Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/32—Alcohol-abuse

Definitions

• the early generations of serotonin-affecting drugs tended to have a variety of different physiological functions, considered from both the mechanistic and therapeutic points of view.
• many of the tricyclic antidepressant drugs are now known to be active as inhibitors of serotonin reuptake, and also to have anticholinergic, antihistaminic or anti- ⁇ -adrenergic activity.
• the present invention provides compounds which have highly selective activity as antagonists and partial agonists of the serotonin 1A receptor and a second activity as inhibitors of reuptake of serotonin.
• A is hydrogen, OH or (Ci-C- ⁇ ) alkoxy:
• B is selected from the group consisting of:
• X is hydrogen, OH or C ⁇ -C 6 alkoxy when represents a single bond in the tropane ring, and X is nothing when represents a double bond in the tropane ring;
• Y is CH 2 , NH or S;
• R 2 is hydrogen, F, Cl, Br, I, OH, C C 6 alkyl or d-Ce alkoxy;
• R 5 is hydrogen, F, Cl, Br, I, OH, C C 6 alkyl or (C C ⁇ alkyl)NR 6 R 7 ;
• R 6 and R 7 are each independently hydrogen or C C ⁇ o alkyl; and p is 0, 1 , 2, 3 or 4; and q is 0, 1 , 2 or 3; or a pharmaceutically acceptable salt thereof.
• the present invention further provides a method of inhibiting the reuptake of serotonin and antagonizing the 5-HTIA receptor which comprises administering to a patient an effective amount of a compound of formula I.
• the present invention provides a method for alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine; a method of treating anxiety; and a method of treating a condition chosen from the group consisting of depression, hypertension, cognitive disorders, Alzheimer's disease, psychosis, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, eating disorders and obesity, substance abuse, obsessive-compulsive disease, panic disorder, and migraine; which methods comprise administering to a patient an effective amount of a compound of formula I.
• the present invention provides a method of potentiating the action of a serotonin reuptake inhibitor comprising administering to a patient an effective amount of a compound of formula I in combination with an effective amount of a serotonin reuptake inhibitor.
• the invention provides pharmaceutical compositions of compounds of formula I, including the hydrates thereof, comprising, as an active ingredient, a compound of formula I in combination with a pharmaceutically acceptable carrier, diluent or excipient. This invention also encompasses novel intermediates, and processes for the synthesis of the compounds of formula I.
• the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof as defined hereinabove for the manufacture of a medicament for inhibiting the reuptake of serotonin and antagonizing the 5-HTIA receptor.
• the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof as defined hereinabove for inhibiting the reuptake of serotonin and antagonizing the
• compounds of the present invention can be inhibitors of serotonin reuptake, dopamine reuptake, and norepinephrine reuptake.
• the terms “Me”, “Et”, “Pr”, “iPr”, “Bu” and “t-Bu” refer to methyl, ethyl, propyl, isopropyl, butyl and tert-butyl respectively.
• the terms “Halo”, “Halide” or “Hal” refer to a chlorine, bromine, iodine or fluorine atom, unless otherwise specified herein.
• C 1 -C 4 alkyl refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
• C-i-Ce alkyl refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.
• C 1 -C- 10 alkyl refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 10 carbon atoms and includes, but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2- methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like.
• C- ⁇ -C 2 o alkyl refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 20 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methyl pentyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n- heptadecyl, n-nonadecyl, n-eicosyl and the like.
• halo(C ⁇ -C 6 )alkyl refers to a straight or branched alkyl chain having from one to six carbon atoms with 1 , 2 or 3 halogen atoms attached to it.
• Typical halo(CrC 6 )alkyl groups include chloromethyl, 2- bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like.
• halo(C ⁇ -C 6 )alkyl includes within its definition the term "halo(C ⁇ -C 4 )alkyl".
• C ⁇ -C 6 alkoxy refers to a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical C ⁇ -C 6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like.
• C ⁇ -C 6 alkoxy includes within its definition the term “C1-C4 alkoxy”.
• the designation " — “ ⁇ ” refers to a bond that protrudes forward out of the plane of the page.
• the designation " ••» ⁇ • 1111 ⁇ refers to a bond that protrudes backward out of the plane of the page.
• This invention includes the hydrates and the pharmaceutically acceptable salts of the compounds of formula I.
• a compound of this invention can possess a sufficiently basic functional group which can react with any of a number of inorganic and organic acids, to form a pharmaceutically acceptable salt.
• pharmaceutically acceptable salt refers to salts of the compounds of formula I which are substantially non-toxic to living organisms.
• Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid. Such salts are also known as acid addition salts.
• Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2-19 (1977) which are known to the skilled artisan.
• Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
• inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
• organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and
• salts examples include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprate, caprylate, acrylate, ascorbate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, propionate, phenylpropionate, salicylate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, mandelate, nicotinate, isonicotinate, cinnamate, hippurate, nitrate, phthalate, teraphthalate, butyne-1 ,4- dioate, butyne-1 ,4- dioate
• Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid, oxalic acid and methanesulfonic acid. It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that such salts may exist as a hydrate.
• the term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three- dimensional structures which are not interchangeable.
• enantiomer refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
• chiral center refers to a carbon atom to which four different groups are attached.
• diastereomers refers to stereoisomers which are not enantiomers.
• epimers two diastereomers which have a different configuration at only one chiral center are referred to herein as “epimers”.
• racemate racemic mixture
• racemic modification refer to a mixture of equal parts of enantiomers.
• enantiomeric enrichment refers to the increase in the amount of one enantiomer as compared to the other.
• a convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee”, which is found using the following equation:
• E 1 is the amount of the first enantiomer and E 2 is the amount of the second enantiomer.
• the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved
• the ee with respect to the first enantiomer is 25%.
• the final ratio is 90:10
• the ee with respect to the first enantiomer is 80%.
• An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred.
• Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art.
• the enantiomers of compounds of formulas I or la can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981.
• Some of the compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.
• R and S are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
• the term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
• the term “S” (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
• the priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice", (J.H.
• the specific stereoisomers and enantiomers can be prepared by stereospecific syntheses using enantiomerically and geometrically pure, or enantiomerically or geometrically enriched starting materials.
• the specific stereoisomers and enantiomers can be resolved and recovered by techniques such as chromatography on chiral stationary phases, enzymatic resolution or fractional recrystallization of addition salts formed by reagents used for that purpose.
• SRI serotonin reuptake inhibitor
• Pg refers to a protecting group on the amine which is commonly employed to block or protect the amine while reacting other functional groups on the compound. Examples of protecting groups (Pg) used to protect the amino group and their preparation are disclosed by T. W. Greene,
• Protected Groups in Organic Synthesis John Wiley & Sons, 1981 , pages 218- 287. Choice of the protecting group used will depend upon the substituent to be protected and the conditions that will be employed in subsequent reaction steps wherein protection is required, and is well within the knowledge of one of ordinary skill in the art. Preferred protecting groups are f-butoxycarbonyl also known as a BOC protecting group, and benzyloxycarbonyl also known as the Cbz protecting group.
• the compounds of formula I can be prepared by techniques and procedures readily available to one of ordinary skill in the art. For example, various starting materials and general procedures which may be employed by one of ordinary skill in the art in the preparation of compounds of formula I are described in U.S. Patent No. 3,929,793, issued December 30, 1975, U.S. Patent No. 4,304,915, issued December 8, 1981 , U.S. Patent No. 4,288,442, issued September 8, 1981 , U.S. Patent No. 4,361 ,562, issued November 30, 1982, U.S. Patent No. 4,460,586, issued July 17, 1984, U.S. Patent No. 4,704,390, issued November 3, 1987, U.S. Patent No. 4,935,414, issued June 19, 1990, U.S. Patent No.
• step A compound (1) is added to tropinone (2) under conditions well known in the art, to provide the alcohols (3a) and (3b).
• an appropriately substituted naphthalene such as 2- bromonaphthalene, 1 -bromo-5-methoxy-naphthalene, 2-bromo-7-methoxy- naphthalene, 6-iodo-1-methoxy-naphthalene, and the like, is dissolved in a suitable organic solvent, such as tetrahydrofuran and cooled to about -78 °C.
• a suitable organic solvent such as tetrahydrofuran
• a suitable base such as t- butyllithium.
• the mixture is stirred for about 1 to 3 hours, and about 1.0 to 1.1 equivalents of the tropinone (2) are added.
• the reaction is allowed to warm to room temperature and the alcohols (3a) and (3b) are isolated and purified by techniques well known in the art.
• the mixture is diluted with water and extracted with a suitable organic solvent, such as ethyl acetate.
• a suitable organic solvent such as ethyl acetate.
• the organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
• the crude alcohol can then be purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexanes to provide the purified alcohols (3a) and (3b) as a mixture.
• the alcohols (3a) and (3b) can be separated from each other using standard techniques, such as flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexanes.
• a suitable eluent such as ethyl acetate/hexanes.
• the crude isolated alcohol mixture of (3a) and (3b) can be carried directly onto the next step.
• step B the alcohols (3a) and (3b), either separately or as a mixture, are dehydrated under standard conditions to provide the olefinic isomers (4a) and (4b) wherein Pg' is maintained as a protecting group and does not represent hydrogen.
• the alcohols (3a) and (3b) are dissolved in a suitable organic solvent, such as toluene, and treated with an excess of a suitable acid, such a p-toluenesulfonic acid monohydrate.
• a suitable organic solvent such as toluene
• a suitable acid such as a p-toluenesulfonic acid monohydrate.
• the reaction mixture is heated at reflux for about 6 to 12 hours and then cooled.
• the isomers (4a) and (4b) are then isolated and purified under conditions well known in the art.
• the cooled reaction mixture is basified with 2 N sodium hydroxide and extracted with a suitable organic solvent, such as ethyl acetate.
• a suitable organic solvent such as ethyl acetate.
• the organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
• the crude residue is then purified by flash chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride to provide the purified olefinic isomers (4a) and (4b).
• step B the alcohols (3a) and (3b), either separately or as a mixture, can be dehydrated and deprotected concomitantly under standard conditions to provide the olefinic isomers (4a) and (4b) wherein Pg' is hydrogen.
• alcohols (3a) and (3b), wherein the protecting group is ⁇ /-£-butoxycarbonyl is dissolved in a suitable organic solvent, such as dry dichloromethane, and the solution is cooled to about 0 °C . To this solution is added excess trifluoroacetic acid and the reaction mixture is stirred at about 0 °C for about 15 hours. The reaction is then quenched at room temperature with saturated aqueous NaHC0 3 solution.
• the product is then isolated by techniques well known in the art, such as extraction and then purified by flash chromatography.
• the mixture is extracted with a suitable organic solvent, such as dichloromethane, the combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the crude olefinic isomers (4a) and (4b).
• This material can be purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexanes.
• step C the olefinic isomers (4a) and (4b) are hydrogenated under conditions well known in the art to provide a mixture of isomers (5a) and (5b).
• the olefinic isomers (4a) and (4b) are dissolved in a suitable organic solvent, such as ethanol and treated with a suitable catalyst, such as 5% palladium on carbon.
• a suitable organic solvent such as ethanol
• a suitable catalyst such as 5% palladium on carbon
• step D wherein Pg' is a protecting group and not hydrogen, the isomers (5a) and (5b) are deprotected under conditions well known to one of ordinary skill in the art to provide piperidines (6a) and (6b).
• the isomers (5a) and (5b) are dissolved in a suitable organic solvent, such as dichloroethane and cooled to about 0 °C.
• a suitable organic solvent such as dichloroethane
• the cooled solution is then treated with an excess of 1 -chloroethylchloroformate.
• the reaction is then allowed to warm to room temperature and then heated at reflux for about 12 hours.
• the solvent is removed under vacuum and the residue is dissolved in a suitable organic solvent, such as methanol.
• the solution is then heated at reflux for about 2 to 4 hours, cooled to room temperature, and concentrated under vacuum.
• the residue is treated with water and a suitable organic solvent, such as ethyl acetate.
• the phases are separated and the aqueous phase is extracted with ethyl acetate.
• the organic extracts, including the first organic phase, are combined, rinsed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude isomers (6a) and (6b).
• the mixture can then be separated into purified individual stereoisomers if they were not already separated in step C using similar techniques, such as flash chromatography, radial chromatography or high performance chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride.
• step C When the protected compounds (4a) and (4b) are hydrogenated in step C and then deprotected according to step D, the exo product is favored over the endo product. However, when the protected compounds (4a) and (4b) are first deprotected following the procedure in step D above, and then hydrogenated according to step C, the endo product is favored over the exo product. It is readily appreciated by one of ordinary skill in the art that the sequence of steps of dehydration, deprotection, and reduction can be varied depending upon the protecting groups utilized and the ultimate products desired. The conditions required for varying the sequence are well within the knowledge of one of ordinary skill in the art. Scheme IA
• R' C,-C 6 alkyl
• alcohols (3a") and (3b") are alkylated under standard conditions to provide the ethers (7a) and (7b).
• alcohols (3a") and (3b") either separately or as a mixture, wherein the protecting group is N-t- butoxycarbonyl, are dissolved in a suitable organic solvent, such as dry MeOH, and the solution is cooled to about 0 °C. To this solution is added excess trifluoroacetic acid. The reaction mixture is then stirred at room temperature for about one to 6 days.
• the reaction is then quenched at room temperature with saturated aqueous NaHC0 3 solution, extracted with a suitable organic solvent such as dichloromethane, the combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the crude ethers (7a) and (7b).
• the crude ethers can then be purified by flash chromatography on silica gel with a suitable eluent, such as 7% (10% cone. NH 4 OH in MeOH)/CH 2 CI 2 .
• alcohols (3a") and (3b") can be deprotected without dehydration under standard conditions well known in the art, through appropriate choice of protecting groups, to provide the deprotected alcohols (8a) and (8b).
• step A compound (9) is coupled with compound (10) under standard conditions well known in the art, to provide compound (11).
• compound (13) is dissolved in a suitable organic solvent, such as DMF, and treated with about one equivalent of a suitable base, such as sodium hydride.
• a suitable base such as sodium hydride.
• To the stirring solution is added about 1.1 equivalents of compound (10) and the reaction is heated at about -10 °C to room temperature for about 20 minutes to about 1 hour..
• Compound (11 ) is then isolated and purified by techniques well known in the art, such as extraction techniques and flash chromatography.
• the reaction mixture is diluted with water and extracted with a suitable organic solvent, such as ethyl acetate.
• the organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the crude material.
• the crude material can be purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexanes.
• step B compound (11) is coupled with compound (12) under standard conditions well known in the art to provide the compound of formula I.
• compound (11) is dissolved in a suitable organic solvent, such as /V, ⁇ /-dimethylformamide with about one equivalent of a suitable neutralizing agent, such as sodium bicarbonate.
• a suitable neutralizing agent such as sodium bicarbonate.
• To this mixture is added about one equivalent of compound (12) and the mixture is heated at about 70 °C to 90 °C for about 4 hours to 12 hours.
• the compound of formula I is then isolated and purified by techniques well known in the art, such as extraction techniques and flash chromatography.
• the reaction mixture is diluted with water and extracted with a suitable organic solvent, such as ethyl acetate.
• the organic extracts are combined, washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the crude material.
• the crude material can be purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexanes to provide compounds of formula I.
• X' OH or C C 6 alkoxy
• step A the compound of structure (9) is coupled with the epoxide (13) to provide the epoxide (14).
• compound (9) is dissolved in a suitable organic solvent, such as dimethylformamide and cooled to 0 °C.
• a suitable organic solvent such as dimethylformamide
• about 1.1 equivalents of sodium hydride is added to the solution which is then stirred for about one hour.
• a solution of one equivalent of the epoxide (13) in dimethylformamide is then added dropwise to the solution.
• the reaction mixture is then stirred for about 1 to 24 hours at 0 °C. It is then quenched with water.
• the resulting solution is extracted with a suitable organic solvent, such as ethyl acetate.
• the organic layers are combined, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to provide the crude epoxide (14).
• the crude product can be purified by crystallization with a suitable solvent, such as dichloromethane, or by flash chromatography on silica gel with a suitable eluent, such as dichloromethane/hexanes.
• step B the epoxide (14) is opened with a compound of either structure (15a) or (15b) under standard conditions well known in the art, such as those disclosed by Krushinski, et al. in U.S. Patent No. 5,576,321 , issued November 19, 1996, to provide the compound of formula la.
• the epoxide (14) such as (S)-(+)-4-(oxiranylmethoxy)-1 H-indole, is dissolved in a suitable organic solvent, such as methanol, and treated with about one equivalent of a compound (15a) or (15b). The solution is heated to reflux for about 8 to 12 hours and then cooled to room temperature.
• reaction mixture is concentrated under vacuum and the crude residue is purified by techniques well known in the art, such as flash chromatography, radial chromatography or high performance liquid chromatography on silica gel, with a suitable eluent, such as methanol/methylene chloride, to provide compounds of formula lb and Ic.
• a suitable eluent such as methanol/methylene chloride
• HPLC showed complete consumption of the starting material in just 0.5 h.
• the mixture was diluted with 1 N HCl (200 mL) and extracted three times with Diethyl ether (100 mL, 25 mL, 25 mL).
• Diethyl ether layers were combined to give a brown hazy mixture (some emulsion).
• decolorizing carbon (10 g, Calgon ADP) and filtration through Hyflo Super Cel®, a clear light yellow solution was obtained.
• This solution was extracted with 3 N NaOH (100 mL, 25 mL), leaving the non-naphtholic byproducts behind.
• the brown NaOH extracts were combined, acidified to pH 1 with cone.
• HPLC showed this to be a mixture of 7-bromo-1-naphthol (48.3%) and 5-bromo-1-naphthol (50.8%).
• 1 H NMR (CDCI 3 ) integration showed that the actual ratio was about 9/1 5-Br/7-Br.
• Preparative reverse phase HPLC gave one peak of 5-bromo-1-naphthol as a white solid (3.22 g, 27.3%).
• Triphenyl phosphine (89.7 g, 0.342 mol) and acetonitrile (350 mL) were combined in a 1-L flask under N 2 atmosphere. The mixture was cooled to 10 °C. Bromine (17.6 mL, 0.342 mol) was added dropwise over 10 minutes. The cooling bath was removed and 2,7-dihydroxynaphthalene (50.0 g, 0.312 mol) was added along with 350 mL of CH 3 CN rinse. The resulting yellow tan mixture was heated at reflux for 3 hours. Acetonitrile was distilled off using a water aspirator over 2 hours resulting in a grayish white solid. The solid was heated to 280 °C over 30 minutes giving a black liquid. The liquid was heated to 310 °C over 20 minutes and the temperature was maintained at 310 °C for an additional
• the solid was dried in vacuo at 50 °C to yield 32.6 g of pale yellow solid (HPLC: 89%).
• the solid was dissolved in 300 mL of boiling MeOH. The hot solution was filtered, then placed in the freezer overnight. The resulting crystals were filtered and washed with 100 mL of cold MeOH. The solid was dried in vacuo at 50 °C to give 27.0 g of pale yellow solid (HPLC: 95%).
• the solid was dissolved in 100 mL of boiling i-PrOH then allowed to cool to room temperature. The resulting solid was filtered and washed with 100 mL of i-PrOH. The solid was dried in vacuo at 50 °C to yield 22.8 g of the final title compound as pale yellow crystals.
• Preparation 3 Preparation of 6-lodo-1-methoxy-naphthalene.
• Preparation of 5-Bromo-2-naphthalenecarboxylic acid 2-Naphthoic acid (50.0 g, 0.290 mol), glacial acetic acid (250 mL), bromine (15 mL, 0.291 mol) and iodine (1.3 g, 0.005 mol) were combined in a flask under N 2 atmosphere. The mixture was heated at reflux for 35 minutes then cooled to room temperature. The thick yellow mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the pale orange solid was rinsed with -100 mL of the filtrate.
• the solid was dried in vacuo at 55 °C overnight to yield 55.5 g of a pale orange solid.
• the solid was slurried in 275 mL of 1 N NaOH for 30 minutes.
• the solid was filtered off and rinsed 3 times with 50 mL portions of the filtrate.
• the solid was air dried in the hood over the weekend to yield 46.7 g of solid.
• the solid was added to 220 mL of water. Concentrated HCl (15 mL) was added to obtain pH of 1.3 and the mixture was stirred for 4 hours.
• the solid was filtered off and washed with 200 mL of water.
• the solid was dried in vacuo at 50 °C to give 37.6 g of the intermediate title compound as white crystals (HPLC: 90% with 9% 2-naphthoic acid, 46% yield).
• the pH was adjusted to 1.0 by addition of concentrated HCl resulting in a white precipitate.
• the mixture was cooled to 10 °C, filtered and the solid was washed with cold water.
• the solid was dried to 11.03 g white0 crystals.
• the solid was taken up in 200 mL of Ethyl acetate and 150 mL of water.
• the pH of the mixture was 3.5.
• the pH was adjusted to 10.0 by addition of 5 N NaOH and maintained for 4 hours.
• the Ethyl acetate was removed by concentration in vacuo then the pH was adjusted to 1.0 by addition of concentrated HCl.
• the mixture was placed in the freezer overnight.
• the mixture5 was filtered and the solid was washed with water until the filtrate stream was colorless.
• the solid was dried in vacuo at 50 °C to give 9.77 g of an off-white solid.
• the solid was added to 50 mL of 2.5 N NaOH and the thick orange mixture was stirred for 3 hours.
• the pH was adjusted to 1.0 with concentrated HCl.
• the mixture was filtered and the solid was washed with water.
• the solid0 was dried to 9.43 g of off-white solid.
• the solid was dissolved in 200 mL of boiling MeOH and the hot solution was filtered, then cooled to room temperature. Water (300 mL) was added and the mixture was stirred at room temperature for 2 hours.
• the solid was filtered off and washed with 100 mL of a 1 :1 mixture of MeOH and water.
• the solid was dried in vacuo at 50 °C to give 7.18 g of the5 intermediate title compound as a white solid (HPLC: 97%, 83% yield).
• the mixture was concentrated in vacuo to 102.0 g of a brown gum plus liquid.
• the mixture was extracted with 50 mL of CH 2 CI 2 .
• the CH 2 CI 2 layer was dried over Na 2 S0 4 , filtered and concentrated in vacuo to provide 1.83 g of the intermediate title compound as a brown oil (HPLC: 91 %, 61% yield).
• the Diethyl ether phase was washed successively with 200 mL of 5% NaHS0 3 (aq), 200 mL of 5% NaHC0 3 (aq), 200 mL of water and 200 mL of saturated NaCl solution.
• the Diethyl ether phase was dried over Na 2 S ⁇ 4 , filtered and concentrated in vacuo to 2.21 g of a dark brown solid (HPLC: 69.5%).
• the solid was adsorbed onto 8.0 g of silica gel 60 in CH2CI2 then concentrated to a powder.
• the powder was slurried in hexanes and chromatographed on 100 g of silica gel 60 at atmospheric pressure, eluting with hexanes.
• the desired final title compound was collected (1.33 g, 50% yield) as a white solid after concentration of the appropriate fractions.
• the intermediate title compound was prepared in 95% crude yield from 3- methoxybenzenethiol in a manner analogous to the procedure described by Graham, S.L., et. al. J. Med. Chem. 1989,32, 2548-2554.
• step B A solution of er?c/o-3-(4-methoxybenzo[b]thiophen-2- yl)-8-azabicyclo[3.2.1]octane (0.075 mg, 0.274 mmol, prepared in example 2) and (S)-4-(oxiranylmethoxy)indole (0.052 g, 0.274 mmol) in MeOH (4 mL) was heated at reflux for 7 h and then cooled and evaporated. The residue was purified using silica gel chromatography [5% (10% cone. NH 4 OH in MeOH)/CH2CI 2 ] to give the free base of the title compound as a light yellow foam (0.111 g, 87%).
• step B A solution of exo-3-(4-methoxybenzo[b]thiophen-2- yl)-8-azabicyclo[3.2.1]octane (0.100 mg, 0.366 mmol, prepared in example 2) and (S)-2-methyl-4-(oxiranylmethoxy)indole (0.074 g, 0.366 mmol) in MeOH (5 mL) was heated at reflux for 16 h and then cooled and evaporated. The residue was purified using silica gel chromatography [3% (10% cone. NH 4 OH in MeOH)/CH 2 CI 2 ] to give the free base of the title compound as a white foam (0.164 g, 94%).
• step B A solution of e/7c/o-3-(4-methoxybenzo[b]thiophen-2- yl)-8-azabicyclo[3.2.1]octane (0.077 mg, 0.282 mmol, prepared in example 2) and (S)-2-methyl-4-(oxiranylmethoxy)indole (0.057 g, 0.282 mmol) in MeOH (4 mL) was heated at reflux for 16 h and then cooled and evaporated. The residue was purified using silica gel chromatography [4% (10% con NH 4 OH in MeOH)/CH 2 CI 2 ] to give the free base of the title compound as a white foam (0.122 g, 91 %).
• Example 11 Preparation of Exo-1-(3-benzorb1thiophen-2-yl-8-aza-bicvclor3.2.1loct-8-v0-3-(- 1 H-indol-4-yloxy)-propan-2-ol oxalate.
• the succinate salt was prepared under standard conditions.
• the compounds of the present invention are active at the serotonin 1A receptor, particularly as antagonists and as partial agonists at that receptor, and are distinguished by their selectivity.
• Previously known compounds with that activity typically have the disadvantage of possessing other non-serotonin related central nervous system activities as well. It is now well understood by pharmacologists and physicians that pharmaceuticals which have a single physiological activity, or which are much more active in the desired activity than in their other activities, are much more desirable for therapy than are compounds which have multiple activities at about the same dose.
• the 5-HTi A receptor binding potency of the present compounds are measured by a modification of the binding assay described by Taylor, et al. (1, Pharmacol. Exp. Ther. 236.
• Membranes for the binding assay are prepared from male Sprague-Dawley rats (150-250 g). The animals are killed by decapitation, and the brains are rapidly chilled and dissected to obtain the hippocampi.
• Membranes from the hippocampi are either prepared that day, or the hippocampi are stored frozen (-70 °C) until the day of preparation.
• the membranes are prepared by homogenizing the tissue in 40 volumes of ice-cold Tris-HCl buffer (50 mM, pH 7.4 at 22 °C) using a homogenizer for 15 sec, and the homogenate is centrifuged at 39800xg for 10 min. The resulting pellet is then resuspended in the same buffer, and the centrifugation and resuspension process is repeated three additional times to wash the membranes. Between the second and third washes the resuspended membranes are incubated for 10 min. at 37 °C to facilitate the removal of endogenous ligands.
• the final pellet is resuspended in 67 mM Tris-HCl, pH 7.4, to a concentration of 2 mg of tissue original wet 5 weight/200 ⁇ L. This homogenate is stored frozen (-70 °C) until the day of the binding assay.
• Each tube for the binding assay has a final volume of 800 ⁇ L and contains the following: Tris-HCl (50 mM), pargyline (10 ⁇ M), CaCl2 (3 mM),
• [3H]8-OH-DPAT (1.0 nM), appropriate dilutions of the drugs of interest, and membrane resuspension equivalent to 2 mg of original tissue wet weight, for a0 final pH of 7.4.
• the assay tubes are incubated for either 10 min. or 15 min. at 37 °C, and the contents are then rapidly filtered through GF/B filters (pretreated with 0.5% polyethylenimine), followed by four one-mL washes with ice-cold buffer.
• IC- 50 values i.e., the concentration required to inhibit 50% of the binding, are determined from 12-point competition curves using nonlinear regression (SYSTAT, SYSTAT, Inc., Evanston, II). IC 50 values are converted to Kj values o using the Cheng-Prusoff equation (Biochem. Pharmacol., 22, 3099-3108 (1973).
• Additional binding assays of some of the present compounds are carried out by an assay method which uses a cloned cell line which expresses the serotonin 1A receptor, rather than the hippocampal membranes.
• cloned cell lines have been described by Fargin, et al., J.Bio. Chem., 264, 14848-148525 (1989), Aune, et al., J. Immunology, 151 , 1175-1183 (1993), and Raymond, et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 346, 127-137 (1992).
• Results from the cell line assay are substantially in agreement with results from the hippocampal membrane assay.
• the 5-HT 1A o receptor is functionally coupled to a G-protein as measured by the ability of serotonin and serotonergic drugs to inhibit forskolin stimulated cAMP production in NIH3T3 cells transfected with the 5-HT ⁇ A receptor.
• Adenylate cyclase activity is determined by standard techniques.
• a maximal effect is achieved by serotonin.
• An E max is determined by dividing the inhibition of a test compound by the maximal effect and determining a percent inhibition.
• Drug dose-effect curves are then conducted by adding 6 different final concentrations of drug, followed immediately by the addition of forskolin (10 mM). Subsequently, the cells are incubated for an additional 10 minutes at 37 °C, 5% carbon dioxide.
• The5 medium is aspirated and the reaction is stopped by the addition of 100 mM hydrochloric acid.
• a dose-response curve for 5-HT is measured in parallel, using a fixed dose of methiothepin (0.32 mM).
• the plates are stored at 4 °C for 15 minutes and then centrifuged for 5 minutes at 500 x g to pellet cellular debris, and the supernatant is aliquoted and o stored at -20 °C before assessment of cAMP formation by radioimmunoassay (cAMP radioimmunoassay kit; Advanced Magnetics, Cambridge, MA). Radioactivity is quantified by a Packard COBRA Auto Gamma counter, equipped with data reduction software. Representative compounds are tested for 5-HT 1A receptor antagonist activity in the cAMP assay. 5
• LLR lower lip retraction
• FBP flat body posture
• a score of "0" indicates normal body posture; "1" indicates that the stomach is on the floor with the back in its normal rounded position; “2" indicates that the stomach is on the floor with the back straightened and rising from the shoulders to the hips; “3” indicates that the stomach is pressed onto the floor and the back is flattened with the shoulders and hips even.
• Core body temperature is recorded by rectal probe inserted 5.0 cm immediately after the behavioral measures. Rats are injected subcutaneous with a compound (at 0, 0.3, 1.0 and 3.0 mg/kg) 35 minutes before scoring and the 8-OH-DPAT (0.1 mg/kg subcutaneous) is injected 20 minutes before scoring.
• the compounds are also tested at a high dose of 10 mg/kg subcutaneous alone to see if they induced 5HT ⁇ A agonist-like hypothermia.
• the efficacy of the compounds of the invention to inhibit the reuptake of serotonin is determined by a paroxetine binding assay, the usefulness of which is set out by Wong, et al., Neuropsvchopharmacoloqy, 8, 23-33 (1993).
• Synaptosomal preparations from rat cerebral cortex are made from the brains of 100-150 g Sprague-Dawley rats which are killed by decapitation.
• the cerebral cortex is homogenized in 9 volumes of a medium containing 0.32 M sucrose and 20 ⁇ M glucose.
• the preparations are resuspended after centrifugation by homogenizing in 50 volumes of cold reaction medium (50 ⁇ M sodium chloride, 50 ⁇ M potassium chloride, pH 7.4) and centrifuging at 50,000g for 10 minutes. The process is repeated two times with a 10-minute incubation at 37 °C between the second and third washes. The resulting pellet is stored at -70 °C until use.
• cold reaction medium 50 ⁇ M sodium chloride, 50 ⁇ M potassium chloride, pH 7.4
• Binding of ⁇ H-paroxetine to 5-HT uptake sites is carried out in 2 mL reaction medium containing the appropriate drug concentration, 0.1 nM ⁇ H-paroxetine, and the cerebral cortical membrane (50 ⁇ g protein/tube). Samples are incubated at 37 °C for 30 minutes; those containing 1 ⁇ M fluoxetine are used to determine nonspecific binding of ⁇ H-paroxetine. After incubation, the tubes are filtered 5 through Whatman GF/B filters, which are soaked in 0.05% polyethylenimine for 1 hour before use, using a cell harvester by adding about 4 ml cold Tris buffer (pH 7.4), aspirating, and rinsing the tubes three additional times.
• the activity of the compounds at the serotonin 1A receptor provides a
• a patient in need of a modification of the effects of the 5-HT- ⁇ A receptor is one having one or more of the specific conditions and problems to be further described, or a condition or problem not yet recognized as created by an imbalance or malfunction of the 5-HT A receptor, since research on the central nervous system is presently ongoing in many fields and newly
• 3 o reuptake of serotonin provides a method of inhibiting the reuptake of serotonin comprising administering to a patient in need of such treatment an effective amount of a compound of that formula.
• the treatment of depression with drugs of the class of which fluoxetine is the leader has become perhaps the greatest medical breakthrough of the past decade. Numerous other treatment methods carried out by the administration of the compounds of formula I will be set out in detail below. 5
• the unique combination of 5-HTi A receptor activity and serotonin reuptake inhibition possessed by the compounds of the invention afford a method of providing to a patient both physiological activities with a single administration of a compound of that formula.
• the activities of compounds of formula I at the 5-HT-IA receptor and in reuptake inhibition are of comparable potencies, so an effective amount as defined hereinabove for affecting the serotonin 1A receptor or for inhibiting the reuptake of serotonin, is effective for affecting the serotonin 1A receptor and for o inhibiting the reuptake of serotonin in a patient.
• the compounds of the present invention are useful for binding, blocking5 or modulating the serotonin 1A receptor, and for the treatment of conditions caused by or influenced by defective function of that receptor.
• the compounds are useful for antagonism at the serotonin 1 A receptor, and accordingly, are useful for the treatment of conditions caused by or affected by excessive activity of that receptor.
• the compounds are useful in the treatment of anxiety, depression, hypertension, cognitive disorders, Alzheimer's disease, psychosis, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, appetite disorders, bulimia, obesity, substance abuse, obsessive- compulsive disease, panic disorder and migraine.
• Depression in its many variations has recently become much more visible to the general public than it has previously been. It is now recognized as an 5 extremely damaging disorder, and one that afflicts a surprisingly large fraction of the human population.
• Suicide is the most extreme symptom of depression, but millions of people, not quite so drastically afflicted, live in misery and partial or complete uselessness, and afflict their families as well by their affliction.
• the introduction of fluoxetine was a breakthrough in the treatment of depression, and lo depressives are now much more likely to be diagnosed and treated than they were only a decade ago.
• Depression is often associated with other diseases and conditions, or caused by such other conditions. For example, it is associated with Parkinson's disease; with HIV; with Alzheimer's disease; and with abuse of anabolic steroids. 15 Depression may also be associated with abuse of any substance, or may be associated with behavioral problems resulting from or occurring in combination with head injuries, mental retardation or stroke. Depression in all its variations is a preferred target of treatment with the compounds of the present invention.
• Fluoxetine is approved in the United States and
• Obesity is a frequent condition in the American population. It has been found that fluoxetine will enable an obese patient to lose weight, with the resulting benefit to the circulation and heart condition, as well as general well
• Urinary incontinence is classified generally as stress or urge incontinence, depending on whether its root cause is the inability of the sphincter muscles to keep control, or the overactivity of the bladder muscles.
• the present treatment methods are useful for treating many other diseases, disorders and conditions as well, as set out below.
• the diseases to be mentioned here are classified in the International Classification of Diseases, 9th Edition (ICD), or in the Diagnostic and Statistical Manual of Mental Disorders, 3rd Version Revised, published by the American Psychiatric
• the unique combination of pharmacological properties possessed by the compounds of formula I permit those compounds to be used in a method of simultaneously treating anxiety and depression.
• the anxiety portion of the combined syndrome is believed to be attacked by the 5HT-1 A receptor- affecting property of the compounds, and the depression portion of the condition is believed to be addressed by the serotonin reuptake inhibition property.
• administration of an effective amount, which is determined in an analogous manner as discussed hereinabove, of a compound of formula I will provide a method of simultaneously treating anxiety and depression.
• the present method of preventing or alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine comprises the previously discussed method of affecting the serotonin 1A receptor, in that the treatment method comprises the administration to a patient an effective amount of a compound of formula I.
• the method of the present invention is broadly useful in assisting persons who want to cease or reduce their use of tobacco or nicotine. Most commonly, the form of tobacco use is smoking, most commonly the smoking of cigarettes.
• the present invention is also helpful, however, in assisting in breaking the habit of all types of tobacco smoking, as well as the use of snuff, chewing tobacco, etc.
• the present method is also helpful to those who have replaced, or partially replaced, their use of tobacco with the use of nicotine replacement therapy. Thus, such patients can be assisted to reduce and even eliminate entirely their dependence on nicotine in all forms.
• a particular benefit of therapy with the present compounds is the elimination or reduction of the weight gain which very often results from reducing or withdrawing from use of tobacco or nicotine.
• the present invention is useful for preventing or alleviating the withdrawal symptoms which afflict patients who are trying to eliminate or reduce their use of tobacco or nicotine.
• the common withdrawal symptoms of such people include, at least, irritability, anxiety, restlessness, lack of concentration, insomnia, nervous tremor, increased hunger and weight gain, light-headedness, and the craving for tobacco or nicotine.
• the prevention or alleviation of such symptoms, when they are caused by or occur in conjunction with ceasing or reducing the patient's use of tobacco or nicotine is a desired result of the present invention and an important aspect of it.
• the invention is carried out by administering an effective amount of a compound of formula I to a patient who is in need of or carrying out a reduction or cessation of tobacco or nicotine use.
• a patient refers to a mammal such as a dog, cat, guinea pig, mouse, rat, monkey, or human being. It is understood that a human being is the preferred patient.
• treating or “to treat” each mean to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder.
• the term "effective amount” refers to the amount of a compound of formula (I) which is effective, upon single or multiple dose administration to a patient, in treating the patient suffering from the named disorder.
• the effective amount of compound to be administered in general, is from about 1 to about 200 mg/day.
• the daily dose may be administered in a single bolus, or in divided doses, depending on the judgment of the physician in charge of the case.
• a more preferred range of doses is from about 5 to about 100 mg/day; other dosage ranges which may be preferred in certain circumstances are from about 10 to about 50 mg/day; from about 5 to about 50 mg/day; from about 10 to about 25 mg/day; and a particularly preferred range is from about 20 to about 25 mg/day.
• an effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
• determining the effective amount or dose a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
• a compound of formula (I) can be administered in any form or mode which makes the compound bioavailable in effective amounts, including oral and parenteral routes.
• compounds of formula (I) can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, and the like.
• Oral administration is generally preferred.
• One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the disease state to be treated, the stage of the disease, and other relevant circumstances.
• serotonin reuptake inhibitors individually provide the benefit of the combination of serotonin reuptake inhibitors and serotonin 1A antagonists, it is entirely possible to administer a compound of formula I in combination with a conventional serotonin reuptake inhibitor in order to obtain still further enhanced results in potentiating serotonin reuptake inhibition.
• serotonin reuptake inhibitors include but are not limited to the following:
• Fluoxetine ⁇ /-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, is marketed in the hydrochloride salt form, and as the racemic mixture of its two enantiomers.
• U. S. Patent 4,314,081 is an early reference on the compound. Robertson, et al., J. Med. Chem. 31. 1412 (1988), taught the separation of the R and S enantiomers of fluoxetine and showed that their activity as serotonin uptake inhibitors is similar to each other.
• the word "fluoxetine” will be used to mean any acid addition salt or the free base, and to include either the racemic mixture or either of the R and S enantiomers.
• Duloxetine ⁇ /-methyl-3-(1 -naphthalenyloxy)-3-(2-thienyl)propanamine, is usually administered as the hydrochloride salt and as the (+) enantiomer. It was first taught by U.S. Patent 4,956,388, which shows its high potency. The word “duloxetine” will be used here to refer to any acid addition salt or the free base of the molecule.
• Venlafaxine is known in the literature, and its method of synthesis and its activity as an inhibitor of serotonin and norepinephrine uptake are taught by U.S. Patent 4,761 ,501. Venlafaxine is identified as compound A in that patent.
• Milnacipran ( ⁇ /,/V-diethyl-2-aminomethyl-1 -phenylcyclopropane- carboxamide) is taught by U.S. Patent 4,478,836, which prepared milnacipran as its Example 4.
• the patent describes its compounds as antidepressants. Moret, et al.. Neuropharmacoloqy 24. 1211-19 (1985), describe its pharmacological activities.
• Citalopram 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1 ,3-dihydro-5- isobenzofurancarbonitrile, is disclosed in U.S. Patent 4,136,193 as a serotonin reuptake inhibitor. Its pharmacology was disclosed by Christensen, et al., Eur. J. Pharmacol. 41. 153 (1977), and reports of its clinical effectiveness in depression may be found in Dufour, et al., Int. Clin. Psvchopharmacol. 2, 225 (1987), and Timmerman, et al., ibid., 239.
• Paroxetine fra/?s-(-)-3-[(1 ,3-benzodioxol-5-yloxy)methyl]-4-(4- fluorophenyl)piperidine, may be found in U.S. Patents 3,912,743 and 4,007,196. Reports of the drug's activity are in Lassen, Eur. J. Pharmacol. 47, 351 (1978); Hassan, et al.. Brit. J. Clin. Pharmacol. 19. 705 (1985); Laursen, et al., Acta Psvchiat. Scand. 71 , 249 (1985); and Battegay, et al., Neuropsvchobiology 13,
• Fluoxetine or duloxetine are the preferred SRI's in pharmaceutical compositions combining a compound of formula I and an SRI, and the corresponding methods of treatment. It will be understood by the skilled reader that all of the compounds used in the present invention are capable of forming salts, and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free bases. In all cases, the use of the pharmaceuticals described above as salts is contemplated in the description herein, and often is preferred, and the pharmaceutically acceptable salts of all of the compounds are included in the names of them.
• the dosages of the drugs used in the present combination must, in the final analysis, be set by the physician in charge of the case, using knowledge of the drugs, the properties of the drugs in combination as determined in clinical trials, and the characteristics of the patient, including diseases other than that for which the physician is treating the patient.
• General outlines of the dosages, and some preferred human dosages, can and will be provided here. Dosage guidelines for some of the drugs will first be given separately; in order to create a guideline for any desired combination, one would choose the guidelines for each of the component drugs.
• Fluoxetine from about 1 to about 80 mg, once/day; preferred, from about 10 to about 40 mg once/day; preferred for bulimia and obsessive-compulsive disease, from about 20 to about 80 mg once/day;
• Duloxetine from about 1 to about 30 mg once/day; preferred, from about 5 to about 20 mg once/day;
• Venlafaxine from about 10 to about 150 mg once-thrice/day; preferred, from about 25 to about 125 mg thrice/day; Milnacipran: from about 10 to about 100 mg once-twice/day; preferred, from about 25 to about 50 mg twice/day;
• Citalopram from about 5 to about 50 mg once/day; preferred, from about 10 to about 30 mg once/day;
• Fluvoxamine from about 20 to about 500 mg once/day; preferred, from about 50 to about 300 mg once/day;
• Paroxetine from about 5 to about 100 mg once/day; preferred, from about 50 to about 300 mg once/day.
• the adjunctive therapy of the present invention is carried out by administering a SRI together with a compound of formula I in any manner which provides effective levels of the two compounds in the body at the same time.
• All of the compounds concerned are orally available and are normally administered orally, and so oral administration of the adjunctive combination is preferred. They may be administered together, in a single dosage form, or may be administered separately. However, oral administration is not the only route or even the only preferred route.
• transdermal administration may be very desirable for patients who are forgetful or petulant about taking oral medicine.
• One of the drugs may be administered by one route, such as oral, and the other may be administered by the transdermal, percutaneous, intravenous, intramuscular, intranasal or intrarectal route, in particular circumstances.
• the route of administration may be varied in any way, limited by the physical properties of the drugs and the convenience of the patient and the caregiver.
• adjunctive combination is particularly preferred, however, for the adjunctive combination to be administered as a single pharmaceutical composition, and so pharmaceutical compositions incorporating both a SRI and a compound of formula I are important embodiments of the present invention.
• Such compositions may take any physical form which is pharmaceutically acceptable, but orally usable pharmaceutical compositions are particularly preferred.
• Such adjunctive pharmaceutical compositions contain an effective amount of each of the compounds, which effective amount is related to the daily dose of the compounds to be administered.
• Each adjunctive dosage unit may contain the daily doses of both compounds, or may contain a fraction of the daily doses, such as one-third of the doses. Alternatively, each dosage unit may contain the entire dose of one of the compounds, and a fraction of the dose of the other compound.
• the patient would daily take one of the combination dosage units, and one or more units containing only the other compound.
• the amounts of each drug to be contained in each dosage unit depends on the identity of the drugs chosen for the therapy, and other factors such as the indication for which the adjunctive therapy is being given.
• the benefit of the adjunctive therapy is its ability to augment the increase in availability of serotonin, norepinephrine and dopamine caused by the SRI compounds, resulting in improved activity in treating the various conditions described below in detail.
• the increase in availability of serotonin is particularly important and is a preferred aspect of the invention.
• the invention provides a more rapid onset of action than is usually provided by treatment with the SRI alone.
• the present invention provides pharmaceutical compositions of compounds of formula I, including the hydrates thereof, comprising, as an active ingredient, a compound of formula I in admixture or otherwise in association with 5 one or more pharmaceutically acceptable carriers, diluents or excipients. It is customary to formulate pharmaceuticals for administration, to provide control of the dosage and stability of the product in shipment and storage, and the usual methods of formulation are entirely applicable to the compounds of formula I. Such pharmaceutical compositions are valuable and novel because of theo presence of the compounds of formula I therein. Although pharmaceutical chemists are well aware of many effective ways to formulate pharmaceuticals, which technology is applicable to the present compounds, some discussion of the subject will be given here for the convenience of the reader.
• compositions contain from about 0.5% to about 50% of the compound of formula (I) in total, depending on the desired o dose and the type of composition to be used.
• the amount of the compound of formula (I) is best defined as the effective amount, that is, the amount of each compound which provides the desired dose to the patient in need of such treatment.
• the activity of the compounds do not depend on the nature of the composition, so the compositions are chosen and formulated solely for5 convenience and economy. Any compound may be formulated in any desired form of composition.
• Capsules are prepared by mixing the compound with a suitable diluent and filling the proper amount of the mixture in capsules.
• the usual diluents o include inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders. Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound.
• Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful.
• Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
• a lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die.
• the lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
• Tablet disintegrators are substances which swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, may be used, as well as sodium lauryl sulfate.
• Enteric formulations are often used to protect an active ingredient from the strongly acidic contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in acidic environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.
• Tablets are often coated with sugar as a flavor and sealant, or with film- forming protecting agents to modify the dissolution properties of the tablet.
• the compounds may also be formulated as chewable tablets, by using large amounts of pleasant-tasting substances such as mannitol in the formulation, as is now well-established practice.
• Instantly dissolving tablet-like formulations are also now frequently used to assure that the patient consumes the dosage form, and to avoid the difficulty in swallowing solid objects that bothers some patients.
• the usual bases may be used. Cocoa butter is a traditional suppository base, which may be modified by addition of waxes to raise its melting point slightly.
• Water- miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use, also.
• Transdermal patches have become popular recently. Typically they comprise a resinous composition in which the drugs will dissolve, or partially dissolve, which is held in contact with the skin by a film which protects the composition. Many patents have appeared in the field recently. Other, more complicated patch compositions are also in use, particularly those having a membrane pierced with pores through which the drugs are pumped by osmotic action.
• Hard gelatin capsules are prepared using the following ingredients:
• substituent R 2 compounds wherein R 2 is hydrogen, F, * CI, methyl and methoxy are preferred, with hydrogen being especially preferred.
• substituent A compounds wherein A is hydroxy are preferred. In addition, it is further preferred that when A is hydroxy, it is in the (S)- configuration.
• substituent X compounds wherein X is hydrogen are preferred.
• substituent Y compounds wherein Y is NH or S are preferred, with NH being especially preferred.
• substituent R 5 compounds wherein R 5 is hydrogen, F, Cl, Br, methyl, ethyl, propyl, isopropyl or butyl are preferred, with methyl, ethyl, and propyl being especially preferred.
• substituent R 6 compounds wherein R 6 is hydrogen, methyl, ethyl, propyl, isopropyl or butyl are preferred.
• ⁇ ⁇ represents a double bond in the indole ring, when Y is NH, and represents a single bond in the tropane ring.

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