Title of Invention

"WRAPPING APPARATUS"

Abstract Compounds of the formula and their pharmaceutically acceptable salts, wherein R1, R2, R3 and n are defined as in the specification, intermediates in the synthesis of such compounds, pharmaceutical compositions containing such compounds and methods of using such compounds in the treatment of neurological and psychological disorders are claimed.
Full Text

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 acetylcholine 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 Crohns 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, amylotropic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (~j, dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbituates, opioids or cocaine), headache, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder, 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 tricyclic 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 muscarinic agonists in order to stimulate both central muscarinic 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 antiinflammatory 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 azapolycyclic compounds of the formula

(Formula Removed)

R' is hydrogen, (C1-C6)alkyl, unconjugated (C3-C6)alkenyl, benzyl, XC(=O)R13 or

-CH2CH2-O-(C1-C4)alkyl;

R2 and R3 are selected, independently, from hydrogen, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, nitro, amino, halo, cyano, -SOq(C1-C6)alkyl wherein q is zero, one or two,

(C1.C6)alkylamino-, [(C1-C6)alkyl]2amino-, -C02R4, -CONR5R6, -502NR7R8, -C(=O)R13, 13
-XC(=O)R 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 heteroary I is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, and X2(C0-C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or X2 is (C1-C6)alkylamino- or [(C1-C6)alkyl]2amino-, and wherein the (C0-C6)alkoxy-(C0-C6)alkyl- moiety of said X2(C0-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)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 (C~C6)alkoxy~(C0-C6)alkyl- may be optionally substituted with from two to seven fluonne 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, (C1-C6)alkoxy optionally substituted with from two to seven fluorine atoms, halo ~ chloro. fluoro, bromo or iodo), (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, nitro, cyano, amino, (C1-


C6)alkylamino-, [(C1-C6) alkyl]2amino-, -C02R4, -CONR R, -502NR7R8, -C(0)R'3 and -XC(=O)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 bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the nonfused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic 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 bicyclic 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)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, amino, (C 1-C6)alkylamino-, [(C 1-C6)alkyl]2amino-, -C02R4, -CON R5R6, ~SO2NR?RB, -C(=O)R13, and -
XC(0)R 4 5 6 7 8 13
each R ,R ,R , R , R and R is selected, independently, from hydrogen and (C1 -C6) alkyl, or R5 and R6, or R7 and R8 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperizine, -N-(C 1-C6)alkylpiperizine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and

each X is, independently, (C1-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 methyl or hydrogen;

and the pharmaceutically acceptable salts of such compounds.

Examples of heteroaryl groups that each of R2 and R3 can be are the following:
thienyl, oxazoyl, isoxazolyl, pyridyl, pynmidyl, thiazolyl, tetrazolyl, isothiazolyl, triazolyl, imidazolyl, tetrazolyl, pyrroyl and the following groups:
(Formula Removed)

wherein one of R9 and R18 is hydrogen or (C1-C6)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 and R ,together with the benzo ring of formula I, form a bicyclic ring system selected from the following:


(Formula Removed)


wherein R'0 and R17 are selected, independently, from (C0-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, cyano, halo, amino, (C1-C6)alkylamino-, [(C1-C6) alkyl]2amino-, -C02R4, -CONR5R6, -502NR7R8, -C(=O)R13

-XC(=O)R'3, 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:
(Formula Removed)

wherein R10 and R'7 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 I, 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 wherein R1 is not methyl.
Examples of specific compounds of. the formula I are the following:

6-methyl-5,7-dioxo-6, 1 3-diazatetracyclo[9.3. 1.02 10.048]pentadeca-2( 10), 3, 8-triene hydrochloride;

6-methyl-5-oxo-6,1 3-diazatetracyclo[9. 3 1 02 10 ~ 8jpentadeca-2 (10), 3, 8-triene

hydrochloride;

5,7-dimethyl-6-oxo-5,7, 1 3-triazatetracyclo[9. 3.1 .0210.04'8]pentadeca-2( 1 0),3,8-tnene hydrochloride;

5,7-dioxo-6, 1 3-diazatetracyclo[9. 3.1. 02'10.0'8]pentadeca-2( 1 0)3,8-triene hydrochloride;

5-oxo-6, 1 3-diazatetracyclo[9.3. 1.0210.048]pentadeca-2( 10), 3,8-triene hydrochloride;

6-oxo-5,7, 1 3-triazatetracyclo[9. 3.1.0210.04 8]pentadeca-2( 1 0)3,8-triene hydrochloride;
4,5-difluoro-1 0-aza-tricyclo[6.3. 1 .02'7]dodeca-2(7),3,5-triene hydrochloride;

5-fluoro-1 0-aza-tricyclo[6. 3.1 .027]dodeca-2(7), 3,5-triene-4-carbonitrile hydrochloride;

4-ethynyl-5-fluoro-1 0-aza-tricyclo[6 3 1 02 7]dodeca-2(7), 3,5-triene hydrochloride;
27

5-ethynyl- 1 0-aza-tricyclo[6 3 1.0 ]dodeca-2(7), 3, 5-triene-4-carbonitrile hydrochloride;
27

5-chloro-1 0-aza-tricyclo[6 3 1 0 ]dodeca-2(7),3,5-triene-4-carbonitrile hydrochloride;

4-ethynyl-5-chloro-1 0-aza-tricyclo[6. 3.1.02 7]dodeca-2(7), 3, 5-triene hydrochloride;

5-oxa-7-methyl-6-oxo-7, 1 3-diazatetracyclo[9. 3.1 . 02'10.048]pentadeca-2( 10), 3, 8-triene hydrochloride;
4-fluoro-5-trifluoromethyl-1 0-aza-tricyclo[6. 3.1 .027]dodeca-2(7), 3,5-triene hydrochloride;
2.7
4-chloro-5-trifluoromethyl-1 0-aza-tricyclo[6. 3.1.0 ]dodeca-2(7), 3,5-triene

hydrochloride;
2.7

5-trifluoromethyl-1 O-aza-tricyclo(6. 3.1.0 ]dodeca-2(7 ),3,5-triene-4-carbonitrile hydrochloride;

4-ethynyl-5-trifluoromethy I-i 0-aza-tricyclo[6. 3.1. 027]dodeca-2(7), 3, 5-triene hydrochloride;
2.10 48

6-methyl-5-thia-5-dioxa-6, 1 3-Diazatetracyclo[9.3. 1.0 .0 ]pentadeca-2( 10), 3.8-triene hydrochloride;

2.10 48

7-dimethylamino-5-thia-5-dioxa-6, 1 3-Diazatetracyclo[9.3. 1.0 .0 Ipentadeca2(1 0)3,8-triene hydrochloride;

6, 7-dioxa-5,8, 1 4-triazatetracyclo[1 0.3.1.0211.04~9]hexadeca-2( 11), 3, 9-triene hydrochloride; and
2.11 4.9
5,8-dimethyl-6,7-dioxa-5,8, 14-triazatetracyclo[1 0.3.1.0 .0 ]hexadeca-2(1 1)3.9-
triene hydrochloride.

This invention also relates to compounds of the formula
(Formula Removed)
wherein P is hydrogen, methyl, C00R16 wherein R'6 is (C1-C6)alkyl, allyl, 2,2.2-trichloroethyl or (C1-C6)alkyl; -C(=O)NR5R6 wherein R5 and R6 are defined as in formula I above; -C(=O)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 or t-butoxycarbonyl (t
14 15
Boc); and R and R 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, amino, -O(C1-C6)alkyl or halo: with the proviso that R'4 and R'5 can not both be hydrogen when P is hydrogen or methyl. Such compounds are useful as intermediates in the synthesis of compounds of the formula I.

Unless otherwise indicated, the term 'halo", as used herein, includes fluoro, chloro, bromo and odo

Unless otherwise indicated, the term "alkyl", as used herein, includes straight, branched or cyclic, and may include straight and cyclic alkyl moieties as well as branched and cyclic moieties.

The term "alkoxy", as used herein, means alkyl-O-", wherein "alkyl" is defined as above.

The term "alkylene, as used herein, means an alkyl radical having two available bonding sites (i.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 enantiomeric configurations. The invention includes all enantiomers, diastereomers, and


other stereoisomers of such compounds of formula I, as well as racemic and other mixtures thereof.

The present invention also relates to all radiolabelled forms of the compounds of the formulae I. Preferred radiolabelled compounds of formula I are those wherein the radiolabels are selected from as 3H, 11C, 14C, 18F, 1231 and 1251 Such radiolabelled compounds are useful as research and diagnostic tools in metabolism pharmacokinetics studies 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, amylotropic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (~j, dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbituates, opioids or cocaine), headache, stroke, traumatic brain injury (TBI), 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 Alzheimers 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, amylotropic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (~j, dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbituates, opioids or cocaine), headache, stroke, traumatic brain injury (TBI), 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 in a mammal, comprising an amount of a compound of the formula I, or a pharmaceutically accepable 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
(Formula Removed)

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, amylotropic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (, dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbituates, opioids or cocaine), headache, stroke, traumatic brain injury (TBI), 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 (ADHO) 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
(Formula Removed)
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, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, malate, di-p-toluoyl tartaric acid, and mandelic acid.

Detailed Description of the Invention

Except where otherwise stated, R1 through R18, m and P, and structural formula I in the reaction schemes and discussion that follow are defined as above.
(Formula Removed)

Scheme 1-10 illustrate methods of synthesizing compounds of the formula I.
Referring to Scheme 1, the starting material of formula Ill 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 00C to about room temperature.

The compound of formula IV is then converted into the dinitro 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 (CF3SO2OH) and 2 to 3 equivalents of nitric acid, in a chlorinated hydrocarbon solvent such as chloroform, dichoroethane (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 -780C 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 118. This reduction can be accomplished, for example, using hydrogen and a palladium catalyst such as palladium hydroxide and running the reaction in methanol at about room temperature.

Referring to Scheme 2, the compound of formula IIA is converted into the corresponding compound wherein the trifluoroacetyl 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-tbutyldicarbonate. 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 (THE) at a temperature from about room temperature to about 700C, preferably at about 700C, 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 THE, dioxane or methylene chloride at a temperature from about 09C 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 dinitro compound of formula IIA into the corresponding diamino compound of formula 118.

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

(Formula Removed)


wherein R'0 is hydrogen, (C1-C6)alkyl 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 heteratoms selected from oxygen, nitrogen and sulfur, and wherein each of the foregoing aryl and heteroryl 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. (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 400C to about 1000C. It is preferably about 600C. 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 Segelstein et al., 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 00C to about 1000C, preferably from about room temperature to about 700C, for about one to 24 hours.

The compound of formula VII can be converted into the corresponding compound of
17 17 10
formula lB by reacting it with a compound of the formula R Z, wherein R is defined as R is defined above, and Z is a leaving group such as a halo or sulfonate (~j, 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
17
removing the protecting group as described above. The reaction with R Z is generally

carried out at a temperature from about room temperature to about 1000C, preferably at about 500C, for about five hours.



Scheme 3 illustrates an alternate method of preparing compounds of the formula lB from the compound of formula VIA. This method is the preferred method of making
17

compounds of the formula lB wherein R is a bulky group such as an aryl or heteroaryl
17

containing group, or when R 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 THE, at a temperature from about room temperature to about 1000C, 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 amino 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 IA into a compound of the formula IIB in Scheme 1, and exemplied in experimental Examples 12B and 18B. Closure of 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
(Formula Removed)


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 lB. 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 R10
17
and R are as defined above. Referring to Scheme 4, the compound of formula VIB is
reacted with a compound of the formula

(Formula Removed)



(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 400C to about 1000C, and is preferably at about the reflux temperature.

Alternatively, the compound of formula VIB can be reacted with a compound of the formula

(Formula Removed)
(double condensation reaction) in a polar solvent such as THE, water, or acetic acid, preferably a mixture of water and THF. This reaction is typically carried out at a temperature from about 400C to about 1000C, preferably at the reflux temperature, for about two to four hours.

The desired quinoxoline of formula IC can then be formed by deprotecting 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.
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, trifluoromethanesulfonate 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 700C to about 1400C. Approximately 1000C 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 00C to about 7000, preferably at about room temperature, to form the corresponding amino derivative. The product of this reaction is then reacted with an acid chloride of the formula R10000I or an acid anhydride of the formula (R10C0)20 wherein R10 is (C1-C6)alkyl, or a compound of the formula R10C(0C2H5)3, in an appropriate inert solvent such as decalin, chlorobenzene or xylenes. A mixture of xylenes is



preferred. This reaction is typically conducted at a temperature from about 120-1500C,
0

preferably at about 1400C. When R COCI is used as a reactant, it is preferable to add a stoicheometric amount of triethylamine (TEA) or another organic tertiary amine base and a

catalytic amount of pyridinium p-toluenesulfonic acid or pyridinum p-toluenesulfonate (PPTs) to the reaction mixture. When R10C(0C2H5)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 500C to about 1 000C, preferably at about 70 C. for about two to six hours.
Scheme 6 illustrates the preparation of compounds of the formula I wherein R1 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 trifluoroacetyl group, and the resulting nitrogen protected compound is then reacted with two equivalents of trifluoromethanesulfonic 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 00C 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 carboxylic acid halide or anhydride of the formula R10COX or (R10C0)20, wherein X is halo and R10 is hydrogen or (C1-C6)alkyl, 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 Xl by reacting it with Lawesson's reagent, which is depicted below.
(Formula Removed)

The reaction with R10COX, wherein X is halo, or (R10C0)20 is generally carried out at a temperature from about 00C 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 Xl with potassium ferricyanide and sodium hydroxide in a mixture of water and methanol (NaOH/H20/CH3OH), at a temperature from about 500C to about 700C, preferably at about 600C 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 1G. 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
1 2

X and X are selected, independently, from chioro, fluoro, bromo and iodo, 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 400C to about 1000C, preferably at about the reflux temperature, to form a compound of the formula XIII. Reaction of the resulting compound of formula XIII with N-methylmorpholine-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 periodate 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 00C to about room temperature, to generate a dialdehyde or glycal intermediate. The product of this reaction is then reacted with benzylamine and

sodium triacetoxyborohydride in a chlorinated hydrocarbon solvent at a temperature from about 00C 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 Ill (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, ~j, hydrochloric acid, (to form the corresponding acid addition salt), followed by hydrogen 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 benzyl amines (~j, 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 by T. W. Greene and G.M. Wuts, "Protective Groups in Organic Synthesis", 1991, John Wiley & Sons, New York. NY.

The procedure of Scheme 7 can also be used to prepare compounds of the formula I
2 3

wherein R and R 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

(Formula Removed)

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 or an alkoxy group (R18 in Scheme 8). This compound is depicted in Scheme 8 as chemical structure 1H. Referring to Scheme 8, where, for example, R'8 is F, 1,3-difluorobenzene 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 -500C, followed by quenching with iodine or N-iodosuccinamide, to form 1,3-difluoro-2-iodobenzene. The compound 1 ,3-difluoro-2-iodobenzene (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 for converting compounds of the formula XIII into those of the formula IG or Ill. 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 or methyl cyclohexane, at a temperature from about -200C to about room temperature, preferably at about 0CC.

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 or an alkoxy group and 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 amino group, converting the amino 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 regioisomeric 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 isomeric products as described above. Also, the trifluoromethanesulfonate salt of such hydroxy derivative can act as a Y-group as described.
2

Preparation of compounds of formula I where R = -O(C1-C6)alkyl, (C1-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 -O-(C1-C6)alkyl, (C1-C6)alkyl or aryl, respectively.

Scheme 9 illustrates methods of preparing compounds of the formula I wherein: (a) R1
2 2 2

is hydrogen and R is R7R8N025-; (b) R1 and R are both chloro; and (c) R' is hydrogen and R is R13C(=O)-. These compounds are referred to in Scheme 9, respectively, as compounds of

formulas IJ, 1K 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 00C to about room temperature. Reaction of the chlorosulfonic acid derivative so formed with an amine having the formula R7R8NH,
7 8

wherein R and R are defined as above, followed by removal of the nitrogen protecting group. yields the desired compound having formula IJ.

Compounds of the formula 1K 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 00C to about room temperature, and is preferably carried out at about room temperature. In a similar fashion, the analogous mono- or dibrominated or mono- or diiododinated compounds can be prepared by reacting the compound of IV with Niodosuccinimide or N-bromosuccinimide in a trifluromethanesulfonic 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
13

anhydride of the formula (R CO)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 00C to about 1000C, 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 Friedel-Crafts acylations methods that are known in the art.

The reactions described herein in which NO2, -502NR7R8, -C0R13, I, Br or Cl 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. (C1-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 0-acyl substituted compounds, i.e., those wherein the -C(=O)R13 group of formula IL is replaced with a -O-C&O)R'3 group, using Baeyer-Villiger 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 substited compounds. Also, as described in Example 36, such 0-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) R1 is hydrogen and R2 is cyano; (c) R1 is hydrogen and R2 is amino; and (d) R' is hydrogen and R2 is R13C(=O)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 (~j, hydrochloric acid, sulfuric 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 00C to about 600C, preferably about 600C 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 00C 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-dimethylpropylurea (DMPU) or DMSO, preferably DMF, at a temperature from about 500C to about 1800C, preferably about 1500C. 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.

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 (R'3C0)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.

Other suitable amine protecting groups that can be used, alternatively, in the procedures described throughout this document include -COCF3, -COCCI3, -COOCH2CCI3,

-COO(C1-C6)alkyl and -COOCH2C6H5. These groups are stable under the conditions


described herein, and may be removed by methods described for each in Greene's "Protective Groups in Organic Chemistry", referred to above.

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, i.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 (~j, through the use of a patch), intranasal, sublingual, rectal, parenteral or topical routes. Transdermal and oral administration are preferred. These compounds are, most desirably, administered in dosages ranging from about 0.25 mg up to about 1500 mg per day, preferably from about 0.25 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 0.01 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, ~j, 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 microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic 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 Fernandes, K. G. (in The Binding of L-[3HlNicotine To A Single Class of High-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-Cystisine, ~

and ~H-MethylcarmbamyIcholine 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 00 in 10 volumes of buffer (w/v)
TM

using a Brinkmann Polytron , setting 6, for 30 seconds. The buffer consisted of 50 mM Tris HCI at a pH of 7.5 at room temperature. The homogenate was sedimented by centrifugation (10

minutes; 50,000 x g; 0 to 40C. The supernatant was poured off and the membranes were gently resuspended with the Polytron and centrifuged again (10 minutes; 50000 x g; 0 to 40C. After the second centrifugation, the membranes were resuspended in assay buffer at a concentration of 1.Og/lOOmL. The composition of the standard assay buffer was 50 mM Tris HCI, 120 mM NaCI, 5 mM KCI, 2 mM MgCI2, 2 mM CaCI2 and has a pH of 7.4 at room temperature.

Routine assays were performed in borosilicate 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 501iL of vehicle, blank, or test compound solution, respectively. To each tube was added 200 l.IL of [3H]-nicotine in assay buffer followed by 750 ~.iL 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 pM. The vehicle consisted of deionized water containing 30 pL of 1 N acetic acid per 50 mL 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 40 C in an iced shaking water bath. Incubations were terminated by rapid filtration under vacuum through
TM TM
Whatman GFIB 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
TM
Ready Safe (Beckman) before quantification of radioactivity. Samples were counted in a LKB

TM
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), i.e., (E) = (D)

-(B).

% Inhibition = (1-((E)/(C)) times 100.

The compounds of the invention that were tested in the above assay exhibited ICR, values of less than 10 tiM.

The following experimental examples illustrate, but do not limit the scope of, this invention.

EXAMPLE 1

1 0-AZA-TRICYCLO[6.3. 1 .027]DODECA-2(7),3,5-TRIENE

A) 1 ,4-Dihydro-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 ethylmagnesium 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 0C 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 (—4x). After —15 minutes, the reaction initiated (exotherrn, and 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-applied and a reflux maintained for 1.5 hours. (TLC 100% hexanes R~ 0.67).

The reaction was cooled to room temperature and quenched with H20 (500 mL) and carefully with iN HCI (200 mL, produces H2 evolution from unconsumed Mg). To this —50 mL

concentrated HCI 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 (KMnO4) active product is removed. (4 x '-250 mL). The combined organic layer was washed with saturated NaHCO3 solution (250 mL), sodium bicarbonate Na2SO4 dried and concentrated to an oil (—200 g). The product was distilled at 78-83 0C @15mm (131 g, 64%). (An alternative workup is described on p.419 Fieser and Fieser, Vol. I, Reagents for Organic Synthesis, Wiley, NY., NY.; 1967).


B) 1,2, 3,4-Tetrahydro-1 ,4-methano-naphthalene-2,3-diol

(Except for the workup method and the quantity of 0504 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-dihydro-1,4-methano-naphthalene (79.5 g, 560 mmol) stirred in acetone (800 mL) and H20 (100 mL) and N-methyl morpholine N-oxide (67.5 g, 576 mmol). To this was added osmium tetroxide (0504) (15 mL of a lSmol% t-BuOH solution, 1.48 mmol. 0.26mo1%) 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 trituration, filtration and acetone rinse provided (27.4 g, total 88.3 g, 89%). (TLC 50% EtOAc/hexanes R~—O.S). mp 176-1 77.5 0C.


C) 1 0-Benzyl-1 0-aza-tricyclo[6. 3.1 .0U]dodeca~2(7), 3, 5-triene

(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-diol (40 g, 227.3 mmol) was stirred in H20 (1050 mL) and 1,2-dichloroethane (DOE) (420 mL) in a 2 L round bottom flask under nitrogen with cool water bath (—10 0C). To this sodium periodate (NalO4) (51 g. 239 mmol) and triethylbenzyl 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 OCE (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 triacetoxyborohydride NaHB(OAc)3 /DCE (see below) over 10 minutes.



In a separate 2 L round botton flask flask under nitrogen was magnetically stirred NaHB(OAc)3 (154 g, 0.727 mmol) in DOE (800 mL) at 0 0C (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 (Na2003)

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 Et2O and filtered

through a Silica pad (3 x 4 inch) eluting with 15% ethyl acetate (EtOAc)/hexanes +1% of 37% aqueous ammonium hydroxide (NH4OH) solution to remove baseline red color. Concentration affords a light yellow oil (48.5 g, 194.8 mmol, 85.7%). (TLC 10% EtOAc/hexanes R~ 0.75). 1H NMR (400 MHz, CDCI3) 8 7.16 (in, 7H), 6.89 (in, 2H), 3.48 (in, 2H), 3.08 (in, 2H), 2.80 (d, J=9.5 Hz, 2H), 2.42 (d, J=9.5 Hz, 2H), 2.27 (in, 1H), 1.67 (d, J=10.0 Hz, 1H). APOI MS mie 250.3 [(M +

27


D) 1 0-Aza-tricyclo[6. 3.1 . 0—]dodeca-2(7), 3, 5-triene (For an alternative synthesis, see; Mazzocchi, P. H.; Stahly, B. C. J. Med. Chem. 1979, 22, 455.)

1 0-Benzyl-1 0-aza-tricyclo[6. 3.1 .027]dodeca-2(7), 3, 5-triene (70.65 g, 284 inmol) was stirred in EtOAc (250 mL) and treated with 3N HOl EtOAc (1.03 eq.) slowly with cooling (ice bath). The resulting precipitate was filtered and rinsed with EtOAc. The solids were dissolved in MeOH (250 mL) in a parr bottle. To this was added Pd(OH)2 (7 g of 20%wtIC) 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 Celite pad and concentrated to an oily solid. This was azeotroped with methanol (MeOH) (3x) then triturated with acetone, treated with ethyl ether (Et2O) to precipitate product and filtered. Concentration of the mother liquors and a second treatment provided an off white solid (48.95 g, 251 inmol, 88%). (TLC 10% MeOH/CH2CI2 (NH3) R1 0.2).

~ NMR (400 MHz, CDCI3) 8 7.18 (in, 4H), 2.97 (in, 4H), 2.68 (d, J12.5 Hz, .2H), 2.41 (in, 1H), 1.95 (d, J=11.0 Hz, 1H). APCI MS mle 160.2 [(M +

EXAMPLE 2

4-FLUORO-1 0-AZA-TRICYCLO[6.3. 1 .0~]DODECA-2(7),3,5-TRlENE

HYDROCHLORIDE

A) 6-Fluoro-1 ,4-dihydro-1 ,4-methano-naphthalene

(Eisch, J. J.; Burlinson, 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 (0.66 g, 27.2 minol) 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 inmol) and 2,5-difluorobromobenzene (5.0 g, 25.9 inmol). Small portions (—0.2 mL) of the intimate mixture were introduced to assist initiation (—4x). 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 iN HOl solution (20 mL) to dissolve the solids. Saturated aqueous NaCI solution (30 mL) was added and product was extracted with hexanes (4 x 25inL). The combined organic layer was washed with saturated aqueous NaHCO3 solution (25 mL), dried (Na2SO4), 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) 87.10 (in. 1H), 6.97 (d, J=8.0 Hz, 1H), 6.80 (br s, 1H), 6.78 (brs, 1H), 6.59 (in, 1H), 3.87 (br 5, 2H). 2.32 (d, J7.0 Hz, 1H), 2.25 (d. J=7.0 Hz, 1 H).


B) 6-Fluoro-1 ,2 ,3,4-tetrahydro-1 ,4-methano-naphthalene-2, 3-diol

6-Fluoro-1 ,4-dihydro-1 ,4-methano-naphthalene (680 ing, 4.22 inmol) and N-methyl morpholine N-oxide (599 mg, 4.43 minol) were stirred in acetone (50 mL) and H20 (5 inL). To this was added a solution of 0s04 (0.2 mL, 2.5%wt. solution in t-BuOH, 0.02 inmol). After 72 hours, florisil (5 g) and saturated aqueous NaHSO3 solution (3 inL) were added and stirred for 1 hour. The florisil 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) 8

7.10 (dd, J=8.0,5.0 Hz, 1H), 6.90 (dd, J8.0,2.3 Hz, 1H), 6.75 (ddd, J=8.0,8.0.2.3 Hz, 1H),

3.79 (5, 2H), 3.18 (d, J=1.5 Hz, 2H), 2.22 (d, J=10.0 Hz, 1H), 1.92 (dd, J=10.0,1.5 Hz, 1H).

GOMS mle 194 (Mt).


C) 1 0-Benzyl-4-fluoro-1 0-aza-tricyclo[6.3. 1 .0~-~]dodeca-2(7),3,5-triene

6-Fluoro- 1 ,2,3,4-tetrahydro-1 ,4-inethano-naphthalene-2, 3-diol (524 mg, 2.68 minol) and Et3NBnCI (10 ing) were vigorously stirred in dichloroethane (15 inL) and H20 (45 mL) then treated with sodium periodate (0.603 ing, 2.82 minol). After 1.5 hours, the layers were separated and the aqueous layer extracted with DCE (2 x 20 inL). The combined organic layer was washed with H20 (4 x 20 inL) until no reaction to starch iodide paper was observed, then with saturated aqueous NaCI solution (20 inL). The organic layer was dried through a cotton plug and treated with benzyl amine (0.308 inL, 2.82 minol) and stirred for 2 minutes then transferred to an addition funnel. This solution was added over '-10 minutes to a vigorously stirred cooled (0 0C) mixture of NaHB(OAc)3 (1.82 g, 8.58 ininol) in DOE (50 inL). After addition was complete, the mixture was stirred without cooling for 2 hours. The mixture was quenched with saturated aqueous Na2003 solution (100 inL) and stirred for 1 hour, then the layers were separated and the aqueous layer was extracted with CH2CI2 (3 x 30 inL). The combined organic layer was washed with saturated aqueous NaCI solution (50 inL), dried through a cotton plug and concentrated. Chromatography on Silica gel provided an oil (520 ing, 80%). (TLC 2% acetone/CH2CI2 R1 0.40). 1H NMR (400 MHz, CDCI3) & 7.18 (in, 1H), 6.88 (in, 2H), 3.48 (5, 2H), 3.06 (in, 2H), 2.78 (in, 2H), 2.41 (in, 2H), 2.27 (in, 1H), 1.69 (d, J10.5 Hz, 1H).


D) 4-Fluoro-1 0-aza-tricyclo[6.3. 1 .0~Idodeca-2(7), 3, 5-triene hydrochloride

1 0-Benzyl-4-fluoro-1 0-aza-tricyclo[6. 3.1 .02'7]dodeca-2(7), 3,5-triene (390 ing, 1.461 minol), aininoniuin forinate (3.04 g, 48.2 inmol) and 10%Pd(OH)2/C (30 ing) were combined in MeOH (50 inL) and brought to reflux under N2 for 1.5 hours. Aininoniuin formate (1.0 g) was added and reflux continued for 0.5 hour. The reaction mixture was filtered through a Celite pad which was rinsed with MeOH. The filtrate was concentrated. The residues were treated with saturated aqueous Na2003 solution (30 inL) and product extracted with methylene chloride (CH2CI2) (3 x 25 inL). The organic layer was washed with saturated aqueous NaCI solution (50 inL), dried through a cotton plug and concentrated. The residue was treated with 2N HCI MeOH (5 mL) and concentrated then taken up in minimum of MeOH and saturated with Et2O. After stirring 18h, the white crystals were collected by filtration (86 mg, 28%). (TLC

5% MeOH/CH2CI2 (NH3) Rf 0.27). (data for free base) 1H NMR (400 MHz, CDCI3) 8 7.06 (in,

1H), 6.83 (in, 2H), 2.89 (in, 4H), 2.61 (dd J=12.0 Hz, 2H), 2.37 (in, 1H), 1.87 (d, J=11.5 Hz,

1H). APOI MS m/e 178.2 [(M + 1)~]. (HOI salt) mp 260-262 ~C.


EXAMPLE 3
27
4-METHYL-i 0-AZA-TRICYCLO[6. 3.1 .0—]DODECA-2(7),3,5-TRIENE

HYDROCHLORIDE

The title compound was prepared by the methods described in Example 1 and 2

starting with 2-fluoro-5-inethylbroinobenzene. (data for free base) 1H NMR (400 MHz, CDCI3)

87.04 (d, J=7.5 Hz, 1H), 6.99 (5, 1H), 6.98 (d, J=7.5 Hz, 1H), 2.98-2.90 (in, 4H), 2.63 (in, 2H),

2.35 (in, 1H), 2.32 (5, 3H), 1.87 (d, J11.5 Hz, 1H). APOI MS mle 174.2 [(M + 1)~]. (HOI salt)

mp 254-255 0C Anal Calcd for C12H,2F~N.HCl.1/3H2O: C, 53.44; H, 5.11; N, 5.19. Found C,

53.73; H, 4.82; N, 5 15

EXAMPLE 4

4-TRIFLUOROMETHYL-1 0-AZA-TRICYCLOf6.3. 1 .0~]DODECA-2(7),3,5-TRlENE

HYDROCHLORIDE (See Grunewald, G. L.; Paradkar, V. M.; Pazhenchevsky, B.; Pleiss, M.

A.; Sail, D. J.; Seibel, W. L.; Rei~, 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 Example 1 and 2

starting with 2-fluoro-5-trifluoroinethylbromobenzene. 'H NMR (400 MHz, CD3OD) 8 7.71 (5,

1H), 7.64 (d, J=8.0 Hz, 1H), 7.57 (d, J=8 0 Hz, 1H). 3.46 (in, 4H), 3.21 (d, J=12.5 Hz, 2H),

2.41 (in, 1H), 2.16 (d, J11.5 Hz, 1H). APOI MS mle 228.2 [(M + 1)]. (HOI salt) mp 244-246

CC Anal Calcd. for C,2H12F3N.HCI.1/3H20: C, 53.44; H, 5.11: N, 5.19. Found C, 53.77; H,

482, N, 5 18


EXAMPLE 5

3-TRIFLUOROMETHYL-1 0-AZA-TRICYCLO[6 3 1 &-~]DODECA-2(7),3,5-TRlENE HYDROCHLORIDE (Grunewald, G. L.; Markovich, K M, SaIl, D. J. J. Med. Chem. 1987, 30, 2 191-2208.)

The title compound was prepared by the methods described in Example 1 and 2 starting with 2-fluoro-6-trifluoroinethylbromobenzene. 1H NMR (400 MHz, CD3OD) 8 7.65 (5, 2H), 7.52 (in, IH), 3.65 (br s, 1H), 3.49-3.43 (in, 3H), 3.20 (in, 2H), 2.42 (in, 1H), 2.18 (d, J=1 1.5 Hz, 1 H). APCI MS mle 228.2 [(M + 1 )~]. (HCI salt) mp 275-277 0C.

EXAMPLE 6
27

3-FLUORO-1 0-AZA-TRICYCLO[6.3.1 .0—1DODECA-2(7),3,5-TRIENE HYDROCHLORIDE

A) 2,6-Difluoroiodobenzene (Roe, A. M.; Burton, R. A.; W;lley, G. L.; Baines, 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.; Arrington, H. S.; Bartlett, W. J.; Reitz, T J, SaIl, D. J. J. Med. Chem. 1986, 29, 1972-1982.) 1,3-Difluorobenzene (57.05 g, 0.5 M) in THF (75 inL) was added to a -78 0C stirred solution of n-butyllithiuin (n-Bu Li) (200 inL, 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 0C. 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 inL) 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 inL) and 10% aqueous Na2S2O3 solution (100 inL) and stirred. The layers were separated and the aqueous layer extracted with hexanes (2 x 250 inL). The combined organic layer was washed with 10% aqueous Na2S2O3 solution (100 inL), H20 (100 inL), saturated aqueous NaCI solution (100 inL), dried (Na2SO4) filtered and concentrated to give a yellow oil (106.5 g). Distillation at —1-5 mm at —80 00 provided a light yellow oil (89.5 g, 75%). 'H NMR (400 MHz, CDCI3)8 7.30 (in, 1H), 6.87 (in, 2H) GOMS m/e 240 (Mt).


B) 5-Fluoro-1 ,4-dihydro-1 ,4-inethano-naphthalene

A solution of 2,6-difluoroiodobenzene (5.0 g, 20.8 ininol) and cyclopentadiene (2.07 g, 31.3 ininol) was stirred at 0 ~C in P. ether (70 inL, 40-60 ~C) under N2 and treated with n-BuLi (8.74 inL, 2.5M in hexanes, 21.8 ininol) dropwise over 10 minutes. The reaction was quenched after 15 minutes by addition of aqueous iN HCI solution and the product was extracted with hexanes (3 x 50 mL). The combined organic layer was washed with H20 (50 inL), saturated aqueous NaCI solution (50 inL), dried (MgSO4), filtered and evaporated. Chromatography on Silica gel provided product as an oil (1.5 g, 45%) (TLC hexanes R~ 0.55). 'H NMR (400 MHz, CDCI3) ~ 7.08 (ddd, J7 0,1 0,08 Hz, 1H), 6.96 (ddd, J=8.5,8.3,7.0 Hz, 1H), 6.86 (brs, 2H), 6.72 (ddd, J~8.5,8.3,0.8 Hz, 1H), 4.25 (brs, 1H), 3.98 (brs, 1H), 2.36 (ddd, J7.2,1.7,1.7 Hz, 1H), 2.30 (ddd, J=7.2,1.7,1.5 Hz, 1H). GOMS m/e 160 (M~).
C) 3-Fluoro-1 0-aza-tricyclo[6.3. 1. &+dodeca-2(7),3, 5-triene hydrochloride

The title compound was prepared by the methods described in Example 2B,C,D

starting with 5-fluoro-1,4-dihydro-1,4-inethano-naphthalene. 1H NMR (400 MHz, CD3OD) 6

7.36 (ddd. J=8.3,7.3,5.0 Hz, 1H), 7.21 (d. J=7.3 Hz, 1H), 7.07 (t, J8.3 Hz, 1H), 3.62 (br s,

1H), 3.42-3.30 (in, 3H), 3.21 (in, 2H), 2.38 (in, 1H), 2.12 (d, J=11.5 Hz, 1H). APOI MS mie

178.4 [(M + 1)]. mp 269-271 0C.

EXAMPLE 7
27
4-NITRO-1 0-AZATRICYCLO[6.3. 1 .0—'-]DODECA-2(7),3,5-TRIENE

HYDROCHLORIDE

All -(1 0-Aza-tricyclo[6. 3.1 .&-~]dodeca-2(7),3, 5-trien-1 0-yl)-2,2,2-trifluoro-ethanone
2.7

1 0-Aza-tricyclo[6.3. 1.0 ]dodeca-2(7), 3, 5-triene hydrochloride salt (12.4 g, 63.9 minol) was stirred in CH2CI2 (200 inL). This was cooled (ice bath) and treated with pyridine

(12.65 g 160 ininol) followed by trifluoroacetic anhydride (TFAA) (16.8 g, 11.3 inL, 80 ininol) from an addition funnel over 10 minutes. After —3 hours, the solution was poured into 0.5N aqueous HCI (200 inL) and the layers separated. The aqueous layer was extracted with CH2CI2 (3 x 50 inL) and the combined organic layer was washed with 0.5N aqueous HOl (50 mL), H20 (2 x 50 inL) and saturated aqueous NaHCO3 solution (50 inL). This solution was dried through a cotton plug, then diluted with '-3% EtOAc and filtered through a 2 inch Silica pad eluted with —3% EtOAc/CH2CI2. Concentration afforded a clear oil which crystallized to give white needles (15.35 g, 60.2 ininol, 94%). (TLC 30% EtOAc/hexanes R~ 0.53). 1H NMR (400 MHz. CDCI3) 8 7.18 (in, 4H), 4.29 (br d, J=12.6 Hz, 1H), 3.84 (br d, J=12.6 Hz, 1H), 3.51 (dd, J=12.6,1.5 Hz, 1H), 3.21 (br s, 1H), 3.10 (br 5, 1H), 3.10 (br d, J=12.6 Hz, 1H), 2.37 (in, 1H), 1.92 (d, J=10.8 Hz, 1H). GCMS mie 255 (Ml). inp67-68 00.

27


B) 1 -(4-Nitro-1 0-aza-tricyclo[6. 3.1 .0—]dodeca-2(7),3, 5-trien-1 0-yl)-2,2,2-trifluoro-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 trifluoroinethanesulfonic acid (2.4 ml, 13.7 minol) in CH2CI2 (10 ml) stirred at 0 00 was slowly added nitric acid (0.58 ml, 27.4 ininol) generating a white precipitate. After 10 minutes the resulting mixture was cooled to -78 0C and treated with 1-
2.7

(1 0-aza-tricyclo[6.3. 1.0 ]dodeca-2(7),3, 5-trien-1 0-yl)-2,2,2-trifluoro-ethanone (3.5 g, 13.7 minol) in CH2CI2 (15 ml) dropwise from an addition funnel over 5 minutes. The reaction was

stirred at -78 00 for 30 minutes then warmed to 0 0C 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 NaHCO3 solution (20 inL) and H20 (20 inL) 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% EtOAc/hexanes Rf 0.23). 'H NMR (400 MHz, CDCI3) 5 8.12 (br d. J=8.0 Hz, 1H), 8.08 (br s, 1H), 7.37 (br d, J=8.0 Hz, 1H), 4.38 (br d, J=12.6 Hz, 1H), 3.94 (br d, J=12.6 Hz, 1H), 3.59 (br d, J=12.6 Hz, 1H), 3.43-3.35 (in, 2H), 3.18 (br d, J=12.6 Hz, 1H), 2.48 (in, 1H), 2.07 (d, J=10.8 Hz, 1H). GCMS mle 300 (M).

27


C) 4-Nitro-1 0-azatricyclo[6. 3.1 .0—]dodeca-2(7), 3,5-triene hydrochloride

1 -(4-Nitro-1 0-aza-tricyclo[6.3. 1.02~7]dodeca-2(7),3,5-trien-1 0-yl)-2,2,2-trifluoro-ethanone (182 ing, 0.61 ininol) was stirred with Na2003 (160 ing, 1.21 minol) in MeOH (3 mL) and H20 (1 inL) at 70 0C 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 HCI (3 x 20 mL) and the acidic layer washed with CH2CI2 (2 x 20 mL). The aqueous layer was basified to pH —10 with Na2003(s) and product was extracted with CH2CI2 (3 x 30 inL). The organic layer was dried through a cotton plug and concentrated to an oil. This was dissolved in MeOH and treated with iN HOl MeOH, concentrated to solids which were recrystallized from MeOH/Et2O to afford product as a white solid (73 ing, 50%). (TLC 5% MeOH/CH2CI2 (NH3) R~ 0.38). 'H NMR (400 MHz, DMSO-d6) 58.21(s, 1H), 8.18 (dd, JZ8.0,2.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 3.43 (br s, 2H), 3.28 (in, 2H), 3.07 (dd, J= 13.0,13.0 Hz, 2H), 2.24 (in, 1H), 2.08 (d, J=11.5 Hz, 1H). APOI MS m/e 205.1 [(M + 1)~] mp 265~27000


EXAMPLE 8

4-AMINO-i 0-AZATRICYCLO[6.3. 1 .0~]DODECA-2(7),3.5-TRlENE

HYDROCHLORIDE
27
4-Nitro-10-azatricyclof6.3.1.0 . ]dodeca-2(7),3,5-triene (500 ing, 2.08 ininol) was

stirred in 1,4-dioxane (40 inL) and treated with saturated aqueous Na2CO3 solution (15 mL). To this was added di-t-butyldicarbonate (1.8 g, 8.31 minol). After stirring 18 hours the reaction was treated with H20 (50 inL), extracted with CH2CI2 (4 x 30 inL), dried through a cotton plug and concentrated to provide an oil (500 ing, 91%).

This oil (500 ing, 1.64 inmol) was dissolved in MeOH (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 Celite pad and concentrated to a clear oil (397 ing, 88%).


This oil (50 ing, 0.18 ininol) was stirred in 3N HCI EtOAc (3 inL) for 2 hours then concentrated to a white solid (25 mg, 56%). 'H NMR (400 MHz, DMSO-d6) 6 7.38-7.10 (3H), 3.60 (br s, 2H), 3.25 (in, 2H), 2.98 (in, 2H), 2.18 (in, iH), 1.98 (d, J11.5 Hz, iH). APOI MS in/e 175.1 [(M + i)*] mp 189-192 0C.


EXAMPLE 9
27
N1-[i 0-AZATRICYCLO[6.3.1 .0-~-]DODECA-2(7),3,5-TRI EN-4-YLJACETAMIDE

HYDROCHLORIDE
27
A) 1 -(4-Amino-i 0-aza-tricyclo[6. 3.1 .0—]dodeca-2(7), 3,5-trien-i 0-yl)-2,2,2-trifluoro-

ethanone
2.7
Hydrogenation of 1 -(4-nitro-1 0-aza-tricyclo[6.3. 1.0 ]dodeca-2(7), 3, 5-trien-1 0-yl)-

2,2,2-trifluoro-ethanone (2.0 g, 6.66 ininol) under a H2 atmosphere (40 psi) and 10%Pd/C (200

ing) in MeOH over 1.5 hours, filtration through Celite and concentration affords a yellow oil

(1.7 g). (TLC 50% EtOAc/hexanes Rf 0.27). ' NMR (400 MHz, CDCI3) 6 6.99 (in, iH), 6.64

(brs, iH), 6.57 (in, iH), 4.25 (in, 1H), 3.82 (in, 1H), 3.50 (in, 1H), 3.17-3.07 (in, 3H), 2.35 (in,

1H), 1.90 (d, J=10.8 Hz, iH). GOMS mle 270 (Mt).


27
B) N-( 1 0-Trifluoroacetyl-i 0-aza-tricyclo[6. 3.1 .0—]dodeca-2(7), 3, 5-trien-4-yl)-

acetainide
2.7
1 -(4-Amino-i 0-aza-tricyclo[6. 3.1 .0 ]dodeca-2(7) 3, 5-trien-1 0-yl)-2,2,2-trifluoro-

ethanone (850 ing, 3.14 minol) was stirred in CH2CI2 (5 inL) and treated with triethyl amine (0.53 inL, 3.76 inmol) and acetyl chloride (0.23 inL, 3.2 minol) then stirred 18 hours. Standard NaHCO3 workup yielded an oil which was chroinatographed to provide a clear oil (850 ing, 87%). (50% EtOAc/hexanes R1 0.28).


C) N~-[i 0-Azatricyclo[6. 3.1. &-~]dodeca-2(7), 3, 5-trien-4-yl]acetamide hydrochloride
2.7
N-( 1 0-Trifluoroacetyl-1 0-aza-tricyclo[6.3. 1.0 ]dodeca-2(7), 3, 5-trien-4-yl)-acetainide

(100 ing, 0.32 ininol) was stirred with Na2003 (70 ing, 0.64 inmol) in MeOH (10 inL) and H20

(2 mL) at 70 0C for 18 hours. The mixture was concentrated, water was added and the

product was extracted with EtOAc. The organic layer was extracted with 1 N aqueous HCI (3 x

20 mL) and the acidic layer washed with EtOAc (2 x 20 mL). The aqueous layer was basified

to pH —10 with Na2003 (5) and product was extracted with EtOAc (3 x 20 inL). The organic

layer was dried (sodium sulfate (Na2SO4)) and concentrated to an oil. This material was

dissolved in MeOH and treated with 3N HCI EtOAc (3 mL), concentrated and recrystallized

from MeOH/Et2O to provide a solid (40 ing, 50%). 1H NMR (400 MHz, DMSO-d6) 5 9.98 (5, iH), 9.02 (br in, NH), 7.65 (5, iH), 7.55 (br 5, NH), 7.38 (d, J8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, iH), 3.33 (in, 4H), 2.96 (in, 2H), 2.13 (in, iH), 2.00 (5, 3H), 1.96 (d, J=10.5 Hz, iH). APOI MS m/e 217.2 [(M + i)]. mp 225-230 00


EXAMPLE 10

6-METHYL-5-THIA-7, I 3-DIAZATETRACYCLOf9.3. 1 ~ 8]PENTADECA-

2(i0),3,6,8-TETRAENE HYDROCHLORIDE

A) N-( 1 0-Trifluorothioacetyl-1 0-aza-tricyclo[6 3.1 .0~]dodeca-2(7), 3,5 -trien-4-yl)-th ioacetainide

N-( 1 0-Trifluoroacetyl- 1 0-aza-tricyclo[6. 3.1 .027]c 3deca-2(7), 3, 5-trien-4-yl)-acetainide

(850 ing, 2.72 ininol) and 2,4-bis(4-methoxyphenyl)-1 ,3-dithia-2,4-diphosphetane-2,4-disulflde (Lawesson's reagent) (1.1 g, 2.72 ininol) were combined in toluene (10 inL) and brought to reflux for 1.5 hours. After cooling the reaction was wori~ed up with EtOAc/saturated aqueous NaHCO3 solution. The organic layer was dried i.Na2SO4), filtered, concentrated and chron,atographed on Silica gel to produce product (410 ing, 44%). (50% EtOAc/hexanes R~ 0.38)


B) 6-Methyl-5-thia-7,1 3-diazatetracyclo[9.3. 1 .O~-20.0~-~1pentadeca-2( 10), 3,6, 8-tetraene hydrochloride
The above oil, 2,2 ,2-trrfluoro-N-( 1 O-trifluorothioacetyl-1 0-aza-
27

tricyclo~6.3.1.0 ]dodeca-2(7),3,5-trien-4-yl)-thioacetamide, (360 ing, 1.05 ininol) was dissolved in MeOH (10 inL) and iN NaOH (5 inL) and added to potassium ferricyanide

(K3Fe(CN)6)(1.72 g, 5.23 inmol) in H20 (10 inL). This mixture was warmed to 60 00 for 1.5 hours, cooled, concentrated and worked up with EtOAc/H20. This material was stirred in dioxane (20 inL) and treated with H20 (50 inL) and Na2003 to achieve pH 10. To this was added di-t-butyldicarbonate (436 ing, 2.0 ininol) and the mixture was stirred for 18 hours. The reaction was concentrated, treated with H20 and extracted with CH2CI2. The product was chroinatographed (Silica 30% EtOAc/hexanes R1 0.41) to yield an oil (100 ing).

The above product was treated with 3N HOI/EtOAc (3 inL) and warmed to reflux for

—15 minutes then concentrated to a solid which was azeotroped with CH2CI2 (2x). These solids were dissolved in a minimum amount of MeOH then saturated with Et2O and stirred. The resulting white crystalline powder was collected by filtration (40 ing, 14%).


'H NMR (400 MHz, DMSO-d6) 8 9.46 (5, NH), 7.65 (s, 1H), 7.82 (5, 1H), 7.65 (br in, NH), 3.36 (in, 2H), 3.24 (in, 2H), 3.02 (in, 2H), 2.76 (5, 3H), 2.23 (in, 1H), 2.06 (d, J10.8 Hz, 1H). APOI MS mle 231.1 [(M + 1)~]. mp 183-184 ~C.


EXAMPLE ii
27
4,5-DINITRO-1 0-AZA-TRICYCLO[6.3. 1 .0—]DODECA-2(7),3,5-TRIENE

A) 1 -(4, 5-Dinitro-i 0-aza-tricyclo[6.3. 1 .&-~1dodeca-2(7),3,5-trien-i 0-yI)-2,2,2-trifluoro-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.; Irie. T.; Tsushiina, T. J. Am. Chem. Soc. 1969, 91, 4512.)

To a solution of trifluoromethanesulfonic acid (79.8 ml, 902.1 ininol) in CH2CI2 (550 ml) stirred at 0 0C was slowly added nitric acid (19.1 ml, 450.9 inmol) generating a white
2,7

precipitate. After 10 minutes, 1 -(1 0-aza-tricyclo[6.3. 1.0 Idodeca-2(7), 3,5-trien-i 0-yl)-2,2,2-trifluoro-ethanone (50 g, 196 inmol) 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 NaHCO3 solution (200 inL) and H20 (200 mL) then dried through a cotton plug and concentrated to solids. Trituration with EtOAc/hexanes produced off white solids which were filtered and dried (52 g, 151 inmol, 77%. The mother liquor was chroinatographed to give an additional 4.0 g for a total of 56.0 g (82.8%). (TLC 50% EtOAc/hexanes R~ 0.29) 'H NMR (400 MHz, CDCI3) 8 7.77 (5, 1H), 7.75 (5, iH), 4.39 (br d, J=13.0 Hz, 1H), 3.98 (br d, J13.0 Hz, iH), 3.65 (d, J=13.0 Hz, 1H), 3.49 (br s, 1H), 3.44 (br s, 1H), 3.24 (br d, J12.6 Hz, 1H), 2.53 (in, 1H), 2.14 (d, J=1 1.5 Hz, 1 H). GOMS mle 345 (M).

27


B) 4, 5-Dinitro-1 0-aza-tricyclo[6. 3.1 . 0—]dodeca-2(7),3, 5-triene

1 -(4, 5-Dinitro-1 0-aza-tricyclo[6. 3.1 .02 7]dodeca-2(7), 3, 5-trien-1 0-yl)-2 .2 .2-trifluoro-ethanone (3.7 g, 10.7 inmol) and Na2003 (2.3 g. 21 .4 inmol) were combined in MeOH (50 inL) and H20 (20 inL) 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 chroinatographed to provide brown solids. (1.9 g, 71%).


(TLC 5% MeOF~/CH2Cl2 (NH3) R1 0.36). 'H NMR (400 MHz, CDCI3) 5 7.69 (5, 2H), 3.17 (br s,

2H), 3.11 (d, J=12.6 Hz. 2H), 2.53 (in, iH), 2.07 (d, J=1 1.0Hz, iH). GCMS mle 249 (M).


EXAMPLE 12

6-METHYL-7-PROPYL-5,7, 1 3-TRIAZATETRACYCLO[9 3 1 O~-~O4 8]PENTADECA-

2(1 0),3,5,8-TETRAENE HYDROCHLORIDE

A) 4, 5-Dinitro-1 0-aza-tricyclo[6. 3.1 .0~-7~]dodeca-2(7),3, 5-triene-1 0-carboxylic acid tertbutyl ester

4,5-Dinitro-1 0-a.za-tricyclo[6.3. 1.02'7]dodeca-2(7). 3,5-triene, (1.9 g, 7.6 minol) was stirred in 1,4-dioxane (75 inL) and treated with saturated aqueous Na2003 solution (10 inL). To this was added di-t-butyldicarbonate (3.31 g, 15.2 ininol). After stirring 6 hours the reaction was treated with H20 ( 50 inL) and extracted with EtOAc (4 x 25 inL), dried (Na2SO4), filtered, concentrated and chroinatographed to provide product (1.9 g, 71%). (TLC 30% EtOAc/hexanes (NH3) Rf 0.58). 'H NMR (400 MHz, CDCI3) 5 7.77 (br s, iH), 7.72 (br s, iH), 4.08 (in, 1H), 3.92 (in, 1H), 3.39 (br 5, 1H), 3.27 (br s, 1H), 3.25 (in, iH), 3.18 (in, 1H), 2.46 (in, 1H), 2.02 (d, J=i1.0 Hz, 1H).


27
B) 4,5-Diainino-1 0-aza-tricyclo[6. 3.1 .0—]dodeca-2(7), 3,5-triene-i 0-carboxylic acid

tert-butyl ester
2.7
4, 5-Dinitro-i 0-aza-tricyclo[6. 3.1.0 ]dodeca-2(7).3, 5-triene-1 0-carboxylic acid tertbutyl ester (1.9 g, 5.44 ininol) was hydrogenated in MeOH under a H2 atmosphere (45 psi) over 10%Pd/C (100 ing) for 1.5 hours then filtered through a Celite pad and concentrated to white solids (1.57 g, 100%). (TLC 5% MeOH/CH2CI2 (NH3) R1 0.14).


C) 6-Methyl-5,7. 1 3-triazatetracyclo[9.3. 1 ~ 10), 3,5, 8-tetraene-i 3-carboxylic acid tert-butyl ester (For conditions, see; Segelstein, B. E.; Chenard, B. L.; Macor, J. E.; Post, R. J. Tetrahedron Lett. 1993, 34,1897.)

4,5-Diamino-i 0-aza-tricyclo[6. 3.1.02~7Jdodeca-2(7),3, 5-triene-1 0-carboxylic acid tertbutyl ester (700 mg, 2.42 inmol) was dissolved in EtOH (10 inL) and acetic acid (HOAc) (1 inL) and treated with 1-ethoxyethyleneinalononitrile (329 mg, 2.42 minol). The resulting mixture was warmed to 60 CC and stirred 18 hours. The reaction was cooled, concentrated treated with H20 and saturated aqueous Na2003 solution and extracted with EtOAc (3 x 50 inL), then dried (Na2SO4). After~ filtration and concentration, the residue was



chroinatographed to provide brown solids (247 mg, 36%). (TLC 5% MeOH/CH2CI2 (NH3) R~ 0.28).

D) 6-Methyl-7-propyl-5, 7,1 3-triazatetracyclo[9.3. 1 .0~—~.0~-~]pentadeca-2(1 0)3,5,8-tetraene-13-carboxylic acid tert-butyl ester (For conditions, see; Pilarski, B. Liebigs Ann. Chem. 1983, 1078.)

6-Methyl-5,7, 1 3-triazatetracyclof9.3.i .02.10. 048]pentadeca-2(i 0),3,5,8-tetraene-i 3-

carboxylic acid tert-butyl ester (80 ing, 0.267 minol) was stirred in 50% aqueous NaOH solution (3 mL) and DMSO (1 inL) then treated with 1-iodopropane (0.03 mL, 0.321 ininol). This mixture was warmed to 40 0C for 2 hours then cooled, treated with H20 and extracted with EtOAc. The organic layer was washed with H20 (3x) then dried (Na2SO4), filtered and concentrated to an oil (90 ing, 0.253 ininol). (TLC 5% MeOH/CH2CI2 (NH3) R~ 0.15).


E) 6-Methyl-7-propyl-5, 7,1 3-triazatetracyclof 9.3.1. ~ 0~-~]pentadeca-2( 10)3,5,8-tetraene hydrochloride
2,10 48
6-Methyl-7-propyl-5,7,13-triazatetracyclo[9 3 1 0 .0 Ipentadeca-2(10),3,5,8-

tetraene-13-carboxylic acid tert-butyl ester (90 ing,~ 0.253 ininol) was dissolved in 3N HOl EtOAc (5 inL) and warmed to 100 ~C for 1/2 hour. The mixture was cooled, concentrated, slurried in EtOAc, and filtered to provide a white solid (25 ing, 34%). 1H NMR (400 MHz, DMSO-d6) 6 9.56 (5, NH), 7.91 (s, 1H), 7.83 (br in, NH), 7.74 (5, 1H), 4.38 (in, 2H), 3.48 (in, 2H), 3.32 (in, 2H), 3.10 (in, 2H), 2.87 (s, 3H), 2.28 (in, 1H), 2.15 (d, J=11.0 Hz, 1H) 1.85 (in, 2H), 0.97 (in, 3H). mp 147-1 50 00


EXAMPLE 13
210 48
5,7,1 3-TRIAZATETRACYCLO[9.3. 1 .0—.0—IPENTADECA-2(1 0),3.5,8-TETRAENE

HYDROCHLORIDE

A) 5,7,1 3-Triazatetracyclo[9.3. 1. ~ oi!Ipentadeca..2( 10)3, 5,8-tetraene-i 3-carboxylic acid tert-butyl ester (For conditions, see; Segelstein, B. E.; Chenard, B. L.; Macor, J. E.; Post, R. J. Tetrahedron Lett. 1993, 34,1897.)

4,5-Diainino-i 0-aza-tricyclo[6.3. 1 .027]dodeca-2(7),3,5-triene-1 0-carboxylic acid tertbutyl ester (1.0 g, 3.45 minol) was dissolved in EtOH (10 inL) and HOAc (1 inL) and treated with ethoxyinethyleneinalononitrile (421 ing, 3.45 inmol). The resulting mixture was warmed to 60 00 and stirred 18 hours. The reaction was cooled, concentrated treated with H20 and saturated aqueous Na2003 solution and extracted with EtOAc (3 x 50 inL), then dried


(Na2SO4). After filtration and concentration, the residue was chroinatographed to provide brown solids (580 ing, 56%). (TLC 5% MeOH/CH2CI2 (NH3) R~ 0.28)


~)- 5,7,1 3-triazatetracyclo[9. 3.1 .0~-'2.0~kpentadeca-2( 1 0),3,5,8-tetraene hydrochloride 5,7,1 3-Triazatetracyclo[9 3 1.02 10 0' 8]pentadeca-2(i 0),3,5,8-tetraene.1 3-carboxylic

acid tert-butyl ester was converted to the title compound by the methods described in Example 12E. 1H NMR (400 MHz, D20) 6 8.95 (5, iH), 7.67 (5, 2H), 3.45 (br s, 2H), 3.31 (d, J=12.5 Hz, 2H), 3.13 (d, J=12.5 Hz, 2H), 2.30 (in, 1H), 1.99 (d, J=1i.5 Hz, iH). APOI MS in/e 200.1 f(M + 1)1. mp >250CC


EXAMPLE 14

7-METHYL-5,7, 1 3-TRIAZATETRACYCLO[9 3 1 0~-~.0~1]PENTADECA-2(i 0)3,5,8-TETRAENE HYDROCHLORIDE

Utilizing the methods described in Example 12D, 5,7,13-triazatetracyclo[9.3. 1 .02'0.0'8]pentadeca-2( 1 0),3, 5,8-tetraene-i 3-carboxylic acid tert-butyl ester was converted to the title compound by reaction with iodomethane followed by deprotection as described in Example 12E. ' NMR (400 MHz, D20) 6 8.97 (s, 1H), 7.71 (5, 1H), 7.67 (5, 1H), 3.94 (5, 3H), 3.48 (in, 2H), 3.33 (d, J12.2 Hz, 2H), 3.14 (d, J=12.2 Hz, 2H),

2.34 (in, 1H), 2.03 (d, J=i1.5 Hz, 1H). APOI MS in/e 214.2 [(M +


EXAMPLE 15
210 48
6-METHYL-5,7,1 3-TRIAZATETRACYCLO[9.3. 1 .0—.0—]PENTADECA-2(1 0)3,5,8-

TETRAENE HYDROCHLORIDE

6-Methyl-5,7, 1 3-triazatetracyclo[9.3. 1 .02'0.0'8]pentadeca-2( 10), 3, 5,8-tetraene-1 3-

carboxylic acid tert-butyl ester was converted to the title compound by the methods described in Example 12E. 1H NMR (400 MHz, DMSO-d8) 6 9.40 (br in, NH), 7.77 (br in, NH), 7.70 (5, 1H), 3.44 (in, 2H), 3.30 (in, 2H), 3.05 (br d, J=1i.0 Hz, 2H), 2.79 (5, 3H), 2.23 (in, 1H), 2.10 (d, J=10.8 Hz, 1H). GOMS inie 213.5 (M4).


EXAMPLE 16
210 48
6,7-DIMETHYL-5,7, 1 3-TRIAZATETRACYCLO[9.3. 1 .0—0—IPENTADECA-

2(1 0),3,5,8-TETRAENE HYDROCHLORIDE

Utilizing the methods described in Example 12D, 6-inethyl-5,7,13-triazatetracyclo[9.3. 1 .02'0.0"8]pentadeca-2( 10), 3,5. 8-tetraene-1 3-carboxylic acid tert-butyl


ester was converted to the title compound by reaction with iodomethane followed by

deprotection as described in Example 12E. 1H NMR (400 MHz, DMSO-d6) 6 9.52 (5, NH),

7.84 (5, 1H), 7.82 (br in, NH), 7.72 (5, 1H), 3.90 (5, 3H), 3.45 (in, 2H), 3.28 (in. 2H), 3.04 (in,

2H), 2.82 (5, 3H), 2.23 (in, 1H), 2.12 (d, J=11.0 Hz, 1H). APOI MS mle 228.2 [(M + 1)]. mp

225-230 0C.


EXAMPLE 17

7-PROPYL-5,7, 1 3-TRIAZATETRACYCLO[9. 3.1 ~ 048]PENTADECA-2( 10), 3,5,8-TETRAENE HYDROCHLORIDE

Utilizing the methods described in Example 12D, 5,7.13-triazatetracyclo[9.3. 1.02~1o.04~6]pentadeca-2( 10), 3,5,8-tetraene-1 3-carboxylic acid tert-butyl ester was converted to the title compound by reaction with iodopropane followed by deprotection as described in Example 12E. 'H NMR (400 MHz, DMSO-d8) 6 9.52 (5, iH), 9.45 (br s, NH), 7.97 (s, 1H), 7.85 (5, 1H), 7.83 (br in, NH), 4.43 (in, 2H), 3.49 (in, 2H), 3.33 (in, 2H), 3.08 (in, 2H), 2.28 (in, iH), 2.15 (d, J=i1.0 Hz, 1H), 1.92 (in, 2H), 0.93 (in, 3H). APCI MS mle 242.2 [(M + i)]. mp 170-171 0C (subl.).


EXAMPLE 18
210 48
7-BUTYL-5,7, 1 3-TRIAZATETRACYCLO[9.3. 1 .0—.0—]PENTADECA-2(1 0),3,5,8-

TETRAENE HYDROCHLORIDE

A) 4-Butylainino-5-nitro-i 0-aza-tricyclo[6.3. 1 .0~-~idodeca-2(7), 3, 5-triene-1 0-carboxylic acid tert-butyl ester (For conditions, see; Senskey, M D, Bradshaw, J. D.: Tessier, C. A.:

Youngs, W. J. Tetrahedron Lett. 1995, 36, 6217.)
2,7

4,5-Dinitro-1 0-aza-tricyclo[6. 3.1.0 ]dodeca-2(7) ,3,5-triene-1 0-carboxylic acid tertbutyl ester (500 mg, 1.43 inmol) and 1-butylamine (1.42 inL, 14.3 ininol) were combined in

THF (5 inL) and stirred 4 hours. The mixture was diluted with EtOAc (50 mL) and washed with H20 (3 x 30 inL) then dried (Na2SO4), filtered and concentrated to an oil This oil was passed through a Silica gel filter column to remove baseline impurities eluting with 30% EtOAc/hexanes (510mg, 1.41 ininol, 99%).


B) 4-Butylamino-5-ainino-1 0-aza-tricyclo[6.3. 1 .0~-~]dodeca-2(7), 3,5-triene-1 0-carboxylic acid tert-butyl ester

4-Butylainino-5-nitro- 1 0-aza-tricyclo[6.3. 1. 027]dodeca-2(7),3, 5-triene-1 0-carboxylic

acid tert-butyl ester (460 ing, 1.27 inmol) was treated with aminoniuin forinate (850 ing, 12.7


minol) and i0%Pd(OH)2/C (50 ing) in MeOH (20 inL) and brought to reflux for 1 hour then filtered through a Celite pad and concentrated. The solids were treated with saturated aqueous Na2CO3 solution, extracted with CH2CI2 (3 x 30 inL) and dried by filtration through a cotton plug to give an oil (440 ing, 100%).


C) 7-Butyl-5, 7,1 3-triazatetracyclof9. 3.1 ~ 10)3, 5,8-tetraene-1 3-carboxylic acid tert-butyl ester

4-Butylainino-5-ainino-i 0-aza-tricyclo[6. 3.1 .027]dodeca-2(7),3, 5-triene- 1 0-carboxylic acid tert-butyl ester (440 ing, 1.27 ininol) was dissolved in EtOH (20 mL) and HOAc (2 inL) and treated with ethoxyinethylenemalononitrile (186 ing, 1.52 ininol). The resulting mixture was warmed to 60 0C and stirred 18 hours. The reaction was cooled, concentrated, treated with H20 and saturated aqueous Na2003 solution then extracted with EtOAc (3 x 50 inL) and dried (Na2SO4). After filtration and concentration, the residue was chroinatographed to provide a yellow oil. (400 ing, 89%). (TLC 5% MeOH/CH2CI2 (NH3) R~ 0.70).

210 48


D) 7-Butyl-5,7, 1 3-triazatetracyclo[9.3. 1.0—. 0—Ipentadeca-2( 10)3,5, 8-tetraene hydrochloride

7-Butyl-5,7, 1 3-triazatetracyclo[9. 3.1.02~1o.04~8]pentadeca-2( 10)3, 5,8-tetraene-1 3-

carboxylic acid tert-butyl ester was converted to the title compound by the methods described

in Example 12E. 1H NMR (400 MHz, DMSO-d6) ~ 9.93 (brs, NH), 9.68 (5, 1H), 7.99 (5, iH),

7.92 (br in, NH), 7.87 (5, IH), 4.50 (in, 2H), 3.49 (in, 2H), 3.30 (in, 2H), 3.08 (in, 2H), 2.26 (in,

1H), 215 (d, J=i1.0 Hz, 1H), 1.88 (in, 2H), 1.32 (in, 2H), 0.82 (t, J=7.0 Hz, 3H). APOI MS mie

256.2 [(M + 1 )]. mp 204-208 CC


EXAMPLE 19
210 48
7-lsobutyl-5,7, 1 3-triazatetracyclo[9.3. 1 .0-~—.0—]pentadeca-2( 10), 3,5,8-tetraene

hydrochloride

4, 5-Dinitro-1 0-aza-tricyclo[6.3. 1. 027]dodeca-2(7), 3, 5-triene-1 0-carboxylic acid tertbutyl ester and isobutylainine were converted to the title compound utilizing the methods described in Example 18A-D. ~ NMR (400 MHz, CDCI3) 87.74 (5, 1H), 7.52 (s, 1H). 7.14 (5, 1H), 3.90 (dd, J=7.5,2.0 Hz, 2H), 3.04-2.97 (in, 4H), 2.70 (dd, J=12.8,2.3 Hz, 2H), 2.42 (in, 1H), 2.19 (in, 1H), 1.98 (d, J=10.5 Hz, 1H), 0.93 (in, 6H). APCI MS mle 256.2 [(M + 1)*I. mp


EXAMPLE 20

6-M ETHYL-7-ISOBUTYL-5, 7,1 3-TRIAZATETRACYCLO[9. 3.1. 0~-~~-.048]PENTADECA-

2(1 0),3,5,8-TETRAENE HYDROCHLORIDE


A) 6-Methyl-7-isobutyl-5.7, 1 3-triazatetracyclo[9.3. 1 .0~-~~.0~1]pentadeca-2( 10), 3,5,8-tetraene-1 3-carboxylic acid tert-butyl ester

4-Amino-5-isobutylamino-1 0-aza-tricyclo[6.3. 1.02~7]dodeca-2(7),3,5-triene-1 0-

carboxylic acid tert-butyl ester (250 mg, 0.74 ininol) from Example 19B was dissolved in EtOH (10 inL) and HOAc (2 mL) and treated with i-ethoxyethylenemalononitrile (118 ing, 0.87 ininol). The reaction proceeded as in Example 180 (18h) and was worked up similarly to provide product (TLC 3% MeOHICH2CI2 (NH3) Rf 0.57).


B) 6-Methyl-7-isobutyl-5. 7,1 3-triazatetracyclo[9. 3.1 . 0~. 0~]pentadeca-2( 10), 3,5,8-tetraene hydrochloride

6-Methyl-7-isobutyl-5,7, 1 3-triazatetracyclo[9. 3.1.02~jo.04•8Ipentadeca-2( 10), 3,5,8-

tetraene-1 3-carboxylic acid tert-butyl ester was converted to the title compound by the methods described in Example 12E. APOI MS mle 270.3 [(M + i)~]. nip 129-130 00 (subl.).


EXAMPLE 21
210 48
7-PHENYL-5,7, 1 3-TRIAZATETRACYCLO[9.3. 1 .0—.0-—]PENTADECA-2(10),3,5,8-

TETRAENE HYDROCHLORIDE

Utilizing the methods described in Example 18A, 4,5-dinitro-lO-aza-tricyclo[6.3.1 .027]dodeca-2(7),3,5-triene-iO-carboxylic acid tert-butyl ester and aniline were converted to 4-phenylainino-5-nitro-1 0-aza-tricyclo[6. 3.1 .027]dodeca-2(7), 3, 5-triene-1 0-carboxylic acid tert-butyl at 75 00 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) 69.08 (1H), 7.78-7.57 (in, 7H), 3.47-3.00 (in, 6H), 2.23 (in, 1H), 2.09 (d, J=11.5 Hz, 1H). APOI MS mle 276.2 [(M + 1)]. mp 210~213CC


EXAMPLE 22
210 48
6-METHYL-7-PHENYL-5,7, 1 3-TRIAZATETRACYCLO[9 3 1 0—0 ]PENTADECA

2(10),3,5,8-TETRAENE HYDROCHLORIDE

Utilizing the methods described in Example 21 and Example 20, 4,5-dinitro-lO-aza-tricyclo[6.3. 1 .027]dodeca-2(7), 3,5-triene-i 0-carboxylic acid tert-butyl ester and aniline were

converted to th~ title compound. 1H NMR (400 MHz, DMSO-d6) 8 7.79 (s, 1H), 7.73-7.56 (in, 5H), 7.32 (5, 1H), 3.46-2.99 (in, 6H), 2.66 (s, 3H), 2.23 (in, iH), 2.08 (d, J11.0 Hz, 1H). APCI MS mle 290.2 [(M + i)*]. mp >250 00


EXAMPLE 23
210 48
7-NEOPENTYL-5,7, 1 3-TRIAZATETRACYCLO[9.3. 1 .0----.0 IPENTADECA

2(1 0),3,5,8-TETRAENE HYDROCHLORIDE

Utilizing the methods described in Example 18A-D, 4,5-dinitro-lO-aza-
27
tricyclo[6.3.i.0 ' Jdodeca-2(7),3,5-triene-i0-carboxylic acid tert-butyl ester and

neopentylainine were converted to the title compound. t-Boc precursor GOMS mle 369 (M~). (HOI salt) mp >250 0C.


EXAMPLE 24

6-METHYL-7-NEOPENTht5,7,i 3-TRIAZATEIRACYCLO(9.3.1 .0~]PENTADEC~2(1 0)3,5,8-TETRAENE HYDROCHLORIDE

Utilizing the methods described in Example 21 and 20, 4,5-dinitro-lO-aza-
27

tricyclof6 3 1.0 ]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester and neopentylainine were converted to the title compound. 1H NMR (400 MHz, DMSO-d6) 8 7.31

(5 ,iH), 7.27 (5 ,iH), 7.02 (br s, , NH), 4.41 (t, J=13.0 Hz, 2H), 3.90 (5, 3H), 3.47-3.26 (in, 6H),

2.20 (in, 1H), 2.00 (d, J=11.5 Hz, 1H), 0.90 (s, 9H). t-Boc precursorAPOl MS mle 384.2 [(M +

1)]. inp>2500C.


EXAMPLE 25

6,7-oIMETHYL-5,8,14-TRIAZATErRACYCLQ1O.3.i .0~".~J-e(ADEQA-2(1 1 ),3,5,7,9-PENTAENE HYDROCHLORIDE (Based on the following procedure: Jones, R. G.; McLaughlin, K. C. Org. Syn. 1963, 4, 824. b) Ehrlich, J., Bobert, M. T. J. Org. Chem. 1947, 522.)

4,5-Diamino-1 0-aza-tricyclo[6 3 1 02 7]dodeca-2(7), 3,5-triene-1 0-carboxylic acid tertbutyl ester (100 mg, 0.35 inmol) was warmed to 80 ~C in H20 (5 inL). To this butane 2,3-dione (0.034 mL, 0.38 ininol) was added under N2 for 2 hours. The reaction was cooled to room temperature and extracted with EtOAc (3 x 40 ml). The combined organic layer was washed with H20 (2 x 30 ml), dried (Na2SO4), filtered, concentrated and chromatographed on Silica gel to provide an oil (120 ing, 100%). The oil was dissolved in 2N HCI MeOH (5 inL) and warmed to reflux for 30 minutes, then concentrated. Recrystallization from MeOH/Et2O provided a white powder (50 ing, 43%). (TLC EtOAc R~ 0.14). 1H NMR (400 MHz, DMSO-d6)



8 7.85 (5, 2H), 3.50 (br s, 2H), 3.32 (d. J=12.5 Hz, 2H), 3.10 (d, J=12.5 Hz, 2H), 2.64 (5, 6H),

2.24 (in, iH), 2.13 (d, J=ii.0 Hz, 1H). t-Boc precursor APCI MS mle 340.3 [(M +


EXAMPLE 26

5,8,14-TRIAZATETRACYCLO[1 0.3.1 .0~-1-1.&-~]HEXADECA-2(1 1 ),3,5,7,9-PENTAENE

HYDROCHLORIDE
27
A) 1 -(4,5-Diamino-i 0-aza-tricyclo[6. 3.1 .0—]dodeca-2(7),3, 5-trien-1 0-yl)-2,2 ,2-trifluoro-

ethanone

1 -(4 ,5-Dinitro-1 0-aza-tricyclo(6. 3.1 .02'7]dodeca-2(7),3,5-trien-i 0-yl)-2,2,2-trifluoro-ethanone (3.0 g, 8.70 ininol) was hydrogenated in MeOH (30 ml) under H2 (45 psi) over Pd(OH)2 (300 ing of 20 wt%/C, 10%wt). After 2.5 hours the reaction was filtered through a Celite pad and rinsed with MeOH (30 ml). The solution was concentrated to a light brown oil which crystallized (2.42 g, 96%). (TLC 10% MeOH/CH2CI2 R~ 0.56). APOI MS mle 286.2 [(M + 1)]. mp 129-131 CC


B) 1 -(5,8,1 4-Triazatetracyclo[1 0.3.1 .0~~1.0~]hexadeca-2(1 I ),3,5,7,9-pentaene)-2,2,2-trifluoro-ethanone

1 -(4 ,5-Diainino-i 0-aza-tricyclo[6.3. 1 .02']dodeca-2(7), 3, 5-trien-i 0-yl)-2,2,2-trifluoro-ethanone (500 ing, 1.75 ininol) was stirred in THF (2 ml). This mixture was treated with H20 (2 inL) and glyoxal sodium bisulfite addition compound hydrate (931 ing, 3.50 ininol) then stirred at 55 0C for 2.5 hours. The reaction was cooled to room temperature and extracted with EtOAc (3 x 40 ml). The combined organic layer was washed with H20 (2 x 30 ml), dried (Na2SO4), filtered, concentrated and chroinatographed on Silica gel to provide an off white powder (329 mg, 60%). (TLC 25% EtOAc/hexanes R1 0.40). mp 164-166 ~C.
211 49


C) 5,8,14-Triazatetracyclof 1 0.3.1 .0—.0—]hexadeca-2(1 1 ),3,5,7,9-pentaene hydrochloride

1-(5,8,14-Triazatetracyclo[1 0 3 1 02 11 049]hexadeca-2(1 1 ),3,5,7,9-pentaene)-2,2,2-trifluoro-ethanone (320 ing, 1.04 inmol) was slurried in MeOH (2.0 ml) and treated with Na2003 (221 ing, 2.08 ininol) in H20 (2.0 ml). The mixture was warmed to 70 00 for 2 hours, then concentrated, treated with H20 (20 inL) 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 ing, 83%) which solidified upon standing (mp 138-140 ~C) This material was dissolved in MeOH (10 inL), treated with 3M HCI/EtOAc (3 ml), concentrated and azeotroped with MeOH

(2 x 20 inL) to give solids which were recrystallized from MeOH/Et2O to afford product as a white solid (208 mg, 97%). (TLC 5% MeOH/CH2CI2 (NH3) R~ 0.26). 1H NMR (400 MHz, CD3OD) 8 8.94 (5, 2H), 8.12 (5, 2H), 3.70 (in, 2H), 3.54 (d, J12.5 Hz, 2H), 3.35 (d, J=12.5 Hz, 2H), 2.49 (in, 1 H), 2.08 (d, J=i 1.0 Hz, 1 H). GCMS mle 211 (Mt). mp 225-230 CC


EXAMPLE 27

14-METHYL-5,8,14-TR~AZATETRACYCL~i0.3.1 .0~.~]HD(ADE~A-2(1 1 ),3,5,7,9-PENTAENE HYDROCHLORIDE

5,8,1 4-Triazatetracyclof 10.3.1.02.11 .049]hexadeca-2( ii ),3,5,7,9-pentaene (207 ing,

0.98 ininol) was treated with 37% aqueous forinaline solution (1 inL) and formic acid (1 inL) then warmed to 80 CC for 1 hour. The reaction was poured into water, made basic (NaOH, pH

—11) and extracted with EtOAc. The organic layer was dried (Na2SO4, concentrated and chroinatographed on Silica gel to provide a yellow solid. This was stirred in MeOH (2 inL) and treated with 3N HOl EtOAc (2 inL). After concentration the solids were recrystallized from MeOH/Et2O to afford product as a white solid (70 ing, 27%). (2% MeOH/CH2CI2 (NH3) R~ 0.47). 1H NMR (400 MHz, CDCI3) 6 8.71 (s, 2H), 7.80 (5, 2H), 3.37 (br s, 2H), 3.03 (in, 2H),

2.47 (in, 2H), 2.32 (in, iH), 2.18 (brs, 3H), 1.84 (d, J=11.0 Hz, iH). APOI MS m/e 226.2 [(M +

1 )~]. mp >250 0C.


EXAMPLE 28
210 48
5-OXA-7, 1 3-DIAZATETRACYCLO[9.3. 1 .0-'---.0 ]PENTADECA-2(1 0)3,6,8-

TETRAENE HYDROCHLORIDE
27
A) 2,2,2-Trifluoro-1 -(4-hydroxy-5-nitro-1 0-aza-tricyclo[6. 3.1 .0—]dodeca-2(7),3, 5-trien-

1 0-yl)-ethanone

1 -(4, 5-Dinitro-1 0-aza-tricyclo[6. 3.1 .02'7]dodeca-2(7), 3, 5-trien-1 0-yl)-2.2 2-trifluoro-ethanone (900 ing, 2.61 minol) and potassium acetate (KOAc) (2.6 g, 26.1 ininol) were dissolved in DMSO (10 inL) and warmed with stirring to 100 00 for 16 hours. The mixture was cooled and diluted with H20 ( 50 inL) then extracted with 80% EtOAc/hexanes (6 x 25 inL). The organic layer was washed with H20 (3 x 20 inL), dried (Na2SO4), filtered and concentrated and purified by chromatography to give an oil (575 ing, 70%). (TLC 50% EtOAc/he~anes (N H3) R1 0.56)
B) 2,2,2-Trifluoro-i -(4-hydroxy-5-ainino-i 0-aza-tricyclo[6.3. 1 .0~-~idodeca-2(7),3,5-

trien-1 0-yl)-ethanone
2,7
2,2,2-Trifluoro-i -(4-hydroxy-5-nitro-i 0-aza-tricyclo[6. 3.1.0 ]dodeca-2(7),3,5-trien-1 0-

yl)-ethanone (575 mg, 1.82 minol) was hydrogenated in MeOH under a H2 atmosphere at (45 psi) over 10%Pd/C (80 ing) for 1.5 hours then filtered through a Celite pad and concentrated to white solids (450 mg, 86%). (TLC 5% MeOH/CH2CI2 (NH3) R~ 0.6). 1H NMR (400 MHz, CD3OD)a6.67-6.59 (in, 2H), 4.12 (in, 1H), 3.73 (in, 1H), 3.73 (in, 1H), 3.51 (in, 1H), 3.07 (in. 2H), 2.24 (in, iH), 1.94 (d, J=10.5 Hz, 1H). GOMS mle 286 (M ~).


C) 2,2,2-Trifluoro-1 -(5-oxa-7, 1 3-diazatetracyclo(9.3. 1 ~ 0),3,6,8-tetraene)-ethanone (Goldstein, S. W.; Dainbek, P. J. J. Het. Chem. 1990, 27, 335.)
2,7
2,2,2-Trifluoro-i -(4-hydroxy-5-amino-1 0-aza-tricyclo[6.3. 1.0 ]dodeca-2(7),3,5-trien-

10-yl)-ethanone (150 ing, 0.524 inmol), triinethyl orthoforinate (0.19 inL, 1.73 inmol) pyridiniuin-p-toluenesulfonic acid (PPTS, 18 ing, 0.07 ininol) and xylenes (10 mL) were combined under nitrogen and stirred at 135 0C for 18 hours. The mixture was cooled, treated with H20 and extracted with EtOAc. The extracts were dried (Na2SO4), filtered, concentrated and purified by chromatography to give an oil (110 mg, 71%). (TLC 20% EtOAc/hexanes R~ 0.40)


D) 5-Oxa-7, 1 3-diazatetracyclo[9 3 1 0~-~ 0i!]pentadeca~2( 10), 3.6,8-tetraene

hydrochloride
2,10 4.8
2,2,2-Trifluoro-1 -(5-oxa-7, 1 3-diazatetracyclo[9. 3.1.0 .0 ]pentadeca-2( 10), 3.6,8-

tetraene)-ethanone (110 ing, 0.37 ininol) was stirred in MeOH (5 mL) and treated with Na2CO3 (78 ing, 0.74 minol) in H20 (2 inL). The stirred mixture was warmed to 80 ~C for 2 hours, concentrated to solids, diluted with H20 and extracted with EtOAc (3 x 40 inL). The product was extracted into aqueous 1 N HCI solution (2 x 40 mL) which was washed with EtOAc then neutralized with saturated aqueous Na2003 solution to pH'-1O. The product was extracted with EtOAc (3 x 40 mL), dried (Na2SO4), concentrated and chromatographed on Silica gel to produce an oil. (TLC 5% MeOH/CH2CI2 (NH3) R~ 0.19).

The oil was dissolved in MeOH and treated with 3N HCI EtOAc (4 mL) then

concentrated, stirred in a minimum of CH2CI2 and saturated with hexanes. After 18 hours, the

product was collected by filtration (55 ing, 63%). 1H NMR (400 MHz, CD3OD) 5 8.47 (5, iH),

7.70 (5, iH), 7.65 (5, 1H), 3.41 (in, 2H), 3.30 (in, 2H), 3.10 (d, J12.5 Hz, 2H), 2.47 (in, 1H),

2.15 (d. J=11.0 Hz, 1H). APOI MS mle 201.03 [(M +


EXAMPLE 29

6-METHYL-5-OXA-7, 1 3-DIAZATETRACYCLO[9.3. 1 .&-'-~.048]PENTADECA-

2(10),3,6,8-TETRAENE HYDROCHLORIDE

A) 2,2,2-Trifluoro-1 -(6-methyl 5-oxa-7, 1 3-diazatetracyclo[9. 3.1 .0~-~.0~-~]pentadeca-2(1 0),3,6,8-tetraene)-ethanone
2,7

2,2,2-Trifluoro-i -(4-hydroxy-5-ainino-1 0-aza-tricyclo[6.3. 1.0 ]dodeca-2(7), 3,5-trien-i0-yl)-ethanone (150 ing, 0.524 minol), triethyl orthoacetate (0.34 mL, 1.83 inmol), pyridiniuinp-toluenesulfonic acid (PPTS, 20 ing, 0.08 minol) and xylenes (10 inL) were combined under nitrogen and stirred at 135 ~C for 18 hours. Workup, isolation and purification as in Example 28C provided the title compound (90 ing, 55%).


B) 6-Methyl-5-oxa-7, 1 3-diazatetracyclo[9. 3.1 .0~-~.0~~1pentadeca-2( 10), 3,6,8-tetraene hydrochloride
2,2 ,2-Trifluoro-i -(6-methyl 5-oxa-7, 1 3-diazatetracyclo[9. 3.1.02.10 048]pentadeca-

2(10),3,6,8-tetraene)-ethanone (90 ing, 0.30 ininol) was stirred in MeOH (5 inL) and treated with Na2CO3 (61 mg, 0.58 inmol) in H20 (2 mL). The stirred mixture was warmed to 80 ~C for 2 hours, concentrated to solids, diluted with H20 and extracted with EtOAc (3 x 40 inL). The solution was dried (Na2SO4), concentrated, and chroinatographed on Silica gel to produce an oil. (TLC 10% MeOH/CH2CI2 (NH3) R~ 0.18). 'H NMR (free base) (400 MHz, CDCI3) 6 7.40 (5, 1H), 7.26 (s, iH), 3.05-2.98 (in, 4H), 2.72 (d, J12.8 Hz, 2H), 2.59 (5, 3H), 2.46 (in, iH), 1.98 (d, J=10.5 Hz, 1H).

The oil was dissolved in MeOH and treated with 3N HCI EtOAc (4 inL) then concentrated, stirred in a minimum of CH2CI2 and saturated with hexanes. After 18 hours, the product was collected by filtration (10 ing, 13%). APCI MS mle 215.2 [(M + 1)]. mp >250 ~C.


EXAMPLE 30

2-FLUORO-N-(5-HYDROXY-1 0-AZA-TRICYCLO[6. 3.1 .0~1DODECA-2(7), 3,5-TRIEN-4-YL)-BENZAMIDE HYDROCHLORIDE

2,2,2-Trifluoro-i -(4-hydroxy-5-ainino-i 0-aza-tricyclo[6 .3.1 .027]dodeca-2(7), 3, 5-trien-

10-yl)-ethanone (150 ing, 0.524 ininol), 2-fluorobenzoyl chloride (0.07 mL, 0.576 ininol), pyridiniuin-p-toluenesulfonic acid (PPTS, 20 ing, 0.08 inmol), pyridine (0.046 inL, 0.576 minol) and xylenes (5 inL) were combined under nitrogen and stirred at 135 00 for 18 hours. After 24 hours, additional PPTS (50 mg) was added and the material stirred at 135 0C for an additional 24 hours. Workup as above provided crude product (145 ing, 0.375 inmol) which was



combined with Na2003(s) (80 ing, 0.75 minol) in MeOH (5 inL) 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% MeOH/CH2CI2 (NH3)). The crude material was treated with excess 3N HCI EtOAc and concentrated, then dissolved in a minimum of MeOH and the solution was saturated with Et2O and stirred. After stirring 4 hours the product was collected by filtration (85 ing, 68%). 'H NMR (400 MHz, CD3OD) 8 7.99 (in. 2H), 7.59 (in, iH), 7.36-7.23 (in, 2H). 6.82 (5, iH), 2.99 (in, 4H), 2.78 (in, 2H), 2.35 (in, 1H), 1.96 (d, J=i0.5 Hz, 1H). APOI MS m/e

313.1 [(M + 1)~]. mp 125-130 00 (subl.).


EXAMPLE 31

4CHLORO-1OAZATRICYCLC~6.3.i #POOECA-2(7),3.5-1ThENE HYDROCHLORIDE

A) 1 -(4-Chloro-1 0-aza-tricyclo[6.3. 1 .0~]dodeca-2(7),3,5-trien-i 0-yl)-2 ,2 2-trifluoro-ethanone

Copper(I)chloride (CuCI) was prepared as follows: CuSO4 (4.3 g) and NaCI (1.2 g) were dissolved in hot H20 (14 inL). sodium bisulfite (NaHSO3) (1 g) and sodium hydroxide (NaOH) (690 ing) 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-Amino-i 0-aza-tricyclo[6.3. 1.027]dodeca-2(7),3, 5-trien- 1 0-yl)-2,2,2-trifluoro-ethanone (460 ing, 1.7 minol) was dissolved in H20 (2 inL) and concentrated HCI solution(1 inL) then cooled to 0 0C and treated with a solution of sodium nitrite (NaNO2) (275 ing) in H20 (1 mL) dropwise. To the resulting solution was added a CuCI (202 ing, prepared as described above, 2.04 ininol) in concentrated HCI 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 EtOAc (4 x 30 inL). After drying over Na2SO4, the solution was filtered and concentrated to an oil which was filtered through a Silica pad to remove baseline material eluting with 50% EtOAc/hexanes to give an oil (470 mg, 95%).


B) 4-Chloro-1 0-azatricyclof6.3. 1. &-~]dodeca-2(7 ),3, 5-triene hydrochloride

1 -(4-Chloro-1 0-aza-tricyclo[6. 3.1 .027]dodeca-2(7), 3,5-trien-i 0-yl)-2,2,2-trifluoro-ethanone (470 ing, 1.62 ininol) and Na2003 (344 ing, 3.24 minol) in MeOH (30 inL) and H20 (10 mL) were heated to reflux. After 2 hours, the reaction was cooled and diluted with water then extracted with EtOAc (4 x 40 inL), dried (Na2SO4), filtered and concentrated to a yellow oil. The crude material was treated with excess 3N HCI EtOAc 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 ing, 42%). 'H NMR (free base) (400 MHz, CDCI3) 8 7.15 (in, 2H), 7.09 (d, J=8.0 Hz, iH), 3.00-2.94 (in, 4H), 2.68, (in, 2H), 2.38 (in, iH), 1.92 (d, J=10.5 Hz, 1H). 'H NMR (HCI salt) (400 MHz, DMSO-d6) 6 7.30-

7.20 (in, 3H), 3.30-3.15 (in, 6H), 2.37 (in, 1H), 1.89 (d, J11.0 Hz, 1H). APOI MS mle 194.1 [(M +


EXAMPLE 32

1 0-AZATRICYCLO[6.3. 1 .0'-2,7-IDODECA-2(7),3,5-TRIEN-4-YL CYANIDE HYDROCHLORIDE

A) 1 -(4-lodo-1 0-aza-tricyclo[6. 3.1 .0~-~Jdodeca-2(7). 3,5-trien-1 0-yl)-2,2,2-trifluoro-ethanone
1 -(4-Amino-i 0-aza-tricyclo[6.3. 1.02 7]dodeca-2(7),3,5-trien-i 0-yl)-2,2,2-trifluoro-ethanone (500 ing, 1.85 minol) was dissolved in H20 (5 mL) and concentrated H2504 solution (0.5 mL) then cooled to 0 "C and treated with a solution of sodium nitrite (NaNO2) (140 ing, 2.04 inmol) in H20 (2 inL) dropwise. Potassium iodide (460 ing, 2.78 inmol) in iN H2504 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 NaHSO3 and water (pH 2.5) then extracted with EtOAc (4 x 30 inL). After drying (Na2SO4), the solution was filtered and concentrated to a yellow oil which was chromatographed on Silica gel to provide a yellow oil. (260 ing, 37%). (TLC 30% EtOAc/hexanes Rf 0.70). (A 5.4 g scale performed as above yielded 5 g, 67%).


B) 4-lodo-i 0-aza-tricyclo[6. 3.1 .0U1dodeca~2(7),3, 5-triene-1 0-carboxylic acid tert-butyl ester

1 .(4-lodo-i 0-aza-tricyclo[6.3. 1 02 7]dodeca-2(7),3 ,5-trien-1 0-yl)-2,2,2-trifluoro-ethanone (5 g, 13.1 minol) and 37% saturated aqueous NH4OH solution (50 inL) were stirred in MeOH (250 ml) for 2 hours then concentrated and azeotroped with MeOH (2 x 50 inL). The resulting product was stirred in 1,4-dioxane (75 inL) and treated with saturated Na2003 solution (15 mL). To this was added di-t-butyldicarbonate (5.71 g, 26.2 minol). After stirring 18 hours the reaction was treated with H20 ( 50 inL) and extracted with CH2CI2 (4 x 30 mL), dried (Na2SO4), filtered, concentrated and chroinatographed on Silica gel (TLC 20% EtOAc/hexanes) to provide product as an oil (4.9 g, 98%).



C) 4-Cyano-1 0-aza-tricyclo[6. 3.1 .0U1dodeca~2(7), 3, 5-triene-i 0-carboxylic acid tertbutyl ester (Utilizing the methods described in: House. H. 0.; Fischer, W. F. J Org Chem 1969, 3626.)

CuCN (108 ing, 1.21 ininol) and NaCN (59 mg, 1.21 inmol) were combined in dry DMF (6 inL) and warmed to 150 "C under N2. Solution occurs in 20 minutes. To this was added 4-iodo-1 0-aza-tricyclo[6. 3.1. 027]dodeca-2(7) , 3, 5-triene-1 0-carboxylic acid tert-butyl ester (232 ing, 0.6 ininol) 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% EtOAc/hexanes (3 x 30 inL). After drying (Na2SO4), filtration and concentration the product was isolated by chromatography (86 ing, 50%). (TLC 20% EtOAc/hexanes R~ 0.28).


D) 1 0-Azatricyclo[6.3. 1.0—2, 7—]dodeca-2(7), 3, 5-trien-4-yl cyanide hydrochloride

4-Cyano-i 0-aza-tricyclo[6.3. 1.02 7]dodeca-2(7),3,5-triene-1 0-carboxylic acid tert-butyl

ester was treated with 3N HOl EtOAc (6 inL) and warmed to reflux for 2 hours, then

concentrated, dissolved in a minimum of MeOH which was saturated with Et2O and stirred 18

hours. The product was collected by filtration (49 ing, 73%). 1H NMR (400 MHz, DMSO-d6) 5

9.66 (br s, NH), 7.86 (br s, NH), 7.74-7.70 (in, 2H), 7.49 (d, J=7.5 Hz, iH), 3.33-2.97 (in, 6H),

2.17 (in, iH), 2.01 (d, J=11.0 Hz, iH). GCMS mle 184 (M4). mp 268~27300


EXAMPLE 33
27
3-(1 0-AZATRICYCLO[6.3. 1 .0—IDODECA-2(7),3,5-TRIEN-4-YL)-5-METHYL-i ,2,4-

OXADIAZOLE HYDROCHLORIDE

4-Cyano-1 0-aza-tricyclo[6. 3.1.02 'Idodeca2(7) .3. 5-triene-1 0-carboxylic acid tert-butyl ester (300 ing, 1.1 ininol) was stirred in EtOH (10 inL). To this hydroxyl amine hydrochloride (382 ing, 5.5 minol) and NaOH (242 ing, 6.05 minol) were added and the mixture was warmed to reflux. After 45 minutes, the reaction was cooled, diluted with H20 and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to afford a yellow solid (110 ing, 0.35 ininol). This solid was dissolved in pyridine (1 inL) and treated with acetyl chloride (0.03 inL, 0.415 inniol) and warmed to 10000 for 18 hours. The reaction was cooled, treated with H20 and extracted with EtOAc. The organic extracts were washed with water and saturated aqueous NaCI solution, dried (Na2SO4) and concentrated. Chromatography on Silica gel afforded product (50 ing, 0.15 minol). (25% EtOAc/hexanes R~ 0.18). This product was treated with 2N HCI MeOH (10 inL), heated to 70 00 for 1 hour, cooled, concentrated and recrystallized from MeOH/Et2O to provide product (15 ing). APOI MS mle 242.2 [(M +


EXAMPLE 34
27

1 -(1 0-AZATRICYCLO[6.3. 1 .0—]DODECA-2(7),3,5-TRIEN-4-YL)-1 -ETHANONE HYDROCHLORIDE
27

A) 1 -(4-Acetyl-1 0-aza-tricyclo[6. 3.1 .0—]dodeca-2(7),3,5-trien-i 0-yI)-2,2,2-trifluoro-ethanone

1 -(1 0-Aza-tricyclo[6. 3 1.027]dodeca-2(7),3, 5-trien-i 0-yl)-2,2,2-trifluoro-ethanone (253 ing, 1.0 minol) and AcCI (0.68 inL, 10 inmol) were dissolved in DCE (3 inL) and treated with aluminum chloride (AICI3) (667 ing, 5.0 inmol). The resulting yellow mixture was stirred for 30 minutes then poured over ice and saturated aqueous NaHCO3 solution. After stirring 20 minutes the mixture was extracted with CH2CI2 (3 x 30 niL). The organic layer was dried through a cotton plug then concentrated to a orange-yellow oil (255 ing, 86%).

27


B) 4-Acetyl-1 0-aza-tricyclol6. 3.1.0 —]dodeca-2(7),3, 5-triene-i 0-carboxylic acid tertbutyl ester

1 -(4-Acetyl-1 0-aza-tricyclo[6. 3.1 .027]dodeca-2(7),3,5-trien-i 0-yl)-2,2,2-trifluoro-ethanone (1.3 g, 4.37 inniol) and 37% aqueous NH4OH solution (10 niL) were stirred in MeOH (30 ml) for 3 hours, then concentrated and azeotroped with MeOH (2 x 50 inL). (This product could be converted to an HCI salt directly: see the next example.) The resulting product was stirred in 1,4-dioxane (20 inL) and treated with saturated aqueous Na2003 solution (5 inL). To this was added di-t-butyldicarbonate (1.91 g, 8.74 ininol). After stirring 2 hours, the reaction was treated with H20 (50 inL), extracted with CH2CI2 (4 x 30 niL), dried (Na2SO4), filtered, concentrated and chroinatographed to provide an oil (1.3 g, 100%). (TLC 40% EtOAc/hexanes R~ 0.56).


27
C) 1 -(1 0-Azatricyclo[6.3 1 .0—]dodeca-2(7), 3,5-trien-4-yl)-1 -ethanone hydrochloride
2.7
4-Acetyl-1 0-aza-tricyclo[6.3. 1.0 ]dodeca-2(7),3,5-triene-1 0-carboxylic acid tert-butyl

ester (190 ing, 0.63 nimol) was treated with excess 3N HCI EtOAc and warmed to 7000 for 1 hour then concentrated and dissolved in a minimum of MeOH. The resulting solution was saturated with Et2O and stirred. After 18 hours the white crystalline product was collected by filtration (81 ing, 54%). 1H NMR (400 MHz, DMSO-d6) 8 9.75 (br s, NH), 7.89 (5, 1H), 7.88 (d, J=8.0 Hz, iH), 7.74 (br s, NH), 7.44 (d, J8.0 Hz, iH), 3.33 (br s, 2H), 3.22 (br s, 2H), 3.00 (br in, 2H), 2.54 (5, 3H), 2.17 (in, 1H), 2.02 (d, J=ii.0 Hz, 1H). GOMS m/e 201 (M*). nip 198-202 ~C.


EXAMPLE 35
27

10-AZATRICYCLO[6.3.1 .0—]DODECA-2(7),3,5-TRIEN-4-oL HYDROCHLORIDE
A) Acetic acid 1 0-trifluoroacetyl- 1 0-aza-tricyclo[6. 3.1 . 027Idodeca-2(7) .3, 5-trien-4-yl

ester

1 -(4-Acetyl-1 0-aza-tricyclo[6.3. 1.0' 7]dodeca-2(7),3, 5-trien- 1 0-yl)-2,2,2-trifluoro-ethanone (2.5 g, 8.41 niniol) and 3-chloroperoxybenzoic acid (m-CPBA) (7.5 g, 42 minol) 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 inL, 40.8 inmol) and stirred 24 hours. The resulting mixture was poured into ice and saturated aqueous Na2CO3 solution (100 mL) then extracted with Et2O (4 x 40 inL). The organic layer was washed saturated aqueous Na2003 solution (3 x 40 mL) then dried (Na2SO4), filtered and concentrated to afford an oil (1.83 g, 69%). (TLC EtOAc R~O.80).


B) 2,2,2-Trifluoro-i -(4-hydroxy-1 0-aza-tricyclo[6.3. 1. 0~-7~Idodeca-2(7),3, 5-trien-1 0-yl)-ethanone

Acetic acid 1 0-trifluoroacetyl-1 0-aza-tricyclo[6. 3.1. 027]dodeca-2(7), 3,5-trien-4-yl ester

(900 ing, 2.87 inmol) was stirred in MeOH (20 inL) and saturated aqueous NaHCO3 solution

(15 niL) for 48 hours. The mixture was concentrated, diluted with H20 and extracted with

CH2CI2 (3 x 20 inL) then dried through a cotton plug. Chromatography on Silica gel provided

pure product (420 nig, 54%). (TLC 5% MeOH/CH2CI2 R~ 0.44). 1H NMR (400 MHz, CDCI3) 6

7.05 (in, iH), 6.70 (in, 1H), 6.62 (in, 1H), 4.32 (in, iH), 3.84 (in, 1H), 3.48 (in, 1H), 3.21 (br s,

1H), 3.16 (br s, 1H), 3.09 (in, 1H), 2.38 (in, 1H), 1.97 (d, J11.0 Hz, 1H).


C) 1 0-Azatricyclo[6.3. 1 .0?~Z]dodeca~2(7),3, 5-trien-4-ol hydrochloride
2.7
2,2,2-Trifluoro-i -(4-hydroxy-i 0-aza-tricyclo(6.3. 1 .0 ]dodeca-2(7),3,5-trien-1 0-yl)-

ethanone (50 ing, 0.184 niinol) was dissolved in MeOH/H20 (3/1, 5 mL), treated with Na2003(s) (40 ing, 0.369 minol) and warmed to 6500 for 2 hours. The mixture was concentrated, diluted with H20 and extracted with CH2CI2 (3 x 20 niL) then dried through a cotton plug. Filtration through a Silica gel plug provided an oil (10% MeOH/CH2CI2) which was treated with 3N HCI EtOAc (3 inL) then concentrated, dissolved in a minimum of MeOH which was saturated with Et2O and stirred. After 18 hours the white crystalline product was collected by filtration (10 ing, 26%). 'H NMR (400 MHz, CDOD3) 67.16 (d, JZ8.0 Hz, 1H), 6.80 (d, J=2.0 Hz, 1H), 6.72 (dd, J8.0,2.0 Hz, 1H), 3.32-3.28 (4H), 3.09 (dd, J=14.5,12.0 Hz, 2H), 2.32 (in, 1H), 2.03 (d, J=ii.0 Hz, 1H). APOI MS mle 176.2 [(M + 1)~]. nip 308 (dec.) 00


EXAMPLE 36

7-METHYL-5-OXA-6,1 3-DIAZATETRACYCLO[9.3. 1 .&-'-~..0481PENTADECA-

2,4(8),6,9-TETRAENE HYDROCHLORIDE
27
A) 1 -(4-Acetyl-5-hydroxy-1 0-aza-tricyclof6.3. 1 .0—]dodeca-2(7), 3,5-trien-i 0-yl)-2,2,2-

trifluoro-ethanone

Acetic acid 1 0-trifluoroacetyl-i 0-aza-tricyclo[6.3. 1 .02Tldodeca-2(7),3, 5-trien-4-yl ester (800 nig, 2.55 inmol) was combined with AICI3 (1.0 g, 7.65 inmol) and warmed to 170"C for 2 hours. The mixture was cooled and treated with iN aqueous HCI solution (20 niL), extracted with EtOAc and dried (Na2SO4). Chromatography affords an oil (190 ing, 24%). (TLC EtOAc Rf 0.75). 'H NMR (400 MHz, CDCI3) 8 12.58 (5, OSH), 12.52 (5, 0.5H), 7.53 (5, 1H), 6.86 (s, 1H), 4.33 (in, iH), 3.91 (in, iH), 3.56 (in, iH), 3.28 (br s, iH), 3.24 (br s, iH), 3.14 (in, 1H),

2.35 (in, 1H), 1.97 (brd, J=11.2 Hz, 1H).


B) 2,2,2-Trifluoro-1 -f4-hydroxy-5-( 1 -hydroxyimino-ethyl)-i 0-aza-
27
tricyclo[6. 3.1 . 0—]dodeca-2(7) 3, 5-trien-1 0-yl]-ethanone

1 -(4-Acetyl-5-hydroxy-1 0-aza-tricyclo[6. 3.1 .02'7]dodeca-2(7) .3, 5-trien-1 0-yl)-2.2,2-

trifluoro-ethanone (190 ing, 0.605 minol), hydroxylainine HCI (99 ing, 1.21 inmol) and NaOAc (118mg, 1.21 nimol) were combined in MeOH (4 mL) and H20 (1 niL) and warmed to 65"C for 18 hours. The mixture was cooled, diluted with H20 and extracted with EtOAc which was dried (Na2SO4), filtered and concentrated to provide a yellow oil (177 ing, 93%).


C) 2,2.2-Trifluoro-7-Methyl-5-oxa-6, 1 3-diazatetracyclo[9. 3.1 . ~ 0~-~]pentadeca-2,4(8),6 ,9-tetraene-ethanone

The above oil, 2 ,2,2-trifluoro-1 -[4-hydroxy-5-( 1 -hydroxyimino-ethyl)-1 0-aza-tricyclo[6. 3.1. 027]dodeca-2(7),3.5-trien-1 0-yl]-ethanone (177 mg, 0.54 inniol) was stirred in DCE (3 inL), treated with triethylamine (0.4 niL, 2.8 inniol) and acetic anhydride (Ac2O) (0.3 inL, 2.8 nimol) then stirred 18 hours. The reaction was treated with H20 and extracted with EtOAc. The extracts were dried (Na2SO4), filtered and concentrated to a yellow oil which was dissolved in anhydrous DMF (3 niL) and treated with 60% NaH in oil (32 nig, 1.08 ininol). After stirring 18 hours, additional 60% NaH in oil was introduced (33 ing) and the mixture was stirred 2 hours. The reaction was quenched with H20 (5 niL) and extracted with 80% EtOAc/hexanes (3 x 30 mL). The organic layer was washed with H20 (3 x 20 mL), dried (Na2SO4), filtered and concentrated and chroinatographed to provide an oil (40% EtOAc/hexanes R1 0.56).



D) 7-Methyl-5-oxa-6, 1 3-diazatetracyclo[9.3. 1. ~ hydrochloride

Utilizing the methods described in Example 90, 2.2,2-Trifluoro-7-Methyl-5-oxa-6,13-
2.10 4,8

diazatetracyclo[9.3.i.0 .0 ]pentadeca-2.4(8),6,9-tetraene-ethanone was converted to the title compound. This was treated with 3N HCI EtOAc (3 niL), 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 ing, 13% overall). 'H NMR (400 MHz, DMSO-d6) 3 7.72 (5, 1H), 7.63 (5, 1H), 342-2.98 (in, 6H), 2.50 (5, 3H), 2.23 (in, iH), 2.08 (d, J=10.5 Hz, 1H). APOI MS m/e 215.2 [(M +


EXAMPLE 37

4-(2-Methyl-2H-pyrazol-3-yl)-1 0-a.za-tricyclo[6.3. 1 .0~-~]dodeca-2(7),3, 5-triene hydrochloride and 4-( 1-Methyl-i H-pyrazol-3-yI)-1 0-aza-tricyclo[6.3. 1. 0~-~dodeca-2(7), 3,5-triene hydrochloride

1 -(4-Acetyl-i 0-aza-tricyclo[6. 3.1 .02 7]dodeca-2(7), 3, 5-trien- 1 0-yl)-2.2,2-trifluoro-ethanone (1.0 g, 3.3 niinol) and diniethylforinainide dimethylacetal (DMF-DMA) (4.0 g, 33.6 niniol) were warmed to 14000 for 18 hours. After cooling, a crystalline precipitate was filtered and rinsed with EtOAc (690 ing, 58%).
The above solid, 3-diniethylaniino-i -(1 0-trifluoroacetyl-1 0-aza-

tricyclo[6. 3.1 .027]dodeca-2(7),3, 5-trien-4-yl)-propenone, (200 nig, 0.56 inniol) was dissolved in EtOH (2 mL) and treated with SN HOl EtOH (0.1 mL) followed by methyl hydrazine (0.6 minol). The resulting mixture was warmed to 70CC for 4 hours. The mixture was cooled, diluted with water and extracted with EtOAc, dried (Na2SO4) and concentrated. Chromatography on Silica gel provided a 3/1 mixture of regioisonieric products (130 ing, 68%). (TLC 50% EtOAc/hexanes R~ 0.40).

The above oil (130 ing, 0.388 ininol) and Na2003(s) (82 ing, 0.775 inmol) were stirred in MeOH (10 niL) and H20 (5 niL) 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 HCI MeOH, concentrated and recrystallized froni MeOH/EtOAc to provide a 3/i mixture of regioisoineric pyrrazoles (85 mg, 58%). (5% MeOH/CH2CI2 (NH3) R1 0.25). TFAprecursor APCI MS mle 336.2 [(M + 1) ].


EXAMPLE 38
27

4,5-DICHLORO-i 0-AZATRICYCLO[6.3. 1 .0-~--]DODECA-2(7),3,5-TRlENE
HYDROCHLORIDE
27

A) 1 -(4, 5-Dichloro-i 0-aza-tricyclo[6.3. 1 .0—]dodeca-2(7). 3,5-trien-1 0-yl)-2,2,2-trifluoro-ethanone (Based on Cainpaigne, E.; Thompson, W. J. Org. Chem. 1950, 72, 629.)
2.7

1 -(1 0-Aza-tricyclo[6. 3.1.0 Jdodeca-2(7),3, 5-trien-1 0-yl)-2,2,2-trifluoro-ethanone (539 ing, 2.1 ininol) was stirred in CH2CI2 (5 inL) and treated with 1013 (5) (982 nig, 4.21 inniol).

The resulting orange solution was stirred 0.5 hours, poured into saturated aqueous NaHSO3 solution (25 inL), extracted with CH2CI2 (3 x 25 niL), dried through a cotton plug and concentrated to an oil (570 nig, 84%) (TLC 50% EtOAc/hexanes Rf 0.62).


B) 4,5-dichloro-i 0-azatricyclo[6. 3.1 .0~-~]dodeca-2(7),3,5-triene hydrochloride
2,7
1 -(4, 5-Dichloro-1 0-aza-tricyclo[6. 3.1.0 ]dodeca-2(7),3,5-trien-i 0-yl)-2,2,2-trifluoro-

ethanone (570 ing, 1 .75 niniol) was stirred in MeOH (25inL) and treated with Na2003(s) (5 g, 47 inniol) in H20 (5 niL). The stirred mixture was warmed to 70"C for 4 hours, concentrated to solids, diluted with H20 and extracted with EtOAc (3 x 40 inL). The product was extracted into iN aqueous HCI solution (2 x 40 inL) which was washed with EtOAc then neutralized with saturated aqueous Na2CO3 solution to pH—ia. Product was extracted with CH2CI2 (3 x 40 inL), filtered through a cotton plug and concentrated to an oil (400 mg, 100%).

The oil was dissolved in MeOH and treated with 3N HOl EtOAc (4 inL) and concentrated, then dissolved in a minimum of MeOH and which was saturated with Et2O and stirred 18 hours. The product was collected by filtration (210 nig, 45%). (TLC 50% EtOAc/hexanes (NH3) R1 0.08). 'H NMR (400 MHz, DMSO-d6) 5 7.58 (5, 2H), 3.33-2.97 (in, 6H). 2.18 (in, 1H), 1.99 (d, J=i0 5 Hz, 1H). '~C NMR (100 MHz.DMSO-d6) 5 141 02, 130.60,

126.58, 45.54, 40.55, 38.30. GOMS mle 227, 229 (Mt). nip 283-291 ~C


EXAMPLE 39

N~-DIMEl1-fYL-10AZAThCYCL~6.3.1 .0~pODEC~2(7),3,5-1PJENE4SULFONAMlDE HYDROCHLORIDE

A) 1 0-Trifluoroacetyl-1 0-aza-tricyclof6. 3.1 .0~-~]dodeca-2(7), 3, 5-triene-4-sulfonyl chloride

1 -(1 0-Aza-tricyclo[6. 3.1.027]dodeca-2(7), 3,5-trien-1 0-yl)-2 ,2 2-trifluoro-ethanone (530 ing. 2.1 inniol) was added to chlorosulfonic acid (2 niL, 30 nimol) and stirred for 5 minutes.


The mixture was quenched with ice, extracted with EtOAc, dried (Na2SO4), filtered and concentrated to provide an oil (640 ing, 87%). (TLC 30% EtOAc/hexanes R~ 0.15).

27

~ N~-Diniethyl-1 0-azatricyclo[6.3. 1 .0—]dodeca-2(7), 3,5-triene-4-sulfonainide hydrochloride

1 0-Trifluoroacetyl-1 0-aza-tricyclo[6.3. 1.02~7]dodeca-2(7),3,5-triene~-sulfonyl chloride

(320 nig, 0.9 inniol) was stirred in THF (10 inL) and treated with 40% Me2NH/H20 (1.5 niL).

After 10 minutes the mixture was concentrated and chroniatographed on Silica gel (TLC 30%

EtOAc/hexanes R1 0.31) to provide an oil (256 ing, 78%). This material was dissolved in

MeOH (6 inL) and NH4OH (2 inL) and stirred 18 hours. The mixture was concentrated and

azeotroped from MeOH (3x) The resulting oil was dissolved in MeOH and treated with 3N HCI

EtOAc (4 niL), concentrated, dissolved in a minimum of MeOH and which was saturated with

Et2O and stirred 18 hours. The product was collected by filtration as a white powder (163 ing,

59%). (TLC 10% MeOH/ CH2CI2 (NH3) Rf 0.54). 'H NMR (data, free base) (400 MHz, CDCI3) 8

7.64 (in, 2H), 7.41 (d, J=8.0 Hz, 1H), 3.30 (in, 2H), 3.20 (d, J12.5 Hz, 2H), 3.07 (dd,

J=12.5,2.2 Hz, 2H), 2.69 (s, 6H) 2.45, (in. 1H), 2.00 (d, J11.0 Hz, 1H). 13C NMR (100 MHz,

ODd3) 8 128,43, 124.16, 122,75, 46.67, 46.55, 42.11, 39,44, 37,81. GCMS mle 266 (M)

(data HCI salt) 'H NMR (400 MHz, DMSO-d6) 8 7.68-7.52 (3H), 3.38 (in, 2H), 3.24 (in, 2H),

3.04 (in, 2H), 2.58 (5, 6H), 2.22 (in, 1H), 2.04 (d, J=1i.0 Hz, iH). GOMS mie 266 (Mt). Anal.

Calcd. for C,3H,8N202HC1: 0,51 56; H, 6.32; N, 9.25. Found 0,51.36; H,6.09; N,9.09.


EXAMPLE 40

4-(1 -PYRROLIDINYLSULFONYL)-i 0-AZATRICYCLO[6.3. 1 .0~~]DODECA-2(7),3,5-TRIENE HYDROCHLORIDE

The pyrrolidine analogue was prepared from lO-trifluoroacetyl-lO-azatricyclo(6.3.1 .02.7 ]dodeca-2(7),3,5-triene-4-sulfonyl chloride (320 ing, 0.9 niinol) as by substituting pyrroline in the coupling step described in Example 39B. The TFA product was isolated as an oil (314 ing, 89%) Deprotection and conversion to the salt as in Example 39B affords a white powder (189 nig. 63%) (TLC 10% MeOH/CH2CI2 (NH3) R~ 0.60). (TLC 50% EtOAc/hexanes Rf 0.65). 'H NMR (400 MHz, CDCI3) a 7.66 (d, J=8.0 Hz, iH), 7.64 (5, 1H), 7.37 (d, J=8.0 Hz, iH), 3.30-3.15 (in, 8H), 3.00 (in 2H), 2.39 (in, 1H), 1.98 (d, J11.5 Hz, iH),

1.72 (in, 4H). ~ NMR (100 MHz. CDCI3) a 146.91, 144.08, 136.65, 127. 90, 124.18, 122.36,

50.43, 47.87, 46.80, 4663,42.11, 39.63, 25.10. APCI MS mle 293 [(M + 1)4 (data HCI salt) 'H NMR (400 MHz, DMSO-d6) 8 9.78 (br s, NH), 8.1 (br s, NH), 7.73 (d, J =1.5 Hz,1H), 7.66





(dd, J=8.0,i.5 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 3.39-3.01 (1OH), 2.21 (in, 1H), 2.04 (d, J=11.0 Hz, 1H), 1.66 (in, 4H). GOMS mle 292 (M~). Anal. Calcd. For C,3H18N202HC1.1/2MeOH: C, 54.07; H, 6.47; N, 8.51. Found C, 53.98; H,6.72; N, 8.12


EXAMPLE 41

5,1 3-DIAZATETRACYCLO[9.3. 1 .0~-~.0~-~]PENTADECA-2,4(8),9-TRlEN-6-ONE

HYDROCHLORIDE (The title compound was prepared following the procedures described in Quallich, G. J.; Morrissey, P. M. Synthesis 1993, 51-53, treating 4,5-dinitro-lO-aza-
27
tricyclo[6.3.1.0 ]dodeca-2(7),3,5-triene-i0-carboxylic acid tert-butyl ester as an equivalent to

an ortho fluoro phenyl moiety.) 1H NMR (400 MHz, DMSO-d6) 6 10.42 (5, NH), 9.88 (br s,

NH), 7.52 (brs, iH), 7.15 (5, iH), 6.79 (5, iH), 3.41 (d, J=5.0 Hz, 2H), 3.35-3.13 (in, 4H), 2.93

(in, 2H), 2.12 (in, iH), 1.95 (d, J=i1.5 Hz, 1H). APOI MS mle 215.2 ((M +


EXAMPLE 42

6-OXO-5-OXA-7, 1 3-DIAZATETRACYCLO[9.3. 1 ~ 0' 8]PENTADECA-2( 10), 3,6,8-

TETRAENE HYDROCHLORIDE (For references, see: Nachinan, R. J. J. Het. Chem. 1982, 1545.)

2,2,2-Trifluoro-1 -(4-hydroxy-5-amino-1 0-aza-tricyclo[6. 3.1 .027]dodeca-2(7),3, 5-trien-

10-yl)-ethanone (317 nig, 1.11 inmol) was stirred in THF (10 inL), treated with carbonyldiiinidazole (269 ing, 1.66 niniol) and warmed to 60CC for 18 hours. The mixture was concentrated, diluted with CH2CI2 (50 inL) and washed with IN aqueous HCI solution (3 x 10 mL). The organic layer was dried through a cotton plug, concentrated and chroinatographed on Silica gel (50% EtOAc/Hexanes) to provide an oil (130 ing). This material converted to the title compound by the methods described in Example 90. 'H NMR (400 MHz, DMSO-d6) 8 11.78 (5, NH), 9.56 (br s, NH), 7.63 (br s, NH), 7.24 (5, 1H), 7.07 (s,1H), 3.26 (br s, 2H), 3.16 (br t, J=9.5 Hz, 1H), 2.93 (br s, 1H), 2.18 (in, iH), 1.97 (d, J11.0 Hz, 1H). APCI MS mie 217.2 [(M +

EXAMPLE 43

3-TRIFLUOROMETHYL-1 0-AZA-TRICYCLO[6.3. 1 .0~]DODECA-2(7),3,5-TRlENE

HYDROCHLORIDE (See Grunewald, G. L.; Paradkar, V. M.; Pazhenchevsky, B.; Pleiss, M.

A.; Sail, D. J., Seibel, W. L.; Rei~, 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 Example 1 and 2 starting with 2~fluoro-6-trifluoroinethylbrOinObenzene. 'H NMR (400 MHz, CD3OD) 6 7.67-7.50



(3H), 3.65 (brs, 1H), 3.49-3.42 (in, 2H), 3.29 (5, 1H), 3.28-3.16 (in, 2H), 2.42 (in, iH), 2.18 (d, J=11.5 Hz, 1H). APOI MS mle 2282 [(M + i)~]. (HCI salt) mp 275-277 ~c Anal. Calcd. for C12H,2F3N.HCI.1/3H20: 0,53.44, H, 5.11 N, 519. Found 0,53.73; H, 4.83; N, 5.16.


EXAMPLE 44

3-PHENYL-i 0-AZA-TRICYCLO[6.3. 1 .0~]DODECA-2(7),3,5-TRlENE HYDROCHLORIDE

A) 5-Fluoro-1 ,4-dihydro-1 ,4-methano-naphthalene and 5-iodo-i ,4-dihydro-1 4-methano-naphthalene

(Eisch, J. J.; Burlinson, 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 inmol) were stirred in anhydrous THF (1000 inL) 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 ininol) and 2,6-difluoro-iodobenzene (88.0 g, 367 minol). Small portions (—1 niL) of the intimate mixture were introduced to assist initiation (—4x). After —15 minutes, the reaction initiated (exotherni, 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 GOMS).

The reaction was cooled to room temperature and quenched with H20 (200 niL) followed by aqueous iN HOl solution (200 inL) to dissolve the solids. Product was extracted with hexanes (4 x 150 mL). The combined organic layer was washed with saturated aqueous NaHCO3 solution (150 niL), dried (Na2SO4), 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-iodo-1 ,4-dihydro-1 4-inethano-naphthalene. (TLC hexanes R1 0.63).

B) 5-lodo-1 ,2,3,4-tetrahydro-1 ,4-methano-naphthalene-2,3-diol

5-Iodo-1 ,4-dihydro-1 ,4-inethano-naphthalene (20 g) and N-methyl inorpholine N-oxide

(17.61 g, 130 inmol) were stirred in acetone (90 niL) and H20 (13 niL). To this was added a

solution of 0504 (0.2 mL, 2.5%wt. solution in t-BuOH, 0.02 niniol). After 144 hours, florisil (5

g) and saturated aqueous NaHSO3 solution (3 inL) 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%

EtOAc to provide a yellow solid (13.73 g). APCI MS mle 301.1 [(M -

C) 1 0-Benzyl-3-iodo-1 0-aza-tricyclo[6.3. 1 .&-~]dodeca-2(7), 3,5-triene

5-lodo-i ,2, 3,4-tetrahydro- 1 ,4-methano-naphthalene-2. 3-diol (8.33 g, 27.6 inmol) and Et3NBnCI (10 nig) were vigorously stirred in dichloroethane (25 mL) and H20 (75 inL) then treated with sodium periodate (6.17 g, 29.0 nimol). After 1.5 hours, the layers were separated and the aqueous layer extracted with DCE (2 x 40 niL). The combined organic layer was washed with H20 (4 x 30 niL) until no reaction to starch iodide paper was observed, then with saturated aqueous NaCI solution (30 inL). The organic layer was dried through a cotton plug and treated with benzyl amine (3.16 inL, 29.0 niniol) and stirred for 2 minutes then transferred to an addition funnel. This solution was added over —10 minutes to a vigorously stirred cooled (0 CC) mixture of NaHB(OAc)3 (18.72 g, 88.0 inmol) in DOE (150 inL). After addition was complete, the mixture was stirred without cooling for 2 hours. The mixture was quenched with saturated aqueous Na2003 solution (100 niL) and stirred for 1 hour, then the layers were separated and the aqueous layer was extracted with CH2CI2 (3 x 50 niL). The combined organic layer was washed with saturated aqueous NaCI solution (50 niL), dried through a cotton plug and concentrated. Chromatography on Silica gel provided an oil (6.3 g, 61%). (TLC 5% EtOAc/hexanes R~ 0.10). 'H NMR (400 MHz, CDCI3) 6 7.61 (d, J 8.0 Hz, iH), 7.28-7.22 (in, 3H), 7.13 (d, J=8.0 Hz,1H), 6.98-6.94 (in, 3H), 3.58 (AB dd, J14.2 Hz, 2H), 3.26 (br s, iH), 3.21 (br s, 1H), 3.04 (br d, J=10.2 Hz, 1H), 2.83 (br d, J=10.2 Hz, 1H), 2.47 (d, J=i0.0 Hz, 1H), 2.39 (d, J=10.0 Hz, iH), 2.34 (in, 1H), 1.72 (d, J=10.5 Hz, iH). APOI MS mle 376.0 [(M +

D) I 0-Benzyl-3-phenyl-1 0-aza-tricyclo[6.3. 1 .&—~-]dodeca-2(7), 3,5-triene

(For a discussion, see: Miyaura, N.; Suzuki. A. Chem. Rev. 1995, 95, 2457-2483.)

1 0-Benzyl-3-iodo-1 0-aza-tricyclo[6.3. 1 .027]dodeca-2(7). 3. 5-triene (375.3 ing, 1.0 inmol), potassium acetate (785 nig, 8.0 niniol) and phenyl boronic acid (183 nig, 1.5 inmol) were combined in 10/1 EtOH/H20 (5 niL) The mixture was degassed (3 vacuum/N2 cycles), treated with tetrakis(triphenylphosphine)palladiuin(0) (57.5 ing, 0.05 ininol) and waned to 90 ~C for 18h. The reaction was cooled, diluted with H20 and extracted with Et2O (3 x 50 inL). The organic layer was washed with brine (50 inL), dried (MgSO4), filtered and concentrated to provide an oil (180 ing, 55%). (TLC 4%EtOAc/hexanes R~ 0.18). GOMS mle 325 (M)4.

E) 3-Phenyl-1 0-aza-tricyclo[6. 3.1 .o?~Zidodeca~2(7),3,5~tnene hydrochloride

1 0-Benzyl-3-phenyl-i 0-aza-tricyclo[6.3. 1.02~7]dodeca-2(7), 3,5-triene was converted

into the title compound utilizing the conditions described in Example 2D. (TLC 10%

MeOH/CH2CI2 (NH3) R1 0.30). (data for free base) 'H NMR (400 MHz, CDCI3) 8 7.46-7.15

(8H), 3.17 (brs, iH), 3.01 (in, 2H), 2.93 (d. J13.0 Hz, 1H), 2.72 (dd, J=10.5,2.5 Hz, iH), 2.63

(dd, J10.5,2.5 Hz, 1H), 2.41 (in, iH), 1.91 (d, J10.5 Hz, 1H). APOI MS m/e 236.2 [(M + i)J.

(HOI salt) mp 262-265 00 Anal. Calcd. for C17H17N.HCI.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-1 O-AZA-TRICYCLO[6. 3.1 .0U]DODECA~2(7),3,5~TRIENE HYDROCHLORIDE

A) 1 0-Benzyl-3-boronic acid-i 0-aza-tricyclo[6. 3.1 .0~-~idodeca-2(7),3,5-triene

1 0-Benzyl-3-iodo-i 0-aza-tricyclo[6. 3.1.02~7]dodeca-2(7),3,5-triene (3.0 g, 7.99 inmol) was stirred in anhydrous THF (40 inL) at -78 0C under nitrogen and treated dropwise with nBuLi (3.84 mL of 2.5M soln. in hexanes, 9.59 niniol). After 10 minutes, tri-isopropylborate (4.61 mL, 20.0 niniol) was added dropwise. After —1/2 hour, the reaction was poured into saturated aqueous NaHCO3 solution, stirred 5 minutes and extracted with EtOAc (3 x 50 inL) and concentrated. The residue was dissolved in 30% Et2O/hexanes and extracted with iN. NaOH aqueous solution (4 x 50 niL). The combined aqueous basic layer was treated with concentrated HCI to achieve pH 8 and extracted with EtOAc (4 x 25 inL), dried (Na2SO4) and stripped. Chromatography on Silica gel eluting first with 3% EtOAc/hexanes to remove nonpolar components, then with 5% MeOH/CH2CI2 provides the title compound. (TLC 25% EtOAc/hexanes Rf 0.60).

B) 1 0-Benzyl-3-hydroxy-1 0-aza-tricyclo[6.3. 1 0?..lldodeca,2(7)3 5-triene

1 0-Benzyl-3-boronic acid-i 0-aza-tricyclo[6. 3.1 .027]dodeca-2(7). 3,5-triene (140 nig.

0.48 niniol) dissolved in THF (5 niL) was treated with N-inethylmorpholine-N-oxide (64.5 ing,

0.48 minol) and brought to reflux for 1 hour. The reaction was concentrated and chromatographed on Silica gel to provide product. (TLC 25% EtOAc/hexanes R~ 0.18). 'H NMR (400 MHz, CDCI3) 87.18-7.15 (3H), 7.04 (dd, J= 8.0,7.0 Hz, 1H), 6.95 (in, 2H), 6.75 (d, J=7.0 Hz, 1H), 6.59 (dd, J=8.0,1.0 Hz, 1H), 3.53 (br s, OH), 3.51 (AB d, J14.0 Hz, 2H), 3.28 (br s, 1H), 3.06 (br s, iH), 2.91 (dd, J8.5.1.5 Hz, 1H), 2.79 (ddd, J=8.5,i.5,1.5 Hz, 1H), 2.42 (d, J=11.0 Hz, iH), 2.39 (d, J11.0 Hz, 1H), 2.23 (in, 1H), 1.65 (d, J=10.5 Hz, 1H). APOI MS mle 266.5 [(M +
27


C) 3-Hy.droxy-i 0-aza-tricyclo[6. 3.1. 0—]dodeca-2(7),3, 5-triene hydrochloride

1 0-Benzyl-3-hydroxy-1 0-aza-tricyclo[6. 3.1 .027]dodeca-2(7), 3,5-triene (160 ing, 0.60

ininol) was converted into the title compound by the methods described in Example iD. 'H

NMR (400 MHz, CDCI3) 8 7.15 (dd, J=8.0,7.5 Hz, 1H), 6.84 (d, J7.5 Hz, iH), 6.76 (d, J=8.0

Hz, iH), 3.51 (br s, iH), 3.33-3.25 (3H), 3.16 (d, J=12.0 Hz, iH), 3.09 (d, J12.0 Hz, iH), 2.29

(in, iH), 2.02 (d, J=11.0 Hz, 1H). APCI MS mle 175.8 [(M + i)~]. (HOI salt) mp 253~255CC EXAMPLE 46

4,5-DIFLUORO-i 0-AZA-TRICYCLO[6.3. 1 .0~-~1DODECA-2(7),3,5-TRlENE HYDROCHLORIDE
The title compound was prepared by the methods described in Example 1 and 2 starting with 2,4,5-trifluorobroniobenzene. 'H NMR (400 MHz, CDCI3) 6 7.31 (t, J=8.5 Hz, 2H), 3.48-3.13 (6H), 2.38 (in, iH), 2.11 (d, J=11.5 Hz, 1H). APOI MS mle 196.2 [(M + 1) ~]. (HOI salt) mp 301-303 0C. Anal. Calcd. for C11H11F2N.HCI.1/6H20: 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, 1 3-DIAZATETRACYCLO[9 3 1 0~-~- ~ 8]PENTADECA-2( 10)3,6,8-TETRAENE HYDROCHLORIDE

2,2,2-Trifluoro-i -(4-hydroxy-5-ainino-1 0-aza-tricyclo[6. 3.1 .027]dodeca-2(7), 3,5-trien-i0-yl)-ethanone and propionyl chloride were converted to the title compound following the procedures described in Example 30 and Goldstein, S. W.; Danibek, P. J. J. Het. Chem. 1990, 27, 335. 'H NMR (400 MHz, CD3OD) 6 7.64 (5, 1H), 7.62 (5, 1H), 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 (in, 1H), 2.17 (d, J=i1.5 Hz, iH), 1.42 (t, J=7.5 Hz, 3H). APOI MS mle 229.2 [(M +


EXAMPLE 48
210 48
6-ISOPROPYL-5-OXA-7.1 3-DIAZATETRACYCLO[9.3. 1 .0-'—.0 PENTADECA2(1 0),3,6,8-TETRAENE HYDROCHLORIDE
2.7

2,2,2-Trifluoro-1 -(4-hydroxy-5-amino-1 0-aza-tricyclo[6. 3.1.0 ]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% EtOAc/hexanes R1 0.14). 'H NMR (400 MHz, CD3OD) 8 7.65 (2H), 3.49 (br s, 2H), 3.41 (d, J=12.0 Hz, 2H), 3.33-3.19 (3H), 2.45 (in, 1H), 2.18 (d, J=11.5 Hz, 1H), 1.45 (d, J=7.0 Hz, 6H). APO! MS mle 243.2 [(M + 1)~]. (HOI salt) mp 249-25 1 CC.



EXAMPLE 49

6-BENZYL-5-OXA-7, 1 3-DIAZATETRACYCLO[9.3. 1 .O2-~.O4 8]PENTADECA-

2(1 0),3,6,8-TETRAENE HYDROCHLORIDE

2,2,2-Trifluoro-i -(4-hydroxy-5-ainino-i 0-aza-tricyclo[6.3. 1 .02'7]dodeca-2(7), 3,5-trien-

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) 8 7.63 (s, iH), 7.58

(5, 1H), 7.36-7.24 (5H), 4.29 (5, 2H), 3.46 (d, J=2.5 Hz, 2H), 3.39 (d, J=12.0 Hz, 2H), 3.18

(2H), 2.42 (in, 1H), 2.15 (d, J=i 1.5 Hz, 1H). APOI MS mle 291.2 [(M +







CLAIMS

1. A compound of the formula
(Formula Removed)


R1 is hydrogen, (C1 -C6)alkyl, unconjugated (C3-C6)alkenyl, XC(=O)R13 or -CH2CH2-O-(C1-C4)alkyl;

R2 and R3 are selected, independently, from hydrogen, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, nitro. amino, halo, cyano, -SQq(Ci-C6)alkyl wherein q is zero, one or two,
56 78
(C1.C6)alkylamino-, [(C1-C6)alkyl]2amino-, -C02R4, -CONR R , -SO2NR R , -C(=O)R13,

-XC(=O)R'3, 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, and X2(C0-C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or is (C1-C6)alkylamino- or [(C1-C6)alkyl]2amino-, and wherein the (C0-C6)alkoxy-(C0-C6)alkyl- moiety of said X2(C0-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)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 (C1~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, (C1-C6)alkoxy optionally substituted with from two to seven fluorine atoms, halo (~j~ chloro, fluoro, bromo or iodo), (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, nitro, cyano, amino, (Cf C6)alkylamino-. [(C1-C6) alkyl]2amino-, -C02R4, -CONR5R6, -SO2NR7R8, -C(0)R'3 and -XC(=O)R 13;
2 3

or R and R , together with the carbons to which they are attached, form a four to seven membered monocyclic. or ten to fourteen membered bicyclic, carbocyclic ring that can be

saturated or unsaturated, wherein from one to three of the nonfused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic 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 bicyclic 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 (C1 -C6) alkyl optionally substituted with from one to seven fluorine atoms, (C1 -C6) alkoxy optionally substituted with from one to seven fluorine atoms, nitro, cyano, halo, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, amino, (C1 -C6)alkylamino and [(C1 -C6) alkyl]2amino, -C02R4, -CONR5R6, -SO2NR7R8, -C(=O)R'3 and -XC(0)R13;

each R', R5, R6, R7, R8 and R13 is selected, independently, from hydrogen and (C1 -C6) alkyl, or R5 and R6, or R7 and R8 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperizine, N-(C 1-C6)alkylpiperizine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and

each X is, independently, (C1-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 both hydrogen, R1 cannot be hydrogen or methyl;

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 bicyclic ring system selected from the following:


(Formula Removed)
wherein R'0 and R'7 are selected. independently, from (C0-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, cyano, halo,


amino, (C1-C6)alkylamino-, [(C1-C6) alkyl]2amino-, -C02R4, -CONR5R6, -502NR7R8, -C(=O)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,

3. A compound according to claim 1, wherein R2 and R3 do not, together with the benzo ring of formula I, form a bicyclic or tricyclic ring system.

4. A compound according to claim 1, wherein one or both of R2 and R3 are

-C(=O)R13 wherein R13 is (C1-C6)alkyl.

5. A compound according to claim 1, wherein one of R2 and R3 is -C0R13 wherein
13

R is (C1-C6)alkyl or (C1-C3)alkyl optionally substituted with from one to seven fluorine atoms.
6. A compound according to claim 1, wherein one of R2 and R3 is CF3 , fluoro,

cyano or C2F5.

7. 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.

8. 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.

9. A pharmaceutical composition for treating a disorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohns 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, amylotropic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscu lar palsy, chemical dependencies and addictions (~j, dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbituates, opioids or cocaine), headache, stroke, traumatic brain injury (TBI), 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 Tourettes 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.

10. A method for treating a disorder or condition selected from inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohns 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, amylotropic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions ~ dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbituates, opioids or cocaine), headache, stroke, traumatic brain injury (TBI), psychosis, Huntingtons 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), Parkinsons 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 according to claim 1 that is effective in treating such disorder or condition.

11. A compound of the formula
(Formula Removed)
wherein P is hydrogen, methyl, COOR wherein R is (C1-C6)alkyl, allyl or 2,2,2-
56 5 6
trichloroethyl; -C(=O)NR R wherein R and R are defined as in formula I above; -C(=O)H,

-C(=O)(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 (t-Boc)

or trifluoroacetyl, 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,
14 15
hydroxy, nitro, amino, -O(C1-C6)alkyl and halo; with the proviso that R and R can not both be hydrogen when P is hydrogen or methyl.

12. ,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
(Formula Removed)


or a pharmaceutically acceptable salt thereof, that is effective in reducing nicotine addiction or aiding in the cessation or lessening of tobacco use.

13. 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, amylotropic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supramuscular palsy, chemical dependencies and addictions (~j, dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines. barbituates, opioids or cocaine), headache, stroke, traumatic brain injury (TBI), 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 in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound of the formula
(Formula Removed)

or a pharmaceutically acceptable salt thereof;

that is effective in treating such disorder or condition.

14. A compound of the formula(Formula Removed)

wherein R and R are defined as in claim 1; and P' is C00R16 wherein R is allyl,
56 5 6
2,2,2-trichloroethyl or (C1-C6)alkyl; -C(0)NR R wherein R and R are defined as in claim 2;

5 -C(=O)H, -C(=O)(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, or tbutoxycarbonyl (t-Boc).
14. A compound of the formula as defirA~d In cl~i1m 1 substantially as hereinbefore described with reference to the foregoing examples.

15. A pharmaceutical composition substantially as hereinbefore described with reference to the foregoing examples.

Documents:

3858-del-1998-abstract.pdf

3858-del-1998-claims.pdf

3858-del-1998-correspondence-others.pdf

3858-del-1998-correspondence-po.pdf

3858-del-1998-description (complete).pdf

3858-del-1998-drawings.pdf

3858-del-1998-form-1.pdf

3858-del-1998-form-13.pdf

3858-del-1998-form-19.pdf

3858-del-1998-form-2.pdf

3858-del-1998-form-3.pdf

3858-del-1998-form-4.pdf

3858-del-1998-form-6.pdf

3858-del-1998-gpa.pdf

3858-del-1998-petition-137.pdf

3858-del-1998-petition-138.pdf

abstract.jpg


Patent Number 245360
Indian Patent Application Number 3858/DEL/1998
PG Journal Number 03/2011
Publication Date 21-Jan-2011
Grant Date 14-Jan-2011
Date of Filing 30-Dec-1998
Name of Patentee OY M. HALOILA AB
Applicant Address RUSKONTIE 16, FIN-212850 MASKU, FINLAND.
Inventors:
# Inventor's Name Inventor's Address
1 PAIGE ROANNE PALMER BROOKS 9 WYASSUP ROAD, NORTH STONINGTON, CONNECTICUT 06359, U.S.A.
2 JOTHAM WADSWORTH COE 8 BUSH HILL DRIVE, NIANTIC, CONNECTICUT 06357, U.S.A.
PCT International Classification Number A61K 31/435
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 980315 1998-02-11 Finland