Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D223/16—Benzazepines; Hydrogenated benzazepines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to novel substituted hexahydroazepinones and tetrahydrobenzazepinones, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment and prevention of central nervous system and gastrointestinal disorders.
• the pharmaceutically active compounds of this invention are selective CCK-B receptor antagonists.
• CCK Cholecystokinin
• Clarke-Davis' CI-988 is a selective CCK-B antagonist that was found to reverse the pentagastrin-induced anxiogenic response in rats. (See Singh et al., Proc. Nat'l. Acad. Sci.. U.S., 88, 1130-33 (1991)).
• the present invention relates to compounds of the formula
• Y 1 and Y 2 are independently selected from the group consisting of phenyl, thienyl, pyridyl, furyl, pyrimidyl, (C 3 -C 8 ) straight or branched alkyl and (C 5 -C 8 ) cycloalkyl, wherein said phenyl, thienyl, pyridyl, furyl, and pyrimidyl may optionally substituted with one or two substituents independently selected from halo (e.g., chloro, fiuoro, bromo or iodo), (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, nitro, amino and trifluoromethyl, and wherein said cycloalkyl may optionally be substituted with one or two substituents independently selected from (C 1 -C 6 ) alkyl;
• halo e.g., chloro, fiuoro, bromo or iod
• Z 1 and Z 2 are independently selected from the group consisting of halo, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) thioalkyl, (C 1 -C 6 ) alkoxy, trifluoromethyl, (C 1 -C 6 ) carboalkoxy, amino and nitro;
• R 1 is phenyl, CO 2 R 2 , SO 2 NR 3 R 8 or CONR 4 R 5 , wherein said phenyl may optionally be substituted with one or two substituents independently selected from halo, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, nitro, amino and trifluoromethyl, and wherein R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, (C 3 -C 12 ) alkyl and fused, saturated carbocyclic systems containing two or three rings.
• the present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formulae I and II.
• the acids which are used to preparethe pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate,saccharate,benzoate,methanesulfonate,ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1 ,1 '-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
• alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
• halo as used herein, unless otherwise indicated, includes chloro, fiuoro, bromo and iodo.
• Preferred compounds of this invention are compounds of the formula I wherein either both of Y 1 and Y 2 are phenyl, or one of Y 1 and Y 2 is cyclohexyl.
• Preferred compounds of the present invention include the following:
• Examples of other compounds of the present invention include:
• This invention also relates to compounds of the formula
• R 7 is hydrogen or one of the radicals set forth in the definition of R 1 above, R 8 is bromine, amino or azido and Y 1 is defined as above.
• the present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from the group consisting of pain, gastrointestinal disorders such as ulcer and colitis, and central nervous system disorders such as anxiety and panic disorder in a mammal, including a human, comprising an amount of a compound of the formula I or II, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such condition, and a pharmaceutically acceptable carrier.
• a condition selected from the group consisting of pain, gastrointestinal disorders such as ulcer and colitis, and central nervous system disorders such as anxiety and panic disorder in a mammal, including a human, comprising an amount of a compound of the formula I or II, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such condition, and a pharmaceutically acceptable carrier.
• the present invention also relates to a method of treating or preventing a condition selected from the group consisting of pain, gastrointestinal disorders such as ulcer and colitis, and central nervous system disorders such as anxiety and panic disorder in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I or II, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such condition.
• the present invention also relates to a pharmaceutical composition for antagonizing the effects of cholecystokinin in a mammal, including a human, comprising a cholecystokinin antagonizing amount of a compound of the formula I or II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the present invention also relates to a method of antagonizing the effects of cholecystokinin in a mammal, including a human, comprising administering to said mammal a cholecystokinin antagonizing amount of a compound of the formula I or II, or a pharmaceutically acceptable salt thereof.
• the present invention also relates to a pharmaceutical composition for treating or preventing a cholecystokinin mediated disorder in a mammal, including a human, comprising a cholecystokinin antagonizing amount of a compound of the formula I or II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the present invention also relates to a method of treating or preventing a cholecystokinin medicated disorder in a mammal, including a human, comprising administering to said mammal a cholecystokinin antagonizing amount of a compound of the formula I or II, or a pharmaceutically acceptable salt thereof.
• the present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from the group consisting of pain, gastrointestinal disorders such as ulcer and colitis, and central nervous system disorders such as anxiety and panic disorder in a mammal, including a human, comprising an amount of a compound of the formula I or II, or a pharmaceutically acceptable salt thereof, effective in antagonizing the effect of cholecystokinin at its receptor site, and a pharmaceutically acceptable carrier.
• the present invention also relates to a method of treating or preventing a condition selected from the group consisting of pain, gastrointestinal disorders such as ulcer and colitis, and central nervous system disorders such as anxiety and panic disorder in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I or II, or a pharmaceutically acceptable salt thereof, effective in antagonizing the effect of cholecystokinin at its receptor site.
• the compounds of the formulae I and II have chiral centers and therefore exist in different enantiomeric and diastereomic forms.
• This invention relates to all optical isomers and all stereoisomers of compounds of the formulae I and II, and mixtures thereof.
• Formula I and formula II above include compounds identical to those depicted but for the fact that one or more hydrogen or carbon atoms are replaced by isotopes thereof. Such compounds are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
• a compound of the formula III is reacted with hydroxylamine hydrochloride in methanol in the presence of sodium bicarbonate or triethylamine, to form a compound of the formula IV.
• This reaction is generally carried out at a temperature from about room temperature to about the reflux temperature of the reaction mixture.
• the compound of formula IV so formed is then converted to a compound of the formula V by reacting it with tosyl chloride in pyridine at about 0°C for about 24 hours.
• compounds of the formula III may be converted directly into the corresponding compounds having formula V in a one step procedure.
• a compound of the formula III is reacted with NH 2 OSO 3 H (hydroxylamine -O- sulfonic acid) in formic acid at about the reflux temperature of the reaction mixture.
• This one step procedure is preferred over the two step procedure described above for all compounds of the formula IV except those wherein Y 1 is phenyl and adjacent to the oxo group.
• Bromination of the compound of formula V yields the corresponding compound having formula VI.
• the bromination is typically carried out by first adding a compound of the formula V to a mixture of phosphorus pentachioride and pyridine in methylene chloride at about 0°C. Then, phenyltrimethylammonium bromide tribromide is added to the reaction mixture, also at a temperature of about 0°C.
• the second step which involves the addition of the brominating agent, may be replaced by a procedure in which bromine is added at a temperature of about 0°C and allowed to react for a period of about 0.5 hours to about 5 hours, preferably about 2 hours, resulting in dibromination of the saturated nitrogen containing seven rriembered ring.
• One of the bromine atoms is then selectively removed by treatment with hydrogen gas in the presence of palladium which has been poisoned with quinoline.
• the brominated compound of formula VI is then alkylated at the ring nitrogen by reaction with a compound of the formula XCH 2 R 1 , wherein X is bromine when R 1 is phenyl and X is iodine for all other R 1 , in tetrahydrofuran (THF) in the presence of sodium hydride.
• This reaction which yields the corresponding compound of formula VII, is usually conducted at a temperature from about room temperature to about 150°C. It is preferably conducted at the reflux temperature of the reaction mixture.
• the compound of formula VII formed in the above step is then reacted with an alkali metal azide to produce a compound of the formula VIII.
• the preferred reactant is sodium azide.
• this reaction is carried out in a reaction inert solvent such as dimethylformamide (DMF) or dimethylsulfoxide (DMSO), preferably DMF, at a temperature from about 60°C to about 100°C, preferably about 80°C.
• Reduction of the azide of formula VIII yields the corresponding amine of formula IX.
• the reduction is typically accomplished using hydrogen gas at a pressure of from about 1 to about 3 atmospheres in the presence of palladium on carbon (Pd/C).
• Suitable reaction inert solvents include halogenated hydrocarbons and (C 1 -C 6 ) alkanols. Ethanol is the preferred solvent.
• the reaction temperature may range from about 15°C to about 70 °C, with about room temperature being preferred.
• the reduction may be accomplished using a trialkyl or triaryl phosphine.
• appropriate reactants are triphenylphosphine and tributylphosphine.
• This reaction is generally conducted in a reaction inert solvent such as THF or another ethereal water miscible solvent in the presence of water, at a temperature from about room temperature to about 100°C. Preferably, it is conducted in THF at about room temperature.
• reaction inert solvents for this reaction include hydrocarbons such as hexane, benzene and toluene, halogenated hydrocarbons such as methylene chloride and 1 ,2-dichloroethane, ethereal solvents such as ethyl ether, THF and glyme, and pyridine.
• the preferred solvent is 1 , 2-dichloroethane or methylene chloride.
• Tertiary organic amines may be useful as catalysts.
• the reaction temperature may range from about 0°C to about 150°C. The reflux temperature is preferred.
• the isocyanate of the formula C 6 H 4 Z 1 Z 2 NCO used in the foregoing reaction can be formed by procedures well known to those skilled in the art.
• One such method involves mixing a benzoic acid derivative with diphenylphosphorylazide, or an analagous reagent, in the presence of an organic base such as a trialkylamine, preferably triethylamine or diisopropylethyiamine.
• This reaction is usually conducted in an ethereal, hydrocarbon or chlorinated hydrocarbon solvent, preferably tetrahydrofuran or benzene, at a temperature from about room temperature to about 100°C, preferably at the reflux temperature of the solvent, for a period from about 20 minutes to about 24 hours, preferably about 1 hour.
• hydrolysis of a compound of the formula IA wherein R 1 is CO 2 R 2 yields the corresponding acid of formula IB.
• the hydrolysis is typically carried out using trifluoroacetic acid in a reaction inert solvent as hexane, an ethereal solvent (e.g., ethyl ether or THF) or a halogenated hydrocarbon solvent (e.g., methylene chloride or 1 , 2-dichloroethane), at a temperature from about - 78°C to about 50°C. It is preferably carried out using trifluoroacetic acid in a halogenated hydrocarbon cosolvent at about 0°C.
• a reaction inert solvent as hexane
• an ethereal solvent e.g., ethyl ether or THF
• a halogenated hydrocarbon solvent e.g., methylene chloride or 1 , 2-dichloroethane
• the acid of formula IB may be converted into the corresponding amide of formula IA, wherein R 1 is CONR 4 R 5 , by reacting the acid with an amine of the formula NHR 4 R 5 in the presence of a dehydrating agent.
• the dehydrating agent is preferably a carbodiimide.
• Other dehydrating agents that may be used are 1 ,1 '-carbonyldiimidazole and isobutylchloroformate/N-methylmorpholine.
• This reaction is generally conducted in a reaction inert solvent selected from hydrocarbons such as benzene, toluene and hexane, halogenated hydrocarbons such as methylene chloride and 1 ,2-dichloroethane, ethereal solvents such as ethyl ether, THF and glyme, and pyridine, preferably THF, at a temperature from about 0°C to about 120°C, preferably at about room temperature.
• a reaction inert solvent selected from hydrocarbons such as benzene, toluene and hexane, halogenated hydrocarbons such as methylene chloride and 1 ,2-dichloroethane, ethereal solvents such as ethyl ether, THF and glyme, and pyridine, preferably THF, at a temperature from about 0°C to about 120°C, preferably at about room temperature.
• Scheme 3 illustrates the preparation of compounds of the formula II wherein R 1 is CO 2 R 2 , C 6 H 5 , CONR 4 R 5 or SO 2 NR 3 R 6 (hereinafter referred to as compounds of the formula IIA).
• a compound of the formula X is converted into the corresponding compound of formula XII by the following two step procedure.
• the compound of formula X is converted into an oxime by the method described above and illustrated in scheme 1 for forming compounds of the formula IV from compounds of the formula III.
• rearrangement of the oxime to form the lactam having formula XI is accomplished by reacting the oxime with polyphosphoric acid. This reaction may be carried out at temperatures ranging from about room temperature to about 200° C. Preferably, the reaction mixture is heated to about 160°C.
• the resulting compound of formula XI is then brominated to form a compound of the formula XII by first reacting it with phosphorous pentachloride and pyridine, and then adding bromine.
• the reaction with phosphorus pentachloride and pyridine is conducted as described above for the first step in the bromination of compounds of the formula V.
• the reaction with bromine, which results in monobromination, is carried out at a temperature from about -78 °C about 0°C, preferably at about -40°C.
• Alkylation of the compound of formula XII yields the corresponding compound of formula XI ll.
• the alkylation is earned out by reacting the compound of formula XII with a compound of the formula XCH 2 R 1 , wherein X is bromine when R 1 is phenyl and X is iodine for all other R 1 , in THF/DMSO in the presence of lithium dialkylamide. It is preferable to add the DMSO cosolvent after adding the lithium dialkylamide.
• the reaction temperature may range from about -78 °C to about 0°C during addition of the base, and is preferably about -78°C.
• the reaction is slowly warmed to a temperature from about -20°C to about 50°C when the DMSO is added.
• the reaction is warmed to about room temperature during addition of DMSO.
• pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 5 atmospheres are generally acceptable, and ambient pressure, i.e. about 1 atmosphere, is preferred as a matter of convenience.
• the compounds of the formulae I and II which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I or II from the reaction mixture as a pharmaceutically Unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
• the acid addition salts of the active base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
• the active compounds of this invention and their pharmaceutically acceptable salts are useful as selective CCK-B receptor antagonists, i.e., they possess the ability to antagonize the effects of CCK at its B receptor site in mammals, and therefore they are able to function as therapeutic agents in the treatment of the aforementioned disorders and diseases in an afflicted mammal.
• the active compounds of this invention and their pharmaceutically acceptable salts can be administered via either the oral, parenteral or topical routes.
• these compounds are most desirably administered in dosages ranging from about 5.0 mg up to about 1500 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen.
• a dosage level that is in the range of about 0.07 mg to about 21 mg per kg of body weight per day is most desirably employed. Variations may nevertheless occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
• 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 small doses for administration throughout the day.
• the active compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the three routes previously indicated, and such administration may be carried out in single or multiple doses.
• the novel therapeutic agents of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
• Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
• oral pharmaceutical compositions can be suitably sweetened and/or flavored.
• the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
• tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably com, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
• disintegrants such as starch (and preferably com, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
• granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
• -lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
• compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
• the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
• solutions of an active compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
• aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes.
• the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
• the activity of the compounds of the present invention as CCK-B antagonists may be determined by an assay that measures their ability to inhibit the binding of 125-l-BH-CCK-8 to the CCK-B receptor in a guinea pig cortical membrane preparation. This procedure is carried out as follows.
• the cortex is dissected from one male Hartley Guinea pig and homogenized (15 strokes) with a teflon homogenizer in 20 volumes (w./v.) of the assay buffer, which consists of 50 mM Tris (i.e., trimethamine, which is 2-amino-2-hydroxymethyl-1 ,3-propanediol) hydrochloric acid having pH 7.4 and 5 mM of manganese chloride at 4°C.
• Tris i.e., trimethamine, which is 2-amino-2-hydroxymethyl-1 ,3-propanediol
• the homogenate is centrifuged at 4°C for 30 minutes at 100,000 ⁇ G.
• the pellet is resuspended in the same buffer and spun as described above.
• the final pellet is diluted to a concentration of 20 mg/ml with the assay buffer for use in the binding assay.
• the tissue is kept on ice at all times.
• An incubation mixture is prepared, which consists of 50uL of the tissue preparation, prepared as described above, 100uL 125-I-BH-CCK-8 (to give a concentration of 50 pM in the final assay), 20uL of a blank or the compound being tested, and 30uL of Tris with 4% DMSO. All drugs and dilutions are made using 4% DMSO in the assay buffer yielding a final assay DMSO concentration of 1%.
• the reaction is initiated with the addition of tissue to a 96-well plate containing 125-I-BH-CCK-8 and the appropriate blank or compound being tested. Non-specific binding is estimated using 1uM sulphated CCK-8.
• the reaction is terminated by spinning the plates in a H1000B rotor fitted on a Sorvall RT6000 refrigerated centrifuge at 4°C. The supernatant is discarded, and the pellets washed with 200uL of assay buffer, and the plate is spun as above.
• the supernatant is decanted again, and the pellet is harvested onto Betaplate filters (which have been soaked in 0.2% polyethyleneimine for a minimum of 2 hours) using a Skatron cell harvester at setting 222 using Tris HCl pH 7.4 as the wash buffer.
• the filtermats are counted on a Betaplate counter for 45 seconds per sample.
• IC 50 values the concentration which inhibits 50% of the specific binding of 125-I-BH-CCK-8.
• the data is analyzed using non-linear regression analysis.
• the diastereomeric bromides may be separated by chromatography or crystallized from ether and hexane; however, the mixture was used directly in the next step (B).
• the solid obtained by crystallization was predominately the more polar isomer while the mother liquor contained more of the less polar isomer as well as traces of the iminochloride and starting material. Recrystallization of the more polar diastereomer from chloroform gave large crystals, mp 191-192°C:
• Example 2 The title compounds of Examples 2 through 10 were prepared using a procedure analogous to that of Example 1.
• step D 3-Amino-7-phenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one
• the azide from step D above (6. 1.0 g, 2.91 mmol) was treated under 45 lb/in 2 hydrogen in the presence of 200 mg 10% palladium-on-carbon in 30 ml ethanol for 4.6 hours.
• the reaction was filtered through Celite ® and evaporated to leave an oil, which was used directly in the following step.
• FAB MS (%): 533/535 (parent+1 , CI 35 /CI 37 , 37/15), 460/462 (81/31), 380 (33), 307 (61), 251 (61), 234 (100), 222 (62), 208 (99), 91 (51).
• Example 25C Prepared from the title compound of Example 25C as in Example 25D, M.P. 184- 186°C, 58% yield.
• FAB MS (%): 533/535 (parent, CI 35 /CI 37 , 100/39), 460 (74), 400 (56), 327 (72), 119 (68), 107 (72), 91 (67).
• FAB MS (%): 553/554/555/556/557/558 (parent, CI 35 /CI 37 , 75/32/54/19/10), 400 (100), 327 (82), 254 (83), 228 (73).
• FAB MS (%): 536 (parent, 5.5), 340 (76), 267 (65), 239 (100), 212 (76), 127 (71 ).
• Example 31 Prepared as in Example 31 above from the title compound of Example 40Afrom the known 4-(4-methylphenyl)-1 ,2,3,4-tetrahydronaphth-1-one (see Koptyug, V.A. and Andreeva, T.P., Zh. Organich. Khim., 7, 2398-2403 (1971)) in 94% yield, M.P. 97-101 °C (from ethyl acetate/hexane).
• FAB MS (%): 566/568 (parent, CI 35 CI 37 , 4/2), 390 (25), 289/291 (42/40), 261 (50), 188 (60), 133 (100), 57 (65).

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• 1992
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