airway constriction may occur in conjunction with such disorders as e. g. asthma, emphysema, chronic bronchitis, and chronic obstructive pulmonary disease.
According to the present invention, several known 5-HT3 antagonist compounds are, unexpectedly, able to enhance a 5-HT-induced airway relaxation. The 5-HT3 receptor is a ligand modulated ion channel . Several potent and specific 5-HT3 antagonists exist today, of which ondan- setron, tropisetron, granisetron, and dolasetron are commercial pharmaceuticals, but not against disorders involving airway constriction.
Some of the 5-HT3 receptor antagonists are at the same time 5-HT4 receptor agonists. However, for a substance to be active as a 5-HT3 receptor antagonist, the distance from the aromatic center to the basic nitrogen should be about 7,5 A and no large substituents are tolerated on the basic nitrogen. In contrast, for 5-HT4 receptor agonists the corresponding distance is about 8 A, and a large lipophilic group may be bound to the basic nitrogen, thereby obtaining a better binding to 5-HT . The 5-HT3 antagonists may be divided into certain classes on the basis of chemical structure. Some are un- specific, e.g.
Figure imgf000005_0001
benzazepines , e .g . mirtazapine
Figure imgf000005_0002
benztiazephines, e.g. diltiazem
Figure imgf000005_0003
and fentiazin.es
Figure imgf000006_0001
e.g. perphenazine, chlorpromazine, stemetil.
Some are at the same time 5-HT4 agonists, e.g. ben- zamides
,
Figure imgf000006_0002
and
Figure imgf000006_0003
2 , 3 -dihydro-benzofuran-7-carboxamides
Figure imgf000007_0001
(e.g. zatosetron=LY 277359, ADR 851); 1, 4-bensoxazin-8-carboxamides
Figure imgf000007_0002
e.g. azasetron (=Y25130)
benzimidazolones
Figure imgf000008_0001
e.g. itasetron (=DAU 6215); indazol-3 -carboxamides
Figure imgf000008_0002
e.g. N 3389, LY 278584, DAT 582 (= (R) AS-5370)
The latter group reminds most of the specific 5-HT3 antagonists, which contains the group
Figure imgf000008_0003
in different forms, such as
ondansetron (---GR 38032 F)
Figure imgf000009_0001
Figure imgf000009_0002
alosetron cilansetron (=KC 9946)
In one group of substances the structure has been inverted and the carbonyl group has been placed on the indoline nitrogen
Figure imgf000009_0003
This substance is unique by being an antagonist against both 5-HT3 and 5-HT receptors.
Figure imgf000010_0001
BRL 46470A binds to two different positions of the receptor.
A further development is the so-called bisindoles
Figure imgf000010_0002
Another group is the isoquinoline-1-ones
Figure imgf000010_0003
palonosetron (=RS 25259-197) RS 42358-197
and the quinoline-3-carboxamides
Figure imgf000010_0004
WAY-SEC 579 Mirisetron (=WAY 100579) Also the quinoline-4-carboxylates are active antagonists
Figure imgf000011_0001
e.g. KF 17643
Figure imgf000011_0002
e.g. KF 18259
Other compounds are benzimidazolones
Figure imgf000011_0003
e.g. droperidol (neurolidol, etc.), itasetron (DAU6215) , and the naphtimides
Figure imgf000011_0004
e.g. RS 56532
A unique single structure is MDL 72222, which also is a specific 5-HT3 antagonist
Figure imgf000012_0001
Other specific structures are
Figure imgf000012_0002
Talipexole
Figure imgf000012_0003
i odophenprop i t
Figure imgf000012_0004
thi operand de, and
Figure imgf000013_0001
2-piperidin- and 2-piperazin-
Figure imgf000013_0002
benzimidazoles .
According to the present invention, the following compounds can also be used as antagonists to the 5-HT3 receptor: (R) -zacopride, 2-methyl-5HT, 3- (1-piperazinyl) - 2-quinoxalinecarbonitrile, 3- (4-allylpiperazin-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, Anpirtoline, AS-5370, Batanopride, BIMU 1, BRL 24682, BRL 43694, BRL 46470 (=Ricasetron) , BRL 47204, Bufoten- ine, CF 109203 (=BIM) , Cizapride, Clozapine, CP-93318, Cyameazine, Cyproheptadine, Dolasetron mesilat (=MDL 73147 EF) , Fluphenazone, Galdansetron, GR 38032 F, GR 67330, Granisetron (=Kytril=BRL 43694), GR-H, GYKl- 48903, ICS 205-930, Imipramine, Indalpine, KAE-393/YM- 114, KB-6922, KB-6933, KB-R 6933, KF-20170, Lerisetron,' Lurosetron, LY 258-458, LY 278-989, LY-211-000, McNeil-A- 343, MCPP, MDL 72699, Mepyramine, Metergoline, Methyser- gide, Mianserin, MK 212, N-3256, NA -190, N-metylquipa- zin, 3- (1-piperazinyl) -2-quinoxalinecarbonitrile, ONO- 3051, Pancopride, Phenylbiguanide , Pitozifen, Prochlor- perazine (Stemetil), QICS 205-930, R (+) zacopride,
Renzapride, RG 12915, Ritanserin, RP 62203, RS-25259-197 , RS-056812-198, RS-25259, RU 24969, S (-) Zacopride, S- apo orfin, SC-52491, SC-53116, SDZ 206-792, SDZ 206-"830, SDZ 210-204, SDZ 210-205, SDZ 214-322, SDZ 322, SN-307, TFMPP, TMB 8, trifluoperzine, tropanyl-3 , 5-di- methylbenzoate, 3-tropanyl-indole-3-carboxylate methio- dide, VA' 21 B 7, Y 2513, SEC 579, BRL 46470 A, Pizotifen, Dolasetron (=MDL 74156), Galanolactone, GR 65 630, Ifen- prodil, L-683877, Litoxetine, Quipazine, QX 222, Ramose- tron (=YM 060), RS 56812, SDZ 216-525, Trimebutine, GR 65630, Tropisetron (=ICS 205-930=Rifenserin) , Bemese- tron, L-683,877, LY-278,584 maleate and pharmaceutically acceptable salts thereof with the same or essentially the same relaxation enhancing effect and capability of reducing abnormal airway constriction as specified above.
In the following, an alternative presentation of useful compounds according to the present invention and references thereto is presented. N-substi uted benzamides
Metoclopramide
Figure imgf000014_0001
• 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 . ci5-4-Amino-jV- l-[3-(p-.fluoro enoxi)propvl]-3-rnetoxi-4-piperi yl]-5- -kloro-o-anisa id
Figure imgf000015_0001
Pancopride ( ( (+-) N- (1-azabicyclo- [2,2,2] -oct-3-yl) - 2-eye1opropylmethoxy-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 mi- crogram/kg) or p.σ. 60 min (ID50 = 8.7 micro- grams/kg) before 5-HT challenge. A single oral dose (10 micrograms/kg) of pancopride produced a signifi- cant inhibition of the bradycardic reflex over "an 8-h period. Pancopride dose dependently inhibited the number of vomiting episodes and delayed the 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 mechlor- ethamine- and dacarbazine-induced emesis. Unlike metoclopramide, pancopride was shown to lack any measurable antidopaminergic activity both in vitro and in vivo. These results support clinical data, indicating that pancopride will be a useful drug for treating cytostatic-induced emesis in humans.
(R) -zacopride (R+ zacopride, zacopride) IUPAC name: 4-amino-N- (1-azabicyclo [2.2.2] oct-3yl) -5-chloro-2- methoxy-benzamide .
The differential activities of R (+) - and S(-) -zacopride as 5-HT3 receptor antagonists. Barnes JM, Barnes NM, Costal1 B, Domeney AM, Johnson
DN, Kelly ME, Munson HR, Naylor RJ, Young R; Pharwa - col 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 scopolamine-induced impairment, and to antagonise the inhibitory effect of 2 -methyl- 5-hydroxytryptamine to reduce [3H] acetylcholine re- lease in slices of the rat entorhinal cortex. In binding assays, [3H] S (-) -zacopride and [3H]R(+)~ zacopride labelled homogenous populations of high- affinity binding sites in the rat entorhinal cortex, R(+) -zacopride compete for a further 10 to 20% of the binding of [3H] R(+) /S (-) -zacopride or [3H]R(+)- zacopride in excess of that competed for by (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). Batano- pride is also known by the name BMY-25801.
• WAY 100289 Indoles, Indole -l -carboxamides and Imidazole derivatives
• 2 -methyl-5-HT
• 5,7-DHT= 5, 7-dihydroxy-tryptamine
• Bisindoles
• Bufotenine = (5-hydroxy-N,N-dimethyltryptamine)
• BRL 46470A (endo-N- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) 2 , 3-dihydro-3 , 3 dimethyl -indole-1- carboxamide, hydrochloride)
BRL 46470 (endo-N- (8-methyl-8-azabicyclo [3.2.1] oct-
3yl) -2,3-dihydro-3,3- dimethyl -indole-1-carboxamide HCI)
• BRL 47204
FK 1052 ( (+) -8,9-dihydro-10-methyl-7- [ (5-methyl-lH- imidazol-4- yl) methyl] pyrido [1,2 -a] indol-6 (7H) -one hydrochloride)
Pharmacological characterization of FK1052, a dihy- dropyridoindole derivative, as a new serotonin 3 and 4 dual receptor antagonist., Nagakura Y, Kadowaki M, Tokoro K, Tomoi M, Mori J, Kohsaka M; J" Pharmacol EXΌ Ther 1993 May, 265:2:752-8
(+) -8, 9-Dihydro-10-dihydro-10 -methyl -7- [ (5-methyl-4- imidazolyl) methyl] pyrido- [1, 2-a] indol-6 (7H) -one hydrochloride (FK1052) is a newly designed and synthe- sized 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 πdcro- gram/kg, i.v., 5.23 micrograms/kg, i.d.) to be more potent than ondansetron (5.23 micrograms/kg, i.v., 170 micrograms/kg, i.d.) and granisetron (0.70 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-methoxytryp- tamine-induced contractions of guinea pig isolated ileum. FK1052, ondansetron and granisetron concen- tration-dependently inhibited 2 -methyl-5-HT, a 5-HT3 agonist-induced contraction. The pA2 values for the 5-HT3 receptor indicated that FK1052 (8.36) was 40 times and three times more potent than ondansetron
(6.79) and granisetron (7.86), respectively. FK1052, unlike ondansetron and granisetron, inhibited the 5- HT4 -mediated component of concentration-response curve to 5-HT. Furthermore, FK1052 suppressed 5- methoxytrypta ine, 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 mem- branes of NG 108-15 neuroblastoma-glio a cells with [3H] ICS 205-930. Neijt HC, Karpf A, Schoeffter P, Engel G, Hoyer D Naunyn Schmiedebergs Arch Pharmacol 1988 May, 337:5:493-9
1. The binding characteristics of [3H] ICS 205-930, a potent and selective 5-hydroxytryptamine 5-HT3 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 206-792 greater than BRL 43694 greater than quipazine greater than BRL 24924 greater than SDZ 210-204 greater than MDL 72222 greater than SDZ 210-205. Metoclopramide, mCP and mianserin showed submicromolar affinity.
• Ondansetron=GR 38032F=SN-307-=Zofran® Ondansetronum INN (Ondansetron)
2,3-Dihydro-9-metyl-3-[(2-metylimidazol-l-yl)metyl]karba2ol-4(l -T -on
Figure imgf000021_0001
The compound is both an indole derivative and ah 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 EXΌ 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 recep- tors 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 acti- vation 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)
Figure imgf000022_0001
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, Boun- tra C, Humphrey PP; Neurocrastroenterol Mo til 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), re- spectively. 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= Anzemet .
IUPAC name: (2 , 6, 8 , 9aβ) -octahydro-3-oxo-2 , 6-methano- 2H-quinolizin-8-yl-lH-indole-3-carboxylate monomethanesulfonate, monohydrate .
Figure imgf000024_0001
• Dolasetron=MDL74156
• Tropisetron =Navoban®
IUPAC name: laH,5aH - Tropane - 3a - yl-3 - indole- carboxylate
Figure imgf000025_0001
• Zatosetron =LY 277359. The compound is also called LY 19617.
The effect of acute and chronic LY 277359, a selec- tive 5-HT3 receptor antagonist, on the number of spontaneously active midbrain dopamine neurons., Mi- nabe Y, Ashby CR Jr, Wang RY; Eur J Pharmacol 1991 Dec 17, 209:3:151-6
In this study, we have examined the effect of acute and chronic administration of LY 277359, a putative 5-HT3 receptor antagonist, on the number of spontaneously active dopamine cells in the substantia nigra pars compacta (SNC or A9) and ventral tegmental area (VTA or A10) . 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 A10, but not A9, dopamine cells compared to saline controls. The acute administration of 10 mg/kg of LY 277359 did not significantly alter the number of spontaneously active dopamine cells in either area. In contrast to its acute effects, the administration of 0.1 mg/kg per day of LY 277359 for 21 days decreased the 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 trea - ment 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 va- gus nerve. At the higher concentrations used (0.3 nmol/1-1 nmol/1) this was accompanied by a marked reduction in the maximum response to 5-HT. The calculated pKB value was 10.2. The binding of the tri- tiated derivative of GR67330 to homogenates of rat entorhinal cortex was examined. Kinetic analysis revealed that specific [3H] GR67330 (0.1 nmol/1) binding was rapid and reversible. Association and disso- ciation rate constants were 1.48 +/- 0.36 x 10 ("8) mol/1-1 s-1 and 7.85 +/- 0.41 x 10 (-3) s-1 respectively. Equilibrium saturation analysis revealed specific binding was to a single site JBmax 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 un- labelled GR67330 was used to define non-specific binding two sites were evident (Kdl 0.066 +/- 0.007 nmol/1, Kd2 20.1 +/- 9.7 nmol/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-Tropanyl) -lH-Indole-3 -carboxylic acid ester)
Comparison of the 5-HT3 receptor antagonist proper- ties of ICS 205-930, GR38032F and zacopride., Cohen ML, Bloomquist W, Gidda JS, Lacefield W J Pharmacol EXΌ 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 ileu . After i.v. admini- st'ration to anesthetized rats, zacopride was ap- proximately 10-fold more potent than either ICS 205-930 or GR38032F, which were equipotent as inhibitors of serotonin-induced bradycardia (5-HT3- mediated activation of the von Bezold Jarisch re- flex) . After oral administration to anesthetized rats, zacopride remained approximately 10-fold more potent than ICS 205-903, which was approximately 2-fold more potent than GR38032F as an inhibitor of serotonin-induced bradycardia. Furthermore, the in- hibitory effectiveness of GR38032F persisted for less than 3 hr after oral administration and for less than 15 min after intravenous administration. ICS 205-930 produced maximal inhibition of 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] -IH-indole)
• VA21B7 (3- [2- (4 ' -piperonylpiperazinyl) indolyl] car- boxaldehyde)
The pharmacology of VA21B7: an atypical 5-HT3 recep- tor antagonist with anxiolytic-like properties in animal models. Artaiz I, Romero G, Zazpe A, Monge A, Calderδ JM, Roca J, Lasheras B, Del Rio J Psycho - Oharmacologγ (Berl) 1995 Jan, 117:2:137-48
VA21B7 (3- [2- (4 ' -piperonylpiperazinyl) indolyl] car- boxaldehyde) was synthesized as a potential 5-HT3 receptor antagonist. Even though VA21B7 showed a higher affinity towards 5-HT3 receptors as compared to other receptors studied, it was not a potent 5- HT3 receptor antagonist either in the periphery or in the brain. In a simple animal model of anxiety such as the two-compartment box in mice, a 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 of anxiety in rats such as the elevated plus-maze and punished- drinking. VA21B7 was compared with standard 5-HT3 receptor antagonists such as ondansetron, tropise- tron and granisetron, with the 5-HT1A agent buspi- rone and with diazepam. In the plus-maze, VA21B7 showed an anxiolytic-like profile after doses of 0.25-0.5 mg/kg IP or 2-4 mg/kg PO which did not modify the number of total entries into the open and closed arms of the maze. Diazepam, granisetron and tropisetron were also effective in this test but not ondansetron and buspirone. VA21B7 was also able to release suppressed behaviour in the punished-drink- ing test. The dose-response curve was bell-shaped with a peak at 2-4 mg/kg. At variance with other studies, 5-HT3 receptor antagonists also increased the number of shocks taken in this test and the dose-response curve was also bell-shaped. VA21B7 was not anticonvulsant like diazepam, its anxiolytic ac- tion in the light/dark test was not flumazenil- sensitive and there was no rebound anxiogenic effect on withdrawal from chronic VA21B7 treatment for- 15 consecutive days. Moreover, VA21B7 was not amnesic like the benzodiazepines but low doses of 2-4 mg/kg reduced the memory deficits induced in rats by sco- polamine. Much higher doses were necessary to 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 inter- est as an anxiolytic in humans.
Benzimidazolones , benzimidazoles and other imidazoles
The common chemical structure of a benzimidazolone is:
Figure imgf000030_0001
• Iodophenpropit (4- (lH-imidazol-4-yl-methyl) - piperidine) • ■
• BIMU 1 (endo-N- (8-methyl-8-azabicyclo [3.2.1. ]oct-3- yl) - 2,3-dihydro-3-ethyl-2-oxo-lH-benzimidazole-l- carboxamide hydrochloride) • 2-piperazin-benzimidazole
• 2-piperidin-benzimidazole
• • • Cilansetron (1-10- [ (2-methyl-lH-imidazol-l- yl) methyl] -5, 6, 8, 9, 10, ll-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) recep- tor-mediating contractions and relaxations in the guinea-pig isolated distal colon using various 5-HT3 receptor agonists and antagonists, including GK-128 (2- [ (2-methylimidazol-l-yl) methyl] benzo [f] thio- chromen-1-one monohydrochloride hemihydrate) . 2. Selective 5-HT3 receptor agonists, 2-methyl-5-HT and m-chlorophenylbiguanide, produced spantide- insensitive contraction and atropine-insensitive contraction and the relaxation. These agonists showed a small, but significant, difference of po- tency between contraction and relaxation. 3. GK-128 competitively blocked both 2 -methyl-5-HT- and - 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 af- finity 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. sig- nificant differences in their affinity values among- the three responses. 5. These results suggest that the 5-HT3 receptors which mediate contraction and relaxation in the guinea-pig distal colon may not be the same, and that GK-128 is a 5-HT3 receptor an- tagonist with a stronger potency for contraction.
• Droperidol. Ingar i Dridol, Janssen-Cilag
Droperi olum INN ( Droperidol)
L-[l-(3-(4-FIuorobensoyl)propyl)- .6-tetrahydro-4-pyridyl1-l,3- -dιhydro-2//-beπsimidazol-2-on
Figure imgf000032_0001
• KAE-393/YM-114
( (R) -5- [ (2, 3-dihydro-1-indolyl) carbonyl] -4,5,6,7- tetrahydro-lH-benzimidazole
Comparison of the effects of trimebutine and YM114 (KAE-393) , a novel 5-HT3 receptor antagonist, on stress-induced defecation. Miyata K, Ito H, Yamano M, Hidaka K, Kamato T, Nishida A, Yuki H; Eur J Pharmacol 1993 Dec 7, 250:2:303-10
YM114 (KAE-393), (R) -5- [ (2 , 3-dihydro-1-indolyl) - carbonyl] -4, 5, 6, 7- tetrahydro-lH-benzimidazole hy- drochloride, is a derivative of YM060, a potent 5- HT3 receptor antagonist. We investigated the effects of YM114 on 5-HT3 receptors, both in vitro and in vivo, and on bowel dysfunction induced by restraint stress, 5-HT and thyrotropin-releasing hormone (TRH) , and compared them with the effect of trime- butine. YM114 dose dependently inhibited the 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 af- fected stress-, 5-HT- and TRH-induced increases in fecal pellet output. Thus, YM114 is a potent and stereoselective 5-HT3 receptor antagonist with much greater protective effects against stress-induced defecation than trimebutine .hydrochloride) .
Itasetron=DAU6215 ( (3 -alpha-tropanyl) lH-benzimida- zolone- 3 -carboxamide chloride) Intravenous itasetron: establishing the effective dose range for the prophylactic control of acute emesis in cancer patients undergoing high-dose cisplatin chemotherapy. , Patoia L, Del Favero A, Gigli- etti A, Malacarne P, Donati D, Indelli M, Bensi G,
Palladino MA, Cigarini P, Kempe R, Voigt T; Clin 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-hydroxytryptamlne3 (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 bio- transformation before elimination. The aim of this open, uncontrolled study was to establish the effective dose range of itasetron hydrochloride given in- travenously (i.v.) to patients due to receive high- dose cisplatin chemotherapy (50-120 mg/m2) for the first time. Thirty-nine patients were enrolled in the trial and received a single i.v. infusion of itasetron hydrochloride at a dose of 17-280 mi- crog/kg body weight before commencing the cisplatin infusion (median dose 90-110 mg/m2) . Antiemetic 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' assess- ments 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 dos'e 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 posi- tions 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 hydro- chloride]
Indazole carboxamide derivatives
The compounds have the general structure .
Figure imgf000036_0001
• AS5370 ((+/-) -N- [1-methyl-4- (3 -methyl-benzyl) - hexahydro-lH-l,4-diazepin-6- yl] -IH- indazole-3- carboxamide dihydrochloride) . The compound is also a diazepin derivative.
DAT582 (the compound is the R- enantimer of compound AS5370)
5-HT3 receptor antagonist effects of DAT-582, (R) enantiomer of AS-5370.
Yoshida N, Omoya H, Kato S, Ito T, Eur J Pharmacol 1992 Jun 17, 216:3:435-40
The serotonin 5-HT3 receptor antagonist effects of DAT-582, the (R) enantiomer of AS-5370 ((+/-) -N- [1- methyl-4- (3 -methyl-benzyl) exahydro-IH-1 , 4-diazepin- 6- yl] -IH- 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 mi- crogram/kg i.v., whereas the (S) enantiomer was without effect even at 1000 micrograms/kg i.v. In antagonizing the bradycardia, DAT-582 was as potent as granisetron, slightly more potent than AS-5370, and 2, 5 and 18 times more potent than ondansetron, ICS 205-903 and renzapride, respectively, although it was less potent than zacopride. DAT-582 inhibited cisplatin (10 mg/kg i .v. ) -induced emesis in ferrets with an ED50 value of 3.2 micrograms/kg i.v. twice. The antiemetic activity of DAT-582 was more potent than that of the existing 5-HT3 receptor antagonists examined, except zacopride. In contrast, the (S) enantiomer had little effect at 1000 micrograms/kg i.v. twice. In isolated guinea-pig ileum, DAT-582 inhibited 5-HT-induced contractions with an IC50 value of 91 nM, whereas the (S) enantiomer hardly inhibited them even at 1000 nM. These results suggest that DAT-582, the (R) enantiomer of AS-5370, potently and selectively blocks 5-HT3 receptors.
N-3389 (N-3389 (endo-3 , 9-dimethyl-3 , 9- diazabicy- clo [3 , 3 , 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, Aral T, Eguchi H, Mino S, Kawase S, Eur J Pharmacol 1994 Dec 12, 271:1:159-66
The antagonistic activities of compound N-3389 (endo-3 , 9-dimethyl-3 , 9- diazabicyclo [3,3,1] non-7-yl lH-indazole-3 -carboxamide dihydrochloride) at 5-HT3 and 5-HT4 receptors were examined using in vitro and in vivo assays. N-3389 showed potent 5-HT3 receptor antagonistic activities in a radioligand binding as- say (pKi = 8.77), against 2-methyl-5-HT (2-Me-5-HT) - induced bradycardia in rats (ED50 = 0.73 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 con- centrations of 5-HT (10 (-8) -10 (-6) M) . N-3389 (10 (- 7) -10 (-5) M) inhibited both phases of contraction induced by 5-HT. In addition, N-3389 (3 x 10 (-7) -3 x 10 (-6) M) was found to inhibit the increase of 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
Granisetronuπi INN (Granisetron) l-Metyl- /-(en^o-9-metyl-9-azabicyklo[3.3.1]non-3-yl)-l/-f-indazol-3- -karboxamid
Figure imgf000039_0001
Selective and functional 5-hydroxytryptamine3 recep- tor antagonism by BRL 43694 (granisetron) . ; Sanger GJ, Nelson DR Eur J Pharmacol 1989 Jan 10, 159:2:113-24
The activity of BRL 43694 (granisetron) was investi- gated using established models of 5-HT3 receptor 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 af- feet the contractions of similar preparations of ileum, evoked by electrical field stimulation (cholin- ergically mediated) , the nicotinic agonist dimethyl- phenyl piperazinium (DMPP) or by cholecystokinin oc- tapeptide. Similarly, BRL 43694 did not affect elec- trically evoked, cholinergically mediated 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, Gar- reau M, Langer SZ.; Eur J Pharmacol 1993 Mar 2, 232:2-3:139-45
The selective 5HT uptake inhibitor, litoxetine (SL 81.0385), currently under development as an antide- pressant was shown to have antiemetic properties in the ferret. Litoxetine (at 1 and 10 mg/kg i.v.) dose dependently reduced the number of retches and 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 af- finity for this receptor (Ki = 6.5 microM) . It is proposed that litoxetine inhibits cisplatin-induced emetic responses due to its moderate 5HT3 antagonist properties. The clinical use of the majority of se- rotonergic antidepressants (e.g. fluoxetine, flu- voxamine etc.) is associated with gastrointestinal discomfort (particularly nausea and vomiting) as a major side-effect. If nausea and vomiting associated with the use of 5 HT uptake inhibitors are due "to stimulation of 5HT3 receptors, the concomitant 5HT3 antagonism of litoxetine may limit the 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- 1989 Jul 4, 166:1:107-10
Binding of [3H]LY278584 a 1-methyl-indazole-carboxamide, 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 an- tagonists of 5-HT3 receptors supports the conclusion that 3H]LY278584 binds to putative 5-HT3 receptors in cortical membranes.
LY-278,584 maleate, see above.
LY258-458
• LY 278989
Specific [3H]LY278584 binding to 5-HT3 recognition sites in rat cerebral cortex.
Wong DT, Robertson DW, Reid LR; JSur J Pharmacol 1989 Jul 4, 166:1:107-10 Binding of [3H]LY278584 a 1-methyl-indazole-carboxamide, 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, benso- thiazepines
A general structure for these classes of compounds is :
Figure imgf000042_0001
• 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- (4 -fluorophenyl) -piperazinyl) - propyl] naphto [1,8- ca] isothiazole-1, 1-dioxide) Clozapine. Ingar i Leponex, Novartis
Clozapinum INN (Klozapin)
8-Kloro-ll-(4-metyl-l-piperazinyl)-5H-dibenso[b,e][l,4]diazepin
Figure imgf000044_0001
Amitryptiline
Amitriptylinum INN ( Amitriptylin) 5-(3-Di etylarainopropyliden)-l0,ll-dihydro-5H- -dibens[ , djcyklohepten
Figure imgf000044_0002
Cyproheptadine. Is the active ingredient of Periac- tin, MSD
Diltiazem Is the active ingredient in Cardizem, Pharmacia" Corporation
DHtiazemum INN (Diltiazem)
(2S,3S)-3-(Acetyloxi)-5-[2-(dimetylamino)etyl]-2-(4-metoxifenyl)-2,3-
-dihydro-l,5-bensotiazepin-4(5H)-on
Figure imgf000045_0001
Imipramin
-(3-Dimetylaminopropyl)-10,ll-dihydro-5f -dibenso[6, 3azepin
Figure imgf000045_0002
Mianserin
Figure imgf000046_0001
• Mirtazapine (1, 2 , 3 , , 10, 14b-hexahydro-2 -methyl- pyrazino [2 , 1-a] pyrido [2,3-c] benzazepine)
• Pizotifen
Pizotifenura INN (Pizotifen) 4-(l-Metyl-4-piperidyliden)-9,10-dihydro-4H-benso- -[4,5]cyklohepta[l ,2-6]tiofen
Figure imgf000046_0002
Quinolines, guinolicines and isoquinolines
The common structure of quinoline is :
Figure imgf000046_0003
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) -l-isobutyl-2-oxo-l, 2 - dihydro- 4 -quinoline - carboxylate hydrochloride)
• KF 20170 (endo-N- (8-methyl-8-aza-bicyclo [3.2.1] oct- 3-yl) -4-hydroxy-3- quinolinecarboxamide
• Palonosetron=RS 25259-197
(3aS) -2- [ (S) -1-azabicyclo [2.2.2] oct-3-yl] - 2 , 3 , 3a, 4, 5, 6-hexahydro- 1- oxo-lH-benzo [de] - isoquino.line -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] isoquinoline-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 unsur- mountable fashion and the apparent affinity (pKB) , estimated at 10 nM, was 8.8 +/-0.2. In this tissue, the -log KB values for the other three enantiomers were 6.7 +/- 0.3 (R,R), 6.7 +/- 0.1 (S,R) and 7.4 +/- 0.1 (R,S), respectively. The apparent affinities of RS 25259-197 and RS 25259-198, RS 25233-197 and RS 25233-198 at 5-HT3 receptors in membranes from NG-108-15 cells were evaluated by a [3H] -quipazine binding assay. The -log Ki values were 10.5 +/- 0.2, 8.4 +/- 0.1, 8.6 +/- 0.1 and 9.5 +/- 0.1, respec- tively, with Hill coefficients not significantly- different from μnity. 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-pig ileal myenteric plexus, with affinity (pKi) values of 10.1 +/- 0.1, 10.2 +/■ 0.1, 10.1 +/- 0.1 and 8.3 +/- 0.2, respectively.
Phenthiazines and Benzoxazines
• Chlorpromazine
Chlorpromazinum INN (Klorpromazm) 10-(3-Dimetylaminopropyl)-2~klorofentiazin
Figure imgf000049_0001
• Cyamemazine (10- (3-Dimethylamino-2- methylpropyl)phenothiazine-2-carbonitrile)
• Fluphenazin
Fluphena--inum INN (Flufcna/.in) lO-[3-(4-(2-Hydroxietyl)-l-piperazinyl)propyll-2- -trifl uoromety Ifentiazm
Figure imgf000049_0002
Prochlorperazine=Stemetil
Figure imgf000050_0001
• KB-6933 (6-amino-5-chloro-l-isopropyl-2- ( -methyl-1- piperazinyl) benzimidazole dimaleate)
• Perfenazine. Ingar i Trilafon. Cl istallet for CF3 i formeln for Flufenazine
• Trifluoperazine
Figure imgf000050_0002
• Azasetron=Y25130 (+/-) -N- (1-azabicyclo [2.2.2] oct-3- yl) -6-chloro-4-methyl-3-oxo-3 , 4-dihydro-2H-l, 4- benzoxazine-8-carboxamide monohydrochloride
Pharmacokinetics of azasetron (Serotone) , a selective 5-HT3 receptor antagonist. Tsukagoshi S Gan To Kaαaku Rvoho 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-lH-indol-3- yl) -1,2, 4 -oxadiazole
• 1, 4-Benzoxazin-8 -Carboxamide
Other compounds, including piperidines , piperazines, al - kaloides, benzoates and ureas
• Anpirtoline (6-Chloro-2- [piperidinyl-4-thio] - pyridine)
• Ritanserin
• NAN-190 (1- (2-methoxyphenyl) -4- [4- (2-phthalimido) - butyl] piperazine)
• Naphtimides. • TFMPP (1- (3 -trifluoromethylphenyl) piperazine) Ifenprodil (dl-erythro-4 -benzyl -alpha- (4-hydroxy- phenyl) -beta-methyl-1-piperidine-ethanol tartrate) (ifenprodil tartrate)
MCPP (Meta-chlorophenylpiperazine) (mCPP)
MK-212 (6-chloro-2- [1-piperazinyl] -pyrazine)
Metergoline ( [ [ (8 {BETA}) -1, 6-dimethylergolin-8- yl] methyl] -Carbamic acid phenylmethyl ester)
Methysergide (1-methyl-D-lysergic acid butanolamide)
S-apomorfin
Tropanyl-3 , 5-dimethylbensoate
Trimebutine, ett 3 , 4, 5-trimetoxybensoate derivat
Figure imgf000052_0001
TMB-8 (8- (N,N-diethylamino) octyl 3 , 4 , 5-trimethoxy - benzoate)
Phenylbiguanide
Functional characterization of a 5-HT3 receptor which modulates the release of 5-HT in the guinea- pig brain. , Blier P, Bouchard C Br J Pharmacol 1993 Jan, 108:1:13-22 1. The aims of the present study were to confirm the modulation by 5-HT3 receptors of the electrically evoked release of tritium from slices preloaded with [3H] -5-HT of guinea-pig frontal cortex, hippocampus and hypothalamus, and to assess their functional role in 5-HT release. 2. The selective" 5-HT3 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 cortex and hypothalamus slices. 3. In hypothalamus slices, this response was lost when 2-methyl-5-HT was intro- duced 20 min before the stimulation, thus indicating that these 5-HT3 receptors desensitize rapidly. When 2-methyl-5-HT was added 20-min before the first stimulation period to desensitize the 5-HT3 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 recep- tor antagonists m-chloro-phenylpiperazine = quip- azine = ondansetron > or = ICS 205-930 = BRL 24924 > MDL 72222 = zacopride. 5. The 5-HT reuptake blocker, paroxetine, enhanced the electrically evoked release of tritium when introduced 8 min before stimulation; this effect of paroxetine was blocked by ICS 205-
930, thus indicating that these 5-HT3 receptors can be activated by endogenous 5-HT. 6. In the absence of electrical stimulation, 2-methyl-5-HT (10 microM) produced a marked enhancement of the basal release of [3H] -5-HT which was calcium-dependent and blocked by S-zacopride but not by paroxetine. 7. The 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-chlorophenylcarbamoyl- oxy) -2-butynyl-trimethylammonium chloride) .
MDL 72222 (1 alpha H, 3 alpha, 5 alpha H-tropan-3- yl-3 , 5-dichlorobenzoate)
MDL 72222 : a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors., Fozard JR Naunyn Schmiedebergs Arch Pharmacol 1984 May, 326:1:36-44
The properties of MDL 72222 (1 alpha H, 3 alpha, 5 alpha H-tropan-3-yl-3 , 5-dichlorobenzoate) , a novel compound with potent and selective blocking actions at certain excitatory 5-hydroxytryptamine (5-HT) 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 sym- pathetic fibres. The threshold for antagonism was approximately 0.1 nM and the negative logarithm of the molar concentration of MDL 72222 which reduced the chronotropic response of the isolated rabbit heart to twice an ED50 of 5-HT to that of the ED50 was 9.27. MDL 72222 was also highly selective since responses to the nicotine receptor agonist, dimeth- ylphenylpiperazinum iodine (DMPP) , were inhibited only at concentrations more than 1000 times those necessary to inhibit 5-HT. In the anaesthetized rat, MDL 72222 produced marked blockade of the Bezold-
Jarisch effect of 5-HT. Again, inhibition was 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 cholino- ceptors or histamine Hl-receptors except at rela- tively high concentrations.
• MDL 72699 MDL 72699 ar kvartenara saltet av MDL 72222..
• Mepyramine (N,N-dimethyl N' - (methoxy-4 benzyl) -N'-' (pyridyl-2) ethylenediamine) .
• Galanolactone= Gingerol
The irregularly shaped roots (rhizomes) of ginger ( zingiber officinale) are used extensively in 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 treat- ment of nausea and vomiting associated with hyper- emesis gravidarum, anesthesia, and chemotherapy, this review will focus on ginger for motion sickness .
• Talipexole
Figure imgf000055_0001
Additional compounds
• YM 26103 -2
• YM 26308 -2 • M-840 ( [ [3- (1-methyl-lH-indol-3 -yl) -1, 2 , -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 Exy 0 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 electri- cal shocks (sender) . The responder mice revealed rather depressed gastric secretion, but developed gastric lesions which are significantly attenuated by pretreatment of dl-p-chlorophenylalanine methyl ester :HC1 (PCPA; 200-400 mg/kg p.o.), but not 6- hydroxydopamine (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), ke- tanserin (0.01-10 mg/kg) and sulpiride (32-320 mg/kg) dose-dependently attenuated the psychological stress lesion formation, and the activity was ar- ranged in the order of their in vitro binding affinities for the 5-HT3, but not 5-HT1A or 5-HT2 re- ceptors . In contrast, a peripherally acting 5-HT3 antagonist, M-840 ([ [3- (1-methyl-lH-indol-3 -yl) - 1, 2 ,4-oxadiazol-5- yl] -methyl] trimethyl-ammonium io- dide) , dopamine acting compounds, haloperidol and FR64822 [N- (4-pyridylcarbamoyl) amino-1,2, 3, 6-tetra- hydropyridine) , and antisecretory drugs, atropine and famotidine,. minimally affected the- lesion forma- ' tion.
• SDZ ICT 322, an indole-3-carboxylic acid scopine 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 arylpipera- zines at 5-HT3 receptors. Arylpiperazines, as mentioned earlier, are relatively nonselective agents; however, many bind at 5-HT3 receptors with significantly higher affinity that phenylbiguanide. We identified some structural similarities between the arylpiperazines and phenylbiguanide and, in 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/rag/serotonin/ - seven on jmCPBG 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 .
Figure imgf000058_0001
MD-354
S 21007 (21007 [5-(4-benzyl piperazin-1-yl) 4H pyr- rolo [1, 2-a] thieno [3 , 2-e] yrazine] ) .
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 bio- chemical, electrophysiological and functional assays. Binding studies using membranes from NlE-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 stimu- lated 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 NlE-115 cells. The 5-HT3 receptor agonist action of S 21007 was also demonstrated in urethane- anaesthetized rats as this drug (120 micrograms/kg i.v.) triggered the Bezold-Jarisch reflex (rapid fall in heart rate) , and this action could be pre- vented by pretreatment with the potent 5-HT3 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-substituted benzamides
• EP0417746 (September 1990, G.D. Searle & Co) Ν-Aza- bicyclo/3.3.0/octane amides of aromatic acids. See also US5126343.
Figure imgf000059_0001
or a pharmaceutically acceptable salt thereof wherein n is 0 or 1; Ar can be
Figure imgf000060_0001
benzamide
Figure imgf000060_0002
Figure imgf000060_0003
R1 is alkoxy of 1 to 6 carbon atoms; and R2 and R3 are the same or different and are hydrogen, halogen, CF3 , hydroxy, Cι_g alkoxy, C2-7 acryl, amino, amino substituted by one or two C]__g alkyl groups, C2-7 acylamino, aminocarbonyl or aminosul- fone, optionally substituted by one or two Cj__g alkyl groups, Cι_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-CONH- .
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 C]__g alkoxy (optionally substituted with phenyl), lower Cι_ alkyl, nitro, amino. aminocarbonyl, (lower Cι_ alkyl) amino, di (lower C]__g al- kyl) amino, and (lower Cχ_g alkanoyl) amino,- each R2 is lower C _ alkyl; and R3 is selected from
Figure imgf000062_0001
Figure imgf000062_0002
in which u, x, y and z are all independently an integer from 1 to 3 ; and
R4 and R5 are independently ^-η alkyl, C3.-8 cycloalkyl, C3_8 cycloalkyl-Cχ_2 alkyl, or a group
(CH2--tR6 where t is 1 or 2 ant Rg i thienyl, pyr- rolyl or furyl optionally further substituted by one or two substituents selected from Cj.g alkyl, Cι_ alkoxy, trifluoromethyl or halogen, or is phenyl optionally substituted by one or two substituents selected from Cχ_4 alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and Cχ_ alkyl
(optionally substituted by hydroxy, Cχ_ 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 Rl' is halogen, hydroxy, alkoxy (optionally substituted with phenyl) , alkyl, nitro, amino, amino carbonyl, (alkyl) amino, di (alkyl) amino, and (alkanoyl) amino; each R2 is alkyl; and R3 is in which u, x, y and z are all independently an integer from 1 to 3; and R4 and R5 are independently alkyl, cycloalkyl, cycloal- kylalkyl, or a group (CH2)tR6 where t is 1 or 2 and R6 is thienyl, pyrrolyl or furyl optionally further substituted by one or two substituents selected from alkyl, alkoxy, trifouoromehtyl or halogen, or is phenyl optionally substituted by alkoxy, trifluoromethyl, halogen, nitro, carboxy, esterified carboxy, and alkyl (optionally substituted) .
Indoles, Indole -l -carboxamides and Imidazole derivatives
EP0721949 (September 1993, Tokyo Tanabe Coompany Limited) Indoline compound and 5-HT3 receptor antagonist containing the same as active ingredient.
Figure imgf000063_0001
wherein R^ represents the group
Figure imgf000064_0001
H
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) Rl represents the group (a) or (b) , R2 represents optionally substituted phenyl or het- eroaryl; and R3 represents hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy, carbamoyl or lower alkoxycarbonyl . The compound has a potent antagonism against 5-HT3 receptors in the intestinal tract as compared with the known 5-HT3 receptor antagonists and is excellent in the persistence of the activity. Hence it is useful for preventing or treating vomiting or nausea induced by chemotherapy or radiation, irritable bowel syndrome and diarrhea.
EP0711299 (May 1994, Pharmacia S.p.A) Azabicycloalkyl Derivatives Of Imidazol (1, 5-A) Indol-3-One As 5HT 3 Antagonists
Figure imgf000065_0001
wherein each of R, R]_ and R2 , which may be the same or different, is hydrogen, halogen, hydroxy, cyano, C3.- Cg alkyl, CF3 , C^-Cg alkoxy, Cχ-Cg alkylthio, formyl, C.2-Cg alkanoyl, carboxy, Cχ-Cg alkoxycarbonyl, nitro, -N(R4 R5) in which each of R4 and R5 inde- pendently is hydrogen, Cχ-Cg alkyl, formyl or C2~Cg alkanoyl; or a (Rg R7)N-Sθ2 group, in which each of R4 and R7 independently is hydrogen or Cι~Cg alkyl; R3 is a group a)
Figure imgf000065_0002
or b)
Figure imgf000065_0003
wherein n is an integer of 1 or 2 and Rs is hydrogen, C;L-Cg alkyl unsubstituted or substituted by phenyl, C2-C4 alkenyl, C2-C4 alkynyl, formyl or C2~C alkanoyl; and the pharmaceutically acceptable salts thereof.
Novel 5-HT3 receptor antagonist compounds having general formula (I) wherein each of R, Rl 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.
Figure imgf000066_0001
wherein n, 1, 2 or 3 is; each of R, Rη_ and R2 , which may be the same or different, is hydrogen, halogen, hydroxy, cyano C]_-Cg alkyl, CF3 , Ci-C alkoxy, Cχ-Cg alkylthio, formyl, C2-C6 alkanoyl, carboxy, C^Cg alkoxycarbonyl, nitro, -N(R4)R5 in which each of R4 and R5 independ- ently is hydrogen, Cι~C alkyl, formyl or C2~Cg alkanoyl; or a Rg.(R7)N-S02 group, in which each of Rg and R7 independently is hydrogen or C^-C alkyl; R3 is an imidazolyl group having the formula
0
Figure imgf000067_0001
T
R. or b)
Figure imgf000067_0002
γ
Figure imgf000067_0003
wherein each of Rg and Rio , which may be the same or different, is hydrogen or C^-Cg alkyl, R9 is hydrogen, Cχ-Cg alkyl or a nitrogen protection group chosen from triphenylmethyl, t-butyloxycarbonyl, benzy- loxycarbonyl, acetyl, formyl, di (p-methoxyphenyl) - methyl and (p-methoxyphenyl) diphenylmethyl; and the pharmaceutically acceptable salts thereof.
Novel 5-HT3 receptor antagonist compounds having formula (I), wherein n is 1, 2 or 3; each of R, Rl 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 is hydrogen, C1-C6 alkyl, formyl or C2-C6 alkanoyl; or a (R6 R7)N-S02 group, in which each of R6 and R7 independently is hydrogen or C1-C6 alkyl; R3 is an imidazolyl group of formula (a) or (b) , wherei 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.
Figure imgf000068_0001
This invention relates to the novel salt 6-fluoro- 2,3,4, 5-tetrahydro-5-methyl-2-[ (5-methyl -IH-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 .
Figure imgf000068_0002
wherein Im represents an imidazolyl group of the formula:
Figure imgf000069_0001
and one of the groups represented by R3 , R4 and R5 is a hydrogen atom, or a C _g alkyl, C3-.7 cycloalkyl, C3--g alkenyl, phenyl or phenyl C --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;
R1and 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 Cχ_g alkyl group; Z-Y represents the group CH-CH2 or C=CH; and physiologically acceptable salts and solvates thereof, which comprises:
(A) for the production of a compound of formula (I) in which Z-Y represents the group CH-CH2, hydrogen- ating a compound of formula (II) :
Figure imgf000069_0002
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; Rl and R2 each represent a hydrogen atom, or together with the carbon atoms to which they are attached form a phenyl ring; X represents an oxygen or a 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 sol- vates thereof. The compounds of formula (I) are potent and selective antagonists of 5-hydroxytrypta- mine at 5-HT3 receptors and are useful, for example, in the treatment of psychotic disorders, anxiety and nausea and vomiting.
EP0392663 (March 1989, One Pharmaceutical Co Ltd) Car- boline derivative as a 5-HT3 receptor antagonist.
A γ-carboline of the formula I
Figure imgf000071_0001
or pharmaceutically acceptable acid addition salt and/or hydrate thereof for use in a method of treatment or prophylaxis of diseases or conditions in- duced by the action of 5-hydroxytryptamine on 5- hydroxytryptamine 3 -receptors in a mammal, including man.
The present invention provides 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)
Figure imgf000072_0001
wherein n represents 2 or 3;
Im represents an imidazolyl group of the formula
Figure imgf000072_0002
wherein one of the groups represented by R1, R2 and R3 is a hydrogen atom or a Cχ_g alkyl, C3_7 cycloalkyl, C3_ alkenyl, phenyl or phenyl 03.-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_, Cχ_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 Rl, 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 rep- resents an oxygen or a sulphur atom or a group NR4, where R4 is a Cl-6 alkyl group, and X is attached to the benzene ring moiety of the molecule; and 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
Figure imgf000073_0001
and a pharmaceutical
H composition containing an effective amount of compound
and a pharmaceutically
Figure imgf000073_0002
H acceptable carrier showing activity of a 5-HT3 receptor antagonist.
US5, 045,545 (May 1989, Glaxo Group Limited) [(Imidazol- 4 (and 5) -yl) methyl] tetracyclic ketones having 5-HT3 antagonist activity.
The invention relates to tetracyclic ketones of the general formula (I)
Figure imgf000074_0001
wherein n represents 1, 2 or 3 ;
Im represents an imidazolyl group of the formula:
Rl .RJ
T T T
Figure imgf000074_0002
wherein one of the groups represented by R1, R2 and R3 is a hydrogen atom or a C^.g alkyl, C3-.7 cycloalkyl, C3_6 alkenyl, phenyl or phenyl C]__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 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 C _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 represented, by R.sup.l, R.sup.2 and R.sup.3 is a hydrogen atom or a C. sub.1-6 alkyl, C. sub.3-7 cycloalkyl, C. sub.3-6 alkenyl, phenyl or phenyl C. sub.1-3 alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C. sub.1-6 alkyl group; Y represents a group -- (CH. sub.2)m--, where m represents 2, 3 or 4, or a group -X (CH. sub.2) . sub.p-- , where p represents 2 or 3, X represents an oxygen or a sulphur atom or a group NR . sup .4 , where R . sup .4 is a C . sub .1-6 alkyl group, and X is attached to the benzene ring moiety of the molecule; and physiologically acceptable salts and solvates thereof. The compounds are potent and selective antagonists of the effect of 5-HT at 5-HT. sub.3 receptors and are useful, for example, in the treatment of psychotic disorders, anxiety, and nausea and vomiting.
Indazole carboxamide derivatives
EP0630893 (March 1992 , Kyorin Pharmaceutical Co . Ltd . ) N, N ' -Disubstituted Amide Derivative .
Figure imgf000076_0001
A 5-HT3 antagonist containing a novel N,N'-disub- stituted 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 Rl 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
Figure imgf000076_0002
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, cy- cloalkylalkyl, alkoxyalkyl, oxoalkyl, alkoxy- cabonylalkyl, alkoxycarbonyl, acyl, dialkylaminoal- kyl, hydroxyalkyl, haloalkyl, cyanoalkyl, heterocy- cloalkyl, aryl, heteroarylalkyl or arylalkyl, the aryl group and the aryl moiety being optionally 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, Rl does not represent hydrogen, alkyl, unsubstituted benzyl or dimethylaminoethyl ; having 5-HT3 receptor antagonist activity.
Quinolines and Isocpiinolines
09964421 (June 1999, Arena Pharmaceuticals, Inc) Ace- tylcholine enhancers.
An acetylcholine enhancer selected from the group consisting of the chemical compounds represented by the following structures :
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000078_0002
Disclosed herein are quinoline derivatives having dual mechanistic properties, referred to in this patent documents as "acetylcholine enhancers", i.e., compounds which evidence acetylcholinesterase (AChE) inhibition activity, and 5-HT3 receptor antagonist activity. A particularly preferred compound is 2-[2- (1-benzylpiperizin-4-yl) ethyl]-2 , 3 -dihydro-9-methoxy- lH-pyrrolo[3 ,4-b]quinolin-l-one hemifumarate, referred to herein as Compound A ("Cm.A") .
EP0526545 (April 1991, Beecham Group p. I.e.) Isoquin- oline Amides And Esters As 5-HT3 Receptor Antagonists
A compound of formula (I) , or a pharmaceutically acceptable salt thereof:
Figure imgf000079_0001
wherein
E is NH or O,
Rl is hydrogen, halogen, C]_„4 alkyl, Cι_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 Cχ_g alkoxy, or R2 is in the 4- position and is hydrogen, halogen, CF3 , C]__ alkyl, C -.7 acyl, Cχ_ acylamino, phenyl optionally substituted by one or two C]__g alkyl, Cι--g alkoxy or halogen groups, or amino, amino- carbonyl or aminosulphonyl , optionally substituted by oone or two C]__g alkyl or C3-.3 cycloalkyl groups or by C4-.5 polymethylene or by phenyl, Cχ_g alkylsulphonyl , C]__g alkylsulphi- nyl, 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, C]__g alkyl or Cχ_g alkoxy, or R2 is in the 4- position and is hydrogen or C _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 pharmaceuticals. In formula (I) E is NH or O, Rl 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, acylamino (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 :
Figure imgf000080_0001
where
R is hydrogen or alkyl;-
R 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 R' and R and R" groups may be -(CH2)n- where n is 2 to δ;
Z is
,
Figure imgf000081_0001
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 en- dogenous 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) Isoqui- nolinone derivative.
Figure imgf000082_0001
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 R^ is hydrogen, C --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 C -.4 alkyl;
1 is 1, 2, 3 or 4; m is 1 or 2 ; n is 1 or 2 and
=^-= is a single bond or double bond; or a non-toxic acid addition salt thereof or a hydrate thereof. Isoquinolinone derivatives of the formula: wherein Rl is hydrogen, Cl-4 alkyl, Cl-4 alkoxy or a group of formula: -NR4R5 wherein R4 is hydrogen, halogen, Cl-4 alkyl or C2-4 alkanoyl and R5 is hydrogen, Cl-4 alkyl or benzyl; R2 is hydrogen or 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) .
Benzofuranes, Benzooxazines and Benzo (di) azepines
US4935511 (September 1989, Rorer Pharmaceutical Corporation) Benzoxazine benzooxazipine carboxamide 5-HT3 antagonists .
Figure imgf000083_0001
where
X is hydrogen, halo, sulfamyl, alkylsulfamyl or alkylsulfonyl; Y is hydrogen, amino, mono- or di-alkylamino or halo; Z is
-(CRiRtfj,—N 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, R]_, R2 , R3 and R4 are independently: hydrogen or alkyl ; x is 2 or 3 ; y is 1 to 4; and pharmaceutically acceptable salts thereof.
This invention relates to benzoxazine and benzoxaze- pine carboxamide compounds which exhibit 5-HT. sub.3 antagonist properties including CNS, anti-emetic and gastric prokinetic activity and which are void of any significant D.sub.2 receptor binding affinity. This invention also relates to pharmaceutical 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
Rl and R2 represent hydrogen, or
Rl and R2 taken together from a bivalent radical of formula
-CH=CH-CH--=CH- (a)
-CH=C (Cl) -CH=CH- (b) or
-CH=CH-C (Cl) =CH- (c) ; n represents 2, 3 or 4; R3 represents hydrogen or methoxy; m represents 1 or 2 ; R4 represents hydrogen, amino or Cl .3alkylcarbonyl- amino; and
R5 represents hydrogen or halo, for the manufacture of a medicament for treating 5-
HT3 -mediated disorders.
US5288731 (August 1992, Rhone-Poulenc Rorer Pharmaceuticals Inc) 2 , 6-Methano-2H-l-Benzoxacincarboxylic acids, esters and amides.
Figure imgf000085_0001
and its steroisomers, enantiomers, diasteroisomers and racemic mixtures with an amine of the formula H2N-Z; where
R 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:
Figure imgf000085_0002
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:
Figure imgf000086_0001
wherein
R is C _ alkoxy, C3_g cycloalkoxy or C3_g cycloalkyl Cχ_4 alkoxy; R2 is hydrogen, halo, Cι_g alkyl, Cι_g alkoxy or amino optionally substituted by one or two Cι_ 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 Rl 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 op- tionally substituted by one or two Cl-6 alkyl groups; R3 is hydrogen, halo or Cl-6 alkyl; L is O or NH; and Z is a di-azacyclic or azabicyclic side chain; having 5-HT3 receptor antagonist activity.
• EP0607233 (October 1991, Smithkline Beecham Pic) 3,9- Diazabicyclo (3.3.1) Nonane Derivatives With 5-HT3 Receptor Antagonist Activity
A compound of formula (I) , or a pharmaceutically ac- ceptable salt thereof:
Figure imgf000087_0001
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 satu- rated 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:
Figure imgf000088_0001
wherein
Ai, 2 , A3 and the carbon atoms to which they are attached form a 5- or 6-membered non-aromatic heterocyclic ring containing at least one -0-, -CO- or
-N-;
Rl and R2 are hydrogen or Cι_g alkyl;
Y is hydrogen, halo, Cι_g alkyl or Cι_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 accep- table salts thereof, wherein Al, A2 , A3 and the carbon atoms to which they are attached form a 5- or 6-membered non-aromatic heterocyclic ring containing at least one -0-, -CO- or -N- ; Rl and R2 are 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 activi- ty.
808588 (July 1987, Beecham Group) Heterocyclic ureand carbonates useful as pharmaceuticals.
Figure imgf000089_0001
wherein
Het is monocyclic heteroaryl having two adjacent carbon atoms, a and b, depicted in formula (I) selected from the group consisting of pyridine, pyri- midine, pyrazine, pyrrole, imidazole, thiophene, fu- ran, oxazole and thiazole;
Rl and R2 are independently selected from hydrogen, halogen, CF3 , Cι_g alkyl and Cι_g alkoxy;
R3 is hydrozy, Cι_g alkoxy, 03.7 alkenyl-methoxy, phenoxy or phenyl C1--4 alkoxy in which either phenyl moiety may be substituted by one or two Cι_g alkyl, Cι_g alkoxy or halo; CC^Rg wherein Rg is hydrogen or ι_g alkyl, CONR7R8 or S02NR7R8 wherein R7 and Rβ are independently hydrogen or Cι_ alkyl or together are C4_g polymethylene, NO2 , (CH2)mOR9 wherein m is 1 or 2 and R9 is Cι_g alkyl or S(0)nRιo wherein n is 0, 1 or 2 and RIQ is Cι_ alkyl; L is NH or 0;
Z is a group of formula (a) , (b) or (c) :
Figure imgf000090_0001
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 Cι_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.l- 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 antagonists for the present indications are tropanyl 3 , 5-dimethylbenzo- ate, MDL 72222, SDZ 216-525, ICI 169369, Zacopride, Tropisetron, Ramosetron, Ondansetron, Granisetron, Azasetron, Dolasetron, and Cilansetron. Brief Description of the Drawing
Fig. 1 depicts the effects of 5-HT and the selective 5-HT4 agonist RS 67333 on the spontaneous tone in a human airway preparation in vitro. Note that 5-HT only gives a transient relaxation, while the selective 5-HT4 agonist causes a strong sustained relaxation effect. Detailed Description of the Invention
As appears from Fig. 1, the contractile component often manifests itself as a reduction or a complete elimination of the 5-HT induced relaxation, rather than in an increase of force from the control (pre-exposure) level. In the case of "specific" agonists to the 5-HT4 receptor, this sustained relaxing effect is achieved because the contractile 5-HT3 receptor is not affected; only the relaxing 5-HT4 receptor is activated. In the case of antagonists to the 5-HT3 receptor, this effect is achieved due to direct blocking of the 5-HT3 receptor, whereby the unspecific agonists to the 5-HT4 receptor, such as 5-HT, can act without also causing contraction by the 5-HT3 receptor. It should be noted that the medicament prepared according to present invention in each embodiment may op- tionally include two or more of the above outlined compounds .
Further, in the embodiment when the compound having 5-HT3 antagonist activity- is administered, optionally to- gether with complementary serotonin or derivatives thereof, a serotonin uptake inhibitor can be added with a view to amplifying the relaxing effect, e.g. fluoxetin, cita- lopram, paroxetine, sertralin, and fluvoxamine.
The typical daily dose of the medicament prepared according to the invention varies within a wide range and will depend on various factors such as the individual requirement of each patient and the route of administration.
Said medicament may be prepared as a composition adapted either for administration via the respiratory tract or for oral, intravenous, intramuscular, intrathe- cal, topical, intraperitoneal or subcutaneous administration, in association with one or more pharmaceutically acceptable carriers, diluents or adjuvants that are well known in the art .
Moreover, said medicament is preferably administered via the respiratory tract in the form of e . g. an aerosol or an air-suspended fine powder. However, in some cases useful alternative administration forms are tablets, cap- sules, powders, microparticles, granules, syrups, suspensions, solutions, transdermal patches or suppositories.
The subject-matter of the present invention was inter alia deduced from animal experiments, where a specific behavior of the airway smooth muscle called "spontaneous tone" was examined. The spontaneous tone, which involves a spontaneous continuous contraction in the airway smooth muscle, was studied due to a suspicion that defective regulation of the spontaneous tone could be an important cause of the bronchoconstriction observed in asthmatic patients.
The examinations of the spontaneous tone were performed in accordance with the methods disclosed in the thesis "Regulation of spontaneous tone in guinea pig trachea" by S. Skogvall, Department of Physiological Sciences, Lund University, 1999, which is incorporated herein by reference. As evidenced by these examinations, the airways normally display a highly regular type of oscillating tone if exposed to physiological conditions, and this oscillating tone can be reversibly affected by administration of various substances. When the epithelium is removed, the preparations instead displays a strong, smooth type of tone.
In short, the animal experiments in said thesis showed that the spontaneous tone to a large degree is controlled by powerful regulating factors released from a specific type of airway epithelium cells, so called neu- roepithelial endocrine (NEE) cells.
Later experiments, not included in the thesis, have revealed that one of the regulating factors is serotonin (5-HT) , which activiates 5-HTι, 5-HT3/ 5-HT4, 5-HT5, 5-HT6 and 5-HT7 as well as 5-HT2 receptors, in particular 5-HT2, 5-HT3, and 5-HT4 receptors.
Additional experiments have shown that when a small dose (1 μM) serotonin (5-HT) was added to denuded guinea- pig airway smooth muscle preparations displaying a strong, smooth spontaneous tone, the average force level was increased significantly, i.e. a transient contraction was observed. A contractile effect of serotonin (5-HT) on airways (smooth muscle) has previously been reported, see e . g. Skogvall, S., Korsgren, M. , Grampp, W. , J. Appl . Phys . , 86:789-798, 1999. However, when a large dose (100 μM) of 5-HT was used, the spontaneous tone was, after a transient contraction, significantly suppressed to a level of about half the force observed in control (drug-free) conditions. The spontaneous tone returned to approximately its normal pre-treatment level when the preparations were again exposed to control, drug-free conditions. Thus, it has now surprisingly been shown that serotonin causes a contraction of guinea-pig airways at low concentrations and relaxation at high concentrations, i.e. a dual effect.
Similar experiments have also been performed on human airway preparations from patients undergoing lobec- tomy or pulmectomy due to lung cancer. In humans, 5-HT was even more potent in relaxing the airway smooth muscle than in guinea pig: even as low a concentration as 1 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. Nevertheless, examinations on 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) . The relaxation, which has a maximum after 10-15 min, disappears gradually during the follow- ing 30-45 min (see Fig 1) . In guinea pig trachea, the first 5-HT-induced effect is a contraction which reaches a maximum after approximately 10 min, and this is followed, within approximately 30 min, by a considerable reduction of tone, i.e. a relaxation below the pre-treat- ment level. The transient nature of the 5-HT relaxation in human airways is most likely caused by a simultaneous activation of the fast relaxing 5-HT4 receptor, and an activation of the slower contracting receptor, which in human airways surprisingly has been found to be the 5-HT3 receptor. This is clear, because activation of the relaxing 5-HT4 receptor by a substance that lacks 5-HT3 receptor activating properties (such as RS 67333) , results in a relaxation that is persistent and not transient (see Fig. 1) . It has previously been suggested that 5-HT may be useful in the treatment of bronchoobstructive diseases. In SU 1 701 320 it is suggested that the 5-HT, i.e. sero- tonin, may be of use as an addition to standard beta2 receptor stimulation for the treatment of acute asthma attacks. However, from the presently described experiments it seems clear that 5-HT alone is unsuitable, i.e. not effective or useful, for the treatment of said diseases, e.g. asthmatic disorders, because of the only transient relaxing effect by 5-HT (see Fig. 1). Also, reports from other groups indicate that 5-HT if anything tends to induce a weak bronchoconstriction rather than a relaxation in asthmatics (see e.g. Dupont et al . 1999, Eur Resp J 14:642-649 and Takahashi et al . 1995, Am J Respir Crit Care Med 152:377-380, which are incorporated herein by reference) .
In summary, it has now been discovered that agonist action on the 5-HT4 receptor results in a relaxing effect, whereas agonist action on 5-HT3 receptors results in a contractile effect. In conclusion, the dual effect of 5-HT is most' likely a result of its agonist action on the relaxing 5-HT4 receptor as well as on the contracting 5 -HT3 receptor .
It was also deduced from these experiments that compounds having agonist activity to the 5-HT4 receptor, while having only low or no agonist activity to a 5-HT3 receptor, therefore are useful as agents for treatment of disorders involving airway constriction, as defined above .
In the above mentioned experiments it has been shown that compounds having antagonist activity to a 5-HT3 receptor are useful as agents for treatment of disorders involving airway constriction, since they are capable of blocking the contractile effect of a compound having agonist activity to a 5-HT3 receptor. Administration of serotonin, a serotonin reuptake inhibitor or any other substance having 5-HT4 receptor agonist activity results in increased relaxation of the bronchi.

Claims

1. Compound having antagonist activity to a 5-HT3 receptor, and derivatives and pharmaceutically acceptable salts thereof having antagonist activity to the 5-HT3 receptor for use as a medicament for treatment of disorders involving airway constriction.
2. Compound according to claim 1, wherein said compound has the capacity of reducing pathological broncho- contraction by at least 30%, preferably at least 60%, and most preferably at least 90%, and wherein said compound is chosen from the group comprising
Figure imgf000096_0001
benzazepines, preferably mirtazapine
Figure imgf000096_0002
benztiazephines, preferably diltiazem
and fentiazines
Figure imgf000097_0001
Figure imgf000097_0002
preferably perphenazine, chlorpromazine, stemetil; compounds also having 5-HT4 receptor agonist acti- - vity, preferably benzamides
,
an
Figure imgf000097_0003
2 , 3-dihydro-benzofuran-7-carboxamides
Figure imgf000098_0001
(preferably zatosetron=LY 277359, ADR 851) ; 1, -bensoxazin-8-carboxamides
Figure imgf000098_0002
preferably azasetron (=Y25130) ; benzimidazolones
Figure imgf000098_0003
preferably itasetron (=DAU 6215) indazol-3-carboxaπddes
Figure imgf000099_0001
preferably N 3389, LY 278584, DAT 582 (= (R) AS-5370) ; wherein the latter group reminds most of the specific 5-HT3 antagonists, which contains the group
Figure imgf000099_0002
in different forms, such as
ondansetron
Figure imgf000099_0003
Figure imgf000099_0004
alosetron cilansetron (=KC 9946) substances the structure of which has been inverted and the carbonyl group has been placed on the indoline nitrogen
Figure imgf000100_0001
also being an antagonist against both 5-HT3 and 5-HT4 receptors,
Figure imgf000100_0002
isoquinoline-1-ones
Figure imgf000100_0003
palonosetron (=RS 25259-197) RS 42358-197 and the quinoline-3 -carboxamides
Figure imgf000101_0001
WAY-SEC 579 Mirisetron (=WAY 100579) ,
quinoline-4 -carboxylates
Figure imgf000101_0002
preferably KF 17643
Figure imgf000101_0003
preferably KF 18259 ; benzimidazolones
Figure imgf000102_0001
preferably droperidol (neurolidol) , itasetron (DAU6215) , and the naphtimides
Figure imgf000102_0002
preferably RS 56532 ;
MDL 72222, which also is a specific 5-HT3 antagonist;
Figure imgf000102_0003
Figure imgf000103_0001
Talipexole
Figure imgf000103_0002
iodophenpropit
thioperamide, and
Figure imgf000103_0003
30
2-piperidin- and 2-piperazin-
35 benzimidazoles; and also
Figure imgf000103_0004
(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-IH-indol-3-yl) -1,2 , 4-oxadizole, 5,7-DHT, 5- [ (dimethylamino) methyl] -3- (1-methyl-IH-indol- 3-yl) -1,2, 4-oxadizole, ADR-882, Amitriptyline, Anpirto- line, AS-5370, Batanopride, BIMU 1, BRL 24682, BRL 43694, BRL 46470 (=Ricasetron) , BRL 47204, Bufotenine, CF 109203 (=BIM) , Cizapride, Clozapine, CP-93318, Cyameazine, Cyproheptadine, Dolasetron mesilat (=MDL 73147 EF) , Fluphenazone, Galdansetron, GR 38032 F, GR 67330, Granisetron (=Kytril=BRL 43694) , GR-H, GYKl-48903, ICS 205-930, Imipramine, Indalpine, KAΞ-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, NAN-190, N- metylquipazin, 3- (1-piperazinyl) -2-quinoxalinecarbonitrile, ONO-3051, Pancopride, Phenylbiguanide, Pitozifen, Prochlorperazine (Stemetil) , QICS 205-930, R(+) zacopride, Renzapride, RG 12915, Ritanserin, RP 62203, RS-25259-197, RS-056812-198 , RS-25259, RU 24969, S(-) Zacopride, S-apomorfin, SC-52491, SC-53116, SDZ 206-792, SDZ 206-830, SDZ 210-204, SDZ 210-205, SDZ 214-322, SDZ 322, SN-307, TFMPP, TMB 8, trifluoperzine, tropanyl-3 , 5-dimethylbenzoate, 3-tropanyl-indole-3- carboxylate ethiodide, VA 21 B 7, Y 2513, SEC 579, BRL 46470 A, Pizotifen, Dolasetron (=MDL 74156) , Galano- lactone, GR 65 630, Ifenprodil, L-683877, Litoxetine, Quipazine, QX 222, Ramosetron (=YM 060), RS 56812, SDZ
216-525, Trimebutine, GR 65630, Tropisetron (=ICS 205-930 -=Rifenserin) , Bemesetron, L-683,877, LY-278,584 maleate and derivatives and pharmaceutically acceptable salts thereof with the same or essentially the same relaxation enhancing effect.
3. Compound according to claim 3, wherein it preferably is tropanyl 3, 5-dimethylbenzoate, MDL 72222, SDZ 216-525, ICI 169369, Zacopride, Tropisetron, Ramosetron, Ondansetron, Granisetron, Azasetron, Dolasetron and Cilansetron.
4. Compound according to claim 3, wherein said air- way constriction appears in asthma, emphysema, chronic bronchitis, and chronic obstructive pulmonary disease, preferably asthma.
5. Use of one or more of the compounds according to any of claims 1-3, and derivatives and pharmaceutically acceptable salts thereof having antagonist activity to the 5-HT3 receptor, in the manufacture of a medicament for therapeutic or prophylactic treatment of disorders involving airway constriction, (optionally together with a serotonin uptake inhibitor) .
6. Use according to claim 5, wherein said one or more compounds has the capacity of reducing the pathological bronchocontraction by at least 30%, preferably at least 60%, and most preferably at least 90%.
7. Use according to any one of claims 5 and 6 , wherein said disorder involving airway constriction is asthma and disorders related thereto, emphysema, chronic bronchitis, and chronic obstructive pulmonary disease, preferably asthma.
8. A method for treatment of disorders involving airway constriction, wherein said method comprises administering to a human or animal patient a therapeutically effective amount of a compound according to claims 1-3.
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