EP0559656A1 - Verfahren zur herstellung von multicyclischen sauerstoffhaltigen ringsystemen - Google Patents

Verfahren zur herstellung von multicyclischen sauerstoffhaltigen ringsystemen

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Publication number
EP0559656A1
EP0559656A1 EP19910917621 EP91917621A EP0559656A1 EP 0559656 A1 EP0559656 A1 EP 0559656A1 EP 19910917621 EP19910917621 EP 19910917621 EP 91917621 A EP91917621 A EP 91917621A EP 0559656 A1 EP0559656 A1 EP 0559656A1
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EP
European Patent Office
Prior art keywords
acid
compound
hydrogen
formula
halo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP19910917621
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English (en)
French (fr)
Inventor
John E. Airey
William L. Studt
Matthew R. Powers
Rick G. Woodward
Frederick A. Golec
Walter Rodriguez
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rhone Poulenc Rorer International Holdings Inc
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Rhone Poulenc Rorer International Holdings Inc
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Application filed by Rhone Poulenc Rorer International Holdings Inc filed Critical Rhone Poulenc Rorer International Holdings Inc
Publication of EP0559656A1 publication Critical patent/EP0559656A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • 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

Definitions

  • This invention relates to multicyclic oxy-containing ring system compounds such as dibenzofuran and benzoxocine-type compounds which exhibit 5HT3-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 stereospecific processes for the preparation, separation and purification of said compounds.
  • 5-Hydroxytryptamine is commonly known as serotonin.
  • Serotonin found throughout the body including the gastrointestinal tract, platelets, spleen and brain, 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.
  • serotonin receptors The various physiological activities exerted by serotonin are related to the variety of different receptors found on the surface membrane of cells in different body tissue.
  • the first classification of serotonin receptors included two pharmacologically distinct receptors discovered in the guinea pig iieum.
  • the M D" receptor mediates smooth muscle contraction and the "M H receptor involves the depolarization of cholinergic nerves and release of acetylcholine.
  • 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-j -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-HT3-receptors are located on peripheral neurones where they are related to serotonin's (excitatory) depolarizing action.
  • 5-HT3-receptor activity 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 (5-HT3A 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 axon 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-HT3-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.
  • 5-HT3 agents originated from work carried out with metoclopramide (Beecham's axolon, 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 BRL-43694, Glaxo's GR-38032F 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-pos ⁇ tion of indole or N- methyl indole.
  • MDL-72222 is a bridged azabicyclic 2,4-dichlorobenzoate, while Zacopride, BRL-24924, BRL-43694 and ICS-205-930 have also bridged azabicyclic groups in the form of a carboxamide or carboxylic ester.
  • Bicyclic oxygen containing carboxamide compounds wherein the carboxamide is ortho to the cyclic oxygen moiety are reported to have antiemetic and antipsychotic properties in EPO Publ. No. 0234872.
  • stereoisomers which are synthesized by using chiral synthesis, i.e., asymmetric induction methods of synthesis.
  • syntheses with asymmetric induction have been known in the prior art.
  • a synthesis with asymmetric induction is commonly defined as a process in which a chiral unit in an ensemble of substrate molecules induces, by a reaction with achiral units, resulting molecules in such a manner that the stereoisomeric products are produced in unequal amounts.
  • Such an asymmetric synthesis may be of great economic value for excluding or reducing the amount of unwanted isomers when only one of the diastereomers is of use or interest.
  • the reactants used in an asymmetric synthesis can be at least one chiral component consisting of a chemical reagent, solvent or catalyst.
  • the preferred stereoisomer in a predominant amount can be induced.
  • selection of enantiomericalfy pure intermediates does not always result in a stereoselective synthesis since chirality of an intermediate could be lost due to racemization under one or more sets of reaction conditions. Consequently, synthetic processes typically involve extra reaction steps to accomplish the stereoselective result as well as involve a tedious recrystallization step.
  • the present invention is based on a discovery that acid sensitive intermediates can be used in a stereoselective synthesis using conditions which do not affect the product's chiral centers.
  • specific stereoisomers of two basic fused and bridged ring systems can be prepared without recourse to known separation techniques to obtain the desired enantiomers.
  • Compounds prepared by this process are disclosed and claimed in co-pending U.S. Patent Application Serial No. 07/620,241 assigned to the same assignee and filed November 29, 1990.
  • This invention relates to a process for the preparation of a substantially optically pure compound comprising a multicyclic oxy- containing ring system having at least two chiral centers at either fused or bridged ring positions.
  • the preferred compounds prepared by the present processes are described
  • R' is hydroxy, alkoxy, aralkoxy, halo, OM where M is an alkali or alkaline earth metal , or NH-X where X is hydrogen, alkyl, acyl or Z where Z is
  • are independently hydrogen, alkyl, halo, alkoxy, aryl, aralkyi, haloalkyi, amino, alkylamino, sulfonyl, alkylsulfamyl or alkylsulfonyl;
  • R2, R3, R4, R5 and Rg are independently hydrogen, alkyl, halo, alkoxy, aryl, aralkyi or haloalkyi; and vicinal R2, R3, R4, R5 and R ⁇ groups may together form double bonds.
  • the compounds of formula I are preferably prepared by subjecting a salicyclic acid, ester, amide, acid halide or acid salt having a chiral center- containing cycloalkenyl in the 3-position to acidic cyclization conditions which do not racemize said chiral center-containing cycloalkenyl substituent.
  • a preferred aspect of the present process invention is the stereospecific synthesis of a compound of either formula II or III below:
  • a more preferred aspect of the invention is the stereospecific synthesis of an intermediate compound of either formula IV or V
  • R' is hydroxy, alkoxy or NH-X where X is Z and Z is
  • R is hydrogen or halo
  • R-j are independently hydrogen, amino or mono- and dialkylamino ;
  • R2, R3, R4, R5 and Re are hydrogen; and vicinal R2, R3, R4, R5 and Rg groups may together form a double bond;
  • Alkyl means, either alone or within the various substituents, defined hereinbefore, a hydrocarbon having one to about 10 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 are Cl and Br.
  • Aryl means a mononuclear and polynuclear aromatic hydrocarbon radical which can be substituted or unsubstituted.
  • aryl groups include phenyl and naphthyl.
  • Preferred substituents include hydrogen, alkyl, alkoxy, amino, halo, aryl, aryloxy, carboalkoxy, nitro, dialkylamino, trifluoromethyl, thioalkyl and carbamoyl.
  • Alkyi means an alkyl group substituted by an aryl radical.
  • the preferred aralkyi groups are benzyl and phenethyl.
  • Multicydic denotes a substituted or unsubstituted polynuclear aromatic hydrocarbon group in which one or more ring carbons have been replaced by a nitrogen, oxygen or sulfur atom.
  • Alkali or alkaline earth metals include those metals capable of forming a salt with a carboxylic acid.
  • Preferred metals include Na, K, Ca, Mg, Li and Cs. The nomenclature used throughout this invention is shown in Formulae Via, - VIII:
  • the present invention involves the process of manipulating acid sensitive chiral compounds under acid conditions and permits the surprising synthesis of bridged or fused ring mulicyclic compounds which retain their chiral character.
  • the more preferred compounds used in this process are acid sensitive carboxylic acid, ester and amide chiral compounds described by Formulae IV and V.
  • the present process can result in either the formation of compounds of Formulae IV and/or V starting from the 3-cyclohexenyl salicylates of Formulae XI and XII, which are in turn prepared from chiral intermediates of Formulae IX and X below.
  • the bridged ring compounds of Formula V are prepared by subjecting the corresponding compound of Formulae XI or XII to sulfuric acid conditions, preferably about 10 - about 50% aqueous sulfuric acid, and most preferably about 35% aqueous sulfuric acid for a time of about 5 minutes to about 12 hours, and most preferably 30 minutes to about 2 hours.
  • the fused ring compounds of Formula IV are prepared by utilizing a weak acid, such as trifluoroacetic acid, alone or in admixture with a strong acid such as sulfuric acid.
  • a weak acid such as trifluoroacetic acid
  • a strong acid such as sulfuric acid.
  • fused compounds of Formula IV may be converted into the bridged compounds V by using strong acid conditions.
  • esters hydrofyzing said esters is preferably carried out in the presence of an aqueous organic media (such as dioxane, diglyme, THF, DMF, DMSO, etc.) with an alkali base (preferably with an aqueous base such as NaOH, KOH, LiOH, etc. however LiOH is most preferred) which selectively isolates the dibenzofuran acid as a salt (8) from the benzoxocine acid salt (9); and
  • an aqueous organic media such as dioxane, diglyme, THF, DMF, DMSO, etc.
  • an alkali base preferably with an aqueous base such as NaOH, KOH, LiOH, etc. however LiOH is most preferred
  • the final chiral acids produced are the dibenzofuran acid (5aR,9aR) (13) and the chiral benzoxocine acid (2R.6S) (14).
  • the process is enabling for synthesizing all four possible stereoisomers of not only the dibenzofuran acids(10) and (13) and the benzoxocine acids (11) and (14) without the necessity of separating the desired enantiomers by cumbersome techniques, but also the corresponding esters, amides, acid halides and acid salts as well.
  • the resolution of the compounds of this invention and their starting materials may be carried out by known procedures. Incorporation by reference is hereby made to U.S. Patent No. 4,863,921 and the four volume compendium Optical Resolution Procedures for Chemical Compounds: Optical Resolution Information Center, Manhattan College, Riverdale, New York. Such procedures are useful in the practice of this invention. A further useful reference is Enantiomers. Racemates and Resolutions: Jean Jacques, Andre Collet and Samuel H. Wilen; John Wiley & Sons, Inc., New York, 1981. Basically, the resolution of the compounds is based on the differences in the physical properties of diastereomers.
  • Novel intermediate compounds of this invention include those compounds of Formulae XIII-XVI.
  • R" is halo, OM where M is an alkali or alkaline earth metal , or NH-X where X is hydrogen, alkyl, acyl or Z where Z is
  • R and R-j are independently hydrogen, alkyl, halo, alkoxy, aryl, aralkyi, haloalkyi, amino, alkylamino, sulfonyl, alkylsulfamyl or alkylsulfonyl; and
  • R2, R3, R4, R5 and Re are independently hydrogen, alkyl, halo, alkoxy, aryl, aralkyi or haloalkyi provided at least one of RQ is hydrogen ; and vicinal R2, R3, R4, R5 and Rg groups may together form double bonds;
  • 0.42g of the product from Example 2 above is sealed in a tube under nitrogen with 0.5g of silica gel and 0.2g of cesium carbonate. The tube is placed in an oil bath and is heated to 150°C for 5 hours. TLC (hexane.ethyl acetate; 3:1) shows the product and 5-chlorosalicylic acid. A 5 ml quantity of isopropanol is added to the reaction mixture and it is filtered through a bed of cel ⁇ te. The celite bed is then washed with another 5 ml of isopropanol. The isopropanol solutions are combined,, evaporated to one third its volume and placed in the freezer.
  • TLC hexane.ethyl acetate; 3:1
  • NMR shows this to be a 3:1 mixture of methyl 2-chloro-[5a(S)- 9a(S)-(5a,6,7,8,9,9a-hexahydro)]-dibenzofuran-4-carboxylate and methyl 8-chloro-[2(S)-6(R)-methano-2H-3,4,5,6-tetrahydro]-1-benzoxocine-10- carboxylate products.
  • 5-Chlorosalicyl[N-(1-azabicyclo[2.2.2]oct-3(S)-yl)]carboxamide (0.56 grams .002 mol) and triphenylphosphine (0.4g) is charged to a dry 3 neck flask and 20 ml of anhydrous THF is added by canula under nitrogen pressure. A 0.2g portion of 2-cyclohexen-1 (S)-ol is added by syringe and the reaction is cooled to 0°C. A solution of 10 ml of THF and 0.23g of diethylazodicarboxylate is added dropwise over 1 hour, holding the temperature at 0°C.
  • the ethyl acetate is removed and the acidic aqueous layer is further extracted with ethyl acetate (500ml). The ethyl acetate extracts are combined, dried with sodium sulfate, filtered and evaporated to dryness to give 327.7g of material.
  • the NMR shows this product to be the 8- chloro-3,4.5-6-tetrahydro-2,6-methano-2H-1 -benzoxocin-10-carboxylic acid.
  • 1H NMR CDCL 3 ⁇ 10.2(s, 1H), 7.9(d, 1 H), 7.2(d, 1H), 4.9(m, 1H), 3.3(m, 1 H), 1.2-2.4(m, 8H).
  • non-toxic 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, succinic acid, glycolic acid, lactic acid, salicylic acid, benzoic acid, nicotinic acid, phthalic acid, stearic acid, oleic acid, etc.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid
  • organic acids such as methane sulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, maleic acid, succinic acid, glycolic acid, lactic acid, salicylic acid, benzoic acid, nic
  • Compounds within the scope of this invention exhibit useful gastric prokinetic and anti-emetic properties and lack D2 receptor binding activity.
  • the compounds of this invention may be useful in the treatment of disorders related to impaired gastrointestinal motility such as retarded gastric emptying, dyspepsia, flatulence, esophageal reflux, peptic ulcer and emesis.
  • disorders related to impaired gastrointestinal motility such as retarded gastric emptying, dyspepsia, flatulence, esophageal reflux, peptic ulcer and emesis.
  • Compounds within the scope 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.
  • Compounds of this invention are selective in that they have little or no dopaminergic antagonist activity.
  • the study is designed to assess the effects of a test agent on gastric emptying of a solid meal in the rat.
  • the procedure is a modification of those used in LE. Borella and W. Lippmann (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 1.4mm 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-Dawley 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 intragastrically.
  • the beads are delivered via a 3 inch piece of PE205 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 in 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:
  • Statistical significance may be determined using a t-test for independent samples with a probability of 0.05 or less considered to be significant.
  • Cisplatin had been shown to cause emesis in the dog and cat. Florezyk, et al. 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.
  • ferrets are again dosed with the 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 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.
  • 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: 377-183 (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 K-
  • 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 SS-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.
  • Specific 3 H-spiroperidol binding is assayed in a total 2 ml reaction volume consisting of 500 ⁇ l of caudate homogenate, 50 mM tris buffer (pH 7.4 at 35°C), 5 mM MgS0 , 2 mM EDTA » 2NA, 120 mM NaCI, 0.1% ascorbic acid, 0.4 nM 3 H-spiroperidol and test compound or assay buffer.
  • 10 ⁇ M pargyline should be included in the reaction mixture to inhibit monoamine oxidase.
  • Male rats 260-290 g are anaesthetized with urethane 1.25 g/kg -1 i.p., and 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. In each 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 the compound on the 5-HT-evoked bradycardia is calculated as a percent of the bradycardia evoked by 5-HT before injection of compound.
  • the 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, transepithelially 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 capsules, 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 ingestible 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 varied 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, corn starch or gelating; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic 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, corn starch or gelating
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic 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 peppermint
  • tablets, pills or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose a rs 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 intraperiotonealiy.
  • Solutions of the active compound as a freebase or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose.
  • Dispersion can also be prepared in glycerol, 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 syringability exists. It must 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 (e.g. glycerol, 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.
  • agent delaying absorption for example, aluminum monostearate and gelatin may be incorporated.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with the various other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and the freeze drying technique which yields a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
  • the therapeutic compounds of this invention may be administered to a mammal alone or in combination with pharmaceutically acceptable carriers, 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 and, if necessary, increase the dosage 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Furan Compounds (AREA)
  • Pyrane Compounds (AREA)
EP19910917621 1990-11-29 1991-09-12 Verfahren zur herstellung von multicyclischen sauerstoffhaltigen ringsystemen Withdrawn EP0559656A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US62024090A 1990-11-29 1990-11-29
US620240 1990-11-29

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EP0559656A1 true EP0559656A1 (de) 1993-09-15

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EP (1) EP0559656A1 (de)
JP (1) JPH06502849A (de)
AU (1) AU8659391A (de)
CA (1) CA2097190A1 (de)
WO (1) WO1992009592A1 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10914711B2 (en) 2015-04-16 2021-02-09 Alma Mater Studiorum-Universita Di Bologna Device, method and system for real time structural diagnostics with guided elastic waves

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US4668690A (en) * 1985-12-30 1987-05-26 Hoechst Roussel Pharmaceuticals Inc. 1,2,3,4,4a,9b-hexahydro-4a-aminoalkyldibenzofurans useful as analgesics, anticonvulsants or antidepressants
US4924010A (en) * 1988-02-04 1990-05-08 Rorer Pharmaceutical Corporation Benzoxepins as intermediates to 5HT3 antagonists
US4863921A (en) * 1988-04-27 1989-09-05 Rorer Pharmaceutical Corporation Dibenzofurancarboxamides and their pharmaceutical compositions and methods

Non-Patent Citations (1)

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Title
See references of WO9209592A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10914711B2 (en) 2015-04-16 2021-02-09 Alma Mater Studiorum-Universita Di Bologna Device, method and system for real time structural diagnostics with guided elastic waves

Also Published As

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AU8659391A (en) 1992-06-25
JPH06502849A (ja) 1994-03-31
CA2097190A1 (en) 1992-05-30
WO1992009592A1 (en) 1992-06-11

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