AU2006235898A1 - 3-(diarylmethylene)-8-azabicyclo[3.2.1]octane derivatives - Google Patents

Description

-1-

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name of Applicant/s: Actual Inventor/s: Ortho-McNeil Pharmaceutical, Inc.

John R. Carson and Robert E. Boyd and Steven J Coats and Lou Anne Neilson and Philip M Pitis and Wu-Nan Wu Address for Service is: SHELSTON IP Margaret Street SYDNEY NSW 2000 CCN: 3710000352 Attorney Code: SW Telephone No: Facsimile No.

(02) 97771111 (02) 9241 4666 Invention Title: 3-(DIARYLMETHYLENE)-8-AZABICYCLO[3.2.1 ]OCTANE

DERIVATIVES

Details of Original Application No. 2001241676 dated 22 Feb 2001 The following statement is a full description of this invention, including the best method of performing it known to me/us:- File: 36466AUP01 501015657 1.DOC/5844 la- 3-(DIARYLMETHYLENE)-8-AZABICYCLO[3.2. I]OCTANE DERIVATIVES The present application is a divisional application of Australian Application No.

2001241676, which is incorporated in its entirety herein by reference.

FIELD OF THE INVENTION The present invention is directed to compounds useful as delta-opioid and muopioid receptor modulators. More particularly, the present invention is directed to 3- (diarylmethylene)-8-azabicyclo[3.2.1]octane derivatives useful as delta-opioid or muopioid receptor modulators.

BACKGROUND OF THE INVENTION WO 97/23466 describes compounds as having an analgesic effect of a general and one preferred formula: N R R R4 R NR R3 G A B

R

2

N

WO 98/28270 describes compounds as having an analgesic effect of a general and one preferred formula: -2- AN B (CH2)m, (CH2)n

N

R

1

N

1

N

WO 98/28275 describes compounds as having an analgesic effect of a general and one preferred formula: A B

R

3 N 2R 2 NH2 Amide derivatives of 3-aminotropane have been prepared and described as having potential pharmacological activity (Gutkowska, et al., Acta Pol.

Pharm., 1984, 41(6), 613-617), of the formula:

CIN

0

N

00 00 WO 93/15062 describes compounds as delta-oploid (6-opioid) and mu-opioid L-opioid) receptor agonists of (approximately) the general formula:

R

HO".'

R R RN R The synthesis and binding affinities for 4 -Diarylaminotropane compounds as &,opioid agonists; have been described (Boyd, Carson, Codd, Gauthier, Neilson, L.A and Zhang, Biorg. Med.

Chem. Lett., 2000, 10: 1109-1111 of the general formula: 0 IND -4- 0 wherein R is hydrogen, methyl, propyl, hexyl, 2-ethylbutyl, allyl, 3,3-dimethallyl, cyclohexylmethyl, phenethyl, phenylpropyl, 2,2-diphenylethyl,

O

z 3,4-dimethoxyphenethyl, 4-fluorophenethyl, 2-furylmethyl, 3,4-methylenedioxybenzyl, cyano and X is N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, N-methyl-N-ethylamino, 00 N-methyl-N-propylamino, N-methyl-N-phenylamino, N-ethyl-N-(4- 0o methyl)benzylamino, N-butyl-N-ethylamino, N-butyl-N-propylamino, n [N-ethyl-N-(2-methyl)allyl]amino, hydroxy, O-t-butyl and 1-pyrrolidinyl; and, Y is D0 hydrogen, methoxy and methylthio.

0 Other selective 4-[(8-alkyl-8-azabicyclo[3.2.1] octyl-3-yl)-3-arylanilino]- N,N-diethylbenzamide 8-opioid ligands have also been described (Thomas, Atkinson, Rothman, Burgess, Mascarella, Dersch, Xu, H. and Carroll, Biorg. Med. Chem. Lett., 2000, 10: 1281-1284).

The present invention is directed to compounds useful as delta-opioid and mu-opioid receptor modulators. More particularly, the present invention is directed to delta-opioid and mu-opioid receptor modulators.

It is an object of the present invention to provide 3-(diarylmethylene)-8azabicyclo[3.2.1]octane derivatives useful as -opioid or -opioid receptor modulators. It is also an object of the present invention to provide 8-opioid and p-opioid receptor selective agonists as analgesics having reduced side-effects.

It is another object of the present invention to provide -opioid and g-opioid receptor selective antagonists as immunosuppressants, antiinflammatory agents, agents for the treatment of neurological and psychiatric conditions, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and agents for the treatment of respiratory diseases, having reduced side-effects. It is also another object of the present invention to provide a useful pharmaceutical composition comprising a compound of the present invention useful as a 5-opioid or p-opioid receptor modulator. It is a further object of the present invention to provide a useful IND pharmaceutical composition comprising a 6-opioid or ji-opioid receptor modulator compound of Formula in combination with a g-opioid receptor Z modulator or a 8-opioid or p.-opioid receptor modulator compound of Formula wherein the combination has a synergistic therapeutic effect.

00 5 SUMMARY OF THE INVENTION 00 The present invention provides an opioid receptor modulator compound IND selected from the group consisting of a 8-opioid and a g-opioid receptor modulator compound of Formula R 2 R-A-Z

N

R

WI

wherein: R' is selected from the group consisting of hydrogen, CI- 4 alkyl, halo 1 -3(C, 1 )alkyl,

C

24 6alkenyl, Cl 8 al koxy(C 24 8)alkenyl, C 2 4 al kynyl, C 1 -,aikoxy(C 2 4 .)alkynyl, cycloalkyl, cycloalkyl(C 18 ,)alkyl, cycloalkylcarbonyl(C 14 ,)alkyl, cycloalkyl(C 24 ,)aI kenyl, cycloalkyl(C 24 ,)alkynyl, heterocyclyl, heterocyclyl(C 14 ,)alkyl, heterocyclylcarbonyl(C 14 ,)alkyl, heterocyclyl(C 24 ,)alkenyl, heterocyclyl(C 24 ,)alkynyl, aryl, aryl(C 14 )alkyl, aryicarbonyl(Cl-8)alkyl, aryl(0 24 )alkenyl, aryl(C 24 ,)alkynyl, arylaminocarbonyl(C 14 ,)alkyl, heteroaryl(C, 1 ,)alkyl, heteroarylcarbonyl(0 1 4 ,)alkyl, heteroaryl(C 2 -8)alkenyl, heteroaryl(C 2 -,)alkynyl, heteroarylaminocarbonyl(0 14 8)alkyl, (R'a) 2

-N-(C

14 ,)alkyl, R la -O-(Cta)alkyl, Rla-S-(C 1 ,)alkyl, Rla-SO-(C 1 ,)alkyI and Rla-S0 2 wherein IND -6heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of C, 4 6alkyl, C 2 -6alkenyl, Z Clalkoxy, amino, C 14 6alkylamino, di(C 1 -6alkyI)amino, C 14 alkylcarbonyl,

C

1 -,alkylcarbonyloxy, C 1 ,al kylcarbo nyl amino, Cl 14 alkylthio, C 14 ,alkylsulfonyl, halogen, hydroxy, oxo, cyano, trifluoromethyl and trifluoromethoxy; and, 00 wherein aryl and heteroaryl are optionally substituted with one to three 00 substituents; independently selected from the group consisting of C 14 6a~kyl,

C

2 ,alkenyl, C, 14 alkoxy, amino, Cl.

8 alkylamino, di(C, 14 alkyl)amino,

C,

1 6alkylcarbonyl, C, 14 alkylcarbonyloxy, C 14 ,alkylcarbonylamino, C, 14 alkylthio, C,,alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy;

R

1 is. independently selected from the group consisting of hydrogen, C 1 -,alkyI, C,.,alkoxy(C, 1 ,)alkyl, hydroxy(C 14 ,)alkyl, halo 1 -3(C 14 ,)alkyl, halo 1 -3(C 14 ,)alkoxy(C, 1 8)alkyl, C 2 -,alkenyl, C 2 -,alkynyl, cycloalkyl, cycloalkyl(C 1 ,)alkyl, heterocyclyl, heterocyclyl(C 14 )alkyl, heterocycly](C 1 4 ,)alkenyl, heterocyclyl(C, 14 )alkynyl, aryl, aryl (0 14 )akyl, aryl(C 14 a)alkenyl, aryl(C 1 -8)alkynyl, arylcarbonyl(C 14 ,)alkyl, heteroaryl, heteroaryl(Cl-8)alkyl, heteroaryl(C 14 8)alkenyl, heteroaryl(C 14 ,)alkynyl and heteroarylcarbonyl(C 14 ,)alkyl; wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of Cl.,alkyl, C 2 6alkenyl, C 14 ,alkoxy, amino, Cl.,alkylamino, di(C 14 ,alkyl)amino, C 1 .,alkylcarbonyl, C 14 ,alkylcarbonyloxy,

C

1 .,akylcarbonylamino,

C,

1 ,alkylthio, Cl.,alkylsulfonyl, halogen, hydroxy, oxo, cyano, trifluoromethyl and trfuoromethoxy; and, wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C, 14 alkyI, C, 2 ,alkenyl, C,.,alkoxy, amino, C, 4 6alkylamino, di(C, 14 alkyl)amino, Cl-,alkylcarbonyl, Cl.,alkylcarbonyloxy, Cl-6alkylcarbonylamino, Cl 14 alkylthio, C 14 ,alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy;

R

2 is selected from the group consisting of aryl and heteroaryl optionally substituted with one to three substituents independently selected from the IN7D group consisting of C 14 6alkyl, C 2 akey, 1 alkoxy, amino, C, a kylamino, di(C, 14 alkyl)amino, C 1 .,alkylcarbonyl, C 14 alkylcarbonyloxy, Z Cl 4 alkyloxycarbonyl, C 16 alkylaminocarbonyl, C,.,alkylcarbonyiamino, Cl 1 ,alkylthio, C 1 -,alkylsulfonyI, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy; alternatively, when aryl and heteroaryl are substituted with 0C) two substituents attached to adjacent carbon atoms, the two substituents 00 can together form a single fused moiety; wherein the moiety is selected from the group consisting of -(CH 23 1 5 and -O(CH 2 1 3 0-; RI is selected from the group consisting of aryl and heteroaryl optionally substituted with one or two substituents in addition to the -A-Z moiety independently selected from the group consisting of C, 4 ,alkyl, C 2 .,alkenyl,

C,

1 ,alkoxy, amino, C 1 ~alkylamino, di(C,.6alkyl)amino, Cl-6alkylcarbonyl,

C

14 ,alkylcarbonyloxy,

C,

1 ,alkyloxycarbonyI,

C

1 .alkylaminocarbonyl,

C

14 alkylcarbonylamino, C,.,alkylthio, Cl.,alkylsuffonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy; alternatively, when aryl and heteroaryl are substituted with two optional substituents attached to adjacent carbon atoms, the two substituents can together form a single fused moiety; wherein the moiety is selected from the group consisting of

-(CH

2 and -O(CH 2 1 -3O-; A is selected from the group consisting of and -SO 2 X is selected from the group consisting of 0 and S; Z is selected from the group consisting of -0(R 4) and -N(R 5 6 R 4 is selected from the group consisting of hydrogen, C 1 -,alkyl (optionally substituted with one to three halogen substituents), C 14 ,alkoxy(C 1 -,)alkyl,

C

24 ,alkenyl, cycloal kyl, cycloa lkyl(C 1 kyl, heterocyclyl, heterocycyl(C, 14 )al kyl, aryl, aryl(Cl-8)alkyl, heteroaryl, heteroaryl(Cl,)alkyl, amino(C 1 .,)alkyl, C 1 -8alkylamino(C,,)alkyl, di(C 1 -8)alkylamino(C 1 -8)alkyl and hydroxy(C 1 ,)alkyl; wherein heterocyclyl is optionally substituted with one to INO -8three substituents independently selected from the group consisting of

C

1 -6alkyl, Cl 1 ,alkoxy, C 26 alkenyl, cycloalkyl, tnifluoromethyl, halogen, Z hydroxy, oxo and cyano: and, wherein aryl is optionally substituted with one to four substituents independently selected from the group consisting of

C

14 ,alkyl, Cl 1 ,alkoxy, C, 2 ,alkenyl, cycloalkyl, -OCH 2

-O(CH

2 2 0-, 00 trifluoromethyl, halogen, hydroxy and cyano; and, 00 M R' and R' are independently selected from the group consisting of hydrogen, INO C 14 ,alkyI (optionally substituted with one to three halogen substituents),

C

14 ,alkoxy(C 1 .,)alkyl, C 24 ,alkenyl, cycloalkyl, cycloalkyl(C, 4 ,)alkyl, heterocyclyl, heterocyclyl(C,,)alkyl, aryl, aryl(C 1 -,)alkyl, heteroaryl, heteroary(Cl-8)alkyl, amino(C 14 ,)alkyl, C, 4 ,alkylamino(C 1 -,)alkyl, di(C 14 ,)alkylamino(C 14 )alkyl, aminoimino, aminocarbonyl, aminocarbonyl(C-,)alky, aryloxycarbonylamino(C 1 -,)alkyl, heteroaryloxycarbonylamino(C.

8 )alkyl, hydroxy(C 1 .8)alkyl and trifluoro(C,)alkoxy; wherein heterocyclyl is optionally substituted with one to three substituents; independently selected from the group consisting of

C,

1 8alkyI, C 1 .8alkoxy, C 24 ,alkenyl, cycloalkyl, trifluoromethyl, halogen, hydroxy, oxo and cyano; and, wherein aryl is optionally substituted with one to four substituents independently selected from the group consisting of

C,

1 8alkyl, C 14 6alkoxy, C 2 ,alkenyl, cycloalkyl, -OCH 2

-O(CH

2 2 0-, trifiuoromethyl, halogen, hydroxy and cyano; alternatively, R 5 and R" may, together with the nitrogen to which they are attached, form a fused heterocyclyl moiety optionally substituted with one to four substituents independently selected from the group consisting of C 14 ,alkyl, C 14 6alkoxy,

C

2 6alkenyl, cycloalkyl, tnifluoromethyl, halogen, hydroxy and cyano; and pharmaceutically acceptable enantiomers, diastereomers; and salts thereof.

DETAILED DESCRIPTION OF THE INVENTION Embodiments of a compound of Formula include those compounds I-9wherein, preferably, R' is selected from the group consisting of hydrogen, Cl 1 ,alkyl, C 2 -,alkenyl, C 2 -,alkynyl, cycloalkyl, cycloalkyl(C 1 .,)alkyl, heterocyclyl, z heterocyclyl(C,,)alkyl, heterocyclylcarbonyl(C 1 4 ,)alkyl, aryl(C 1 -,)alkyl, arylcarbonyl(C 1 -,)alkyl, aryl(C 2 8 )alkynyl, arylaminocarbonyl(C.

8 )alkyl, heteroaryl(C 14 ,)alkyl, (Rla) 2

-N-(C

1 .)alkyl and Rla-O-(C, 14 )alkyI; wherein 00 heterocyclyl is optionally substituted with one to three substituents 00 independently selected from the group consisting of C, 14 alkyl, C,,alkoxy, rn halogen, hydroxy, oxo and cyano; and, wherein aryl is optionally substituted with one to three substituents independently selected from the group consisting of Cl 14 alkyl, C, 14 alkoxy, halogen, hydroxy and cyano.

More preferably, R' is selected from the group consisting of hydroge n, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-hexyl, butenyl, allyl, 3,3-dimethallyi, cyclopropyl, cyclopropyl(C 14 3)alkyl, cyclohexyl, cyclohexyl(C.

3 )alkyl, pyrrolidinyl, pyrrolidinyl(C 1 -3)alkyl, 1 ,3-dioxoanyl(C.-,)alkyl, 2-pyrdazolinyl, 2-yrazolinyl(C 4 )alkyl, pyrazolidinyl, yrazol idinyl(C-3)alkyl, piperidinyl, piperidinyl(C 14 3)alkyl, morpholinyl, morpholinyl(C 14 3)alkyl, thiomorpholinyl, thiomorpholinyl(C,,)alkyl, piperazinyl, piperazinyl(C.

3 )alkyl, [4-

(C

1 ,)alkyl-5-oxo-1 ,4-dihydrotetrazol-1-yl(C 14 3)akyl, piperanyl, (1 ,3-benzodioxol- 5-yl)(C2.)alkyl, (2,3-dihydro-1 ,4-benzodioxin-6-yl)carbonyl(C 1 -3)alkyl, (3,4dihydro-2H-1 ,5-benzodioxepin-7-yl)carbonyl(c 4 -)alkyl, benzyl, phenyl(C 2 .3)alkyl, phenyl(C 2 4 3)alkynyl, diphenyl(C 14 3)alkyi, phenylcarbonyl(C,,)alkyl, phenylaminocarbonyl(C 14 )alkyl, furyl(C 14 3)alkyl, thienyl(C,-3alkyl, pyrrolyl(Cj~alkyll, oxazolyl(Cl-3)alkyl, thiazolyl(C 14 )alkyl, imidazolyi(C 14 ,)alkyl, oxadiazolyl(C..

3 )alkyl, I ,2,3-triazolyl(C 1 ~)alkyl, 1 ,3,4-thiad iazoly](C,.

3 )alkyl, pyridinyl(0 14 )alkyl, pyddazinyl(C, 4 3)alkyl, pyri mid inyl(C, )alkyl.

pyrazinyl(C 1 3 )alkyl, 1 ,3,5-triazinyl(C 1 -3)alkyl, indolyi(C 1 3 )alkyl, benzo[b]furyl(C 1 -3)alkyl, benzo[b]thienyl(C 1 3 )alkyl, (Rla) 2 -N-(Cl 13 )alkyl and

R

18

-O-(C

1 -3)alkyl; wherein pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are optionally substituted with one to three substituents selected from oxo; and, wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, methoxy, ethoxy, propoxy, butoxy, chlorine, fluorine, hydroxy and cyano.

00 Most preferably, R' is selected from the group consisting of hydrogen, methyl, n-propyl, n-butyl, allyl, 3,3-dimethallyl, cyclopropylmethyl, cyclohexylethyl, 2-(4-ethyl-5-oxo-1 ,4-dihydrotetrazol-1-yl)ethyl, piperonyl, 2- IND(1,3-benzodioxol-5-yl)ethyl, 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl, 2- (3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-2-oxoethyl, benzyl, phenethyl, phenylpropyl, phenoxyethyl, phenylcarbonylmethyl, phenylcarbonylethyl, phenylaminocarbonylmethyl, thienylmethyl, thienylethyl, imidazolylmethyl, pyridinylmethyl and indolylethyl; wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of methoxy, fluorine, hydroxy and cyano.

Embodiments of a compound of Formula include those compounds wherein, preferably, is independently selected from the group consisting of hydrogen, C,.alkyl and aryl; wherein aryl is optionally substituted with one to three substituents independently selected from the group consisting of

C,

4 alkyl, C 24 alkenyl, C, 4 alkoxy, amino, C, 4 alkylamino, di(C, 4 alkyl)amino,

C,

4 alkylcarbonyl, C,,alkylcarbonyloxy, Cjalkylcarbonylamino, C,,alkylthio, C,.alkylsuffonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy.

More preferably, is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl and phenyl; wherein phenyl is optionally substituted with one to three substituents independently selected from the group consisting of C, 4 alkyl, C, 4 alkoxy, di(C, 4 alkyl)amino, halogen, trifluoromethyl and trifluoromethoxy. Most preferably, is independently selected from the group consisting of methyl, ethyl and phenyl.

Embodiments of a compound of Formula include those compounds wherein, preferably, R 2 is selected from the group consisting of phenyl, naphthalenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1 .2,3-oxadiazolyl, 1 ,2,3-triazolyl, 1,.3,4-thiadiazolyl, pynidinyl, pyridazinyl, pyriniidinyl, pyrazinyl, 1 ,3,5-triazinyl, indolyl, benzo[b~furyl Z and benzo~b]thienyl optionally substituted with one to three substituents independently selected from the group consisting of C 13 alkyl, C 23 alkenyl,

C,-

3 alkoxy, amino, C, 13 alkylamino, di(C, 14 alkyI)amino, C 13 alkylcarbonyl, 00 C 1 -3alkylcarbonyloxy, C 13 alkylcarbonylamino, chlorine, fluorine, hydroxy, 00 trifluoromethyl and trifluoromethoxy.

IND More preferably, R 2 is selected from the group consisting of phenyl, furyl, thienyl, pyridinyl and benzo~b]furyl optionally substituted with one substftuent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, d imethylamnino, diethylamino, methylcarbonyl, methylcarbonyloxy, methylcarbonylamino, fluorine, hyd roxy, trifluoromethyl and trifluoromethoxy.

Most preferably, RI is selected from phenyl optionally substituted with one substituent selected from the group consisting of methoxy and hydroxy.

Embodiments of a compound of Formula include those compounds wherein, preferably, R' is selected from the group consisting of phenyl, naphthalenyl, furyl, thienyl, pyrrolyl, oxazolyll, thiazolyl,. imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, I .2,3-oxadiazolyl, 1 ,2,3-triazolyl, I .3,4-thiadiazolyl, pynidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazinyl, indolyl, benzo~b]furyl and benzo[b]thienyl optionally substituted with one or two substituents in addIftion to the -A-Z moiety independently selected from the group consisting of methyl, ethyl, n-propyl, i-propyll, allyl, methoxy, ethoxy, amino, C,-3alkylamino, di(C 1 -3)alkylamino, C, 1 3alkylcarbonyl, C, 1 3alkylcarbonyloxy,

C

1 3 alkylcarbonyl,

C

1 -3alkylaminocarbonyl,

C

1 3 alkylcarbonylamino,

C

14 3alkylthio, Cl- 3 alkylsulfonyl, chloro, fluoro, hydroxy, cyano, trifluoromethyl and trifluoromethoxy; alternatively, when phenyl is substituted with two optional substituents attached to adjacent carbon atoms, the two substituents can together form a single fused moiety; wherein the moiety is selected from the group consisting of

-(CH

2 and -O(CH 2 1 3 0-.

IN -12- O More preferably, R 3 is phenyl substituted with the moiety -A-Z at the 3 or Z 4 position.

Embodiments of a compound of Formula include those compounds oo wherein, preferably, A is 00 CI Embodiments of a compound of Formula include those compounds 0 wherein, preferably, Z is cN An embodiment of a compound of Formula includes those compounds wherein, preferably, R 4 is selected from the group consisting of C,,alkyl (optionally substituted with one to three halogen substituents),

C

2 -alkenyl, aryl and aryl(C,,)alkyl; wherein aryl is optionally substituted with one to two substituents independently selected from the group consisting of

C,

1 alkyl, -OCH20-, -O(CH 2 2 0- and halogen.

More preferably, R 4 is selected from the group consisting of C, 1 alkyl (optionally substituted with one or three fluorine substituents), C 24 alkenyl, phenyl and benzyl; wherein phenyl is optionally substituted with one to two substituents independently selected from the group consisting of C,3alkyl,

-O(CH

2 2 0- and fluorine.

Most preferably, R 4 is selected from the group consisting of methyl, ethyl, 3-methallyl, phenyl and benzyl; wherein phenyl is optionally substituted with one substituent selected from the group consisting of methyl and fluorine.

An embodiment of a compound of Formula includes those compounds wherein, preferably, R 5 and R 6 are independently selected from the group consisting of hydrogen, C,.

4 alkyl, fluoro(C,.

3 )alkyl, trifluoro(C.

3 )alkyl,

C,.

3 alkoxy(C,.3)alkyl, C 2 5 alkenyl, cyclopropyl, cyclopropyl(C,.

3 )alkyl, cyclopentyl, cyclopentyl(C.

3 )alkyl, cyclohexyl, cyclohexyl(C,.

3 )alkyl, pyrrolidinyl, pyrrolidinyl(C,.

3 )alkyl, 1,3-dioxolanyl, 1,3-dioxolanyl(C, 3 )alkyl, 2-imidazolinyl, -13- 2-imidazolinyl(C,- 3 )alkyl, irnidazolidinyl, imidazol idinyl(C 13 )alkyl, 2-pyrazolinyl, o 2-pyrazolinyl(C 1 3 )alkyl, pyrazolidinyl(G 1 3 )alkyl, piperidinyl, piperidinyl(C,.

3 )alkyl, Z morpholinyl, morpholinyl(C,- 3 )akyl, thiomorpholinyl, thiomorpholinyl(C 1 3 )alkyl, piperazinyl, piperazinyl(Cl- 3 )alkyl, piperonyl, phenyl, benzyl, phenyl(C 23 )alkyl, furyl, furyl(C 13 )alkyl, thienyl, thienyl(C 1 3 )alkyl, pyrrolyl(C,..

3 )alkyl, oxazolyl, 00 oxazolyl(C 1 3 )alkyl, thiazolyl, thiazolyl(C 1 ~alkyl, imidazolyl, imidazolyl(C 1 3 )alkyl, 00 pyrazolyl, pyrazolyI(C, 1 3)alkyl, isoxazolyl, isoxazolyl(Cl 1 3 )alky, isothiazolyl, isothiazolyl(C 1 3 )alkyl, 1 ,2,3-oxadiazolyl, I ,2,3-oxadiazolyl(Cl- 3 )alkyl, 1 ,2,3-triazolyl, 1,2, 3-triazolyl(C 1 3 )alkyl, 1 ,3,4-thiadiazolyl, 1 ,3,4-thiadiazolyl(Cl.

3 )alkyl, pyridinyl, pyhdinyl(C..

3 )alkyl, pynidazinyl, pyridazinyl(C,-)alkyl, pynimidinyl, pyhmidinyl(C 1 -3)alkyl, pyrazinyl, pyrazinyl(C,- 3 )alkyl, 1 .3,5-triazinyl, 1 ,3,5-triazinyl(Cl.3)alky, indoYl(C..

3 )alkyl' benzo[blfuryl, benzo[b]furyl(C 1 -3)alkyl, benzo~b]th lenyl, benzo[b]thieny(C 1 4 3)alkyl, benzimidazolyl, benzimidazolyl(C 1 -)alkyl, amino(C 1 3 alkyl, Cl.

3 alkylamino(C 1 3 )alkyl, di(C 1 -3)alkylamino(C, 1 3)alkyl, amninoimino, hydroxy(C 1 -3)alkyl and trifluoro(C 1 4 )alkoxy; wherein pyrrolidinyl, I ,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomnorpholinyl, piperazinyl are optionally substituted with one to three substituents independently selected from the group consisting of C 14 alkyl and oxo; and, wherein phenyl is optionally substituted with one to four substituents independently selected from the group consisting of C 1 4 alkyI, C,,alkoxy, -OCH 2

-O(CH

2 2 halogen, hydroxy and cyano; alternatively, R and R' may, together with the nitrogen to which they are attached, form a fused heterocyclyl moiety selected from the group consisting of pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pipenidinyl, morpholinyl, thiomnorpholinyl and piperazinyl optionally substituted with one to four substituents independently selected from C 1 ~alkyl.

More preferably, R 5 and R' are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, t-butyl, fluoro(Cl.

3 )alkyl, methoxy(C 1 3 )alkyl, methallyl, cyclopropyl, cyclohexyl, phenyl, thiazolyl, imidazoly(C.-,)alkyl, benzirnidazolyl(C.

3 )alkyl, dimethylamino(C,- 3 )alkyl and hydroxy(C, 1 3)alkyl; wherein phenyl is optionally substituted with one to three -14c substituents selected from fluorine; alternatively, R 5 and R 6 may, together with Sthe nitrogen to which they are attached, form a fused heterocyclyl moiety Sselected from the group consisting of pyrrolidinyl, piperidinyl and morpholinyl 0 optionally substituted with one to four substituents independently selected from the group consisting of methyl, ethyl, n-propyl and n-butyl.

0o 0 Most preferably, R 5 and R 8 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, t-butyl, 2-fluoroethyl, Smethoxyethyl, methallyl, cyclopropyl, cyclohexyl, phenyl, thiazolyl, c 2-(2-imidazolyl)ethyl, benzimidazolylmethyl, dimethylaminopropyl and hydroxyethyl; wherein phenyl is optionally substituted with fluorine; alteratively, R 5 and R 6 may, together with the nitrogen to which they are attached, form a fused heterocyclyl moiety selected from the group consisting of pyrrolidinyl, piperidinyl and morpholinyl; wherein piperidinyl is substituted with two or four substituents selected from methyl.

Table 1 lists compounds exemplified in the present invention of the formula: Table 1

X

z

N

R

1 wherein the moiety is substituted on phenyl at the 3 or 4 position and and Z are dependently selected from the group consisting of: Ex R 1

Z

1 methyl N,N-diethylamino; 2 H allyl 7 2-(4-fluorophenyl )ethyl 8 2-(2-thienyl)ethyl 9 2-(3-indolyl)ethyl 2-cyciohexylethyl 11 2-phenoxyethyl 12 2-(4-ethyl-5-oxo-1,4dihydrotetrazol-1 -yl )ethyl 13 2-pheny!-2-oxoethyl 14 2-(4-methoxyphenyl)-2oxoethyl 2-(3-.cyanophenyl)-2oxoethyl 16 2-(2,3-dihydro-1 14benzodioxin-6-yl)-2oxoethyl 17 2-(3,4-dihydro-2H-1 15benzodioxepin-7-yl oxoethyl 18 propyl 19 2-phenylethyl piperonyl 21 3-phenylpropyl 22 methyl 2-phenylethyl 26 2-phenylethyl 29 2-phenylethyl 2-phenylethyl 31 2-phenylethyl 32 2-phenylethyl 33 -hnlty 34 2-phenylethyl 34 2-phenylethyl -4-C(=Oy -4-C(=Oy -4-C(=Oy N,N-diethylamino; N,N-diethylamino; N,N-diethylamino; N, N-d iethyla mino; N ,N-diethylamino; N,N-diethylamino; N,N-diethylamino; N,N-diethylamino; N,N-diethylamino; N ,N-diethylamino; N,N-diethylamino; N,N-diethylamino; N ,N-diethylamino; N,N-diethylamino; N,N-diethylamino; N ,N-diethylamino; N, N-diethylamino; N-methyl-N-(3fluorophenyl)amino; N,N-diethylamino; N-ethylamino; amino; 4-morpholinyl; N,N-diisopropylamino;

N,N-

bis(methoxyethyl )amino; 1 -pyrrolidinyl; 2,6-dimethyl-1 -piperidinyl; N-ethyl-N- (methylallyl)amino; -4-C(=Oy -4-C(=Oy -4-C(=Sy -4-C(=Oy -4-C(=Oy -4-C(=O -4-C(=Oy -4-C(=Oy -16- 36 2-phenylethyl 37 2-phenylethyl 38 2-phenylethyl 39 2-phenylethyl 2-phenylethyl 41 2-phenylethyl 42 2-phenylethyl 43 2-phenylethyl 44 2-phenylethyl 2-phenylethyl 46 2-phenylethyI 47 2-phenylethyl 48 2-(1 ,3-benzodioxol-5yl )ethyl 49 2-(1 ,3-benzodioxol-5yI)ethyl methyl 51 H 52 allyl 53 2-(4-methoxyphenyl )ethyl 54 2-(4-methoxyphenyl )ethyl 2-(4-methoxyphenyl )ethyl 56 2-(4-methoxyphenyi )ethyl 57 2-(4-methoxyphenyl )ethyl 58 2-(4-methoxyphenyl )ethyl 59 2-(4-methoxyphenyl)ethyl 2-(4-methoxyphenyl )ethyl 61 2-(4-methoxyphenyl )ethyl 62 2-(4-methoxyphenyl)ethyl -4-C(=Oy -4-C(=Oy N,N-dipropylamino; N-t-butylamino; N-(2-fluoroethyl)amino; N-(2-thiazolyl)amino; N-(2-methoxyethyl)amino; I H-benzimidazol-2ylmethyl)amino; N-cyclohexylamino; N-phenylamino; N-12-(2imidazolyl)ethyl]amino; N-cyclopropylamino;

N,N-

(dimethylaminopropyl) amino; N-ethyl-N- (hydroxyethyl)amino; N-ethylamino; N,N-diethylamino; N-ethylamino; N-ethylamnino; N-ethylamnino; N, N-diethylamino; 4-morpholinyl; N-ethylamino; N, N-bis(2methoxyethyl)amino; 1 -pyrrolidinyl; 2,6-dimethyl-1 -piperidinyl; N-ethyl-N- (methylallyl)amino; N, N-(di-n-propyl)amino; 2,2,6,6-tetramethyl-1 piperidinyl; N, N-(di-2-propyl)amino; -17- 2-(4-hydroxyphenyl)ethyl 2-(4-hydroxyphenyl)ethyl N-ethylamino; and, N,N-diethylamino; and pharmaceutically acceptable enantiomers, diastereomers and salts thereof.

Table 2 lists compounds exemplified in the present invention of the formula: Table 2 wherein R 1

R

2

R

s and R 6 are dependently selected from the group consisting of: Ex# R' R2 63 methyl 4-MeOPh 64 H 4-HOPh methyl 4-MeOPh Et 2 66 H 4-HOPh Etz; 67 2-(4-MeOPh)ethyl 4-MeOPh Et 2 and, 68 2-(4-HOPh)ethyl 4-HOPh Et 2 and pharmaceutically acceptable enantiomers, diastereomers and salts thereof.

Instant compounds of the invention may also be present in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salt 8 -18 generally takes a form in which the basic nitrogen is protonated with an inorganic or organic acid. Representative organic or inorganic acids include Z hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, 0o oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, 00 salicylic, saccharic or trifluoroacetic.

IN It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

The compounds of this invention are chiral and, thus, may exist as enantiomers. In addition, the compounds may exist as diastereomers. It is to be understood that all such enantiomers and diastereomers, as well as all mixtures thereof, are encompassed within the scope of the present invention.

Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention.

In addition, some of the compounds may form solvates with water hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

The present invention also contemplates a pharmaceutical composition comprising a combination of a 6-opioid or 4-opioid receptor modulator compound of Formula and a opioid receptor modulator compound known to those skilled in the art or a 5-opioid or 4-opioid receptor modulator O -19compound of Formula wherein the combination has a synergistic therapeutic effect.

O

Suitable g-opioid receptor modulator compounds known to those skilled in the art for use in such a combination include, without limitation, the 0o 5 compounds alfentanil, allylprodine, alphaprodine, anileridine, bezitramide, 00 buprenorphine, clonitazene, cyclazocine, dextromoramide, dihydrocodeine, C dihydromorphine, ethoheptazine, ethylmorphine, etonitazene, fentanyl, heroin, Shydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, 0 levorphanol, lofentanil, meperidine, meptazinol, metazocine, methadone, morphine, nalbuphine, norievorphanol, normethadone, nalorphine, normorphine, opium, oxycodone, oxymorphone, phenazocine, piritramide, propiram, propoxyphene, sufentanil, tramadol and diastereomers, salts, complexes and mixtures thereof of any of the foregoing.

The terms used in describing the invention are commonly used and known to those skilled in the art. However, the terms that could have other meanings are hereinafter defined. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.

An "independently" selected substituent refers to a group of substituents, wherein the substituents may be different. Therefore, designated numbers of carbon atoms C,-Ce) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

The term "alkyl" refers to straight and branched-chain alkyl radical groups with 1 to 8 carbon atoms or any number within this range. The terms "alkenyl" and "alkynyl" refer to radical groups having straight and branched chains with 2 to 8 carbon atoms or any number within this range. For alkenyl chains, one double bond is formed between adjacent members of a two or three carbon chain and one or two double bonds are formed between adjacent

INO

0 cN members of a four to eight carbon chain. For alkynyl chains, one triple bond is formed between adjacent members of a two or three carbon chain and one or Z two triple bonds are formed between adjacent members of a four to eight carbon chain. Correspondingly, the terms "alkylene," "alkenylene" and "alkynylene" refer to alkyl, alkenyl and alkynyl linking groups wherein alkyl, 00 alkenyl and alkynyl are as defined supra. Preferably, alkenylene and 0 alkynylene linking group chains have at least one saturated carbon atom on Seach side of the unsaturated bond. More preferably, when an aryl or Sheteroaryl substituent is attached to the terminal carbon of an alkenylene or c 10 alkynylene linking group, at least one saturated carbon atom is between the unsaturated bond and the substituent. The term "alkoxy" refers to O-alkyl groups wherein alkyl is as defined supra.

Whenever the term "alkyl" appears in the name of a substituent hydroxy(C .)alkyl) it shall be interpreted as including those limitations given above for "alkyl." Designated numbers of carbon atoms C, shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyi portion of a larger substituent in which alkyl appears as its prefix root.

The term "cycloalkyl" refers to branched or unbranched cyclic aliphatic hydrocarbon chains of three to seven carbon atom members. Examples of such cyclic alkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "heterocyclyl" refers to a nonaromatic cyclic ring of five to seven members in which one to four members are nitrogen or a nonaromatic cyclic ring of five to seven members in which zero, one or two members are nitrogen and one member is oxygen or sulfur and in which, a) optionally, the ring contains zero, one or two unsaturated bonds; b) optionally, up to three carbon members adjacent to nitrogen members may be oxo substituted.

-21ci Optionally, the heterocyclyl ring is fused: O a) to a benzene ring; Z b) to a 5 or 6 membered heteroaryl containing one of O, S or N and, 0 optionally, one additional nitrogen; c) to a 5 to 7 membered alicyclic ring; 00 d) to a 5 to 7 membered heterocyclyl ring of the same definition as above but 00 00 absent the option of a further fused ring.

O For instant compounds of the invention, the carbon atom ring members cNl 10 that form the heterocyclyl ring are fully saturated. Other compounds of the invention may have a partially saturated heterocyclyl ring. Preferred partially unsaturated heterocyclyl rings may have one or two double bonds. Such compounds are not considered to be fully aromatic and are not referred to as heteroaryl compounds. Therefore, a five member heterocyclyl ring may optionally have a double bond formed in the ring between adjacent ring members; a six or seven member heterocyclyl ring may have two double bonds formed in the ring between adjacent ring members.

The term aryl refers to a single aromatic ring of six carbon members or a bicyclic aromatic ring of ten carbon members. Examples of such aryl rings include phenyl and naphthyl.

The term heteroaryl refers to an aromatic ring of five or six members wherein the ring has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen or sulfur. In the case offive-membered rings, the heteroaryl ring contains one member of nitrogen, oxygen or sulfur and, in addition, may contain up to two additional nitrogens. In the case of sixmembered rings, the heteroaryl ring may contain from one to three nitrogen atoms. For the case wherein the six member ring has three nitrogens, at most two nitrogen atoms are adjacent.

The terms "halo,.

3 (C,,)alkyl," "cycloalkyl(C,.)alkyl" or "hydroxy(C, 4 )alkyl" refer to an alkylene group substituted at the terminal carbon with a halo, 0 -22- N cycloalkyl or hydroxy group, respectively. Similarly, the term O "C, 4 alkoxy(C, 4 )alkenyl" or alkoxy(C 8 )alkynyl" refers to an alkenylene or Z alkynylene group substituted at the terminal carbon with an alkoxy group. The 0term "carbonyl" refers to the linking group Furthermore, the term "methylenedioxy" refers to the substituent moiety -OCH20-, the term S"ethylenedioxy" refers to the substituent moiety -O(CH 2 2 0- and the term 00 2 "trimethylenedioxy" refers to the substituent moiety -O(CH 2 3 The term C "hydroxy" refers to the group -OH and the term "oxo" refers to the group =0.

SThe term "halo" or "halogen" refers to the group iodine, bromine, chlorine and c 10 fluorine.

Where the compounds according to this invention are chiral, they may accordingly exist as enantiomers. In addition, the compounds may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

The terms used in describing the invention are commonly used and known to those skilled in the art. As used herein, the following abbreviations have the indicated meanings: DCE 1,2-dichloroethane Et2O Diethyl ether EtOH Ethanol h Hour KCO, Potassium carbonate MeOH Methanol NaBH 4 Sodium borohydride NaBH(OAc) 3 Sodium triacetoxyborohydride min Minute 2-PrOH 2-Propanol rt Room temperature TiCI, Titanium(IV) tetrachloride General Synthetic Methods Representative compounds of the present invention can be synthesized C -23c in accordance with the general synthetic methods described below and are illustrated in the schemes that follows. Since the schemes are an illustration, Z the invention should not be construed as being limited by the chemical reactions and conditions expressed. The preparation of the various starting materials used in the schemes is well within the skill of persons versed in the 00 art.

00 oO M Scheme 1 describes a general scheme for the preparation of certain Starget 3-(diarylmethylene)-8-azabicyclo[3.2.1]octane derivatives of the Sinvention using synthetic methods to prepare intermediate compounds also intended to be within the scope of the present invention.

A Suzuki reaction is used to couple a boronic acid Compound la with an iodinated Compound lb in the presence of carbon monoxide to produce an intermediate Compound 1c. Alternatively, Compound lb may also be substituted with bromine or OTF (trifluoromethylsulfonyloxy) in place of iodine.

For Compound la and Compound 1 b, the R 2 and R 3 substituents and -A-Z moiety may be varied by using appropriate starting materials or may be added in later steps.

For example, the portion of the -A-Z moiety may be varied using or (more preferably, and the portion of the -A-Z moiety may be varied using -OH, -O(R 4 or (more preferably, -O(R 4 or -N(R 5 to produce other intermediate compounds of the present invention. Similarly, target compounds wherein Z is -O(R 4 and R 4 is hydrogen may be conveniently produced by conventional hydrolysis of the Z is -N(R 5

)(R

6 group; furthermore, other compounds wherein Z is -O(R 4 and R 4 is hydrogen may be esterified by conventional methods to produce other target compounds wherein R 4 is C,.,alkyl.

A Robinson-Schopf condensation is used to prepare tropinone intermediate Compounds le bearing an R 1 substituent on nitrogen by mixing an R' substituted amine Compound le with a succinaldehyde precursor such -24as 2,5-dimethoxytetrahydrofuran and acetonedicarboxylic acid. For a Compound le, the R' substituent may be varied by using appropriate starting materials or may be added in later steps.

Compound Ic and Compound le may be coupled using a titanium mediated "McMurray" reaction to produce a target Compound If.

Scheme 1 00 0O Ci R2-B(OH) 2 Z-A-R3-l CO la lb PdCI 2 (Ph 3

P)

2

R

2

-CO-R

3

-A-Z

Ic CO(CH2COOH) 2) CO(CH 2 COOH) R 1

-NH

2 Id 0

R'

3) NaOH Ic le Scheme 2 describes another general scheme for the preparation of certain 3-(diarylmethylene)-8-azabicyclo[3.2.1]octane derivatives.

As shown below in Scheme 2, the intermediate Compound 1c may be coupled with an 8-methyl-8-azabicyclo[3:2:1]octanone compound using titanium mediated coupling to produce an intermediate Compound 2a.

The intermediate Compound 2a may be treated with 2,2,2-trichloroethyl chloroformate followed by reflux with zinc powder in MeOH to obtain the N-demethylated Compound 2b. Compound 2c is produced by alkylation of Compound 2b with an alkyl halide or reductive alkylation with sodium triacetoxyborohydride and a carbonyl compound.

As desired, the identity of the -A-Z moiety may be varied by conversion of one -A-Z moiety to another. For example, an -A-Z moiety where the -Aportion is and the portion is -O(R 4 the portion may be hydrolyzed to the acid, wherein -O(R 4 becomes -OH. Subsequently, the resulting carboxyl group may be converted to the desired amide; and, conversely, an amide group may be hydrolyzed to an acid.

Scheme 2 0

I

CH

3 R2 R3 A Z 2b

N

I 2a

CH

3 R2 R 3 Z R 2 R3 Z N N H 2b 2c

R

1 As shown in Scheme 3, a Compound 3a wherein X is O may also be further treated with a suitable thionating agent such as P 2

S

5 or Lawesson's Reagent to prepare a Compound 3b wherein X is S.

-26ci Scheme 3

R

5

R

R R N 6 R R N R R R O S 00 Lawesson's \Reagent o0 N 3a N N 3b eC R R Ci The compounds of the present invention may be used to treat mild to moderately severe pain in warm-blooded animals such as humans by administration of an analgesically effective dose. The dosage range would be from about 0.01 mg to about 15,000 mg, in particular from about 0.1 mg to about 3500 mg or, more particularly from about 0.1 mg to about 1000 mg of active ingredient in a regimen of about 1 to 4 times per day for an average kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for active compounds of the invention will vary as will the types of pain being treated.

Examples of pain intended to be within the scope of the present invention include, but are not limited to, centrally mediated pain, peripherally mediated pain, structural or soft tissue injury related pain, progressive disease related pain, neuropathic pain and acute pain such as caused by acute injury, trauma or surgery and chronic pain such as caused by neuropathic conditions, diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-stroke pain syndromes or cluster or migraine headaches.

In regard to the use of the present compounds as immunosuppressants, antiinflammatory agents, agents for the treatment of neurological and psychiatric conditions, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and agents for the treatment of respiratory diseases, a therapeutically effective dose can be determined by persons skilled in the art by the use of established animal N -27- C models. Such a dose would likely fall in the range of from about 0.01 mg to about 15,000 mg of active ingredient administered 1 to 4 times per day for an Z average (70 kg) human.

Pharmaceutical compositions of the invention comprise the formula (I) 0compounds as defined above, particularly in admixture with a pharmaceutically 00 acceptable camrer. Illustrative of the invention, therefore, is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the IDcompounds described above. Another illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. A further illustration of the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrer.

To prepare the pharmaceutical compositions of this invention, one or more compounds of the invention or salt thereof, as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed.

Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding -28c solubility or for preservation, may be included. Injectable suspensions may >also be prepared, in which case appropriate liquid carriers, suspending agents Z and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an oO effective dose as described above.

00oO MThe term "subject" as used herein, refers to an animal, preferably a IDmammal, most preferably a human, who has been the object of treatment, c 10 observation or experiment.

The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

Specific Synthetic Methods Specific compounds which are representative of this invention may be prepared as per the following examples offered by way of illustration and not by way of limitation. For the sake of clarity, bracketed numbers following compound names indicate the stoichiometric salt associated with the compound, which is further exemplified by the calculated analytical data. Also, examples specifically used to prepare intermediates for the further synthesis of compounds of the invention are designated by "Procedure." As well, instant compounds may also be used as starting materials in subsequent examples to produce additional compounds of the present invention. No attempt has been made to optimize the yields obtained in any of the reactions. One skilled in the art would know how to increase such yields through routine variations in reaction times, temperatures, solvents and/or reagents.

Procedure A IN -29c N,N-Diethyl-4-benzoylbenzamide A solution of 25 g (110 mmol) 4-benzoylbenzoic acid [611-95-0] and 20 mL Z SOCI, was allowed to reflux for 2 h then allowed to cool. The excess SOCI 2 was evaporated off and the resulting clear oil was dissolved in 10 mL CH 2

CI,

then slowly added to 12 mL (116 mmol) diethylamine in a mixture of 10 mL 3N 00 NaOH and 50 mL CH 2 CI,. The mixture was allowed to stir for 30 min then 00 partitioned between H 2 0 and CH 2

CI

2 The organic layer was washed with brine, dried over KCO 3 filtered and concentrated. The product precipitated N from EtOAc/hexane to give 29.6 g (105 mmol) white crystals. MS m/z (MH') 282.

Example 1 N,N-Diethyl-4-[(8-methyl-8-azabicyclo[3.2.1] oct- 3 -ylidene)phenylmethyl]benzamide Hydrochloride [1:1] A 100 mL dry THF slurry of 18.6 g (284 mmol) zinc powder and 15.6 mL (142 mmol) TiCI 4 was stirred and allowed to reflux for 2 h under Ar. The reaction was allowed to cool then a 20 mL THF solution of 10 g (35.5 mmol) N,N-diethyl-4-benzoylbenzamide and 5 g (35.5 mmol) tropinone was added slowly. Once the addition was complete, the reaction was allowed to reflux for 3 h, cooled, then quenched with 10% K 2 COz in H 2 0. The resulting slurry was partitioned between water and EtzO. The organic fraction was washed with brine, dried over MgSO, filtered, and concentrated. The remaining yellow oil was absorbed onto silica gel then purified by flash chromatography eluted with 0.5 M NH 3 in MeOH 90% CHCI 2 to produce the product N,N-diethyl-4-[(8methyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzamide (4.27g, 11 mmol). The HCI salt was precipitated from EtO after the addition of ethereal HCI; mp 145-147 0 C. MS m/z 389. 1 H NMR 300 MHz (DMSO-de) 5 7.2- 7.45 9H), 3.8-3.9 2H), 3.15-3.25 2H), 2.75-2.95 4H), 2.65 (s, 3H), 2.25-2.4 2H), 2.15-2.25 2H), 1.75-1.9 2H), 0.95-1.2 6H).

Anal calc C,H 32

N

2 0-HCI (3%H0O): C, 71.21; H, 7.93; N, 6.39. Found: C, 71.16; H, 7.95; N, 6.27.

ci Exam~le 2 N,N-Diethyl-4-[(B-azabicyclo[3.2.1J Zoct-3-yl idene)phenylm ethyl] benzamnide Hydrochloride (1:1] 0 A 100 mL benzene suspension of 3.1 g (5.6 mmol) N,N-diethyl-4-[(8-methyl-8azabicyclo[3.2.1]oct-3-ylidene)phenylmethyqbenzamide, 3.45 g (25 mnmol) 00 K 2 C0 3 and 1.5 mL (10 rmcl) 2,2,2-trichioroethyl chloroformate was allowed to 00\ 00 refiux for 2 h. The reaction was cooled, filtered, and the solvent evaporated.

The residual oil was dissolved in MeOH then stirred at refiux with 2.6 g IND mmol) zinc powder for 1 h. After cooling, the reaction was filtered through ci 10 celite and partitioned between 3N NaOH and CH 2

CI

2 The organic layer was washed with brine, dried over K 2 00 3 filtered, and concentrated (2.1 g, 5.6 mmol). The resulting clear oil was dissolved in Et 2 O, filtered, and the product precipitated after the addition of ethereal HCI; mp 128-132"C. MS m/z (MH*) 375. 'H NMVR 300 MHz (DMSO-d.) 8 7.15-7.4 (in, 3.9-4.0 (in, 3.15- 3.3 (in, 2.55-2.65 (in, 2.25-2.35 (in, 4H1), 1.9-2.0 (in, 2H), 1.75-1.85 (in, 1.0-1.2 (in, Anal calc C,5H,,N 2 O.HCI H 2 C, 70.89; H, 7.71; N, 6.61. Found: C, 70.52; H, 7.41; N, 6.24.

Examlle 3 (4)-N,N-Dlethyl.4.[[(IR,5S)-8-azabicyclo[3.2.11 oct-3-ylidenejphenylmethyl]benzamlde Fumarate [1:1] N ,N-Diethyl-4-[(8-azabicyclof3 .2.1 Joct-3-ylidene)phenylmethyl]benzamide was chromatographed on a CHIRALPAK® AS eluting with 90:9.9:0.1 acetonitrile:2-propa nol:d iethyla mine. The first enantiomer to elute was converted to its fumnarate salt in 2-PrOH. [a] 0 2 5 +290. MS ml/z 375.

Examtole 4 (-)-N,N-Diethyl-4-[(1 R,5S)-8-azabicyclo[3.2.1J oct-3-ylidene]phenylmethyl]benzamide Fumnarate [1:1] The second enantiomer to elute in the chromatography from the foregoing example was collected. 2 5 -220. MVS m/lz 375.

IND -31- Exa mlle N,N-Diethyl-4[(8-allyl8azabicyclo[3.2.1 oct- 3 .ylidene)phenylmethyl]benzamide Hydrochloride [1:11 A 20 mL acetonitrile suspension of 0.4 g (1.0 mmol) N,N-diethyl-4-[(8azabicyclo[3.2. 1 oct- 3 -ylidene)phenylmethyl]benzamide, 0.4 g (3.0 mmol) 00

K

2 C0 3 and 0.09 mL allyl bromide was allowed to stir for 3 h. The reaction was 00 filtered and concentrated. The remaining oil was absorbed onto silica gel then purified by flash chromatography eluted with 5% 0.5 M NH 3 in MeOH IND

CH

2

C

2 The pure product (0.2 g, 0.4 mmol) was taken up in Et 2 O, filtered, and precipitated after the addition of ethereal HCI. MS mlz 415. 1 H NMR 300 MHz (DMS0-l 6 8 7.15-7.45 (in, 5.95-6.10 (in, 1 5.4-5.55 (in. 21H), 3.85-3.95 (in, 21H), 3.55-3.65 2H1), 3.35-3.45 (in, 2H), 3.1-3.25 (in, 2H), 2.75- 2.85 2H), 2.2-2.3 (in, 2H), 2.1-2.25 (in, 2H), 1.75-1.9 (in, 2H), 1.0-1.2 (in, 6H).

Example 6 (-)-N,N-Diethyl-4-[[(1 R,5S)-8-aflyl-8-azabicyclo[3.2.1] oct-3-ylidene~phenylmethyllbenzamide Hydrochloride Following the protocol for Example 5 and substituting (+)-N,N-diethyl-4- R,5S)-8-azabicyclo[3.2.1I]oct- 3 -ylidene]phenylmethybenide for.N,Ndiethyl-4..[(8-azabicyclo[3.2 I]oct- 3 -ylidene)phenylmethyl]benide the title compound was obtained: MS 415. -3.80. 'H NMR 300 MHz 6 8 7.15-7.45 (in, 9H), 5.95-6.10 (in, 1KH), 5.4-5.55 (in, 2H), 3.85-3.95 (in, 2H), 3.55-3.65 2H), 3.35-3.45 (in, 21H), 3.1-3.25 (in, 2H), 2.75-2.85 (t, 2H), 2.2-2.3 (in, 2H1), 2.1-2.25 (in, 2H), 1.75-1.9 (in, 2H), 1.0-1.2 (in, 61H).

Examnles 7-17 N,N-Diethyl-4[(B-R 1 -8aabicyclo[321] oct-3-ylidene)phenylmethyl] benzamides +Following the procedure of Exampl *e 5 and substituting the appropriate alkyl bromide for allyl bromide the following compounds were prepared: -32- Ex# Alkyl bromide 7 2-(4-fluorophenyl)ethyl bromide 8 2-(2-thienyl)ethyl bromide 9 3-(2-bromoethyl)indole 1 -b romo-2-cyclohexyl ethane 11 2-phenoxyethyl bromide 12 1 -(bromoethyl)-4-ethyl-1 ,4- 13 2-bromo-1 -phenylethanone 14 2-bromo-1-(4methoxyphenyl)etha none 2-bromo-1 cyanophenyl)ethanone 16 2-bromo-1 (ethylenedioxy)phenyl]ethanone 17 2-bromo-1-[3,4- (trimethylenedioxy)phenyl]ethanone 2-(4-fluorophenyl)ethyl 2-(2-thienyl )ethyl 2-(3-indolyl )ethyl 2-cyclohexylethyl 2-phenoxyethyl 2-(4-ethyl-5-oxo-1,4ciihydrotetrazol-1 -yl )ethyl phenylcarbonylmethyl (4-methoxyphenyl) carbonylmethyl (3-cyanophenyl) carbonylmethyl 3 ,4-(ethylenedioxy phenyl)carbonylmethyl 3 ,4-(tNmethylened joxy phenyl)carbonylmethyl MVS MlZ

(MH-)

497 485 518 485 495 515 493 523 518 551 565 Example 18 N,N-Dlethyl-4-[(8-propyl-8-azbicyclo[3.2.1 I oct-3-ylidene)phenylmethyljbenzamide Hydrochloride [1:11 A slurry of 0.4 g (1.0 mmol) N,N-diethyl-4-t(8-azabicyclo[3.2.1]oct-3ylidene)phenylmethyl~benzamide, 0.11 mL (1.5 mmol) propionaldehyde, 0.1 mL (1.7 mmol) HOAc, and 0.5 g (2.3 mmol) NaBH(OAc) 3 in 20 mL DOE was allowed to stir for 16 h. The reaction was made strongly basic with 3N NaCH and diluted with CH 2

C

2 The organic layer was separated, washed with brine, dried over K 2 C0 3 filtered, and concentrated. The remaining oil was absorbed onto silica gel and purified by flash chromatography eluted with 5% 0.5 M NH 3 in MeOH 95% CH 2

CI

2 The pure product (0.25 g, 0.6 mmol) was taken up in Et 2 O. filtered, and precipitated after the addition of ethereal IH~l; mp 184- 184-C. MVS m/z 417. 'H NMR 300 MHz (CDOD) 8 7.2-7.45 (in, 91-), 3.95-4.05 (in, 3.45-3.6 (mn, 2H), 3.2-3.3 (in, 2H), 2.95-3.05 (mn, 2H), 2.55- -33- 2.7 (in, 4H), 2.2-2.3 (in, 2H), 1.95-2.05 (in, 2H), 1.7-1.85 (in, 2H), 1.0-1.35 (br m, 9H). Anal calc C 2

,H

3

,N

2 0*HCI0.5H 2 0: C, 72.78; H, 8.29; N, 6.06. Found: Z C, 73.01; H, 7.94; N, 5.85.

Examples 19-21 00 N,N-Diethyl-4-[(8-R-8-azabicyclo[3.2.1] 00 oct-3-ylidene)phenylmethyljbenzamides Following the procedure of Example 18 and substituting the appropriate IND carbonyl compound for propionaldehyde the following compounds were prepared: Ex# Carbonyl Compound MIIVS mlz (MH) 19 phenylacetaldehyde 2-phenylethyl 479 piperonal piperonyl 509 21 hydrocinnamaldehyde 3-phenylpropyl 493 Procedure B N-(3-Fluorophenyl)-N-mthy3benzoylbenzamide Following Procedure A with the substitution of 20 g (88 mmol) 3benzoylbenzoic acid [579-18-0] and 8.5 mL (88 mmol) 3-fluoroaniline for 4benzoylbenzoic acid and diethyl amine, the product N-(3-fluorophenyl)-3benzoylbenzamide was generated (28 g, 88 mmol) as a clear oil. The oil was dissolved in 50 mL dry THE to which a 10 mL THF slurry of 2.1 g (90 mmol) NaH was slowly added. The mixture-was allowed to stir for 5 min then 5.6 mL (90 mmol) of Mel was added and continued stirring for 16 h. The reaction was carefully quenched with water and partitioned between water and CH 2

C

2 The organic layer was washed with brine, dried over K 2 00 3 filtered, and concentrated to yield 29.3 g (88 mmol) product. MS m/iz 334.

Example 22

N-

3 Fluorophenyl).N-methyl..3-(8..methyl-8-azabicyclo[3.21] oct- 3 -ylidene)phenylmethyljbenzamide Fumnarate [1:1] Following the procedure of Example 1 with the substitution of N-(3fluorophenyl)..N-methyl-3.benzoylbenzamide obtained in Procedure B for N,N- -34- N- diethyl-4-benzoyl benzamide, the product N-(3-fluorophenyl)-N-methyl-3-[(8o methyl-8-azabicyclo[3.2. I]oct-3-ylidene)phenylmethyl]benzamide was Z produced. The fumnarate salt was precipitated from 2-PrOH/hexane, mp 122- 0 125-C. MS m/z 441. 'H NMR 300 MHz (DMSO-d6 8 6.85-7.35 (in, 13H), 3.4 3.3-3.5 (in, 1 3.15-3.2 (in, 1 3.4-3.55 (in, 2H), 2.35 (s, 00 C 3H), 2.15-2.25 (in, I1H), 2.05-2.15 (in, 1 1.9-2.05 (in, 2H), 1.55-1.65 (in, 1IH), 00 kn 1.35-1.55 (br ins, 1 Anal caic CH2,FNO.CH, 4

O

4 C, 71.21; H, 5.98; N, Ni 5.03. Found: C, 71.50; H, 6.20; N, 4.92.

ci 10 Examgle 23 (-)-N,N-Diethyl-4-[[(1 R,5S)-8-phenethyl-8-azabicyclo[3 :2:11 oct-3-ylidenelphenylmethyllbenzamide Hydrochloride [1:11 A suspension of 52 g (0.8 mole) of zinc powder and 800 mL of THE was cooled in an ice bath 44 mL (0.4 mole) of 1iCI 4 was added dmopwise with stirring. The ice bath was removed and the reaction refluxed for 2 h. A solution of 26.45 g (0.094 mole) of N,N-diethyl-4-benzoytbenzainide and 23.9 g (0.094 mole) of phenethyl-8-azabicyclo[3.2.1I]octan-3-one, in .100 mL of THEF was added dropwise and the reaction was refluxed 4h. After cooling, the reaction mixture was poured into a beaker containing excess K 2 C0 3 and ice. The mixture was extracted with ether, washed with brine, dried (K 2 C0 3 and concentrated.

There was obtained 47 g mol) of crude (±)-N,N-diethyl-4-[(8-phenethyl-8azabicyclo[3:2:1]oct-3-ylidene)phenylmethylgbenzamide as an oil. A sample of the oil and 38.33g (0.1 mole) of (4-)-ditoluoyl-D-tartaric acid were combined in 600 mL of acetonitrile. The solid was collected and recrystallized twice from acetonitrile. The solid was collected and partitioned between dilute sodium hydroxide and CH 2

CI

2 The organic solution was dried (K 2 C0 3 and concentrated. The residue was converted to a hydrochloride salt (Et 2 OIHCI). It was recrystallized from 2-PrOH to give 5.6g of white solid. Et 2 O, filtered, and precipitated after the addition of ethereal HCI; mp 210-211 OC. MS m/z (MH*) 479. 'H NMR 300 MHz (CDCI 3 6 12.6 1 7.2-7.45 (in, 14H), 3.85 2H), 3.5-3.1 (mn, 10H), 2.6 1H), 2.5 2H), 2.05 (in, 2H), 1.2 (br. s, 3H), 1.1 (br.

s, -3.70 Cl Examile 24 (+)-N,N-Diethyl-4-[(1 S,5R)-8-phenethyl-8-azabicyclo[3:2:1

J

Z act-3-ylidenejphenylmethyl]benzamide Hydrochloride [1:1] The mother liquors from the foregoing example were concentrated and partitioned between dilute sodium hydroxide and CH 2

CI

2 The organic solution 00 was concentrated (40.5 g, 0.084 mole) and 32.7 g (0.084 mole) of (-)-dftoluoyl- 00 L-tartanic acid were combined in 500 mL of acetonitrile. The solid was collected and recrystallized twice from acetonitnile. The solid was collected and IDpartitioned between dilute sodium hydroxide and CHCI.Teogncsltn was dried (K 2 C0 3 and concentrated. The residue was converted to a hydrochloride salt (Et 2 O/HCI) and recrystallized from 2-PrOH to give a white solid; mp 21 1-212 0 C. MS m/z 479. 'H NMR 300 MHz (CDC 3 8 12.6 (s,I1H), 7.2-7.45 (in, 14H), 3.85 3.5-3.1 (in, 101H), 2.6 1IH), 2.5 (d, 2H), 2.05 (in, 1.2 (br. s, 3H), 1.1 (br. s, 3H). [aD 2 1 +3.70.

Exam~le (-)-N,N-Diethyl-4.[8.phenethyl-8-aza(1 R, 5S)bicycfo[3:2:11 oct-3-ylidenelphenylmethyljthlobenzamlde A mixture of 1.48 g (3.1 minol) of (-)-NN-diethyl-4-[[8-phenethyl-8-aza(1

R,

5S)bicydlo(3:2:1]oct-3..ylidenejphenylmethyqbenzamide and 1.87 g of Lawesson's reagent was heated at 60 0 C in 50 mL of benzene for 2 h. The resulting mixture was flash chromatographed using 5% MeOH in CH 2

CI

2

MS

mlz 495. 1 H1 NMR 300 MHz (C~DC 3 6 8.2 (in, 2H), 7.3-7.0 (in, 10H), 6.8 (in, 2H) 4.0 (in, 4H), 3.7-3.2 (in, I1OH), 2.7-2.4 (in, 3H), 2.1-1.6 (in, 4H), 1.4 (t, 311), 1.1 3H).

Procedure C Ethyl 4-[(8-phenethyl-8-azabicyclo[3.2.1

J

oct-3-ylidene)phenylmethyljbenzoate After a mixture of 52 g (0.8 mole) of zinc powder and 800 mL of THF was cooled in an ice bath 44 mL (0.4 mole) Of 1TIC1 4 was added dropwise with stirring. The ice bath was removed and the reaction refluxed for 2 h. A solution of 21.5 g (0.094 mole) of ethyl 4-benzoylbenzoate, 23.9 g (0.094 mole) -36- N of 8-phenethyl-8-azabicyclo[3.2. 1 octa- -3-one, in 100 mL of THE was added 0 dropwise and the reaction was refluxec .vemight. After cooling the reaction Z mixture was poured into a beaker containing K 2 C0 3 and ice. Enough K 2 00 3 was added until basic. The solid was filtered off and the organics from the filtrate were separated. The aqueous layer was extracted with Et 2 O and the 00 C organics were combined, washed with brine and dried over K 2 00 3 The knf solvent was evaporated in vacua. The residue was first passed through a flash N column, silica gel, CH 2

CI

2 :MeOH) then a second column using silica gel 0 ~with 3:1 hexane:acetone to give 21.8 g of the title compound. MS m/z (MW*) Cl 10 452. 1 1- NMVR (DMS0-l 6 8 8.0 2H); 7.35-7.1 (Ar, 12H); 4.3 2H); 2.8 (in, 2H); 2.7 (in, 2H); 2.4 (bd, 2H); 2.3-2.2 (in, 3H); 1.9 (mn, 2H); 1 .6 (in, 3H); 1.3 (q, 3H).

Procedure 0 4.{(8-Phenethyl-8-azabicyclo[3.2.1 J oct-3-ylidene)phenylmethyl]benzoic Acid A mixture of 22 g (0.048 mole) of ethyl 4-[(8-phenethyl-8-azabicyclo[3.2.1]oct- 3-ylidene)phenylmethyl]benzoate, 86 mL of 3N NaOH and 200 mL of EtOH was refluxed for 1 h. After cooling the mixture was made acidic with conc. HCI.

The solvent was decanted away from the gum which formed. The gum was titurated with Bt 2 O and Et 2 O/HCI and was placed into a drying oven overnight at 45 0 C to yield 19.2 g of 4-[(8-phenethyl-8-azabicyclo[3.2. 1 ]oct-3ytidene)phenytinethyljbenzoic acid; mp. 285-290 0 C. MS mlz 425. 1H NMR 5 7.9 2H); 7.4-7.2 (ar, 12H); 3.7 (bs, 2H); 3.0 (bs, 4H); 2.8 (bdI, 2H); 2.2 2H); 2.0 (in, 2H); 1.65 (mn, 2H-).

Procedure E 4-[(8-Phenethyl-8-azabicyclo[3.2.1 I oct-3-ylidene)phenylmethyljbenzoyI Chloride A mixture of 6 g (0.014 mole) of 4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3ylide ne)phenylmethyl] ben zoi c acid, 20 ml of CHCJ 2 and 3 mL (0.042 mole) of thionyl chloride were refluxed for 1.5 h. The solvent was evaporated in vacua to give 6.2 g of 4-[(8-phenethyl-8-azabicyclo[3.2. 1 oct-3- -37- 0ylidene)phenylmethyl]benzoyl chloride. MS m/z (MHW) of CH 3 O unh47 4 Example 26 N-Ethyl-4-[(8-phenethyl-8-azabicyclo[3 .2.11 oct-3-ylidene)phenylmethyljbenzamide 00 A mixture of 11.4 g (0.14 mole) of ethylamine hydrochloride and 150 mL of 3N 00 NaOH and 100 mL of CH 2

CI

2 were cooled in an ice bath. A solution of 4.7 g (0.015 mole) of 4-[(8-phenethyl-8-azabicyclo[3.2. 1]oct-3- IND ylidene)phenylmethyljbenzoyl chloride prepared using Procedure E in 60 mL of

CH

2 C1 2 was added. After the addition was complete, the ice bath was removed and the reaction stirred at room temperature for 2 h. The organics were separated off and washed with water, brine and dried (K 2 C0 3 The solvent was evaporated in vacuo and converted to the HCl salt with Et 2 O/HCl to give 1.86 g of N-ethyl-4-(8-phenethylk8-azabicyclo[3.2.1]oct-3 ylidene)phenylmethyilbenzamide; mp 296-298*C (Decomp). MS m/z (MHW) 451. 1H NMR (DMSO-d 6 8 8.5 (ar, 1IH); 7.8 2H); 7.4-7.1 (ar, 12H); 4.05 (bs, 2H); 3.4-3.2 (in, 3H); 3.1 3H); 2.9 2H); 2.4 -2.1 (in, 4H); 1.8 (in, 2H); 1. 1 3H).

Example 27 (-)44[8-Phenethyll.8-aza(1 R,5S)blcyclo[3.2.1] oct-3-ylidenelphenylmethyljbenzamide 4-[18-Phenethyl-8-aza( I R,5S )bicyclo(3.2. 1 ]oct-3ylidenelphenylmethyljbenzamide was chromatographed on a CHIRALPAK® Ad'~ column eluting with EtOH+ 0.1 dea. The first enantiomer to elute was collected and converted to the hydrochloride with Et 2 OIHCl. [aba 9.70. MS mlz 451. 'H NMR (DMSO-d 6 858.5 (ar, 1IH); 7.8 2H); 7.4-7.1 (ar, 12H); 4.05 (bs, 2H); 3.4-3.2 (in, 3H); 3.1 3H); 2.9 2H); 2.4 -2.1 (in, 4H); 1.8 (mn, 2H); 1.1 3H).

Examrle 28 (4.)-4-[[8-Phenethyl-8-aza(1 S,5R)bicyclo[3.2.1] oct-3-ylidenejphenylmethyl]benzamide IND -38- The second enantiomer to elute was collected and converted to the ohydrochloride with Et 2 O/HCI. [a]D 25 MS m/z 451. 1 1H NMR Z(DMSO-d.) 858.5 (ar, 1 7.8 2H); 7.4-7.1 (ar, 12H); 4.05 (bs, 3.4-3.2 (in, 3H); 3.1 2.9 2H); 2.4 -2.1 (in, 1.8 (in, 1. 1 3H).

00 xrge2 Exaol 2 00 4-[(8-Phenethyl-8-azabicyclo[3.2.1] oct.3-ylidene)phenylmethyl]benzamide Hydrochloride

IND

A 1.5 g (0.0034 mole) sample of 4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3ci 10 'ylidene)phenylmethyllbenzoyl chloride was cooled in an ice bath. 30 mL of

NH

4 0H was added dropwise. The ice bath was removed and the mixture was stirred at room temperature for 2 h. The solid was filtered off and dried. The product was passed through a Biotage Flash 40 L (silica gel, 9:1;

CH

2

CI

2 :MeOH). Conversion to the HCI salt and recrystallization from EtOH/Et 2 O gave 0.45 g of 4-[(8-phenethyI-8-azabicyclo[3.2.1]oct-3ylidene)phenylmethyl~benzamide; mnp. 210-212*C. MS m/z 423. 'H NMVR (DMSO-d6)5 7.95 1 7.9 2H); 7.4-7.2 (ar, 12H); 4.05 (bs, 1 H); 3.6 2.9 2.4-2.1 (in, 1.8 (mn, 3H); 1.1 3H-).

Examales 30-47 N,N-R,R4(8-Phensthyl-8-azabicyclo[3.2.1 J oct-3-ylidene)phenylmethyllbenzamides By the method of Example 26 and substituting the appropriate amine for ethylainine hydrochloride, the title compound was prepared.

Ex Amnine CIMS (MW-) morpholine 493 31 diisopropylamine 506 32 bis(methoxyethyl)amine 538 33 pyrrolidine 477 34 cis-2,6-dimethylpiperidine 519 N-ethyl-N-(inethylallyl)amine 505 36 dipropylamine 507 -39t-butylamine 2-fluoroethylamine 2-aminothiazole 2-methoxyethylamine (1 H-benzimidazol-2-yl methyl )amine cyclohexylamine aniline histamine cyclopropylamine N,N-(dimethylaminopropyl)amine N-eth yl-N-(hyd roxyethyl )a mine 479 469 507 481 553 505 499 517 463 508 495 Procedure F 8-(2-Benzo[1 3 ]dioxol-5-yiethyl)-8azabicyco[321]octan..3-ne A 41 g sample of 2,5-d imethoxytetrahyd rofu ran (0.32 ml) was suspended in 300 mL of H.0 and 40 mL of a-phosphoric acid was added. The mixture was stirred for 3 h then brought to pH 7 by addition of 3N NaOH. Samples of acetone dicarboxylic acid (51 g, 0. 15 mol) and (3,4-methylenedioxy) phenethylamine (20 g, 0.12 mol) were added and the mixture stirred at 25 0

C

for two days. The mixture was made basic by addition of 100 mL of 3N NaOH, was extracted with EtOAc, washed with brine, dried (K 2 C0 3 and concentrated.

The residue was flash chromatographed using 20% acetone in hexane. The product was a crystalline solid. MVS m/'lz 274. 'H NMVR 300 MHz (CoDC 3 6.6 (in, 3H), 5.9 2H), 3.5 (br. m, 2H), 2.85 4H), 2.65 (dd, 2H), 2.2 (d, 2H), 2.05 (in, 2H), 1.7 2H).

Procedure G Ethyl [[8-(2-benzo[1 3 idioxol-5-ylethyl)-8-azabicyclo[3 :2:1] oct- 3 -ylidene]phenylmethyl]benzoate Following the protocol of Procedure C and substituting 8-(2-benzo[1 ,3]dioxof ylethyl).8-azabicyclo[32.1 ]octa n-3-one for 8-phenethyl-8azabicyclo[3.2.1]octan.3.one, the title compound was obtained. MS rn/z (MH*) 496.

Procedure H Z [[8-(2-Benzo[1 ,3]dioxol-5-ylethyl)-8-azabicyclo[3 :2:11 oct-3-yiidene]phenylmethyl]benzoic Acid Following the protocol of Procedure D and substituting ethyl-[[8-(2- 00 benzo[1 ,3]dioxol-5-ylethyl)-8-azabicyclo[3:2:1]oct-3- 00 yl idene]phenyl methyl]benzoate for ethyl-4-[(8-phenethyl-8-azabicyclo[3.2.l1 oct- 3-ylidene)phenylmethyljbenzoate, the title compound was obtained. MS m'z IND 468.

Procedure J [[8-(2-Benzo(1 ,3]dioxol-5-ylethyl)-8-azabicyclo[3 :2:11 oct-3-ylidenelphenylmethyljbenzoyl Chloride Following the protocol of Procedure E and substituting [[-(2-benzo[1 ,3]dioxol- 5-ylethyl)-8-azabicyclo[3:2:1 ]oct-3-ylidenelphenylmethyl]benzoic acid for phenethyl-8-azabicyclo[3 .2.1 ]oct-3-ylidene)phenylmethyl]benzoic acid, the title compound was obtained.

Examrle 48 N -Ethyl -[[8-(2-Benzo[1 dlioxol-5-ylethyl)-8-azabicyclo[3:2:1] oct-3-ylidene]phenylmethyl]benzamide Following the procedure of Example 23 and substituting f[8-(2benzo(1 .3]dioxol-5-ylethyl)-B-azabicyclo[3:2:l1loct-3ylidenelphenylmethylbenzoyl chloride for 4-{(B-phenethyl-8azabicyclo[3.2.1 I oct-3-ylidene)phenylmethyljbenzoyI chloride, the tite compound was obtained. MS m/~z 495.

Examgle 49 N,N.Diethyl-[[8-(2-Benzo[1 ,3]dioxol-5-ylethyl)-8-azabicyclo[3 :2:11 oct-3-ylidene]phenylmethyl]benzamide Following the procedure of Example 23 and substituting benzo[1, 3]dioxol-5-ylethyl )-8-aza bicyclo[3:2: 1]oct-3ylidenelphenylmethyllbenzoyl chloride for 4-[(8-phenethyl-8- IND -41c-i azabicyclo[3.2. 1]oct-3-ylidene)phenylmethyl]benzoyl chloride and diethyl amine for ethylamine hydrochloride, the title compound was obtained. MS m/z (MH*) Z 523.

Procedure K 00 Ethyl 4-[(8-methyl-8-azabicyclo[3.2.1] 00 oct-3.ylidene)phenylmethyljbenzoate Following the protocol of Procedure C and substituting tropinone for 8- IND phenethyl-8-azabicyclo[3.2.1]octan-3-one, the title compound was obtained.

MS m/z(MH-) 362.

Procedure L 4-[(8-Methyl-8-azabicyclo[3.2.1] oct-3-ylidene)phenylmathyl]benzoic Acid Following the protocol of Procedure 0 and substituting ethyl 4-[(8-methyl-8azabicyclo[3.2.1I]oct-3-ylidene)phenylmethyl]benzoate for ethyl 4-18-phenethyl- 8-azabicyclo[3 .2.1 ]oct-3-ylidene)phenylmethyl]benzoate, the title compound was obtained. MIS m/z 334 Procedure M 4-[(8-Methyl-8-azablcycto[3.2.1

J

oct-3-yl idene)phenylmethyljbenzoyl Chloride Following the protocol of Procedure E and substituting 4+[8-methyl-8azabicyclo[3.2. 1 ]oct-3-ylidene)phenylmethylqbenzoic acid for 4-(8-phenethyl-8azabicyclo[3.2.1I]oct-3-ylidene)phenylmethylqbenzoic acid, the title compound was obtained.

Examole N-Ethyl-4-[(8-Methyl-8-azablcyclo[3.2.1

J

oct-3-ylidene)phenylmethyl~benzamide Following the protocol of Example 26 and substituting 4-[8-methyl-8azabicyclo[3.2. 1 ]oct-3-yiidene)phenylmethyljbenzoyI chloride for 4-[8phenethyl-8-azabicyclo[3.2. 1]oct-3-ylidene)phenyl methyl] benzoyl chloride, the IND -42title compound was obtained. MS m/z 361.

Z Example 51 N-Ethyl-4-[8-azabicyclo[3.2.1] oct-3-ylidene)phenylmethyljbenzamide 00 Following the protocol of Example 2 and substituting N-ethyl-4-[(8-methyl-8- 00 azabicyclo[3.2.l1 oct-3-ylidene)phenylmethyl]benzamide for N ,N-d iethyl-4-[(8methyl-8-azabicyclo[3.2.1 ]oct-3-yiidene)phenylmethyl] benzamide, the title IND compound was obtained. MS m/z 347.

Examr)le 52 N-Ethyl-4-[(8-allyl-8-azabicycfo[3.2.1] oct-3-ylidene)phenylmethyl]benzamide Following the protocol of Example 6 and substituting N-ethyl-4+[8azabicyclo[3.2. 1]oct-3-yl idene)phenylmethyl]benzamide for N ,N-diethyl-4-[(8azabicyclo[3.2. 1 ]oct-3-ylidene)phenylmethylqbenzamide, the title compound was obtained. MS m/lz (MW) 387.

Procedure N 8-[2-(4-Methoxyphenyl)ethyl]-8.azablcyclo[3 :2:1 Joctanone Following the protocol of Procedure F and substituting (4methoxy)phenethylamine for (3,4-methylenedioxy)phenethylamine, the title compound was obtained. MS m/z 260.

Procedure 0 Ethyl 4-[[8-[2-(4-methoxyphenyl)ethyl]-8-azabicyclo[3 :2:1] oct-3-ylidenelphenylmethy] benzoate Following the protocol of Procedure C and substituting methoxyphenyl)ethyl]-8-azabicyclo[3 :2:1 locta none for 8-phenethyl-8azabicyclo[3.2.1]octan-3-ane, the title compound was obtained. MS m/lz (MW*) 482.

Procedure P IND -43- (Ni 4-[[8-[2-(4-Methoxyphenyl)ethyl]-8-azabicyclo[3 :2:1] oct-3-ylidenelphenylmethyl]benzoic Acid Z Following the protocol of Procedure D and substituting ethyl methoxyphenyl )ethylj-8-azabicyclo[3:2:1 I oct-3-ylidene] phenyl methyl] benzoate for ethyl 4-[(8-phenethyl-8-azabicyclo[3.2. 1 ]oct-3- 00 ylidene)phenylmethyl]benzoate, the title compound was obtained.

00 Procedure Q IND 4-II8-[2-(4-Methoxyphenyl)ethyl]-8-azabicyclo[3:2:1] oct-3-ylidenejphenylmethyl]benzoyI Chloride Following the protocol of Procedure E and substituting methoxyphenyl )ethyl]-8-azabicyclo[3:2: 1 oct-3-ylidene]phenylmethyl]benzoic acid for 4-[((-phenethyl-8-azabicyclo[3 .2.1 ]oct-3-yl idene)phenymethyl]benzoic acid, the title compound was obtained.

Examgle 53 N,N-Diethyl-4-18-[2-(4-methoxyphenyl)ethyU..8.azabicyc o[3 :2:1] oct-3-ylidenejphenylmethyl]benzamide Following the protocol of Procedure F and substituting 4-g18-[2-(4methoxyphenyl)ethyl]-8-azabicyclo[3:2:1I oct-3-ylidene]phenylmethygbenzoyI chloride for 4-[(8-phenethyl-8-azabicyclo[3.2. 1 ]oct-3ylidene)phenylmethyl]benzoyl chloride, the title compound was obtained. MS m/lz 509.

Examples 54-63 N,N-DI-WR 1 3 4[-[2-(4methoxyphnyl)ethylj..8.azabicyclo[3:2:11 oct-3-yI idene~phenylmethyllbenzamides Using the method of Example 26 and substituting the material from Procedure Q for the material from Procedure E, the following compounds were prepared: Ex Amine CIMS (MH-) 54 morpholine 523 ethylamine 481 IND -44- N56 bis(methoxyethyl)a mine 569 >-57 pyrrolidine 507 Z58 cis-2,6-dimethylpiperidine 549 59 N-ethyl-(N-methylallyl)a mine 535 di-n-propylamine 537 0061 2,2,6,6-tetramethylpiperidine 577 0062 di-2-propylamine 537 Procedure R N-Ethyl-4-(4-methoxybenzoyl)benzamide Following the protocol of Procedure A and substituting 4-(4methoxybenzoyl)benzoic acid for 4-benzoylbenzoic acid and ethylamine hydrochloride for diethylamine, the title compound was obtained. MS m/z 284.

Examgle 63 N-Ethyl-4-[(4-methoxyphenyl)-(8-methyl-8-azabicyclo[3 :2:1] oct-3-ylidene)mnethyl] benzamide Following the protocol of Example 1 and substituting N-ethyl-4-(4methoxybenzoyl )benzamide for N,N-diethyl-4-benzoylbenzamide, the title compound was obtained. MS m/z 391.

Procedure S 2A22-Trichloroethyl 3-[(ethylcarbamnoylphenyl)- (4-methoxyphenyl)methyleneJ--azabicyclo[3:2:1 ]octanecarboxylate A solution of 1.95 g (5.0 mmol) of N-ethyl-4-[(4-methoxyphenyl)-(8-methyl-8azabicyclo[3:2:1]oct-3-ylidene)methyllbenzamide, 1.03 mL (7.5 mmol) of 2,2,2trichloroethyl chloroformate and 0.43 mL (2.5 mmol) of diisopropylethylamine was stirred in 50 mL of benzene and 1.38 g (10 mmol) of K 2 C0 3 added. The mixture was heated at under reflux for 18 h. Another 0.51 mL of (3.75 mmol) of 2,2,2-trichioroethyl chloroforrnate and 0.21 mL (1.25 mmol) of diisopropylethylamine was added. The mixture was heated under reflux for 3h.

The reaction was cooled and poured into HO. The organic layer was washed with dilute HCl and brine, dried (MgSO,,) and concentrated to give 2.09 g of a >o yellow gum. MS m/z 553. 'H NMR 300 MHz (CDCI 3 5 7.7 2H), 7.2 Z 2H), 7.0 2H), 6.8 2H), 6.2 br. s, 1 4.'9 1 4.7 1 4.3 (br.

m, 2H), 3.8 3H), 3.4 2H), 2.4 (br. m, 4H), 1.9 (in, 2H), 1.7 (in, 2H), 1.2 (t, 3H).

00 00 Procedure T 2,2,2-Trichioroethyl 3-[(ethylcarbamoylpheny)- IND (4-hydroxyphenyl)methylene]-8-azabicyclo[3:2:1 loctanecarboxylate A solution of 1.03 g (1.82 mmol) of 2,2,2-trichloroethyl 3- [(ethylcarbamoyl phenyl)-(4-methoxyphenyl )methylene]-8azabicyclo[3:2:ljoctanecarboxylate in 10 mL of CHC 3 was cooled to -60 0

C

under N 2 and 9.1 mL of 1 M BBr 3 in CH 2

CI

2 was added dropwise. The cooling bath was removed and the mixture stirred at 25 0 C for 18 h. Saturated aqueous NaHCO 3 was added and the CH 2

CI

2 was evaporated. The solid (1 g) was collected. 'H NMR 300 MHz (CDCI 3 8 7.8 2H), 7.2 2H), 6.9 2H), 6.7 2H), 6.2 (br. s, 1IH), 4.9 1 4.7 1 4.4 (br. m, 2H), 3.4 2H), 2.4 (br. m, 4H), 1.9 (in, 2H), 1.7 (in, 2H), 1.2 3H).

Examgle 4 4-[(8-Azablcyclo[3:2:1 Joct-3-ylidene)- (4-hydraxyphenyl)methyl]-N-ethylbenzamlde A 0.73 g sample (11 mmol) of zinc dust was added to a solution of 0.89 g (1.61 minol) of 2,2,2-tnichloroethyl 3+{ethylcarbamnoylphenyl hydroxyphenyl)methylene]-8-azabicyclo[3 :2:1 loctanecarboxylate in 9 mL of glacial HOAc. The mixture was heated under reflux for 5 h then cooled and the solid removed by filtration and washed with HOAc. The solvent was evaporated and K 2 C0 3 was added. The mixture was extracted six times with EtOH in CHCI 3 The solution was dried (Na 2 SO,) and concentrated. The residue was crystallized from EtOH/2-PrOH to give 0.24 g of a white solid. MS m/z 363. 'H NMR (DMSO-d 6 8 8.5 1 7.8 2H), 7.2 2H), 6.9 2H), 6.7 2H), 3.3 (br. m, 4H), 2.2 (br. mn, 4H), 1.5 (in, 4H), 1.1 3H).

-46c-i Procedure U N-Diethyl-4-(4-methoxybenzoyl)benzamide Z A mixture of 0.75 g (5.5 mmol) of 4-methoxybenzeneboronic acid, 1.5 g mmol) N,N-diethyl-4-iodobenzamide, 0.1 g (0.15 mmol) bistriphenylphosphine palladium(ll)dichloride and 2.07 g (15 mmol) of K 2 C0 3 in 30 mL of anisole was 00 flushed with carbon monoxide then heated at 80 0 C under a CO atmosphere for 00 5 h. The mixture was filtered and the solvent evaporated. The residue was flash chromnatographed 20% acetone in hexane to give the title compound. MS m/z 312.

cI Example N,N -Diethyl-4-[(4-methoxyphenyl)-(8-methyl-8-azabicyclo[3 :2:1] oct-3.ylidene)methyljbenzam ide Following the protocol of Example I and substituting N,N-diethyl-4-(4methoxybenzoyl)benzamide for N,N-diethyl-4-benzoylbenzamide, the title compound was obtained. MS m/z 419.

Procedure V 2,2,2-Trichloroethyl 3+{dlethylcarbamnoyl phenyl)- (4-methoxyphenyl)methylenej4-azabicyclo[3:2:1 Joctanecarboxylate Following the protocol of Procedure S and substituting N,N-diethyl-4-[(4methoxyphenyl)-(8-methyl-8-azabicyclo[3:2: 1]oct-3-ylidene)methyllbenzamide for N-ethyl-4-[(4-methoxyphenyl )(8-miethyl-8-azabicyclo[3 :2:1 ]oct-3ylidene)methyqbenzamide, the title compound was obtained.

Procedure W 2,2,2-Trichioroethyl 3-[(diethylcarbamoylphenyl)- (4-hydroxyphenyl)methylene]-8-azabicyclo[3:2:1I]octanecarboxylate Following the protocol of Procedure T and substituting 2,2,2-trichloroethyl 3- [(diethylcarbamoylphenyl)-(4-methoxyphenyl )methylene]-8azabicyclo[3:2: 1 ]octa necarboxyl ate for 2,2,2-trichloroethyl 3- [(ethylcarbamoylphenyl )-(4-methoxyphenyl )methylene]-8azabicyclo[3:2: 1 octanecarboxylate, the title compound was obtained.

IND -47- Example 66 Z 4-[(8-Azabicyclo[3 :2:1 Joct-3-ylidene)- (4-hydroxyphenyl)methyl-N -diethylbenzamide Following the protocol for Example 64 and substituting 2,2,2-trichloroethyl 3- 00 [(diethylcarbamoylphenyl-(4-hydroxyphenyl )methylene]-8- 00 azabicyclo[3:2:1 ]octanecarboxylate for 2,2,2-tdchloroethyl 3- [(ethylcarbamoylphenyl)-(4-hydroxyphenyl )methylene]-8- IND azabicyclo[3:2:1]octanecarboxylate, the title compound was obtained. MS m/z (M H)391.

Example 67 N,N -D iethyl-4-[(4-methoxyphenyl)-[8-[2-(4-methoxyphenyl)ethyl]- 8-azabicyclo[3:2:1 ]oct-3-ylidene]methyl]benzamide Following the protocol of Example I and substituting methoxyphenyl)ethyl]-8-azabicyclo[3:2:1 I octanone for tropinone, the title compound was obtained. MS rn'z 539.

Example 68 N,N-Diethyl-4-[(4-hydroxyphenyl)-[8-(2-(4-hydroxyphenyl)ethyl]- 8-azabicyclo[3:2:1 Joct-3-ylidene]methyl]benzamide Following the protocol of Example 64 and substituting N,N-diethyl-4-[(4methoxyphenyl )-[8-[2-(4-methoxyphenyl)ethyl]-8-azabicyclo[3:2: 1 ]oct-3ylidene]methyl]benzamide for 2,2,2-trichloroethyl 3-[(ethylcarbamoylphenyl)-(4hydroxyphenyl)methylene]-8-azabicyclo[3 :2:1 loctanecarboxylate, the title compound was obtained. MS m/z 511.

Examole 69 N-Ethyl-4-[[8-[2-(4-hydroxyphenyl)ethyl]-8-azabicyclo[3 :2:1] oct-3-ylidene]phenylmethyl]benzamide Following the protocol of Procedure T and substituting N-ethyl-4-fl8-[2-(4methoxyphenyl)ethyl]-8-azabicyclo[3:2: 1 ]oct-3-ylidene]phenylmethyl] benzamide for 2,2 .2-trichloroethyl 3-[(ethylcarba moyl phenyl )-(4-methoxy N -48- O phenyl)methylene]-8-azabicyclo[3:2:1]octanecarboxylate, the title compound was obtained. MS m/z 467.

0 Example N,N-Diethyl-4-[[8-[2-(4-hydroxyphenyl)ethyl]- 00 8-azabicyclo[3:2:1]oct-3-ylidene]phenylmethyl]benzamide oO Following the protocol of Procedure T and substituting N,N-diethyl-4-[[8-[2-(4m methoxyphenyl)ethyl]-8-azabicyclo[3:2:1]oct-3- NO ylidene]phenylmethyl]benzamide for 2,2,2-trichloroethyl 3- S 10 [(ethylcarbamoylphenyl)-(4-methoxyphenyl)methylene]-8azabicyclo[3:2:1]octanecarboxylate, the title compound was obtained. MS m/z 495.

Biological Examples Screening Assay for 6Opioid and -Opioid Receptor Binding Rat Brain -Opioid Receptor Binding Assay The activity of the compounds of the invention as analgesics was demonstrated by the rat brain 5-opioid receptor binding assay as described below.

Procedure Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, NY) are killed by cervical dislocation, and their brains removed and placed immediately in ice cold Tris HCI buffer (50 mM, pH The forebrains are separated from the remainder of the brain by a coronal transection, beginning dorsally at the colliculi and passing ventrally through the midbrain-pontine junction. After dissection, the forebrains are homogenized in Tris buffer in a Teflon®-glass homogenizer. The homogenate is diluted to a concentration of 1 g of forebrain tissue per 100 mL Tris buffer and centrifuged at 39,000 X G for 10 min. The pellet is resuspended in the same volume of Tris buffer with several brief pulses from a Polytron homogenizer. This particulate preparation is used for the 5-opioid binding assays. Following incubation with the 8-selective peptide ligand 3 H]DPDPE at 25 0 C, the tube contents are filtered through Whatman 0 -49- GF/B filter sheets on a Brandel cell harvester. The tubes >and filters are rinsed three times with 4 mL of 10 mM HEPES (pH and the Z radioactivity associated with the filter circles determined using Formula 989 scintillation fluid (New England Nuclear, Boston, MA) in a scintillation counter.

00 Analysis oo The data are used to calculate either the inhibition compared to control m binding (when only a single concentration of test compound is evaluated) or a IO K, value (when a range of concentrations is tested).

Inhibition was calculated as follows: F (test compound dpm-nonspecific dpm) 1- (total dpm-nonspecific dpm) X 100% K, value is calculated using the LIGAND (Munson, P.J. and Rodbard, Anal.

Biochem. 107: 220-239, 1980) data analysis program.

Table 3 shows the biological activity (in K, value) for 10nM solutions of the present compounds as measured in the rat brain 8-opioid receptor binding assay.

Table 3 Example 5 K (nM) Example 5 K (nM) Example 8 K, (nM) 1 1.2 25 9.9 48 48.2 2 0.1 26 7.5 49 4.96 3 0.023 27 46.7 50 4 0.36 28 4.7 51 5.7 0.06 29 35.9 52 0.75 6 0.025 30 35.2 53 2.9 7 2.6 31 49 54 57 8 13 32 16.6 55 225 9 3.5 33 24 56 24 1.4 34 11 57 11 0.38 35 2.9 58 18 12 18.5 36 7.4 59 3.9 13 6.3 37 352 60 12 14 1.1 38 32 61 15.5 6.8 39 49 62 30.7 17 0.23 40 102 64 18 0.39 41 331 66 0.58 19 0.7 42 924 67 24.7 0.01 43 1520 68 0.41 21 0.56 44 178 69 1.08 22 92 45 19.8 70 0.7 23 0.23 46 404 24 42.1 47 3.2 Rat Brain I-Opioid Receptor Binding Assay The activity of compounds of the invention as analgesics is demonstrated by the rat brain l-opioid receptor binding assay as described below.

Procedure o -51- Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, NY) are killed by cervical dislocation and their brains removed and placed immediately in ice Z cold Tris HCI buffer (50 mM, pH The forebrains are separated from the remainder of the brain by a coronal transection, beginning dorsally at the colliculi and passing ventrally through the midbrain-pontine junction. After oo dissection, the forebrains are homogenized in Tris buffer in a Teflon-glass 0o homogenizer. The homogenate is diluted to a concentration of 1 g of forebrain tissue per 100 mL Tris buffer and centrifuged at 39,000 X G for 10 min. The IN pellet is resuspended in the same volume of Tris buffer with several brief pulses from a Polytron homogenizer. This particulate preparation is used for the p.-opioid binding assays. Following incubation with the m-selective peptide ligand 3 H]DAMGO at 25 OC, the tube contents are filtered through Whatman GF/B filter sheets on a Brandel cell harvester. The tubes and filters are rinsed three times with 4 mL of 10 mM HEPES (pH 7.4) and the radioactivity associated with the filter circles determined using Formula 989 scintillation fluid (New England Nuclear, Boston, MA) in a scintillation counter.

Analysis The data are used to calculate either the inhibition compared to control binding (when only a single concentration of test compound is evaluated) or a K, value (when a range of concentrations is tested).

Inhibition is calculated as follows: I (test compound dpm-nonspecific dpm) 1- (total dpm-nonspecific dpm) X 100% Ki value is calculated using the LIGAND (Munson, P.J. and Rodbard, Anal.

Biochem. 107: 220-239, 1980) data analysis program.

Mouse Acetylcholine Bromide-Induced Abdominal Constriction Assay The activity of compounds of the invention as analgesics was further demonstrated by the mouse acetylcholine bromide-induced abdominal o -52- O constriction assay as described below.

0 Z Procedure The mouse acetylcholine-induced abdominal constriction assay (as described by Collier et al. in Brit. J. Pharmacol. Chem. Ther., 1968, 32: 295-310 with 00 minor modifications) was used to assess analgesic potency of the compounds 00 of formula The test drugs or appropriate vehicles were administered orally and 30 min later the animal received an intraperitoneal injection of N 5.5 mg/kg acetylcholine bromide (Matheson, Coleman and Bell, East Rutherford, NJ). The mice were then placed in groups of three into glass bell jars and observed for a ten min observation period for the occurrence of an abdominal constriction response (defined as a wave of constriction and elongation passing caudally along the abdominal wall, accompanied by a twisting of the trunk and followed by extension of the hind limbs). For compounds of the present invention, the percent inhibition of this response to a nociceptive stimulus (equated to analgesia) was calculated as follows: Inhibition of response analgesia) (No. of control animal responses No. of drug-treated animal responses) x 100 No. of control animals responding.

As a result of the mouse acetylcholine bromide-induced abdominal constriction assay, the compound of Example 1 measured an 87% inhibition response at a dose of 150 pmole/Kg p.o.

Claims (7)

1. 2. The compound of claim 1 wherein R' is selected from the group consisting of doe, C 1 -,alkyl, C 24 ,alkenyl, C 24 ,alkynyl, cycloalkyl, cycloalkyl(C 14 ,)alkyl, heterocyclyl, heterocyclyl(C,..)alkyl, heterocyc~ylcarbonyl(Cl 1 a)alkyl, aryl(Cl 1 a)alkyl, arylcarbonyl(C,.,)al kyl, aryl(C 2 -,)alkynyl, arylaminocarbonyl(C.,)alkyl, heteroaryl(C, 4 ,)alkyl, (R'a) 2 -N-(C 1 -,)alkyl and Rla-O-(C 14 ,)alkyI; wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of Cl 1 ,alkyl, C 1 -6alkoxy, halogen, hydroxy, oxo and cyano; and, wherein aryl is optionally substituted with one to three substituents independently selected from the group consisting of Cl.,alkyl, C,-,alkoxy, halogen, hydroxy and cyano. IND -57-
2. 3. The compound of claim 1 wherein R' is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, Z n-hexyl, butenyl, allyl,.3,3-d imethallyl, cyclopropyl, cyclopropyl(C,-)alkyl, cyclohexyl, cyclohexyl(C,-,)alkyl, pyrrolidinyl, pyrrolidinyl(C,.,)alkyl, 1 ,3-dioxolanyl(C. 3 )alkyl, 2-imidazolinyl, 2-imidazolinyl(C,- 3 )alkyl, 00 imidazolidlinyl, imidazolidinyl(Cl. 3 )alkyl, 2-pyrazolinyl, 00 2-pyrazolinyl(0 1 .,)alkyl, pyrazolidinyl, pyrazol idinyl(C 1 3 )alkyl, piperidinyl, piperidinyl(C 1 3 )alkyl, morpholinyl, morpholinyl(C, 1 3 )alkyl, thiomorpholinyl, thiomorpholinyl(C 1 3 )alkyl, piperazinyl, piperazinyl(C 1 3 )alkyl, [4-(C 1 3 )alkyl-
3. 5-oxo-1 ,4-dihydrotetrazol-1 -yl](C 13 )alkyl, piperonyl, (1 yI )(C 2 -3)alkyl, (2 ,3-clihydro-1 ,4-benzodioxin-6-yl )carbonyl(C 1 3 )alkyl, (3,4- dihydro-2H-1 ,5-benzodioxepin-7-yl )carbonyl(C 1 3 )al kyl, benzyl, phenyl(C 23 )alkyl, phenyl(C 23 )alkynyl, diphenyl(C 1 3 )alkyl, phenylcarbonyl(C, 3 )alkyl, phenylaminocarbonyl(C 1 -,)alkyl, furyl(C 1 3 )alkyl, thienyl(C,. 3 )alkyl, pyrrolyl(Cl. 3 )alkyl, oxazolyl(C 14 )alkyl, thiazolyl(C 1 3 )alkyl, imidazolyl(Cl- 3 )alkyl, pyrazolyl(C 1 3 )alkyl, isoxazolyl(C,.,)alkyl, isothiazolyl(Cl. 3 )alkyl, I ,2,3-oxadiazolyl(C 1 3 )alkyl, 1 ,2,3-triazolyl(C 1 3 )alkyl, I ,3,4-thiadiazolyl(C.. 3 )alkyl, pyridinyl(C 1 3 )alkyl, pynidazinyl(C 14 3)aikyl, pyrimidinyl(C 1 3 )alkyl, pyrazinyl(C,- 3 )alkyl, 1 ,3,5-triazinyl(C 1 -)alkyll, indolyt(Cl-3)alkyl, benzo~b]fu ryl(C.,. 3 )alkyl, benzo[b~thienyl(C 1 -3)alkyl, (R 18 2 3 )alkyl and Rla-O-(C 14 3)alkyl; wherein pyrrolid inyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidlinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl are optionally substituted with one to three substituents selected from oxo; and, wherein phenyl is optionally substituted with one to three substituents; independently selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, methoxy, ethoxy, propoxy, butoxy, chlorine, fluorine, hydroxy and cyano. 4. The compound of claim 1 wherein R' is selected from the group consisting of hydrogen, methyl, n-propyl. n-butyl. allyl. 3,3-dimethallyl, cyclopro pylmethyl, cyclohexylethyl, 2-(4-ethyl-5-oxo- 1,4-d ihydrotetrazol- 1 -yl)ethyl, piperonyl, 1,3-benzodioxol-5-yl)ethyl, 2-(2,3-dihydro-1 ,4- IND -58- benzod ioxin-6-yl)-2-oxoethyl, 2-(3 ,4-d ihydro-2H-1, 5-benzod ioxepin-7-yl 2-oxoethyl, benzyl, phenethyl, phenyipropyl, phenoxyethyl, Z phenylcarbonylmethyl, phenylcarbonylethyl, phenylaminocarbonylmethyl, thienylmethyl, thienylethyl, imidazolylmethyl, pyridinylmethyl and indolylethyl; wherein phenyl is 00 optionally substituted with one to three substituents independently 00 selected from the group consisting of methoxy, fluorine, hydroxy and cyano. 5. The compound of claim 1 wherein R" 8 is independently selected from the group consisting of hydrogen, C,.8alkyl and aryl; wherein aryl is optionally substituted with one to three substituents; independently selected from the group consisting of C,.,alkyl, C 2 .,alkenyl, C, 14 alkoxy, amino, C 14 ,alkylamino, di(C 1 .,alkyl)amino, C, 14 alkylcarbonyl, C, 14 alkylcarbonyloxy, C 1 6 alkylcarbonylamino, Cl. 0 alkylthio, C 14 ,alkylsulfonyl, halogen, hydroxy, cyano, tnifluoromethyl and trifluomomethoxy.
4. 6. The compound of claim 1 wherein R a is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl and phenyl; wherein phenyl is optionally substituted with one to three substituents; independently selected from the group consisting of C, 1 ,alkyl, C 1 -,alkoxy, di(C,.,alkyl)amino, halogen, tnifluoromethyl and trifluoromethoxy.
5. 7. The compound of claim 1 wherein R'O is independently, selected from the group consisting of methyl, ethyl and phenyl.
6. 8. The compound of claim 1 wherein R' is selected from the group consisting of phenyl, naphthalenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,3-triazolyl, 1 .3,4-thiadiazolyl, pynidinyl, pyridazinyl, pynimidinyl, pyrazinyl, 1 ,3,5-triazinyl, indolyl, benzo~b]furyl and benzo[b]thienyl IND
7. 59.. optionally substituted with one to three substituents independently selected from the group consisting of 0 1 3 a1 kyl, C,-,alkenyl, C,-,alkoxy, Z amino, C 1 ,alkylamino, di (C 1 3 alkyl)amino, Cl-3alkylcarbonyl, C 1 3 alkylcarbonyloxy, C, 13 alkylcarbonylamino, chlorine, fluorine, hydroxy, trifluoromethyl and trifluoromethoxy. 00 00 9. The compound of claim 1 wherein R 2 is selected from the group consisting of phenyl, furyl, thienyl, pyridinyl and benzo~b]furyll optionally IND substituted with one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, methylcarbonyl, methylcarbonyloxy, methylcarbonylamino, fluorine, hydroxy, trifluoromethyl and trifluoromethoxy. 10. The compound of claim 1 wherein R' is selected from phenyl optionally substituted with one substituent selected from the group consisting of methoxy and hydroxy. 11. The compound of claimn 1 wherein R 3 is selected from the group consisting of phenyll, naphthalenyl, furyll, thienyl, pynvlyll, oxazolyl, thiazollyll, imidazollyl, pyrazolyl, isoxazollyl, isothiazollyl, I ,2,3-oxadiazolyl, 1 ,2,3-triazolyl, 1 ,3.4-thiadiazolyl, pyridinyl, pynidazinyl, pynimidinyl, pyrazinyl, 1 ,3,5-tniazinyl, indolyl, benzo[b]furyl and benzo[b]thienyl optionally substituted with one or two substituents in addition to the -A-Z moiety independently selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, allyl, methoxy, ethoxy, amino, C,-3alkylamino, di(C 1 3 )alkylamino, Cl-3alkylcarbonyl, C 1 -3alkylcarbonyloxy, C 1 -3alkylcarbonyl, Cl. 3 alkylaminocarbonyl, C 1 3 alkylcarbonylamino, C 1 3 alkylthio, C 1 .3alkylsulfonyl, chloro, fluoro, hydroxy, cyano, trifluoromethyl and trifluoromethoxy; alternatively, when phenyl is substituted with two optional substituents attached to adjacent carbon atoms, the two substituents can together form a single fused moiety; wherein the moiety is selected from the group consisting of -(CH 2 )3- 5 Sand -O(CH 2 3 0-. 0 Z 12. The compound of claim 1 wherein R 3 is phenyl substituted with the moiety -A-Z at the 3 or 4 position. 00 13. The compound of claim 1 wherein A is 00 OO c 14. The compound of claim 1 wherein Z is O 15. The compound of claim 1 wherein R 4 is selected from the group consisting of C, 4 alkyl (optionally substituted with one to three halogen substituents), C 2 .alkenyl, aryl and aryl(C,.)alkyl; wherein aryl is optionally substituted with one to two substituents independently selected from the group consisting of C, 4 alkyl, -OCHO-, -O(CH 2 2 0- and halogen. 16. The compound of claim 1 wherein R' is selected from the group consisting of Cl. 3 alkyl (optionally substituted with one or three fluorine substituents), C 2 zalkenyl, phenyl and benzyl; wherein phenyl is optionally substituted with one to two substituents independently selected from the group consisting of C,3alkyl, -OCH2O-, -O(CH 2 2 0- and fluorine. 17. The compound of claim 1 wherein R' is selected from the group consisting of methyl, ethyl, 3-methallyl, phenyl and benzyl; wherein phenyl is optionally substituted with one substituent selected from the group consisting of methyl and fluorine. 18. The compound of claim 1 wherein R 5 and R 6 are independently selected from the group consisting of hydrogen, C 1 .alkyl, fluoro(Cl. 3 )alkyl, trifluoro(C,. 3 )alkyl, C,.3alkoxy(C,.3)alkyl, C 2 ,alkenyl, cyclopropyl, cyclopropyl(C .3)alkyl, cyclopentyl, cyclopentyl(C,. 3 )alkyl, cyclohexyl, cyclohexyl(C,.3)alkyl, pyrrolidinyl, pyrrolidinyl(C,. 3 )alkyl, 1,3-dioxolanyl, IND -61- I ,3-dioxolanyl(C 1 3 )alkyl, 2-imidazolinyl, 2-imidazolinyl(Cl 1 3 )alkyl, >o imidazolidinyl, imidazol id inyl(Cl 13 )alkyl, 2-pyrazolinyl. Z 2-pyrazolinyl(Cl 1 3 )alkyl, pyrazolidinyl(Cl 1 3 )alkyl, piperidinyl, pipenidinyl(C 1 3 )alkyl, morpholinyl, morphol inyl(Cl 1 3 )alkyl, thiomorpholinyl, thiomorpholinyl(Cl. 3 )alkyl, piperazinyl, piperazinyl(0 1 3 )alkyl, piperonyl, 00 phenyl, benzyl, phenyl(C 2 3 )alkyl, furyl, furyl(C 14 3)alkyl, thienyl, 00 thieny(Cl. 3 )alkyl, pyrrolyl(C,. 3 )alkyl, oxazolyl, oxazolyl(C,.. 3 )alkyl, thiazolyl, thiazoyl(C. 3 )alkyl, imidazolyl, imidazolyl(C 1 3 )alkyl, pyrazoy, IND pyrazolyl(Cl. 3 )alkyl, isoxazolyl, isoxazolyl(C 1 -3)alkyl, isothiazolyl, isothiazolyl(C,. 3 )alkyl, 1 ,2,3-oxadiazolyl, 1 ,2,3-oxadiazolyl(Cl. 3 )alkyl, 1 ,2,3-triazolyl, 1 ,2,3-triazoyl(C 1 3 )alkyl, 1 .3,4-thiadiazolyl, I ,3,4-thiadiazolyl(Cl- 3 )alkyl, pyid inyl, pyrddinyl(C 1 3 )alkyl, pyridazinyl,- pyridaziny(C,- 3 )alkyl, pyrimidinyl, pyrimidinyl(C, 1 3)alkyl, pyrazinyl, pyrazinyl(0 1 3 )alkyl, I ,3,5-tniazinyl, I ,3,5-triazinyl(C 1 3 )alkyl, indolyl(C.. 3 )alkyl, benzo[b~furyl, benzo[b]furyl(C. 3 )alkyl, benzo~b]thienyl, benzo[bthienyl(Cl- 3 )alkyl, benzimidazolyl, benzimidazolyl(Cl-3)alkyl, amino(C. 3 )alkyl, Cl-3alkylamino(C 1 ,)alkyl, di(Cl-3)alkylamino(Cl-3)alkyl, aminoimino, hydroxy(C 14 3)alkyl and trifluoro(C 1 ,)alkoxy; wherein pyrrolidinyl, I ,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazol inyl, pyrazolidinyt, pipenidinyl, morpholinyl, thiomorpholinyl, piperazinyl are optionally substituted with one to three substituents independently selected from the group consisting of C 1 ~alkyl and oxo; and, wherein phenyl is optionally substituted with one to four substituents independently selected from the group consisting of C 14 alkyl, C 1 alkoxy, -OCH 2 -O(CH 2 2 halogen, hydroxy and cyano; alternatively, R 5 and R 6 may, together with the nitrogen to which they are attached, fornm a fused heterocyclyl moiety selected from the group consisting of pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pipenidinyl, morpholinyl, thiomnorpholinyl and piperazinyl optionally substituted with one to four substituents independently selected from C 14 alkyl. 19. The compound of claim 1 wherein R 5 and RW are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, ID -62- ct-butyl, fluoro(C,. 3 )alkyl, methoxy(C,. 3 )alkyl, methallyl, cyclopropyl, Scyclohexyl, phenyl, thiazolyl, imidazolyl(C,-)alkyl, Z benzimidazolyl(Cl. 3 )alkyl, dimethylamino(C,. 3 )alkyl and hydroxy(C,. 3 )alkyl; wherein phenyl is optionally substituted with one to three substituents selected from fluorine; alternatively, R 5 and R 6 may, 00 together with the nitrogen to which they are attached, form a fused 00 heterocyclyl moiety selected from the group consisting of pyrrolidinyl, piperidinyl and morpholinyl optionally substituted with one to four IN substituents independently selected from the group consisting of methyl, ethyl, n-propyl and n-butyl. The compound of claim 1 wherein R s and R 6 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, t-butyl, 2-fluoroethyl, methoxyethyl, methallyl, cyclopropyl, cyclohexyl, phenyl, thiazolyl, 2-(2-imidazolyl)ethyl, benzimidazolylmethyl, dimethylaminopropyl and hydroxyethyl; wherein phenyl is optionally substituted with fluorine; alteratively, R 5 and R' may, together with the nitrogen to which they are attached, form a fused heterocyclyl moiety selected from the group consisting of pyrrolidinyl, piperidinyl and morpholinyl; wherein piperidinyl is substituted with two or four substituents selected from methyl. 21. The compound of claim 1 of the formula: wherein the moiety is substituted on phenyl at the 3 or 4 position and -63- and Z are dependently selected from the group consisting of: methyl H allyl 2-(4-fluorophenyl)ethyl 2-(2-thienyl )ethyl 2-(3-indolyl )ethyl 2-cyclohexylethyl 2-phenoxyethyl 2-(4-ethyl-5-oxo-1 ,4- dihydrotetrazol-1 -yI)ethyl 2-phenyl-2-oxoethyl 2-(4-methoxyphenyl)-2- oxoethyl 2-(3-cyanophenyl)-2-oxoethyl 2-(2,3-dihydro-1,4- benzod ioxi n-6-yl )-2-oxoethyl 2-(3,4-dihydro-2H-1 15- benzodioxepin-7-yl)-2-oxoethyl propyl 2-phenylethyl piperonyll 3-phenylpropyl methyl 2-phenylethyl 2-phenylethyl 2-phenylethyl 2-phenylethyl 2-phenylethyl 2-phenylethyl 2-phenylethyl 2-phenylethyl -4-C(=Oy -4-C(=Oy -4-C(=Oy -4-C(=Oy -4-C(=Oy -4-C(=Oy -4-C(=Oy -4-C(=Oy -4-C(=Oy N, N-d iethyl amino; N,N-diethylamino; N ,N-diethylamino; N ,N-diethylamino; N, N-diethylamino; N, N-diethylamino; N, N-diethylamino; N, N-diethylamino; N, N-d iethylamino; N, N-diethylamino; N ,N-diethylamino; N, N-diethylamino; N,N-diethylamino; N,N-diethylamino; N,N-diethylamino; NN-diethylamino; N ,N-diethylamino; N,N-diethylamino; N-methyl-N-(3- fiuorophenyl)amino; N,N-diethylamino; N-ethylamino; amino; 4-morpholinyl; N ,N-diisopropylamino; N,N- bis(methoxyethyl)amino; 1 -pyrrolidinyl; 2,6-dimethyl-1 -piperidinyl; -64- 2-phenylethyl 2-phenylethyl 2-phenylethyl 2-phenylethyl 2-phenylethyl 2-phenylethyl 2-phenyl ethyl 2-phenylethyl 2-phenylethyl 2-phenylethyl 2-phenylethyl 2- ph enyl ethyl 2-phenylethyl -4-C(=Oy 1,3-benzodioxol-5-yl)ethyl 2-(1 ,3-benzodioxol-5-yl)ethyl methyl H allyl 2-(4-methoxyphenyl)ethyl 2-(4-rnethoxyphenyl)ethyl 2-(4-methoxyphenyl )ethyl 2-(4-rnethoxyphenyl)ethyl 2-{4-methoxyphenyl)ethyl 2-(4-methoxyphenyl)ethyl 2-(4-methoxyphenyl )ethyl 2-(4-methoxyphenyl )ethyl 2-(4-methoxyphenyl )ethyl 2-(4-methoxyphe nyl )ethyl 2-(4-hydroxyphenyl )ethyl N-ethyl-N- (methylallyl)amino; N ,N-dipropylamino; N-t-butylamnino; N-(2-fluoroethyl )amino; N-(2-thiazolyl)amino; N-(2-methoxyethyl )amino; N-(1 H-benzimidazol-2- ylmethyl )amino; N-cyclohexylamino; N-phenylamino; imidazolyl)ethyl]amino; N-cyclopropylamino; N, N-(dimethylaminopropyl) amino; N-ethyl-N- (hydroxyethyl )amino; N-ethylamnino; N,N-diethylamino; N-ethylamnino; N-ethylamnino; N-ethylamnino; N,N-diethylamino; 4-morpholinyl; N-ethylamnino; N,N-bis(2- methoxyethyl )amino; 1 -pyrrolidinyl; 2,6-dimethyl-1 -pipenidinyl; N-ethyl-N- (methylal Iyl)ami no; N ,N-(di-n-propyl)amino; 2,2,6,6-tetramethyl-1 piperid inyl: N, N-(di-2-propyl)amino; N-ethylamino; and, 2-(4-hydroxyphenyl)ethyl N,N-diethylamino; and pharmaceutically acceptable enantiomers, diastereomers and salts thereof. 22. The compound of claim 1 of the formula: \R6 wherein R 2 R 5 and R 6 are dependently selected from the group consisting of R' R 2 methyl 4-MeOPh H 4-HOPh methyl 4-MeOPh Et 2 H 4-HOPh Et 2 2-(4-MeOPh)ethyl 4-MeOPh Et 2 and, 2-(4-HOPh)ethyl 4-HOPh Et 2 and pharmaceutically acceptable enantiomers, diastereomers and salts thereof. 23. The compound of claim 1 which is an effective analgesic. 24. The compound of claim 1 which is an effective immunosuppressant, antiinflammatory agent, agent for the treatment of neurological and psychiatric conditions, medicament for drug and alcohol abuse, agent IND -66- for treating gastritis and diarrhea, cardiovascular agent or agent for the treatment of respiratory diseases. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 00 00\ 00 26. A method for the treatment of a pharmacological condition in a subject in need thereof comprising administering to the subject a therapeutically IND effective amount of an opioid receptor modulator compound selected 0 10 from the group consisting of a &-opioid and a p.-opioid receptor modulator compound of Formula R 2 R-A-Z N wherein: R' is selected from the group consisting of hydrogen, C 14 ,alkyl, halol. 3 (C, 4 ,)alkyl, C 2 -,alkenyl, C 1 .,alkoxy(C 24 ,)alkenyl, C 2 .,alkynyl, C 14 ,alkoxy(C 24 ,)alkynyl, cycloalkyl, cycfoalkyl(C 14 ,)alkyl, cycloalkylcarbonyl(C 14 ,)alkyl, cycloal kyl(C 24 ,)alkenyl, cycloalkyl(C 2 4 ,)alkynyl, heterocyclyl, heterocyclyl(C,J)alkyI, heterocyclylcarbonyl(C 14 ,)alkyl, heterocycly(C 2 4 ,)alkenyl, heterocyclyl(C 24 ,)al kynyl, aryl, arlCakyl, arytcarbonyl(C 14 )alkyl, ary](C 2 -,)alkenyl, aryl(C 2 8 )alkynyl, arytaminocarbonyl(C, 4 )alkyl, heteroaryi(Cl-8)alkyl, heteroarylcarbonyl(C 4 ,)alkyl, heteroaryl(C 24 ,)alkenyl, heteroaryl(C 2 4 ,)alkynyl, heteroarylaminocarbonyl(C 14 ,)alkyl, (Rla) 2 -N-(C,,)alkyl, R 18 -O-(C 14 ,)alkyl, Rla-S-(C 1 -,)alkyl, Rla-SO-(C 14 )alkyl and R' 8 -S0 2 -(C 1 -8)alkyl; wherein heterocyclyl is optionally substituted with one to three substituents IND -67- 0 ~independently selected from the group consisting of C,.,alkyl, C,,alkenyl, C 14 ,alkoxy, amino, C 1 -,alkylamino, di(C 16 ,alkyl)amino, C 1 6 ,alkylcarbonyl, Z C 1 6 alkylcarbonyloxy, Cl. 6 alkylcarbonylamino, C, 1 ,alkylthio, Cl 1 ,alkylsulfonyl, halogen, hydroxy, oxo, cyano, trifluoromethyl and tnifluoromethoxy; and, wherein aryl and heteroaryl are optionally substituted with one to three 00 substituents independently selected from the group consisting of C 1 -6alkyl, 00 C, 24 alkenyl, C, 1 ,alkoxy, amino, C 14 ,alkylamino, di(C 14 ,alkyI)amino, Cl 1 ,alkylcarbonyl, C 14 6al kylcarbonyloxy, C,-6alkylcarbonylamino, C, 14 alkylthio, C, 4 ,alkylsulfonyl, halogen, hydroxy, cyano, tnifluoromethyl and trifluoromethoxy; R la is independently selected from the group consisting of hydrogen, C 14 8alkyl, Cl 1 8alkoxy(C 14 ,)alkyl, hydroxy(C 1 -,)alkyl, halo 1 -3(C 1 -,)alkyI, halo, )al koxy(C 1 -)alky[, C 24 alkenyl, C 2 -,alkynyl, cycloalkyl, cycloalky((Cl-8)alkyl, heterocyclyl, heterocyclyl(C 14 8)alkyl, heterocyclyl(C, 4 )alIke nyl, heterocycly(C 1 ,)alkynyl, aryl, aryl(C, 1 4alkyl, aryl(C 1 4 8)alkenyl, aryl(C, 14 )alkynyl, arylcarbonyl(C 14 ,)alkyl, heteroaryl, heteroaryi(Cl 14 )alkyl, heteroaryl(C,.8)alkenyl, heteroaryl(C 1 .,)alkynyl and heteroarylcarbonyl(C, 14 )alkyl; wherein heterocyclyl is optionally substituted with one to three substituents; independently selected from the group consisting of C, 14 alkyl, C, 24 alkenyl, C, 1 6alkoxy, amino, C 14 alkylamino, di(C 14 ,alkyl)amino, C 14 6alkylcarbonyl, C,.,alkylcarbonyloxy, C, 1 .alkylcarbonylamino, Cl-6alkyfthio, C, 4 6alkylsuffonyl, halogen, hydroxy, oxo, cyano, trifluoromethyl and trifluoromethoxy; and, wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C 14 6alkyI, C 2 6alkenyl, C 1 .6alkoxy, amino, C, 14 alkylamino, di(C 14 6alkyl)amino, C 1 .6alkylcarbonyl, C, 1 6alkylcarbonyloxy, C,,alkylcarbonylamino, C 14 alkylthio, C 14 ,alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy;, R 2 is selected from the group consisting of aryl and heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of C 1 -6alkyl, C 24 ,alkenyI, C 1 ,alkoxy. amino, C 1 -,alkylamino, -68- c- d i(C 1 -,alkyl )amino, C 1 -6alkylcarbonyl, Cl-6alkylcarbonyloxy, C 1 -6alkyloxyc-arbonyI, Cl. 6 alkylaminocarbonyl, Cl. 6 alkylcarbonylamino, Z Cl-alkylthio, C 1 -,alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and 0 trifluoromethoxy; alternatively, when aryl and heteroaryl are substituted with two substituents attached to adjacent carbon atoms, the two substituents 00 can together form a single fused moiety; wherein the moiety is selected 00 ~from the group consisting of -(CH 2 and -O(CH 2 1 3 IND R 3 is selected from the group consisting of aryl and heteroaryl optionally ci 10 substituted with one or two substituents in addition to the -A-Z moiety independently selected from the group consisting of Cl 14 alkyl, C 24 ,alkenyl, C 14 ,atkoxy, amino, C 14 6alkylamino, di(C 14 ,alkyi)amino, C 1 -,alkylcarbonyl, C 1 .,alkylcarbonyloxy, C, 14 alkyloxycarbonyl, C, 1 ,alkylaminocarbony, C.alkylcarbonylamino, C 1 .,alkylthio, C 1 -6alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy; alternatively, when aryl and heteroaryl are substituted with two optional substituents attached to adjacent carbon atoms, the two substituents can together form a single fused moiety; wherein the moiety is selected from the group consisting of and -O(CH 2 1 A is selected from the group consisting of and -SO 2 X is selected from the group consisting of 0 and S; Z is selected from the group consisting of -0(R 4 and -N(R 5 Ris selected from the group consisting of hydrogen, C 14 ,alkyI (optionally substituted with one to three halogen substituents), C 14 ,alkoxy(C 14 ,)alkyl, C 2 -,alkenyl, cycloalkyl, cycloalkyl(C 14 ,)alkyl, heterocyclyl, heterocycly](C,,)alkyl, aryl, aryl(C 1 -8)alkyl, heteroaryl, heteroaryi(C 1 -8)alkyI, amino(C 14 8)alkyl, C 1 .,alkylamino(C 14 ,)alkyl, di(C 1 -,)alkylamino(Cl-8)alkyl and hydroxy(C,-,)alkyl; wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of IND -69- C 1 ~alkyI, C 14 alkoxy, C 2 -,alkenyl, cycloalkyl, trifluoromethyl, halogen, hydroxy, oxo and cyano; and, wherein aryl is optionally substituted with one Z to four substituents independently selected from the group consisting of C 14 alkyl, C 14 alkoxy, C 2 ,alkenyl, cycloalkyl, -OCH 2 -O(CH 2 2 0-, trifluoromethyl, halogen, hydroxy and cyano; and, 00 00 R 5 and R 8 are independently selected from the group consisting of hydrogen, Cl 1 ,alkyI (optionally substituted with one to three halogen substituents), C 1 -,alkoxy(C 1 8 )al kyl, C 2 ,alkenyl, cycloalkyl, cycloalkyl(C 1 ,)alkyl, heterocyclyl, heterocyclyl(C, 14 )alkyl, aryl, aryl(C 14 ,)alkyl, heteroaryl, heteroaryl(C 1 ~)alkyl, amino(C 1 -,)alkyl, C, 14 alkylamino(C, 14 )alkyl, di(Cj.,)alkylamino(C 14 )alkyl, aminoimino, aminocarbonyl, aminocarbonyl(C,,)alkyl, aryloxycarbonylamino(C 4 ,)alkyl, heteroaryloxycarbonylamino(C. 8 )alkyl, hydroxy(C 14 ,)alkyl and trifluoro(C 14 )alkoxy; wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of C 14 alkyl, C 14 alkoxy, C 2 .,alkenyI, cycloalkyl, trifluoromethyl, halogen, hydroxy, oxo and cyano; and, wherein aryl is optionally substituted with one to four substituents independently selected from the group consisting of C., 4 alkyI, C 14 ,alkoxy, C 24 .alkenyl, cycloalkyl, -OCH 2 -O(CH 2 2 0-, trifluoromethyl, halogen, hydroxy and cyano; alternatively, R 5 and W 6 may, together with the nitrogen to which they are attached, form a fused heterocyclyl moiety optionally substituted with one to four substituents independently selected from the group consisting of C 14 6alkyl, C 14 alkoxy, C 24 .alkenyl, cycloalkyl, trifl uorom ethyl, halogen, hydroxy and cyano; and pharmaceutically acceptable enantiomers. diastereomers and salts thereof. 27. The method of claim 26 wherein the therapeutically effective amount is from about 0.01 mg/day to about 15,000 mg/day. 28. The method of claim 26 wherein the 5-opioid or i-opioid receptor IND modulator compound is an effective analgesic. Z29. The method of claim 26 wherein the 8-opicid or j±-opioid receptor 0 modulator compound is an effective immunosuppressant, antiinflammatory agent, agent for the treatment of neurological and 00 psychiatric conditions, medicament for drug and alcohol abuse, agent 00 for treating gastritis and diarrhea, cardiovascular agent or agent for the treatment of respiratory diseases. ci 10 30. The method of claim 26 wherein the pharmacological condition is pain. 31. A pharmaceutical composition comprising a combination of a 4-opioid receptor modulator compound and an opioid receptor modulator compound selected from the group consisting of a 6-opioid and a pg-opioid receptor modulator compound of Formula R 2 R -A-Z N 1I1 wherein: R' is selected from the group consisting of hydrogen, C 14 alkyl, halo,,(C, 14 )alkyl, C 24 ,alkenyl, Cl 1 ,alkoxy(C 24 ,)alkenyl, C 24 ,alkynyl, C 1 .,alkoxy(C 24 ,)alkynyl, cycloalkyl, cycloalkyl(C 14 ,)alkyl, cycloalkylcarbonyl(C 14 ,)alkyl, cycloalkyl(C 24 ,)alkenyl, cycloalkyl(C 2 ,,)alkynyl, heterocyclyl, heterocyclyl(C 1 -)alkyl, heterocyclylcarbonyl(C, 1 4 )alkyl, heterocyclyl(C 24 8)alkenyl, heterocyclyl(C 2 1)alkynyl, aryl, aryl(C 1 -,)alkyl, arylcarbonyl(C 1 .,)alkyl, aryi(C 2 -,)alkenyl, aryl(C 2 .8)alkynyl, -71- arylaminocarbonyl(C,- )alkyl, heteroaryl(C,- 8 )alkyl, ~heteroarylcarbonyl(C 18 ,)alkyl, heteroaryl(C 2 -8)al kenyl, heteroaryl(C 2 -,)alkynyl, Z heteroarylaminocarbonyl(C-)alkyl, (R"a) 2 -N-(C 18 )alkyI, Rla-O-(C, )alkyl, Rla-S-(C, 14 )alkyl, R' 8 -SO-(C,,)alkyl and R' 8 -SO 2 -(C,,)alkyl; wherein heterocyclyl is optionally substituted with one to three substituents 00 independently selected from the group consisting of C 1 -,alkyl, C 24 "alkenyl, 00 C 14 6alkoxy, amino, C 1 -6alkylamino, di(C, 14 alkyl )amino, C 1 6 alkylcarbonyl, C, 1 ,alkylcarbonyloxy, C, 14 alkylcarbonylamino, C 14 6alkylthio, C,.,alkylsulfonyl, halogen, hydroxy, oxo, cyano, trifluoromethyl and trifluoromethoxy; and, wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C 1 -6alkyl, C 2 ,alkenyl, C,.6alkoxy, amino, C 14 ,alkylamino, di(C 1 -,alkyl )amino,- C, 1 ,alkylcarbonyl, Cl-6alkylcarbonyloxy, C 14 ,alkylcarbonylamino, C 14 6alkylthio, C, 1 ,alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy; R 1 is independently selected from the group consisting of hydrogen, C 1 ~alkyl, C 14 ,alkoxy(Cl 14 )alkyl, hydroxy(C 14 )alkyl, halo 14 3(C 14 ,)alkyl, halo 14 3(C 14 ,)alkoxy(C 1 8 )alkyl, C 2 8alkenyl, C 2 -8alkynyl, cycloalkyl, cycloalkyl(C.,)alkyl, heterocyclyl, heterocyclyl(C 14 ,)alkyl, heterocyclyl(C 14 ,)alkenyl, heterocyclyt(C 14 ,)alkynyl, aryl. aryl(C, 14 )alkyl, aryl(C 14 )alkenyl, aryi(C 1 -,)alkynyI, arylcarbonyl(C 1 -,)alkyl, heteroaryl, heteroaryi(Cl-8)alkyl, heteroaryl(C 14 ,)alkenyl, heteroaryl(C 1 4 )alkynyl and heteroarylcarbonyl(C 1 -,)alkyl; wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of C 1 -,alkyl, C 24 8alkenyl, C 1 -aalkoxy, amino, C 14 ,alkylamino, di(C,. 6 alkyl)amino, Cl,alkylcarbonyl, C 1 -,alkylcarbonyloxy, Cl 1 ,alkylcarbonylamino, C,.6alkylthio, C 14 ,alkylsulfonyl, halogen, hydroxy, oxo, cyano, trifluoromethyl and trifluoromethoxy; and, wherein aryl and heteroaryl are optionally substituted with one to three substituents; independently selected from the group consisting of C 1 -,alkyl, C,,alkenyl, C 1 -6alkoxy, amino, Cl 1 ,alkylamino, di(C 1 .6alkyl )amino, Cl 16 alkylcarbonyl, C 14 ,al kyl carbon yloxy, C 1 -6alkylcarbonylamino, Cl 14 alkylthio, Cl-6alkylsulfonyl, -72- halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy; SR 2 is selected from the group consisting of aryl and heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of C,alkyl, C 2 4 ,alkenyl, C 1 6alkoxy, amino, C,.,alkylamino, oo00 di(C,6alkyl)amino C,,alkylcarbonyl, C,6alkylcarbonyloxy, 00 C,.,alkyloxycarbonyl, C,.alkylaminocarbonyl, C,,alkylcarbonylamino, C,6alkythio, C, 4 alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy; alternatively, when aryl and heteroaryl are substituted with two substituents attached to adjacent carbon atoms, the two substituents can together form a single fused moiety; wherein the moiety is selected from the group consisting of -(CH,)3 5 and -O(CH 2 )1- 3 0-; R 3 is selected from the group consisting of aryl and heteroaryl optionally substituted with one or two substituents in addition to the -A-Z moiety independently selected from the group consisting of C,,alkyl, C 24 alkenyl, C,.,alkoxy, amino, C, 4 alkylamino, di(C 1 -alkyl)amino, C, 4 alkylcarbonyl, C,.,alkylcarbonyloxy, C 1 .alkyloxycarbonyl, C,.alkylaminocarbonyl, C,.alkylcarbonylamino, C, 1 alkylthio, C, 4 alkylsulfonyl, halogen, hydroxy, cyano, trifluoromethyl and trifluoromethoxy; alternatively, when aryl and heteroaryl are substituted with two optional substituents attached to adjacent carbon atoms, the two substituents can together form a single fused moiety; wherein the moiety is selected from the group consisting of and -O(CH 2 1 A is selected from the group consisting of and -SO 2 X is selected from the group consisting of O and S; Z is selected from the group consisting of -O(R 4 and -N(R)(R 6 R 4 is selected from the group consisting of hydrogen, C,.alkyl (optionally substituted with one to three halogen substituents), C,,alkoxy(C,)alkyl, -73- C 2 -,alkenyl, cycloalkyl, cycloalkyl(C,,)alkyl heterocyclyl, heterocyclyl(C, 14 )alkyl, aryl, aryl(C 1 -,)alkyl, heteroaryl, heteroaryl(C 14 )alkyl, Z amino(C,,)alkyl, C,.8alkylamino(C 14 )alkyl, di(C,. 8 )alkylamino(C 14 ,)alkyl and hydroxy(C 14 ,)alkyl; wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of 00 C 14 alkyl, C,,alkoxy, C 2 -,alkenyl, cycloalkyl, tnifluoromethyl, halogen, 00 hydroxy, oxo and cyano; and, wherein aryl is optionally substituted with one to four substituents independently selected from the group consisting of C 14 alkyl, C, 14 alkoxy, C, 24 alkenyl, cycloalkyl, -OCH 2 -O(CH 2 2 0-, tnifluoromethyl, halogen, hydroxy and cyano; and, R' and R 6 are independently selected from the group consisting of hydroge-n, C 1 .,alkyl (optionally substituted with one to three halogen substituents), C 1 -,alkoxy(C 14 ,)alkyl, C 2 -,alkenyl, cycloalkyl, cycloalkyl(C, 4 ,)alkyl, heterocyclyl, heterocyclyl(C 1 -,)alkyl, aryl, aryl(C 1 .,)alkyl, heteroaryl, heteroaryl(C 1 -)alkyl, amino(Cl-8)alkyl, C, 1 ,alkylamino(C 1 .,)alkyl, di(C 14 )alkylamino(Cj 14 )alkyl, aminoimino, aminocarbonyl, aminocarbonyl(Cl 1 8)alkyl, aryloxycarbonylamino(C 14 ,)alkyl, heteroaryloxycarbonylamino(Cl 1 a)alkyl, hydroxy(C. 8 )alkyl and trifluoro(C 14 )alkoxy; wherein heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of C 14 ,alkyl, C 14 ,alkoxy, C 2 -,alkenyl, cycloalkyl, trifluoromethyl, halogen, hydroxy, oxo and cyano; and, wherein aryl is optionally substituted with one to four substituents independently selected from the group consisting of C 14 ,alkyl, C 14 ,alkoxy, C 2 .,alkenyl, cycloalkyl, -OCH 2 -O(CH 2 2 0-, trifluoromethyl, halogen, hydroxy and cyano; alternatively, R 5 and R 6 may, together with the nitrogen to which they are attached, form a fused heterocyclyl moiety optionally substituted with one to four substituents; independently selected from the group consisting of Cl.,alkyl, C,.,alkoxy, C,,alkenyl, cycloalkyl, trifluoromethyl, halogen, hydroxy and cyano; and pharmaceutically acceptable enantiomers, diastereomers and salts thereof. -74- O 32. The pharmaceutical composition of claim 31 wherein the p-opioid Z receptor modulator compound is selected from alfentanil, allylprodine, 0 alphaprodine, anileridine, bezitramide, buprenorphine, clonitazene, cyclazocine, dextromoramide, dihydrocodeine, dihydromorphine, S 5 ethoheptazine, ethylmorphine, etonitazene, fentanyl, heroin, 00 hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, lofentanil, meperidine, meptazinol, Smetazocine, methadone, morphine, nalbuphine, norlevorphanol, c normethadone, nalorphine, normorphine, opium, oxycodone, oxymorphone, phenazocine, piritramide, propiram, propoxyphene, sufentanil, tramadol or diastereomers, salts, complexes and mixtures thereof of any of the foregoing. 33. A method for the treatment of a pharmacological condition in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 31. 34. The method of claim 33 wherein the therapeutically effective amount is from about 0.01 mg/day to about 15,000 mg/day. The method of claim 33 wherein the pharmaceutical composition is an effective analgesic. 36. The method of claim 33 wherein the pharmaceutical composition is an effective immunosuppressant, antiinflammatory agent, agent for the treatment of neurological and psychiatric conditions, medicament for drug and alcohol abuse, agent for treating gastritis and diarrhea, cardiovascular agent or agent for the treatment of respiratory diseases. 37. The method of claim 33 wherein the pharmacological condition is pain. INO O 0 DATED this 7 th Day of November 2006 Shelston IP O Z Attorneys for: Ortho-McNeil Pharmaceutical, Inc. 0 oO 00 oO tc 0',