WO2002028815A1 - Pharmaceutical compounds - Google Patents

Pharmaceutical compounds Download PDF

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Publication number
WO2002028815A1
WO2002028815A1 PCT/US2001/027725 US0127725W WO0228815A1 WO 2002028815 A1 WO2002028815 A1 WO 2002028815A1 US 0127725 W US0127725 W US 0127725W WO 0228815 A1 WO0228815 A1 WO 0228815A1
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Prior art keywords
bicyclo
methyl
benzothien
hept
oct
Prior art date
Application number
PCT/US2001/027725
Other languages
French (fr)
Inventor
Martine Keenan
Vincent Patrick Rocco
Kumiko Takeuchi
David Edward Tupper
Vincent Vivien
Original Assignee
Eli Lilly And Company
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Filing date
Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to CA002419777A priority Critical patent/CA2419777A1/en
Priority to AU2001292578A priority patent/AU2001292578A1/en
Priority to US10/363,781 priority patent/US20040030131A1/en
Priority to JP2002532402A priority patent/JP2004510754A/en
Priority to EP01972947A priority patent/EP1326824A1/en
Publication of WO2002028815A1 publication Critical patent/WO2002028815A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • This invention relates to novel compounds having pharmaceutical properties .
  • Certain aminoalkyl bicycloheptanes having a pharmacological effect on the central nervous system are disclosed in British Patent 1 586 249. Also, British Patents 1 444 717 and 1 549 174 describe aminoalkyl bicyclooctyl derivatives with similar properties.
  • the compounds of the invention are of the following formula :
  • R 1 and R 2 are each hydrogen or C]__4 alkyl
  • R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholino group, said group being optionally substituted with 1 to 3 substituents selected from C ⁇ _ 4 alkyl, hydroxymethyl, C ⁇ - alkoxymethyl and amido, R 3 is a naphthyl, indolyl, benzothienyl, benzofuranyl, benzothiazolyl, quinolinyl or isoquinolinyl group, said group being optionally substituted, and n is 1 or 2 and m is 0 or 1, provided that when m is 1 then n is 1; or a salt or ester thereof.
  • the compounds of the invention and their pharmaceutically acceptable salts and esters are indicated for use in the treatment of disorders of the central nervous system.
  • R 1 and R 2 are preferably hydrogen or C ⁇ _4 alkyl.
  • a C ⁇ _4 alkyl group can be methyl, ethyl, propyl or
  • butyl can be branched or unbranched and includes
  • R 1 and R 2 are each hydrogen, methyl or ethyl, and especially hydrogen or
  • the -NR 1 R 2 group is preferably -N (013)2 an
  • a C]__ alkoxy is an alkyl group linked to an oxygen
  • the R 3 substituent is attached to the bicyclo ring at
  • R 3 groups are ⁇ -naphthyl, ⁇ -naphthyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuranyl, 2-, 3-, 4-, 5-, 6- or 7- benzothiazolyl, 2-, 3-, 4-, 5-, 6- or 7-quinolinyl or
  • R 3 group can also be substituted, substitution being in one or both rings, with one or more, preferably 1 to 3, substituents.
  • Preferred substituents include C]__4
  • alkyl C ⁇ _4 alkoxy, carboxy, nitro, hydroxy, cyano,
  • halo trifluoromethyl , trifluoromethoxy, optionally substituted benzyl, optionally substituted benzyloxy, -NR'R'', -CONR'R'', -S0 2 NR'R'' and -S0 2 R', where R' and R' ' are each hydrogen or C ⁇ _4 alkyl.
  • substituents are C ⁇ - 4 alkyl, halo and cyano.
  • a halo substituent is preferably chloro, bromo or fluoro.
  • a benzyl or benzyloxy group is optionally substituted on the phenyl ring with one of the substituents listed above or with 1 to 3 of the substituents listed above, i.e., selected from C]__4 alkyl, C ⁇ _4 alkoxy, carboxy,
  • salts of the compound of the invention are included in the invention.
  • Such salts are preferably the pharmaceutically acceptable, non-toxic salts.
  • acid addition salts in particular those with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, maleic, fumaric, tartaric or citric acid.
  • suitable acids such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids
  • organic acids such as organic carboxylic acids, for example, maleic, fumaric, tartaric or citric acid.
  • salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically acceptable, acid addition salts, or are useful for identification, characterisation or purification.
  • esters when a substituent on an R 3 group is acidic such as, for example, a carboxy group, the opportunity exists for esters. These can be aliphatic or aromatic, being preferably alkyl esters derived from C]__4 alkanols, especially methyl and ethyl
  • esters An example of an ester substituent is -COOR' where R' is C ⁇ _4 alkyl.
  • the bicyclo compounds of the 2.2.1 and 3.2.1 systems contain asymmetric carbon atoms as indicated by asterisks in the following structures:
  • R and S enantiomeric forms of these compounds exist.
  • the compounds can be prepared as racemic mixtures and can conveniently be used a such, but individual isomers can be isolated by conventional techniques, or are preferably prepared by chiro- selective methods. Both racemic mixtures and individual isomers are included in the present invention.
  • a preferred group of compounds of formula (I) is one in
  • Ri and R 2 are each hydrogen or C ] __4 alkyl, and R 3
  • R 3 is an optionally substituted benzothienyl group attached at 5- position and preferably wherein said benzothienyl is substituted in the 3- position with Halogen or C ] __4 alkyl, preferably methyl .
  • An even further preferred group of compounds of the invention can be represented as follows :
  • R 1 and R 2 are each hydrogen or C x - 4 alkyl
  • R s and R 7 are each C ⁇ _ 4 alkyl, C ⁇ _ 4 alkoxy, carboxy, hydroxy, ' cyano, halo, trifluoromethyl, -NR'R'', -CONR'R'', -S0 2 NR'R' ' or -S0 2 R' where R' and R' ' are each hydrogen or C ⁇ - 4 alkyl, and p and q are each 0, 1 or 2 ; or a salt thereof.
  • the bicyclo moiety can be attached at the 4-, 5-, 6- or 7- position, preferably the 4- or 7- position, and most preferably at the 4- position.
  • Examples of compounds of the invention which can be as free base or in the form of a pharmaceutically acceptable salt, and in isomeric or racemic forms, are as follows : dimethyl- [3- (4-methoxybenzo [b] thiophen-2- yl)bicyclo [2.2.1] hept-2-en-2-yl] methanamine, N,N-dimethyl [3- (2 -naphthyl) bicyclo [2.2.1] hept-2-en-2- y1] methana ine,
  • the invention also includes processes for the production of compounds of the formula (I) above.
  • One process for producing the compounds of formula (I) comprises dehydrating a compound of formula
  • a dehydrating agent such as for example trifluoroacetic acid or p-toluene sulfonic acid.
  • the reaction is preferably carried out in an organic solvent, such as for example dichloromethane, at a temperature of from 0°C to 100°C.
  • compounds of formula (II) can be prepared by reaction of a compound of formula (III) with a suitable lithium derivative of formula R 3 Li .
  • Such cyclic ketones can, in their turn, be prepared by reacting the appropriate amine of formula HNR X R 2 with a compound of formula
  • Compound (IV) can be made from the cyclic ketone by the Mannich reaction, to yield a compound of formula (III) in which R 1 and R 2 are both methyl, followed by quaternisation and elimination.
  • a further process for preparing compounds of formula (I) comprises reacting a compound of the formula
  • R 4 is a leaving group
  • a suitable aryl metal complex that displaces R 4 with the desired R 3 group.
  • the reaction is preferably carried out in an organic solvent at a temperature of from 0°C to 100°C.
  • a suitable leaving group is triflate.
  • the compounds of the invention and their pharmaceutically acceptable salts have useful central nervous system activity.
  • the compounds inhibit the uptake of neurotransmitters such as serotonin, dopamine and noradrenalin. They are surprisingly effective serotonin reuptake inhibitors, as evidenced by
  • the compounds of the present invention are indicated for use in treating a variety of conditions such as depression, obesity, bulimia, alcoholism, pain, hypertension, ageing, senile dementia, Alzheimer's, memory loss, attention-deficit hyperactivity disorder, sexual dysfunction, Parkinsonism, anxiety, chronic fatigue syndrome, panic disorders, obsessive compulsive disorder, schizophrenia, gastrointestinal disorders, headache, cardiovascular disorders, smoking cessation, drug addiction including cocaine abuse, emesis and sleep disorders.
  • conditions such as depression, obesity, bulimia, alcoholism, pain, hypertension, ageing, senile dementia, Alzheimer's, memory loss, attention-deficit hyperactivity disorder, sexual dysfunction, Parkinsonism, anxiety, chronic fatigue syndrome, panic disorders, obsessive compulsive disorder, schizophrenia, gastrointestinal disorders, headache, cardiovascular disorders, smoking cessation, drug addiction including cocaine abuse, emesis and sleep disorders.
  • the compounds of the invention are effective over a wide dosage range, the actual dose administered being dependent on such factors as the particular compound being used, the condition being treated and the type and size of mammal being treated. However, the dosage required will normally fall within the range of 0.01 to 20 mg/kg per day, for example in the treatment of adult humans, dosages of from 0.5 to 100 mg per day may be used.
  • the compounds of the invention will normally be administered orally or by injection and, for this purpose, the compounds will usually be utilised in the form of a pharmaceutical composition. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound .
  • the invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, associated with a pharmaceutically acceptable excipient .
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
  • the excipient may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
  • compositions of the invention may, if desired, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient .
  • compositions may be formulated as tablets, capsules or suspensions for oral use and injection solutions or suspensions for parenteral use or as suppositories.
  • compositions are formulated in a dosage unit form, each dosage containing from 0.5 to 100 mg, more usually 1 to 100 mg, of the active ingredient.
  • (+/-) -dimethyl ( (2- (5- fluorobenzo [b] thiophen-2-yl) bicyclo [3.2.1] -oct-2 -en-3- yl) methyl) amine (0.1346 g, 0.426 mmol) in MeOH (1 mL) • was added HCl (0.42 mL, 0.426 mmol, 1.0 M in Et 2 0) , while stirring. The mixture was stirred for 10 min and diluted with H 2 0 (15 mL) and just enough CH 3 CN to dissolve the salt (1 mL) . The mixture was then lyophilized to afford a white powder, (0.1487 g, 99%) . mp 197.9-203.8 °C. Ion Spray MS 316.3 (M + H) + ; 271.2 (M - N(CH 3 ) 2 ) + .
  • Vials were sealed, and their contents stirred and heated to 80°C overnight .
  • the Vials were then unsealed and in each case, the contents were treated with methanol (1ml) .
  • Each mixture was passed through its own methanol-conditioned 500mg SCX ion-exchange cartridge (under gravity) into a collection tank.
  • Each cartridge was then washed with fresh methanol (2x2.5ml) such that the washings also passed into the tank.
  • a clear glass vial was then placed underneath each cartridge, which were then eluted with 2M ammonia in methanol to release the products. Solvents were removed in vacuo to recover the target materials .
  • FIA POS MASS SPEC M+H ,466 & [M-N (CH 3 ) 2 ] + , 421) .
  • Tablets each containing 10 mg of active ingredient are made up as follows:
  • the active ingredient, starch and cellulose are mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders and passed through a sieve.
  • the granules so produced are dried and re-passed through a sieve .
  • the sodium carboxymethyl starch and magnesium stearate are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 300 mg.
  • Capsules each containing 20 mg of medicament are made as follows :

Abstract

A compound of the formula in which R?1 and R2¿ are each hydrogen or C¿1-4? alkyl, or R1 and R2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholino group, said group being optionally substituted with 1 to 3 substituents selected from C1-4 alkyl, hydroxymethyl, C1-4 alkoxymethyl and amido, R?3¿ is a naphthyl, indolyl, benzothienyl, benzofuranyl, benzothiazolyl, quinolinyl or isoquinolinyl group, said group being optionally substituted, and n is 1 or 2; and m is 0 or 1, provided that when m is 1 then n is 1; or a salt or ester thereof.

Description

PHARMACEUTICAL'"'COMPOUNDS
This invention relates to novel compounds having pharmaceutical properties . Certain aminoalkyl bicycloheptanes having a pharmacological effect on the central nervous system, are disclosed in British Patent 1 586 249. Also, British Patents 1 444 717 and 1 549 174 describe aminoalkyl bicyclooctyl derivatives with similar properties.
The compounds of the invention are of the following formula :
Figure imgf000002_0001
(i) in which R1 and R2 are each hydrogen or C]__4 alkyl, or
R1 and R2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholino group, said group being optionally substituted with 1 to 3 substituents selected from Cι_4 alkyl, hydroxymethyl, Cι- alkoxymethyl and amido, R3 is a naphthyl, indolyl, benzothienyl, benzofuranyl, benzothiazolyl, quinolinyl or isoquinolinyl group, said group being optionally substituted, and n is 1 or 2 and m is 0 or 1, provided that when m is 1 then n is 1; or a salt or ester thereof. The compounds of the invention and their pharmaceutically acceptable salts and esters are indicated for use in the treatment of disorders of the central nervous system.
In the above formula (I) , R1 and R2 are preferably hydrogen or C^_4 alkyl. When R1 and R2 combine to form
one of the cyclic rings mentioned above, they can be substituted with Cι_4 alkyl, hydroxymethyl, Cι_4 alkoxymethyl or amido. An amido group is preferably a C2-5 acylamido substit-uent of the formula Cι_4 alkyl CONH- , and is most preferebly acetamido. A Cχ_4 alkyl group can be methyl, ethyl, propyl or
butyl , and can be branched or unbranched and includes
isopropyl and tert-butyl. Preferably R1 and R2 are each hydrogen, methyl or ethyl, and especially hydrogen or
methyl. The -NR1R2 group is preferably -N (013)2 an
most preferably -NH(α_3). A C]__ alkoxy is an alkyl group linked to an oxygen
atom, where the alkyl is as defined above. A C^_ alkoxy
group includes for example methoxy and ethoxy. Compounds of formula (I) in which n is 1 and m is 0, are 2.2.1 bicycloheptyl derivatives of the structure:
Figure imgf000004_0001
Compounds of formula (I) in which n is 1 and m is 1, are 3.2.1 bicyclooctyl derivatives of the structure
Figure imgf000004_0002
Compounds of formula (I) in which n is 2 and m is 0 are 2.2.2 bicycloocyl derivatives of the structure:
Figure imgf000004_0003
The R3 substituent is attached to the bicyclo ring at
certain positions on the substituent, and examples of R3 groups are α-naphthyl, β-naphthyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuranyl, 2-, 3-, 4-, 5-, 6- or 7- benzothiazolyl, 2-, 3-, 4-, 5-, 6- or 7-quinolinyl or
3-, 4-, 5-, 6- or 7-isoquinolinyl . Preferred R3 substituents are, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, and especially 4-, 5- or 7-benzothienyl .
The R3 group can also be substituted, substitution being in one or both rings, with one or more, preferably 1 to 3, substituents. Preferred substituents include C]__4
alkyl, Cχ_4 alkoxy, carboxy, nitro, hydroxy, cyano,
halo, trifluoromethyl , trifluoromethoxy, optionally substituted benzyl, optionally substituted benzyloxy, -NR'R'', -CONR'R'', -S02NR'R'' and -S02R', where R' and R' ' are each hydrogen or Cχ_4 alkyl. Especially
preferred substituents are Cι-4 alkyl, halo and cyano. A halo substituent is preferably chloro, bromo or fluoro. A benzyl or benzyloxy group is optionally substituted on the phenyl ring with one of the substituents listed above or with 1 to 3 of the substituents listed above, i.e., selected from C]__4 alkyl, Cχ_4 alkoxy, carboxy,
nitro, hydroxy, cyano, halo, trifluoromethyl , trifluoromethoxy, benzyl, benzyloxy -NR'R'1, -CONR'R'', -S02NR'R' ' and -S02R', where R' and R' ' are as defined above . As indicated above, it is possible to prepare salts of the compound of the invention and such salts are included in the invention. Such salts are preferably the pharmaceutically acceptable, non-toxic salts. Of special interest are acid addition salts, in particular those with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, maleic, fumaric, tartaric or citric acid.
In addition to the pharmaceutically acceptable salts, other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically acceptable, acid addition salts, or are useful for identification, characterisation or purification.
It will be appreciated that when a substituent on an R3 group is acidic such as, for example, a carboxy group, the opportunity exists for esters. These can be aliphatic or aromatic, being preferably alkyl esters derived from C]__4 alkanols, especially methyl and ethyl
esters. An example of an ester substituent is -COOR' where R' is C^_4 alkyl. The bicyclo compounds of the 2.2.1 and 3.2.1 systems contain asymmetric carbon atoms as indicated by asterisks in the following structures:
Figure imgf000007_0001
Thus R and S enantiomeric forms of these compounds exist. The compounds can be prepared as racemic mixtures and can conveniently be used a such, but individual isomers can be isolated by conventional techniques, or are preferably prepared by chiro- selective methods. Both racemic mixtures and individual isomers are included in the present invention.
A preferred group of compounds of formula (I) is one in
which Ri and R2 are each hydrogen or C]__4 alkyl, and R3
is optionally substituted benzothienyl, said optionally substituted benzothienyl preferably being attached at the 4- or 7- position. A further preferred group of compounds of the invention
is one in which R3 is an optionally substituted benzothienyl group attached at 5- position and preferably wherein said benzothienyl is substituted in the 3- position with Halogen or C]__4 alkyl, preferably methyl . An even further preferred group of compounds of the invention can be represented as follows :
Figure imgf000008_0001
in which R1 and R2 are each hydrogen or Cx-4 alkyl, Rs and R7 are each Cι_4 alkyl, Cι_4 alkoxy, carboxy, hydroxy,' cyano, halo, trifluoromethyl, -NR'R'', -CONR'R'', -S02NR'R' ' or -S02R' where R' and R' ' are each hydrogen or Cχ-4 alkyl, and p and q are each 0, 1 or 2 ; or a salt thereof.
The bicyclo moiety can be attached at the 4-, 5-, 6- or 7- position, preferably the 4- or 7- position, and most preferably at the 4- position. Examples of compounds of the invention, which can be as free base or in the form of a pharmaceutically acceptable salt, and in isomeric or racemic forms, are as follows : dimethyl- [3- (4-methoxybenzo [b] thiophen-2- yl)bicyclo [2.2.1] hept-2-en-2-yl] methanamine, N,N-dimethyl [3- (2 -naphthyl) bicyclo [2.2.1] hept-2-en-2- y1] methana ine,
[3- (l-benzothien-2-yl) bicyclo [2.2.1] hept-2-en-2-yl] -N,N- dimethylmethanamine ,
[3- (3-bromo-l-benzothien-2-yl)bicyclo [2.2.1] hept-2-en-2- yl] -N,N-dimethylmethanamine,
[3- (6-methoxy-2 -naphthyl) bicyclo [2.2.1] hept-2-en-2-yl] - ,N-dimethylmethanamine,
6- (3- [ (dimethylamino) methyl] bicyclo [2.2.1] hept-2-en-2- yl}-2-naphthol,
[3- (6-bromo-2 -naphthyl) bicyclo [2.2.1] hept-2-en-2-yl] - N, N-dimethylmethanamine ,
[3- (l-benzofuran-2-yl) bicyclo [2.2.1] hept-2-en-2-yl] -N,N- dimethylmethanamine,
[3- (6-fluoro-2 -naphthyl) bicyclo [2.2.1] hept-2-en-2-yl] - N, N-dimethylmethanamine ,
(l-benzothien-5-yl) bicyclo [2.2.1] hept-2-en-2-yl] -N,N- dimethylmethanamine , [3- (1-benzothien-3 -yl) bicyclo [2.2.1] hept-2-en-2-yl] -N-dimethylmethanamine,
N,N-dimethyl [3- (3-quinolinyl) bicyclo [2.2.1] hept-2-en-2- yl] methanamine,
N,N-dimethyl [3- (5-methyl-l-benzothien-2- yl) bicyclo [2.2.1] hept-2-en-2-yl] methanamine,
N,N-dimethyl [3- (6-methyl-2-naphthyl) bicyclo [2.2.1] hept- 2-en-2-yl] methanamine,
[3- (l-benzothien-6-yl) bicyclo [2.2.1] hept-2-en-2-yl] -N,N- dimethylmethanamine,
[3- (6-chloro-l, 3-benzothiazol-2-yl) bicyclo [2.2. l]hept-2- en-2-yl] -N, N-dimethylmethanamine,
N,N-dimethyl {3- [6- (methylsulfonyl) -2 - naphthyl] bicyclo [2.2.1] hept-2-en-2 -yl }methanamine,
[3- (6-methoxy-l-benzothien-2-yl) bicyclo [2.2.1] hept-2-en- 2-yl] -N,N-dimethylmethanamine, - IO ¬
CS- (5-methoxy-l-benzothien-2-yl) bicyclo [2.2.1] hept-2-en- 2-yl] -N,N-dimethylmethanamine,
[3- (8-methoxy-2 -naphthyl) bicyclo [2.2.1] hept-2-en-2-yl] - N,N-dimethylmethanamine,
N,N-dimethyl [3- (2-quinolinyl) bicyclo [2.2.1] hept-2-en-2- yl] methanamine ,
[3- (4-isoquinolinyl) bicyclo [2.2.1] hept-2-en-2-yl] -N,N- dimethylmethanamine,
N,N-dimethyl [3- (6-quinolinyl) bicyclo [2.2.1] hept-2-en-2- yl] methanamine ,
N,N-dimethyl [3- (2-quinolinyl) bicyclo [2.2.1] hept-2-en-2- yl] methanamine ,
[3- (4-isoquinolinyl) bicyclo [2.2.1] hept-2-en-2-yl] -N,N- dimethylmethanamine,
N,N-dimethyl [3- (8-quinolinyl) bicyclo [2.2.1] hept-2-en-2- yl] methanamine,
N,N-dimethyl [3- (5-quinolinyl) bicyclo [2.2.1] hept-2-en-2- yl] methanamine, [3- (6-fluoro-l-benzothien-3-yl) bicyclo [2.2.1] hept-2-en- 2-yl] -N, -dimethylmethanamine,
N,N-dimethyl [3- (2-methyl-6- quinolinyl) bicyclo [2.2.1] hept-2-en-2-yl] methanamine,
N,N-dimethyl [3- (4-methyl-2- - quinolinyl) bicyclo [2.2.1] hept-2 -en-2-yl] methanamine,
N,N-dimethyl [3- (2-methyl-l, 3-benzothiazol-5- yl) bicyclo [2.2.1] hept-2 -en-2-yl] methanamine,
[3- (5-methoxy-2 -naphthyl) bicyclo [2.2.1] hept-2 -en-2 -yl] * N, N-dimethylmethanamine,
[3- (6-fluoro-1, 3-benzothiazol-2-yl) bicyclo [2.2.1] hept-2- en-2-yl] -N, N-dimethylmethanamine,
[3- (4-chloro-l,3-benzothiazol-2-yl)bicyclo [2.2.1] hept-2- en-2-yl] -N, N-dimethylmethanamine,
[3- (6-methoxy-1, 3 -benzothiazol-2 -yl) bicyclo [2.2. l]hept- 2-en-2-yl] -N,N-dimethylmethanamine, N,N-dimethyl [3- (1-naphthyl) bicyclo [2.2.1] hept-2-en-2- yl] ethanamine ,
[3- (6-chloro-l-benzothien-2-yl) bicyclo [2.2.1] hept-2-en- 2 -yl] -N, N-dimethylmethanamine,
[3- (4-methoxy-1, 3-benzothiazol-2-yl) bicyclo [2.2.1] hept- 2-en-2-yl] -N, N-dimethylmethanamine ,
[3- (7-bromo-4-methoxy-1, 3-benzothiazol-2- yl) bicyclo [2.2.1] hept-2-en-2-yl] -N,N- dimethylmethanamine ,
N,N-dimethyl {3- [6- (trifluoromethyl) -l-benzothien-2- yl] bicyclo [2.2.1] hept-2-en-2 -yl}methanamine,
[3- (6-chloro-l-benzothien-3-yl) bicyclo [2.2.1] hept-2-en- 2-yl] -N, N-dimethylmethanamine,
N,N-dimethyl{3- [6- (trifluoromethyl) -l-benzothien-3- yl] bicyclo [2.2.1] hept-2-en-2-yl}methanamine,
[3- (4 -fluoro-1-naphthyl) bicyclo [2.2.1] hept-2-en-2-yl] - N, N-dimethylmethanamine , N,N-dimethyl [3- (6-methyl-l-benzothien-2- yl) bicyclo [2.2.1] hept-2 -en-2-yl] methanamine,
l-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2 -en-2- yl] methyl}piperidine,
4-{ [3- (2 -naphthyl) bicyclo [2.2.1] hept-2-en-2- yl] methyl }morpholine ,
l-methyl-4-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2-en-2- yl] methyl }piperazine,
l-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2-en-2- yl] methyl }piperazine
N-ethyl-N-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2 -en-2- yl] methyl }ethanamine ,
4- (6-methoxy-2 -naphthyl) -2-methyl-l- { [3- (2- naphthyl) bicyclo [2.2.1] hept-2 -en-2-yl] methyl }piperidine
2-methyl-l- { [3- (2-naphthyl) bicyclo [2.2.1] hept-2-en-2- yl] methyl }pyrrolidine,
methyl (-1- { [3- (2-naphthyl) bicyclo [2.2.1] hept-2-en-2- yl] methyl} -2-pyrrolidinyl) methyl ether, (-l-{ [3- (2 -naphthyl) bicyclo [2.2.1] hept-2 -en-2- yl] methyl } -2 -pyrrolidinyl) methanol ,
N- (2,5-Dimethyl)pyrrolidyl- [2- (2- naphthyl) bicyclo [2.2.1] -2-hepten-3-yl] methylamine,
N- (2R-Hydroxymethyl) pyrrolidyl- [2- (2-naphthyl) bicyclo [2.2.1] -2-hepten-3-yl]methylamine,
N- (-Hydroxymethyl) yrrolidyl- [2- (2-naphthyl) bicyclo [2.2.1] -2-hepten-3-yl] methylamine,
l-{ [3- (2 -naphthyl) bicyclo [2.2.1] hept-2 -en-2-yl] methyl} - 3 -pyrrolidinol,
N- (l-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2 -en-2- yl] methyl } -3-pyrrolidinyl) acetamide,
l-{ [3- (6-fluoro-l-benzothien-3-yl) bicyclo [2.2. l]hept-2- en-2 -yl] methyl }pyrrolidine ,
l-{ [3- (3-methyl-l-benzothien-5-yl) bicyclo [2.2.1] hept-2- en-2-yl] ethyl }pyrrolidine , 2, 2 -dimethyl-l-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2 -en- 2 -yl] methyl }pyrrolidine ,
N-{ [3- (l-benzothien-7-yl) bicyclo [2.2.1] hept-2-en-2- yl] methyl } -N-methyl-2 -propen- 1-amine ,
[3- (l-benzothien-7-yl) bicyclo [2.2.1] hept-2-en-2-yl] -N- methylmethanamine ,
N,N-Pyrrolidyl- [2- (2-naphthyl) bicyclo [2.2.1] -2-hepten-3- yl] methanamine ,
dimethyl- [3- (5-fluorobenzo [b] thiophen-2-yl) bicyclo [2.2.1] hept-2-en-2-yl] methanamine,
dimethyl- [3- (4-fluorobenzo [b] thiophen-2- yl) bicyclo [2.2.1] hept-2-en-2-yl] methanamine,
dimethyl- [3- (6-fluorobenzo [b] thiophen-2- yl) bicyclo [2.2.1] hept-2-en-2-yl] methanamine,
dimethyl- [3- (7-fluorobenzo [b] thiophen-2- yl) bicyclo [2.2.1] hept-2 -en-2-yl] methanamine,
dimethyl- [3- (7-methoxybenzo [b] thiophen-2- yl) bicyclo [2.2.1] hept-2-en-2-yl] methanamine, (3- (6-fluorobenzo [jb] thiophen-2-yl) bicyclo [2.2. l]hept-2- en-2 -yl) methyl) methanamine,
[3- (l,3-benzothiazol-2-yl)bicyclo [2.2.1] hept-2-en-2-yl] - N-methylmethanamine,
[3- (6-chloro-l, 3-benzothiazol-2-yl) bicyclo [2.2.1] hept-2 - en-2-yl] -N-methylmethanamine,
N-benzyl-N-{ [3- (6-methoxy-2 -naphthyl) bicyclo [2.2.1] hept- 2-en-2-yl] methyl} -N-methanamine,
( (3- (benzo [b] thiophen-4-yl) bicyclo [2.2.1] -hept-2-en-2- y1) methyl) dimethanamine ,
dimethyl (2- (5-fluorobenzo [b] thiophen-2- yl) bicyclo [3.2.1] -oct-2-en-3-yl) methanamine,
N,N-dimethyl [2- (2-naphthyl) bicyclo [3.2.1] oct-2-en-3- yl] methanamine,
N,N-dimethyl [2- (6-fluoro-2 -naphthyl) bicyclo [3.2.1] oct- 2 -en-3-yl] methanamine,
N,N-dimethyl [2- (6-fluoro-2 -naphthyl) bicyclo [3.2.1] oct-2-en-3 -yl] methanamine, [2- (7-fluoro-l-benzothien-2-yl) bicyclo [3.2.1] oct-2-en-3* yl] -N, N-dimethylmethanamine,
[2- (4-fluoro-l-benzothien-2-yl)bicyclo [3.2.1] oct-2-en-β* yl] -N,N-dimethylmethanamine,
[2- (6-fluoro-l-benzothien-2-yl) bicyclo [3.2.1] oct-2-en-3- yl] -N, N-dimethylmethanamine,
[2- (6-fluoro-l-benzothien-2-yl) bicyclo [3.2.1] oct-2-en- 3-yl] -N, -dimethylmethanamine,
[2- (6-fluoro-l-benzothien-3-yl) bicyclo [3.2.1] oct-2-en-3- yl] -N, N-dimethylmethanamine,
2- {3- [ (dimethylamino) methyl] bicyclo [3.2.1] oct-2-en-2- yl} -1-benzothiophene-6-carbonitrile,
[2- (6-trifluoro-l-benzothien-3-yl) bicyclo [3.2.1] oct-2- en-3-yl] -N, N-dimethylmethanamine,
N,N-dimethyl [3- (2-naphthyl) bicyclo [2.2.2] oct-2-en-2- yl] methanamine, [3- (6-methoxy-2 -naphthyl) bicyclo [2.2.2] oct-2-en-2-yl] - N, N-dimethylmethanamine,
[3- (l-benzothien-3-yl) bicyclo [2.2.2] oct-2-en-2-yl] -N,N- dimethylmethanamine,
6- {3- [ (dimethylamino) methyl] bicyclo [2.2.2] oct-2-en-2- yl } -2-naphthol ,
[3- (6-fluoro-2 -naphthyl) bicyclo [2.2.2] oct-2-en-2-yl] - N, N-dimethylmethanamine ,
[3- (6-fluoro-l-benzothien-3-yl) bicyclo [2.2.2] oct-2-en-2- yl] -N, N-dimethylmethanamine,
l-{ [3- (1-benzothien-5-yl) bicyclo [3.2.1] oct-2-en-2- yl] methyl }pyrrolidine,
l-{ [3- (l-benzothien-5-yl) bicyclo [3.2.1] oct-2-en-2- yl] methyl }azetidine,
l-{ [3- (3-methyl-l-benzothien-5-yl) bicyclo [2.2.2]oct-2- en-2 -yl] methyl }pyrrolidine , [3- (1-benzothien-7-yl) bicyclo [2.2.2] oct-2-en-2-yl] -N- methylmethanamine ,
[2- (l-benzothien-5-yl) bicyclo [3.2.1] oct-2-en-3-yl] -N,N- dimethylmethanamine,
2- (1-benzothien-5-yl) bicyclo [3.2.1] oct-2-en-3-yl] -N,N- dimethylmethanamine,
2- (1-benzothien-5-yl) bicyclo [3.2.1] oct-2-en-3-yl] -N,N- dimethylmethanamine,
[2- (l-benzothien-6-yl) icyclo [3.2.1] oct-2-en-3-yl] -N,N- dimethylmethanamine,
[2- (l-benzothien-4-yl) bicyclo [3.2.1] oct-2-en-3-yl] -N,N- dimethylmethanamine,
[2- (l-benzothien-4-yl) bicyclo [3.2.1] oct-2-en-3-yl] -N,N- dimethylmethanamine,
[2- (1-benzothien-7-yl) bicyclo [3.2.1] oct-2-en-3-yl] -N,N- dimethylmethanamine,
[2- (1-benzothien-7-yl) bicyclo [3.2:1] oct-2-en-3-yl] -N,N- dimethylmethanamine, [2- (3 -chloro-1-benzothien-5-yl) bicyclo [3.2.1] oct-2-en-3- yl] -N, N-dimethylmethanamine,
N,N-dimethyl [2- (3-methyl-l-benzothien-5-yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine,
N,N-dimethyl [2- (3-methyl-l-benzothien-5-yl) bicyclo
[3.2.1] oct-2-en-3-yl] methanamine,
N,N-dimethyl [2- (3 -methyl-1-benzothien-7-yl) bicyclo
[3.2.1] oct-2-en-3-yl] methanamine,
[3- (l-benzothien-5-yl) bicyclo [2.2.2] oct-2-en-2-yl] -N,N- dimethylmethanamine,
[3- (l-benzothien-6-yl) bicyclo [2.2.2] oct-2-en-2-yl] -N,N- dimethylmethanamine,
[3- (3-chloro-l-benzothien-5-yl)bicyclo [2.2.2] oct-2-en-2* yl] -N, N-dimethylmethanamine,
N,N-dimethyl [3- (3 -methyl-l-benzothien-5-yl) bicyclo [2.2.2] oct-2 -en-2 -yl] methanamine, [3- (1-benzothien-7-yl) bicyclo [2.2.2] oct-2-en-2-yl] -N,N- dimethylmethanamine ,
[3- (l-benzothien-4-yl) bicyclo [2.2.2] oct-2-en-2-yl] -N,N- dimethylmethanamine,
N-methyl-N- { [2- (3-methyl-l-benzothien-5-yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine,
[3- (6- luoro-2-naphthyl)bicyclo[3.2.1]oct-2-en-2-yl] -N- methylmethanamine,
N,N-dimethyl [3- (6- { [4- (trifluoromethyl) benzyl] oxy} -2- " naphthyl) bicyclo [2.2.2] oct-2-en-2-yl] methanamine,
[3- (6-methoxy-2-naphthyl) bicyclo [2.2.2] oct-2-en-2-yl] - N, N-dimethylmethanamine,
[3- (6-butoxy-2 -naphthyl) bicyclo [2.2.2] oct-2-en-2-yl] - N, N-dimethylmethanamine ,
{3- [6- (benzyloxy) -2-naphthyl] bicyclo [2.2.2] oct-2-en-2- yl } -N, N-dimethylmethanamine,
(3- {6- [ (4-bromobenzyl) oxy] -2 -naphthyl}bicyclo [2.2.2] oct- 2 -en-2 -yl) -N,N-dimethylmethanamine, 4-{ [(6-{3- [ (dimethylamino) methyl] bicyclo [2.2.2] oct-2-en- 2-yl} -2-naphthyl) oxy] ethyl}benzonitrile,
(3- {6- [ (3-chlorobenzyl) oxy] -2-naphthyl }bicyclo [2.2.2] oct-2 -en-2 -yl) -N, N-dimethylmethanamine ,
N,N-dimethyl (3-{6- [ (4-methylbenzyl) oxy] -2- naphthyl}bicyclo [2.2.2] oct-2 -en-2-yl) methanamine,
(3-{6- [ (2 , 6-dichlorobenzyl) oxy] -2 -naphthyl}bicyclo [2.2.2] oct-2-en-2-yl) -N, N-dimethylmethanamine,
[3- (6-ethoxy-2 -naphthyl) bicyclo [2.2.2] oct-2-en-2-yl] - N, N-dimethylmethanamine,
(3- {6- [ (4-tert-butylbenzyl) oxy] -2-naphthyl}bicyclo [2.2.2] oct-2-en-2-yl) -N, N-dimethylmethanamine,
(3- {6- [ (2-chlorobenzyl) oxy] -2 -naphthyl}bicyclo [2.2.2] oct-2-en-2-yl) -N, N-dimethylmethanamine,
(3- {6- [ (4-fluorobenzyl) oxy] -2 -naphthyl }bicyclo [2.2.2] oct-2-en-2-yl) -N,N-dimethylmethanamine, N,N-dimethyl [3- (6-propoxy-2 -naphthyl) bicyclo [2.2.2] oct- 2 -en-2 -yl] methanamine ,
(3- {6- [ (4-methoxybenzyl) oxy] -2-naphthyl }bicyclo [2.2.2] oct-2-en-2-yl) -N, N-dimethylmethanamine,
N,N-dimethyl (3- {6- [ (4-nitrobenzyl) oxy] -2- naphthyl}bicyclo [2.2.2] oct-2-en-2-yl) methanamine,
N,N-dimethyl [3- (6-{ [4- (trifluoromethoxy) benzyl] oxy} -2- naphthyl) bicyclo [2.2.2] oct-2-en-2-yl] methanamine,
[ (1R,4S) -N,N-dimethyl-3- (l-benzothien-4-yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride,
[ (IS, 4R) -N,N-dimethyl -3- (l-benzothien-4-yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride,
[N-methyl- (3- (3-methyl-l-benzothien-7-yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride,
[ (1R,4S) -N,N-dimethyl-3- (1-benzothien-7-yl) bicyclo [2.2.1] hept-2 -en-2-yl] - methanamine hydrochloride,
[ (1S,4R) -N,N-dimethyl-3- (1-benzothien-7-yl) bicyclo [2.2.1] hept-2-en-2-yl] - methanamine hydrochloride,
[N,N-dimethyl 3- (2 -methoxymethyl-1-benzothien-6- yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride, [N,N-dimethyl 3- (2-hydroxymethyl-1-benzothien-6- yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride,
[N,N-dimethyl 3- (2- {prop-2-enyl} -l-benzothien-6- yl) bicyclo [2.2.1] hept-2 -en-2-yl] -methanamine hydrochloride,
[N-methyl-3- (l-benzothien-4-yl) bicyclo [2.2.1] hept-2 -en- 2-yl] -methanamine hydrochloride,
[N-methyl-3- (6-fluoro-1-benzothien-3 -yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride,
[ (1R,4S) -N-methyl-3- (l-benzothien-7-yl) bicyclo
[2.2.1] hept-2-en-2-yl] - methanamine hydrochloride,
[ (1S,4R) -N-methyl-3- (l-benzothien-7-yl) bicyclo [2.2.1] hept-2-en-2-yl] - methanamine hydrochloride,
[(1R,4S) -N,N-dimethyl-3- (3 -methyl-1-benzothien-7- yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride,
[ (1S,4R) -N,N-dimethyl-3- (3 -methyl-1-benzothien-7- yl) bicyclo [2.2.1] hept-2 -en-2-yl] -methanamine hydrochloride,
[ (1R,4S) -N,N-dimethyl-3- (l-benzothien-2-yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride,
[ (1S,4R) -N,N-dimethyl-3- (l-benzothien-2-yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride, (1R,4S) -N-methyl- (3- (3 -methyl-1-benzothien-7-yl) bicyclo 2.2.1] hept-2-en-2-yl] -methanamine hydrochloride,
(1S,4R) -N-methyl- (3- (3-methyl-l-benzothien-7-yl) bicyclo 2.2.1] hept-2 -en-2-yl] -methanamine hydrochloride,
N-methyl- (3- (3 -methyl-1-benzothien-6-yl) bicyclo 2.2.1] hept-2 -en-2-yl] -methanamine hydrochloride,
(1R,4S) -N-methyl- (3- (l-benzothien-7-yl) bicyclo 2.2.1] hept-2-en-2-yl] -methanamine hydrochloride,
(1S,4R) -N-methyl- (3- (l-benzothien-7-yl) bicyclo 2.2.1] hept-2-en-2-yl] -methanamine hydrochloride,
N-methyl- (3- (5-fluoro-l-benzothien-7-yl) bicyclo 2.2.1] hept-2 -en-2-yl] -methanamine hydrochloride,
N-methyl- (3- (3 -cyano-l-benzothien-5-yl) bicyclo 2.2.1] hept-2-en-2-yl] -methanamine hydrochloride,
N-methyl- (3- (1-benzofuran-5-yl) bicyclo [2.2.1] hept-2-en- -yl] -methanamine hydrochloride,
(1R,4S) -N-methyl-3- (6-fluoro-l-benzothien-3-yl) bicyclo 2.2.1] hept-2 -en-2-yl] -methanamine hydrochloride,
(1S,4R) -N-methyl-3- (6-fluoro-l-benzothien-3-yl) bicyclo 2.2.1] hept-2 -en-2-yl] -methanamine hydrochloride,
N-allyl-N-methyl- [3- (1-benzothien-5-yl) bicyclo [2.2.2] oct-2-en-2-yl] -methanamine hydrochloride, N,N-dimethyl- [3- (3-methyl-l-benzothien-7-yl) bicyclo [2.2.2] oct-2-en-2-yl] -methanamine hydrochloride,
N,N-dimethyl- [3- (l-benzothien-2-yl) bicyclo [2.2.2] oct-2- en-2-yl] -methanamine hydrochloride,
N,N-dimethyl- [ (1S,5R) -2- (3-chloro-l-benzothien-5- yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride,
N,N-dimethyl- [ (1R, 5S) -2- (3-chloro-l-benzothien-5- yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride,
N,N-dimethyl- [ (IS, 5R) -2- (6-fluoro-l-benzothien-3- yl) bicyclo [3.2.1] oct-2 -en-3 -yl] methanamine hydrochloride,
N,N-dimethyl- [ (1R, 5S) -2 - (6-fluoro-l-benzothien-3- yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride,
N,N-dimethyl- [ (IS, 5R) -2- (3-methyl-l-benzothien-7- yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride,
N,N-dimethyl- [ (IS, 5R) -2- (3 -methyl-1-benzothien-7- yl) bicyclo [3.2.1] oct-2-en-3 -yl] methanamine hydrochloride,
N,N-dimethyl- [ (1S,5R) -2- (6-fluoro-naphth-2-yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride, N,N-dimethyl- [ (1R, S) -2- (6-fluoro-naphth-2-yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride,
N-methyl- [3- (3 -methyl-1-benzothien-7 -yl) bicyclo [2.2.2] oct-2 -en-2-yl] -methanamine hydrochloride,
N-methyl- [3- (6-fluoro-l-benzothien-3-yl) bicyclo [2.2.2] oct-2-en-2-yl] -methanamine hydrochloride,
N-methyl- [3- (l-benzothien-4-yl) bicyclo [2.2.2] oct-2-en-2- yl] -methanamine hydrochloride,
N-methyl- [3- (3-methyl-l-benzothien-5-yl) bicyclo [2.2.2] oct-2-en-2-yl] -methanamine hydrochloride,
N-methyl- [3- (l-benzothien-5-yl) bicyclo [2.2.2] oct-2-en-2- yl] -methanamine hydrochloride,
N-methyl- [2- (3-methyl-l-benzothien-5-yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride,
N-methyl- [2- (1-benzothien-7-yl) bicyclo [3.2.1] oct-2-en-3- yl] methanamine hydrochloride,
N-methyl- [2- (3 -methyl-1-benzothien-7 -yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride,
N-methyl- [2- (6-fluoro-l-benzothien-3-yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride,
N-methyl- [ (1S,5R) -2- (6-fluoro-naphth-2-yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride, N-methyl- [ (1R,5S) -2- (6-f luoro-naphth-2-yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride,
N-methyl- [2- (l-benzothien-4-yl) bicyclo [3.2.1] oct-2-en-3- yl] methanamine hydrochloride,
N-methyl- [ (1S,2R) -2- 6-cyano-1-benzothien-2-yl) bicyclo [3.2.1] oct-2-en-3-yl methanamine hydrochloride,
N-methyl- [ (1R,2S) -2- 6-cyano-1-benzothien-2-yl) bicyclo [3.2.1] oct-2 -en- 3 -yl methanamine hydrochloride,
N-methyl- [ (1S,2R) -2- 1-benzothien-7-yl) bicyclo [3.2.l]oct-2-en-3-yl methanamine hydrochloride,
N-methyl- [(1R,2S) -2- 1-benzothien-7-yl) bicyclo [3.2.1] oct -2 -en- 3 -yl methanamine hydrochloride,
N-methyl- [ (1S,2R) -3- 3 -methyl-1-benzothien-5-yl) bicyclo [2.2.2]oct-2-en-2-yl -methanamine hydrochloride,
N-methyl- [ (1R,2S) -3- 3 -methyl-1-benzothien-5-yl) bicyclo [2.2.2]oct-2-en-2-yl -methanamine hydrochloride,
N-methyl- [ (IS, 2R) -2- l-benzothien-4-yl) bicyclo [3.2.1]oct-2-en-3-yl methanamine hydrochloride,
N-methyl- [(1R,2S) -2- l-benzothien-4-yl) bicyclo [3.2.1] oct-2 -en-3 -yl methanamine hydrochloride,
N-methyl-2- (3-cyano-l-benzothien-5-yl) bicyclo [3.2.1] oct- 2-en-3-yl] methanamine hydrochloride, N-methyl- [2- (1-benzothien-2-yl) bicyclo [3.2.1] oct-2-en-3- yl] methanamine hydrochloride ,
N-methyl- [2- (5-methyl-l-benzothien-2-yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride,
N-methyl- [2- (6-fluoro-l-benzothien-2-yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride,
N-methyl- [2- (7-fluoro-l-benzothien-4-yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride,
N-methyl- [2- (3-methyl-l-benzothien-4-yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride,
N-methyl- [2- (5-methylthio-l-benzothien-2-yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride,
N-methyl- [2- (1-benzofuran-7-yl) bicyclo [3.2.1] oct-2 -en-3- yl] methanamine hydrochloride, and
N-methyl- [2- (1-benzofuran-6-yl) bicyclo [3.2.1] oct-2 -en-3- yl] methanamine hydrochloride.
The invention also includes processes for the production of compounds of the formula (I) above. One process for producing the compounds of formula (I) comprises dehydrating a compound of formula
Figure imgf000031_0001
(ID
preferably employing a dehydrating agent, such as for example trifluoroacetic acid or p-toluene sulfonic acid. The reaction is preferably carried out in an organic solvent, such as for example dichloromethane, at a temperature of from 0°C to 100°C.
Compounds of formula (II) can be prepared, for example, by reaction of a Grignard reagent of formula R3 MgBr, conveniently prepared in situ, with a cyclic ketone of the formula
Figure imgf000031_0002
(III)
Alternatively, compounds of formula (II) can be prepared by reaction of a compound of formula (III) with a suitable lithium derivative of formula R3Li . Such cyclic ketones can, in their turn, be prepared by reacting the appropriate amine of formula HNRXR2 with a compound of formula
Figure imgf000032_0001
(IV) Compound (IV) can be made from the cyclic ketone by the Mannich reaction, to yield a compound of formula (III) in which R1 and R2 are both methyl, followed by quaternisation and elimination.
A further process for preparing compounds of formula (I) , comprises reacting a compound of the formula
Figure imgf000032_0002
(V) where R4 is a leaving group, with a suitable aryl metal complex that displaces R4 with the desired R3 group. The reaction is preferably carried out in an organic solvent at a temperature of from 0°C to 100°C. A suitable leaving group is triflate. It will be appreciated that substituents on the naphthyl or heterocyclyl ring can be introduced at the outset, or in the final stages of the synthesis. Sometimes it will be convenient to convert one substituent to another as, for example, C _4 alkoxy to hydroxy, at an intermediate
stage or in the final product .
As mentioned above, the compounds of the invention and their pharmaceutically acceptable salts have useful central nervous system activity. The compounds inhibit the uptake of neurotransmitters such as serotonin, dopamine and noradrenalin. They are surprisingly effective serotonin reuptake inhibitors, as evidenced by
their displacement of [3H] citalopram at the binding sites on membranes derived from rat cortex, as in the test described below (see Example 29) . In a similar test, also employing rat cortex membrane, the compounds displaced nisoxetine, demonstrating their ability to inhibit noradrenalin reuptake, see Journal of Pharmacology and Experimental Therapeutics Vol. 272, No. 3, 1176-1186, 1995. The dopamine reuptake properties of the compounds of the invention are demonstrated in the test described in Molecular
Pharmacology 45: 125-135, using membranes derived from rat striatum. In this test displacement of WIN 35,428 from its reuptake site, is measured.
Because of their profile of neurotransmitter reuptake properties, the compounds of the present invention are indicated for use in treating a variety of conditions such as depression, obesity, bulimia, alcoholism, pain, hypertension, ageing, senile dementia, Alzheimer's, memory loss, attention-deficit hyperactivity disorder, sexual dysfunction, Parkinsonism, anxiety, chronic fatigue syndrome, panic disorders, obsessive compulsive disorder, schizophrenia, gastrointestinal disorders, headache, cardiovascular disorders, smoking cessation, drug addiction including cocaine abuse, emesis and sleep disorders.
The compounds of the invention are effective over a wide dosage range, the actual dose administered being dependent on such factors as the particular compound being used, the condition being treated and the type and size of mammal being treated. However, the dosage required will normally fall within the range of 0.01 to 20 mg/kg per day, for example in the treatment of adult humans, dosages of from 0.5 to 100 mg per day may be used. The compounds of the invention will normally be administered orally or by injection and, for this purpose, the compounds will usually be utilised in the form of a pharmaceutical composition. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound .
Accordingly the invention includes a pharmaceutical composition comprising as active ingredient a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, associated with a pharmaceutically acceptable excipient . In making the compositions of the invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. The excipient may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Some examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin syrup, methyl cellulose, methyl- and propyl- hydroxybenzoate, talc, magnesium stearate or oil. The compositions of the invention may, if desired, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient .
Depending on the route of administration, the foregoing compositions may be formulated as tablets, capsules or suspensions for oral use and injection solutions or suspensions for parenteral use or as suppositories. Preferably the compositions are formulated in a dosage unit form, each dosage containing from 0.5 to 100 mg, more usually 1 to 100 mg, of the active ingredient.
The following Examples illustrate the synthesis of the compounds of invention.
EXAMPLE 1
(±) -3- (W,__,-Dimethylamino)methylbicyclo [2.2.1] heptan-2- one
To a solution of 81.8 mL of 2.0 M dimethylamine in THF (164 mmol) was added 3-methylene-bicyclo [2 , 2 , 1] heptan-2- one (10.0 mL, 81.9 mmol) . The solution was stirred at room temperature for 24 h. The reaction mixture was then concentrated to give the crude title compound as an orange oil(13.50 g, 99% yield). IR (CHC13) 1732 cm"1. Ion Spray MS 168 (M+H)+.
Similarly prepared were: {1R/S, AR/S) -3- (N-pyrrolidyl)methylbicyclo[2.2. l]heptan- 2 -one, FDMS m/e = 194 (M++H) .
( 1R/S, 4R/S) -3- (N-piperidinyl)methylbicyclo [2.2. l]heptan- 2-one , FDMS m/e = 208 (M++H) .
{ 1R/S, AR/S) -3- (N-morpholino)methylbicyclo [2.2. l]heptan- 2 -one ,FDMS m/e = 210 (M++H) .
( 1R/S, 4R/S) -3- (N- (4-tert-butyloxycarbonylpiperazinyl) ) ethylbicyclo [2.2.1] heptan-2-one, FDMS m/e = 309 (M++H) .
(1R/S, <1R/S) -3- (N- (4-methylpiperazinyl) ) methylbicyclo [2.2.1] heptan-2 -one, FDMS m/e = 223 (M++H) .
( 1R/S, 4i?/S) -3- (N,N-diethyl) methylbicyclo [2.2.1] heptan-2 - one, FDMS m/e = 196 (M++H) .
C1S ( R/S, 4R/S) -3 - (N- (4- (2- (6-methoxy) naphthyl) -2-methyl piperidinyl) ) methylbicyclo [2.2.1] heptan-2-one, FDMS m/e = 378 (M++H) . trans- (1R/S, AR/S) -3- (N- (4- (2- (6-methoxy) naphthyl) -2- Methylpiperidinyl) ) methylbicyclo [2.2.1] heptan-2 -one, FDMS m/e = 378 (M++H) .
(1JR/S,4JR/S) -3- (N- (2-methyl) pyrrolidyl) methyl bicyclo [2.2.1] heptan-2 -one, FDMS m/e = 208 (M++H) .
( 1R/S, 4R/S) -3- (N- (2S-hydroxymethyl) pyrrolidyl) methylbicyclo [2.2.1] heptan-2-one, FDMS m/e = 224 (M++H) .
{ 1R/S, 4R/S) -3- (N- (2R-hydroxymethyl) pyrrolidyl) methylbicyclo [2.2.1] heptan-2 -one, FDMS m/e = 224
(M++H) .
( 1R/S, R/S) -3- (N- (2S-methoxymethyl) pyrrolidyl) methyl bicyclo [2.2.1] heptan-2-one, FDMS m/e = 238 (M++H) .
(1R/S,4R/S) -3- (N- (2R-methoxymethyl) pyrrolidyl) methyl bicyclo [2.2.1] heptan-2 -one, FDMS m/e = 238 (M++H) .
(±R/S, 4R/S) -3- (N- (3 -hydroxy) yrrolidyl) methyl bicyclo[2.2.1] heptan-2 -one, FDMS m/e = 210 (M++H) .
( 1R/S, 4R/S) -3- (N- (2 , 5-dimethyl) pyrrolidyl) methyl bicyclo [2.2.1] heptan-2 -one, FDMS m/e = 222 (M++H)
(li_/S,4i_/S) -3- (N- (3 -S-acetamido) pyrrolidyl) methyl bicyclo [2.2.1] heptan-2-one, FDMS m/e = 251 (M++H)
EXAMPLE 2
(+/-) -3-
Figure imgf000039_0001
N-Dimethylamino) methyl-2 - (4- methoxybenzo [b] thiophen-2-yl) bicyclo [2.2.1] heptan-2 -ol
To a solution of 4-methoxybenzo [b] thiophene (0.500 g,
3.04 mmol) in dry THF (10.0 L) at -78 °C was added 1.6 M n-BuLi in hexanes (2.28 mL, 3.65 mmol) . The solution was stirred at -78 °C for 45 min and then 3- (N,N~ dimethylamino) methyl [2, 2, 1] heptan-2 -one (0.509 g, 3.04 mmol) in THF (3 mL) was added via a cannulla at -78 °C. The reaction mixture was stirred at -78 °C for 1.75 h. The reaction was then quenched with 15 mL of saturated aqueous NH4C1 solution. The mixture was extracted with EtOAc (2 x 100 mL) . The combined organic layers were dried over MgS04 and filtered. The filtrate was concentrated and purified by medium pressure chromatography (silica gel, 2% (2.0 M NH3 in MeOH) /CH2C12) to give the title compound as a white solid (0.283 g, 28%). IR (KBr) 3100 (br) cm"1. EI+ MS 228 (M-103)+ (base peak); 331 (M) + . Similarly prepared were :
(1R/S. 4R/S) -3- (N-pyrrolidyl) methyl-2- (2-naphthyl) bicyclo [2.2.1] heptan-2 -ol FDMS m/e = 322 (M++H) .
( 1R/S, 4R/S) -3- (N-piperidinyl) methyl-2- (2-naphthyl) bicyclo [2.2.1] heptan-2 -ol, FDMS m/e = 336 (M++H) .
(1R/S, R/S) -3- (N-morpholino) methyl-2- (2-naphthyl) bicyclo [2.2.1] heptan-2 -ol, FDMS m/e = 338 (M++H) .
( 1R/S, 4 R/S) -3- (N- (4-tert-butyloxycarbonylpiperazinyl) ) methyl-2- (2-naphthyl) bicyclo [2.2.1] heptan-2 -ol, FDMS m/e = 437 (M++H) .
(1R/S, R/S) -3- (N- (4-methylpiperazinyl) ) methyl-2- (2- naphthyl) bicyclo [2.2.1] heptan-2-ol, FDMS m/e = 351
(M++H) .
( 1R/S, R/S) -3- (N,N-diethylamino) methyl-2- (2-naphthyl) bicyclo [2.2.1] heptan-2 -ol, FDMS m/e = 324 (M++H) .
cis- { 1R/S, 4R/S) -3- (N- (4- (2- (6-methoxy) naphthyl) -2- methylpiperidinyl) )methyl-2- (2-naphthyl) bicyclo [2.2.1] heptan-2 -ol, FDMS m/e = 506 (M++H) . trans- ( 1R/S, 4R/S) -3- (N- (4- (2- (6-methoxy) naphthyl) -2- methylpiperidinyl) ) ethyl-2- (2-naphthyl) bicyclo [2.2.1]heptan-2-ol, FDMS m/e = 506 (M++H) .
( 1R/S, 4R/S) -3- (N- (2-methyl) pyrrolidyl) methyl-2- (2- naphthyl) bicyclo [2.2.1] heptan-2 -ol, FDMS m/e = 336
(M++H) .
3- (N- (2S-hydroxymethyl) pyrrolidyl) methyl-2- (2-naphthyl) bicyclo [2.2.1] heptan-2 -ol, FDMS m/e = 352 (M++H) .
3- (N- (2R-hydroxymethyl) pyrrolidyl) methyl-2- (2-naphthyl) bicyclo [2.2.1] heptan-2 -ol, FDMS m/e = 352 (M++H) .
( 1R/S, R/S) -3 - (N- ( S-methoxymethyl) pyrrolidyl) methyl-2 - (2-naphthyl) bicyclo [2.2.1] heptan-2 -ol , FDMS m/e = 366 (M++H) .
( 1R/S, 4R/S) -3- (N- (2R-methoxymethyl) pyrrolidyl) methyl-2 - (2 -naphthyl) bicyclo [2.2.1] heptan-2 -ol, FDMS m/e = 366 (M++H) .
( 1R/S, 4R/S) -3- (N- (3 -hydroxy) pyrrolidyl) methyl-2- (2- naphthyl) bicyclo [2.2.1] heptan-2 -ol, MS m/e = 338 (M++H) . (1R/S, 4R/S) -3- (N- (2, 5-dimethyl) pyrrolidyl) methyl-2- (2- naphthyl) bicyclo [2.2.1] heptan-2-ol, FDMS m/e = 350 (M++H) .
3- (N- (3-S-acetamido) pyrrolidyl) methyl-2- (2-naphthyl) bicyclo [2.2.1] heptan-2 -ol, FDMS m/e = 379 (M++H) .
EXAMPLE 3 (+/-) Trifluoromethanesulfonic Acid 3-
Dimethylaminomethylbicyclo [2.2.1] hept-2 -en-2-yl Ester.
To a cooled (-78 °C) solution of diisopropylamine (11.8 mL, 84.5 mmol) in anhydrous THF (85 mL) was added 1.6 M n-BuLi in hexanes (52.8 mL, 84.5 mmol) . The
solution was stirred at -78 °C for 1 h. The dry ice bath was removed and the solution was stirred for an additional 0.5 h. The solution was then recooled to -78
°C and (+-) -3-
Figure imgf000042_0001
methylbicyclo [2.2.1] heptan-2-one (13.5 g, 80.5 mmol) in anhydrous THF (85 mL) was added via a cannulla over a period of 15 min. The solution was stirred at -78 °C for 35 min. N- Phenyl-bis (trifluoromethanesulfonimide) (30.2 g, 84.5 mmol) in anhydrous THF (85 mL) was added to the reaction mixture via a canulla over a period of 20 min. at -78 °C. The resulting solution was allowed to slowly warm to room temperature overnight . The reaction mixture was then concentrated under reduced pressure. The residue was diluted with CH2C12 (75 mL) . The mixture was then eluted on a pad of neutral alumina using 5% EtOAc in hexanes (3 L) as eluent . The collected fraction was concentrated and purified by medium pressure chromatography (silica gel, 1.5-2.0% (3.5 M NH3 in MeOH) /CH2C12) to give the title compound as a yellow oil (17.4 g, 72%). IR (CHC13) 1419, 1141 cm"1. Ion Spray MS 300 (M+H)+.
, . EXAMPLE 4
(+/-) (i^ N-Dimethylamino) methyl-2- (6- fluorobenzo [J] thiophen-3-yl) bicyclo [2.2.1] heptan-2-ol
To a solution of crude 3 -bromo-6-fluorobenzo [b] thiophene
(0.960 g, 4.15 mmol) in anhydrous THF (20 mL) was added dibromoethane (0.358 ml, 4.15 mmol) and magnesium turnings (0.202 g, 8.30 mmol) . The solution was stirred at reflux for 2 h. or until the magnesium was consumed. The reaction mixture was removed from the heat and (+- ) (iV/ -dimethylamino) methylbicyclo [2.2.1] heptan-2 -one (0.764 g, 4.57 mmol) in anhydrous THF (6 mL) was added to the solution at room temperature. The solution was stirred for 20 h. The reaction was quenched with saturated aqueous NHC1 solution. (30 mL) . The mixture was extracted with EtOAc (2 x 100 mL) . The combined organic layers were dried over MgS04 and concentrated. The residue was purified by medium pressure chromatography (silca gel, 2.5% (2.0 M NH3 in MeOH) /CH2C12) to give the title compound as a white semi- solid (0.271 g, 20%). Ion Spray MS 320 (M+H)+, 290 (base peak) (M-29) + .
EXAMPLE 5
3- [ (Dimethylamino) methyl] -2- (6-fluoro-2-naphthyl) bicyclo [2.2.1] heptan-2 -ol
The enantiomers of 3- [ (dimethylamino) methyl] -2- (6- fluoro-2 -naphthyl) bicyclo [2.2.1] heptan-2-ol were separated by chiral preparative chromatography, using a CHIRALPAK-AD colunm, and a mixture of Hexane / Ethanol 80/20 as the eluant.
EXAMPLE 6 (+/-) Dimethyl- [3- (4-methoxybenzo [b] thiophen-2* yl) bicyclo [2.2.1] hept-2 -en-2-yl] methylamine hydrochloride
To a solution of (+/-) (N,N-dimethylamino) methyl-2- (4- methoxybenzo [b] thiophen-2-yl) bicyclo [2.2.1] heptan-2 -ol (0.277 g, 0.835 mmol) in dry CH2C12 (7 mL) at 0 °C was added 2 L of trifluoroacetic acid. The solution was stirred at 0 °C for 3 h. The reaction was then quenched with saturated aqueous NaHC03 solution (30 mL) . The mixture was extracted (2 x 40 mL) with CH2C12. The combined organic layers were dried over MgS04 and concentrated. The residue was purified by medium pressure chromatography • (silica gel, 3% (2.0 M NH3 in * MeOH) /CH2C12) to give the free base of the title compound as an off-white semi-solid (0.243 g, 93%). The hydrochloride salt was prepared with 1.0 equiv. of HCl in EtOAc. m.p. (HCl) 239-242 °C . FDMS m/e = 313 M+.
Similarly prepared were:
N,N-dimethyl [3- (2-naphthyl) bicyclo [2.2.1] hept-2-en-2- yl] methanamine hydrochloride, mp 226.3-227.3°C
[3- (l-benzothien-2-yl) bicyclo [2.2.1] hept-2 -en-2-yl] -N,N- dimethylmethanamine hydrochloride, FIA POS MS (M+H, 284)
[3- (3-bromo-1-benzothien-2-yl) bicyclo [2.2.1] hept-2 -en-2 - yl] -N,N-dimethylmethanamine hydrochloride, mp 109° , FIA POS MS (M+H, 362/364)
[3- (6-methoxy-2 -naphthyl) bicyclo [2.2.1] hept-2 -en-2 -yl] - N, N-dimethylmethanamine hydrochloride, mp 201.7-202.5°C
6- (3- [ (dimethylamino) methyl] bicyclo [2.2.1] hept-2 -en-2 - yl}-2-naphthol hydrochloride, mp 222.9-224.5°C [3- (6-bromo-2-naphthyl) bicyclo [2.2.1] hept-2-en-2-yl] - N, N-dimethylmethanamine hydrochloride, mp 225.8-226.6°C
[3- (l-benzofuran-2-yl) bicyclo [2.2.1] hept-2 -en-2-yl] -N,N- dimethylmethanamine hydrochloride , mp 241.5-242.6 °C
[3- (6-fluoro-2 -naphthyl) bicyclo [2.2.1] hept-2-en-2-yl] - N, N-dimethylmethanamine hydrochloride, mp 223.4-224.5°C
(l-benzothien-5-yl) bicyclo [2.2.1] hept-2-en-2 -yl] -N,N- dimethylmethanamine hydrochloride, mp 227.5-228.5°C
[3- (l-benzothien-3-yl) bicyclo [2.2.1] hept-2-en-2-yl] -N,N- dimethylmethanamine hydrochloride,mp 205.0-206.6°C
N,N-dimethyl [3- (3-quinolinyl) bicyclo [2.2.1] hept-2-en-2 - yl] methanamine dihydrochloride,mp 246.4-248.9°C
N,N-dimethyl [3- (5-methyl-l-benzothien-2- yl) bicyclo [2.2.1] hept-2 -en-2 -yl] methanamine hydrochloride, mp 231.6-232.5°C
N,N-dimethyl [3- (6-methyl-2 -naphthyl) bicyclo [2.2.1] hept- 2 -en-2 -yl] methanamine , maleic acid, mp 171-172 °C [3- (1-benzothien-6-yl) bicyclo [2.2.1] hept-2 -en-2 -yl] -N,N- dimethylmethanamine , maleic acid,mp 185-187°C
[3- (6-chloro-l, 3-benzothiazol-2-yl) bicyclo [2.2.1] hept-2 - en-2 -yl] -N, N-dimethylmethanamine succinate, FIA POS MS (M+H, 321.0)
N,N-dimethyl {3- [6- (methylsulfanyl) -2- naphthyl] bicyclo [2.2.1] hept-2 -en-2 -yl}methanamine , maleic acid, MS ESP+ (M+, 324.1)
[3- (6-methoxy-l-benzothien-2-yl) bicyclo [2.2.1] hept-2-en- 2 -yl] -N, N-dimethylmethanamine hydrochloride, Ion Spray MS 269 (M-44 (-N(CH3)2) ) +
[3- (5-methoxy-1-benzothien-2-yl) bicyclo [2.2.1] hept-2-en- 2 -yl] -N, N-dimethylmethanamine hydrochloride, FDMS m/e = 314 M+
[3- (8-methoxy-2-naphthyl) bicyclo [2.2.1] hept-2-en-2-yl] - N, -dimethylmethanamine, maleic acid, MS ESP+ (M+, 308.1)
N,N-dimethyl [3- (2-quinolinyl) bicyclo [2.2.1] hept-2-en-2- yl] methanamine succinate, MS ESP+ (M+ 279.0) [3- (4 -isoquinolinyl) bicyclo [2.2.1] hept-2-en-2-yl] -N,N- dimethylmethanamine succinate, MS ESP+ (M+ 279.0)
N,N-dimethyl [3- (6-quinolinyl) bicyclo [2.2.1] hept-2-en-2- yl] methanamine dihydrochloride, MS ESP+ (M+ 279.0)
N,N-dimethyl [3- (2-quinolinyl) bicyclo [2.2.1] hept-2-en-2 - yl] methanamine dihydrochloride, MS ESP+ (M+ 279.0)
[3- (4-isoquinolinyl) bicyclo [2.2.1] hept-2 -en-2 -yl] -N,N- dimethylmethanamine dihydrochloride, MS ESP+ (M+ 279.0)
N,N-dimethyl [3- (8-quinolinyl) bicyclo [2.2.1] hept-2-en-2- yl] methanamine dihydrochloride, MS ESP+ (M+ 279.0)
N,N-dimethyl [3- (5-quinolinyl) bicyclo [2.2.1] hept-2-en-2- yl] methanamine dihydrochloride, MS ESP+ (M+ 279.0)
[3- (6-fluoro-l-benzothien-3-yl) bicyclo [2.2.1] hept-2-en- 2-yl] -N,N-dimethylmethanamine hydrochloride, Ion Spray MS 302 (M+H)+, 257 (M-44 (-N (CH3) 2) ) +
N,N-dimethyl [3- (2-methyl-6- quinolinyl) bicyclo [2.2.1] hept-2-en-2-yl] methanamine dihydrochloride, MS ESP+ (M+, 293.0) N,N-dimethyl [3- (4-methyl-2- quinolinyl) bicyclo [2.2.1] hept-2 -en-2 -yl] methanamine dihydrochloride, , MS ESP+ (M+,293.2)
N,N-dimethyl [3- (2-methyl-l, 3-benzothiazol-5- yl) bicyclo [2.2.1] hept-2 -en-2 -yl] methanamine hydrochloride, , FIA POS MS (M+H, 299.2)
[3- (5-methoxy-2 -naphthyl) bicyclo [2.2.1] hept-2 -en-2-yl] - N, N-dimethylmethanamine, maleic acid, MS ESP+ (M+,308.2)
[3- (6-fluoro-1, 3-benzothiazol-2-yl) bicyclo [2.2.1] hept-2- en-2-yl] -N, N-dimethylmethanamine hydrochloride, MS (M+H ,303.1)
[3- (4-chloro-1, 3-benzothiazol-2-yl) bicyclo [2.2.1] hept-2 - en-2-yl] -N,N-dimethylmethanamine hydrochloride, MS ESP+ (M+, 319.0)
[3- (6-methoxy-1, 3 -benzothiazol-2-yl) bicyclo [2.2. l]hept- 2-en-2-yl] -N,N-dimethylmethanamine hydrochloride, FIA POS MS (M+H, 315.3)
N,N-dimethyl [3- (1-naphthyl) bicyclo [2.2.1] hept-2-en-2- yl] methanamine , maleic acid, mp 142.9-143.7°C [3- (6-chloro-l-benzothien-2-yl) bicyclo [2.2.1] hept-2-en- 2-yl] -N, -dimethylmethanamine hydrochloride, mp 235-237°C
[3- (4-methoxy-1, 3 -benzothiazol-2-yl) bicyclo [2.2.1] hept- 2-en-2-yl] -N, N-dimethylmethanamine hydrochloride, MS ESP+ (M+, 314.0)
[3- (7-bromo-4-methoxy-l, 3 -benzothiazol-2- yl) bicyclo [2.2.1] hept-2-en-2-yl] -N, N-dimethylmethanamine hydrochloride, FIA POS MS (M+H, 395.0)
N,N-dimethyl {3- [6- (trifluoromethyl) -l-benzothien-2- yl] bicyclo [2.2.1] hept-2-en-2-yl }methanamine hydrochloride, mp 237-239°C
[3- (6-chloro-l-benzothien-3-yl) bicyclo [2.2.1] hept-2-en- 2-yl] -N, -dimethylmethanamine hydrochloride, FIA Pos MS
(M+H, 318.1)
N,N- dime thyl {3- [6- (trifluoromethyl) -l-benzothien-3- yl] bicyclo [2.2.1] hept-2 -en-2 -yl} methanamine hydrochloride, mp 169-171 °C
[3- (4 -f luoro-1 -naphthyl) bicyclo [2.2.1] hept-2-en-2-yl] - N, N-dimethylmethanamine hydrochloride, mp 245.5-247.4°C N,N-dimethyl [3- (6-methyl-l-benzothien-2- yl) bicyclo [2.2.1] hept-2 -en-2-yl] methanamine hydrochloride, mp 228-230°C
l-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2-en-2- yl] methyl}piperidine hydrochloride, FDMS m/e = 318 (M++H of free base) .
4-{[(lR,4S)-3- (2-naphthyl) bicyclo [2.2.1] hept-2 -en-2 - yl] methyl}morpholine hydrochloride, FDMS m/e = 320 (M++H of free base) .
l-methyl-4-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2-en-2- yl] methyl }piperazine hydrochloride, FDMS m/e = 333 (M++H of free base) .
l-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2-en-2- yl] methyl }piperazine dihydrochloride, FDMS m/e = 319 (M++H of free base) .
N-ethyl-N-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2-en-2- yl] methyl }ethanamine hydrochloride, FDMS m/e = 305 (M+ of free base) . 4- (6-methoxy-2-naphthyl) -2-methyl-l- { [ (1R,4S) -3- (2- naphthyl) bicyclo [2.2.1] hept-2 -en-2-yl] methyl }piperidine hydrochloride, FDMS m/e = 488 (M+ of free base).
4- (6-methoxy-2 -naphthyl) -2-methyl-l- { [ (1R,4S) -3- (2- naphthyl) bicyclo [2.2.1] hept-2 -en-2 -yl] methyl }piperidine hydrochloride, FDMS m/e = 488 (M+ of free base).
2-methyl-l- { [3- (2-naphthyl) bicyclo [2.2.1] hept-2 -en-2 - yl] methyl}pyrrolidine hydrochloride, FDMS m/e = 318 (M++H of free base) .
Methyl ( (2R) -l-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2-en- 2 -yl] methyl} -2 -pyrrolidinyl) methyl ether hydrochloride, FDMS m/e = 348 (M++H of free base). α[D]589 = 160 (c =
0.5, methanol) .
Methyl ( (2S) -l-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2 -en- 2-yl] methyl} -2 -pyrrolidinyl) ethyl ether hydrochloride, FDMS m/e = 348 (M++H of free base). α[D]589 = -171.4 (c
0.56, methanol) .
( (2S) -l-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2-en-2- yl] methyl } -2-pyrrolidinyl) methanol hydrochloride, FDMS m/e = 334 (M++H of free base). [D]589 = -183 (c = 0.59 ,
methanol) .
( (2R) -l-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2-en-2- yl] methyl} -2 -pyrrolidinyl) methanol hydrochloride, FDMS m/e = 334 (M++H of free base), α [D] 589 = -15.09(c = 0.53
, methanol) .
N- (2, 5-dimethyl) pyrrolidyl- [ (1R/S, 4R/S) -2- (2- naphthyl) bicyclo [2.2.1] -2-hepten-3-yl] methylamine hydrochloride, FDMS m/e = 332 (M++H of free base) .
N- (2R-hydroxymethyl) pyrrolidyl- [2- (2-naphthyl) bicyclo [2.2.1] -2 -hepten-3-yl] methylamine hydrochloride, FDMS m/e = 334 (M++1 of free base) . α[D]589 = 182.8 (c = 0.58
, methanol) .
N- (2R-hydroxymethyl) pyrrolidyl- [2- (2-naphthyl) bicyclo [2.2.1] -2 -hepten-3-yl] methylamine hydrochloride , FDMS m/e = 334 (M++H of free base). [D]589 = 17.86 (c = 0.56
, methanol) . l- { [3 - (2 -naphthyl) bicyclo [2 . 2 . 1] hept-2 -en- 2 -yl] methyl } - 3 -pyrrol idinol hydrochloride , FDMS m/e = 320 (M++H of free base) . N- ( (3S) -l-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2 -en-2 - yl] methyl} -3-pyrrolidinyl) acetamide hydrochloride, FDMS
m/e = 361 (M++H of free base). α[D]589 = -49.06 (c = 0.53
, methanol) . Mp 122-124 °C.
N- ( (3R) -l-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2 -en-2 - yl] methyl} -3-pyrrolidinyl) acetamide hydrochloride, FDMS m/e = 361 (M++H of free base) . [D]589 = 50.10 (c = 0.50
, methanol) . Mp 124-126 °C.
l-{ [3- (6-fluoro-l-benzothien-3-yl) bicyclo [2.2. l]hept-2- en-2-yl] methyl }pyrrolidine hydrochloride, FIA POS MS (M+H, 328.2)
l-{ [3- (3 -methyl-1-benzothien-5-yl) bicyclo [2.2.1] hept-2 - en-2 -yl] methyl}pyrrolidine hydrochloride, FIA POS MS (M+H, 324.1),
2, 2-dimethyl-l-{ [3- (2-naphthyl) bicyclo [2.2.1] hept-2-en- 2-yl] methyl}pyrrolidine hydrochloride, FIA POS MS (M+H, 332.2) ,
N-{ [3- (l-benzothien-7-yl) bicyclo [2.2.1] ept-2-en-2- yl]methyl} -N-methyl-2-propen-l-amine hydrochloride, FIA POS MS (M+H ,310.1) , [3- (l-benzothien-7-yl) bicyclo [2.2.1] hept-2-en-2-yl] -N- methylmethanamine hydrochloride, FIA POS MS (M+H ,270.1)
I\T,I\. -pyrrol idyl- [ (1R/S, 4R/S) -2- (2-naphthyl) bicyclo
[2.2.1] -2-hepten-3-yl] methylamine hydrochloride, FDMS m/e = 304 (M++H of free base) .
EXAMPLE 7 (+/-) -Dimethyl- [3- (5-fluorobenzo [£>] thiophen-2- yl) bicyclo [2.2.1] hept-2-en-2-yl] methylamine hydrochloride .
To a cooled solution (-78 °C) of 5-fluorobenzo [b] thiophene (1.00 g, 6.57 mmol) in anhydrous THF (20 mL) was added 1.6 M π-BuLi in hexanes (4.11 mL, 6.57 mmol) . The resulting solution was stirred at -78°C for 45 min. The cold bath was removed and 0.5 M zinc chloride in toluene (13.1 mL, 6.57 mmol) was added and the mixture was stirred for 15 min. A slurry of (+-) - trifluoromethanesulfonic acid 3 - dimethylaminomethyl bicyclo [2.2.1] hept-2-en-2-yl ester (1.48 g, 4.93 mmol), triphenylarsine (0.201 g, 0.657 mmol) and tris (dibenzylideneacetone)dipalladium(O) (0.301 g, 0.329 mmol) in anhydrous DMF (20 mL) was added to the reaction mixture via a canulla at room temperature. The reaction mixture was heated to reflux and stirred for 3 days. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. Xylenes were used to remove azeotropically the residual DMF. The residue was then partitioned between CHC12 (70 mL) and H20 (20 mL) .The layers were separated, and the aqueous layer was extracted with CH2C12 (1 x 100 mL) .The combined organic layers were dried over MgS0 and concentrated. The residue was purified by medium pressure chromatography (silica gel, 2% (2.0 M NH3 in MeOH) /CH2C12) to give the free base of the title compound as a clear oil (0.416 g, 28%) . The hydrochloride salt was prepared with 1.0 equiv. of HCl in EtOAc. Ion Spray MS (HCl) 302 (M+H)+, 257 (M-44 (-N (CH3) 2) ) + .
Similarly prepared were:
(+/-) -dimethyl- [3- (4-fluorobenzo [b] thiophen-2- yl) bicyclo [2.2.1] hept-2-en-2-yl] methylamine Hydrochloride , Ion Spray MS (HCl) 302 (M+H)+, 257 (M- 44(-N(CH3)2)) +
(+/-) -dimethyl- [3- (6-fluorobenzo [b] thiophen-2- yl) bicyclo [2.2.1] hept-2 -en-2 -yl] methylamine Hydrochloride , FDMS m/e = 301 M+ (+/-) -dimethyl- [3- (7-f luorobenzo [b] thiophen- 2- yl) bicyclo [2.2.1] hept-2 -en-2 -yl] methylamine Hydrochloride , Ion Spray MS (HCl) 302 (M+H)+, 257 (base peak) (M-44(-N(CH3)2))+ , 258 (M-43)"
EXAMPLE 8
(+/-) -Dimethyl- [3- ( 7 -methoxybenzo [b] thiophen-2- yl) bicyclo [2.2.1] hept-2 -en- 2-yl] methylamine hydrochloride
A slurry containing 7-methoxybenzo [b] thiophene-2- boronic acid (0.500 g, 2.40 mmol), trifluoromethane sulfonic acid 3-dimethylaminomethylbicyclo [2.2.1] hept-2 - en-2-yl ester (0.504 g, 1.68 mmol), lithium chloride (0.214 g, 5.05 mmol), tetrakis (triphenylphosphine) palladium(O) (0.099, 0.097 mmol) and 2.0 N Na2C03 (2.40 mL, 4.81 mmol) in 1, 2 -dimethoxyethane (6 mL) as heated to reflux and stirred for 2h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2C12 (20 mL) , 2.0 N Na2C03 (20 mL) and cone. NH4OH (1 mL) . The layers were separated and the aqueous layer was extracted with CH2C12 (1 x 30 mL) . The organic layers were combined and dried over MgS0 and concentrated. The residue was purified by medium pressure chromatography (silica gel, 1-3% (3.5 M NH3 in
MeOH) /CH2C12) to give the free base of the title compound as a brown semi-solid (0.036 g, 7%). The hydrochloride salt was prepared with 1.0 equiv. of HCl in EtOAc. m.p. 232-235 °C; FDMS m/e = 313 M+ .
EXAMPLE 9
(+/-) -3-
Figure imgf000058_0001
methylbicyclo [2.2.1] heptan-2 -one
To a solution of 3-methylene-bicyclo [2.2.1] eptan- 2-one (6.00 mL, 49.0 mmol) in anhydrous THF (55 mL) was added
Figure imgf000058_0002
. The solution was stirred at room temperature for 7 days. The reaction mixture was then concentrated under reduced pressure. The residue was purified by medium pressure chromatography (silica gel, 2% (2.0 M NH3 in MeOH) /CH2C12) to give the title compound as a yellow oil (11.48 g, 96%) . Ion Spray MS 244 (M+H)+
EXAMPLE 10
(+/-) -3- (N-Benzyl -N-methylamino) methyl-2- (6- fluorobenzo [b] thiophen-2-yl) bicyclo [2.2.1] heptan-2-ol
To a solution of a 1:6 mixture of 4- and 6- fluorobenzo [b] thiophene (1.00 g, 6.57 mmol) and TMEDA (4.96 mL, 32.9 mmol) in dry THF (20 mL) at -78 °C was added 1.6 M __-BuLi in hexanes (4.52 mL, 7.23 mmol). The solution was stirred at -78 °C for 55 min, and then 3- (N-benzyl-N-methylamino) ethylbicyclo [2.2.1] heptan-2 -one (1.60 g, 6.57 mmol) in THF (4 mL) was added via a canulla at -78 °C. The resulting bright red reaction mixture was stirred at -78 °C for 1.75 h. The reaction was then quenched with 30 mL of saturated aqueous NH4C1 solution. The mixture was extracted with CH2C12 (2 x 100 mL) . The combined organic layers were dried over MgS04 and filtered. The filtrate was concentrated and purified by medium pressure chromatography (silica gel, 5% EtOAc in hexanes) to give the title compound as a clear semi-solid (1.27 g, 49%). IR (CHC13) 3200 (br) cm"1 Ion Spray MS 396 (M+H)+.
EXAMPLE 11
(+/-) -2- (6-Fluorobenzo [b] thiophen-2-yl) -3- (N- methylamino) methylbicyclo [2.2.1] heptan-2 -ol
To a solution of ( + - ) -3 - (N-benzyl -N- methylamino) methyl-2- (6-fluorobenzo [b] thiophen-2 - yl) bicyclo [2.2.1] heptan-2 -ol (292 mg, 0.738 mmol) in a
1:1 THF:EtOH mixture (5 mL) was added 10% Pd/C (300 mg) .
The black slurry was stirred vigorously under an H2 atmosphere for 4 days. The slurry was diluted with EtOH, filtered over a pad of diatomaceous earth, and washed with EtOH. The filtrate was concentrated and the residue was purified by medium pressure chromatography (silica gel, 3% (2.0 M NH3 in MeOH) /CH2Cl2) to give the title compound as a white solid (0.031 g, 14%) . Ion Spray MS 306 (M+H)+, 245 (base peak) (M-60)+.
EXAMPLE 12
(+/-) - ( (3- (6-Fluorobenzo [b] thiophen-2- yl) bicyclo [2.2.1] hept-2-en-2-yl) methyl) methylamine hydrochloride
To a solution of (+-) -2- (6-fluorobenzo [Jb] thiophen- 2-yl) -3- (N-methylamino) methylbicyclo [2.2.1] heptan-2 -ol (0.029 g, 0.093 mmol) in dry CH2C12 (1.0 mL) at 0 °C was added 0.4 mL of trifluoroacetic acid. The solution was stirred at 0 °C for 2 h. The reaction was then quenched with saturated aqueous ΝaHC03 solution (7 mL) . The mixture was extracted with CH2C12 (2 x 25 mL) . The combined organic layers were dried over MgS0 and concentrated. The residue was purified by medium pressure chromatography (silica gel, 3% (2.0 M NH3 in MeOH) /CH2C12) to give the free base of the title compound as a brown semi-solid (0.021 g, 78%). The hydrochloride salt was prepared with 1.0 equiv. of HCl in EtOAc. FDMS (HCl) m/e = 287 M+
Similarly prepared were: [ (1R,4S) -3- (1,3 -benzothiazol-2-yl) bicyclo [2.2.1] hept-2- en-2-yl] -N-methylmethanamine succinate, MS ESP+ (M+, 305.0)
[ (1R,4S) -3- (6-chloro-l, 3 -benzothiazol-2- yl) bicyclo [2.2.1] hept-2 -en-2-yl] -N-methylmethanamine succinate, FIA POS MS ( M+H 271.0)
N-benzyl -N- { [3- (6-methoxy-2 -naphthyl) bicyclo [2.2. l]hept- 2 -en-2 -yl] methyl} -N-methylamine hydrochloride, mp 178- 180°C
EXAMPLE 13 (4-Bromobenzo [b] thiophen-2-yl) trimethylsilane
Into a stirred solution of diisopropylamine (1.08 mL,
7.74 mmol) and TMEDA (2.54 mL, 16.89 mmol) in THF (15 mL, freshly distilled) at 0 °C was added 1.6 M n-BuLi
(5.27 mL, 8.44 mmol) via a syringe. The solution was stirred for 30 min at 0 °C and was then cooled to -78 °C, and a solution of 4-bromobenzo [b] thiophene (1.5 g, 7.03 mmol) in THF (7 mL) was added via a cannula. After stirring for 30 min, a solution of TMSCl (1.07 mL, 8.44 mmol) in THF (8 mL) was added via a cannula. The solution was stirred overnight, while allowed to warm to room temperature. The solution was then concentrated under reduced pressure. Saturated aqueous NaHC03 (100 mL) was added and the mixture was extracted with CH2C12 (4 x 80 mL) . The organic layers were combined, dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography [100% hexanes] . The purified fractions were combined and concentrated under reduced pressure to give (4-bromobenzo [b] thiophen-2-yl) trimethylsilane as a clear oil (1.7458 g, 87%). IR (KBr) 2959, 972, 853, 838 cm"1. El MS 286.2 (M + H)+, 271.1 (M - CH3) +
EXAMPLE 14
(+/-) -3- (N, N-Dimethylamino) methyl-2- (2-trimethyl silylbenzo [b] thiophen-4-yl) bicyclo [2.2.1] heptan-2-ol
Into a stirred solution of diisopropylamine (0.493 mL, 3.52 mmol) and TMEDA (1.16 mL, 7.689 mmol) in THF (6.5 mL, freshly distilled) at -78 °C was added 1.6 M n-BuLi (2.40 mL, 3.84 mmol) via a syringe. The' solution was warmed to 0 °C for 20 min and re-cooled to -78 °C. A solution of 4-bromobenzo [b] thiophene (0.6828 g, 3.204 mmol) in THF (3.25 mL) was added via a cannula. After stirring for 20 min, a solution of TMSCl (0.488 mL, 3.84 mmol) in THF (3.25 mL) was added via a cannula. The solution was stirred overnight, while allowed to warm to room temperature. Saturated aqueous NH4C1 (10 mL) was added and the mixture was extracted with Et20 (3 x 15 mL) . The organic layers were combined, dried over MgS04, filtered and concentrated under reduced pressure to give 4-bromo-2 -trimethylsilylbenzo [b] thiophene as a gold oil (0.845 g, 92%). Into a solution of crude 4-bromo-2- trimethylsilylbenzo [b] thiophene (0.500 g, 1.75 mmol) and TMEDA (1.32 L, 8.76 mmol) in THF (5 mL) cooled at -78 °C was added 1.6 M zz-BuLi (1.20 mL, 1.927 mmol) via a syringe. After stirring for 30 min, a solution of (+/- ) -3- (N/ N-dimethylamino) methylbicyclo [2.2.1] heptan-2-one, (0.293 g, 1.75 mmol) in THF (2 mL) was added via a cannula. After stirring overnight, the solution was diluted with H20 (25 mL) and saturated aqueous NHC1 (25 mL) . The mixture was extracted with EtOAc (3 x 50 mL) , dried over MgS0 , filtered and concentrated under reduced pressure. The residue was then purified by silica gel chromatography (2% (2.0 M NH3 in
MeOH) /CH2C12) . The purified fractions were concentrated under reduced pressure and placed under vacuum to give the title compound as a yellow oil. (0.3351 g, 51%) . IR (KBr) 3005, 2959, 1251, 993, 842 cm"1. Ion Spray MS 374.2 (M +H)+. EXAMPLE 15
(+/-) - ( (3- (Benzo [J] thiophen-4-yl) bicyclo [2.2.1] -hept-2- en-2-yl) methyl) dimethylamine
Into a solution of (+/-) -3- (N/ N-dimethylamino) methyl-2- (2 -trimethylsilylbenzo [Jb] thiophen-4-yl) bicyclo [2.2.1] heptan-2-ol, (0.2958 g, 0.791 mmol) in CH2C12 (7.9 mL) cooled at 0 °C was added TFA (3.1 mL) , while stirring. After 2 h, TBAF (1.58 mL, 1.58 mmol, 1.0 M in THF) was added via an addition funnel. The mixture was stirred for 3 h, and then concentrated under reduced pressure. The oily residue was diluted with saturated aqueous NaHC03 (50 mL) and extracted with CH2C12 (3 x 50 mL) . The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3% (2.0 M NH3 in MeOH) /CH2C12) . The purified fractions were concentrated under reduced pressure and placed under vacuum. The title compound turned to a white solid upon standing (0.2095 g, 93%). mp 73.5-76.9 °C. IR (KBr) 2950, 2870, 2820, 2777, 1454 cm"1. Ion Spray MS 284.1 (M + H)+; 239.0 (M - N(CH3)2)'.
Similarly prepared were: - -
(+/-) - ( (3- (Benzo [Jb] thiophen-7-yl) bicyclo [2.2.1] -hept-2 -
en-2 -yl) methyl) dimethylamine , mp 79.6-80.5 °C . IR (KBr) 2949, 2870, 2820, 2777, 1456 cm"1. Ion Spray MS 5 284.1 (M + H)+; 239.0 (M - N(CH3)2) +
(+/-) -Dimethyl ( (3- (2-methylbenzo [b] thiophen-5- yl) bicyclo [2.2.1] -hept-2 -en-2 -yl) methyl) amine , IR (KBr) 2962, 2950, 2921, 2870, 2819, 2775, 1446 cm"1. FD+ MS 10 297.3 (M) +
EXAMPLE 16
(+/-) -Dimethyl ( (3- (2-methylbenzo [b] thiophen-5- yl) bicyclo [2.2.1] -hept-2-en-2-yl) methyl) amine 15. hydrochloride
Into a solution of (+/-) -dimethyl ( (3- (2-methylbenzo [Jb] thiophen-5-yl) bicyclo [2.2.1] -hept-2-en-2- yl) methyl) amine, (0.26740 g, 0.898 mmol) in MeOH (1 mL) 20 was added HCl (0.90 mL, 0.898 mmol, 1.0 M in Et20) , while stirring. The mixture was stirred for 10 min, diluted with H20 (20 mL) , and lyophilized to afford an off-white powder, (0.2953 g, 98%). mp 206.5-214.2 °C. Ion Spray MS 298.1 (M + H) + ; 253.0 (M - N(CH3)2) + .
25
Similarly prepared were: N,N-dimethyl [3- (2-methyl-l-benzothien-4- yl) bicyclo [2.2.1] hept-2-en-2-yl] methanamine
hydrochloride, mp 181.6-189.1 °C . IR (KBr) 2967, 1473 cm"1. Ion Spray MS 298.1 (M + H)+; 253.0 (M - N(CH3)2) +
N,N-dimethyl [ (1R,4S) -3- (2-methyl-l-benzothien-6- yl) bicyclo [2.2.1] hept-2-en-2 -yl] methanamine hydrochloride, mp 68.2 °C (dec.) . Ion Spray MS 298.3 (M
+ H)+; 253.2 (M - N(CH3)2) +
N,N-dimethyl [3- (2-methyl-l-benzothien-7- yl) bicyclo [2.2.1] hept-2-en-2-yl] methanamine hydrochloride, mp 179.5-181.6 °C. Ion Spray MS 298.3 (M
+ H) +; 253.2 (M - N(CH3)2) +
[3- (2-fluoro-l-benzothien-5-yl) bicyclo [2.2.1] hept-2-en-
2-yl] -N, N-dimethylmethanamine , maleic acid, mp 168.1-
168.8°C
[3- (3-chloro-l-benzothien-5-yl) bicyclo [2.2. l]hept-2-en- 2-yl] -N, N-dimethylmethanamine hydrochloride, mp 223-226°C
N,N-dimethyl [3- (3 -methyl-1-benzothien-5- yl) bicyclo [2.2.1] hept-2-en-2-yl] methanamine hydrochloride, FIA POS MS (M+H, 298.1) N,N-dimethyl [3- (3 -methyl -1-benzothien-7- yl) bicyclo [2.2.1] hept-2 -en-2 -yl] methanamine hydrochloride, mp 236-239°C
N,N-dimethyl [3- (3-methyl-1-benzothien-6- yl) bicyclo [2.2.1] hept-2 -en-2-yl] methanamine hydrochloride, mp 131-134 °C
N,N-dimethyl [3- (3-methyl-l-benzothien-4- yl) bicyclo [2.2.1] hept-2 -en-2 -yl] ethanamine hydrochloride, mp 225 °C
[ (1R,4S) -3- (1-benzothien-5-yl) bicyclo [2.2.1] hept-2 -en-2- yl] -N,N-dimethylmethanamine hydrochloride, mp 236.4- 236.7°C
[ (1S,4R) -3- (1-benzothien-5-yl) bicyclo [2.2.1] hept-2-en-2 - yl] -N,N-dimethylmethanamine hydrochloride, mp 236.4- 236.6°C
[ (1R,4S) -N,N-dimethyl-3- (l-benzothien-4- yl) bicyclo [2.2.1] hept-2 -en-2 -yl] -methanamine hydrochloride, mp 254-257°C, [ (IS, 4R) -N,N-dimethyl -3- (l-benzothien-4- yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride, mp 249-251°C,
[N-methyl- (3 - (3 -methyl-1-benzothien-7- yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride,
[ (1R,4S) -N,N-dimethyl-3- (l-benzothien-7- yl) bicyclo [2.2.1] hept-2 -en-2 -yl] - methanamine hydrochloride ,
[ (1S,4R) -N,N-dimethyl-3- (l-benzothien-7- yl) bicyclo [2.2.1] hept-2 -en-2-yl] - methanamine hydrochloride,
[N,N-dimethyl 3- (2 -methoxymethyl-1-benzothien-6- yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride, mp 184 -187 °C,
[N,N-dimethyl 3- (2 -hydroxymethyl-1-benzothien-6- yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride, mp 183 -186 °C,
[N,N-dimethyl 3- (2- {prop-2 -enyl } -1-benzothien-6- yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride, mp 160°C (decomposed),
[N-methyl-3- (l-benzothien-4-yl) bicyclo [2.2.1] hept-2-en- 2-yl] -methanamine hydrochloride, mp 216-218°C,
[N-methyl-3 - (6-fluoro-1-benzothien-3 - yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride, mp 237-240 °C, [(1R,4S) -N-methyl-3- (1-benzothien-7- yl) bicyclo [2.2.1] hept-2 -en-2 -yl] - methanamine hydrochloride, mp 182-183 °C,
[ (1S,4R) -N-methyl-3- (l-benzothien-7- yl) bicyclo [2.2.1] hept-2-en-2-yl] - methanamine hydrochloride, mp 181-183 °C,
[ (1R,4S) -N,N-dimethyl-3- (3-methyl-l-benzothien-7- yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride, mp 256 °C,
[ (1S,4R) -N,N-dimethyl-3- (3-methyl-l-benzothien-7- yl) bicyclo [2.2.1] hept-2 -en-2 -yl] -methanamine hydrochloride, mp 256 °C,
[ (1R,4S) -N,N-dimethyl-3- (l-benzothien-2- yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride, mp 250-251 °C,
[ (IS, 4R) -N,N-dimethyl-3- (l-benzothien-2- yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride, mp 251-252 °C,
[(1R,4S) -N-methyl- (3- (3 -methyl-1-benzothien-7- yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride, mp 196 °C,
[ (1S,4R) -N-methyl- (3- (3-methyl-l-benzothien-7- yl) bicyclo [2.2.1] hept-2 -en-2 -yl] -methanamine hydrochloride, mp 247-249 °C, [N-methyl- (3- (3-methyl-1-benzothien-6- yl) bicyclo [2.2.1] hept-2 -en-2 -yl] -methanamine hydrochloride, mp 205-206°C,
[ (1R,4S) -N-methyl- (3- (l-benzothien-7- yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride, mp 229-233°C,
[ (1S,4R) -N-methyl- (3- (l-benzothien-7- yl) bicyclo [2.2.1] hept-2 -en-2 -yl] -methanamine hydrochloride, mp 224-227°C,
[N-methyl- (3- (5-fluoro-l-benzothien-7- yl) bicyclo [2.2.1] hept-2 -en-2-yl] -methanamine hydrochloride, mp 220 °C,
[N-methyl- (3- (3-cyano-l-benzothien-5- yl) bicyclo [2.2.1] hept-2 -en-2 -yl] -methanamine hydrochloride, mp 260-261°C,
[N-methyl- (3- (1-benzofuran-5-yl) bicyclo [2.2.1] hept-2 -en- 2 -yl] -methanamine hydrochloride, mp 78.8-79.4°C,
[ (1R,4S) -N-methyl-3- (6-fluoro-l-benzothien-3- yl) bicyclo [2.2.1] hept-2-en-2-yl] -methanamine hydrochloride, mp 250-252°C,
[ (1S,4R) -N-methyl-3- (6-fluoro-l-benzothien-3- yl) bicyclo [2.2.1] hept-2 -en-2 -yl] -methanamine hydrochloride, mp 251-253 °C,
EXAMPLE 17 (+/-) -3- (N/ N-Dimethylamino) methylbicyclo [3.2. l]octan-2- one
Into a slurry of bicyclo [3.2.1] octan-2-one (1.50 g, 12.07 mmol), dimethylamine hydrochloride (1.28 g, 15.70 mmol), and paraformaldehyde (0.478 g, 5.31 mmol) in
EtOH (15 mL) was added concentrated HCl (0.4 mL) , while stirring. The mixture was stirred at reflux for 3 days and concentrated under reduced pressure. Upon standing, crystals formed. The crystals were suspended in Et20 (10 mL) and acetone (1 mL) for 15 min. The crystals were filtered and washed with Et20. The crystals were then dissolved in saturated aqueous NaHC03 (50 mL) , forming the free base, and extracted with Et20 (3 x 50 L) . The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. After being placed under vacuum, the title compound was obtained as a yellow oil, (1.1963 g, 54%). IR (KBr) 2947,1703 cm"1. Ion Spray MS 182.1 (M + H)+.
EXAMPLE 18
3- { [allyl (methyl) amino] methyl} -bicyclo [3.2.1] octan-2-one
Bicyclo [3.2.1] octan-2-one (1.24 g, 10 mmol) was place in a 50 mL round bottomed flask equipped with a stirrer bar. A solution of dimethyl amine (10 mL, 20 mmol, 2.0 M solution in MeOH) was added followed by 40% aqueous formaldehyde solution (1.5 mL, 20mmol) and c HCl (1 mL) . The resulting solution was heated with stirring at 70 °C overnight. After cooling to room temperature the solvents were evaporated in vacuo. The residue was then partitioned between EtOAc and saturated aqueous Na2C03 and the layers separated. The organic extract was washed with brine and dried over anh. MgS04, filtered and the solvent evaporated to give a brown oil (1.70 g, 9.4 mmol), FIA [M+l] =182.1. This oil was then taken up in MeOH (15 mL) and Mel (5 mL) added. Resulting solution was stirred at room temperature overnight . The solvents were evaporated in vacuo and the resulting residue taken up in DCM (25 mL) and 5% aqueous NaHC03 (25 mL) added. This solution was stirred at room temperature overnight. Layers separated and aqueous extract re- extracted with DCM. Organic extracts combined, dried over anh. MgS04, filtered and the solvent evaporated in vacuo to give a gum (1.07 g, 8.8 mmol) . This gum was taken up in MeOH (10 mL) and N- methylallyl amine (910 μL, 9.5 mmol) added and stirred at room temperature overnight . The solvent was evaporated to give the desired product as a yellow oil (1.12' g, 5.4mmol). Mass spec, positive FIA [M+H] =208.1.
EXAMPLE 19 3- (1-pyrrolidinylmethyl) bicyclo [3.2.1] octan-2-one
3- (N/ N-Dimethylamino) methylbicyclo [3.2.1] octan-2-one (2.0 g, 11 mmol) was taken up in MeOH (18 mL) and methyl iodide (6 mL) added with stirring. The reaction was stirred at room temperature overnight. Solvents evaporated and the residue re-suspended in DCM (30 mL) and 5% aqueous NaHC03 (30 mL) was added. The resulting solution was stirred at room temperature overnight. Layers separated and aqueous extract re-extracted with DCM. Organic extracts combined, dried over anh. MgS04, filtered and the solvent evaporated in vacuo to give a brown oil (1.38 g, lO.lmmol) . ) . This oil taken up in MeOH (10 mL) and pyrrolidine (763μL, 9.1 mmol) added. The resulting solution was stirred at room temperature overnight and the solvents evaporated in vacuo to the desired product as an oil (1.91 g, 9.22 mmol) . Mass spec, positive FIA [M+H] =208.1.
Similarly prepared was:
3- (1-azetidinylmethyl) bicyclo [3.2.1] octan-2-one, Mass spec, positive FIA [M+H] =193.1. EXAMPLE 20
(+/-) -3- (N,N-Dimethylamino) methyl-2- (5- fluorobenzo [b] thiophen-2-yl) bicyclo [3.2.1] octan-2-ol
Into a stirred solution of 5-fluorobenzo [b] thiophene
(0.209 mL, 1.379 mmol) and TMEDA (1.04 mL, 6.89 mmol) in THF (4 mL, freshly distilled) at -78 °C was added 1.6 M n-BuLi (0.95 mL, 1.51 mmol) via a syringe. After stirring for 40 min, a solution of (+/-) -3- (N, N- dimethylamino) ethylbicyclo [3.2.1] octan-2-one (0.250 g, 1.379 mmol) in THF (2 mL) was added via a cannula. The solution was stirred overnight, while allowed to warm to room temperature, and concentrated under reduced pressure. The residue was diluted with saturated aqueous NaHC03 (50 mL) . The mixture was extracted with CH2C12 (3 x 40 mL) . The organic layers were combined, dried over MgS0 , filtered and concentrated under reduced pressure. The residue was then purified by silica gel chromatography (3.5% (2.0 M NH3 in MeOH) /CH2C12) . The purified fractions were concentrated under reduced pressure and placed under vacuum, resulting in the title compound, (+/-) -3- {N,N- dimethylamino) methyl-2- (5-fluorobenzo [jb] thiophen-2- yl) bicyclo [3.2.1] octan-2-ol as a white foam (0.2912 g, 63%). IR (KBr) 3004, 2952, 2863, 2831, 2787, 1443 cm"1. Ion Spray MS 334.0 (M + H)+. similarly prepared was:
3- { [allyl (methyl) amino] methyl} -2- [3 -methyl-2- (trimethylsilyl) -l-benzothien-5-yl] bicyclo [3.2.1] octan- 2-ol, Mass spec, positive FIA [M+H] =440.
EXAMPLE 21
3- [ (dimethylamino) methyl] -2- (6-fluoro-2-naphthyl) bicyclo [3.2.l]octan-2-ol
The enantiomers of 3- [ (dimethylamino) methyl] -2- (6- fluoro-2 -naphthyl) bicyclo [3.2.1] octan-2-ol were separated by chiral preparative chromatography, using a CHIRALPAK- AD colunm, and a mixture of Hexane / Ethanol 50/50. s the eluant, FIA Pos MS (M+H, 328.1).
EXAMPLE 22
(+/-) -dimethyl ( (2- (5-fluorobenzo [b] thiophen-2- yl) bicyclo [3.2.1] -oct-2 -en-3-yl) methyl) amine hydrochloride
Into a solution of (+/-) -3- (N, N-dimethylamino) methyl-2 - (5-fluorobenzo [Jb] thiophen-2-yl) bicyclo [3.2.1] octan-2-
ol, (0.212 g, 0.637 mmol) in CH2C12 (7 mL) cooled at 0 °C was added TFA (2.5 mL) , while stirring. The mixture was stirred for 3 days, and diluted with saturated aqueous NaHC03 (50 mL) . The mixture was extracted with CH2C12 (3 x 50 mL) . The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (4% (2.0 M NH3 in MeOH) /CH2Cl2) . The purified fractions were concentrated under reduced pressure and placed under vacuum, resulting in (+/-) -Dimethyl ( (2- (5- fluorobenzo [b] thiophen-2-yl) bicyclo [3.2.1] -oct-2-en-3- yl) methyl) amine as a yellow oil, (0.1697 g, 84%) . IR (KBr) 2943, 2864, 2824, 1604, 1444 cm"1. Ion Spray MS 316.1 (M + H)+; 271.1 (M - N(CH3)2) + .
Into a solution of (+/-) -dimethyl ( (2- (5- fluorobenzo [b] thiophen-2-yl) bicyclo [3.2.1] -oct-2 -en-3- yl) methyl) amine, (0.1346 g, 0.426 mmol) in MeOH (1 mL) • was added HCl (0.42 mL, 0.426 mmol, 1.0 M in Et20) , while stirring. The mixture was stirred for 10 min and diluted with H20 (15 mL) and just enough CH3CN to dissolve the salt (1 mL) . The mixture was then lyophilized to afford a white powder, (0.1487 g, 99%) . mp 197.9-203.8 °C. Ion Spray MS 316.3 (M + H)+; 271.2 (M - N(CH3)2) + .
Similarly prepared were :
N,N-dimethyl [2- (2-naphthyl) bicyclo [3.2.1] oct-2-en-3- yl] methanamine, maleic acid, mp 164-166°C N,N-dimethyl [2- (6-fluoro-2-naphthyl) bicyclo [3.2.1] oct- 2 -en-3-yl] methanamine, maleic acid,mp 172-174°C
N,N-dimethyl [ (IS, 5R) -2- (6-fluoro-2 -naphthyl) bicyclo
[3.2.1] oct-2 -en-3-yl] methanamine , maleate, FIA Pos mass spec, (M+H 310.2)
N,N-dimethyl [ (IR, 5S) -2- (6-fluoro-2 -naphthyl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine , maleate, FIA Pos mass spec, (M+H 310.2/ 311.1)
[2- (7-fluoro-l-benzothien-2-yl) bicyclo [3.2. l]oct-2-en- 3-yl] -N,N-dimethylmethanamine hydrochloride, mp 210.3- 214.7 °C. Ion Spray MS 316.3 (M + H)+; 271.1 (M - N(CH3)2) +
[2- (4-fluoro-1-benzothien-2-yl) bicyclo [3.2.1] oct-2 -en-3- yl] -N, N-dimethylmethanamine hydrochloride, mp 216.1- 218.4 °C. Ion Spray MS 316.0 (M + H) +
[2- (6-fluoro-l-benzothien-2-yl) bicyclo [3.2.1] oct-2 -en-3- yl] -N,N-dimethylmethanamine hydrochloride, mp 207.4- 211.1 °C. Ion Spray MS 316.0 (M + H)+; 270.9 (M - N(CH3)2) + [ (1S,5R) -2- (6-fluoro-l-benzothien-2-yl) bicyclo [3.2.1] oct-2-en-3-yl] -N, N-dimethylmethanamine hydrochloride, LC-MS (M+H, 316.1, 98.1%)
[ (IR, 5S) -2- (6-fluoro-l-benzothien-2-yl) bicyclo [3.2.1] oct-2-en-3-yl] -N, N-dimethylmethanamine hydrochloride, FIA POS MS (M+H, 316.1)
[2- (6-fluoro-l-benzothien-3-yl) bicyclo [3.2.1] oct-2 -en-3* yl] -N, N-dimethylmethanamine hydrochloride, FIA POS MS (M+H, 316.2)
2- {3- [ (dimethylamino) methyl] bicyclo [3.2.1] oct-2 -en-2 - yl}-l-benzothiophene-6-carbonitrile hydrochloride, FIA POS MS (M+H, 323)
[2- (6-trifluoro-l-benzothien-3-yl) bicyclo [3.2.1] oct-2- en-3-yl] -N,N-dimethylmethanamine hydrochloride , mp 155- 158°C
N,N-dimethyl [3- (2-naphthyl) bicyclo [2.2.2] oct-2-en-2- yl] methanamine, maleate, mp 205 °C
[3- (6-methoxy-2-naphthyl)bicyclo[2.2.2] oct-2-en-2-yl] - N, N-dimethylmethanamine, maleate, mp 177 °C [3- (l-benzothien-3-yl) bicyclo [2.2.2] oct-2-en-2-yl] -N,N- dimethylmethanamine , maleate ,mp 181°C
6- {3- [ (dimethylamino) methyl] bicyclo [2.2.2] oct-2-en-2- yl}-2-naphthol , maleate, mp 196 °C
[3- (6-fluoro-2 -naphthyl) bicyclo [2.2.2] oct-2-en-2-yl] - N, N-dimethylmethanamine , maleate, mp 198 °C
[3- (6-fluoro-1-benzothien-3 -yl) bicyclo [2.2.2] oct-2 -en-2 - yl] -N, N-dimethylmethanamine hydrochloride, FIA POS MS (M+H, 316.1)
l-{ [3- (1-benzothien-5-yl) bicyclo [3.2.1] oct-2 -en-2 - yl] methyl}pyrrolidine hydrochloride, LC-MS pos m/z (M+H, 324, 100%), mp 135-138°C
l-{ [3- (l-benzothien-5-yl) bicyclo [3.2.1] oct-2-en-2- yl] methyl }azetidine hydrochloride, LC-MS pos m/z (M+H, 310, 100%) , mp 97-99°C
l-{ [3- (3-methyl-l-benzothien-5-yl) bicyclo [2.2.2]oct-2- en-2-yl] methyl}pyrrolidine hydrochloride, FIA POS MS (M+H ,338.6) [3- (l-benzothien-7-yl) bicyclo [2.2.2] oct-2-en-2-yl] -N- methylmethanamine hydrochloride, FIA POS MS (M+H ,284.1)
N-allyl-N-methyl- [3- (l-benzothien-5- yl) bicyclo [2.2.2] oct-2 -en-2-yl] -methanamine hydrochloride, mp 218-221°C,
N,N-dimethyl- [3- (3-methyl-l-benzothien-7- yl) bicyclo [2.2.2] oct-2-en-2-yl] -methanamine hydrochloride, mp 236-237°C,
N,N-dimethyl- [3- (l-benzothien-2-yl) bicyclo [2.2.2] oct-2- en-2-yl] -methanamine hydrochloride, mp 226-228°C,
EXAMPLE 23
(+/-) -dimethyl [3 -methyl-1-benzothien-5- yl] bicyclo [3.2.1] octan-2-ol
3-methyl-2- [3-methyl-2- (trimethylsilyl) -l-benzothien-5- yl] bicyclo [3.2. l]octan-2-ol (2.47 g, 6.2 mmol) was taken up in THF (20 mL) with stirring. A solution of TBAF (6.2 mL, IM solution in THF with 5 wt . % water ex. Aldrich) was added and the resulting solution stirred at room temperature for 3 h. The solvents were evaporated and the residue taken up in ethyl acetate and washed with 5% NaHC03 solution and brine. After drying over MgS04 the solvent was removed in vacuuo to give an oil which was purified by column chromatography (hex: EtOAc, 8:2) . Gave the desired product as an oil (1.12 g, 3.2 mmol) . Mass spec, positive FIA [M+H] =330.2.
EXAMPLE 24 [2- (1-Benzothien-5-yl) bicyclo [3.2.1] oct-2-en-3-yl] -N,N- dimethylmethanamine hydrochloride
[2- (1-benzothien-5-yl) -3- [ (dimethylamino) methyl] bicyclo [3.2.1] octan-2-ol (1.0 g, 3.1 mmol) was treated with p-toluene sulfonic acid (2.67 g, 15 mmol, 5 equiv) in DCM (30 mL) . The reaction was heated at reflux overnight . DCM was removed in vacuo and the residue taken up in ethyl acetate and washed successively with IM NaOH solution (x5) , brine, dried over anh. MgS04 and concentrated in vacuo to give an oil (880 mg, 2.83 mmol), Ion Spray MS 298.2 (M + H)+; 253.1 (M - N(CH3)2) + Into a solution of [2- (l-benzothien-5-yl) bicyclo [3.2.1] oct-2 -en-3 -yl] -N, N-dimethylmethanamine (880 mg, 2.83 mmol) in MeOH (1 mL) was added HCl (0.29 mL, 2.83 mmol, 1.0 M in Et20) , while stirring. The mixture was stirred for 10 min and diluted with H20 (15 mL) and just enough CH3CN to dissolve the salt (1 mL) . The mixture was then lyophilized to afford a white powder, [2- (1-benzothien- 5-yl) bicyclo [3.2.1] oct-2 -en-3-yl] -N,N- dimethylmethanamine hydrochloride , mp 57.8 °C. Similarly prepared was:
N-allyl-N-methyl-N-{ [2- (3-methyl-l-benzothien-5- yl) bicyclo [3.2.1] oct-2-en-3 -yl] methyl}amine, Mass spec. positive FIA [M+H] =338.3.
[ (1R,5S) -2- (l-benzothien-5-yl) bicyclo [3.2.1] oct-2-en-3- yl] -N, N-dimethylmethanamine hydrochloride, mp 225.3- 225.6°C
[ (IS, 5R) -2- (1-benzothien-5-yl) bicyclo [3.2.1] oct-2-en-3- yl] -N,N-dimethylmethanamine hydrochloride, mp 225.6- 226.0°C
[2- (1-benzothien-6-yl) bicyclo [3.2.1] oct-2 -en-3 -yl] -N-dimethylmethanamine hydrochloride, mp 81.5 °C. Ion Spray MS 298.1 (M + H)+; 253.0 (M - N(CH3)2) +
[2- (l-benzothien-4-yl) bicyclo [3.2.1] oct-2-en-3-yl] -N,N- dimethylmethanamine hydrochloride, mp 182.4 °C. Ion Spray MS 298.2 (M + H) +; 253.1 (M - N(CH3)2) +
[ (1S,5R) -2- (l-benzothien-4-yl) bicyclo [3.2.1] oct-2 -en-3- ' yl] -N, N-dimethylmethanamine hydrochloride, LC-MS (M+H, 298.1, 100%) [ (1R,5S) -2- (l-benzothien-4-yl) bicyclo [3.2.1] oct-2 -en-3- yl] -N,N-dimethylmethanamine hydrochloride, LC-MS (M+H, 298.1, 100%)
[2- (l-benzothien-7-yl) bicyclo [3.2.1] oct-2-en-3-yl] -N,N- dimethylmethanamine hydrochloride, mp 205.0 °C (dec.) . Ion Spray MS 298.1 (M + H)+; 253.1 (M - N(CH3)2) +
[ (1S,5R) -2- (1-benzothien-7-yl) bicyclo [3.2.1] oct-2 -en-3- yl] -N,N-dimethylmethanamine hydrochloride, mp 244-245°C
[ (1R,5S) -2- (l-benzothien-7-yl) bicyclo [3.2.1] oct-2-en-3- yl] -N, N-dimethylmethanamine hydrochloride, mp 245-246°C
[2- (3-chloro-l-benzothien-5-yl) bicyclo [3.2.1] oct-2-en-3- yl] -N,N-dimethylmethanamine hydrochloride, mp 233-235°C
N,N-dimethyl [-2- (3 -methyl-1-benzothien-5- yl) bicyclo [3.2.1] oct-2-en-3-yl] ethanamine hydrochloride, FIA POS- MS (M+H , 312.1)
N,N-dimethyl [ (IS, 5R) -2- (3 -methyl-1-benzothien-5- yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride, FIA POS MS (M+H ,312.1) N,N-dimethyl [ (IR, 5S) -2- (3 -methyl-1-benzothien-5- yl) bicyclo [3.2.1] oct-2 -en-3 -yl] methanamine hydrochloride, FIA POS MS (M+H ,312.1)
N,N-dimethyl [2- (3-methyl-l-benzothien-7-yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride,
[3- (1-benzothien-5-yl) bicyclo [2.2.2] oct-2 -en-2-yl] -N,N- dimethylmethanamine hydrochloride ,mp 209.7-210.0°C
[3- (1-benzothien-6-yl) bicyclo [2.2.2] oct-2 -en-2 -yl] -N,N- dimethylmethanamine hydrochloride, mp 206.4-206.9°C
[3- (3-chloro-l-benzothien-5-yl)bicyclo [2.2.2] oct-2-en-2* yl] -N, N-dimethylmethanamine hydrochloride, mp 224.6- 225.9°C
N,N-dimethyl [3- (3 -methyl-1-benzothien-5-yl) bicyclo [2.2.2] oct-2-en-2-yl] methanamine hydrochloride, FIA POS MS (M+H ,312.1)
[3- (1-benzothien-7-yl) bicyclo [2.2.2] oct-2 -en-2 -yl] -N,N- dimethylmethanamine hydrochloride,mp 254-256°C [3- (l-benzothien-4-yl) bicyclo [2.2.2] oct-2-en-2-yl] -N,N- dimethylmethanamine hydrochloride, mp 207.8-209.9 °C
N,N-dimethyl- [ (IS, 5R) -2- (3-chloro-l-benzothien-5- yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride,
N,N-dimethyl- [ (1R,5S) -2- (3-chloro-l-benzothien-5- yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride,
N,N-dimethyl- [ (IS, 5R) -2- (6-fluoro-l-benzothien-3- yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride, mp 248-249°C,
N,N-dimethyl- [ (1R,5S) -2- (6-fluoro-l-benzothien-3- yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride, mp 248-249 °C,
N,N-dimethyl- [ (1S,5R) -2- (3 -methyl-1-benzothien-7- yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride, mp 254 °C,
N,N-dimethyl- [ (1S,5R) -2- (3 -methyl-1-benzothien-7- yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride, mp 256-258°C, N,N-dimethyl- [ (1S,5R) -2- (6-fluoro-naphth-2- yl) bicyclo [3.2.1] oct-2 -en-3 -yl] methanamine hydrochloride, mp 207-208°C,
N,N-dimethyl- [ (IR, 5S) -2- (6-fluoro-naphth-2- yl) bicyclo [3.2.1] oct-2 -en-3 -yl] methanamine hydrochloride, mp 214-215 °C,
EXAMPLE 25
N-Methyl-N-{ [2- (3-methyl-l-benzothien-5- yl) bicyclo [3.2.1] oct-2-en-3 -yl] methyl}amine, hydrochloride salt,
N-allyl-N-methyl-N-{ [2- (3 -methyl-l-benzothien-5- yDbicyclo [3.2.1] oct-2 -en-3-yl] methyl}amine (880 mg, 2.61 mmol) was taken up in dry, degassed DCM (10 mL) under N2 atmosphere. This solution was transferred via a cannular into a second flask containing Pd(PPh3)4 (59 mg, 0.052 mmol) and 1, 3-dimethylbarbituric acid (1.22 g, 7.83 mmol) . The resulting solution was stirred at 40 °C for 5 h. Reaction cooled to room temperature and diluted with DCM. The resulting solution was washed with saturated Na2C03 solution (x5) , dried over anh. MgS04 and concentrated in vacuo to give an oil which was purified by column chromatography (MeOH:DCM, 1:9 an 1% of 2M NH3/MeOH solution) to give a gum (360 mg, 1.21 mmol) . This was converted to the HCl salt using 1. OM solution HCl in ether to give the desired product as a white solid. MP=204.5-206.7 and mass spec, positive FIA [M+H] =298.2
Similarly prepared was:
[3- (6-fluoro-2 -naphthyl) bicyclo [3.2.1] oct-2-en-2-yl] -N- methylmethana ine , hydrochloride salt,mp 200.4-202.8°C,
N-methyl- [3- (3-methyl-l-benzothien-7- yl) bicyclo [2.2.2] oct-2 -en-2 -yl] -methanamine hydrochloride, mp 200 °C (decomposed) ,
N-methyl- [3- (6-f luoro- l-benzothien-3- yl) bicyclo [2.2.2] oct-2 -en-2 -yl] -methanamine hydrochloride, mp 269-270 °C,
N-methyl- [3- (l-benzothien-4-yl) bicyclo [2.2.2] oct-2-en-2- yl] -methanamine hydrochloride,
N-methyl- [3- (3-methyl-l-benzothien-5- yl) bicyclo [2.2.2] oct-2 -en-2 -yl] -methanamine hydrochloride, mp 229-233°C,
N-methyl- [3- (1-benzothien-5-yl) bicyclo [2.2.2] oct-2 -en-2- yl] -methanamine hydrochloride, mp 218-221°C, N-methyl - [2 - (3 -methyl - l -benzothien- 5 - yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride, mp 204.5-206.7°C,
N-methyl- [2- (1-benzothien-7-yl) bicyclo [3.2.1] oct-2-en-3* yl] methanamine hydrochloride, mp 212-213 °C,
N-methyl- [2- (3 -methyl-1-benzothien-7- yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride, mp 130 °C,
N-methyl- [2- (6-fluoro-l-benzothien-3- yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride, mp 244-246°C,
N-methyl- [ (IS, 5R) -2- (6-fluoro-naphth-2- yl) bicyclo [3.2.1] oct-2 -en-3 -yl] methanamine hydrochloride, mp 219-220 °C,
N-methyl- [ (1R,5S) -2- (6-fluoro-naphth-2- yl) bicyclo [3.2.1] oct-2 -en-3 -yl] methanamine hydrochloride, mp 223-224°C,
N-methyl- [2- (l-benzothien-4-yl) bicyclo [3.2.1] oct-2-en-3- yl] methanamine hydrochloride, mp 231-233°C,
N-methyl- [ (1S,2R) -2- (6-cyano-l-benzothien-2- yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride,
N-methyl- [ (1R,2S) -2- (6-cyano-l-benzothien-2* yl) bicyclo [3.2.1] oct-2 -en-3-yl] methanamine hydrochloride, N-methyl- [ (1S,2R) -2- (l-benzothien-7- yl) bicyclo [3.2.1] oct-2 -en-3 -yl] methanamine hydrochloride, mp 224-227°C,
N-methyl- [ (IR, 2S) -2- (l-benzothien-7- yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride, mp 226-227°C,
N-methyl- [ (IS, 2R) -3- (3 -methyl-1-benzothien-5- yl) bicyclo [2.2.2] oct-2-en-2-yl] -methanamine hydrochloride, mp 200-202°C,
N-methyl- [ (1R,2S) -3- (3-methyl-l-benzothien-5- yl) bicyclo [2.2.2] oct-2-en-2-yl] -methanamine hydrochloride, mp 204-205°C,
N-methyl- [ (1S,2R) -2- (l-benzothien-4- yl) bicyclo [3.2.1] oct-2-en-3 -yl] methanamine hydrochloride, mp 235-237°C,
N-methyl- [ (IR, 2S) -2- (l-benzothien-4- yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride, mp 235-237°C,
N-methyl-2- (3-cyano-l-benzothien-5-yl) bicyclo [3.2.1] oct- 2 -en- 3 -yl] methanamine hydrochloride, mp 226-227°C,
N-methyl- [2- (l-benzothien-2-yl) bicyclo [3.2.1] oct-2-en-3- yl] methanamine hydrochloride, mp 215-216°C,
N-methyl- [2- (5-methyl-l-benzothien-2- yl) bicyclo [3.2.1] oct-2-en-3 -yl] methanamine hydrochloride, mp 169-170°C, N-methyl- [2- (6-fluoro-l-benzothien-2- yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride, mp 173-176°C,
N-methyl- [2- (7-fluoro-l-benzothien-4- yl) bicyclo [3.2.1] oct-2-en-3-yl] methanamine hydrochloride, mp 234-236 °C,
N-methyl- [2- (3 -methyl-l-benzothien-4- yl) bicyclo [3.2.1] oct-2 -en-3 -yl] methanamine hydrochloride ,
N-methyl- [2- (5-methylthio-l-benzothien-2- yl) bicyclo [3.2.1] oct-2 -en-3 -yl] methanamine hydrochloride, mp 169-171 °C,
N-methyl- [2- (1-benzofuran-7-yl) bicyclo [3.2.1] oct-2-en-3- yl] methanamine hydrochloride, mp 249-251°C,
N-methyl- [2- (1-benzofuran-6-yl) bicyclo [3.2.1] oct-2 -en-3- yl] methanamine hydrochloride, mp 278.2-279.1°C,
EXAMPLE 26
N,N-Dimethyl [3- (6-{ [4- (trifluoromethyl) benzyl] oxy} -2- naphthyl) bicyclo [2.2.2] oct-2 -en-2 -yl] methanamine,
A 100ml round bottomed flask was charged with a 0.06M solution of 7- {3- [ (dimethylamino) methyl] - bicyclo [2.2.2] oct-2 -en-2 -yl} -2 -naphthol (220mg, 0.716mmol) in amine-free N,N-dimethylformamide (DMF, 11.92mls) . To this solution was added a solution of sodium bis (trimethylsilyl) amide (IM in tetrahydrofuran, 1.073ml, 1.073mmol, 1.5eq) . The flask was flushed with nitrogen, stoppered and its contents stirred at r.t. for one hour, during which time the solution changed in colour from yellow to dark brown. Twenty alkyl and benzyl halides were each dissolved in amine-free DMF (550μl to
lOOOμl) such that in each case, a 0.12M solution was
made up. An aliquot of each (500μl, 0.06mmol) was placed in its own 4ml Reacti-Vial. To each Vial, under a blanket of nitrogen, was added an aliquot of the naphtholate solution prepared above (500μl, 0.03mmol).
The twenty Vials were sealed, and their contents stirred and heated to 80°C overnight . The Vials were then unsealed and in each case, the contents were treated with methanol (1ml) . Each mixture was passed through its own methanol-conditioned 500mg SCX ion-exchange cartridge (under gravity) into a collection tank. Each cartridge was then washed with fresh methanol (2x2.5ml) such that the washings also passed into the tank. A clear glass vial was then placed underneath each cartridge, which were then eluted with 2M ammonia in methanol to release the products. Solvents were removed in vacuo to recover the target materials . FIA POS MASS SPEC (M+H ,466 & [M-N (CH3) 2] +, 421) .
Similarly prepared were: [3- (6-methoxy-2 -naphthyl) bicyclo [2.2.2] oct-2 -en-2-yl] - N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H ,322 & [M-N(CH3)2]+,277)
[3- (6-butoxy-2 -naphthyl) bicyclo [2.2.2] oct-2 -en-2-yl] - N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H ,364 & [M-N(CH3)2]+,319)
{3- [6- (benzyloxy) -2-naphthyl] bicyclo [2.2.2] oct-2-en-2- yl}-N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H , 39E & [M-N(CH3)2]+,353)
(3- {6- [ (4-bromobenzyl) oxy] -2 -naphthyl}bicyclo [2.2.2] oct- 2-en-2 -yl) -N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H ,475/477 & [M-N (CH3) 2] +, 430/432)
4- { [ (6- {3- [ (dimethylamino) methyl] bicyclo [2.2.2] oct-2-en- 2-yl} -2-naphthyl) oxy] methyl }benzonitrile, FIA POS MASS SPEC (M+H ,423 & [M-N (CH3) 2] +, 378)
(3 - { 6- [ (3 -chlorobenzyl ) oxy] -2 -naphthyl } bicyclo [2 .2 . 2 ] oct -2 -en- 2 -yl ) -N, N-dimethylmethanamine , FIA POS MASS SPEC (M+H , 432 & [M-N (CH3) 2] +, 387) N,N-dimethyl (3-{6- [ (4-methylbenzyl) oxy] -2- naphthyl}bicyclo [2.2.2] oct-2 -en-2-yl) methanamine, FIA
POS MASS SPEC (M+H ,412 & [M-N (CH3) 2] +, 367)
(3- {6- [ (2, 6-dichlorobenzyl) oxy] -2-naphthyl}bicyclo
[2.2.2] oct-2-en-2-yl) -N,N-dimethylmethanamine, FIA POS MASS SPEC (M+H ,466/468 & [M-N (CH3) 2] +, 421/423)
[3- (6-ethoxy-2 -naphthyl) bicyclo [2.2.2] oct-2-en-2-yl] - N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H ,336 & [M-N(CH3)2]+,291)
(3-{6- [ (4-tert-butylbenzyl) oxy] -2-naphthyl }bicyclo [2.2.2] oct-2-en-2-yl) -N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H ,454& [M-N (CH3) 2] +, 409)
(3- {6- [ (2-chlorobenzyl) oxy] -2 -naphthyl}bicyclo [2.2.2] oct-2-en-2-yl) -N, -dimethylmethanamine, FIA POS MASS SPEC (M+H ,432 & [M-N (CH3) 2] +, 387)
(3- {6- [ (4-fluorobenzyl) oxy] -2 -naphthyl }bicyclo [2.2.2] oct-2 -en-2 -yl) -N,N-dimethylmethanamine, FIA POS MASS SPEC (M+H ,416 & [M-N (CH3) 2] +, 371) N,N-dimethyl [3- (6-propoxy-2 -naphthyl) bicyclo [2.2.2] oct- 2 -en-2 -yl] methanamine, FIA POS MASS SPEC (M+H ,350 & [M- N(CH3)2]+,305)
(3- {6- [ (4-methoxybenzyl) oxy] -2-naphthyl}bicyclo
[2.2.2] oct-2-en-2-yl) -N, N-dimethylmethanamine, FIA POS MASS SPEC (M+H ,428 & [M-N (CH3) 2] +, 383 )
N,N-dimethyl (3- {6- [ (4-nitrobenzyl) oxy] -2- naphthyl}bicyclo [2.2.2] oct-2-en-2-yl) methanamine, FIA POS MASS SPEC (M+H ,443 & [M-N (CH3) 2] +, 398)
N,N-dimethyl [3- (6- { [4- (trifluoromethoxy) benzyl] oxy} -2- naphthyl) bicyclo [2.2.2] oct-2 -en-2-yl] methanamine, FIA POS MASS SPEC (M+H ,482 & [M-N (CH3) 2] +, 437)
EXAMPLE 27
Tablets each containing 10 mg of active ingredient are made up as follows:
Active ingredient .10 mg
Starch 160 mg Microcrystalline cellulose 100 mg
Polyvinylpyrrolidone (as 10% solution in water) 13 mg Sodium carboxymethyl starch 14 mg
Magnesium stearate 3 mg
Total 300 mg
The active ingredient, starch and cellulose are mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders and passed through a sieve. The granules so produced are dried and re-passed through a sieve . The sodium carboxymethyl starch and magnesium stearate are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 300 mg.
EXAMPLE 28
Capsules each containing 20 mg of medicament are made as follows :
Active ingredient 20 mg
Dried starch 178 mg
Magnesium stearate 2 mg
Total 200 mg The active ingredient, starch and magnesium stearate are passed through a sieve and filled into hard gelatine capsules in 200 mg quantities.
EXAMPLE 29
[3H] -Citalopram Binding Assay
The ability of compounds of the invention to displace
[3H] -citalopram from binding sites on rat cerebral cortical membranes was measured in the following way:
In each well of a 96 deep well plate was added:
100ml 2nM[3H] -citalopram
600ml 50mM Tris.HCl pH 7.4 containing 150mM NaCl and
5mM KC1 100ml Diluted compound, 50mM Tris.HCl pH 7.4 containing 150mM NaCl and 5mM KCl (total binding) or lOOmM fluoxetine (non-specific binding) 200ml Membrane preparation (0.75mg protein per ml) The microtitre plates were incubated at 37DC for 90minutes followed by filtration through GF/B filters soaked in 50mM Tris .HCl/0.1% (w/v) polyethylenimine pH 7.4. The filter was washed 5 times with 50mM Tris.HCl. pH 7.4. The filters were removed, dried and the bound tritium determined by liquid scintillation spectrometry. The results were analysed using an automatic spline fitting programme to provide Ki values for each of the compounds .

Claims

A compound of the formula
Figure imgf000098_0001
in which Ri and R2 are each hydrogen or C _4 alkyl, or Ri and R2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholino group, said group, being optionally substituted with 1 to 3 substituents selected from Cι_4 alkyl , hydroxymethyl , Cι_4 alkoxymethyl and amido, R3 is a naphthyl, indolyl, benzothienyl, benzofuranyl, benzothiazolyl, quinolinyl or isoquinolinyl group, said group being optionally substituted with 1 to 3 substituents selected from C _4 alkyl, C _4 alkoxy, carboxy, nitro, hydroxy, cyano, halo, trifluoromethyl , trifluoromethoxy, optionally substituted benzyl, optionally substituted benzyloxy, -NR'R' ' , -CONR'R' ' , -S02NR'R' ' and -S02R', where R' and R'' are each hydrogen or Cχ_4 alkyl; n is 1 or 2 and m is 0 or 1, provided that when m is 1 then n is 1; ■ or a salt or ester thereof.
A compound according to Claim 1, in which R1 and R2 are each hydrogen or Cχ_4 alkyl.
A compound according to either of Claims 1 and 2, in which R3 is optionally substituted 2-, 3-, 4-, 5-, 6- or 7- benzothienyl.
A compound according to Claims 3 , in which R3 is optionally substituted 4-, 5- or 7-benzothienyl .
A compound according to Claim 1, of the formula
Figure imgf000099_0001
in which R1 and R2 are each hydrogen or Ci_4 alkyl, R6 and R7 are each Cι_ alkyl, Cι_4 alkoxy, carboxy, hydroxy, cyano, halo, trifluoromethyl, -NR'R'1, -CONR'R'', -S02NR'R' ' or -SO2R1 where R' and R'' are each hydrogen or Cj*._4 alkyl, and p and q are each 0, 1 or 2; or a salt thereof .
A pharmaceutical formulation comprising a compound according to any of Claims 1 to 5, or pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable diluent or carrier therefor.
A compound according to any of Claims 1 to 5, or a pharmaceutically acceptable salt or ester thereof, for use as a pharmaceutical .
A compound according to any of Claims 1 to 5, or a pharmaceutically acceptable salt or ester thereof, for treating a disorder of the central nervous system.
9. The use of a compound according to any of Claims 1 to 5, or a pharmaceutically acceptable salt or ester thereof; for the manufacture of a medicament for treating a disorder of the central nervous system.
10. A method of treating an animal, including a human, suffering or susceptible to a disorder of the central nervous system, which comprises administering a compound according to Claim 1, or a pharmaceutically acceptable salt or ester thereof.
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Publication number Priority date Publication date Assignee Title
US7037932B2 (en) 2001-05-18 2006-05-02 Eli Lilly And Company Heteroaryloxy 3-substituted propanamines as serotonin and norepinephrine reuptake inhibitors
JP2006523182A (en) * 2002-12-20 2006-10-12 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Saturated and unsaturated heteroarylcycloalkylmethyl-amines as antidepressants
US7674822B2 (en) 2004-11-24 2010-03-09 Wyeth PTP1b inhibitors

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US8119625B2 (en) 2006-04-26 2012-02-21 Toyama Chemical Co., Ltd. Neurogenesis inducer or neuropathy therapeutic agent comprising alkyl ether derivative or salt thereof
NZ571975A (en) * 2006-04-26 2011-04-29 Toyama Chemical Co Ltd Neurogenesis inducer or neuropathy therapeutic agent comprising benzothiopene alkyl ether derivative or salt thereof

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7037932B2 (en) 2001-05-18 2006-05-02 Eli Lilly And Company Heteroaryloxy 3-substituted propanamines as serotonin and norepinephrine reuptake inhibitors
JP2006523182A (en) * 2002-12-20 2006-10-12 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Saturated and unsaturated heteroarylcycloalkylmethyl-amines as antidepressants
US7674822B2 (en) 2004-11-24 2010-03-09 Wyeth PTP1b inhibitors

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GB2367554A (en) 2002-04-10
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CA2419777A1 (en) 2002-04-11
EP1326824A1 (en) 2003-07-16
GB0024318D0 (en) 2000-11-15

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