WO1997038692A1 - Binsindoles pour traiter la douleur ou les phenomenes nociceptifs - Google Patents

Binsindoles pour traiter la douleur ou les phenomenes nociceptifs Download PDF

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Publication number
WO1997038692A1
WO1997038692A1 PCT/US1997/005996 US9705996W WO9738692A1 WO 1997038692 A1 WO1997038692 A1 WO 1997038692A1 US 9705996 W US9705996 W US 9705996W WO 9738692 A1 WO9738692 A1 WO 9738692A1
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Prior art keywords
indol
acetyl
acetamido
propanamine
methoxybenzyl
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PCT/US1997/005996
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English (en)
Inventor
Philip Arthur Hipskind
Karen Lynn Lobb
Lee Alan Phebus
John Mehnert Schaus
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Eli Lilly And Company
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Priority to AU26112/97A priority Critical patent/AU2611297A/en
Publication of WO1997038692A1 publication Critical patent/WO1997038692A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines

Definitions

  • 5-HT has been implicated as being involved in the expression of a number of behaviors, physiological responses, and diseases which originate in the central nervous system. These include such diverse areas as sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, schizophrenia, and other bodily states.
  • R.W. Fuller
  • Serotonin plays an important role in peripheral systems as well. For example, approximately 90% of the body's serotonin is synthesized in the gastrointestinal system, and serotonin has been found to mediate a variety of contractile, secretory, and electrophysiologic effects in this system. Serotonin may be taken up by the platelets and, upon platelet aggregation, be released such that the cardiovascular system 9
  • - 2 - provides another example of a peripheral network that is very sensitive to serotonin.
  • receptor-specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, compulsive disorders, schizophrenia, autism, neurodegenerative disorders, such as Alzheimer's disease, Parkinsonism, and Huntington's chorea, and cancer chemotherapy-induced vomiting.
  • Serotonin produces its effects on cellular physiology by binding to specialized receptors on the cell surface. It is now recognized that multiple types of receptors exist for many neurotransmitters and hormones, including serotonin. The existence of multiple, structurally distinct serotonin receptors has provided the possibility that subtype- selective pharmacological agents can be produced. The development of such compounds could result in new and increasingly selective therapeutic agents with fewer side effects, since activation of individual receptor subtypes may function to affect specific actions of the different parts of the central and/or peripheral serotonergic systems.
  • Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence.
  • Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's.
  • neurokinin A also known as substance K, neuromedin L, and neurokinin ⁇
  • neurokinin B also known as neuromedin K and neurokinin ⁇
  • Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
  • NK-1 The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
  • Substance P is beUeved inter alia to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis.
  • These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease.
  • Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra. Tachykinins play a major role in mediating the sensation and transmission of pain or nociception, especially migraine headaches, see. e.g.. S.L. Shepheard, et al.. British Journal of Pharmacology. 108: 11-20 (1993); S.M. Moussaoui, et al... European Journal of Pharmacology. 238:421-424 (1993); and W.S. Lee, et al.. British Journal of Pharmacology. 112:920-924 (1994).
  • This invention provides the compounds of Formula I
  • R 1 , R ⁇ , and R"* are independently hydrogen, halo, C J-CG alkoxy, C i-Cg alkylthio, nitro, trifluoromethyl, or C J-CG alkyl;
  • A is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -;
  • R a is hydrogen or hydroxy
  • R b is hydrogen, or R a and R b are taken together to form a bond
  • R 4 and R 5 are independently taken from the group consisting of halo, trifluoromethyl, hydrogen, C j-C ⁇ alkoxy, C i-C ⁇ alkyl, C I-CG alkylthio, C i -C ⁇ alkylamino, hydi-oxy, cyano, C 2 -C 7 alkanoyl, C2-C 7 alkanoyloxy, benzamido, phenoxy, O 97/38692 PC17US97/059
  • said benzamido, phenoxy, benzyloxy, phenyl(C 2 - C7 alkanoyl)-, and phenyl(C 2 -C 7 carbamoyl)- being optionally substituted with one or more groups selected from the group consisting of halo, trifluoromethyl, C j-C ⁇ alkyl, C ⁇ -C(; alkoxy, cyano, hydroxy, amino and nitro;
  • This invention also provides methods for treating or preventing a number of disorders characterized by their being affected, in a synergistic manner, by a combination of a serotonin agonist and a tachykinin receptor antagonist, which comprise administering to a mammal in need thereof an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.
  • a psychiatric disorder selected from the group consisting of panic disorder, panic attack, depression, anxiety, buhmia nervosa, obsessive-compulsive disorder, premenstrual dysphoric disorder, substance abuse, substance dependence, agoraphobia, post-traumatic stress disorder, dementia of Alzheimer's type, social phobia, attention deficit hyperactivity disorder, disruptive behavior disorder, intermittent explosive disorder, borderUne personaUty disorder, chronic fatigue syndrome, premature ejaculation, and depression and behavioral problems associated with head injury, mental retardation, and stroke.
  • This invention also provides pharmaceutical formulations which comprise a compound of Formula I, or a pharmaceuticaUy acceptable salt or solvate thereof, in combination with one or more pharmaceuticaUy acceptable carriers, diluents, or excipients therefor.
  • pharmaceutical formulations which comprise a compound of Formula I, or a pharmaceuticaUy acceptable salt or solvate thereof, in combination with one or more pharmaceuticaUy acceptable carriers, diluents, or excipients therefor.
  • C J -CG alkyl refers to straight or branched, monovalent, saturated aUphatic chains of 1 to 6 carbon atoms and includes, but is not Umited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ⁇ -butyl, pentyl, isopentyl, and hexyl.
  • C I-CG alkyl includes within its definition the term "C1-C4 alkyl”.
  • Halo represents chloro, fluoro, bromo or iodo.
  • Ci-C ⁇ alkylthio represents a straight or branched alkyl chain having from one to six carbon atoms attached to a sulfur atom.
  • C J-CG alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio and the Uke.
  • C I-CG alkylthio includes within its definition the term "C 1 -C 4 alkylthio”.
  • C J-CG alkylamino represents a straight or branched alkylamino chain having from one to six carbon atoms attached to an amino group.
  • Typical C J-CG alkyl-amino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the Uke.
  • C I-CG alkoxy represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom.
  • C J-CG alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, f-butoxy, pentoxy and the Uke.
  • C J-CG alkoxy includes within its definition the term "C 1 -C 4 alkoxy”.
  • C 2 -CG alkanoyl represents a straight or branched alkyl chain having from one to five carbon atoms attached through a carbonyl moiety.
  • Typical C 2 -CG alkanoyl groups include ethanoyl (also referred to as acetyl), propanoyl, isopropanoyl, butanoyl, f-butanoyl, pentanoyl, hexanoyl, and the Uke.
  • C I -CG alkylenyl refers to a straight or branched, divalent, saturated aUphatic chain of one to six carbon atoms and includes, but is not Umited to, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl, i-butylenyl, pentylenyl, isopentylenyl, hexylenyl, and the Uke.
  • C 2 -C7 carbamoyl refers to a moiety having one of the foUowing two structures.
  • heterocycle represents a stable 5- to 7-membered monocycUc or 7- to 10-membered bicycUc heterocycUc ring which is saturated or unsaturated and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionaUy be oxidized, and the nitrogen heteroatom may optionaUy be quaternized and including a bicycUc group in which any of the above- defined heterocycUc rings is fused to a benzene ring.
  • the heterocycUc ring may be attached at any heteroatom or carbon atom which affords a stable structure.
  • amino-protecting group refers to substituents of the amino group commonly employed to block or protect the amino functionaUty while reacting other functional groups on the compound.
  • amino-protecting groups include formyl, trityl, phthaUmido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
  • amino-protecting group employed is usuaUy not critical so long as the derivatized amino group is stable to the condition of subsequent reactions on other positions of the intermediate molecule and can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other amino-protecting groups.
  • Preferred amino-protecting groups are trityl, -butoxycarbonyl (t-BOC), aUyloxycarbonyl and benzyloxycarbonyl.
  • t-BOC t-butoxycarbonyl
  • aUyloxycarbonyl benzyloxycarbonyl.
  • Further examples of groups referred to by the above terms are described by E. Haslam, PROTECTIY ⁇ GROUPS IN ORGANIC CHEMISTRY, (J.G.W. McOmie, ed., 1973), at Chapter 2; and T.W. Greene and P.G.M. Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (1991), at Chapter 7.
  • 'leaving group refers to a group of atoms that is displaced from a carbon atom by the attack of a nucleophile in a nucleophilic substitution reaction.
  • the term "leaving group” as used in this document encompasses, but is not Umited to, activating groups.
  • activating groups are weU-known to those skiUed in the art and may be, for example, succinimidoxy, phthaUmidoxy, benzotriazolyloxy, benzenesulfonyloxy, methanesuUOnyloxy, toluenesulfonyloxy, azido, or -0-CO-(C 4 -C 7 alkyl).
  • haloformate refers to an ester of a haloformic acid, this compound having the formula
  • X is halo
  • R e is C ⁇ -CQ alkyl.
  • Preferred haloformates are bromoformates and chloroform ates. EspeciaUy preferred are chloroformates. Those haloformates wherein R ; * is CS-CG alkyl are preferred. Most preferred is isobutyl chloroformate.
  • the compounds used in the method of the present invention may have one or more asymmetric centers. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as weU as diastereomers and mixtures of diastereomers. AU asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
  • the terms "R” and “S” are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
  • the term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • S sinister
  • S refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the priority of groups is based upon their atomic number (in order of decreasing atomic number).
  • COMPOUNDS PRINCIPLES AND PRACTICE, (J.H. Fletcher, et al.. eds., 1974) at pages 103-120.
  • the older D-L system is also used in this document to denote absolute configuration, especiaUy with reference to amino acids.
  • a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top.
  • the prefix "D” is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and "L", that of the isomer in which it is on the left.
  • the skiUed practitioner can proceed by one of two routes.
  • the practitioner may first prepare the mixture of enantiomers and then separate the two enantiomers.
  • a commonly employed method for the resolution of the racemic mixture (or mixture of enantiomers) into the individual enantiomers is to first convert the enantiomers to diastereomers by way of forming a salt with an opticaUy active acid or base. These diastereomers can then be separated using differential solubiUty, fractional crystalUzation, chromatography, or Uke methods. Further details regarding resolution of enantiomeric mixtures can be found in J. Jacques, et al. ENANTIOMERS, RACEMATES, AND RESOLUTIONS, (1991).
  • the practitioner of this invention may also choose an enantiospecific protocol for the preparation of the compounds of Formula I.
  • a protocol employs a synthetic reaction design which maintains the chiral center present in the starting material in a desired orientation.
  • reaction schemes usuaUy produce compounds in which greater than 95 percent of the title product is the desired enantiomer.
  • this invention includes the pharmaceuticaUy acceptable salts of the compounds defined by Formula I.
  • generaUy neutral a compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic bases, and inorganic and organic acids, to form a pharmaceuticaUy acceptable salt.
  • pharmaceuticaUy acceptable salt refers to salts of the compounds of the above formula which are substantiaUy non-toxic to Uving organisms.
  • Typical pharmaceuticaUy acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceuticaUy acceptable mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts.
  • Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the Uke, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxahc acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the Uke.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the Uke
  • organic acids such as p-toluenesulfonic, methanesulfonic acid, oxahc acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the Uke.
  • Examples of such pharmaceuticaUy acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenyl
  • Preferred pharmaceuticaUy acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
  • Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, alkenyl, alkynyl, or aralkyl moiety.
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkaU or alkaUne earth metal hydroxides, carbonates, bicarbonates, and the Uke.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the Uke.
  • the potassium and sodium salt forms are particularly preferred.
  • any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmacologicaUy acceptable and as long as the counterion does not contribute undesired quaUties to the salt as a whole.
  • This invention further encompasses the pharmaceuticaUy acceptable solvates of the compounds of Formula I.
  • Many of the Formula I compounds can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceuticaUy acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
  • This invention also encompasses the pharmaceuticaUy acceptable prodrugs of the compounds of Formula I.
  • a prodrug is a drug which has been chemicaUy modified and may be biologicaUy inactive at its site of action, but which may be degraded or modified by one or more enzymatic or other in vivo processes to the parent bioactive form.
  • This prodrug should have a different pharmacokinetic profile than the parent, enabUng easier absorption across the mucosal epitheUum, better salt formation or solubiUty, or improved systemic stabUity (an increase in plasma half-life, for example).
  • TypicaUy such chemical modifications include:
  • ester or amide derivatives which may be cleaved by esterases or Upases;
  • the preferred methods of the present invention employ the preferred compounds of the present invention.
  • the preferred compounds of the present invention are those compounds of Formula I in which:
  • R 1 , R 2 , and R ' ⁇ is not hydrogen;
  • A is methylene or ethylene;
  • R a and R b are both hydrogen, or R a and R b combine to form a bond
  • R 4 and R 5 is chloro, fluoro, hydroxy, trifluoromethyl, methoxy, ethoxy, methyl, benzamido, and phenyl(C 2 -C7 carbamoyl)-, or a substituted derivative thereof.
  • A is methylene
  • R 1 , R 2 , and R ⁇ together with the phenyl group to which they are bound, form, 2-methoxyphenyl, 2- chlorophenyl, 2-methylphenyl, 2- trifluoromethylphenyl, 3, 4-dimethoxyphenyl, 3,4- dichlorophenyl, 3,4-bis(trifluoromethyl)phenyl, 3,4,5- trimethoxyphenyl, 3,4,5-trichlorophenyl, 3,4,5- trimethylphenyl, 3,4,5-tri(trifluoromethyl)phenyl, 3,5- dimethoxyphenyl, 3,5-dichlorophenyl, 3,5- dimethylphenyl, or 3,5-bis(trifluoromethyl)phenyl;
  • R a and R b are both hydrogen, or R a and R b combine to form a bond
  • R 4 and R 5 is chloro, fluoro, hydroxy, trifluoromethyl, methoxy, ethoxy, methyl, benzamido, and phenyl(C 2 -C7 carbamoyl)-, or a substituted derivative thereof, substituted at the five and/or six position of the indolyl moiety.
  • the compounds of the present invention may be prepared by reacting a compound of Formula II
  • X is a leaving group, preferably a halo group, most preferably bromo or iodo, with a compound of Formula III.
  • This reaction is generaUy performed in an organic solvent, at a temperature between -78°C and 120°C, and the resulting product is isolated.
  • This reaction is generaUy performed using equimolar amounts of the two reactants, even though other ratios may also be employed.
  • the organic solvent used is preferably a polar aprotic solvent, for example, acetonitrile, N,N-dimethylformamide, N,N-dimethylphenylacetamide, dimethylsulfoxide, or hexamethylphosphoric triamide.
  • a polar aprotic solvent it is also possible to use an ether, such as tetrahydrofuran, dioxane, or methyl f-butyl ether, or a ketone, such as methyl ethyl ketone.
  • ether such as tetrahydrofuran, dioxane, or methyl f-butyl ether
  • ketone such as methyl ethyl ketone.
  • Acetonitrile is the most preferred such solvent. In the temperature range indicated above, the preferred temperature is 30-90°C. If acetonitrile is employed as a solvent, the reaction is advantageously carried out at the reflux point of the reaction mixture.
  • the product obtained in this way is isolated by the usual techniques, for example, by concentration of the solvents, foUowed by washing of the residue with water, and then purification by conventional techniques, such as chromatography or recrystaUization.
  • the compounds of the present invention may also be prepared by reacting a compound of Formula IV
  • X is a leaving group, preferably a halo group, most preferably bromo or iodo.
  • the reaction conditions and the solvent employed for this reaction are essentiaUy the same as for the reaction of the compounds of Formula II and III, supra.
  • the most preferred method of synthesizing the intermediates of Formulae II and IV is depicted in Scheme I, infra. Many of the steps of this synthesis are described in Patent Cooperation Treaty PubUcation WO 95/14017, pubUshed May 26, 1995, and European Patent AppUcation PubUcation 693,489, to be pubUshed January 24, 1996.
  • Tr refers to a trityl group
  • NMM refers to N- methylmorphoUne
  • the couphng of the protected amine to the substituted benzylamine can be performed by many means known in the art, the particular methods employed being dependent upon the particular benzylamine which is used as the starting material and the type of protected amine used in the couphng reaction.
  • These couphng reactions frequently employ commonly used couphng reagents such as 1, 1- carbonyl dUmidazole, dicyclohexylcarbodnmide, diethyl azodicarboxylate, 1-hydroxybenzotriazole, alkyl chloroformate and triethylamine, phenyldichlorophosphate, and chlorosutfonyl isocyanate. Examples of these methods are described infra.
  • step (c) the intermediate amides are reduced to amines using procedures weU known in the art. These reductions can be performed using Uthium aluminum hydride as weU as by use of many other different aluminum-based hydrides.
  • An especiaUy preferred reagent employed in this reduction is RED-AL®, which is the tradename of a 3.4 M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene.
  • the amides can be reduced by catalytic hydrogenation, though high temperatures and pressures are usuaUy required for this.
  • Sodium borohydride in combination with other reagents may be used to reduce the amide.
  • Borane complexes such as a borane dimethylsulfide complex, are especiaUy useful in this reduction reaction.
  • the acylation of the secondary amine can be done using any of a large number of techniques regularly employed by those skiUed in organic chemistry.
  • One such reaction scheme is a substitution using an anhydride such as acetic anhydride.
  • Another reaction scheme often employed to acylate a secondary amine employs a carboxyUc acid preferably with an activating agent.
  • An amino-de-alkoxylation type of reaction uses esters as a means of acylating the amine.
  • Activated esters which are attenuated to provide enhanced selectivity are very efficient acylating agents.
  • One preferred such activated ester is p-nitrophenyl ester, such as p-nitrophenyl acetate.
  • the amine is then deprotected using standard techniques.
  • the particular deprotecting agents and conditions employed wiU depend upon the amino-protecting group utiUzed.
  • a suitable solvent such as dry ethyl ether
  • the foUowing Preparations and Examples further Ulustrate the compounds of the present invention and the methods for their synthesis.
  • the Preparations and Examples are not intended to be Umiting to the scope of the invention in any respect, and should not be so construed.
  • AU solvents and reagents were purchased from commercial sources and used as received, unless otherwise indicated.
  • Dry tetrahydrofuran (THF) was obtained by distfllation from sodium or sodium benzophenone ketyl prior to use.
  • the starting materials described herein are commerciaUy avaUable or may be prepared by methods weU known to those in the art.
  • D-tryptophan 40.0 g, 0.196 mol
  • acetonitrile 240 ml
  • 1, 1, 1,3,3,3-hexamethyldisflazane 39.5 g, 0.245 mol
  • the resulting mixture was heated to 50-60°C and stirred until homogeneous.
  • trityl chloride 60.06 g, 0.215 mol
  • acetonitrile 120 ml
  • N-trityl-D-tryptophan N-methylmophoUne salt 108.0 g, 0.196 mol
  • acetonitrile 800 ml
  • 2-chloro-4,6-dimethoxy- 1,3, 5-triazine 38.63 g, 0.22 mol
  • N-methylmorphoUne 29.1 ml
  • the title compound is prepared essentiaUy as described above in Preparation B except that 2 -methylbenzylamine is employed instead of 2-methoxybenzylamine.
  • RED-AL ® ' [a 3.4 M, solution of sodium bis(2- methoxyethoxy)aluminum hydride in toluene] (535 ml, 1.819 mol), dissolved in anhydrous tetrahydrofuran (400 ml) was slowly added using an addition funnel to a refluxing solution of the acylation product, (R)-3- (lH-indol-3-yl)-N-(2-methoxybenzyl)-2-(N- triphenylmethylamino)propanamide (228.6 g, 0.404 mol) produced supra, in anhydrous tetrahydrofuran (1.0 L) under a nitrogen atmosphere. The reaction mixture became a purple solution.
  • the reaction was quenched after at least 20 hours by the slow addition of excess saturated RocheUe's salt solution (potassium sodium tartrate tetrahydrate).
  • the organic layer was isolated, washed with brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to an oU on a rotary evaporator. No further purification was done and the product was used directly in the next step.
  • the compounds of Formulae III and V may be prepared by methods weU known to one of ordinary sltiU in the art.
  • a majority of the starting indoles are commerciaUy available, however, they may be prepared by the Fischer indole synthesis (Robinson, THE FISCHER INDOLE SYNTHESIS, WUey, New York, 1983).
  • the indoles are condensed with 4-piperidone • HCl • H2O in the presence of a suitable base to give the corresponding 3-(l, 2,3,6- tetrahydro-4-pyridinyl)-lH-indoles as iUustrated in the foUowing scheme.
  • the reaction is performed by first dissolving an excess of the base, typicaUy sodium or potassium hydroxide, in a lower alkanol, typicaUy methanol or ethanol.
  • the indole and two equivalents of 4- piperidone • HCl • H2O are then added and the reaction refluxed for 8-72 hours.
  • the resulting 3-(l,2,3,6-tetrahydro-4-pyridinyl)- lH-indoles may be isolated from the reaction mixture by the addition of water.
  • Compounds which precipitate may be isolated directly by filtration while others may be extracted with a water immiscible solvent such as ethyl acetate or dichloromethane.
  • the compounds recovered may be used directly in subsequent steps or first purified by siUca gel chromatography or recrystaUization from a suitable solvent.
  • the 3-(l,2,5,6-tetrahydro-4-pyridinyl)-lH-indoles may next be hydrogenated to give the corresponding 3-(piperidin-4-yl)-lH-indoles as shown below.
  • the catalyst may be a precious metal catalyst such as platinum oxide, or paUadium or platinum on a suitable support such as carbon.
  • X is a functional group that is labile to hydrogenolysis, such as halo or benzyloxy
  • a deactivated catalyst such as sulfided platinum on carbon or a mixed catalyst system of sulfided platinum on carbon with platinum oxide may be used to prevent hydrogenolysis.
  • the solvent may consist of a lower alkanol, such as methanol or ethanol, tetrahydrofuran or a mixed solvent system of tetrahydrofuran and ethyl acetate.
  • the hydrogenation may be performed at an initial hydrogen pressure of 20-80 p.s.i, preferably from 50-60 p.s.i, at 0-60°C, preferably at ambient temperature to 40°C, for 1 hour to 3 days. Additional charges of hydrogen may be required to drive the reaction to completion depending on the specific substrate.
  • the 3-(piperidin-4-yl)-lH-indoles prepared in this manner are isolated by removal of the catalyst by filtration foUowed by concentration of the reaction solvent under reduced pressure.
  • the product recovered may be used directly in a subsequent step or further purified by chromatography or recrystaUization from a suitable solvent.
  • AU of the 3-[l,2,3,6-tetrahydro-4-pyridinyl]- lH-indoles useful as intermediates for compounds of this invention may be prepared as described in the foUowing procedure.
  • AU of the 3-[piperidin-4-yl]-lH-indoles useful as intermediates for compounds of this invention may be prepared as described in the foUowing procedure.
  • the other compounds of Formula III may be prepared essentiaUy as described above using commerciaUy avadable starting materials.
  • the compounds of Formula V may be prepared from the corresponding compound of Formula III essentiaUy as described in Preparation R.
  • the foUowing compounds were prepared essentiaUy as described supra.
  • This table also provides the physiological distribution of these receptors as weU as biological responses mediated by the receptor class or subtype, if any such response is known.
  • This table is derived from D. Hoyer, et al.. "VII. International Union of Pharmacology Classification of Receptors for 5-Hydroxytryptamine (Serotonin)", Pharmacological Reviews. 46: 157-203 (1994), a pubUcation of the Serotonin Club Receptor Nomenclature Committee of the IUPHAR
  • the Hoyer, et al.. reference describes for each class or subtype one or more compounds which have efficacy as antagonists or agonists for the receptor.
  • the 5-HT] famfly includes subtypes which can be grouped together based on the absence of introns in the cloned genes, a common G- coupled protein transduction system (inhibition of adenylate cyclase), and similar operational characteristics.
  • the 5-HT ⁇ famUy of inhibitory receptors includes subtypes A, B, D, E, and F.
  • the 5-HT ⁇ G protein- Unked receptors general inhibit the production of cychc adenosine monophosphate (cAMP), whUe the 5-HT 2 G protein Unked receptors stimulate phosphoinosytol hydrolysis.
  • the 5-HT IA receptor was the first cloned human serotonin receptor. Activated 5-HT i A receptors expressed in HeLa ceUs inhibit forskoUn-stimulated adenylate cyclase activity.
  • the 5-HT I D receptor was originaUy identified in bovine brain membrane by Heuring and Peroutka.
  • the 5-HTID receptors are the most common 5-HT receptor subtype in the human brain and may be identical to the 5-HT i -Uke receptor in the cranial vasculature. S.D. SUberstein, Headache. 34:408-
  • the 5-HT I F subtype of receptor has low affinity for 5- carboxamidotryptamine (5-CT) unhke the other 5-HT receptors, except for the 5-HT I E subtype. UnUke the 5-HT I E receptors, however, the 5-HT I F receptors do show affinity for sumatriptan.
  • 5-CT 5- carboxamidotryptamine
  • 5-HT 5-HT
  • 5-HTI A Neuronal, mainly in Neuronal
  • CNS CNS
  • heart urinary release in gut, tachycardia, bladder upregulates cAMP in CNS neurones
  • binding to the 5-HTIF receptor The abiUty of a compound to bind to a serotonin receptor was measured using standard procedures. For example, the ability of a compound to bind to the 5-HT IF receptor subtype was performed essentiaUy as described in N. Adham, et al., Proceedings of the National Academy of Sciences (USA). 90:408-412 (1993). The cloned 5-HT I F receptor was expressed in stably transfected LM(tk”) ceUs. Membrane preparations were made by growing these transfected ceU Unes to confluency.
  • the ceUs were washed twice with phosphate-buffered saline, scraped into 5 ml of ice-cold phosphate- buffered saUne, and centrifuged at 200 x g for about five minutes at 4°C.
  • the peUet was resuspended in 2.5 ml of cold Tris buffer (20 mM Tris HCl, pH 7.4 at 23°C, 5 mM EDTA) and homogenized.
  • the lysate was centrifuged at 200 x g for about five minutes at 4°C to peUet large fragments.
  • the supernatant was then centrifuged at 40,000 x g for about 20 minutes at 4°C.
  • the membranes were washed once in the homogenization buffer and resuspended in 25 mM glycylglycine buffer, pH 7.6 at 23°C.
  • Radiohgand binding studies were performed using [*H]5-HT (20-30 Ci/mmol). Competition experiments were done by using various concentrations of drug and 4.5-5.5 nM [ :;! H]5-HT. Nonspecific binding was defined by 10 ⁇ M 5-HT. Binding data were analyzed by nonUnear- regression analysis. IC 5 0 values were converted to Kj values using the
  • the binding affinities of compounds for various serotonin receptors may be determined essentiaUy as described above except that different cloned receptors are employed in place of the 5-HT I F receptor clone employed therein.
  • Serotonin Agonist Activity Adenylate Cyclase Activity.
  • Adenylate cyclase activity was determined in initial experiments in LM(tk-) ceUs, using standard techniques. See, e.g.. N. Adham, et al.. supra.: R.L. Weinshank, et al.. Proceedings of the National Academy of Sciences (USA). 89:3630-3634 (1992), and the references cited therein.
  • IntraceUular levels of cAMP were measured using the clonally derived ceU Une described above. CeUs were preincubated for about 20 minutes at 37°C in 5% carbon dioxide, in Dulbecco's modified Eagle's medium containing 10 mM HEPES, 5 mM theophyUine, and 10 ⁇ M pargyUne. Varying concentrations of the test compounds were added to the medium to determine inhibition of forskoUn-stimulated adenylate cyclase.
  • the compounds of the present invention in addition to having activity as a serotonin agonist also possess tachykinin receptor activity.
  • the biological efficacy of a compound beheved to be effective as a tachykinin receptor antagonist may be confirmed by employing an initial screening assay which rapidly and accurately measured the binding of the tested compound to known NK-1 and NK-2 receptor sites.
  • Assays useful for evaluating tachykinin receptor antagonists are weU known in the art. See, e.g.. J. Jukic, et al.. Life Sciences. 49: 1463-1469 (1991); N. Kucharczyk, et al.. Journal of Medicinal Chemistry. 36: 1654-1661 (1993); N. Rouissi, et al.. Biochemical and Biophysical Research Communications, 176:894-901 (1991).
  • Radioreceptor binding assays were performed using a derivative of a previously pubUshed protocol.
  • reaction was terminated by filtration through a glass fiber filter harvesting system using filters previously soaked for 20 minutes in 0.1% polyethylenimine. Specific binding of labeled substance P was determined in the presence of 20 nM unlabeled Ugand.
  • the CHO-hNK-2R ceUs a CHO-derived ceU Une transformed with the human NK-2 receptor, expressing about 400,000 such receptors per ceU, were grown in 75 cm 2 flasks or roUer bottles in minimal essential medium (alpha modification) with 10% fetal bovine serum.
  • minimal essential medium alpha modification
  • the gene sequence of the human NK-2 receptor is given in N.P. Gerard, et al.. Journal of Biological Chemistry. 265:20455-20462 (1990).
  • Membranes were prepared by homogenization of the ceU peUets in 300 ml 50 mM Tris buffer, pH 7.4 with a Tekmar ® homogenizer for 10-15 seconds, foUowed by centrifugation at 12,000 RPM (20,000 x g) for 30 minutes using a Beckman JA-14 ® rotor. The peUets were washed once using the above procedure, and the final peUets were resuspended in 100-120 ml 50 mM Tris buffer, pH 7.4, and 4 ml aUquots stored frozen at -70°C. The protein concentration of this preparation was 2 mg/ml.
  • one 4-ml aUquot of the CHO-hNK-2R membrane preparation was suspended in 40 ml of assay buffer containing 50 mM Tris, pH 7.4, 3 mM manganese chloride, 0.02% bovine serum albumin (BSA) and 4 ⁇ g/ml chymostatin.
  • BSA bovine serum albumin
  • a 200 ul volume of the homogenate (40 ⁇ g protein) was used per sample.
  • the radioactive Ugand was [ 125 I]iodohistidyl-neurokinin A (New England Nuclear, NEX-252), 2200 Ci/mmol.
  • the Ugand was prepared in assay buffer at 20 nCi per 100 ⁇ l; the final concentration in the assay was 20 pM.
  • Non-specific binding was determined using 1 ⁇ M eledoisin. Ten concentrations of eledoisin from 0.1 to 1000 nM were used for a standard concentration-response curve.
  • AU samples and standards were added to the incubation in 10 ⁇ l dimethylsulfoxide (DMSO) for screening (single dose) or in 5 ⁇ l
  • DMSO dimethylsulfoxide
  • the compounds of the present invention have demonstrated efficacy as both tachykinin receptor antagonists and serotonin agonists.
  • the especiaUy preferred methods of the present invention are those methods treating conditions in which the synergistic combination of tachykinin receptor antagonists and serotonin agonists are recognized.
  • Charles River Laboratories (225-325 g) were anesthetized with sodium phenobarbitol (65 mg/kg or 45 mg/kg, respectively, intraperitoneaUy) and placed in a stereotaxic frame (David Kopf Instruments) with the incisor bar set at -3.5 mm for rats or -4.0 mm for guinea pigs.
  • a stereotaxic frame (David Kopf Instruments) with the incisor bar set at -3.5 mm for rats or -4.0 mm for guinea pigs.
  • the femoral vein was exposed and a dose of the test compound was injected intravenously (1 ml/kg). Approximately seven minutes later, a 50 mg/kg dose of Evans Blue, a fluorescent dye, was also injected intravenously. The Evans Blue complexed with proteins in the blood and functioned as a marker for protein extravasation. Exactly ten minutes post-injection of the test compound, the left trigeminal gangUon was stimulated for three minutes at a current intensity of 1.0 mA (5 Hz, 4 msec duration) with a potentiostat/galvanostat. Fifteen minutes foUowing the stimulation, the animals were killed and exanguinated with 20 ml of saUne.
  • Evans Blue a fluorescent dye
  • the top of the skuU was removed to faciUtate the coUection of the dural membranes.
  • the membrane samples were removed from both hemispheres, rinsed with water, and spread flat on microscopic sUdes. Once dried, the tissues were covershpped with a 70% glycerol/water solution.
  • a fluorescence microscope equipped with a grating monochromator and a spectrophotometer was used to quantify the amount of Evans Blue dye in each tissue sample.
  • An excitation wavelength of approximately 535 nm was utiUzed and the emission intensity at 600 nm was determined.
  • the microscope was equipped with a motorized stage and was interfaced with a personal computer. This faciUtated the computer-controUed movement of the stage with fluorescence measurements at 25 points (500 ⁇ m steps) on each dural sample. The mean and standard deviation of the measurements were determined by the computer.
  • the dural extravasation induced by electrical stimulation of the trigeminal gangUon was an ipsUateral effect (i.e. it occurs only on the side of the dura in which the trigeminal gangUon was stimulated). This aUowed the other, unstimulated, half of the dura to be used as a control.
  • the ratio of the amount of extravasation in the dura from the stimulated side compared to the unstimulated side was calculated. SaUne controls yielded a ratio of approximately 2.0 in rats and 1.8 in guinea pigs. In contrast, a compound which effectively prevented the extravasation in the dura from the stimulated side would have a ratio of approximately 1.0.
  • a dose-response curve was generated and the dose that inhibited the extravasation by 50% (ID50) was estimated.
  • a combination of a serotonin agonist and a tachykinin receptor antagonist are superior to either class of compound alone in the treatment of migraine, the combination demonstrating a synergistic efficacy profile.
  • This combination therapy greatly increases the therapeutic index of a composition in treating these nociceptive disorders.
  • a markedly decreased amount of a serotonin agonist may now be administered to a patient, presumably greatly lessening the UkeUhood and severity of any adverse events.
  • the reduced amount of active ingredient necessary for a therapeutic effect makes possible other routes of formulation than those currently employed. Rapid onset formulations such as buccal or subUngual may now be developed. Sustained release formulations are now more feasible due to the lower amounts of active ingredient necessary.
  • the methods of the present invention are particularly advantageous in the treatment or prevention of pain. These methods are especiaUy preferred in the treatment or prevention of types of pain generaUy considered refractory to standard non-sedating, non-addictive therapies.
  • pains include chronic pain, such as neuropathic pain, and post-operative pain, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom Umb pain, central pain, dental pain, neuropathic pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and deUvery, pain resulting from burns, including sunburn, post partum pain, angina pain, and genitourinary tract-related pain including cystitis.
  • Animal and human chnical models demonstrating the effectiveness of the compounds of the present invention in treating psychiatric disorders are weU known to those skiUed in the art.
  • the foUowing models may be employed.
  • the antianxiety activity of the compositions employed in the method of the present invention is estabUshed by demonstrating that these compositions increase punished responding. This procedure has been used to estabhsh antianxiety activity in cUnicaUy estabUshed compositions.
  • the responding of rats or pigeons is maintained by a multiple schedule of food presentation.
  • responding produces food peUet presentation only.
  • responding produces both food peUet presentation and is also punished by presentation of a brief electric shock.
  • Each component of the multiple schedule is approximately 4 minutes in duration, and the shock duration is approximately 0.3 seconds.
  • the shock intensity is adjusted for each individual animal so that the rate of punished responding is approximately 15 to 30% of the rate in the unpunished component of the multiple schedule.
  • Sessions are conducted each weekday and are approximately 60 minutes in duration.
  • Vehicle or a dose of composition are administered 30 minutes to 6 hours before the start of the test session by the subcutaneous or oral route.
  • Composition effects for each dose for each animal are calculated as a percent of the vehicle control data for that animal. The data are expressed as the mean ⁇ the standard error of the mean.
  • the antianxiety activity of the compositions is estabUshed by demonstrating that the compositions are effective in the monkey taming model.
  • Plotnikoff, Res. Comm. Chem. Path. & Pharmacol.. 5: 128-134 (1973) describes the response of rhesus monkeys to pole prodding as a method of evaluating the antiaggressive activity of a test composition.
  • the antiaggressive activity of a composition is considered to be indicative of its antianxiety activity.
  • Hypoactivity and ataxia are considered to be indicative of a sedative component of the composition.
  • the present study is designed to measure the pole prod response- inhibition induced by a composition of this invention in comparison with that of a standard antianxiety composition employing a compound such as diazepam as a measure of antiaggressive potential, and to obtain an indication of the duration of action of the compound.
  • compositions or appropriate vehicle are administered oraUy or subcutaneously and the animals are observed by a trained observer at varying times after drug administration. A minimum of three days (usuaUy a week or more) elapses between treatments.
  • Treatments are assigned in random fashion except that no monkey receives the same composition two times consecutively.
  • Aggressiveness and motor impairment are graded by response to a pole being introduced into the cage as described in Table II.
  • the individuals responsible for grading the responses are unaware of the dose levels received by the monkeys.
  • Monkey touched the pole only in attempting to avoid it or rode on the pole (avoidance).
  • Ataxia 2 Monkey exhibited a marked loss of coordination.
  • the patient to be benefited by practice of the present invention is a patient having one or more of the disorders discussed in detaU below, or who is at a heightened risk of contracting such disorder. Diagnosis of these disorders, or the identification of a patient at risk of one or more of them, is to be made by a physician or psychiatrist. It is presently beUeved that the combination of serotonin receptor agonists and tachykinin receptor antagonists results in the aUeviation of the effects of the disorder from which the patient suffers, or even the eUmination of the disorder completely.
  • a patient with a heightened risk of contracting one of the present disorders is a patient, in the present contemplation, who is more Ukely than is a normal person to faU victim to that disorder.
  • the patient may have suffered from the disorder in the past, and be at risk of a relapse, or may exhibit symptoms which demonstrate to the physician or psychiatrist that the patient is under an abnormal risk of developing the disorder in its fuU form.
  • the disorders which are treated or prevented in the practice of the present invention may be described as foUows.
  • buUmia nervosa obsessive-compulsive disorder premenstrual dysphoric disorder substance abuse substance dependence panic disorder panic attack agoraphobia post-traumatic stress disorder dementia of Alzheimer's type social phobia attention deficit hyperactivity disorder disruptive behavior disorder intermittent explosive disorder borderUne personaUty disorder chronic fatigue syndrome premature ejaculation depression and behavioral problems associated with head injury, mental retardation or stroke.
  • DSM DSM Association
  • BuUmia nervosa DSM 307.51
  • DSM 307.51 is characterized by uncontroUable binge eating, foUowed by setf-induced purging, usuaUy vomiting. Its prevalence is as high as l%-3% among adolescent and young adult females.
  • the disorder is weU characterized and recognized by the health professions. The essential features of it are binge eating and inappropriate compensatory methods to prevent weight gain. Further, individuals with the disorder are excessively influenced by body shape and weight.
  • Obsessive-compulsive disorder DSM 300.3
  • DSM 300.3 is characterized by recurrent obsessions or compulsions which are severe enough to be time consuming or cause distress or impairment of the patient's life.
  • Obsessions are persistent ideas, thoughts, impulses or images which are recognized by the patient to be intrusive and inappropriate and cause anxiety or distress. The individual senses that the obsession is aUen, not under control and not the kind of thought that the patient would expect to have.
  • Common obsessions include repeated thoughts about contamination, repeated doubts, a need to arrange things in a particular order, aggressive or undesirable impulses and sexual imagery.
  • Compulsions are repetitive behaviors, such as hand washing, or mental acts, such as counting or repeating words sflently, the goal of which is to prevent or reduce anxiety or distress. By definition, compulsions are either clearly excessive or not reaUsticaUy connected with that which they are designed to neutraUze or prevent.
  • Obsessive-compulsive disorder is rather common, with an estimated lifetime
  • Substance abuse and substance dependence come about when the patient becomes addicted or habituated to the improper use of a drug or other substance.
  • substance abuse and dependence wiU be discussed in detail below. It wiU be understood that substance abuse or dependence often results in additional disorders, including intoxication, withdrawal symptoms, deUrium, psychotic disorders, haUucinations, mood disorders, anxiety disorders, sexual dysfunctions, or sleep disorders. Recognized substance abuse and substance dependence disorders which are part of the present invention include the foUowing:
  • DSM 304.40 amphetamine abuse, DSM 305.70 cannabis dependence, DSM 304.30 cannabis abuse, DSM 305.20 cocaine dependence, DSM 304.20 cocaine abuse, DSM 305.60 hallucinogen dependence, DSM 304.50 haUucinogen abuse, DSM 305.30 inhalant dependence, DSM 304.60 inhalant abuse, DSM 305.90 nicotine dependence, DSM 305.10 opioid dependence, DSM 304.00 opioid abuse, DSM 305.50 phencycUdine dependence, DSM 304.90 phencychdine abuse, DSM 305.90 sedative, hypnotic or anxiolytic dependence. DSM 304.10 sedative, hypnotic or anxiolytic abuse, DSM 305.40 polysubstance dependence, DSM 304.80
  • Panic attack, panic disorder and agoraphobia categorized as DSM 300.01, 300.21 and 300.22, affect between 1.5% and 3.5% of the population.
  • the disorders are characterized by irrational sense of imminent danger or doom, an urge to escape, or a fear of being in a situation from which escape might be difficult.
  • the patient exhibits symptoms such as palpitations, accelerated heart rate, sweating, sensations of shortness of breath, chest pain, nausea, dizziness, fear of dying, and the Uke, and may have such attacks very frequently.
  • Post-traumatic stress disorder afflicts patients foUowing exposure to a traumatic stress involving personal experience of an event involving actual or threatened death of injury.
  • Such traumatic events include experiences such as miUtary combat, personal assault, kidnapping, terrorist attack, torture, natural or man-made disasters, severe accidents, or being diagnosed with a dreaded Ulness. Learning about such events occurring to others, particularly a famUy member or close friend, also may produce the disorder.
  • Triggering events which symboUze the traumatic event, such as an anniversary may recreate the stress and bring on the disorder long after the event is passed.
  • Patients strive to avoid stimuU associated with the trauma, even to the point of amnesia or reduced responsiveness to other people in general.
  • Prevalence of post-traumatic stress disorder has been reported at from 1% to as much as 14%, and has been reported at 50% and more in studies of individuals who are at risk of the disorder.
  • Dementia of the Alzheimer's type DSM 290.11, 290.12, 290.13, 290.10, 290.3, 290.20, 290.21 and 290.0, affects between 2% and 4% of the population over 65 years old.
  • the prevalence increases with age, particularly after 75 years of age, and is associated with Alzheimer's disease.
  • brain atrophy or deterioration is present, and is associated with the dementia.
  • Attention deficit hyperactivity disorder DSM 314.01 and 314.00
  • DSM 314.01 and 314.00 Attention deficit hyperactivity disorder, is primarily recognized as a disorder of chfldren, but may weU be found in adults as weU. It is characterized by symptoms such as lack of attention, impulsivity, and excessive activity, resulting in high expenditure of effort accompanied with a low degree of accomphshment. Patients have difficulty or find it impossible to give attention to detaUs, cannot sustain attention in tasks or even play, and make careless mistakes. They faU to Usten to or foUow through on instructions, lose things, and are easfly distracted by extraneous events. The difficulty of such patients in carrying out useful Uves is obvious from the mere recital of the symptoms.
  • Disruptive behavior disorder is a condition characterized by aggressive, destructive, deceitful and defiant activity.
  • Intermittent explosive disorder, DSM 312.34 is characterized by episodes of fadure to resist aggressive impulses, resulting in assault or destruction of property. The degree of aggressiveness expressed during episodes of this disorder is grossly disproportionate to any provocation or triggering stress.
  • the Southeastern Asian condition of amok is an episode of this disorder, cases of which have been reported in Canada and the United States as weU.
  • BorderUne personaUty disorder is marked by a pervasive pattern of instabiUty of interpersonal relationships and self- image, and marked impulsivity which begins by early adulthood. Patients have a pattern of unstable and intense relationships, very quickly developing a very close relationship and then quickly devaluing the other person. Patients may gamble, spend irresponsibly, binge eat, abuse substances, engage in unsafe sex or drive recklessly. Patients often display recurrent suicidal behavior or self-injurious behavior. The prevalence is estimated to be about 2% of the population.
  • Premature ejaculation DSM 302.75, is characterized by the inability of a male to delay orgasm as long as is desired.
  • Depression and behavioral problems associated with head injury, mental retardation or stroke are treated in the exercise of the present invention. Such depression and behavioral problems are distinct from the usual such disorders, because of their origin. Depression, of course, of the general type is quite prevalent and is now weU-known, being weU treated with pharmaceuticals such as, for example, fluoxetine.
  • Chronic fatigue syndrome is a condition which has been variously described and diagnosed. It is sometimes categorized as a low- grade viral infection, particularly caused by the Epstein-Barr virus. Since that virus is very widely found in the population, however, the diagnosis is problematic.
  • An alternative characterization of chronic fatigue syndrome is a physical-psychological disorder of the depression type, characterized primarily by lack of energy and Ustlessness.
  • Premenstrual dysphoric disorder is characterized by symptoms such as feeUngs of sadness, hopelessness or self-deprecation; anxiety or tenseness; tearfulness and labiUty of mood; persistent irritability and anger; decreased interest in usual activities or withdrawal from relationships; difficulty concentrating and the hke. It is not classified formaUy by DSM but is discussed in detaU there. The pattern of symptoms occurs in most cycles, frequently beginning the week prior to menses. Frequently, the disorder markedly interferes with the patient's life in aU respects during the attack of the disorder. The prevalence of the disorder in its most profound form has been estimated at 3%-5%, but there has been Uttle systematic study on the course and stabihty of the condition.
  • compositions comprising a pharmaceuticaUy acceptable excipient and at least one active ingredient.
  • These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions.
  • Such compositions are prepared in a manner weU known in the pharmaceutical art and comprise at least one active compound. See, e.g.. REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
  • the active ingredient is usuaUy mixed with an excipient, dUuted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • an excipient dUuted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a dUuent, it can be a soUd, semi-soUd, or Uquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, piUs, powders, lozenges, sachets, cachets, eUxirs, suspensions, emulsions, solutions, syrups, aerosols (as a soUd or in a Uquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to miU the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantiaUy insoluble, it ordinarily is miUed to a particle size of less than 200 mesh. If the active compound is substantiaUy water soluble, the particle size is normaUy adjusted by miUing to provide a substantiaUy uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium sihcate, microcrystaUine ceUulose, polyvinylpyrroUdone, ceUulose, water, syrup, and methyl ceUulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oU; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usuaUy about 1.0 to about 30 mg, of the active ingredient.
  • unit dosage form refers to physicaUy discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compounds are generaUy effective over a wide dosage range. For examples, dosages per day normaUy faU within the range of about 0.01 to about 30 mg/kg of body weight.
  • the range of about 0.1 to about 15 mg/kg/day, in single or divided dose is especiaUy preferred.
  • the amount of the compound actuaUy administered will be determined by a physician, in the Ught of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to Umit the scope of the invention in any way.
  • dosage levels below the lower Umit of the aforesaid range may be more than adequate, whUe in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaUer doses for administration throughout the day.
  • Hard gelatin capsules containing the foUowing ingredients are prepared:
  • Quantity Ingredient (mg/capsule)
  • Magnesium stearate 5.0 The above ingredients are mixed and fiUed into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • a dry powder inhaler formulation is prepared containing the foUowing components:
  • Quantity Ingredient (mg/tablet)
  • the active ingredient, starch and ceUulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrroUdone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • Capsules each containing 40 mg of medicament are made as foUows:
  • Quantity Ingredient (mg/capsule)
  • ceUulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient are made as foUows:
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and aUowed to cool.
  • the medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystaUine ceUulose and sodium carboxymethyl ceUulose in water.
  • the sodium benzoate, flavor, and color are dUuted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • Capsules each containing 15 mg of medicament, are made as foUows:
  • Quantity Ingredient (mg/capsule)
  • ceUulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and fiUed into hard gelatin capsules in 425 mg quantities.
  • An intravenous formulation may be prepared as foUows:
  • a topical formulation may be prepared as foUows:
  • the white soft paraffin is heated until molten.
  • the Uquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
  • the active ingredient is added and stirring is continued untU dispersed. The mixture is then cooled until soUd.
  • SubUngual or buccal tablets each containing 10 mg of active ingredient, may be prepared as foUows:
  • the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrroUdone are admixed together by continuous stirring and maintaining the temperature at about 90°C.
  • the solution is cooled to about 50-55°C and the medicament is slowly admixed.
  • the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
  • transdermal deUvery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controUed amounts.
  • transdermal patches for the deUvery of pharmaceutical agents is weU known in the art. See, e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand deUvery of pharmaceutical agents.
  • Direct techniques usuaUy involve placement of a drug deUvery catheter into the host's ventricular system to bypass the blood-brain barrier.
  • a drug deUvery catheter into the host's ventricular system to bypass the blood-brain barrier.
  • implantable dehvery system used for the transport of biological factors to specific anatomical regions of the body, is described in U.S. Patent 5,011,472, issued April 30, 1991, which is herein incorporated by reference.
  • indirect techniques which are generaUy preferred, usuaUy involve formulating the compositions to provide for drug latentiation by the conversion of hydrophiUc drugs into Upid-soluble drugs or prodrugs.
  • Latentiation is generaUy achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more Upid soluble and amenable to transportation across the blood-brain barrier.
  • the deUvery of hydrophiUc drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • the type of formulation employed for the administration of the compounds employed in the methods of the present invention may be dictated by the particular compounds employed, the type of pharmacokinetic profile desired from the route of administration and the compound, and the state of the patient.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention porte sur une série de bisindoles agissant à la fois comme antagonistes des récepteurs de tachikinine et comme agonistes de la sérotonine. Elle propose des méthodes d'utilisation de ces bisindoles dans le traitement des douleurs et des phénomènes nociceptifs liés à la migraine, aux rhinites allergiques, aux rhinites banales ainsi que dans le traitement d'une variété de troubles psychiatriques.
PCT/US1997/005996 1996-04-12 1997-04-11 Binsindoles pour traiter la douleur ou les phenomenes nociceptifs WO1997038692A1 (fr)

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AU26112/97A AU2611297A (en) 1996-04-12 1997-04-11 Bisindoles for treating pain or nociception

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US1533196P 1996-04-12 1996-04-12
US1532996P 1996-04-12 1996-04-12
US1531896P 1996-04-12 1996-04-12
US60/015,329 1996-04-12
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US60/015,318 1996-04-12

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998018466A2 (fr) * 1996-10-31 1998-05-07 Harbor Branch Oceanographic Institution, Inc. Composes et compositions anti-inflammatoires antineurogenes et leurs procedes d'utilisation
US5792760A (en) * 1997-04-23 1998-08-11 Eli Lilly And Company Bisindoles as tachykinin receptor antagonists
WO1998047513A1 (fr) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Utilisation des antagonistes du recepteur de nk-1 dans le traitement des troubles alimentaires
WO1998047514A1 (fr) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Utilisation d'un antagoniste du recepteur nk-1 et d'un inhibiteur selectif de reabsorption de la serotonine (ssri) dans le traitement de l'obesite
WO1999007375A1 (fr) * 1997-08-04 1999-02-18 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 pour le traitement de troubles du comportement agressifs
EP1027011A1 (fr) * 1997-10-28 2000-08-16 Vivus, Inc. Administration d'agents actifs, notamment d'agonistes et antagonistes du recepteur de 5-ht, afin de traiter l'ejaculation precoce
EP1410798A2 (fr) * 1999-01-08 2004-04-21 Maxim Pharmaceuticals, Inc. Traitement et prévention des dommages cellulaires induits par des métabolites réactives d'oxygène
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques
WO2010000073A1 (fr) 2008-07-03 2010-01-07 Neuraxon, Inc. Benzoxazines, benzothiazines et composés apparentés ayant une activité d'inhibition de nos
US7713984B2 (en) 1998-08-25 2010-05-11 Novartis Ag Pharmaceutical uses

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5328922A (en) * 1990-09-13 1994-07-12 Beecham Group P.L.C. Indole ureas as 5 ht receptor antagonist
US5328927A (en) * 1992-03-03 1994-07-12 Merck Sharpe & Dohme, Ltd. Hetercyclic compounds, processes for their preparation and pharmaceutical compositions containing them
WO1995014017A1 (fr) * 1993-11-17 1995-05-26 Eli Lilly And Company Antagonistes non peptidiques des recepteurs a la tachykinine
US5565568A (en) * 1995-04-06 1996-10-15 Eli Lilly And Company 2-acylaminopropanamides as tachykinin receptor antagonists

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5328922A (en) * 1990-09-13 1994-07-12 Beecham Group P.L.C. Indole ureas as 5 ht receptor antagonist
US5328927A (en) * 1992-03-03 1994-07-12 Merck Sharpe & Dohme, Ltd. Hetercyclic compounds, processes for their preparation and pharmaceutical compositions containing them
WO1995014017A1 (fr) * 1993-11-17 1995-05-26 Eli Lilly And Company Antagonistes non peptidiques des recepteurs a la tachykinine
US5565568A (en) * 1995-04-06 1996-10-15 Eli Lilly And Company 2-acylaminopropanamides as tachykinin receptor antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TIPS REVIEWS, April 1992, Vol. 13, BOCKAERT et al., "The 5-HT4 Receptor: A Place in the Sun", pages 141-145. *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998018466A3 (fr) * 1996-10-31 1998-08-13 Harbor Branch Oceanographic Composes et compositions anti-inflammatoires antineurogenes et leurs procedes d'utilisation
WO1998018466A2 (fr) * 1996-10-31 1998-05-07 Harbor Branch Oceanographic Institution, Inc. Composes et compositions anti-inflammatoires antineurogenes et leurs procedes d'utilisation
US5792760A (en) * 1997-04-23 1998-08-11 Eli Lilly And Company Bisindoles as tachykinin receptor antagonists
US6162805A (en) * 1997-04-24 2000-12-19 Merck Sharp & Dohme Limited Use of an NK-1 receptor antagonist and an SSRI for treating obesity
WO1998047513A1 (fr) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Utilisation des antagonistes du recepteur de nk-1 dans le traitement des troubles alimentaires
WO1998047514A1 (fr) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Utilisation d'un antagoniste du recepteur nk-1 et d'un inhibiteur selectif de reabsorption de la serotonine (ssri) dans le traitement de l'obesite
WO1999007375A1 (fr) * 1997-08-04 1999-02-18 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 pour le traitement de troubles du comportement agressifs
EP1027011A1 (fr) * 1997-10-28 2000-08-16 Vivus, Inc. Administration d'agents actifs, notamment d'agonistes et antagonistes du recepteur de 5-ht, afin de traiter l'ejaculation precoce
EP1027011A4 (fr) * 1997-10-28 2002-03-06 Vivus Inc Administration d'agents actifs, notamment d'agonistes et antagonistes du recepteur de 5-ht, afin de traiter l'ejaculation precoce
US7713984B2 (en) 1998-08-25 2010-05-11 Novartis Ag Pharmaceutical uses
EP1410798A2 (fr) * 1999-01-08 2004-04-21 Maxim Pharmaceuticals, Inc. Traitement et prévention des dommages cellulaires induits par des métabolites réactives d'oxygène
EP1410798A3 (fr) * 1999-01-08 2004-10-13 Maxim Pharmaceuticals, Inc. Traitement et prevention des dommages cellulaires induits par des metabolites reactives d'oxygene
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques
WO2010000073A1 (fr) 2008-07-03 2010-01-07 Neuraxon, Inc. Benzoxazines, benzothiazines et composés apparentés ayant une activité d'inhibition de nos

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