WO1992009284A1 - 2,6-methano-2h-1-benzoxocincarboxamides en tant qu'antagonistes de 5-ht¿3? - Google Patents

2,6-methano-2h-1-benzoxocincarboxamides en tant qu'antagonistes de 5-ht¿3? Download PDF

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Publication number
WO1992009284A1
WO1992009284A1 PCT/US1991/008806 US9108806W WO9209284A1 WO 1992009284 A1 WO1992009284 A1 WO 1992009284A1 US 9108806 W US9108806 W US 9108806W WO 9209284 A1 WO9209284 A1 WO 9209284A1
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methano
chloro
tetrahydro
benzoxocine
compound according
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PCT/US1991/008806
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English (en)
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John E. Airey
Matthew R. Powers
Walter Rodriguez
Raymond D. Youssefyeh
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Rhone-Poulenc Rorer International (Holdings), Inc.
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Publication of WO1992009284A1 publication Critical patent/WO1992009284A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/16—Eight-membered rings
    • C07D313/20—Eight-membered rings condensed with carbocyclic rings or ring systems

Definitions

  • This invention relates to 2,6-methano-2H-1 -benzoxocincarboxamide compounds which exhibit 5-HT 3 -antagonist properties including unique CNS, anti- emetic and gastric prokinetic activity and which are void of any significant D2 receptor binding affinity.
  • This invention relates also to processes for the preparation, separation and purification of said compounds.
  • 5-Hydroxytryptamine abbreviated “5-HT”
  • Serotonin is found throughout the body including the gastrointestinal tract, platelets, spleen and brain and appears to be involved in a great number of physiological processes such as neurotransmission at certain neurones in the brain, and is implicated in a number of central nervous system (CNS) disorders. Additionally, serotonin appears to act as a local hormone in the periphery; it is released in the gastrointestinal tract, where it increases small intestinal motility, inhibits stomach and colon motility, and stimulates stomach acid production. Serotonin is most likely involved in normal intestinal peristalsis .
  • D-receptors are 5-HT2- receptors
  • M-receptors are termed 5-HT3-receptors
  • all other receptors which are clearly not 5-HT2 or 5-HT3, have been referred to as 5-HT- ⁇ -like and work is being continued on this classification.
  • 5-HT3-receptors have been located in non-neurological tissue, brain tissue, and a number of peripheral tissues related to different responses. It has been reported that 5-HT 3 -receptors are located on peripheral neurones where they are related to serotonin's (excitatory) depolarizing action.
  • 5- HT3-receptor activity has been reported: action involving postganglionic sympathetic and parasympathetic neurones, leading to depolarization and release of noradrenaline and acetylcholine, respectively (5-HT3B subtype); action on enteric neurones, where serotonin may modulate the level of acetylcholine (5-HT3C subtype); and action on sensory nerves such as those involved in the stimulation of heart nerve endings to produce a reflex bradycardia (5HT3A subtype), and also in the perception of pain.
  • 5-HT3-antagonists have been shown to be very effective at controlling and preventing emesis (vomiting) induced by chemotherapy and radiotherapy in cancer patients.
  • the anti-emetic effects of 5-HT3-antagonists in animals exposed to cancer chemotherapy or radiation are similar to those seen following abdominal vagotomy.
  • the antagonist compounds are believed to act by blocking 5-HT3-receptors situated on the cell membranes of the tissue forming the vagal afferent input to the emetic coordinating areas on the brain stem.
  • Serotonin is also believed to be involved in the disorder known as migraine headache. Serotonin released locally within the blood vessels of the head is believed to interact with elements of the perivascular neural plexus of which the afferent, substance P-containing fibers of the trigeminal system are believed relevant to the condition. By activating specific sites on sensory neuronal terminals, serotonin is believed to generate pain directly and also indirectly by enhancing the nociceptive effects of other inflammatory mediators, for example bradykinin. A further consequence of stimulating the afferent neurones would be the local release of substance P and possibly other sensory mediators, either directly or through an reflex mechanism, thus providing a further contribution to the vascular changes and pain of migraine.
  • Serotonin is known to cause pain when applied to the exposed blister base or after an intradermal injection; and it also greatly enhances the pain response to bradykinin. In both cases, the pain message is believed to involve specific 5-HT3-receptors on the primary afferent neurones.
  • 5-HT 3 -antagonists are also reported to exert potential antipsychotic effects, and are believed to be involved in anxiety. Although not understood well, the effect is believed to be related to the indirect blocking of serotonin 5-HT3-mediated modulation of dopamine activity. Many workers are investigating various compounds having 5-HT 3 -antagonist activity.
  • 5-HT3 agents originated from work carried out with metoclopramide (Beecham's Maxolon, A.H. Robins' Reglan), which is marketed for use in the treatment of nausea and vomiting at high doses.
  • Metoclopramide is a dopamine antagonist with weak 5-HT3-antagonist activity, which becomes more prominent at higher doses. It is reported that the 5-HT3 activity and not the dopamine antagonism is primarily responsible for its anti-emetic properties. Other workers are investigating this compound in connection with the pain and vomiting accompanying migraine.
  • Merrell Dow's compound MDL-72222 is reported to be effective as an acute therapy for migraine, but toxicity problems have reportedly ended work on this compound.
  • Currently four compounds, A.H. Robins' Zacopride, Beecham's BR -43694, Glaxo's GR-380-32F and Sandoz' ICS-205-930 are in clinical trials for use in chemotherapy-induced nausea and vomiting.
  • GR-38032F is also in clinical trials in anxiety and schizophrenia, and reportedly, Zacopride in anxiety, while ICS-205-930 has been shown to be useful in treating carcinoid syndrome.
  • gastroprokinetic agents include Beecham's BRL- 24924, which is a serotonin-active agent for use in gut motility disorders such as gastric paresis, audition reflux esophagitis, and is known to have also 5-HT3- antagonist activity.
  • Metoclopramide, Zacopride, Cisapride and BRL-24924 are characterized by a carboxamide moiety situated para to the amino group of 2-chloro-5-methoxy aniline.
  • BRL-43694, ICS-205-930, GR-38032F and GR-65630 are characterized by a carbonyl group in the 3-position of indole or N-methyl indole.
  • MDL-72222 is a bridged azabicyclic 2,4-dichlorobenzoate, while Zacopride, BRL-24924, BRL- 43694 and ICS-205930 have also bridged azabicyclic groups in the form of a carboxamide or carboxylic ester.
  • Bicyci ⁇ c oxygen containing carboxamide compounds wherein the carboxamide is ortho to the cyclic oxygen moiety are reported to have antiemetic and antipsychotic properties in EPO Publication No. 0234872.
  • Dibenzofurancarboxamides and 2-carboxamide-substituted benzoxepines are reported to have 5-HT3-antagonist and gastroprokinetic activity in U.S. Patent Nos. 4,859,683, 4,857,517, 4,924,010 and 4,863,921 , all of which are assigned to the same assignee as the present application .
  • stereo ⁇ somers which are synthesized by using chiral synthesis, i.e., asymmetric induction methods of synthesis.
  • U.S. Patent No. 4,863,921 discloses dibenzofurancarboxamides having 5-HT3-antagonist properties.
  • the synthesis of these dibenzofurans is described in the specification by first esterifying salicyclic acid and then reacting the phenol with 3-bromocyclohexene under basic conditions to obtain the phenyl cyclohexenyl ether. Claisen rearrangement at high temperature results in the methyl 3-(3'-cyclohexene)salicylate. Ring closure using trifluoroacetic acid results in formation of the 5a,6,7,8,9,9a-hexahydrodibenzofuran ring.
  • this invention comprises compounds having selective 5HT 3 - antagonist properties, processes for their preparation, their use in the treatment of various gastric prokinetic disorders and pharmaceutical preparations.
  • R is hydrogen or alkyl
  • Ri 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 hydrogen or alkyl
  • geminal R and R' or R and R" groups may be -(CH2)n- where n is 2 to 6;
  • Alkyl means, either alone or within the various substituents, defined hereinbefore, a hydrocarbon having one to about 20 carbon atoms.
  • Lower alkyl means alkyl having one to about six carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl and hexyl.
  • Preferred lower alkyl includes methyl, ethyl and propyl.
  • Halo means Cl, Br, I and F. Preferred halo is Cl and Br, while preferred haloalkyl is CF3.
  • acyl means an organic radical derived from an organic acid, a carboxylic acid, by the removal of its acid hydroxy group.
  • Preferred acyl groups are benzoyi and lower alkyl carboxylic acid groups such as acetyl and propionyl.
  • Preferred compounds of this invention include those compounds of Formulae II and III
  • More preferred compounds include those of Formula II where
  • R is amino or loweralkylamino and R2 is hydrogen
  • Ri is hydrogen and R2 is halo, or
  • Ri is amino and R2 is halo.
  • the present compounds are prepared by the following general procedure.
  • this reaction is carried out at decreased temperatures, such as 0°C by adding ethyl chloroformate to a reaction mixture of the acid in chloroform in the presence of triethylamine. This is then reacted with the amine of the formula H2N-Z to obtain the desired product. Condensation may also be carried out in the presence of a dehydrating catalyst such as a carbodiimide in a solvent at normal temperatures.
  • a dehydrating catalyst such as a carbodiimide in a solvent at normal temperatures.
  • the most preferred compounds are prepared by reacting the Ri and R2 substituted 2,6-methano-2H-3,4,5,6-tetrahydro-1 -benzoxocin-10-carboxylic acids, acid halides or esters with 3-aminoquinuclidine to obtain Ri and R2 substituted 10- [N-(1-azabicyclo[2.2.2.]octan-3-yl)carboxamido]-2,6-methano-2H-3 , 4,5,6- tetrahydro-1 -benzoxocines.
  • This reaction may take place with optically pure starting materials such as the acid or amine which have a specific configuration to obtain the desired stereospecific amide. Further, the amide may be formed as above and then separated by known techniques into the desired stereoisomers. Preparation and separation will be described in more detail later in this application.
  • the starting materials that is the substituted 2,6-methano-2H-3,4,5,6- tetrahydro-1 -benzoxocin-10-carboxylic acid, 2,6-methano-2H-3,4-dihydro-1 - benzoxocin-10-carboxylic acid, 2,6-methano-2H-5,6-dihydro-1-benzoxocin-10- carboxylic acid, 2,6-methano-2,3,4,5-tetrahydro-1-benzoxocin-10-carboxylic acid and 2,6-methano-2H-1 -benzoxocin-10-carboxylic acids are also novel. Their preparation will be described in more detail later.
  • Salicyclic acid is first esterified and then the phenol(2) is treated with 3- bromocyclohexene under basic conditions in a polar medium to obtain the phenyl cyclohexenyl ether (3). Claisen rearrangement at high temperature results in the methyl 3-(3'-cyclohexene)salicylate (4). Ring closure using trifluoroacetic acid results in the formation of the 5a,6,7,8,9,9a-hexahydrodibenzofuran ring (5). This is then be hydrolyzed to the acid (6) with aqueous base and then reacted with an amine of the formula H2N-Z to obtain the desired dibenzofurancarboxamides (7).
  • Example 24 of U.S. Patent No. 4,863,921 and PCT/US89/01739 which is described in detail at the end of the examples of this application, describes the preparation of methyl 2-chloro-cj ⁇ -5a,6,7,8,9,9a-hexahydrodibenzofuran-4- carboxylate and methyl 2-chloro-trans-5a.6.7.8.9.9a-hexahydrodibenzofuran-4- carboxylate.
  • the first fraction was stated to be a mixture of at least two materials.
  • the second fraction was stated to be the £is isomer.
  • the third fraction was stated to be a mixture of cjs and trans isomers.
  • the fourth fraction was stated to be the trans isomer.
  • the present inventors with the aid of X-ray crystallography determined that the second fraction was indeed methyl 2-chloro-cis-5a.6.7.8.9.9a- hexahydrodibenzofuran-4-carboxylate. However, it was unexpectedly found that the fourth fraction was not 2-chloro-trans-5a.6.7.8.9.9a-hexahvdrodibenzofuran-4- carboxylate but rather 8-chloro-cis-2.6-methano-2H-3.4.5.6-tetrahydro-1- benzoxoc ⁇ n-10-carboxylate.
  • the starting materials of this invention are prepared by the following reaction scheme:
  • dihydrochromone (A) Treatment of the dihydrochromone (A) with strong base such as potassium t-butoxide ring closes to obtain the dihydrobenzoxocine ketone (C).
  • This may also be prepared from the triphenylphosphonate (B).
  • Wolff-Kishner reduction of the ketone compound (C) with hydrazine to form the hydrazide followed by reduction with potassium hydroxide results in 2,6-methano-2H-3,4- dihydro-1 -benzoxocin-10-carboxylate (D).
  • R2 is sulfamyl
  • this group be protected initially with an acetyl group or the like and then deacetylated.
  • Halogenation may also be carried out on the 7-acetylamino compounds of the est Halogenation occurs in the 8-position.
  • hydrolysis gives the desired 7-amino-8-halo-10- carboxylic acids of this invention.
  • Certain compounds of this invention have at least one asymmetric carbon atom su
  • the product may exist as mixtures of two or four diastereomers.
  • certain other compounds within the scope of this invention could have a number of stereocenters.
  • a compound with x stereocenters can have a maximum of 2 X stereoisomers. Therefore, a compound having three such centers gives rise to a maximum of eight stereoisomers, while one having four produces sixteen, etc.
  • the product may be synthesized as a mixture of the isomers and then the desired isomer, separated by conventional techniques such as chromatography or fractional crystallization from which each diastereomer is resolved.
  • synthesis may be carried out by known stereospecific processes using the desired form of the intermediate which would result in obtaining the desired stereospecificity
  • one of the most preferred compounds of this invention is 10-[N-(1-azabicyclo[2.2.2.]octan-3(S)- yl)carboxamido]-8-chloro-cis-2(S),6(R)-methano-2H-3,4,5,6-tetrahydro-1 - benzoxocine. This has three asymmetric centers. These are at the 2 and 6 positions of the benzoxocine ring and at the 3 position of the quinuclidine moiety.
  • the stereoisomeric mixture can be divided into cjs and trans configurations having their own specific properties and are also within the scope of this invention.
  • the cjs configuration for example, has four ⁇ j ⁇ stereoisomers consisting of two racemates and four diastereoisomeric mixtures.
  • the £i ⁇ racemates and diastereoisomeric mixtures can also be considered to be separate entities because of their unique chemical, physical and pharmacological properties and are further included within the scope of this invention.
  • resolution of 3-aminoquinuclidine results in S- (-)-3-aminoquinuclidine and R-(+)-3-aminoquinuclidine.
  • the remaining various stereospecific compounds are prepared by reacting S-(-)-3- amino-quinuclidine or R-(+)-3-aminoqui ⁇ uclidine with the cj ⁇ (S,R) or cj ⁇ (R,S) configuration orthe trans (R,R) or trans (S,S) configuration of 8-chloro-2,6-methano- 2H-3,4,5,6-tetrahydro-1-benzoxocin-10-carboxylic acid, acid halide or ester.
  • the remaining compounds of Formula I are so prepared. Ring closure of methyl 3-(3- hexenyl)-5-chlorosalicylate results in predominantly cis formation.
  • the compounds of this invention may be readily converted to their non-toxic acid addition salts by customary methods in the art.
  • the nontoxic salts of this invention are those salts the acid component of which is pharmacologically acceptable in the intended dosages, including those prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and from organic acids such as methane sulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, maleic acid, oxalic acid, suc ⁇ nic acid, giycolic acid, lactic acid, salicylic acid, benzoic acid, nicotinic acid, phthalic acid, stearic acid, oleic acid, abietic acid, etc.
  • compounds of this invention have gastric prokinetic and anti-emetic properties and lack D2 receptor binding activity. As such they possess therapeutic value in the treatment of upper bowel motility and gastroesophageal reflux disorders. Further, compounds within the scope of this invention are useful in the treatment of disorders related to impaired gastrointestinal motility such as retarded gastric emptying, dyspepsia, flatulence, esophageal reflux, peptic ulcer and emesis. Further, compounds of this invention exhibit 5-HT3 antagonism and are considered to be useful in the treatment of psychotic disorders such as schizophrenia and anxiety and in the prophylaxis treatment of migraine and cluster headaches. We have further found that certain compounds are selective in that they have little or no dopaminergic antagonist activity.
  • the test is designed to assess the effects of a test agent on gastric emptying of amberlite beads in the rat.
  • the procedure is a modification of those used in LE. Borella and W. Lippman (1980) Digestion 20: 26-49.
  • Amberlite ® beads are placed in a phenol red solution and allowed to soak for several hours. Phenol red serves as an indicator, changing the beads from yellow to purple as their environment becomes more basic. After soaking, the beads are rinsed with 0.1 NaOH to make them purple and then washed with deionized water to wash away the NaOH.
  • the beads are filtered several times through 1.18 and 1.4 mm sieves to obtain beads with diameters in between these sizes. This is done using large quantities of deionized water. The beads are stored in saline until ready to use.
  • Rats Male Sprague-Dawiey rats are fasted 24 hours prior to the study with water ad_ libitum. Rats are randomly divided in treatment groups with an N of 6 or 7.
  • Test agents are prepared in 0.5% methylcellulose and administered to the rats orally in a 10 ml/kg dose volume.
  • Control rats receive 0.5% methylcellulose, 10 ml/kg p.o.
  • rats are given 60 Amberlite® beads intragastricalfy.
  • the beads are delivered via a 3 inch piece of PE 205 tubing attached to a 16 gauge tubing adapter and syringe.
  • a small piece of PE 50 tubing is placed inside the tubing adapter to prevent the beads from being pulled back into the syringe.
  • the beads are flushed into each rat's stomach with 1 ml saline.
  • Rats are sacrificed 30 minutes after receiving the beads and their stomachs are removed. The number of beads remaining ion each stomach is counted after rinsing the beads with NaOH.
  • the number of beads remaining in each stomach is subtracted from 60 to obtain the number of beads emptied.
  • the mean number of beads ⁇ S.E.M. is determined for each treatment group. The percent change from control is calculated as follows:
  • Cisplatin had been shown to cause emesis in the dog and cat. Florczyk, e a have used the ferret to demonstrate the same effects.
  • ferrets are dosed with the compound in 0.9% saline (i.v.) at a dose volume of 2.0 ml/kg.45 minutes after administration of cisplatin, ferrets are again dosed with the
  • Cisplatin 0.9% saline (i.v.) mixture at a dose volume of 2.0 ml/kg.
  • Cisplatin is administered (i.v.) 30 minutes after the first dosing with the 0.9% saline.
  • Cisplatin 10 mg/kg is administered in a dose volume of 2.0.ml/kg.
  • the time of cisplatin administration is taken as time zero. Ferrets are observed for the duration of the experiment (4 hours). The elapsed time to the first emetic episode is noted and recorded, as are the total number of periods of emesis.
  • An emetic (vomiting) episode is characterized by agitated behavior, such as pacing around the cage and rapid to and fro movements. Concurrent with this behavior are several retching movements in a row, followed by a single, large, retch which may or may not expulse gastric contents. Immediately following the single large retch, the ferret relaxes. Single coughs or retches are not counted as vomiting episodes.
  • ⁇ -HT ⁇ receptor binding may be assayed by the method of C. A. Milburn and S. J. Peroutka: Mol. Pharmacol. 16: 687-699, 1979.
  • D-2 Dopamine Receptor Binding Assay The D-2 dopamine receptor binding assay has been developed with slight modifications using the method of Ian Cresse, Robert Schneider and Solomon H. Snyder, Europ. J. Pharmacol. 46: 377-381 (1977). Spiroperidol is a butyrophenone neuroleptic whose affinity for dopamine receptors in brain tissue is greater than that of any other known drug. It is a highly specific D-1 dopamine (non- cyclase linked) receptor agent with K1 values of 0.1-0. for D-2 inhibition and 300 nM for D-1 inhibition.
  • Sodium ions are important regulators of dopamine receptors.
  • the affinity of the D-2 receptor is markedly enhanced by the presence of millimolar concentrations of sodium chloride.
  • the Kd in the absence and presence of 120 mM sodium chloride is 1.2 and 0.086 nM respectively.
  • Sodium chloride (120 mM) is included in all assays as a standard condition .
  • the caudate nucleus (corpus striatum) is used as the receptor source because it contains the highest density of dopamine receptors in the brain and periphery.
  • Tissue can be stored indefinitely at -70°C.
  • caudate is homogenized in 30 ml of tris buffer (pH 7.7 at 25°C) using the polytron homogenizer. The homogenate is centrifuged at 40,000g (18,000-19,000 RPM in SSp-34 rotor) for 15 minutes. Pellet is resuspended in fresh buffer and centrifuged again. The final pellet is resuspended in 150 volumes of assay buffer.
  • Male rats 260-290g are anaesthetized with urethane 1.25 g/kg -1 i.p., and the trachea cannulated.
  • the jugular vein is cannulated for intravenous (i.v.) injection of drugs.
  • Blood pressure is recorded from a cannula in the left carotid artery and connected to a heparin/saline-filled pressure transducer. Continuous heart rate measurements are taken from the blood pressure recordings.
  • the Bezold-Jarisch effect is evoked by rapid, bolus i.v. injections of 5-HT and measurements are made of the fall in heart rate.
  • consistent responses are first established with the minimum dose of 5-HT that evokes a clear fall in heart rate.
  • Injections of 5-HT are given every 12 minutes and a dose-response curve for the test compound is established by injecting increasing doses of compound 5 minutes before each injection of 5-HT.
  • the effect of a compound on the 5-HT-evoked bradycardia is calculated as a percent of the bradycardia evoked by 5-HT before injection of compound.
  • Compounds of the present invention can be administered to a mammalian host in a variety of forms adapted to the chosen route of administration, i.e., orally, or parenterally.
  • Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepthelially including transdermal, ophthalmic, sublingual and buccal; topically including ophthalmic, dermal, ocular, rectal and nasal inhalation via insufflation and aerosol and rectal systemic.
  • the active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsuled, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the active compound may be incorporated with excipient and used in the form of ingestibie tablets, buccal tablets, trochees, capsules, elixirs, suspensions, syrups, wafers and the like.
  • Such compositions and preparations should contain at least 0.1 % of active compound.
  • the percentage of the compositions and preparations may, of course, be varies and may conveniently be between about 2 to about 6% of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 50 and 300 mg of active compound.
  • the tablets, trochees, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, genie acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring.
  • a binder such as gum tragacanth, acacia, com starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as com starch, potato starch, genie acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermin
  • tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound.
  • Sucrose as a sweetening agent
  • methyl and propylparabens as preservatives
  • a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and formulations.
  • the active compound may also be administered parenterally or intraperiotoneally.
  • Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hyd ro xy pro py [cellulose.
  • Dispersion can also be prepared in giycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringeability exists. It may be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, giycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions of agent delaying absorption for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and the freeze drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
  • Therapeutic compounds of this invention may be administered to a mammal alone or in combination with pharmaceutically acceptable earners, as noted above, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice.
  • the physician will determine the dosage of the present therapeutic agents which will be most suitable for prophylaxis or treatment and will vary with the form of administration and the particular compound chosen, and also, it will vary with the particular patient under treatment. He will generally wish to initiate treatment with small dosages by small increments until the optimum effect under the circumstances is reached.
  • the therapeutic dosage will generally be from 0.1 to 20 mg or from about 0.01 mg to about 50 mg/kg of body weight per day and higher although it may be administered in several different dosage units from once to several times a day. Higher dosages are required for oral administration.
  • Methyl-5-chloro-2-.3'-cvclohexenyloxy.benzoate A mixture of methyl-5-chlorosaIicylate (5509, 2.95 mol), 3- bromocyclohexene (597.4g, 3.71 mol), finely grounded potassium carbonate (815.0g, 5.90 mol) and acetone (48609, 83.7 mol) are slowly heated to reflux and maintained at reflux for 24 hours. The mixture is cooled to 3040°C, the solids filtered, washed with acetone and the filtrate concentrated to dryness to give methyl- 5-chloro-2-(3'-cyclohexenyloxy)benzoate as an oil which is used directly in the next step.
  • Methyl-5-chloro-3-i3'-cyclohexenyl.salicylate A slurry of methyl-5-chloro-2-(3'-cyclohexenyloxy)benzoate (603.6g, 2.26 mol) and cesium carbonate (33.5g, 0.1 mol) are heated, under a nitrogen blanket, to 155-175°C. On completion of the reaction, the mixture is cooled to 80°C and toluene (500 ml) added. The mixture is stirred for 1 hour and the solids removed by filtration.
  • the ester, methyl 8-chloro-2,6-methano-2H-3,4,5,6-tetrahydro-1- benzoxocin-10-carboxylate (351 .6g) is added to a solution of lithium hydroxide, monohydrate (131.0g, 3.12 mol) in water (2.6L) and the mixture heated to reflux for 1.5 hours. This results in the formation of a heavy precipitate.
  • the reaction mixture is cooled to room temperature, ethyl acetate (1.7L) is added followed by acidification with concentrated hydrochloric acid (276 ml). The ethyl acetate is removed and the acidic aqueous layer further extracted with ethyl acetate (500 ml).
  • the racemic acid 8-chloro-2,6-methano-2H-3,4,5,6-tetrahydro-1- benzoxocin-10-carboxylic acid (173.79, 0.69 mol) is added to the above methanolic solution and stirred to give a homogeneous solution. Within 0.5 hours a white precipitate forms. The solvent is removed under reduced pressure and the crude salt mixture suspended in ethyl acetate (700 ml) and methanol (500 ml) and heated to reflux to give a clear solution. On cooling to room temperature the solids are filtered and washed with ethyl acetate.
  • reaction mixture is evaporated to dryness by means of azeotroping with toluene, to give the acid chloride as an oil which is dissolved in toluene (2 ml).
  • (S)-3-aminoquinuclidine dihydrochloride (5g, 0.025 mol) is dissolved in a solution of 50% aqueous sodium hydroxide (4.1g) and methanol (20 ml) and stirred for 5 minutes.
  • the mixture is filtered and the filtrate evaporated to dryness to give a semi-solid. This is treated with toluene and stirred at 50°C for 5 minutes, filtered, and the filtrate evaporated to dryness.
  • the methanol is removed in vacuum, diluted with water, filtered, acidified with acetic acid, filtered, extracted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to dryness to obtain 7-amino-8-chloro-2,6-methano-2H- 3,4,5,6-tetrahydro-1-benzoxocin-10-carboxylic acid. This is purified by crystallization from ethyl acetate/ether.
  • the fourth fraction is methyl 8-chloro-cis- 2,6-methano-2H-3,4,5,6-tetrahydro-1 -benzoxocin-10-carboxylate.
  • Example 25 Based on X-ray data the product prepared in Example 25 is 8-chloro-cis- 2,6-methano-2H-3,4,5,6-tetrahydro-1 -benzoxocin-10-carboxylic acid.
  • Example 27 Based on the X-ray data forthe acid starting material prepared in Example 26, the product prepared in Example 27 is 10-[N-(1-azab ⁇ cyclo[2.2.2.]octan-3- vl)carboxamido]-8-chloro-cis-2.6-methano-2H-3.4.5.6-tetrahydro-1 -benzoxocine.
  • Example 36 Based on X-ray crystallographic data from the acid starting material prepared in Example 26, the starting material to be resolved in Example 36 is 8-chloro-cis- 2,6-methano-2H-3,4,5,6-tetrahydro-1-benzoxocin-10-carboxylic acid and the materials resolved are be 8-chloro-cJs-2(R),6(S)-methano-2H-3,4,5,6-tetrahydro-1- benzoxocin-10-carboxylic acid and 8-chloro-cjs-2(S),6(R)-methano-2H-3,4,5,6- tetrahydro-1-benzoxocin-10-carboxylic acid.

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Abstract

Des nouveaux composés qui sont des 2,6-méthano-2H-1-benzoxocincarboxamides ayant des propriétés inhibitrices de 5-HT3, y compris une action unique sur le système nerveux central, anti-émétique et gastrique procinétique, et qui sont exempts de toute affinité de liaison importante au récepteur D2, des procédés de préparation desdits composés,des compositions thérapeutiques et des méthodes de traitement des troubles qui résultent de l'activité de 5-HT3 faisant appel auxdits composés sont décrits.
PCT/US1991/008806 1990-11-29 1991-11-22 2,6-methano-2h-1-benzoxocincarboxamides en tant qu'antagonistes de 5-ht¿3? WO1992009284A1 (fr)

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US4921982A (en) * 1988-07-21 1990-05-01 Eli Lilly And Company 5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acids useful as intermediates for 5-HT3 antagonists
US4920227A (en) * 1988-11-29 1990-04-24 Rorer Pharmaceutical Corp. Benzobicyclic carboxamide 5-HT3 antagonists
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