AU695682B2 - 7-azabicyclo-(2.2.1)-heptane and -heptene derivatives as analgesics and anti-inflammatory agents - Google Patents

Description

NO 94/22868 PCT/US94/03573 7-AZABICYCLO-[2.2.1]-HEPTANE

AND

-HEPTENE DERIVATIVES AS ANALGESICS AND ANTI-INFLAMMATORY AGENTS 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 nec- 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 approximately 500 SUBSTITUTE SHEET I I WO 94/22868 PCT/US94/03573 2 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. Since epibatidine was isolated from the skins of the Ecuadoran poison frog, its identification and characterization was not based on the synthesis of the compound. In fact, compounds in the family of 7-azabicyclo[2.2.1]-heptanes and -heptenes (also referred to as 7-azanorbornane and 7-azanorbornenes, respectively) have historically been difficult to synthesize.

A possible entry into the 7-azabicyclo[2.2. 1] -heptane and -heptene ring systems involves the construction of the bicyclic ring through the 2 4 cycloaddition of appropriately substituted 3-vinyl pyridine and pyrrole fragments, as indicated below.

H H.

N N H ON

ON

Unfortunately, pyrrole and its derivatives readily undergo substitution reactions upon treatment with dienophiles (Diels, 0. and Alder, Ann. 1932 498, with only a few exceptions reported (Wittig, Angew Chem. 1957 69, 245). The partial aromatic character of pyrrole limits its SUBSTITUTE SHEET

,I

WO 94/22868 PCT/US94/03573 3 reactivity as a diene and Michael-type addition products usually dominate. (Jones, The Chemistry of Heterocyclic Compounds, v.48 Pyrroles Wiley Sons: New York. 1990.) Rate and yield enhancement of the Diels-Alder reaction between pyrroles and olefins have been obtained using Lewis acids (Donnini, Just, G. J. Heterocycl. Chem.

1977, 14, 1423; Bansal, McCulloch, A.W.;McInnes, A.G. Can. J. Chem. 1969, 47, 2391), and high pressures(Kotsuki, Mori, Y; Nishizawa, Masamitsu, Matsuoka, K. Heterocycles, 1982, 19, 1915; Drew, George, Isaacs, is Rzepa, H.S. T.C.S. Perkin Trans 1, 1985, 1277), but thus far these approaches have been limited in scope. The limitation in these reactions can often be traced to the inherent instability of the 7-azabicyclo[2-2.1]hept-2-ene products with respect to either retro-cycloaddition or retro-Mannich and re-aromatization pathways.

This is especially true for cases where the resulting olefin is functionalized by electron-withdrawing groups. (Altenbach, H.J.; constant, Martin, Mayer, Muller, M.; Vogel, E. Chem. Ber. 1991, 124, 791.) An alternative method for the synthesis of the 7-azanorbornane system was reported by Fraser, et al. (Can. J. Chem. 1970, 8, 2065) but the long synthetic route and drastic reaction conditions involved are unsuitable for the synthesis of epibatidine. For a review of 7-azanorbornene chemistry see: Kricka, Vernon, J.M. Adv. in Heterocycl. Chem. 1974, 16, 87.

N-Carboalkoxypyrrole has been used in Diels-Alder reactions with several acetylenic dienophiles to prepare norbornane derivatives.

None of these reported schemes, however, place an aromatic or heteroaromatic group in the important SUSTITUE SHEET

I

WO 94/22868 PCT/US94/03573 4 is 2-position of the heptane or heptene ring.

(Alcenbach, et al., Chem. Ber. 1991, 124, 791; Altenbach, et al., Angew. Chem. Int. Ed.

Engl. 1992 21(10), 778; Gabel, J. Org. Chem.

1962, 27, 301; Toube, T.P.(1992) in: Pyrroles, Part 2 (Jones, ed.) John Wiley, New York. pp 92-95.) In light of the analgesic potency of epibatidine as well as the strong need for new potent, non-opiate analgesics, it would be useful to provide methods for the synthesis of 7azabicyclo[2.2.1]-heptane and -heptene derivatives that have pharmacological activity, and in particular, analgesic activity, or that can be derivatized to compounds with pharmacological activity.

Therefore, it is an object of the present invention to provide new 7--azabicyclo[2.2.1]heptane and -heptene derivatives with analgesic .activity.

It is another object of the present invention to provide methods for the synthesis of 7-azabicyclo[2.2.1]-heptane and -heptene derivatives with analgesic activity.

It is still another object of the present invention to provide new methods for the treatment of pain.

SUBSTITUTE

SHEET

WO 94/22868 WO 9422868PCTIUS94/03573 SUMMARY OF THE INVENTION 7-Azabicyclo [12.2 -heptane anid -heptene compounds are disclosed of Formula R7

RR

wherein R' and R 4 neednl hdoeakl incldingCH 3 ;alklhydoxyincldin C 2

O

alkyloxyalkyl,~~~~~ inldn1C 2 C 3 lytiakl whrin: n R r ndpnetl yrgeak including -CH 3 alkylhydroxy, including CH 2

H;

alkyloxyalkyl, including -CH 2

OCH

3 alkylthioalkyl, including -CII 2

SCH

3 alkylamino, including -CH 2

NH

2 alkylaminoalkyl or alkylaminodialkyl, including 2 NH (C 3 and CHIN (C 3 2 oxyalkyl, including -OC 3 athioalkyl, including -SChlicldn

CF

alkyoalkyl, including F 3 Nil 2 alkylinoalr SUBSTITUTE SHEET WO 94/22868 WO 9422868PCT/tIS94/03 573 6 dialkylamino, including -N(CH- 3 and -NHCH- 3 Cyclic dialkylarnino, including -N N-CH 3 -N -H 2

CH

2

OH

amidine, cyclic amidine including

NN

and their N-alkyl derivatives; H 0-N- I 11 -N-alkyl 0 0

-CO

2 H; CO 2 alkyl, including -CO 2

CH

3 -C(O)alkyl, including -C(O)CH 3 -CN, -C(O)NH 2 -C(O)NH(alkyl), -C(O)N(alkyl) 2 including -C(O)NCCH 3 2 allyl, -S0 2 (alkyl), -SO,,aryl, including -S0 2

(C

6

H

5 -S(O)alkyl, -S(O)aryl, aryl, heteroaryl; or

W.

-So 2 SUBSTITUTE SHEET WO 94/22868 WO 9422868PCT/(JS94/03573 7 R, and R 6 together can be alkylidene or haloalkylidene, including and epoxide episulfide imino (-N(alkyl)- or or a fused aryl or heteroaryl ring including a fused phenyl ring;

R

2 is independently hydrogen, alkyl, including

CH

3 alkenyl including -CH 2

-HC=C

2 alkyihydroxy, including -CH 2 -OH; alkyloxyalkyl including -CH 2 -0- (alkyl) alkylamine, including -CH,NH 2 carboxylate, CCO)Oalkyl, including CO 2 Me; C(0)Oaryl, C(0)Oheteroaryl, COOaralkyl, -CN, Q, C(0)Q, alkyl(Q), -alkenyl(Q), -alkynyl(Q), NH-Q or -N~alkyl)-Q;

R

2 and R 3 together can be -C -NR 8 or CH (OH) -N(RI) -C wherein R 8 can be alkyl, aryl including phenyl, or heteroaryl; R7, is hydrogen, alkyl, including CH 3 or CH 2

CH

3 alkyl substituted with one or more halogens, including CH 2

CH

2 Cl; -CU 2 (cycloalkyl) including

-CU

2 (cyclopropyl) -CH 2

CH=CH

2

CU

2

CH

2 (CA1),I alkylhydroxy, including CU 2

CH

2 0H, alkyl amino (alkyl) 2' including CH 2

CH

2 N (CH 3 2 alkyloxyalkyl, alkylthioalkyl, aryl, dialkyl to form a quarternary amnmonium including N48 9 N(CH3) 1

N-(R

9

N-(R

9

N-(R

9 -0-lky C-ayl C.-akl N( N-(R 9

N-(R

9 N-(RIf

II

-CNNR2 -C-NHY' -C..(alkyl)

H

N Nlower alkyl SUBSTITUTE SHEET WO 94/22868 7 PCT/IJS94/03573 or z

-(CH

2 0)0- 1 PP RI z -(H)R9 p-I (CH 2 )N 4 P- Rlo A" 11) 0

-"S-R

I,

0 0 11

-CH

2 0CC(CH 3 3 0 if

-CH

2 00- aryl 0 11

-CH

2 0-aky wherein R' is hydrogen or alkyl; wherein Y' is CN, NO 2 alkyl, OH-, -0-alkyl; wherein Z is 0 or S; wherein R1 0 and R 1 1 are each independently -0O, -OH, -O-aJlkyl, -0-aryl, -Nil 2 -NH(aJlkyl) -N(alky.) 2 -NH~aryl) and -N(aryl) 2 SUBSTITTE SHEET o is

"N

0~ *e a a a a a a a S a a a..

C~)

CON

S

CN

N1 12 and wherein the Qmoiety can be optionally sub ituted with 1 to 3 W substituents; and W is alkyl, including CH 3 halo, including C1 and F, aryl, heteroaryl, OH, oxyalkyl, including -OCH 3 SH; thioalkyl, including -SCH3; -SO(alkyl) including

-SOCH

3 -SOzalkyl, including -SO 2 CH3; -OCH 2

CH=CH

2 -OCH2(CoHs), CF., CN, alkylenedioxy, including -methylenedioxy-, -CO 2 H, -COzalkyl, including -COzCH,;

-OCH

2 CHzOH, -NO 2 -NHz, -NH(alkyl), including -NHCH3; -N(alkyl) 2 including

-N(CH

3 2 -NHC(O)alkyl, including -NHC(O)CH 3

-SO

2

CF

3 or -NHCH 2 aryl, including

-NHCH

2 (CoHs); and wherein the indicates an optional double bond, provided that when R 1

R

2

R

4 and R 5 are H, R 7 is H, alkyl, -CHz- (cycloalkyl), alkyl substituted with one or more halogens, -CH 2 CH=CH, or alkylhydroxy, and one of R 3 and R° is H, then the other of R 3 and R" is not aryl or heteroaryl; and further provided that when R 1

R

4 R' and R" are H and R 7 is H or methyl, R 2 and R 3 are not both -COzCH, and when R 1

R

2

R

3 and R 4 are H and R 7 is H or methyl, R 5 and R° are not both -CO 2

CH

3 These compounds have central and peripheral analgesic activity, and, or alternatively, anti-inflammatory activity, and thus can be administered to a 20 mammal, including a human, to treat pain and inflammatory disord-rs. 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.

Facile processes for the preparation of the disclosed 7-azabicycio[2.2.1] -heptane and -heptene derivatives are also provided. In one embodiment, the pharmaceutically active compounds, or their precursors, are prepared by the cycloaddition reaction of pentaammineosmium (II) complexes of pyrroles with dipoloraphiles, including 3-vinyl pyridine derivatives, In one embodiment, pharmaceutically active compounds or their precursors, are prepared by the Diels- Alder reaction of an N-(electron withcrawing-substituted) pyrrole with an WO 94/22868 PCT/US94/03573 13 arylsulfonyl(optionally substituted aryl, alkyl, heterocyclic or heteroaryllacetylene.

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.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions The term alkyl, as used herein, refers to a saturated straight, branched, or cyclic (or a cotnbination thereof) hydrocarbon of C, to Clo, 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 CI to C 6 saturated straight, branched, or cyclic (in the case of C 56 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.

SUBSTITUTE SHEET WO 94/22868 PCT/US94/03573 14 The term alkylanin, rs to an amino group that has an alkyl substitu.it.

The term alkynyl, as referred to herein, refers to a C 2 to CI 0 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 substituents.

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, car'.azolyl, oxazolyl, thiazoly., isothiazolyl, 1,2,5-thiadiazolyl, isooxazolyl, pyrrolyl, pyrazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, SUE*TrMyrE SHEET I -I iP~P bls~Ppl~-P---- WO 94/22868 I'CT/U1S94/0357? 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 application" 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 salt.

The term enantiomerically enriched composition or compound" refers to a composition or compound that includes at least 95% 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 dienrphile 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 3C pi-orbital complex of an unsaturated ,-ompound 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 SUBSTITUTE

SHEET

WO 94/22868 PCT/US94/03573 16 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 have central and peripheral analgesic and, or alternatively, anti-inflammatory activi and thus can be administered to a mammal, including a human, to treat pain and inflammation. A metiod for the treatment of pain is also presented that includes administering an effective amount of :he compound or its pharmaceutically acceptable ralt 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 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 cyc] -addition reaction of a dienophile with a SUBSTTUTE

SHEET

I_ WO 94/22868 PCTIUS94/03573 17 pyirole, 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 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[.2.1]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 carbon 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.

SUBSTIVrTE

SHEET

1. Bb r WO 94/22868 PCT/US94/03573 18 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 diastereomeric salts that may possess significantly different solubility properties. Nonlimiting examples of chiral acids include malic acid, mandelic acid, dibenzoyl tartaric aciC 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.

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-chloro- SUBSTrIUTE SHEET -I L~CI~~ WO 94/22868 WO 9422868PCT/IS94/03 573 19 bicycloll2.2.l]1 heptane ind its pharmaceutically acceptable salts, including the hydrochloride salts; d arnd 12 enantiomers of the 7-aza-bicyclo[2.2.lilheptane 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, 7forrnamidinyl, 7- (2-chloroethyl), 7-disodium phosphate and 7- (4-methoxybeizyl) substituents with a 2-exo- (2-chloro-5-pyridyl) substituent; 2-exo- (3-pyridyl); 2-ezndo- (3-pyridyl); 7-methyl-2-exo- (3-pyridyl); 7-cyclopropylmethyl-2-exo- (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-exo- (2-methoxy-S-pyridyl); 2-exo- (2-methylthio- 2-exo- 2-exo- (2-dimethylamino-5-pyridyl); 2-exo- (2and 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-f luorophenyl); 2- (4-hydroxyphenyl); 2- (4-methylthiophenyl); SUBSTITUTE SHEET WO 94/22868 WO 9422868PCT/tIS9.4/03573 2-(4-methylsulfonylphenyl) 2-(3,5difluorophenyl); 2- (2-chiorophenyl); 2- (2-naphthyl); 2- (7-rethoxy-2-naphthyl); 2-(5-chloro-2-thienyl); 2- 2-(4-pyrimidyl) 2-C2-chloro-5-pyrimidyl); chloro-2-pyridazinyl); 2-(1,2,5-thiadiazol-3-yl); 2- (5-dimethylamino-2-furyl); 2-(5-fluoro-3-indolyl); 2- (5-methoxy-3-indolyl); 2- (4-chlorobenzyl); 2- (5-chloro-3-pyridylmethyl); 2-(4-pyridylmethyl); 2-nicotinyl; 2-(6chioronicotinyl); 2- isonicotinyl; 2- (3-chloro-isonicotinyl) 2 (4-chlorobenzoyl); 2-(4-dirnethylaminobenzoyl); ;-34 dimethoxybenzoyl) 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; l,4-bis(hydroxymethyl); 1,4-bis(methoxymethyl); 1,6 or 4,5 -butylidene; Endo or exo-3-methyl; 3 -hydroxymethyl; 3 -methoxymethyl; 3 -carbornethoxy; 3-carboxy; 3-carbamyl; 3-cyano; 3-acetyl; 3- aminomethyl; 3- dirnethylaminomethyl; 3 -methylthiomethyl; 3 -phenylsulfonyl; 3-methanesulfonyl; 3-benzy2; 3-allyl; 3-cyano- 1, 4-dimethyl; 3-hydroxymethyl-1,4-dimethyl, 3-methoxymethyl-1, 4-dimethyl; 3-methylthiomethyl-1,4-dimethyl; 5,6bis(trifluoromethyl); 5 or 6-methoxy; 5 or 6-methyl; 5, 6-dimethyl; 5, 6-dicarbomethoxy; SUBSTITUTE SHEET WO 94/22868 WO 9422868PCTIUS94IO3 573 21 5,6-bis(hydroxrmethyl); 5,6-bis(rnethoxymethyl) or 6-chloro; 5 or 6-hydroxy; 5,6-dehydro; 5,G-dehydro-l,4-dimethyl; 3,3-dimethyl; 2-methyl; 2, 3-dimethyl, 5, 6-methylene; and their corresponding 7-methyl, 7cyclopropylmethyl, 7-allyl, 7-phenethy. and 7- (4-f luorobenzyl) derivatives.

7-Aza-2- (2-chloro-5-pyridyl) bicyclo[2.2.l)hept-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,Galepibatidine and its N-methyl derivative; 2, 3-dehydroepibatidine; 5,6bis (trifluoromethyl) deschloroepibatidine; 2carbomethoxy-7-methyl-7-azabicyclo [2.2 .13heptane; 2-cyano-7-methyl-7-azabicyclo[2.2.llheptane; trans- 2,3-bis-carbomethoxy-7-azabicyclof2.2.l] heptane; exo-2-amino-7-methyl-7-azabicyclo[2.2.l] heptane; exo-2- (1-pyrrolylmethyl) -7-methyl-7-azabicyclo [2.2.11 heptane; exo-2-hydroxymethyl-7-methyl-7azabicyclo [2.2 .1)heptane; exo-2-hydroxymethyl-7methyl-2-azabicyclo [2.2 .1]heptane.

111. Methods for the Synthesis of optionally Substituted 7-Azabicyclo [2.2.13 -heptanes and -heptenes A. SYNTHESIS OF THE 7-AZABICYCLO(2.2.1J-HEPTANE OR -HEPTENE RING SYSTEM FROM PYRROLES VIA PENTAAMMINEOSMIUM (II) COMPLEXES It has been discovered that 7-azabicyclo [2 .2 .13-heptane and -heptene derivatives can be prepared by combining a dipolarophile with an optionally substituted SUBSTITUTE SHEET WO 94/22868 PCT/US94/03573 22 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-azabicyclol2.2.1 heptane. Examples of dipolarophiles include compounds of the is structure z 1

-C=C-Z

2 wherein Z, and Z 2 are independently electron withdrawing groups, including without limitation, esters, nitriles, ketones, aldehydes, amides, -NO, sulfones, anhydrides, -CF 3 pyridinium salts, and for example, CO(alkyl, aryl or heteroaryl), C(0)H, C0 2 (alkyl, aryl, or heteroaryl), 50 2 (alkyl, aryl, or heteroaryl), or wherein Z, and Z 2 are together

(CO),

2 0, or Specific compounds include N-methylated and 6-carboxylated pyridyl acrylates, alkyl acrylate, alkyl methacrylate, pyridyl substituted vinyl sulfones, acrylonitriles, anhydrides, maleimides, alpha-methylene-6-butyrolactone, 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 include 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 -base pentaammineosmium(II) in which the osmium coordinates the heterocycle across C2 and C3. At 200C, this species is in equilibrium with SUBSTITUTE SHEET

I~

WO 94/22868 PCT/US94/03573 23 its linkage isomer in which the metal binds across C3 and C4. Although the 3,4-7 species is only a minor component (AG 0 kcal/mol), the metal coordination in this species renders the remaining portion of the pyrrole an azomethine ylide

(R

2 2

C=N+(R)-C-R

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

N R 3 Os(NH 3 5 (OTf) 2 2 .N R R N R/ Mg°, DMAC; 0.5 h. RJ 3 4 s()

NR,

RA

3 z2 Z Z 2 R2 Z1 Scheme 1. Dipolar cycloaddition of -pyrrole complex with dipolarophile.

Os(II) [Os(NH 3 (OTf),.

The resulting 7-azabicyclo[2.2.1]hept-5-ene ligand is unstable with respect to cycloreversion, but metal coordination greatly stabilizes the complex 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 SUBSTITUTE SHEET WO 94/22868 W'O 9422868 CTIUS94/03573 24 the corresponding alcohol and oxidatively decomplexed to yield the relatively inaccessible 5-hydroxymethyl-7-azanorbornene 3. NH H 1. OS(N~i3)5(OTf) 3 Mg 0

CH

HH N MC; 0.5 h.O C0 2

CH

3 C~2.J~ CH 2

CH-CO

2

CH

3 .5

OH

3 87%

NH

1. Li-9BBNH/THF, 0.5 h \\CH 3 2. Ce(N0 3 6 (NH1 4 2 /HOTf C H 2 0H

CH

3 71% overall Scheme 2. Synthesis of a 7-azanorbornene (Os (11) (Os(NH 3 5 (Otf) 2 DMAc N,Ndime thylac etanide; 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.

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.

SUBSTITUTE SHEET WO 94/22868 PCT/US94/03573 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.

NCH3

NCH

3 Os(II) Os(ll)

CO

2

CH

3 0 C0 2

CH

3 O -oTf

NO

CH3

CO

2

CH

2

CH

3 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 example of this method is shown in Scheme 3 below for the synthesis of the 1,4-dimethyl-exocarbomethoxy-norchloroepibatidine 7.

SUBSTITUTE

SHEET

I WO 94/22868 PCT/US94/03573 26

H,

N H,

H

(osN N (0s 2. oN N 1. HOW Q01 o

H

2 2

N

COOMe 2. Ce(V) N coom" cC()OOM Pd/c Co Scheme 3. Decomplexation and hydrogenation to generate a 7-azanorbornane.

=[Os (NHE3)s] (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

SO

3

PF

6 and (alkyl or aryl)SO3".

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.

In a preferred embodiment, activated magnesium powder is used.

SUBSTITUTE

SHEET

c WO 94/22868 PCT/US94/03573 27 The optionally substituted pyrrole, pentaammineosmium(III), and reducing agent are stirred at a temperature ranging between 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[2.2.1]hept-5-ene. Any molar ratio of 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 using the Barton decarboxylation procedure. High temperatures and strong bases should be avoided in SUBSTITUTE SHEET I WO 94/22868 PCTIUS94/03573 28 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]hept-5-ene 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(N0 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 of 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 SUBSTITUTE SHEET WO 94/22863 WO 9422863rcr/IiS94/03 573 Table 1 7-azabicyclo[2.2. I] heptae 7-azabicyr.lo[2.2. 1]hept-5-ene

R,

H

H

H

H

H

H

H

CBz Cbz

H

R

2 exo-CH 2

OH

exo-CH 2

OH

3 exo-CH 2

OH

exo-CO 2

CH

3 eXO-CO 2

CH

3 exo-S0 2 Ph endo-SO 2 Ph exo-CH 2

OH

exo-CH 2

OH

exo-OCBz exo-CH 2

OH

R3

H

Hno3p endo-3-py exo-3-py endo-3-py e&o-3-py

H

H

H

endo-3-py SUBSTITUTE SHEET 94/22868 dO 942868PTIVS94IO3573 Table 2 Example 1s 16 16 17 18 18 19 21 22 23 24

R,

3

CH

3

C'.

3

CH

3

H

H

H

Et

H

CH

3

CH

3

CH

3

CH

3

R

2

R

exo- COOMe en do- COOMe exo- C-N en do- C-N exo- COOMe exo- -N(Ph) exo- -C -N (Ph) CG) exo- exo CH 2

NH

2 exo- CH 2

NC

4

H

4 exo CH 2 0H exo -CH 2 00CPh

R

3

H

H

H

H

endo- COOMe

H

H

H

H

SUBSTITUTE

SHEET

WO 94/22868 PCT/US94/03573 31 Methods for preparing compounds of Formula (I) vie. derivatization of a 5,6-n 2 -7 aza-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]hept-5-ene (8) A solution of the 5,6-i2 osmium complex of compound 8 (727 mg, 1.0 mmcl) 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, Rr 'H NMR (300 MHz, CDCl 3 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); 3 C NMR (75 MHz, CDC1 3 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 COsH 18

N

4 0g: C, 47.12; H, 4.75; N, 14.65. Found: C, 46.96; H, 4.52; N, 14.66.

SUBSTITUTE

SHEET

WO 94/22868 PCTIUS94/03573 32 Example 2 Preparation of N-CBZ-1,4-Dimethyl-2exo-(hydroxymethyl)-7azabicyclo[2.2.1]hept-5-ene and N,O-Bis-CBZ-1,4-Dimethyl-2-exo- (hydroxymethyl)-7azabicyclo[2.2.11hept-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 (R r 0.5 and 0.1, respectively) For 9: 'H NMR(300 MHz, CDC1 3 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, CH3), 1.7 overlap, 1H), 1.55 2H); 'C NMR MHz, CDC13) d 155.2 140.5 (CH, L5 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 (CH 2 45.6 37.7 (CH 2 19.4 (CH 3 16.8 (CH 3 For 10: 'H NMR(300 MHz, CDC1 3 d 7.37 5H, Phenyl), 7.32 Phenyl), 6.07 (ABq, J 5.5 Hz, 2H, H5 and H6), 5.16 2H, OCH 2 Ph), 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 0CBZ) 1.94 1H, H2), 1.79 3H, CH 3 1.75 3H, CH3), 1.60 (dd, J 11.4, 9 Hz, 1H, H3o), 1.4 (dd, J 11.4, 3.6 Hz, H3,) 3 C NMR MHz, CDC1 3 d 155.0 154.9 140.5 (CH, SUBSTITUTE SHEET WO 94/22868 WO 9422868PCT/US94/03573 33 or C6), 140.5 (CH, C6 or C5), 136.4 ipso), 135.2 ipso), 128.5 (overlap of 2 X CH), 128.4 128.3 128.0 127.8 70.8 69.6 (o~erlap of 2X CR 2 68.9 6 6. 3 (CH 2

O),

43.2 (CR, C5), 38.7 2H 2 C6), 19.3 (CR 3 17.0

(CR

3 Example 3 Preparation of 1,4-Dimethyl-2-endo- -pyridyl) -3-exo- (hydroxyinethyl) 7-azabicyclo[2.2.l1hept-5-ene (11) The corresponding 5,6 _n 2 osmium complex was treated as described above for compound 8.

Diagnostic 1 H NMR information: 6.43 J 6R, 1H, or H6) 6. 0 LT 6 Hz, 1H, R6 or H5) (dd, J 10, 2. 5 Hz, 1H, 1/2 CR 2 OR) 3. 75 (dd, 7 10, 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 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% NH 3 in MeOH, CH 2 Cl 2 yielded 14 mg (1616) of pure 12 (Rf 0.5) 1H NMR(300 MHz, CDC1 3 d 3.89 (br, 2H, NH and OH), 3.82 (d J 10.6 Hz, 1/2 CR 2 OR) 3.38 J 10. 6 Hz, 1/2 CH 2 OH) 1. 7- 1 .5 (in, 7RH, 3 X CR 2 CR) 1 41 (s 31-H, CR 3 1.3 7 3H, CR 3 1 3 C NMP. (75 MHz, CDC1,) d 66.8, 64.0,, 63.8, 45.5, 40.0, 39.1, 39.07, 20.6, 17.8 SUBSTITUTE SHEET WO 94/22868 WO 9422868PCT/US94/03573 34 Example 5 Preparation of 1,4-Dimethyl-2-exocarboxymethyl-7 azabicyclo £2.2 heptane (13) The corresponding 2,3-vn2-osrnium complex 18 was protonated andi 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 (s 3 H, CH 3 O) 2. 63 (dd, LT 8 5. 1 Hz, 1H, H2) 2.49 (br s, 111, NH) 1. 82 (dd, JL= 12.2, 8.1 Hz, 1H, 1.75-1.2 (in, overlap, 1. 32 CH 3 1. 2 3 H, CH 3 11C NNR (7 5 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- -pyridyl) -3-exo-carboxymethyl-7azabicyclo£2 .2 .1J heptane (14a) and its exo-pyridyl- endo-carboxyl isomer (14b) These isomers were obtained as an inseparable 94:6 mixcture from the corresponding mixt~re of osmium, complexes following the procedure for 13.

For 14a, 'H NMR(300 MHz, CDCl 3 d 8.45 (in, 2H, H21 and H61 overlap), 7.49 (dt, LT 7.8, 1.5 Hz, 1H, H41) 7.23 (dd, LT 7.8, 4.8 Hz, 1H, H51) 3.64 (s, 3H, CH 3 O) 3. 29 (dd, LT= 5. 9, 2. 1 Hz, 1H, H2) 2.9 JT 5.9 Hz, 1H, H3) 2.62 (br s, 1H, NH) 1.85- 1.6 (in, 2H, CH 2 S),1 1. 5 (mn, 1H) 1. 35 (in, 1H) 1.2 9 3H, CH 3 1.26 3H, CR 3 1 3 C NMR (75 MHz, CDC1 3 d 175.7 149.8 148.2 135.3 134.1 123.1 67.6 (2XC overlap), 5 8 .7 (CH) 5 8 .3 (CH) 5 1. 7 (CH 3 O) 3 8 .6 (CH 2 3 0. 3

(CH

2 19.3 (CR 3 18.7 (CH 3 Diagnostic features of SUBSTITUTE SHEET WO 94/22868 WO 9422868PCT/1S94/03573 14b: d 3 .3 6 J 6 Hz, 112) 2.8 (dd, J 6, 2 Hz, H13) Example 7 Preparation of 1,4-Dimethyl-.2-endo- -pyridyl) -3-exo- (hydroxymethyl) 7-azabicyclo[2.2.llheptane Compound 14 was reduced with lithium aluminum hydride .in ether, yielding a clear resin after an aqueous workup. Diagnostic 1H1 NMVR resonances: 3.87 (dd, J =10. 6, 2. 8 Hz, 1H1, 1/2 CH 2 OH) 3. 46 (dd, J= 10.6, 3.0 Hz, 1H, 1/2 CH2QH), 3.16 (dd, J 1.9 Hz, 1H1, H2), 1.5 311, CH 3 1.25 3H, CH 3 Example 8 Preparation of 1,4-Dimethyl-2-endo- -pyridyl) -3-exo-phenylsulfonyl-7azabicyclo[2.2.llheptane (16a) and its exo-pyridyl, endo-phenyls't,,fony1 isomer (16b) The procedure for compounds 13 and 14 was followed yielding a mixture of isomeric 7azanorbornanes. Diagnostic 11H NMvR peaks for major isomer: 3.6 J 7 Hz, 1H1, C11 0 2.95 (dd, J= 7, 1.5 Hz, 1H1, CHa,), 1.85 311, CH 3 1.25 (s, 311, CH 3 Example 9 Preparation of [Os(NH 3 5 1 2 dime thylpyrrol e)]I (OTf) 2 (17) To a solution of IOs(NH 3 5 OTfJOTf 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 Mg 0 (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 C11 2 C1 2 giving a light yellow precipitate, which was filtered, washed with CH 2 Cl 2 and ether, then dried.

SUBSTITUTE SHEET WO 94/22868 WO 9422868PCTIUS94/03573 36 The yield of a light-yellow powder was 1.23-1.31 g (92-981).

Examnple 10 Preparation of 5,6-exo-?7 2 -Qs(NH 3 5 -1,4dimethyl-2 -exo-carbomethoxy-7 azabicyclo- [2.2.1]hept-5-ene) (OTf) 2 (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. '11 NNR (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, 2H1, 115 or H16), 3.13 J 6.3 Hz, 1H1, H16 or H15), 2.77 (dd, J 8.1, 4.2 Hz, 1H1, 12), 2.14 (br s, 111, NH), 2.05 (dd, J 11. 6, 8. 1 Hz, 1H, H3, 1. 63 (dd JT 11.6, 4.2 Hz, 1.39 3H, CH 3 1.24 311, C11 3 1 C NMR (75 MHz, CD 3 CN) d 176.4 75.7 71.0 59.1 58.0 (CHI), 55.3 (CH), 51.6 COCH 3 47.1 (C11 2 18.3 (CH 3 15.9 (C11 3 Anal. Calcd. for C, 2

H

3 0

N

6 8

S

2

F

6 0S: C, 19.10; H, 4.01; N, 11.14. Found: C, 18.57; H1, 3.96; N, 11.02.

Example 11 Preparation of Pentaammineosmium- Pyrrole Complexes: 2 3 -n2- [Os (NH 3 5

J

Ligand) (OTE) 2 where Ligand is pyrrole or N-methyl pyrrole A mixture of [Os(N1 3 )sOTfiI (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 SUBSTITUTE SHEET WO 94/22868 PCT/US94/03573 37 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 washed 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 -95% yield.

SUBSTTUTE SHEET 1 11 WO 94/22868 PCT/US94/03573 38 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 NH40H, diluted with an equal volume of methylene chloride (about 30 ml), then filtered directly through 20 cc of silica gel in a 30-ml 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.

SUBSTITUTE

SHEET

i- WO 94/22868 PCT/US94/03573 39 Example 15 Preparation of 2-Carbomethoxy-7methyl-7-azabicyclo [22..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 Rr 0.76; 'H NMR (CDC1 3 6 3.66 3H, CH0O), 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, IH3,), 1.33 2H); "C NMR (CDC13) 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, CH3N), 1.95 (m, 1H), 1.75 overlap, 3H), 1.36 2H); 3 C NMR (CDC13, 50°C) 6 174.3 CO), 64.1 (CH, C1 or C4), 62.1 (CH, C4 or Cl), 51.4 (CH3, 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 0

C);

Anal. Calcd. for C, 5

HIBN

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 SUBSTTUTE SHEET tar WO 94/22868 WO 9422868Pc'rJS94/03573 chloride. Exo isomer 0. 71; 'H NNR (CDC13) 3.53 J 3.3 Hz, 1H, HI), 3.37 J 3.8 Hz, 1H, H4), 2.44 (dd, J 9.3, 5.1 Hz, 1H, H2), 2. 36 3 H, CH 3 N) 2.1 (in, 1H), 1.83 (mn, 2H), 1.75 (dd, J 12.6, 9.3 Hz, 1H, 1. 3 (mn, 2H) 3 NNR (CDC1 3 6 12 2. 7 CN) 6 5. 5 (CH, C1 or C4) 60.8 (CH, C4 or Cl), 35.7 (CE 2 3 5. 3 (CH 3 3 1. 9 (CH) 27-.5 (CH 2 26.9 (CE 2 Endo isomer 0.55; 'H NNR (CDCl 3 6 3.44 LT 4.5 Hz, 1H, Hi or H4), 3.29 J 4.5 Hz, 1H, H4 or Hi), 2.92 (dtd [11 line pattern], J 12, 1.8 Hz, 1H, H2) 2.26 mn overlap, 4H, CH 3 N and 2.0-1.8 (in, 3H), 1.57 (dd, J 12. 3, 5. 1 Hz, lE, H3,d) 1.45 (in, 1H); 1 3 C NNR (CDCl 3 5 0 0 C) 6 12 1. 7 CN) 63.8 (CE, C1 or C4), 61.6 (CE, C4 or CI), 34.6

(CH

2 3 4. 4 (CH 3

CH

3 N) 2 9. 2 (CH, C2) 2 7. 9 (CE 2 ),1 2 4.1I (CE 2 The picrate salt (both isomers combined) was crystallized from ethanol (mp 218-224 OC) Anal. Calcd. for C 14

E

15

N

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

Exaniple 17 Preparation of trans-2,3-BiBcarbomethoxy- 7azabicyclo[2.2.l1heptane This compound was prepared in 4216 overall yield from pyrrole and dimethyl fumarate using the procedures set forth in Examples 11, 12 (using acel:onitrile as a solvent), and 14 (hydrogenation solvent methanol; reaction time 2 h; workup A).

'H NM. (CDCl 3 6 3.95 J 4.5 Hz, 1H, H4), 3.84 J 4.8 Hz, 1H, El), 3.70 3H, CH 3 3.695 3H, CH 3 3.22 (td, J 4.8, 1.8 Hz, IE, H3), 3.03 J 4.8 Hz, 1H, H2), 2.55 (br s, lE, NH), 1.8-1.3 (overlapping in, 4H) 1 3 C NM?. (CDC1 3 6 174.8 CO), 172.1 CO), 61.8 (CE, C1 or C4), 59.1 (CH, C4 or Cl) 5 2. 3 (CE) 5 2. 1 (CE 3 qH 3 0)1 5 2. 0

(CH

3

CH

3 O) 5 0. 1 (CE) 2 8. 7 (CE 2 2 4.-9 (CE 2 SUBS11UM

SHE'ET

Pdlll6B ~L~PIILIIQIgy--~- WO 94/22868 PCT/US94/03573 41 Example 18 Preparation of Hexahydro-2-phenyl-4, 7-imino-1H-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. NH 4 0H 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-petroleurn 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, H1, H4), 2.86 2H, H2, H3), 1.7 4H, 2 X CH 2 1.54 (br s, 1H, NH); "C NMR (CDC1 3 6 177.3 132.1 129.0 128.5 126.5 59.9 (CH, C1, C4), 49.0 (CH, C2, C3), 29.5 (CH2) The second fraction (Rf 0.21) yielded the endo isomer: 'H NMR 6 7.6-7.2 Ph), 4.18 (br s, 2H, H1 and H4), 3.64 (br s, 1H, NH), 3.41 (br s, 2H, H2 and H3), 1.8-1.6 4H); 1 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-lH-iso.indole-,3 (2Hdione was carried out using acetonitrile in the hv.ogenation step of the method set forth in Example 14 (reaction time 18 h, workup The SUBSTITUTE SHEET I-I- ~s~s~ WO 94/22868 PCT/US94/03573 42 crude material was chromatographed on silica gel x 13 cm column). Elution with ether yielded 56 mg of the title product (Rr 0.8; ether containing NH 4 OH) Further elution with ether containing 10% methanol and 3% conc. NH 4 0H yielded a second fraction containing 69 mg of crude hexahydro-2-phenyl-4,7-imino-lH-isoindole-1, 3 (2H) dione (R r 0.2; ether containing NH40H). 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°C. 'H NMR (CDC13) 6 7.5-7.25 5H, Ph), 3.82 J 2.2 Hz, 2H, H1, H4) 2.80 2H, H2, H3), 2.37 J 7.2 Hz, 2H, NCHz), 1.93 2H, 1.51 2H, H5, H6&) 1.04 J 7.2 Hz, 3H, CH 3 NMR (CDCl 3 6 177.8 132.4 129.1 128.5 126.7 62.6 (CH, C1, C4), 49.5 (CH, C2, C3), 40.4 (CH2N), 25.0 (CH2) 14.5 (CH3) Example 20 Preparation of Hexahydro-l-hydroxy-2phenyl-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% NH4OH and methanol) yielded the product (Rr 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, SUBSTITUTE

SHEET

I

WO 94/22868 PCT/US94/03573 43 1H), 2.60 J 2H, 1H), 2.71 J 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 wa6 quenched with methanol (0.1 then water (0.1 acidified with 1 M HC1, then basified with conc., NH 4 0H and extracted with methylene chloride. Drying and evaporation of the extract yielded the corresponding primary amine as an oil (17 mg, 'H NMR (CDC1 3 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°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-(lpyrrolylmethyl) 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 SUFSTITUTE SHEET p-q~CI~R 1~1~- V, 0 94/22868 PCTIUS94/03573 44 7 Hz, 1H, 1/2CH 2 3.22 1H), 2.96 1H), 2.26 3H, CH 3 1.98 1H) 1.83 2H) 1.5-1.22 4H).

Example 23 Preparation of exo- -Hydroxymethyl-7methyl-7-azabicyclo [2.2.1]heptane 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 HC1, basified with conc. NH 4 0H, and extracted with methylene chloride.

Evaporation of the extract yielded the desired product (11 mg, 'H NMR (CDC13) 6 3.80 (dd, J 9, 1 Hz, 1H, 1/2 CH0O), 3.39 (dd, J 9, 2 Hz, 1H, 1/2 CH 2 3.21 J= 5 Hz, 1H, H4), 3.19 J 4 Hz, 1H, H1), 2.18 3H, CH 3 1.82 3H), 1.7 1H), 1.5-1.2 4H).

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

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

NH

4 0H/methanol/ether (Rr Yield: 10 mg 'H NMR (CDC1 3 6 8.05 J 7.2 Hz, 2H, ortho-H), 7.55 J 7.2 Hz, 1H, para-H), 7.44 J =7.2 Hz, 2H, meta-H), 4.18 2H, 3.22 J 3.9 Hz, 1H, H4), 3.18 J 3.6 Hz, 1H, H1), 2.25 3H, CH 3 2.05-1.85 overlap, 3H), 1.48 (dd, J 12, 9 Hz, 1H, H3 1.34 (m, 3H).

SUBSTITUTE

SHEET

I .1 -r I IRI-~--i WO 94/22868 PCT/US94/03573 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 (CDC13) 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, HI and H4), 1.8-1.2 (m, overlap, 8H, 4 X CH 2 13C NMR (CDC13) 6 149.1 (CH), 146.3 142.3 134.0 122.9 44.7 42.5 38.7 (CH 2 36.7 35.9 (CH 2 30.3 (CH 2 28.6 (CH 2 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 SUBSTTfE

SHEET

i 46 substituted aryl or heterocyclic) acetylene. The electron withdrawing group at the

N

7 -position decreases the arom,:itity of the pyrrole ring and activates the ring in favor of the cycloaddition reaction.

The product of the reaction between the N-(electron withdrawingsubstituted) pyrrole with the arylsulfonyl (optionally substituted aryl or heteiocyclic) acetylene is a 7-(electron withdrawing substituted) (optionally substituted aryl or heteroaromatic) -3-arylsulfonyl-7-azabicyclo [2.2.1]-hepta-2, (for example, compounds 23 and 35, respectively Figures 2A and 2B). This diene can be derivatized using conventional to a wide variety of 7-azabicyclo [2.2.1]-heptanes and -heptenes. For example, an R" alkyl or aralkyl group can be added by reacting the saturated bicycloheptane derivative of compound 23 or 32 with n-butyl lithium and R 3 I, followed by treatment with a reducing agent to remove the 3- arylsulfonyl moiety. (Julia, M. and Paris, JM., Tetrahedron Lolters, 49, 4833 (1973).) R and R° 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, sydroboration, hydrohalogenation, hydroxylation, halohydrination, alkylation, carbene and dihalo carbene addition and epoxidation followed by ring opening reactions with nucleophiles such as alkozide, amines, alkylsulfide, halide and hydroxide.

The reactive chloro in compounds 24 and 25 (Figure 2) is easily displaced by nucleophiles such as alkoxy, including methoxy, alkylthio, hydroxy, amino, cyano, azide, bromide, iodide and dimethylamino.

o S C e *0* ea a"* sees e ~L WO 94/22868 PCT/US94/03573 47 The reaction between the N-(electron withdrawing-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 SUBSTITUTE

SHEET

I

WO 94/22868 PCT/US94/.i573 48 ammonia in methanol as the eluent, were racepibatidine (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; 3- SUBSTiTUE

SHEET

WO 94/22868 PCT/US94/03573 49 alkoxypyrrole, including 3--methoy,-;yrrole; 3aryloxypyrrole, including 3-benzyloxypyrrole; 3,4dialkylpyrrole, 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 SUBSTITUTE SHEET -1 WO 94/22868 PCTIUS94/03573 without limitation, the acid chloride of nicotinic acid, isonicotinic acid, 5-chloronicotinic acid, 6methylnicotinic acid, 6-methoxynicotinic acid, 6phenylnicotinic 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 (Sakamotc. et al., SUBSTITUTE

SHEET

CIP _IICI IIP16B~seB~4a9~P"p WO 94/22868 PCT/US94/03573 51 Synthesis, 312 (1983)) with tosyl chloride in the presence of a Lewis acid catalyst such as aluminum trichloride.

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 SUBSTITUTE

SHEET

1113 Ip~llRAR6~ WOr 94/22868 PCT/US94/03573 52 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.

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 aci, 6-phenylnicotinic acid, 6methylthionicotinic acid, 2-chloropyridine-4carboxylic acid, 2,6-dimethylpyridine-4-carboxylic acid, 1-methyl-2(1H)pyridone-3-carboxylic acid, 6methyithionicotinic 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 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 10 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 -78 0 C, and 1.35 g potassium tbutoxide is added in portions. The brown solution was stirred at -78 0 C for another 10 minutes and allowed to warm to ca. -30 0 C. Water was added and SUBSTITUTE Sif-Ef -p~pl ~ll~e~l'ls~ WO 94/22868 PCT/US94/03573 53 the aqueous layer extracted with methylene chloride. After drying and evaporation in vacuo, the residue was purified on a silica gel column, and eluted with 25% ethyl acetate in petroleum ether. The white solid (1.2 g) obtained after evaporation of solvent has a m.p. 140-1410C.

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 Pzeparation 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 10% 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 -20 0

C.

In a similar manner, the N-carbomethoxy, Ncarbobenzyloxy and N-tert-butoxycarbonyl derivatives of 2,5-dimethylpyrrole, 3,4bis(trifluoromethyl)pyrrole, 2-methylpyrrole, 2methoxymethylpyrrole, 2-methylthiomethylpyrrole, 2dimethylaminomethylpyrrole, methyl pyrrole-2- SUBSTITUTE

SHEET

II 4 ldl WO 94/22868 PCT/US94/03573 54 acetate, 2-methoxymethoxyethylpyrrole, 3benzyloxymethylpyrrole, 2-methoxypyrrole, 3methoxypyrrole and 3-benzyloxypyrrole are prepared.

Example 29 Preparation of 7-carbomethoxy-2-(2pyridyl)-3-phenylsulfonyl-7-azabicyclo[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 (56% 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-2-ene (24) Compound 23 (0.726 g, 1.9 mmol) was dissolved in 50 ml anhydrous methanol and 7 ml dried tetrahydrofuran co ntaining 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 SUBSTITUTE

SHEET

5- P~a ~_ls~ WO 94/22868 PCT/US94/03573 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 washed 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, Hi.

4 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[.22.l]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. 1 H-NMR indicates that it is a (102) mixture of exo and endo isomers.

MS(CI) m/z 267, 269 'H-NMR 4.21-4.44(2H,

HI

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.

SUBSTITUTE SHEET 1 a pspll ~Bpls~8~aoa~aoFCLI-~~ e WO 94/122868 PCT/US94/03573 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 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') MS(CI)m/z

H'-NMR

H

14

H

3 epibatidine(13) 209,211(M+1) 3.80(t,3.9Hz), 3.56(br.s) 1.90(dd, 12.0, endo-epibatidine(191) 209,211(M+1) 3.76(q, 4.8Hz) 2.12(tdd,12.3, 4.8, 3.3Hz) The N-acetyl derivatives prepared from epibatidine and of epibatidine can be acetic anhydride in SUBSTITUTE SHEET rW6~8~I~WYIBLsWBb WO 94/22868 PCT/US94/03573 57 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 acids 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 hydrcxide. The mixture was refluxed for one hour, thcn 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 SUBSTITUTE SHEET e~ r WO 94/22868 PCT/US94/03573 58 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 H'-NMR 3.72, 3.66 (2s, N-COOCH 3 Example 35 Preparation of 5, 6-dehydro analogs of epibatidine \rhen 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 -7-carbomethoxy-7 -azabicyclo[2.2.11 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 85 0 C 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

56 3.52(s, 3H, N-COOCH 3 1.96, 1.68(2s, 6H, 2CH 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 SUBSTITUTE SHEET ~y2sls~anra~ra~a~a -a WO 94122868 PCT/US94/03573 59 carbon tetrachloride). m.p. 91-93 0 C (lit, m.p.

93-940C).

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, 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 -2,5-diene 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 SUBSTITUTE SHEET -1PIB WO 94/22868 PCT/US94/03573 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 56 5.51, 5.48(2s, 2H, HI, 4 3.5(br.s. 3H, N-COOCH 3 Using a similar procedure, cycloadditions of substituted pyrroles described in Example 28 and substituted 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]hept- (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-azanorbornanes 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, SUBSM1?UTE SHEET I g l-IC I WO 94/22868 PCT/US94/03573 61 hydroboration, epoxidation followed by ring opening with nucleophiles (alkoxide, amine, azide, alkylsulfide, halide, hydroxide, etc.).

Example 43 Preparation of 3-methyl-7-aza-2-exo- (2-chloro-5-pyridyl)bicyclo[2.2.1] 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-aza-bicyclo[22.2.1]heptane(40).

The alkylation products are each treated with sodium amalgam as in Example 30 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, allvl bromide, benzyl chloride, methoxymethyl chloride and methoxyethyl methanesulfonate, and corresponding 3-ethyl, 3allyl, 3-benzyl, 3-methoxymethyl and 3-methoxyethyl derivatives are obtained.

SUBSTITUTE SHEET I- I I- WO 94/22868 PCT/US94/03573 62 Other 2-aryl or 2-heteroaryl derivatives of 7-N-acyl-7-aza-3-phenylsulfonyl-bicyclo[2.2.11 described in Example 29 are likewise hydrogenated, converted to the sulfonyl carbanion, alkylated, desulfonated and deacylated to give the corresponding 3-alkyl or aralkyl analogs.

Example 44 Preparation of 7-mo~'.y-7-aza- 2-exo-(2-chloro-5-pyridyl) 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.

SUBSTITUTE SHEET I-rr pk'- M

_I

WO 94/22868 PCT/US94/03573 63 Example 45 Resolution of racemic compounds The substituted 7-aza-bicyclo[2.2.11heptane 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 2E the diastereoisomers by HPLC on a chiral column and treatment of each isomer with HBr/AcOH as in Example 32 yields the co-responding 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 SUBSTITUTE SHEET 1. Ip P~P

~C

WO 94/22868 PCT/US94/03573 64 method described above. The chiral pyrrole is treated 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 -2,5-diene 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.

i--CH tBuOK HNBr CHSONH 2

O

CH

2 Br NaH O- -CH

NH

C1 CC-SOPh I jN"SSO 2 Ph NaHg -a 0.

SUBSTITUTE SHEET I U" I I WO 94/22868 PCT/US94/03573 a) 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, 2CH2).

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 SUBSTITUTE SHEET sb -IdL-C BBIIBBs~RiQII~PII~ L WO 94/22868 PCT/US94/03573 66 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) 65.242(d, J=1.5Hz, 1H), 5.362 J=0.9Hz, 1H). (HI or H4).

c) Preparation of exo and endo-benzo [5a,6a]epibatidine (39) Compound 41 (54 mg, 0.237 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, 25S(M+1).

'H-NMR (CDC13), (for exoisomer). 2.753 (dd, J=4.8, 8.4 Hz, 1H, H 2 4.371 1H, HI), 4.656 J=4 Hz, 1H, H4) SUBSTITUTE

SHEET

I aLrql--p~l WO 94/22868 WO 9422868PCT/US94 /03 573 Examiple 49 Preparation of N-rnethyl-benzo [5a,6a] epibatidine (42) Scheme 5 illustrates a method for the production of N-methyl-benzo [5a, 6a] epibatidine 42.

O2 :NCH 3 Na[Hg] C1 C-C-S 2 Ph

N*CH

3 N S0 2 Ph

NI

a) Preparation of N-methyl inoindele (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-imirne (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'-NNR (CDCl 3 6 2.36 (br, 3H1, -NCH- 3 4.805 1H), 4.93 (br.s., 111) or H14) SUBSTITUTE SHEET I~PU I I WO 94/22868 PCT/US94/03573 68 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 zetrahydrofuran. 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 mixture 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 (CDC1 3 (for exoisomer): 2.679 (dd, J=4.5, 8.7Hz, 1H, H 2 3.935 1H, 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

CO^

1

N

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 SUBSTITUTE SHEET -C7 -PP- WO 94/22868 PCT/US94/03573 69 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%.

MS(CI), 236, 238 (free base H'-NMR 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-nitroguandyl and N-acetamidinyl epibatidine.

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

,CH=NH

N

N-Formamidinyl epibatidine (12 mg, 0.04 mmol) 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 (CD3OD), 6 3.5 1H, H 2 SUBSTITUTE

SHEET

I ~I WO 94/22868 PCT/US94/03573 Example 53 Preparation of 1-methyl epibatidine and 4-methyl epibatidine (48)

H

N H

CH

3

SSCI

CHA

\N

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 (CDC13) 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 rmmol, 1.8g) was mixed with 1- (6-chloro-3-pyridyl)-2-phenylsulfonyl acetylene SUBSTITUTE

SHEET

WO 94/22868 PCT/US94/03573 71 (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 (CDC1 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, Hi).

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 SUBSTTUTE SHEET I WO 94/22868 PCT/US94/03573 72 place 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, H2), 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 solution 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+l) H'-NMR (CDC1 3 (for 1-methyl epibatidine, major, exo-isomer). 6 2.657 (dd, J=4.8, 8.7Hz, 1H, H2), 3.694 J=4.7Hz, 1H, H4).

(For 4-methyl epibatidine, minor exo-isomer): 2.887 (dd, J=4.7Hz, 1H, H 2 3.486 J=4.5Hz, 1H, H) SUBSTITUTE

SHEET

WO 94/22868 PCT/JS94/03573 73 Example 54 Preparation of 2-(2-fluoro-5pyridyl) -7-azanorbornane (53)

F

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

Med. Chem, 1990, 33(6) 1667), providing compound 54 as a white cry.stal, mp. 127-128 0 C. Yield 72-1.

MS (CI) 280 H'-NMR (CDCl 3 .6 2.70 2H,

CH

2 b) Preparation of 1- (2-Fluoro-5-pyridyl) -2phenylsulfonayl acetylene Use of the method set forth in Example 27 gave compound 55 in 62-1 yield from compound 54 as a white solid. mp. 97-98.5 0 C. MS (CI) 262 c) Preparation of 7-carbomethoxy-2- (2- -3-Phenylsulfonyl-7azabicyclo[2.2.1J -hepta-2,5-diene (56) Use of the method set forth in Example 29 gave compound 56 in 66!k yield plus 22%k of recovered acetylene 55. Compound 56 is a white cubic crystal, mp. 85-87 0 C. MS (CI) 3 8 7(M+1) .H 1

-NMR

(CDCl 3 3.446 (br. s. 3H1, CH3) 5.459 J=7.2Hz, 2H-, HIA,) SUBSTITUTE SHEET WO 94/22868 WO 9422868PCT/I1S94/03573 74 d) Preparation of 7-carbomethoxy-5- (2- -7azabicyclo[2.2.ljhept-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%r from compound 56.

MS (CI) 249 H'-NMR (CDCl 3 (for endo-isomer).

3. 682 3H, OCH 3 (for exo- isomer) 3. 655 3H,

OCH

3 e) Preparation of 7-carbomethoxy-2-(2- -7azabicyclo [2.2.11 heptane (58) Use of the method set forth in Example 31 gave compound 58 as a colorless oil in a yield of 93.31k f rom compound 57. MS (CI) 251 H 1 -NMR (CDCl 3 (for endo-isomer) 65 3.722 OCH 3 (for exoisomer) 6 3. 671 3H, OCH 3 f. Preparation of 2-(2-fluoro-5-pyridyl)-7azanorbornane (53) The method set forth in Example 32 was used to produce 23 mg (16.216) of the exo-isomer of compound 53 and 54.8 mg (3816) of the endo isomer of compound 53, as an oil from 185 mng of Compound 58 (0.74 mmol). MS (CI) 193 'H-NMR (CDCl 3 5 2.763 (dd, 9.0Hz, 1H, 3.532 1H, HI) 3.769 J=3.6GHz, lH, H 4 (For endo-isomer). 6 3.324 (dt, J=12Hz, 5.7Hz, 1H1, H 2 3.779 J=5.lHz, 2H,

H

14 SUBSTITUTE SHEET WO 94/22868 WO 9422868PCT/IS94O3573 Examiple 55 Prepa-,ation of 2-(2-chloro-3pyridyl) -7-azanorbornane (59) a) Preparation of 1- (2-chloro-3-pyridyl) -2phenylsulfonyl ethanone Use of the method set forth in Example 26 gave compound 60 in 74%; yield from 2-chloronicotinyl chloride as white solid, mp. 103-104 0 C. MS(CI) 296, 297(M+1) H'-NMR (CDCl 3 6 4.871 2H, -CHI-) b) Preparation of 1-(2-chloro-3-pyridyl)-2phenylsulfony. acetylene (61) Use of the method set forth in Example 27 gave compound 61 in 270- yield from compound 60 as a white solid, mp. 90-94 0 C. MS(CI) 278, 280(M+1).

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

OCH-

3 5.429 J=2.lHz, 1H1), 5.497 J=2.lHz, 1H-).

SUBSTITUTE SHEET WO 94/22868 WO 4/2868PCTI)S94/0357.1 76 d) Preparation of 7-carbomethoxy-5- (2chloro-3 -pyridyl) -7azabicyclo[2.2.l1hept-2-ene (63) Use of the method set forth in Example gave compound 63 as the exo-isomer, and the endo-isomer, MS(CI) 265, 267(M+1) 11-NMR (CDCl 3 (for exo-isomer) 6 3.66 3H, OCH 3 6.502 (br.s. 2H1, H5.6). H 1 -NNR (CDCl 3 (for endoisomer) 6 3.686 3H1, OCH 3 4.882, 5.029 (2br.s. 2H1, 5.88, 6.544 (2br.s., 2H1, H 56 e) Preparation of 7-carbomethoxy-2-(2chloro-3-pyridyl) -7azabicyclo (2.2.11 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).

1'-NMR (DCC1 3 6 3.277 (dd, J=4.5, 8.4Hz, 1H1, H 2 3.654 3H, 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(Cl) 209, 211(M+1). H'-NMR (CDC1 3 6 3.162 (dd, J=4.8, 8.7Hz, 1H, 112), 3.681 111), 3.795 J=3.6Hz, 111) (HI, H14) SUBSTITUTE SHEET WO 94/22868 WO 9422868PCTIJS94/03573 77 Example 56 Preparation of 2-(2-chloro-4pyridyl) -7-azabicycloE2.2.l) heptane

C'

N

a) Preparation of 1-(2-chloro-4-pyridyl)-2phenylsulfonylethanone (66) Using the method set forth in Example 26, where 2-chJloroisonicotinyl chloride (see Anderson et al., J. Med. Chem. 1990, 33(b), 1667) was used instead of 6-chloronicotinyl chloride, compound 66 was obtained in 51!k 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-7azabicyclo[2.2.ljhepta-2,5-diele (68) Using the method set forth in Example 29, compound 68 was obtained from compound 67 in 68%6 yield as a slightly brown oil. MS(CI) 403, 405(M+1) H'-NMvR (CDCl 3 6 3. 502 (br 3H-, 0C11 3 5.420, 5.483 (25, 2H1, 11) 7. 065 2H1, H5.6) SUBSTITUE

SHEET

WO 94/22868 WO 9422868PCT1US94/03573 78 d) Preparation of 7-carbomethoxy-5- (2chloro-4-pyridyl) -7azabicyclo[2.2.1]hept-2-ene (69) Using the method set forth in Example compound 69 was obtained from the desulfonation of compound 68 in 13.6?6 yield as a 1:2 mixture of exoand endo-isomers. MS(CI) 265, 267(M+1). 'H-NNR (CDCl 3 I (for endo-isomer) 6 3.682 3H, OCH 3 (for exo-isomer) 6 3.665 3H, OCR 3 e) Preparation of 7-carbomethozcy-2-(2chloro-4-pyridyl) -7azabicyclo (2.2.13 heptane Using the meth.~d set forth in Example 31, compound 70 was obtained from the hydrogenation of compound 69 in 95% yield. MS(CI) 267, 269(M+1).

'H-NMR (CDC1 3 (for endo- isomer) 6 3.694 3.1-,

OCR

3 (for exo-isomer) 6 3. 655 3H-, OCR 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 23.6%; (exo-isomer) MS(CI) 209, 211(M+1) 'H-NMR (CDCl 3 6 2.738 (dd, 5.1Hz, 1H-, H 2 3.629 J=2.4Hz, 1H), 3.791 1H). Some erdo-isomer can be isolated.

SUBSTITUTE SHEET WO 94/22868 PCT/US94/03573 79 Example 57 Preparation of disodium 7epibatidinylphosphate (71) N PO(ONa) 2

N

IC

Epibatidine (40.0 mg) was dissolved in 3 ml phosphorous oxychloride 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 oily 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 -ng 'H-NMR(D20) 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). 3 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.

SUBSTITUTE

SHEET

I

WO 94/22868 WO 9422868PCT/US94/03573 Example 58 Preparation of 2,3-dehydroepibatidine (72) Scheme 7 shows the production of compound 72.

N'C(CH3)3 N' COO(CH3)3 N'H

SO

2 Ph SO 2 Ph S0 2 Ph N C, a) Preparation of 7-carbo-t-butoxy-2- pyridyl) -3 -phanyloulfonyl-7azabicyclo[2.2.llhepta-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 64!k 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 -phenylsulfonyl-7azabicyclof2.2.llhept-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 SUBSTITUTE

SHEET

WO 94/22868 WO 9422868PCTJLUS94/03573 81 catalyst was removed by filtration. The filtrate was concentrated in vacuo to give 440 mg residue.

It was solidified after trituration in methanol.

Yield MS(CI) 447, 449(M+1) H'-NNR (CDCl3) 6 1.266 9H, CI'CH 3 3 4.905, 4.945 (2br.s., 2H, H-2,4).

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 95.4*- yield as a white solid. MS(CI) 347, 349 H 1 -NMR (CDCl 3 64.423 Cd, J=4.2Hz, 1H), 4.500 J=3.GHz, 1H) (H 14 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 ao a colorless oil. Yield 190-. MS(CI) 207, 209(M+1) H 1 -NMR (CDCl 3 6 4.323 1H-, H 1 4.574 J=3.OHz, 111, H 4 6.560 J=2.4Hz, 1H,

H

3 SUBSTITUTE SHEET WO 94/22868 PCT/US94/03573 82 Example 59 Preparation of Chloroethylepibatidine (76) N,CH2CH2CI

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, 4 3.568 (t, J=6.6Hz, 2H).

Example 60 Preparation of 2-(2-hydroxy-5pyridyl)-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 IM 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 an oil. Yield 50%. MS(CI) 191(M+1). 'H-NMR

(CDC

3 6 2.554 1H, H 2 3.503; 3.743 (2br.s., 2H, HI 4 SUBSTITUTE SHEET c WO 94/22868 WO 9422868PCT/US94/03573 Example 61 Preparation of 2-(2-methylthio-5pyridyl) -7-azanorbornane (78) N

H

Using the method set forth in Example 33, compound 78 was obtained in 28k yield from sodium methylmercaptariide in ethanol as a colorless oil.

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

,...COOC(CH

3 3

CF

3

CF

3

H

2 /Pt0 2 SUBSTITUTE SHEET WO 94/22868 PCT/US94/03573 84 a) 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 ;nd the aqueous layer was r.xtracted 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(CDC13) 6 1.427 9H, OC(CH 3 3 2.974 (dd, J=4.2, 8.4Hz, 1H, H2), 4.906, 5.147 (2br.s., 2H, HI,4) The 5-(2-chloro-5-pyridyl) analog was obtained by replacing the iodopyridine in the above reaction with SUBSTITUTE SHEET I WO 94/22868 PCT/US94/03573 c) Preparation of 2,3-bis(trifluoromethyl)- 5-pyridyl-7-azabicyclo[2.2.1]hepta-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 (CDC 3 6 2.02 (dd, J=8.4, 2.1Hz, 2H, H 3 2.88 (dd, J=4.8, 8.4Hz, 1H, H 2 4.36, 4.63 (2br.s., 2H, H, 4 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.

IV. Pharmaceutical Compositions Humans, equine, canine, bovine and other animals, and in particular, mammals, suffering from pain 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 mater.als can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid, cream, gel or solid form.

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 SUBSTITUTE SHEET WO 94/22868 PCT/US94/03573 86 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-dibenzylethylene-diamine, D-glucosamine, tetraethylammonium, or ethylenediamine; or (c) 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. A preferrad dose of the active compound for all of the above-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 0.5% wt/wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of tne 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.

SUBSTITUTE

SHEET

WO 94/22868 PCT/US94/03573 87 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 inert 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 SUBSTITUTE

SHEET

WO 94/22868 PCT/US94/03573 88 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 mixed 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.

SUBSTITUTE SHEET WO 94/22868 PCT/US94/03573 89 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.

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 SUBSTITUTE

SHEET

WO 94/228681 PCT/US94/03573 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 '2 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 induced by acetic acid, phenylbenzoquinone, prostaglandin or bradykinin; and adjuvant arthritis in rat that is induced by Freund's adjuvant.

SUBSTITUTE SHEET WO 94/22868 PCT/US94/03573 91 Example 63 Evaluation of Analgesic Activity Table 4 provides the analgesic activity measured as EDso (gg/Kg) 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.

SUBSTITUTE SHEET WO 94/22868 d PCT/IUS94/03573 Structural formula

H

N

H

H

N

H

N CI

CH

3

N

N

H

H

N

b~NO

H

N

(OCH

3

H

N

H

Table 4 ED gL/Kq Comments 9 (g/Kg) 7.5 epibatidine d-epibatidine >100 10000 Mixture of endo and exo isomers (1.3:1) 750 100 1000 (jg/Kg) SUBSTITUTE SHEET WO 94/22868 PCT/IUS94/03573 Structural for. 'a ED 5 a-gK Comments CH O 2 6 .<1000 250 <1000 10 0-200 ca.

OH

3

N-CH:

3 I

C

H

H

NN

H

SUBSTITUTE SHEET WO 94/22868 WO 9422868PCT/tIS94/03573 Structural formula ICH 2

CH

2

CI

NN

Comments ca. 100 ca.

N

H

NF

H

NN

H

racemic

CH=NH.HCI

H

H

H

99?6 100 ca. 1000 SUBSTITUTE

SHEET

WO 94/22868 PC6rTS94/03573 Example 64 Evaluation of Nicotinic Receptor Binding Activity 7-aza-bicyclo[2.2.1] -heptanes a:.a -heptenes were evaluated for their ability to bind to the aretylcholine 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 SUBSTITUTE SHEET PCT[IIS94/03573 WO 94/22868 96 TABLE Structural Formula Testing L evel1 1 0-1M 1011 io- 7 9 10-1 10-7 a.0o9 1 0-m 1011 1 0 7

M

10-9 Inhibitionl 106 72 13 102 77 102 22 104 103 103 104 100 49 104 49 22 103 .9 71.3 103 24 81 R= H 1 0-m 10- 7 10-o 5 R CH 3 SUBSTITUTE SHEET WO0 94/22868 PCT/US94/03573 c,7 Modifications and tions of the present invention will be obvious to those skilled in the art from the foregoing detailed description of the invention. Such modifications and variations are intended to come within the scope of the appended claims.

SUBSTITUTE

SHEET

ww wm

Claims (35)

1. An -azabicyclo[2.2.1]-heptane or -heptene compound of the formula: R 7 RR 6 RRR R 5 R 3 R 3 wherein: RI and R' are independently hydrogen, alkyl, including CH 3 P-lkylhydroxy, including C11 2 011; alkyloxyalkyl, including -CH 2 OCH 3 alkylthioalkyl, including -CI1 2 SC11 3 alkylamino, including -CH 2 NH 2 alkylaminoalkyl or alkylaminodialkyl, including CH-1N11(CH- 3 and CH 2 N(CH 3 2 oxyalkyl, including -OC{ 3 carboalkoxy, including carbomethoxy; allyl, aryl and thioalkyl, including -SCH 3 R 3 R' and R' ar independently hydrogen, alkyl, including C1 3 alky~hydroxy, including -CH 2 OH; alkyloxyalkyl, including -CH- 2 0CH 3 alkylthioalkyl, including -CH 2 SCH 3 alkylamino, i,,:cluding -CII 2 NH 2 alkylaminoalkyl or alkylaminodialkyl, including CH 2 NH(C{ 3 and CH 2 N(CH 3 2 oxyalkyl, including -OCH 3 thioalkyl, including -SCH 3 halo, including Cl, F; haloalkyl, including CF 3 NH 2 alkylamino or SUBST1TMf SHEET I INO 94/22868 *NO 9422868PCTIUS94/03573 99 dialkylamino, including -N(CH 3 and -N}ICH; cyclic dialkylamino, including N

7- ~NQ N-OH 3 -N N-CH 2 CH 2 0H amidnine, cyclic amidine including N N and their N-alkyl derivatives; -N-Ckalkyl 0 0 -CO 2 H; CO 2 alkyl, including -CO 2 CH 3 -C(O)alkyl, inc _uding C (0)CH 3 CN, C (0)NH 2 C (0)NH(alkyl) -C(O)N(alkyl) 2 including -C(O)N(CH 3 2 allyl, -S0 2 (alkyl), -SO 2 ary"L, including -S0 2 (C 6 HS 5 -S(O)alkyl, -S(O)aryl, aryl, heteroaryl; so 2 R 5 and R 6 together can be alkylidene or haloalkylidene, including -CH2- and epoxide episulf ide imino (alkyl) or SUBSTITUTE SHEET I WO 94/22868 'IVO94/2868PCTIUS94/03573 100 or a fused aryl or heteroaryl ring including a fused phenyl ring; R, is independently hydrogen, alkyl, including CH 3 alkenyl including -CH 2 -HC=CH,; alkyihydroxy, including -CH 2 -OH; alkyloxyalkyl including -CH 2 -O- (alkyl) alkylamine, including -CHNH 2 carboxylace, C (0)Oalkyl, including CO 2 Me; CCO) Oaryl, C(O)Oheteroaryl, COOaralkyl, -CN, Q, C(O)Q, alkyl(Q), -alkenyl(Q), -alkynyl(Q), NqH-Q or -N(alkyl)-Q; R 2 and R 3 together can be -C -C or CH-(OH) C wherein R' can be alkyl, aryl including phenyl, or heteroaryl; R 7 is hydrogen, alkyl, including CH 3 or C11 2 C11 3 alkyl substituted with one or more halogens, including CH 2 CH 2 C'L; -CH 2 (cycloalkyl) including -CH 2 (cyclopropyl); -CH 2 CH=CH 2 -CHCH 2 (C 6 H 5 alkyihydroxy, including CH 2 CH 2 OH, alkyl amino (alkyl) 2 including CHCH 2 N (CH 3 2; alkyloxyalkyl, alkylthioalkyl, aryl, dialkyl to form a quarternary ammonium including N(CH 3 2 N.(R 9 A H Ca DcYi -Caryi -C-O-(alkyl) -C-S.(akyl) N-(R 9 2 -NHY H N lIower alkyl SUBSTITUTE SHEET 1 11/0 94/22868 ~I/O 9422868 CT/US94/03573 101 or z H) -Z /Z -(CH)NR9P.4R10 (CH)N-J~ R 0 -(CH 2 o) 0 -S-R' 0 0 0 0 -CH 2 OCC(CH 3 3 -CH 2 0C. aryl 0 11 -CH 2 0OC'aiKY1 wherein RI is hydrogen or alkyl; wherein Y' is CN, N0 2 alkyl, OH, -0-alkyl; wherein Z is 0 or S; wherein R' 0 and R" are each independently -OH, -0-alkyl, -0-aryl, -NH 2 -NH(alkyl), -N(alkyl) 2 -N14(aryl) and -N(aryl) 2 SUBSTITUTE SHEET 102 N-- 103 C C 0 104 *00 9 N N and wherein the Q moiety can be optionally substituted with 1 to 3 W substituents; and W is alkyl, including CH 3 halo, including 01 and F, aryl, heteroaryl, OH, oxyalkyl, including -00H 3 SH; thioalkyl, including -SCHI,; -SO(alkyl) including -SOOH 3 -SOalkyl, including -SO 2 00CH 2 0H=CH 2 -OCH 2 (OH5), OF 3 ON, alkylenedioxy, including -methylenedioxy-, -C0 2 H, -CO 2 alkyl, including -C0 2 CH 3 -OOH 2 CH 2 OH, -NO 2 -NH 2 -NH(alkyl), including -NHOH- 3 -N(alkyl) 2 including -N(CH 3 2 -NHO(O)alkyl, including -NHCOJH 3 -S0 2 CF 3 or -NHOH 2 aryl, including -NHCH 2 (CO1-1 5 and wherein the indicates an optional double bond, provided that when R1, W 2 R 4 and R 5 are H, R' is H, alkyl, -OH 2 (cycloalkyl), alkyl substituted with one or more halogens, -OH 2 OH=OH, or alkylbydroxy, and one of R 3 and RO is H, then the other of R 3 and R" is not aryl or heteroaryl; and further provided that when R 1 R 4, R 5 and R" are H and R 7is H or methyl, R 2 and R' are not both -00 2 0H 3 and when R 2 W 3 and R" are H and R' is H or methyl, R 5 and R" are not both -00 2 0H.. 2. The compound of claim 1, wherein R 7 is selected from the group consisting of methyl, allyl, rnethylcyclopropyl, methylcyclobutyl, phene thyl, hydroxyethyl, mnethoxyethyl, methylthioethyl, limethylaminopropyl and (4-methioxybenzyl). 3. A compound according to claim 1 wherein the 2 and 7 substituents are *0*.selected from the group consisting of 2-oxo-(3-pyridyl); 2-on do- (3-pyridyll; 7-methyl-2-oxYo-(3-pyridyl); 7-cyclopropylmethiyl-2-oxyo-(3-pyridyl); 2-exo-(6-chloro- 3-pyridyl); 2-exo-(6-fluoro-3-pyridyl) and 7-phenetlhyl-2-ox<u-(3-pyridyl). 4. A compound according to claim 1 wherein the 2 and 7 substituents are selected from the group consisting of 2-oxo-(4-pyridyl); 7-methyl-2-exa-(4-pyridyl); 7-allyl-2-oxo-(4-pyridyl); and 7-cyclopropylmethyl-2-oxyo-(4-pyridyl). A compound according to claim 1 wherein the 2 and 7 subs tituents are selected from the group consisting of 2-oxo-(3-chloro-4-pyridyl); 7- cyclopropylmetlhyl-2-2-oxo-(3 -chloro-4-pyridyl); and 7-phenethlyl-2-oxyo-(3-chloro-4- pyridyl). 106 6. A compound according to claim 1 wherein thile 2 and 7 substituents are selected from the group consisting of 2-exo-(2-fluoro-5-pyridyl); 2-oxo-(2-methoxy-5- pyridyl); 2-oxo-(2-methylthio-5-pyridyl); 2-exo-(2-methyl-5-pyridyl); 2-oxo-(2- and the 7-cyclopropylmethyl derivatives of these compounds. 7. A compound according to claim 1, wherein: the 2-substituent is selected from the group consisting of the oxo and Ondo isomers of 2-(5-indolyl), 2-(5-fluoro-3-indolyl), 2-(5-methoxy-3-indolyl), 3-pyridylmethyll), and 2-(4-pyridylmethl), and the 7-substituent is selected from the group consisting of hydrogen, methyl, cyclopropylmethyl, allyl and phenethyl.

8. The compound of claim 1, wherein R 1 and R 4 are independently selected from the group consisting of methyl, hydroxymethyl. methoxymethyl, carbomethoxy and allyl.

9. The compound of claim 1, wherein R 3 is selected from the group consisting of methyl, hydroxymethyl, methoxymethyl, carbomethoxy, carbamyl, cyano, acetyl, aminomethyl, dimethylaminomethyl, methythiomethyl, phenylsulfonyl, methanesulfonyl and allyl. The compound of claim 1, wherein R5 and RO are selected from the group .consisting of trifluoromethyl, methoxy, methyl, carbomethoxy, hydroxymethyl, methoxymethyl and chloro.

11. The compound of claim 1 that has a double bond between C 2 and C 3

12. The compound of claim 1 that has a double bond between C" and C.O, 107

13. The compound of claim 1, wherein: the 2-substituent is selected from the group consisting of 2-oxo-(3-pyridyl, 2- exo-(6-ch'oro-3-pyridyl), and 2-exo-(6-fluoro-3-pyridyl); and the 7 substitubnt i.9 selected from the group consisting of NH NH NH NH N -H C 3 -8-isoPr ,-C-NHCH 3 8NO NH NH NHNN -C-NHNH 2 -C-NHNO 2 -C-NHC-=N -CH 2 00C(CH3)a

14. A ifietho'd for imparting analge'sia to a mammal, comprising administering an effective amount of an azabicyclo[2.2.i]-heptane or -heptene compound of the formula: an-Iaeidpednl yrN, lyicuigC 3 lyhdoy R1,R and R are independently hydrogen, alkl, including C 3 lyhdov inldn H0;alkylhd oxy aly, including -CH20OM: alkyloxyoalkyl, including -COC: alkylthio alkla, including -C CH 3 alklinoinlin orCH 2 NH 2 oialy akamnakloalyaioikl.including CH 2 N(CH 3 and CH2N(CH3);oylyicuig-C3 abakox oalkyl.ro including -CH20; toalkl incldng-CM hl, including Cl, F:H3 haloalkyl, including CF 3 NH 2 alkylamino or dialkylamino, including -N(CH 3 J and -NHCH 3 cyclic dialkylainino. including -ND -N N-CH 3 -N N-CH 2 CH 2 0H amidine, cyclic amidi ae including and their N-alkyl derivatives; HO0 -N ]WI -NN 0 0 -00 2 H; CO 2 alkYl, including -C0 2 CH 3 -O(O)alkyl, including -O(O)CH 3 -CN, C(O)NH 2 -O(O)NH(alkyl), -C(O)N(alkyl) 2 including -O(O)N(0H 3 2 allyl, -S0 2 (alkyl), -SO2arvl, including -S0 2 (CaHs), -S (O)alkyl, -S (0)aryl, aryi. heteroaryl; or -1 -3 R 5 and RO together can be alkylidene or haloalkylidene, including -OH 2 and OF 2 epoxide episulfide imino (-N(alkyl)- or or a fused aryl or heteroaryl ring including a fused phenyl ring; R 2 is independently hydrogen, alkyl, including CH3; alkenyl including -OH 2 HO=OH 2 alkylhydroxy, including -0H 2 OH; alkyloxyalkyl including -0H 2 -O- (alkyl), alkylarnine, including -OH 2 NH 2 carboxylate, CO)Oalkyl. including OO 2 Me; O(O)Oaryl, CO)Oheteroaryl, COOaralkyl, -ON, Q, CO0)Q, -alkyl(Qj, -alkenyl alkynyl(QJ, -NH-Q or -N(alkyl)-Q; R 2 and R 3 together can be or OH(OH)-N(R 8 wherein Rcan be alkyl, aryl including phenyl or heteroaryl; R 7 is hydrogen, alkyl, including OH 3 or 0H 2 0H, alkyl substituted with one or more halogens, including 0H 2 0H 2 01; -0H 2 -(cycloalkyl), including -OH 2 109 (cyclopropyl); -CI- 2 CH-=CH 2 -CH 2 CH 2 (G 0 H 5 alkyihydroxy, including CH 2 CH 2 OH, alkylamino(alkyl) 2 including CH 2 CH- 2 N(CH 3 2 alkyloxyalkyl, alkylthioalkyl, aryl, dialkyl to form a quarternary aminoniun including N(CH;) 2 (R A -C-H; N.(RlI) NII l N(9 C4 -C-ayl -C.O.(ahyf) -CS(Ry) N-(Rl) N.(RI) -CN-N(R) 2 -C-NHY? H NIower alkyj or z -(CH 2 O) 0 0 z 11 I -(CH 2 O 0 6, 0 0 0 *-CH 2 OCC(CH2). -CH 2 OC- aryi wherein RD is hydrogen or alkyl; wherein Y is CN, NO 2 alkyl, OH, -0-alkyl; V. wherein Z isO0 or S; wherein R' 0 and R" 1 are each independently -OH. -0-alkyl, -0-aryl, -NH 2 -NH(alkyrll, -N(alkyl) 2 -NH(arvl) and -N(aryl) 2 110 N S S S S S j~ N 7 I TT 112 -00 @I00N "N N S S 9 7- I -<I N N DIC~Ol~yl-l~ r and wherein the Q moiety can be optionally substituted with 1 to 3 W substituents; and W is alkyl, including CHa; halo, including Cl and F, aryl, heteroaryl, OH, oxyalkyl, including SH; thioalkyl, including -SCH3; -SO(alkyl) including -SOCH,; -SOzalkyl, including-SO 2 CH 3 -OCH 2 CH=CH 2 -OCH2(CoHS), CF,, CN, alkylenedioxy, including -methylenedioxy-, -COzH, -CO 2 alkyl, including -COzCHa; -OCH 2 CH 2 OH, -NO 2 -NH 2 -NH(alkyl), including -NHCH 3 -N(alkyl) 2 including -NHC(O)alkyl, including -NHC(O)CH 3 -SO 2 CF 3 or -NHCHzaryl, including -NHCH 2 (CaHs); and wherein the indicates an optional double bond, provided that when R 2 R 4 and R 5 are H, R7 is H, alkyl, -CH2- (cylcoalkyl), alkyl substituted with one or more halogens, -CH 2 CH=CH, or alkyihydroxy, and one of R' and RO is H, then the other of R and R 0 is not aryl or heteroaryl; and further provided that when R 1 R 4 R 5 and R° are H and R 7 is H or methyl, R 2 and R 3 are not both -CO2CH 3 and when R 1 R 2 R 3 and R 4 are H and R 7 is H or methyl, R 5 and R° are not both -CO 2 CH,.

15. The method of claim 14, wherein the compound is administered in an amount ranging between 0.002 and 10 mg/kg per day. S

16. The method of claim 14, wherein the compound is administered in an amount ranging between 0.02 and 0.2 mg/kg per day.

17. The method of claim 14, wherein the compound is applied topically in a dosage rangirng between 0.001% and 0.5% wt/wt in a carrier suitable for topical administration.

18. The method of claim 14, wherein the compound is administered by intravenous injection.

19. The method of claim 14, wherein the compound is administered orally. The method of claim 14, wherein the compound is administered topically. 113/1

21. method for the treatment of inflamnnatory conditions in a mammal, comprising administering to a mammal an effective amount of an azabicyclo[2.2.1] heptane or -heptone compound of the formula: 114 R 3 wherein: R' and R' are independently hydrogen, alkyl, including CHI; alkyihydroxy, including GH 2 OH; alkyloxyalkyl, including -CH 2 0CH 3 alkylthioalkyl, including CH 2 SCH 3 alkylamino, including -CH 2 NH 2 alkylaminoalkyl or alkylaninodialkyl, including CH 2 NH(CH 3 and CH 2 N(CH) 2 oxyalkyl, including -OCH 3 carboalkoxy, including carnomethoxy; allyl, aryl and thioalkyl, including -SCH1 3 R 3 R 5 and R 6 are independently hydrogen, alkyl, including -OH 3 alkyihydroxy. including -CH 2 OH; alkyloxyalkyl, including -CH 2 0CH 3 alkylthioalkyl, including -CH 2 SCH 3 alkylanino, including -CH 2 NH 2 alkylaminoalkyl or alkylaminodialkyl, including CH 2 NH(CH 3 and CH2N(CH 3 oxyalkyl, including -OCH 3 thioalkyl, including -SCH 3 halo, including C1. F; haloalkyl, including CF:; NH 2 alkylamino or dialkyle-idw.h, including -N(CH 3 2 and -NHCH 3 cyclic dialkylamino, including o -No -NN -N CH 3 -N N-CH 2 CH 2 OH ainidine, cyclic amidine including and their N-alkyl derivatives; 0 0 -CO 2 H; OO 2 alkYl, including -C0 2 CH 3 -O(O)alkyl, including -O(O)0H 3 -CN, C(O)NH 2 -O(O)NH(alkyl), -C(Oj)N(alkyl) 2 including -C(O)N(CH.j 2 allYl, -S0 2 (alkYl), -SO2aryl, including -S0 2 ,(COH 5 J, -S (O)alkyl, -S (Ojaryl, aryl, heteroaryl; or -S 2 a) R 5 and R,3 together can be alkylidene or haloalkylidene, including -OH 2 and OF 2 epoxide episulfide imino (-N(alkylj- or or a fused aryl or heteroaryl ring including a fused phenyl ring; R, is independently hydrogen, alkyl, including 0H3; alkenyl including -OH 2 HO=CH,; alkyihydroxy, including -0H 2 -OH; alkyloxyalkyl including -CH 2 -O- (alkyl), alkylamine, including -OH 2 NH 2 carboxylate, C(O)Oalkyl, including OO 2 Me; C(O)Oaryl, O(O)Oheteroaryl, GO~aralkyl, -ON, Q, C(Oj)Q, -alkyl(Qj, -alkenyi 0: alkynyl(Q), -NH-Q or -N(alkyl)-Q; R 2 and R 3 together can be or OH(OH)-N(R 8 wherein R' can be alkyl, aryl including phenyl or heteroaryl; R 7 is hydrogen, alkyl, including CHS, or CH 2 CH 3 alkyl substituted with one or more halogens, including 0H 2 0H 2 01; -CH 2 -(cycloalkyl), including -OH 2 (cyclopropyl); -OH 2 OH=0H 2 -0H 2 0H 2 .(0 6 H 5 alkyihydroxy, including OH',OH 2 OH, alkylamino(alkyl) 2 including OH 2 OH 2 N(0H,) 2 alkyloxyalkyl, alkylthioalkyl, aryl, *dialkyl to form a quarternary ammonium including 116 irII2 -C-H; N N-fR' 14"y N-R -C-",Vi-C.Hyi H N ~N jower alkyl: or z AllAl z -(CH)NR-P-FOO(CHK)N (P-R 0 -(CH 2 0O}1.-S -R' 0 0 0 0 -CH 2 CC(CH3)h, -C 2 0C- aryl -C 2 OC-S4 wherein Rg is hydrogen or alkyl; wherein Yis CN, NO 2 alkyk, OH, -0-alkyl; wherein Z is 0 or S wherein R' and R" are each independently -OH, -0-alkyl, -0-aryl, -NH 2 -NH(alkyl), -N(alkyl) 2 -NH(aryl) and -N(aryl) 2 N 13 0 be C 0**e V LTI 118 N 55CH 3 N CH3 119 NC N C. N 0% a CO as 0 .00 0 0* SC \N NI ~n~nrr~qlus~-- and wherein the Q moiety can be optionally substituted with 1 to 3 W substituents; and W is alkyl, including CH3; halo, including C1 and F, aryl, heteroaryl, OH, oxyalkyl, including -OCHa; SH; thioalkyl, including -SCH;; -SO(alkyl) including -SOCHa; -SO 2 alkyl, including -SOzCH 3 -OCH2CH=CHz, -OCH 2 (CH5), CF., CN, alkylenedioxy, including -methylenedioxy-, -COzH, -COzalkyl, including -CO 2 CHa; -OCH2CH20H, -NOz, -NH 2 -NH(alkyl), including -NHCH,; -N(alkyl), including -N(CH 3 2 -NHC(O)alkyl, including -NHC(O)CH;; -S0 2 CFa, or -NHCHzaryl, including -NHCH,(CoHs); and wherein the indicates an optional double bond, provided that when R 1 R Z R 4 and R' are H, R7 is H, alkyl, -CHz- (cylcoalkyl), alkyl substituted with one or more halogens, -CH2CH=CH, or alkylhydroxy, and one of R 3 and RO is H, then the other of R 3 and R 6 is not aryl or heteroaryl: and further provided that when R 1 R 4 R 5 and RO are H and R 7 is H or methyl, R 2 and R are not both -CO 2 CH 3 and when R 2 R 3 and R 4 are H and R 7 is H or methyl, R 5 and RO are not both -CO 2 CHa.

22. The method of claim 21, wherein the compound is administered in an amount ranging between 0.002 and 10 mg/kg per day.

23. The method of claim 21, wherein the compound is administered in an amount ranging between 0.02 and 0.2 mg/kg per day.

24. The method of claim 21, wherein the compound is applied topically in a See, dosage ranging between 0.001% and 0.5% wt/wt in a carrier suitable for topical administration.

25. The method of claim 21, wherein the compound is administered by intravenous injection.

26. The method of claim 21, wherein the compound is administered orally.

27. The method of claim 21, wherein the compound is administered topically. I~ea 120/1

28. A process for the preparation of 7-azabicyclo [2.2.1I]-heptanes and -heptenes, comprising the steps of combining a pentaammineosmium(II) complex of an optionally substituted pyrrole and a dipolarophile to form an optionally substituted 7- azabicyclo[2.2.1]heptene osmium complex; and then (ii) removing the pentaammineosmium from the 7- azabicyclo[2.2.1]heptene.

29. The process of claim 28, wherein the pyrrole is selected from the group consisting of 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, 2,5-dialkoxypyrrole, and 3,4-dialkoxypyrrole. The process of claim 28, wherein the dipolarophile is wherein Z' and Z 2 are electron-withdrawing groups.

31. The process of claim 30, wherein Z 1 and Z' are independently selected from the group consisting of CO(alkyl, aryl or heteroaryl), C(0)H, C0 2 (alkyl, aryl or heteroaryl), or S 2 Oz(alkyl, aryl or heteroaryl), or wherein Z' and Z 2 are together (CO) 2 0 or (CO) 2 NR 6 wherein R" is alkyl including CH 3 or C 2 H 5 aryl including phenyl or heteroaryl.

32. The process of claim 28, wherein the dipolarophile is selected from the :group consisting of 3-vinyl-pyridine, N-methylated and 6-carboxylated pyridyl acrylates, alkyl acrylate, alkyl methacrylate, pyridyl substituted vinyl sulfones, acrylonitriles, anhydrides, maleimides, alpha-methylene-5-butyrolactone, maleate and fumarate.

33. The process of claim 28, wherein 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.

34. The process of claim 28, wherein the counteranion of the pentaammineosmium is selected from the group consisting of CF3SO 3 PFG, and (alkyl or aryl) SO, The process of claim 33, wherein the reducing agent is selected from the group consisting o1 magnesium, zinc, aluminium, sodium, lithium and cobaltacene. I I~

36. The process of claim 33, wherein the optionally substituted pyrrole, pentaammineosmium(III), and reducing agent are stirred at a temperature ranging between 0 and 50 degrees C, until the desired organometallic complex is formed.

37. The process of claim 28, further comprising derivatizing functional groups on the 7-azabicyclo{2.2.1}heptene while pentaammineosmium is complexed to the pi-orbital of the heptene moiety.

38. The process of claim 28, further comprising reducing the optionally substituted 7-azabicyclo[2.2.1]heptene to an optionally substituted 7- azabicyclo[2.2.1]heptane.

39. A process for the preparation of optionally substituted 7-azabicyclo[2-2.1]- heptanes and -heptenes, comprising the steps of combining a N-(electron withdrawing substituted)-optionally substituted pyrrole with an arylsulfonyl(optionally substituted aryl or heterocyclic)acetylene. The process of claim 39, wherein the pyrrole is selected from the group consisting of 3,4-di(CF3)pyrrole, 3-(thioalkyl)pyrrole, 2,5-dialkylpyrrole, 3,4- .bis(trifluoromethyl)-pyrrole, 2-akylpyrrole, 2-alkoxyalkylpyrrole, 2- alkylthioalkylpyrrole, 2-dialkylaminoalkylpyrrole, alkylpyrrole 2-acetate, 2- alkoxyalkoxyalkylpyrrole, 3-aryloxyalkylpyrrole, 2-alkoxypyrrole, 3-alkoxypyrrole, 3-aryloxypyrrole, 3,4-dialkylpyrrole, and 3-alkylpyrrole.

41. The process of claim 39, wherein the N-electron-withdrawing group is selected from the group consisting of carbomethoxy, carbobenzyloxy, and tert- butoxycarbonyl. o

42. A pharmaceutical composition comprising an effective amount to impart analgesia to a mammal of the compound of claim 1 or its pharmaceutically acceptable salt, in a pharmaceutically acceptable carrier or diluent.

43. A pharmaceutical composition comprising an effective amount to treat infio-,.ation in a mammal of the compound of claim 1 or its pharmaceutically acceptable salt, in a pharmaceutically acceptable carrier or diluent. g -I, MIS-6 123

44. The method of claim 14, wherein the mammal is a human. The method of claim 21, wherein the mammal is a human.

46. The pharmaceutical composition of claim 43, wherein the mammal is a human. I