WO1995017382A1 - Antagonistes non peptidiques des recepteurs des tachykinines - Google Patents

Antagonistes non peptidiques des recepteurs des tachykinines

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Publication number
WO1995017382A1
WO1995017382A1 PCT/US1994/014312 US9414312W WO9517382A1 WO 1995017382 A1 WO1995017382 A1 WO 1995017382A1 US 9414312 W US9414312 W US 9414312W WO 9517382 A1 WO9517382 A1 WO 9517382A1
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WIPO (PCT)
Prior art keywords
ethoxy
benzoyl
phenyl
benzo
methoxyphenyl
Prior art date
Application number
PCT/US1994/014312
Other languages
English (en)
Inventor
Thomas Alan Crowell
Bruce Donald Gitter
Charles David Jones
William Henry Walker Lunn
Original Assignee
Eli Lilly And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to EP95904891A priority Critical patent/EP0736007A4/fr
Priority to AU13397/95A priority patent/AU1339795A/en
Priority to JP7517478A priority patent/JPH09506898A/ja
Publication of WO1995017382A1 publication Critical patent/WO1995017382A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • C07D209/12—Radicals substituted by oxygen atoms

Definitions

  • Tachykinins are a family of peptides which share the 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. Substance P has the following amino acid sequence,
  • SEQ ID NO:2 hereinafter referred to as SEQ ID NO:2.
  • neurokinin A also known as substance K, neuromedin L, and neurokinin ⁇
  • neurokinin B also known as neuromedin K and neurokinin ⁇
  • neurokinin B is the amino acid sequence
  • 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.
  • Substance P is believed 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.
  • tachykinin receptor antagonists In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions.
  • the earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.
  • this invention provides a class of potent non-peptide tachykinin receptor antagonists.
  • the compounds of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of known peptide-based tachykinin receptor antagonists.
  • This invention encompasses methods for the treatment or prevention of a physiological disorder associated with an excess of tachykinins, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula I
  • n 0, 1, or 2;
  • X is a bond or C 1 -C 4 alkylidenyl
  • R 2 is a group of the formula
  • R 4 and R 5 are independently Ci-C ⁇ alkyl or combine to form, along with the nitrogen to which they are attached, a heterocyclic ring selected from the group consisting of hexamethyleneiminyl, piperazino, heptamethyleneiminyl, 4-methylpiperidinyl, imidazolinyl, piperidinyl, pyrrolidinyl, or morpholinyl;
  • R is hydroxy, halo, hydrogen, C 3 -Cs cycloalkyl, C -
  • C ⁇ alkanoyloxy, Ci-C ⁇ alkoxy, or phenyl said phenyl being optionally substituted with one, two, or three moieties selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro, chloro, fluoro, trifluoromethyl -OSO 2 - (C 1 -C 10 alkyl)
  • R 1 is hydroxy, halo, hydrogen, C 3 -C 8 cycloalkyl, C 2 - C7 alkanoyloxy, Ci-C ⁇ alkoxy, or phenyl, said phenyl being optionally substituted with one, two, or three moieties selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro, chloro, fluoro, trifluoromethyl -OSO 2 - (C 1 -C 10 alkyl) O
  • each R 3 is independently Ci-Ce alkyl, C 3 -C 8 cycloalkyl, unsubstituted or substituted phenyl where the substituent is halo, C ⁇ C ⁇ alkyl or Ci-C ⁇ alkoxy;
  • R and R 1 are not both selected from the group consisting of hydroxy, methoxy, and C 2 -C 7 alkanoyloxy;
  • Z is -0- or -N(R 12 )
  • R 12 is hydrogen or Ci-C ⁇ alkyl
  • R 6a is hydroxy, hydrogen, or Ci-C ⁇ alkoxy
  • R 7 is hydroxy, hydrogen, or C ⁇ -C 6 alkoxy
  • n 1-6;
  • R 8a is a group of the formula
  • R 9 and R 10a are independently Ci-Cg alkyl or combine to form, along with the nitrogen to which they are attached, a heterocyclic ring selected from the group consisting of hexamethyleneiminyl, piperazinyl, heptamethyleneimino, imidazolinyl, piperidinyl, pyrrolidinyl, and morpholinyl;
  • R 6a and R 7a are both methoxy, -O- (CH 2 ) P -R 8a is not 2- (piperidin-1-yl)ethoxy; and the pharmaceutically acceptable salts thereof.
  • the current invention concerns the discovery that a select group of substituted benzofurans, benzothiophenes, indoles, naphthalenes, and dihydronaphthalenes, those of Formula I, are useful as in treating or preventing conditions associated with an excess of tachykinins.
  • Ci-Cio alkyl refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 10 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl.
  • C ⁇ -C ⁇ o alkyl includes within its definition the terms “C 1 -C 4 alkyl” and "C 1 -C 6 alkyl” .
  • C 1 -C 6 alkoxy represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical C 1 -C 6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pen oxy and the like.
  • the term "Ci-C ⁇ alkoxy” includes within its definition the term “C 1 -C 4 alkoxy”.
  • Ci-C ⁇ alkylidenyl refers to a straight or branched, divalent, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl, t-butylenyl, pentylenyl, isopentylenyl, hexylenyl, and the like.
  • the term “C 1 -C 4 alkylidenyl” is encompassed within the term “C 1 -C 6 alkylidenyl”.
  • halo encompasses chloro, fluoro, bromo and iodo.
  • 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 limited to, activating groups.
  • activating groups are well-known to those skilled in the art and may be, for example, succinimidoxy, phthalimidoxy, benzotriazolyloxy, benzenesulfonyloxy, methanesulfonyloxy, toluenesulfonyloxy, azido, or -O-CO- (C4-C7 alkyl) .
  • Some of the compounds of the present invention are derivatives of benzofb]thiophene which are named and numbered according to the RING INDEX as follows.
  • R 1 is hydrogen, hydroxy, C1-C3 alkoxy, or -OSO2- (C1-C10 alkyl) ;
  • X is a bond or methylene; and
  • R 2 is piperidinyl, hexamethyleneiminyl, pyrrolidinyl, or -NR 4 R 5 , where R 4 and R 5 are C1-C4 alkyl; and the pharmaceutically acceptable acid addition salts and solvate ⁇ .
  • the most preferred compounds employed in the methods of this invention are those compounds of Formula I wherein a) A is -S-; b) R is hydrogen, hydroxy, C1-C3 alkoxy, or -OSO2- (C1-C10 alkyl) ; c) R 1 is hydrogen, hydroxy, C1-C 3 alkoxy, or -OSO2-
  • R 2 is piperidinyl, hexamethyleneiminyl, pyrrolidinyl, or -NR R 5 , where R 4 and R 5 are C1-C4 alkyl; and f) at least one of R and R 1 is -OS0 2 - (C1-C10 alkyl); and the pharmaceutically acceptable acid addition salts and solvates thereof.
  • the compounds of the present invention can be prepared by a variety of procedures well known to those of ordinary skill in the art.
  • the particular order of steps required to produce the compounds of Formula I is dependent upon the particular compound being synthesized, the starting compound, and the relative lability of the substituted moieties.
  • A Preparation of Dihydronapthalenyl Compounds
  • naphthalenes and dihydronaphthalenes employed in the methods of the instant invention may be prepared by reacting a tetralone of Formula II
  • R c is hydrogen, Ci-C ⁇ alkoxy, or benzyloxy with a phenyl benzoate of Formula III
  • Y 1 is methoxy, benzyloxy, or -0- (CH 2 ) n -NR a R b , where n is 1-6, and -NR a R b is R 2 .
  • This reaction is generally carried out in the presence of a moderately strong base such as sodium amide and at room temperature or below.
  • the product which is obtained is a substituted tetralone of Formula IV.
  • R la is hydrogen, Ci-Cg alkoxy, or benzyloxy and Y a is a bond, methylene, or ethylene.
  • a compound of Formula V can be treated with pyridine hydrochloride at reflux to produce the corresponding hydroxy compound. Under these conditions, should R c or R la be alkoxy or benzyloxy, these groups will also be cleaved, resulting in hydroxy groups.
  • the group at Y 1 can be selectively cleaved by treating a compound of
  • Formula V with an equivalent of sodium thioethoxide in N,N- dimethylformamide at a moderately elevated temperature of about 80°C to about 90°C.
  • the process of the selective cleavage may be monitored by periodic thin layer chromatography analysis. The reaction is complete when little or no starting material remains.
  • L is a good leaving group such as halo, especially chloro.
  • alkylation will be effected at each of the unprotected hydroxy groups which are present in the molecule. This can be avoided, and alkylation at the 4-benzoyl groups alone can be achieved, by carrying out the reaction in the presence of an excess of finely powdered potassium carbonate and using an equivalent or slight excess of the compound of Formula VII.
  • the compound containing the substituent of Formula VII can then be further treated with an additional quantity of sodium thioethoxide in N,N-dimethylformamide as aforedescribed to effect cleavage of any remaining alkoxy or benzyloxy groups, thereby providing another sequence for achieving formation of those compounds employed in this invention in which R 1 and/or R 2 are hydroxy.
  • R 1 and/or R 2 are hydroxy.
  • R 2a is -H or Ci-C ⁇ alkoxy
  • Y c is Ci-C ⁇ alkoxy- substituted phenyl or benzyl
  • a tetralone as described above, or a salt thereof, is acylated using standard Friedel Crafts conditions to provide a highly enolized diketone of formula
  • R 2a is -H or Ci-C ⁇ alkoxy.
  • R 2a is as defined above.
  • R 2 and Y c are as defined above.
  • R 2b is -H or -OH and Y d is phenyl, benzyl, hydroxyphenyl, or hydroxybenzyl.
  • the compounds of Formula Vlf can be substituted using standard means, if desired, to produce the corresponding dihydronaphthenyl compounds of Formula I.
  • naphthalenes are readily prepared from the corresponding dihydronaphthalenyl compounds.
  • Selective dehydrogenation of the dihydronaphthalene structure to produce specifically the corresponding naphthalene can be accomplished by treatment with 2,3-dichloro-5, 6-dicyano-l, 4-benzoquinone (DDQ) at a temperature of from about 50°C to about 100°C.
  • DDQ 2,3-dichloro-5, 6-dicyano-l, 4-benzoquinone
  • the naphthalene which is produce may be further converted to other naphthalene compounds by means of the derivatizing reactions described supra.
  • the title compound was prepared as described in United States Patent 4,230,862. To a suspension of sodium amide (15.2 g, 0.38 mol) in 250 ml of tertrahydrofuran were added 50 grams (0.34 mol) of ⁇ -tetralone. The mixture was stirred for 15-20 minutes, and 78 grams of phenyl p- methoxybenzoate dissolved in tetrahydrofuran were added. The temperature of the reaction mixture was maintained below 10°C, and the mixture was then stirred at room temperature overnight. The reaction mixture was concentrated and the water was added to the residue. The aqueous mixture was extracted with ethyl acetate, and the ethyl acetate extract was washed and concentrated.
  • a mixture of 11.1 grams (0.03 mol) of the above dimethoxy product, 7.2 grams of sodium hydride (50 percent in oil) , and 11 ml of ethyl mercaptan in N,N-dimethylformamide was prepared.
  • the mixture was heated to 65-70°C and maintained at that temperature for about two hours.
  • the mixture was then cooled and conetrated.
  • the concentrate was acidified and extracted with ethyl acetate. The ethyl acetate extract was washed, dried, and evaporated.
  • the residue was extracted with hexanes, the insoluble portion was dissolved in ethyl acetate, and the ethyl acetate solution was extracted with 1 N hydrochloric acid.
  • the acid extract was rendered alkaline, and then was extracted with ethyl acetate.
  • the ethyl acetate extract was washed and concentrated.
  • One equivalent of citric acid in acetone then was added to the concentrate, and the mixture was concentrated to drynes ⁇ .
  • the residue was dissolved in a large volume of methyl ethyl ketone.
  • the title product was prepared as described iin United States Patent 4,230,862.
  • To 300 ml of N,N- dimethylformamide were added 107 grams of phenyl p- hydroxybenzoate and 26 grams of sodium hydride (50 percent in oil). The mixture was heated to 60°C and maintained at this temperature for about two hours.
  • To this mixture was added l-chloro-2-pyrrolidin-l-ylethane (67 g) , and the mixture was stirred overnight at 85°C
  • the bulk of the N,N- dimethylformamide then was evaporated from the mixture. Water was added to the residue, and the aqueous mixture was extracted with ethyl acetate.
  • the ethyl acetate extract was concentrated, and the residue was dissolved in a 1:1 mixture of ether and ethyl acetate.
  • the organic solution was then extracted with 2 N hydrochloric acid, and the acid extract was added dropwise to 2 N sodium hydroxide.
  • the resulting mixture was extracted with ethyl acetate, and the ethyl acetate extract was washed and then dried over magnesium sulfate.
  • the ethyl acetate was concentrated to obtain 110 grams of crude phenyl p- (2-pyrrolidin-l-ylethoxy)benzoate.
  • the resulting mixture was poured into a mixture of ice and hydrochloric acid, and the acid mixture was extracted with ethyl acetate.
  • the ethyl acetate extract was washed, dried, and concentrated to obtain 10.5 grams of a red-brown oil.
  • the oil was added to 500 ml of acetic acid, and the mixture was heated on a steam bath for about 30 minutes. The acid was stripped off, and water as added to the residue.
  • the aqueous mixture was rendered alkaline by addition of base, and the alkaline mixture was extracted with ethyl acetate. The extract was dried and concentrated to obtain 8.7 grams of product which was dissolved in acetone, and one equivalent of citric acid was added to the mixture. The acetone was stripped off, and methyl ethyl ketone was added to the residue. The mixture was maintained at 0°C overnight, and the crystals which formed were collected by filtration and washed with cold methyl ethyl ketone and vacuum dried. The solid was recrystallized from acetone to obtain the title compound in the form of its citrate salt, mp 98-100°C Analysis of C 3 6H 39 NO 10 :
  • the resulting mixture was added at about 10°C to a mixture of 20 ml of N,N-dimethylformamide containing 120 mg (5.0 mmol) of sodium hydride and 800 mg of l-chloro-2- (pyrrolidin-1-yl) ethane.
  • the mixture was heated to 80°C and maintained at that temperature for about three hours, during which time sodium chloride precipitated.
  • the mixture was cooled and evaporated to dryness.
  • the resulting residue was partitioned between water and ethyl acetate.
  • the organic fraction was washed with brine (5 x 25 ml) .
  • the organic fraction was dried and evaporated to give 1.62 grams of l-[4- [2- (pyrrolidin-1-yl)ethoxy]benzoyl] -2-phenylnaphthalene as a yellow oil.
  • the title compound was prepared as described in United States Patent 4,230,862. To 50 ml of acetone were added 4.0 grams (11.2 mmol) of 3- (4-methoxyphenyl) -4- (4- hydroxybenzoyl) -1,2-dihydronaphthalene, prepared as described in Example 1, 1.81 grams (16.8 mmol) of l-chloro-2- dimethylaminoethane (freshly prepared from the hydrohloride) , and 2.32 grams (16.8 mol) of finely powdered potassium chloride. The resulting mixture was refluxed under nitrogen with stirring for about 72 hours. The progress of the reaction was monitored by thin layer chromatography. The resulting mixture was then poured over ice, and the resulting mixture was extracted with ether.
  • the acylation of this invention is a Friedel-Crafts acylation, and is carried out in the usual way, using aluminum chloride or bromide, preferably the chloride, as the acylation catalyst.
  • the acylation is ordinarily carried out in a solvent, and any inert organic solvent which is not significantly attacked by the conditions may be used.
  • halogenated solvents such as dichloromethane, 1,2- dichloroethane, chloroform, and the like may be used, as can aromatics such as benzene, chlorobenzene, and the like. It is preferred to use a halogenated solvent, especially dichloromethane.
  • toluene is rather easily acylated under the conditions used in the Friedel-Craft ⁇ acylation, and so it is important, when toluene is used in an earlier step of the process, to remove it as completely as possible from the protected starting compound, to avoid wasting the acylating agent.
  • the acylations may be carried out at temperatures from about -30'C to about 100"C, preferably at about ambient temperature, in the range of from about 15'C to about 30'C
  • the acylating agent is an active form of the appropriate benzoic acid of Formula VIII
  • R a is chloro or bromo.
  • the preferred acylating agents are those wherein R a is chloro.
  • the most highly preferred individual acylating agents are 4- [2- (piperidin-1- yl)ethoxy]benzoyl chloride, 4-[2- (hexamethyleneimin-1- yl)ethoxy]benzoyl chloride, 4- [2- (pyrrolidin-1- yl)ethoxy]benzoyl chloride, 4- [2- (dimethylamino)ethoxy] - benzoyl chloride, 4- [2- (diethylamino)ethoxy]benzoyl chloride, and 4- [2- (diisopropylamino)ethoxy]benzoyl chloride.
  • the acyl chloride used as an acylating agent may be prepared from the corresponding carboxylic acid by reaction with a typical chlorinating agent such as thionyl chloride. Care must be taken to remove any excess chlorinating agent from the acyl chloride. Most conveniently, the acyl chloride is formed in situ, and the excess chlorinating agent is distilled off under vacuum. It is generally preferred that an equimolar amount of the compounds of Formula VII and VIII are reacted together. If desired, a small excess of either reactant may be added to assure the other is fully consumed. It is generally preferred to use a large excess of the acylation catalyst, such as about 2-12 moles per mole of product, preferably about 5-10 moles of catalyst per mole of product.
  • the acylation is rapid. Economically brief reaction times, such as from about 15 minutes to a few hours provide high yields of the acylated intermediate. Longer reaction times may be used if desired, but are not usually advantageous. As usual, the use of lower reaction temperatures call for relatively longer reaction times.
  • the acylation step is ended and the optional demethylation step is begun by the addition of a sulfur compound selected from the group consisting of methionine and compounds of the formula
  • X 1 is hydrogen or unbranched C 1 -C 4 alkyl
  • Y ⁇ is C 1 -C 4 alkyl or phenyl.
  • the sulfur compounds are, preferably, the alkylthiols, such as methanethiol, ethanethiol, isopropanethiol, butanethiol, and the like; dialkyl sulfide ⁇ , such as diethyl sulfide, ethyl propyl sulfide, butyl isopropyl sulfide, dimethyl sulfide, methyl ethyl sulfide, and the like; benzenethiol; methionine; and alkyl phenyl sulfides, such as methyl phenyl sulfide, ethyl phenyl sulfide, butyl phenyl sulfide, and the like.
  • the demethylation reaction goes well at about ambient temperature, in the range of from about 15'C to about 30'C, and such operation is preferred.
  • the demethylation may be carried out, however, at temperatures in the range of from about -30'C to about 50'C if it is desired to do so. Short reaction times, in the range of about one hour, have been found to be sufficient.
  • the product After the product has been demethylated, it is recovered and isolated by conventional means. It is customary to add water to decompose the complex of the acylation catalyst. Addition of dilute aqueous acid is advantageous. The product precipitates in many instances, or may be extracted with an organic solvent according to conventional methods. The examples below further illustrate the isolation.
  • Lower alkyl alcohols are usually added to the non-polar solvent so as to retain more of the hydrochloric acid created in situ, with ethanol and methanol being especially preferred.
  • the reaction is performed at temperatures ranging from ambient temperature up to the reflux temperature of the mixture. This reaction results in the synthesis of a compound of Formula X
  • the intermediate of Formula X may be isolated or may preferably be converted to the compound of Formula IX in the same reaction vessel.
  • the ether of the compounds of Formula I is then produced by the substitution of the hydrogen on the hydroxy group by an alkyl or halide.
  • Those compounds of Formula I in which m is one or two may be prepared by oxidation of the corresponding benzothiophene in which m is zero. Oxidation may be carried out by treating the benzothiophene with an oxidizing agent, for example, m-chloroperbenzoic acid, or the like, for a time sufficient to achieve formation of the sulfoxide group. The progress of the oxidation reaction may be monitored by thin layer chromatography methods.
  • an oxidizing agent for example, m-chloroperbenzoic acid, or the like
  • the compounds used in the methods of this invention form pharmaceutically acceptable acid and base addition salts with a wide variety of organic and inorganic acids and bases and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention.
  • Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like.
  • Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, ⁇ -hydroxybutyrate, butyne-1, 4-dicarboxylate, hexyne-1,4- dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, hydrochloride, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate, mono
  • the pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of Formula I with an equimolar or excess amount of acid.
  • the reactants are generally combined in a mutual solvent such as diethyl ether or benzene.
  • the salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means.
  • Bases commonly used for formation of salts include ammonium hydroxide and alkali and alkaline earth metal hydroxides and carbonates, as well as aliphatic and aromatic amines, aliphatic diamines and hydroxy alkylamines.
  • Bases especially useful in the preparation of addition salts include ammonium hydroxide, potassium carbonate, calcium hydroxide, methylamine, diethylamine, ethylene diamine, cyclohexylamine and ethanolamine.
  • the pharmaceutically acceptable salts frequently have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions.
  • Method B Alkylation of 2- (4-methoxyphenyl) -3- (4- hydroxybenzoyl) -6-methoxybenzofuran.
  • Example la supra.
  • ethylene chloride 50 ml
  • aluminum trichloride 9.60 g, 72 mmol
  • ethanethiol 6.39 g, 103 mmol
  • To this liquid was then added the product of Example la (5.00 g, 10.3 mmol) in a gradual fashion.
  • a red oil precipitated and the mixture was stirred for about 20 minutes.
  • 100 ml of tetrahydrofuran was added and the mixture was allowed to stir until all of the oil had gone into solution.
  • the title compound is prepared essentially as described in the process for preparing the compound of Example 18 except that 4- [2- (pyrrolidin-1-yl)ethoxy]benzoyl chloride is employed in the synthesis of Method A in place of 4- [2- (piperidin-1-yl)ethoxy]benzoyl chloride or 2- (pyrrolidin-1-yl)ethyl chloride is employed in the synthesis of Method B in place of the 2- (piperidin-1-yl)ethyl chloride.
  • the title compound was prepared by reacting the compound of Preparation 4a supra.
  • 2- ( -methoxypheny1) -3- (4- hydroxybenzoyl) -6-methoxybenzofuran (10 g, 26.7 mmol) which is dissolved in 200 ml of N,N-dimethylformamide with an equimolar amount of 2- (N,N-diethylamino)ethyl chloride (6.4 g, 32 mmol) and potassium carbonate (11.06 g, 80.2 mmol).
  • the mixture was heated to 100'C and was maintained at that temperature for about two hours.
  • the reaction mixture was then cooled to room temperature and maintained at this temperature overnight while stirring.
  • the title compound was prepared by reacting the compound of Preparation 4a supra.
  • 2- (4-methoxypheny1) -3- (4- hydroxybenzoyl) -6-methoxybenzofuran (10 g, 26.7 mmol) which is dissolved in 200 ml of N,N-dimethylformamide with 2-(N,N- diisopropylamino)ethyl chloride (6.4 g, 32 mmol) and potassium carbonate (11.06g, 80.2 mmol).
  • the mixture was heated to 100"C and was maintained at that temperature for about two hours.
  • the reaction mixture was then cooled to room temperature and maintained at this temperature overnight while stirring.
  • Zinc chloride (66.5 g, 0.49 mole) was added to a 3- neck round bottom flask under a nitrogen atmosphere. The flask and its contents were then heated to 200'C at which time the hydrazone (26.4 g, 0.098 mole) prepared supra was added. The mixture was stirred for about 17 minutes, resulting in the formation of a brown tar and the evolution of some gas. The brown tar was then poured into two liters of 0.075 N hydrochloric acid and this mixture was stirred for about 48 hours, resulting in the formation of a yellow solid.
  • the 2- (4-methoxyphenyl) -6-methoxyindole (2.0 g, 8 mmol) was dissolved in 40 milliliters of N,N- dimethylformamide. This solution was added dropwise to a solution of sodium hydride (0.48 g, 12 mmol) in ten milliliters of N,N-dimethylformamide. This reaction mixture was then stirred at room temperature for 1 hour at which time a solution of ethyl iodide (1.9 g, 12 mmol) in N,N- dimethylformamide (10 ml) was added dropwise over five minutes. This mixture was then stirred at room temperature for about two hours.
  • the preceding intermediate was acylated at the 3- position by first placing N,N-dimethyl-4-methoxybenzamide (1.43 g, 8 mmol), in a 100 ml flask cooled to O'C. To this was then added phosphorous oxychloride (6.1 g, 40 mmol) dropwise at such a rate that the reaction temperature never exceeded 20 * C The reaction mixture was allowed to warm to room temperature and was stirred for about 30 minutes.
  • reaction mixture was then cooled to O'C and the l-ethyl-2- (4- ethoxyphenyl) -6-methoxyindole (1.5 g, 5.33 mmol) prepared supra, was added and the reaction mixture was then heated to 75'C and maintained at this temperature for about three hours.
  • reaction mixture was poured over ice and diluted with water. The layers were separated and the organic phase was washed with water (150 ml) . The organic layer was dried over sodium sulfate and the oslvents were removed in vacuo to yield a dark brown/black oil. This oil was taken up in 50 milliliters of methanol and cooled to O'C. This solution was then basified by the dropwise addition of 2N sodium hydroxide (50 ml) . The mixture was then heated to reflux for about 5 minutes, then cooled overnight at 4'C
  • This intermediate (1.5 g, 3.74 mmol) was then reacted with 2- (piperidin-1-yl) ethyl chloride hydrochloride (1.38 g, 7.5 mmol) in N,N-dimethylformamide (60 ml) in the presence of cesium carbonate (3.26 g, 10 mmol) .
  • This admixture was heated to 80'C and maintained at this temperature for about two hours.
  • This intermediate (1.0 g, 1.82 mmol) was dissolved in dichloromethane (10 ml) and cooled to O'C. To this mixture was then added the Lewis acid aluminum chloride (1.2 g, 9 mmol) and the reaction mixture was then stirred for five minutes. Ethanol (3 ml) were then added and the reaction mixture was stirred on ice for about 15 minutes. The temperature of the reaction mixture was slowly raised to reflux and maintained at reflux for about 1.5 hours.
  • reaction mixture was then cooled to O'C and this temperature was maintained as tetrahydrofuran (5 ml) was added.
  • To this mixture was then added 20% hydrochloric acid in water (5 ml) and the reaction mixture was cooled back to O'C at which time five milliliters of water was then added, resulting in the formation of a yellow gum.
  • This suspension was then placed at -40'C and kept at this temperature for about 48 hours, after which time a grayish material was removed from the mixture by filtration. Thin layer chromatography confirmed this precipitate as the desired title product.
  • R or R 1 are -OSO 2 - (C ⁇ -C ⁇ o alkyl) or
  • O -OCN-R 3 were made essentially as described in European
  • X 1 is a leaving group, preferably a chloro or bromo group.
  • This reaction is usually performed in a basic environment in the presence of a coupling catalyst such as 4- dimethylaminopyridine (DMAP) .
  • DMAP 4- dimethylaminopyridine
  • Most preferred solvents include the lower alkyl amines, especially triethylamine. While this thioester formation reaction may be performed at equal molar ratios of the two reactants, it is usually preferred to employ a 2-3 molar excess of the alkyl sulfonyl compound so as to complete the reaction.
  • the reaction mixture was placed under a nitrogen atmosphere and allowed to warm slowly to room temperature and continued for 72 hours.
  • the reaction mixture was filtered and evaporated to an oil.
  • the oily residue was dissolved in chloroform and chromatographed on a silica gel column and eluted with a linear gradient of chloroform to chloroform-methanol (19:1; V:V) .
  • the desired fractions were combined and evaporated to dryness to afford 5.60 g of the title compound as a tan amorphous powder.
  • the reaction was allowed to proceed at room temperature and under nitrogen for eighteen hours.
  • the reaction mixture was filtered and the volatiles were removed in vacuo.
  • the resulting material was dissolved in a small amount of chloroform and chromatographed (HPLC) on a silica gel column eluted with a linear gradient starting with chloroform and ending with chloroform-methanol (19:1 v/v) .
  • the desired fractions were determined by thin layer chromatography, combined and evaporated down to afford 3.82 g of the title compound as thick oil.
  • the reaction was allowed to proceed at room temperature and under nitrogen for 3 days.
  • the reaction mixture was evaporated down in vacuo and resuspended in ethyl acetate and washed with water.
  • the organic layer was dried by filtering it through anhydrous sodium sulfate and evaporated to a yellow oil.
  • the oil was dissolved in chloroform and chromatographed (HPLC) on a silica gel column and eluted with a linear gradient starting with chloroform and ending with chloroform-methanol (19:1 v/v) .
  • the desired fractions were determined by thin layer chromatography, combined and evaporated down to afford 3.14 g of the title compound as a thick oil.
  • the reaction was allowed to proceed for eighteen hours at room temperature and under nitrogen. The reaction was quenched with the addition of 25 ml methanol and volume reduced in vacuo. The crude product was chromatographed on a silica gel column, eluted with chloroform-methanol (19:1 v/v) . The desired fractions were determined by thin layer chromatography, combined, and evaporated to a tan oil.
  • the reaction mixture was stirred for eighteen hours at room temperature and under a nitrogen atmosphere.
  • the reaction mixture was evaporated to a gum n vacuo.
  • the crude product was suspended in 100 ml of ethyl acetate and washed with sodium bicarbonate solution and subsequently with water.
  • the organic layer was dried by filteration through anhydrous sodium sulfate and evaporated to a yellow oil.
  • the final product was crystallized from hot ethyl acetate-hexane to afford 410 mg of the title compound.
  • n-butylsulfonylchloride (0.04 mol) was dissolved in 25 ml of tetrahydrofuran and slowly added to the reaction mixture over a period of twenty minutes. The reaction was allowed to continue for 5 days at room temperature and under nitrogen atmosphere. The reaction mixture was evaporated to a gum and suspended in ethyl acetate. The ethyl acetate mixture was washed successively with water, dilute sodium bicarbonate, and water. The ethyl acetate solution was dried by filteration through anhydrous sodium sulfate and evaporated to an amorphous solid.
  • the solid was triturated (2x) with diethyl ether and dried.
  • This compound was prepared by substantially following the procedures of Example 75 to afford 3.58 g of the title compound as a white crystalline powder.
  • the biological activity of the compounds of the present invention was evaluated employing initial screening assays which rapidly and accurately measured the binding of the tested compound to known NK-1 receptor sites.
  • Assays useful for evaluating tachykinin receptor antagonists are well known in the art. See, e. ⁇ .. J. Jukic, et al.. Life Sciences, 49:1463-1469 (1991); N. Kucharczyk, et al.. Journal of Medicinal Chemistry, 36:1654-1661 (1993); N. Rouissi, e_t al. , Biochemical and Biophysical Research Communications, 176:894-901 (1991).
  • Radioreceptor binding assays were performed using a derivative of a previously published protocol. D.G. Payan, et al.. Journal of Immunology. 133:3260-3265 (1984). In this assay an aliquot of IM9 cells (1 x 10 6 cells/tube in RPMI 1604 medium supplemented with 10% fetal calf serum) was incubated with 20 pM 125 l-labeled substance P in the presence of increasing competitor concentrations for 45 minutes at 4'C
  • the IM9 cell line is a well-characterized and readily available human cell line. See, e.g.. Annals of the New York Academy of Science. 190: 221-234 (1972); Nature (London) . 251:443-444 (1974); Proceedings of the National
  • 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 ligand.
  • mice Male Hartley guinea pigs (Charles River Laboratories, Portage, Michigan) (350-400 grams) were euthanized by intravenous or intraperitoneal injection of T- 61. Unperfused lungs from five to eight animals were used for each preparation. The lungs were excised, trimmed of unwanted connective tissue, and placed in five volumes (wt/vol) ice cold 10 mM Tris (pH 7.4) containing 250 M sucrose, 5 mM dipotassium EDTA, 10 mg/ml soybean trypsin inhibitor, 100 mg/ml bacitracin, 10 mM phenylmethyl ⁇ ulfonylfluoride, and 100 mM benzamidine.
  • Tris pH 7.4
  • the tissue was minced and then homogenized in a 40 ml dounce homogenizer using a Brinkman PolytronTM (setting #6, 6 strokes) .
  • the homogenate was centrifuged 1000 x g for about 10 minutes at 4 * C
  • the supernatant fluid was collected and centrifuged at 12,000 x g for about 20 minutes at 4'C and the resulting supernatant was centrifuged at 100,000 x g for about 60 minutes at 4'C
  • the supernatant * was then discarded and the resulting pellet was resuspended in ice cold 5 mM Tris (pH 7.4) and then centrifuged at 100,000 x g for about 45 minutes at 4'C This washing procedure was repeated at least twice.
  • the final pellet was resuspended in 5 mM Tris (pH 7.4) and assayed for protein content using standard techniques.
  • Ligand binding assays were performed in an assay buffer consisting of 50 mM Tris (pH 7.4), 3 mM magnesium chloride, 1 mg/ml bovine serum albumin, 2 mg/ml chymostatin, 4 mg/ml leupeptin, 40 mg/ml bacitracin, and 2.5 mg/ml thiorphan.
  • the reaction mixture consisted of 0.1 mg/ml lung membrane preparation, prepared as described supra. 20 pM [I 25 ] _substance P (New England Nuclear, Wilmington, Delaware) , and the desired concentration of the potential competitive binding substance.
  • binding was terminated by filtration through a Whatman glass fiber filter (Brandel, Gaithersburg, Maryland) which had been previously pre-soaked in 1.0% polyethyleneimine for at least 20 minutes. After passing the reaction mixture through it, the filter was immediately washed with about 5 ml 50 mM Tris (pH 7.4) containing 0.1% bovine serum albumin. Bound radioactivity was measured using a gamma counter. Specific binding of labeled substance P was determined in the presence of a 1000- fold excess (20 nM) of unlabeled ligand. All samples were run in triplicate.
  • the compounds of Formula I are effective tachykinin receptor antagonists, these compounds are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of tachykinin.
  • the invention provides methods for the treatment or prevention of a physiological disorder associated with an excess of tachykinins, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • physiological disorder associated with an excess of tachykinins encompasses those disorders associated with an inappropriate stimulation of tachykinin receptors, regardless of the actual amount of tachykinin present in the locale.
  • physiological disorders may include disorders of the central nervous system such as anxiety, depression, psychosis, and schizophrenia; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer's type, Alzheimer's disease, AIDS-associated dementia, and Down's syndrome; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as peripheral neuropathy, such as diabetic and chemotherapy-induced neuropathy, and post-herpetic and other neuralgias; acute and chronic obstructive airway diseases such as adult respiratory distress syndrome, bronchopneumonia, bronchospasm, chronic bronchitis, drivercough, and asthma; inflammatory diseases such as inflammatory bowel disease; allergies such as eczema and rhinitis; hypersen ⁇ itivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic derma
  • the compounds of Formula I may suitably be used in the treatment of disorders of the central nervous system such as anxiety, psychosis, and schizophrenia; neurodegenerative disorders such as Alzheimer's disease and Down's syndrome; respiratory diseases such as bronchospasm and asthma; inflammatory diseases such as inflammatory bowel disease; adverse immunological disorders such as rejection of transplanted tissues; gastrointestinal disorders and diseases such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and irritable bowel syndrome; incontinence; disorders of blood flow caused by vasodilation; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions or the transmission of pain in migraine.
  • the results of several experiments demonstrate that many of the compounds of Formula I are selective tachykinin receptor antagonists. These compounds preferentially bind one tachykinin receptor subtype compared to other such receptors. Such compounds are especially preferred.
  • NK-1 antagonists are most especially preferred in the treatment of pain, especially chronic pain, such as neuropathic pain, post-operative pain, and migraines, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, opiod-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, post partum pain, angina pain, and genitourinary tract-related pain including cystitis.
  • chronic pain such as neuropathic pain, post-operative pain, and migraines, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, opiod-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, post partum pain, angina pain, and gen
  • NK-1 antagonists are especially preferred in the treatment and prevention of urinary incontinence; motility disorders of the gastrointestinal tract, such as irritable bowel syndrome; acute and chronic obstructive airway diseases, such as bronchospasm, bronchopneumonia, asthma, and adult respiratory distress syndrome; inflammatory conditions, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, neurogenic inflammation, allergies, rhinitis, cough, urticaria, conjunctivitis, irritation-induced miosis; tissue transplant rejection; plasma extravasation resulting from cytokine chemotherapy and the like; spinal cord trauma; stroke; cerebral stroke (ischemia); Alzheimer's disease;
  • Parkinson's disease multiple sclerosis; amyotrophic lateral sclerosis; schizophrenia; anxiety; and depression.
  • NK-2 antagonists are especially preferred in the treatment of urinary incontinence, bronchospasm, asthma, adult respiratory distress syndrome, motility disorders of the gastrointestinal tract, such as irritable bowel syndrome, and pain.
  • the compounds of Formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the present invention also includes pharmaceutical compositions which contain, as the active ingredient, the compounds of Formula I associated with pharmaceutically acceptable carriers.
  • the active ingredient is usually mixed with an excipient, diluted 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 diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid 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 mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending 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 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages 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 compound is effective over a wide dosage range.
  • dosages per day normally fall within the range of about 0.5 to about 30 g/kg of body weight. In the treatment of adult humans, the range of about 1 to about 15 mg/kg/day, in single or divided dose, is especially preferred.
  • the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound 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 limit the scope of the invention in any way.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while 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 smaller doses for administration throughout the day.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is dipsersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutiona, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compsoitions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • Quantity Ingredient (mg/capsule)
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • a dry powder inhaler formulation is prepared containing the following components:
  • the active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Tablets each containing 30 mg of active ingredient, are prepared as follows:
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone 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 follows:
  • Quantity Ingredient (mg/capsule)
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • 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 allowed to cool.
  • Suspensions each containing 50 mg of medicament per 5.0 ml dose are made as follows:
  • Purified water to 5.0 ml 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 microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted 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 follows:
  • Quantity Ingredient (mg/caosule)
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
  • An intravenous formulation may be prepared as follows:
  • a topical formulation may be prepared as follows:
  • Sublingual or buccal tablets each containing 10 mg of active ingredient, may be prepared as follows:
  • the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone 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 delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well 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 delivery of pharmaceutical agents.
  • Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier.
  • One such implantable delivery 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 refernce.
  • Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.

Abstract

La présente invention décrit une série de benzofurannes et d'indoles substitués utiles comme antagonistes non peptidiques des récepteurs des tachykinines. Elle décrit également des procédés pour traiter ou prévenir des états pathologiques associés à un excès de tachykinines. Ces procédés consistent à administrer un ou plusieurs des composés décrits ainsi que des formulations les mettant en ÷uvre.
PCT/US1994/014312 1993-12-21 1994-12-14 Antagonistes non peptidiques des recepteurs des tachykinines WO1995017382A1 (fr)

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EP95904891A EP0736007A4 (fr) 1993-12-21 1994-12-14 Antagonistes non peptidiques des recepteurs des tachykinines
AU13397/95A AU1339795A (en) 1993-12-21 1994-12-14 Non-peptide tachykinin receptor antagonists
JP7517478A JPH09506898A (ja) 1993-12-21 1994-12-14 非ペプチドタキキニン受容体アンタゴニスト

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US08/171,134 1993-12-21

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Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0668075A2 (fr) * 1993-12-21 1995-08-23 Eli Lilly And Company Antagonistes de récepteurs tachykiniques de nature non-peptidiques
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EP0709090A3 (fr) * 1994-10-14 1996-08-28 Lilly Co Eli Compositions pour le traitement de tumeurs résistantes
EP0735821A1 (fr) * 1993-12-21 1996-10-09 Eli Lilly And Company Procedes permettant de traiter ou de prevenir les pathologies associees aux peptides amylo dogenes
EP0816360A1 (fr) * 1996-07-02 1998-01-07 Eli Lilly And Company Composés de benzothiophène, intermédiaires, procédés et méthodes d'utilisation
JP2000507268A (ja) * 1996-03-26 2000-06-13 イーライ・リリー・アンド・カンパニー ベンゾチオフェン類、それを含む製剤、および方法
US6133262A (en) * 1998-10-28 2000-10-17 Eli Lilly And Company Antithrombotic agents
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WO2003051859A1 (fr) * 2001-12-19 2003-06-26 Amersham Plc Composes d'imagerie de la maladie d'alzheimer
US6962928B2 (en) 2001-05-22 2005-11-08 Eli Lilly And Company Tetrahydroquinoline derivatives for the inhibition of osteoporosis, estrogen dependent breast cancer, endometriosis and uterine fibrosis
US7056931B2 (en) 2001-05-22 2006-06-06 Eli Lilly And Company 2-substituted 1,2,3,4-tetrahydroquinolines and derivatives thereof, compositions and methods
WO2006123182A2 (fr) 2005-05-17 2006-11-23 Merck Sharp & Dohme Limited Sulfones de cyclohexyle pour le traitement du cancer
WO2007011820A2 (fr) 2005-07-15 2007-01-25 Amr Technology, Inc. Tetrahydrobenzazepines substituees par aryle et heteroaryle, et leur utilisation pour bloquer la reabsorption de la noradrenaline, de la dopamine, et de la serotonine
WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
WO2007093827A1 (fr) 2006-02-15 2007-08-23 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Dérivés de trifluoroéthanone substitués par thiophène et thiazole en tant qu'inhibiteurs d'histone désacétylase (hdac)
WO2008120653A1 (fr) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Dérivé d'indoledione
WO2009002495A1 (fr) 2007-06-27 2008-12-31 Merck & Co., Inc. Dérivés de 4-carboxybenzylamino utilisés en tant qu'inhibiteurs de l'histone désacétylase
WO2009111354A2 (fr) 2008-03-03 2009-09-11 Tiger Pharmatech Inhibiteurs de la tyrosine kinase
WO2010114780A1 (fr) 2009-04-01 2010-10-07 Merck Sharp & Dohme Corp. Inhibiteurs de l'activité akt
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US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US9085531B2 (en) 2004-07-15 2015-07-21 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9156812B2 (en) 2008-06-04 2015-10-13 Bristol-Myers Squibb Company Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
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US11096950B2 (en) 2006-11-01 2021-08-24 Barbara Brooke Jennings Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3413305A (en) * 1965-05-21 1968-11-26 Bristol Myers Co 2-phenyl-3[para(beta-pyrrolidino ethoxy)-phenyl]-6-methoxy benzo[b]thiophene
US3880891A (en) * 1973-09-21 1975-04-29 Smithkline Corp Substituted benzofurans
US3947470A (en) * 1974-06-20 1976-03-30 Smithkline Corporation Substituted benzofurans and benzothiophenes
US3975537A (en) * 1973-09-21 1976-08-17 Smith Kline Pharmaceutical compositions and methods of producing coronary vasodilation
US4133814A (en) * 1975-10-28 1979-01-09 Eli Lilly And Company 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents
US4230862A (en) * 1975-10-28 1980-10-28 Eli Lilly And Company Antifertility compounds
US4418068A (en) * 1981-04-03 1983-11-29 Eli Lilly And Company Antiestrogenic and antiandrugenic benzothiophenes

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4024273A (en) * 1974-06-20 1977-05-17 Smithkline Corporation Coronary vasodilator and anti-anginal compositions comprising substituted benzofurans and benzothiophenes and methods of producing coronary vasodilation and anti-anginal activity

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3413305A (en) * 1965-05-21 1968-11-26 Bristol Myers Co 2-phenyl-3[para(beta-pyrrolidino ethoxy)-phenyl]-6-methoxy benzo[b]thiophene
US3880891A (en) * 1973-09-21 1975-04-29 Smithkline Corp Substituted benzofurans
US3975537A (en) * 1973-09-21 1976-08-17 Smith Kline Pharmaceutical compositions and methods of producing coronary vasodilation
US3947470A (en) * 1974-06-20 1976-03-30 Smithkline Corporation Substituted benzofurans and benzothiophenes
US4133814A (en) * 1975-10-28 1979-01-09 Eli Lilly And Company 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents
US4230862A (en) * 1975-10-28 1980-10-28 Eli Lilly And Company Antifertility compounds
US4418068A (en) * 1981-04-03 1983-11-29 Eli Lilly And Company Antiestrogenic and antiandrugenic benzothiophenes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF NANJING COLLEGE OF PHARMACY, Volume 17, No. 3, issued September 1986, HUANG, WENLONG et al., "Non-Steroidal Contraceptive Agents. (V). Synthesis of 3-Substituted Aminoalkoxybenzoyulindole Derivatives", pages 225-227. *
See also references of EP0736007A4 *

Cited By (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0668075A2 (fr) * 1993-12-21 1995-08-23 Eli Lilly And Company Antagonistes de récepteurs tachykiniques de nature non-peptidiques
EP0735821A1 (fr) * 1993-12-21 1996-10-09 Eli Lilly And Company Procedes permettant de traiter ou de prevenir les pathologies associees aux peptides amylo dogenes
EP0668075A3 (fr) * 1993-12-21 1996-10-16 Lilly Co Eli Antagonistes de récepteurs tachykiniques de nature non-peptidiques.
EP0735821A4 (fr) * 1993-12-21 1998-04-01 Lilly Co Eli Procedes permettant de traiter ou de prevenir les pathologies associees aux peptides amylo dogenes
EP0820769A2 (fr) * 1994-10-14 1998-01-28 Eli Lilly And Company Utilistaion de benzotiophénes pour la fabrication d'un médicament pour le traitement de maladies associées à un exés de tachykinines
US6124311A (en) * 1994-10-14 2000-09-26 Eli Lilly And Company Methods for treating resistant tumors
EP0820769A3 (fr) * 1994-10-14 1998-08-19 Eli Lilly And Company Utilistaion de benzotiophénes pour la fabrication d'un médicament pour le traitement de maladies associées à un exés de tachykinines
EP0709090A3 (fr) * 1994-10-14 1996-08-28 Lilly Co Eli Compositions pour le traitement de tumeurs résistantes
EP0895781A2 (fr) * 1994-10-20 1999-02-10 Eli Lilly And Company Utilisation de benzofuranes, benzothiophénes ou d'indoles pour la fabrication d'un médicament pour le tratement de consitions provoquèes par un excés de tachykinines
EP0716854A3 (fr) * 1994-10-20 1996-08-28 Lilly Co Eli Compositions pour inhiber le récepteur de la neuropeptide Y
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EP0895781A3 (fr) * 1994-10-20 1999-07-07 Eli Lilly And Company Utilisation de benzofuranes, benzothiophénes ou d'indoles pour la fabrication d'un médicament pour le tratement de consitions provoquèes par un excés de tachykinines
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JP2009019057A (ja) * 1996-03-26 2009-01-29 Eli Lilly & Co ベンゾチオフェン類、それを含む製剤、および方法
JP2000507268A (ja) * 1996-03-26 2000-06-13 イーライ・リリー・アンド・カンパニー ベンゾチオフェン類、それを含む製剤、および方法
US8030330B2 (en) 1996-03-26 2011-10-04 Eli Lilly And Company Benzothiophenes, formulations containing same, and methods
US6432983B1 (en) 1996-07-02 2002-08-13 Eli Lilly And Company Benzothiophene compounds intermediates processes and methods of use
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US6133262A (en) * 1998-10-28 2000-10-17 Eli Lilly And Company Antithrombotic agents
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US7173061B2 (en) 2001-12-19 2007-02-06 Ge Healthcare Limited Compounds for imaging alzheimer's disease
WO2003051859A1 (fr) * 2001-12-19 2003-06-26 Amersham Plc Composes d'imagerie de la maladie d'alzheimer
US9085531B2 (en) 2004-07-15 2015-07-21 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
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WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
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WO2008120653A1 (fr) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Dérivé d'indoledione
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WO2009002495A1 (fr) 2007-06-27 2008-12-31 Merck & Co., Inc. Dérivés de 4-carboxybenzylamino utilisés en tant qu'inhibiteurs de l'histone désacétylase
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WO2013063214A1 (fr) 2011-10-27 2013-05-02 Merck Sharp & Dohme Corp. Nouveaux composés qui sont des inhibiteurs d'erk
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AU1339795A (en) 1995-07-10
CA2176130A1 (fr) 1995-06-29
JPH09506898A (ja) 1997-07-08
ZA9410040B (en) 1996-06-18
MXPA99001870A (es) 2004-09-06
EP0736007A1 (fr) 1996-10-09
EP0736007A4 (fr) 1997-03-19

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