AU708112B2 - 7-azabicyclo{2.2.1}-heptane and -heptene derivatives as cholinergic receptor ligands - Google Patents

Description

WO 96/06093 PCTIUS95/10884 7-AZABICYCLO[2.2.1]-HEPTANE

AND

-HEPTENE DERIVATIVES

AS

CHOLINERGIC RECEPTOR

LIGANDS

This invention is in the area of 7 -azabicyclo[2.2.1]heptane and -heptene derivatives and their method of manufacture and pharmaceutical use.

BACKGROUND OF THE INVENTION Opiates, and in particular, morphine, are routinely administered for the treatment of moderate to severe pain. Agents that are less potent than morphine, such as codeine, mixed agonist-antagonist opioids, and non-opiate analgesics, including non-steroidal anti-inflammatory drugs (NSAIDS) are often used to relieve mild to moderate pain. Because of the well-known side effects of opiates, including chemical dependence and respiratory depression, there is a strong need for a non-opiate based analgesic for moderate to severe pain that would equal or exceed the potency of opiate analgesics, yet lack the serious side effects associated with the administration of opiates.

Spande, et al., reported in 1992 that a potent nonopiate analgesic had been isolated from the skins of the Ecuadoran poison frog, Epipedobates tricolor. Spande, et al., 1992 J. Am. Chem. Soc., 114, 3475-3478. The structure of the compound was determined by mass spectroscopy, infrared spectroscopy, and nuclear magnetic resonance as exo-2-( 2 -chloro-5-pyridyl)-7-azabicyclo [2.2.1]heptane (see Figure -The compound, which was named epibatidine, is the first member of the class of 7 -azabicyclo[2.2.1]heptane compounds to be found in nature. Limited pharmacological evaluation of epibatidine indicated that it is WO 96/06093 PCT/US95/10884 -2approximately 500 times more potent than morphine in eliciting the Straub-tail response, and that this effect is not reversed by the opiate antagonist naloxone. In the hot plate analgesia assay, epibatidine is approximately 200 times as potent as morphine. It has also been determined that epibatidine has a negligible affinity for opiate receptors (1/8000 times that of morphine).

Based on this data, it appears that epibatidine is a very potent analgesic that acts via a non-opiate mechanism.

In 1993, it was reported that epibatidine is a nicotinic cholinergic receptor agonist. Qian,

C.;

Li, Shen, Libertine, Eckman,

J.;

Biftu, Ip, S. Epibatidine is a nicotinic analgesic. European J. Pharmacology, 1993, 250(3):R-13-14; Fletcher, Baker, Chambers, Herbert, Hobbs, Thomas,

S.R.;

Veerler, Watt, Ball, R.G. Total synthesis and determination of the absolute configuration of epibatidine. J. Org. Chem., 1994, 59(7):1771-1778; Baldio, Daly, J.W.; Epibatidine. A potent analgetic and nicotinic agonist. FASEB Journal, 1994, 8(4-5):A875. Mol.

Pharmacol., 1994, 45:563-569; Dukat, Damaj, Glassco, Dumas, May, Martin, Glennon, R.A. Epibatidine: A very high affinity nicotine-receptor ligand. Medicinal Chem.

Res., 1994, 4:131-139.

Cholinergic receptors play an important role in the functioning of muscles, organs and generally in the central nervous system. There are also complex interactions between cholinergic receptors and the function of receptors of other neurotransmitters such as dopamine, serotonin and catecholamines.

Acetylcholine (ACh) serves as the WO 96/06093 1 0 8 8 4 -3neurotransmitter at all autonomic ganglia, at the postganglionic parasympathetic nerve endings, and at the postganglionic sympathetic nerve endings innervating the eccrine sweat glands. Different receptors for ACh exist on the postganglionic neurons within the autonomic ganglia and at the postjunctional autonomic effector sites. Those within the autonomic ganglia and adrenal medulla are stimulated predominantly by nicotine and are known as nicotinic receptors. Those on autonomic effector cells are stimulated primarily by the alkaloid muscarine and are known as muscarinic receptors.

The nicotinic receptors of autonomic ganglia and skeletal muscle are not homogenous because they can be blocked by different antagonists. For example, d-tubocurarine effectively blocks nicotinic responses in skeletal muscle, whereas hexamethonium and mecamylamine are more effective in blocking nicotinic responses in autonomic ganglia. The nicotinic cholinergic receptors are named the NM and NN receptors, respectively.

Muscarinic receptors are divided into at least four subtypes (M-1 through An M-5 receptor has been cloned in human cells. The M-1 receptor is localized in the central nervous system and perhaps parasympathetic ganglia. The M-2 receptor is the non-neuronal muscarinic receptor on smooth muscle, cardiac muscle and glandular epithelium.

Muscarinic receptors can be blocked by administration of atropine. Bethanechol is a selective agonist for the M-2 receptor and pirenzepine is a selective antagonist of the M-1 receptor.

In light of the fact that epibatidine is a strong cholinergic receptor ligand, it would be of interest to provide new 7-azabicyclo[2.2.11-heptane 4 and -heptene derivatives with pharmacological activity.

Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

SUMMARY OF THE

INVENTION

In one aspect, the present invention is directed to an 7-azabicyclo[2.2.heptane compound of the formula: wherein:

R

3

R

3 and R6 are independently hydrogen; alkcyl; hydroxy; hydroxyalkyl; alkyloxyalkyl; alkylthioalkyl; aniinoalkyl; alkylaminoalkyl; dialkylaminoalkyl; alkyloxy; alkylthio; halo; haloalkyl;

-NH

2 alkylamino; dialkylamino; cyclic dialkylamino; amidine, cyclic amidine and their N-alkyl derivatives;

-CO

2 H; -CO 2 alkyl; -CN; -C(O)NH 2 -C (0)NH (alkyl.); -C (0)N (alkyl) 2 allyl; -S0 2 (alkyl)

-SO

2 aryl; -S (0)alkyl; -S (0)aryl; heteroaryl selected from the group consisting of isothiazolyl, benzofuranyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, 1 ,2,5-thiadiazolyl, isooxazolyl, pyrrolyl, pyrazolyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5 -azacytidinyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl;

W-

-NHC alkyl; or R 5 and R 6 together are selected f rom. the group consisting of alkylidene or haloalkylidene, episulfide imino (-N(alkyl)- or and a fused heteroaryl ring;

R

2 is hydrogen, alkyl, alkenyl, hydroxyalkyl, alkyloxyalkyl, aminoalkyl, carboxylate, C(O)Oalkyl, C(O)Oaryl, C(O)Oheteroaryl, C(O)Oaralkyl, -CN, -NHC(O)R1 2

-CH

2 NHC R 12 Q' -alkyl -alkenyl(Q), -alkynyl(Q),-a-(Q), -NH-Q, or -N(alkyl)-Q;

R

2 and R 3 together can be (R 8 -C or -CH (OH) -C wherein R" can be alkyl, aryl, or heteroaryl;

R

7 is hydrogen, alkyl, alkyl substituted with one or more halogens, cycloalkylmethyl,

-CH

2

CH=CH

2

-CH

2

CH

2

(C

6 Hs), hydroxyalkyl, (alkyl) 2 aminoalkyl, alkyloxyalkyl, alkylthioalkyl, aryl, 4 -methoxybenzyl, and dialkyl to form a quaternary ammonium moiety; R 12 is alyl ayl alkaryl,~ aralkvl, heteroary.l, alkenyl, alkynyl, or heteroaralkyl; Q is selected from the group consisting of:

*CHI

NI ~-N

N

N OH 3 Sr

N

N~

-N

N

Cl lNo oS! Cl

N

*9 a a a

A

NI

*Oo se*

N

9*

CG-

0 N)

N-N

s N

N

Z

I cc-

DCH

N

N

CC

H

N

N-N

II

jN

H

4I N 1-0 NN (7

N"

N N

N-N

N N -H0 N-N 0OC N-0

H-NS

000NN 0NN N N N 4tt.N 0 /wV~ j ,~0f

NN

H

H

MI-.

z

R/\

I-'

/7 5* 9 5 00 0 5 9 590999 9 5 0059 S 9S5* S 0 5 9 *e 9* 5 0 .5 5* 5 55 55 55 55 5* 5 5.

2: -z d

O

0

I

'Ii z tit) 2: zJ 0

S

47 z 00 00 a g L4 VY 5*go 5 0 go 5 00 000**

H

N 6

N

-Cs, N

I-N

N

N

N'J

*N-N

N N 7 N ~NH N-N N N-0 0-

N

N K

*S*S

5* S S S S

S

5.

5

S

0 NN

N

N

S.

S S S S 55 .5.5

OS

S S 505.5.

S

S

S

S S S S Mill x v#/o 2: 2:/ i- 2 Ile Z I 13 wherein Q or Q1 can each be optionally substituted by 1 to 3 W substituents; and wherein W is alkyl, halo, aryl, heteroaryl, -OH, alkyloxy, -SH, alkylthio, -SO(alkyl),

-SO

2 alkyl, -OCH 2

CH--GH

2

-OCH

2

(C

6

H

5

CF

3 -CN, alkylenedioxy,

-CO

2 H, -CO 2 alkyl, -OCH 2

CH

2 OH, -NO 2

-NH

2 -NH (alkyl) -N (alkyl) 2 -NHC alkyl, -SO 2

CF

3 and -NHCH 2 aryl; provided that when R 2 and R 5 are H, R 7 is H, alkyl, cycloalkylmethyl, alkyl substituted with one or more halogens, -CH 2 CH=GH, or hydroxyalkyl, and one of

R

3 and R 6 is H, then the other of R 3 and R 6 is not H, C 3 -C8 cycloalkyl, or 6-chloro-3-pyridyl; when R 7 is H or methyl and R 2 and R 3 are both H, then R 5 and R 6 are not both -CO 2 H or -CO 2 Me; when R 7 is H or methyl and R 5 and R 6 are both H, then R 2 and R 3 are *not both -CO 2 Me; and when R 2

R

3

R

6 and R 7 are H, R 5 is not -OH.

Preferably, R 3

R

5 and R6 are independently hydrogen,

-CH

3

-CH

2 OH, -CH 2

OCH

3

-GH

2

SCH

3

-CH

2

NH

2

-CH

2 NH (CH 3

CH

2

N(CH

3 2

-OCH

3

-SCH

3 Cl, F, CF 3

NH

2

-N(CH

3 2 and -NHCH 3 -N N-C14 3 -14 1-CM 2

CH

2 0H *t C C -9 0 0 2 H, -CO 2

CH

3 -C (0)GH 3 -CN, -C (0)NH 2 -C (0)N (CHA) 2 1 N SO 2

(C

6

H)

Preferably, R 7 is hydrogen, -CH 3

-CH

2

CH

3

-CH

2

CH

2 Cl, cyclopropylmethyl, -CH 2

CH

2 OH, -CH 2

CH

2 N (CH 3 2, and dialicyl to form a quarternary amnmonium or is selected from the group consisting of:

N-(R

0 11 aryl;

N-(RO)

11 C-alkyl;

N-(ROJ

11 C-O-(alkyl);

N-(RD)

11 -C-S-(alkyl); III

H;

z

III

-(C1111

CH

2

OCC(CH

3 3 z 11

R

KN~~%lower alkyl z 11 0

S.

S

S

*5 S *5 S

S

S.

S S 0 11

-CH

2 0C-aryl 0 1I -CHOC-alkyl 20 wherein R 9 is hydrogen or alkyl; wherein Y' is CN, NO 2 alkyl, OH, -0-alkyl; wherein Z is 0 or S; and wherein R 10 and are each independently -OH, -0-alicyl, -0-aryl, -NH 2 -NH (alkyl) -N (alkyl) 2 -NH (aryl), or -N(aryl) 2

I

More preferably, R 7 is selected from the group consisting of methyl, allyl, cyclopropylmethyl, cyclobutylmethyl, phenethyl, hydroxyethyl, methoxyethyl, methylthioethyl, dimethylaminopropyl, and (4-methoxybenzyl).

These compounds are cholinergic receptor ligands, and thus act as nicotinic or muscarinic agonists or antagonists. Therefore, the compounds can also be used in the treatment of cognitive, neurological, and mental disorders, as well as other disorders characterized by decreased or increased cholinergic function.

The selectivity of the selected compound for various receptor subtypes is easily determined by routine in vitro and in vivo pharmacological assays known to those skilled in the art, and described in more detail below. The receptor subtype selectivity is expected to vary based on the substituents on the 7-aza-norbornane or norbornene ring.

Compounds that act as nicotinic receptor agonists have central or peripheral analgesic activity, and, or alternatively, anti-inflammatory activity, and thus can be administered to a mammal, oo« *o o ooo WO 96/06093 PCT/US95/10884 including a human, to treat pain and inflammatory disorders. A method for the treatment of pain is also presented that includes administering an effective amount of the compound or its pharmaceutically acceptable salt or derivative, or mixtures thereof, to a host in need of analgesic therapy, optionally in a pharmaceutically acceptable carrier or diluent.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is an illustration of the chemical structure of exo-2-(2-chloro-5-pyridyl)-7azabicyclo[2.2.1]heptane (epibatidine).

Figures 2a and 2b are schematic illustrations of processes for the preparation of active compounds through the Diels-Alder reaction of an N-(electron withdrawing substituted)pyrrole with an arylsulfonyl(optionally substituted aryl or heterocyclic)acetylene.

Figure 3 is a schematic illustration of the synthesis of 7-aza-2-[oxazole and oxadiazole]bicyclo[2.2.1]heptane from exo-2-carbomethoxy-7methyl-7-azanorbornane.

Figure 4 is a schematic illustration of the synthesis of 7-aza-2-[heterocycles]bicyclo[2.2.1]heptane from exo-2-cyano-7-methyl-7azanorbornane.

Figure 5 is a schematic illustration of the conversion of exo-2-carbomethoxy-7-methyl-7azanorbornane and exo-2-cyano-7-methyl-7azanorbornane to 7 -methyl-7-aza-2-[methylamino and methylacetamido]-bicyclo[2.2.1]heptane.

Figure 6 is a schematic illustration of the synthesis of 7-methyl-7-aza-2-[isoxazolyl]- -bicyclo[2.2.1]heptane.

WO 96/06093 PCT/US95/10884 -16- DETAILED DESCRIPTION OF THE INVENTION I. Definitions The term alkyl, as used herein, refers to a saturated straight, branched, or cyclic (or a combination thereof) hydrocarbon of C, to CIo, and specifically includes methyl, ethyl, propyl, isopropyl, cyclopropylmethyl, cyclobutylmethyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, heptyl, octyl, nonyl, and decyl.

The term lower alkyl, as used herein, refers to a C, to C 6 saturated straight, branched, or cyclic (in the case of C 5 hydrocarbon, and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropylmethyl, pentyl, cyclopentyl, cyclobutylmethyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

The term alkylamino refers to an amino group that has an alkyl substituent.

The term alkynyl, as referred to herein, refers to a C 2 to Cio straight or branched hydrocarbon with at least one triple bond.

The term lower alkynyl, as referred to herein, refers to a C 2 to C 6 alkynyl group, specifically including acetylenyl and propynyl.

The term aryl, as used herein, refers to phenyl, or substituted phenyl, wherein the substituent is halo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, alkoxyalkyl, methylenedioxy, cyano, C(0)(lower alkyl), carboxy, CO0alkyl, amide, amino, alkylamino and dialkylamino, and wherein the aryl group can have up to 3 WO 96/06093 PCTIS95/10884 -17substituents.

The term halo, as used herein, includes fluoro, chloro, bromo, and iodo.

The term aralkyl refers to an aryl group with an alkyl substituent.

The term alkaryl refers to an alkyl group that has an aryl substituent, including benzyl, substituted benzyl, phenethyl or substituted phenethyl, wherein the substituents are as defined for aryl groups.

The term heteroaryl or heteroaromatic, as used herein, refers to an aromatic moiety that includes at least one sulfur, oxygen, or nitrogen in the aromatic ring. Nonlimiting examples are furyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, isooxazolyl, pyrrolyl, pyrazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl.

The term organic or inorganic anion refers to an organic or inorganic moiety that carries a negative charge and can be used as the negative portion of a salt.

The term "pharmaceutically acceptable cation" refers to an organic or inorganic moiety that carries a positive charge and that can be administered in association with a pharmaceutical agent, for example, as a counteraction in a salt.

The term enantiomerically enriched composition or compound" refers to a composition or compound WO 96/06093 PCT/US95/10884 -18that includes at least 95%, and typically 98, 99, or 100 by weight of a single enantiomer of the compound.

The term pharmaceutically active derivative refers to any compound that upon administration to the recipient, is capable of providing directly or indirectly, the compounds disclosed herein.

As used herein, the term dipolarophile refers to a compound or moiety that reacts with a dipolar species to form a cycloaddition product.

As used herein, the term dienophile refers to a compound or moiety that reacts with a diene to form a cycloaddition product.

As used herein, the term n refers to a pi-orbital complex of an unsaturated compound with a metal, and wherein the superscript after the n refers to the number of sp 2 carbon atoms bonded to the metal.

The term electron withdrawing substituent as used herein refers to a substituent that pulls electron density from the moiety to which it is attached through induction or resonance. A wide variety of electron withdrawing substituents are well known to those skilled in organic synthesis.

II. Examples of Active Compounds 7-Azabicyclo[2.2.1]-heptane and -heptene derivatives of Formula are provided that are cholinergic receptor ligands. These compounds typically act as nicotinic or muscarinic receptor agonists or antagonists. The compounds can be used in the treatment of cognitive, neurological, and mental disorders, as well as other disorders characterized by decreased or increased cholinergic function.

Some of the compounds have central and WO 96/06093 PCT/US95/10884 -19peripheral analgesic and, or alternatively, anti-inflammatory activity, and thus can be administered to a mammal, including a human, to treat pain and inflammation. A method for the treatment of pain is also presented that includes administering an effective amount of the compound or its pharmaceutically acceptable salt or derivative, or mixtures thereof, to a host in need of analgesic therapy, optionally in a pharmaceutically acceptable carrier or diluent.

The numbering scheme for 7-azabicyclo [2.2.1]-heptane and -heptene derivatives is as illustrated below.

7 N 1 6 3 The 7-azabicyclo[2.2.1]-heptanes and -heptenes disclosed herein can exhibit a number of stereochemical configurations. As discussed above, the compounds are prepared in a Diels-Alder cycloaddition reaction of a dienophile with a pyrrole, or a modification of the Diels Alder reaction involving the reaction of a dipolarophile with a pentaammineosmium(II) activated pyrrole. In the transition state of the cycloaddition reaction, there are two possible relative orientations of the diene or dienophile, referred to as endo and exo.

Endo configurations are formed when other WO 96/06093 PCT/US95/10884 unsaturated groups in the dienophile (or dipolarophile) lie near the developing double bond in the diene. Exo configurations are formed when other unsaturated groups in the dienophile (or dipolarophile) lie away from the developing double bond in the diene. Depending on the substitution on the carbon atoms, the endo and exo orientations can yield different stereoisomers.

Carbon atoms 2, 3, 5 and 6 in 7-azabicyclo[2.2.1]heptanes and carbon atoms 2 and 3 or 5 and 6 in 7-azabicyclo[2.2.1]heptenes are chiral when attached to different substituents. If at least one of the carbons in the molecule are chiral, the unsymmetrically substituted bicyclic compounds exist as one or more diastereomeric pairs. The R groups in the active compounds described herein can also include chiral carbons, and thus, optically active centers.

It is sometimes found that one or more enantiomers of a biologically active compound is more active, and perhaps less toxic, than other enantiomers of the same compound. Such enantiomerically enriched compounds are preferred for pharmaceutical administration to humans or other hosts.

One of ordinary skill in the art can easily separate the enantiomers of the disclosed compounds using conventional processes, and can evaluate the biological activity of the isolated enantiomers using methods disclosed herein or otherwise known.

Through the use of chiral NMR shift reagents, polarimetry, or chiral HPLC, the optical enrichment of the compound can be determined.

Classical methods of resolution include a variety of physical and chemical techniques. For example, since the compound has a basic amine (N 7 it can be reacted with a chiral acid to form WO 96/06093 PCT/US95/10884 -21diastereomeric salts that may possess significantly different solubility properties. Nonlimiting examples of chiral acids include malic acid, mandelic acid, dibenzoyl tartaric acid, 3-bromocamphor-B-sulfonic acid, acid, and di-p-toluoyltartaric acid, and (-)-menthyl chloroformate. Similarly, acylation of a free amine or hydroxyl group in the molecule with a chiral acid also results in the formation of a diastereomeric amide or ester whose physical properties may differ sufficiently to permit separation. Enantiomerically pure or enriched compounds can be also obtained by passing the racemic mixture through a chromatographic column that has been designed for chiral separations, including cyclodextrin bonded columns marketed by Rainin Corporation.

Chiral benzylated pyrrole complexes such as [Os(NH 3 5 2-(ArRHC-(pyrrole)))]2+) can be used for enantioselective syntheses of 7-azanorbornanes.

The following are nonlimiting examples of specific compounds that fall within the scope of the invention. These examples are merely exemplary, and are not intended to limit the scope of the invention.

Epibatidine isomers: l-7-aza-2-exo-(2-chloro-5-pyridyl)-bicyclo[2.2.1] heptane and its pharmaceutically acceptable salts, including the hydrochloride salt; 1-7-aza-2-exo- (2-chloro-5-pyridyl)-bicyclo[2.2.1] heptane and its pharmaceutically acceptable salts, including the hydrochloride salt; d and 1-7-aza-endo-(2-chlorobicyclo[2.2.1] heptane and its pharmaceutically acceptable salts, including the hydrochloride salts; WO 96/06093 PCTIUS95/10884 -22- (B3) d and 12 enantiomers of the 7 -aza-bicyclo[2.2.1]heptane derivatives containing the following substituents: A combination of 7-methyl, 7-allyl-, 7-cyclopropylmethyl, 7-cyclobutylmethyl, 7-phenethyl, 7-hydroxyethyl, 7-methoxyethyl, 7-methylthioethyl, 7 -dimethylaminopropyl, 7formamidinyl, 7- (2-chioroethyl), 7-disodium .phosphate and 7-(4-methoxybenzyl) substituents with a 2-exo- (2-chloro-5-pyridyl) substituent; 2-exo- (3-pyridyl); 2-endo- (3-pyridyl); 7-methyl-2-exo- (3-pyridyl); 7 -cyclopropylmethyl.2exo.(3-pyridyl); 7phenethyl-2-exo- (3-pyridyl); 2-exo- (4-pyridyl); 7-methyl-2-exo- (4-pyridyl); 7- allyl-2-exo-(4-pyridyl); 7 -cyclopropylmethyl-2-exo. (4-pyridyl); 2-exo- (3-chloro-4-pyridyl); 7 -cyclopropylmethyl-2- exo- 3 -chloro-4-pyridyl); 7-phenethyl-2-exo- (3-chloro-4-pyridyl) 2-exo- (2 chloro-3--pyridyl); 2-exo- (2-chloro-.4-pyridyl); 2-exo- 2 2-exo- (2-methoxy-5-pyridyl); 2-exo- (2-methylthio- 2-exo- 2-exo- (2-dimethylamino-5-pyriayl); 2-exo- (2hydroxy- 5-pyridyl) and their 7 -cyclopropylmethyl derivatives; The exo and endo isomers of: 2-phenyl; 2- (3-chiorophenyl); 2- (3-dimethylaminophenyl); 2- (3trifluoromethylphenyl); 2- (3,4-methylenedioxyphenyl); 2- (3,4dimethoxyphenyl); 2- (4 -fluorophenyl); 2- (4-hydroxyphenyl); 2- (4-methylthiophenyl); 2- (4-methylsulfonylphenyl) 2- difluorophenyl); 2- (2-chiorophenyl); 2- (2-naphthyl); 2- (7-methoxy-2-naphthyl); WO 96/06093 WO 9606093PCTIUS95/10884 -23- 2-(5--chloro-2-thienyl) 2-(chloro-5 -thiazolyl); 2-(4-pyrimidyl); 2 -(2-chloro-5-pyrimidyl); chloro-2-pyridazinyl) 2- (1,2,5-thiadiazol-3-y1); 2- (5-dimethylamino-2-furyl); 2- 2-(5-fluoro-3-indolyl) 2-(5--methoxy-3-indolyl); 2- (4-chlorobenzyl); 2- (5-chloro-3-pyridylmethyl); 2- (4-pyridylinethyl); 2-nicotinyl; 2- (6chioronicotinyl); 2- isonicotinyl; 2- (3-chioro-isonicotinyl); 2 (4-chlorobenzoyl); 2-(4-dimethylaminobenzoyl); 2-(3,4dirnethoxybenzoyl) and their 7-methyl, 7-cyclopropylmethyl, 7-allyl and 7-phenethyl derivatives.

The exo and endo isomers of 7-aza-2- (2-chloro-5-pyridyl) -bicyclo[2.2.1]heptane containing the following substituents at the 1, 2, 3, 4, 5 or 6 positions: 1 or 4-methyl; 1 or 4-hydroxymethyl; 1 or 4- methoxymethyl; 1 or 4-carbomethoxy; 1 or 4-allyl; 1 or 4-benzyl; 1 or 4-(4-fluorobenzyl); 1 or 4- (4-methoxybenzyl); 1,4-dimethyl; 1,4-bis (hydroxymethyl) 1,4-bis(methoxymethyl); 1,6 or 4, Endo or exo-3-methyl; 3-hydroxymethyl; 3-methoxymethyl; 3 -carbomethoxy; 3-carboxy; 3-carbamyl; 3-cyano; 3-acetyl; 3 -aminomethyl; 3 -dimethylaminomethyl; 3 -methyithiomethyl; 3 -phenylsulfonyl; 3-methanesulfonyl; 3-benzyl; 3-allyl; 3-cyano- 1, 4-dimethyl; 3-hydroxymethyl-1, 4-dimethyl, 3 -methoxymethyl -1,4 -dimethyl; 3-methylthiomethyl-i, 4-dimethyl; 5,6bis(trifluoromethyl); 5 or 6-methoxy; 5 or 6-methyl; 5, 6-dimethyl; 5, 6-dicarbomethoxy; 5,6-bis (hydroxymethyl); 5,6-bis(methoxymethyl); or 6-chioro; 5 or 6-hydroxy; 5,6-dehydro; 5,6-dehydro-1,4-dimethyl; 3,3-dimethyl; 2-methyl; WO 96/06093 WO 9606093PCTIUS95/10884 -24- 2, 3-dimethyl, 5, 6-methylene; and their corresponding 7-methyl, 7cyclopropylmethyl, 7- allyl, 7 -phenethyl and 7- (4-f luorobenzyl) derivatives.

7-Aza-2-(2-chloro-5-pyridyl)bicyclo[2.2.llhept-2-ene and its 7-methyl, 7-allyl, 7-cyclopropylmethyl, 7-phenethyl and 7- (4-methoxyphenethyl) derivatives; and the corresponding 1,4-dimethyl; 1 or 4-methyl; 5,6-dimethyl and 5,6-bis (trifluoromethyl) analogs.

Benzo[5a,6a]epibatidine and its N-methyl derivative; 2,3 -dehydroepibatidine; 5,6bis (trifluoromethyl) deschloroepibatidine; 2carbomethoxy-7-methyl-7-azabicyclo heptane; 2-cyano-7-methyl-7-azabicyclo[2.2.l]heptane; trans- 2,3-bis-carbomethoxy-7-azabicyclo[2.2.1] heptane; exo-2-amino-7-methyl-7-azabicyclo[2.2.1] heptane; exo-2- (1-pyrrolylmethyl) -7-methyl-7-azabicyclo heptane; exo-2-hydroxymethyl-7-methyl-7azabicyclo heptane; exo-2-hydroxymethyl-7methyl-2-azabicyclo heptane.

exo-2-acetamidomethyl-7-methyl-7azabicyclo heptane; exo-2-benzamidomethyl-7methyl-7-azabicyclol2.2.llheptane; N-[exo-2-(7methyl -7 -azabicyclo 2.2. 1] heptyl) methyl]I -N 1 -phenyl urea; exo-2,5'-(3'-methyl-1',2',4'-ozadiazolyl)-7methyl-7-azabicyclo heptane; -methyl-l' ,4'-oxadiazolyl) -1,4dimethyl-7-azabicyclo[2.2.1]heptane; -methyl-l' ,2'1,4'-oxadiazolyl) -7methyl-7-azabicyclo[2.2.1]heptane; exo-2,5'-(3'- -methoxyphenyl] ,4'-oxadiazolyl) -7-methyl- 7-azabicyclo[2.2.llheptane; endo-2,2'-(5'-methyl- 1',3',4'-oxadiazolyl)-7-methyl-7azabicyclo[2.2.1]heptane; exo-2,2' -methyl- ,4'-oxadiazolyl)-7-methyl-7- WO 96/06093 WO 9606093PCTUS95/10884 azabicyclo[2.2.lIjheptane; 2-carbome thoxy-7- (3',51dimethylbenzyl) -7-azabicyclo[2.2.llheptane; 2-carbomethoxy-7-azabicyclo heptane; -(exo) (1,1-dimethylethoxycarbonyl) -7azabicyclo [2 .2 .1]heptan-2 -one; (1,1-dimethyl-ethoxycarbonyl) -7azabicyclo heptan-2-ylidene; -(exo) 1-dimethylethoxycarbonyl) -2hydroxymethyl-7-azabicyclo heptane; -(exo) (i,1-dimethylethoxycarbonyl) -2formyl-7-azabicyclo[2.2.llheptane; -dibromo-1' -ethenyl)] (1,1dimethylethoxycarbonyl) -7-azabicyclo heptane; -(exo) -ethynyl) (1,1dimethylethoxycarbonyl) -7-azabicyclo heptane; (dimethylethoxycarbonyl) methyl) isoxazolyl] -7-azabicyclo heptane; 2- -(3'-methyl) isoxazolyl] -7azabicyclo[2.2.1]heptane; methyl) isoxazolyl] -7-azabicyclo[2.2.1]heptane; -(exo) (methoxycarbonyl) -quinolyl) -7azabicyclo[2.2.1]heptane; quinolyl) -7-azabicyclo[2.1.1]heptane; -(exo) 7-methyl-2- -quinolyl) -7azabicyclo[2.2.llheptane; 2- -oxazole) -7-methyl- 7-azanorbornane; 2- ,4'-oxadiazole) -7-methyl- 7-azanorbornane; 2- (tetrazole) -7-methyl-7azanorbornane; 2- (imidazole) -7-methyl-7azanorbornane; 2- (benzopyrirnidinone) -7-methyl-7azanorbornane; 2- (acylamino) -7-methyl-7azanorbornane and 2- (acylaminomethyl) -7-methyl-7azanorbornane.

WO 96/06093 PCTIUS95/10884 -26- XII. Methods for the Synthesis of Optionally Substituted 7-Azabicyclo[2.2.1]-heptanes and -heptenes A. SYNTHESIS OF THE 7 -AZABICYCLO[2.2.1]-HEPTANE OR -HEPTENE RING SYSTEM FROM PYRROLES VIA PENTAAMMINEOSMIUM(II)

COMPLEXES

It has been discovered that 7-azabicyclo[2.2.1]-heptane and -heptene derivatives can be prepared by combining a dipolarophile with an optionally substituted pyrrole that has been complexed with pentaammineosmium(II).

Any dipolarophile can be used in this reaction that reacts with the pentaammineosmium pyrrole complex to provide an optionally substituted 7-azabicyclo[2.2.1]-heptene, which is easily converted to the corresponding 7-azabicyclo[2.2.1] -heptane. Examples of dipolarophiles include compounds of the structure ZI-C=C-Z 2 wherein Z, and

Z

2 are independently electron withdrawing groups, including without limitation, esters, nitriles, ketones, aldehydes, amides, -NO 2 sulfones, anhydrides,

-CF

3 pyridinium salts, and for example, CO(alkyl, aryl or heteroaryl), C(0)H, C0 2 (alkyl, aryl, or heteroaryl), S0 2 (alkyl, aryl, or heteroaryl), or wherein Z, and Z 2 are together

(CO)

2 0, or (CO) 2 N. Specific compounds include N-methylated and 6-carboxylated pyridyl acrylates, alkyl acrylate, alkyl methacrylate, pyridyl substituted vinyl sulfones, acrylonitriles, anhydrides, maleimides, alpha-methylene-6butyrolactone, maleates, and fumarates.

Analogously, any optionally substituted pyrrole can be used that on complexation with pentaammineosmium(II) will react with a dipolarophile. Examples of suitable pyrroles WO 96/06093 PCT/US95/10884 -27include 2,5-dialkylpyrrole, 2-alkylpyrrole, 3-alkylpyrrole, 1-alkylpyrrole, 3, 4 -dialkylpyrrole, pyrrole, 1-silylated pyrrole, 2, or 3)alkoxy or amino pyrrole, 2,3-dialkoxypyrrole, dialkoxypyrrole, and 3,4-dialkoxypyrrole.

As shown below in Scheme 1, a complex is readily formed between pyrrole and the 7-base pentaammineosmium(II) in which the osmium coordinates the heterocycle across C2 and C3. At 20 0 C, this species is in equilibrium with its linkage isomer in which the metal binds across C3 and C4. Although the 3,4-n species is only a minor component (AGi,o>3 kcal/mol), the metal coordination in this species renders the remaining portion of the pyrrole an azomethine ylide

(R

2

C+-N(R)-C-R

2

*R

2

-CR

2 and thereby dramatically enhances the tendency of the ligand to undergo a 1,3-dipolar cycloaddition with suitable dipolarophiles.

.RR.

gs DMAC. 0.5 S 4 Os)ll

NR,

Os(ll) z 2 Z2

R

2 Zi Scheme 1. Dipolar cycloaddition of 4 2 -pyrrole complex with dipolarophile.

Os(II) [Os(NH 3 (OTf) 2 The resulting 7-azabicyclo[2.2.1]hept-5-ene ligand is unstable with respect to cycloreversion, but metal coordination greatly stabilizes the WO 96/06093 PCT/US95/10884 -28complex and thus provides the opportunity to carry out functional group transformations while keeping the bicyclic framework intact. For example, derivatization of electron-withdrawing groups in the 2- or 3-positions of the norbornene framework, using conventional processes, provides a wide array of functionalized 7-azanorbornenes. Specifically, as shown in Scheme 2 below, the exo-carbonyl cycloadduct complex 2, prepared in a one-pot synthesis from 2,5-dimethylpyrrole, is reduced to the corresponding alcohol and oxidatively decomplexed to yield the relatively inaccessible 5-hydroxymethyl-7-azanorbornene 3.

NH

1. Os(NH,) 5 (OTin

H

CH3 C H 3 DMAC: 0.5 h. Os0)

COCH

2. CH-=CH-CO;CH. 0.5 h

CH

3 87%

NH

1. Li-9BPN THF. 0.5 h CH 2. Ce(N0 3 6

(NH

4 2 /HOTf CH 2

OH

CH

3 71% overall Scheme 2. Synthesis of a 7-azanorbornene (Os (II) [Os(NH 3 DMAc N,Ndimethylacetamide; Otf CF 3

SO

3 This approach can be used to construct the epibatidine ring system if a 3-vinyl pyridine is used as the dipolarophile. The use of methyl-trans-3-(3-pyridyl)-acrylate in the above reaction sequence (using the complex shown in Scheme yields compound 4, shown below, which contains the carbon skeleton of the natural product.

WO 96/06093 PCT/US95/10884 -29- CH, CH2OH CHi

ON

Epibatidine has no substitution at the bridgehead carbons (C 1 and C 4 The reactivity of simple pentaammineosmium(II)- pyrrole complexes with dipolarophiles decreases in the order 2,5-dimethylpyrrole >N-methylpyrrole>pyrrole.

Generally, additional activation of the dipolarophile, by careful selection of the electron withdrawing group attached to the olefin, or high pressure is required to obtain cycloadducts without substitution at the bridgehead positions. Although the parent pyrrole complex gives complex mixtures, the N-methyl pyrrole reacts with the N-methylated and 6-carboxylated pyridyl acrylates to yield cycloadducts 5 and 6 as single diastereomers.

NCH

3

NCH

3 00 2

CH

3

'CO

2

CH

3 QN+ OTf Q N COCCH2CHC 'CH3 6 An alternative method for stabilization of the azabicyclo[2.2.1]heptane nucleus involves protonation of the secondary amine (and pyridyl group) followed by oxidative removal of the metal and in situ hydrogenation of the azanorbornene. An WO 96/06093 PCT/US95/10884 example of this method is shown in Scheme 3 below for the synthesis of the 1,4-dimethyl-exocarbomethoxy-norchloroepibatidine 7.

H

O HOTF HH 2 Co oM 2. CeIV) PdO Scheme 3. Decomplexation and hydrogenation to generate a 7 -azanorbornane.

([Os]2+=[Os(NH 3 (Otf) 2 The process for preparing optionally substituted 7-azabicyclo[2.2.1]heptanes and 7-azabicyclo[2.2.1]hept-5-enes via pentaammineosmium(II) complexes proceeds in three steps. In the first step, the optionally substituted pyrrole is treated with pentaammineosmium(II). An excess of the pyrrole complex is usually preferred.

Pentaammineosmium(II) is generated in situ by the reduction of pentaammineosmium(III) with a one electron reducing agent that has a reducing potential of less than -0.75 volts versus hydrogen.

The counteranion of pentaammineosmium (II) can be any anion that does not adversely affect the overall reaction. Typical counteranions are CF 3 SO3

PF

6 and (alkyl or aryl)S0 3 Any chemical or electrochemical reducing agent that can reduce the osmium complex from a III valence state to a II valence state and which does not cause or participate in undesired side reactions is suitable. Examples of appropriate reducing agents include magnesium, zinc, aluminum, sodium, cobaltocene and electrochemical reduction.

WO 96/06093 PCT/US95/10884 -31- In a preferred embodiment, activated magnesium powder is used.

The optionally substituted pyrrole, pentaammineosmium(III), and reducing agent are stirred at a temperature ranging between 0 0 C and 0 C until the desired organometallic complex is formed, typically between 0.1 and 1.0 hours. The reaction can be carried out in a polar or nonpolar solvent, including but not limited to N,N-dimethylacetamide, N,N-dimethylformamide, water, methanol, acetonitrile, acetone, dimethylsulfoxide,

CH

2 Cl 2 or dimethoxyethane. The reaction is carried out in the absence of 02, and typically under nitrogen, at a pressure of 1 atm or greater.

In the second step of the process, the dipolarophile is added to the stirring solution of the pyrrole pentaammineosmium (II) complex to produce an optionally substituted 7azabicyclo[2.2.hept-5-ene. Any molar ratio ol dipolarophile to pyrrole can be used that provides the desired results. Typically, a molar ratio of dipolarophile to pyrrole ranging between approximately 1 and 10 provides a suitable yield of product. The reaction solution is stirred at a temperature ranging between 10 and 50 0 C until the product is formed, typically between 1 and 24 hours.

In an optional step after the bicyclic ring system is formed, and while pentaammineosmium is still complexed to the pi-orbital of the heptene moiety, functional groups on the bicyclic ring can be derivatized using conventional processes. For example, esters can be reduced to alcohols, nitriles to amines, sulfones to sulfides, nitro groups to amines, and amides to amines. Sulfones and carboxylates can be reductively eliminated WO 96/06093 PCTfUS95/10884 -32using the Barton decarboxylation procedure. High temperatures and strong bases should be avoided in the functionalization procedures to avoid ring disruption and unwanted side reactions.

In the third step of the reaction, the pentaammineosmium (II) complex is removed from the optionally substituted 7-azabicyclo[2.2.1]by, for example, treatment with cerium (IV) or oxygen in acidic solution. For example, the 7-azabicyclo[2.2.1]hept-5-ene can be treated with one equivalent of cerium reagent at 20 0 C in a polar solvent such as acetonitrile. Appropriate reagents include Ce(NO 3 6

(NH

4 2 DDQ, and other inorganic or organic oxidants with E +.70 volts versus hydrogen. Alternatively, the osmium reagent can be removed by heating the complex as necessary, usually between approximately 50 0 C and 100 0

C.

Using the method of synthesis described above, a wide variety of substituted 7-azanorbornanes and 7-azanorbornenes can be prepared. Examples oi representative compounds are summarized in Tables 1 and 2.

Some of them are useful as intermediates for the synthesis of desired compounds containing complex heteroaryl or polar substituents as R 2 and/or

R

3 IWO 96/06093PCJSI 08 PCTIUS95/10884 -33- Table 1 R,

N

7-azabicyclo H exo- CH 2 0H H heptane H exo- CH 2

OH

3

H

H exo- CH 2 0H endo-3 -py H exo- CO 2

CH

3 endo-3-py H exo-C 2

CH

3 exo-3-py H exo-SO 2 Ph endo-3-py H endo- SO 2 Ph exo-3-py 7-azabicyclo H exo -CH 2 0H H CBz exo- CH 2 0H H Cbz exo-OCBz H H exo -CH 2 0H endo-3-py .WO 96/06093PCISI 08 PCTIUS95/10884 -34- Table 2 R,11N Example 16 16 17 18 18 19 21 22 23 24

R,

3

CH

3

CH

3

CE

3

H

H

H

Et

H

CH

3

CH

3

CH

3

CH

3 exo- COOMe en do- COOMe exo- C=N endo- C=N exo- COOMe exo- endo- -N(Ph) exo- -N(Ph) exo- -N(Ph) exo- CE 2

NH

2 exo -CH 2

NC

4

H

4 exo -CH 2

OH

exo-CH 2 00CPh-

R

3

H

H

H

H

en do- COOMe

H

H

H

H

WO 96/06093 PCT/US95/10884 Methods for preparing compounds of Formula (I) via derivatization of a 5,6-n2-7aza-bicyclo[2.2.1]hept-5-ene are set out below.

These examples are merely illustrative, and are not intended to limit the scope of the invention.

Example 1 Preparation of 1,4-Dimethyl-2-exo- (hydroxymethyl)7-azabicyclo[2.2.1] (8) A solution of the 5,6-72 osmium complex of compound 8 (727 mg, 1.0 mmol) in 2 grams acetonitrile was protonated with excess triflic acid (250 mg, 1.67 mmol) and treated at -10 0 C with a likewise-cooled solution of ceric ammonium nitrate (560 mg, 1.02 mmol) and triflic acid (560 mg, 3.73 mmol) in 2 grams acetonitrile. Water (1-2 ml) was added to dissolve the precipitated salts, the mixture made basic with 40 ml 10% aqueous sodium carbonate and the product extracted with 5 X ml methylene chloride. The extract was dried over MgSO 4 and the solvent evaporated, yielding 147 mg of brown oil. The crude product was purified by silica gel column chromatography using 1:10 of wt NH 3 in methanol/methylene chloride, yielding 62 mg of pure 8. (oil, Rf 'H NMR (300 MHz, CDC13) d 6.31 J 5.3 Hz, 1H), 6.09 J 5.3 Hz, 1H), 3.99 (dd, J 10.3, 2.1 Hz, 1H), 3.67 (dd, J 10.3, 2.1, 1H), 3.6-2.8 (v br, -2H, OH and NH), 1.4-1.8 3H), 1.48 3H), 1.47 3H); 1 3 C NMR (75 MHz, CDC13) d 145.2 141.5 (CH), 69.9 67.0 61.5 (CH 2 41.7 37.0

(CH

2 18.9 (CH 3 15.7 (CH 3 This material was further characterized by conversion to the picrate salt. m.p. 186-188 0 C; Anal. Calcd. for C 15 HigN 4 0 8 C, 47.12; H, 4.75; N, 14.65. Found: C, 46.96; H, 4.52; N, 14.66.

WO 96/06093 PCT/US95/10884 -36- Example 2 Preparation of N-CBZ-1,4-Dimethyl-2-exo- (hydroxymethyl)-7-azabicyclo[2.2.1]heptand N,O-Bis-CBZ-1,4-Dimethyl-2exo-(hydroxymethyl)-7azabicyclo[2.2.1]hept-5-ene The crude aminoalcohol 8 obtained from mmol of the osmium complex as described above was suspended in a solution of aqueous Na 2

CO

3 (0.38 grams in 2 grams water), and the mixture chilled to 0°C. Benzyl chloroformate (510 mg, 3 mmol) was added, and the mixture allowed to warm to room temperature with vigorous stirring. After 20 hours at 25 0 C the mixture was extracted with methylene chloride, and the extracts dried and rotoevaporated, yielding 0.4 grams of brown oil.

The crude material was chromatographed twice using 1:8 ethyl acetate/petroleum ether, yielding 43 mg of 9 and 64 mg of 10 (Rf 0.5 and 0.1, respectively) For 9: 'H NMR(300 MHz, CDC13) d 7.32 5H, Phenyl), 6.06 (ABq, J 5.7 Hz, 2H, and H6), 5.04 2H, OCH2Ph) 3.69 2H,

CH

2 OH), 2.18 (br s, 1H, OH), 1.75 (2Xs, 6H, CH 3 1.7 overlap, 1H), 1.55 2H); 13C NMR MHz, CDC1 3 d 155.2 140.5 (CH, C5 or C6), 140.2 (CH, C6 or C5), 136.4 ipso), 128.3 (CH), 127.9 127.8 71.1 69.0 66.4 (CH 2 OH) 63.0 (CH2) 45.6 37.7 (CH 2 19.4 (CH 3 16.8 (CH 3 For 10: 'H NMR(300 MHz, CDCl 3 d 7.37 5H, Phenyl), 7.32 Phenyl), 6.07 (ABq, J 5.5 Hz, 2H, H5 and H6), 5.16 2H, OCHzPh), 5.05 (ABq, J 13.5 Hz,2H,

OCH

2 Ph) 4.33 (dd, J 10.5, 7 Hz, 1H, 1/2

CH

2 OCBZ), 4.06 (dd, J 10.5, 7..5 Hz, 1H, 1/2CH 2 OCBZ) 1.94 1H, H2), 1.79 3H, CH 3 1.75 3H, CH3), 1.60 (dd, J 11.4, 9 Hz, 1H, H3do), 1.4 (dd, J 11.4, 3.6 Hz, H3,) 13C NMR (75 MHz, CDC1 3 d 155.0 154.9 140.5 (CH, C5 or WO 96/06093 PCT/US95/10884 -37- C6), 140.5 (CH, C6 or C5), 136.4 ipso), 135.2 ipso), 128.5 (overlap of 2 X CH), 128.4 (CH), 128.3 128.0 127.8 70.8 69.6 (overlap of 2X CH 2 68.9 66.3 (CH 2 0) 43.2 (CH, C5), 38.7 (CH, C6), 19.3 (CH3), 17.0 (CH 3 Example 3 Preparation of 1,4-Dimethyl-2-endo-(3'pyridyl)-3-exo-(hydroxymethyl)-7azabicyclo[2.2.1]hept-5-ene (11) The corresponding 5,6-r 2 osmium complex was treated as described above for compound 8.

Diagnostic 'H NMR information: 6.43 J 6H, 1H, or H6), 6.0 J 6 Hz, 1H, H6 or H5), (dd, J 10,2.5 Hz, 1H, 1/2 CH 2 OH), 3.75 (dd, J 2.5 Hz, 1/2 CH 2 OH), 1.55 CH 3 1.38 CH 3 Example 4 Preparation of 1,4-Dimethyl-2-exo- (hydroxymethyl)-7azabicyclo[2.2.1]heptane (12) A sample of crude compound 8 (85 mg, 0.56 mmol) was stirred with 30 mg 10% Pd-on-C and 0.5 g methanol in a 5-ml round-bottomed flask under 1 atmosphere of H 2 for 30 minutes. The reaction mixture was filtered through celite and evaporated, yielding 78 mg of oil. Purification by preparative thin layer chromatography (0.25 mm, 20 X 20 cm; Eluent 1:6 15% NH3 in MeOH, CH2C1 2 yielded 14 mg of pure 12 (Rf 0.5) 'H NMR(300 MHz, CDC1 3 d 3.89 (br, 2H, NH and OH), 3.82 (d J 10.6 Hz, 1/2 CH2OH), 3.38 J 10.6 Hz, 1/2 CHzOH), 1.7- 7H, 3 X CH 2 CH), 1.41 3H, CH3), 1.37 3H, CH 3 3 C NMR (75 MHz, CDC1 3 d 66.8, 64.0, 63.8, 45.5, 40.0, 39.1, 39.07, 20.6, 17.8 WO 96/06093 PCTUS95'10884 -38- Example 5 Preparation of 1 4 -Dimethyl2-exocarboxymethyl-7 -azabicyclo heptane (13) The corresponding 2 3 -n2-osmium complex 18 was protonated and decomplexed with Ce(IV) as described for 8. The acetonitrile was evaporated and the unstable, protonated 7-azanorbornene hydrogenated in methanol as described for 12. Compound 13 was obtained as an oil following an aqueous workup see procedure for 8) and preparative thin layer chromatography purification. 1H NMR(300 MHz, CDCl 3 d 3. 60 3H, CH 3 O) 2. 63 (dd, J 8.1, 5.1 Hz, 1H, H2), 2.49 (br s, 1H, NH), 1.82 (dd, J 12.2, 8.1 Hz, 1H, H 3 fldO), 1.75-1.2 (in, overlap, 1. 32 CH 3 1 1. 2 3 H, CH 3 1 3 C NMR (75 MHz, CDCl 3 d 176.5 67.7, 63. 4, 53.0, 51.3, 44.0, 38.3, 36.7, 20.5, 18.3.

Example 6 Preparation of 1,4-Dimethyl-2-endo-(3..

pyridyl) exo- carboxymethyl -7azabicyclo[2.2.1]heptane (14a) and its exo-pyridyl- endo-carboxyl isomer (14b) These isomers were obtained as an inseparable 94:6 mixture from the corresponding mixture of osmium complexes following the procedure for 13.

For 14a, 'H NMR(300 M4Hz, CDCl 3 d 8.45 (in, 2H, H2' and H61 overlap) 7.49 (dt, JT 7.8, 1.5 Hz, 1H, 7.23 (dd, J 4.8 Hz, 1H, H51), 3.64 (s, 3H, CH 3 O) 3.29 (dd, J 5.9, 2.1 Hz, 1H, H2) 2.95 J 5.9 Hz, 1H, H3), 2.62 (br s, 1H, NH), 1.85- 1.6 (in, 2H, CH 2 1 1.5 (in, 1H), 1.35 (in, 1H), 1.29 3H, CH 3 1.26 3H, CHO) 1 3 C NNR (75 MHz, CDCl 3 d 175. 7 (Ca) 14 9. 8 148.2 (CHi), 135.3 (CHi), 134.1 123.1 (Cli), 67.6 (2XC overlap), 58.7 (CHi), 58.3 51.7 (CH 3 O) 3 8. 6 (CH 2 3 0. 3

(CH

2 19.3 (CH3),1 18.7 (CH 3 Diagnostic features of 14b: d 3.36 J 6 Hz, H2), 2.8 (dd, J 6, 2 Hz, H3) ,WO 96/06093 PCT/US95/10884 -39- Example 7 Preparation of 1,4-Dimethyl-2-endo-(3'pyridyl)-3-exo-(hydroxymethyl)-7azabicyclo[2.2.1]heptane Compound 14 was reduced with lithium aluminum hydride in ether, yielding a clear resin after an aqueous workup. Diagnostic 'H NMR resonances: 3.87 (dd, J 10.6, 2.8 Hz, 1H, 1/2 CH 2 OH), 3.46 (dd, J 10.6, 3.0 Hz, 1H, 1/2 CH20H), 3.16 (dd, J 1.9 Hz, 1H, H2), 1.5 3H, CH 3 1.25 3H, CH 3 Example 8 Preparation of 1,4-Dimethyl-2-endo-(3'pyridyl)-3-exo-phenylsulfonyl-7azabicyclo[2.2.1]heptane (16a) and its exo-pyridyl, endo-phenylsulfonyl isomer (16b) The procedure for compounds 13 and 14 was followed yielding a mixture of isomeric 7azanorbornanes. Diagnostic !H NMR peaks for major isomer: 3.6 J 7 Hz, 1H, CHdo), 2.95 (dd, J 7, 1.5 Hz, 1H, 1.85 3H, CH 3 1.25 (s, 3H, CH 3 Example 9 Preparation of [Os(NH 3 5 1 2 dimethylpyrrole)] (OTf) 2 (17) To a solution of [Os(NH 3 ),OTf]OTf 2 (1.445 grams, 2.00 mmol) in 1.5 grams N,N-dimethylacetamide was added 2,5-dimethylpyrrole (1.5 g, 16 mmol) and activated Mgo (1.0 g, 41 mmol) and the slurry stirred for 45-60 minutes. The slurry was filtered through a medium-porosity frit into 150 ml CH 2 C1 2 giving a light yellow precipitate, which was filtered, washed with CH 2 C1 2 and ether, then dried.

The yield of a light-yellow powder was 1.23-1.31 g (92-98%).

WO 96/06093 PCT/US95/10884 Example 10 Preparation of 5,6-exo- 2 -Os (NH 3 5 1,4-dimethyl-2-exo-carbomethoxy-7azabicyclo- 2 .2.]hept-5-ene) (OTf), (18) The 2,5-dimethylpyrrole complex (669 mg, mmol) was suspended in 2 grams methyl acrylate and the slurry stirred for 1 hour. Acetonitrile 1 ml) was added to dissolve the solids and the resulting solution added dropwise to 50 ml of ether while stirring. The precipitate was filtered, washed with ether and dried, yielding 730 mg (97%) of an off-white powder. 'H NMR (300 MHz, CD 3 CN) d 3.97 (br s, 3H, trans-NH 3 3.65 3H, CH 3 3.34 (br s, 12H, cis-NH 3 3.17 J 6.3 Hz, 2H, H5 or H6), 3.13 J 6.3 Hz, 1H, H6 or H5), 2.77 (dd, J 8.1, 4.2 Hz, 1H, H2), 2.14 (br s, 1H, NH), 2.05 (dd, J 11.6, 8.1 Hz, 1H, H3,e), 1.63 (dd J 11.6, 4.2 Hz, 1.39 3H, CH 3 1.24 3H,

CH

3 13C NMR (75 MHz, CD 3 CN) d 176.4 75.7 71.0 59.1 58.0 55.3 (CH), 51.6 (OCH 3 47.1 (CH) 18.3 (CH 3 15.9 (CH 3 Anal. Calcd. for C 2

H

3 0

N

6 OgS 2

F

6 0Os: C, 19.10; H, 4.01; N, 11.14. Found: C, 18.57; H, 3.96; N, 11.02.

Example 11 Preparation of Pentaammineosmium- Pyrrole Complexes: 2,3-q 2 [Os (NH 3 Ligand] (OTf) 2 where Ligand is pyrrole or N-methyl pyrrole A mixture of [Os(NH 3 5 OTf] (OTf 2 (723 mg, mmol), N,N-dimethylacetamide (1 DME (3 g), pyrrole or N-methyl pyrrole (1 g) and magnesium g) was stirred for 1 hour.- The solution was filtered through a 60-ml medium fritted glass funnel with the aid of 10-15 ml of DME, and the filtrate added dropwise to methylene chloride (150 ml). The resulting precipitate was filtered, and WO 96/06093 PCT/US95/10884 -41washed with portions of methylene chloride (20 ml) and ether (2 X 20 ml), and dried under nitrogen.

The yield of this reaction is typically 90-95% of a yellow-orange solid containing approximately 8% of a binuclear impurity.

Example 12 Preparation of Pentaammineosmium- Cycloadduct Complexes The pentaammineosmium-pyrrole complex obtained from Example 11 was treated with an excess (3-30 eq) of a dipolarophile in either acetonitrile or N,N-dimethylacetamide solution. After 1-10 hours, the solution was added to ether or methylene chloride with stirring (20 ml of ether per gram of acetonitrile or 75 ml methylene chloride per gram of N,N-dimethylacetamide). The resulting precipitate was worked up as described in Example 11 providing a yield of 85-95%.

Example 13 One-Pot Process for the Synthesis of Pentaammineosmium-Cycloadduct Complexes A dipolarophile methyl acrylate) was added directly to the reaction mixture in the synthesis of the parent pyrrole complex as described in Example 11. After a suitable reaction time 1-10 hours), the mixture was filtered to remove the magnesium, and the filtrate was added to 1:1 methylene-chloride/ether (100 ml for every gram of N,N-dimethylacetamide used in the synthesis) with stirring. The solid was isolated as described in Example 11 yielding the cycloadduct complex as mono-N,N-dimethylacetamide solvate in yield.

WO 96/06093 PCT/US95/10884 -42- Example 14 One-Pot Process for the Synthesis of 7 -Azanorbornanes from the Pentaammineosmium-Cycloadduct Complex The cycloadduct complex (1.0 mmol) prepared in Example 13 was dissolved in acetonitrile (4 g), protonated with triflic acid (3-5 eq), and treated with DDQ (1 eq). The dark solution was transferred to a 50-ml round-bottomed flask with the aid of an additional 20 ml of acetonitrile, treated with palladium-on-carbon (approximately 0.5 g, mole%), and hydrogenated under 1 atm H 2 (balloon) for a suitable period of time (2-20 hours) (The pyrrole-derived complexes, lacking a substituent on nitrogen, underwent reductive amination to N-ethyl derivatives in acetonitrile. In these cases the solvent was evaporated and the reduction carried out in methanol). Workup A: The reaction mixture was filtered through celite to remove the Pd/C, the cake washed with acetonitrile (or methanol), and the filtrate evaporated. The residue was dissolved in water (approximately 10-15 ml), transferred to a separatory funnel, rendered basic with 10% aqueous Na 2

CO

3 (20 ml) and extracted with methylene chloride (3 x 40 ml). The extract was dried over MgSO 4 and evaporated, yielding the crude 7 -azanorbornanes.

Workup B: The hydrogenation reaction mixture was treated with 1 ml NH 4 0H, diluted with an equal volume of methylene chloride (about 30 ml), then filtered directly through 20 cc of silica gel in a medium fritted glass funnel. The flask and silica were washed with an additional 2 X 30 ml of 1:1 methylene chloride/acetonitrile (or methanol) containing

NH

4 OH, and the combined eluent evaporated, yielding the crude 7-azanorbornanes.

,WO 96/06093 PCT/US95/10884 -43- Example 15 Preparation of 2 -Carbomethoxy-7methyl-7-azabicyclo[2.2.1]heptanes These compounds, obtained as a 1:1 mixture of isomers, were prepared in 66% overall yield from Nmethyl pyrrole and methyl acrylate using the method set forth in Examples 13 and 14 (workup The isomers were separated by preparative thin layer chromatography using 1:1:5 HMDS/Methanol/methylene chloride: Exo isomer Rf 0.76; 'H NMR (CDC1 3 6 3.66 3H, CH3O), 3.62 J 4.2 Hz, 1H, H4), 3.30 J 4.0 Hz, 1H, H4), 2.40 (dd, J 9.6, 5.4 Hz, 1H, H2), 2.21 3H, CH 3 2.18 1H), 1.86 2H), 1.57 (dd, J 12.6, 9.6 Hz, 1H, 1.33 2H); 13C NMR (CDC1 3 6 174.6 CO), 64.2 (CH, C1 or C4), 61.1 (CH, C4 or Cl), 51.9 (CH 3

CH

3 47.4 (CH, C2), 34.5 (CH 3

CH

3 33.3 (CH 2 26.7 (CH 2 26.2 (CH 2 Endo isomer Rf 0.62; 'H NMR (CDC13) 6 3.65 3H, CH30), 3.44 J Hz, 1H, H1 or H4), 3.21 J 4.5 Hz, 1H, H4 or HI), 3.08 1H, H2), 2.26 3H, CH 3 1.95 (m, 1H), 1.75 overlap, 3H), 1.36 2H); 3 C NMR (CDC1 3 50 0 C) 6 174.3 CO), 64.1 (CH, C1 or C4), 62.1 (CH, C4 or Cl), 51.4 (CH 3

CH

3 45.2 (CH, C2), 34.4 (CH 3

CH

3 30.6 (CH 2 28.0 (CH 2 24.2

(CH

2 The picrate salt (both isomers combined) was crystallized from wet ethanol 102-108 oC); Anal. Calcd. for C 1 5

H,

8

N

4 0 9 C, 45.23; H, 4.55; N, 14.07. Found: C, 45.42; H, 4.59; N, 14.10.

Example 16 Preparation of 2 -Cyano-7-methyl-7azabicyclo[2.2.1] heptanes These compounds, obtained as a 1:1 mixture of isomers, were prepared in 57% overall yield from Nmethyl pyrrole and acrylonitrile using the method set forth in Examples 13 and 14 (workup The isomers were separated by preparative thin layer chromatography, using 1:1:8 HMDS/methanol/methylene WO 96/06093 PTU9,08 PCTIUS95/10884 -44chloride. Exo isomer Rf 71; 1H NMR (CDCl 3 3.53 Cd, J 3.3 Hz, lH, HI), 3.37 J =3.8 Hz, lH, H14), 2.44 (dd, J 9.3, 5.1 Hz, 1H, H2), 2.36 3H, CH 3 N) 2.1 (in, 1H), 1.83 2H), 1.75 (dd, J 12.6, 9.3 Hz, 1H, H 3 1.3 (in, 2H); ;3 NMR (CDCl 3 6 12 2. 7 CN) 6 5. 5 (CH, Cl or C4) 60.8 (CHI, C4 or Cl), 35.7 (CH 2 3 5. 3 (CH 3 3 1. 9 (CH) 27.5 (CH 2 26. 9 (CH 2 Endo isomer Rf 0.55; 'H NMR (CDC1 3 6 3.44 J =4.5 Hz, 1H, Hi or H4), 3.29 Ct, J 4.5 Hz, 111, 114 or Hi), 2.92 (dtd [11 line pattern], J 12, 1.8 Hz, 1H1, 112), 2.26 m overlap, 411, CH 3 N and 2.0-1.8 (in, 3H), 1.57 (dd, J =12.3, 5.1 Hz, 1H, H3W) 1. 45 Cm, 1H) 3 C NIVR CCDC1 3 5 0 0 C) 6 12 1. 7 CC, CN) 63.8 (CI, Cl or C4), 61.6 (CI, C4 or Cl), 34.6 (CHO), 3 4. 4 (CH 3

CII

3 N) 2 9.2 (CI, C2) 2 7. 9 (CHO) 24. 1 (CH 2 .The picrate salt (both isomers combined) was crystallized from ethanol (mp 218-224 OC) Anal. Calcd. for C1 4

HI

5

N

5 0 7 C, 46.03; H, 4.14; N, 19.17. Found: C, 45.85; H, 4.08; N, 18.88.

Example 17 Preparation of trana-2,3-Biscarbomethoxy- 7azabicyclo heptane This compound was prepared in 42*- overall yield from pyrrole and dimethyl fumarate using the procedures set forth in Examples 11, 12 (using acetonitrile as a solvent), and 14 (hydrogenation solvent methanol; reaction time 2 h; workup A).

'H1 NMR (CDCl 3 .6 3.95 J 4.5 Hz, 111, H4), 3.84 Cd, J 4. 8 Hz, 111, El) 3. 70 Cs, 3H, CH 3 O) 3. 69 Cs, 3H, CH 3 O) 3.22 (td, J 4.8, 1.8 Hz, 1H1, H3), 3.03 Cd, J 4.8 Hz, 1 H, HI2), 2.55 Cbr s, 1H1, NH), 1.8-1.3 (overlapping in, 4H); 1 3 C NMR CCDCl 3 6 174. 8 CO), 172.1 CC, CO), 61.8 (CH, C1 or C4), 59.1 (CH, C4 or Cl) 5 2. 3 (CHI), 5 2. 1 (CE 3

CH

3 O) 5 2. 0

CCH

3

CII

3 5 0.1 (CHI), 2 8. 7 (CE 2 2 4. 9 (CH 2 ,WO 96/06093 PCTUS9/10884 Example 18 Preparation of Hexahydro-2-phenyl-4, 7-imino-lH-isoindole-1,3(2H)-dione This compound was obtained as a 4:1 mixture of exo and endo isomers, respectively, in 39% overall yield from pyrrole and N-phenylmaleimide using the procedures set forth in Examples 11, 12 (using acetonitrile as a solvent), and 14 (hydrogenation solvent methanol; reaction time 2 hours; workup The crude material was chromatographed on a preparative thin layer chromatography plate (20 X cm, 2 mm) using a gradient elution of ether containing conc. NH40H and 5, 10, and methanol. Two bands were extracted with ethermethanol: Fl (Rf 0.75, ether containing 3% NH 4

OH

and 10% methanol). This material was recrystallized from ethyl acetate-petroleum ether, yielding colorless crystals (mp 206-209 0 exo isomer. 'H NMR (CDC13) 6 7.5-7.3 5H, Ph), 4.15 J 2 Hz, 2H, HI, H4), 2.86 2H, H2, H3), 1.7 4H, 2 X CH 2 1.54 (br s, 1H, NH); 13 C NMR (CDC13) 6 177.3 132.1 129.0 128.5 126.5 59.9 (CH, C1, C4), 49.0 (CH, C2, C3), 29.5 (CH 2 The second fraction (Rf 0.21) yielded the endo isomer: 'H NMR 6 7.6-7.2 Ph), 4.18 (br s, 2H, HI and H4), 3.64 (br s, 1H, NH), 3.41 (br s, 2H, H2 and H3), 1.8-1.6 4H); 3 C NMR 6 175.9 132.0 129.7 129.3 126.9 59.6 51.5 26.5 (CH 2 Example 19 Preparation of 8-Ethylhexahydro-2phenyl-exo-4, 7 -imino-1H-isoindole- 1,3(2H)-dione This compound was formed when the synthesis of hexahydro-2-phenyl-4,7-imino-IH-isoindole-1,3(2Hdione was carried out using acetonitrile in the hydrogenation step of the method set forth in Example 14 (reaction time 18 h, workup The WO 96/06093 PCT/US95/10884 -46crude material was chromatographed on silica gel x 13 cm column). Elution with ether yielded 56 mg of the title product 0.8; ether containing NH 4 OH). Further elution with ether containing 10% methanol and 3% conc. NH40H yielded a second fraction containing 69 mg of crude hexahydro-2-phenyl-4,7-imino-1H-isoindole-, 3 (2H)dione (Rf 0.2; ether containing NHOH) The first fraction was treated with decolorizing charcoal, filtered, evaporated, and the residue recrystallized from ethyl acetate/petroleum ether.

Yield 21 mg of lustrous colorless crystals mp 126-128 0 C. 'H NMR (CDC13) 6 7.5-7.25 5H, Ph), 3.82 J 2.2 Hz, 2H, HI, H4), 2.80 2H, H2, H3), 2.37 J 7.2 Hz, 2H, NCH 2 1.93 2H, H6,o), 1.51 2H, H5, 0. H6 1.04 J= 7.2 Hz, 3H, CH 3 "C NMR (CDC13) 6 177.8 132.4 129.1 128.5 126.7 62.6 (CH, C1, C4), 49.5 (CH, C2, C3), 40.4 (CH 2 25.0

(CH

2 14.5 (CH 3 Example 20 Preparation of Hexahydro-l-hydroxy- 2-phenyl-4,7-imino-lH-isoindole- 3(2H)-one The exo imide formed in Example 18 (25 mg.

-0.1 mmol) was treated with excess sodium borohydride (40 mg, -1.0 mmol) in 5 ml ethanol and the mixture refluxed for 20 minutes. The ethanol was evaporated, the residue acidified with 1 M HC1, and treated with Na 2

CO

3 and methylene chloride.

Evaporation of the extract yielded 20 mg of crude material. Preparative thin layer chromatography (gradient elution; ether containing 5% NH40H and methanol) yielded the product (Rf 0.25, ether with 3% NH40H and 10% methanol), still contaminated with a minor product. 'H NMR (CDC13) 6 7.55-7.2 (m, Ph), 5.22 1H, NCH(OH)), 3.82 J 2 Hz, WO 96/06093 PCTf[JS95/10884 -47- 1H), 2.60 J 2H, 1H), 2.71 10 Hz, 1H), 2.08 J 10 Hz, 1H), 1.63-1.3 overlap, 6H, 2 X CH 2 NH, OH).

Example 21 Preparation of exo-2-aminomethyl-7methyl-7-azabicyclo[2.2.1]heptane The nitrile formed in Example 16 (55 mg, 0.4 mmol) was treated with excess lithium aluminum hydride (30 mg, 0.79 mmol) in 10 ml ether with stirring. After 5 minutes (a white suspension formed), the reaction was quenched with methanol (0.1 then water (0.1 acidified with 1 M HC1, then basified with conc., NH40H, and extracted with methylene chloride. Drying and evaporation of the extract yielded the corresponding primary amine as an oil (17 mg, 'H NMR (CDC13) 6 3.18 J 3.9 Hz, 1H, H4), 3.03 J 3.9 Hz, 1H, HI), 2.70 (dd, J 12, 7.8 Hz, 1H, 1/2 CH 2 2.51 (dd, J 12, 6 Hz, 1H, 1/2 CH 2 2.22 3H, CH 3 1.86 2H), 1.6-1.2 7H, CH 2

NH

2 overlap).

Example 22 Preparation of exo-2-(l- Pyrrolylmethyl)-7-methyl-7azabicyclo[2.2.1]heptane The primary amine formed in Example 21 (17 mg, 0.121 mmol) was treated with dimethoxytetrahydrofuran (25 mg, 0.189 mmol) in acetic acid (0.1 g) at 150 0 C for 5 minutes in an oil bath. Extraction of the basified (10% aqueous Na 2

CO

3 reaction mixture with methylene chloride yielded a mixture of products from which was obtained 8 mg of crude exo-2-(1pyrrolylmethyl) product by preparative thin layer chromatography using 1:1:8 hexamethyldisilazane/methanol/methylene chloride.

'H NMR (CDC1 3 6 6.68 2H), 6.18 2H), 3.92 (dd, J 15, 12 Hz, 1H, 1/2CH 2 3.72 (dd, J WO 96/06093 PCTUS95/10j884 -48- 7 Hz, 1H, l/2CH 2 N) 3.22 (in, 1HI), 2.'96 (mn, 1Hi), 2 .26 3H, CHON), 1. 98 (in, 1H) 1. 83 (in, 2H-) 1.-5-1.22 Example 23 Preparation of exo-2-Hydroxymethyl.

7 -methyl- 7 -azabicyclo[22.lheptane The aminoester formed in Example 15 (41 mg, 0.243 mmol) was treated with lithium aluminum hydride (10 mg, 0.264 mmol) in 5 ml ether. After minutes, the reaction mixture was quenched with methanol, acidified with 1 M Nd1, basified with conc. NH 4 OH, and extracted with methylene chloride.

Evaporation of the extract yielded the desired product (11 mg, 32-1). 'H NMR (CDC1 3 6 3.80 (dd, J 9, 1 Hz, 1H, 1/2 CH 2 3.39 (dd, LT= 9, 2 Hz, 1H, 1/2 CH 2 3.21 T= 5 Hz, 1H, H4), 3.19 LT 4 Hz, 1H, Hi) 2. 18 3H, CH 3 N) 1. 82 (in, 3H) 1. 7 (in, 1H), 1.5-1.2 (in, 4H).

Example 24 Preparation of exo-2benzoyloxymethyl-7 -methyl-7 azabicyclo [2.2 .1]heptane The alcohol formed in Example 23 (11 ing, 0.078 mmol) was treated with benzoic anhydride (34 mg, 0.15 iniol) and DMAP (10 mg) in methylene chloride.

The product was purified by preparative thin layer chromatography (20 X 20 cm X 0.25 mm) using 1:3:80

NH

4 OH/methanol /ether (Rf Yield: 10 mg (52-1) 'H NMR (CDCl 3 6 8.05 J 7.2 Hz, 2H, ortho-H), 7.55 J 7.2 Hz, 1H1, para-H), 7.44 J =7.2 Hz, 2H, meta-H), 4.18 (in, 2H, CH2O), 3.22 J 3.9 Hz, 1H, H4), 3.18 J =3.6 Hz, 1H, Hi) 2.25 3H, CH 3 N) 2.0-5-1.85 (in, overlap, 3H) 1. 48 (dd, J 12, 9 Hz, 1H, 1.34 (in, 3H).

.WO 96/06093 PCTItJS95/10884 -49- Example 25 Preparation of Norbornane Analog of Epibatidine using Reductive Heck Methodology: exo-2-(3-pyridyl) bicyclo[ 2 .2.1]heptane This procedure is based on that described by R. Larock et al. Chem. Soc. Chem. Comm. 1989, 1368). A mixture of norbornene (101 mg, 1.07 mmol), 3-iodopyridine (205 mg, 1.0 mmol), tetra-nbutylammonium chloride (287 mg. 1.03 mmol), potassium formate (255 mg, 3.03 mmol), and palladium acetate (28 mg, 0.125 mmol) was stirred in DMF (1.2 g) at room temperature for 72 hours.

The mixture was diluted with 10 ml of 10% Na 2

CO

3 (aq) and 10 ml of ether and the aqueous phase extracted again with ether. The combined extracts were dried over MgSO 4 filtered and evaporated, and the residue purified by preparative thin layer chromatography (20 X 20 cm, 2.0 mm, 1:1 petroleum ether/ethyl acetate, Rf yielding the title product as an oil (73 mg, 'H NMR (CDC1 3 6 8.42 1H, 8.33 J 4.5 Hz, 1H, H6'), 7.43 J 7.8 Hz, 1H, 7.11 (dd, J 7.8, Hz, 1H, 2.67 (dd, J 8.7, 5.7 Hz, 1H, H2), 2.30 2H, 1H, Hl and H4), 1.8-1.2 (m, overlap, 8H, 4 X CH 2 1 3 C NMR (CDC13) 6 149.1 (CH), 146.3 142.3 134.0 122.9 44.7 42.5 38.7 (CH2), 36.7 35.9 (CH 2 30.3 (CH 2 28.6 (CH2).

B. SYNTHESIS OF THE 7-AZABICYCLO[2.2.1]-HEPTANE OR -HEPTENE RING SYSTEM USING DIELS-ALDER

APPROACH

In an alternative embodiment, as illustrated in Figures 2a and 2b, active compounds, or their precursors, are prepared through the Diels-Alder reaction of an N-(electron withdrawingsubstituted)pyrrole with an arylsulfonyl(optionally substituted aryl or heterocyclic)acetylene. The WO 96/06093 PCT/US95/10884 electron withdrawing group at the N 7 -position decreases the aromaticity of the pyrrole ring and activates the ring in favor of the cycloaddition reaction.

The product of the reaction between the N- (electron withdrawing-substituted)pyrrole with the arylsulfonyl(optionally substituted aryl or heterocyclic)acetylene is a 7-(electron withdrawing substituted)-2-(optionally substituted aryl or heteroaromatic)-3-arylsulfonyl-7-azabicyclo[2.2.1 (compounds 23 and 32, Fig. 2).

This diene can be derivatized using conventional methods to a wide variety of 7-azabicyclo[2.2.1]heptanes and -heptenes. For example, an R 3 alkyl or aralkyl group can be added by reacting the saturated bicycloheptane derivative of compound 23 or 32 with n-butyl lithium and R3I, followed by treatment with a reducing agent to remove the 3arylsulfonyl moiety. (Julia, M. and Paris, J-M., Tetrahedron Letters, 49, 4833 (1973).) R 5 and R 6 groups can be added to compound 24 (Figure 2) by appropriate and conventional reactions of the double bond. (See Advanced Organic Chemistry F.A.

Carey and R.J. Sundberg (1990) pp. 167-218 Plenum Publishing Co.) Nonlimiting examples of addition reactions include hydrogenation, hydroboration, hydrohalogenation, hydroxylation, halohydrination, alkylation, carbene and dihalo carbene addition and epoxidation followed by ring opening reactions with nucleophiles such as alkoxide, amines, alkylsulfide, halide, and hydroxide.

The reactive chloro in compounds 24 and (Figure 2) is easily displaced by nucleophiles such as alkoxy, including methoxy, alkylthio, hydroxy, amino, cyano, azide, bromide, iodide, and dimethylamino.

The reaction between the N-(electron WO 96/06093 PCTIUS95/10884 -51withdrawing-substituted)pyrrole with the arylsulfonyl(optionally substituted aryl or heterocyclic)acetylene is carried out in excess N- (electron withdrawing substituted)-pyrrole or in a solvent, for example, toluene, tetrahydrofuran, dimethylformamide, diethoxyethane or other inert solvents. Any molar ratio of pyrrole to dienophile can be used that provides an acceptable yield of product, and typically ranges between 0.5:1 to 50:1, preferable The reaction is conducted at any temperature that produces the desired product, and typically, between room temperature and 150 0 C, until the reaction is completed, for typically between 1 hour and 72 hours at 1 atm. or elevated pressure in a sealed reactor.

Several methods have been investigated for the removal of the N-electron withdrawing group, and specifically, the N-carbomethoxy protecting group, after synthesis of the desired 7-azabicyclo[2.2.1] -heptane or -heptene framework. Hydrolysis of compound 25 (Figure 2) with potassium hydroxide in methanol results in substitution of the moderately reactive chlorine in the pyridine ring by a methoxy group. Treatment of 25 with methyllithium stopped at the formation of N-acetyl epibatidine (identical with an authentic sample from acetylation of racepibatidine as described below), which resisted further cleavage by methyllithium even after a prolonged treatment. This is in accordance with the known stability of N-acetyl epibatidine.

Compound 25 is successfully deblocked by treatment with hydrobromic acid in acetic-acid for 24 hours at room temperature. The products isolated from silica gel chromatography, with a mixed solvent system of ethyl acetate, methylene chloride and ammonia in methanol as the eluent, were rac- WO 96/06093 PCT/US95/10884 -52epibatidine (19, rac-endo-epibatidine (19', 28.4%) and unchanged carbamate (25, Notably, the recovered starting material is essentially the pure endo isomer of 25, indicating some stereoselectivity in the cleavage of the Ncarbomethoxy group with hydrobromic acid. The exoisomer was apparently cleaved at a higher rate than the endo-isomer, presumably influenced by the proximity of the pyridyl group and the carbamate group. The rac-epibatidine thus obtained, m.p. 510, is very pure, as evidenced by its spectral data.

N-(electron withdrawingsubstituted)pyrrole Many substituted pyrroles are known and are easily converted to N-(electron withdrawingsubstituted)-pyrroles for use in the Diels-Alder process to prepare 7 -azabicyclo[2.2.1]heptanes and -heptenes. For example, 3 -(thioalkyl)pyrrole, including 3-(SCH 3 )pyrrole; including 2,5-dimethylpyrrole; 3,4dihaloalkylpyrrole, including 3,4bis(trifluoromethyl)pyrrole, 2-alkylpyrrole, including 2-methylpyrrole; 2-alkoxyalkylpyrrole, including 2-methoxymethylpyrrole; 2alkylthioalkylpyrrole, including 2methylthiomethylpyrrole; 2dialkylaminoalkylpyrrole, including 2dimethylaminomethylpyrrole; alkyl pyrrole 2acetate, including dimethylaminomethylpyrrole; alkyl pyrrole 2-acetate, including methyl pyrrole 2-acetate; 2-alkoxyalkoxyalkylpyrrole, including 2methoxymethoxyethylpyrrole; 3-aryloxyalkylpyrrole, including 3-benzyloxymethylpyrrole; 2alkoxypyrrole, including 2-methoxypyrrole; 3alkoxypyrrole, including 3-methoxypyrrole; 3aryloxypyrrole, including 3-benzyloxypyrrole; 3,4- WO 96/06093 Tl/^'TPTTC'ft «r* -53dialkylpyrrole, and 3-alkylpyrrole, including 3methylpyrrole and 3,4-dimethylpyrrole; 1,6 and alkylidene pyrrole, including 4,5,6,7tetrahydroindole and 2-methyl-4,5,6,7tetrahydroindole.

The N-substituent on the pyrrole ring is any moiety that is electron withdrawing and that activates the ring toward cycloaddition with a dienophile. The N-substituent is preferably carbomethoxy, however, other electron withdrawing moieties, including carbobenzyloxy, tertbutoxycarbonyl and optically active alkoxycarbonyl, including and (-)-menthyloxycarbonyl can also be used.

ii). Arylsulfonyl(optionally substituted aryl or heteroaromatic)acetylene In this process, a compound of the formula aryl-SO 2 C=C- (optionally substituted aryl or heteroaromatic) is reacted with the N-(electron withdrawing-substituted)pyrrole or its derivative.

The arylsulfonyl-(optionally substituted aryl or heteroaromatic)-acetylene can be prepared by methods known to those of skill in the art. In one embodiment, described in detail in the Example 26 below, the compound is prepared by reacting the lithium salt of methyl(aryl)sulfone with the desired optionally substituted aryl or heteroaromatic acid chloride to produce a 1-(aryl or heteroaromatic)-2-arylsulfonylethanone, that is converted to the corresponding acetylene via an enolphosphate intermediate as described in Example 27 below. Any optionally substituted aryl or heteroaromatic acid chloride can be used, including without limitation, the acid chloride of nicotinic acid, isonicotinic acid, 5-chloronicotinic acid, 6methylnicotinic acid, 6-methoxynicotinic acid, 6- /108U4 .WO 96/06093 PCT/US95/10884 -54phenylnicotinic acid, 6-methylthionicotinic acid, 2-chloropyridine-4-carboxylic acid, 2,6dimethylpyridine-4-carboxylic acid, l-methyl-2(1H)pyridone-3-carboxylic acid, 6-methylthionicotinic acid, 3-quinolinic acid, 4-quinolinic acid, 7chloro-3-quinolinic acid, 6-methoxy-3-quinolinic acid, isoquinoline-4-carboxylic acid, thiophene-2-carboxylic acid, carboxylic acid, 5-methoxyindole-3-carboxylic acid, 1,2,5-thiadiazole-2-carboxylic acid, carboxylic acid, acid, and 5-chloropyridazine-2-carboxylic acid.

Substituents that can be positioned on the aromatic or heteroaromatic group include, but are not limited to, alkyl, halo, aryl, alkoxy, dialkylamino, alkylthio, hydroxy, hydroxyalkyl, and C(O) (alkyl or aryl).

The aryl group attached to the sulfone can be any group that sufficiently activates the acetylenic group to act as a dienophile toward the activated pyrrole and which does not interfere with the cycloaddition reaction. Nonlimiting examples are phenyl, p-alkylphenyl, including pmethylphenyl; halophenyl, and including pchlorophenyl, p-fluorophenyl, and p-nitrophenyl.

Fluoroalkanesulfonyl, including CF 3

SO

2 and C 4

F

9

SO

2 can also be used to activate an aryl- or heteroarylacetylene.

Methods to prepare a wide variety of arylsulfonyl-<aryl or heteroaromatic)-acetylenes are described in Bhattacharya, et al, Organomet. Chem. Synth. 1, 145 (1970), and the reaction of an aryl or heteroaromatic trimethylsilyl acetylene (Sakamoto, et al., Synthesis, 312 (1983)) with tosyl chloride in the presence of a Lewis acid catalyst such as aluminum trichloride.

.WO 96/06093 PCT/US95/10884 The process for preparing active compounds through the Diels-Alder reaction of an N-(electron withdrawing-substituted)pyrrole with an arylsulfonyl(optionally substituted aryl or heterocyclic)acetylene is set out in detail in the working examples below. These examples are merely illustrative, and not intended to limit the scope of the process or the compounds that can be made according to the process. As discussed above, this is a general method that can be combined with conventional synthetic techniques to provide a wide variety of products, all of which are considered to fall within the scope of the invention. The compounds are numbered as illustrated in Figure 2.

Example 26 Preparation of 1-(2-chloro-5pyridyl)-2-phenylsulfonylethanone (9) To a cold solution (-30 0 C) of 20 g methyl phenyl sulfone in 400 ml dried tetrahydrofuran was added 128 ml 2.5M n-butyllithium (2.4 eq) slowly.

The resulting solution was stirred at -30 0 C for minutes. A solution of 26 g 6-chloronicotinyl chloride in 100 ml tetrahydrofuran was then added during a 20 minute period. After stirring at the same temperature for 30 minutes, the mixture was quenched by addition of sat. ammonium chloride (ca.

100 ml). The organic layer was separated and the aqueous layer extracted with chloroform three times. The combined organic layer was washed with sat. brine and dried over magnesium sulfate. After removal of solvent, the brown solid was triturated with methanol (150 ml) to give 7.06 g of a slightly yellow solid. Another crop of the product (11.75 g) was obtained from the mother liqueur by chromatography on a short silica gel column using ethyl acetate in petroleum ether as the eluent.

The total yield is 18.81 g m.p. 152-3 0

C.

WO 96/06093 PCTUS95/10884 -56- MS(CI) m/z 296, 298(M+1).

In a similar manner, when the acid chlorides of nicotinic acid, isonicotinic acid, chloronicotinic acid, 6-methylnicotinic acid, 6methoxynicotinic acid, 6-phenylnicotinic acid, 6methylthionicotinic acid, 2-chloropyridine-4carboxylic acid, 2,6-dimethylpyridine-4-carboxylic acid, l-methyl-2(lH)pyridone-3-carboxylic acid, 6methylthionicotinic acid, 3-quinolinic acid, 4quinolinic acid, 7 -chloro-3-quinolinic acid, 6methoxy-3-quinolinic acid, isoquinoline-4carboxylic acid, 5-chloro-thiophene-2-carboxylic acid, pyrimidine-5-carboxylic acid, methoxyindole-3-carboxylic acid, 1,2,4-thiadiazole- 2-carboxylic acid, thiazole-5-carboxylic acid, 2acid, chloropyridazine-2-carboxylic acid are used in place of 6-chloronicotinyl chloride in the condensation reaction, the corresponding ketosulfones are obtained.

Example 27 Preparation of 2 phenylsulfonyl acetylene (22) A solution of 3.34 g (11.3 mmol) of 20 in 100 ml dried tetrahydrofuran was added to a suspension of 840 mg 60% sodium hydride (washed with ethyl ether) in 100 ml tetrahydrofuran. After stirring minutes, 1.88 ml (11.3 mmol) diethyl chlorophosphate was added in one portion. The mixture was stirred at room temperature overnight, then cooled to -780C, and 1.35 g potassium tbutoxide is added in portions. The brown solution was stirred at -780C for another 10 minutes and allowed to warm to ca. -30 0 C. Water was added and the aqueous layer extracted with methylene chloride. After drying and evaporation in vacuo, the residue was purified on a silica gel column, WO 96/06093 PCT/US95/10884 -57and eluted with 25% ethyl acetate in petroleum ether. The white solid (1.2 g) obtained after evaporation of solvent has a m.p. 140-141 0

C.

MS(CI) m/z 278, 280(M+1), yield 38%.

In a similar manner, when other heterocyclic ketosulfones described in Example 26 are used in place of compound 20, the corresponding acetylenes are obtained.

Example 28 Preparation of N-carbomethoxy pyrrole (21) Potassium (5.85 g, 0.15 mol) was added to a solution of 10 ml pyrrole (0.145 mol) in 80 ml hot cyclohexane in several portions. The mixture was refluxed for 1 hour. To this cold solution was added 15 g (0.16 mol) methyl chloroformate slowly.

After addition, the mixture was stirred at room temperature for 30 minutes. During this period, ml dimethyl sulfoxide was added for catalysis.

After quenching with ice-water, the organic layer was separated and the aqueous layer extracted with ether. The combined organic layer was washed with sodium bicarbonate, sat. sodium chloride and dried over magnesium sulfate. Removal of solvent yielded 17.4 g of a liquid. Bulb to bulb distillation gives 16.5 g N-carbomethoxy pyrrole 21 as a colorless liquid, yield 91%. The product requires storage at -200C.

In a similar manner, the N-carbomethoxy,

N-

carbobenzyloxy and N-tert-butoxycarbonyl derivatives of 2,5-dimethylpyrrole, 3,4bis(trifluoromethyl)pyrrole, 2-methylpyrrole, 2methoxymethylpyrrole, -2-methylthiomethylpyrrole, 2dimethylaminomethylpyrrole, methyl pyrrole-2acetate, 2-methoxymethoxyethylpyrrole, 3benzyloxymethylpyrrole, 2-methoxypyrrole, 3methoxypyrrole and 3-benzyloxypyrrole are prepared.

WO 96/06093 PCT/US95/10884 -58- Example 29 Preparation of 7-carbomethoxy-2-(2chloro-5-pyridyl)-3-phenylsulfonyl- 7-aza-bicyclo[2.2.1]- 2 5 -diene (23) phenylsulfonyl acetylene 22 (1.12 g, 40.3 mmol) was dissolved in 8.0 g Ncarbomethoxy pyrrole 21. The mixture was stirred in a covered flask at 80-85 0 C for 24 hours. After evaporation in vacuo to recover N-carbomethoxy pyrrole, the residue was chromatographed on a silica gel column using 25% to 50% ethyl acetate in petroleum ether as eluent to recover 0.2 g of the acetylene 22 and obtain 1.21 g of a slightly dark product. The crude product was triturated with methanol to yield 0.94 g (58% or 70% according to recovered starting material) of a white solid.

m.p. 101 0 C. MS(CI) m/z 403, 405 When the arylsulfonyl acetylene derivatives described in Example 27 are used in place of compound 22 in this experiment, the corresponding Diels-Alder adducts are obtained.

Example 30 Preparation of 7-carbomethoxy-5-(2chloro-5-aza-bicyclo[2.2.1]hept-2ene (24) Compound 23 (0.726 g, 1.9 mmol) was dissolved in 50 ml anhydrous methanol and 7 ml dried tetrahydrofuran containing 1.0 g (8.0 mmol) of sodium dihydrophosphate. To this mixture was added g 6% sodium amalgam in two portions at -20 0

C

under nitrogen. The stirred mixture was allowed to warm spontaneously to room temperature during a 2 hour period and stirred at room temperature for another hour. The upper layer was decanted and the residue washed with methanol. Water and 10% HC1 were added to the combined methanolic extracts to bring the pH to 6 and most of the methanol removed in vacuo. The mixture was then extracted with methylene chloride. The combined organic layer was WO 96/06093 PCT/US95/10884 -59washed with sat. brine and dried over magnesium sulfate. After removal of solvent, the residue was purified on a silica gel column using 33% ethyl acetate in petroleum ether as the eluent to yield 215.3 mg of a colorless oil. 'H-NMR shows that it is a mixture of exo and endo isomers.

MS (CI) m/z 265, 267 'HNMR 6.01-6.53(2H,

H

56 4.61-4.91(2H,

H

14 When other Diels-Alder adducts described in Example 29 are treated with sodium amalgam in a similar manner, the corresponding substituted 7 -aza-bicyclo [2.2.1]hept-2-enes are obtained.

Example 31 Preparation of 7-carbomethoxy-2-(2-chloro-5pyridyl)-7-aza-bicyclo[2.

2 .1]heptane Compound 24 (178.4 mg, 0.674 mmol) (mixture of isomers) was dissolved in 10 ml methanol containing mg 10% Pd-C. The mixture was hydrogenated under 1 atm. of hydrogen. After 18 ml of hydrogen was absorbed (5 minutes), the catalyst was removed by filtration and methanol removed in vacuo to give 165 mg of colorless oil. 'H-NMR indicates that it is a mixture of exo and endo isomers.

MS(CI) m/z 267, 269 'H-NMR 4 .21-4.44(2H,

H,

4 In a similar manner, other substituted 7 -aza-bicyclo[2.2.1]hept-2-enes described in Example 30 are hydrogenated to the corresponding substituted 7-aza-bicyclo[2.2.1]heptane analogs.

Example 32 Preparation of racemic epibatidine (19) and endo-epibatidine (19') Compound 25 (90 mg, 0.338 mmol) was dissolved in 2.5 ml hydrobromic acid (33% in acetic acid).

The mixture was stirred at room temperature for hours. After evaporation of the mixture in vacuo ,.WO 96/06093 PCT/US95/10884 the residue was dissolved in water and extracted with ethyl ether to recover the starting material (26 mg). The aqueous layer was neutralized with potassium hydroxide to pH 11 and extracted with methylene chloride. The combined organic layer was washed with saturated brine and dried over magnesium sulfate. After removal of the solvent, the 56 mg residue was chromatographed on silica gel column using ethyl acetate, methylene chloride and sat. ammonia methanol (2:1:0.03) to give 18 mg of epibatidine (19) m.p. 50-510 and 20 mg of endo-epibatidine The spectral data for these compounds is provided in Table 3.

Table 3 Spectra data for epibatidine (19) and endo-epibatidine(19') epibatidine(19) endo-epibatidine(191) MS(CI)m/z 209,211(M+1) 209,211(M+1)

H'-NMR

HI

4 3.80(t,3.9Hz), 3.76(q, 4.8Hz) 3.56(br.s)

H

3 e 1.90(dd, 12.0, 2.12(tdd,12.3, 4.8, 3.3Hz) The N-acetyl derivatives of epibatidine can be prepared from epibatidine and acetic anhydride in the presence of triethylamine. Likewise, other N-substituted 7-azabicyclo[2.2.1]heptanes described in Example 31 are deprotected to the corresponding free amine. The amines are readily acylated to the amide, alkylated to the tertiary amine and quaternary ammonium derivatives by using conventional methods. The amines also form stable and water-soluble salts with organic and inorganic ,WO 96/06093 PCTIUS95/10884 -61acids as preferred in the pharmaceutical formulation.

Example 33 Preparation of 7-carbomethoxy-2-(2methoxypyridyl)- 7 -aza-bicyclo[2.2.1] heptane (29) 7-Carbomethoxy-2-(2-chloro-5-pyridyl)- 7 -aza-bicyclo[2.2.1]heptane 25 (20 mg, 0.076 mmol) was dissolved in 1.0 ml methanol containing 12.8 mg (0.2 mmol) potassium hydroxide. The mixture was refluxed for one hour, then concentrated and partitioned between ethyl ether and water. The aqueous layer was extracted with ether again and the combined organic layer was washed with sat.

sodium bicarbonate, and dried over magnesium sulfate. Removal of solvent yielded a 10 mg residue. H'-NMR shows it is a 1:2 mixture of exo and endo isomers of the title compound. H'-NMR 3.92, 3.90(2s, Py-OCH 3 3.71, 3.66(2s,

NCOOCH

3 Example 34 Preparation of deschloro analogues of epibatidine N-carbomethoxy-5-(2-chloro-5-pyridyl)- 7 -aza-bicyclo[2.2.1]hept-2-ene 25 (16 mg) was dissolved in 3 ml methanol containing 7 mg palladium on carbon. The mixture was hydrogenated under a slightly elevated pressure of hydrogen for one hour. After removal of catalyst and solvent, the residue was partitioned between ether and aqueous sodium bicarbonate. The aqueous layer was extracted with ether and the combined organic layer was dried over magnesium sulfate. Removal of solvent gave 10 mg of 7 -carbomethoxy-2-(3-pyridyl)- 7-azanorbornane (12) MS (CI) m/z 233 HI-NMR 3.72, 3.66 (2s, N-COOCH3).

i .WO 96/06093 PCTIUS95/10884 -62- Example 35 Preparation of 5,6-dehydro analogs of epibatidine When the N-acylated 7-aza-bicyclo[2.2.1] derivatives prepared in Example 30 are acid hydrolyzed under conditions similar to that described in Example 32, the corresponding 5,6-dehydro analogs of epibatidine (19) and its endo-isomer are obtained.

Example 36 Preparation of 1,4-dimethyl-2- (6-chloro-3-pyridyl)-3-phenylsulfonyl-7carbomethoxy-7-azabicyclo[2.2.1]hept-2,5-diene A mixture of 0.14 g (0.5 mmol) phenylsulfonyl acetylene(22) and 0.7 g 2 ,5-dimethyl-N-carbomethoxypyrrole (31) was heated and maintained at 850C for 48 hour. The excess pyrrole (31) was removed in vacuo and the dark residue chromatographed on silica gel using 25%-33% ethyl acetate in petroleum ether as eluent, yielding 76 mg of the title compound. MS(CI) m/z 431, 433 H'-NMR 6.79, 6.55 (AB J=5.4Hz,

H

5 3.52(s, 3H, N-COOCH 3 1.96, 1.68(2s, 6H, 2 CH 3 Example 37 Preparation of benzoyl phenylsulfonyl methane (32) A procedure similar to the preparation of compound 20 was used. The product was obtained in yield as a white crystal (crystallized from carbon tetrachloride). m.p. 91-93 0 C (lit, m.p.

93-94 0

C).

When the acid chloride of 4-chlorobenzoic acid, 3-methoxybenzoic acid, 3,4-methylenedioxybenzoic acid, 3,4,5trimethoxybenzoic acid, 3-trifluoromethylbenzoic acid, 3-dimethylaminobenzoic acid, ,WO 96/06093 PCT/US95/10884 -63- 4-methylthiobenzoic acid, 4methylsulfinylbenzoic acid, 4 -methylsulfonylbenzoic acid, 3 ,5-difluorobenzoic acid, 2-naphthoic acid, 4-dimethylamino-2-naphthoic acid, 6-methoxy-2-naphthoic acid, 2 -phenylpropionic acid and 2-(3,4-methylenedioxyphenyl) propionic acid are used in place of benzoyl chloride above, the corresponding substituted ketosulfones are prepared.

Example 38 Preparation of phenyl phenylsulfonyl acetylene (34) A procedure similar to the preparation of compound 22 was used. Chromatography of the crude product on silica gel using 5% ethyl acetate in petroleum ether as the eluent yielded 20% of the acetylene 34 as a solid.

Using a similar procedure, the other ketosulfones described in Example 37 are converted to the corresponding substituted aryl and aralkyl acetylenic derivatives.

Example 39 Preparation of 7-carbomethoxy-2phenyl-3-phenylsulfonyl-7-azanorborna-2, Phenyl phenylsulfonyl acetylene 34 (84.3 mg, 0.35 mmol) was mixed with 0.42 g of N-carbomethoxy pyrrole The mixture was heated to and maintained at 85 0 C for 48 hours. After removal of the excess pyrrole, the residue was chromatographed on silica gel column and eluted with 25-33% ethyl acetate in petroleum ether to give 30 mg of the adduct as a colorless oil. -MS(CI) m/z 368(M+1). H -NMR 7.05(s, 2H, H, 6 5.51, 5.48(2s, 2H, H 14 3.5(br.s. 3H, N-COOCH 3 Using a similar procedure, cycloadditions of substituted pyrroles described in Example 28 and ,WO 96/06093 PCTIUS95/10884 -64substituted acetylenic derivatives prepared in Example 38 give the corresponding 7 -aza-bicyclo[2.2.1]hepta-2,5-diene adducts.

Example 40 Preparation of 2 -phenyl-7-aza-bicyclo [2.2.1]heptane (36) The bicyclic adduct 35 was reductively desulfonated, hydrogenated and acid hydrolyzed as described in Examples 30, 31 and 32 to yield 36.

Similarly, the other bicyclic adducts in Example 39 are converted to the corresponding 2-substituted aryl-7-aza-bicyclo[2.2.1]heptanes.

Example 41 Preparation of 2 -phenyl-7-aza-bicyclo 2 2 .1]hept5-ene (37) The bicyclic adduct 35 is reductively desulfonated and acid hydrolyzed as described in Examples 30 and 32 to yield 37. Similarly, the other bicyclic adducts in Example 39 are converted to the corresponding 2-substituted aryl-7-azabicyclo[2.2.1]hept-5-enes.

Example 42 Preparation of 5 and/or 6 substituted 2-aryl (or heteroaryl)- 7 -aza-norbornanes from the corresponding 7-N-acyl or 7-aza-2-aryl (or The 5 and/or 6-substituents are introduced by functioning the 5,6-double bond through conventional reactions, additions, hydroboration; epoxidation followed by ring opening with nucleophiles (alkoxide, amine, azide, alkylsulfide, halide, hydroxide, etc.).

UI'

.WO 96/06093 PCTIUS95/10884 Example 43 Preparation of 3-methyl-7-aza-2-exo-(2chloro-5-pyridyl)bicyclo[2.2.] heptane (38) 7-Carbomethoxy-2-(2-chloro-5-pyridyl)- 3-phenylsulfonyl-7-azabicyclo[2.2.1]hept-2,5-diene (23) is hydrogenated in methanol containing Pd-C until both double bonds are saturated. The product, 7-carbomethoxy-2-(2-chloro-5-pyridyl)-3phenylsulfonyl-7-aza-bicyclo[2.2.1]heptane 39, is dissolved in dry tetrahydrofuran and treated with n-butyl lithium (1.1 eq) at -30 to 0°C, followed by methyl iodide (1-1 eq) in tetrahydrofuran. The reaction mixture is then stirred at room temperature and poured into iced water. The product is extracted with ether and washed with water. After drying and evaporation of the ether solution, the crude product is chromatographed on a silica gel column, using a mixture of petroleum ether and ethyl acetate (3:1 by volume) to yield stereoisomers of 7-carbomethoxy-2-(2-chloro- 5-pyridyl)-3-methyl-3-phenylsulfonyl-7-azabicyclo[2.2.1]heptane(40). The alkylation products are each treated with sodium amalgam as in Example to remove the phenylsulfonyl group, followed by acid cleavage of the 7-carbomethoxy group as in Example 32 to yield isomeric 3-methyl analogs of compound 8 and 8'.

Similarly, when methyl iodide is replaced by ethyl bromide, allyl bromide, benzyl chloride, methoxymethyl chloride and methoxyethyl methanesulfonate, and corresponding 3-ethyl, 3allyl, 3-benzyl, 3-methoxymethyl and 3-methoxyethyl derivatives are obtained.

Other 2-aryl or 2-heteroaryl derivatives of 7-N-acyl-7-aza-3-phenylsulfonyl-bicyclo[2.2.1] described in Example 29 are likewise hydrogenated, converted to the sulfonyl .WO 96/06093 PCT/US95/10884 -66carbanion, alkylated, desulfonated and deacylated to give the corresponding 3-alkyl or aralkyl analogs.

Example 44 Preparation of 7-methyl-7-aza-2-exo-(2-chloro-5pyridyl)bicyclo[2.2.1]heptane (41) Epibatidine 19 prepared in Example 32 is alkylated with methyl iodide (1.1 eq) in dry tetrahydrofuran at room temperature, followed by the usual isolation procedure, to give the 7-N-methyl derivative.

Similarly, alkylation with ethyl iodide, isopropyl bromide, allyl bromide, cyclopropylmethyl bromide, benzyl chloride, 4-methoxybenzyl chloride, 3,4-dimethoxybenzyl chloride, phenethyl bromide, propargyl bromide, hydroxyethyl chloride and methoxyethyl iodide yield the corresponding 7-N-alkylated derivatives.

Other substituted 7-aza-bicyclo[2.2.1]heptane analogs described in the examples above are alkylated to their 7-N-alkyl is derivatives in the same manner.

The N-acetyl derivative of epibatidine in Example 7 is reduced to the N-ethyl derivative by the treatment of lithium aluminum hydride in dry tetrahydrofuran at room temperature. Similarly, the 7-N-propionyl, N-benzoyl, N-phenylacetyl and N-2-furoyl derivative of epibatidine are reduced to the corresponding 7-propyl, 7-benzyl, 7-phenethyl and 7-(2-furfuryl) derivatives.

.WO 96/06093 PCTIUS95/10884 -67- Example 45 Resolution of racemic compounds The substituted 7-aza-bicyclo[2.2.1]heptane derivatives are resolved to their optical isomers by conventional methods including chromatography on a chiral column, fractional crystallization of diastereomeric salts of chiral acids and separation of the chiral ester or amide derivatives followed by regeneration of the optically pure enantiomers.

(See Optical Resolution Procedures for Chemical Compounds, Vol. 1, Amines. by P. Newman, 1980 Optical Resolution Information Center, N.Y. 10471.) Example 46 Resolution of racemic epibatidine (19).

To a solution of racemic epibatidine 19 and triethylamine 1.1 eq) in methylene chloride is added (-)-menthyl chloroformate (1.1 eq). The reaction mixture is stirred at room temperature for 6 hours, washed with iced water and dried over magnesium sulfate. After evaporation of solvent, the residue is chromatographed on a silica gel column, using a mixture of petroleum ether and ethyl acetate (5:1 by volume) to yield a mixture of two diastereoisomers of 7 -N-(-)-menthyloxycarbonyl derivatives of d- and 1-epibatidine. Separation of the diastereoisomers by HPLC on a chiral column and treatment of each isomer with HBr/AcOH as in Example 32 yields the corresponding d and 1-epibatidine.

Example 47 Preparation of optical isomers of substituted 7-aza-bicyclo[2.2.1] heptane derivatives from chiral intermediates N-carbo-(-)-menthyloxy pyrrole is prepared from pyrrole and (-)-menthyl chloroformate by the method described above. The chiral pyrrole is WO 96/06093 PCT/US95/10884 -68treated with the sulfonyl acetylene 22 or 34 as in Example 29 to give a diastereoisomeric mixture of the chiral cycloadduct 7-aza-bicyclo[2.2.1]hepta derivative. After treatment with sodium amalgam as in Example 30, the diastereoisomeric mixture of 2 -exo-aryl-7-aza-bicyclo[2.2.1] derivatives is obtained. These diastereomers are separated by chromatography to give the d and 1 enantiomers. The optically active intermediates are each reduced and treated with HBr/AcOH to yield optically active epibatidine enantiomers. Similarly, other substituted 7-aza-bicyclo[2,2,1] heptane analogs are prepared from the corresponding chiral pyrroles and chiral cycloadducts.

Example 48 Preparation of benzo[5a,6a] epibatidine (39) Scheme 4 illustrates the preparation of compound 39.

CHBr CH 3

SO

2

NH

2

-S-CH

3 tBuOK

'CH

2 Br NaH OGo

NH

H

N

C ccso 2

PSO

2 Ph Na(Hg) a 03- .WO 96/06093 PCT/US95/10884 -69a) Preparation of N-methanesulfonyl isoindole Sodium hydride (0.88g) was suspended in 3 ml dimethyl formamide. To this stirred solution was added methanesulfonamide (0.95 g, 10 mmol) in 5 ml dimethyl formamide dropwise under nitrogen. After stirring at 60 0 C for 0.5 hours, a solution of 2.64g mmol) a,a'-dibromo-o-xylene in 7 ml DMF was added at a rate appropriate to maintain the temperature at 60-70 oC. The mixture was stirred at room temperature for another hour, then quenched by pouring into water. The resulting precipitate was collected and washed with water, petroleum ether and ether successively. Weight 1.57g 'H-NMR 62.37 3H, -CH 3 4.709 4H, 2CH 2 7.25 7.35 4H, ArH).

b) Preparation of 2-(6-chloro-3-pyridyl)-3phenylsulfonyl-1,4-dihydronaphthalene- 1,4-imine (41) Potassium t-butoxide (560 mg, 5.0 mmol) was dissolved in 3 ml DMSO under nitrogen. To this stirred solution was added 197 mg (1.0 mmol) Nmethanesulfonyl isoindole in portions. After addition, the mixture was stirred at room temperature for 1.5 hours and quenched by addition of 3 ml water. After extraction with 45 ml ether, the combined organic layer was washed with saturated brine and dried over magnesium sulfate for 10 minutes. After filtration, the filtrate was combined with 83 mg (0.3 mmol) 1-(6-chloro-3pyridyl)-2-phenylsulfonyl acetylene 22. The reaction mixture was stirred at-room temperature overnight to evaporate in vacuo and chromatographed on silica gel column. Eluting with a mixed solvent (ethyl acetate, methylene chloride and ammonia in methanol) gave 108 mg blue residue. The color material was removed by washing the acidified m I -O 96/06093 PCT/US95/10884 material. After basification and extraction with ether, 62 mg of pure compound 41 was obtained as a foam. Yield 52%. MS(CI), 395, 397(M+1). 'H-NMR (CDC13) 55.242(d, J=1.5Hz, 1H), 5.362 J=0.9Hz, 1H). (HI or H 4 c) Preparation of exo and endo-benzo [5a,6a]epibatidine (39) Compound 41 (54 mg, '0.137 mmol) was dissolved in a mixture of 3 ml methanol and 1 ml tetrahydrofuran. The solution was cooled to -20 0

C

and 66 mg 6% sodium amalgam was added. The mixture was stirred for 2 hours. The excess reagent was decomposed by water and the liquid layer was decanted out. After concentration of the liquid in vacuo, the residue was extracted with methylene chloride (3x5 ml). The combined organic layer was washed with saturated brine and dried over magnesium sulfate. After removal of solvent, the residue was separated on preparative thin layer chromatography with 33% methylene chloride in ethyl acetate to give 5.5 mg exo-benzo [5a,6a] epibatidine and 8.5 mg endo-benzo [5a,6a] epibatidine. Both isomers are an oil. Yields are and 25% respectively. MS(CI), 257, 259(M+1).

'H-NMR (CDC1 3 (for exoisomer). 2.753 (dd, J=4.8, 8.4 Hz, 1H, H 2 4.371 1H, 4.656 J=4 Hz, 1H, H 4 Example 49 Preparation of N-methyl-benzo [5a,6a] epibatidine (42) Scheme 5 illustrates a method for the production of N-methyl-benzo [5a, 6a] epibatidine 42.

mm I WO 96/06093 PCTfUS95/10884 -71- N CH3 CI CC-S02P h NCH3

S

N CH3 Na[Hg]

CI

a) Preparation of N-methyl isoindole (43) N-methyl isoindole was prepared according to the method set forth in B. Zeeh and K. H. K6nig, Synthesis 1972, b) Preparation of 2 -(6-chloro-3-pyridyl)-3phenylsulfonyl-1,4-dihydronaphthalene- 1,4-imine (44) N-methyl isoindole (91 mg, 0.7 mmol) was mixed with 1-(6-chloro-3-pyridyl)-2-phenylsulfonyl acetylene 22 (139 mg, 0.5 mmol) in ethyl ether.

After stirring at room temperature for 1 hour, the mixture was concentrated and chromatographed on silica gel column, eluting with ethyl acetate.

This gave 204 mg of compound 44 as a clear oil.

Yield 100%. MS(CI), 409, 411(M+1). H'-NMR (CDC1 3 6 2.36 (br, 3H, NCH 3 4.805 1H), 4.93 (br.s., 1H), (Hi, or H 4 c) Preparation of N-methyl-benzo [5a,6a] epibatidine (42) Compound 44 (125 mg, 0.306 mmol) was dissolved in 10 ml methanol together with 4 ml tetrahydrofuran. The solution was cooled to -20 0

C

and 216 mg sodium dihydrophosphate was added to the solution followed by 1.0g 6% sodium amalgam. The NWO 96/06093 PrCT/IT4Cci n 0, -72mixture was then stirred at room temperature for 3 hours and quenched with water. The organic layer was decanted out and concentrated in vacuo. The residue was extracted with methylene chloride (2x10 ml). The combined organic layer was washed with saturated brine and dried over magnesium sulfate.

After removal of solvent, the residue was chromatographed on silica gel column eluting with ethyl acetate in petroleum ether. This gave 19 mg exo-N-methyl-benzo[5a,6a]epibatidine.

Further elution with a mixed solvent (ethyl acetate, methylene chloride and ammonia in methanol) yielded 55 mg of the endo-isomer.

Total yield 85%. MS(CI), 271, 273(M+1). H'-NMR (CDC13), (for exoisomer): 2.679 (dd, J=4.5, 8.7Hz, 1H, H 2 3.935 1H, HI), 4.203 J=4.0Hz, 1H,

H

4 2.072 3H, NCH 3 Example 50 Preparation of N-formamidinyl epibatidine dihydrochloride Scheme 6 shows the preparation of compound

H

N

N-CH=NH

CI EtOCH=NH 19 Racemic-epibatidine 19 (42 mg, 0.2 mmol) was mixed with 77 mg (0.7 mmol) freshly prepared ethyl formamidinate hydrochloride and 129 mg (1.0 mmol) diisopropyl ethylamine in 1 ml acetonitrile. After stirring at room temperature for 48 hours, the mixture was acidified with 1.0 M hydrogen chloride in ether. After evaporation in vacuo, the residue was separated on silica gel preparative thin layer chromatography, using a solvent system of methanol in chloroform, to give 25 mg of the compound 45 as a hygroscopic solid. Yield 36%.

.1A UOO WO 96/06093 PCTIUS95/10884 -73- MS(CI), 236, 238 (free base H'-NMR (CD 3

OD).

6 3.40 1H, H 2 Example 51 The process of Example 50 was repeated with the replacement of ethyl formamidinate by S-methyl pseudothiourea, S-methyl-N-methyl pseudothiourea, S-methyl-N-nitro pseudothiourea, or methyl acetamidinate to form the N-guanidyl, N-methylguanidyl, N-nitroguanidyl and N-acetamidinyl epibatidine.

Example 52 Preparation of N-formamidinyl deschloroepibatidine dihydrochloride (46)

,CH=NH

N

N-Formamidinyl epibatidine (12 mg, 0.04 mmol) 45 was dissolved in 2 ml methanol containing 5 mg palladium on carbon. After hydrogenation under 1 atm hydrogen for 3 hours, the catalyst was removed by filtration. The filtrate was concentrated in vacuo to give 10 mg compound 46 as a hygroscopic solid. Yield 100%. MS(CI), 202(M+1 -2HC1). H'-NMR (CD 3 OD), 6 3.5 1H, H 2 ,WO 96/06093 PCT/US95/10884 -74- Example 53 Preparation of 1-methyl epibatidine and 4-methyl epibatidine (48)

H

N H

N

N

CH3

CI

CH

3 N 1 a) Preparation of 2-methylpyrrole (49) 2-Methylpyrrole was prepared according to the method set forth in J. Org. Chem. 28, 3052.

b) Preparation of N-t-butoxycarbonyl-2methylpyrrole 2-Methyl pyrrole (2.5g) was dissolved in 6 ml tetrahydrofuran, and was slowly added to a suspension of 2.4g 60% sodium hydride (washed with ether) in 30 ml tetrahydrofuran. A solution of 7.6g di-t-butyl-dicarbonate in 20 ml of the same solvent was added to this cooled mixture. After shaking occasionally for 3 hours, it was decomposed carefully with water, and extracted with ether.

The combined organic layer was washed with saturated brine and dried over magnesium sulfate.

Removal of the solvent gave 6g residue. Bulb-tobulb distillation gave 4.5g slightly yellow oil (ca. 80 0 C/5mmHg). Yield 80%. MS(CI), 183(M+2).

H'-NMR (CDC1 3 6 1.584 9H, 3CH 3 2.421 3H,

CH

3 c) Preparation of 1- (and 4) -methyl-2-(6chloro-3-pyridyl)-3-phenylsulfonyl-7-tbutoxycarbonyl-7-azanorborna-2,5-diene (51) Compound 50 (10 mmol, 1.8g) was mixed with 1- (6-chloro-3-pyridyl)-2-phenylsulfonyl acetylene WO 96/06093 PCT/US95/10884 (22) 555 mg (2.0 mmol). The mixture was heated at 78 0 C in a tightly covered flask under nitrogen for 24 hours. The mixture was separated on silica gel column eluting with 25% of ethyl acetate in petroleum ether. After recovery of 1.5g of compound 50 and 120 mg compound 22, 636 mg of compound 51 was obtained as a yellow oil. Yield 69.3%. 'H-NMR showed that the oil is a 2:1 mixture of 1-methyl isomer and 4-methyl isomer. MS(CI), 459, 461. H'-NMR (CDCl 3 (for major isomer): 1.37 9H, 3CH 3 1.748 3H, CH 3 5.45 J=3Hz, 1H, H 4 (For the minor isomer), 1.346 9H, 3CH 3 1.958 3H, CH 3 5.26 (d, 1H, J=3Hz, H).

d) Preparation of N-t-Boc-1 (and 4) -methyl epibatidine (52) Compound 51 (1.0 mmol, 459 mg) was dissolved in a mixture of 20 ml methanol and 10 ml tetrahydrofuran. The solution was stirred and cooled to -20 0 C. To this solution was added 720 mg sodium dihydrophosphate followed by 1.5g (6.0 mmol) 6% sodium amalgam. After stirring at room temperature for 2 hours, another 0.8g of 6% sodium amalgam was added and stirring was continued for another 2 hours. The excess reagent was decomposed by water, and the solution was decanted out. After concentration of the solution at ambient temp in vacuo, the residue was extracted with methylene chloride (4x15 ml). The combined organic layer was washed with saturated brine and dried over magnesium sulfate. After removal of solvent, the residue (372 mg) was hydrogenated under latm hydrogen in the presence of 8.4 mg platinum oxide for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to a residue (360 mg). Separation took WO 96/06093 PCT/US95/10884 -76place on a silica gel column eluting with 17% ethyl acetate in petroleum ether. 95 mg of the endoisomers and 65 mg of the exo-isomers were obtained.

Total yield 50%. MS(CI), 323, 325(M+1). H'-NMR (CDC13) (for exo isomer major), 2.78 (dd, 1H, J=5.4Hz, 7.8Hz, H 2 4.45 1H, J=4.5Hz, H 4 e) Preparation of 1-methyl epibatidine (47) and 4-methyl epibatidine (48) The exo-isomer of compound 52 (65 mg) was dissolved in 5 ml methylene chloride. To this cooled solut-ion was added 2.5 ml trifluoroacetic acid. The resulting pink solution was then stirred at room temperature for 1.5 hours.

After neutralization with 4.5g potassium carbonate in 10 ml water, the organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined organic layer was washed with saturated brine and dried over magnesium sulfate. Removal of solvent and separation on silica gel preparative thin layer chromatography developing with a mixed solvent (ethyl acetate, methylene chloride and ammonia in methanol) gave 6 mg of 4-methyl epibatidine 48 and 12 mg 1-methyl epibatidine 47. Total yield 40.2% MS(CI), 223, 225(M+1). H'-NMR (CDC1 3 (for 1-methyl epibatidine, major, exo-isomer). 6 2.657 (dd, J=4.8, 8.7Hz, 1H, H 2 3.694 J=4.7Hz, 1H, H4).

(For 4-methyl epibatidine, minor exo-isomer): 2.887 (dd, J=4.7Hz, 1H, H2), 3.486 J=4.5Hz, 1H, Hi).

MWO 96/06093 PTU9/o8 PCTIUS95/10884 -77- Example 54 Preparation of 2-(2-fluoro-5pyridy)7azanorbornane (53)

H

N

F

A

a) Preparation of 1- 2 -fluoro-5-pyridyl) -2phenylsulfonyl ethanone (54) The method set forth in Example 26 was used, replacing 6-chioronicotinyl chloride with 6fluoronicotinyl chloride (see Anderson et al; J.

Med. Chem, 1990, 33(6) 1667), providing compound 54 as a white crystal, mp. 127-128 0 C. Yield 72%i.

MS (CI) 280 H 1 -NMR (CDCl 3 2.70 211,

OH

2 b) Preparation of 1- 2 -Fluoro-5-pyridyl) -2phenylsulfonyl acetylene Use of the method set forth in Example 27 gave compound 55 in 6211 yield from compound 54 as a white solid. mp. 97-98.50C. MS(CI) 262(M+1-).

c) Preparation of 7-carbomethoxy-2- (2- -3-Phenylsulfonyl-7azabicyclo[2.2.l] -hepta-2,5-diene (56) Use of the method set forth in Example 29 gave compound 56 in 6616 yield plus 22%0 of recovered acetylene 55. Compound 56 is a white cubic crystal, mp. 85-870C. MS(CI) 387(M+1). H1-NMR (CDCl 3 3.446 3H, C113), 5.459 J=7.2Hz, 2H1, H11,) WO 96/06093 WO 9606093PCTIUS95/10884 -78d) Preparation of 7-carbomethoxy-5-(2- -7azabicyclo[2.2.llhept-2-ene (57) Use of the method set forth in Example 30 gave compound 57 as a 1:2.5 mixture of exo and endo isomers in a total yield of 64*- from compound 56.

MS (CI) 24 9(M+1) H 1 -NMR (CDCl 3 I (f or endo- isomer).

3.682 3H-, OCH 3 (for exo-isomer) 3 .655 3H-,

OCH

3 e) Preparation of 7-carbomethoxy-2-(2- -7azabicyclo heptane (58) Use of the method set forth in Example 31 gave compound 58 as a colorless oil in a yield of 93.301 f rom compound 57. MS (CI) 251 H 1 -NMR (CDCl 3 (f or endo- isomer) 6 3. 722 0C1 3 (f or exoisomer) 6 3.671 3H, OCH 3 f. Preparation of 2-0(-f luoro-5-pyridyl) -7azanorbornane (53) The method set forth in Example 32 was used to produce 23 mg of the exo-isomer of compound 53 and 54.8 mg (3816) of the endo isomer of compound 53, as an oil from 185 mg of Compound 58 (0.74 mmol) MS (CI) 193 'H-NMR (CDCl 3 6 2. 763 (dd, 8, 9.0OHz, 111, H 2 3. 53 2 1H, HI) 3. 76 9 J=3.611z, 1H-, H 4 (For endo-isomer). 6 3.324 (dt, J=l2Hz, 5.7Hz, 1H, H 2 3.779 J=5.lHz, 2H, -WO 96/06093 PCT/US95/10884 -7-9- Example 55 Preparation of 2- 2 -chloro-.3-pyridyl) -7azanorbornane (59)

N

NN

C1 a) Preparation of l-( 2 -chloro-3-pyridyl)2phenylsulfonyl ethanone Use of the method set forth in Example 26 gave compound 60 in 74k yield from 2-chloronicotiny.

chloride as white solid, mp. 103-104 0 C. MS(CI) 296, 297(M+1). H'-NMR (CDCl 3 6 4.871 2H1,

-CU

2 b) Preparation of l-( 2 -chloro-3-pyridyl).2.

phenylsulfonyl acetylene (61) Use of the method set forth in Example 27 gave compound 61 in 27k yield from compound 60 as a white solid, mp. 90-94 0 C. MS (CI) 278, 280 C) Preparation of 7-carbomethoxy-2-(2.

chloro-3 -pyridyl) -3 -phenylsulfonyl-7 azabicyclo[2.2.]hepta-2,5-.diene (62) Use of the method set forth in Example 29 gave compound 62 in 62.4t from 61 as an oil. MS(CI) 403, 405 HI-NMR (CDCl 3 6 3.612 3H,

OCH

3 5.429 J=2.lUz, 1H), -5.497 J=2.1Hz, 1H).

-WO 96/06093 PCTIIUS95/10884 d) Preparation of 7 -carbomethoxy.s.(2.

chloro-3-pyridyl) 7 -azabicyclo [2.2.l]hept-2-ene (63) Use of the method set forth in Example gave compound 63 as the exo-isomer, and the endo-isomer, 35% MS(CI) 265, 267(M+1). 11-NMR (CDCl 3 (for exo-isomer). 6 3.66 311, OCH 3 6.502 (br.s. 211, H56). W1-NMR (CDCl 3 (for endoisomer) 6 3.686 311, 0CI4 3 4.882, 5.029 (2br.s. 2H, 11,4). 5.88, 6.544 (2br.s., 211, 1156).

e) Preparation of 7-carbomethoxy-2.(2chloro-3-pyridyl) -7azabicyclo [2.2 .1]heptane (64) Using the method set forth in Example 31, the exo-compound 63 was hydrogenated to give compound 64 in quantitative yield. MS(CI) 267, 269(M+1).

I-1'-NMR (DCCl 3 6 3.277 (dd, J=4.5, 8.4Hz, 111, 112).

3.654 311, 0CH 3 f) Preparation of 2- (2-chloro-3-pyridyl) -7azanorbornane (59) Use of the method set forth in Example 32, gave compound 59 from exo-compound 64, in 41*% yield as an oil. MS (CI) 209, 211 1'-NMR (CDC1 3 6 3.162 (dd, J=4.8, 8.7Hz, 111, 112), 3.681 111), 3.795 J=3.611z, 1H) (HI, 14).

Examiple 56 Preparation of 2- 2 -chloro-4-pyridyl) -7azabicyclo[2.2.1] heptane I WO 96/06093 PTU9/08 PCTIUS95/10884 -81a) Preparation of 1- 2 -chloto-4-pyridyl) -2phenylsulfonylethanone (66) Using the method set forth in Example 26, where 2-chloroisonicotinyl chloride (see Anderson et al., J. Med. Chem. 1990, 33(b), 1667) was used instead of 6-chioronicotinyl chloride, compound 66 was obtained in 51?c yield as a white crystal, mp.

124-125.5 0 C (methanol). MS(CI) 296, 298(M+1).

b) Preparation of 1- (2-chloro-4-pyridyl) -2phenylsulfonyl acetylene (67) Using the method set forth in Example 27, compound 67 was obtained in 54% yield from compound 66 as a white crystal, mp. 78-79 0 C. MS(CI) 278, 280 c) Preparation of 7-carbomethoxy-2- (2chloro-4-pyridyl) -3 -phenylsulfonyl-7 azabicyclo[2.2.llhepta-2,5-diene (68) Using the method set forth in Example 29, compound 68 was obtained from compound 67 in 68% yield as a slightly brown oil. MS(CI) 403, 405(M+1). H'-NMR (CDCl 3 5 3.502 (br.s. 3H1, OCH 3 5.420, 5.483 (25, 2H1, H 14 7.065 2H1, H 56 d) Preparation of 7-carbomethoxy-5- (2chloro-4-pyridyl) -7azabicyclo[2.2.llhept-2-ene (69) Using the method set forth in Example compound 69 was obtained from the desulfonation of compound 68 in 13.6t yield as a 1:2 mixture of exoand endo-isomers. MS(-CI) 265, 267(M+1). 'H-NMVR (CDCl 3 (for endo-isomer) 5 3.682 311, OCH 3 (for exo-isomer) 6 3.665 311, OCHO WO 96/06093 WO 9606093PCTJUS95/10884 -82e) Preparation of 7-carbomethoxy-2-(2chloro-4-pyridyl) -7azabicyclo(2 .2 .1]heptane Using the method set forth in Example 31, compound 70 was obtained from the hydrogenation of compound 69 in 95*- yield. MS(CI) 267, 269(M+1).

1 H-NMR (CDC1 3 (for endo- isomer) 6 3 .694 3H,

OCH

3 (for exo-isomer) 6 3. 655 3H, OC 3 f) Preparation of 2- (2-chloro-4-pyridyl) -7azabicyclo[2.2.1]heptane Using the method set forth in Example 32, compound 65 was obtained from the deprotection of compound 70 in 23.616 (exo-isomer). MS(CI) 209, 211(M+1) 'H-NNR (CDCl 3 6 2.738 (dd, j=9.o, 5.1Hz, 1H, H 2 3.629 J=2.4Hz, lH), 3.791 1H). Some endo-isomer can be isolated.

Example 57 Preparation of disodium 7epibatidinyiphosphate (71) PO(ONa) 2 C1 Epibatidine (40.0 mg) was dissolved in 3 ml phosphorous oxychioride and the mixture was refluxed for 3 hours in the absence of moisture.

The excess reagent was removed in vacuo to give 100 mg 7-epibatidinyl phosphoryl dichloride as a brown WYO 96/06093 PCT/US95/10884 -83oily residue. To 28 mg of this residue in 2 ml tetrahydrofuran was added 2 ml 1M sodium hydroxide in ice bath. The mixture was stirred at room temperature for another 4 hours. After evaporation of the organic solvent, the aqueous solution was washed with ethyl ether (2x5 ml). The aqueous layer was then evaporated in vacuo to ca. 0.5 ml and left to stand at room temperature for several hours to give compound 71 as a white crystal.

Yield 14 mg 'H-NMR(D 2 0) 62.745 1H, H2), 3.723 1H), 3.920 1H).

7.357 J=8.4Hz, 1H). 8.073 (dd, J=2.4, 8.4Hz, 1H), 8.263 J=2.4Hz, 1H). "P-NMR (D 2 5.332.

Chlorosulfonic acid or other N-sulfate reagents can be used in place of phosphorus oxychloride, under these reaction conditions to prepare the N-sulfate derivative of epibatidine and analogs thereto.

Example 58 Preparation of 2,3-dehydroepibatidine (72) Scheme 7 shows the production of compound 72.

NNH

soph o 0 2 Ph SOPh NN N N ci Na(Hg) WO 96/06093 WO 9606093PCT/US95/10884 -84a) Preparation of 7-carbo-t-butoxy-2- (2- -3-phenylsulfonyl-7azabicyclo[2.2.1]hepta-2,5-diene (73) Using the method set forth in Example 29, compound 73 was obtained from the Diels-Alder reaction of 1- (2-chloro-5-pyridyl) -2phenylsulfonylacetylene 22 with N-carbo--t-butoxy pyrrole (N-t-Boc-pyrrole) in 64t yield as a white solid. mp. 133-134 0 C. MS(CI) 445, 447(M+1).

b) Preparation of 7-t-boc-2-(2-chloro-5pyridyl) -3 -phenylsul fonyl -7azabicyclo[2.2.1]hept-2-ene (73) Adduct 73 (445 mg) was dissolved in a mixture of 20 ml methanol and 10 ml tetrahydrofuran containing 8 mg platinum oxide. After hydrogenation under latin hydrogen for 3 hours, the catalyst was removed by filtration. The filtrate was concentrated in vacuo to give 440 mg residue.

It was solidified after trituration in methanol.

Yield 98t. MS(CI) 447, 449(M+1) 11-NMR (CDCl3) 6 1. 266 9H1, C (CH 3 3 4.-905, 4. 945 (2br. s. 2H1, H2,4).

C) Preparation of 2- (2-chloro-5-pyridyl) -3phenylsulfonyl-7 -azabicyclo hept- 2-ene Using the method set forth in Example 53e, the t-Boc of compound 74 was easily deprotected by trifluoro acetic acid at 0 0 C to give compound 75 in 95.40- yield as a white solid. MS(CI) 347, 349 H 1 -NMR (CDCl 3 64.423 J=4.21z, 1H) 4.500 J=3.6Hz, 1H). (H11,4) WO 96/06093 PCT/US95/10884 d) Preparation of 2 3 -dehydroepibatidine (72) Compound 75 (365 mg) was desulfonated using the method set forth in example 30 to give 23 mg of compound 72 as a colorless oil. Yield 19%. MS(CI) 207, 209(M+1). H'-NMR (CDC13) 6 4.323 1H, H 4.574 J=3.0Hz, 1H, H 4 6.560 J=2.4Hz, 1H,

H

3 Example 59 Preparation of Chloroethylepibatidine (76) N CH 2 CH 2

CI

CI

NN

Using the method set forth in Example 44, epibatidine 19 was alkylated with l-chloro-2bromoethane to give compound 76 in a 35% yield as a clear oil. MS(CI) 271,273, 275(M+1). H'-NMR (CDC1 3 6 3.225, 3.476 (25, 2H, H 14 3.568 (t, J=6.6Hz, 2H).

Example 60 Preparation of 2-(2-hydroxy-5-pyridyl)- 7-azanorbornane (77) Compound 53 (8.5 mg, 0.044 mmol) was dissolved in 1 ml tert-butanol. To this solution was added 1 ml 2M potassium hydroxide. After reflux for hours and evaporation of butanol, the mixture was adjusted with 1M hydrochloric acid to pH 6-7.

Evaporation of solvent in vacuo and purification of product with silica gel preparative thin layer chromatography developing with 20% 7N ammonia methanol in chloroform gave 4.2 mg compound 77 as WO 96/06093 PCT/US95/10884 -86an oil. Yield 50%. MS(CI) 191(M+1). 'H-NMR (CDC1 3 6 2.554 1H, H 2 3.503; 3.743 (2br.s., 2H, HI, 4 Example 61 Preparation of 2-(2-methylthio-5pyridyl)-7-azanorbornane (78) SCH3 Using the method set forth in Example 33, compound 78 was obtained in 28% yield from sodium methylmercaptanide in ethanol as a colorless oil.

MS(CI) 221, 223(M+1). 'H-NMR(CDCl 3 6 2.542 3H, SCH3), 2.757 (dd, J=5.1, 8.7Hz, 1H, H 2 3.546, 3.781 (2br.s., 2H, H, 4 Example 62 Preparation of 5,6-bis(trifluoromethyl) deschloroepibatidine (79) Scheme 8 shows the preparation of compound 79.

NCOOqCH_) C NCOOC(CH)3

CF

3

CF

3

CF

3

H

2 /PO2 CF3.

WO 96/06093 PCT/US95/10884 -87a) Preparation of 7-t-Boc-1,2bis(trifluoromethyl)-7azabicyclo[2.2.1]hepta-2,5-diene Compound 80 was prepared according to the procedure set forth in J. Leroy et al, Synthesis, 1982 313.

Preparation of 7-t-Boc-2,3bis(trifluoromethyl)-5-(pyridyl)-7azabicyclo[2.2.1]hept-2-ene (81) Compound 80 (165 mg, 0.5 mmol) and 105 mg 3iodopyridine (0.5 mmol) were dissolved in 1 ml dimethyl formamide containing 9 mg palladium acetate, 21 mg triphenyl phosphine, 120 mg piperidine and 60 mg 88% formic acid. The mixture was stirred at 60-70 0 C under nitrogen for 1.5 hours and at room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and water. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined organic layer was washed with saturated brine and dried over magnesium sulfate. After removal of solvent in vacuo, the residue (218 mg) was separated in silica gel column eluting with ethyl acetate in petroleum, to give 48 mg unstable compound 81 as a red oil. MS(CI) 409(M+1). Yield 23%. 'H-NMR(CDC1 3 6 1.427 9H, OC(CH 3 2.974 (dd, J=4.2, 8.4Hz, 1H, H 2 4.906, 5.147 (2br.s., 2H,

H,

4 The 5-(2-chloro-5-pyridyl) analog was obtained by replacing the iodopyridine in the above reaction with SWO 96/06093 PCTIUS95/10884 -88c) Preparation of 2,3-bis(trifluoromethyl)- -pyridyl-7-azabicyclo[2.2.1hepta-2-ene (82) Using the method set forth in Example 53e, compound 81 was easily deprotected with trifluoroacetic acid to give compound 82 in yield. 'H-NMR (CDCl 3 6 2.02 (dd, J=8.4, 2.1Hz, 2H, H3), 2.88 (dd, J=4.8, 8.4Hz, 1H, H 2 4.36, 4.63 (2br.s., 2H, H 14 The 5-(2-chloro-5-pyridyl) analog was obtained in the manner set forth above.

d) Preparation of 5 6 -bis(trifluoromethyl) deschloroepibatidine (79) Compound 82 was hydrogenated under high pressure of hydrogen, providing compound 79.

5,6-Bis(trifluoromethyl) epibatidine was obtained in the manner set forth above.

C. SYNTHESIS OF 7-AZA-2-HETEROCYCLIC- BICYCLO[2.2.1]HEPTANES or HEPTENES.

The syntheses described herein can be used to prepare 7 -aza- 2 -heterocyclic-bicyclo[2.2.1]heptanes and heptenes. As described above, the dipolar cycloaddition of pentaamminesosmium-pyrrole complexes affords 2-carbomethoxy-7-azanorbornanes which are useful starting materials for 7-aza-2heterocyclic-bicyclo[2.2.1]heptanes and heptenes.

Reactions of these esters with acetamidoxime affords 7-aza-(1',2',4'-oxadiazoles)bicyclo[2.2.1]heptanes and heptenes. Specific examples of these compounds are-shown in Table 4.

The analogous 7-benzyl and 7-unsubstituted compounds can be synthesized from the corresponding methyl esters described in Examples 66 and 67. The corresponding 3'-methyl-5'-2-(7-azanorbornyl) .WO 96/06093 PCT/US95/10884 -89isoxazoles, can be synthesized via the reaction of the methyl esters such as those produced in Examples 72 and 73 with the dianion of acetone oxime.

It, MO 96/06093 ~WO 9606093PCT/US95/10884 TABLE 4 R, ~R 2 R

CH

3 exo- CH 2

NHCOCH

3

H

CH

3 exo- CH 2 NHCOPh H

CH

3 exo-CH 2 NHCONHPh H

CH

3 exo N C3H 0

N

CH

3 exo- )-Ij)NCH 3

CH

3

CH

3 endo- C 3

H

CH

3 exo- CH 3 3 H ACH eno- COCH 3

H

H endo

COCH

MO 96/06093 'WO 9606093PCTIUS95/10884 -91- Table 4 Continued

CH

3

CH

3

CH

3 endo- or exoendo- or exoendo- or exo endo- or exoendo-or exoendo-or exo- H3C~NHN

H

3

CN

Any of these compounds can be administered in enantiomerically enriched form enriched in either the or enantiomer.

WO W96/06093 PTU9/08 PCT/US95/10884 -92- Example 63 Preparation of exo- 2 -acetamidomethyl7methyl-7 -azabicyclo(2 .2 .1]heptane A solution of the exo- 2 -aminomethyl-7-methyl.

7-azabicycloii2.2.1]heptane formed in Example 21 (27 S mg, 0.19 mmol) in ether (3 mL) was treated with acetic anhydride (30 mg, 0.3 mmol). After minutes, the reaction mixture was extracted with aqueous 101i Na 2

CO

3 The organic phase was dried over MgSO 4 filtered, and evaporated, affording 29 mg of the title product. 1H1 NNR (CDCl 3 7.66 (br s, 111,.NH), 3.24-3.14 (in, 311, overlap of

CH

2 N and H4) 3. 06 J 3. 9 Hz, 1H, H11) 2.18 (s, 3H1, CH 3 N) 1. 91 3H1, CH 3 CO, 1. 87-1.75 (in, 311), 1.45 (mn, 211), 1.25 (in, 211); 1 3 C NMR (CDCl 3 6 170.5 64.9 61.5 44.2 (C11 2 40.6 (CH, C2), 35.3 (CHO), 34.0 (CH 3 25.8 (CH 2 25.4 (CH 2 2 3 .2 (CH 3 Example 64 Preparation of exo-2-benzamidomethyl- 7 -methyl-7-azabicyclo[2 .2 .1]heptane The procedure described in Example 63 was followed, replacing acetic anhydride with benzoyl chloride. Purification of the crude product by column chromatography on silica gel (using ether containing 2% NH 4 0H and 8% methanol) afforded the title product in 71% yield. 111 NNR (CDCl 3 6 9.16 (br s, 111, NH), 7.86-7.4 (in, 511, Ph), 3.5-3.3 (in, 311 overlap of CH 2 N and 114), 3.18 J 3.6 Hz, 111, Hl1), 2.32 311, CH 3 1.99-1.91 (in, 311), 1.69- 1.51 (in, 211), 1.41-1.37 (in, 211); 1 3 C NMR (CDCl 3 6 167.4 134.8 130.9 128.3 (CH), 12 6.8 (CH) 65. 4 (CH) 6 1. 4 (CH) 4 4. 8 (CH 2 N) 4 0. 0 (CH, C2) 3 5. 4 (CH 2 3 4. 0 (CHO), 2 5. 6 (CHO), 25. 7

(CHO).

-WO 96/06093 PCT/US95/10884 -93- Example 65 Preparation of N-[exo-2-(7-methyl-7azabicyclo[2.2.1]heptyl)methyl]

-N

1 phenyl urea The procedure described in Example 63 was followed, replacing acetic anhydride with phenyl isocyanate. Purification by column chromatography on silica gel (ether containing 5% NH 4 OH and methanol) afforded the title product in 67% yield.

'H NMR (CDC13) 6 7.30-6.9 5H, Ph), 6.89 (br s, 1H, NH) 3.3-3.2 3H, overlap of CH 2 N and H4), 3.04 J 3.3 Hz, 1H, HI), 2.6 (br s, 1H, NH), 2.07 3H CH 3 1.86-1.81 3H), 1.51-1.43 (m, 2H), 1.33-1.29 2H); 13C NMR (CDC13) 5 156.6 (CO), 138.9 129.0 123.3 121.0 64.8 61.4 44.9 (CH 2 41.4 (CH, C2), 35.2

(CH

2 34.1 (CH 3 25.8 (CH 2 25.5 (CH 2 Example 66 Preparation of exo- 2 ,5'-(3'-methyl- 1',2',4'-ozadiazolyl)-7-methyl-7azabicyclo[2.2.1]heptane The procedure set forth in Carrol et al., J.

Med. Chem, 1993 36, 2846 was used to prepare this compound. Sodium hydride (27 mg, 1.1 mmol) was added to a solution of acetamidoxime (77 mg, 1.04 mmol, 5 eg) in THF (10 mL) and the mixture was stirred and refluxed under nitrogen for 1 hour.

Exo- 2 -carbomethoxy-7-methyl-7-azabicyclo[2.2.1] heptane (34 mg, 0.2 mmol) and powdered molecular sieves (85 mg) were added to the mixture and the reaction was refluxed and stirred for an additional 3 hours. The mixture was filtered, the cake was washed with THF, the filtrate was evaporated, and the residue was chromatographed on silica gel using 1% NH40H, and 3% methanol in ether. This provided the exo product as a colorless resin (12 mg, 31%).

'H NMR (CDC 3 6 3.66 J 4.2 Hz, 1H, HI), 3.39 J 4.2 Hz, 1H, H4), 2.93 (dd, J 9.3, 5.1 Hz, 1H, H2), 2.36 3H), 2.3 1H), 2.23 3H), WO 96/06093 PCTIUS95/10884 -94- 8 (in, 311), 1. 45 (in, 2H) 3 C Nivip (CDCl 3 6 18 2.3 16 7. 4 6 5. 8 (CH) 6.1. 5 (CH) 4 1. 4 36. 3 (0112), 35. 1 (CH 3 N) 2 6.-8 (CE 2 2 6. 3

(CE

2 12. 0 (CE 3 Example 67 Preparation of exo- 2 1 -(3'-methyl- 1',2'14'-oxadiazolyl) -l,4-dimethyl-7azabicyclo heptane The procedure of Example 66 was used except that exo-2-carbomethoxy-1, 4-diinethyl-7azabicyclo[2.2.1]heptane was used in place of exo- 2-carbomethoxy-7-methyl-7-azabicyclo heptane.

The product was purified by prep. GC on a OV-17 column (1800C). 'H NMR (CDC1 3 6 3. 30 (dd, lE) 2.37 3H), 2.15 (dd, 1H), 1.90 (mn, 1H), 1.6-1.8 (5H) 1. 44 3H) 1. 05 3H); 13C NNR (CDCl 3 6 181.9 166.8(C), 68.1(C), 66.6 46.4 (CH), 4 5 .9 (CE 2 3 8 .6 (CE 2 3 7. 0 (OH 2 2 0 .6 (CE 3 18 .3 6

(CE

3 11. 5 (OH 3 Example 68 Preparation of endo-2,5'-(3'-methyll 1 21 1 -oxadiazolyl)-7-methyl-7azabicyclo [2.2 .1]heptane The procedure of Example 67 was repeated in the absence of molecular sieves using 2.25 eq of acetamidoxime and 3 eq NaH. This provided of exo and endo isomers. The isomers were separated by preparative TLC (2.0 mm plate, 2% saturated NH 3 methanol in ether; exo endo Rf=0.3) (isolated yields after chromnatographic separation: 17%, 15-0, respectively) Data for endo isomer: 'H NNR (CDCl 3 6 3.61 (in, 2H, overlap of Hi and H2), 3.35 J Hz, IE, H4), 2.40 3H), 2.36 3H), 2.3 (mn, 1H) 1.-9 (in, 1H) 1.-8 (mn, 1H) 1. 6 (mn, 1H) 1. 4 (in, 1H) 1. 15 (mn, 1H) 1 3 C NMR (CDCl 3 6 18 0.-5 166.8 65.0 61.9 37.9 (br, CE), 3 4. 5 (NCH 3 3 2. 7 (br, CE 2 28. 1 (br, CE 2 2 3. 6 (br, CE 2 11. 5 (CE 3 *WO 96/06093 PCTIUS95/10884 Example 69 Preparation of methoxyphenyl]-1',2',4'-oxadiazolyl)-7methyl-7-azabicyclo[2.2.1]heptane This compound was prepared using the procedure set forth in Example 68, replacing acetamidoxime with 4-methoxybenzamidoxime. 'H NMR (CDC13) 6 J 9 Hz, 2H), 6.96 J 9 Hz, 2H), 3.89 (s, 3H, CH 3 3.77 J 4.2 Hz, 1H, H1), 3.41 J 4.2 Hz, 1H, H4), 3.00 (dd, J 8.1, 4.2 Hz, 1H, H2), 2.47-2.38 1H), 2.24 3H, CH 3 2.04- 1.85 3H), 1.55-1.42 2H); 13C NMR (CDC13) 6 181.8 167.9 161.7 129.1 119.5 114.1 65.5 61.1 55.3 (CH 3 0), 41.2 (CH, C2), 35.6 (CH 2 34.8 (CH 3 26.7 (CH 2 26.1 (CH 2 Example 70 Preparation of endo-2,2'-(5'-methyl- 1',3',4'-oxadiazolyl)-7-methyl-7azabicyclo[2.2.1]heptane This compound was prepared using the method set forth in Ainsworth et al., J. Org. Chem., 1966, 31, 3442. A mixture of endo-2-carbomethoxy-7methyl-7-azabicyclo[2.2.1]heptane (108 mg, 0.64 mmol), ethanol (2 mL), and hydrazine hydrate (0.44 g, 13.8 eq) was refluxed for 14 hours and the volatiles were removed in vacuo. The resulting crude hydrazide was refluxed in excess triethyl orthoacetate (0.86 g, 8.3 eq) for 18 hours. The mixture was acidified with HC1 and the unreacted orthoester was evaporated. The residue was made basic with NH 3 -methanol, triturated with methylene chloride, and filtered to remove the insoluble

NH

4 C1. The filtrate was evaporated, and the crude material purified by preparative TLC (ether containing 7% of saturated NH 3

-CH

3 OH), providing 29 mg of the title product. 'H NMR (CDC1 3 3.51-3.45 2H, overlap of H2 with H1 or H4), 3.31 J 4.8 Hz, 1H, H4 or HI), 2.47 3H), -WO 96/06093 PCTIUS95/10884 -96- 2.33 3H), 2.29-2.19 1H), 1.95 1H), 1.86-1.74 1H), 1.68-1.59 1H), 1.46-1.38 (m, 1H), 1.22-1.14 1H); 13 C NMR (CDC1 3 6 168.5 164.3 65.6 62.4 37.5 (br, CH), 35.1 (NCH 3 32.8 (br, CH) 28.4 (br, CH2, 23.8 (br,

CH

2 11.4 (CH 3 Example 71 Preparation of exo-2,2'-(5'-methyl- 1',3',4'-oxadiazolyl)-7-methyl-7azabicyclo[2.2.1]heptane The endo isomer produced in Example 70 (21 mg, 0.11 mmol) was refluxed in methanol (1 mL) containing potassium hydroxide (20 mg, 0.3 mmol) for 45 minutes. The methanol was evaporated, the residue was dissolved in water, and the resulting mixture was extracted with methylene chloride. The extract was dried and evaporated, affording 10 mg of a 1:1 mixture of exo and endo isomers. The isomers were separated using preparative TLC (acetonitrile containing 10% NH 3 -methanol), affording the title product (3 mg, 15% based on recovered endo isomer). 'H NMR (CDC13) 6 3.59 J 3.9 Hz, 1H, Hi), 3.37 J 4.2 Hz, 1H, H4), 2.93 (dd, J 9.3, 5.1 Hz, 1H, H2), 2.46 3H), 2.24 3H), 2.0-1.7 4H), 1.5-1.37 2H).

Example 72 Preparation of 2-carbomethoxy-7-(3',5'dimethylbenzyl)-7azabicyclo[2.2.1]heptane The procedure used in the synthesis of 2carbomethoxy-7-methyl-7-azabicyclo[2.2.1]heptane was used to make the title compound from dimethylbenzylpyrrole using the procedures set forth in Example 13 and 14. This title compound was obtained as a 1:3 mixture of exo/endo isomers in 27% yield. Data for major (endo) product: 'H NMR (CDCI 3 6 7.0 2H), 6.9 1H), 3.85 (s, 3H), 3.53 (br s, 2H), 3.35 2H), 3.13 1H), WO 96/06093 PCT/US95/10884 -97- 2.4 1H), 2.35 6H) 2.0 IH), 1.

9 -1.32(m, 4H).

Example 73 Preparation of 2-carbomethoxy-7azabicyclo[2.2.1]heptane The product formed in Example 72 was treated with an equal weight of 10% Pd-on-C and refluxed in 96% formic acid for 12 hours. The mixture was filtered, the filtrate was partitioned between aqueous Na 2

CO

3 and methylene chloride, and the extract dried and evaporated, affording a 48% yield of the title-compound. Major (endo) isomer: 'H NMR

(CDCI

3 6 4.12 1H), 3.92 3H), 3.8 3H), 3.2 1H), 2.3 (br s, 1H), 2.2-1.55 6H).

Figure 6 provides examples of a synthetic route for production of 7-aza-2-isoxazolebicyclo[2.2.1]heptane. This procedure is set forth in detail below in Examples 74 through 82.

Example 74 Preparation of dimethylethoxycarbonyl)-7azabicyclo[2.2.1]heptan-2-one (83) A procedure similar to that set forth in Dess et al. J. Org. Chem. 1983, 48, 4156 was used prepare compound 83. The Dess-Martin periodinane g, 4.70 mmol) was added to a stirred solution of 2-hydroxy-7-(1,1-dimethylethoxycarbonyl)-7azabicyclo[2.2.1]heptane 82 (1.0 g. 4.72 mmol).

After 12 hours the mixture was diluted with EtO2 and poured into saturated aqueous NaHCO 3 containing a sevenfold excess of Na 2

SO

3 The organic layer was washed with saturated aqueous NaHCO 3 with H 2 0, dried over MgSO 4 filtered and concentrated. The resulting residue was purified by chromatography EtOAc/hexanes) to give compound 83 (0.83 g, 84%) as a clear oil that solidified on standing.

'WO 96/06093 PCT/US95/10884 -98- Example 75 Preparation of 7 -(1,1-dimethylethoxycarbonyl)-7azabicyclo[2.2.1]heptan-2-ylidene (84) A procedure similar to that set forth in Fitjer, et al., Synthetic Communications 1985, 855 was used to prepare compound 84. Methyl triphenylphosphonium bromide (1.55 g, 4.34 mmol) was added to a stirred solution of potassium tertbutoxide (0.53 g, 4.34 mmol) in absolute benzene (8.0 mL). The mixture was refluxed for 15 minutes and most of the solvent was evaporated off. Ketone 83 (0.83 g, 3.93 mmol) was added to the remaining slurry at 900C. The reaction mixture was stirred at 900C for 2 hours, cooled, and partitioned between H 2 0 (25 mL) and Et20 (80 mL). The aqueous layer was extracted with EtO2 (3x80 mL). The combined organic layers were dried over MgSO 4 filtered and concentrated. The resulting residue was purified by chromatography (10% EtOAc/hexanes) to give compound 84 (0.52 g, 63%) as a clear oil.

Rf 0.72 (10% EtOAc/hexanes) 'H-NMR (CDCl 3 300 MHz) 6 4.93 1 4.73 1 4.50-4.36 1 H), 4.34-4.20 1 2.53-1.54 5 H) 1.43 9

H).

Example 76 Preparation of dimethylethoxycarbonyl)-2hydroxymethyl-7 azabicyclo[2.2.1]heptane BH3 (CH 3 2 S (1.75 mL, 2.0 M in THF) was added to a stirred, cooled (0 0 C) solution of 84 (0.52 g, 2.49 mmol) in hexanes (6.0 mL). The cooling bath was removed. After 3 hours, ethanol (2 mL) was added followed by a mixture of NaOH (3 mL, 3 M), and H 2 0 2 3 mL). The mixture was heated at 400C for 2 hours, cooled and partitioned between brine and Et 2 O. The aqueous layer was extracted with Et20 (3x25 mL). The combined organic layers

I

WO 96/06093 PCT/US95/10884 -99were dried over MgS04, filtered, and concentrated to give compound 85 as a clear oil. Rf 0.54 EtOAc/hexanes). 'H-NMR (CDC13, 300 MHz) 6 4.34-4.00 2 3.82-3.26 2 3.00 1 2.51- 2.28 1 2.08-0.68 15 H).

Example 77 Preparation of dimethylethoxycarbonyl)-2-formyl-7azabicyclo[2.2.1]heptane (86) A procedure similar to that set forth in Danishefsky et al. J. Org. Chem. 1991, 56, 2535 was used to preare compound 86. The Dess-Martin periodinane (0.89 g, 2.09 mmol) was added to a stirred solution of 85 (0.49 g, 2.17 mmol) and pyridine (0.62 g, 7.80 mmol). After 2 hours, the mixture was diluted with Et 2 0 and poured into saturated aqueous NaHCO 3 containing a sevenfold excess of Na 2

S

2 0 3 The organic layer was washed with saturated aqueous NaHCO 3 with H20, dried over MgSO 4 filtered and concentrated. The resulting residue was purified by chromatography (40 EtOAc/hexanes) to give the title compound 86 (0.22 g, 45%) as a clear oil and a mixture of isomeric aldehydes (0.8 Rf 0.86 (40% EtOAc/hexanes). 'H NMR (CDC13, 300 MHz) 6 9.79 1 4.68-4.45 1 4.41-3.83 1 3.17-2.94 1 2.11-1.05 15 H).

Example 78 Preparation of (2',2'-dibromo-1'-ethenyl)]-7-(1,1dimethylethoxycarbonyl)-7azabicyclo[2.2.1]heptane (87) A procedure similar to that set forth in Corey, et al., Tetrahedron Lett. 1972, 3769 was used to prepare compound 87. Aldehyde 86 (0.22 g, 0.98 mmol) dissolved in CH 2 C12 was added to a stirred, cooled solution of CBr4 (0.72 g, 2.17 mmol) and triphenylphosphine (1.05 g, mmol) in CHzC1 2 (5.0 mL). The reaction mixture was WO 96/06093 PCT/US95/10884 -100stirred 10 minutes, diluted with pentane and filtered through a Celite pad. The filter cake was washed with Et 2 O and the filtrate concentrated. The resulting residue was purified by chromatography (a linear gradient of 0-10% Et20/pentane) to give compound 87 as a clear oil that solidified on standing. R, 0.75 (10% Et2O/pentane) 'H-NMR (CDCl 3 300 MHz) 6 6.35 J 8.7 Hz, 1 4.40- 4.00 2 3.05-2.80 1 2.32-2.05 1 1.90-1.32 12 H).

Example 79 Prepared of 7-(1,1-dimethylethoxycarbonyl)-7azabicyclo[2.2.1]heptane (88) A procedure similar to that set forth in Corey, et al., Tetrahedron Lett. 1972, 3769 was used to prepare compound 88. n-BuLi(0.56 mL, 2.69 M in hexanes) was added to a stirred cooled (-78 0

C)

solution of the dibromide 87 (0.26g, 0.68 mmol) in THF (7.0 mL). The reaction mixture was stirred at -78 0 C for 1 hour, warmed to room temperature, and stirred 1 hour more. The reaction was quenched by the addition of H 2 0 and partitioned with Et 2 O. The aqueous layer was extracted with Et20. The combined organic layers were dried over MgSO 4 filtered and concentrated. The resulting residue was purified by chromatography (10% EtOAc/hexanes) to give compound 88 (0.16 g, 60%) as a clear yellow oil. Rf 0.75 (10% EtOA/hexanes). 'H-NMR (CDC13, 300 MHz) 6 4.35-4.05 2.94-2.73 1 2.28-1.97 2 1.89-1.24 13 H).

Example 80 Preparation of (dimethylethoxycarbonyl)-2-[5'-(3'methyl)isoxazolyl]-7azabicyclo[2.2.1]heptane (89) A procedure similar to that set forth in Kozikowski et al. J. Org. Chem. 1985, 50, 778 was -WO 96/06093 PCT/US95/10884 -101used to prepare compound 89. A stirred solution of the alkyne 88 (0.16 g, 0.73 mmol), phenylisocyanate (0..69 g, 5.79 mmol), triethylamine (3 drops), and nitroethane (0.11 g, 1.45 mmol) in benzene was heated at 75-850C for 16 hours. The reaction mixture was cooled, and filtered. The filtrate was partitioned between H 2 0 and hexanes. The organic layer was washed with saturated aqueous NaHC03, and with H 2 0, dried over MgSO 4 filtered and concentrated. The resulting residue was purified by chromatography (linear gradient of 10-20% EtOAc/hexanes) to give compound 89 (0.12 g, 60%) as a light yellow semisolid. Rf 0.33 EtOAc/hexanes). 'H-NMR (CDCl 3 300 MHz) 6 5.89 (s, 1 4.50-4.37 1 4.34-4.24 1 3.50- 3.37 1 2.45-1.16 18H) ppm.

Example 81 Preparation of methyl)isoxazolyl] -7azabicyclo [2.2.1heptane, Trifluoroacetic acid (1.49 g, 13.0 mmol) was added to a stirred, cooled (0 0 C) solution of the isoxazole 89 (56.4 mg, 0.212 mmol) in CHC1 3 (2 mL).

After stirring for 18 hours, the volatile components were evaporated and the remaining residue partitioned between saturated aqueous K 2

CO

3 and CHC1 3 The aqueous layer was extracted with CHC1 3 The combined organic layers were dried over Na 2

SO

4 filtered, and concentrated to give compound (41.2 mg, 69%) as a clear oil that formed a waxlike solid upon standing. The product could be further purified by chromatography

CH

3 OH/CHCl 3 R, 0.33 (10% CH 3

OH/CH

2 C1 2 'H-NMR (CDC1 3 300 MHz) 6 5.92 1 4.10-3.87 2 3.63-3.13 2 2.42-2.11 4H), 1.89-1.32 5 H).

*WO 96/06093 PCT/US95/10884 -102- Example 82 Preparation of methyl)isoxazolyl]-7-methyl-7azabicyclo[2.2.1]heptane (91) A procedure similar to that set forth in Garvey et al. J. Med Chem. 1994, 37, 1055 was used to prepare compound 91. A stirred solution of the isoxazole 90 (19.3 mg, 0.18 mmol), formalin (0.32 mL, 37% in H 2 and formic acid (0.22 mL, 88% in

H

2 0) was heated at 85-90 0 C for 20 hours. The mixture was cooled to room temperature, treated with HC1 (6M) and extracted with EtzO. The aqueous layer was basified with saturated aqueous K 2

CO

3 and extracted with CHC1 3 The combined organic layers were dried over MgSO 4 filtered, and concentrated.

The resulting residue was purified by chromatography (10% CH 3

OH/CH

2 C1 2 to give compound 91 (11.5 mg, 55%) as an oil. Rf 0.52

CH

3

OH/CH

2 Cl 2 H-NMR (CDC13, 300 MHz) 6 5.89 1 3.63-3.24 3 2.58-2.08 7 1.97- 1.13 Example 83 Preparation of (methoxycarbonyl)-2-(2'-quinolyl) -7azabicyclo[2.2.1]heptane (92) A procedure similar to that set forth in Regen, et al., Tetrahedron Lett. 1993, 7493 was used to prepare compound 92. N-Methoxycarbonyl-7azabicyclo[2.2.1]heptene was added to a stirred solution of palladium acetate (5.6 mg, 0.0249 mmol), triphenylphosphine (12 mg, 0.046 mmol), piperidine (90 mg, 0.11 mmol), formic acid (38 mg, 0.83 mmol), and 2-iodoquinoline (21.8 mg, 0.86 mmol) in DMF (0.3 mL). The mixture was heated at 750C for 7 hours cooled, and partitioned between EtOAc (30 mL) and H 2 0 (10 ml). The organic layer was washed with H 2 0 (3x10 mL). The organic layer was dried over MgSO 4 filtered, and concentrated.

The resulting residue was purified by ,WO 96/06093 PCT/US95/10884 -103chromatography (linear gradient of 20-40% EtOAc/hexanes) to give compound 92 (45.4 mg, 49%) as an oil. R, 0.33 (40% EtOAc/hexanes).

'H-NMR

(CDC1 3 300 MHz) 6 9.00-7.45 6 4.84-4.05 (m, 2 3.64 3 3.29-2.95 1H), 2.34-1.42 6 H).

Example 84 Preparation of quinolyl)-7-azabicyclo[2.1.1]heptane (93) A solution of 92 (45.4 mg, 0.168 mmol) in 33% HBr in HOAc (con 9.0 ML)] was stirred for hours. The solvent was evaporated and the resulting solid residue was dissolved in H 2 0. The aqueous solution was basified with NaOH (2 N) and extracted with CH 2 C1 2 (4x10 mL). The combined organic layers were dried over MgSO 4 filtered and concentrated. The resulting residue was purified by chromatography

CH

3 OH saturated with

NH

3

/CH

2 C1 2 to give compound 93 (21.5 mg, 60%) as an oil. Rf 0.28 CH30H saturated with NH 3

/CH

2 Cl 2 'H-NMR (CDC13, 300 MHz) 6 9.03-7.37 6 4.00- 3.57 2 3.10-2.87 1 2.32-1.13 (m, 7H).

Example 85 Preparation of (+/-)-(exo)-7-methyl-2- (2'-quinolyl)-7azabicyclo[2.2.1]heptane (94) A procedure similar to that set forth in Garvey et al J. Med. Chem. 1994, 37, 1055 was used to prepare compound 94. A stirred solution of the quinoline 93 (12.5 mg, 0.059 mmol), formalin (0.32 mL, 37% in H20), and formic acid (0.22 mL, 88% in

H

2 0) was heated at 85-90 0 C for 20 hours. The mixture was cooled to room temperature, treated with HC1 (6M) and extracted with Et 2 O. The aqueous layer was basified with saturated aqueous K 2 C0 3 and extracted with CHC1 3 The combined organic layers WUO 96106093 PCTIUS95/10884 -104were dried over MgSO 4 filtered, and concentrated.

The resulting residue was purified by chromatography (10% CH 3

OH/CH

2 Cl 2 to give compound 94 (9.3 mg, 70%) as an oil. Rf 0.32 (10% CH 3

OH/CH

2 Cl 2 'H-NMR (CDC13, 300 MHz) 6 8.97-7.89 6 3.63- 3.39 2 3.11-2.92 1 2.45 3 H), 2.29-1.00 6 H).

Example 86 Preparation of 2-(5'-oxazole)-7-methyl- 7-azanorbornane 2-Carbomethoxy-7-methyl-7-azanorbornane is obtained as set forth in Example 15. The compound is chromatographed on a silica gel column to separate the exo- and endo- isomers.

Exo-2-carbomethoxy-7-methyl-7-azanorbornane is reacted with lithiomethyl isocyanide (the Schollkopf Reaction), as disclosed by Jacobi, P.A.

et al., J. Org. Chem. 1981, 46, 2065, to produce 2-(5'-oxazole)-7-methyl-7-azanorbornane 95. This process is set forth in Figure 3.

Example 87 Preparation of 2 -(1',3',4'-oxadiazole)- 7-methyl-7-azanorbornane (96) 2-Carbomethoxy-7-methyl-7-azanorbornane is obtained as set forth in Example 15. The compound is chromatographed on a silica gel column to separate the exo- and endo- isomers.

Exo-2-carbomethoxy-7-methyl-7-azanorbornane is reacted using the procedure disclosed by Ainsworth, C. et al., J. Org. Chem. 1966, 31, 3442 to form the 2-(1',3',4'-oxadiazole)-7-methyl-7-azanorbornane.

This reaction occurs by cyclizing an ethoxymethylene hydrazide intermediate with triethyl orthoformate, to produce the oxzdiazole)-7-methyl-7-azanorbornane 96.

Ill WO 96/06093 PCT/US95/10884 -105- Example 88 Preparation of 2-(tetrazole)-7-methyl- 7-azanorbornane (97) 2-Cyano-7-methyl-7-azanorbornane is obtained as set forth in Example 16. The compound is chromatographed on a silica gel column to separate the exo- and endo- isomers.

Exo-2-cyano-7-methyl-7-azanorbornane is converted in one step to the tetrazole 97, as shown in Figure 4, using the procedures described by Kadaba, P.K. Synthesis 1973, 71.

Example 89 Preparation of 2-(imidazole)-7-methyl- 7-azanorbornane (98) 2-Cyano-7-methyl-7-azanorbornane is obtained as set forth in Example 16. The compound is chromatographed on a silica gel column to separate the exo- and endo- isomers.

Exo-2-cyano-7-methyl-7-azanorbornane is converted to the imidate ester intermediate 99, as shown in Figure 4, using the Pinner reaction, as described by Patai, ed. The Chemistry of Amidines and Imidates, Wiley, 1975.

The imidate ester intermediate 99, is then converted to the the 2-substituted imidazole 98, as shown in Figure 4, using the reaction disclosed by Lawson, J. Chem. Soc. 1957, 4225.

Example 90 Preparation of 2-(benzopyrimidinone)-7methyl-7-azanorbornane (100) 2-Cyano-7-methyl-7-azanorbornane is obtained as set forth in Example 16. The compound is chromatographed on a silica gel column to separate the exo- and endo- isomers.

Exo-2-cyano-7-methyl-7-azanorbornane is converted to the imidate ester intermediate 99, as shown in Figure 4, using the Pinner reaction, as i NWO 96/06093 PCTIUS95/10884 -106described by Patai, ed. The Chemistry of Amidines and Imidates, Wiley, 1975.

The imidate ester intermediate 99, is then converted to the the 2-substituted benzopyrimidinone 100 using the reaction disclosed by Ried, W. et al, Chem. Ber. 1962, 95, 3042, as shown in Figure 4.

Example 91 Preparation of 2-(acylamino)-7-methyl- 7-azanorbornane and 2- (acylaminomethyl)-7-methyl-7azanorbornane Either exo-2-cyano-7-methyl-7-azanorbornane or the exo-2-carbomethoxy-7-methyl-7-azanorbornane is converted to the exo-2-amino intermediate 101, as shown in Figure 5. The exo-2-amino compound 101 may either be reacted to form heterocyclic rings, or may be acylated to provide open chain analogs, such as 102 and 103, as shown in Figure 5. For example, the Hoffman rearrangement, using the method of Wallis, E.S. et al., Org. Reactions 1946, 3, 267, of the amide obtained by mild alkaline hydrolysis of the nitrile, or the Schmidt reaction of the corresponding acid, using the method of Wolff, H. Organic Reactions 1946, 3, 307, yields the the exo-2-amine 101. Alternatively, hydrazinolysis of the exo-2-carbomethoxy compound, followed by a modified Curtius rearrangement may be used to prepare the carbamate 104, as shown in Figure Alternatively, the 2-cyano moiety is reduced with lithium aluminum hydride to yield exo-2aminomethyl compound 105, which may be acylated to give amide or carbamate open chain compounds 106.

WO 96/06093 PCT/US95/10884 -107- Example 92 Optical Resolution of methyl-1,2,4-oxadiazol-5-yl)-7-methyl- 7-azabicyclo[.22.1]heptane (±)-exo-2-(3-Methyl-l,2,4-oxadiazol-5-yl)-7methyl-7-azabicyclo[2.2.1]heptane (356 mg, 1.85 mmol) was treated with a solution of O,O-dibenzoyl- (L)-tartaric acid (661 mg, 1.85 mmol) in anhydrous ethanol (20 mL). The solution was evaporated, leaving a semi-solid residue. This residue was dissolved in boiling isopropanol (20mL), diluted with water (5mL), and allowed to crystallize overnight at -200C. The crystals were filtered, washed with 4:1 isopropanol-water (5mL), and dried in vacuo, affording a white solid (456 mg); mp 132- 134°C. To this solid was added 2:1 methanol/isopropanol (30 mL), and the resulting slurry concentrated to a volume of approx 10 mL on a hotplate. After cooling for 2 h at -200C, the crystals were filtered, washed with isopropanol (3mL), and dried in vacuo, affording the levo salt (374 mg); mp 150 0 C, [a]D -63.60 (c 0.22, MeOH).

This solid was stirred with a mixture of aqueous Na 2

CO

3 (20 mL), and methylene chloride The organic phase was dried over Na 2

SO

4 concentrated to a small volume, and filtered through a plug of basic alumina in a pipette to remove suspended solids. Careful evaporation of the solution afforded the dextro free base as a colorless oil (149 mg, 0.77 mmol); [a]D+3.20 (c 7.45, CH 2 C1 2 The mother liquors from the crystallization of the levo salt were evaporated, and the residue partitioned between aqueous Na 2

CO

3 and CH 2 Cl 2 as described above, affording a slightly yellow oil (204 mg, 1.06 mmol). This was dissolved in isopropanol (20mL), and treated with O,O-dibenzoyl- (D)-tartaric acid (379 mg, 1.06 mmol). As the acid dissolved, a precipitate of the salt began to form.

I

I WO 96/06093 PCT/US95/10884 -108- It is recommended that one dissolve the tartaric acid in isopropanol prior to mixing with a solution of the free base. In the described procedure, the tartaric acid goes into solution slowly, but the tartarate salt crystallizes quickly, affording a solid mixture. The digestion with methanol as described herein was intended to achieve full mixing of the reactants prior to completion of the crystallization. The slurry was treated with methanol (10 mL), and boiled for min, then placed in the freezer (-20 0 C) overnight.

The crystals were filtered, washed with isopropanol and dried in vacuo, affording the dextro salt as a white solid (386 mg); mp 149-150 0

C;

[c]D+59.1 0 (c 0.22, MeOH). This solid was converted to the free base as described above, affording the levo base as a colorless oil (146 mg, 0.756 mmol); [a]D-3.4 0 (c 3.23, CH 2 C1 2 The combined yield of both enantiomers was 295 mg IV. Pharmaceutical Compositions Humans, equine, canine, bovine and other animals, and in particular, mammals, suffering from disorders characterized by increased or decreased cholinergic function, as described in more detail herein, can be treated by administering to the patient an effective amount of one or more of the above-identified compounds or a pharmaceutically acceptable derivative or salt thereof in a pharmaceutically acceptable carrier or diluent.

The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid, cream, gel or solid form.

I WO 96/06093 PCT/US95/10884 -109- As used herein, the term pharmaceutically acceptable salts or complexes refers to salts or complexes that retain the desired biological activity of the above-identified compounds and exhibit minimal undesired toxicological effects.

Nonlimiting examples of such salts are acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid; base addition salts formed with metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with a cation formed from ammonia, N,N-dibenzylethylenediamine, D-glucosamine, tetraethylammonium, or ethylenediamine; or combinations of and a zinc tannate salt or the like.

The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated for any of the disorders described herein. A preferred dose of the active compound for all of the herein-mentioned conditions is in the range from about 0.0001 to 20 mg/kg, preferably 0.001 to 2 mg/kg per day, more generally 0.05 to about 0.5 mg per kilogram body weight of the recipient per day.

A typical topical dosage will range from 0.001% to wt/wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable q -WO 96/06093 PCT/US95/10884 -110derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.

The compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing 0.001 to 1000 mg, preferably 0.01 to 500 mg of active ingredient per unit dosage form. A oral dosage of 0.1 to 200 mg is usually convenient.

The active ingredient can be administered by the intravenous injection of a solution or formulation of the active ingredient, optionally in saline, or an aqueous medium or administered as a bolus of the active ingredient.

The concentration of active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions,.and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.

Oral compositions will generally include an 4 O 96/06093 PCT/US95/10884 -111inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.

The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.

In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.

The active compound or pharmaceutically acceptable salt or derivative thereof can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.

A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

The active compound or pharmaceutically acceptable derivatives or salts thereof can also be WO 96/06093 PCT/US95/10884 -112mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, antiinflammatories, or antiviral compounds.

Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline

(PBS).

In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.

Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation.

WO 96/06093 PCT/US95/10884 -113- V. Analgesic Activity of 7-Azabicyclo[2.2.1] -heptanes and -heptenes A wide variety of biological assays have been used to evaluate the ability of a compound to act as an analgesic. Any of these known assays can be used to evaluate the analgesic ability of the compounds disclosed herein. The Straub-tail reaction, which is characteristic of opiate alkaloids, has been used as an assay for opiate agonists and antagonists. The assay is described in detail in Br. J. of Pharmacol. 1969, 36, 225.

Another accepted assay for analgesic activity is the hot plate analgesia assay, described in J. of Pharmacol. Exp. Therap. 1953, 107, 385. An assay for the evaluation of the ability of a compound to bind to an opiate receptor is described in Mol.

Pharmacol. 1974, 10, 868.

In addition to their potent central analgesic effects, some of the substituted 7-aza-bicyclo[2.2.1]-heptanes and -heptenes described herein also possess varying degrees of peripheral anti-inflammatory and analgesic effects which are useful for therapeutic applications. The following assays for the evaluation peripheral anti-inflammatory activities are described in Barber, A. and Gottschlich, Opioid Agonists nd Antagonists: An Evaluation of Their Peripheral Actions in Inflammation, Medicinal Research Review, Vol. 12, No.5, 525-562 (September, 1992) paw hyperalgesia in rat that has been induced by prostaglandin E2 or carrageenan; inflamed knee joint in cat that has been induced by carrageenan, bradykinin or PGE 2 formalin test in mouse or rat that has been induced by formalin; neurogenic inflammation in rat, cat or guinea pig that has been induced by antidromic stimulation of sensory nerves; and the writhing test in mouse that is 4 -VO 96/06093 PCT/US95/10884 -114induced by acetic acid, phenylbenzoquinone, prostaglandin or bradykinin; and adjuvant arthritis in rat that is induced by Freund's adjuvant.

Example 93 Evaluation of Analgesic Activity Table 5 provides the analgesic activity measured as ED 50 for selected compounds disclosed herein, as determined using the Straub- Tail assay, as describe by J. Daly et al. J. Am.

Chem. Soc., 1980, 102, 830; T. F. Spande, et al. J.

Am. Chem. Soc. 1992, 114, 3475; T. Li, et al.

Bioorganic and Medicinal Chemistry Letters 1993, 3, 2759.

WO 96/06093 PTU9/08 PCTIUS95/10884 -115- Structural formula Table Comments 9 (g/Kg) l-epibatidine d- epibat idine

H

N

H

N CI C

H

3

NN

Hc

H

H

N~

H

>100 10000 Mixture of endo and exo isomers (1.3:1) 750 10001@ 100.0 (jig/Kg) 4WO 96/06093 PCTIUS95/10884 -116- Structural formula EDO ucg..j Comments C H 2

CH

2 CsHs

N

rCI H<1000

H

H

N

250

SN

H

H

Cl <1000

H

CH

3

NCH

3 1 100-200

H

H

ca.

H

WO 96/06093 WO 9606093PCTfUS95/10884 -117- Structural formula

ED

5 -g/ Comment-s

ICH

2

CH

2

CI

NN

H

ca. 100 ca. racemic

CH=NHJ-ICI

N

H

99% 100

H

N

L r'rOC(CH)3 ca. 1000 "WO 96/06093 PCTfUS95/10884 -118- Example 94 Evaluation of Nicotinic Receptor Binding Activity 7-Aza-bicyclo[2.2.1] -heptanes and -heptenes were evaluated for their ability to bind to the acetylcholine nicotinic receptor using a standard binding assay, e.g. X. Zhang and A. Nordberg, Arch.

Pharmacol., 348, 28 (1993); R. E. Middleton and J.

B. Cohen, Biochemistry, 30, 6987 (1991), with nicotine sulfate as the reference compound, rat cortex as the tissue substrate, and a 3

H]-NMCI

radioligand. The results are provided in Table 6.

WO 96/06093 WO 9606093PCTIUS95/10884 -119- TABLE 6 Structural Formula

C%

OAI

Testing Level 7

M

10-9 1011 10-7 10-9' 10-11 10-7 10-9 10-7 1 0- 7

M

10.8 10-9 1 0- 5

M

1 0-7 10-5 Inhibition *6 106 72 13 102 77 102 22 104 103 103 104 100 49 104 49 22 ~cr01 103 .9 71.3 103 24 81 R H R CH 3 'WO 96/06093 PCTIUS95/10884 -120- Example 95 Competition with Cytisine for Binding to Rat Cortex (Brain) Receptors [3H](-)-Cytisine is a nicotinic cholinergic receptor ligand that binds with high affinity to the a4b2 subtype receptor, the major subtype in rodent brain accounting for >90% of (-)-nicotine binding sites (Flores, et al., 1992; Whiting, et al., 1992). This nicotinic receptor subtype is most sensitive to (-)-nicotine compared to other receptor subtypes (Connolly, et al., 1992).

Compounds that compete with cytisine for the nicotinic cholineric receptor are considered nicotine receptor agonists.

A membrane fraction from rat brain cortex (Harlan Laboratories) was prepared using an adaptation of an established method (Pabreza, et al., 1991). Compound and 3 H]-(-)-cytisine (New England Nuclear, 42 Ci/mmol) were mixed before addition of membrane (0.5 mg protein) and incubated in glass tubes for 75 minutes on ice; total assay volume was 0.24 ml. Parallel assays to determine nonspecific binding were incubated in the presence of 10 uM (-)-nicotine (Sigma). Bound radioactivity was isolated by vacuum filtration onto glass microfiber filters (Whatman, GF-B) using millipore tubs, followed by 3x4 ml buffer wash. Filters were prerinsed with 0.5% polyethyleneimine prior to sample filtration to reduce nonspecific binding.

Bound radioactivity was quantitated by scintillation.counting.

Tables 7 and 8 provide the nicotine receptor

IC

50 in nanomolar concentration for selected compounds.

WNO 96/06093 PCT/US95/10884 -121- Table 7 Nicotine Receptor Cytisime Structure IC. (nM)

CH

3 Tail-Flick Assay ED30 Ef fect After 5 and 60 min.

-(mg/kcr) 32,000 150 -2.9 -3.6 6.7 24.6 0"IyCH3

N-N

WO 96/06093 PCTIUS95/10884 -122- Table 8 Tail-Flick Nicotine Receptor Assay ED, Structure IC (nM) (ma/ka)

CH

N 100 0.230 CH3 7 N630 >2,000

C,

3 N24 -1,000 77

-N

4 1 7 >2,000 *WO 96/06093 PCTIUS95/10884 -123- Example 96 Tail-Flick Assay in Mice and Rats Female CD-1 mice (20-25 g, Charles River Labs) and male CD rats (300-400 g, Charles River Labs) were housed in groups of two and five, respectively. Animals were given food and water ad libitum. Most studies were performed using groups of 5 animals per treatment unless otherwise noted.

Antinociceptive effects analgesia) of test compounds in mice and rats were measured by the tail-flick test using a tail-flick analgesia meter (EMDIE Instrument A maximum latency of sec was imposed if no response occurred within that time. Antinociceptive activity, measured as MPE, was calculated as [(test- control)/(10 control) x 100)].

Duration of compound and (-)-nicotine-induced antinociception was assessed in mice by measuring antinociception at 2, 5, 10, 20 min after compound gg/kg, or nicotine (5 mg/kg, Mice (7/group) or rats were pretreated i.v.

saline or antagonist, mecamylamine, hexamethonium, atropine, naloxone or yohimbine) minutes before administration of compound or nicotine at different doses. A control response (1.5-4 sec) was determined for each animal before treatment and test latencies were assessed at minutes after compound administration (5 ml/kg, or 2 min after nicotine (5 ml/kg, Tables 6, 7, 8 and 9 provide the tail-flick data for selected compounds.

WO 96/06093 WO 9606093PCT1UJS95/10884 -124- Table 9 rat brain, 3 H-cytisine binding

IC

50 (nM) tail-flick

ED

50 (mg/kg, S.C. rat mouse additional visible pharrnacol.

effects Compound rat mouse racemic 100 2.2 0.2 nic. musc.

A 1400 <0.1 MUSC.

,B >1.0 musc.

nic.

MUSC.

nicotinic agonist-like effects including sedation, tremors and cardiovascular effects muscarinic agonist-like effects including sedation and salivation OMI Sa0 j 0-N isomer CMI 981

-N

-)isomer WO 96/06093 PCT/US95/10884 -125- VI. Identification and Use of Nicotinic and Muscarinic Agonists and Antagonists Methods for the determination of the specific cholinergic receptor activity profile for a selected compound is easily determined using known assays. For example, to determine which type or types of acetylcholinergic receptors a compound is interacting with, in vitro competitive binding assays can be performed using specific radioligands. A compound's ability to compete with a specific radioligand for receptor binding indicates an affinity for that receptor type.

Radiolabelled nicotine (or cytisine) and quinuclidinyl benzilate are commonly used for nicotine and muscarinic receptor types, respectively. However, whether or not the compound is an agonist or antagonist is typically not determined by these assays.

To differentiate between agonists or antagonists, cell, tissue or animal-based in vitro or in vivo assays are typically employed. For nicotinic receptor ligands, one assay involves treating an animal with compound, then measuring a pharmacological activity associated with nicotinic receptor agonism, such tail-flick analgesia. If compound treatment resulted in analgesic activity, the compound is considered a nicotinic agonist.

The compound's agonist activity should also be blocked by known nicotinic receptor antagonists.

A

similar protocol can be utilized if a cell-based assay, such as release of dopamine from striatal synaptosomes, is used.

If there is no nicotinic agonist activity, e.g. analgesia, in this example, after compound treatment, an effective dose of a known nicotinic agonist (such as nicotine) is subsequently given to WO 96/06093 PCTIUS95/10884 -126the compound-treated animal. If the compound is an antagonist with the ability to block the effects of a known agonist, then the resulting analgesic activity would be less than that expected for the given dose of agonist.

Muscarinic agonists/antagonists can be characterized using appropriate muscarinic receptor-mediated in vitro and in vivo assays.

Pharmacologic approaches can include, for example, include receptor-mediated mobilization of Ca 2 in cultured cells, depolarization of the rate superior cervical ganglion, or contraction of the longitudinal muscle myenteric-plexus preparation of the guinea pig.

Compounds which act as nicotinic receptor agonists are useful in the treatment of cognitive neurological and mental disorders, including Parkinson's disease, Tourette's Syndrome, Alzheimer's disease, attention deficit disorder, dementia, multi-infart dementia, vascular dementia, cognitive impairment due to organic brain disease including due to alcoholism and brain diseases, general problems with information processing, deficient regional cerebral blood flow and cerebral glucose utilization, psychiatric disorders schizophrenia and depression), as well as other conditions such as analgesia, ulcerative colitis, aphthous ulcer, cessation of smoking, body weight loss and treatment of the symptoms of anxiety and frustration associated with withdrawal from other addictive substances, such as, cocaine, diazepam or alcohol. Nicotinic receptor agonists can also be used for veterinary purposes, including as respiratory stimulants, ectoparasiticides, and anthelmitics.

Compounds which act as nicotinic receptor antagonists are useful as ganglion-blocking agents, WO 96/06093 PCT/US95/10884 -127in the control of blood pressure in hypertension, in autonomic hyperreflexia regulation, in the control of hypotension during surgery and in the reduction of bleeding during operations. These compounds can also be used as stabilizing neuromuscular blocking agents which are extensively used as adjuvants in anesthesia for the relaxation of skeletal muscles, treatment for severe muscle spasms and ventilatory failure from various causes such as obstructive airway disorders. In addition, nicotinic receptor antagonists are useful as depolarizing-neuromuscular blocking agents, for example, as skeletal muscle relaxants in endotracheal intubation or psychiatric electroshock therapy to prevent muscle and bone damage.

Nicotine antagonists are also useful in blocking both the secretagogue and mitogenic effects of nicotine on cancer cells such as human small cell lung carcinoma. Finally, nicotine antagonists can be used as antidotes for curare/nicotine poisoning.

Muscarinic receptor agonists are widely used for ophthalmic purposes, for example, in the treatment of glaucoma to reduce intraocular pressure, applied alone or in combination with 0-adrenergic blocking drugs or sympathomimetic agents, or for the treatment of accomodative esotropia. These agonists are also useful for one or more of the following indications: breaking adhesions between the iris and the lens; for the treatment of various disorders involving the depression of smooth muscle activity without obstruction (postoperative atony, congenital megacolon); in stimulating smooth muscle activity in the urinary and gastrointestinal tract; in reflux esophagitis, in the treatment of postoperative atonia of the stomach or bowel; for gastric retention following bilateral vagotomy; for WO 96/06093 PCT/US95/10884 -128congenital megacolon and combating esophageal reflux; in the treatment of urinary retention and inadequate emptying of the bladder postoperatively or post partum; and in the treatment of memory disorders and cognitive functions of Alzheimer's patients. The efficacy and side-effects of muscarinic receptors may be improved by optimizing their differential activity on various muscarinic receptor subtypes, M1 vs. M2/M3 receptors, as described by Showell, et al., Medicinal Chemical Research, 1993, 3:171-177.

Muscarinic receptor antagonists (antimuscarinic agents) are widely used in ophthalmology to produce mydriasis and/or cycloplegia. Selective M1 receptor antagonists are effective in treating peptic ulcer disease, and in the inhibition of gastric acid secretion.

Antimuscarinic agents are also useful in treating increased tone or motility of the gastrointestinal tract, such as diarrheas, and in combating biliary and renal colics frequently in combination with an analgesic drug. Antimuscarinic agents, including quaternary ammonium compounds, are useful in treating obstructive pulmonary diseases such as chronic bronchitis or bronchial asthma.

Cardioselective antimuscarinic agents are useful in treating symptomatic sinus bradycardia, in acute myocardial infarction, higher degree heart block and certain types of ventricular arrhythmias.

Muscarinic receptor antagonists are also used in preoperative medication to counteract the vegal effects, to reduce excessive bronchial secretion, and to produce some sedation and amnesia.

Centrally acting antimuscarinic agents are useful in the treatment of Parkinson's disease, by restoring the normal balance of cholinergic and dopaminergic neurotransmission in the basal WO 96/06093 PCTIUS95/10884 -129ganglia, in the prevention of motion sickness, as a sedative, to relieve the symptoms of myasthenia gravis, in the antagonism of skeletal muscle relaxant effects of neuromuscular blocking agents, and in the treatment of poisoning by cholinesterase inhibitors such as those used in insecticides and chemical warfare. Such compounds are also useful to counteract anaesthesia effects, and in mushroom poisoning.

The clinical efficacy and safety of muscarinic receptor antagonists can be optimized by adjusting tissue selectivity, receptor subtype specificity and a balance of antagonism and agonism vs.

different receptor subtypes, as well as by selective local (topical, aerosol, eye drop) or systemic administration of the drug.

Claims (27)

1. An 7-azabicyclo[2.2.llheptane compound of the formula: wherein: 0 R 3 R and R 6 are independently hydrogen; alkyl; hydroxy; hydroxyalkyl; alkyloxyalkyl; alkyl thioalkyl; aminoalkyl; alkylarninoalkyl; dialkylaminoalkyl; alkyloxy; alkylthio; halo; haloalkyl; -NH 2 alkylamino; dialkylamino; cyclic dialkylamino; amidine, cyclic amidine and their N-alkyl derivatives; -CO 2 H; -CO 2 alkyl; -CN; -C(O)NH 2 -C (0)NH (alkyl) -C N(alkyl) 2 allyl; -S0 2 (alkyl) -SO 2 aryl; -S (0)alkyl; -S (0)aryl; heteroaryl selected from the group consisting of isothiazolyl, benzofuranyl, indojlyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazo.yl, 1,2, 5-thiadiazolyl, isooxazolyl, pyrrolyl, pyrazolyl, quinazolinyl, cinnolinyl, phthalaz-lnyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl; 300 -NHC (0)alkyl; or R 5 and R 6 together are selected from the group consisting of alkylidene or haloalkylidene, episulfide imino (-N(alkyl)- or and a fused heteroaryl ring; R 2 is hydrogen, alkyl, alkenyl, hydroxyalkyl, alkyloxyalkyl, aminoalkyl, carboxylate, C alkyl, C(0)Oaryl, C(0)Oheteroaryl, C(0)Oaralkyl, -CN, -NHC(0)R 12 -CH 2 NHC(0)R 1 2 Q' -alkyl(Q), -alkenyl(Q), -alkynyl(Q),-0-(Q), -NH-Q, or -N(alkyl)-Q; R 2 and R3 together can be -C -N -C or -CH (OH) -N wherein Ra can be alkyl, aryl, or heteroaryl; R 7 is hydrogen, alkyl, alkyl substituted with one or more halogens, cycloalkylmethyl, -CH 2 CH=CH 2 -CH 2 CH 2 (CgHs), hydroxyalkyl, (alkyl) 2 aminoalkyl, alkyloxyalkyl, alkylthioalkyl, aryl, 4-methoxybenzyl, and dialkyl to form a quaternary ammnonium moiety; R 1 2 is alkyl, aryl, alkaryl, aralkyl, heteroaryl, alkenyl, alkynyl, or heteroaralkyl; Q is selected from the group consisting of: N C a. a a a Wa. *a a. a a a a a a a. a a a. a a H3C N CH P'J~TPTO CH 3 N c N Cl N C: N CH 3 H 3 C N CI Br OH 2 N OH3 tW3 1 AMENDED SE PCTiUS 95/10884 I Rec'd PCT/PTO P~ J AN 1997 N H 3 C N -00o N N -C60 -i§0 N N N N N-N 2 N 0 <S <0 -0 N N 335633 1 PCTIUS 95/1084 Rec'd PCT/PTO C JAN 1997 N N N 1' N 0 K N N N--N N N NN 0 N 0 N 0 N N N-j/ 0 /C N 0) N-N S -t/ S N 7KNr N-N 0 N N--N-0 0 H-N S N (N N N 0 0 N 0 H C) K) 0 N/ S 000 N N H 335633 WOSRe'd PCTPTO 23JAN 1997 H N 1/ K> N N 'N N I 'N 0 N 0 335633 1 AMENDED SHEET S 5 *O 5* 0. 5 5*0 S S S S 5555 5 S S S Se 5 SW *55 555 55 0. 06% S 555 Z\ z 0 z /4Z z 0 z m -S 4) 5 0 /E2 Z\/H IPCTIUS 95/1O884 ReC'd P CT/PTO 0 C'o" JAN A 19 9 H N NN H N CN I-N N-N H N J 0N N N-/ 2 0) N-N N N H N 0 0> H-N z S N I 0 1 N rN N N 1NkN- 335633 1OB~CTP70 J AN ~9 N H 0 -s N N 0S H N N N N N N N 33S633 1 Or 139 wherein Q or Q1 can each be optionally substituted by 1 to 3 W substituents; and wherein W is alkyl, halo, aryl, heteroaryl, -OH, alkyloxy, -SH, alkylthio, -SO(alkyl), -SO 2 alkyl, -OCH 2 CH=CH 2 -OCH 2 (CsH 5 CF 3 -CN, alkylenedioxy, -CO 2 H, -CO 2 alkcyl, -OCH 2 CH 2 OH, -NO 2 -NH 2 -NH (alkyl) -N (alkyl) 2 -NHC (0)alkyl, -SO 2 CF 3 and -NHCH 2 aryl; provided that when R 2 and R are H, R 7 is H, alkyl, cycloalkylmethyl, alkyl substituted with one or more halogens, -CH 2 CH=CH, or hydroxyalkyl, and one of R 3 and R 6 is H, then the other of R 3 and R 6 is not H, C 3 -CS cycloalkyl, or 6-chloro-3-pyridyl; when R 7 is H or methyl and R 2 and R 3 are both H, then R 5 and R 6 are not both -CO 2 H or -CO 2 Me; when R 7 is H or methyl and R 5 and R 6 are both H, then R 2 and R 3 are 'not both -CO 2 Me; and when R 2 R 3 and R 7 are H, R 5 is not -OH.

2. The compound according to claim 1, wherein R 3 R 5 and R: 6 are independently hydrogen, -CH 3 -CH 2 OH, -CH 2 OCH 3 -CH 2 SCH 3 -CH 2 NH 2 -CH 2 NH (CH 3 CH 2 N (CH 3 2 -OCH 3 -SCH 3 Cl, 20 F, CF 3 NH 2 -N(CH 3 2 and -NHCH 3 *H 0 *ak -N P-c1N 3 5 -C2H C\CHJCP)H, CN C(H2CH2, CH(H3 -S0

3. The compound of claim, 1, wherein R 7 is hydrogen, -CH,, -CH 2 CH 3 -CH 2 CH 2 Cl, cyclopropylmethyl, -CH 2 CH 2 OH, -CH 2 CH 2 N (CH 3 2 and dialkyl. to form a quarternary amnmonium or is selected from the group consisting of: aryi; N-(R 0 11 -C-alkyl; N-(R 9 O--(alkyl); N-(RO) N-(RO) 11 11 -C-NHY H; z II -(CHO)( 1 -PR 1 R 1 1 -(CH 2 )NL{RJ 2 z II /lower alkyl z 0 -(CH 2 0)o 0 -S-R 1 0 11 0 04 S S S a S a. a. S. S @9 a *r* a 9 a 5* a S S S S. S S Se a a a @SSaS. S .5 a a a 0 11 -CI-I 2 OCC(CH,,) 3 0 11 CH 2 OC-aryl 0 I' -CH- 2 tOC-ftlkyl wherein R 9 is hydrogen or alkyl; wherein Y is CN, NO 2 alkyl, OH, -0-alkyl; wherein Z is 0 or S; and 141 PCT/IUS 95/10884 1 T f ,'7dCPTO 3 AN 997 wherein R'i and R" 1 are each independently -OH, -O-alkyl, -O-aryl, -NH 2 -NH(alkyl), -N(alkyl) 2 -NH(aryl), or -N(aryl) 2

4. The compound of claim 1, wherein R 7 is selected from the group consisting of methyl, allyl, cyclopropylmethyl, cyclobutylmethyl, phenethyl, hydroxyethyl, methoxyethyl, methylthioethyl, dimethylaminopropyl, and (4- methoxybenzyl). A method for treating a disorder in a mammal characterized by an increase or decrease in cholinergic function, comprising administering an effective amount of the compound of claim 1.

6. The method of claim 5, wherein the compound is administered in an amount ranging between 0.002 and 10 mg/kg per day.

7. The method of claim 5, wherein the compound is administered in an amount ranging between 0.02 and 0.2 mg/kg per day. 8 The method of claim 5, wherein the compound is applied topically in a dosage ranging between 0.001% and 0.5% wt/wt in a carrier suitable for topical administration.

9. The method of claim 5, wherein the compound is administered by intravenous injection. The method of claim 5, wherein the compound is administered orally.

11. The method of claim 5, wherein the compound is administered topically.

12. The method of claim 5. wherein the mammal is a human. IAMEED SHEET AMENDED SHEET 142

13. A method for the treatment of an inflammatory condition in a mammal, comprising administering to a mammal an effective amount of the compound of claim 1.

14. The method of claim 12, wherein the compound is administered in an amount ranging between 0.002 and mg/kg per day. A method for imparting analgesia in a mammal, comprising administering to a mammal an effective amount of the compound of claim 1.

16. A pharmaceutical composition comprising an effective amount to treat a disease characterized by an increase or decrease in cholinergic activity in a mammal of the compound of claim 1 or its pharmaceutically acceptable salt, in a pharmaceutically acceptable carrier or diluent.

17. The composition of claim 16, wherein the mammal is human.

18. The compound of claim 1, wherein R 7 is H or CH 3 and wherein R 2 is selected from the group consisting of endo- or exo- N\N C1 H3ICNN

19. The compound of claim 1, wherein R 7 is H or CH3, and wherein R 2 is selected from the group consisting of endo- or exo- O-N N CH3 S The compound of claim 1, wherein R 7 is H or CH 3 and wherein R 2 is selected from the group consisting of endo- and exo- §-PCTUS 95/10884 1 D8Ree'dPCTTO C3%, J AN 1q 91

21. The compound of claim 1, wherein Q is C1 N N.. 0 N N Q' I i lot edPCTIPTQ C, 0 JAN 19V N N O N.r 0 I- 0 0o 000 SN-H (0y N NN N -0 N N 0 N-N s y 73 0 N' s I I H H 0 S S N-N 335633 AMENDED SHEET U 1rI i A 1197 H s Ii c N H 0\ S O N 0 0 0 H .N1 N N 4aH CCN NN NON (X) N NN 0 33S633 1 AMENDED SHEET

22. The compound of claims 16, 17, or 18 that is at least free of the enantiomer.

23. The compound of claims 16, 17, or 18 that is at least free of the enantiomer.

24. The method of claim 5, wherein R 7 is H or CH 3 and wherein R 2 is selected from the group consisting of endo- or exo- N'CH H 2 C~-NN The method of claim 5, wherein R 7 is H or CH 3 and wherein R 2 is selected from the group consisting of endo- or exo- O--N S S S..2 S

26. The method of claim 5, wherein R 7 is H or CH 3 and wherein R 2 is selected from the group consisting of endo- and exo- N^s a

27. The method of claims 24, 25, or 26 that is at least free of the enantiomer.

28. The method of claims 24, 25, or 26 that is at least free of the enantiomer. 147

29. The method of claim 5, wherein said disorder involves inhibition or stimulation of the muscarinic cholinergic receptor. The method of claim 5, wherein said disorder involves inhibition or stimulation of the nicotinic cholinergic receptor.

31. An 7 -azabicyclo[2.2.1]heptane compound according to claim 1 wherein: R 3 R 5 and R 6 are independently hydrogen; alkyl; -CF 3 hydroxy; hydroxyalkyl; alkyloxyalkyl; alkylthioalkyl; aminoalkyl; alkylminoalkyl; dialkylaminoalkyl; alkyloxy; alkylthio; halo; haloalkyl; -NH 2 :alkylamino; dialkylamino; amidine, -CO 2 H; -CO 2 alkyl; -CN; -C(O)NH 2 -C(O)NH(alkyl); -C(O)N(alkyl) 2 allyl; -SO 2 (alkyl); -SO 2 aryl; -S(O)alkyl; -S(O)aryl and -NHC(O)alkyl, R 2 is 1,2,3-thiadiazolyl, 1,3,4-thiadiazoyl, 1,2,3-miazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, isoxazolyl,isothiazolyl, 1, 2 3 4 -oxatriazolyl, 1,2,3,5-oxatriazolyl, or tetrazolyl, 20 any of which R 2 groups is optionally substituted with a member of the group consisting of C 1 -6alkyl, halo, Ci- 6 -alkoxy, S* with a proviso that when the azabicyclo[2.2.1]heptane ring system is further substituted at the 1- or 4-position 25 by a methyl substituent, the term R 2 may represent pyridyl, thienyl, furyl and imidazolyl rings optionally substituted by halogen, OH, methoxy or methyl; with a further proviso that if the azabicyclo[2.2.1]heptane ring is further substituted at the 5 and 6 positions by CF 3 and at the 3 position by sulfonyl aryl, then the term R 2 may represent pyridyl, thienyl, furyl or imidazolyl rings optionally substituted by halogen, hydroxy, methoxy or methylthio substituents; R 7 is hydrogen, -CH 3 -CH 2 CH 3 -CH 2 CH 2 Cl, cyclopropyl, -CH 2 CH 2 OH, -CH=CH 2 -N(CH 3 2 C1- alkyl, C 1 -6 substituted 7 /N 5/with one or more halogens, cycloalkylmethyl, allyl, 148 hydroxy-C 1 6 alkyl, di (C 16 alkyl) amino, di (C 1 -6 alkyl) amino- C 1 -6 alkyl, CI- alkoxy-Cl. 6 alkyl,C 1 6 alkylthio-Cl 1 6 alkyl, methoxy aryl, -CH 2 CH 2 (C 6 H, 5 wherein W is alkyl, halo, aryl, -OH, alkyloxy, -SH, alkyithio, -SO(alkyl), -SO 2 alkyl, -OCH 2 CH=CH 2 -OCH 2 (CsH 5 CF 3 -CN, alkylenedioxy, -CO 2 H, -CO 2 alkyl, -OCH 2 CH 2 OH, -NO 2 -NH 2 -NH(alkyl), -N(alkyl) 2 -NHC(O)alkyl, -SO 2 CF 3 and -NHCH 2 aryl; or endo or exo stereoisomers thereof, optical isomers or racemates thereof, or a pharmaceutically acceptable salt thereof.

32. The compound-according to claim 3, wherein R 3 R 5 and Rare independently hydrogen, -CH 3 -CH 2 OH, -CH 2 OCH 3 -CH 2 SCH 3 -CH 2 NH 2 -CH 2 NH(CH 3 -CH 2 N(CH 3 2 -OCH3, -SCH 3 Cl, -CF 3 NH 2 -N(CH 3 2 -NHCH 3 -NHC(O)alkyl, -CO 2 H,- CO 2 CH, -C(O)CH 3 -CN, -C(O)NH 2 -C(O)N(CH 3 2 or -SO 2 (C 6 H 5

33. A compound of formula 9 9 9 9*9* 9 9 **99 9 9999 99 9 9 99 9 999 9 9* 99 99 9 9 9 9

999. 99 9* 9 9y 99*s 9999 that is at least 95% free of the enantiomer. 34. A compound of formula N 0-N N that is at least 95% free of the enantiomer. 35. A pharmaceutical composition comprising an effective amount to treat a disease characterised by an increase or decrease in cholinergic activity in a mammal of the compound according to claim 33 or 34 or their pharmaceutically acceptable salts, in a pharmaceutically acceptable carrier or diluent. V, 149 36. A method for treating a disorder in a mammal characterised by an increase or decrease in cholinergic function, comprising administering an effective amount of the compound of claim 33 or 34. 37. The method of claim 36, wherein the compound is administered in an amount ranging between 0.002 and mg/kg per day. 38. The method of claim 34, wherein the compound is administered in an amount ranging between 0.02 and 0.2 mg/kg per day. 39. The method of claim 34, wherein the compound is applied topically in a dosage ranging between 0.001% and wt/wt in a carrier suitable for topical administration. 40. The method of claim 34, wherein the compound is administered by intravenous injection. 41. The method of claim 34, wherein the compound is administered orally. 42. The method of claim 34, wherein the compound is 20 administered topically. 43. The method of claim 34, wherein the mammal is a human. 44. A method for the treatment of an inflammatory condition in a mammal, comprising administering to a 25 mammal an effective amount of the compound of claim 33 or S 34. 45. The method of claim 44, wherein the compound is administered in an amount ranging between 0.002 and mg/kg per day. 30 46. A method for imparting analgesia in a mammal, comprising administering to a mammal an effective amount of the compound of claim 33 or 34. 47. The method of claim 36, wherein said disorder involves inhibition or stimulation of the muscarinic cholinergic receptor. [l r W 150 48. The method of claim 36, wherein said disorder involves inhibition or stimulation of the nicotinic cholinergic receptor. DATED this 26th day of April 1999 UNIVERSITY OF VIRGINIA Patent Attorneys for the Applicant: F.B. RICE CO. a. a a. a 9 a. a a a a a a. a a a a. a a.. a. a a a a. a