AU2003220725B2 - 4-[aryl(piperidin-4-yl)] aminobenzamides which bind to the delta-opioid receptor - Google Patents

Description

-1-

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name of Applicant/s: Actual Inventor/s: Address for Service:

CCN:

Ortho-McNeil Pharmaceutical, Inc.

John R. Carson and Richard J Carmosin and Louis J. Fitzpatrick, and Allen B. Reitz and Michele C. Jetter Baldwin Shelston Waters MARGARET STREET SYDNEY NSW 2000 3710000352 4-[ARYL(PIPERIDIN-4-YL)] AMINOBENZAMIDES WHICH BIND TO THE DELTA-OPIOID RECEPTOR Invention Title: Details of Original Application No. 20097/99 dated 23 Dec 1998 The following statement is a full description of this invention, including the best method of performing it known to me/us:- File: 28475AUP01 500197871_1.DOC/5844 -1A- 4-[ARYL(PIPERIDIN-4-YL)] AMINOBENZAMIDES WHICH BIND TO THE DELTA-OPIOID RECEPTOR The present application is a divisional application of Australian Application No. 20097/99 which is incorporated in its entirety herein by reference.

The present invention relates to delta-opioid receptor agonists/antagonists.

More particularly, the present invention relates to 4 -[aryl(piperidin-4-yl)]aminobenzamides which are delta-opioid receptor agonists useful as analgesics.

BACKGROUND OF THE INVENTION W09723466 to Plobeck N. et al., discloses compounds (approximately) of the formula:

R

R

which are mu-opioid antagonists.

W09636620 to Dondio discloses compounds (most relevantly) of the formula: -2

R

RR

which are delta-opioid agonists/antagonists.

W097.10230 to Dondio G. et al., discloses compound s (most relevantly) ef the formula: 0 R F< ~R which are delta-opioid, kappa-opioid and mu-opioid receptor agonists/antagonists.

W093 15062 to Chang K. et al., discloses compounds (approximately) of the formula: \0 -3-

OHO

R

0 N R 0 SN R cR

R

Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

SUMMARY OF THE INVENTION According to the first aspect, the present invention provides a compound which binds to the delta-opioid receptor of the general formula: 0 R 1

N

R2 R7.3-Ar\

R

8 0-2

R

3 R N R 4

I

R6 where Ar is phenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with 1 to 3 R 7 R' and R 2 are independently selected from the group consisting of hydrogen, Ci.galkyl; phenyl, optionally mono-, di-, or tri-substituted with halo, Ci-6alkyl, Cl-6alkoxy or trifluoromethyl; or benzyl, optionally mono-, di, or tri-substituted with halo, Ci- 6 alkyl,

C

1 -6alkoxy or trifluoromethyl, or alternatively, R' and R 2 are taken together with their N of attachment to form a ring which is selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl and hexamethyleneiminyl, each said ring optionally substituted with 1 to 4 methyl groups; IND -4- R3 is selected from hydrogen and Ct- 4 alkyl;

R

4 and R 5 are hydrogen; R6 is selected from the group consisting of hydrogen; Cis 8 alkyl; C3-6cycloalkylCl-3alkyl, 00 C 3 6 alkenyl; CI-6alkoxyC 1- 3 alkyl; and phenylCl4alkyl, where the phenyl is optionally mono-, di-, or tri-substituted with R 7

R

7 is independently selected from the group consisting of hydroxy, halo, CI- 3 alkyl, C 3 alkoxy, CI- 3 acyl, CI- 3 acyloxy, cyano, amino, C 1 3 acylamino, C 1 3 alkylamino, di(Ci.

3 alkyl)amino, C1- 3 alkylthio, Cl- 3 alkylsulfonyl, trifluoromethyl and trifluoromethoxy, and two R can together form a single moiety selected from the group consisting of-(CH 2 3 5 and -O(CH 2 )1- 3 0- attached to adjacent carbon atoms of Ar; and R is independently selected from the group consisting of halo, CI-6alkyl, CI-6alkoxy and trifluoromethyl wherein the compounds of the formulae; 0 2003220725 18 May 2006 z i)0 z z- 2003220725 18 May 2006

~^J

^LK

z_ 0 0 z,, and tq

N

00

N

0 OO H cKI N

H

Cc are disclaimed.

As delta-opioid receptor agonists, such compounds are useful as analgesics.

Depending on their agonist/antagonists effect, such compounds may also be useful immunosuppressants, anti-inflammatory agents, agents for treatment of mental illness, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents, and agents for the treatment of respiratory diseases.

According to the second aspect, the present invention provides the use of a compound of the first aspect in the manufacture of a medicament for use as an immunosuppressants, anti-inflammatory agents, agents for the treatment of mental illness, medicament for drug and alcohol abuse, agents for treating gastritis and diarrhoea, cardiovascular agent, agents for treatment of respiratory diseases or analgesic.

According to the third aspect, the present invention provides the use of a compound of the first aspect in the manufacture of a medicament for treatment of pain in a mammal.

According to the fourth aspect, the present invention provides a compound of the first aspect for use as an immunosuppressant, anti-inflammatory agent, agent for the treatment of mental illness, medicament for drug and alcohol abuse, agent for treating gastritis and diarrhoea, cardiovascular agent, agent for the treatment of respiratory diseases or analgesic.

According to the fifth aspect, the present invention provides a method for treating a condition selected from the group consisting of inflammation, mental illness, drug and alcohol abuse, gastritis and diarrhoea, cardiovascular disease, respiratory diseases, pain or a condition requiring immunosuppression, comprising the administration to a mammal requiring such treatment of an effective amount of a compound of the first aspect.

O

O

-o According to the sixth aspect, the present invention provides a method for the treatment of pain in a mammal comprising administering to a mammal requiring such treatment an effective amount of a compound of the first aspect.

According to the seventh aspect, the present invention provides a method to make a compound of the formula: 0 R' R2

\R

comprising the step of arylating a compound of the formula:

R

7 o- 3 Ar

NH

in the presence of a palladium catalyst, a phosphine ligand and a base with a compound of the formula:

R'

0

N

R

R 0-2 X =Br, I, OSO 2

CF

3 where Ar, R 2

R

3

R

4

R

5

R

6

R

7 and R 8 are as defined in the first aspect.

Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an INO O inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

DETAILED DESCRIPTION OF THE INVENTION 00 The core structure of the compounds of the present invention can be made in a two step process. This process must be modified as required by the strategy employed to Iobtain the various substituents. In a first strategy, the starting materials are substituted as desired with the final substituents and, where the substituents or their protected forms Care stable to the reaction conditions, the core structure may be subsequently made by the two step process. In a second strategy, the final core structure is obtained and, where the core structure is stable to the modifying reaction conditions, the substituents are modified as desired. Variations might include modifying the substituents on intermediates or replacing precursor substituents on the finished core structure. -6- Scheme A generally describes the manufacture of the compounds of the present invention. The first step of Scheme A is a reductive alkylation of piperidone Al and amine A2 to produce N-aryl-piperidineamine A3. The reductive alkylation is carried out by combining the ketone A1, amine A2, and an appropriate solvent/reducing agent combination to form a reaction mixture which is cooled or heated as necessary. Suitable solvent/reducing agent combinations include I1,2-dichloroethane or acetonitrile/NaBH(OAc) 3 acid catalyst; methanol/NaBH 3 CN acid catalyst; methanol or ethanol or isopropanol/NaBH 4 or alcoholic solvent/H 2 noble metal catalyst. The use of the 1,2-dichloroethane or acetonitrile/NaBH(OAc) 3 acid catalyst combination is further described by Abdel-Magid, A. et al.. J. Org.Chem., Vol. 61, pp 3849-3862 (1996). In the second step of Scheme A, the N-aryl-piperidineamine A3 is reacted with a bromo, iodo or trifluoromethanesulfonyloxy substituted benzamide A4 in the presence of a palladium catalyst, phosphine ligand and base to give the (N-aryl, N-piperidin-4-yl)aminobenzamide. Preferred palladium catalysts include PdCl 2 phosphine ligand, tris(dibenzylideneacetone)dipalladium(0) which is Pd 2 (dba)3 phosphine ligand, Pd(OAc) 2 phosphine ligand and Pd(Ph 3

P)

4 Suitable phosphine ligands include BINAP and tri(o-tolyl phosphine). Suitable bases include NaOtBu and Cs 2 CO3. The reaction of the second step is an arylation further described by Buchwald, S. J. Org. Chem., Vol. 61, p i 133 (1996). The manufacture of the various starting materials for Scheme A is well within the skill of persons versed in this art.

SCHEME A 0

R

3 R 7l3 1 -Ar

R

5 4

NH

2 R 0 3 H0 N

R

3 k2

R

5 N R 1R 6 X =Br, 1, OSO 2

CF

3 A3 A4

R

3

R

R

5

N

R

6

R

PrRre Ar is3 pheny

AN

PrfrrdR'adR 2 ae nepnetl elce fo tegru onitigo R hy r g n m e h l et yl-2 l r p l u y t. u y i b t l h n l ~Preferred Ar. is ahnylaeidpnetl.eetdfo yroemtyehl Preferred R' n are ine nd tl selected from the group consisting of hdoemtyehl yrgn ehl tyn-propyl, i-propyl, n-butyl, t-butyl, -butyl, pylpoymtyehenyl, ll methloxyetybenzyl, p- chlorobenzyl, p- urobenzyl n p-fumethylbenzyl, o -8 p-trifluoromethybenzyl, p-aminobenzyl, thien-2-yICH 2 CHr-, thien-3-yCH 2

CH

2 pyridin-3-yCH 2

CH

2 Pyridin-4-yICH 2

CH

2 thiazol-2-ylCH 2 CH2- anid phenylCl{ 2 CHr, any of' which may be R 7 substituted as taught above. It is a preferred embodiment of R6, that where it contains a phenyl or heteroaromatic group, that th e moiety linking the phenyl or heteroaromatic group to the piperidinyl moiety be at least two carbon atoms long. Thus this linking moiety might be ethyl or propyl which is beta substituted with the phenyl or heteroaromatic group, or propyl, which is gamma, substituted.

Preferred

R

7 are independently selected from the group consisting of hydroxy, chloro, bromo, fluoro, methyl, ethyl, n-propyl, i-propyl, n-butyL, i-butyl, t-butyL, mfethoxy, ethoxy, formyl. acyl, acetoxy, cyano, amino, methylamido, methylamino, N,N-dimethylamino, methylthio, methylsulfonyl, trifluoromethoxy and tnifluoromethyl, and preferred moieties where two R' together form a single moiety are selected from the group consisting of propylene, butylene and -OCH- 2 0-.

Preferred R" are independently selected from the group- consisting of chloro, bromo, fluoro, methyl, ethyl, n-propyl, i-propyl, t-butyl, methoxy, ethoxy and trifluoromethyl.

Preferred compounds of the present invention have the general structure: 0 R 3 or4N 2 4 2

N

R 3

N

R

6 where and R 7 are dependently selected from the groups consisting of- -9 Cpd# R 7 amide R' subst.

P6 P7 P8 P9

PIO

P11 P12 P13 P14 P16 P17 P18 P19 P21I P22 P23 P24 P26 P27 P28 none none 3-OH 3-OH 3-OH 3-OH 3-OH 3-OH 3-OH 3-OH 3-OH 3-OH 3-OH none none none 3 -F 3-F 3-F 3-OCH3 3-OCH 1 3-OCH 3 3 ,4-OCH 2

O-

3 ,4-OCHzO- 3,4-OCH 2 0- 3 ,4-OCH 2

O-

3-N(CH 3 2 3 -N(CH 1 2

-CH

2

CH=CH

2

-CH

2 -c1

-CH

2

CH=CH

2

-CH.;

-CH

2

CH

3

-CH

2

CH

2 Ph

-CH-

-CH

2

CH

1

-CH

2 CH2Ph

-CH.,

-CH

2

CH-,

-CH

2

CH

2 Ph

-CH

3

-CH

2

CH

3

-CH

2

CH

2 Ph -CH3

-CH

2

CH-,

-CH

2

CH

2 Ph

-CH-

3

-CH

2 CH3 -nC 4 Hq -nC 3

H

7 -nCH 7 -nC..H 7 -nC 3 -nC- 1

H

7 -nC3H 7

-CH

2

CH

3

-CH

2

CH

3

-CHICH

3

-CH

2

CH

3

-CH

2

CH

3

-CH

2

CH

3

-CH

2 CH3 -nC 1

H

7 -nC3H7 -nC H 7 -nCJ-1 9 -nCJ-1 9 -nCJ-1 9 -nCJ-1 9 -nCd-1 9 -nCJ-1g -nC4Hq -n C4H9 -nC 4

H

9 -nC4H 9 -nCJ-1 9 -nCJ-1 9

-CH

2

CH

3 -nC 1

H,

2-CH 7 -nCJ-1 9

-CH

2

CH

3 -nC 3

H

7

-CH

2

CH

3

-CH

2

CH

3

-CH

2

CH

3

-CH

2

CH

3

-CH

2

CH

3

-CH

2

CH.,

-CH

2

CH

3 -nC3H 7 -nCH 7 -nC 3 H,7 -nC 4

H-

9 -nC4-1 9 -nC 4 Hq -nC 4

H

9 -nC 4

H

9 -nCJ-1 9 -nC 4

H

9 -nC 4

H

9 -nC 4

H-

9 -nCJ-1g -nC 4

H-

9 -nC4-1 9

-CH

2

CH

3 -nC 3

H-

7 2-CH 7 -nCJ-1 9

-CH

2

CH-{

-nC3H7 P29 3-N(CH.,) 2 1 -nC 1

H

7 2-C.,H 7 2-C 3

H

7 4 H 3-N(CH.-) 2 -nC.AH 7 -nC 4 Hq -nCJ-1 9 4 H P31 4-F -nC 3

H

7 -CH 2

CH

3

-CH

2

CH

3 .4 H P32 .4-F -nC 3

H

7 -nC 3 H7 -nC 3

H

7 4 H P33 4-F -nC.;H 7 2-C 3

H

7 2-C 3

H

7 4 H P34 4-F -nCH 7 -nCH 9 i -nC 4

H

9 4 H 2-F -nC- 3 H7

-CH

2

CH

3 -CHf 2

CH

3 4. H P36, 2-F -nC 1

.H

7 -nC 3

H

7 -nC 3

H

7 4 H P37 2-F -nC 3

H

7 2-C 3

H

7 2-C 3

H

7 4 H P38 .2-F -nC 3

H

7 -nC 4

H

9 -nC 4

H

9 4 H P39 3-Cl, 4-0GW' -nC 3

,H

7 -CH 2

CH

3

-CH

2

CH

3 4 H 3-Cl. 4-QCIH -nC 3

H

7 -nC 1 iH 7 -nC 3

H

7 4 H P41 3-Cl, 4-QCH.- -nC 3

H

7 2-C 3 4H 7 2-C3H 7 4 H P42 3-Cl, 4-OCHW -nC 3 tH 7 -nCJ-1 9 -nC 4

H

9 4 H P43 3-CF 3 -nC-AH7

-CH

2 CH3 -CH 2 CH. 4 H P44 3-CF 3 a-nC.l-1 7 -nC.,H7 -nC 3

H

7 4 H 3-CF 3 -nC 3

H

7 2-C.,H 7 2-C 3

H

7 4 H P46 3-CF 3 -nC 1 H7 -nC 4

H

9 -nCJ-Ig 4 H P47 3-0GW 5-0GW. -nC3H 7 -CH 2

CH.

3

-CH

2

CH

3 4 H P48 3-0GW3 5-OCH 3 -nC3H7 -nCIH 7 -nC 3

H

7 4 H P49 3-QCH 3 .5-OCH; nC.4H, 2 2 C 2-C 1 H 4 H 3-QCHi 1 5-OCHW -nCtH7 -nC.H 9 -nC 4 Hq 4 H P51 -3-CH3 -nC:H7

-CH

2 CH, -CH 2

CH.

1 4 H P52 3 -nC 1 4H 7 -nC 3

H

7 -nC 3 H7 4 H P53 3-CH., -nC 3

H

7 2-C 3

.H

7 2-C 3

H

7 -4

H

P54 3-Cl-! 3 -nC 3

H

7 -nC 4

H

9 -nC 4

H

9 4 H 4-CH., -nC.,H 7 -CH 2

CH.

1

-CH

2

CH

3 4 H P56 4-CH., -nC 1

H

7 -nC.IH 7 -nC 1

H

7 4 H P57 4-CH., -nC 3 H7 2-C 3

H

7 2-C 3

H

7 4 H P58 4-CH 3 -nC- 1

H

7 -nC 4

H

9 -nC 4 Hq 4 H P59 2-CTHi, 3-CT-, -nC 3

H

7 -CH 2 CH, -CH 2 CH., 4 H 2-CH3, 3-CH.- -nC.-H 7 -nC3H7 -nC 1

H

7 4 H :11 P61 P62 P63 P64 P66 P67 P68 P69 P71 P72 P73 P74 P76 P77 P78 P79 P81 P82 P83 P84 2-CH3, 3-CH, 2-CHi, 3-CH 3 3-OCF 3 3-OCF 3 3-OCF 3 3-OCF 3 3-SCH 3 3-SCH 3 3-SCH 3 3-SCH-1 none none none none 3-QOCH 3 3-OCH 3 3-OCH 3 3-OCH 3 none none none none none none none -nC 1

,H

7 -nCjHb -nC7H 7 -nCiH 7 -nC 3

H

7 -nC H7 -nC 1

IH

7 -nC 3 I-1 -nCH 7 -nC,.H7

-CH

2 Ph

-H

-CH

2

CH=CH

2

-CH

2 Ph

-H

-CH

2

CH=CH

2 -nC 1 tH7

-CH

2 Ph

-H

-CH

2

CH=CH

2 -nC- 3

H-,

-nC..H, -nCH7 -nC 1

H

7 -nC.,H 7 -nC3H 7 -nC3H 7 -nC: 1

H,

-nC3H 7 2-C 3

,H

1 2-C 3 H, 4 H -nC 4

H

9 -nC4-1 4 H

-CH

2

CH

3

-CH

2

CH

3 4 H -nC 3

H

7 -nC 3

H

7 4 H 2-C 3

H

7 2-C 3 H7 4 H -nC 4

H

9 -nC 4

H

9 4 H

-CH

2

CH

3

-CH

2

CH

3 .4 H -nC 3 H7 -nC 3

H

7 4 H 2-C 3 H7 2-C 3

H

7 4 H -nC.

4

H

9 -nC 4

H

9 4 H

-CH

2 CH.- -CH 2 CH, .4 ci-Me

-CH

2

CH

1

-CH

2 CH.; 4 ci-Me

-CH

2 CH -CH 2

CH

3 4 ci-Me

!-CH

2 CH3 -CH 2

CH

3 4 ci-Me

-CH

2

CH

3

-CH

2 C-1, 4 ci-Me

-CH

2

CH

3

-CH

2 CH3 4 ci-Me

-CH

2

CH

3

-CH

2 CH3 4 ci-Me

-CH

2

CH

3

-CH

2

CH

3 4 ci-Me

-CH

2

CH

3

-CH

2

CH

1 4 tr-Me

-CH

2

CH

3

-CH

2

CH

3 4 tr-Me

-CH

2 CH., -CH 2 CH- 4 tr-Me

-CH

2 CH3 -CH 2

CH

3 4 tr-Me

-CH

2 C-1 3

-CH

2 CH3 .4 H -nC 3

H

7 -nC 3 H7 3 H

-CH

2 Ph -CH 2 CH, 3 H -(H25- 3 H

-CH

2 CH3 -CH 2 CH., 3 H -nC 3

H

7 -nC 3

H

7 4 H none P87 *2,3

CH=CHCH=C--

P88 *2,3

CH=CHCH=CH-

P89 3,4-(CH 2 4 3,4-(CH 2

-CH

2 CH1 -nCjH 7

-CH

2

CH

-nC3H7 12 P91 P92 P93 P94 P96 .P97 P98 P99 P100 P101 P102 3,4-CH 2

CH

2

CH

2 3,4-CH 2

CH-

2

CH

2 none rn-F m-sCH 3 none m-oCH., rn-OH none o-F o-CH 1 none -nC.,H 7 -nC 3

H

7 Omc \flfj OMe OMc OMc V\0-0

I

V\

F

-N

-CH

2

CH

3 -nC 3

H

7

-CH

2

CH

3

-CH

2

CH

3

-CH

3

-CH

2

CH

3 -nC.,H 7 -CH-4

-CH

2 CH3 -nCd.4H 7

-CH

3

-CH

2

CHW-

-CH

2 CH3

-CH

2

CH

3 -nC 3

H

7

-CH

2

CH

3

-CH

2

CH

3

-CH

2

CH

3

-CH

2

CH

3 -nC 3

H

7

-CH

2 C-i~

-CH

2 CHi -nC 3

H

7

-CH

2 CH3

-CH

2

CHI

-nC- 3

H

H

.H

H

ci-Me

H

H

4 tr-Me 4 H 4 H 4 ci-Me 4 H 4

H

P103 p-OH P104 p-F -nC.,H 7 -nC H,7 4 tr-Me P105 P106 P107 none rn-sCH-, m-oCF-,

-CH

2

CH

-nC 1 H7 -CH3

-CH

2

CH,

-nC 1

.H

7 -nCi- 7

H

H

ci-me 13 P108 none CF, -CH 2 CH -CH 2

CH

3 4 H P109 m-CH 3 CF 3

-CH

3

-CH

2 CH3 4 H P110 2, 3-oCH 3 CF 3 -CH3 -nC 3 H 4 H Ar naphthyl is depicted as R 7 for convenience 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 I to 3000 mg, in particular about 10 to 1000 mg or about 25 to 500 mg, of active ingredient I to 4 times per day for an average (70 kg) human although it is apparent that activity of individual compounds of the invention will vary as will the pain being treated. In regards to the use of these compounds as immunosuppressants, antiinflammatory agents, agents for the treatment of mental illness, 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 ar by use of established animal models. Such dosage would likely fall in the range of from about I to 3000 mg of active ingredient I to 4 times per day for an average (70 kg) human. Pharmaceutical compositions of the invention comprise the formula

(I)

compounds as defined above, particularly in admixture with a pharmaceuticallyacceptable carrier.

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 14 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, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents 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 effective dose as described above.

The pharmaceutically acceptable salts referred to above generally take a form in which the nitrogen of the piperidinyl ring is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic, 2 -naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic or saccharic.

The following examples are offered by way of illustration and not by way of limitation.

EXAMPLES

Procedure A N-(3-Methoxyphenyl)--propyl-4-piperidinamine, 11. A solution of 4.5 mL (30 mmol) ofN-propyl-4-piperidone, 3.4 mL (30 mmol) of n-anisidine and 1.7 mL of glacial acetic acid was stirred in 120 mL of 1, 2 -dichloroethane (DCE) and 9.49 g (45 mmol) of sodium triacetoxyborohydride was added. The solution was stirred at 25C for 3h. The solution was washed with NaHCO3 solution and brine. It was dried and the solvent was evaporated. The m-anisidine excess was distilled off in a Kugelrohr 15 at 100*C /0.05 Torr. There was obtained 3.5 g (47% yield) of N-(3-methoxyphenyl)- I -propyl-4-piperidinamine as a solid. M.S miz =249 300 M~lz IH NMvR 8 7.1 1H); 6.15-6.35 (mn, 3H); 3.75 3.25 (n 114); 2.9 (mn, 2H), 2.3 (mn, 2H); 2.15 (in, 4H), 1.5 (mn, 4Hf); 3H). Anal calcd. for CjsH 2

N

2 O: C, 72.54; H, 9.74, N, 11.28. Found: C, 72.55; H,9.51; N, 11.21.

Example I N,N-Diethyl-4-[3-methoxyphenyl( I-propylpiperidin-4-yl)aminoj benzamide Fumarate 11: 11, C 1. A solution of 3.5 g (14.1 minol) of N-(3-mhethoxyphenyl)- Ip ropyl-4-piperidinamine, 3.61 g (14.1 inmol) of N,N-diethyl-4-bromobenzamide, 129 mng 141 minol) tris(dibenzylideneacetone)-dipalladium(O) (Pd:?dba 3 263 mg (0.423 inmol) of (R)-(+)-22'-bis(diphenylphosphino)- 1, I'-binapthyl BINAP) and 1.89 g (19.7 inmol) of sodium i-butoxide in 25 mL of dry toluene was heated at I I10 0 C under Ar in a pressure vessel for 16 h. The mixture was cooled and partitioned between

CH

2

CI

2 and H 2 0. The organic layer was washed with brine, dried (K 2 and the solvent was evaporated. The residue was chromatographed on a Biotage Flash 75 unit using CH 2

CI-

2 :MeOH:.NH 4 QH, 92:8:0.8 as eluent. There was obtained 3.2 g (53% yield) of N,N-diethyl-4-[3 -methoxyphenyl( I -propylpiperidin-4-yl)amino]benzamide as a solid.

Afumarate salt was prepared out of 2-PrOH: mp 168-169*C. MS m~z =424 H).

300 MHz H NMR (DMSO-d,) 5 7.3 IlH).2 (H H;6. d 6.6 (in, 4H), 2Hf); 4.0 (mn, I 3.75 3 3.3 4H), 3. 1 2Hf); 2.4 (in, 4H), 1.9 2H); 1.4 (i,4f;1. 1 6H), 0.8 3H). Anal calcd. for C26HyN.-Q 2 *C4L 4

Q

4 C6.7;H, 7.65; N. 7.78. Found: C, 66.69; H, 7.76. N. 7.68.

Example 2 N,N-D iethyl-4-13-hyd roxyp henyl( I -pro pylpiperid in-4-yl)a mino Ibenzamid e Oxalate Hydrate 11.0:0.5:0.251, C2. A solution of 1.248g(2.93 inmol) of N,Ndiethyl-4-[3-methoxypheny( I-propylpiperidin-4-yl)ainino]benzainide, C1, in 5 mL of CH2C1 2 was cooled to -60'C under Ar and a solution of 17.58 mL (17.58 mmol) of 16 M BMr 3 in CH 2

CI

2 was added dropwise. The temperature was allowed to rise to 250C and the mixture was stirred for 18 h. It was partitioned between NaI-0 solution and EtQH in CH 2

CI

2 The organic layer was dried (Na 2

SO

4 and the solvent evaporated. The residue was was heated under reflux in 100 rnL of saturated NaH-C0 3 solution. The solution was cooled and extracted with CH 2 Cl 2 The solution was dried (Na 2

SO

4 and concentrated to give 1 1 g (92% yield) of N,N-diethyl-4.[3hydroxyphenyl( I -propylpiperidin-4-yl)amino]benzamide as a gum. An oxalate salt was prepared in CH 3 CN, mp, 196-197*C. MS nv~z =41 0 (M 300 MI-Iz 'H NMvR (DMSO-d 6 6 7.2(m, 3H); 6..6 (in, 3H); 6.5(d, 1H); 6.4(s, IM!; 4.1(m, IH); 3.3(q, 4H), 3.2 (mi, 2H); .2.6 (in, 4H), 2.1 2H); 1.5 (mn, 4H), 1. 1 6H); 0.8 3H). Anal calcd.

for C 25

H

3 5 N.%0 2 *0.5 C 2 H-10 4 *0.25 H 2 0: C. 68.03, H, 8.01, N, 9.15; H 2 0, 0.98. Found: C, 67.73; H, 7.73 N, 9.11,; H 2 0, 0.46.

Example 3 N,N-Diethyl-4-l p hen y1(1 -p ropylp iperidi1n-4-yI)am ino benzam id e Fu ma rate[ 1: 11.

C3. Following the protocol of Procedure A and employing aniline in place of manisidine, N-pheny I- I -propyl-4-piperidinamine was obtained as a solid: mp 71 -72*C.

MS in.: 217 (M 300 MHz H NMR (CDCI3) 5 7.1 6.65-6.5 (in, 3H); IH)M 3.+25 (mn, I 3.3 (in, IH) 2.9 (in. 2H), 2.3 2.15 (in. 4H), 1. 5 (mn, 4H); 0.9 3H).

Then, following the procedure of Example I and employing N-phenyl-1-propyl- 4-piperidinamine in place of 3-methoxyphenyl)- I -propyl-4-piperidinamine, N,Ndiethyl-4-[phenyl( I -propylpiperidin-4-yl)aminobenzamide fumarate was obtained as the product: mp 152-154*C. MIS rn'.z =394 (M 300 NMz H NMI( (DMSO04 6 7.45 2H); 7.3(t, I 7.2 2H), 7.05 2H); 6.55 6.5 2H); 4.0 (mn, 1IH), 3.3 4H), 3. 1 2.4 (in, 4 1. 9(d, 2H) 1. 4 4H); 1. 1 6H); 0. 8 (t.

3H).

17 Example 4 N-Methyl-N-phenvl-3-jphenyl( I-propylpiperidin-4-yi)auminol benzamide Fnnlaratell:1.41. C4. Following the procedure of Example I and employing Nphenyl- I-propyl-4-piperidinamine in place of N-(3 -methoxyphenyl)-1I propyl-4piperidinamine and 3-bromo-N-methylbenzanilide in place of N,N-diethyl-4bromobenzamide, N,N-diethyl-4-[phenyl( I -propylpiperidin4-yl)amino~benzaride finnarate was obtained as the product: mp 190-1916C. MS m/z= 428 300 MIHz H NMR (DMSO-d 6 5 7.35 4H); 7.2-6.9 (in, 411) 6.55 2H1); 6.5 (s, 2H); 3.85 (in, 1H); 3.3 3H), 2.9 2H); 2.4 2H), 2.2 2H1); 1.6 2H). 1.4 (in, 211); 1. 1 (in, 2H); 0.8 3H).

Procedure B Following the protocol of.Procedure A and employing the appropriate aryl amine in place of m-anisidine and the requisite N-substituted piperidine in place of Npropylpiperidine. the following N-aryl- I -substituted-4-piperidinamines, 12 1 10, were prepared: Ar" 7

NH

N

16

R

where R(6 and R 7 are dependently selected from the groups consisting of: Cpd# R 7 -Ar R6MS nii: H) 3-CH3O-Ph I -Propyl24 249 18 12 13 14 16 18 19 110 3-Cl-Ph 2-CH- 3 0-Ph I -Naphthyl Ph 3-CH.,O-Ph 3-F-Ph Ph 3-F-Ph Ph I1-Propyl I -Propyl I -Propyl Methyl Methyl Methyl Ethyl Ethyl Benzyl 253 249 .191 22 1 209 205 223 267 Following the procedure of Example I and employing the appropriate N-aryl-4piperidinamine in place of N-(3 -methoxyphenyl)- I -propyl-4-piperidinamine and the requisite 4-bromobenzamide in place of N,N-diethyl-4-bromobenzamide, the following compounds CS C45 were obtained: 0 2

N

22 Ar,

R

R 0-3

N

R

6 where R1, R 2 R 6 and R 7 -Ar are dependently selected from the groups consisting of: Cpd# R 7-Ar 3-Cl-Ph MS Isol'n I -Propyl Ethyl Ethyl 48 A 428 A 19 C6 C7 C8 C9

CIO

CI

C12 C13 C14 cis C16 C17 C18 C19 C21I C22 C23 C24 C26 C27 C28 C29 C3 0 C31I C3 2 C33 C34 C36 C37 3-Cl-Ph I1-Propyl 2-CH-4O-Ph I -Propyl I -Naphthyl I -Propyl I -Napht hyl I -Pro pyl Ph Methyl Ph Methyl 'Ph Methyl Ph Methyl Ph Methyl Ph Methyl Ph Methyl 3-CH 1 O0-Ph Methyl 3-CH- 3 O-Ph Methyl 3-CH 3 O-Ph Methyl 3-CH-O-Ph Methyl 3-CH 3 O-Ph Methyl 3-CH 3 O-Ph M ethyl 3-CH 3 O-Ph Methyl 3-F-Ph Methyl 3-F-Ph Methyl 3-F-Ph Methyl 3-F-Pb Methyl 3-F-Ph Methyl 3-F-Ph Methyl 3-F-Ph M ethyl Ph Ethyl Ph Ethyl Ph Ethyl Ph Ethyl Ph Ethyl Ph Ethyl Ph Ethyl 2 4 Ethyl Ethyl Ethyl Ethyl Ethyl Ethyl I -Propyl I -Propyl Methyl Ethyl 2-Propyl 2-Propyl Ethyl Ethyl I-Propyl 1-Propyl Methyl Ethyl 2-Propyl 2-Propyl

-(CH

2 2

-O-(CH

2 h2- Ethyl Ethyl 1-Propyl I -Propyl Methyl Ethyl 2-Propyl 2-Propyl

-(CH

2 2

-O-(CH

2 2 -(GCl 2 5 -(GCl 2 4 Ethyl Ethyl I -Propyl I -Propyl Methyl Ethyl 2-Propyl 2-Propyl

-(CH

2 )z-O-(CH 2 2

-(CH

2 5

-(CH

2 4 426 424 416 456 .366 394 352 394 380 378 364 396 424 382 424 410 408 394 384 412 370 412 398 396 382 380 408 366 408 394 392 378 20 C38 3-F-Ph Ethyl Ethyl Ethyl 398 B C39 3-F-Ph Ethyl I1-Propyl I -Propyl 426 B 3-F-Ph Ethyl Methyl Ethyl 384 B C41I 3-F-Ph Ethyl 2-Propyl 2-Propyl 426 B !C42 3-F-Ph Ethyl -(CH2)rO-(CH 2 2 412 B C43 3-F-Ph Ethyl

-(CH

2 5 410 B C44 3-F-Ph Ethyl

-(CH

2 4 396 B* Ph Benzyl Ethyl E thyl 442 A Isolation, Method A: chromatography on SiO 2 With CH 2

CI

2 \MeOH \Ni 4

QH,

95\5\0.5.

Method B3: Reverse phase HPLC on YM C Y sphere H80 (20/80 MeCN/0. 1 aq. TFA to 90/10 MeCN/0.1I% aq. TFA) Example 6 N,N-Diethyl-4-.(3-acetoxyphenyl( 1 -pro pylpiperid in-4-yI~aminoj benza mide Hydrochloride[1: 1I C46. A solution of 0.96 g (2.3 mmol) of N,N-diethyl-4-[3.

hydroxyphenyl( I -propylpiperidin.4-yl)amino)benzamide was stirred in 20 mL of CH 2

CI

2 and 0. 17 m.L of acetyl chloride was added. -The mixture was stirred for 2 h. The solvent was evaporated and the residue recrystallized from 2-PrOH to give 0.7g (62% yield) o f the title compound as a white crystalline solid: mp 218-219*C. MS rn~lz 452 (M 300MHz NMvR (DMSO-d 6 8 7.3 (d 2H); 7.2 (in, IH);6.9 2H)-,6.7 (in, 2H);4.1 3.6 2H), 3.4 2.8 (in, 4H), 2.4(m, 2H), 2.2(s, 3H) 2.1 (d, 2H-I); 1.9 (in, 1.2 1.0 3H1). Anal calcd. for C2 7 Hn 3 0iO*HCI: C, 66.45; H, 7.45; N, 8.61. Found: C, 66.07, H, 7.83; N, 8.32.

Biological Testing Delta- and niu-opioid receptor binding of the above compounds was determined according to the following procedures and the following results were obtained.

21 1) High Throughput Screening Assay for Delta-Opioid Receptor Binding Materials: This is a receptor based screen to detect the competitive binding of test compounds at the opioid delta receptor against the radioligand, 3l-bremazocine (S.A.=25.5 Ci/mmol, Dupont/NEN, Cambridge, Massachusetts). The receptor is a cloned human cDNA expressed in mammalian CHO cells. Membranes prepared from these cells are purchased from Receptor Biology, Baltimore, MD. The reaction buffer is composed as follows: HEPES (50 mM final), MgCl*6H 2 0 (5 mM final), ophenanthroline (20 mg/1), aprotinin (10 mg/1), Pefabloc SC (250 mg/l), leupeptin mg/1), pepstatin A (0.7 mg/1), trypsin inhibitor (25 mg/l), chymostatin (10 mg/1), pH 7.2. Naloxone, 10 uM, is used to define non-specific binding. The assay employs filtration to capture receptor and bound ligand.

Procedure: The receptor (membrane) preparation (28 ug protein) is allowed to incubate with the opioid receptor radioligand ([H]bremazocine, 2.4 nM) in 96-well plates until equilibrium is reached hr). Following incubation with the radioligand at 23 0 C, the well contents are filtered onto 96-well Whatman GF/C filter plates using a Packard cell harvester. Radioligand bound to the receptor also remains on the filter. The filters are rinsed three times with 0.5 mL of physiological saline NaCI) to remove any unbound radioligand from the filters. Filters are dried and scintillation fluid is then added to the filters which emits light in proportion to the amount of radioactivity on the filter which is determined using an Packard Topcount scintillation counter.

Principle: Unknown drugs included in the incubation which bind to the same receptor is the radioligand will compete for the receptor and reduce the amount of radioligand which binds to the receptor. This is detected as a decreased scintillation signal from that particular incubation. The better an unknown competes for the receptor, the larger the observed decrease in radioligand bound to the receptor; thus the assay is in the format of an inhibition study. Data are reported as percent inhibition of control binding.

Results: The following compounds were tested with the following results.

Cpd# %1@25pM Cpd# %1 25 gM C1 97 CI1 101 C3 94 C12 22 C4 41 C13 100 102 C14 93 C6 101 C15 68 C7 100 C16 81 C8 69 C17 98 C9 103 C18 100 100 C19 98 C34 100 C21 70 C35 64 C22 89 C36 92 C23 91 C37 88 C24 97 C38 98 100 C39 101 C26 96 C40 97 C27 97 C41 88 C28 77 C42 64 C29 85 C43 89 85 C44 87 C31 100 C45 99 C32 100 C46 100 C33 98 2) Manual Tissue Screening Assay for Delta- and Mu-Opioid Receptor Binding A) Rat Brain 5-Opioid Receptor Binding Assay 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 I g of forebrain tissue per 100 mL Tris 23 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 6-opioid binding assays. Following incubation with the 5-selective peptide ligand ['H]DPDPE at 25 0 C, the tube contents 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 (pH7.4), 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: I-(test compound dpm-nonspecific dpm)/(total dpmnonspecific dpm)* 100 K, values are calculated using the LIGAND (Munson, P.J. and Rodbard, Anal.

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

B) Rat Brain 4-Opioid Receptor Binding Assay 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 I g offorebrain 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 p-opioid binding assays. Following incubation with the m- selective peptide ligand ['H]DAMGO at 25 0 C. 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 (pH7.4), and -the radioactivity associated with the filter circles determined using Formula 989 scintillation fluid (New England Nuclear, Boston, MA) in a scintillation counter.

24 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: I-(test compound dpm-nonspecific dpm)/(total dpmnonspecific dpm)* 100 Ki values are calculated using the LIGAND (Munson, P.J. and Rodbard, Anal.

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

Results: N,N-Diethyl-4-[phenyl( 1-propylpiperidin-4-yl)amino]benzamide fumarate, C4, exhibited a K, of 25 nM in binding to the 8-opioid receptor and a Ki of 153 nM in binding to the p-opioid receptor. N,N-Diethyl-4-[3-hydroxyphenyi( -propylpiperidin- 4-yl)amino]benzamide fumarate, C2, exhibited a Ki of 0.83 nM in binding to the opioid receptor and a K, of 2,762 nM in binding to the p-opioid receptor.

The activity of compounds of the invention as analgesics may be demonstrated by the mouse acetylcholine-bromide induced constriction assay as described below: C) Mouse Acetylcholine Bromide-Induced Abdominal Constriction Assay Procedure: The mouse acetylcholine-induced abdominal constiction assay, as described by Collier et al. in Brit. J. Pharmacol. Chem. Ther., 32: 295-310, 1968, with minor modifications was used to assess analgesic potency of the compounds of formula The test drugs or appropriate vehicles were administered orally and minutes later the animal received an intraperitoneal injection of 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 minute 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).

The percent inhibition of this response to a nociceptive stimulus (equated to analgesia) was calculated as follows: The inhibition of response, analgesia is equal to the difference between the No. of control animal responses and the No. of drug-treated animal responses times 100 divided by the No. of control animals responding.

Results: N,N-Diethyl-4-[phenyl( 1-propylpiperidin-4-yl)amino]benzamide fumarate, C4, exhibited an EDs, of 4.2 pmol/kg in this assay.

Claims (6)

1. A compound which binds to the delta-opioid receptor of the general formula: 0 R 1 R7 0 3 Ar R 8 0-2 ON N R 3 N R 4 k6 where Ar is phenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with 1 to 3 R 7 R' and R 2 are independently selected from the group consisting of hydrogen, Ci.-alkyl; phenyl, optionally mono-, di-, or tri-substituted with halo, Cl.6alkyl, Ci. 6 alkoxy or trifluoromethyl; or benzyl, optionally mono-, di, or tri-substituted with halo, Ci- 6 alkyl, Ci-6alkoxy or trifluoromethyl, or alternatively, R' and R 2 are taken together with their N of attachment to form a ring which is selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl and hexamethyleneiminyl, each said ring optionally substituted with 1 to 4 methyl groups; R 3 is selected from hydrogen and Ci-4alkyl; R 4 and R 5 are hydrogen; R 6 is selected from the group consisting of hydrogen; Ci.8alkyl; C36cycloalkylC-3alkyl, C 3 -6alkenyl; C 1 .6alkoxyC 3 alkyl; and phenylC14alkyl, where the phenyl is optionally mono-, di-, or tri-substituted with R 7 R 7 is independently selected from the group consisting of hydroxy, halo, C1.3alkyl, Ci- 3 alkoxy, C 1 .3acyl, C 1 -3acyloxy, cyano, amino, C-_3acylamino, C1.3alkylamino, di(Ci_ 3 alkyl)amino, C._ 3 alkylthio, Ci- 3 alkylsulfonyl, trifluoromethyl and trifluoromethoxy, and two R 7 can together form a single moiety selected from the group consisting of-(CH 2 3 and -O(CH 2 1 -30- attached to adjacent carbon atoms of Ar; and R 8 is independently selected from the group consisting of halo, Ci-6alkyl, Ci-6alkoxy and trifluoromethyl wherein the compounds of the formulae; 2003220725 18 May 2006 z z z 0 z z 0 z 2003220725 18 May 2006 z 2003220725 18 May 2006 zi 0 z- z- =0 S-2; 0 -26c- O are disclaimed.

2. The compound of claim 1 wherein Ar is phenyl.

3. The compound of claim 1 wherein R 1 and R 2 are independently selected from the 00 group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, phenyl, p-chlorophenyl, p-fluorophenyl, p-methylphenyl, p-trifluoromethylphenyl, Sbenzyl, p-chlorobenzyl, p-fluorobenzyl, p-methylbenzyl and p-trifluoromethylbenzyl, or alternatively, R' and R 2 are taken together with their N of attachment to form a ring CI which is selected from the group consisting of pyrrolidinyl and piperidinyl. c 4. The compound of claim 1 wherein R is selected from hydrogen, methyl, ethyl, n-propyl, i-propyl and t-butyl. The compound of claim 1 wherein R 6 are selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropylmethyl, ethenyl, allyl, methoxymethyl, benzyl, p-chlorobenzyl, p-fluorobenzyl, p-methylbenzyl, p-trifluoromethylbenzyl, p-aminobenzyl, and phenylCH 2 CH 2

6. The compound of claim 1 wherein R 7 are independently selected from the

27..- group consisting of hydroxy, chioro, bromo, fluoro, methyl, ethyl, n-proppyl. i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, formyl, acyl, acetoxy, cyano, amino, methylatnido, methylamino, N.N-dimethylamino, methylthio, methylsulfonyl, trifluoromethoxy and trifluoromethyl, and preferred moieties where two R 7 together* form a single moiety are selected from the group consisting of propylene, butylene and -QCH 2 O-. 7. The compound of claim I wherein R M are independen tly selected from the group consisting of chioro, bromo, fluoro, methyl, ethyl, n-propyl, i-propyl, t-butyl, methoxy, ethoxy and trifluoromethyl. 8. The compound of claim I having the general structure: 0R 3 or4 4N I N 2 R 3 N where R 2 R 6 and R 7 are dependently selected from the groups consisting of: Cpd# R 7R6R R 2 amide- R 3 subst. PI none -CH 2 CH=CH 2 -CH 2 CH., -CH 2 CH., 4 H P2 none -C2- -CH 2 CH-, -CH 2 CH 4, H P3 3-OH -CH 2 CH=CH 2 -CH 2 CH, -CH 2 CH3 4 H P4 3-OH -CH 2 KJl -CH 2 CH;- -CH 2 CHFV 4 H 28 PS P6 P7 P8 P9 Plo P11 P 12 P13 P 14 P 16 P17 P18 P 19 P21 P22 P23 P24 P26 P27 P28 P29 P31 P32 P33 P34 P36. 3-OH 3-OH 3-OH 3-OH 3-OH 3-OH 3-OH 3-OH 3-OH none none none 3-F 3-F 3-F 3-OCH3. 3-OCH., 3-OCH 3 3,4-OCH 2 O- 3,4-OCH 2 O- 3,4-QCH 2 O- 3 ,4-QCH 2 O- 3-N(CH 3 2 3-N(CH 3 2 3-N(CH 3 2 3-N(CH 1 2 4-F 4-F 4-F 4-F 2-F 2-F -CH,, -CH 2 CH 3 -C H 2 CH 2 Ph -CH, -CH 2 GH., -CH. 2 CH 2 Ph SC H., -CH 2 CH 3 -CH 2 CH 2 Ph -CH 2 CH.- -CH- 2 C'1 2 Ph -CH 2 CH 2 Ph -CH., -CH 2 CH.; -nC 4 Ho -nCH 7 -nCd-1 7 -nC3H 7 -nC 1 H 7 -nC H 7 -nCH 7 -nC3H 7 -nC3H 7 -nC H., -nC-.H 7 -nC3H 7 -nC H 7 -nCH7 -nC3H-, -CH 2 CH) -CH 2 CH3 -CH 2 CH 3 -nC 1 H 7 -nC 3 H 7 -nC 3 H 7 -nC4H9 -nCJ-1g -nCJ-1 9 -nC 4 H 9 -nC 4 H 9 -nC 4 H,) -nC 4 Hq -nC 4 H 9 -nC 4 H 9 -nC 4 9 -nCJ-Ig -nC 4 H-1 -CH 2 CH-. -nC-.H 7 2-C 3 H 7 -nC 4 H 9 -CH- 2 CH. 3 -nC- 3 H 7 2-C 3 H 7 -nC 4 H 9 -CH 2 CH., -nCIH 7 2-CiH 7 -nC 4 Hq -CH 2 CH., -nC H 7 -CHCH3 -CH 2 CH., -CH 2 CH 3 -nC 3 H 7 -nC 3 H 7 -nC 3 H 7 -nC 4 H 9 -nC4H 9 -nC4H 9 -nC 4 H 9 -nC 4 H 9 -nC 4 H 9 -nC 4 H 9 -nC 4 H 9 -nC4H 9 -nC 4 Hq -nC 4 H 9 -nC 4 H 9 -CH 2 CH3 -nC3H- 7 2-C 3 ,H 7 -nC 4 H 9 -CH 2 CH., -nC3H 7 2-CH, -nC 4 H 9 -CH 2 CH., -nC3H{, 2-C 3 H, -nC 4 H 9 -CH- 2 CH 3 -nC:%H 7 29 P37 .2-F -nC 3 H 7 2-C.-H7 2-C 3 H 7 ,4 H P38. 2-F -nC3H7 -nC 4 H 9 nC4H9 4, H P39 .3-Cl, 4-OCH 3 -nC3H 7 -CH 2 CH 3 -CH 2 CH 3 4 H 3C,4-OCH 3 -nC 3 H7 -nC 3 H 7 -nC 3 H 7 4 H P41 3-Cl, 4-OCH 3 -nC.,H 7 2-C.,H 7 2-C 3 H 7 4 H P42 3-Cl, 4-OCH 3 -nC 3 ;H 7 -nC 4 H 9 -nC 4 H 9 4 H P43 .3-CF 3 -nC3H7 -CHCH -CH 2 CH 3 4 H P44 3-CF 3 -nC.,H 7 -nc3H 7 -nC 3 H 7 4 H P451 3-CF 3 -nC 3 %H7 2-C 3 H7 2-C 3 H 7 4 H P46 3-CF 3 -nC 3 ,H 7 -nC 4 1H1 -nC 4 H 9 4 H P47 3-QCH.- 5-OCH.- -nC 1 H 7 CH 2 CH 3 -CH 2 CH3 4 H P48 3-OCH-, 5-QCH 3 -nC.,H7 -nC 1 H 7 -nC 3 H 7 4 H P4.9 3-OCH, 5-OCH., -nC 3 H 2CH 7 2-CH 4 H 3-QCH 3 5-QCH,, -nC.-H 7 -nC.&H 9 -nC 4 Hq 4 H P51 3.-CH 3 -nc 3 H 7 -CH 2 CH 1 -CH 2 CH 3 4 H P52 3-CH 3 -nCd-b -nC 3 H7 -nC 3 H 7 4 H P53 3-CH., -nC3H 7 2-C 3 H 7 2-C 3 H7 4 H P54 3-CH3 -nCd-b -nC jHI9 -nC.H 9 4 H 4-CH 3 -n C.-H7 -CH 2 CH 3 -CH 2 CH.- 4 H P56 4-CH., -nC3H 7 -nC3H 7 -nC 3 H 7 4 H P57 4-CH, -nC.-H 7 2-C 3 -H 7 2-C.4H 7 4- H P58 4-CH 3 -nCH-, -nC 4 H 9 -nC 4 H 9 4 H P59 2-CH 3 3-CH -nC 1 AH 7 -CH 2 CH 3 -CH 2 CH, 4 H 2-CH -nCd-b -nC 1 H 7 -nC 3 H 7 4 H P61 2-CHI. 3-CH.- -nC 3 H 7 2-C 1 kH7 2-C 1 H 7 4 H P62 2-CH 3 3-CH.- -nC 1 H 7 -nC 4 H 9 -nC 4 H 9 4 H P63 3-OCF., -nC3H 7 -CH~ 2 CH;- -CH 2 CH., 4 H P64 3-OCF. -nC3H. -nC.H-1 -nC 3 H 7 4 H 3-QCF- -nCIH 7 2-C 3 H 7 2-C 3 H 7 4 H -P66 3-OCF., -nC 3 H 7 -nC..H 9 -nC 4 H 9 4 H P67 3-SCIH3 -nC.IH 7 -CH 2 CH 1 -CH 2 CH 3 4 H P68 3-SCH3 -nCH 7 -riC 3 H7 -nC3H7 4 H- 30 P69 P71 P72 P73 P74 P76 P77 P78 P79 P81 3-SCH 3 3-SCH 1 none none none none 3-OCH., 3-OCH 3 3-OCH 3 3-OCH 3 none none none P52 none P83 none P84 none none P86 none P87 *2,3 CH=CHCH=CH- P88 *2,3 CH=CHCH=CH- P89 3.4-(CH 2 4 3,4-(CH 2 4 P91 3,4-CH 2 C H 2 C H 2 P92 3,4-CH 2 C H 2 C H 2 P93 none -nCH 7 -CH 2 P h -H -CH 2 CH=CH 2 -nC 3 IH 7 -CH 2 P h -H -CH 2 CH=-CH 2 -nCiH 7 -CH- 2 Ph H -CH 2 CH=CH 2 -nCH 7 -nC.-H 7 -nC 3 H 7 I-nC3H 7 -nC.-H. 7 -nC 1 ,H7 -nC3H 7 -nC-,H 7 -nC3H 7 -nC 3 H 7 -nCH 7 OMc S/OMc OMe \/OMc 2-C.,H7 2-C.,H 7 4 H -nC 4 H 9 -nC 4 H 9 .4 H -CH 2 CH 3 -CH7CH 3 4 ci-Me -CH 2 CH 3 -CH 2 CH 3 4 ci-Me -CH 2 CH 3 -CH 2 CH 3 4 ci-Me -CH 2 CH 3 -CH 2 CH 3 4 ci-Me -CH 2 CH 3 -CH 2 CH 3 4 ci-Me -CH 2 CH 3 -CH 2 CH 3 4 ci-Me -CH 2 CH 3 -CH 2 CH 3 4 ci-Me -CH 2 CH 1 -CH 2 C-1, 4 ci-Me -CH 2 CH -CH 2 CH3I 4 tr-Me -CH 2 CH., -CH 2 CH3 4 tr-Me -CH 2 CH.- -CH 2 CI-b 4 tr-Me -CH 2 CH, -CH 2 C-1 1 4 tr-Me -CH 2 CH-, -CHXCW 4 H -nC.IH 7 -nC 3 H, 3 H -CH 2 Ph -CH 2 C~i- 3 H -(H25- 3 H -CH 2 CH.% -CH 2 CH, 3 H -nC 1 H 7 -nC 3 Hj 4 H -CH 2 CH 3 -nCH 7 -CH 2 CT-b -CH 2 CI-b -CH 2 CH 3 -nC- 1 H 7 -CH 2 CH 1 i -nC 3 H 7 -CH 2 CH 1 P94 rn-F -CH 2 CH 3 -CH 2 CIL '4 H -31- rn-sCH 3 P96 none P97 m-oCH 3 P98 rn-OH P102 none P103 p-OH P104 p-F -CH 3 -CH 2 CH 3 4 ci-Me -CH 2 CH 3 -CH 2 CH 3 4 H -nC 3 H 7 -nC 3 H 7 4 H -CH 3 -CH 2 CH 3 4 tr-Me -CH 2 CH 3 -CH 2 CH 3 4 H -CH 2 CH 3 -nC 3 H 7 4 H -nC 3 H 7 -nC 3 H 7 4 tr-Me P108 none CF3 P10 nne F 3 -CH 2 CH 3 -CH 2 CH 3 4 H -3 1a- P109 m-CH 3 P110 2,3-oCH 3 43 -CH 3 43 -CH9 3 -CH 2 CH 3 4 -nC 3 H 7 4 H 3 2 00 9. The compound of claim .1 having the general structure: 0 21 Ar NJ RR where R 2 R" and R 7 -Ar are dependently selected from the groups consistifig of: Cpd# R 7 -Ar R 6R IR2 ClI C2 C3 C4 C 5 C6 C7 CS C9 CIO Cli C12 C13 C14 C16 3-CO-Ph 3-HO-Ph Ph Ph 3-Cl-Ph 3-Cl-Ph 2-CH O-Ph: I -Naphthyl I -Naphthyl Ph Ph Ph Ph Ph Ph Ph I -Propyl I -Propyl I -Propyl I -Pro pyl I -Pro pyl 1 -Propyl I -propyl 1 -Propyl I1-Propyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Ethyl Ethyl E thyl Ethyl Ethyl Ethyl Methyl Ph Ethyl Ethyl Ethl hyl4 Ethyl Ethyl -(C-i 2 4 Ethyl Ethyl I1-Propyl I -Propyl Methyl Ethyl 2-Propyl 2-Propyl -(CH- 2 2 -O-(CH- 2 00 33 C17 C18 c 19 C20 C21 C22 C23 C24 C26 C27 C28 C31 C32 C33 C34 036 C37 C39 IC39 C41 C42 C43 C44 3-CHIO-Ph 3-CH 3 iO-Ph 3-CH 3 O-Ph 3-CH-1O-Ph 3-CH 3 O-Ph 3-CH 3 Q-Ph 3-CH 3 O-Ph 3-F-Ph 3-F-Ph 3-F-Ph 3-F-Ph 3-F-Ph. 3-F-Ph 3-F-Ph Ph Ph Ph Ph ph Ph Ph 3-F-Ph 3-F-Ph 3-F-Ph

37-F-.Ph 3-F-Ph 3-F-Ph 3-F-Ph Ph Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl Ethyl Ethyl Ethyl Ethyl Ethyl: Ethyl Ethyl Ethyl Ethyl Ethyl Ethyl Ethyl Ethyl Ethyl Benzyl. Ethyl Ethyl I -Propyl 1-Or'opyl Methyl Ethyl 2-Propyl 2-Propyl -(CH 2 2 -Q-(CH 2 2 -(CH 2 )4- Ethyl Ethyl 1-Peo-pyl 1-Propyl Methyl Ethyl 2-Propyl 2-Propyl -(CH- 2 2 -O-(CH! 2 2 Ethyl Ethyl I-Propyl 1-Propyl Methyl Ethyl 2-Propyl 2-Propyl -(CH- 2 2 -0-(CH 2 )r. Ethyl Ethyl I-Propyl 1-Propyl Methyl Ethyl 2-Propyl 2 -Propyl Ethyl Ethyl Ethyl Ethyl C46 3-CH 3 C(O)O-Pli n-Propyl ID -34- The use of a compound of any one of claims 1 to 9 in the manufacture of a medicament for use as an immunosuppressants, antiinflammatory agents, agents for the treatment of mental illness, medicament for drug and alcohol abuse, agents for treating 00 gastritis and diarrhoea, cardiovascular agent, agents for treatment of respiratory diseases or analgesic. tn 11. The use of a compound of any one of claims 1 to 9 in the manufacture of a medicament for treatment of pain in a mammal. S12. A compound of any one of claims 1 to 9 for use as an immunosuppressant, antiinflammatory agent, agent for the treatment of mental illness, medicament for drug and alcohol abuse, agent for treating gastritis and diarrhoea, cardiovascular agent, agent for the treatment of respiratory diseases or analgesic. 13. A method for treating a condition selected from the group consisting of inflammation, mental illness, drug and alcohol abuse, gastritis and diarrhoea, cardiovascular disease, respiratory diseases, pain or a condition requiring immunosuppression, comprising the administration to a mammal requiring such treatment of an effective amount of a compound of any one of claims 1 to 9. 14. A method for the treatment of pain in a mammal comprising administering to a mammal requiring such treatment an effective amount of a compound of any one of claims 1 to 9. 15. A method to make a compound of the formula: 0 R 1 \R2 R 7 0 3 -ArN 8 R3 R 0-2 R N R) N'R comprising the step of arylating a compound of the formula: 07 (R 0-3- Ar, NH R6 00 R In in the presence of a palladium catalyst, a phosphine ligand and a base with a compound C of the formula: C7 R O o N R82 R 0-2 X =Br, I, OSO 2 CF 3 where Ar, R 2 R 3 R 4 R 5 R R 7 and R 8 are as defined in claim 1. 16. A compound which binds to the delta-opioid receptor, substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompanying examples. 17. A method to make a compound, substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompanying examples. 18. A method for treating a condition selected from the group consisting of inflammation, mental illness, drug and alcohol abuse, gastritis and diarrhoea, cardiovascular disease, respiratory diseases, pain or a condition requiring immunosuppression, substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompanying examples. 19. A method for the treatment of pain in a mammal, substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompanying examples. DATED this 18 th day of May 2006 Shelston IP Attorneys for: ORTHO-MCNEIL PHARMACEUTICAL, INC.