Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• CCK central cholecystokinin
• CCK-peptides have been found in the brains of schizophrenic patients compared with controls (Roberts, Ferrier, Lee, Crow, Johnstone,
• CCK peptides modulate dopaminergic function in the basal ganglia and particularly the nucleus accumbens (Weiss, Tanzer, and Ettenberg, Pharmacology, Biochemistry and Behaviour 30:309-317, 1988; Schneider, Allpert, and Iversen, Peptides 4:749-753, 1983). It may therefore be expected that agents modifying CCK receptor activity may have therapeutic value in conditions associated with disturbed function of central dopaminergic function such as schizophrenia and Parkinson's disease.
• CCK and gastrin peptides share a common carboxy terminal pentapeptide sequence and CCK peptides can bind to the gastrin receptor of the stomach mucosa and elicit acid secretion in many species including human (Konturek, Gastrointestinal Hormones, Ch. 23, pp 529-564, 1980, ed. G. B. J. Glass, Raven Press, NY) .
• Antagonists of the CCK-B receptor would also be expected to be antagonists at the stomach gastrin receptor and this would also be of value for conditions involving excessive acid secretion.
• CCK and gastrin peptides have trophic effects on the pancreas and various tissues of the gastro ⁇ intestinal tract (Johnson, ibid., pp 507-527), actions which are associated with increased DNA and RNA synthesis.
• gastrin secreting cells are associated with certain gastrointestinal tumors as in the Zollinger-Ellison syndrome (Stadil, ibid., pp 729-739) , and some colorectal tumors may also be gastrin/CCK dependent (Singh, Walker, Townsend, and
• CCK/gastrin receptors could therefore be of therapeutic value as antitumor agents.
• the CCK peptides are widely distributed in various organs of the body including the gastrointestinal tract, endocrine glands, and the nerves of the peripheral and central nervous systems.
• Various biologically active forms have been identified including a 33-amino acid hormone and various carboxyl- terminus fragments of this peptide (e.g., the octapeptide CCK26-33 and the tetrapeptide CCK30-33) . (G. J. Dockray, Br. Med. Bull. 38 (3) :253-258, 1982).
• CCK peptides are thought to be involved in the control of smooth muscle contractility, exocrine and endocrine gland secretion, sensory nerve transmission, and numerous brain functions. Administration of the native peptides cause gall bladder contraction, amylase secretion, excitation of central neurons, inhibition of feeding, anticonvulsive actions and other behavioral effects.
• Cholecystokinin Isolation, Structure and Functions, G. B. J. Glass, Ed., Raven Press, New York, 1980, pp 169-221; J. E. Morley, Life Sciences 27:355-368, 1980; Cholecystokinin in the Nervous System, J. de Belleroche and G. J. Dockray, Ed., Ellis Horwood, Chichester, England, 1984, pp 110-127.
• CCK peptides The high concentrations of CCK peptides in many brain areas also indicate major brain functions for these peptides (G. J. Dockray, Br. Med. Bull. 38 (3) :253-258, 1982) .
• the role of central nervous system CCK is not known with certainty, but it has been implicated in the control of feeding (Della-Fera and Baile, Science 206:471-473, 1979).
• appetite suppressant drugs either act peripherally, by increasing energy expenditure (such as thyroxine) , or in some other manner (such as the biguanides) , or act by exerting a central effect on appetite or satiety.
• Centrally acting appetite suppressants either potentiate central catecholamine pathways and tend to be stimulants (for example, amphetamine), or influence serotonergic pathways (for example, fenfluramine) .
• Other forms of drug therapy include bulking agents which act by filling the stomach, thereby inducing a "feeling" of satiety.
• CCK is known to be present in some cortical inter- neurones which also contain gamma-aminobutyric acid (GABA) (H. Demeulemeester et al, J. Neuroscience 8:988-1000, 1988).
• GABA gamma-aminobutyric acid
• Agents that modify GABA action may have utility as anxiolytic or hypnotic agents (S. C. Harvey, The Pharmacological Basis of Therapeutics (7th ed.) 1985, pp 339-371, MacMillan) .
• agents which modify CCK action may have parallel anxiolytic or hypnotic activities.
• the role of CCK in anxiety is disclosed in TIPS 11:271-273, 1990, and is fully detailed in Woodruff, G. N. and Hughes, J., 1991, Ann. Rev. Pharmacol, and Toxicol. 31, 469-501.
• WO 92/04045 published March 19, 1992, concerns dipeptoids useful, for example, as anxiolytics.
• the invention relates to a novel compound of the formula
• the present invention relates to a pharmaceutical composition containing an effective amount of a compound according to Formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for appetite suppression.
• the compounds are also useful as anxiolytics, antipsychotics, especially for treating schizophrenic behavior, as agents in treating disorders of the extrapyramidal motor system, as agents for blocking the trophic and growth stimulating actions of CCK and gastrin, and as agents for treating gastrointestinal motility.
• Compounds of the invention are also useful as analgesics, and they potentiate the effect of morphine. They can be used as an adjunct to morphine and other opioids in the treatment of severe pain such as cancer pain, and reduce the dosage of morphine required in the treatment of pain where morphine is contraindicated.
• radiolabeled isotope gives an agent suitable for treatment of gastrin dependent tumors such as those found in colonic cancers.
• 1-125 radiolabeled compounds of the invention can also be used as diagnostic agents by localization of gastrin and CCK-B receptors in both peripheral and central tissue.
• the invention further relates to a method of appetite suppression in mammals which comprises administering an amount effective to suppress appetite of the composition described above to a mammal in need of such treatment.
• the invention also relates to a pharmaceutical composition for reducing gastric acid secretion containing an effective amount of a compound of Formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for reducing gastric acid secretion.
• the invention also relates to a method for reducing gastric acid secretion in mammals which comprises administering an amount effective for gastric acid secretion reduction of the composition described above to a mammal in need of such treatment.
• the invention also relates to a pharmaceutical composition containing an effective amount of a compound of Formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for reducing anxiety.
• the invention also relates to a method for reducing anxiety in mammals which comprises administering an amount effective for anxiety reduction of the composition described above to a mammal in need of such treatment.
• the invention also relates to a pharmaceutical composition containing an effective amount of a compound of Formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for treating gastrointestinal ulcers.
• the invention further relates to a method for treating gastrointestinal ulcers in mammals which comprises administering an amount effective for gastrointestinal ulcer treatment of the composition as described above to a mammal in need of such treatment.
• the invention also relates to a pharmaceutical composition containing an effective amount of a compound of Formula I in combination with a pharma ⁇ ceutically acceptable carrier in unit dosage form effective for treating psychosis, i.e., schizophrenia.
• the invention further relates to a method for treating psychosis in mammals which comprises • administering an amount effective for treating psychoses of a composition as described above to a mammal in need of such treatment.
• the invention also relates to pharmaceutical compositions effective for stimulating or blocking CCK or gastrin receptors, for altering the activity of brain neurons, for schizophrenia, for treating disorders of the extrapyramidal motor system, for blocking the trophic and growth stimulating actions of CCK and gastrin, and for treating gastrointestinal motility.
• the invention also relates to a pharmaceutical composition for preventing the withdrawal response produced by chronic treatment for abuse of drugs or alcohol.
• the invention further relates to a method for treating the withdrawal response produced by withdrawal from chronic treatment or withdrawal from abuse of drugs or alcohol.
• drugs include benzodiazepines, especially diazepam, ***e, alcohol, and nicotine.
• Withdrawal symptoms are treated by administration of an effective withdrawal treating amount of a compound of the invention.
• the invention also relates to a pharmaceutical composition containing an effective amount of a compound of Formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for treating and/or preventing panic.
• the invention also relates to a method for treating and/or preventing panic in mammals which comprises administering an amount effective for panic treatment and/or prevention of the composition described above to a mammal in need of such treatment.
• the invention further relates to the use of the compounds of Formula I to prepare pharmaceutical and diagnostic compositions for the treatment and diagnosis of the conditions described above.
• the invention further provides processes for the preparation of compounds of Formula I.
• the compound of Formula I and its pharmaceutically acceptable salts have an absolute oral bioavailability in rats of 30%. This bioavailability is substantially higher than other CCK-B antagonists of the dipeptoid type. DETAILED DESCRIPTION
• the compounds of the present invention have multiple chiral centers.
• the compounds of the present invention exist as diastereomers, mixtures of diastereomers, or as the mixed or the individual optical enantiomers.
• the present invention contemplates all such forms of the compounds.
• the mixtures of diastereomers are typically obtained as a result of the reactions described more fully below. Individual diastereomers may be separated from mixtures of the diastereomers by conventional techniques such as column chromatography, HPLC, or repetitive recrystallizations.
• the individual substituted alpha amino acid starting materials are generally known or, if not known, may be synthesized and, if desired, resolved by methods within the skill of the art. (Synthesis of race ic [DL]-o-methyl tryptophan methyl ester - see Brana, M. F., et al, J. Heterocyclic Chem., 1980, 17:829.)
• a key intermediate in the preparation of compounds of Formula I is a compound of formula
• R is selected from 9-fluorenylmethyl, Bz, and other suitable N-blocking groups. These are useful as intermediates in the preparation of compounds of Formula I.
• R is 1-adamantyl
• the compound of Formula I exhibits an absolute bioavailability of 30%. It is, therefore, unique in the area of CCK selective dipeptoids.
• the method involved liquid-liquid extraction of the compound and internal standard carbamic acid, (R)-[2- [ (hexahydro- lH-azepin-1-yl)amino]-1- (lH-indol-3-ylmethyl)-1-methyl- 2-oxoethyl]-, tricyclo[3.3.l.l 3,7 ]dec-2-yl ester, liquid chromatographic separation of the analytes on a C-18 column, and quantitation by fluorescence detection.
• Mean ( ⁇ SD) pharmacokinetic parameters are presented in Table 1. Following IV dosing, the compound plasma concentrations declined rapidly in a multiexponential manner with a harmonic mean terminal elimination half-life of 0.87 ( ⁇ 0.02) hours.
• Cmax Maximum observed drug plasma concentration (ng/ml) .
• tmax Time to reach Cmax (hr) .
• t Terminal elimination half-life, harmonic mean (hr) .
• AUC(O-tldc) Area under the plasma concentration-time curve from zero to time of last detectable concentration (ng*hr/mL) .
• AUC(0-») Area under the plasma concentration-time curve from zero to infinite time (ng*hr/ ⁇ r_L) .
• %F Absolute bioavailability based on ratio of mean PO and IV AUC(0- «) values.
• inert, pharmaceutically acceptable carriers can be either solid or liquid.
• Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
• a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
• the carrier is a finely divided solid which is in a mixture with the finely divided active component.
• the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
• a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
• the powders and tablets preferably contain 5% to about 70% of the active component.
• Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
• Preferred pharmaceutically acceptable salts are the N-methyl glucamine salt and sodium.
• Pharmaceutically acceptable salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate.
• preparation is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.
• Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
• Liquid form preparations include solutions, suspensions, and emulsions.
• Sterile water or water- propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration.
• Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
• Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
• Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
• the pharmaceutical preparation is in unit dosage form. In such form, the preparation is divided into unit doses containing appropriate quantities of the active component.
• the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampoules.
• the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
• the title compound was synthesized by coupling trans-2-aminocyclohexanol with (R)-2-adamantyloxycarbonyl-2-methyltryptophan using DCC and HOBt.

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• 1994
  • 1994-03-10 KR KR1019960704968A patent/KR100311329B1/ko not_active IP Right Cessation
  • 1994-03-10 NZ NZ266052A patent/NZ266052A/xx unknown
  • 1994-03-10 JP JP52341095A patent/JP3361100B2/ja not_active Expired - Fee Related
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• 1996
  • 1996-09-04 FI FI963463A patent/FI109689B/fi not_active IP Right Cessation
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