WO2001062736A1 - Aryl fused azapolycyclic compounds - Google Patents

Aryl fused azapolycyclic compounds Download PDF

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Publication number
WO2001062736A1
WO2001062736A1 PCT/IB2001/000153 IB0100153W WO0162736A1 WO 2001062736 A1 WO2001062736 A1 WO 2001062736A1 IB 0100153 W IB0100153 W IB 0100153W WO 0162736 A1 WO0162736 A1 WO 0162736A1
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WO
WIPO (PCT)
Prior art keywords
dodeca
pentadeca
aza
tetraene
methyl
Prior art date
Application number
PCT/IB2001/000153
Other languages
French (fr)
Inventor
Paige Roanne Palmer Brooks
Jotham Wadsworth Coe
Original Assignee
Pfizer Products Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to HU0204580A priority Critical patent/HU229482B1/en
Priority to EP01953630A priority patent/EP1259489B1/en
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Priority to MXPA02008311A priority patent/MXPA02008311A/en
Priority to SI200130584T priority patent/SI1259489T1/en
Priority to EA200200716A priority patent/EA005316B1/en
Priority to EEP200200475A priority patent/EE200200475A/en
Priority to NZ519973A priority patent/NZ519973A/en
Priority to APAP/P/2002/002604A priority patent/AP1860A/en
Priority to DE60120366T priority patent/DE60120366T2/en
Priority to SK1204-2002A priority patent/SK12042002A3/en
Priority to CA002401229A priority patent/CA2401229C/en
Priority to IL15063901A priority patent/IL150639A0/en
Priority to JP2001562518A priority patent/JP2003524002A/en
Priority to AU28748/01A priority patent/AU784081B2/en
Priority to KR10-2002-7011140A priority patent/KR100537976B1/en
Priority to BR0108610-3A priority patent/BR0108610A/en
Priority to PL01365163A priority patent/PL365163A1/en
Priority to DZ013328A priority patent/DZ3328A1/fr
Priority to UA2002075792A priority patent/UA74813C2/en
Publication of WO2001062736A1 publication Critical patent/WO2001062736A1/en
Priority to IS6459A priority patent/IS2293B/en
Priority to BG106908A priority patent/BG65891B1/en
Priority to IL150639A priority patent/IL150639A/en
Priority to NO20024042A priority patent/NO323608B1/en
Priority to HRP20020700 priority patent/HRP20020700A2/en
Priority to HK03103024A priority patent/HK1050894A1/en
Priority to AU2005234671A priority patent/AU2005234671B2/en
Priority to CY20061101011T priority patent/CY1105301T1/en

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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • This invention relates to aryl fused azapolycyclic compounds, as defined more specifically by formula I below
  • Compounds of formula I bind to neuronal nicotinic acetylcholme specific receptor sites and are useful in modulating cholinergic function
  • Such compounds are useful in the treatment of inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, ce ac sprue, pouchitis, vasoconst ⁇ ction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e q ,
  • the compounds of this invention may also be used in combination with an antidepressant such as, for example, a t ⁇ cyclic antidepressant or a serotonin reuptake inhibiting antidepressant (SRI), in order to treat both the cognitive decline and depression associated with AD, PD, stroke, Huntington's chorea or traumatic brain injury (TBI), in combination with musca ⁇ nic agonists in order to stimulate both central musca ⁇ nic and nicotinic receptors for the treatment, for example, of ALS, cognitive dysfunction, age-related cognitive decline, AD, PD, stroke, Huntington's chorea and TBI, in combination with neurotrophic factors such as NGF in order to maximize cholinergic enhancement for the treatment, for example, of ALS, cognitive dysfunction, age-related cognitive decline, AD, PD stroke, Huntington's chorea and TBI, or in combination with agents that slow or arrest AD such as cognition enhancers, amyloid aggregation inhibitors, secretase inhibitors, tau kinase
  • heteroaryl groups within the definition of R 2 and R 3 are the following thienyl, oxazoyi, isoxazolyl, pyridyl, pynmidyl, thiazolyl, tetrazolyl, isothiazolyl, t ⁇ azolyl, imidazolyl, tetrazolyl, pyrrolyl and the following groups
  • R 9 and R 18 are hydrogen or (CrC ⁇ alkyl, and the other is a bond to the benzo ring of formula I
  • examples of compounds of this invention are compounds of the formula I, and their pharmaceutically acceptable salts, wherein R 2 and R 3 , together with the benzo ring of formula I form a bicyc c ring system selected from the following
  • R 10 and R 17 are selected, independently, from hydrogen, (C 1 -C 6 )alkyl; and (C CeJalkoxy- (C 0 -C 6 )alkyl- wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; nitro, cyano, halo, amino, (C 1 -C 6 )alkylamino-, [(C ⁇ Ce) alkyl] 2 amino-, -C0 2 R 4 , -C0NR 5 R 6 , -S0 2 NR 7 R 8 , -
  • R 10 and R 17 are defined as above, and m is zero, one or two, and wherein one of the carbon atoms of ring A can optionally be replaced with oxygen or N(C 1 -C 6 )alkyl
  • Other embodiments of this invention relate to compounds of the formula and their pharmaceutically acceptable salts, wherein neither R 2 nor R 3 is attached to the benzo ring of formula I via an oxygen atom
  • Examples of specific compounds of the formula I are the following compounds, which, in the instances where there is a center or centers of asymmetry in the molecule, may comprise a racemic mixture or the single enantiomer
  • compounds of the invention include but are not limited to 6-methyl-5,7-d ⁇ oxo-6,13-d ⁇ azatetracyclo[9 3 1 0 2 10 0 48 ]pentadeca-2(10),3,8-t ⁇ ene, 6-methyl-5-oxo-6,13-d ⁇ azatetracyclo[9 3 1 0 2 10 0 48 ]pentadeca-2(10),3,8-tr ⁇ ene, 5,7-d ⁇ methyl-6-oxo-5,7,13-tr ⁇ azatetracyclo[9 3 1 O 2 10 0 8 ]pentadeca-2(10),3,8-t ⁇ ene
  • This invention also relates to compounds of the formula
  • halo includes fluoro, chloro bromo and lodo
  • alkyl includes straight chain moieties, and where the number of carbon atoms suffices, branched and cyclic moieties
  • alkoxy means “-O-alkyl” or “alkyl-O-”, wherein “alkyl” is defined as above
  • alkylene as used herein, means an alkyl radical having two available bonding sites (j_e_, -alkyl-), wherein “alkyl” is defined as above
  • substituents refers to from one to the maximum number of substituents possible based on the number of available bonding sites
  • treatment refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such condition or disorder
  • treatment refers to the act of treating, as “treating” is defined immediately above
  • the compounds of formula I may have optical centers and therefore may occur in different enantiome ⁇ c configurations
  • the invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of formula I, as well as racemic and other mixtures thereof
  • Particularly, preferred enantiomers of the invention include
  • enantiomers of the compounds of the invention include (-)-5,13-d ⁇ azatetracyclo[9 3 1 0 2 10 0 4 8 ]pentadeca-2,4(8),9-tr ⁇ en-6-one, -6-oxo-5-oxa-7,13-d ⁇ azatetracyclo[9 3 1 0 2 10 0 4 8 ]pentadeca-2(10),3,6,8-tetraene -2-fluoro-N-(4-hydroxy-10-aza-tr ⁇ cyclo[6 3 1 0 2 7 ]dodeca-2(7),3,5-tr ⁇ en-5-yl)- benzamide
  • the present invention also relates to all radiolabeled forms of the compounds of the formula I
  • Preferred radiolabeled compounds of formula I are those wherein the radiolabels are selected from as 3 H, 11 C, 14 C, 18 F, 123 l and 125 l
  • Such radiolabeled compounds are useful as research and diagnostic tools in metabolism studies, such as pharmacokinetics studies, etc , and in binding assays in both animals and man
  • the present invention also relates to a pharmaceutical composition for use in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a mammal, including a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use and a pharmaceutically acceptable carrier
  • the present invention also relates to a method for reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use
  • the present invention also relates to a method of treating a disorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder depression, bipolar disorder, autism, sleep disorders jet lag, amyotrophic lateral sclerosis (ALS) cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e g , dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or ***e), headache migraine stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD),
  • the present invention also relates to a pharmaceutical composition for treating a disorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e g , dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or ***e), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compuls
  • the present invention also relates to a method for reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a mammal, comprising administering to said mammal an amount of a compound comprising an amount of a compound of the formula
  • R is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, or unconjugated (C 3 -C 6 )alkenyl, or a pharmaceutically acceptable salt thereof, that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use
  • the present invention also relates to a method for treating a disorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e g , dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or ***e), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive
  • R 19 is defined above, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition
  • This invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I
  • pharmaceutically acceptable acid addition salts of the compounds of formula I are the salts of hydrochloric acid, p-toluenesulfonic acid, fuma ⁇ c acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartanc acid, malic acid, di-p-toluoyl tartanc acid, and mandelic acid, as well salts formed from other acids known to those of skill in the art to form pharmaceutically acceptable acid addition salts to basic compounds
  • Other possible acid addition salts are, e , salts containing pharmaceutically acceptable anions, such as the hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate
  • the present invention also relates to methods for the preparation of the novel compounds of formula I
  • the invention is directed to a process for the preparation of a compound of formula IA
  • R ,10 is defined above, comprising the step of reacting a compound of formula
  • R 20 and R 21 are each independently (C 1 -C 6 )alkyl, and wherein R 10 is defined above, and
  • the nitrogen protecting group Q may be chosen from suitable groups known to those of skill in the art including -COCF 3 , -COCCI 3 , -COOCH 2 CCI 3 , -COO(C 1 -C 6 )alkyl and -COOCH 2 C 6 H 5 These groups may be added or removed by methods described for each in T. W Greene and G M Wuts, Protective Groups in Organic Synthesis (John Wiley & Sons, New York, 1991)
  • the nitrogen protecting group Q is a tnfluoroacetyl or a t- butoxycarbonyl group
  • the invention also relates to a process for the preparation of a compound of formula IB
  • R 20 and R 21 are each independently (C ⁇ -C 6 )alkyl, and wherein R 10 is defined above and
  • step (n) allowing the product of step (i) to react with a compound of the formula R 17 Z wherein R 17 is defined above, and Z is a leaving group, in the presence of a base,
  • the leaving group is selected from the group consisting of halo, halosulfonate, mesylate and tosylate, and the base is an alkali metal hydride, hydroxide or carbonate
  • the protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group
  • the invention also relates to another process for the preparation of a compound of formula IB
  • R 10 and R 17 are defined above, comprising the steps of (i) of reacting a compound of formula XXIIIA XXIVA wherein Q is a nitrogen protecting group, with a compound of formula XXIIB:
  • R 20 and R 21 are each independently (C CsJalkyl, and wherein R 1C is defined above, and
  • the protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group.
  • the invention is also directed to a process for preparing a compound of formula IC
  • Y is an alkali metal or alkaline earth metal cation; or a compound of formula
  • step (i) is conducted in a polar solvent, more preferably, water, THF DMF DMSO, a mixture of water and any of THF, DMF or DMSO
  • a polar solvent more preferably, water, THF DMF DMSO, a mixture of water and any of THF, DMF or DMSO
  • the processes to make each of compounds IA, IB and IC preferably comprise the further step of reducing the nitro groups of a compound of formula IIC
  • the reduction is conducted in the presence of hydrogen gas employing a palladium catalyst
  • the protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group
  • the invention is also directed to a process for the preparation of a compound of formula IE
  • R 10 is defined above, comprising the steps of
  • step (i) is conducted by hydrogenation with a palladium or platinum catalyst
  • the protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group
  • the invention is further related to a process for the preparation of a compound of formula IF
  • R 10 is as defined above, comprising the steps of (i) allowing a compound of formula XA
  • R , 10 is as defined above, and Q is a nitrogen protecting group, to react with Lawesson s reagent,
  • step (II) allowing the product of step (i) to react with potassium fer ⁇ cyanide and sodium hydroxide,
  • the protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group
  • the invention also relates to a process for preparing compounds the formula
  • step (II) partially reducing the resulting ozonide product of step (i) to a dialdehyde or product of equivalent oxidation state
  • step (HI) allowing the product of step (n) to react with an arylmethylamine, and (iv) removing the arylmethyl group
  • the ozonolysis conditions used may be any of those known to those of skill in the art
  • the ozonolysis conditions are ozone in methanol or dichloromethane, preferably methanol
  • the reduction of the ozonolysis product or ozonide is preferably conducted by hydrogenation, e_g_, in the presence of hydrogen gas and a platinum or palladium catalyst with or without carbon/charcoal
  • the arylmethyiamine employed in step (in) is benzylamine 4-methoxybenzylam ⁇ ne or 3,4-d ⁇ methoxybenzylam ⁇ ne, preferably benzylamine, and is preferably added in the presence of an acid catalyst, preferably formic acid
  • the removal of the arylmethyl group in step (iv) is preferably a hydrogenolysis reaction conducted, e g , in the presence of hydrogen gas and a platinum or palladium catalyst with or without carbon/charcoal, and in the presence of an acid catalyst
  • the invention also relates to a novel process for the preparation of a compound of formula
  • step (i) obtained from step (i) to form a lactam ring compound of formula XXX
  • step (i) reducing the carbonyl moiety
  • the preferred starting material in step (i) is the t ⁇ methylsiloxy compound
  • the hydrogenation of step (i) is preferably conducted with a palladium or platinum catalyst under hydrogen gas, preferably in the presence of an acid catalyst
  • the lactam formation of step (u) is preferably performed in the presence of a base, preferably an alkoxyalkahde compound in a nonaqueous protic solvent, more preferably sodium fert-butoxide in methanol
  • the reduction of step (in) is preferably performed in the presence of a borane tetrahydrofuran complex diborane, borane dimethysulfide complex, lithium aluminum hydride or a combination of sodium borohydnde and boron t ⁇ fluoride, more preferably a combination of sodium borohyd ⁇ de and boron t ⁇ fluoride
  • R 8 is, e.g., F, (C 1 -C 6 )alkoxy or any suitable R 2 and/or R 3 group member
  • the starting material of formula III is reacted with trifluoroacetic anhydride, in the presence of pyridine, to form the compound of formula IV
  • This reaction is typically conducted in methylene chloride at a temperature from about 0°C to about room temperature
  • Other methods of generating a trifluoroacetate protecting group that may be used are recognized by those of skill in the art
  • the compound of formula IV is then converted into the dmitro derivative of formula IIA by the following process
  • the compound of the formula IV is added to a mixture of 4 or more equivalents of trifluoromethanesulfonic acid (CF 3 S0 2 OH) and 2 to 3 equivalents of nitric acid, in a chlorinated hydrocarbon solvent such as chloroform, dichloroethane (DCE) or methylene chloride
  • a chlorinated hydrocarbon solvent such as chloroform, dichloroethane (DCE) or methylene chloride
  • DCE dichloroethane
  • methylene chloride methylene chloride
  • Both of the foregoing reactions are generally conducted at a temperature ranging from about -78°C to about 0°C for about 2 hours, and then allowed to warm to room temperature for the remaining time
  • Reduction of the compound of formula IIA using methods well known to those of skill in the art, yields the compound of formula IIB
  • This reduction can be accomplished, for example, using
  • the compound of formula IIA is converted into the corresponding compound wherein the tnfluoroacetyl protecting group is replaced by a t-Boc protecting group (VIA) by reacting it first with an alkali metal or alkaline earth metal (or ammonium) hydroxide or carbonate, and then reacting the isolated product from the foregoing reaction with di-t- butyldicarbonate
  • t-Boc is used in this instance, other approp ⁇ ate nitrogen-protecting groups known to those of skill in the art may be used
  • the reaction with the alkali or alkaline earth metal (or ammonium) hydroxide or carbonate is generally carried out in an aqueous alcohol, dioxane or tetrahydrofuran (THF) at a temperature from about room temperature to about 70°C, preferably at about 70°C, for about one to about 24 hours
  • THF aqueous alcohol, dioxane or tetrahydrofuran
  • the conversion of the compound of formula VIB into the desired compound of the formula VII can be accomplished by reacting the compound of formula VIB with a compound of the formula XXIIA XXIIA wherein R 10 is hydrogen, (C C ⁇ Jalkyl optionally substituted with from one to seven fluorine atoms, aryl-(C 0 -C 3 )alkyl wherein said aryl is selected from phenyl and naphthyl, or heteroaryl-(C 0 -C 3 )alkyl wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C C 6 )alkyl optionally substituted with from one to seven fluorine atoms, (C 1 -C 6 )alkoxy optionally substituted with
  • the compound of formula VII can be treated with an anhydrous acid such as hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, preferably hydrochloric acid in ethyl acetate, at a temperature from about 0°C to about 100°C, preferably from about room temperature to about 70°C, for about one to 24 hours.
  • anhydrous acid such as hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, preferably hydrochloric acid in ethyl acetate
  • the compound of formula VII can be converted into the corresponding compound of formula IB by reacting it with a compound of the formula R 17 Z, wherein R 17 is defined as R 10 is defined above, and Z is a leaving group such as a halo or sulfonate (e q , chloro, bromo, mesylate or tosylate), in the presence of a base such as an alkali metal hydride, hydroxide or carbonate, preferably potassium hydroxide, in a polar solvent such as water, dimethylsulfoxide (DMSO), THF or DMF, preferably a mixture of DMSO and water, and then removing the protecting group as described above
  • the reaction with R 17 Z is generally carried out at a temperature from about room temperature to about 100°C, preferably at about 50°C, for about five hours
  • Scheme 3 illustrates an alternate method of preparing compounds of the formula IB from the compound of formula VIA
  • This method is the preferred method of making compounds of the formula IB wherein R 17 is a bulky group such as an aryl or heteroaryl containing group, or when R 17 can not be attached, as illustrated in Scheme 2, by alkylation or aryl substitution methods
  • the compound of formula VIA is reacted with the appropriate compound of formula R 17 NH 2 in a polar solvent such as THF, DMF or DMSO, preferably THF, at a temperature from about room temperature to about 100°C, preferably at the reflux temperature, for about four to eighteen hours
  • the resulting compound of formula XXIII is then converted into the corresponding compound of the formula XXIV by reducing the nitro group to an ammo group using methods well known to those of skill in the art Such methods are referred to above for the conversion of the compounds of the formula IIA into a compound of the formula IIB in Scheme 1 , and exemplified in experimental Examples
  • Scheme 4 illustrates a method of preparing compounds of the formula IC, wherein R 0 and R 17 are as defined above
  • the compound of formula VIB, or analogously formula IIB in Scheme I is reacted with a compound of the formula
  • reaction temperature can range from about 40°C to about
  • Scheme 5 illustrates a method of preparing compounds of the formula I wherein R 2 and R 3 , together with the benzo ring to which they are attached, form a benzoxazole ring system
  • a compound wherein R 1 is hydrogen
  • Scheme 5 the compound of formula XXII, wherein Y is nitro halo t ⁇ fluoromethanesulfonate or a diazonium salt, is reacted with potassium acetate or another alkali or alkaline earth metal carboxylate in a solvent such as dimethylsulfoxide (DMSO), DMF or acetonitrile, preferably DMSO
  • DMSO dimethylsulfoxide
  • DMF dimethylsulfoxide
  • acetonitrile preferably DMSO
  • the above reaction yields the compound of formula VIII, which can then be converted into the desired compound having formula IE by the following procedure
  • the compound of formula VIII is reduced by reaction with hydrogen and a palladium or platinum catalyst such as palladium hydroxide in methanol at a temperature from about 0°C to about 70°C, preferably at about room temperature, to form the corresponding ammo derivative
  • the product of this reaction is then reacted with an acid chloride of the formula R 10 COCI or an acid anhydride of the formula (R 10 CO) 2 O wherein R 10 is or a compound of the formula R 10 C(OC 2 H 5 ) 3l in an appropriate inert solvent such as deca n, chlorobenzene or xylenes
  • R 10 COCI is used as a reactant, it is preferable to add a stoichiomet ⁇ c amount of t ⁇ ethylamine
  • the compound of formula IX' is then reacted with a carboxyhc acid halide or anhydride of the formula R 10 COX or (R 10 CO) 2 O, wherein X is halo and R 10 is hydrogen or (d-CeJalkyl, and pyridine, TEA or another tertiary amine base, to form a compound of the formula X, which can then be converted to the desired compound having formula XI by reacting it with Lawesson's reagent
  • the reaction with R COX, wherein X is halo, or (R CO) 2 0 is generally carried out at a temperature from about 0°C to about room temperature, preferably at about room temperature
  • the reaction with Lawesson's reagent is generally carried out in a reaction inert solvent such as benzene or toluene, preferably toluene, at a temperature from about room temperature to about the reflux temperature of the reaction mixture, preferably at about the reflux temperature
  • Closure to the benzothiazole ring and nitrogen deprotection to form the desired compound of formula IF can be accomplished by reacting the compound of formula XI with potassium ferncyanide and sodium hydroxide in a mixture of water and methanol (NaOH/H 2 0/CH 3 OH), at a temperature from about 50°C to about 70°C, preferably at about 60°C for about 1 5 hours
  • Scheme 7 illustrates a method of preparing the compound of formula III which is used as the starting material for the process of Scheme 1 , or a compound of the formula IG wherein R 2 and R 3 form a ring (labeled "A" in the Scheme), as defined above in the definition of compounds of the formula I
  • the compound of formula XII wherein X 1 and X 2 are selected, independently, from chloro, fluoro, bromo and lodo, but where at least one of X 1 and X 2 is Br- or I-, reacted with cyclopentadiene, in the presence
  • the compound having formula XIIIA is then converted into the corresponding compound of formula XIV using the following procedure
  • the compound of formula XIIIA is reacted with sodium penodate in a mixture of a chlorinated hydrocarbon, preferably dichloroethane (DCE), and water, or with lead tetraacetate in a chlorinated hydrocarbon solvent, at a temperature from about 0°C to about room temperature, to generate a dialdehyde or glycal intermediate
  • the product of this reaction is then reacted with benzylamine and sodium tnacetoxyborohydride in a chlorinated hydrocarbon solvent at a temperature from about 0°C to about room temperature, preferably at about room temperature, to form the desired compound of formula XIV
  • Removal of the benzyl group from the compound of formula XIV yields the compound of formula III (when ring A is absent) or IG, (when ring A is present) This can be accomplished using methods well known to those of skill in the art, for example
  • benzyl amine such as ammonia, hydroxylamine, alkoxy amines, methyl amine, allyl amine, and substituted benzylamines (e g , diphenylmethyl amine and 2- and 4-alkoxy substituted benzyl amines) can also be used They can be used as free bases, or as their salts, preferably their acetate salts, and can be subsequently removed by methods described for each in T W Greene and G M Wuts, Protective Groups in Organic Synthesis (John Wiley & Sons, New York 1991)
  • step 1 of is an este ⁇ fication of a carboxyhc acid
  • a carboxyhc acid of formula XXVI is treated with a Lewis acid catalyst such as boron tnfluoride or with an acid catalyst such as sulfu ⁇ c acid, hydrochloric acid, p-toluenesulfonic acid methane sulfonic acid, trifluoroacetic acid, or hydrobromic acid, preferably sulfunc acid, in an alcohol solvent such as methanol, ethanol, propanol, butanol, pentanol, or hexanol, preferably methanol, at a temperature between 25 and 120 °C, preferably 65 °C, for a period of 30 minutes to 24 hours, preferably 4 hours, to afford a compound of formula XXVIIA
  • Step 2 of Scheme 7A is a cyanohyd ⁇ n formation
  • a ketone of formula XXVIIA is treated with a Lewis acid catalyst such as zinc iodide, zinc t ⁇ flate, t ⁇ methylsilyl t ⁇ flate, t ⁇ methylsilyl iodide, aluminum chloride, tin (II) chloride, or t ⁇ methyl aluminum, preferably zinc iodide, or with catalytic potassium cyanide and 18-crown-6, and t ⁇ methylsilyl cyanide, in a solvent such as acetonitrile, toluene, methylene chloride, ethyl acetate, isopropyl acetate methyl- ert-butyl ether, or tetrahydrofuran, preferably a mixture of acetonitrile and toluene, at a temperature between 0 and 100 °C, preferably at 50 °C, for a period of time between 1
  • Step 3 of Scheme 7A is a hydrogenolysis reaction
  • a nit ⁇ le of formula XXVIIIA is treated with an acid catalyst such as p-toluenesulfonic acid, methane sulfonic acid hydrochloric acid, sulfunc acid, phosphoric acid, or trifluoroacetic acid, preferably p-toluenesulfonic acid, and a palladium catalyst such as palladium on carbon or palladium hydroxide on carbon, preferably palladium hydroxide on carbon, in a solvent such as methanol, ethanol, isopropanol, butanol, propanol, ethyl acetate, isopropyl acetate, or toluene preferably methanol, under a hydrogen pressure of 15 to 100 psi, preferably 50 psi, for a time period between 2 and 72 hours, preferably 24 hours, to afford a compound of formula XXIXA
  • Step 4 of Scheme 7A is an amide formation
  • An amine of formula XXIXA is treated with a base such as sodium ferf-butoxide, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium fert-butoxide, potassium methoxide, potassium ethoxide, potassium hydroxide, sodium carbonate, potassium carbonate cesium carbonate, sodium hydride t ⁇ ethylamine, methylimidazole, lutidine, pyridine, methylmorphohne ethylmorphohne, or diisopropylethylamme, preferably sodium tert-butoxide, in a solvent such as methanol, ethanol isopropanol, ethyl acetate, acetonitrile or toluene, preferably methanol, at a temperature between 0 and 120 °C, preferably 65 °C, for a time period between 30 minutes and 72 hours preferably 2 hours, to afford a compound of
  • Step 5 of Scheme 7A is a reduction of an amide
  • An amide of formula XXX is treated with a reducing agent such as borane tetrahydrofuran complex, diborane, borane dimethylsulfide complex, lithium aluminum hydride, or a combination of sodium borohydnde and boron trifluonde, preferably a combination of sodium borohydnde and boron t ⁇ fluo ⁇ de, in a solvent such as tetrahydrofuran, 1 ,2-d ⁇ methoxyethane, 1 ,2-d ⁇ ethoxyethane, dnsopropyl ether, 1 ,4-d ⁇ oxane, or methyl-ferf-butyl ether, preferably tetrahydrofuran, at a temperature between 0 and 80 °C, preferably 50 °C, for time period between 1 and 24 hours, preferably 5 hours
  • the product is isolated by crystallization as a salt of
  • Scheme 8 illustrates a variation of the process shown in Scheme 7, which can be used to make a compound identical to that of formula III except that the benzo ring is substituted with a fluoro group, an alkoxy group or any other suitable R 2 and/or R 3 group (R 18 in Scheme 8)
  • This compound is depicted in Scheme 8 as chemical structure 1 H
  • a strong base such as an alkali metal dialkylamine or an alkali metal alkyl (or aryl) in an ethereal solvent such as ethyl ether or THF, at a temperature below -50°C, followed by quenching with iodine or N-iodosuccinamide, to form 1 ,3-d ⁇ fluoro-2- ⁇ odobenzene
  • the compound 1 ,3-d ⁇ fluoro-2- ⁇ odobenzene (structural formula XVI in Scheme 8) is
  • Scheme 8A illustrates an alternative procedure for obtaining compounds of formula I, where R 2 and R 3 are as defined above, with the exception of (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyi or nitro (IH', as depicted)
  • Step 1 of Scheme 8A is an oxidation followed by a reductive animation
  • a benzonorbornadiene derivative of formula XVII' is first treated with ozone until the solution develops a blue color between 0 °C and -78 C C, preferably -78 °C, in a solvent such as methanol, or dichloromethane, preferably methanol
  • the ozonide formed is reduced by hydrogenolysis between -78 °C and room temperature, preferably between 0 °C and room temperature, with platinum or palladium catalyst such as platinum oxide, platinum on carbon palladium on carbon, or palladium hydroxide on carbon, preferably 5% platinum on carbon for a period of time between
  • Step 2 of Scheme 8A is a hydrogenolysis reaction
  • a compound of formula II is treated with an acid such as p-toluenesulfonic acid, hydrochloric acid, sulfunc acid, acetic acid, formic acid, or methane sulfonic acid, preferably p-toluenesulfonic acid, and a palladium catalyst such as palladium hydroxide on carbon or palladium on carbon, preferably palladium hydroxide on carbon, in a solvent such as methanol, ethanol, isopropanol, ethyl acetate or methyl acetate, preferably methanol, under a hydrogen pressure between 15 and 100 psi preferably 50 psi, at a temperature between room temperature and 60 °C, preferably 40 °C, for a period of time between 1 and 48 hours, preferably 15 hours
  • the product is crystallized as a salt depending on which acid catalyst is used in a solvent such as isopropanol,
  • compounds of the formula IJ can be prepared by reacting the compound of formula IV with two or more equivalents of a halosulfonic acid, preferably chlorosulfonic acid, at a temperature from about 0°C to about room temperature Reaction of the chlorosulfonic acid derivative so formed with an amine having the formula R 7 R 8 NH, wherein R 7 and R 8 are defined as above, followed by removal of the nitrogen protecting group, yields the desired compound having formula IJ
  • a halosulfonic acid preferably chlorosulfonic acid
  • the analogous mono- or di-brominated or mono- or di- lodinated compounds can be prepared by reacting the compound of IV with N- lodosuccinamide or N-bromosuccinimide in a tnfluoromethanesulfonic acid solvent, followed by removal of the nitrogen protecting group as described above
  • a reaction inert solvent such as a chlorinated hydrocarbon solvent, preferably methylene chloride
  • Lewis acid such as aluminum chloride
  • Compounds of formula IM can be prepared from compounds of the formula IX' by generation of a diazonium salt with, for instance, an alkali metal nitrite and strong mineral acid (e g , hydrochloric acid, sulfunc acid, hydrobromic acid) in water, followed by reaction with a copper halide salt, such as copper (I) chloride Nitrogen deprotection by the methods described above yields the desired compound of formula IM
  • Alternative methods for the generation of diazonium salts as known and practiced by those of skill in the art, can also be used
  • the foregoing reaction is generally carried out by temperatures ranging from about 0°C to about 60°C, preferably about 60°C for about 15 minutes to one hour
  • Reaction of the diazodium salt, prepared as described above, with potassium iodide in an aqueous medium provides the analogous iodide derivative This reaction is generally carried out at a temperature from about 0°C to about room temperature, preferably at about room temperature
  • Nitrogen deprotection of the compound of formula IX' provides the compound of the formula IP
  • the compound of formula IX' can be reacted with a acyl group having the formula R 13 COCi or (R 13 CO) 2 0 using the methods described above, followed by nitrogen deprotection to provide compounds of the formula IQ
  • treatment of the protected amine with a compound having the formula R 13 S0 2 X, when X is chloro or bromo, followed by nitrogen deprotection provides the corresponding sulfonamide derivative
  • suitable amine protecting groups that can be used, alternatively, in the procedures described throughout this document include -COCF 3 , -COCCI 3 , -COOCH 2 CCI 3 , -COO(d-C 6 )alkyl and -COOCH 2 C 6 H 5
  • protecting groups may be removed by methods described for each in Greene et al 's Protective Groups in Organic Chemistry, referred to above Instances where protecting groups would be modified under the reaction conditions, such as, e g , a -COOCH 2 C 6 H 5 group during nitration, still permit said procedures to operate as described with said modified protecting group Modifying the order of protecting group incorporation and/or methods of functional group introduction or modification may also be applied where appropriate
  • pressure is not critical unless otherwise indicated Pressures from about 0 5 atmospheres to about 5 atmospheres are generally acceptable, with ambient pressure, j_e_, about 1 atmosphere, being preferred as a matter of convenience
  • the compounds of the formula I and their pharmaceutically acceptable salts can be administered via either the oral, transdermal (e g , through the use of a patch), tranasal, sublmgual, rectal, parenteral or topical routes Transdermal and oral administration are preferred
  • Transdermal and oral administration are preferred
  • These compounds are, most desirably, administered in dosages ranging from about 0 01 mg up to about 1500 mg per day, preferably from about 0 1 to about 300 mg per day in single or divided doses, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen
  • a dosage level that is in the range of about 0 001 mg to about 10 mg per kg of body weight per day is most desirably employed Variations may nevertheless occur depending upon the weight and condition of the persons being treated and their individual responses to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out
  • dosage levels below the lower limit of the aforesaid range may
  • the active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the several routes previously indicated More particularly, the active compounds can be administered in a wide variety of different dosage forms, e_g_, they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, transdermal patches, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored
  • the active compounds are present in such dosage forms at concentration levels ranging from about 5 0% to about 70% by weight
  • tablets containing various excipients such as microcrystal ne cellulose, sodium citrate, calcium carbonate, dical ⁇ um phosphate and glycme may be employed along with various disintegrants such as starch (preferably corn, potato or tapioca starch), algmic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia
  • disintegrants such as starch (preferably corn, potato or tapioca starch), algmic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc can be used for tabletting purposes
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules, preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glyco
  • the assay mixture typically consisted of 0 9 mg of membrane protein in a final incubation volume of 1 0 mL
  • Three sets of tubes were prepared wherein the tubes in each set contained 50 ⁇ L of vehicle, blank, or test compound solution, respectively
  • To each tube was added 200 ⁇ L of [ 3 H]-n ⁇ cot ⁇ ne in assay buffer followed by 750 ⁇ L of the membrane suspension
  • the final concentration of nicotine in each tube was 0 9 nM
  • the final concentration of cytisine in the blank was 1 ⁇ M
  • the vehicle consisted of deionized water containing 30 ⁇ L of 1 N acetic acid per 50 L of water
  • the test compounds and cytisine were dissolved in vehicle Assays were initiated by vortexing after addition of the membrane suspension to the tube
  • the samples were incubated at 0 to 4° C in an iced shaking water bath Incubations were terminated by rapid filtration under vacuum through Whatman GF/BTM glass fiber filters using a Brande
  • DODECA-2(7).3.5-TRIENE HYDROCHLORIDE See Grunewald, G L , Paradkar, V M , Pazhenchevsky, B , Pleiss, M A , Sail D J Seibel, W L , Reitz, T J J Org Chem 1983, 48, 2321-2327 Grunewald, G L , Markovich, K M , Sail, D J J Med Chem 1987, 30, 2191-2208 )
  • This oil (500 mg, 1 64 mmol) was dissolved in methanol (30 mL), treated with 10%Pd/C (-50 mg) and hydrogenated under a H 2 atmosphere (45 psi) for 1 hour The mixture was filtered through a Cehte pad and concentrated to a clear oil (397 mg, 88%)
  • EXAMPLE 18 7-BUTYL-5.7.13-TRIAZATETRACYCLOf9 3 1 0 2 10 0 48 1- PENTADECA-2(10).3.5.8-TETRAENE HYDROCHLORIDE A) 4-Butylam ⁇ no-5-n ⁇ tro-10-aza-tr ⁇ cvclof6 3 1 0 2 7 ldodeca-2(7).3.5-tr ⁇ ene-10-carboxyl ⁇ c acid tert-butyl ester (For conditions, see, Senskey, M D , Bradshaw, J D Tessier, C A Youngs, W J Tetrahedron Lett 1995, 36, 6217 )
  • Copper(l)chlor ⁇ de was prepared as follows CuS0 4 (4 3 g) and NaCI (1 2 g) were dissolved in hot H 2 0 (14 mL) sodium bisulfite (NaHS0 3 ) (1 g) and sodium hydroxide (NaOH) (690 mg) were dissolved in H 2 0 (7 mL) and added to the hot acidic solution over 5 minutes The precipitated white solids were filtered and washed with water 1-(4-Am ⁇ no-10-aza-tr ⁇ cyclo[6 3 1 0 2 7 ]dodeca-2(7),3,5-tr ⁇ en-10-yl)-2,2,2-t ⁇ fluoro- ethanone (460 mg, 1 7 mmol) was dissolved in H 2 0 (2 mL) and concentrated HCl solut ⁇ on(1 mL) then cooled to 0 °C and treated with a solution of sodium nitrite (NaN0 2 ) (275 mg) in H 2 0
  • Acetic acid 10-tr ⁇ fluoroacetyl-10-aza-tr ⁇ cyclo[6 3 1 0 2 7 ]dodeca-2(7),3,5-tr ⁇ en-4-yl ester (800 mg, 2 55 mmol) was combined with AICI 3 (1 0 g, 7 65 mmol) and warmed to 170°C for 2 hours The mixture was cooled and treated with 1 N aqueous HCl solution (20 mL), extracted with ethyl acetate and dried (Na 2 S0 4 ) Chromatography affords an oil (190 mg, 24%) (TLC ethyl acetate R f 0 75) 1 H NMR (400 MHz, CDCI 3 ) ⁇ 12 58 (s, 0 5H), 12 52 (s, 0 5H), 7 53 (s 1 H), 6 86 (s, 1 H), 4 33 (m, 1 H), 3 91 (m, 1 H), 3 56 (m, 1 H), 3 28 (br s, 1
  • EXAMPLE 38 4.5-DICHLORO-10-AZATRICYCLOf6 3 1 0 2 7 1DODECA-2(7),3.5-TRIENE HYDROCHLORIDE A) 1-(4.5-D ⁇ chloro-10-aza-t ⁇ cvclof6 3 1 0 2 7 1dodeca-2(7).3.5-tr ⁇ en-10-yl)-2.2.2-tr ⁇ fluoro- ethanone (Based on Campaigne, E , Thompson, W J Org Chem 1950, 72, 629 ) 1-(10-Aza-tr ⁇ cyclo[6 3 1 0 2 7 ]dodeca-2(7),3,5-tr ⁇ en-10-yl)-2,2,2-t ⁇ fluoro-ethanone (539 mg, 2 1 mmol) was stirred in CH 2 CI 2 (5 mL) and treated with ICI 3 (s) (982 mg, 4 21 mmol) The resulting orange solution was stirred 0 5 hours, poured into saturated aqueous NaHS0
  • EXAMPLE 47 6-ETHYL-5-OXA-7.13-DIAZATETRACYCLOr9.3.1.0 2 10 .0 8 1- PENTADECA-2(10).3.6.8-TETRAENE HYDROCHLORIDE 2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0 2,7 ]dodeca-2(7),3,5-tr ⁇ en- 10-yl)-ethanone and propionyl chloride were converted to the title compound following the procedures described in Example 30 and Goldstein, S. W.; Dambek, P. J. J. Het. Chem 1990, 27, 335.
  • EXAMPLE 56 6-METHOXY-5.14-DIAZATETRACYCLOH0 3 1 0 2 11 0 49 1HEXADECA- 2(1 D.3.5.7.9-PENTAENE HYDROCHLORIDE A) 6-Chloro-5.14-d ⁇ azatetracvclof10 3 1 0 2 11 0 49 lhexadeca-2(11 ).3.5.7.9-pentaen-10- carboxyhc acid tert-butyl ester
  • EXAMPLE 58 5.8.14-TRIAZATETRACYCLOMO 3 1 0 2 11 0 49 1HEXADECA- 2(1 D.3.7.9-TETRAEN-6-ONE HYDROCHLORIDE

Abstract

This invention is directed to compounds of formula (I) and their pharmaceutically acceptable salts, wherein R?1, R2, and R3¿ are as defined herein; intermediates for the synthesis of such compounds, pharmaceutical compositions containing such compounds; and methods of using such compounds in the treatment of neurological and psychological disorders.

Description

ARYL FUSED AZAPOLYCYCLIC COMPOUNDS
Background of the Invention This invention relates to aryl fused azapolycyclic compounds, as defined more specifically by formula I below Compounds of formula I bind to neuronal nicotinic acetylcholme specific receptor sites and are useful in modulating cholinergic function Such compounds are useful in the treatment of inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, ce ac sprue, pouchitis, vasoconstπction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e q , dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or ***e), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD) psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi- infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome
The compounds of this invention may also be used in combination with an antidepressant such as, for example, a tπcyclic antidepressant or a serotonin reuptake inhibiting antidepressant (SRI), in order to treat both the cognitive decline and depression associated with AD, PD, stroke, Huntington's chorea or traumatic brain injury (TBI), in combination with muscaπnic agonists in order to stimulate both central muscaπnic and nicotinic receptors for the treatment, for example, of ALS, cognitive dysfunction, age-related cognitive decline, AD, PD, stroke, Huntington's chorea and TBI, in combination with neurotrophic factors such as NGF in order to maximize cholinergic enhancement for the treatment, for example, of ALS, cognitive dysfunction, age-related cognitive decline, AD, PD stroke, Huntington's chorea and TBI, or in combination with agents that slow or arrest AD such as cognition enhancers, amyloid aggregation inhibitors, secretase inhibitors, tau kinase inhibitors, neuronal anti-inflammatory agents and estrogen-like therapy
Other compounds that bind to neuronal nicotinic receptor sites are referred to in United States Patent Application 08/963,852, which was filed on November 4, 1997 The foregoing application is owned in common with the present application, and is incorporated herein by reference in its entirety Summary of the Invention This invention relates to aryl fused azapoiycyclic compounds of the formula
Figure imgf000003_0001
R1 is hydrogen, (Cι-C6)alkyl, unconjugated (C3-C6)alkenyl, benzyl, XC(=0)R13 or -CH2CH2-0-(C1-C4)alkyl,
R2 and R3 are selected, independently, from hydrogen, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, nitro, ammo, halo, cyano, -SOq(CrC6)alkyl wherein q is zero, one or two, (Cι.Cβ)alkylamιno-, [(C,-C6)alkyl]2amιno-, -C02R4, -CONR5R6, -S02NR7R8, -C(=0)R13, -XC(=0)R13, aryl-(C0-C3)alkyl- or aryl-(C0-C3)alkyl-O-, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl- or heteroaryl-(C0-C3)alkyl-O-, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, X2(C0-C6)alkyl- and X (C1-C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or X2 is (Ct-C6)alkylamιno- or
Figure imgf000003_0002
and wherein the (C0- C6)alkyl- or (C C6)alkoxy-(C0-C6)alkyl- moieties of said X2(C0-C6)alkyl- or X2(C1-C6)alkoxy-(C0- C6)alkyl- contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C0- C6)alkyl- or
Figure imgf000003_0003
groups may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(C0-C3)alkyl- and said heteroaryl-(C0-C3)alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C C6)alkoxy optionally substituted with from two to seven fluorine atoms, halo (e q , chloro, fluoro, bromo or lodo), (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, nitro, cyano, ammo, (C C6)alkylamιno-, [(C C6)alkyl]2amιno-, -C02R4, -CONR5R6, -S02NR7R8, -C(=0)R13 and -XC(=0)R13, or R2 and R3, together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyc c, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the non-fused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicychc rings that are not part of the benzo ring shown in formula I, may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicychc rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently from (C0-C6)alkyl- or (Cι-C6)alkoxy-(C0-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms, nitro, oxo, cyano, halo, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy ammo, (C1-C6)alkylamιno-, [(C C6)alkyl]2amιno-, -C02R4, -C0NR5R6, -S02NR7R8, -C(=0)R13 and -XC(=0)R13, each R4, R5, R6, R7 , R8 and R13 is selected, independently, from hydrogen and (C, -C6) alkyl, or R5 and R6, or R7 and R8 together with the nitrogen to which they are attached form a pyrrolidine, pipendine, morpho ne, azetidme, piperazine, -N-(Cι-C6)alkylpιperazιne or thiomorpholine ring, or a thiomorphoiine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone, and each X is, independently, (C-i-CβJalkylene, with the proviso that (a) at least one of R1, R2 and R3 must be the other than hydrogen, and (b) when R2 and R3 are hydrogen, R1 cannot be hydrogen, (C C^alkyl, or unconjugated (C3- C6)alkenyl, and pharmaceutically acceptable salts of such compounds
Examples of possible heteroaryl groups within the definition of R2 and R3 are the following thienyl, oxazoyi, isoxazolyl, pyridyl, pynmidyl, thiazolyl, tetrazolyl, isothiazolyl, tπazolyl, imidazolyl, tetrazolyl, pyrrolyl and the following groups
Figure imgf000004_0001
wherein one of R9 and R18 is hydrogen or (CrC^alkyl, and the other is a bond to the benzo ring of formula I Examples of compounds of this invention are compounds of the formula I, and their pharmaceutically acceptable salts, wherein R2 and R3, together with the benzo ring of formula I form a bicyc c ring system selected from the following
Figure imgf000005_0001
Figure imgf000005_0002
wherein R10 and R17 are selected, independently, from hydrogen, (C1-C6)alkyl; and (C CeJalkoxy- (C0-C6)alkyl- wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; nitro, cyano, halo, amino, (C1-C6)alkylamino-, [(C^Ce) alkyl]2amino-, -C02R4, -C0NR5R6, -S02NR7R8, -
C(=0)R , -XC(=0)R , phenyl and monocyclic heteroaryl wherein said heteroaryl is defined as R2 and R3 are defined in the definition of compounds of the formula I above;
Other embodiments of this invention relate to compounds of the formula I, and their pharmaceutically acceptable salts, wherein R2 and R3, together with the benzo ring of formula I, form a bicyclic or tricyclic ring system selected from the following:
Figure imgf000005_0003
Figure imgf000006_0001
wherein R10 and R17 are defined as above, and m is zero, one or two, and wherein one of the carbon atoms of ring A can optionally be replaced with oxygen or N(C1-C6)alkyl Other embodiments of this invention relate to compounds of the formula and their pharmaceutically acceptable salts, wherein neither R2 nor R3 is attached to the benzo ring of formula I via an oxygen atom
Other embodiments of this invention relate to compounds of the formula I, and their pharmaceutically acceptable salts, wherein R2 and R3 do not, together with the benzo ring of formula I, form a bicychc or tπcychc ring system
Other embodiments of this invention relate to compounds of the formula I wherein one or both of R2 and R are -C(=0)R ,1'3J, wherein R ,1'3° is (d-CeJalkyl Further embodiments of this invention relate to compounds of the formula I wherein one or both of R2 and R3 are -C(=0)R13 wherein R13 is (C1-C6)alkyl or (C C3)alkyl optionally substituted with from one to seven fluorine atoms Other embodiments relate to compounds of the formula I wherein one of R2 and R3 is CF3, fluoro, cyano, (C2-C6)alkynyl or C2F5
Other further embodiments of the present invention relates to compounds of formula I having the structure
Figure imgf000006_0002
wherein R1 is as defined above, and R2 and R3 are hydrogen, (Cι-C6)alkyl optionally substituted with from one to seven fluorine atoms, -C(=0)(Ci-C6)alkyl, cyano, hydroxy, nitro ammo, -0(C C6)a\ky\ or halo, with the proviso that R2 and R3 can not both be hydrogen when R1 is hydrogen, (Cr C6)alkyl, or unconjugated (C3-C6)alkenyl
Examples of specific compounds of the formula I are the following compounds, which, in the instances where there is a center or centers of asymmetry in the molecule, may comprise a racemic mixture or the single enantiomer
5,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2,4(8),9-trιen-6-one, 6-oxo-5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10),3,6,8-tetraene,
2-fluoro-N-(4-hydroxy-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-trιen-5-yl)-benzamιde 6-methyl-5-thιa-7,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,6,8-tetraene, 6-methyl-7-propyl-5,7,13-trιazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10), 3,5,8- tetraene, 5,7,13-tπazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10),3,5,8-tetraene,
7-methyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8-tetraene 6-methyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8-tetraene, 6,7-dιmethyl-5,7,13-tπazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10),3,5,8-tetraene, 7-propyl-5,7,13-tπazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8-tetraene, 7-butyl-5,7,13-trιazatetracyclo[9 3 1 02 0 048]pentadeca-2(10),3,5,8-tetraene,
6-methyl-7-ιsobutyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8- tetraene,
7-phenyl-5,7,13-trιazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10),3,5,8-tetraene, 6-methyl-7-phenyl-5,7,13-trιazatetracyclot9 3 1 02 10 04 8]pentadeca-2(10),3,5,8- tetraene,
7-neopentyl-5,7,13-trιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5,8-tetraene, 6-methyl-7-neopentyl-5,7,13-trιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10), 3,5,8- tetraene,
6,7-dιmethyl-5,8,14-trιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,5,7,9-pentaene 5,8,14-trιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11),3,5,7,9-pentaene,
14-methyl-5,8,14-trιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,5,7,9-pentaene, 5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10),3,6,8-tetraene, 6-methyl-5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,6,8-tetraene, 7-methyl-5-oxa-6,13-dιazatetracycio[9 3 1 02 10 048]pentadeca-2,4(8),6,9-tetraene, 4-methyl-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-trιene,
4-nιtro-10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, 4-amιno-10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, N1-[10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-4-yl]acetamιde, 4,5-dιnιtro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, 4,5-dιfluoro-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, 4-chloro-10-azatrιcyclo|6 3 1 027]dodeca-2(7),3,5-trιene,
3-(10-azatπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-4-yl)-5-methyl-1 ,2,4-oxadιazole, 10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-4-ol, 4,5-dιchloro-10-azatπcyclo[6 3 1 027]dodeca-2(7),3,5-trιene, N ,N4-dιmethyl-10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-4-sulfonamιde, 4-(1-pyrrohdιnylsulfonyl)-10-azatπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene,
1-(10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-4-yl)-1-ethanone, 3-tπfluoromethyl-10-aza-trιcyclo[6 3 1 0 7]dodeca-2(7),3,5-trιene, 4-trιfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene,
2 7,
3-fluoro-10-aza-trιcyclo[6 3 1 0 ]dodeca-2(7),3,5-trιene
2 7, 10-azatrιcyclo[6 3 1 0 ]dodeca-2(7),3,5-tπen-4-yl cyanide,
4-fluoro-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-trιene, 5,14-dιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11),3,5,7,9-pentaene, 6-methyl-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,5,7,9-pentaene, 7-methyl-5,14-dιazatetracyclo[10 3 1 02 11 0 9]hexadeca-2(11),3,5,7,9-pentaene, 7-ethyl-5,14-dιazatetracyclo[10 3 1 02 11 0 9]hexadeca-2(11),3,5,7,9-pentaene,
8-methyl-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11),3,5,7,9-pentaene, 5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11),3,7,9-tetraen-6-one, 6-chloro-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,5,7,9-pentaene, 6-methoxy-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,5,7,9-pentaene, 6-chloro-10-fluoro-5,14-dιazatetracycio[10 3 1 O2 11 049]hexadeca-2(11), 3,5,7,9- pentaene,
5,8,14-tπazatetracyclo[10 3 1 02 11 049]hexadeca-2(11),3,7,9-tetraen-6-one, 6-chloro-3-fluoro-5,14-dιazatetracyclo[10 3 1 02 11 0 9]hexadeca-2(11),3,5,7,9- pentaene, and pharmaceutically acceptable salts thereof
Other embodiments compounds of the invention include but are not limited to 6-methyl-5,7-dιoxo-6,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,8-tπene, 6-methyl-5-oxo-6,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,8-trιene, 5,7-dιmethyl-6-oxo-5,7,13-trιazatetracyclo[9 3 1 O2 10 0 8]pentadeca-2(10),3,8-tπene
5,7-dιoxo-6,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,8-trιene, 5-0x0-6, 13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,8-tπene, 6-oxo-5,7, 13-tπazatetracyclo[9 3 1 O2 10 04 8]pentadeca-2(10),3,8-trιene, 6-methyl-5-thιa-5-dιoxo-6,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10), 3,6,8- tetraene,
7-dιmethylamιno-5-thιa-5-dιoxo-6,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca- 2(10),3,6,8-tetraene
6,7-dιoxo-5,8, 14-tπazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,9-tπene, 5,8-dιmethyl-6,7-dιoxo-5,8,14-trιazatetracyclo[10 3 1 02 11 0 9]hexadeca-2(11),3,9- tnene, 5-oxa-7-methyl-6-oxo-7,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,8-tπene
5-fluoro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-4-carbonιtπle, 4-ethynyl-5-fluoro-10-aza-trιcyclo[6 3 1 0 7]dodeca-2(7),3,5-trιene, 5-ethynyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-4-carbonιtrιle, 5-chloro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-4-carbonιtrιle, 4-ethynyl-5-chloro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene,
4-fluoro-5-trιfluoromethyl-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, 4-chloro-5-tπfluoromethyl-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, 5-trιfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene-4-carbonιtrιle, 4-ethynyl-5-tπfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, 4,5-bιstrιfluoromethyl-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, and pharmaceutically acceptable salts thereof Other embodiments of the invention are the hydrochlonde salts of the above enumerated compounds
This invention also relates to compounds of the formula
Figure imgf000009_0001
wherein P is hydrogen, methyl, COOR16 wherein R is (C C6)alkyl, allyl, 2,2,2-trιchloroethyl or (C CeJalkyl, -C(=0)NR5R6 wherein R5 and R6 are defined as in formula I above, -C(=0)H
Figure imgf000009_0002
wherein the alkyl moiety may optionally be substituted with from 1 to 3 halo atoms, preferably with from 1 to 3 fluoro or chloro atoms, benzyl or t-butoxycarbonyl (t-Boc) and R14 and R15 are selected, independently, from hydrogen, (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, -C(=0)(C1-C6)alkyl, cyano, hydroxy nitro ammo,
Figure imgf000010_0001
or halo, with the proviso that R14 and R15 can not both be hydrogen when P is hydrogen, (C1-C6)alkyl, or unconjugated (C3-C6)alkenyl Such compounds are useful as intermediates in the synthesis of compounds of the formula I The invention also relates to compounds of the formula
Figure imgf000010_0002
wherein R2 and R3 are defined above, and P' is COOR16 wherein R16 is allyl, 2,2,2-trιchloroethyl or (CVCf alkyl, -C(=0)NR5R6 wherein R5 and R6 are also as defined above, -C(=0)H -
Figure imgf000010_0003
wherein the alkyl moiety may optionally be substituted with from 1 to 3 halo atoms, preferably with from 1 to 3 fluoro or chloro atoms, benzyl, or t-butoxycarbonyl
Unless otherwise indicated, the term "halo", as used herein, includes fluoro, chloro bromo and lodo
Unless otherwise indicated, the term "alkyl", as used herein, includes straight chain moieties, and where the number of carbon atoms suffices, branched and cyclic moieties The term "alkoxy", as used herein, means "-O-alkyl" or "alkyl-O-", wherein "alkyl" is defined as above
The term "alkylene, as used herein, means an alkyl radical having two available bonding sites (j_e_, -alkyl-), wherein "alkyl" is defined as above
Unless otherwise indicated, the term "one or more substituents", as used herein, refers to from one to the maximum number of substituents possible based on the number of available bonding sites
The term "treatment", as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such condition or disorder The term "treatment", as used herein, refers to the act of treating, as "treating" is defined immediately above
The compounds of formula I may have optical centers and therefore may occur in different enantiomeπc configurations The invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of formula I, as well as racemic and other mixtures thereof Particularly, preferred enantiomers of the invention include
(+)-5,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2,4(8),9-trιen-6-one, (+)-6-oxo-5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,6,8-tetraene, (+)-2-fluoro-N-(4-hydroxy-10-aza-tπcyclo[6 3 1 027]dodeca-2(7) 3 5-trιen-5-yl)- benzamide,
((+)-6-methyl-5-thιa-7 13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10), 3,6,8- tetraene,
((+)-6-methyl-7-propyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5 8- tetraene,
(+)-7-methyl-5,7,13-trιazatetracyclo[9 3 1 0 10 04 8]pentadeca-2(10),3,5,8-tetraene (+)-6,7-dιmethyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5 8-tetraene (+)-7-propyl-5,7,13-tπazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5,8-tetraene (+)-7-butyl-5,7,13-tπazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8-tetraene,
(+)-6-methyl-7-ιsobutyl-5,7,13-tπazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5 8- tetraene,
(+)-7-phenyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8-tetraene (+)-6-methyl-7-phenyl-5,7,13-tπazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10), 3,5,8- tetraene,
+)-7-neopentyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8-tetraene +)-6-methyl-7-neopentyl-5,7,13-tπazatetracyclo[9 3 1 02 10 048]pentadeca-2(10), 3,5,8- tetraene
+)-5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,6,8-tetraene, +)-6-methyl-5-oxa-7,13-dιazatetracyclo[9 3 1 02 1° 048]pentadeca-2(10), 3,6,8- tetraene
+)-7-methyl-5-oxa-6,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2,4(8),6,9-tetraene, +)-4-methyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, +)-4-nιtro-10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, +)-4-amιno-10-azatrιcyclo[6 3 1 027]dodeca-2(7),3,5-trιene, +)-N1-[10-azatrιcyclo[6 3 1 027]dodeca-2(7),3,5-trιen-4-yl]acetamιde, +)-4-chloro-10-azatπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene,
+)-3-(10-azatrιcyclo[6 3 1 0 ,27 '.]dodeca-2(7),3,5-trιen-4-yl)-5-methyl-1 ,2,4-oxadιazole ι27
+)-10-azatrιcyclo[6 3 1 0 ]dodeca-2(7),3,5-tπen-4-ol,
2 7,
+)-N ,N -dιmethyl-10-azatrιcyclo[6 3 1 0 ]dodeca-2(7),3,5-tπene-4-sulfonamιde
+)-4-(1-pyrrolιdιnylsulfonyl)-10-azatrιcyclo[6 3 1 0 2 7, ]dodeca-2(7),3,5-trιene,
+)-1-(10-azatrιcyclo[6 3 1 0 ■,2 '.]dodeca-2(7),3,5-trιen-4-yl)-1-ethanone,
2 7,
+)-3-trιfluoromethyl-10-aza-trιcyclo[6 3 1 0 ]dodeca-2(7),3,5-trιene
,2 7,,
+)-4-trιfluoromethyl-10-aza-trιcyclo[6 3 1 0 ]dodeca-2(7),3,5-trιene, 2 7,
(+ -3-fluoro-10-aza-trιcyclo[6 3 1 0 ]dodeca-2(7),3,5-trιene, (+ -10-azatrιcyclo[6 3 1 0 -.2 7 ]dodeca-2(7),3,5-trιen-4-yl cyanide, (+ •4-fluoro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene, (+ •6-methyl-5-oxo-6,13-dιazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10),3,8-tπene (+ ■5-0X0-6,13-d ιazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10) 3 8-tπene,
(+ ■6-methyl-5-thιa-5-dιoxo-6,13-dιazatetracyclo[9 3 1 02 10 O4 8]pentadeca-2(10), 3,6,8- tetraene,
(+ -7-dιmethylamιno-5-thιa-5-dιoxo-6,13-dιazatetracyclo[9 3 1 02 10 0 8]pentadeca- 2(10),3,6,8 -tetraene,
(+ ■5-oxa-7-methyl-6-oxo-7,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10) 3,8- tπene,
-.2 7
(+ 5-fluoro-10-aza-trιcyclo[6 3 1 0 ]dodeca-2(7),3,5-trιene-4-carbonιtrιle,
2 7, (+ ■4-ethynyl-5-fiuoro-10-aza-tπcyclo[6 3 1 0 ]dodeca-2(7),3,5-trιene,
-2 7 (+ 5-ethynyl-10-aza-tπcyclot6 3 1 0 ]dodeca-2(7),3,5-tπene-4-carbonιtrιle, ι2 7. (+ 5-chloro-10-aza-trιcyclo[6 3 1 0 ]dodeca-2(7),3,5-trιene-4-carbonιtrιle,
2 7, (+ -4-ethynyl-5-chloro-10-aza-trιcyclo[6 3 1 0 ]dodeca-2(7),3,5-trιene
27, (+ -4-fluoro-5-trιfluoromethyl-10-aza-tπcyclo[6 3 1 0 ]dodeca-2(7),3,5-trιene
27, (+ -4-chloro-5-trιfluoromethyl-10-aza-tπcyclo[6 3 1 0 ]dodeca-2(7),3,5-trιene
2 7, (+ -5-trιfluoromethyl-10-aza-trιcyclo[6 3 1 0 ]dodeca-2(7),3,5-trιene-4-carbonιtrιle, (+ 4-ethynyl-5-trιfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, (+ 5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11),3,5,7,9-pentaene, (+ 6-methyl-5,14-dιazatetracyclo[10 3 1 O2 11 049]hexadeca-2( 1),3,5,7,9-pentaene (+ 7-methyl-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(1 1 ),3,5,7,9-pentaene (+ 7-ethyl-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,5,7,9-pentaene (+ 8-methyl-5,14-dιazatetracyclo[10 3 1 O2 11 049]hexadeca-2(11 ),3,5,7,9-pentaene (+ -5,14-dιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11),3,7,9-tetraen-6-one,
(+: -6-chloro-5,14-dιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11 ),3,5,7,9-pentaene, (+ -6-methoxy-5,14-dιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11 ),3,5,7,9-pentaene, (+ -6-chloro-10-fluoro-5,14-dιazatetracydo[10 3 1 02 11 04 9]hexadeca-2(11),3,5,7,9- pentaene,
(+ 5,8,14-trιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11),3,7,9-tetraen-6-one,
(+ ■6-chloro-3-fluoro-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11),3,5,7,9- pentaene, and pharmaceutically acceptable salts thereof
In addition, other preferred enantiomers of the compounds of the invention include (-)-5,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2,4(8),9-trιen-6-one, -6-oxo-5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,6,8-tetraene -2-fluoro-N-(4-hydroxy-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-5-yl)- benzamide
■6-methyl-5-thιa-7,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,6,8-tetraene, ■6-methyl-7-propyl-5,7,13-trιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5,8- tetraene
-7-methyl-5,7,13-tπazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10),3,5,8-tetraene, -6,7-dιmethyl-5,7,13-trιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5,8-tetraene ■7-propyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8-tetraene, -7-butyl-5,7,13-tπazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8-tetraene, -6-methyl-7-ιsobutyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5 8- tetraene
-7-phenyl-5,7,13-tπazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10),3,5,8-tetraene, -6-methyl-7-phenyl-5,7,13-trιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5 8- tetraene
•7-neopentyl-5,7,13-trιazatetracyclo[9 3 1 O2 10 048]pentadeca-2(10),3,5,8-tetraene, -6-methyl-7-neopentyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10), 3,5,8- tetraene
-5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,6,8-tetraene, -6-methyl-5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,6,8-tetraene, -7-methyl-5-oxa-6,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2,4(8),6,9-tetraene -4-methyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene,
27,
■4-nιtro-10-azatπcyclo[6 3 1 0 ]dodeca-2(7),3,5-tπene,
-4-amιno-10-azatπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, -N1-[10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-4-yl]acetamιde, -4-chloro-10-azatrιcyclo[6 3 1 0 7]dodeca-2(7),3,5-tπene, -3-(10-azatrιcyclo[6 3 1 027]dodeca-2(7),3,5-tπen-4-yl)-5-methyl-1 ,2,4-oxadιazole, -10-azatπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-4-ol,
-N4,N4-dιmethyl-10-azatπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-4-sulfonamιde, -4-(1-pyrrohdιnylsulfonyl)-10-azatrιcyclo[6 3 1 0 7]dodeca-2(7),3,5-tπene, -1-(10-azatrιcyclo[6 3 1 027]dodeca-2(7),3,5-tπen-4-yl)-1-ethanone, -3-trιfluoromethyl-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, -4-tπfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene,
■3-fluoro-10-aza-trιcyclo[6 3 1 0 27, ]dodeca-2(7),3,5-tπene,
10-azatπcyclo[6 3 1 0 -,2 7 ]dodeca-2(7),3,5-trιen-4-yl cyanide,
-4-fluoro-10-aza-tπcyclo[6 3 1 0 ,2 7, ]dodeca-2(7),3,5-trιene, ■6-methyl-5-oxo-6,13-dιazatetracycIo[9 3 1 02 10 04 8]pentadeca-2(10),3,8-trιene, •5-0X0-6, 13-dιazatetracyclo[9 3 1 02 0 048]pentadeca-2(10),3,8-tπene,
(- •6-methyl-5-thιa-5-dιoxo-6,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10), 3,6,8- tetraene,
•7-dιmethylamιno-5-thιa-5-dιoxo-6,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-
2(10),3,6,8-tetraene,
•5-oxa-7-methyl-6-oxo-7,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,8- tnene,
-5-fluoro-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-4-carbonιtπle, -4-ethynyl-5-fluoro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene, -5-ethynyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-4-carbonιtrιle, -5-chloro-10-aza-trιcyclo[6 3 1 0 7]dodeca-2(7),3,5-tπene-4-carbonιtrιle, •4-ethynyl-5-chloro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, -4-fluoro-5-tπfluoromethyl-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene, -4-chloro-5-trιfluoromethyl-10-aza-tπcyclo[6 3 1 027]dodeca-2(7),3,5-tπene, -5-trιfluoromethyl-10-aza-tπcyclo[6 3 1 027]dodeca-2(7),3,5-trιene-4-carbonιtπle, -4-ethynyl-5-trιfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene, -5,14-dιazatetracyclo[10 3 1 02 11 0 9]hexadeca-2(11), 3,5,7, 9-pentaene, -6-methyl-5,14-dιazatetracyclo[10 3 1 02 11 0 9}hexadeca-2(11 ),3,5,7,9-pentaene, -7-methyl-5,14-dιazatetracyclo[10 3 1 O2 11 04 9]hexadeca-2(11 ),3,5,7,9-pentaene,
(-: -7-ethyl-5,14-dιazatetracyclo[10 3 1 O2 11 049]hexadeca-2(11 ),3,5,7,9-pentaene, -8-methyl-5,14-dιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11 ),3,5,7,9-pentaene, -5,14-dιazatetracyclo[10 3 1 02 11 0 9]hexadeca-2(11),3,7,9-tetraen-6-one, -6-chloro-5,14-dιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11 ), 3,5,7, 9-pentaene, -6-methoxy-5,14-dιazatetracyclo[10 3 1 O2 11 049]hexadeca-2(11), 3,5,7, 9-pentaene
(- •6-chloro-10-fluoro-5,14-dιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11),3,5,7,9- pentaene
(- ■5,8,14-tπazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11 ),3,7,9-tetraen-6-one,
(-: ■6-chloro-3-fIuoro-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11),3, 5,7,9- pentaene, and pharmaceutically acceptable salts thereof
The present invention also relates to all radiolabeled forms of the compounds of the formula I Preferred radiolabeled compounds of formula I are those wherein the radiolabels are selected from as 3H, 11C, 14C, 18F, 123l and 125l Such radiolabeled compounds are useful as research and diagnostic tools in metabolism studies, such as pharmacokinetics studies, etc , and in binding assays in both animals and man The present invention also relates to a pharmaceutical composition for use in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a mammal, including a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use and a pharmaceutically acceptable carrier
The present invention also relates to a method for reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use
The present invention also relates to a method of treating a disorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder depression, bipolar disorder, autism, sleep disorders jet lag, amyotrophic lateral sclerosis (ALS) cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e g , dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or ***e), headache migraine stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dysk esia, hyperkinesia, dyslexia, schizophrenia multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mat absence epilepsy senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition
The present invention also relates to a pharmaceutical composition for treating a disorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e g , dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or ***e), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD) psychosis, Huntington's chorea, tardive dyskmesia, hyperkinesia, dyslexia, schizophrenia, multi- mfarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome in a mammal, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier
The present invention also relates to a method for reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a mammal, comprising administering to said mammal an amount of a compound comprising an amount of a compound of the formula
Figure imgf000016_0001
wherein R is selected from the group consisting of hydrogen, (C1-C6)alkyl, or unconjugated (C3-C6)alkenyl, or a pharmaceutically acceptable salt thereof, that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use
The present invention also relates to a method for treating a disorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e g , dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or ***e), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskmesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound of the formula
Figure imgf000016_0002
where R19 is defined above, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition This invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I Examples of pharmaceutically acceptable acid addition salts of the compounds of formula I are the salts of hydrochloric acid, p-toluenesulfonic acid, fumaπc acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartanc acid, malic acid, di-p-toluoyl tartanc acid, and mandelic acid, as well salts formed from other acids known to those of skill in the art to form pharmaceutically acceptable acid addition salts to basic compounds Other possible acid addition salts are, e , salts containing pharmaceutically acceptable anions, such as the hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, and pamoate (i e , 1 1'-methylene-bιs- (2-hydroxy-3-naphthoate) salts)
The present invention also relates to methods for the preparation of the novel compounds of formula I The invention is directed to a process for the preparation of a compound of formula IA
Figure imgf000017_0001
wherein R ,10 is defined above, comprising the step of reacting a compound of formula
VI
Figure imgf000017_0002
wherein Q is a nitrogen protecting group, with a compound of formula XXIIB
XXIIB
Figure imgf000017_0003
wherein R20 and R21 are each independently (C1-C6)alkyl, and wherein R10 is defined above, and
(II) removing the protecting group Q
The nitrogen protecting group Q may be chosen from suitable groups known to those of skill in the art including -COCF3, -COCCI3, -COOCH2CCI3, -COO(C1-C6)alkyl and -COOCH2C6H5 These groups may be added or removed by methods described for each in T. W Greene and G M Wuts, Protective Groups in Organic Synthesis (John Wiley & Sons, New York, 1991) Preferably the nitrogen protecting group Q is a tnfluoroacetyl or a t- butoxycarbonyl group
The invention also relates to a process for the preparation of a compound of formula IB
Figure imgf000018_0001
wherein R10 and R17 are defined above, comprising the steps of (i) of reacting a compound of formula VI
Figure imgf000018_0002
wherein Q is a nitrogen protecting group, with a compound of formula XXIIB
XXIIB
Figure imgf000018_0003
wherein R20 and R21 are each independently (Cι-C6)alkyl, and wherein R10 is defined above and
(n) allowing the product of step (i) to react with a compound of the formula R17Z wherein R17 is defined above, and Z is a leaving group, in the presence of a base,
(MI) removing the protecting group Q
Preferably, in this method to prepare IB the leaving group is selected from the group consisting of halo, halosulfonate, mesylate and tosylate, and the base is an alkali metal hydride, hydroxide or carbonate Preferably, the protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group
The invention also relates to another process for the preparation of a compound of formula IB
Figure imgf000018_0004
wherein R10 and R17 are defined above, comprising the steps of (i) of reacting a compound of formula XXIIIA XXIVA
Figure imgf000019_0001
wherein Q is a nitrogen protecting group, with a compound of formula XXIIB:
XXIIB
Figure imgf000019_0002
wherein R20 and R21 are each independently (C CsJalkyl, and wherein R1C is defined above, and
(iii) removing the protecting group Q.
Preferably, in this method to prepare IB, the protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group.
The invention is also directed to a process for preparing a compound of formula IC
Figure imgf000019_0003
wherein R10 and R17 are as defined above, comprising the steps of (i) allowing a compound of formula VI:
Figure imgf000019_0004
wherein Q is a nitrogen protecting group, to react with a compound of formula
Figure imgf000019_0005
wherein Y is an alkali metal or alkaline earth metal cation; or a compound of formula
Figure imgf000019_0006
wherein R 0 and R17 are as defined above; and (ii) removing the protecting group Q. The protecting group Q is preferably a trifluoroacetate group or a t-butoxycarbonyl group Preferably, step (i) is conducted in a polar solvent, more preferably, water, THF DMF DMSO, a mixture of water and any of THF, DMF or DMSO In addition, the processes to make each of compounds IA, IB and IC, preferably comprise the further step of reducing the nitro groups of a compound of formula IIC
Figure imgf000020_0001
wherein Q is a nitrogen protecting group to form a compound of formula VI
Figure imgf000020_0002
More preferably, the reduction is conducted in the presence of hydrogen gas employing a palladium catalyst Preferably, the protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group
The invention is also directed to a process for the preparation of a compound of formula IE
Figure imgf000020_0003
wherein R10 is defined above, comprising the steps of
(i) reducing the nitro group of a compound of formula VINA
VIIIA
Figure imgf000020_0004
wherein Q is a nitrogen protecting group,
,10,
(n) allowing the ammo product to react with an acid chloride of the formula RluCOCI or an acid anhydride of the formula (R10CO)2O wherein R10 is (C C6)alkyl, or a compound of the formula R10C((C1-C6)alkoxy)3,
(MI) removing the protecting group Q
Preferably, in this process to prepare IE, the reduction of step (i) is conducted by hydrogenation with a palladium or platinum catalyst Preferably, the protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group The invention is further related to a process for the preparation of a compound of formula IF
Figure imgf000021_0001
wherein R10 is as defined above, comprising the steps of (i) allowing a compound of formula XA
Figure imgf000021_0002
wherein R , 10 is as defined above, and Q is a nitrogen protecting group, to react with Lawesson s reagent,
(II) allowing the product of step (i) to react with potassium ferπcyanide and sodium hydroxide,
(in) removing the protecting group Q
Preferably, the protecting group Q is a trifluoroacetyl or a t-butoxycarbonyl group
The invention also relates to a process for preparing compounds the formula
Figure imgf000021_0003
wherein R2 and R3 are defined above, comprising the steps of (i) subjecting a compound of formula XIIIB
XIIIB
Figure imgf000021_0004
to ozonolysis conditions,
(II) partially reducing the resulting ozonide product of step (i) to a dialdehyde or product of equivalent oxidation state,
(HI) allowing the product of step (n) to react with an arylmethylamine, and (iv) removing the arylmethyl group
The ozonolysis conditions used may be any of those known to those of skill in the art
Preferably, the ozonolysis conditions are ozone in methanol or dichloromethane, preferably methanol In step (n), the reduction of the ozonolysis product or ozonide is preferably conducted by hydrogenation, e_g_, in the presence of hydrogen gas and a platinum or palladium catalyst with or without carbon/charcoal The arylmethyiamine employed in step (in) is benzylamine 4-methoxybenzylamιne or 3,4-dιmethoxybenzylamιne, preferably benzylamine, and is preferably added in the presence of an acid catalyst, preferably formic acid The removal of the arylmethyl group in step (iv) is preferably a hydrogenolysis reaction conducted, e g , in the presence of hydrogen gas and a platinum or palladium catalyst with or without carbon/charcoal, and in the presence of an acid catalyst
The invention also relates to a novel process for the preparation of a compound of formula
Figure imgf000022_0001
comprising the steps of
(i) hydrogenatmg a compound having the formula XXVIII or XXVIN'
XXVIII' C6)alkyl
Figure imgf000022_0002
wherein R2 and R3 are defined above,
(II) cyclizmg the amine-ester compound of formula XXIX
Figure imgf000022_0003
obtained from step (i) to form a lactam ring compound of formula XXX
Figure imgf000022_0004
(MI) reducing the carbonyl moiety The preferred starting material in step (i) is the tπmethylsiloxy compound The hydrogenation of step (i) is preferably conducted with a palladium or platinum catalyst under hydrogen gas, preferably in the presence of an acid catalyst The lactam formation of step (u) is preferably performed in the presence of a base, preferably an alkoxyalkahde compound in a nonaqueous protic solvent, more preferably sodium fert-butoxide in methanol The reduction of step (in) is preferably performed in the presence of a borane tetrahydrofuran complex diborane, borane dimethysulfide complex, lithium aluminum hydride or a combination of sodium borohydnde and boron tπfluoride, more preferably a combination of sodium borohydπde and boron tπfluoride
Detailed Description of the Invention Except where otherwise stated, R1 through R19, m, P and P', and structural formula I in the reaction schemes and discussion that follow are defined as above Schemes 1-10, below illustrate methods of synthesizing compounds of the formula I
SCHEME 1
Figure imgf000023_0001
MA IIB
SCHEME 2
Figure imgf000024_0001
IIA VIA
Figure imgf000024_0002
IA IB
SCHEME 3
Figure imgf000025_0001
VIA XXIII
Figure imgf000025_0002
IB
SCHEME 4
Figure imgf000025_0003
VI B IC
SCHEME 5
Figure imgf000025_0004
XXII VIII
Figure imgf000025_0005
SCHEME 6
Figure imgf000026_0001
XI
Figure imgf000026_0002
IF
SCHEME 7
Figure imgf000026_0003
(ring A = present or (ring A = present or absent) (ring A = present or absent) absent) XIIIA XIII
Figure imgf000026_0004
(ring A = present or absent) IG: (R2 and R3 form ring A) XIV III: (ring A = absent)
SCHEME 7A
Figure imgf000027_0001
XXVI XXVI IA XXVII I A LisH-or((C C6)alkyl)3Sι-
OS02R2 or "OCOR2
Figure imgf000027_0002
IG': where R2 and R3 form a ring A (see Scheme 7) III': where R2 and R3 do not form a ring
SCHEME 8
Figure imgf000028_0001
XV XVI XVII XVIII
(R 8 is, e.g., F, (C1-C6)alkoxy or any suitable R2 and/or R3 group member)
Figure imgf000028_0002
XXI
SCHEME 8A
Figure imgf000028_0003
XVII' XIX IH'
SCHEME 9
Figure imgf000029_0001
SCHEME 10
Figure imgf000030_0001
IQ
Referring to Scheme 1 , the starting material of formula III is reacted with trifluoroacetic anhydride, in the presence of pyridine, to form the compound of formula IV This reaction is typically conducted in methylene chloride at a temperature from about 0°C to about room temperature Other methods of generating a trifluoroacetate protecting group that may be used are recognized by those of skill in the art
The compound of formula IV is then converted into the dmitro derivative of formula IIA by the following process The compound of the formula IV is added to a mixture of 4 or more equivalents of trifluoromethanesulfonic acid (CF3S02OH) and 2 to 3 equivalents of nitric acid, in a chlorinated hydrocarbon solvent such as chloroform, dichloroethane (DCE) or methylene chloride The resulting mixture is allowed to react for about 5 to 24 hours Both of the foregoing reactions are generally conducted at a temperature ranging from about -78°C to about 0°C for about 2 hours, and then allowed to warm to room temperature for the remaining time Reduction of the compound of formula IIA, using methods well known to those of skill in the art, yields the compound of formula IIB This reduction can be accomplished, for example, using hydrogen and a palladium catalyst such as palladium hydroxide or palladium on carbon and running the reaction in methanol at about room temperature The steps of Scheme 1 can also be performed with a nitrogen-protecting group, other than an a tnfluoroacetyl group, that would be deemed suitable by those of skill in the art Other suitable nitrogen protecting groups that can be used in the procedures described throughout this document include -COCF3, -COCCI3, -COOCH2CCI3, -COO(C C6)alkyl and -COOCH2C6H5 These groups may be added or removed by methods described for each in T W Greene and G M Wuts Protective Groubs in Organic Synthesis (John Wiley & Sons, New York, 1991 )
Referring to Scheme 2, the compound of formula IIA is converted into the corresponding compound wherein the tnfluoroacetyl protecting group is replaced by a t-Boc protecting group (VIA) by reacting it first with an alkali metal or alkaline earth metal (or ammonium) hydroxide or carbonate, and then reacting the isolated product from the foregoing reaction with di-t- butyldicarbonate Although t-Boc is used in this instance, other appropπate nitrogen-protecting groups known to those of skill in the art may be used The reaction with the alkali or alkaline earth metal (or ammonium) hydroxide or carbonate is generally carried out in an aqueous alcohol, dioxane or tetrahydrofuran (THF) at a temperature from about room temperature to about 70°C, preferably at about 70°C, for about one to about 24 hours The reaction of the isolated, unprotected amine or an acid addition salt of such amine, from the above reaction with di-t-butyldicarbonate is preferably carried out in a solvent such as THF, dioxane or methylene chloride at a temperature from about 0°C to about room temperature This reaction may or may not be conducted in the presence of a base When the reactant is a salt of the amine, use of a base is preferred The resulting compound of formula VIA can be converted into the corresponding diamino derivative of formula VIB using the procedure described above for converting the dmitro compound of formula IIA into the corresponding diamino compound of formula IIB, or other generally accepted nitro group reduction methods known to those of skill in the art, e_g_, zinc-, tin-, or iron-mediated reductions, etc
The conversion of the compound of formula VIB into the desired compound of the formula VII can be accomplished by reacting the compound of formula VIB with a compound of the formula XXIIA XXIIA
Figure imgf000031_0001
wherein R10 is hydrogen, (C CεJalkyl optionally substituted with from one to seven fluorine atoms, aryl-(C0-C3)alkyl wherein said aryl is selected from phenyl and naphthyl, or heteroaryl-(C0 -C3)alkyl wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C C6)alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6)alkoxy optionally substituted with from one to seven fluorine atoms and cyano The preferred solvent for this reaction is a 10 1 mixture of ethanol/acetic acid The reaction temperature can range from about 40°C to about 100°C It is preferably about 60°C Other appropriate solvents include acetic acid, ethanol and isopropanol Alternate methods of preparing compounds of the formula VII the compound of formula VIB are described by Segelstem et a , Tetrahedron Lett . 1993, 34, 1897
Removal of the t-Boc protecting group from the compound of formula VII yields corresponding compound of formula IA The protecting group can be removed using methods well known to those of skill in the art For example, the compound of formula VII can be treated with an anhydrous acid such as hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, preferably hydrochloric acid in ethyl acetate, at a temperature from about 0°C to about 100°C, preferably from about room temperature to about 70°C, for about one to 24 hours.
The compound of formula VII can be converted into the corresponding compound of formula IB by reacting it with a compound of the formula R17Z, wherein R17 is defined as R10 is defined above, and Z is a leaving group such as a halo or sulfonate (e q , chloro, bromo, mesylate or tosylate), in the presence of a base such as an alkali metal hydride, hydroxide or carbonate, preferably potassium hydroxide, in a polar solvent such as water, dimethylsulfoxide (DMSO), THF or DMF, preferably a mixture of DMSO and water, and then removing the protecting group as described above The reaction with R17Z is generally carried out at a temperature from about room temperature to about 100°C, preferably at about 50°C, for about five hours
Scheme 3 illustrates an alternate method of preparing compounds of the formula IB from the compound of formula VIA This method is the preferred method of making compounds of the formula IB wherein R17 is a bulky group such as an aryl or heteroaryl containing group, or when R17 can not be attached, as illustrated in Scheme 2, by alkylation or aryl substitution methods Referring to Scheme 3, the compound of formula VIA is reacted with the appropriate compound of formula R17NH2 in a polar solvent such as THF, DMF or DMSO, preferably THF, at a temperature from about room temperature to about 100°C, preferably at the reflux temperature, for about four to eighteen hours The resulting compound of formula XXIII is then converted into the corresponding compound of the formula XXIV by reducing the nitro group to an ammo group using methods well known to those of skill in the art Such methods are referred to above for the conversion of the compounds of the formula IIA into a compound of the formula IIB in Scheme 1 , and exemplified in experimental Examples 12B and 18B Closure to the imidazole ring to form the corresponding compound of formula XXV can then be accomplished by reacting the compound of formula XXIV from the above reaction with a compound of the formula XXIIA
XXIIA
Figure imgf000033_0001
wherein R10 is defined as above, as described above for converting compounds of the formula
VIB into those of the formula VII Removal of the protecting group from the compound of formula XXV yields the corresponding compound of formula IB This can be accomplished using methods well known in the art, for example, as described above for forming compounds of the formula IA from the corresponding compounds of the formula VII
Scheme 4 illustrates a method of preparing compounds of the formula IC, wherein R 0 and R17 are as defined above Referring to Scheme 4, the compound of formula VIB, or analogously formula IIB in Scheme I, is reacted with a compound of the formula
Figure imgf000033_0002
(sodium bisulfite ethane dione addition adduct) in water or another polar solvent such as THF,
DMF or DMSO, preferably a mixture of water and a water miscible solvent such as THF, for about one to four hours The reaction temperature can range from about 40°C to about
100°C, and is preferably at about the reflux temperature
Alternatively, the compound of formula VIB can be reacted with a compound of the formula
Figure imgf000033_0003
(double condensation reaction) in a polar solvent such as THF, water, or acetic acid preferably a mixture of water and THF This reaction is typically carried out at a temperature from about 40°C to about 100°C, preferably at the reflux temperature, for about two to four hours The desired qumoxoline of formula IC can then be formed by deprotectmg the compound formed in either of the foregoing reactions, using the method described above for converting a compound of the formula VII into one of the formula IA Alternatively, in place of compound VIB in Scheme 4, the compound IIB of Scheme 1 may be used analogously in this procedure with deprotection/reprotection as outlined in Scheme 2 (i e , the process of transforming IIA to VIA) in order to arrive at ultimately the compound IC In general alternative nitrogen protection groups are equally suited to the procedure of Scheme 4
Scheme 5 illustrates a method of preparing compounds of the formula I wherein R2 and R3, together with the benzo ring to which they are attached, form a benzoxazole ring system Such a compound, wherein R1 is hydrogen, is depicted in Scheme 5 as chemical formula IE Referring to Scheme 5, the compound of formula XXII, wherein Y is nitro halo tπfluoromethanesulfonate or a diazonium salt, is reacted with potassium acetate or another alkali or alkaline earth metal carboxylate in a solvent such as dimethylsulfoxide (DMSO), DMF or acetonitrile, preferably DMSO This reaction is generally allowed to run for about 12-24 hours Appropriate reaction temperatures range from about 70°C to about 140°C Approximately 100°C is preferred
The above reaction yields the compound of formula VIII, which can then be converted into the desired compound having formula IE by the following procedure First, the compound of formula VIII is reduced by reaction with hydrogen and a palladium or platinum catalyst such as palladium hydroxide in methanol at a temperature from about 0°C to about 70°C, preferably at about room temperature, to form the corresponding ammo derivative The product of this reaction is then reacted with an acid chloride of the formula R10COCI or an acid anhydride of the formula (R10CO)2O wherein R10 is
Figure imgf000034_0001
or a compound of the formula R10C(OC2H5)3l in an appropriate inert solvent such as deca n, chlorobenzene or xylenes A mixture of xylenes is preferred This reaction is typically conducted at a temperature from about 120-150°C preferably at about 140°C When R10COCI is used as a reactant, it is preferable to add a stoichiometπc amount of tπethylamine (TEA) or another organic tertiary amine base and a catalytic amount of pyndinium p-toluenesulfonic acid or pyndinium p-toluenesulfonate (PPTs) to the reaction mixture When R10C(OC2H5)3 is used as a reactant, it is preferable to add a catalytic amount of PPTs to the reaction mixture Removal of the trifluoroacetyl nitrogen protecting group yields the desired compound of the formula IE This can be accomplished using methods well known to those of skill in the art for example, reacting the protected compound with a lower alkanol and an aqueous alkali or alkaline earth metal (or ammonium) hydroxide or carbonate, aqueous sodium carbonate at a temperature from about 50°C to about 100°C, preferably at about 70 °C, for about two to six hours Scheme 6 illustrates the preparation of compounds of the formula I wherein R is hydrogen and R2 and R3, together with the benzo ring to which they are attached, form a benzothiazole ring system Referring to Scheme 6, the compound of formula III is reacted with trifluoroacetic anhydride to form the corresponding compound wherein the ring nitrogen is protected by a tnfluoroacetyl group, and the resulting nitrogen protected compound is then reacted with two equivalents of tπfluoromethanesulfonic anhydride and one equivalent of nitric acid to form the corresponding compound of formula IX, wherein there is a single nitro substituent on the benzo ring The reaction with trifluoroacetic acid is typically conducted in the presence of pyridine Both of the above reactions are typically conducted in a reaction inert solvent such as a chlorinated hydrocarbon solvent, preferably methylene chloride, at a temperature from about 0°C to about room temperature, preferably at about room temperature
The above transformation can also be accomplished using other nitration methods known to those skill in the art Reduction of the nitro group to an amine group can be accomplished as described above to provide a compound of the formula IX'
The compound of formula IX' is then reacted with a carboxyhc acid halide or anhydride of the formula R10COX or (R10CO)2O, wherein X is halo and R10 is hydrogen or (d-CeJalkyl, and pyridine, TEA or another tertiary amine base, to form a compound of the formula X, which can then be converted to the desired compound having formula XI by reacting it with Lawesson's reagent
Figure imgf000035_0001
, 10, ,10,
The reaction with R COX, wherein X is halo, or (R CO)20 is generally carried out at a temperature from about 0°C to about room temperature, preferably at about room temperature The reaction with Lawesson's reagent is generally carried out in a reaction inert solvent such as benzene or toluene, preferably toluene, at a temperature from about room temperature to about the reflux temperature of the reaction mixture, preferably at about the reflux temperature
Closure to the benzothiazole ring and nitrogen deprotection to form the desired compound of formula IF can be accomplished by reacting the compound of formula XI with potassium ferncyanide and sodium hydroxide in a mixture of water and methanol (NaOH/H20/CH3OH), at a temperature from about 50°C to about 70°C, preferably at about 60°C for about 1 5 hours Scheme 7 illustrates a method of preparing the compound of formula III which is used as the starting material for the process of Scheme 1 , or a compound of the formula IG wherein R2 and R3 form a ring (labeled "A" in the Scheme), as defined above in the definition of compounds of the formula I Referring to Scheme 7, the compound of formula XII, wherein X1 and X2 are selected, independently, from chloro, fluoro, bromo and lodo, but where at least one of X1 and X2 is Br- or I-, reacted with cyclopentadiene, in the presence of magnesium metal, in a THF, dioxane or other ethereal solvent, at a temperature from about 40°C to about 100°C, preferably at about the reflux temperature, to form a compound of the formula XIII Reaction of the resulting compound of formula XIII with N-methylmorphohne-N-oxide (NMO) and osmium tetroxide in acetone at about room temperature yields the corresponding compound of the formula XIIIA
The compound having formula XIIIA is then converted into the corresponding compound of formula XIV using the following procedure First, the compound of formula XIIIA is reacted with sodium penodate in a mixture of a chlorinated hydrocarbon, preferably dichloroethane (DCE), and water, or with lead tetraacetate in a chlorinated hydrocarbon solvent, at a temperature from about 0°C to about room temperature, to generate a dialdehyde or glycal intermediate The product of this reaction is then reacted with benzylamine and sodium tnacetoxyborohydride in a chlorinated hydrocarbon solvent at a temperature from about 0°C to about room temperature, preferably at about room temperature, to form the desired compound of formula XIV Removal of the benzyl group from the compound of formula XIV yields the compound of formula III (when ring A is absent) or IG, (when ring A is present) This can be accomplished using methods well known to those of skill in the art, for example, optionally reacting the free base with one equivalent of acid e q , hydrochloric acid, (to form the corresponding acid addition salt), followed by hydrogenolysis and palladium hydroxide in methanol at about room temperature
In the reductive animation step described above and throughout this document, alternatives to benzyl amine, such as ammonia, hydroxylamine, alkoxy amines, methyl amine, allyl amine, and substituted benzylamines (e g , diphenylmethyl amine and 2- and 4-alkoxy substituted benzyl amines) can also be used They can be used as free bases, or as their salts, preferably their acetate salts, and can be subsequently removed by methods described for each in T W Greene and G M Wuts, Protective Groups in Organic Synthesis (John Wiley & Sons, New York 1991)
The procedure of Scheme 7 can also be used to prepare compounds of the formula I wherein R2 and R3 do not form a ring and are not both hydrogen, by replacing the starting material of formula XII with the appropriate compound having the formula XII'
Figure imgf000037_0001
Alternatively, a compound of formula XIII can be converted, via methods described below and in Scheme 8, to compounds of formula XIV or formula IG or formula III
An alternative means of preparing a compound of formula III', or as appropriate IG' is illustrated in Scheme 7A This process can be applied to produce compounds of compounds of formula I, where R1 is hydrogen, and R2 and R3 are as defined above, with the exception of when R2 and R3 are hydroxy, am o, (d-d alkylamino,
Figure imgf000037_0002
-C(=0)R13, or -
(d-C6)alkylene-C(=0)R13
Referring to Scheme 7A, step 1 of is an esteπfication of a carboxyhc acid A carboxyhc acid of formula XXVI is treated with a Lewis acid catalyst such as boron tnfluoride or with an acid catalyst such as sulfuπc acid, hydrochloric acid, p-toluenesulfonic acid methane sulfonic acid, trifluoroacetic acid, or hydrobromic acid, preferably sulfunc acid, in an alcohol solvent such as methanol, ethanol, propanol, butanol, pentanol, or hexanol, preferably methanol, at a temperature between 25 and 120 °C, preferably 65 °C, for a period of 30 minutes to 24 hours, preferably 4 hours, to afford a compound of formula XXVIIA
Step 2 of Scheme 7A is a cyanohydπn formation A ketone of formula XXVIIA is treated with a Lewis acid catalyst such as zinc iodide, zinc tπflate, tπmethylsilyl tπflate, tπmethylsilyl iodide, aluminum chloride, tin (II) chloride, or tπmethyl aluminum, preferably zinc iodide, or with catalytic potassium cyanide and 18-crown-6, and tπmethylsilyl cyanide, in a solvent such as acetonitrile, toluene, methylene chloride, ethyl acetate, isopropyl acetate methyl- ert-butyl ether, or tetrahydrofuran, preferably a mixture of acetonitrile and toluene, at a temperature between 0 and 100 °C, preferably at 50 °C, for a period of time between 1 and 24 hours, preferably 5 hours, to afford a compound of formula XXVIIIA
Step 3 of Scheme 7A is a hydrogenolysis reaction A nitπle of formula XXVIIIA is treated with an acid catalyst such as p-toluenesulfonic acid, methane sulfonic acid hydrochloric acid, sulfunc acid, phosphoric acid, or trifluoroacetic acid, preferably p-toluenesulfonic acid, and a palladium catalyst such as palladium on carbon or palladium hydroxide on carbon, preferably palladium hydroxide on carbon, in a solvent such as methanol, ethanol, isopropanol, butanol, propanol, ethyl acetate, isopropyl acetate, or toluene preferably methanol, under a hydrogen pressure of 15 to 100 psi, preferably 50 psi, for a time period between 2 and 72 hours, preferably 24 hours, to afford a compound of formula XXIXA
Step 4 of Scheme 7A is an amide formation An amine of formula XXIXA is treated with a base such as sodium ferf-butoxide, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium fert-butoxide, potassium methoxide, potassium ethoxide, potassium hydroxide, sodium carbonate, potassium carbonate cesium carbonate, sodium hydride tπethylamine, methylimidazole, lutidine, pyridine, methylmorphohne ethylmorphohne, or diisopropylethylamme, preferably sodium tert-butoxide, in a solvent such as methanol, ethanol isopropanol, ethyl acetate, acetonitrile or toluene, preferably methanol, at a temperature between 0 and 120 °C, preferably 65 °C, for a time period between 30 minutes and 72 hours preferably 2 hours, to afford a compound of formula XXX
Step 5 of Scheme 7A is a reduction of an amide An amide of formula XXX is treated with a reducing agent such as borane tetrahydrofuran complex, diborane, borane dimethylsulfide complex, lithium aluminum hydride, or a combination of sodium borohydnde and boron trifluonde, preferably a combination of sodium borohydnde and boron tπfluoπde, in a solvent such as tetrahydrofuran, 1 ,2-dιmethoxyethane, 1 ,2-dιethoxyethane, dnsopropyl ether, 1 ,4-dιoxane, or methyl-ferf-butyl ether, preferably tetrahydrofuran, at a temperature between 0 and 80 °C, preferably 50 °C, for time period between 1 and 24 hours, preferably 5 hours The product is isolated by crystallization as a salt of an acid such as p-toluenesulfonic acid, methane sulfonic acid, hydrochloric acid, oxalic acid, citric acid or acetic acid, preferably p-toluenesulfonic acid, in a solvent such as isopropanol, hexane, acetone, ethyl acetate, methyl ethyl ketone, or toluene, preferably isopropanol, to afford the salt form of compound of formula IG or III Scheme 8, 9 and 10 illustrate methods of preparing compounds of the formula I wherein R1 is hydrogen, and R2 and R3 represent a variety of different substituents as defined above, but do not form a ring
Scheme 8 illustrates a variation of the process shown in Scheme 7, which can be used to make a compound identical to that of formula III except that the benzo ring is substituted with a fluoro group, an alkoxy group or any other suitable R2 and/or R3 group (R18 in Scheme 8) This compound is depicted in Scheme 8 as chemical structure 1 H Referring to Scheme 8, where, for example, R18 is F, 1 ,3-dιfluorobenzene is reacted with a strong base such as an alkali metal dialkylamine or an alkali metal alkyl (or aryl) in an ethereal solvent such as ethyl ether or THF, at a temperature below -50°C, followed by quenching with iodine or N-iodosuccinamide, to form 1 ,3-dιfluoro-2-ιodobenzene The compound 1 ,3-dιfluoro-2-ιodobenzene (structural formula XVI in Scheme 8) is then converted into the compound of formula IH by a series of reactions (represented in Scheme 8 as XVI→XVII→XVIII-→XIX→IH) that are analogous to the series of reactions described above and illustrated in Scheme 7 or Scheme 8A for converting compounds of the formula XIII into those of the formula IG or III Conversion of the compound of formula XVI into the compound of formula XVII can also be accomplished by treating a mixture of the compound of formula XVI and cyclopentadiene with an alkyl lithium reagent, preferably n-butyl lithium, in an inert hydrocarbon solvent such as petroleum ether, toluene or methyl cyclohexane at a temperature from about -20°C to about room temperature, preferably at about 0CC This procedure is equally effective to effect the conversion as set forth in Scheme 7 with or without the R18 group present The compound of formula IH can then be converted into the corresponding nitrogen protected derivative of formula XX, using the methods described above for synthesizing the compound of formula IV in Scheme 1 Nitration of the compound of formula XX using the method described above for preparing the compound of formula IX in Scheme 6, yields the compound of formula XXI wherein the benzo ring is substituted with both a fluoro and nitro group, an alkoxy group and nitro group, or an R18 substituent and a nitro group The compound of formula XXI can be used to make a variety of compounds of the formula I wherein one of R2 and R3 is fluoro, using methods that are well known to those of skill in the art, for example, by first converting the nitro group to an am o group, converting the ammo group to a variety of other substituents, as illustrated in Scheme 10, and then removing the nitrogen protecting group The compound of formula XXI acts as a regioisomeπc functional equivalent of the compounds having formulas IIA, VIA and XXII, in that the fluorine atom of formula XXI reacts similarly to the nitro and Y groups of formula IIA, VIA, and XXII, and thus can be subjected to the same series of reactions as those described above for the latter three compounds, providing an alternate means for preparing the products of such reactions Similarly, the alkoxy group of formula XXI (R18=alkoxy) may be converted into a hydroxyl group before or after introduction of the nitro group, and then converted to isomeπc products as described above Also the tπfluoromethanesulfonate ester of such hydroxy derivative can act as a Y-group as described
Preparation of compounds of formula I where R2 = -0(d-C6)alkyl, (d-C6) alkyl or aryl wherein aryl is defined as above in the definition of formula I, and R3 is H or one of the other substituents described above in the definition of formula I, can be prepared as described above and illustrated in Scheme 8 by replacing one of the fluorine atoms of the compound of formula XV with -0-(C1-C6)alkyl, (d-C6)alkyl or aryl, respectively
Scheme 8A illustrates an alternative procedure for obtaining compounds of formula I, where R2 and R3 are as defined above, with the exception of (C2-C6)alkenyl, (C2-C6)alkynyi or nitro (IH', as depicted) Step 1 of Scheme 8A is an oxidation followed by a reductive animation A benzonorbornadiene derivative of formula XVII' is first treated with ozone until the solution develops a blue color between 0 °C and -78 CC, preferably -78 °C, in a solvent such as methanol, or dichloromethane, preferably methanol The ozonide formed is reduced by hydrogenolysis between -78 °C and room temperature, preferably between 0 °C and room temperature, with platinum or palladium catalyst such as platinum oxide, platinum on carbon palladium on carbon, or palladium hydroxide on carbon, preferably 5% platinum on carbon for a period of time between 5 minutes and 6 hours, preferably 1 hour, under a hydrogen atmosphere between 15 and 100 psi, preferably between 30 and 50 psi Next an arylmethylamine, such as benzylamine, 4-methoxybenzylamιne, or 3,4-dιmethoxybenzylamιne preferably benzylamine is added to the reaction mixture at room temperature with an acid catalyst such as formic acid, acetic acid, p-toluenesulfonic acid, oxalic acid or hydrochloric acid, preferably formic acid, and hydrogenolysis is resumed for a period of time between 1 and 12 hours, preferably 4 hours, at a hydrogen pressure between 15 and 100 psi, preferably 50 psi, to afford a compound of formula XIX', where Ar is an aryl group
Step 2 of Scheme 8A is a hydrogenolysis reaction A compound of formula II is treated with an acid such as p-toluenesulfonic acid, hydrochloric acid, sulfunc acid, acetic acid, formic acid, or methane sulfonic acid, preferably p-toluenesulfonic acid, and a palladium catalyst such as palladium hydroxide on carbon or palladium on carbon, preferably palladium hydroxide on carbon, in a solvent such as methanol, ethanol, isopropanol, ethyl acetate or methyl acetate, preferably methanol, under a hydrogen pressure between 15 and 100 psi preferably 50 psi, at a temperature between room temperature and 60 °C, preferably 40 °C, for a period of time between 1 and 48 hours, preferably 15 hours The product is crystallized as a salt depending on which acid catalyst is used in a solvent such as isopropanol, hexane, acetone, ethyl acetate, methyl ethyl ketone, or toluene, preferably in a mixture of isopropanol and hexane, to afford a compound of formula IH' Scheme 9 illustrates methods of preparing compounds of the formula I wherein (a) R1 is hydrogen and R2 is R7R8N02S-, (b) R1 and R2 are both chloro, and (c) R1 is hydrogen and R2 is R13C(=0)- These compounds are referred to in Scheme 9, respectively, as compounds of formulas IJ, IK and IL
Referring to Scheme 9, compounds of the formula IJ can be prepared by reacting the compound of formula IV with two or more equivalents of a halosulfonic acid, preferably chlorosulfonic acid, at a temperature from about 0°C to about room temperature Reaction of the chlorosulfonic acid derivative so formed with an amine having the formula R7R8NH, wherein R7 and R8 are defined as above, followed by removal of the nitrogen protecting group, yields the desired compound having formula IJ Compounds of the formula IK can be prepared by reacting the compound of formula
IV with iodine trichloride in a chlorinated hydrocarbon solvent, followed by removal of the nitrogen protecting group The reaction with iodine trichloride is typically carried out at a temperature from about 0CC to about room temperature, and is preferably carried out at about room temperature In a similar fashion, the analogous mono- or di-brominated or mono- or di- lodinated compounds can be prepared by reacting the compound of IV with N- lodosuccinamide or N-bromosuccinimide in a tnfluoromethanesulfonic acid solvent, followed by removal of the nitrogen protecting group as described above
Reaction of the compound of IV with an acid halide of the formula R13COCI or an acid anhydride of the formula (R13CO)20, with or without a reaction inert solvent such as a chlorinated hydrocarbon solvent, preferably methylene chloride, in the presence of Lewis acid such as aluminum chloride, at a temperature from about 0°C to about 100°C, followed by nitrogen deprotection, yields the compound of formula IL The reaction with the acid halide or anhydride can be carried out using other known Lewis acids or other Fπedel-Crafts acylation methods that are known in the art The reactions described herein in which -N02, -S02NR7R8, -COR13, I, Br or CI are introduced on the compound of formula IV, as depicted in Scheme 9 and described above, can be performed on any analogous compound wherein R2 is hydrogen, (C1-C6)alkyl, halo (d-C6)alkoxy or -NHCONR7R8, producing compounds of the formula I wherein R2 and R3 are defined as in the definition of compounds of the formula I above Compounds that are identical to those of the formula IL, but which retain the nitrogen protecting group, can be converted into the corresponding O-acyl substituted compounds, ι_e_, those wherein the -C(=0)R13 group of formula IL is replaced with a -0-C(=0)R13 group, using Baeyer-Vilhger processes well known to those skilled in the art The resulting compounds can be partially hydrolyzed, as described in Example 35, to yield the corresponding hydroxy substituted compounds, and then alkylated to form the corresponding alkoxy substituted compounds Also, as described in Example 36, such O-acyl substituted compounds can be used to prepare variably substituted benzisoxazoles
Scheme 10 illustrates methods of making compounds of the formula I wherein (a) R is hydrogen and R2 is chloro, (b) R is hydrogen and R2 is cyano, (c) R1 is hydrogen and R2 is ammo, and (d) R is hydrogen and R2 is R13C(=0)N(H)- These compounds are referred to in Scheme 10, respectively, as compounds of the formula IM, IN, IP and IQ
Compounds of formula IM can be prepared from compounds of the formula IX' by generation of a diazonium salt with, for instance, an alkali metal nitrite and strong mineral acid (e g , hydrochloric acid, sulfunc acid, hydrobromic acid) in water, followed by reaction with a copper halide salt, such as copper (I) chloride Nitrogen deprotection by the methods described above yields the desired compound of formula IM Alternative methods for the generation of diazonium salts, as known and practiced by those of skill in the art, can also be used The foregoing reaction is generally carried out by temperatures ranging from about 0°C to about 60°C, preferably about 60°C for about 15 minutes to one hour Reaction of the diazodium salt, prepared as described above, with potassium iodide in an aqueous medium provides the analogous iodide derivative This reaction is generally carried out at a temperature from about 0°C to about room temperature, preferably at about room temperature The resulting compound, or its analogous N-tert-butylcarbonate protected form, can be used to prepare the corresponding cyano derivative by reaction with copper (I) cyanide and sodium cyanide in DMF, N,N-dιmethylpropylurea (DMPU) or DMSO, preferably DMF, at a temperature from about 50°C to about 180°C, preferably about 150°C Nitrogen deprotection as described above provides the desired compound of formula IM
The above described iodide derivative can also be used to access a variety of other substituents such as aryl, acetylene and vinyl substituents, as well as the corresponding carbonyl esters and amides, by palladium and nickel catalyzed processes known to those of skill in the art, such as Heck, Suzuki and Stille couplings and Heck carbonylations These compounds and others, wherein R2 is halo, alkyl, alkoxy, etc , may be similarly functionalized to generate compounds wherein R2 and R3 are as defined above
Nitrogen deprotection of the compound of formula IX' provides the compound of the formula IP The compound of formula IX' can be reacted with a acyl group having the formula R13COCi or (R13CO)20 using the methods described above, followed by nitrogen deprotection to provide compounds of the formula IQ In a similar fashion, treatment of the protected amine with a compound having the formula R13S02X, when X is chloro or bromo, followed by nitrogen deprotection, provides the corresponding sulfonamide derivative
As noted above, suitable amine protecting groups that can be used, alternatively, in the procedures described throughout this document include -COCF3, -COCCI3, -COOCH2CCI3, -COO(d-C6)alkyl and -COOCH2C6H5 These groups may be removed by methods described for each in Greene et al 's Protective Groups in Organic Chemistry, referred to above Instances where protecting groups would be modified under the reaction conditions, such as, e g , a -COOCH2C6H5 group during nitration, still permit said procedures to operate as described with said modified protecting group Modifying the order of protecting group incorporation and/or methods of functional group introduction or modification may also be applied where appropriate
In each of the reactions discussed above, or illustrated in Schemes 1-10, above, pressure is not critical unless otherwise indicated Pressures from about 0 5 atmospheres to about 5 atmospheres are generally acceptable, with ambient pressure, j_e_, about 1 atmosphere, being preferred as a matter of convenience
The compounds of the formula I and their pharmaceutically acceptable salts (hereafter "the active compounds") can be administered via either the oral, transdermal (e g , through the use of a patch), tranasal, sublmgual, rectal, parenteral or topical routes Transdermal and oral administration are preferred These compounds are, most desirably, administered in dosages ranging from about 0 01 mg up to about 1500 mg per day, preferably from about 0 1 to about 300 mg per day in single or divided doses, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen However, a dosage level that is in the range of about 0 001 mg to about 10 mg per kg of body weight per day is most desirably employed Variations may nevertheless occur depending upon the weight and condition of the persons being treated and their individual responses to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day
The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the several routes previously indicated More particularly, the active compounds can be administered in a wide variety of different dosage forms, e_g_, they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, transdermal patches, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents In addition, oral pharmaceutical compositions can be suitably sweetened and/or flavored In general, the active compounds are present in such dosage forms at concentration levels ranging from about 5 0% to about 70% by weight
For oral administration, tablets containing various excipients such as microcrystal ne cellulose, sodium citrate, calcium carbonate, dicalαum phosphate and glycme may be employed along with various disintegrants such as starch (preferably corn, potato or tapioca starch), algmic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc can be used for tabletting purposes Solid compositions of a similar type may also be employed as fillers in gelatin capsules, preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glycols When aqueous suspensions and/or elixirs are desired for oral administration the active ingredient may be combined with various sweetening or flavoring agents, coloring matter and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof For parenteral administration, a solution of an active compound in either sesame or peanut oil or in aqueous propylene glycol can be employed The aqueous solutions should be suitably buffered (preferably pH greater than 8), if necessary, and the liquid diluent first rendered isotonic These aqueous solutions are suitable for intravenous injection purposes The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art
It is also possible to administer the active compounds topically and this can be done by way of creams, a patch, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice
Biological Assay The effectiveness of the active compounds in suppressing nicotine binding to specific receptor sites is determined by the following procedure which is a modification of the methods of Lippiello, P M and Femandes, K G (in The Binding of L-[3HlNιcotιne To A Single Class of Hiqh- Affinity Sites in Rat Brain Membranes. Molecular Pharm , 29, 448-54, (1986)) and Anderson D J and Arnenc, S P (in Nicotinic Receptor Binding of 3H-Cystιsιne, 3H-Nιcotιne and 3H-Methylcarmbamylcholιne In Rat Brain, European J Pharm , 253, 261-67 (1994))
Procedure Male Sprague-Dawley rats (200-300 g) from Charles River were housed in groups in hanging stainless steel wire cages and were maintained on a 12 hour light/dark cycle (7 a m -7 p m light period) They received standard Purina Rat Chow and water ad libitum The rats were killed by decapitation Brains were removed immediately following decapitation Membranes were prepared from brain tissue according to the methods of Lippiello and Fernandez (Molec Pharmacol, 29, 448-454, (1986) with some modifications Whole brains were removed, rinsed with ice-cold buffer, and homogenized at 0° in 10 volumes of buffer (w/v) using a Bnnkmann Polytron™, setting 6, for 30 seconds The buffer consisted of 50 mM Tπs HCl at a pH of 7 5 at room temperature The homogenate was sedimented by centrifugation (10 minutes, 50,000 x g, 0 to 4°C The supernatant was poured off and the membranes were gently resuspended with the Polytron and centrifuged again (10 minutes, 50,000 x g, 0 to 4°C After the second centrifugation, the membranes were resuspended in assay buffer at a concentration of 1 0g/100mL The composition of the standard assay buffer was 50 mM Tπs HCl, 120 mM NaCI, 5 mM KCI, 2 mM MgCI2, 2 mM CaCI2 and has a pH of 74 at room temperature
Routine assays were performed in borosiiicate glass test tubes The assay mixture typically consisted of 0 9 mg of membrane protein in a final incubation volume of 1 0 mL Three sets of tubes were prepared wherein the tubes in each set contained 50μL of vehicle, blank, or test compound solution, respectively To each tube was added 200 μL of [3H]-nιcotιne in assay buffer followed by 750 μL of the membrane suspension The final concentration of nicotine in each tube was 0 9 nM The final concentration of cytisine in the blank was 1 μM The vehicle consisted of deionized water containing 30 μL of 1 N acetic acid per 50 L of water The test compounds and cytisine were dissolved in vehicle Assays were initiated by vortexing after addition of the membrane suspension to the tube The samples were incubated at 0 to 4° C in an iced shaking water bath Incubations were terminated by rapid filtration under vacuum through Whatman GF/B™ glass fiber filters using a Brandel™ multi-manifold tissue harvester Following the initial filtration of the assay mixture, filters were washed two times with ice-cold assay buffer (5 m each) The filters were then placed in counting vials and mixed vigorously with 20 ml of Ready Safe™ (Beckman) before quantification of radioactivity Samples were counted in a LKB Wallach Rackbeta™ liquid scintillation counter at 40-50% efficiency All determinations were in triplicate
Calculations Specific binding (C) to the membrane is the difference between total binding in the samples containing vehicle only and membrane (A) and non-specific binding in the samples containing the membrane and cytisine (B), i e , Specific binding = (C) = (A) - (B)
Specific binding in the presence of the test compound (E) is the difference between the total binding in the presence of the test compound (D) and non-specific binding (B), ι_e_, (E) = (D) - (B) % Inhibition = (1-((E)/(C)) times 100
The compounds of the invention that were tested in the above assay exhibited IC50 values of less than 10 μM
The following experimental examples illustrate, but do not limit the scope of, this invention EXAMPLE 1
10-AZA-TRICYCLOr6 3 1 02 7lDODECA-2(7),3.5-TRIENE A) 1 ,4-Dιhvdro-1 ,4-methano-naphthalene
(Based wholly or in part on a) Wittig, G , Knauss, E Chem Ber 1958, 91, 895 b) Muir, D J , Stothers, J B Can J Chem 1993, 71, 1290 ) Magnesium turnings (36 5 g, 1 5 M) were stirred in anhydrous THF (250 mL) in a dried 2 L 3 neck round bottom flask equipped with a 250 mL non-equalizing addition funnel with a nitrogen (N2) flow adapter, mechanical stirrer and efficient condenser equipped with a N2 flow adapter The flask was stirred and warmed to reflux by a removable heating mantle 2-Fluorobromobenzene (2g) was added followed by 1 mL of 3N ethylmagπesium bromide (EtMgBr in THF) The addition funnel was charged with a mixture of cyclopentadiene (94 4 g 1 43 M, Prepared by the method described in Org Syn Col , Vol V, 414-418) and bromofluorobenzene (250 g, 1 43 M) which was maintained at 0 °C in a separate flask by an ice bath, and transferred to the addition funnel via cannula Small portions (~1 mL) of the intimate mixture were introduced to assist initiation (~4 times) After ~15 minutes, the reaction initiated (exothermic, vapor condensation), the heating mantle was removed and the contents of the addition funnel was added dropwise at such rate as to maintain reflux (1 5 hours) The heating mantle was re-apphed and a reflux maintained for 1 5 hours (TLC 100% hexanes Rf 0 67)
The reaction was cooled to room temperature and quenched with H20 (500 mL) and carefully with 1N HCl (200 mL, produces H2 evolution from unconsumed Mg) To this -50 mL concentrated HCl was added to dissolve solids Total addition/quench time -1 hour Saturated aqueous sodium chloride (NaCI) solution (300mL) was added and product hexanes extracted until no potassium permanganate (KMn04) active product is removed (4 x -250 mL) The combined organic layer was washed with saturated NaHC03 solution (250 mL) sodium bicarbonate Na2S04 dried and concentrated to an oil (-200 g) The product was distilled at 78-83 °C at 15mm (131 g, 64%) (An alternative work-up is described on p 419 Fieser and Fieser, Vol I, Reagents for Organic Synthesis, Wiley, NY , NY , 1967)
B) 1 ,2.3.4-Tetrahvdro-1 ,4-methano-naphthalene-2,3-dιol
(Except for the work-up method and the quantity of Os0 used, based on VanRheenen, V , Cha, D Y , Hartley, W M Org Syn 1988, 6, 342 ) In a 2 L 3 neck round bottom flask equipped with a N2 flow adapter, mechanical stirrer was placed 1 ,4-dιhydro-1 ,4-methano-naphthalene (79 5 g, 560 mmol) stirred in acetone (800 mL) and H20 (100 mL) and N-methyl morphohne N-oxide (67 5 g, 576 mmol) To this was added osmium tetroxide (Os04) (15 mL of a 15mol% t-butyl alcohol solution, 1 48 mmol, 0 26mol%) and the mixture was stirred vigorously After 60 hours, the reaction was filtered, and the white product rinsed with acetone and air dried (60 9 g) The mother liquor was concentrated to an oily solid acetone tπturation, filtration and acetone rinse provided (27 4 g total 88 3 g, 89%) (TLC 50% ethyl acetate/hexanes Rf ~0 5) M p 176-177 5 °C
C) 10-Benzyl-10-aza-trιcvclof6 3 1 027ldodeca-2(7),3,5-tnene
(Based on Abdel-Magid, A F , Carson, K G , Harris, B D , Maryanoff, C A , Shah, R D J Org Chem 1996, 61, 3849, and Mazzocchi, P H , Stahly, B C J Med Chem 1979, 22, 455 )
1,2,3,4-Tetrahydro-1 ,4-methano-naphthalene-2,3-dιol (40 g, 227 3 mmol) was stirred in H20 (1050 mL) and 1 ,2-dιchloroethane (DCE) (420 mL) in a 2 L round bottom flask under nitrogen with cool water bath (~10 °C) To this sodium penodate (Nal04) (51 g, 239 mmol) and tnethylbenzyl ammonium chloride (Et3BnNCI) (50 mg) were added The resulting mixture was stirred for 1 hour (slight initial exotherm), then the layers were separated and the aqueous layer was extracted with DCE (200 mL) The organic layer was washed with H20 (4 x 200 mL or until no reaction to starch iodide is observed in the aqueous wash) then dried through a cotton plug To this was added benzyl amine (25 5 g, 238 6 mmol) and the mixture was stirred for 2 minutes then immediately transferred into the sodium tπacetoxyborohydride NaHB(OAc)3 /DCE (see below) over 10 minutes
In a separate 2 L round-bottomed flask under nitrogen was magnetically stirred NaHB(OAc)3 (154 g, 0 727 mmol) in DCE (800 mL) at 0 °C (ice bath) To this was added the above mixture over 10 minutes, without delay after the dialdehyde and amine were mixed The resulting orange mixture was allowed to warm to room temperature and stirred for 30-60 minutes
The reaction was quenched by addition of saturated sodium carbonate (Na2C03) solution (-300 mL) carefully at first and the mixture was stirred for 1 hour (pH 9) The layers were separated and the aqueous layer was extracted with CH2CI2 (2 x 300 mL) The organic layer was washed with saturated aqueous NaCI solution (200 mL), dried through a cotton plug then evaporated to a red oil This was dissolved in a minimum of Et20 and filtered through a Silica pad (3 x 4 inch) elutmg with 15% ethyl acetate (ethyl acetate Vhexanes +1 % of 37% aqueous ammonium hydroxide (NH OH) solution to remove baseline red color Concentration affords a light yellow oil (48 5 g, 194 8 mmol, 85 7%) (TLC 10% ethyl acetate/hexanes R, 0 75) 1H NMR (400 MHz, CDCI3) 5 7 16 (m, 7H), 6 89 (m, 2H), 3 48 (m, 2H), 3 08 (m, 2H), 2 80 (d, J = 9 5 Hz, 2H), 2 42 (d, J = 9 5 Hz, 2H), 2 27 (m, 1 H), 1 67 (d, J = 10 0 Hz, 1 H) APCI MS m/e 250 3 [(M + 1)+]
D) 10-Aza-trιcvclof6 3 1 02 7ldodeca-2(7),3,5-trιene
(For an alternative synthesis, see, Mazzocchi, P H , Stahly, B C J Med Chem 1979, 22, 455 )
10-Benzyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene (70 65 g, 284 mmol) was stirred in ethyl acetate (250 mL) and treated with 3N HCl ethyl acetate (1 03 eq ) slowly with cooling (ice bath) The resulting precipitate was filtered and rinsed with ethyl acetate The solids were dissolved in methanol (250 mL) in a Parr bottle To this was added Pd(OH) (7 g of 20%wt/C) and the mixture was shaken under 50-40 psi of H2 for 24 hours or until done by TLC The reaction was filtered through a Cehte pad and concentrated to an oily solid This was azeotroped with methanol (methanol) (3 times) then triturated with acetone, treated with ethyl ether (Et20) to precipitate product and filtered Concentration of the mother liquors and a second treatment provided an off white solid (48 95 g, 251 mmol, 88%) (TLC 10% methanol/CH2CI2 (NH3) R, 0 2) 1H NMR (400 MHz, CDCI3) δ 7 18 (m, 4H), 2 97 (m, 4H) 2 68 (d, J = 12 5 Hz, 2H), 2 41 (m, 1 H), 1 95 (d, J = 11 0 Hz, 1 H) APCI MS m/e 160 2 [(M + 1)+] EXAMPLE 2 4-FLUQRO-10-AZA-TRICYCLOP6 3 1 02 71DODECA-2(7).3.5-TRIENE HYDROCHLORIDE
A) 6-Fluoro-1 ,4-dιhydro-1 ,4-methano-naphthalene (Eisch, J J , Burhnson, N E J Amer Chem Soc 1976, 98, 753-761 Paquette L A
Cottrell, D M , Snow, R A Amer Chem Soc 1977, 99, 3723-3733 )
Magnesium turnings (0 66 g, 27 2 mmol) were stirred in anhydrous THF (10 mL) in a flame dried 75 mL 3 neck round bottom flask equipped with a non-equalizing addition funnel with a N2 flow adapter, magnetic stirrer and efficient condenser equipped with a N2 flow adapter The flask was stirred and warmed to reflux by a removable heating mantle 2 5- Difluorobromobenzene (0 1 g) was added followed by of 3N EtMgBr in THF (0 1 mL) The addition funnel was charged with an intimate mixture of cyclopentadiene (1 71 g, 25 9 mmol) and 2,5-dιfluorobromobenzene (5 0 g, 25 9 mmol) Small portions (-0 2 mL) of the intimate mixture were introduced to assist initiation (-4 times) After -15 minutes, the reaction initiated (exotherm, and vapor condensation) and heating was maintained as necessary during the addition of the contents of the addition funnel The reaction was then maintained at reflux for 1 hour
The reaction was cooled to room temperature and quenched with H20 (20 mL) followed by aqueous 1 HCl solution (20 mL) to dissolve the solids Saturated aqueous NaCI solution (30 mL) was added and product was extracted with hexanes (4 x 25mL) The combined organic layer was washed with saturated aqueous NaHC03 solution (25 mL) dried (Na2S04), filtered through a Silica plug with hexanes rinse and concentrated to an oil Chromatography on Silica gel eluting with hexanes provided an oil (780 mg, 19%) (TLC hexanes R, 0 38) 1H NMR (400 MHz, CDCI3) δ 7 10 (m, 1H), 6 97 (d, J = 8 0 Hz, 1 H), 6 80 (br s, 1 H), 6 78 (br s, 1 H), 6 59 (m, 1 H), 3 87 (br s, 2H), 2 32 (d, J = 7 0 Hz, 1 H), 2 25 (d, J = 7 0 Hz, 1 H)
B) 6-Fluoro-1 ,2,3.4-tetrahvdro-1 ,4-methano-naphthalene-2,3-dιol
6-Fluoro-1 ,4-dιhydro-1 ,4-methano-naphthalene (680 mg, 4 22 mmol) and N-methyl morphohne N-oxide (599 mg, 4 43 mmol) were stirred in acetone (50 mL) and H20 (5 mL) To this was added a solution of Os04 (0 2 mL, 2 5%wt solution in t-butyl alcohol, 0 02 mmol) After 72 hours, Floπsil (5 g) and saturated aqueous NaHS03 solution (3 mL) were added and stirred for 1 hour The Floπsil was filtered and the filtrate concentrated to produce a crystalline product which was triturated with acetone and filtered (524 mg, 64%) 1H NMR (400 MHz CDCI3) 5 7 10 (dd, J = 8 0,5 0 Hz, 1 H), 6 90 (dd, J = 8 0,2 3 Hz, 1 H), 6 75 (ddd, J = 8 0 8 0,2 3 Hz, 1 H), 3 79 (s, 2H), 3 18 (d, J = 1 5 Hz, 2H), 2 22 (d, J = 10 0 Hz, 1 H), 1 92 (dd, J = 10 0 1 5 Hz, 1 H) GCMS m/e 194 (M+)
C) 10-Benzyl-4-fluoro-10-aza-tπcvclor6 3 1 02 7]dodeca-2(7),3,5-tπene 6-Fluoro-1 ,2,3,4-tetrahydro-1 ,4-methano-naphthalene-2,3-dιol (524 mg, 2 68 mmol) and Et3NBnCI (10 mg) were vigorously stirred in dichloroethane (15 mL) and H20 (45 mL) then treated with sodium penodate (0 603 mg, 2 82 mmol) After 1 5 hours, the layers were separated and the aqueous layer extracted with DCE (2 x 20 mL) The combined organic layer was washed with H20 (4 x 20 mL) until no reaction to starch iodide paper was observed then with saturated aqueous NaCI solution (20 mL) The organic layer was dried through a cotton plug and treated with benzyl amine (0 308 mL, 2 82 mmol) and stirred for 2 minutes then transferred to an addition funnel This solution was added over -10 minutes to a vigorously stirred cooled (0 °C) mixture of NaHB(OAc)3 (1 82 g, 8 58 mmol) in DCE (50 mL) After addition was complete, the mixture was stirred without cooling for 2 hours The mixture was quenched with saturated aqueous Na2C03 solution (100 mL) and stirred for 1 hour then the layers were separated and the aqueous layer was extracted with CH2CI2 (3 x 30 mL) The combined organic layer was washed with saturated aqueous NaCI solution (50 mL), dried through a cotton plug and concentrated Chromatography on Silica gel provided an oil (520 mg, 80%) (TLC 2% acetone/CH2CI2 Rf 0 40) 1H NMR (400 MHz, CDCI3) 5 7 18 (m, 1 H), 6 88 (m, 2H), 3 48 (s, 2H), 3 06 (m, 2H), 2 78 (m, 2H), 2 41 (m, 2H), 2 27 (m, 1 H) 1 69 (d, J = 10 5 Hz, 1H)
D) 4-Fluoro-10-aza-trιcvclo[6 3 1 02 71dodeca-2(7),3,5-trιene hydrochlonde 10-Benzyl-4-fluoro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene (390 mg, 1 461 mmol), ammonium formate (3 04 g, 48 2 mmol) and 10%Pd(OH)2/C (30 mg) were combined in methanol (50 mL) and brought to reflux under N2 for 1 5 hours Ammonium formate (1 0 g) was added and reflux continued for 0 5 hour The reaction mixture was filtered through a Cehte pad which was rinsed with methanol The filtrate was concentrated The residues were treated with saturated aqueous Na2C03 solution (30 mL) and product extracted with methylene chloride (CH2CI2) (3 x 25 mL) The organic layer was washed with saturated aqueous NaCI solution (50 mL), dried through a cotton plug and concentrated The residue was treated with 2N HCl methanol (5 mL) and concentrated then taken up in minimum of methanol and saturated with Et20 After stirring 18h, the white crystals were collected by filtration (86 mg, 28%) (TLC 5% methanol/CH2CI2 (NH3) Rf 0 27) (data for free base) 1H NMR (400 MHz, CDCI3) 5 7 06 (m, 1H), 6 83 (m, 2H), 2 89 (m, 4H), 2 61 (dd, J = 12 0 Hz, 2H), 2 37 (m, 1 H), 1 87 (d, J = 11 5 Hz, 1 H) APCI MS m/e 178 2 [(M + 1)+] (HCl salt) M p 260-262 °C EXAMPLE 3 4-METHYL-10-AZA-TRICYCLOf6 3 1 02 7lDODECA-2(7).3.5-TRIENE HYDROCHLORIDE The title compound was prepared by the methods described in Examples 1 and 2 starting with 2-fluoro-5-methylbromobenzene (data for free base) 1H NMR (400 MHz, CDCI3) δ 7 04 (d, J = 7 5 Hz, 1 H), 6 99 (s, 1 H), 6 98 (d, J = 7 5 Hz, 1 H), 2 98-2 90 (m 4H), 2 63 (m, 2H), 2 35 (m, 1 H), 2 32 (s, 3H), 1 87 (d, J = 11 5 Hz, 1 H) APCI MS m/e 174 2 [(M + 1 ) +] (HCl salt) M p 254-255 °C Anal Calcd for C12H12F3N HCl 1/3H20 C, 53 44 H 5 11 N, 5 19 Found C, 53 73, H, 4 82, N, 5 15
EXAMPLE 4 4-TRIFLUOROMETHYL-10-AZA-TRICYCLO[6 3 1 02 71- DODECA-2(7).3.5-TRIENE HYDROCHLORIDE (See Grunewald, G L , Paradkar, V M , Pazhenchevsky, B , Pleiss, M A , Sail D J Seibel, W L , Reitz, T J J Org Chem 1983 48, 2321-2327 Grunewald, G L Markovich K M , Sail, D J J Med Chem 1987, 30, 2191-2208 )
The title compound was prepared by the methods described in Examples 1 and 2 starting with 2-fluoro-5-trιfluoromethylbromobenzene 1H NMR (400 MHz, CD3OD) 5 7 71 (s, 1 H), 7 64 (d, J = 8 0 Hz, 1 H), 7 57 (d, J = 8 0 Hz, 1 H), 3 46 (m, 4H), 3 21 (d, J = 12 5 Hz 2H), 2 41 (m, 1 H), 2 16 (d, J = 11 5 Hz, 1 H) APCI MS m/e 228 2 [(M + 1)+] (HCl salt) M p 244-246 °C Anal Calcd for C12H12F3N HCl 1/3H20 C, 53 44, H, 5 11 , N, 5 19 Found C, 53 77, H 4 82, N, 5 18
EXAMPLE 5 3-TRIFLUOROMETHYL-10-AZA-TRICYCLO[6 3 1 0271-
DODECA-2(7).3.5-TRIENE HYDROCHLORIDE (See Grunewald, G L , Paradkar, V M , Pazhenchevsky, B , Pleiss, M A , Sail D J Seibel, W L , Reitz, T J J Org Chem 1983, 48, 2321-2327 Grunewald, G L , Markovich, K M , Sail, D J J Med Chem 1987, 30, 2191-2208 ) The title compound was prepared by the methods described in Examples 1 and 2 starting with 2-fluoro-6-trιfluoromethylbromobenzene 1H NMR (400 MHz, CD3OD) δ 7 67-7 50 (3H), 3 65 (br s, 1 H), 3 49-3 42 (m, 2H), 3 29 (s, 1 H), 3 28-3 16 (m, 2H), 2 42 (m, 1 H), 2 18 (d J = 11 5 Hz, 1 H) APCI MS m/e 228 2 [(M + 1)+] (HCl salt) M p 275-277 °C Anal Calcd for C12H12F3N HCl 1/3H20 C, 53 44, H, 5 11 , N, 5 19 Found C, 53 73, H, 4 83, N, 5 16 EXAMPLE 6 3-FLUORO-10-AZA-TRICYCLOf6 3 1 02 71DODECA-2(7),3.5-TRIENE HYDROCHLORIDE
A) 2,6-Dιfluoroιodobenzene (Roe, A M , Burton, R A , Willey, G L , Barnes, M W Rasmussen, A C J Med Chem 1968, 11, 814-819 Tamborski, C , Soloski, E J Org
Chem 1966, 31, 746-749 Grunewald, G L , Arπngton, H S , Bartlett, W J , Reitz, T J , Sail D J J Med Chem 1986, 29, 1972-1982 ) 1 ,3-Dιfluorobenzene (57 05 g, 0 5 M) in THF (75 mL) was added to a -78 °C stirred solution of n-butylhthium (n-BuLi) (200 mL, 2 5 M/hexanes 0 5 M) and THF (500 mL) under N2 By controlling the addition rate the internal temperature was maintained below -70 °C The total addition time was -1/2 hour The resulting slurry was stirred an additional 1/2 hour, then the dispersion was treated with a solution of iodine (126 9 g, 0 5 M) in THF (300 mL) at a rate that maintained an internal temperature below -70 °C After complete addition the mixture was allowed to warm to room temperature, and was treated with H20 (100 mL) and 10% aqueous Na2S203 solution (100 mL) and stirred The layers were separated and the aqueous layer extracted with hexanes (2 x 250 mL) The combined organic layer was washed with 10% aqueous Na2S203 solution (100 mL), H20 (100 mL), saturated aqueous NaCI solution (100 mL), dried (Na2S04) filtered and concentrated to give a yellow oil (106 5 g) Distillation at -1-5 mm at -80 °C provided a light yellow oil (89 5 g, 75%) 1H NMR (400 MHz, CDCI3) δ 7 30 (m, 1 H), 6 87 (m, 2H) GCMS m/e 240 (M+)
B) 5-Fluoro-1 ,4-dιhvdro-1 ,4-methano-naphthalene
A solution of 2,6-dιfluoroιodobenzene (5 0 g, 20 8 mmol) and cyclopentadiene (2 07 g, 31 3 mmol) was stirred at 0 °C in P ether (70 mL, 40-60 °C) under N2 and treated with n-BuLi (8 74 mL, 2 5M in hexanes, 21 8 mmol) dropwise over 10 minutes The reaction was quenched after 15 minutes by addition of aqueous 1 N HCl solution and the product was extracted with hexanes (3 x 50 mL) The combined organic layer was washed with H20 (50 mL), saturated aqueous NaCI solution (50 mL), dried (MgS04), filtered and evaporated Chromatography on Silica gel provided product as an oil (1 5 g, 45%) (TLC hexanes R 0 55) 1H NMR (400 MHz, CDCI3) δ 7 08 (ddd, J = 7 0,1 0,0 8 Hz, 1H), 6 96 (ddd, J = 8 5,8 3,7 0 Hz, 1 H), 6 86 (br s, 2H), 6 72 (ddd, J = 8 5,8 3,0 8 Hz, 1 H), 4 25 (br s, 1 H) 3 98 (br s, 1 H), 2 36 (ddd, J = 7 2,1 7,1 7 Hz, 1 H), 2 30 (ddd, J = 7 2,1 7,1 5 Hz, 1 H) GCMS m/e 160 (M+)
C) 3-Fluoro-10-aza-tπcyclo[6 3 1 02 7ldodeca-2(7),3,5-trιene hydrochloπde
The title compound was prepared by the methods described in Examples 2B, C, and D starting with 5-fluoro-1 ,4-dιhydro-1 ,4-methano-naphthalene 1H NMR (400 MHz
CD3OD) δ 7 36 (ddd, J = 8 3,7 3,5 0 Hz, 1 H), 7 21 (d, J = 7 3 Hz, 1H), 7 07 (t, J = 8 3 Hz, 1 H) 3 62 (br s, 1 H), 3 42-3 30 (m, 3H), 3 21 (m, 2H), 2 38 (m, 1 H), 2 12 (d, J = 11 5 Hz, 1 H) APCI MS m/e 178 4 [(M + 1)+] M p 269-271 °C
EXAMPLE 7 4-NITRO-10-AZATRICYCLOf6 3 1 027lDODECA-2(7).3.5-TRIENE HYDROCHLORIDE
A) 1-(10-Aza-trιcvclof6 3 1 02 7ldodeca-2(7),3,5-trιen-10-yl)-2.2,2-tπfluoro-ethanone 10-Aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene hydrochloπde salt (12 4 g, 63 9 mmol) was stirred in CH2CI2 (200 mL) This was cooled (ice bath) and treated with pyridine (12 65 g, 160 mmol) followed by trifluoroacetic anhydride (TFAA) (16 8 g, 11 3 mL, 80 mmol) from an addition funnel over 10 minutes After -3 hours, the solution was poured into 0 5N aqueous HCl (200 mL) and the layers separated The aqueous layer was extracted with CH2CI2 (3 x 50 mL) and the combined organic layer was washed with 0 5N aqueous HCl (50 mL), H20 (2 x 50 mL) and saturated aqueous NaHC03 solution (50 mL) This solution was dried through a cotton plug, then diluted with -3% ethyl acetate and filtered through a 2 inch Silica pad eluted with -3% ethyl acetate/CH2CI2 Concentration afforded a clear oil which crystallized to give white needles (15 35 g, 60 2 mmol, 94%) (TLC 30% ethyl acetate/hexanes R, 0 53) 1H NMR (400 MHz, CDCI3) 5 7 18 (m, 4H), 4 29 (br d, J = 12 6 Hz, 1 H), 3 84 (br d, J = 12 6 Hz, 1 H), 3 51 (dd, J = 12 6,1 5 Hz, 1 H), 3 21 (br s, 1 H), 3 10 (br s, 1 H), 3 10 (br d, J = 12 6 Hz, 1 H), 2 37 (m, 1 H), 1 92 (d, J = 10 8 Hz, 1 H) GCMS m/e 255 (M+) M p 67-68 °C
B) 1-(4-Nιtro-10-aza-trιcvclof6 3 1 02 7ldodeca-2(7).3.5-trιen-10-yl)-2.2.2-tπfluoro- ethanone
(Based on the method described by Coon, C L , Blucher, W G , Hill, M E J Org Chem 1973, 25, 4243 ) To a solution of tπfluoromethanesulfonic acid (2 4 ml, 13 7 mmol) in CH2CI2 (10 ml) stirred at 0 °C was slowly added nitric acid (0 58 ml, 27 4 mmol) generating a white precipitate After 10 minutes the resulting mixture was cooled to -78 °C and treated with 1-(10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-trιfluoro-ethanone (3 5 g, 13 7 mmol) in CH2CI2 (15 ml) dropwise from an addition funnel over 5 minutes The reaction was stirred at -78 °C for 30 minutes then warmed to 0 °C for 1 hour The reaction mixture was poured into a vigorously stirred ice (100 g) The layers were separated and the aqueous layer extracted with CH2CI2 (3 x 30 ml) The organic layer was combined and washed with H20 (3 x 30 ml) The combined organic layer was washed with saturated aqueous NaHC03 solution (20 mL) and H20 (20 mL) then dried through a cotton plug and concentrated to give an orange oil that solidified on standing (4 2 g) Chromatography yielded pure product as a crystalline solid (3 2 g, 78%) (TLC 30% ethyl acetate/hexanes Rf 0 23) 1H NMR (400 MHz, CDCI3) 5 8 12 (br d, J = 8 0 Hz, 1 H), 8 08 (br s, 1 H), 7 37 (br d, J = 8 0 Hz, 1 H), 4 38 (br d, J = 12 6 Hz, 1 H), 3 94 (br d, J = 12 6 Hz, 1 H), 3 59 (br d, J = 12 6 Hz, 1 H), 3 43-3 35 (m, 2H), 3 18 (br d, J = 12 6 Hz, 1 H), 2 48 (m, 1 H), 2 07 (d, J = 10 8 Hz, 1 H) GCMS m/e 300 (M+)
C) 4-Nιtro-10-azatπcvclor6 3 1 02 71dodeca-2(7),3,5-trιene hvdrochlonde 1-(4-Nιtro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-trιfluoro- ethanone (182 mg, 0 61 mmol) was stirred with Na2C03 (160 mg, 1 21 mmol) in methanol (3 mL) and H20 (1 mL) at 70 °C for 18 hours The mixture was concentrated, water was added and the product was extracted with CH2CI2 The organic layer was extracted with 1 N aqueous HCl (3 x 20 mL) and the acidic layer washed with CH2CI2 (2 x 20 mL) The aqueous layer was basified to pH -10 with Na2C03(s) and product was extracted with CH2CI2 (3 x 30 mL) The organic layer was dried through a cotton plug and concentrated to an oil This was dissolved in methanol and treated with 1 N HCl in methanol, concentrated to solids which were recrystalhzed from methanol/Et20 to afford product as a white solid (73 mg, 50%) (TLC 5% methanol/CH2CI2 (NH3) Rf 0 38) H NMR (400 MHz, DMSO-d6) δ 8 21 (s, 1 H), 8 18 (dd, J = 8 0,2 0 Hz, 1 H), 7 59 (d, J = 8 0 Hz, 1 H), 3 43 (br s, 2H), 3 28 (m, 2H), 3 07 (dd, J = 13 0,13 0 Hz, 2H), 2 24 (m, 1 H), 2 08 (d, J = 11 5 Hz, 1 H) APCI MS m/e 205 1 [(M + 1 )+] M p 265- 270 °C
EXAMPLE 8 4-AMINO-10-AZATRICYCLOr6 3 1 02 7lDODECA-2(7).3.5-TRIENE HYDROCHLORIDE
4-Nιtro-10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene (500 mg, 2 08 mmol) was stirred in 1 ,4-dιoxane (40 mL) and treated with saturated aqueous Na2C03 solution (15 mL)
To this was added di-t-butyldicarbonate (1 8 g, 8 31 mmol) After stirring 18 hours the reaction was treated with H20 (50 mL), extracted with CH2CI2 (4 x 30 mL), dried through a cotton plug and concentrated to provide an oil (500 mg, 91%)
This oil (500 mg, 1 64 mmol) was dissolved in methanol (30 mL), treated with 10%Pd/C (-50 mg) and hydrogenated under a H2 atmosphere (45 psi) for 1 hour The mixture was filtered through a Cehte pad and concentrated to a clear oil (397 mg, 88%)
This oil (50 mg, 0 18 mmol) was stirred in 3N HCl in ethyl acetate (3 mL) for 2 hours then concentrated to a white solid (25 mg, 56%) 1H NMR (400 MHz, DMSO-d6) δ 7 38-7 10 (3H), 3 60 (br s, 2H), 3 25 (m, 2H), 2 98 (m, 2H), 2 18 (m, 1 H), 1 98 (d, J = 11 5 Hz, 1 H) APCI MS m/e 175 1 [(M + 1)+] M p 189-192 °C EXAMPLE 9
N1-πθ-AZATRICYCLOf6 3 1 02 7lDODECA-2(7).3.5-TRIEN-4-YL1-
ACETAMIDE HYDROCHLORIDE
A) 1-(4-Amιno-10-aza-trιcvclof6 3 1 02 71dodeca-2(7).3,5-trιen-10-yl)-2.2.2-trιfluoro- ethanone
Hydrogenation of 1-(4-nιtro-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)- 2,2,2-trιfluoro-ethanone (2 0 g, 6 66 mmol) under a H2 atmosphere (40 psi) and 10%Pd/C (200 mg) in methanol over 1 5 hours, filtration through Cehte and concentration affords a yellow oil (1 7 g) (TLC 50% ethyl acetate/hexanes R, 0 27) H NMR (400 MHz, CDCI3) δ 6 99 (m, 1 H), 6 64 (br s, 1 H), 6 57 (m, 1 H), 4 25 (m, 1 H), 3 82 (m, 1 H), 3 50 (m, 1 H), 3 17-3 07 (m 3H), 2 35 (m, 1 H), 1 90 (d, J = 10 8 Hz, 1 H) GCMS m/e 270 (M+)
B) N-(10-Trιfluoroacetyl-10-aza-trιcvclor6 3 1 0271dodeca-2(7).3.5-trιen-4-yl)- acetamide 1 -(4-Amιno-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-tπfluoro- ethanone (850 mg, 3 14 mmol) was stirred in CH2CI2 (5 mL) and treated with tπethyl amine (0 53 mL, 3 76 mmol) and acetyl chloride (0 23 mL, 3 2 mmol) then stirred 18 hours Standard NaHC03 work-up yielded an oil which was chromatographed to provide a clear oil (850 mg, 87%) (50% ethyl acetate/hexanes Rf 0 28)
C) N -πθ-Azatrιcvclof6 3 1 02 7ldodeca-2(7).3.5-tπen-4-yllacetamιde hvdrochlonde N-(10-Trιfluoroacetyl-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-4-yl)-acetamιde
(100 mg, 0 32 mmol) was stirred with Na2C03 (70 mg, 0 64 mmol) in methanol (10 mL) and H20 (2 mL) at 70 °C for 18 hours The mixture was concentrated, water was added and the product was extracted with ethyl acetate The organic layer was extracted with N aqueous HCl (3 x 20 mL) and the acidic layer washed with ethyl acetate (2 x 20 mL) The aqueous layer was basified to pH -10 with Na2C03 (s) and product was extracted with ethyl acetate (3 x 20 mL) The organic layer was dried (sodium sulfate (Na2S0 )) and concentrated to an oil This material was dissolved in methanol and treated with 3N HCl ethyl acetate (3 mL), concentrated and recrystallized from methanol/Et20 to provide a solid (40 mg, 50%) 1H NMR (400 MHz, DMSO-de) 5 9 98 (s, 1 H), 9 02 (br m, NH), 7 65 (s, 1 H), 7 55 (br s, NH), 7 38 (d, J = 8 0 Hz, 1H), 7 20 (d, J = 8 0 Hz, 1H), 3 33 (m, 4H), 2 96 (m, 2H), 2 13 (m, 1 H), 2 00 (s, 3H) 1 96 (d, J = 10 5 Hz, 1 H) APCI MS m/e 217 2 [(M + 1)+] M p 225-230 °C EXAMPLE 10 6-METHYL-5-THIA-7.13-DIAZATETRACYCLOf9 3 1 02 10 04 81PENTADECA-2(10).3,6.8-
TETRAENE HYDROCHLORIDE
A) N-(10-Trιfluorothιoacetyl-10-aza-tπcvclo[6 3 1 027ldodeca-2(7).3.5 -tπen-4-vD- thioacetamide
N-(10-Trιfluoroacetyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπen-4-yl)-acetamιde (850 mg, 2 72 mmol) and 2,4-bιs(4-methoxyphenyl)-1 ,3-dιthιa-2,4-dιphosphetane-2 4-dιsulfιde (Lawesson's reagent) (1 1 g, 2 72 mmol) were combined in toluene (10 mL) and brought to reflux for 1 5 hours After cooling the reaction was worked up with ethyl acetate/saturated aqueous NaHC03 solution The organic layer was dried (Na2S0 ), filtered concentrated and chromatographed on Silica gel to produce product (410 mg, 44%) (50% ethyl acetate/hexanes Rf 0 38)
B) 6-Methyl-5-thιa-7.13-dιazatetracvclo[9 3 1 02 10 04 8lpentadeca-2(10).3.6.8-tetraene hvdrochloride
The above oil, 2,2,2-tπfluoro-N-(10-trιfluorothιoacetyl-10-aza-trιcyclo[6 3 1 02 7]dodeca- 2(7),3,5-tπen-4-yl)-thιoacetamιde, (360 mg, 1 05 mmol) was dissolved in methanol (10 mL) and 1 N NaOH (5 mL) and added to potassium ferπcyanide (K3Fe(CN)6)(1 72 g, 5 23 mmol) in H20 (10 mL) This mixture was warmed to 60 °C for 1 5 hours, cooled, concentrated and worked up with ethyl acetate/H20 This material was stirred in dioxane (20 mL) and treated with H20 (50 mL) and Na2C03 to achieve pH 10 To this was added di-t-butyldicarbonate (436 mg, 2 0 mmol) and the mixture was stirred for 18 hours The reaction was concentrated treated with H20 and extracted with CH2CI2 The product was chromatographed (Silica 30% ethyl acetate/hexanes Rf 0 41 ) to yield an oil (100 mg) The above product was treated with 3N HCI/ethyl acetate (3 mL) and warmed to reflux for -15 minutes then concentrated to a solid which was azeotroped with CH2CI2 (two times) These solids were dissolved in a minimum amount of methanol then saturated with Et20 and stirred The resulting white crystalline powder was collected by filtration (40 mg, 14%)
1H NMR (400 MHz, DMSO-d6) 5946 (s, NH), 7 65 (s, 1H), 7 82 (s, 1H) 7 65 (br m, NH), 336 (m, 2H), 324 (m, 2H), 302 (m, 2H), 276 (s, 3H), 223 (m, 1H), 206 (d, J = 108 Hz, 1 H) APCI MS m/e 2311 [(M + 1)+] M p 183-184 °C EXAMPLE 11 4.5-DINITRO-10-AZA-TRICYCLOf6 3 1 02 7lDODECA-2(7).3.5-TRIENE
A) 1-(4.5-Dιnιtro-10-aza-trιcvclor6 3 1 02 7ldodeca-2(7 .3.5-trιen-10-yl)-2.2.2-trιfluoro- ethanone (Based on the method described in Coon, C L , Blucher, W G , Hill, M E J Org
Chem 1973, 25, 4243 For an additional related example of dinitration see Tanida, H , Ishitobi, H , Ine, T , Tsushima, T J Am Chem Soc 1969, 91, 4512 )
To a solution of tπfluoromethanesulfonic acid (79 8 ml, 902 1 mmol) in CH2CI2 (550 ml) stirred at 0 °C was slowly added nitric acid (19 1 ml, 450 9 mmol) generating a white precipitate After 10 minutes, 1-(10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπen-10-yl)-2,2,2- tπfluoro-ethanone (50 g, 196 mmol) in CH2CI2 (300 ml) was added dropwise from an addition funnel over 30 minutes The reaction was stirred at 0 °C for 2 5 hours and then stirred at room temperature for 24 hours The reaction mixture was poured into a vigorously stirred mixture of H20 (500 ml) and ice (400 g) The layers were separated and the aqueous layer back extracted with CH2CI2 (3 x 300 ml) The organic layer was combined and washed with H20 (3 x 300 ml) The combined aqueous layers were re-extracted with CH2CI2 (2 x 100 ml) The organic layer was combined and washed with saturated aqueous NaHC03 solution (200 mL) and H20 (200 mL) then dried through a cotton plug and concentrated to solids Tnturation with ethyl acetate/hexanes produced off white solids which were filtered and dried (52 g, 151 mmol, 77% The mother liquor was chromatographed to give an additional 4 0 g for a total of 56 0 g (82 8%) (TLC 50% ethyl acetate/hexanes R, 0 29) 1H NMR (400 MHz CDCI3) 5 7 77 (s, 1 H), 7 75 (s, 1 H), 4 39 (br d, J = 13 0 Hz, 1 H), 3 98 (br d, J = 13 0 Hz, 1 H) 3 65 (d, J = 13 0 Hz, 1 H), 3 49 (br s, 1 H), 3 44 (br s, 1 H), 3 24 (br d, J = 12 6 Hz, 1 H), 2 53 (m 1 H), 2 14 (d, J = 11 5 Hz, 1 H) GCMS m/e 345 (M+)
B) 4.5-Dιnιtro-10-aza-trιcvclor6 3 1 02 7ldodeca-2(7),3,5-trιene 1-(4,5-Dιnιtro-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-tπfluoro- ethanone (3 7 g, 10 7 mmol) and Na2C03 (2 3 g, 21 4 mmol) were combined in methanol (50 mL) and H20 (20 mL) then warmed to reflux for 18 hours The reaction was cooled concentrated, treated with H20 and extracted with CH2CI2 (3 x 50 mL) then dried through a cotton plug After concentration, the residue was chromatographed to provide brown solids (1 9 g, 71%) (TLC 5% methanol/CH2CI2 (NH3) Rf 0 36) 1H NMR (400 MHz, CDCI3) δ 7 69 (s 2H), 3 17 (br s, 2H), 3 11 (d, J = 12 6 Hz, 2H), 2 53 (m, 1 H), 2 07 (d, J = 11 0 Hz, 1 H) GCMS m/e 249 (M+) EXAMPLE 12 6-METHYL-7-PROPYL-5.7.13-TRIAZATETRACYCLOr9 3 1 02 10 04 81-
PENTADECA-2(10).3.5.8-TETRAENE HYDROCHLORIDE
A) 44.,55--DDιnιtro-10-aza-trιcyclor6 3 1 02 7ldodeca-2(7).3.5-trιene-10-carboxyhc acid tert- butyl ester
4,5-Dιnιtro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, (1 9 g, 7 6 mmol) was stirred in 1 ,4-dιoxane (75 mL) and treated with saturated aqueous Na2C03 solution (10 mL) To this was added di-t-butyldicarbonate (3 31 g, 15 2 mmol) After stirring 6 hours the reaction was treated with H20 ( 50 mL) and extracted with ethyl acetate (4 x 25 mL), dried (Na2S04) filtered, concentrated and chromatographed to provide product (1 9 g, 71 %) (TLC 30% ethyl acetate/hexanes (NH3) Rf 0 58) 1H NMR (400 MHz, CDCI3) δ 7 77 (br s, 1 H), 7 72 (br s, 1 H) 4 08 (m, 1 H), 3 92 (m, 1 H), 3 39 (br s, 1 H), 3 27 (br s, 1 H), 3 25 (m, 1 H), 3 18 (m, 1 H), 2 46 (m, 1 H), 2 02 (d, J = 11 0 Hz, 1 H)
B) 4,5-Dιamιno-10-aza-tπcvclof6 3 1 02 7ldodeca-2(7),3.5-trιene-10-carboxylιc acid tert-butyl ester
4,5-Dιnιtro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-10-carboxyhc acid tert- butyl ester (1 9 g, 5 44 mmol) was hydrogenated in methanol under a H2 atmosphere (45 psi) over 10%Pd/C (100 mg) for 1 5 hours then filtered through a Cehte pad and concentrated to white solids (1 57 g, 100%) (TLC 5% methanol/CH2CI2 (NH3) R, 0 14)
C) 6-Methyl-5.7.13-tπazatetracvclor9 3 1 02 10 04 8lpentadeca-2M0).3.5.8-tetraene-13- carboxyhc acid tert-butyl ester (For conditions, see, Segelstem, B E , Chenard, B L , Macor J E , Post, R J Tetrahedron Lett 1993, 34, 1897 ) 4,5-Dιamιno-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-10-carboxyhc acid tert- butyl ester (700 mg, 2 42 mmol) was dissolved in ethanol (10 mL) and acetic acid (HOAc) (1 mL) and treated with 1-ethoxyethylenemalononιtrιle (329 mg, 2 42 mmol) The resulting mixture was warmed to 60 °C and stirred 18 hours The reaction was cooled, concentrated treated with H20 and saturated aqueous Na2C03 solution and extracted with ethyl acetate (3 x 50 mL), then dried (Na2S04) After filtration and concentration, the residue was chromatographed to provide brown solids (247 mg, 36%) (TLC 5% methanol/CH2CI2 (NH3) Rf 0 28)
D) 6-Methyl-7-propyl-5.7.13-tπazatetracvclo[9 3 1 02 10 04 8lpentadeca-2(10).3.5.8- tetraene-13-carboxyhc acid tert-butyl ester (For conditions, see, Pilarski, B Uebigs Ann Chem 1983, 1078 ) 6-Methyl-5,7,13- trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8-tetraene-13-carboxyhc acid tert-butyl ester (80 mg, 0 267 mmol) was stirred in 50% aqueous NaOH solution (3 mL) and DMSO (1 mL) then treated with 1-ιodopropane (0 03 mL, 0 321 mmol) This mixture was warmed to 40 °C for 2 hours then cooled, treated with H20 and extracted with ethyl acetate The organic layer was washed with H20 (3 times) then dried (Na2S04), filtered and concentrated to an oil (90 mg, 0 253 mmol) (TLC 5% methanol/CH2CI2 (NH3) Rf 0 15)
E) 6-Methyl-7-propyl-5.7,13-trιazatetracvclor9 3 1 02 10 04 81pentadeca-2(10 .3.5.8- tetraene hydrochloπde
6-Methyl-7-propyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10), 3,5,8- tetraene-13-carboxylιc acid tert-butyl ester (90 mg, 0 253 mmol) was dissolved in 3N HCl ethyl acetate (5 mL) and warmed to 100 °C for 1/2 hour The mixture was cooled, concentrated, slurπed in ethyl acetate, and filtered to provide a white solid (25 mg, 34%) 1H NMR (400 MHz, DMSO-d6) δ 9 56 (s, NH), 7 91 (s, 1 H), 7 83 (br m, NH), 7 74 (s, 1 H), 4 38 (m, 2H), 3 48 (m, 2H), 3 32 (m, 2H), 3 10 (m, 2H), 2 87 (s, 3H), 2 28 (m, 1 H), 2 15 (d, J = 11 0 Hz, 1 H) 1 85 (m, 2H), 0 97 (m, 3H) M p 147-150 °C
EXAMPLE 13
5.7.13-TRIAZATETRACYCLOr9 3 1 02 10 0481-
PENTADECA-2(10).3.5.8-TETRAENE HYDROCHLORIDE A) 5.7.13-Trιazatetracvclor9 3 1 02 10 0481pentadeca-2(10).3.5.8-tetraene-13-carboxylιc acid tert-butyl ester (For conditions, see, Segelstem, B E , Chenard, B L , Macor, J E , Post,
R J Tetrahedron Lett 1993, 34, 1897 )
4,5-Dιamιno-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene-10-carboxylιc acid tert- butyl ester (1 0 g, 3 45 mmol) was dissolved in ethanol (10 mL) and HOAc (1 mL) and treated with ethoxymethylenemalononitrile (421 mg, 3 45 mmol) The resulting mixture was warmed to 60 °C and stirred 18 hours The reaction was cooled, concentrated treated with H20 and saturated aqueous Na2C03 solution and extracted with ethyl acetate (3 x 50 mL), then dried (Na2S04) After filtration and concentration, the residue was chromatographed to provide brown solids (580 mg, 56%) (TLC 5% methanol/CH2CI2 (NH3) R, 0 28)
B) 5,7,13-trιazatetracvclor9 3 1 02 10 0481pentadeca-2(10),3,5,8-tetraene hvdrochloπde
5,7,13-Tπazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5,8-tetraene-13-carboxyhc acid tert-butyl ester was converted to the title compound by the methods described in Example
12E 1H NMR (400 MHz, D20) 5 8 95 (s, 1 H), 7 67 (s, 2H), 3 45 (br s, 2H), 3 31 (d, J = 12 5 Hz, 2H), 3 13 (d, J = 12 5 Hz, 2H), 2 30 (m, 1 H), 1 99 (d, J = 11 5 Hz, 1 H) APCI MS m/e
200 1 [(M + 1)+] M p >250 °C EXAMPLE 14
7-METHYL-5.7.13-TRIAZATETRACYCLOf9 3 1 02 10 04 81-
PENTADECA-2(10).3.5.8-TETRAENE HYDROCHLORIDE Utilizing the methods described in Example 12D, 5 7,13- trιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5,8-tetraene-13-carboxylιc acid tert-butyl ester was converted to the title compound by reaction with lodomethane followed by deprotection as described in Example 12E 1H NMR (400 MHz, D20) δ 8 97 (s, 1 H), 7 71 (s,
1 H), 7 67 (s, 1 H), 3 94 (s, 3H), 3 48 (m, 2H), 3 33 (d, J = 12 2 Hz, 2H) 3 14 (d, J = 12 2 Hz, 2H), 2 34 (m, 1 H), 2 03 (d, J = 11 5 Hz, 1 H) APCI MS m/e 214 2 [(M + 1 )+]
EXAMPLE 15 6-METHYL-5.7.13-TRIAZATETRACYCLOr9 3 1 02 10 0 81- PENTADECA-2(10 .3.5.8-TETRAENE HYDROCHLORIDE 6-Methyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10) 3,5,8-tetraene-13- carboxyhc acid tert-butyl ester was converted to the title compound by the methods described in Example 12E 1H NMR (400 MHz, DMSO-d6) 5 9 40 (br m, NH), 7 77 (br m, NH), 7 70 (s, 1 H), 3 44 (m, 2H), 3 30 (m, 2H), 3 05 (br d, J = 11 0 Hz, 2H), 2 79 (s, 3H), 2 23 (m, 1 H), 2 10 (d, J = 10 8 Hz, 1 H) GCMS m/e 213 5 (M+)
EXAMPLE 16 6.7-DIMETHYL-5.7.13-TRIAZATETRACYCLOr9 3 1 02 0 04 81- PENTADECA-2(10).3.5.8-TETRAENE HYDROCHLORIDE Utilizing the methods described in Example 12D, 6-methyl-5,7,13- tπazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5,8-tetraene-13-carboxylιc acid tert-butyl ester was converted to the title compound by reaction with lodomethane followed by deprotection as described in Example 12E 1H NMR (400 MHz, DMSO-d6) δ 9 52 (s NH) 7 84 (s, 1H), 7.82 (br m, NH), 7 72 (s, 1 H), 3 90 (s, 3H), 3 45 (m, 2H), 3 28 (m, 2H), 3 04 (m, 2H), 2 82 (s, 3H), 2 23 (m, 1 H), 2.12 (d, J = 11 0 Hz, 1 H) APCI MS m/e 228 2 [(M + 1 )+] M p 225-230 °C
EXAMPLE 17
7-PROPYL-5.7.13-TRIAZATETRACYCLOf9 3 1 02 1° 0481-
PENTADECA-2(10).3.5.8-TETRAENE HYDROCHLORIDE Utilizing the methods described in Example 12D, 5,7,13- trιazatetracyclo[9 3 1 02 0 04 8]pentadeca-2(10),3,5,8-tetraene-13-carboxylιc acid tert-butyl ester was converted to the title compound by reaction with lodopropane followed by deprotection as described in Example 12E 1H NMR (400 MHz, DMSO-d6) δ 9 52 (s 1 H), 9 45 (br s, NH), 7 97 (s, 1 H), 7 85 (s, 1 H), 7 83 (br m, NH), 4 43 (m, 2H), 3 49 (m, 2H), 3 33 (m 2H), 3 08 (m, 2H), 2 28 (m, 1 H), 2 15 (d, J = 11 0 Hz, 1 H), 1 92 (m, 2H), 0 93 (m, 3H) APCI MS m/e 242 2 [(M + 1 )+] M p 170-171 °C (subl )
EXAMPLE 18 7-BUTYL-5.7.13-TRIAZATETRACYCLOf9 3 1 02 10 0481- PENTADECA-2(10).3.5.8-TETRAENE HYDROCHLORIDE A) 4-Butylamιno-5-nιtro-10-aza-trιcvclof6 3 1 02 7ldodeca-2(7).3.5-trιene-10-carboxylιc acid tert-butyl ester (For conditions, see, Senskey, M D , Bradshaw, J D Tessier, C A Youngs, W J Tetrahedron Lett 1995, 36, 6217 )
4,5-Dιnιtro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene-10-carboxylιc acid tert- butyl ester (500 mg, 1 43 mmol) and 1-butylamιne (1 42 mL, 14 3 mmol) were combined in THF (5 mL) and stirred 4 hours The mixture was diluted with ethyl acetate (50 mL) and washed with H20 (3 x 30 mL) then dried (Na2S04), filtered and concentrated to an oil This oil was passed through a Silica gel filter column to remove baseline impurities elutmg with 30% ethyl acetate/hexanes (510 mg, 1 41 mmol, 99%)
B) 4-Butylamιno-5-amιno-10-aza-trιcvclor6 3 1 027ldodeca-2(7),3,5-trιene-10- carboxyhc acid tert-butyl ester
4-Butylamιno-5-nιtro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-10-carboxylιc acid tert-butyl ester (460 mg, 1 27 mmol) was treated with ammonium formate (850 mg, 12 7 mmol) and 10%Pd(OH)2/C (50 mg) in methanol (20 mL) and brought to reflux for 1 hour then filtered through a Celite pad and concentrated The solids were treated with saturated aqueous Na2C03 solution, extracted with CH2CI2 (3 x 30 mL) and dried by filtration through a cotton plug to give an oil (440 mg, 100%)
C) 7-Butyl-5.7.13-trιazatetracvclof9 3 1 02 1° 048lpentadeca-2f10 .3.5.8-tetraene-13- carboxyhc acid tert-butyl ester
4-Butylamιno-5-amιno-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-10-carboxylιc acid tert-butyl ester (440 mg, 1 27 mmol) was dissolved in ethanol (20 mL) and HOAc (2 mL) and treated with ethoxymethylenemalononitrile (186 mg, 1 52 mmol) The resulting mixture was warmed to 60 °C and stirred 18 hours The reaction was cooled, concentrated, treated with H20 and saturated aqueous Na2C03 solution then extracted with ethyl acetate (3 x 50 mL) and dried (Na2S0 ) After filtration and concentration, the residue was chromatographed to provide a yellow oil (400 mg, 89%) (TLC 5% methanol/CH2CI2 (NH3) R, 0 70)
D) 7-Butyl-5.7.13-tπazatetracvclo[9 3 1 02 10 04 8]pentadeca-2(10).3.5,8-tetraene hvdrochloπde
7-Butyl-5,7,13-tπazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5,8-tetraene-13- carboxylic acid tert-butyl ester was converted to the title compound by the methods described in Example 12E 1H NMR (400 MHz, DMSO-d6) δ 9 93 (brs, NH), 9 68 (s, 1 H) 7 99 (s, 1 H) 7 92 (br m, NH), 7 87 (s, 1 H), 4 50 (m, 2H), 3 49 (m, 2H), 3 30 (m, 2H), 3 08 (m, 2H), 2 26 (m 1 H), 2 15 (d, J = 11 0 Hz, 1 H), 1 88 (m, 2H), 1 32 (m, 2H), 0 82 (t, J = 7 0 Hz, 3H) APCI MS m/e 256 2 [(M + 1)+] M p 204-208 °C
EXAMPLE 19 7-ISOBUTYL-5.7.13-TRIAZATETRACYCLOr9 3 1 02 0 04 81- PENTADECA-2(10).3.5.8-TETRAENE HYDROCHLORIDE
4,5-Dιnιtro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-10-carboxyhc acid tert- butyl ester and isobutylamine were converted to the title compound utilizing the methods described in Example 18A-D 1H NMR (400 MHz, CDCI3) δ 7 74 (s, 1 H), 7 52 (s, 1 H), 7 14 (s 1 H), 3 90 (dd, J = 7 5,2 0 Hz, 2H), 3 04-2 97 (m, 4H), 2 70 (dd, J = 12 8,2 3 Hz, 2H), 2 42 (m 1H), 2 19 (m, 1 H), 1 98 (d, J = 10 5 Hz, 1H), 0 93 (m, 6H) APCI MS m/e 256 2 [(M + 1)+] M p 147-150 °C (subl )
EXAMPLE 20 6-METHYL-7-ISOBUTYL-5.7.13-TRIAZATETRACYCLOf9 3 1 02 100 81- PENTADECA-2M0).3.5.8-TETRAENE HYDROCHLORIDE
A) 6-Methyl-7-ιsobutyl-5.7.13-trιazatetracvclor9 3 1 02 10 048lpentadeca-2(10).3.5.8- tetraene-13-carboxyhc acid tert-butyl ester
4-Amιno-5-ιsobutylamιno-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene-10- carboxy c acid tert-butyl ester (250 mg, 0 74 mmol) from Example 19B was dissolved in ethanol (10 mL) and HOAc (2 mL) and treated with 1-ethoxyethylenemalononιtrιle (118 mg 0 87 mmol) The reaction proceeded as in Example 18C (18h) and was worked up similarly to provide product (TLC 3% methanol/CH2CI2 (NH3) Rf 0 57) B) 6-Methyl-7-ιsobυtyl-5.7.13-trιazatetracvclor9 3 1 02 10 04 81pentadeca-2(10).3.5.8- tetraene hvdrochloπde
6-Methyl-7-ιsobutyl-5,7,13-tπazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5 8- tetraene-13-carboxyhc acid tert-butyl ester was converted to the title compound by the methods described in Example 12E APCI MS m/e 270 3 [(M + 1 )+] M p 129-130 °C (subl )
EXAMPLE 21 7-PHENYL-5.7.13-TRIAZATETRACYCLOI9 3 1 02 10 0 81- PENTADECA-2(10).3.5.8-TETRAENE HYDROCHLORIDE Utilizing the methods described in Example 18A, 4,5-dιnιtro-10-aza- tπcyclo[6 3 1 027]dodeca-2(7),3,5-tπene-10-carboxylιc acid tert-butyl ester and aniline were converted to 4-phenylamιno-5-nιtro-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-10- carboxyhc acid tert-butyl at 75 °C for 4 hours in the coupling step This was then converted to the title compound utilizing the methods described in Example 18B,C,D 1H NMR (400 MHz DMSO-d6) 59 08 (1H), 7 78-7 57 (m, 7H), 3 47-3 00 (m, 6H), 2 23 (m, 1H), 2 09 (d, J = 11 5 Hz, 1 H) APCI MS m/e 276 2 [(M + 1)+] M p 210-213 °C
EXAMPLE 22 6-METHYL-7-PHENYL-5.7.13-TRIAZATETRACYCLOr9 3 1 02 10 0481- PENTADECA-2(10 .3.5.8-TETRAENE HYDROCHLORIDE
Utilizing the methods described in Example 21 and Example 20, 4,5-dιnιtro-10-aza- trιcyclo[6 3 1 027]dodeca-2(7),3,5-trιene-10-carboxyhc acid tert-butyl ester and aniline were converted to the title compound 1H NMR (400 MHz, DMSO-d6) 57 79 (s, 1 H), 7 73-7 56 (m, 5H), 7 32 (s, 1 H), 3 46-2 99 (m, 6H), 2 66 (s, 3H), 2 23 (m, 1 H), 2 08 (d, J = 11 0 Hz, 1 H) APCI MS m/e 290 2 [(M + 1)+] M p >250 °C
EXAMPLE 23
7-NEOPENTYL-5.7.13-TRIAZATETRACYCLQ[9 3 1 02 10 0481-
PENTADECA-2(10).3.5.8-TETRAENE HYDROCHLORIDE Utilizing the methods described in Example 18A-D, 4,5-dιnιtro-10-aza- trιcyclo[6 3 1 027]dodeca-2(7),3,5-trιene-10-carboxylιc acid tert-butyl ester and neopentylamme were converted to the title compound t-Boc precursor GCMS m/e 369 (M+) (HCl salt) M p
>250 °C EXAMPLE 24
6-METHYL-7-NEOPENTYL-5.7.13-TRIAZATETRACYCLOf9 3 1 02 10 04 81-
PENTADECA-2(10).3.5.8-TETRAENE HYDROCHLORIDE
Utilizing the methods described in Examples 21 and 20 4,5-dιnιtro-10-aza- trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene-10-carboxylιc acid tert-butyl ester and neopentylamine were converted to the title compound 1H NMR (400 MHz, DMSO-d6) δ 7 31 (s ,1 H) 7 27 (s
,1 H), 7 02 (br s, , NH), 4 41 (t, J = 13 0 Hz, 2H), 3 90 (s, 3H), 3 47-3 26 (m, 6H), 2 20 (m, 1 H)
2 00 (d, J = 11 5 Hz, 1 H), 0 90 (s, 9H) t-Boc precursor APCI MS m/e 384 2 [(M + 1) +] M p
>250 °C
EXAMPLE 25 6.7-DIMETHYL-5.8.14-TRIAZATETRACYCLOf10 3 1 02 11 0491- HEXADECA-2M 1 .5.7.9-PENTAENE HYDROCHLORIDE (Based on the following procedure Jones, R G , McLaughlin, K C Org Syn 1963 4 824 b) Ehrhch, J , Bobert, M T J Org Chem 1947, 522 )
4,5-Dιamιno-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-tπene-10-carboxylιc acid tert- butyl ester (100 mg, 0 35 mmol) was warmed to 80 °C in H20 (5 mL) To this butane 2,3- dione (0 034 mL, 0 38 mmol) was added under N2 for 2 hours The reaction was cooled to room temperature and extracted with ethyl acetate (3 x 40 ml) The combined organic layer was washed with H20 (2 x 30 ml), dried (Na2S04), filtered concentrated and chromatographed on Silica gel to provide an oil (120 mg, 100%) The oil was dissolved in 2N HCl methanol (5 mL) and warmed to reflux for 30 minutes then concentrated Recrystalhzation from methanol/Et20 provided a white powder (50 mg, 43%) (TLC ethyl acetate R, 0 14) 1H NMR (400 MHz, DMSO-d6) δ 7 85 (s, 2H), 3 50 (br s, 2H), 3 32 (d, J = 12 5 Hz, 2H), 3 10 (d, J = 12 5 Hz, 2H), 2 64 (s, 6H), 2 24 (m, 1 H), 2 13 (d, J = 11 0 Hz 1 H) t- Boc precursor APCI MS m/e 340 3 [(M + 1)+]
EXAMPLE 26 5.8.14-TRIAZATETRACYCLθπθ 3 1 02 11 04 91- HEXADECA-2(1 D.3.5.7.9-PENTAENE HYDROCHLORIDE
A) 1-(4.5-Dιamιno-10-aza-tπcvclor6 3 1 02 7ldodeca-2(7),3,5-tπen-10-yl)-2,2.2-tπfluoro- ethanone
1-(4,5-Dιnιtro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπen-10-yl)-2,2,2-trιfluoro- ethanone (3 0 g, 8 70 mmol) was hydrogenated in methanol (30 ml) under H2 (45 psi) over Pd(OH)2 (300 mg of 20 wt%/C, 10%wt) After 2 5 hours the reaction was filtered through a Celite pad and rinsed with methanol (30 ml) The solution was concentrated to a light brown oil which crystallized (2 42 g, 96%) (TLC 10% methanol/CH2CI2 Rf 0 56) APCI MS m/e 286 2 [(M + 1)+] M p 129-131 CC
B) 1-(5.8.14-TπazatetracvcloH0 3 1 02 11 049lhexadeca-2(11 ).3.5.7.9-pentaene)-2,2.2- tπfluoro-ethanone
1-(4,5-Dιamιno-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2 2,2-tπfluoro- ethanone (500 mg, 1 75 mmol) was stirred in THF (2 ml) This mixture was treated with H20 (2 mL) and glyoxai sodium bisulfite addition compound hydrate (931 mg, 3 50 mmol) then stirred at 55 °C for 2 5 hours The reaction was cooled to room temperature and extracted with ethyl acetate (3 x 40 ml) The combined organic layer was washed with H20 (2 x 30 ml), dried (Na2S04), filtered, concentrated and chromatographed on Silica gel to provide an off white powder (329 mg, 60%) (TLC 25% ethyl acetate/hexanes R, 0 40) M p 164-166 °C
C) 5.8.14-Trιazatetracvcloπθ 3 1 02 11 04 9lhexadeca-2(11).3.5.7.9-pentaene hvdrochloπde
1-(5,8,14-Trιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11 ),3,5,7,9-pentaene)-2,2,2- tnfluoro-ethanone (320 mg, 1 04 mmol) was slurned in methanol (2 0 ml) and treated with Na2C03 (221 mg, 2 08 mmol) in H20 (2 0 ml) The mixture was warmed to 70 °C for 2 hours, then concentrated, treated with H20 (20 mL) and extracted with CH2CI2 (3 x 10 ml) The organic layer was dried through a cotton plug and concentrated to give a light yellow oil (183 mg, 83%) which solidified upon standing (M p 138-140 °C) This material was dissolved in methanol (10 mL), treated with 3M HCI/ethyl acetate (3 ml), concentrated and azeotroped with methanol (2 x 20 mL) to give solids which were recrystallized from methanol/Et20 to afford product as a white solid (208 mg, 97%) (TLC 5% methanol/CH2CI2 (NH3) Rf 0 26) 1H NMR (400 MHz, CD3OD) δ 8 94 (s, 2H), 8 12 (s, 2H), 3 70 (m, 2H), 3 54 (d, J = 12 5 Hz, 2H) 3 35 (d, J = 12 5 Hz, 2H), 2 49 (m, 1 H), 2 08 (d, J = 11 0 Hz, 1 H) GCMS m/e 21 1 (M+) M p 225- 230 °C
EXAMPLE 27 14-METHYL-5.8.14-TRIAZATETRACYCLOM 0 3 1 02 11 0491-
HEXADECA-2(11).3.5.7.9-PENTAENE HYDROCHLORIDE 5,8,14-Tπazatetracyclo[10 3 1 02 11 0 9]hexadeca-2(11),3,5,7,9-pentaene (207 mg, 0 98 mmol) was treated with 37% aqueous formaline solution (1 mL) and formic acid (1 mL) then warmed to 80 °C for 1 hour The reaction was poured into water, made basic (NaOH, pH -11) and extracted with ethyl acetate The organic layer was dried (Na2S0 ), concentrated and chromatographed on Silica gel to provide a yellow solid This was stirred in methanol (2 mL) and treated with 3N HCl ethyl acetate (2 mL) After concentration the solids were recrystallized from methanol/Et20 to afford product as a white solid (70 mg, 27%) (2% methanol/CH2CI2 (NH3) Rf 0 47) 1H NMR (400 MHz, CDCI3) δ 8 71 (s, 2H), 7 80 (s, 2H), 3 37 (br s, 2H), 3 03 (m, 2H), 2 47 (m, 2H), 2 32 (m, 1 H), 2 18 (br s, 3H), 1 84 (d, J = 11 0 Hz, 1 H) APCI MS m/e 226 2 [(M + 1)+] M p >250 °C
EXAMPLE 28 5-OXA-7.13-DIAZATETRACYCLOf9 3 1 02 10 0481-
PENTADECA-2(10).3.6.8-TETRAENE HYDROCHLORIDE A) 2,2,2-Trιfluoro-1-(4-hvdroxy-5-nιtro-10-aza-trιcvclor6 3 1 02 7ldodeca-2(7),3.5-tπen-
10-yl)-ethanone
1-(4,5-Dιnιtro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπen-10-yl)-2,2,2-trιfluoro- ethanone (900 mg, 2 61 mmol) and potassium acetate (KOAc) (2 6 g, 26 1 mmol) were dissolved in DMSO (10 mL) and warmed with stirring to 100 °C for 16 hours The mixture was cooled and diluted with H20 ( 50 mL) then extracted with 80% ethyl acetate/hexanes (6 x 25 mL) The organic layer was washed with H20 (3 x 20 mL), dried (Na2S0 ), filtered and concentrated and purified by chromatography to give an oil (575 mg, 70%) (TLC 50% ethyl acetate/hexanes (NH3) Rf 0.56)
B) 2,2,2-Trιfluoro-1-(4-hvdroxy-5-amιno-10-aza-tπcvclor6 3 1 02 71dodeca-2(7),3,5- trιen-10-yl)-ethanone
2,2,2-Trifluoro-1-(4-hydroxy-5-nιtro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10- yl)-ethanone (575 mg, 1 82 mmol) was hydrogenated in methanol under a H2 atmosphere at (45 psi) over 10%Pd/C (80 mg) for 1.5 hours then filtered through a Celite pad and concentrated to white solids (450 mg, 86%) (TLC 5% methanol/CH2CI2 (NH3) R, 0 6) H NMR (400 MHz, CD3OD) δ 6 67-6 59 (m, 2H), 4 12 (m, 1 H), 3 73 (m, 1 H), 3 73 (m, 1 H), 3 51 (m, 1 H), 3 07 (m, 2H), 2 24 (m, 1 H), 1 94 (d, J = 10 5 Hz, 1 H) GCMS m/e 286 (M +)
C) 2.2.2-Tπfluoro-1-(5-oxa-7.13-dιazatetracvclof9 3 1 02 10 048lpentadeca-2(10).3.6.8- tetraene)-ethanone (Goldstein, S W , Dambek, P. J J Het Chem 1990, 27, 335 )
2,2,2-Tπfluoro-1-(4-hydroxy-5-amιno-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπen-
10-yl)-ethanone (150 mg, 0.524 mmol), tnmethyl orthoformate (0 19 mL, 1 73 mmol), pyπdinium-p-toluenesulfonic acid (PPTS, 18 mg, 0 07 mmol) and xylenes (10 mL) were combined under nitrogen and stirred at 135 °C for 18 hours The mixture was cooled, treated with H20 and extracted with ethyl acetate The extracts were dried (Na2S04), filtered, concentrated and purified by chromatography to give an oil (110 mg, 71 %) (TLC 20% ethyl acetate/hexanes Rf 0 40)
D) 5-Oxa-7.13-dιazatetracvclor9 3 1 02 10 04 8lpentadeca-2(10).3,6.8-tetraene hvdrochloπde
2,2,2-Trιfluoro-1-(5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10) 3 6 8- tetraene)-ethanone (110 mg, 0 37 mmol) was stirred in methanol (5 mL) and treated with Na2C03 (78 mg, 0 74 mmol) in H20 (2 mL) The stirred mixture was warmed to 80 °C for 2 hours, concentrated to solids, diluted with H20 and extracted with ethyl acetate (3 x 40 mL) The product was extracted into aqueous 1 N HCl solution (2 x 40 mL) which was washed with ethyl acetate then neutralized with saturated aqueous Na2C03 solution to pH~10 The product was extracted with ethyl acetate (3 x 40 mL) dried (Na2S04), concentrated and chromatographed on Silica gel to produce an oil (TLC 5% methanol/CH2CI2 (NH3) Rf 0 19)
The oil was dissolved in methanol and treated with 3N HCl ethyl acetate (4 mL) then concentrated stirred in a minimum of CH2CI2 and saturated with hexanes After 18 hours the product was collected by filtration (55 mg, 63%) 1H NMR (400 MHz, CD3OD) δ 8 47 (s 1 H) 7 70 (s, 1 H), 7 65 (s, 1 H), 3 41 (m, 2H), 3 30 (m, 2H), 3 10 (d, J = 12 5 Hz, 2H), 2 47 (m 1 H) 2 15 (d, J = 11 0 Hz, 1H) APCI MS m/e 201 03 [(M + 1)+]
EXAMPLE 29
6-METHYL-5-OXA-7.13-DIAZATETRACYCLQ[9 3 1 02 10 0481- PENTADECA-2(10).3.6.8-TETRAENE HYDROCHLORIDE
A) 2.2.2-Tnfluoro-1-(6-methyl 5-oxa-7.13-dιazatetracvclof9 3 1 02 10 048lpentadeca- 2(10),3,6,8-tetraene)-ethanone 2,2,2-Trιfluoro-1-(4-hydroxy-5-amιno-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7) 3 5-trιen-
10-yl)-ethanone (150 mg, 0 524 mmol), tnethyl orthoacetate (0 34 mL, 1 83 mmol) pyπdinium- p-toluenesulfonic acid (PPTS, 20 mg, 0 08 mmol) and xylenes (10 mL) were combined under nitrogen and stirred at 135 °C for 18 hours Work-up, isolation and purification as in Example 28C provided the title compound (90 mg, 55%)
B) 6-Methyl-5-oxa-7.13-dιazatetracvclof9 3 1 02 1° 0 8lpentadeca-2(10).3.6 8-tetraene hvdrochloπde
2,2,2-Trιfluoro-1 -(6-methyl 5-oxa-7, 13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-
2(10),3,6,8-tetraene)-ethanone (90 mg, 0 30 mmol) was stirred in methanol (5 mL) and treated with Na2C03 (61 mg, 0 58 mmol) in H20 (2 mL) The stirred mixture was warmed to
80 °C for 2 hours, concentrated to solids, diluted with H20 and extracted with ethyl acetate (3 x 40 mL) The solution was dried (Na2S04), concentrated, and chromatographed on Silica gel to produce an oil (TLC 10% methanol/CH2CI2 (NH3) R, 0 18) 1H NMR (free base) (400 MHz, CDCI3) δ 7 40 (s, 1 H), 7 26 (s, 1 H), 3 05-2 98 (m, 4H), 2 72 (d, J = 12 8 Hz, 2H), 2 59 (s 3H) 246 (m, 1 H), 1 98 (d, J = 10 5 Hz, 1H) The oil was dissolved in methanol and treated with 3N HCl ethyl acetate (4 mL) then concentrated, stirred in a minimum of CH2CI2 and saturated with hexanes After 18 hours, the product was collected by filtration (10 mg, 13%) APCI MS m/e 215 2 [(M + 1 )+] M p >250 °C
EXAMPLE 30 2-FLUORO-N-(4-HYDROXY-10-AZA-TRICYCLOr6 3 1 02 71-
DODECA-2(7 .3.5-TRIEN-5-YL)-BENZAMIDE HYDROCHLORIDE 2,2,2-Trιfluoro-1-(4-hydroxy-5-amιno-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπen- 10-yl)-ethanone (150 mg, 0 524 mmol), 2-fluorobenzoyl chloride (0 07 mL, 0 576 mmol) pyndinium-p-toluenesulfonic acid (PPTS, 20 mg, 0 08 mmol), pyridine (0 046 mL, 0 576 mmol) and xylenes (5 mL) were combined under nitrogen and stirred at 135 °C for 18 hours After 24 hours, additional PPTS (50 mg) was added and the material stirred at 135 °C for an additional 24 hours Work-up as above provided crude product (145 mg, 0 375 mmol) which was combined with Na2C03(s) (80 mg, 0 75 mmol) in methanol (5 mL) and H20 (2 mL) and heated to reflux After 3 hours, the reaction was cooled and diluted with water then extracted with CH2CI2 (4 x 40 mL), dried through a cotton plug then chromatographed to remove baseline impurity (5% methanol/CH2CI2 (NH3)) The crude material was treated with excess 3N HCl ethyl acetate and concentrated, then dissolved in a minimum of methanol and the solution was saturated with Et20 and stirred After stirring 4 hours the product was collected by filtration (85 mg, 68%) 1H NMR (400 MHz, CD3OD) δ 7 99 (m, 2H), 7 59 (m, 1 H), 7 36-7 23 (m, 2H) 6 82 (s, 1H), 2 99 (m, 4H), 2 78 (m, 2H), 2 35 (m, 1H), 1 96 (d, J = 10 5 Hz, 1 H) APCI MS m/e 313 1 [(M + 1)+] M p 125-130 °C (subl )
EXAMPLE 31 4-CHLORO-10-AZATRICYCLOr6 3 1 02 7lDODECA-2(7),3.5-TRIENE HYDROCHLORIDE A) 1-(4-Chloro-10-aza-trιcvclor6 3 1 027ldodeca-2(7).3.5-tπen-10-yl)-2.2.2-tπfluoro- ethanone
Copper(l)chlorιde (CuCI) was prepared as follows CuS04 (4 3 g) and NaCI (1 2 g) were dissolved in hot H20 (14 mL) sodium bisulfite (NaHS03) (1 g) and sodium hydroxide (NaOH) (690 mg) were dissolved in H20 (7 mL) and added to the hot acidic solution over 5 minutes The precipitated white solids were filtered and washed with water 1-(4-Amιno-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-tπfluoro- ethanone (460 mg, 1 7 mmol) was dissolved in H20 (2 mL) and concentrated HCl solutιon(1 mL) then cooled to 0 °C and treated with a solution of sodium nitrite (NaN02) (275 mg) in H20 (1 mL) dropwise To the resulting solution was added a CuCI (202 mg, prepared as described above, 2 04 mmol) in concentrated HCl solution (2 mL) over 10 minutes (gas evolution observed) The resulting solution was warmed to 60 °C for 15 minutes, then was cooled to room temperature and extracted with ethyl acetate (4 x 30 mL) After drying over Na2S0 , the solution was filtered and concentrated to an oil which was filtered through a Silica pad to remove baseline material eluting with 50% ethyl acetate/hexanes to give an oil (470 mg, 95%)
B) 4-Chloro-10-azatrιcyclo[6 3 1 02 71dodeca-2(7),3,5-trιene hvdrochloπde 1-(4-Chloro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-tπfluoro- ethanone (470 mg, 1 62 mmol) and Na2C03 (344 mg, 3 24 mmol) in methanol (30 mL) and H20 (10 mL) were heated to reflux After 2 hours, the reaction was cooled and diluted with water then extracted with ethyl acetate (4 x 40 mL), dried (Na2S04), filtered and concentrated to a yellow oil The crude material was treated with excess 3N HCl ethyl acetate and concentrated, then dissolved in a minimum of CH2CI2 and the solution was saturated with hexanes and stirred After stirring 4 hours the product was collected by filtration (155 mg, 42%) 1H NMR (free base) (400 MHz, CDCI3) 5 7 15 (m, 2H), 7 09 (d, J = 8 0 Hz, 1 H), 3 00- 2 94 (m, 4H), 2 68, (m, 2H), 2 38 (m, 1 H), 1 92 (d, J = 10 5 Hz, 1 H) 1H NMR (HCl salt) (400 MHz, DMSO-d6) 5 7 30-7 20 (m, 3H), 3 30-3 15 (m, 6H), 2 37 (m, 1 H), 1 89 (d, J = 11 0 Hz, 1 H) APCI MS m/e 194 1 [(M + 1)+]
EXAMPLE 32 10-AZATRICYCLθr6 3 1 02 7lDODECA-2(7).3.5-TRIEN-4-YL
CYANIDE HYDROCHLORIDE A) 1-(4-lodo-10-aza-trιcvclof6 3 1 0271dodeca-2(7).3.5-trιen-10-yl)-2.2.2-trιfluoro- ethanone
1-(4-Amιno-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-trιfluoro- ethanone (500 mg, 1 85 mmol) was dissolved in H20 (5 mL) and concentrated H2S04 solution (0 5 mL) then cooled to 0 °C and treated with a solution of sodium nitrite (NaN02) (140 mg, 2 04 mmol) in H20 (2 mL) dropwise Potassium iodide (460 mg, 2 78 mmol) in 1 N H2S04 solution (0 5 mL) was added over 10 minutes (reaction becomes dark red) The resulting solution was warmed to room temperature and stirred 18 hours The reaction was quenched with NaHS03 and water (pH 2 5) then extracted with ethyl acetate (4 x 30 mL) After drying (Na2S04), the solution was filtered and concentrated to a yellow oil which was chromatographed on Silica gel to provide a yellow oil. (260 mg, 37%). (TLC 30% ethyl acetate/hexanes Rf 0.70). (A 5.4 g scale performed as above yielded 5 g, 67%).
B) 4-lodo-10-aza-tricvclor6.3.1.02 71dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester
1-(4-lodo-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro- ethanone (5 g, 13.1 mmol) and 37% saturated aqueous NH OH solution (50 mL) were stirred in methanol (250 ml) for 2 hours then concentrated and azeotroped with methanol (2 x 50 mL). The resulting product was stirred in 1 ,4-dioxane (75 mL) and treated with saturated Na2C03 solution (15 mL). To this was added di-t-butyldicarbonate (5.71 g, 26.2 mmol). After stirring 18 hours the reaction was treated with H20 ( 50 mL) and extracted with CH2CI2 (4 x 30 mL), dried (Na2S04), filtered, concentrated and chromatographed on Silica gel (TLC 20% ethyl acetate/hexanes) to provide product as an oil (4.9 g, 98%).
C) 4-Cvano-10-aza-tricvclo[6.3.1.02 7ldodeca-2(7),3,5-triene-10-carboxylic acid tert- butyl ester (Utilizing the methods described in: House, H. O.; Fischer, W. F. J. Org. Chem. 1969, 3626.)
CuCN (108 mg, 1.21 mmol) and NaCN (59 mg, 1.21 mmol) were combined in dry DMF (6 mL) and warmed to 150 °C under N2. Solution occurs in 20 minutes. To this was added 4-iodo-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (232 mg, 0.6 mmol) in DMF (3.5 mL) and the mixture was stirred for 18 hours at 150 °C. The reaction was cooled and diluted with 50% saturated aqueous NaCI solution and extracted with 50% ethyl acetate/hexanes (3 x 30 mL). After drying (Na2S0 ), filtration and concentration the product was isolated by chromatography (86 mg, 50%). (TLC 20% ethyl acetate/hexanes Rf 0.28).
D) 10-Azatricvclor6.3.1.02,7ldodeca-2(7),3,5-trien-4-yl cyanide hvdrochloride 4-Cyano-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester was treated with 3N HCl ethyl acetate (6 mL) and warmed to reflux for 2 hours, then concentrated, dissolved in a minimum of methanol which was saturated with Et20 and stirred 18 hours. The product was collected by filtration (49 mg, 73%). 1H NMR (400 MHz, DMSO- d6) δ 9.66 (br s, NH), 7.86 (br s, NH), 7.74-7.70 (m, 2H), 7.49 (d, J = 7.5 Hz, 1 H), 3.33-2.97 (m, 6H), 2.17 (m, 1 H), 2.01 (d, J = 11.0 Hz, 1 H). GCMS m/e 184 (M+). M.p. 268-273 °C. EXAMPLE 33 3-(10-AZATRICYCLOr6 3 1 02 71DODECA-2(7),3.5-TRIEN-4-YD- 5-METHYL-1 ,2.4-OXADIAZOLE HYDROCHLORIDE 4-Cyano-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-10-carboxyhc acid tert-butyl ester (300 mg, 1 1 mmol) was stirred in ethanol (10 mL) To this hydroxyl amine hydrochloπde (382 mg, 5 5 mmol) and NaOH (242 mg, 6 05 mmol) were added and the mixture was warmed to reflux After 45 minutes, the reaction was cooled, diluted with H20 and extracted with ethyl acetate The organic layer was dried (Na2S04) and concentrated to afford a yellow solid (110 mg, 0 35 mmol) This solid was dissolved in pyridine (1 mL) and treated with acetyl chloride (0 03 mL, 0 415 mmol) and warmed to 100°C for 18 hours The reaction was cooled treated with H20 and extracted with ethyl acetate The organic extracts were washed with water and saturated aqueous NaCI solution, dried (Na2S0 ) and concentrated Chromatography on Silica gel afforded product (50 mg, 0 15 mmol) (25% ethyl acetate/hexanes Rf 0 18) This product was treated with 2N HCl methanol (10 mL) heated to 70 °C for 1 hour, cooled, concentrated and recrystallized from methanol/Et20 to provide product (15 mg) APCI MS m/e 242 2 [(M + 1)+]
EXAMPLE 34 1-(10-AZATRICYCLOf6 3 1 0271DODECA- 2(7).3.5-TRIEN-4-YL)-1-ETHANONE HYDROCHLORIDE
A A) 1-(4-Acetyl-10-aza-trιcvclof6 3 1 027ldodeca-2(7 .3.5-trιen-10-yl)-2.2.2-tπfluoro- ethanone
1-(10-Aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-trιfluoro-ethanone (253 mg, 1 0 mmol) and AcCI (0 68 mL, 10 mmol) were dissolved in DCE (3 mL) and treated with aluminum chloride (AICI3) (667 mg, 5 0 mmol) The resulting yellow mixture was stirred for 30 minutes then poured over ice and saturated aqueous NaHC03 solution After stirring 20 minutes the mixture was extracted with CH2CI2 (3 x 30 mL) The organic layer was dried through a cotton plug then concentrated to a orange-yellow oil (255 mg, 86%)
B) 4-Acetyl-10-aza-trιcvclor6 3 1 027ldodeca-2(7),3,5-trιene-10-carboxylιc acid tert- butyl ester
1-(4-Acetyl-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-tπfluoro- ethanone (1 3 g, 4 37 mmol) and 37% aqueous NH4OH solution (10 mL) were stirred in methanol (30 ml) for 3 hours, then concentrated and azeotroped with methanol (2 x 50 mL) (This product could be converted to an HCl salt directly see the next example ) The resulting product was stirred in 1 ,4-dιoxane (20 mL) and treated with saturated aqueous Na2C03 solution (5 mL) To this was added di-t-butyldicarbonate (1 91 g, 8 74 mmol) After stirring 2 hours, the reaction was treated with H20 (50 mL), extracted with CH2CI2 (4 x 30 mL) dried (Na2S04), filtered, concentrated and chromatographed to provide an oil (1 3 g, 100%) (TLC 40% ethyl acetate/hexanes R, 0 56)
C) 1-(10-Azatπcvclof6 3 1 02 7ldodeca-2(7), 3.5-trιen-4-yl)-1 -ethanone hydrochloπde 4-Acetyl-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-tπene-10-carboxylιc acid tert-butyl ester (190 mg, 0 63 mmol) was treated with excess 3N HCl ethyl acetate and warmed to 70°C for 1 hour then concentrated and dissolved in a minimum of methanol The resulting solution was saturated with Et20 and stirred After 18 hours the white crystalline product was collected by filtration (81 mg, 54%) 1H NMR (400 MHz, DMSO-d6) δ 9 75 (br s NH), 7 89 (s, 1 H) 7 88 (d, J = 8 0 Hz, 1 H), 7 74 (br s, NH), 7 44 (d, J = 8 0 Hz, 1 H), 3 33 (br s 2H), 3 22 (br s, 2H) 3 00 (br m, 2H), 2 54 (s, 3H), 2 17 (m, 1 H), 2 02 (d, J = 11 0 Hz, 1 H) GCMS m/e 201 (M+) M p 198-202 °C
EXAMPLE 35 10-AZATRICYCLθr6 3 1 02 71DODECA-2(7).3.5-TRIEN-4-OL HYDROCHLORIDE
A) Acetic acid 10-trιfluoroacetyl-10-aza-trιcyclof6 3 1 02 71dodeca-2(7),3,5-tπen-4-yl ester 1-(4-Acetyl-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-tπfluoro- ethanone (2 5 g, 8 41 mmol) and 3-chloroperoxybenzoιc acid (m-CPBA) (7 5 g, 42 mmol) were stirred in CH2CI2 (20 mL) and warmed to 40°C for 18 hours The mixture was cooled to room temperature, then treated with dimethylsulfide (Me2S) (3 mL, 40 8 mmol) and stirred 24 hours The resulting mixture was poured into ice and saturated aqueous Na2C03 solution (100 mL) then extracted with Et20 (4 x 40 mL) The organic layer was washed saturated aqueous Na2C03 solution (3 x 40 mL) then dried (Na2S04), filtered and concentrated to afford an oil (1 83 g, 69%) (TLC ethyl acetate R, 0 80)
B 2.2.2-Tπfluoro-1-(4-hvdroxy-10-aza-trιcvclor6 3 1 027ldodeca-2(7).3.5-trιen-10-yl)- ethanone
Acetic acid 10-trιfluoroacetyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-4-yl ester
(900 mg, 2 87 mmol) was stirred in methanol (20 mL) and saturated aqueous NaHC03 solution (15 mL) for 48 hours The mixture was concentrated, diluted with H20 and extracted with CH2CI2 (3 x 20 mL) then dried through a cotton plug Chromatography on Silica gel provided pure product (420 mg, 54%) (TLC 5% methanol/CH2Cl2 Rf 0 44) 1H NMR (400 MHz CDCI3) 5 7 05 (m, 1 H), 6 70 (m, 1 H), 6 62 (m, 1 H), 4 32 (m, 1 H), 3 84 (m, 1 H), 3 48 (m, 1 H) 3 21 (br s, 1 H), 3 16 (br s, 1 H), 3 09 (m, 1 H), 2 38 (m, 1 H), 1 97 (d, J = 11 0 Hz, 1 H)
C) 10-Azatπcvclof6 3 1 02 7ldodeca-2(7),3,5-trιen-4-ol hydrochlonde 2,2,2-Trιfluoro-1-(4-hydroxy-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπen-10-yl)- ethanone (50 mg, 0 184 mmol) was dissolved in methanol/H20 (3/1 , 5 mL), treated with Na2C03(s) (40 mg, 0 369 mmol) and warmed to 65°C for 2 hours The mixture was concentrated, diluted with H20 and extracted with CH2CI2 (3 x 20 mL) then dried through a cotton plug Filtration through a Silica gel plug provided an oil (10% methanol/CH2CI2) which was treated with 3N HCl ethyl acetate (3 mL) then concentrated, dissolved in a minimum of methanol which was saturated with Et20 and stirred After 18 hours the white crystalline product was collected by filtration (10 mg, 26%) H NMR (400 MHz, CDOD3) δ 7 16 (d, J = 8 0 Hz, 1H), 6 80 (d, J = 2 0 Hz, 1H), 6 72 (dd, J = 8 0,2 0 Hz, 1H), 3 32-3 28 (4H), 3 09 (dd, J = 14 5,12 0 Hz, 2H), 2 32 (m, 1 H), 2 03 (d, J = 11 0 Hz, 1 H) APCI MS m/e 176 2 [(M + 1 )+] M p 308 (dec ) °C
EXAMPLE 36 7-METHYL-5-OXA-6.13-DIAZATETRACYCLO[9 3 1 02 10 04 81
PENTADECA-2.4(8).6.9-TETRAENE HYDROCHLORIDE A) 1-(4-Acetyl-5-hvdroxy-10-aza-trιcvclof6 3 1 02 7ldodeca-2(7),3,5-trιen-10-vn-2.2.2- tπfluoro-ethanone
Acetic acid 10-trιfluoroacetyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-4-yl ester (800 mg, 2 55 mmol) was combined with AICI3 (1 0 g, 7 65 mmol) and warmed to 170°C for 2 hours The mixture was cooled and treated with 1 N aqueous HCl solution (20 mL), extracted with ethyl acetate and dried (Na2S04) Chromatography affords an oil (190 mg, 24%) (TLC ethyl acetate Rf 0 75) 1H NMR (400 MHz, CDCI3) δ 12 58 (s, 0 5H), 12 52 (s, 0 5H), 7 53 (s 1 H), 6 86 (s, 1 H), 4 33 (m, 1 H), 3 91 (m, 1 H), 3 56 (m, 1 H), 3 28 (br s, 1 H), 3 24 (br s 1 H) 3 14 (m, 1 H), 2 35 (m, 1H), 1 97 (br d, J = 11 2 Hz, 1 H)
B) 2,2,2-Trιfluoro-1-r4-hvdroxy-5-(1-hvdroxyιmιno-ethyl)-10-aza-trιcvclo[6 3 1 02 71- dodeca-2(7),3.5-trιen-10-vn-ethanone
1-(4-Acetyl-5-hydroxy-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2- tπfluoro-ethanone (190 mg, 0 605 mmol), hydroxylamine HCl (99 mg, 1 21 mmol) and sodium acetate (118 mg, 1 21 mmol) were combined in methanol (4 mL) and H20 (1 mL) and warmed to 65°C for 18 hours The mixture was cooled, diluted with H20 and extracted with ethyl acetate which was dried (Na2S0 ), filtered and concentrated to provide a yellow oil (177 mg 93%)
C) 2.2.2-Tnfluoro-7-Methyl-5-oxa-6.13-dιazatetracvclof9 3 1 02 10 04 8lpentadeca- 2,4(8),6,9-tetraene-ethanone
The above oil, 2,2,2-trιfluoro-1-[4-hydroxy-5-(1-hydroxyιmιno-ethyl)-10-aza- trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl]-ethanone (177 mg, 0 54 mmol) was stirred in DCE (3 mL), treated with tnethylamine (0 4 mL, 2 8 mmol) and acetic anhydride (Ac20) (0 3 mL, 2 8 mmol) then stirred 18 hours The reaction was treated with H20 and extracted with ethyl acetate The extracts were dried (Na2S0 ), filtered and concentrated to a yellow oil which was dissolved in anhydrous DMF (3 mL) and treated with 60% NaH in oil (32 mg 1 08 mmol) After stirring 18 hours, additional 60% NaH in oil was introduced (33 mg) and the mixture was stirred 2 hours The reaction was quenched with H20 (5 mL) and extracted with 80% ethyl acetate/hexanes (3 x 30 mL) The organic layer was washed with H20 (3 x 20 mL) dried (Na2S0 ), filtered and concentrated and chromatographed to provide an oil (40% ethyl acetate/hexanes Rf 0 56)
D) 7-Methyl-5-oxa-6.13-dιazatetracvclor9 3 1 02 10 048lpentadeca-2.4(8).6.9-tetraene hvdrochloride Utilizing the methods described in Example 9C, 2,2,2-Trιfluoro-7-MethyI-5-oxa-6,13- dιazatetracyclo[9 3 1 02 10 0 8]pentadeca-2,4(8),6,9-tetraene-ethanone was converted to the title compound This was treated with 3N HCl ethyl acetate (3 mL), concentrated and dissolved in a minimum of CH2CI2 which was saturated with hexanes and stirred After 18 hours the white crystalline product was collected by filtration (18 mg, 13% overall) H NMR (400 MHz, DMSO-d6) δ 7 72 (s, 1 H), 7 63 (s, 1 H), 3 42-2 98 (m, 6H), 2 50 (s, 3H), 2 23 (m 1 H), 2 08 (d, J = 10 5 Hz, 1 H) APCI MS m/e 215 2 [(M + 1)+]
EXAMPLE 37
4-(2-METHYL-2H-PYRAZOL-3-YL)-10-AZA-TRICYCLOr6 3 1 02 71DODECA-2(7).3.5-TRIENE HYDROCHLORIDE and 4-(1-METHYL-1 H-PYRAZOL-3-YL -10-AZA-
TRICYCLOrø 3 1 02 71DODECA-2(7).3,5-TRIENE HYDROCHLORIDE
1-(4-Acetyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-tπfluoro- ethanone (1 0 g, 3 3 mmol) and dimethylformamide dimethylacetal (DMF-DMA) (4 0 g, 33 6 mmol) were warmed to 140°C for 18 hours After cooling, a crystalline precipitate was filtered and rinsed with ethyl acetate (690 mg, 58%) The above solid, 3-dιmethylamιno-1-(10-trιfluoroacetyl-10-aza-trιcyclo[6 3 1 02 7]- dodeca-2(7),3,5-tπen-4-yl)-propenone, (200 mg, 0 56 mmol) was dissolved in ethanol (2 mL) and treated with 5N HCl ethanol (0 1 mL) followed by methyl hydrazme (0 6 mmol) The resulting mixture was warmed to 70°C for 4 hours The mixture was cooled, diluted with water and extracted with ethyl acetate, dried (Na2S0 ) and concentrated Chromatography on Silica gel provided a 3/1 mixture of regioisomeπc products (130 mg, 68%) (TLC 50% ethyl acetate/hexanes Rf 0 40)
The above oil (130 mg, 0 388 mmol) and Na2C03(s) (82 mg, 0 775 mmol) were stirred in methanol (10 mL) and H20 (5 mL) for 18 hours After cooling the reaction was diluted with water, extracted with CH2CI2 dried through a cotton plug and concentrated The product was purified by chromatography on Silica gel and concentrated to an oil The salt was generated with 2N HCl methanol, concentrated and recrystallized from methanol/ethyl acetate to provide a 3/1 mixture of regioisomeπc pyrrazoies (85 mg, 58%) (5% methanol/CH2CI2 (NH3) Rf 0 25) TFA-precursor APCI MS m/e 336 2 [(M + 1) +]
EXAMPLE 38 4.5-DICHLORO-10-AZATRICYCLOf6 3 1 02 71DODECA-2(7),3.5-TRIENE HYDROCHLORIDE A) 1-(4.5-Dιchloro-10-aza-tπcvclof6 3 1 02 71dodeca-2(7).3.5-trιen-10-yl)-2.2.2-trιfluoro- ethanone (Based on Campaigne, E , Thompson, W J Org Chem 1950, 72, 629 ) 1-(10-Aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-tπfluoro-ethanone (539 mg, 2 1 mmol) was stirred in CH2CI2 (5 mL) and treated with ICI3 (s) (982 mg, 4 21 mmol) The resulting orange solution was stirred 0 5 hours, poured into saturated aqueous NaHS03 solution (25 mL), extracted with CH2CI2 (3 x 25 mL), dried through a cotton plug and concentrated to an oil (570 mg, 84%) (TLC 50% ethyl acetate/hexanes Rf 0 62)
B) 4.5-dιchloro-10-azatπcvclo[6 3 1 02 7ldodeca-2(7).3.5-trιene hvdrochlonde 1-(4,5-Dιchloro-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-trιfluoro- ethanone (570 mg, 1 75 mmol) was stirred in methanol (25mL) and treated with Na2C03(s) (5 g, 47 mmol) in H20 (5 mL) The stirred mixture was warmed to 70°C for 4 hours, concentrated to solids, diluted with H20 and extracted with ethyl acetate (3 x 40 mL) The product was extracted into 1 aqueous HCl solution (2 x 40 mL) which was washed with ethyl acetate then neutralized with saturated aqueous Na2C03 solution to pH~10 Product was extracted with CH2CI2 (3 x 40 mL), filtered through a cotton plug and concentrated to an oil (400 mg, 100%) The oil was dissolved in methanol and treated with 3N HCl ethyl acetate (4 mL) and concentrated, then dissolved in a minimum of methanol and which was saturated with Et20 and stirred 18 hours The product was collected by filtration (210 mg, 45%) (TLC 50% ethyl acetate/hexanes (NH3) Rf 0 08) 1H NMR (400 MHz, DMSO-d6) δ 7 58 (s, 2H), 3 33-2 97 (m, 6H), 2 18 (m, 1 H), 1 99 (d, J = 10 5 Hz, 1 H) 13C NMR (100 MHz,DMSO-d6) 5 141 02, 130 60, 126 58, 45 54, 40 55, 38 30 GCMS m/e 227, 229 (M+) M p 283-291 °C
EXAMPLE 39
N4.N4-DIMETHYL-10-AZATRICYCLOf6 3 1 02 1-
DODECA-2(7).3.5-TRIENE-4-SULFONAMIDE HYDROCHLORIDE
A) 10-Trιfluoroacetyl-10-aza-trιcvclor6 3 1 02 7]dodeca-2(7),3,5-tπene-4-sulfonyl chloride
1-(10-Aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-trιfluoro-ethanone (530 mg, 2 1 mmol) was added to chlorosulfonic acid (2 mL, 30 mmol) and stirred for 5 minutes The mixture was quenched with ice, extracted with ethyl acetate, dried (Na2S04), filtered and concentrated to provide an oil (640 mg, 87%) (TLC 30% ethyl acetate/hexanes Rf 0 15)
B) N4,N4-Dιmethyl-10-azatπcvclor6 3 1 02 71dodeca-2(7),3,5-tπene-4-sulfonamιde hydrochloride
10-Trιfluoroacetyl-10-aza-tπcyclo[6 3 1 027]dodeca-2(7),3,5-tπene-4-sulfonyl chloride (320 mg, 0 9 mmol) was stirred in THF (10 mL) and treated with 40% Me2NH/H20 (1 5 mL) After 10 minutes the mixture was concentrated and chromatographed on Silica gel (TLC 30% ethyl acetate/hexanes Rf 0 31 ) to provide an oil (256 mg, 78%) This material was dissolved in methanol (6 mL) and NH4OH (2 mL) and stirred 18 hours The mixture was concentrated and azeotroped from methanol (3 times) The resulting oil was dissolved in methanol and treated with 3N HCl ethyl acetate (4 mL), concentrated, dissolved in a minimum of methanol and which was saturated with Et20 and stirred 18 hours The product was collected by filtration as a white powder (163 mg, 59%) (TLC 10% methanol/ CH2CI2 (NH3) Rf 0 54) 1H NMR (data, free base) (400 MHz, CDCI3) δ 7 64 (m, 2H), 7 41 (d, J = 8 0 Hz, 1 H), 3 30 (m, 2H), 3 20 (d, J = 12 5 Hz, 2H), 3 07 (dd, J = 12 5,2 2 Hz, 2H), 2 69 (s, 6H), 2 45, (m, 1 H), 2 00 (d, J = 11 0 Hz, 1H) 3C NMR (100 MHz, CDCI3) 5 128,43, 124 16, 122,75, 46 67 46 55, 42 11, 39,44, 37,81 GCMS m/e 266 (M+) (data HCl salt) 1H NMR (400 MHz, DMSO-d6) 5 7 68-7 52 (3H), 3 38 (m, 2H), 3 24 (m, 2H), 3 04 (m, 2H), 2 58 (s, 6H), 2 22 (m, 1 H), 2 04 (d, J = 11 0 Hz, 1 H) GCMS m/e 266 (M+) Anal Calcd for C13H18N202HCI C, 51 56, H, 6 32, N, 9 25 Found C, 51 36, H,6 09, N,9 09 EXAMPLE 40 4-(1-PYRROLIDINYLSULFONYL)-10-AZATRICYCLO[6 3 1 027l- DODECA-2(7).3.5-TRIENE HYDROCHLORIDE The pyrrohdine analogue was prepared from 10-trιfluoroacetyl-10-aza- trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene-4-sulfonyl chloride (320 mg, 0 9 mmol) as by substituting pyrro ne in the coupling step described in Example 39B The TFA product was isolated as an oil (314 mg, 89%) Deprotection and conversion to the salt as in Example 39B affords a white powder (189 mg, 63%) (TLC 10% methanol/CH2CI2 (NH3) Rf 0 60) (TLC 50% ethyl acetate/hexanes Rf 0 65) 1H NMR (400 MHz, CDCI3) δ 7 66 (d, J = 8 0 Hz, 1 H), 7 64 (s, 1 H), 7 37 (d, J = 8 0 Hz, 1 H), 3 30-3 15 (m, 8H), 3 00 (m 2H), 2 39 (m, 1 H), 1 98 (d, J = 11 5 Hz, 1 H), 1 72 (m, 4H) 13C NMR (100 MHz, CDCI3) 5 146 91 , 144 08, 136 65, 127 90, 124 18, 122 36, 50 43, 47 87, 46 80, 46 63, 42 11 , 39 63, 25 10 APCI MS m/e 293 [(M + 1 ) +] (data HCl salt) H NMR (400 MHz, DMSO-d6) δ 9 78 (br s, NH), 8 1 (br s, NH), 7 73 (d, J =1 5 Hz,1H), 7 66 (dd, J = 8 0,1 5 Hz, 1H), 7 53 (d, J = 8 0 Hz, 1 H), 3 39-3 01 (10H), 2 21 (m, 1H) 2 04 (d, J = 11 0 Hz, 1 H), 1 66 (m, 4H) GCMS m/e 292 (M+) Anal Calcd For C13H18N202HCI 1/2methanol C, 54 07, H, 6 47, N, 8 51 Found C, 53 98, H,6 72, N, 8 12
EXAMPLE 41 5.13-DIAZATETRACYCLOf9 3 1 02 10 0 81- PENTADECA-2.4(8).9-TRIEN-6-ONE HYDROCHLORIDE
(The title compound was prepared following the procedures described in Qualhch, G J , Morπssey, P M Synthesis 1993, 51-53, treating 4,5-dιnιtro-10-aza- trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-10-carboxyhc acid tert-butyl ester as an equivalent to an ortho fluoro phenyl moiety ) 1H NMR (400 MHz, DMSO-d6) δ 10 42 (s, NH), 9 88 (br s, NH), 7 52 (br s, 1 H), 7 15 (s, 1 H), 6 79 (s, 1 H), 3 41 (d, J = 5 0 Hz, 2H), 3 35-3 13 (m, 4H), 2 93 (m, 2H), 2 12 (m, 1 H), 1 95 (d, J = 11 5 Hz, 1 H) APCI MS m/e 215 2 [(M + 1 )+]
EXAMPLE 42 6-OXO-5-OXA-7.13-DIAZATETRACYCLOr9 3 1 02 10 048l- PENTADECA-2(10 .3.6.8-TETRAENE HYDROCHLORIDE
(For references, see Nachman, R J J Het Chem 1982, 1545 ) 2,2,2-Tπfluoro-1-(4- hydroxy-5-amιno-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-ethanone (317 mg, 1 11 mmol) was stirred in THF (10 mL), treated with carbonyldiimidazole (269 mg, 1 66 mmol) and warmed to 60°C for 18 hours The mixture was concentrated, diluted with CH2CI2 (50 mL) and washed with 1 N aqueous HCl solution (3 x 10 mL) The organic layer was dried through a cotton plug, concentrated and chromatographed on Silica gel (50% ethyl acetate/Hexanes) to provide an oil (130 mg) This material converted to the title compound by the methods described in Example 9C 1H NMR (400 MHz, DMSO-d6) δ 11 78 (s, NH), 9 56 (br s, NH), 7 63 (br s, NH), 7 24 (s, 1 H), 7 07 (s,1 H), 3 26 (br s, 2H), 3 16 (br t, J = 9 5 Hz, 1 H), 2 93 (br s, 1 H), 2 18 (171, 1 H), 1 97 (d, J = 11 0 Hz, 1 H) APCI MS m/e 217 2 [(M + 1)+]
EXAMPLE 43 6-BENZYL-5-OXA-7.13-DIAZATETRACYCLOr9 3 1 02 10 04 8l- PENTADECA-2(10).3.6.8-TETRAENE HYDROCHLORIDE 2,2,2-Trιfluoro-1-(4-hydroxy-5-amιno-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen- 10-yl)-ethanone and phenyl-acetyl chloride were converted to the title compound following the procedures described in Example 47 1H NMR (400 MHz, CD3OD) δ 7 63 (s, 1 H), 7 58 (s 1 H) 7 36-7 24 (5H), 4 29 (s, 2H), 3 46 (d, J = 2 5 Hz, 2H), 3 39 (d, J = 12 0 Hz, 2H), 3 18 (2H) 2 42 (m, 1 H), 2 15 (d, J = 11 5 Hz, 1 H) APCI MS m/e 291 2 [(M + 1)+]
EXAMPLE 44
3-PHENYL-10-AZA-TRICYCLOr6 3 1 02 7lDODECA-2(7).3.5-TRIENE HYDROCHLORIDE A) 5-Fluoro-1 ,4-dιhvdro-1 ,4-methano-naphthalene and 5-ιodo-1 ,4-dιhydro-1 ,4- methano-naphthalene
(Eisch, J J , Bur nson, N E J Amer Chem Soc 1976, 98, 753-761 Paquette, L A Cottrell, D M , Snow, R A J Amer Chem Soc 1977, 99, 3723-3733 )
Magnesium turnings (9 37 g, 385 mmol) were stirred in anhydrous THF (1000 mL) in a flame dried 2L 3 neck round bottom flask equipped with a non-equalizing addition funnel with a N2 flow adapter, magnetic stirrer and efficient condenser equipped with a N2 flow adapter The flask was stirred and warmed to reflux by a removable heating mantle 2,6- Difluoro-iodobenzene (0 3 g) was added followed by of 3N EtMgBr in THF (0 3 mL) The addition funnel was charged with an intimate mixture of cyclopentadiene (24 24 g, 367 mmol) and 2,6-dιfluoro-ιodobenzene (88 0 g, 367 mmol) Small portions (-1 mL) of the intimate mixture were introduced to assist initiation (-4 times) After -15 minutes, the reaction initiated (exotherm, and vapor condensation) and heating was maintained as necessary during the addition of the contents of the addition funnel The reaction was then maintained at reflux for -1 hour (no SM by GCMS)
The reaction was cooled to room temperature and quenched with H20 (200 mL) followed by aqueous 1 N HCl solution (200 mL) to dissolve the solids Product was extracted with hexanes (4 x 150 mL) The combined organic layer was washed with saturated aqueous NaHC03 solution (150 mL), dried (Na2S04), filtered through a Silica plug with hexanes rinse and concentrated to an oil (70 g) Chromatography on Silica gel eluting with hexanes provided two lots (9 0 and 21 0 g), which contained primarily 5-ιodo-1 ,4-dιhydro-1 4-methano- naphthalene (TLC hexanes Rf 0 63)
B) 5-lodo-1 ,2,3,4-tetrahvdro-1 ,4-methano-naphthalene-2,3-dιol 5-lodo-1 ,4-dιhydro-1 ,4-methano-naphthalene (20 g) and N-methyl morpholine N-oxide
(17 61 g, 130 mmol) were stirred in acetone (90 mL) and H20 (13 mL) To this was added a solution of Os04 (0 2 mL, 2 5%wt solution in t-butanol, 0 02 mmol) After 144 hours Floπsil (5 g) and saturated aqueous NaHS03 solution (3 mL) were added and stirred for 1/2 hour The mixture was filtered through a Celite pad and the filtrate concentrated to produce an oil which was purified by chromatography on Silica gel eluting with a gradient of hexanes to 100% ethyl acetate to provide a yellow solid (13 73 g) APCI MS m/e 301 1 [(M - 1 )+]
C) 10-Benzyl-3-ιodo-10-aza-trιcvclol6 3 1 02 7ldodeca-2(7),3,5-trιene 5-lodo-1,2,3,4-tetrahydro-1 ,4-methano-naphthalene-2,3-dιol (8 33 g, 27 6 mmol) and Et3NBnCI (10 mg) were vigorously stirred in dichloroethane (25 mL) and H20 (75 mL) then treated with sodium peπodate (6 17 g, 29 0 mmol) After 1 5 hours, the layers were separated and the aqueous layer extracted with DCE (2 x 40 mL) The combined organic layer was washed with H20 (4 x 30 mL) until no reaction to starch iodide paper was observed, then with saturated aqueous NaCI solution (30 mL) The organic layer was dried through a cotton plug and treated with benzyl amine (3 16 mL, 29 0 mmol) and stirred for 2 minutes then transferred to an addition funnel This solution was added over -10 minutes to a vigorously stirred cooled (0 °C) mixture of NaHB(OAc)3 (18 72 g, 88 0 mmol) in DCE (150 mL) After addition was complete, the mixture was stirred without cooling for 2 hours The mixture was quenched with saturated aqueous Na2C03 solution (100 mL) and stirred for 1 hour, then the layers were separated and the aqueous layer was extracted with CH2CI2 (3 x 50 mL) The combined organic layer was washed with saturated aqueous NaCI solution (50 mL), dried through a cotton plug and concentrated Chromatography on Silica gel provided an oil (6 3 g, 61%) (TLC 5% ethyl acetate/hexanes R, 0 10) 1H NMR (400 MHz, CDCI3) 5 7 61 (d, J = 8 0 Hz 1 H), 7 28-7 22 (m, 3H), 7 13 (d, J = 8 0 Hz,1 H), 6 98-6 94 (m, 3H), 3 58 (AB dd, J = 14 2 Hz, 2H), 3 26 (br s, 1 H), 3 21 (br s, 1 H), 3 04 (br d, J = 10 2 Hz, 1 H), 2 83 (br d, J = 10 2 Hz, 1 H), 2 47 (d, J = 10 0 Hz, 1H), 2 39 (d, J = 10 0 Hz, 1H), 2 34 (m, 1 H), 1 72 (d, J = 10 5 Hz, 1 H) APCI MS m/e 376 0 [(M + 1)+]
D) 10-Benzyl-3-phenyl-10-aza-trιcvclor6 3 1 02 7ldodeca-2(7),3,5-tnene
(For a discussion, see Miyaura, N , Suzuki, A Chem Rev 1995, 95, 2457-2483 ) 10-Benzyl-3-ιodo-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene (375 3 mg, 1 0 mmol) potassium acetate (785 mg, 8 0 mmol) and phenyl boronic acid (183 mg, 1 5 mmol) were combined in 10/1 ethanol/H20 (5 mL) The mixture was degassed (3 vacuum/N2 cycles) treated with tetrakιs(trιphenylphosphιne)palladιum(0) (57 5 mg, 0 05 mmol) and warmed to 90 °C for 18h The reaction was cooled, diluted with H20 and extracted with Et20 (3 x 50 mL) The organic layer was washed with brine (50 mL), dried (MgS0 ), filtered and concentrated to provide an oil (180 mg, 55%) (TLC 4%ethyl acetate/hexanes R, 0 18) GCMS m/e 325 (M)+
E) 3-Phenyl-10-aza-trιcvcloP6 3 1 02 71dodeca-2(7),3,5-trιene hydrochlonde 10-Benzyl-3-phenyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene was converted into the title compound utilizing the conditions described in Example 2D (TLC 10% methanol/CH2CI2 (NH3) R, 0 30) (data for free base) 1H NMR (400 MHz, CDCI3) δ 7 46-7 15 (8H), 3 17 (br s, 1 H), 3 01 (m, 2H), 2 93 (d, J = 13 0 Hz, 1 H), 2 72 (dd J = 10 5,2 5 Hz, 1 H) 2 63 (dd, J = 10 5,2 5 Hz, 1 H), 2 41 (m, 1 H), 1 91 (d, J = 10 5 Hz, 1 H) APCI MS m/e 236 2 [(M + 1)+] (HCl salt) M p 262-265 °C Anal Calcd for C17H17N HCl 1/3H20 C, 73 26, H, 6 86 N, 5 19 Found C, 73 50, H, 6 77, N, 5 04
EXAMPLE 45 3-HYDROXY-10-AZA-TRICYCLOf6 3 1 02 71DODECA-2(7).3.5-TRIENE HYDROCHLORIDE A) 10-Benzyl-3-boronιc acιd-10-aza-tπcvclof6 3 1 02 71dodeca-2(7) 3,5-trιene 10-Benzyl-3-ιodo-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-tπene (3 0 g, 7 99 mmol) was stirred in anhydrous THF (40 mL) at -78 °C under nitrogen and treated dropwise with n- BuLi (3 84 mL of 2 5M solution in hexanes, 9 59 mmol) After 10 minutes, tn-isopropylborate (4 61 mL, 20 0 mmol) was added dropwise After -1/2 hour, the reaction was poured into saturated aqueous NaHC03 solution, stirred 5 minutes and extracted with ethyl acetate (3 x 50 mL) and concentrated The residue was dissolved in 30% Et20/hexanes and extracted with 1 N NaOH aqueous solution (4 x 50 mL) The combined aqueous basic layer was treated with concentrated HCl to achieve pH 8 and extracted with ethyl acetate (4 x 25 mL), dried (Na2S04) and stripped Chromatography on Silica gel eluting first with 3% ethyl acetate/hexanes to remove non-polar components, then with 5% methanol/CH2CI2 provides the title compound (TLC 25% ethyl acetate/hexanes Rf 0 60) B) 10-Benzyl-3-hvdroxy-10-aza-trιcvclo[6 3 1 02 7ldodeca-2(7),3 5-tπene
10-Benzyl-3-boronιc acιd-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene (140 mg, 0 48 mmol) dissolved in THF (5 mL) was treated with N-methylmorpholine-N-oxide (64 5 mg 0 48 mmol) and brought to reflux for 1 hour The reaction was concentrated and chromatographed on Silica gel to provide product (TLC 25% ethyl acetate/hexanes Rf 0 18) H NMR (400 MHz, CDCI3) δ 7 18-7 15 (3H), 7 04 (dd, J = 8 0,7 0 Hz, 1 H), 6 95 (m, 2H), 6 75 (d, J = 7 0 Hz, 1 H), 6 59 (dd, J = 8 0,1 0 Hz, 1 H), 3 53 (br s, OH), 3 51 (AB d, J = 14 0 Hz, 2H), 3.28 (br s, 1 H), 3.06 (br s, 1 H), 2.91 (dd, J = 8.5,1.5 Hz, 1 H), 2.79 (ddd, J = 8.5,1.5,1 5 Hz, 1 H), 2.42 (d, J = 11.0 Hz, 1 H), 2.39 (d, J = 11.0 Hz, 1 H), 2.23 (m, 1 H), 1.65 (d, J = 10 5 Hz, 1 H). APCI MS m/e 266.5 [(M + 1 )+].
C) 3-Hvdroxy-10-aza-tricyclor6.3.1.02 7ldodeca-2(7),3,5-triene hydrochloride
10-Benzyl-3-hydroxy-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene (160 mg, 0 60 mmol) was converted into the title compound by the methods described in Example 1 D. 1H NMR (400 MHz, CDCI3) δ 7.15 (dd, J = 8.0,7.5 Hz, 1 H), 6.84 (d, J = 7.5 Hz, 1 H), 6.76 (d, J = 8.0 Hz, 1 H), 3.51 (br s, 1 H), 3.33-3.25 (3H), 3.16 (d, J = 12.0 Hz, 1 H), 3.09 (d, J = 12.0 Hz, 1 H), 2.29 (m, 1 H), 2.02 (d, J = 11.0 Hz, 1 H). APCI MS m/e 175.8 [(M + 1)*]. (HCl salt) M.p 253-255 °C.
EXAMPLE 46 4.5-DlFLUORO-10-AZA-TRICYCLO[6.3 1.02 7lDODECA-2(7).3,5-TRIENE HYDROCHLORIDE The title compound was prepared by the methods described in Examples 1 and 2 starting with 2,4,5-trifluorobromobenzene. 1H NMR (400 MHz, CDCI3) 5 7.31 (t, J = 8 5 Hz, 2H), 3.48-3.13 (6H), 2.38 (m, 1H), 2.11 (d, J = 11.5 Hz, 1 H). APCI MS m/e 196.2 [(M + 1 ) +] (HCl salt) M.p. 301-303 °C. Anal. Calcd. for CnH^FzN.HCI.I/ΘHzO: C, 56.30; H, 5.30; N, 5.97. Found C, 56.66; H, 5.41 ; N, 5.96.
EXAMPLE 47 6-ETHYL-5-OXA-7.13-DIAZATETRACYCLOr9.3.1.02 10.0 81- PENTADECA-2(10).3.6.8-TETRAENE HYDROCHLORIDE 2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trιen- 10-yl)-ethanone and propionyl chloride were converted to the title compound following the procedures described in Example 30 and Goldstein, S. W.; Dambek, P. J. J. Het. Chem 1990, 27, 335. 1H NMR (400 MHz, CD3OD) 5 7.64 (s, 1 H), 7.62 (s, 1 H), 3.48 (d, J = 2.5 Hz, 2H), 3.41 (d, J = 12.0 Hz, 2H), 3.20 (2H), 3.01 (q, J = 7.5 Hz, 2H), 2.45 (m, 1H), 2.17 (d, J = 11.5 Hz, 1 H), 1.42 (t, J = 7.5 Hz, 3H). APCI MS m/e 229.2 [(M + 1 )*]. EXAMPLE 48
6-ISOPROPYL-5-OXA-7.13-DIAZATETRACYCLOr9.3.1.02 10.04'8l-
PENTADECA-2M 0).3.6.8-TETRAENE HYDROCHLORIDE
2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.02'7]dodeca-2(7),3,5-trien-
10-yl)-ethanone and isobutyryl chloride were converted to the title compound following the procedures described in Example 47. (TLC 25% ethyl acetate/hexanes Rf 0.14). 1H NMR
(400 MHz, CD3OD) 5 7.65 (2H), 3.49 (br s, 2H), 3.41 (d, J = 12.0 Hz, 2H), 3.33-3.19 (3H), 2.45 (m, 1 H), 2 18 (d, J = 11 5 Hz, 1 H), 1 45 (d, J = 7 0 Hz, 6H) APCI MS m/e 243 2 [(M + 1 )+] (HCl salt) M p 249-251 °C
EXAMPLE 49 5.14-DIAZATETRACYCLθπθ 3 1 02 11 0 91HEXADECA- 2(1 D.3.5.7.9-PENTAENE HYDROCHLORIDE
A) 1-(5.14-DιazatetracvcloM0 3 1 02 11 04 9lhexadeca-2(11).3.5.7.9-pentaen-10-vD- 2.2,2-trιfluoro-ethanone (Based on the method of Campbell. K N , Schaffner, I J J Am Chem Soc 1945. 67, 86 )
1-(4-Amιno-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπen-10-yl)-2,2,2-tπfluoro- ethanone (607 mg, 1 98 mmol) was dissolved in 95% ethanol/H20 (5 mL) and treated with FeCI3 6H20 (800 mg, 2 97 mmol), ZnCI2 (27 mg, 0 20 mmol) in ethanol (2 mL) The mixture was warmed to 65 °C for 15 mm , treated with acrolein (0 2 mL, 2 97 mmol) and warmed to reflux for 2 5 hours The mixture was judged complete by TLC, cooled and quenched into saturated aqueous NaHC03 solution (40 mL) The mixture (pH 8 5) was extracted with CH2CI2 (8 x 30 mL) The organic layer was washed with H20 and saturated aqueous NaCI solution then dried through a cotton plug Concentration afforded a dark oil which was chromatographed on Silica gel to provide a yellow oil (105 mg, 17%) (TLC 50% ethyl acetate/hexanes Rf 0 08)
B) 5,14-Dιazatetracyclo[10 3 1 02 11 04 9lhexadeca-2(11 ).3.5.7.9-pentaene hydrochloride
1-(5,14-Dιazatetracyclo[10 3 1 02 11 0 9]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2 2- tπfluoro-ethanone (94 7 mg, 0 31 mmol) was converted to the title compound using methods described in Example 7 to provide a crystalline solid (36 9 mg) 1H NMR (400 MHz, CD3OD) δ 9 19 (m, 2H), 8 33 (s, 1 H), 8 27 (s, 1 H), 8 10 (dd, J = 8 3, 5 6 Hz, 1 H), 3 78 (br s, 1 H), 3 74 (br s, 1 H), 3 58 (br d, J = 11 4 Hz, 2H), 3 40 (M, 2H), 2 50 (m, 1 H), 2 34 (d, J = 11 6 Hz, 1 H) APCI MS m/e 210 9 [(M + 1)*], M p 260 °C (dec ), Anal Calcd for C14H14N2 2HCI C, 59 38, H, 5 69, N, 9 89 Found C, 59 69, H, 5 82, N, 9 79
EXAMPLE 50 6-METHYL-5.14-DIAZATETRACYCLOM0 3 1 02 11 0491HEXADECA- 2(1 D.3.5.7.9-PENTAENE HYDROCHLORIDE
A) 1-((6-Methyl-5.14-dιazatetracvclof10 3 1 02 11 0491hexadeca-2(11 ).3.5.7.9-pentaen- 10-yl)-2,2,2-trιfluoro-ethanone
Following the method described in Example 49A, 1-(4-Amιno-10-aza- trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-trιfluoro-ethanone (686 mg, 2 00 mmol) was reacted with (E)-2-butenal (0 2 mL, 2 97 mmol) to provide a yellow oil (335 6 mg, 52%) (TLC 75% ethyl acetate/hexanes Rf 0 25)
B) 6-Methyl-5.14-dιazatetracvclof10 3 1 02 11 04 9lhexadeca-2(11 ).3.5.7.9-pentaene hydrochloπde 1-(6-Methyl-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,5,7,9-pentaen-10- yl)-2,2,2-tπfluoro-ethanone (308 mg, 0 96 mmol) was converted to the title compound using methods described in Example 7 to provide a crystalline solid (186 mg) 1H NMR (400 MHz, CD3OD) δ 9 00 (d, J = 8 5 Hz, 1 H), 8 25 (s, 1 H), 8 17 (s, 1 H), 7 94 (d, J = 8 5 Hz, 1 H), 3 76 (br s, 1 H), 3 71 (br s, 1 H), 3 57 (br d, J = 11 8 Hz, 2H), 3 38 (M, 2H), 3 01 (s, 3H), 2 49 (m, 1 H), 2 32 (d, J = 11 6 Hz, 1 H) APCI MS m/e 225 2 [(M + 1 )*], M p >300 °C (dec ), Anal Calcd for C15H16N2 2HCI 1/2H20 C, 58 83, H, 6 25, N, 9 15 Found C, 58 49, H, 6 22, N, 9 02
EXAMPLE 51 7-METHYL-5.14-DIAZATETRACYCLOM0 3 1 02 11 0 91HEXADECA- 2(1 D.3.5.7.9-PENTAENE HYDROCHLORIDE A) 1-(7-Methyl-5.14-dιazatetracvcloπθ 3 1 02 11 049lhexadeca-2(11).3.5.7 9-pentaen-
10-yl)-2,2,2-trιfluoro-ethanone
Following the method described in Example 49A, 1-(4-Amιno-10-aza- trιcyclo[6 3 1 027]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-trιfluoro-ethanone (686 mg, 2 00 mmol) was reacted with 2-methylpropenal (0 25 mL, 3 00 mmol) to provide a yellow oil (94 mg, 15%) (TLC 10% methanol/CH2CI2 R, 0 16)
B) 7-Methyl-5.14-dιazatetracvcloM0 3 1 02 11 0 9lhexadeca-2(11 ).3,5.7.9-pentaene hydrochlonde
1-(7-Methyl-5,14-dιazatetracyclo[10 3 1 02 11 0 9]hexadeca-2(11),3,5,7,9-pentaen-10- yl)-2,2,2-tπfluoro-ethanone (86 mg, 0 27 mmol) was converted to the title compound using methods described in Example 7 to provide a crystalline solid (12 6 mg) 1H NMR (400 MHz, CD3OD) 5 9 10 (s, 1 H), 9 00 (s, 1 H), 8.22 (s, 1 H), 8 20 (s, 1 H), 3 76 (br s, 1 H), 3 72 (br s, 1 H), 3 57 (br d, J = 11 5 Hz, 2H), 3 39 (M, 2H), 2 71 (s, 3H), 2 48 (m, 1 H), 2 32 (d, J = 11 6 Hz, 1 H) APCI MS m/e 225 0 [(M + 1)+]
EXAMPLE 52 7-ETHYL-5.14-DIAZATETRACYCLOM0 3 1 02 11 0491HEXADECA-
2(1 P.3.5.7.9-PENTAENE HYDROCHLORIDE A) 1-(7-Ethyl-5.14-dιazatetracvclof10 3 1 02 11 0 9lhexadeca-2(11).3.5.7.9-pentaen- 10-yl)-2,2,2-trιfluoro-ethanone
Following the method described in Example 49A, 1-(4-Amιno-10-aza- trιcyclo[6 3 1 027]dodeca-2(7),3,5-tπen-10-yl)-2,2,2-trιfluoro-ethanone (686 mg, 2 00 mmol) was reacted with 2-ethylpropenal (0 35 mL, 3 60 mmol) to provide a yellow oil (110 mg, 16%) (TLC 75% ethyl acetate/hexanes Rf 0 32)
B) 7-Ethyl-5,14-dιazatetracvcloM0 3 1 02 11 04 9lhexadeca-2(11 ),3.5.7.9-pentaene hvdrochloπde 1-(7-Ethyl-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11),3,5 7,9-pentaen-10- yl)-2,2,2-tπfluoro-ethanone (94 mg, 0 28 mmol) was converted to the title compound using methods described in Example 7 to provide a crystalline solid (33 mg) H NMR (400 MHz, CD3OD) 5 9 12 (s, 1H), 9 00 (s, 1 H), 8 23 (s, 1H), 8 18 (s, 1H), 3 76 (br s, 1 H), 3 72 (br s, 1 H) 3 56 (br d, J = 11 5 Hz, 2H), 3 37 (M, 2H), 3 05 (q, J = 7 5 Hz, 2H), 2 48 (m, 1 H), 2 32 (d, J = 11 6 Hz, 1 H), 1 44 (t, J = 7 5 Hz, 3H) APCI MS m/e 239 1 [(M + 1)+], M p 288-291 °C (dec ) Anal Calcd for C16H18N2 2HCI H20 C, 58 36, H, 6 73, N, 8 51 Found C 57 98, H, 5 99 N 8 41
EXAMPLE 53 8-METHYL-5.14-DIAZATETRACYCLOH0 3 1 02 11 04 91HEXADECA- 2(11 .5.7.9-PENTAENE HYDROCHLORIDE
A) 1-(8-Methyl-5.14-dιazatetracvcloπ0 3 1 02 11 049lhexadeca-2(11 .3.5.7.9-pentaen- 10-yl)-2,2,2-trιfluoro-ethanone
Following the method described in Example 49A, 1-(4-Amιno-10-aza- trιcyclo[6 3 1 027]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-tπfluoro-ethanone (775 mg, 2 52 mmol) was reacted with 1-buten-3-one (0 32 mL, 3 79 mmol) to provide a yellow oil (424 mg, 52%) (TLC 50% ethyl acetate/hexanes Rf 0 08)
B) 8-Methyl-5.14-dιazatetracvcloM0 3 1 02 11 049lhexadeca-2(11 ).3.5.7.9-pentaene hvdrochloπde
1-(8-Methyl-5,14-dιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11), 3,5,7, 9-pentaen-10- yl)-2,2,2-trιfluoro-ethanone (403 mg, 1 26 mmol) was converted to the title compound using methods described in Example 7 to provide a crystalline solid (266 mg) 1H NMR (400 MHz CD3OD) δ 9 01 (d, J = 5 6 Hz, 1 H), 849 (s, 1H), 8 22 (s, 1H), 7 97 (d, J = 5 6 Hz, 1 H), 3 76 (br m, 2H), 3 58 (br d, J = 11 5 Hz, 2H), 3 40 (m, 2H), 3 06 (s, 3H), 2 48 (m, 1 H), 2 33 (d, J =11 6 Hz, 1 H) Anal Calcd for C15H16N2 2HCI H20 C, 57 15, H, 6 39, N, 8 89 Found C, 57 43, H 6 44, N, 8 82 EXAMPLE 54 5.14-DIAZATETRACYCLOMO 3 1 02 11 04 91HEXADECA- 2(11 ),3,7,9-TETRAEN-6-ONE HYDROCHLORIDE A) 3,3-Dιmethoxypropanoιc acid lithium salt (Related to methods described in Alabaster, C T et al , J Med Chem 1988 31
2048-2056 ) 3,3-Dιmethoxypropanoιc acid methyl ester (14 25 g, 96 2 mmol) in THF (100 mL) was treated with LiOH H20 (2 5 g, 106 mmol) and H20 (2 mL) The mixture was brought to reflux for 4 hours, cooled to room temperature and azeotropically dried from THF (4 times) to provide white solids (13 3 g) B) 1-(4-(N-3',3'-Dιmethoxy-propιonamιde)-10-aza-tπcyclof6 3 1 02 7ldodeca-2(7),3,5- tπen-10-yl)-2,2,2-trιfluoro-ethanone
3,3-Dιmethoxypropanoιc acid lithium salt (840 mg, 6 0 mmol) in THF (15 mL) was treated with trifluoroacetic anhydride (0 85 mL 6 0 mmol) dropwise and stirred for 15 minutes The resulting yellow solution was added dropwise to a vigorously stirred mixture of 1-(4- amιno-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-tπfluoro-ethanone (540 mg 2 mmol) in THF (5 mL) and saturated aqueous NaHC03 solution (2 mL) After 3 hours the reaction mixture was diluted with H20 and extracted with ethyl acetate (3 times) The organic layer was washed with brine, dried over Na2S04, filtered and concentrated to an oil which was purified by chromatography on Silica gel to provide a white solid (477 mg, 62%) (TLC 50% ethyl acetate/hexanes Rf 0 37)
C) 1-(5.14-Dιazatetracvclo[10 3 1 02 11 049lhexadeca-2(11),3.7.9-tetraen-6-one-10-yl)- 2.2,2-trιfluoro-ethanone
1-(4-(N-3',3'-Dιmethoxy-propιonamιde)-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3 5-trιen- 10-yl)-2,2,2-trιfluoro-ethanone (460 mg, 1 19 mmol) was treated with trifluoroacetic acid (4mL) and stirred 18 hours, concentrated, diluted with CH2CI2 and H20 The aqueous layer was extracted with CH2CI2 (4 times) and the organic layer was washed with saturated aqueous NaHC03 solution (40 mL) and saturated aqueous NaCI solution then dried through a cotton plug Concentration afforded a yellow solid (320 mg, 83%)
D) 5.14-DιazatetracvcloMO 3 1 02 11 0491hexadeca-2(11).3.7.9-tetraen-6-one hydrochlonde
1-(5,14-Dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,7,9-tetraen-6-one-10-yl)- 2,2,2-trιfluoro-ethanone (540 mg, 2 mmol) was converted to the title compound using methods described in Example 7 to provide the title compound a pink crystalline solid (72 mg, 71%) 1H NMR (400 MHz, CD3OD) 5 8 42 (d, J = 8 8 Hz, 1 H), 7 90 (s, 1H), 7 66 (s, 1 H), 6 98 (d, J = 8 8 Hz, 1H), 3 59 (br s, 1H), 3 56 (br s, 1H), 3 49 (dd, J = 12 4, 5 8 Hz, 2H), 3 29 (m, 2H), 2 42 (m 1 H), 2 23 (d, J = 11 6 Hz, 1 H) APCI MS m/e 227 [(M + 1 )+], M p 300 °C (dec ), Anal Calcd for C14H14N20 2HCI C, 56 20, H, 5 39, N, 9 36 Found C, 56 40, H, 5 63, N, 9 25
EXAMPLE 55 6-CHLORO-5.14-DIAZATETRACYCLθπ0 3 1 02 11 04 91HEXADECA-
2( 1 .5.7.9-PENTAENE HYDROCHLORIDE
A) 1-(6-Chloro-5.14 ^-ddιazatetracvclof10 3 1 02 11 0491hexadeca-2M 1).3.5.7.9-pentaen 10-yl)-2.2.2-tnfluoro-ethanone
1-(5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,7,9-tetraen-6-one-10-yl)- 2,2,2-trιfluoro-ethanone (156 mg, 0 49 mmol) was treated with POCI3 (5 mL) and warmed to 100 °C with stirring for 3 hours After concentration in vacuo, the residue was diluted with CH2CI2 (15 mL) and carefully treated with saturated NaHC03 solution (10 mL) with stirring Once C02 evolution slowed the mixture was separated and the aqueous layer extracted CH2CI2 (3 times) The organic layer was washed with H20 and saturated NaCI solution, filtered through cotton and concentrated to a brown oil (217 mg, 93%) (TLC ethyl acetate, Rf 0 3) 1H NMR (400 MHz, 2HCCI3) δ 8 03 (d, J = 8 5 Hz, 1 H), 7 83 (s, 1 H), 7 62 (s, 1 H), 7 35 (d, J = 8 5 Hz, 1 H), 4 43 (m, 1 H), 4 01 (m, 1 H), 3 62 (m, 1 H), 3 29 (m, 2H), 3 23 (m, 1 H), 2 45 (m, 1 H), 2 10 (d, J = 11 6 Hz, 1H) APCI MS m/e 341 1 [(M + 1)+]
B) 6-Chloro-5,14-dιazatetracvcloM0 3 1 02 11 049lhexadeca-2(11 ),3,5,7,9-pentaene hvdrochloπde 1-(6-Chloro-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,5,7,9-pentaen-10- yl)-2,2,2-trιfluoro-ethanone (26 mg, 0 076 mmol) was converted to the title compound using methods described in Example 7 to provide the title compound a solid (5 8 mg, 24%) 1H NMR (free base, 400 MHz, 2HCCI3) δ 8 01 (d, J = 8 5 Hz, 1 H), 7 77 (s, 1 H), 7 57 (s, 1 H), 7 30 (d, J = 8 5 Hz, 1 H), 3 28 (br s, 1 H), 3 24 (br s, 1 H), 3 12 (br d, J = 12 5 Hz, 2H), 2 96 (br d, J = 12 5 Hz, 2H), 2 41 (m, 1 H), 2 02 (d, J = 11 6 Hz, 1 H) APCI MS m/e 245 1 [(M + 1 )+]
EXAMPLE 56 6-METHOXY-5.14-DIAZATETRACYCLOH0 3 1 02 11 0491HEXADECA- 2(1 D.3.5.7.9-PENTAENE HYDROCHLORIDE A) 6-Chloro-5.14-dιazatetracvclof10 3 1 02 11 049lhexadeca-2(11 ).3.5.7.9-pentaen-10- carboxyhc acid tert-butyl ester
6-Chloro-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,5,7,9-pentaene (2 82 g, 11 53 mmol) was converted into the title compound as described in Example 12 A to provide a brown oil (3 55 g, 89%) (TLC 5% methanol/CH2CI2, R, 0 37) B) 6-Methoxy-5,14-dιazatetracvcloπ0 3 1 02 11 049lhexadeca-2(11 ),3,5,7.9-pentaen- 10-carboxyhc acid tert-butyl ester
Sodium metal (-12 mg) was dissolved in methanol (1 mL) under nitrogen with stirring and treated with a solution of 6-chloro-5,14-dιazatetracyclo[10 3 1 02 11 04 9]hexadeca- 2(11),3,5,7,9-pentaen-10-carboxyhc acid tert-butyl ester (118 mg, 0 33 mmol) in methanol (3 mL) and brought to reflux for 18 hours The mixture was cooled, concentrated, treated with H20 and extracted with CH2CI2 The organic layer was washed with saturated NaCI solution and filtered through a cotton plug then concentrated to an oil (165 mg) (TLC 5% methanol/CH2CI2 Rf 0 55) C) 6-Methoxy-5,14-dιazatetracvcloπ0 3 1 02 11 049lhexadeca-2(11 ),3,5,7.9-pentaene hvdrochlonde
6-Methoxy-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11), 3,5,7, 9-pentaen-10- carboxylic acid tert-butyl ester (138 mg, 0 41 mmol) was dissolved in trifluoroacetic acid (4 mL) brought to reflux for 4 hours The mixture was cooled and concentrated to an oil which was dissolved in ethyl acetate and treated with 3N HCI/ethyl acetate (1 mL) After concentration the residue was recrystallized from methanol/diethyl ether to provide a beige solid (51 mg, 26%) 1H NMR (400 MHz, CD3OD) δ 8 77 (d, J = 9 5 Hz, 1 H), 8 01 (s 1 H) 7 90 (s, 1H), 7 54 (d, J = 9 5 Hz, 1 H), 4 30 (s, 3H), 3 65 (br s, 1H), 3 61 (br s, 1H), 3 50 (dd J = 12 4, 3 8 Hz, 2H), 3 29 (m, 2H), 2 44 (m, 1 H), 2 24 (d, J = 11 6 Hz, 1 H) APCI MS m/e 241 2 [(M + 1)+] M p 240, (darkens), 275 °C (dec ), (TLC 10% methanol (NH3)/CH2CI2, Rf 0 38)
EXAMPLE 57 6-CHLORO-10-FLUORO-5.14-DIAZATETRACYCLOf10 3 1 02 11 04 91HEXADECA- 2(1 D.3.5.7.9-PENTAENE HYDROCHLORIDE A) 1-(6-Chloro-10-fluoro-5.14-dιazatetracvcloπθ 3 1 02 1 04 9lhexadeca-2(1 1 ).3.5.7, 9- pentaen-10-yl)-2,2,2-trιfluoro-ethanone
3-Fluoro-10-aza-trιcyclo[6 3 1 027]-dodeca-2(7),3,5-trιene was converted to 1-(3- Fluoro-10-aza-tπcyclo[6 3 1 02 7]-dodeca-2(7),3,5-trιen-10-yl)-2,2,2-trιfluoro-ethanone by the methods described in Example 7A This product was nitrated as described in Example 7B The resulting mixture of nitrated products was reduced as described in Example 8 then converted to a chloroquinohne as described in Examples 54 and 55 These products were separated by column chromatography on silica gel to provide the title compound (TLC 50% ethyl acetate/hexanes , Rt 0 50) B) 6-Chloro-10-fluoro-5.14-dιazatetracvcloπθ 3 1 02 11 0491hexadeca-2(1 D.3.5.7.9- pentaene hydrochloπde
1-(6-Chloro-10-fluoro-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,5,7,9- pentaen-10-yl)-2,2,2-tπfluoro-ethanone was converted to 6-chloro-10-fluoro-5, 14- dιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11),3,5,7,9-pentaene by methods described in Example 7C 1H NMR (400 MHz, CDCI3) δ 8 03 (dd, J = 8 5, 1 5 Hz, 1 H) 7 36 (d, J = 8 5 Hz, 1 H), 7 24 (s, 1 H), 3 52 (br s, 1 H), 3 16 (br s, 1 H), 3 11 (dd, J = 12 8, 1 6 Hz, 2H), 2 97 (ddd, J = 12 8, 2 5, 2 5 Hz, 1 H), 2 85 (ddd, J = 12 8, 2 5, 2 5 Hz, 1 H), 2 46 (m, 1 H), 2 06 (d, J = 10 8 Hz, H) El MS m/e 263 [M+] This material was converted to the title compound as described in Example 7C
EXAMPLE 58 5.8.14-TRIAZATETRACYCLOMO 3 1 02 11 0491HEXADECA- 2(1 D.3.7.9-TETRAEN-6-ONE HYDROCHLORIDE
A) 1-(5.8.14- ■TTrriιaazzatetracvcloπ 0 3 1 02 11 049lhexadeca-2(11 .3.7.9-tetraen-6-on-10- yl)-2.2,2-tπfluoro-ethanone
1-(4,5-Dιamιno-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-10-yl)-2,2,2-tπfluoro- ethanone (536 mg, 1 88 mmol) was stirred in ethanol (4 ml) This mixture was treated with methyl-2-hydroxyl-2-methoxy acetate (0 203 mL, 2 07 mmol) and stirred at 70 °C for 2 5 hours The reaction was cooled to room temperature and concentrated Tπturation with methanol and filtration provided light yellow solids (337mg, 55%) (TLC 10% methanol/CH2CI2 Rf 0 57)
B) 5,8,14-Trιazatetracvclo[10 3 1 02 11 049lhexadeca-2(11 ).3.7,9-tetraen-6-one hydrochloπde
1-(5,8,14-Trιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11),3,7 9-tetraen-6-on-10-yl)- 2,2,2-tπfluoro-ethanone (145 mg, 0 45 mmol) was converted to the title compound by the methods described in Example 7C to provide a brown solid (26 mg, 46%) 1H NMR (400 MHz, D20) δ 7 94 (s, 1 H), 7 58 (s, 1 H), 7 18 (s, 1 H), 3 39 (br s, 2H), 3 28 (br d, J = 12 5 Hz, 1 H), 3 12 (br d, J = 12 5 Hz, 1 H), 2 29 (m, 1 H), 1 99 (d, J = 12 0 Hz, 1 H) APCI MS m/e 228 2 [(M + 1)+], M p 296, (darkens), 310 °C (dec ), (TLC 10% CH2CI2/methanol(NH3), Rf 0 10) EXAMPLE 59
10-AZA-TRICYCLQ[6 3 1 027lDODECA-2(7).3,5-TRIENE TOSYLATE A) 3-Λ/-Benzyl-2,3,4.5-tetrahydro-1 ,5-methano-1/-/-3-benzazepιne A stream of ozone was bubbled through a solution of 4 00 g of benzonorbornadiene (1 ,4-dιhydro-1 ,4-methanonaphthalene) (28 1 mmol, 1 0 equivalent) in 80 mL of methanol at -78 °C Once the solution developed a blue color, ozone generation was stopped after another few minutes and then oxygen was bubbled through for five minutes to dispel the blue color Then the solution was purged with nitrogen for 20 to 40 minutes to deoxygenate the solution To the cold solution was added 0 199 g of 5% platinum on carbon, 55% wet by weight, ( 0281 mmol, 0 001 equivalent) The system was passivated with hydrogen, pressurized to 40 psi of hydrogen, and gradually warmed to room temperature Once the ozonide was reduced completely (within 45-60 minutes), an additional 0 798 g of 5% platinum on carbon (0 112 mmol, 0 004 equivalent) was added to the reaction mixture at 0 °C, followed by 3 07 mL of benzylamine (28 1 mmol, 1 0 equivalent) and 0 561 mL of 96% formic acid (14 0 mmol, 0 50 equivalent) The system was repressuπzed to 50 psi of hydrogen and allowed to warm to room temperature After 4 hours, the reaction mixture was removed from the reactor and filtered through a pad of Celite, washing with 20 mL of methanol This reaction mixture was used in the next step (Example 59B), but isolation of the intermediate was carried out as follows the filtrate was concentrated in vacuo and partitioned between 40 mL of methylene chloride and 30 mL of a saturated aqueous solution of sodium carbonate, the aqueous layer was extracted with another 30 mL of methylene chloride, the combined organic layers were dried over anhydrous sodium sulfate and concentrated, the residue was dissolved in 10 mL of 9 1 hexane/ethyl acetate and passed through a plug of silica gel, and after concentrating the filtrate, the title compound was obtained as an oil (3 34 g, 48%) 1H NMR (400 MHz, CD3OD) 5 7 22-7 19 (m, 7H), 6 93 (d, J = 8 0 Hz, 2H), 3 52 (s, 2H), 3 13-3 11 (m, 2H), 2 85 (d, J = 9 5 Hz, 2H), 2 47 (d, J = 9 5 Hz, 2H), 2 32-2 29 (m, 1 H), 1 71 (d, J = 10 0 Hz, 1 H)
B) 2,3,4,5-Tetrahvdro-1 ,5-methano-1 /-/-3-benzazepine tosylate A pressure reactor was charged with the crude 3-Λ/-benzyl-2,3,4,5-tetrahydro-1 ,5- methano-1H-3-benzazepιne (from Example 59A prior to workup) in 100 mL of methanol To the reaction mixture was added 3 74 g of p-toluenesulfonic acid monohydrate (19 7 mmol, 0 7 equivalent) and 0 986 g of 20% palladium hydroxide on carbon, 50% wet by weight (0 703 mmol, 0 025 equivalent) The reactor was pressurized to 50 psi of hydrogen and heated to 40 °C After heating for 15 hours the reactor was cooled to room temperature The reaction mixture was filtered through Celite, washing with methanol The filtrate was concentrated in vacuo and stripped down from 20 mL of isopropanol The residue was redissolved in 32 mL of isopropanol and heated to 70 °C To the hot solution was added 16 mL of hexane and the resulting solution was allowed to slowly cool with stirring Crystals formed and were stirred at room temperature for 12 hours The white crystals were filtered and dried to give 2 65 g (28%) of the tosylate salt of 2,3,4,5-tetrahydro-1,5-methano-1H-3-benzazepιne tosylate, mp 207-208 °C, 1H NMR (400 MHz, CD3OD) δ 7 69 (d, J = 7 9 Hz, 2H), 7 43-7 32 (m, 4H), 7 23 (d, J = 7 9 Hz, 2H), 3 37 (d, J = 11 2 Hz, 4H), 3 30 (bs, 2H), 3 15 (d, J = 12 4 Hz, 2H), 2 36 (s 3H), 2 40-2 35 (m, 1 H), 2 08 (d, J = 11 2 Hz, 1 H), 13C NMR (100 MHz, CD3OD) δ 140 8 140 5, 139 1 , 127 2, 127 2, 124 3, 122 3, 45 1 , 39 7, 37 3, 18 7, IR (KBr, cm"1) 3438, 3021 , 2958, 2822, 2758, 2719, 2683, 2611 , 2424, 1925, 1606, 1497, 1473, 1428, 1339, 1302, 1259, 1228, 1219, 1176, 1160, 1137, 1122, 1087, 1078, 945, 914, 876, 847, 829, 818, 801 , 710, 492, Anal Calcd for d8H21N03S C, 65 23, H, 6 39, N, 4 23, Found C, 65 05, H, 6 48 N 4 26
EXAMPLE 60 10-AZA-TRICYCLOf6 3 1 02 71DODECA-2(7 .3.5-TRIENE TOSYLATE
A) 3-Oxo-ιndan-1 -carboxyhc acid methyl ester A solution of 10 0 g of 3-oxo-ιndan-1 -carboxyhc acid (56 8 mmol, 1 0 equivalent) and
0 25 mL of concentrated sulfunc acid in 20 mL of methanol was heated to a reflux for 4 hours The reaction mixture was then cooled to room temperature and diluted with 100 mL of methyl- fert-butyl alcohol The organic solution was washed twice with 60 mL of a saturated aqueous sodium bicarbonate solution, and once with 50 mL of a saturated aqueous sodium chloride solution The organic layer was dried over anhydrous sodium sulfate and concentrated The title compound crystallized as a white solid upon concentration, (10 4 g, 96%), mp 46-47 °C, 1H NMR (400 MHz, CDCI3) δ 7 74 (d, J = 7 6 Hz, 1 H), 7 68 (d, J = 7 6 Hz, 1 H), 7 62 (t, J = 7 6 Hz, 1H), 7 44 (t, J = 7 6 Hz, 1 H), 4 29 (dd, J = 8 0, 3 4 Hz, 1 H), 3 76 (s, 3H), 3 13 (dd, J = 19 1 , 3 4 Hz, 1 H), 2 86 (dd, J = 19 1 , 8 0 Hz, 1 H), 13C NMR (100 MHz, CD3OD) δ 204 4 172 5, 151 3, 136 5, 135 2, 129 1 , 126 7, 124 1 , 52 9, 43 8, 39 7, IR (neat, cm"1) 2954, 1710, 1602, 1462, 1435, 1403, 1319, 1241 , 1206, 1168, 1092, 1044, 1014, 986, 881 , 837, 760, 686, 580, 538
B) 3-Cvano-3-trιmethylsιlanyloxy-ιndan-1 -carboxyhc acid methyl ester
To a solution of 3 80 g of 3-oxo-ιndan-1 -carboxyhc acid methyl ester (20 0 mmol, 1 equivalent) in 6 mL of toluene and 2 mL of acetonitrile was added 192 mg of zinc iodide (0 600 mmol, 0 03 equivalent) followed by 3 47 mL of tπmethylsilyl cyanide (26 0 mmol, 1 3 equivalent) The reaction mixture was heated to 50 °C for 5 hours The reaction mixture was then cooled to room temperature and diluted with 12 mL of toluene and 8 mL of a saturated aqueous sodium bicarbonate solution After stirring the mixture for 1 hour the layers were separated The organic layer was washed with another 8 mL of a saturated aqueous sodium bicarbonate solution followed by 8 mL of a saturated aqueous sodium chloride solution The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give 3- cyano-3-trιmethylsιlanyloxy-ιndan-1 -carboxyhc acid methyl ester as an oil (5 61 g, 97%) The silylated cyanohydnn title compound was obtained as a mixture of two diastereomers in a 2 1 ratio 1H NMR (400 MHz, CDCI3) (major isomer) 5 7 54-7 50 (m, 1H), 7 42-7 38 (m, 3H), 4 14 (t, J = 7 7 Hz, 1 H), 3 78 (s, 3H), 3 01 (dd, J = 13 3, 7 5 Hz, 1 H), 2 79 (dd, J = 13 3, 7 5 Hz 1 H), 0 26 (s, 9H), (minor isomer) δ 7 59-7 55 (m, 1 H), 7 48-7 44 (m, 3H), 4 29 (t, J = 7 5 Hz, 1 H), 3 78 (s, 3H), 3 03 (dd, J = 13 7, 7 5 Hz, 1 H), 2 70 (dd, J = 13 7, 7 5 Hz, 1 H), 0 14 (s 9H), 3C NMR (100 MHz, CDCI3) (unassigned) δ 172 3, 172 0, 142 3, 142 1 , 140 1 , 138 8, 130 8, 130 5, 129 1 , 128 9, 125 8, 125 6, 124 7, 124 3, 120 8, 120 6, 75 4, 75 3, 52 7, 52 7 47 4 46 8, 45 6, 45 3, 1 4, 1 3, IR (neat, cm"1) 2956, 1739, 1477, 1436, 1253, 1197 1169 1135 1092, 1033, 1011 , 880, 843, 756, 623, Anal Calcd for C15H119N03Sι C, 62 25 H, 6 62, N, 4 84, Found C, 62 20, H, 6 53, N, 4 92
C) 3-Amιnomethyl-ιndan-1 -carboxyhc acid methyl ester To a solution of 5 79 g of 3-cyano-3-tnmethylsιlanyloxy-ιndan-1 -carboxyhc acid methyl ester (20 0 mmol, 1 0 equivalent) in 25 mL of methanol was added 5 71 g of p-toiuenesulfonic acid monohydrate (30 0 mmol, 1 5 equivalent) The solution was stirred for 15 minutes and then 4 21 g of 20% palladium hydroxide on carbon, 50% wet by weight, (3 00 mmol, 0 15 equivalent) was added The reaction mixture was subjected to hydrogenolysis at 50 psi of hydrogen over 24 hours After this time, the reaction mixture was filtered through Celite and typically used filtrate in the next step (Example 60D) The isolation of the title compound was conducted as follows the filtrate was concentrated in vacuo, the residue was partitioned between 30 mL of methylene chloride and 20 mL of a saturated aqueous solution of sodium carbonate, the aqueous layer was extracted with 15 mL of methylene chloride, the combined aqueous layers were washed with 40 mL of a saturated aqueous solution of sodium chloride, the organic solution was dried over anhydrous sodium sulfate and concentrated to afford the title compound as an oil (3 65 g 89%) with approximately a 10 1 ratio of diastereomers, (major diastereomer) 1H NMR (400 MHz, CDCI3) δ 743 (dd, J = 6 9, 1 6 Hz, 1 H), 7 29-725 (m, 3H), 409 (t, J = 8 1 Hz, 1 H), 3 80 (s, 3H), 3 31-3 24 (m, 1 H), 3 14 (dd, J = 12 8, 4 7 Hz, 1 H), 2 98 (dd, J = 12 8, 7 3 Hz, 1 H), 2 62-2 52 (m 1H), 2 31-242 (m, 1H), 1 3 (bs, 2H)
D) 9-Oxo-l 0-aza-trιcvclo[6 3 1 02 7ldodeca-2(7),3,5-trιene
To a solution of 3-amιnomethyl-ιndan-1 -carboxyhc acid methyl ester (assume 20 0 mmol, 1 equivalent) in 50 mL of methanol (this was the crude reaction mixture from the prior step, Example 60C) was added 3 84 g of sodium tert-butoxide (40 0 mmol, 2 0 equivalent) The reaction mixture was heated to a reflux for 2 hours The reaction was cooled to room temperature and concentrated in vacuo The residue was partitioned between 60 mL of ethyl acetate and 40 mL of 5% aqueous solution of sodium bicarbonate The aqueous layer was extracted twice more with 50 mL of ethyl acetate The combined organic layers were dried over anhydrous sodium sulfate and concentrated to provide a solid material Recrystallization of the solid from 10 mL of toluene provided white crystals of the title compound (1 78 g 51%) mp = 172-173 °C, 1H NMR (400 MHz, CDCI3) δ 733 (d, J = 76 Hz, 1H), 731 (d, J = 76 Hz, 1H), 722 (t, J = 76 Hz, 1H), 718 (t, J = 76 Hz, 1H), 562 (s, 1H), 368 (dd, J = 112, 41 Hz, 1H), 355(d, J=37Hz, 1H), 343-337 (m, 1H), 318 (d, J = 112 Hz, 1H), 252-245 (m 1H), 232 (d, J = 112 Hz, 1H), 13C NMR (100 MHz, CDCI3) δ 1736, 1447, 1446, 1280, 1277, 1232, 1229, 493, 479, 391, 384, IR (neat, cm"1) 3218, 2949, 2872 1666, 1485, 1459, 1400, 1328, 1303, 1288, 1250, 1215, 1122, 1104, 1045, 1004, 946, 910, 756, 730, 643, 613, Anal Calcd for CnH121NO C 7628, H, 640, N, 809, Found C, 7594, H, 627, N, 799
E) 10-Aza-tπcvclo[6 3 1 02 7ldodeca-2(7),3,5-tnene tosylate
To a solution of 1 38 g of 9-oxo-10-aza-tπcyclo[6 3 1 027]dodeca-2(7),3,5-tπene (8 00 mmol, 1 equivalent) in 8 mL of tetrahydrofuran was added 603 mg of sodium borohydnde (16 0 mmol, 2 0 equivalent) followed by slow addition of 2 77 mL of boron tπfluoπde diethyl etherate (21 6 mmol, 2 7 equivalent) Once the effervescence subsided, the reaction mixture was heated to 50 °C for 5 hours The reaction was then cooled to room temperature for addition of 10 mL of methanol (added dropwise at first) and 0 125 mL of concentrated hydrochloric acid Heating was resumed at a reflux for 12 hours The reaction mixture was then cooled to room temperature and concentrated in vacuo The residue was diluted with 20 mL of 20% aqueous sodium hydroxide followed by 30 mL of methyl-ferf-butyl ether The mixture was stirred for 30 minutes and then the aqueous layer was extracted with another 30 mL of methyl-fert-butyl ether The combined organic layers were washed with 40 mL of a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate After concentrating in vacuo, 1 67 g of p-toluenesulfonic acid monohydrate (8 80 mmol, 1 1 equivalent) was added with 20 mL of isopropanol The solution was heated until homogeneous and then allowed to gradually cool to room temperature with stirring White crystals of the title compound formed and were collected by filtration (2 17 g, 81%) mp 207- 208 °C, 1H NMR (400 MHz, CD3OD) δ 7 69 (d, J = 7 9 Hz, 2H), 7 43-7 32 (m, 4H), 7 23 (d, J = 7 9 Hz, 2H), 3 37 (d, J = 11 2 Hz, 4H), 3 30 (bs, 2H), 3 15 (d, J = 12 4 Hz, 2H), 2 36 (s, 3H), 2 40-2.35 (m, 1 H), 2 08 (d, J = 11.2 Hz, 1 H), 13C NMR (100 MHz, CD3OD) δ 140 8, 140 5, 139 1 , 127 2, 127.2, 124 3, 122 3, 45 1 , 39 7, 37 3, 18 7, IR (KBr, cm"1) 3438, 3021 , 2958, 2822, 2758, 2719, 2683, 2611 , 2424, 1925, 1606, 1497, 1473, 1428, 1339, 1302, 1259, 1228, 1219, 1176, 1160, 1137, 1122, 1087, 1078, 945, 914, 876, 847, 829, 818, 801 , 710, 492, Anal Calcd for C18H21N03S C, 65 23, H, 6 39; N, 4 23, Found C, 65 05, H, 6 48, N, 4 26

Claims

A compound of the formula
Figure imgf000092_0001
R1 is hydrogen, (CrC6)alkyl, unconjugated (C3-C6)alkenyl, benzyl, XC(=0)R13 or -CH2CH2-0-(C1-C4)alkyl,
R2 and R3 are selected, independently, from hydrogen, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, nitro, ammo, halo, cyano, -SOq(CrC6)alkyl wherein q is zero, one or two, (d^alkylam o-, [(C CeJalkylkamino-, -C02R4, -CONR5R6, -S02NR7R8, -C(=0)R13, -XC(=0)R13, aryl-(Co -C3)alkyl- or aryl-(C0-C3)alkyl-O-, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl- or heteroaryl-(C0-C3)alkyl-O-, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, X2(C0-C6)alkyl- and X2(C1-C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or X2 is (C1-C6)alkylamιno- or
Figure imgf000092_0002
and wherein the (C0- C6)alkyl- and (C1-C6)alkoxy-(C0-C6)alkyl- moiety of said X2(C0-C6)alkyl- or X2(C C6)alkoxy-(C0- C6)alkyl-, contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C0-C6)aikyl- or (Cι-C6)alkoxy-(C0-C6)alkyl- moiety may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C0- C6)alkyl- or (Cι-C6)alkoxy-(C0-C6)alkyl- may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl- (C0-C3)alkyl- and said heteroaryl-(C0-C3)alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C CβJalkoxy optionally substituted with from two to seven fluorine atoms, halo, (C2- C6)alkenyl, (C2-C6)alkynyl, hydroxy, nitro, cyano, ammo, (Cι-C6)alkylamιno-, [(d-Ce) alkyl]2amιno-, -C02R4, -CONR5R6, -S02NR7R8, -C(=0)R13 and -XC(=0)R13, or R2 and R3, together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicychc, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the non-fused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicychc rings that are not part of the benzo ring shown in formula I, may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicychc rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyc c rings, that are selected, independently, from (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms, nitro, oxo, cyano, halo, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, am o (C C6)alkylamιno-, [(C C6)alkyl]2amιno-, -C02R4, -CONR5R6, -S02NR7R8, -C(=0)R13 and -XC(=0)R13, wherein R4, R5, R6, R7 , R8 and R13 are selected, independently, from hydrogen and (C-, - C6) alkyl, or R5 and R6, or R7 and R8 together with the nitrogen to which they are attached, form a pyrrohd e, pipeπdine, morphohne, azetidine, piperaz e,
Figure imgf000093_0001
or thiomorphohne ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone, and each X is, independently, (C C6)alkylene, with the proviso that (a) at least one of R1, R2 and R3 must be the other than hydrogen and (b) when R2 and R3 are hydrogen, R1 cannot be hydrogen, (C1-C6)alkyl, or unconjugated (C3-C6)alkenyl, or a pharmaceutically acceptable salt thereof
2 A compound according to claim 1 , wherein R2 and R3, together with the benzo ring of formula I, form a bicychc ring system selected from the following
Figure imgf000093_0002
wherein R10 and R Ϊ117' a . re selected, independently, from hydrogen, (C1-C6)alkyl, and (C1-C6)alkoxy- (C0-C6)alkyl-, wherein the total number of carbon atoms in the (CιC6)alkoxy-(C0-C6)alkyl- does not exceed six, and wherein any of the above alkyl moieties may optionally be substituted with from one to seven fluorine atoms, nitro, cyano, halo, ammo, (C CβJalkylamino-, [(CrC6) alkyl]2amιno-, -C02R4, -CONR5R6, -S02NR7R8, -C(=0)R13, -XC(=0)R13, phenyl and monocyclic heteroaryl, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, and wherein R4, R5, R6, R7, R8 and R13 are as defined in claim 1
A compound according to claim 1 , wherein R2 and R3 do not, together with the benzo ring of formula I, form a bicychc or tncychc ring system
A compound according to claim 1, wherein one or both of R2 and R3 are
-C(=0)R13 wherein R13 is (d-CeJalkyl
A compound according to claim 1 , wherein one of R2 and R3 is -COR13 wherein
R ,13 is (CrCβJalkyl or (d-C^alkyl optionally substituted with from one to seven fluorine atoms
A compound according to claim 1 , wherein one of R2 and R3 is CF3 , fluoro, cyano, (C2-C6)alkynyl or C2F5
A compound according to claim 1, wherein R2 and R3, together with the benzo ring of formula I, form a bicychc or tncychc ring system selected from the following
Figure imgf000094_0001
Figure imgf000095_0001
wherein R10 and R17 are defined as defined in claim 1, and m is zero, one or two, and wherein one of the carbon atoms of ring A can optionally be replaced with oxygen or N(Cι-Cβ)alkyl
8 A pharmaceutical composition for use in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a mammal, comprising an amount of a compound according to claim 1 that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use and a pharmaceutically acceptable carrier
9 A method for reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a mammal, comprising administering to said mammal an amount of a compound according to claim 1 that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use
10 A pharmaceutical composition for treating a disorder or condition selected from inflammatory bowel disease, ulcerative colitis, pyoderma gangrenosum, Crohn's disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions, dependencies on, or addictions to, nicotine, tobacco products, alcohol, benzodiazepines, barbiturates, opioids or ***e, headache, migraine, stroke, traumatic brain injury, obsessive-compulsive disorder, psychosis, Huntington's chorea, tardive dyskmesia, hyperkinesia, dyslexia, schizophrenia, multi- mfarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy senile dementia of the Alzheimer's type, Parkinson's disease, attention deficit hyperactivity disorder and Tourette's Syndrome in a mammal, comprising an amount of a compound according to claim 1 that is effective in treating such disorder or condition and a pharmaceutically acceptable carrier
11 A method for treating a disorder or condition selected from inflammatory bowel disease, ulcerative colitis, pyoderma gangrenosum, Crohn's disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis, cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions, dependencies or, or addictions to, nicotine, tobacco products, alcohol, benzodiazepines, barbiturates, opioids or ***e, headache, migraine, stroke, traumatic brain injury, obsessive-compulsive disorder, psychosis, Huntington's chorea tardive dyskmesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type, Parkinson's disease, attention deficit hyperactivity disorder and Tourette's Syndrome in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound according to claim 1 that is effective in treating such disorder or condition
12 A compound of the formula
Figure imgf000096_0001
wherein P is hydrogen, methyl, COOR16 wherein R16 is (Cι-C6)alkyl, allyl or 2,2,2-tπchloroethyl,
-C(=0)NR5R6 wherein R5 and R6 are defined as in claim 1 , -C(=0)H, -C(=0)(C1-C6)alkyl wherein the alkyl moiety may optionally be substituted with from 1 to 3 halo atoms, preferably with from 1 to 3 fluoro or chloro atoms, benzyl, t-butoxycarbonyl or tnfluoroacetyl, and R14 and R15 are selected, independently, from hydrogen (Cι-C6)alkyl optionally substituted with from one to seven fluorine atoms,
Figure imgf000097_0001
cyano, hydroxy nitro ammo, -0(C1-C6)alkyl and halo, with the proviso that R14 and R15 can not both be hydrogen when P is hydrogen (C C6)alkyl, or unconjugated (C3-C6)alkenyl
13 A method for reducing nicotine addiction or aiding in the cessation or lessening of tobacco use in a mammal, comprising administering to said mammal an amount of a compound comprising an amount of a compound of the formula
Figure imgf000097_0002
wherein R19 is selected from the group consisting of hydrogen, (C1-C6)alkyl, or unconjugated (C3-C6)alkenyl, or a pharmaceutically acceptable salt thereof, that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use
14 A method for treating a disorder or condition selected from inflammatory bowel disease, ulcerative colitis, pyoderma gangrenosum, Crohn's disease, irritable bowel syndrome spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis, cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy chemical dependencies and addictions, dependencies on, or addictions to, nicotine tobacco products, alcohol, benzodiazepines, barbiturates, opioids or ***e, headache, migraine, stroke, traumatic brain injury, obsessive-compulsive disorder, psychosis, Huntington's chorea tardive dyskmesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type, Parkinson's disease, attention deficit hyperactivity disorder and Tourette's Syndrome in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound of the formula
Figure imgf000097_0003
wherein R19 is selected from the group consisting of hydrogen, (d-C6)alkyl, or unconjugated (C3-C6)alkenyl, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition 15 A compound of the formula
Figure imgf000098_0001
wherein R2 and R3 are defined as in claim 1 , and P' is COOR16 wherein R16 is allyl 2,2,2-tπchloroethyl or (d-C6)alkyl, -C(=0)NR5R6 wherein R5 and R6 are defined as in claim 1 -C(=0)H, -C(=0)(d-C6)alkyl wherein the alkyl moiety may optionally be substituted with from 1 to 3 halo atoms, preferably with from 1 to 3 fluoro or chloro atoms benzyl, or t-butoxycarbonyl
16 A compound according to claim 1 of the formula
Figure imgf000098_0002
wherein R is as defined in claim 1 , aanndd RR22 aanndd RR33 aarree hhyyddrrooggeenn,, ((dC1--CC6)alkyl optionally substituted with from one to seven fluorine atoms, -C(=0)(C C6)a illkkyyll,, ccyyaannoo, hydroxy, nitro, am o, -0(d-C6)alkyl or halo wwiitthh tthhee pprroovviissoo tthhaatt RR22 aanndd F R3 can not both be hydrogen when P is hydrogen, (d- C6)alkyl, or unconjugated (C3-C6)alkenyl
17 A compound according to claim 1 selected from the group consisting of 5,13-dιazatetracyclo[9 3 1 02 10 0 8]pentadeca-2,4(8),9-tπen-6-one, 6-oxo-5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,6,8-tetraene
2-fluoro-N-(4-hydroxy-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-tπen-5-yl)-benzamιde, 6-methyl-5,7-dιoxo-6,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,8-tπene 6-methyl-5-oxo-6,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,8-tπene, 5,7-dιmethyl-6-oxo-5,7,13-tπazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,8-tπene 5,7-dιoxo-6,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3 8-tπene, 5-0X0-6, 13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,8-trιene, 6-oxo-5,7, 13-tπazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3 8-trιene, 6-methyl-5-thιa-5-dιoxo-6,13-dιazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10),3,6,8- tetraene,
7-dιmethylamιno-5-thιa-5-dιoxo-6,13-dιazatetracyclo[9 3 1 02 10 O4 8]pentadeca-
2(10),3,6,8-tetraene,
6,7-dιoxo-5,8,14-tπazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ) 3,9-trιene,
5,8-dιmethyl-6,7-dιoxo-5,8,14-tπazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11 ),3,9- tπene, 5-oxa-7-methyl-6-oxo-7,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,8-trιene,
1-(10-azatπcyclot6 3 1 02 7]dodeca-2(7),3,5-tπen-4-yl)-1 -ethanone, and pharmaceutically acceptable salts thereof
18 A compound according to claim 2 selected from the group consisting of 6-methyl-5-thιa-7,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,6,8-tetraene,
6-methyl-7-propyl-5,7,13-trιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10), 3,5,8- tetraene,
5,7,13-tπazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5,8-tetraene, 7-methyl-5,7,13-tπazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8-tetraene, 6-methyl-5,7,13-tπazatetracyclo[9 3 1 02 10 048]pentadeca-2(10) 3,5,8-tetraene,
6,7-dιmethyl-5,7,13-tπazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5 8-tetraene, 7-propyl-5,7,13-tπazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5,8-tetraene, 7-butyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3 5,8-tetraene,
6-methyl-7-ιsobutyl-5,7,13-tπazatetracyclo[9 3 1 02 10 048]pentadeca-2(10), 3,5,8- tetraene,
7-phenyl-5,7,13-tπazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5,8-tetraene, 6-methyl-7-phenyl-5,7,13-tπazatetracyclo[9 3 1 02 10 048]pentadeca-2(10), 3,5,8- tetraene,
7-neopentyl-5,7,13-tπazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5,8-tetraene, 6-methyl-7-neopentyl-5,7,13-tπazatetracyclo[9 3 1 02 0 048]pentadeca-2(10),3,5,8- tetraene,
6J-dιmethyl-5,8,14-tπazatetracyclo[10 3 1 02 11 049]hexadeca-2(1 1),3,5,7,9-pentaene, 5,8,14-tπazatetracyclo[10 3 1 02 11 0 9]hexadeca-2(11),3,5,7,9-pentaene, 14-methyl-5,8,14-tπazatetracyclo[10 3 1 02 11 049]hexadeca-2(1 1 ),3,5,7,9-pentaene 5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,6,8-tetraene,
6-methyl-5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,6,8-tetraene, 7-methyl-5-oxa-6,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2,4(8),6,9-tetraene, 5,8,14-tπazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,7,9-tetraen-6-one, and pharmaceutically acceptable salts thereof
19 A compound according to claim 3 selected from the group consisting of
4-methyl-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene, 4-nιtro-10-azatπcyclo[6 3 1 027]dodeca-2(7),3,5-trιene, 4-amιno-10-azatπcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene, N1-[10-azatπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen~4-yl]acetamιde, 4,5-dιnιtro-10-aza-tπcyclo[6 3 1 027]dodeca-2(7),3,5-tπene
4,5-dιfluoro-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene, 4-chloro-10-azatπcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene, 3-(10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπen-4-yl)-5-methyl-1 ,2,4-oxadιazole, 10-azatπcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπen-4-ol, 4,5-dιchloro-10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene,
N4,N4-dιmethyl-10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-4-sulfonamιde, 4-(1-pyrrohdιnylsulfonyl)-10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene, 5-fluoro-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-tπene-4-carbonιtrιle, 4-ethynyl-5-fluoro-10-aza-tπcyclo[6 3 1 027]dodeca-2(7),3,5-tπene, 5-ethynyl-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-trιene-4-carbonιtrιle,
5-chloro-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene-4-carbonιtπle, 4-ethynyl-5-chloro-10-aza-tπcyclo[6 3 1 027]dodeca-2(7),3,5-tπene, 4-fluoro-5-trιfluoromethyl-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, 4-chloro-5-trιfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, 5-tπfluoromethyl-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene-4-carbonιtrιle,
4-ethynyl-5-trιfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, 4,5-bιstπfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, and pharmaceutically acceptable salts thereof
20 A compound according to claim 6 selected from the group consisting of
3-trιfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, 4-tπfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, 3-fluoro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, 10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-4-yl cyanide, 4-fluoro-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-trιene, and pharmaceutically acceptable salts thereof
21. A compound according to claim 7 selected from the group consisting of: 5,14-diazatetracyclo[10.3.1.02'11.04'9]hexadeca-2(11),3,5,7,9-pentaene; 6-methyl-5,14-diazatetracyclo[10.3.1.02'11.04'9]hexadeca-2(11),3,5,7,9-pentaene; 7-methyl-5,14-diazatetracyclo[10.3.1.0 , .04,9]hexadeca-2(11),3,5,7,9-pentaene;
7-ethyl-5,14-diazatetracyclo[10.3.1.02'11.04'9]hexadeca-2(11 ),3,5,7,9-pentaene; 8-methyl-5,14-diazatetracyclo[10.3.1.02'11.04,9]hexadeca-2(11 ),3,5,7,9-pentaene; 5,14-diazatetracyclo[10.3.1.0 l11.04'9]hexadeca-2(11 ),3,7,9-tetraen-6-one; 6-chloro-5,14-diazatetracyclo[10.3.1.0 ,11.04,9]hexadeca-2(11 ), 3,5,7, 9-pentaene; 6-methoxy-5,14-diazatetracyclo[10.3.1.02'11.049]hexadeca-2(11),3,5,7,9-pentaene;
6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.02'11.04'9]hexadeca-2(11), 3,5,7,9- pentaene;
6-chloro-3-fluoro-5,14-diazatetracyclo[10.3.1.02'1 .04'9]hexadeca-2(11 ),3,5,7,9- pentaene; and pharmaceutically acceptable salts thereof.
22. A compound according to claim 1 which is a racemic mixture.
23. A compound according to claim 1 selected from the group consisting of (+)-5,13-diazatetracyclo[9.3.1.02' 0.04'8]pentadeca-2,4(8),9-trien-6-one; (+)-6-oxo-5-oxa-7, 13-diazatetracyclo[9.3.1.02,10.04'8]pentadeca-2(10),3,6,8-tetraene; (+)-2-fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.02'7]dodeca-2(7),3,5-trien-5-yl)- benzamide;
(+)-6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.02'10.04'8]pentadeca-2(10),3,8-triene; (+)-5-oxo-6,13-diazatetracyclo[9.3.1.0 '10.04'8]pentadeca-2(10),3,8-triene; (+)-6-methyl-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.02'10.04'8]pentadeca-2(10), 3,6,8- tetraene;
(+)-7-dimethylamino-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.02,10.0 '8]pentadeca- 2(10),3,6,8-tetraene;
(+)-5-oxa-7-methyl-6-oxo-7,13-diazatetracyclo[9.3.1.02'10.04,8]pentadeca-2(10),3,8- triene; (+)-1-(10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl)-1 -ethanone; and pharmaceutically acceptable salts thereof.
24. A compound according to claim 2 selected from the group consisting of: (+)-6-methyl-5-thia-7,13-diazatetracyclo[9.3.1.02'10.04'8]pentadeca-2(10),3,6,8- tetraene; (+)-6-methyl-7-propyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5 8- tetraene,
■7-methyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8-tetraene •6,7-dιmethyl-5,7,13-trιazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10),3,5,8-tetraene ■7-propyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10) 3,5,8-tetraene, -7-butyl-5,7,13-tπazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8-tetraene, •6-methyl-7-ιsobutyl-5,7,13-trιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3 5 8- tetraene
-7-phenyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8-tetraene •6-methyl-7-phenyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3 5 8- tetraene
•7-neopentyl-5,7,13-trιazatetracyclo[9 3 1 02 10048]pentadeca-2(10),3,5,8-tetraene ■6-methyl-7-neopentyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10) 3,5,8- tetraene
■5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,6,8-tetraene, -6-methyl-5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,6,8- tetraene
•7-methyl-5-oxa-6,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2,4(8),6,9-tetraene, ■5,8,14-tnazatetracyclo[10 3 1 02 11 049]hexadeca-2(11),3,7,9-tetraen-6-one and pharmaceutically acceptable salts thereof
25 A compound according to claim 3 selected from the group consisting of
+)-4-methyl-10-aza-trιcyclo[6 3 1 0 ,27, ]dodeca-2(7),3,5-trιene, +)-4-nιtro-10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene, +)-4-amιno-10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, +)-N1-[10-azatrιcyclo[6 3 1 027]dodeca-2(7),3,5-trιen-4-yl]acetamιde, +)-4-chloro-10-azatrιcyclo|6 3 1 02 7]dodeca-2(7),3,5-trιene, +)-3-(10-azatrιcyclo[6 3 1 027]dodeca-2(7),3,5-trιen-4-yl)-5-methyl-1 ,2,4-oxadιazole +)-10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-4-ol,
+)-N4,N4-dιmethyl-10-azatrιcyclo[6 3 1 027]dodeca-2(7),3,5-trιene-4-sulfonamιde, +)-4-(1-pyrrolιdιnylsulfonyl)-10-azatrιcyclo[6 3 1 027]dodeca-2(7),3,5-tπene, +)-5-fluoro-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-trιene-4-carbonιtrιle, +)-4-ethynyl-5-fluoro-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-tπene, +)-5-ethynyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-4-carbonιtrιle, +)-5-chloro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-4-carbonιtrιle, +)-4-ethynyl-5-chioro-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-trιene, (+)-4-fluoro-5-trιfluoromethyl-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, (+)-4-chloro-5-trιfluoromethyl-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, (+)-5-trιfluoromethyl-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene-4-carbonιtrιle, (+)-4-ethynyl-5-tπfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene, and pharmaceutically acceptable salts thereof
26 A compound according to claim 6 selected from the group consisting of (+)-3-tπfluoromethyl-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-tπene, (+)-4-trιfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3 5-tπene, (+)-3-fluoro-10-aza-tπcyclo[6 3 1 0 7]dodeca-2(7),3,5-trιene,
(+)-10-azatπcyclo[6 3 1 027]dodeca-2(7),3,5-tπen-4-yl cyanide, (+)-4-fluoro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, and pharmaceutically acceptable salts thereof
27 A compound according to claim 7 selected from the group consisting of
(+)-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11),3,5,7,9-pentaene, (+)-6-methyl-5,14-dιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11 ),3,5,7,9-pentaene, (+)-7-methyl-5,14-dιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11 ),3,5,7,9-pentaene, (+)-7-ethyl-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11),3,5,7,9-pentaene, (+)-8-methyl-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,5,7,9-pentaene,
(+)-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,7,9-tetraen-6-one, (+)-6-chloro-5,14-dιazatetracyclo[10 3 1 02 11 0 9]hexadeca-2(11),3,5,7,9-pentaene, (+)-6-methoxy-5,14-dιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11 ),3,5,7,9-pentaene, (+)-6-chloro-10-fluoro-5,14-dιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11),3,5,7,9- pentaene,
(+)-6-chloro-3-fluoro-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11),3,5,7,9- pentaene, and pharmaceutically acceptable salts thereof
28 A compound according to claim 1 selected from the group consisting of
(-)-5,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2,4(8),9-trιen-6-one, (-)-6-oxo-5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,6,8-tetraene, (-)-2-fluoro-N-(4-hydroxy-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπen-5-yl)- benzamide, (-)-6-methyl-5-oxo-6,13-dιazatetracyclo[9 3 1 0 10 048]pentadeca-2(10),3,8-tπene,
(-)-5-oxo-6,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,8-trιene, (-)-6-methyl-5-thιa-5-dιoxo-6,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,6,8- tetraene,
(-)-7-dιmethylamιno-5-thιa-5-dιoxo-6,13-dιazatetracyclo[9 3 1 02 10 O4 8]pentadeca- 2(10), 3,6, 8-tetraene, (-)-5-oxa-7-methyl-6-oxo-7,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,8- tnene,
(-)-1-(10-azatrιcyclo[6 3 1 027]dodeca-2(7),3,5-tπen-4-yl)-1 -ethanone, and pharmaceutically acceptable salts thereof
29 A compound according to claim 2 selected from the group consisting of
(-)-6-methyl-5-thιa-7,13-dιazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10),3,6,8-tetraene, (-)-6-methyl-7-propyl-5,7,13-trιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10), 3,5,8- tetraene,
(-)-7-methyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8-tetraene, (-)-6,7-dιmethyl-5,7,13-trιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5,8-tetraene,
(-)-7-propyl-5,7,13-trιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,5,8-tetraene, (-)-7-butyl-5,7,13-trιazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10),3,5,8-tetraene, (-)-6-methyl-7-ιsobutyl-5,7,13-tπazatetracyclo[9 3 1 02 0 04 8]pentadeca-2(10), 3,5,8- tetraene, (-)-7-phenyl-5,7,13-tπazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,5,8-tetraene,
(-)-6-methyl-7-phenyl-5,7,13-trιazatetracyclo[9 3 1 02 0 048]pentadeca-2(10), 3,5,8- tetraene,
(-)-7-neopentyl-5,7,13-trιazatetracyclo[9 3 1 02 10 0 8]pentadeca-2(10),3,5,8-tetraene, (-)-6-methyl-7-neopentyl-5,7,13-trιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10), 3,5,8- tetraene,
(-)-5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 04 8]pentadeca-2(10),3,6,8-tetraene, (-)-6-methyl-5-oxa-7,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2(10),3,6,8-tetraene, (-)-7-methyl-5-oxa-6,13-dιazatetracyclo[9 3 1 02 10 048]pentadeca-2,4(8),6,9-tetraene, (-)-5,8,14-trιazatetracyclo[10 3 1 02 11 04 9]hexadeca-2(11 ),3,7,9-tetraen-6-one, and pharmaceutically acceptable salts thereof
30 A compound according to claim 3 selected from the group consisting of (-)-4-methyl-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, (-)-4-nιtro-10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, (-)-4-amιno-10-azatrιcyclo[6 3 1 027]dodeca-2(7),3,5-trιene,
(-)-N1-[10-azatrιcyclo[6 3 1 027]dodeca-2(7),3,5-trιen-4-yl]acetamιde, ■)-4-chloro-10-azatπcyclo[6 3 1 0 ]dodeca-2(7),3,5-trιene,
)-3-(10-azatrιcyclo[6 3 1 0 1- 7 ]dodeca-2(7),3,5-tπen-4-yl)-5-methyl-1 ,2,4-oxadιazole,
-)-10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιen-4-ol,
■)-N ,N4-dιmethyl-10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene-4-sulfonamιde, •)-4-(1-pyrrolιdιnyisulfonyl)-10-azatrιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, ■)-5-fluoro-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene-4-carbonιtrιle,
-)-4-ethynyl-5-fluoro-10-aza-tπcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene,
-)-5-ethynyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-4-carbonιtrιle, )-5-chloro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene-4-carbonιtrιle, )-4-ethynyl-5-chloro-10-aza-trιcyclo[6 3 1 027]dodeca-2(7),3,5-trιene, )-4-fluoro-5-trιfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, )-4-chloro-5-trιfluoromethyl-10-aza-tπcyclo[6 3 1 027]dodeca-2(7),3,5-trιene, )-5-trιfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-tπene-4-carbonιtrιle, )-4-ethynyl-5-trιfluoromethyl-10-aza-trιcyclo[6 3 1 0 7]dodeca-2(7),3,5-trιene, and pharmaceutically acceptable salts thereof
31 A compound according to claim 6 selected from the group consisting of
2 7,
(-)-3-trιfluoromethyl-10-aza-trιcyclo[6 3 1 0 ]dodeca-2(7),3,5-trιene, (-)-4-trιfluoromethyl-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, (-)-3-fluoro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, (-)-10-azatrιcyclo[6 3 1 027]dodeca-2(7),3,5-tπen-4-yl cyanide, (-)-4-fluoro-10-aza-trιcyclo[6 3 1 02 7]dodeca-2(7),3,5-trιene, and pharmaceutically acceptable salts thereof
32 A compound according to claim 7 selected from the group consisting of )-5,14-dιazatetracyclo[10 3 1 02 11 0 9]hexadeca-2(11),3,5,7,9-pentaene, )-6-methyl-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,5,7,9-pentaene, )-7-methyl-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,5,7,9-pentaene, )-7-ethyl-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11),3,5,7,9-pentaene, )-8-methyl-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3,5,7,9-pentaene, )-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11),3,7,9-tetraen-6-one, )-6-chloro-5,14-dιazatetracyclo[10 3 1 02 11 0 9)hexadeca-2(11),3,5,7,9-pentaene, )-6-methoxy-5,14-dιazatetracyclo[10 3 1 02 11 0 9]hexadeca-2(11),3,5,7,9-pentaene,
•)-6-chloro-10-fluoro-5,14-dιazatetracyclo[10 3 1 02 11 049]hexadeca-2(11 ),3, 5,7,9- pentaene, (-)-6-chloro-3-fluoro-5,14-dιazatetracyclo[10.3.1.02'11.0 '9]hexadeca-2(11),3,5,7,9- pentaene; and pharmaceutically acceptable salts thereof.
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