U.S. patent number RE40,838 [Application Number 11/874,253] was granted by the patent office on 2009-07-07 for 2-azabicyclo[3.3.1]nonane derivatives.
This patent grant is currently assigned to Pfizer Inc.. Invention is credited to Jotham W. Coe, Stanton F. McHardy.
United States Patent |
RE40,838 |
Coe , et al. |
July 7, 2009 |
2-azabicyclo[3.3.1]nonane derivatives
Abstract
The subject invention relates to 2-azabicyclo[3.3.1]nonane
derivatives, pharmaceutical compositions comprising such
derivatives and methods of using such derivatives to treat disease
states, disorders and conditions mediated by opioid receptors. The
subject invention also particularly relates to using such
derivatives to treat certain disorders and conditions, for example
irritable bowel syndrome, drug addiction, including alcohol
addiction, depression, anxiety, schizophrenia and eating disorders,
among others, as are more fully described herein.
Inventors: |
Coe; Jotham W. (Niantic,
CT), McHardy; Stanton F. (Helotes, TX) |
Assignee: |
Pfizer Inc. (New York,
NY)
|
Family
ID: |
33159854 |
Appl.
No.: |
11/874,253 |
Filed: |
October 18, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
60462605 |
Apr 14, 2003 |
|
|
|
Reissue of: |
10762730 |
Jan 22, 2004 |
07056930 |
Jun 6, 2006 |
|
|
Current U.S.
Class: |
514/299;
546/112 |
Current CPC
Class: |
A61P
1/08 (20180101); A61P 17/02 (20180101); A61P
17/04 (20180101); A61P 25/00 (20180101); A61P
17/06 (20180101); A61P 17/00 (20180101); A61P
1/10 (20180101); A61P 25/24 (20180101); A61P
25/16 (20180101); A61P 25/30 (20180101); A61P
1/04 (20180101); A61P 25/32 (20180101); A61P
25/28 (20180101); A61P 25/22 (20180101); A61P
43/00 (20180101); C07D 221/22 (20130101); A61P
15/10 (20180101); A61P 25/18 (20180101) |
Current International
Class: |
A61K
31/439 (20060101); C07D 221/22 (20060101) |
Field of
Search: |
;514/299 ;546/112 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
European Patent Office Action, Application No. 04725453.7, dated
Jun. 8, 2007, 4 pages. cited by other .
Froimowitz, E., et al., "Phenylmorphans and Analogues: Opioid
Receptor Subtype Selectivity and Effect of Conformation on
Activity", Journal of Medicinal Chemistry, 1992, pp. 1521-1525,
vol. 35, No. 9. cited by other .
May, E., et al., "Structures Related to Morphine. II. An isomer of
N-Methylmorphinan", Journal of Organic Chemistry, 1954, pp.
618-622, vol. 19, No. 4. cited by other .
May, E., et al., "Structures Related to Morphine. VI. N-Phenylethyl
Derivatives of Some Phenyl-and Benz-Morphans", Journal of Organic
Chemistry, 1956, pp. 899-901, vol. 21, No. 8. cited by other .
Thomas, J., et al., "N-Substituted
9.beta.-Methyl-5-(3-hydroxyphenl) Morphans Are Opioid Receptor Pure
Antagonists", Journal of Medicinal Chemistry, 1998, pp. 4143-4149,
vol. 41, No. 21. cited by other .
PCT/IB2004/001237, International Search Report, 8 pages. cited by
other .
PCT/IB2004/001237, International Preliminary Report on
Patentability, 7 pages. cited by other.
|
Primary Examiner: Aulakh; Charanjit S
Attorney, Agent or Firm: Benson; Gregg C. Musser; Arlene
K.
Parent Case Text
.Iadd.This application claims priority under 35 USC .sctn. 119(e)
of provisional Application No. 60/462,605, filed Apr. 14,
2003..Iaddend.
Claims
What is claimed is:
1. A compound of formula 1: ##STR00023## wherein R.sup.a is H or a
##STR00024## group; wherein X is H, halogen, --CN,
--C.ident.C--R.sup.3a or a --C.sub.1-C.sub.4 alkyl group optionally
substituted with from one to three halogen atoms; Q is halogen, a
C.sub.1-C.sub.6 alkyl, --CN, --NH.sub.2, --NH(C.sub.1-C.sub.4
alkyl), --N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-C.sub.4 alkyl),
--C(.dbd.O)N(C.sub.1-C.sub.4 alkyl) (C.sub.1-C.sub.4 alkyl),
--NHC(.dbd.O)H, --NHC(.dbd.O)R.sup.8, or
--NHS(.dbd.O).sub.2R.sup.8; R.sup.1 and R.sup.2 are independently
H, a C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.j-aryl,
--(CH.sub.2).sub.j-heteroary, wherein said alkyl,
--(CH.sub.2).sub.j-aryl or --(CH.sub.2).sub.j-heteroaryl group is
optionally substituted with one or more R.sup.10 groups, or with
the carbon to which R.sup.1 and R.sup.2 are attached, R.sup.1 and
R.sup.2 form a C.sub.3-C.sub.7 carbocyclic or 4- or 7-membered
heterocyclic group, wherein said heterocyclic group comprises from
one to three heteroatoms selected from the group consisting of O, S
and N and said carbocyclic or heterocyclic group optionally
contains a --C(.dbd.O) group or optionally contains one or more
double bonds and is optionally fused to or substituted with a
C.sub.6-C.sub.14 aryl or a 5-14 membered heteroaryl group; wherein
said C.sub.3-C.sub.7 carbocyclic or 4- or 7-membered heterocyclic
group formed by R.sup.1 and R.sup.2 may optionally be substituted
with from one to three R.sup.10 groups, and said optionally fused
or substituted aryl or heteroaryl group may each optionally
independently be substituted with from one to six R.sup.10 groups;
R.sup.10 group are independently selected from R.sup.11, H,
halogen, --OR.sup.11, --NO.sub.2, --CN, --C.sub.1-C.sub.6 alkyl,
--C.sub.3-C.sub.6 cycloalkyl, --C(R.sup.3)R.sup.10aR.sup.10b, aryl
optionally substituted with from 1 to 3 R.sup.3 groups,
--(CH.sub.2).sub.v--NR.sup.11R.sup.12,
--NR.sup.11C(.dbd.O)R.sup.12, --C(.dbd.O)NR.sup.11R.sup.12,
--OC(.dbd.O) R.sup.11, --C(.dbd.O)OR.sup.11, C(.dbd.O)R.sup.11,
--NR.sup.11C(.dbd.O) OR.sup.12,
--NR.sup.11C(.dbd.O)NR.sup.12R.sup.13,
--NR.sup.12S(.dbd.O).sub.2R.sup.11,
--NR.sup.11S(.dbd.O).sub.2NR.sup.12R.sup.13, and
--S(.dbd.O).sub.2R.sup.11; R.sup.3 is absent or is H,
--C.sub.1-C.sub.4 alkyl, which optionally contains one or two
unsaturated bonds, --OH, --O(C.sub.1-C.sub.4)alkyl,
--(C.sub.1-C.sub.4)alkylOH,
--(CH.sub.2).sub.n--NR.sup.10aR.sup.10b, --(CH.sub.2).sub.n
--NHC(.dbd.O)(C.sub.1-C.sub.4 alkyl), --(CH.sub.2).sub.n--NO.sub.2,
--(CH.sub.2).sub.n--C.ident.N, --(CH.sub.2).sub.n--C
(.dbd.O)NH.sub.2, --(CH.sub.2).sub.n --C(.dbd.O)NH(CH.sub.1-C.sub.4
alkyl) or --(CH.sub.2).sub.v--C(.dbd.O)NR.sup.10aR.sup.10b;
R.sup.3a is H or C.sub.1-C.sub.6 alkyl which may be optionally
substituted with one or more halogen groups; each R.sup.4,
R.sup.4a, R.sup.9 and R.sup.9a is independently H,
--C.sub.1-C.sub.4 alkyl or --O--C.sub.1-C.sub.4 alkyl; each
R.sup.8, R.sup.11, R.sup.12 and R.sup.13 is independently selected
from H, --C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, aryl,
--(C.sub.2-C.sub.4 alkyl)--O--(C.sub.1-C.sub.4alkyl), aryl,
--(CH.sub.2).sub.m--NR.sup.14R.sup.15, or a 4- to 7-membered
heterocyclic group, or where any two groups selected from R.sup.11,
R.sup.12 and R.sup.13 can form a heterocyclic ring with the atom to
which they are attached, wherein said heterocyclic group or said
heterocyclic ring is optionally substituted with at least one
C.sub.1-C.sub.4 alkyl group; each R.sup.10a and R.sup.10b is
independently selected from H, --C.sub.1-C.sub.4 alkyl; or,
independently in each instance of
--C.sup.1(R.sup.3)R.sup.10aR.sup.10b, R.sup.10a and R.sup.10b
connect to form a C.sub.3-C.sub.7 carbocyclic ring or a 4-7
membered heterocyclic ring or in each instance of
--(CH.sub.2).sub.v--C(.dbd.O) NR.sup.10aR.sup.10b, R.sup.10a and
R.sup.10b connect to form a 4-7 membered heterocyclic ring;
R.sup.14 and R.sup.15 are independently H, C.sub.1-C.sub.6 alkyl or
together may form a 4- to 7-membered carbocyclic or heterocyclic
ring; j is in each instance independently an integer from 0 to 5; m
is 0 or an independently variable integer 2 or greater; n is in
each instance independently an integer from 0 to 5; v is in each
instance independently an integer from 0 to 5; and pharmaceutically
acceptable salts thereof, with the provisos that a) when R.sup.a is
##STR00025## and n is 0, and when the carbon to which R.sup.1,
R.sup.2 and R.sup.3 are bound is sp.sup.3 hybridized (i.e.,
"saturated"), then none of R.sup.1, R.sup.2 and R.sup.3 can be a
heteroatom or contain a heteroatom which is directly linked to the
carbon of said ##STR00026## group; b) R.sup.8 cannot be H when part
of a --NHS(.dbd.O).sub.2R.sup.8 group, R.sup.11 cannot be H when
part of a --NR.sup.12S(.dbd.O).sub.2R.sup.11 and
--S(.dbd.O).sub.2R.sup.11; and c) v of --(CH.sub.2).sub.v-- cannot
be 1 when said methylene unit is connected to N, O or S.
2. A compound according to claim 1 wherein R.sup.a is a
##STR00027## group.
3. A compound according to claim 1 wherein Q is C(.dbd.O)NH.sub.2
or NHSO.sub.2R.sup.8.
4. A compound according to claim 1 wherein Q is
NHSO.sub.2R.sup.8.
5. A compound according to claim 3, wherein R.sup.a is a
##STR00028## group.
6. A compound according to claim .[.1 or.]. 2 wherein X is H or
F.
7. A compound according to claim 6 wherein Q is --C(.dbd.O)NH.sub.2
or --NHSO.sub.2R.sup.8.
8. A compound according to claim 1 wherein R.sup.1 and R.sup.2
taken together with the carbon to which they are attached form a
cyclobutane, cyclopentane, cyclohexane, indane-2-yl or
1,2,3,4-tetrahydronaphth-2-yl, which may be unsubstituted or
substituted with R.sup.10 groups.
9. A compound according to claim 8 wherein Q is --C(.dbd.O)NH.sub.2
or --NHSO.sub.2R.sup.8.
10. A compound according to claim 1, wherein Q is C(.dbd.O)NH.sub.2
or NHSO.sub.2R.sup.8; R.sup.a is a ##STR00029## group; and R.sup.1
and R.sup.2 taken together with the carbon to which they are
attached form a cyclobutane, cyclopentane, cyclohexane, indane-2-yl
or 1,2,3,4-tetrahydronaphth-2-yl which may be unsubstituted or
substituted with R.sup.10 groups.
11. A compound according to claim 10 wherein R.sup.3 is H, OH,
.[.--NH(.dbd.O)--CH.sub.3,.]. --C(.dbd.O)NH.sub.2, --CH.sub.2OH or
--OCH.sub.3.
12. A compound according to claim 10 wherein R.sup.3 is OH.
13. A compound according to claim 2 wherein n is 1, 2 or 3.
14. A compound according to claim 1 wherein R.sup.4 and R.sup.9 are
independently H or a --C.sub.1-C.sub.4 alkyl.
15. A compound according to claim 1 wherein R.sup.4 and R.sup.9 are
independently H or CH.sub.3.
16. A compound according to claim 1 wherein R.sup.4 and R.sup.9 are
both CH.sub.3.
17. A compound according to claim 1 wherein Q is
--C(.dbd.O)NH.sub.2 or --NHSO.sub.2R.sup.8 and R.sup.8 is CH.sub.3,
--(CH.sub.j).sub.2--O--CH.sub.3 or -4-(1-methylimidazole).
18. A compound according to claim 1 wherein Q is
--C(.dbd.O)NH.sub.2, --NHSO.sub.2CH.sub.3 or
--NHSO.sub.2CH.sub.2CH.sub.2OCH.sub.3 and X is H.
19. A compound according to claim 1 selected from:
3-(2-Ethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Cyclopropylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Isobutyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-[2-(3-Methyl-butyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-(2-Pentyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-[2-(1H-Pyrrol-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(1H-Imidazol-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(1-Hydroxy-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide-
; 3-(2-Hexyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-[2-(2Ethyl-butyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(1-Methyl-1H-pyrrol-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzam-
ide;
3-(2-Thiophen-3-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Thiazol-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-[2-(1-Hydroxymethyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-ben-
zamide; 3-(2-Heptyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Phenethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-[2-(3-Cyclopentyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(2-Ethyl-hexyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-(2-Octyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-[2-(3-Phenyl-prop-2-ynyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(3-Phenyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(4-Methoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(3-Cyclohexyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-{2-[3-(1-Hydroxy-cyclopentyl)-propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-ben-
zamide;
3-[2-(1H-Indol-3-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamid-
e;
3-(2-Benzofuran-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Indan-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Naphthalen-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Naphthalen-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-{2-[3-(1-Hydroxy-cyclohexyl)-propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-benz-
amide;
3-{2-[3-(1-Hydroxymethyl-cyclopentyl)-propyl]-2-aza-bicyclo[3.3.1]-
non-5-yl}-benzamide;
3-(2-Quinolin-4-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Quinolin-3-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-[2-(4-Chloro-2-fluoro-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(1-Methyl-1H-indol-3-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzami-
de;
3-[2-(1,2,3,4-Tetrahydro-naphthalen-2-ylmethyl)-2-aza-bicyclo[3.3.1]n-
on-5-yl]-benzamide;
3-[2-(3-Phenyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(2-Hydroxy-indan-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamid-
e;
3-[2-(2-Phenethyloxy-ethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(4-Hydroxy-naphthalen-1-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benz-
amide;
3-[2-(3-Indan-2-yl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide-
;
3-[2-(4-Pyrrolidin-1-yl-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide-
;
3-[2-(2-Hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-2-aza-bicyclo-
[3.3.1]non-5-yl]-benzamide;
3-[2-(1-Hydroxy-3-phenyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]--
benzamide;
3-[2-(3-Methyl-benzo[b]thiophen-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-
-benzamide;
3-{2-[2-(4-Chloro-phenyl)-2-cyano-ethyl]-2-aza-bicyclo[3.3.1]non-5-yl}-be-
nzamide;
3-(2-Biphenyl-4-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide- ;
3-[2-(3-Trifluoromethoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamid-
e;
3-{2-[3-(2-Hydroxy-indan-2-yl)-propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-b-
enzamide;
3-[2-(9H-Fluoren-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benz-
amide;
3-[2-(3-Phenoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
and
3-[2-(4-Dimethylamino-naphthalen-1-ylmethyl)-2-aza-bicyclo[3.3.1]non-
-5-yl]-benzamide; and pharmaceutically acceptable salts
thereof.
20. A compound according to claim 1 selected from:
N-[3-(2-Ethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamide;
N-[3-(2-Cyclopropylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesu-
lfonamide;
N-[3-(2-Isobutyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamide-
;
N-{3-[2-(3-Methyl-butyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-methanes-
ulfonamide;
N-[3-(2-Pentyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamide;
N-{3-[2-(1II-Pyrrol-2ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-meth-
anesulfonamide;
N-{3-[2-(1H-Imidazol-2ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-met-
hanesulfonamide;
N-{3-[2-(1-Hydroxy-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl-
}-methanesulfonamide;
N-[3-(2-Hexyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamide;
N-{3-[2-(2-Ethyl-butyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-methanesulf-
onamide;
N-{3-[2-(1-Methyl-1H-pyrrol-2ylmethyl)-2-aza-bicyclo[3.3.1]non-5-
-yl]-phenyl}-methanesulfonamide;
N-[3-(2-Thiophen-3-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methane-
sulfonamide;
N-[3-(2-Thiazol-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanes-
ulfonamide;
N-{3-[2-(1-Hydroxymethyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]--
phenyl}-methanesulfonamide;
N-[3-(2-Heptyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamide;
N-[3-(2-Phenethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamid-
e;
N-{3-[2-(3-Cyclopentyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-m-
ethanesulfonamide;
N-{3-[2-(2-Ethyl-hexyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-methanesulf-
onamide;
N-[3-(2-Octyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfo-
namide;
N-{3-[2-(3-Phenyl-prop-2-ynyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phen-
yl}-methanesulfonamide;
N-{3-[2-(3-Phenyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-methanesu-
lfonamide;
N-{3-[2-(4-Methoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-methanes-
ulfonamide;
N-{3-[2-(3-Cyclohexyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-metha-
nesulfonamide;
N-(3-{2-[3-(1-Hydroxy-cyclopentyl)-propyl]-2-aza-bicyclo[3.3.1]non-5-yl}--
phenyl)-methanesulfonamide;
N-{3-[2-(1H-Indol-3-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-metha-
nesulfonamide;
N-[3-(2-Benzofuran-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-metha-
nesulfonamide;
N-[3-(2-Indan-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesul-
fonamide;
N-[3-(2-Naphthalen-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phe-
nyl]-methanesulfonamide;
N-[3-(2-Naphthalen-1-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-metha-
nesulfonamide;
N-(3-{2-[3-(1-Hydroxy-cyclohexyl)propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-ph-
enyl)-methanesulfonamide;
N-(3-{2-[3-(1-Hydroxymethyl-cyclopentyl)-propyl]-2-aza-bicyclo[3.3.1]non--
5-yl}-phenyl)-methanesulfonamide;
N-[3-(2-Quinolin-4-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methane-
sulfonamide;
N-[3-(2-Quinolin-3-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methane-
sulfonamide;
N-{3-[2-(4-Chloro-2-fluoro-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}--
methanesulfonamide;
N-{3-[2-(1-Methyl-1H-indol-3-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phen-
yl}-methanesulfonamide;
N-{3-[2-(1,2,3,4-Tetrahydro-naphthalen-2-ylmethyl)-2-aza-bicyclo[3.3.1]no-
n-5-yl]-phenyl}-methanesulfonamide;
N-{3-[2-(3-Phenyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-
-methanesulfonamide;
N-{3-[2-(2-Hydroxy-indan-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl-
}-methanesulfonamide;
N-{3-[2-(2-Phenethyloxy-ethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-meth-
anesulfonamide;
N-{3-[2-(4-Hydroxy-naphthalen-1-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-p-
henyl}-methanesulfonamide;
N-{3-[2-(3-Indan-2-yl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-metha-
nesulfonamide;
N-{3-[2-(4-Pyrrolidin-1-yl-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}--
methanesulfonamide;
N-{3-[2-(2-Hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-2-aza-bicycl-
o[3.3.1]non-5-yl]-phenyl}-methanesulfonamide;
N-{3-[2-(1-Hydroxy-3-phenyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-y-
l]-phenyl}-methanesulfonamide;
N-{3-[2-(3-Methyl-benzo[b]thiophen-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5--
yl]-phenyl}-methanesulfonamide;
N-(3-{2-[2-(4-Chloro-phenyl)-2-cyano-ethyl]-2-aza-bicyclo[3.3.1]non-5-yl}-
-phenyl)-methanesulfonamide;
N-[3-(2-Biphenyl-4-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methane-
sulfonamide;
N-{3-[2-(3-Trifluoromethoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-
-methanesulfonamide;
N-(3-{2-[3-(2-Hydroxy-indan-2-yl)-propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-p-
henyl)-methanesulfonamide;
N-{3-[2-(9H-Fluoren-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-met-
hanesulfonamide;
N-{3-[2-(3-Phenoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-methanes-
ulfonamide;
N-{3-[2-(4-Dimethylamino-naphthalen-1-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-
-yl]-phenyl}-methanesulfonamide; and pharmaceutically acceptable
salts thereof.
21. A compound according to claim 1 selected from:
2-Methoxy-ethanesulfonic acid
[3-(2-ethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-cyclopropylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-isobutyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
{3-[2(3-methyl-butyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-pentyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(1H-pyrrol-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(1H-imidazol-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amid-
e; 2-Methoxy-ethanesulfonic acid
{3-[2-(1-hydroxy-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}--
amide; 2-Methoxy-ethanesulfonic acid
[3-(2-hexyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(2-ethyl-butyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(1-methyl-1H-pyrrol-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-pheny-
l}-amide; 2-Methoxy-ethanesulfonic acid
[3-(2-thiophen-3-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-thiazol-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(1-hydroxymethyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-ph-
enyl}-amide; 2-Methoxy-ethanesulfonic acid
[3-(2-heptyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-phenethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(3-cyclopentyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(2-ethyl-hexyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-octyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(3-phenyl-prop-2-ynyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(3-phenyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(4-methoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(3-cyclohexyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
(3-{2-[3-(1-hydroxy-cyclopentyl)-propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-ph-
enyl)-amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(1H-indol-3-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-benzofuran-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-indan-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-naphthalen-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-naphthalen-1-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
(3-{2-[3-(1-hydroxy-cyclohexyl)propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-phen-
yl)-amide; 2-Methoxy-ethanesulfonic acid
(3-{2-[3-(1-hydroxymethylcyclopentyl)-propyl]-2-aza-bicyclo[3.3.1]non-5-y-
l}-phenyl)-amide; 2-Methoxy-ethanesulfonic acid
[3-(2-quinolin-4-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-quinolin-3-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(4-chloro-2-fluoro-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-am-
ide; 2-Methoxy-ethanesulfonic acid
{3-[2-(1-methyl-1H-indol-3-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl-
}-amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(1,2,3,4-tetrahydro-naphthalen-2-yl
methyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(3-phenyl-cyclobutyl-methyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}--
amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(2-hydroxy-indan-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}--
amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(2-phenethyloxy-ethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(4-hydroxy-naphthalen-1-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phe-
nyl}-amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(3-indan-2-yl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(4-pyrrolidin-1-yl-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-am-
ide; 2-Methoxy-ethanesulfonic acid
{3-[2-(2-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-2-aza-bicyclo[-
3.3.1]non-5-yl]-phenyl}-amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(1-hydroxy-3-phenyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-
-phenyl}-amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(3-methyl-benzo[b]thiophen-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl-
]-phenyl}-amide; 2-Methoxy-ethanesulfonic acid
(3-{2-[2-(4-chloro-phenyl)-2-cyano-ethyl]-2-aza-bicyclo[3.3.1]non-5-yl}-p-
henyl)-amide; 2-Methoxy-ethanesulfonic acid
[3-(2-biphenyl-4-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(3-trifluoromethoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-a-
mide; 2-Methoxy-ethanesulfonic acid
(3-{2-[3-(2-hydroxy-indan-2-yl)-propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-phe-
nyl)-amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(9II-fluoren-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amid-
e; 2-Methoxy-ethanesulfonic acid
{3-[2-(3-phenoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
and 2-Methoxy-ethanesulfonic acid
{3-[2-(4-dimethylamino-naphthalen-1-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-y-
l]-phenyl}-amide and pharmaceutically acceptable salts of said
compounds.
22. A pharmaceutical composition comprising an effective amount of
a compound according to claim 1 in combination with a
pharmaceutically acceptable carrier, excipient or additive.
Description
FIELD OF THE INVENTION
The subject invention relates to 2-azabicyclo[3.3.1]nonane
derivatives, pharmaceutical compositions comprising such
derivatives and methods of using such derivatives to treat disease
states, disorders and conditions mediated by opioid receptors. The
subject invention also particularly relates to using such
derivatives to treat certain disorders and conditions, for example
irritable bowel syndrome, drug addiction, including alcohol
addiction, depression, anxiety, schizophrenia and eating disorders,
among others as will be more fully described herein.
BACKGROUND OF THE INVENTION
The compounds of the subject invention bind to opioid receptors
(e.g. mu, kappa and delta opioid receptors). Compounds that bind to
such receptors are likely to be useful in the treatment of diseases
modulated by opioid receptors, for example irritable bowel
syndrome; constipation; nausea; vomiting; and pruritic dermatoses,
such as allergic dermatitis and atopy in animals and humans.
Compounds that bind to opioid receptors have also been indicated in
the treatment of eating disorders, opioid overdoses, depression,
anxiety, schizophrenia, alcohol addiction, including alcohol abuse
and dependency, sexual dysfunction, shock, stroke, spinal damage
and head trauma.
Certain 4-arylpiperidine-based compounds are disclosed in European
patent applications EP 287339, EP 506468 and EP 506478 as opioid
receptor binding agents. In addition, International Patent
Application WO 95/15327 discloses azabicycloalkane derivatives
useful as neuroleptic agents. 3-Azabicyclo[3.1.0] hexane
derivatives useful as opioid receptor agents are also disclosed in
WO 00/39089.
SUMMARY OF THE INVENTION
The subject invention is directed to compounds of formula I:
##STR00001## wherein R.sup.a is H or a ##STR00002## R group;
Wherein X is H, halogen, --CN, --C.ident.C--R.sup.3a or a
--C.sub.1-C.sub.4 alkyl group optionally substituted with from one
to three halogen atoms;
Q is H, halogen, a C.sub.1-C.sub.6 alkyl, --CN, --NH.sub.2, --NH
(C.sub.1-C.sub.4 alkyl), N(C.sub.1-C.sub.4 alkyl)(C.sub.1 C.sub.4
alkyl), C(.dbd.O) NH.sub.2, --C(.dbd.O)NH(C.sub.1-C.sub.4 alkyl),
--C(.dbd.O)N(C.sub.1-C.sub.4 alkyl) (C.sub.1 C.sub.4 alkyl),
NHC(.dbd.O)H, NHC(.dbd.O)R.sup.8, or NHS (.dbd.O).sub.2R.sup.8;
R.sup.1 and R.sup.2 are independently H, a C.sub.1-C.sub.6 alkyl,
--(CH.sub.2).sub.j-aryl, --(CH.sub.2).sub.j-heteroary, wherein said
alkyl, --(CH.sub.2).sub.j-aryl or --(CH.sub.2).sub.j-heteroaryl
group is optionally substituted with one or more R.sup.10 groups,
or with the carbon to which R.sup.1 and R.sup.2 are attached,
R.sup.1 and R.sup.2 form a C.sub.3-C.sub.7 carbocyclic or 4- or
7-membered heterocyclic group, wherein said heterocyclic group
comprises from one to three heteroatoms selected from the group
consisting of O, S and N and said carbocyclic or heterocyclic group
optionally contains a --C(.dbd.O) group or optionally contains one
or more double bonds and is optionally fused to or substituted with
a C.sub.6-C.sub.14 aryl or a 5-14 membered heteroaryl group;
wherein said C.sub.3-C.sub.7 carbocyclic or 4- or 7-membered
heterocyclic group formed by R.sup.1 and R.sup.2 may optionally be
substituted with from one to three R.sup.10 groups, and said
optionally fused or substituted aryl or heteroaryl group may each
optionally independently be substituted with from one to six
R.sup.10 groups;
R.sup.10 group are independently selected from R.sup.11, H,
halogen, --OR.sup.11, --NO.sub.2, --CN, --C.sub.1-C.sub.6 alkyl,
--C.sub.3-C.sub.6 cycloalkyl, --C(R.sup.3)R.sup.10aR.sup.10b, aryl
optionally substituted with from 1 to 3 R.sup.3 groups,
--(CH.sub.2).sub.v--NR.sup.11R.sup.12, --NR.sup.11C
(.dbd.O)R.sup.12, --C(.dbd.O)NR.sup.11R.sup.12,
--OC(.dbd.O)R.sup.11, --C(.dbd.O) OR.sup.11, C(.dbd.O)R.sup.11,
--NR.sup.11C(.dbd.O)OR.sup.12, --NR.sup.11C(.dbd.O)
NR.sup.12R.sup.13, --NR.sup.12S(.dbd.O).sub.2R.sup.11,
--NR.sup.11S(.dbd.O).sub.2NR.sup.12R.sup.13, and
--S(.dbd.O).sub.2R.sup.11;
R.sup.3 is absent or is H, --C.sub.1-C.sub.4 alkyl, which
optionally contains one or two unsaturated bonds, --OH,
--O(C.sub.1-C.sub.4) alkyl, --(C.sub.1-C.sub.4)alkylOH,
--(CH.sub.2).sub.n--NR.sup.10aR.sup.10b, --(CH.sub.2).sub.n
--NHC(.dbd.O)(C.sub.1-C.sub.4 alkyl), --(CH.sub.2).sub.n--NO.sub.2,
--(CH.sub.2).sub.n--C.ident.N,
--(CH.sub.2).sub.n--C(.dbd.O)NH.sub.2, --(CH.sub.2).sub.n--C
(.dbd.O)NH(CH.sub.1-C.sub.4 alkyl) or
--(CH.sub.2).sub.v--C(.dbd.O)NR.sup.10aR.sup.10b;
R.sup.3a is H or C.sub.1-C.sub.6 alkyl which may be optionally
substituted with one or more halogen groups;
each R.sup.4, R.sup.4a, R.sup.9 and R.sup.9a is independently H,
--C.sub.-C.sub.4 alkyl or --O--C.sub.1-C.sub.4 alkyl;
each R.sup.8, R.sup.11, R.sup.12 and R.sup.13 is independently
selected from H, --C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, aryl, --(C.sub.2-C.sub.4
alkyl)--O--(C.sub.1-C.sub.4alkyl), aryl,
--(CH.sub.2).sub.m--NR.sup.14R.sup.15, or a 4- to 7-membered
heterocyclic group, or where any two groups selected from R.sup.11,
R.sup.12 and R.sup.13 can form a heterocyclic ring with the atom to
which they are attached, wherein said heterocyclic group or said
heterocyclic ring is optionally substituted with at least one
C.sub.1-C.sub.4 alkyl group;
each R.sup.10a and R.sup.10b is independently selected from H,
--C.sub.1-C.sub.4 alkyl; or, independently in each instance of
--C.sup.1(R.sup.3)R.sup.10aR.sup.10b, R.sup.10a and R.sup.10b
connect to form a C.sub.3-C.sub.7 carbocyclic ring or a 4-7
membered heterocyclic ring or in each instance of
--(CH.sub.2).sub.v--C(.dbd.O)NR.sup.10a, R.sup.10b, R.sup.10a and
R.sup.10b connect to form a 4-7 membered heterocyclic ring;
R.sup.14 and R.sup.15 are independently H, C.sub.1-C.sub.6 alkyl or
together may form a 4- to 7-membered carbocyclic or heterocyclic
ring;
j is in each instance independently an integer from 0 to 5;
m is 0 or an independently variable integer 2 or greater;
n is in each instance independently an integer from 0 to 5;
v is in each instance independently an integer from 0 to 5;
and pharmaceutically acceptable salts thereof,
with the provisos that
a) when R.sup.a is ##STR00003## and n is 0, and when the carbon to
which R.sup.1, R.sup.2 and R.sup.4 are bound is sp.sup.3 hybridized
(i.e., "saturated"), then none of R.sup.1, R.sup.2 and R.sup.4 can
be a heteroatom or contain a heteroatom which is directly linked to
the carbon of said ##STR00004## group;
b) R.sup.8 cannot be H when part of a --NHS(.dbd.O).sub.2R.sup.8
group, R.sup.11 cannot be H when part of a
--NR.sup.12S(.dbd.O).sub.2R.sup.11 and --S(.dbd.O).sub.2R.sup.11;
and
c) v of --(CH.sub.2).sub.v-- cannot be 1 when said methylene unit
is connected to N, O or S.
Preferred embodiments of the subject invention include compounds
according to formula 1, above, Q is --C(.dbd.O) NH.sub.2 or
--NHS(.dbd.O.sub.2)R.sup.8, more preferably
--NHS(.dbd.O.sub.2)R.sup.8, wherein R.sup.8 is CH.sub.3,
--(CH.sub.2).sub.2--O--CH.sub.3 or -4-(1-methylimidazole).
Preferably, X is selected from H or F.
In other preferred embodiments of the subject invention, including
the above-described preferred embodiments, R.sup.a is ##STR00005##
n is 1-3, more preferably 1.
In still further aspects of the subject invention, R.sup.1 and
R.sup.2 taken together with the carbon to which they are attached,
are preferably selected from cyclobutane, cyclopentane,
cyclohexane, indane-2-yl, 1,2,3,4-tetrahydronaphth-2-yl, wherein
each may be substituted with R.sup.10 groups as previously
described.
In still other preferred embodiments, R.sup.3 is H, OH, --NH
(.dbd.O)--CH.sub.3, --C(.dbd.O)NH.sub.2, --CH.sub.2OH or OCH.sub.3,
more preferably OH.
In still other preferred embodiments of the subject invention, each
R.sup.4 and R.sup.9 is independently H or --C.sub.1-C.sub.4 alkyl,
more preferably H or methyl. Even more preferably, R.sup.4 or
R.sup.9 are both methyl.
In more preferred embodiments of the subject invention, in the
above formula 1, Q is --C(.dbd.O)NH.sub.2, --NHSO.sub.2CH.sub.3 or
--NHSO.sub.2CH.sub.2CH.sub.2OCH.sub.3 and X is H.
Preferred embodiments of the invention also include compounds, and
therapeutic methods and pharmaceutical compositions comprising such
compounds, where R.sup.a is a ##STR00006## group; and R.sup.1 and
R.sup.2 taken together with the carbon to which they are attached
form a cyclobutane, cyclopentane, cyclohexane, indane-2-yl or
1,2,3,4-tetrahydronaphth-2-yl which may be unsubstituted or
substituted with R.sup.10 groups as described above. In such
embodiments, R.sup.3 is more preferably H, --OH,
--NH(.dbd.O)--CH.sub.3, --C(.dbd.O)NH.sub.2, --CH.sub.2OH or
--OCH.sub.3. Most preferably in such embodiments R.sup.3 is OH. In
the preferred embodiments described above, n is preferably 1-3,
more preferably 1. In the subject invention, the following
compounds of formula 1 are also preferred:
3-(2-Ethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Cyclopropylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Isobutyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-[2-(3-Methyl-butyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-(2-Pentyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-[2-(1II-Pyrrol-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(1H-Imidazol-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-|2-(1-Hydroxy-cyclobutylmethyl)-2-aza-bicyclo|3.3.1|non-5-yl]-benzamide-
; 3-(2-Hexyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-[2-(2Ethyl-butyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(1-Methyl-1H-pyrrol-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzam-
ide;
3-(2-Thiophen-3-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Thiazol-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-[2-(1-Hydroxymethyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-ben-
zamide; 3-(2-Heptyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Phenethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-[2-(3-Cyclopentyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(2-Ethyl-hexyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-(2-Octyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzam ide;
3-[2-(3-Phenyl-prop-2-ynyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(3-Phenyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(4-Methoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-|2-(3-Cyclohexyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yi|-benzamide;
3-{2-[3-(1-Hydroxy-cyclopentyl)propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-benz-
amide;
3-[2-(1H-Indol-3-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-(2-Benzofuran-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Indan-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Naphthalen-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Naphthalen-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-{2-[3-(1-Hydroxy-cyclohexyl)-propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-benz-
amide;
3-{2-[3-(1-Hydroxymethyl-cyclopentyl)-propyl]-2-aza-bicyclo[3.3.1]n-
on-5-yl}-benzamide;
3-(2-Quinolin-4-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-(2-Quinolin-3-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-[2-(4-Chloro-2-fluoro-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-[2-(1-Methyl-1H-indol-3-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzami-
de;
3-[2-(1,2,3,4-Tetrahydro-naphthalen-2-ylmethyl)-2-aza-bicyclo[3.3.1]no-
n-5-yl]-benzamide;
3-[2-(3-Phenyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(2-Hydroxy-indan-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide-
;
3-[2-(2-Phenethyloxy-ethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(4-Hydroxy-naphthalen-1-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benz-
amide;
3-[2-(3-Indan-2-yl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(4-Pyrrolidin-1-yl-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(2-Hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-2-aza-bicyclo[3-
.3.1]non-5-yl]-benzamide;
3-[2-(1-Hydroxy-3-phenyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]--
benzamide;
3-[2-(3-Methyl-benzo[b]thiophen-2-ylmethyl)-2-aza-bicyclo[3.3.1-
]non-5-yl]-benzamide;
3-{2-(4-Chloro-phenyl)-2-cyano-ethyl]-2-aza-bicyclo[3.3.1]non-5-yl}-benza-
mide;
3-(2-Biphenyl-4-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide;
3-[2-(3-Trifluoromethoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-{2-[3-(2-Hydroxy-indan-2-yl)-propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-benz-
amide;
3-[2-(9H-Fluoren-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamid-
e; 3-[2-(3-Phenoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-benzamide;
3-[2-(4-Dimethylamino-naphthalen-1-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl-
]-benzamide;
N-[3-(2-Ethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamide;
N-[3-(2-Cyclopropylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesu-
lfonamide;
N-[3-(2-Isobutyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanes-
ulfonamide;
N-{3-[2-(3-Methyl-butyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-methanesul-
fonamide;
N-[3-(2-Pentyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulf-
onamide;
N-{3-[2-(1II-Pyrrol-2ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phen-
yl}-methanesul fonamide;
N-{3-[2-(1H-Imidazol-2ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-met-
han esulfonamide;
N-{3-[2-(1-Hydroxy-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl-
}-methanesul fonamide;
N-[3-(2-Hexyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamide;
N-{3-[2-(2-Ethyl-butyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-methanesulf-
onamide;
N-{3-[2-(1-Methyl-1H-pyrrol-2ylmethyl)-2-aza-bicyclo[3.3.1]non-5--
yl]-phenyl}-methanesulfonamide;
N-[3-(2-Thiophen-3-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methane-
sulfonamide;
N-[3-(2-Thiazol-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanes-
ulfonamide;
N-{3-[2-(1-Hydroxymethyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]--
phenyl}-methanesulfonamide;
N-[3-(2-Heptyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamide;
N-[3-(2-Phenethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamid-
e;
N-{3-[2-(3-Cyclopentyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-me-
thanesulfonamide;
N-{3-[2-(2-Ethyl-hexyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl)-methanesulf-
onamide;
N-[3-(2-Octyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfon-
amide;
N-{3-[2-(3-Phenyl-prop-2-ynyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl-
}-methanesul fonamide;
N-{3-[2-(3-Phenyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-methanesu-
lfonamide;
N-{3-[2-(4-Methoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl-
}-methanesulfonamide;
N-{3-[2-(3-Cyclohexyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-metha-
nesulfonamide;
N-(3-{2-[3-(1-Hydroxy-cyclopentyl)propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-p-
henyl)-methanesulfonamide;
N-{3-[2-(1H-Indol-3-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-metha-
nesulf onamide;
N-[3-(2-Benzofuran-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-metha-
nesulfonamide;
N-[3-(2-Indan-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesul-
fonamide;
N-[3-(2-Naphthalen-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phen-
yl]-methanesulfonamide;
N-[3-(2-Naphthalen-1-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-metha-
nesulfonamide;
N-(3-{2-[3-(1-Hydroxy-cyclohexyl)propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-ph-
enyl)-methanesulfonamide;
N-(3-{2-[3-(1-Hydroxymethyl-cyclopentyl)-propyl]-2-aza-bicyclo[3.3.1]non--
5-yl}-phenyl)-methanesulfonamide;
N-[3-(2-Quinolin-4-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methane-
sulfonamide;
N-[3-(2-Quinolin-3-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methane-
sulfonamide;
N-{3-[2-(4-Chloro-2-fluoro-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}--
methan esulfonamide;
N-{3-[2-(1-Methyl-1H-indol-3-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phen-
yl}-methanesulfonamide;
N-{3-[2-(1,2,3,4-Tetrahydro-naphthalen-2-ylmethyl)-2-aza-bicyclo[3.3.1]no-
n-5-yl]-phenyl}-methanesulfonamide;
N-{3-[2-(3-Phenyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-
-methanesulfonamide;
N-{3-[2-(2-Hydroxy-indan-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl-
}-metha nesulfonamide;
N-{3-[2-(2-Phenethyloxy-ethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-meth-
anesulfonamide;
N-{3-[2-(4-Hydroxy-naphthalen-1-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-p-
henyl}-methanesulfonamide;
N-{3-[2-(3-Indan-2-yl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-metha-
ne sulfonamide;
N-{3-[2-(4-Pyrrolidin-1-yl-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}--
methan esulfonamide;
N-{3-[2-(2-Hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-2-aza-bicycl-
o[3.3.1]non-5-yl]-phenyl}-methanesulfonamide;
N-{3-[2-(1-Hydroxy-3-phenyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-y-
l]-phenyl}-methanesulfonamide;
N-{3-[2-(3-Methyl-benzo[b]thiophen-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5--
yl]-phenyl}-methanesulfonamide;
N-(3-{2-[2-(4-Chloro-phenyl)-2-cyano-ethyl]-2-aza-bicyclo[3.3.1]non-5-yl}-
-phenyl)-methanesulfonamide;
N-[3-(2-Biphenyl-4-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methane-
sulfonamide;
N-{3-[2-(3-Trifluoromethoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-
-methan esulfonamide;
N-(3-{2-[3-(2-Hydroxy-indan-2-yl)-propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-p-
henyl)-methanesulfonamide;
N-{3-[2-(9H-Fluoren-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-met-
hanesu lfonamide;
N-{3-[2-(3-Phenoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-methanes-
ulfonamide;
N-{3-[2-(4-Dimethylamino-naphthalen-1-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-
-yl]-phe nyl}-methanesulfonamide; 2-Methoxy-ethanesulfonic acid
[3-(2-ethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-cyclopropylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-isobutyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
{3-[2(3-methyl-butyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-pentyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(1H-pyrrol-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(1H-imidazol-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amid-
e; 2-Methoxy-ethanesulfonic acid
{3-[2-(1-hydroxy-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}--
amide; 2-Methoxy-ethanesulfonic acid
[3-(2-hexyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(2-ethyl-butyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(1-methyl-1H-pyrrol-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-pheny-
l}-amide; 2-Methoxy-ethanesulfonic acid
[3-(2-thiophen-3-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-thiazol-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(1-hydroxymethyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-ph-
enyl}-amide; 2-Methoxy-ethanesulfonic acid
[3-(2-heptyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-phenethyl-2-aza-bicyclo|3.3.1|non-5-yl)-phenyl|-amide;
2-Methoxy-ethanesulfonic acid
(3-[2-(3-cyclopentyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(2-ethyl-hexyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-octyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(3-phenyl-prop-2-ynyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(3-phenyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(4-methoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(3-cyclohexyl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
(3-{2-[3-(1-hydroxy-cyclopentyl)-propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-ph-
enyl)-amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(1H-indol-3-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-benzofuran-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-indan-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-naphthalen-2-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-naphthalen-1-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
(3-{2-[3-(1-hydroxy-cyclohexyl)propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-phen-
yl)-amide; 2-Methoxy-ethanesulfonic acid
(3-{2-[3-(1-hydroxymethylcyclopentyl)-propyl]-2-aza-bicyclo[3.3.1]non-5-y-
l}-phenyl)-amide; 2-Methoxy-ethanesulfonic acid
[3-(2-quinolin-4-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
[3-(2-quinolin-3-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(4-chloro-2-fluoro-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-am-
ide; 2-Methoxy-ethanesulfonic acid
{3-[2-(1-methyl-1II-indol-3-ylmethyl)-2-aza-bicyclo|3.3.1|non-5-yl|-pheny-
l}-amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(1,2,3,4-tetrahydro-naphthalen-2-yl
methyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(3-phenyl-cyclobutyl-methyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}--
amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(2-hydroxy-indan-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}--
amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(2-phenethyloxy-ethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(4-hydroxy-naphthalen-1-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phe-
nyl}-amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(3-indan-2-yl-propyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(4-pyrrolidin-1-yl-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-am-
ide; 2-Methoxy-ethanesulfonic acid
{3-[2-(2-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-2-aza-bicyclo[-
3.3.1]non-5-yl]-phenyl}-amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(1-hydroxy-3-phenyl-cyclobutylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-
-phenyl}-amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(3-methyl-benzo[b]thiophen-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl-
]-phenyl}-amide; 2-Methoxy-ethanesulfonic acid
(3-{2-[2-(4-chloro-phenyl)-2-cyano-ethyl]-2-aza-bicyclo[3.3.1]non-5-yl}-p-
henyl)-amide; 2-Methoxy-ethanesulfonic acid
[3-(2-biphenyl-4-ylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide;
2-Methoxy-ethanesulfonic acid
{3-[2-(3-trifluoromethoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-a-
mide; 2-Methoxy-ethanesulfonic acid
(3-{2-[3-(2-hydroxy-indan-2-yl)-propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-phe-
nyl)-amide; 2-Methoxy-ethanesulfonic acid
{3-[2-(9II-fluoren-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amid-
e; 2-Methoxy-ethanesulfonic acid
{3-[2-(3-phenoxy-benzyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-amide
and 2-Methoxy-ethanesulfonic acid
{3-[2-(4-dimethylamino-naphthalen-1-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-y-
l]-phenyl}-amide and pharmaceutically acceptable salts of said
compounds.
The compounds of the present invention may be used to bind to and
modulate (i.e., inhibit, partially inhibit, activate or partially
activate) an opioid receptor or receptors in a mammal, including a
human. The present compounds exhibit pharmacological activity
consistent with such binding. Compounds according to the present
invention may also be used as reference materials, reference
standards, including calibration standards and as synthetic
intermediates.
The subject invention is also directed to pharmaceutical
compositions comprising an effective amount of one or more
compounds according to the invention as otherwise described herein,
optionally in combination with a pharmaceutically acceptable
additive, carrier or excipient.
The subject invention also provides a pharmaceutical composition
for treating in a mammal, including a human, in need thereof a
disease state, disorder or condition mediated by an opioid receptor
or receptors which composition comprises an amount of a compound
according to formula I or a pharmaceutically acceptable salt
thereof effective in modulating an opioid receptor or receptors and
a pharmaceutically acceptable carrier.
The subject invention also provides a pharmaceutical composition
for treating in a mammal, including a human, in need thereof a
disorder or condition mediated by an opioid receptor or receptors
which composition comprises an amount of a compound according to
formula I or a pharmaceutically acceptable salt thereof effective
in treating said disorder or condition and a pharmaceutically
acceptable carrier.
The subject invention also provides a pharmaceutical composition
for treating in a mammal, including a human, in need thereof a
disorder or condition selected from irritable bowel syndrome;
constipation; nausea; vomiting; pruritic dermatoses, for example
allergic dermatitis or contact dermatitis; psoriasis; eczema; an
insect bite; an eating disorder, for example anorexia, bulimia, or
obesity; depression, anxiety, schizophrenia; drug addiction, for
example alcohol addiction, amphetamine addiction, cocaine addiction
or addiction to an opioid, for example morphine, opium, or heroin;
an opioid overdose; a sexual dysfunction, for example erectile
dysfunction or impotence; stroke; head trauma; traumatic brain
injury; spinal damage; Parkinson's disease; Alzheimer's disease,
age-related cognitive decline; and Attention Deficit and
Hyperactivity Disorder; which composition comprises an amount of a
compound of formula I or a pharmaceutically acceptable salt thereof
effective in modulating an opioid receptor or receptors and a
pharmaceutically acceptable carrier.
The subject invention also provides a pharmaceutical composition
for treating in a mammal, including a human, in need thereof, a
disorder or condition selected from irritable bowel syndrome;
constipation; nausea; vomiting; pruritic dermatoses, for example
allergic dermatitis or contact dermatitis; psoriasis; eczema; an
insect bite; an eating disorder, for example anorexia, bulimia, or
obesity; depression, anxiety, schizophrenia; drug addiction, for
example alcohol addiction, amphetamine addiction, cocaine addiction
or addiction to an opioid, for example morphine, opium, or heroin;
an opioid overdose; a sexual dysfunction, for example erectile
dysfunction or impotence; stroke; head trauma; traumatic brain
injury; spinal damage; Parkinson's disease; Alzheimer's disease,
age-related cognitive decline; and Attention Deficit and
Hyperactivity Disorder: which composition comprises an amount of a
compound of formula I or a pharmaceutically acceptable salt thereof
effective in treating said disorder or condition and a
pharmaceutically acceptable carrier.
Another aspect of the subject invention is directed to treating in
a mammal, including a human, in need thereof, a disorder or
condition mediated by an opioid receptor or receptors which method
comprises administering to said mammal an amount of a compound
according to formula I, or a pharmaceutically acceptable salt
thereof, effective in modulating an opioid receptor or
receptors.
The subject invention also provides a method for treating in a
mammal, including a human, in need thereof, a disease state,
disorder or condition selected from irritable bowel syndrome;
constipation; nausea; vomiting; pruritic dermatoses, for example
allergic dermatitis or contact dermatitis; psoriasis; eczema; an
insect bite; an eating disorder, for example anorexia, bulimia, and
obesity; depression, anxiety, schizophrenia; drug addiction, for
example alcohol addiction, amphetamine addiction, cocaine addiction
or addiction to an opioid, for example morphine, opium, or heroin;
an opioid overdose; a sexual dysfunction, for example erectile
dysfunction or impotence; stroke; head trauma; traumatic brain
injury; spinal damage; Parkinson's disease; Alzheimer's disease,
age-related cognitive decline; and Attention Deficit and
Hyperactivity Disorder; which method comprises administering to
said mammal an amount of a compound of formula I or a
pharmaceutically acceptable salt thereof as described above
effective to modulate an opioid receptor or receptors in said
mammal.
The subject invention also provides a method for treating in a
mammal, including a human, in need thereof, a disease state,
disorder or condition selected from irritable bowel syndrome;
constipation; nausea; vomiting; pruritic dermatoses, for example
allergic dermatitis or contact dermatitis; psoriasis; eczema; an
insect bite; an eating disorder, for example anorexia, bulimia, or
obesity; depression, anxiety, schizophrenia; drug addiction, for
example alcohol addiction, amphetamine addiction, cocaine addiction
and addiction to an opioid, for example morphine, opium, or heroin;
an opioid overdose; a sexual dysfunction, for example erectile
dysfunction or impotence; stroke; head trauma; traumatic brain
injury; spinal damage; Parkinson's disease; Alzheimer's disease,
age-related cognitive decline; and Attention Deficit and
Hyperactivity Disorder; which method comprises administering to
said mammal an amount of a compound of formula I or a
pharmaceutically acceptable salt thereof as described above
effective in treating said disease state, disorder or condition in
said mammal.
Thus, compounds of the present invention are useful because they
possess pharmacological activity in animals, especially mammals,
including humans. These compounds may also find use as standards in
analytical assays or as intermediates in the synthesis of final
compounds exhibiting pharmacological activity.
The subject invention also provides a method for treating in a
mammal, including a human, in need thereof a disorder or condition
mediated by an opioid receptor or receptors which method comprises
administering to said mammal an amount of a compound according to
formula I or a pharmaceutically acceptable salt thereof effective
in treating said disorder or condition.
In the therapeutic methods of the subject invention as described
above, the disease state, disorder or condition that is being
treated is preferably irritable bowel syndrome, drug addiction,
depression, anxiety, schizophrenia, or an eating disorder.
Methods of synthesizing compounds according to the present
invention and key intermediates which can be in such methods are
additional aspects of the present invention. These methods are
described in greater detail hereinbelow.
DETAILED DESCRIPTION OF THE INVENTION
The following terms shall be used to describe the subject
invention.
The term "compound", as used herein, unless otherwise indicated,
refers to any specific chemical compound disclosed herein. Within
its use in context, the term generally refers to a single compound,
but in certain instances may also refer to stereoisomers and/or
optical isomers (including racemic mixtures), as well as specific
enantiomers or enantiomerically enriched mixtures of disclosed
compounds.
The term "effective" is used herein, unless otherwise indicated, to
describe an amount of a compound which, in context, is used to
produce or effect an intended result, whether that result relates
to the treatment of a disease state, disorder or condition or
alternatively, is used to produce another compound, agent or
composition.
The terms "treatment", "treating", and the like, refers to
reversing, alleviating, or inhibiting the progress of the disorder
or condition to which such term applies, or one or more symptoms of
such disorder or condition. As used herein, there terms also
encompass, depending on the condition of the patient, preventing
the onset of a disorder or condition, or of symptoms associated
with a disorder or condition, including reducing the severity of a
disorder or condition or symptoms associated therewith prior to
affliction with said disorder or condition. Thus, "treatment", as
used herein, can refer to administration of a compound of the
invention to a subject that is not at the time of administration
afflicted with the disorder or condition. "Treating" thus also
encompasses preventing the recurrence of a disorder or condition or
of symptoms associated therewith.
The term "addiction", as used herein, for example in "drug
addiction" and "alcohol addiction", unless otherwise indicated,
refers to a maladaptive use of a substance, which may be either
with physiological dependence or without. The term "addiction" thus
includes both substance abuse (e.g. alcohol, amphetamine, cocaine
or an opioid, for example morphine, opium, or heroin abuse) and
substance dependence (e.g. alcohol, amphetamine, cocaine or an
opioid, for example morphine, opium, or heroin dependence). The
maladaptive pattern of substance use may manifest itself in
recurrent and significant adverse consequences related to the
repeated use of the substance. The recurrent substance use may
result in a failure to fulfill major role obligations at work,
school, or home. The maladaptive use of a substance may involve
continued use of the substance despite persistent or recurrent
social or interpersonal problems caused or exacerbated by the
effects of the substance (e.g., arguments with spouse, physical
fights). The maladaptive pattern of substance use may involve
clinically significant impairment or distress, for example
manifested by tolerance for the substance, withdrawal symptoms,
self-injurious behavior, unsuccessful efforts to cut down or
control the substance use, and/or taking larger amounts of the
substance and/or taking amounts of the substance over a longer
period than was intended. Substances to which an addiction may be
formed include, but are not limited to, the drugs recited above
(including alcohol), as well as others, for example benzodiazepines
such as Valium.RTM..
The term "mammal", as used herein, and unless otherwise indicated,
means any mammal. The term "mammal" includes, for example and
without limitation, dogs, cats, and humans. The term "patient" or
"subject" may be alternatively used to describe such a mammal,
including a human, to whom treatment or use with the compounds or
compositions according to the subject invention is provided. For
treatment or use with/or of those disease states, conditions or
disease states which are specific for a specific animal
(especially, for example, a human subject or patient), the term
patient or subject refers to that particular animal.
References herein to disease states, disorders and conditions
"mediated by an opioid receptor or receptors" indicate disorders or
conditions the treatment of which can be facilitated by modulating
(i.e. inhibiting, partially inhibiting, activating, or partially
activating) an opioid receptor or receptors. Examples of disorders
and conditions the treatment of which is facilitated by modulation
of an opioid receptor or receptors include, but are not limited to,
irritable bowel syndrome, eating disorders, sexual dysfunction,
depression anxiety, schizophrenia and drug addictions, as well as
the other specific disorders and conditions recited herein.
The term "alkyl", as used herein, unless otherwise indicated,
includes saturated monovalent hydrocarbon radicals having straight,
cyclic or branched moieties. Examples of alkyl groups include, but
are not limited to, methyl, ethyl, propyl, isopropyl, sec-butyl and
t-butyl. Within context, the use of the term "alkyl" may also
subsume the use of or refer to alkylene groups, i.e., a hydrocarbon
radical derived from alkyl groups which are diradicals, rather than
monoradicals.
The term "cycloalkyl", as used herein, unless otherwise indicated,
includes non-aromatic saturated cyclic alkyl moieties wherein alkyl
is as defined above. Examples of cycloalkyl include, but are not
limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
cycloheptyl.
The term "carbocyclic", as used herein, unless otherwise indicated,
refers to a cyclic group in which all of the atoms of the ring are
carbon atoms. Representative carbocyclic groups include cycloalkyl
groups as described above. The term carbocyclic subsumes the term
aryl within it.
The term "heterocyclic", as used herein, unless otherwise
indicated, refers to a cyclic group in which at least one atom of
the ring is a heteroatom (i.e., O, S or N). The term heterocyclic
subsumes the term heteroaryl within it. Thus, a 5- to 7-membered
heterocyclic gruop subsumes a 5- to 7-membered heteroaryl group
within it.
The term "aryl", as used herein, unless otherwise indicated,
includes an organic radical derived from an aromatic hydrocarbon by
removal of one hydrogen, such as phenyl, naphthyl, indenyl, and
fluorenyl.
The term "heteroaryl", as used herein, refers to aromatic groups
containing one or more heteroatoms (O, S, or N), preferably from
one to four heteroatoms. A multicyclic group containing one or more
heteroatoms wherein at least one ring of the group is aromatic is a
"heteroaryl" group. The heteroaryl groups of this invention can
also include ring systems substituted with one or more oxo
moieties. Examples of heteroaryl groups are pyridinyl, pyridazinyl,
imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl,
isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,
oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl,
benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,
triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl,
furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl,
benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl,
dihydroisoquinolyt, tetrahydroisoquinolyl, benzofuryl,
furopyridinyl, pyrolopyrimidinyl, and azaindolyl. The foregoing
groups, as derived from the compounds listed above, may be
C-attached or N-attached where such is possible. For instance, a
group derived from pyrrole may be pyrrol-1-yl (N-attached),
pyrrol-2-yl or pyrrol-3-yl (C-attached). The terms referring to the
groups also encompass all possible tautomers.
The term "phenyl-fused" or "heteroaryl-fused", as used herein,
refers to a heterocyclic or carbocyclic group which forms a ring by
attaching or bonding two atoms (carbon and/or heteroatoms) of the
heterocyclic or carbocyclic group to two atoms of the phenyl or
heteroaryl group.
The term "reductive amination", as used herein, refers to any
process whereby the combination of an aldehyde or a ketone, or
aldehyde or ketone equivalent, such as a bisulfite addition complex
of an aldehyde, is combined with, in reference to the subject
invention, a primary amine, secondary amine or ammonia, or ammonia
source, such that the compounds condense to generate an
intermediate imine or iminium ion that may be subjected to
reduction by means of hydrogenation, such as mediated by a metal
species such as palladium or platimum in many forms useful for
reduction and a hydrogen source, such as hydrogen gas, or any
precursor to hydrogen gas, including but not limited to formate
derivatives or cyclohexadiene, or other hydride sources whereby
hydride delivery from said source occurs by mechanisms commonly
understood and employed. These include hydride reagents such as
boron or aluminum hydride sources, for instance borohydrides, such
as [(X).sub.nBH.sub.4-n].sup.- (n=0, 1, 2, 3) or aluminum hydrides
such as [(X).sub.nAlH.sub.4-n].sup.- (n-0, 1, 2, 3) (wherein X may
be any of the commonly cited ligands for transformations such a
reductive amination including but not limited to acetoxy,
trifluoroacetoxy, alkoxy, or lower alkyl for boron or alkoxy or
lower alkyl for aluminum). Other hydrides may be equally suited to
these transformations (for instance silanes or stannanes).
The term "reducing" or "reductive conditions", as used herein,
refers to any process whereby dehydrohalogenation, hydrogenolysis,
hydrogenation, or reduction of unsatured bonds occurs as
desired.
The term "leaving group", as used herein, refers to any group
suitable in the conversion of a primary amine, secondary amine or
ammonia or ammonia source that effectively departs in a
bond-forming event from a carbon atom of interest, such as in an
alkylation reaction. Suitable groups include halides (iodide,
bromide or chloride), sulfonates (such methane sulfonate,
trifluoromethanesulfonate or, aryl sulfonates such as tosyl or
nosyl groups), epoxides or aziridines or any variation that is well
known to those of skill in the art. In addition, the processes
involving leabing groups may be employed in the formation of other
C-X bonds where the nucleophile X is oxygen, sulfur, or carbon
centered.
The term "carbonyl protecting group", as used herein, refers to any
group that can withstand chemistry performed on other portions of
the molecule without being substantially structurally compromised.
Such groups must withstand reduction, reductive amination and
alkylation chemistry as defined. These groups may include alkoxy
groups such as dimethoxy, diethoxy, other C.sub.1-C.sub.6 dialkoxy,
diphenoxy, or cyclic ketals such as cyclic dialkoxy groups such as
dioxolanes, 1,3-dioxanes or catechols, among others.
Pharmaceutical salts of compounds according to the present
invention are an important aspect. Pharmaceutical salts of
compounds of formula I can be obtained by forming salts with any
acidic or basic group present on a compound of formula I. Examples
of pharmaceutically acceptable salts of the compounds of formula I
are the salts of hydrochloric acid, p-toluenesulfonic acid, fumaric
acid, citric acid, succinic acid, salicylic acid, oxalic acid,
hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric
acid, maleic acid, di-p-toluoyl tartaric acid, acetic acid,
sulfuric acid, hydroiodic acid, mandelic acid, sodium, potassium,
magnesium, calcium, and lithium. Mesylate and/or citrate salts may
be particularly preferred in the subject invention.
As noted above, the compounds of formula I may have optical centers
and therefore may occur in different enantiomeric and other
stereoisomeric configurations. The invention includes all
enantiomers, diastereomers, and other stereoisomers of such
compounds of formula I, as well as racemic and other mixtures
thereof.
The synthetic methods described below in the "Detailed Description"
section and in Examples produce primarily compounds of formula I
having the relative stereochemistry illustrated by compounds of
formula I below: ##STR00007## wherein R.sup.a is H or a
##STR00008## group.
Note that the two depictions of formula I above are equivalent
(identical) chemical structures.
Isolation and purification of the products is accomplished by
standard procedures which are known to a chemist of ordinary skill
in the art. In addition, by following the disclosed chemistry more
generically and/or by analogy, one of ordinary skill may readily
provide all of the compounds according to the subject
invention.
Scheme I--XI illustrate methods for the preparation of compounds
having the basic structure of formula I, where Q--NH.sub.2,
NHSO.sub.2R.sup.8, CONH.sub.2, R.sup.6 and R.sup.9--H or alkyl, and
j, m, n, v, R.sup.1, R.sup.2 and R.sup.15 are described as above.
Other compounds according to the present invention may be readily
synthesized by analogy following the specific methods described in
detail herein and following well-known synthetic methods in the
art.
As used herein, the expression "reaction inert solvent" refers to a
solvent system in which the components do not interact with
starting materials, reagents, or intermediates of products in a
manner that adversely affects the yield of the desired product.
During any of the following synthetic sequences it may be necessary
and/or desirable to protect sensitive or reactive groups on any of
the molecules concerned. This may be achieved by means of
conventional protecting groups, such as those described in T. W.
Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry,
3.sup.rd edition, John Wiley & Sons, 1999.
The stereochemistry of compounds of formula I synthesized according
to the methods described above can be determined using standard
spectroscopic methods. Isolation of the desired diastereomer of a
compound of formula I from a diastereomeric mixture can be
accomplished using standard separation methods know to those of
ordinary skill in the art, for example crystallization or
chromatographic methods. ##STR00009##
Referring to Scheme I above, certain compounds of formula I are
known wherein Q=OH and R.sup.a=H and described in the literature
(see Werner, J. A.; Cerbone, L. R.; Frank, S. A.; Ward, J. A.;
Labib, P.; Tharp-Taylor, R. W.; Ryan, C. W. J. Org. Chem. 1996, 61,
587-597 and WO2002060445A1). In these known preparations certain
intermediates such as 1 as shown above in Scheme I have been
described. These citations also include methods of the preparation
of optically enriched and optically pure materials. These materials
may be prepared as described therein or by adapted methods, as for
instance in Scheme I whereby the ketone intermediate 2 is reduced
under Wolff-Kishner conditions to give 3. Other methods of reducing
ketones to methylene groups are equally applicable. Removal of the
nitrogen radical by standard methods as known to those skilled in
the art and described in the above articles affords intermediate 4.
This intern may be converted to a nitrogen protected material
suitable for further elaboration. Such materials may be accessed by
known method such as alkylation, reductive alkylation or acylation
and hydride reduction. Such methods are more fully described in
Scheme IX, X and XI and in the Examples section. For the purposes
of this description the conversion to a N-benzyl radical is
convenient and sufficient. As shown in Scheme I such a conversion
is shown from intermediate 4 which, after standard dealkylation of
the phenyl alkyl ether, as by, for instance HBr in acetic acid at a
temperature of room temperature to 100.degree. C., provides 5. For
the purposes of illustration this scheme demonstrates an approach
to compounds of the invention where the R.sup.4 radical, as
described previously, is methyl. ##STR00010##
Referring to Scheme II above and in a parallel approach, methods
have been described that prepare intermediate 6 wherein the R.sup.9
radical as defined above is methyl (Thomas, J. B.; Zheng, X.;
Mascarella, S. W.; Rothman, R. B.; Dersch, C. M. Partilla, J. S.;
Flippen_Andrson, J. L.; George, C. F.; Cantrell, B. E.; Zimmerman,
D. M.; Carrol, F. I. J. Med. Chem. 1998, 41, 4143-4149). As shown
in Scheme II and as described for Scheme I, the conversion of this
intermediate 6 provides N-protected intermediate 7, whereby, for
the purposes of illustration, the N-radical is benzyl.
##STR00011##
Referring to Scheme III above methods are shown for the preparation
of compounds wherein both the R.sup.4 and R.sup.9 radicals are
hydrogen and the N-protection is again a benzyl group introduced by
methods described below in Scheme IX, X and XI. Methods have been
described to prepare intermediate 8 (Bertha, C. M.; Mattson, M. V.;
Flippen-Anderson, J. L.; Rothman, R. B.; Xu, H.; J. Med. Chem.
1994, 37, 3163-3170) and the conversion to a N-protected version
compatible with subsequent chemical transformations is shown, via
intermediate 9, to prepare intermediate 10. ##STR00012##
Scheme IV shows a method of preparation of compounds of formula I
wherein Q--NH.sub.2 (R.sup.a--Bn, R.sup.4 or R.sup.9 are as
described above). These compounds may be derived from related
precursors whereby Q=OH. Referring to Scheme IV, treatment of a
compound of formula 11 (5, 7 and 10 being examples thereof) with
C.sub.6H.sub.5N(SO.sub.2CF.sub.3).sub.2 in the presence of a
suitable base, such as triethylamine in a solvent such as methylene
chloride, will produce the trifluoromethanesulfonate (triflate) of
formula 12. Treatment of a triflate of formula 12 with benzophenone
imine with a suitable catalyst such as palladium (11) acetate, a
suitable phosphine ligand such as BlNAP, and a suitable base, such
as sodium t-butoxide, in a suitable solvent such as toluene, at
temperatures ranging from room temperature to about the reflux
temperature, produces an intermediate imine, which is then treated
with aqueous acid at temperatures ranging from room to reflux,
preferably at 80-100.degree. C., producing the aniline of formula
13. ##STR00013##
Referring to Scheme V, treatment of an aniline of formula 14 with
an appropriately substituted sulfonyl chloride or anhydride such as
methanesulfonyl chloride or 2-methoxy-ethanesulfonyl chloride, in
the presence of a suitable base, such as pyridine, in a solvent
such as methylene chloride, at temperatures ranging from 0.degree.
C. to room temperature, preferably at about room temperature,
produces the desired sulfonamide of formula 15. ##STR00014##
Referring to Scheme VI above, treatment of a triflate of formula 12
with zinc cyanide, in the presence of a suitable catalyst, such as
tetrakistriphenylphosphine palladium (0), in solvents such as
dimethylformamide, at temperatures ranging from room temperature to
about reflux temperature, preferably at about 85.degree. C.,
produces the corresponding nitrile of formula 16. Conversion of a
nitrile of formula 16 by the action of for instance dilute hydrogen
peroxide, in the presence of a suitable alkali metal base, such as
potassium carbonate, in solvents such as dimethylformamide or
dimethylsulfoxide, at temperatures ranging from 0.degree. C. to
about room temperature, preferably at about room temperature,
produces the corresponding amide of formula 17. ##STR00015##
Referring to Scheme VII above, compounds of formula I (R.sup.a H)
can be prepared by the reduction or hydrogenolysis of compounds of
formula 15 or 17 with hydrogen gas (at pressures ranging from
atmospheric to 50 psi) in the presence of a suitable catalyst such
as palladium on carbon, in alcoholic solvents such as methanol, at
temperatures ranging from room temperature to reflux, preferably at
about 60.degree. C. Alternatively, compounds of formula I
(R.sup.a=H) can be prepared by treatment of compounds of formula 15
or 17 with ammonium salts of formic acid, such as ammonium formate,
or more preferably, that formed by contacting piperidine and formic
acid, in the presence of a suitable catalyst, such as palladium on
carbon, in alcoholic solvents, such as methanol or ethanol, at
temperatures ranging from room temperature to about the reflux
temperature, preferably at about reflux temperature. These methods
are useful for the conversion of any compound wherein Q or X as
described previously is stable to the conditions as described here
as may be determined by one skilled in the art. ##STR00016##
As shown above in Scheme VII, compounds of formula I (R.sup.1=H,
18) can be converted to derivatives that allow for ready
purification and isolation. It is often sufficient to remove
protective R.sup.a groups as described in Scheme VII and purify
these products by standard methods such as crystallization or
chromatography. On occasion it is convenient to prepare protected
intermediates that are readily purified by standard methods such as
crystallization or chromatography, and which are then readily
converted back to compounds where R.sup.a=H. In such an approach,
the t-butyloxy-carbonyl protecting group may be introduced, or any
other convenient protecting group, by standard methods, such as by
contacting di-t-butyldicarbonate with compounds of formula I where
R.sup.a is H, 18. This may be done in any solvent that allows the
conversion to occur, such as a chlorinated solvent like
dichloromethane or dichloroethane, an ethereal solvent such as THF
or dioxane or water. Base may or may not me necessary, for instance
alkali carbonates or bicarbonates or the like. An effective method
calls for adding di-t-butyidicarbonate to compounds of formula I
where R.sup.a is H (18) in dichloromethane or THF in the presence
of aqueous sodium bicarbonate or carbonate solutions. The product
materials 19 are then readily separated from byproducts of the
transfer hydrogenolysis reaction in Scheme VII, if still present,
for instance t-piperidine-1-carboxylic acid tert-butyl ester, by
chromatographic methods. Removal of this group is readily
accomplished by any of the methods known to those in the art, such
as in the conversion to the HCl or trifluoroacetate salts of
compounds of formula I (R.sup.a=H, 18) by expose of 19 to the acid
in a non-aqueous medium. ##STR00017##
Referring to Scheme IX, treatment of a compound of formula I
(R.sup.a--H, 18) with an appropriately substituted aldehyde of
formula 20 (or the corresponding alkali metal bisulfite addition
compound of said aldehyde) and a reducing agent such as sodium
triacetoxyborohydride, in the presence of acetic acid, in solvents
such as chlorinated solvents, such as dichloromethane or
dichloroethane or an alcohol, such as methanol, or an ethereal
solvent such as THF, or any combination of these solvents, at
temperatures ranging from 0.degree. c. to about room temperature,
preferably at about room temperature, produce the corresponding
compounds of formula I. Precursors to this step can be prepared
using methods that are known to one of ordinary skill in the art.
Equally useful in this step is the use of ketones of formula 20a
such that compounds wherein n=0 may be prepared. ##STR00018##
Referring to Scheme X above, compounds of formula I can be prepared
by treatment of a compound of formula I (R.sup.a=H, 18) with a
reagent of formula 21 wherein R.sup.16 is oxygen or --NH or
--NSO.sub.2R or --NCOOR, or a compound of formula 22 wherein LG
(leaving group) is a suitable sulfonate, such as methansulfonate,
trifluoromethanesulfonate or arylsulfonate, or a halide, such as
chloride, bromide or iodide. This reaction should be carried out in
the presence of a suitable base such as a tertiary amine, for
instance triethylamine, in alcoholic solvents such as ethanol or
isopropanol at temperatures ranging from room temperature to about
the reflux temperature, preferably at about the reflux temperature
to produce the desired compound of formula I. ##STR00019##
Alternatively, referring to Scheme XI compounds of formula I can
also be prepared by treatment of a compound of formula I
(R.sup.a--H, 18) with an appropriately substituted acid chloride of
formula 23. The reaction should be carried out in the presence of a
suitable base such as hydroxide ion, Et.sub.3N or pyridine, in
solvents such as water, tetrahydrofuran or methylene chloride, at
temperature ranging from 0.degree. C. to room temperature,
preferably at about room temperature. Any of the suitable methods
for preparing amides known to those skilled in the art are
appropriate for use in this transformation. The amide products from
this reaction (not depicted) are then reduced with a suitable
reducing agent, such as lithium aluminum hydride Dibal-H or borane
in solvents such as ethyl ether or tetrahydrofuran, at temperatures
ranging from room temperature to about the reflux temperature,
preferably at about the reflux temperature, which produce the
desired products of formula I. Any of the suitable methods for
reducing amides known to those skilled in the art that will not
affect other functionalities present in the target compound are
appropriate for use in this transformation. In reference to Schemes
X and XI reagents 21, 22 and 23 can be prepared using methods that
are readily known to one of ordinary skill in the art.
The subject invention also includes isotopically-labeled compounds,
which are identical to those recited in formula I, but for the fact
that one or more atoms are replaced by an atom having an atomic
mass or mass number different from the atomic mass or mass number
usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous fluorine, iodine,
and chlorine, such as .sup.3II, .sup.11C, .sup.14C, .sup.18F,
.sup.123I and .sup.125I. Compounds of the subject invention and
pharmaceutically acceptable salts of said compounds that contain
the aforementioned isotopes and/or other isotopes of other atoms
are within the scope of this invention. Isotopically labeled
compounds of the subject invention, for example those into which
radio-active isotopes such as .sup.3H and .sup.14C are
incorporated, are useful in drug and/or substrate tissue
distribution assays. Tritiated, i.e., .sup.3H, and carbon-14, i.e.,
.sup.14C, isotopes are particularly preferred for their ease of
preparation and detectability. .sup.11C and .sup.18F isotopes are
particularly useful in PET (positron emission tomography), and
.sup.125I isotopes are particularly useful in SPECT (single photon
emission computerized tomography), all useful in brain imaging.
Further, substitution with heavier isotopes such as deuterium,
i.e., .sup.2H, can afford certain therapeutic advantages resulting
from greater metabolic stability, for example increased in vivo
half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically labeled compounds of
formula I of this invention can generally be prepared by carrying
out the procedures disclosed in the Schemes and/or in the Examples
above, by substituting a readily available isotopically labeled
reagent for a non-isotopically labeled reagent.
Accordingly, the subject invention also provides a compound of
formula I wherein one or more atoms thereof have an atomic mass or
mass number different from the atomic mass or mass number usually
found in nature, or a pharmaceutically acceptable salt of such
compound. The subject invention also provides a method for
obtaining an image of opioid receptors in a mammalian, including a
human, subject which method comprises administering to said subject
an amount of an isotopically-labeled compound of formula I, or
pharmaceutically acceptable salt thereof, effective in imaging
opioid receptors in said subject.
Pharmaceutically acceptable salts of a compound of formulas I or II
can be prepared in a conventional manner by treating a solution or
suspension of the corresponding free base or acid with a
pharmaceutically acceptable acid or base. Conventional
concentration or crystallization techniques can be employed to
isolate the salts. Illustrative of suitable acids are acetic,
lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic,
benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric,
hydrobromic, hydroiodic, sulfamic, sulfonic acids such as
methanesulfonic, benzene sulfonic, p-toluene-sulfonic, and related
acids. Illustrative bases are sodium, potassium, and calcium.
A compound of this invention may be administered alone or in
combination with pharmaceutically acceptable carriers, in either
single or multiple doses. Suitable pharmaceutical carriers include
inert solid diluents or fillers, sterile aqueous solutions and
various organic solvents. The pharmaceutical compositions formed by
combining a compound of formula I or a pharmaceutically acceptable
salt thereof can then be readily administered in a variety of
dosage forms such as tablets, powders, lozenges, syrups, injectable
solutions and the like. These pharmaceutical compositions can, if
desired, contain additional ingredients such as flavorings,
binders, excipients and the like. Thus, for purposes of oral
administration, tablets containing various excipients such as
sodium citrate, calcium carbonate and calcium phosphate may be
employed along with various disintegrants such as starch,
methylcellulose, alginic acid and certain complex silicates,
together with binding agents such as polyvinylpyrrolidone, sucrose,
gelatin and acacia. Additionally, lubricating agents such as
magnesium stearate, sodium lauryl sulfate and talc are often useful
for tabletting purposes. Solid compositions of a similar type may
also be employed as fillers in soft and hard filled gelatin
capsules. Preferred materials for this include lactose or milk
sugar and high molecular weight polyethylene glycols. When aqueous
suspensions or elixirs are desired for oral administration, the
essential active ingredient therein may be combined with various
sweetening or flavoring agents, coloring matter or dyes and, if
desired, emulsifying or suspending agents, together with diluents
such as water, ethanol, propylene glycol, glycerin and combinations
thereof.
For parenteral administration, solutions containing a compound of
this invention or a pharmaceutically acceptable salt thereof in
sesame or peanut oil, aqueous propylene glycol, or in sterile
aqueous solution may be employed. Such aqueous solutions should be
suitably buffered if necessary and the liquid diluent first
rendered isotonic with sufficient saline or glucose. These
particular aqueous solutions are especially suitable for
intravenous, intramuscular, subcutaneous and intraperitoneal
administration. The sterile aqueous media employed are all readily
available by standard techniques known to those skilled in the
art.
A compound of formula I or a pharmaceutically acceptable salt
thereof can be administered orally, transdermally (e.g., through
the use of a patch), parenterally (e.g. intravenously), rectally,
topically, or by inhalation. In general, the daily dosage for
treating a disorder or condition as described herein using a
compound of formula I will be about from about 0.01 to about 100 mg
per kg, preferably from about 0.1 to about 10 mg per kg, of the
body weight of the animal to be treated. As an example, a compound
of the formula I, or a pharmaceutically acceptable salt thereof,
can be administered for treatment to an adult human of average
weight (about 70 kg) in a dose ranging from about 0.5 mg up to
about 10 g per day, preferably from about 1 mg to about 1 g per
day, in single or divided (i.e., multiple) portions. Variations
based on the aforementioned dosage ranges may be made by a
physician of ordinary skill taking into account known
considerations such as the weight, age, and condition of the animal
being treated, the severity of the affliction, and the particular
route of administration chosen.
Biological Activity
Compounds of formula I of the subject invention have been found to
display activity in opioid receptor binding assays selective for
the mu, kappa and delta opioid receptors. Assays for mu, kappa and
delta opioid receptor binding can be performed according to the
following procedures.
Affinity of a compound for the delta opioid receptor can be
assessed using binding of the delta opioid receptor ligand
[.sup.3H]-naltrindole to NG108-15 neuroblastoma-glioma cells
according to modification of the protocol described in Law et al.
(Law, P. Y., Koehler, J. E. and Loh, H. H., "Comparison of Opioid
Inhibition of Adenylate Cyclase Activity in Neuroblastoma N18TG2
and Neuroblastoma X Glioma NG108-15 Hybrid Cell Lines", Molecular
Pharmacology, 21: 483-491 (1982)). Law et al. is incorporated
herein in its entirety by reference. Affinity of a compound for the
kappa opioid receptor can be assessed using binding of
[.sup.3H]-bremazocine to kappa receptors as described in Robson, L.
E., et al., "Opioid Binding Sites of the Kappa-type in Guinea-pig
Cerebellum", Neuroscience (Oxford), 12(2): 621-627 (1984). Robson
et al. is incorporated herein it its entirey by reference. For
assessment of a compound for mu opioid receptor activity, the mu
receptor ligand [.sup.3H]-DAMGO (Perkin Elmer Life Sciences,
Boston, Mass.; specific activity 55 Ci/mmol, 1.5 nM) is used with
rat forebrain tissue. Briefly, the binding is initiated with the
addition of a crude membrane preparation of rat forebrain tissue to
96-well polypropylene plates containing the radioligand
[.sup.3II]-DAMGO and test compound, and are incubated for about 90
minutes at about 25.degree. C. The assay is terminated by rapid
filtration with 50 mM Tris HCl pH 7.4 onto Wallac Filtermat B and
counted on a Betaplate reader (Wallac).
The data generated can be analyzed using IC.sub.50 analysis
software in Graphpad Prism. Ki values can be calculated using
Graphpad Prism according to the following formula:
Ki-IC.sub.50/1+[.sup.3H ligand]/K.sub.D
where lC.sub.50 is the concentration at which 50% of the .sup.3H
ligand is displaced by the test compound and K.sub.D is the
dissociation constant for the .sup.3H ligand at the receptor
site.
The Ki values of certain compounds of formula 1 of the Examples, as
described, infra, in a mu opioid receptor binding assay to brain
tissue such as that described above, were determined. All of the
compounds tested in this manner were all found to have Ki values of
about 800 nM or less for the mu opioid receptor.
The inhibition (%) of [.sup.3H]-DAMGO binding by certain compounds
of formula I of the Examples, as described, infra, in a mu opioid
receptor binding assay to brain tissue such as that described
above, were determined. Most of the compounds tested at 100 nM were
found to inhibit [.sup.3H]-DAMGO binding at the mu opioid receptor
in a range of 10-100%.
Other assays which may be used for determining the binding of
compounds according to the present invention to opioid receptors
are well known in the art. These assays may be used to assess the
ability of a compound to modulate (i.e., inhibit, partially
inhibit, activate or partially activate) an opioid receptor or
receptors by determining a compound's agonist or antagonist
activity in the in vitro or in vivo assay. These assays include,
for example, the GTP gamma S binding assay as described in Martin,
et al., J. Pharm. Exp. Ther., 301, 661-671 (2003) and Zaki, et al.,
J. Pharm. Exp. Ther., 298, 1015-1020 (2002), as well as other
binding assays, such as the isolated guinea pig ileum and receptor
binding assay as disclosed, for example, by Takayama, et al., J.
Med. Chem., 45, 1949-1956 (2002) and the guinea pig brain binding
assay as described by Wentland, et al., J. Med. Chem., 46, 838-849
(2003). The use of mouse brain tissue to determine the functional
activity of the compounds of interest is another binding assay
which can be used for characterizing the modulation of the present
compounds at opioid receptors, as disclosed by Martin, et al.,
Idem. Other binding assays include the tail-flick assay in mice or
the radiant heat paw-withdrawal hyperalgesic testing in mice, as
described by Hosohata, et al., J. Pharm. Exp. Ther., 304, 683-688
(2003), among others. These assays or variations of these assays
are well-known to those of ordinary skill in the art.
EXAMPLES
Preparation 1
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenol
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.55 (m, 2H), 7.46 (m,
3H), 7.10 (t, J=7.9 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.74 (dd,
J=2.1, 0.8 Hz, 1H), 6.61 (dd, J=7.9, 1.6 Hz, 1H), 4.42 (s, 2H),
3.70 (m, 2H), 3.36 (m, 1H), 2.42 (m, 1H), 2.31 (brd, J=14.5 Hz,
1H), 2.23 (m, 1H), 2.20-210 (m, 3H), 1.94 (m, 1H), 1.84 (m, 2H),k
1,70 (m, 1H); .sup.13C NMR (100 MHz, HCl salt, DMSO.sub.d6) .delta.
.quadrature.157.9, 151.8, 131.8, 130.9, 129.9, 129.9, 129.5, 129.4,
115.8, 113.6, 112.3, 56.9, 53.7, 49.6, 37.4, 35.1, 34.2, 34.0,
21.9, 21.2; APCl MS m/z 308.3 (M+1).sup.+.
Trifluoro-methanesulfonic acid
3-(2-benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl ester
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenol (31.51 g, 102
mmol) was dissolved in CH.sub.2Cl.sub.2 (250 mL) with triethylamine
(20 mL, 143 mmol) and N-phenyltrifluoromethanesulfonimide (43.94 g,
123 mmol). The reaction was judged complete by TLC after 18 h, then
quenched with saturated aqueous NaHCO.sub.3 solution (100 mL). The
product was extracted with CH.sub.2Cl.sub.2 (3.times.100 mL),
washed with water (200 mL), saturated aqueous NaCl solution (200
mL), dried through a cotton plug and concentrated to an oil. This
was filtered through a silica pad (6.times.6 in), eluted with
15-20% EtOAc/hexanes and concentrated to a semi-solid (37.4 g,
83%). (TLC 25% EtOAc/hexanes R.sub.f 0.30); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.46 (m, 2H), 7.34 (m, 3H), 7.28 (m, 1H), 7.13
(m, 1H), 7.08 (m, 1H), 6.95 (m, 1H), 3.90 (AB q, .DELTA.AB=14.8,
J=13.3 Hz, 2H), 3.27 (m, 1H), 3.16 (m, 1H), 3.04 (m, 1H), 2.22 (m,
2H), 2.03 (m, 4H), 1.81 (br d. J=12.9 Hz, 1H), 1.76 (m, 1H), 1.60
(m, 1H), 1.44 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
.quadrature. 154.4, 149.9, 130.2, 129.7, 129.0, 128.8, 128.0,
125.2, 125.1, 128.3, 118.2, 59.5, 52.4, 49.3, 38.1, 37.7, 36.5,
35.2, 24.2, 22.4; APCl MS m/z 440.1 (M+1).sup.+.
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenylamine
Trifluoro-methanesulfonic acid
3-(2-benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl ester (13.33 g,
30.33 mmol) was azeotroped with THF (2.times.50 mL) then dissolved
in anhydrous THF (150 mL) with benzophenone imine (6.3 mL, 17.61
mmol), cesium carbonate (14.23 g, 43.67 mmol) and BlNAP (racemic,
1.89 g, 3.03 mmol). The reaction vessel was degassed (evac./N.sub.2
purge 3.times.) before charging with palladium (11) acetate (410
mg, 1.82 mmol). The reaction was warmed to 80.degree. C. for 18 h,
at which point it was judged incomplete by APCl MS. After cooling
additional BlNAP (racemic, 1.89 g, 3.03 mmol) and palladium (11)
acetate (410 mg, 1.82 mmol) were introduced and the reaction was
warmed to 80.degree. C. for 60 h. at which point it was judged
complete by APCl MS. The reaction was cooled and filtered through
Celite, rinsed with THF and concentrated. The resulting oil was
dissolved in CH.sub.2Cl.sub.2 (200 mL), washed with water (100 mL)
and saturated aqueous NaCl solution (100 mL), dried through a
cotton plug and concentrated to give the crude product. To this was
added fresh THF (150 mL) followed by 2N HCl (150 mL) and this
stirred solution was warmed to 65.degree. C. for 60 min then at
room temperature for 18 h. The reaction mixture was treated with
hexanes (150 mL). The resulting orange solid is filtered. (On
occasion an orange gum separates and is separated by decantation or
filtration.) The biphasic filtrate was separated and the hexane
layer discarded. The aqueous layer was extracted with Et.sub.2O
(150 mL) and the Et.sub.2O layer discarded. The aqueous layer was
then neutralized with 25% aqueous NaOH solution to achieve pH 9 and
the product was extracted with CH.sub.2Cl.sub.2 (5.times.40 mL),
washed with saturated aqueous NaCl solution (1.times.30 mL), dried
over Na.sub.2SO.sub.4 and concentrated to give the crude product.
Flash chromatography provided the title compound as a thick yellow
oil (3.36 g, 36%). (TLC 50% EtOAc/hexanes R.sub.f 0.30); .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.24 (m, 2H), 7.36 (m, 2H), 7.26
(m, 2H), 7.07 (t, J=7.9 Hz, 1H), 6.71 (dd, J=7.9, 1.6 Hz, 1H). 6.64
(m, 1H), 6.50 (dd, J=7.9, 2.0 Hz, 1H), 3.80 (m, 2H), 3.61 (m, 1H),
3.15 (m, 2H), 2.80 (m, 1H), 2.17 (br d, J=14.2 Hz, 2H), 2.00 (m,
3H), 1.79 (br d, J=12.5 Hz, 1H), 1.72 (m, 1H), 1.64 (m, 1H), 1.38
(m, 1H); APCl MS m/z 307.1 (M+1).sup.+.
2-Methoxy-ethanesulfonic acid
[3-(2-benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenylamine (2.71 g, 8.84
mmol) stirred in pyridine (25 ml) at 0.degree. C. was charged with
2-methoxy-ethanesulfonyl chloride (2.1 g, 13.26 mmol) dropwise
causing a color change from yellow to bright orange. The reaction
was allowed to warm to room temperature gradually and stirred 18 h.
The reaction mixture was diluted with toluene and concentrated in
vacuo. The residue was dissolved in CH.sub.2Cl.sub.2 and washed
with saturated aqueous NaHCO.sub.3 solution (100 mL). The aqueous
layer was extracted with CH.sub.2Cl.sub.2 (2.times.50 ml) and the
organic layer was concentrated to an oil. This was dissolved in
EtOAc which caused an oil to separate. The EtOAc layer was
separated and washed with saturated aqueous NaHCO.sub.3 solution
(100 mL). The aqueous layer was extracted with EtOAc (2.times.50
ml) and the combined organic layer was washed with saturated
aqueous NaCl solution (50 ml), dried over Na.sub.2SO.sub.4,
filtered and concentrated to a crude orange liquid (3.77 g,
.about.100%). (TLC 75% EtOAc/hexanes R.sub.f 0.48);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.31 (t, J=7.9 Hz, 1H),
7.28-7.15 (m, 6H), 7.14 (br d, J=7.9 Hz, 1H), 7.03 (br d, J=7.9 Hz,
1H), 3.82 (m, 1H), 3.80 (dd, J=5.3, 4.6 Hz, 2H), 3.39 (s, 3H), 3.37
(m, 1H), 3.18 (dd, J=5.3, 4.6 Hz, 2H), 2.30-1.45 (m, 10H); .sup.13C
NMR (100 MHz, CDCl.sub.3) .delta. 154.0, 137.0, 129.3, 129.1,
128.5, 127.1, 122.4, 119.5, 119.2, 67.0, 60.1, 59.4, 52.3, 50.0,
49.4, 38.8, 38.7, 37.4, 35.3, 25.0, 23.0.
5-[3-(2-Methoxy-ethanesulfonylamino)-phenyl]-2-aza-bicyclo[3.3.1]nonane-2--
carboxylic acid tert-butyl ester
2-Methoxy-ethanesulfonic acid
[3-(2-benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide
(3.41 g, 7.96 mmol) was dissolved in EtOAc (20 ml), charged with
2.5 N HCl/EtOAc (6 ml), stripped in vacuo then azeotroped with MeOH
(2.times.50 ml) to yield the HCl salt. This salt was dissolved in
MeOH (30 ml). In a separate vessel, MeOH (10 mL) and piperidine
(3.9 mL, 39.8 mmol) were stirred at 0.degree. C. and treated with
formic acid (0.92 mL, 23.88 mmol) dropwise. This solution was added
to the mixture in the first vessel. To the combined mixture was
added 20% Pd(OH).sub.2/C (680 mg) and the resulting mixture was
stirred and heated under reflux at 65.degree. C. for 18 h. The
reaction was not complete (TLC) at this time. Heating was continued
for an additional 60 h at which time it was deemed complete by TLC
analysis. The reaction was filtered through a Celite pad and
concentrated to afford the crude product that was dissolved in
CH.sub.2Cl.sub.2 (40 mL) and saturated aqueous Na.sub.2CO.sub.3
solution (40 mL) and cooled to 0.degree. C. This was treated with
t-Boc.sub.2O (di-tert-butyldicarbonate, 2.08 g, 9.55 mmol) in
CH.sub.2Cl.sub.2 (10 mL) dropwise and the mixture was vigorously
stirred for 18 h at ambient temperature. Dilute HCl solution was
added to achieve pH 9 and the mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.40 mL). The organic layer was washed with
saturated aqueous NaCl solution (50 mL), dried through a cotton
plug and concentrated to a red oil. This was chromatographed on
silica gel eluting with 10 to 30% EtOAc/hexanes to provide product
as a clear oil (2.44 g, 70%). (TLC 50% EtOAc/hexanes R.sub.f 0.42);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.23 (t, J=7.9 Hz, 1H),
7.18 (br s, 1H), 7.12 (br d, J=7.9 Hz, 1H), 7.03 (br d, J=7.9 Hz,
1H), 6.35 (s, NH), 4.31 (m, 1H), 3.81 (t, J=5.6 Hz, 2H), 3.61 (m,
2H), 3.40 (s, 3H), 3.19 (t, J=5.6 Hz, 2H), 2.10 (m, 2H), 1.95 (m,
2H), 1.82 (m, 2H), 1.82 (m, 2H), 1.65 (m, 1H), 1.50-1.35 (m, 3H),
1.44 (s, 9H); APCl MS m/z 424.1 (M-14).sup.+.
2-Methoxy-ethanesulfonic acid
[3-(2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide
5-[3-(2-Methoxy-ethanesulfonylamino)-phenyl]-2-aza-bicyclo[3.3.1]nonane-2-
-carboxylic acid tert-butyl ester (2.42 g, 5.52 mmol) in EtOAc (30
mL) was charged with 2.5 N HCl/EtOAc (30 ml) and the resulting
mixture was heated under reflux 18 h. The mixture was stripped in
vacuo to yield the HCl salt as a white foam (1.56 g, 83%). .sup.1H
NMR (400 MHz, CD.sub.3OD, HCl salt) .delta. 7.28 (t, J=7.9 Hz, 1H),
7.25 (m, 1H), 7.14 (m, 1H), 7.10 (m, 1H), 3.87 (br s, 1H), 3.72 (t,
J=5.8 Hz, 2H), 3.71 (m, 1H), 3.27 (t, J=5.8 Hz, 2H) , 3.25 (s, 3H),
2.34 (m, 1H), 2.18 (m, 5H), 1.98-1.78 (m, 3H), 1.64 (m, 1H);
.sup.13C NMR (100 MHz, CD.sub.3OD) .delta. 151.1, 138.4, 129.4,
120.7, 118.6, 117.1, 66.3, 57.9, 50.4, 48.9, 40.5, 36.9, 34.1,
33.8, 33.6, 25.6, 20.7.
Preparation 2
N-[3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamide
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenylamine (3.37 g, 9.24
mmol) in pyridine (30 ml) at 0.degree. C. was charged with
methanesulfonylchloride 1.3 ml, 16.5 mmol) dropwise, causing a
color change from yellow to bright orange. The reaction was warmed
to room temperature and judged complete by TLC after 3 h. The
mixture was diluted with toluene and stripped twice. Following a
water quench (20 ml), the product was extracted with EtOAc
(4.times.30 ml), washed with saturated aqueous NaHCO.sub.3 solution
(6.times.30 ml) and with saturated aqueous NaCl solution
(3.times.30 ml), dried over Na.sub.2SO.sub.4, filtered and
concentrated to a crude orange liquid. Flash chromatography on
silica gel eluting with 2 to 5% MeOH/CH.sub.2Cl.sub.2 provided the
title compound as orange oil (3.59 g, 85%). (TLC 5%
MeOH/CH.sub.2Cl.sub.2 R.sub.f 0.24); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.37-7.19 (m, 7H), 7.11 (br d, J=7.9 Hz, 1H),
7.05 (ddd, J=7.9, 2.1, 0.8 Hz, 1H), 3.73 (AB q, .DELTA.AB 59.9,
J=13.3 Hz, 2H), 3.71 (m, 1H), 3.09 (br, s, 1H), 3.04 (m, 1H), 2.94
(s, 3H), 2.80 (m, 1H), 2.18 (m, 2H), 2.07-1.95 (m, 4H), 1.82 (br d,
J=12.0 Hz, 1H), 1.72 (m, 1H), 1.57 (m, 1H), 1.17 (m, 1H). .sup.13C
154.2, 137.1, 132.3, 129.5, 129.4, 129.1, 128.6, 128.4, 127.1,
122.0, 118.3, 117.9, 60.1, 52.3, 49.4, 39.3, 38.9, 38.7, 37.4,
35.8, 24.9, 23.0; APCl MS m/z 385.1 (M+1).sup.+.
5-(3-Methanesulfonylamino-phenyl)-2-aza-bicyclo[3.3.1]nonane-2-carboxylic
acid tert-butyl ester
N-[3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamide
(3.32 g, 8.63 mmol) (3.41 g, 7.96 mmol) was dissolved in EtOAc (20
ml), charged with 2.5 N HCl/EtOAc (6 ml), stripped in vacuo then
azeotroped with MeOH (2.times.50 ml) to yield the HCl salt. This
salt was dissolved in MeOH (30 ml). In a separate vessel, MeOH (10
mL) and piperidine (4.3 mL, 43.15 mmol) were stirred at 0.degree.
C. and treated with formic acid (0.99 mL, 25.89 mmol) dropwise.
This solution was added to the mixture in the first vessel. To the
combined mixture was added 20% Pd(OH).sub.2/C (660 mg) and the
resulting mixture was stirred and heated under reflux at 65.degree.
C. for 60 h at which time it was deemed complete by TLC analysis.
The reaction was filtered through a Celite pad and concentrated to
afford the crude product that was dissolved in CH.sub.2Cl.sub.2 (40
mL) and saturated aqueous Na.sub.2CO.sub.3 solution (40 mL) and
cooled to 0.degree. C. This was treated with t-Boc.sub.2O
(di-tert-butyldicarbonate, 2.26 g, 10.36 mmol) in CH.sub.2Cl.sub.2
(10 mL) dropwise and the mixture was vigorously stirred for 2 h at
ambient temperature. The reaction was deemed incomplete at this
time and was treated with t-Boc.sub.2O (di-tert-butyldicarbonate,
950 mg, 4.32 mmol) in CH.sub.2Cl.sub.2 (10 mL) dropwise and the
mixture was vigorously stirred for 18 h. Dilute HCl solution was
added to achieve pH 9 and the mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.40 mL). The organic layer was washed with
saturated aqueous NaCl solution (50 mL), dried through a cotton
plug and concentrated to an oil. This was chromatographed on silica
gel eluting with a gradient from 5 to 25% EtOAc/hexanes to provide
product as a clear oil (1.18 g, 35%). (TLC 50% EtOAc/hexanes
R.sub.f 0.39); APCl MS m/z 336.2 (M-57).sup.+; 380.2
(M-14).sup.+.
N-[3-(2-Aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamide
5-(3-Methanesulfonylamino-phenyl)-2-aza-bicyclo[3.3.1]nonane-2-carboxylic
acid tert-butyl ester (1.07 g, 2.71 mmol) in EtOAc (10 ml) was
charged with 2.5 N HCl/EtOAc (10 ml) and the resulting mixture was
heated under reflux 18 h. The mixture was stripped in vacuo and
recrystallized from MeOH/Et.sub.2O to yield the HCl salt (0.64 g,
71%). .sup.1H NMR (400 MHz, CD.sub.3OD, HCl salt) .delta. 7.30 (t,
J=7.9 Hz, 1H), 7.25 (t, J=2.0 Hz, 1H), 7.15 (ddd, J=7.9, 2.0, 0.8
Hz, 1H), 7.09 (ddd, J=7.9, 2.0, 0.8 Hz, 1H), 3.86 (br s, 1H), 3.72
(m, 1H), 3.27 (m, 2H), 2.91 (s, 3H), 2.35 (m, 1H), 2.18 (m, 5H),
1.91 (m, 3H), 1.67 (m, 1H); APCl MS m/z 295.2 (M+1).sup.+.
Preparation 3
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzonitrile
Trifluoro-methanesulfonic acid
3-(2-benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl ester (5.00 g,
11.4 mmol) and zinc cyanide (1.47 g, 12.5 mmol) were combined in
DMF (110 ml), degassed (evac./N.sub.2 purge 3.times.) then charged
with tetrakis(triphenylphosphine) palladium (0) (1.8 g, 1.60 mmol).
The resulting reaction mixture was heated to 85.degree. C. in an
oil bath for 6 h. Upon cooling to room temperature, the reaction
mixture was filtered through a Celite pad and rinsed with EtOAc
(200 ml). The filtrate was washed with water and saturated aqueous
NaCl solution (1.times.200 ml each), dried over Na.sub.2SO.sub.4,
filtered, and concentrated and chromatographed on silica gel
eluting with 50% EtOAc/hexanes to provide an oil (1.95 g, 54%).
(TLC 50% EtOAc/hexanes R.sub.f 0.28); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.49-7.52 (m, 2H), 7.45-7.48 (m, 3H), 7.35-7.39
(m, 2H), 7.10-7.14 (m, 1H), 7.00-7.02 (m, 1H), 3.98 (ABq,
.quadrature.AB=48.9 Hz, J=13.0 Hz, 2H), 3.31--3.33 (m, 1H),
3.16-3.21 (m, 2H), 2.21-2.25 (m, 2H), 1.95 2.07 (m, 4H), 1.76 1.80
(m, 2H), 1.41 1.59 (m, 2H); APCl MS m/z 317.2 (M+1).sup.+.
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzonitrile (1.95 g,
6.16 mmol) in DMSO (55 ml) was charged with potassium carbonate
(120 mg, 0.86 mmol) then 30% aqueous hydrogen peroxide (3.2 ml,
30.8 mmol). The reaction mixture was allowed to stir at room
temperature for 23 h at which time it was determined not to have
proceeded. Additional potassium carbonate (850 mg, 6.16 mmol) and
30% aqueous hydrogen peroxide (6.4 ml, 61.6 mmol) were introduced
and stirred for 5.5 h. After a water quench (50 ml), the product
was extracted with EtOAc (3.times.50 ml), washed with 50% saturated
aqueous NaCl solution (5.times.50 ml), dried over Na.sub.2SO.sub.4,
filtered and concentrated to a white solid which was triturated
with hexanes and collected (1.0 g, 49%). (TLC 50% EtOAc/hexanes
R.sub.f 0.08); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.83-7.85
(m, 1H), 7.49-7.57 (m, 1H), 7.40-7.47 (m, 1H), 7.38 7.28 (m, 5H),
7.21 7.25 (m, 1H), 6.10 (brs, 1H), 5.63 (brs, 1H); 3.74-3.82 (m,
2H), 3.06-3.15 (m, 2H), 2.86-2.96 (m, 1H), 2.16 2.26 (m, 2H), 1.96
2.08 (m, 4H), 1.84-1.89 (m, 1H), 1.68 1.74 (m, 1H), 1.59 1.65 (m,
1H), 1.34-1.42 (m, 1H): APCl MS m/z 335.1 (M+1).sup.+.
3-(2-Aza-bicyclo[3.3.1]non-5-yl)-benzamide
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide (920 mg, 2.61
mmol) was dissolved in EtOAc (20 ml), charged with 2.5 N HCl/EtOAc
(6 ml), then azeotroped with MeOH (2.times.50 ml) to yield the HCl
salt. This salt was dissolved in MeOH (20 ml) in a 500 ml Parr
bottle. To this was added 20% Pd(OH).sub.2/C (Pearlman's catalyst,
180 mg) and the mixture was shaken under 45 psi of H.sub.2 for 4 h
or until judged complete by TLC. The reaction was filtered through
a Celite pad and concentrated to a yellow solid (1.0 g, >100%).
.sup.1H NMR (400 MHz, CD.sub.3OD, HCl salt) .delta. 7.86-7.88 (m,
1H), 7.72-7.74 (m, 1H), 7.55-7.57 (m, 1H), 7.42 (t, J=7.88 Hz, 1H),
3.87 (brs, 1H), 3.71-3.73 (m, 1H), 3.28-3.31 (m, 1H), 2.35-2.37 (m,
1H), 2.13-2.25 (m, 5H), 1.81-1.96 (m, 4H); APCl MS 245.1
(M+1).sup.+. ##STR00020##
General Procedure for the Reductive Alkylation of Compounds of
Formula 1 R.sup.a=H
A compound of the general formula 1 where R.sup.a=H in
dichloromethane or dichloroethane (0.2 M) at room temperature was
treated with an appropriate aldehyde of formula (1.2 equiv),
glacial acetic acid (catalytic .about.2 drops) and sodium
triacetoxyborohydride (1.5 equiv). The reaction mixture was stirred
at room temperature for up to 24 h. The mixture was concentrated in
vacuo and the resulting crude material was purified by flash
chromatography to yield the desired tertiary amines in 40 95%.
The following compounds were made using the above procedure,
starting with the appropriate starting amine and the appropriate
corresponding aldehyde reagent.
Furthermore, pharmaceutically acceptable salts of the compounds
listed below can be prepared as follows. To a stirring solution of
compounds of the general formula 1 (prepared as described above,
1.0 equiv) in a suitable solvent such as methyl ethyl ketone,
dichloromethane/methanol (1:1) or methanol (0.1 M) at room
temperature was added the appropriate acid, such as citric acid,
p-toluenesulfonic acid, methanesulfonic acid or benzene sulfonic
acid (1.0 equiv) in one portion. The resulting mixture was stirred
at room temperature for up to 18 h, during which time a precipitate
formed. Filtration of the solid and drying under reduced pressure
afforded the desired salts.
Example 1
N-[3-(2-Cyclopropylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesul-
fonamide
.sup.1H NMR (400 MHz, CD.sub.3OD, HCl salt) .delta. 7.30 (t, J=7.9
Hz, 1H), 7.26 (m, 1H), 7.15 (dd, J=7.9, 2.1 Hz, 1H), 7.07 (m, 1H),
3.97 (br s, 1H), 3.58 (m, 2H), 3.27 (m, 1H), 3.01 (dd, J=13.3, 8.2
Hz, 1H), 2.91 (s, 3H), 2.40 1.62 (m, 1OH), 1.84 (m, 1H), 0.74 (m,
2H), 0.45 (m, 2H); APCl MS m/z 349.2 (M+1).sup.+.
Example 2
N-(3-{2-[3-(1-Hydroxy-cyclohexyl)-propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-ph-
enyl)-methanesulfonamide
.sup.1H NMR (400 MHz, CD.sub.3OD, Citrate salt) .delta. 7.28 (t,
J=7.9 Hz, 1H), 7.23 (m, 1H), 7.14 (dd, J=7.9, 0.8 Hz, 1H), 7.09
(dd, J 7.9, 1.3 Hz, 1H), 3.84 (br s, 1H), 3.54 (m, 2H), 3.17 (m,
2H), 2.91 (m, 3H), 2.76 (AB q, AB .DELTA. 27.9, J 15.8 Hz, 4H),
2.31-2.00 (m, 5H), 1.82 (m, 3H), 1.70-1.23 (m, 8H).
##STR00021##
General Procedure for the Alkylation of Compounds of Formula 1
where R.sup.a=H
A compound of formula 1 where R.sup.a=H in ethanol (0.1 M) at room
temperature was treated with triethylamine (3.0 equiv) and the
appropriate alkylation reagent (1.2 equiv). The resulting mixture
was heated to 80.degree. C. for 1-5 h and then cooled to room
temperature. The mixture was concentrated in vacuo and the
resulting crude material was purified by flash chromatography to
yield the desired tertiary amines in 50-90% yield
The following compounds were made using the above procedure,
starting with the appropriate starting amine and the appropriate
alkylation reagent.
Furthermore, pharmaceutically acceptable salts of the compounds
listed below can be prepared as follows. To a stirring solution of
compounds of the general formula 1 (prepared as described above,
1.0 equiv) in a suitable solvent such as methyl ethyl ketone,
dichloromethane/methanol (1:1) or methanol (0.1 M) at room
temperature was added the appropriate acid, such as citric acid,
p-toluenesulfonic acid, methanesulfonic acid or benzene sulfonic
acid (1.0 equiv) in one portion. The resulting mixture was stirred
at room temperature for up to 18 h, during which time a precipitate
formed. Filtration of the solid and drying under reduced pressure
afforded the desired salts.
Example 3
N-{3-[2-(2-Hydroxy-indan-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-
-methanesulfonamide
.sup.1H NMR (400 MHz, CD.sub.3OD 27.9 salt) .delta. 7.29 (t, 7.9
Hz, 1H), 7.25 (m, 1H), 7.26-7.07 (m, 6H), 3.88 (br s, 1H), 3.57 (m,
1H), 3.49-3.39 (m, 3H), 3.18 (AB d, J=16.2 Hz, 2H), 3.08 (AB dd,
J=16.2, 4.1 Hz, 2H), 2.91 (s, 3H), 2.70 (AB q, .DELTA.AB=27.9,
J=15.4 Hz, 2H), 2.44 (m, 1H), 2.36 (m, 1H), 2.25 (m, 1H), 2.14 (m,
3H), 1.83 (m, 2H), 1.71 (m, 1H); APCl MS m/z 441.2 (M+1).sup.+.
General Procedure (a) for the Reductive Alkylation of Salts of
Compounds of Formula 1 (R.sup.a--H)
An appropriate aldehyde (2.0 equiv) in dichloroethane (0.1 M) at
room temperature was treated with triethylamine (4.0 equiv) and an
amine of formula 1 R.sup.a=H (1 equiv) as the HCl salt. The
reaction vessel was sealed and briefly shaken to mix these
materials. The vessel was then opened and sodium
triacetoxyborohydride (approximately 2.0 or more equiv) was
introduced. The reaction vessel was again sealed then briefly
vortexed. The reaction vessel was then shaken at room temperature
for up to 24 h. The mixture was then quenched with the addition of
1 N NaOH (2.0 mL) and extracted with dichloromethane (3.times.2.45
mL). Each sequential extract was loaded onto SPE cartridges that
contained 1 g of preconditioned SCX adsorbent. (The SCX adsorbent,
"strong cation exchange modified silica", was preconditioned by
pre-eluting with methanol (1.times.5 mL) then dichloromethane
(2.times.5 mL). After the extract solutions were passed through the
adsorbent, the adsorbent was washed with methanol (5 mL). These
filtrates were eventually discarded. Crude product was then eluted
into separate tared collection vessels with 1 N triethylamine in
methanol (5 mL). The material was concentrated under a stream of
nitrogen and weighed. The resulting crude material was purified by
reverse phase HPLC to yield the desired tertiary amines.
The following compounds were made using the above procedure,
starting with the appropriate starting amine of formula 1
(R.sup.a=H) and the appropriate aldehyde reagent.
General Procedure (b) for the Reduction Alkylation of Salts of
Compounds of Formula 1 (R.sup.a=H)
An appropriate aldehyde (2.0 equiv) at room temperature was treated
with a slurry of an amine of formula 1 R.sup.a=H (1 equiv) as the
HCl salt in 9:1 dichloroethane:methanol. The reaction vessel was
sealed and briefly shaken to mix these materials. The vessel was
then opened and sodium triacetoxyborohydride (approximately 5.0 or
more equiv) was introduced. The reaction vessel was shaken at room
temperature for up to 24 h. The mixture was then quenched by the
addition of water (0.75 mL) and extracted with dichloromethane
(3.times.2.45 mL). Each sequential extract was loaded onto SPE
cartridges that contained 1 g of preconditioned SCX adsorbent. (The
SCX adsorbent, "strong cation exchange modified silica", was
preconditioned by pre-eluting with MeOH (1.times.5 mL) then
dichloromethane (2.times.5 mL). After the extract solutions were
passed through the adsorbent, the adsorbent was washed with
dichloromethane (5 mL) then methanol (5 mL). These filtrates were
eventually discarded. Crude product was then eluted into separate
tared collection vessels with 1N triethylamine in methanol (5 mL).
The material was concentrated under a stream of nitrogen and
weighed. The resulting crude material was purified by reverse phase
HPLC to yield the desired tertiary amines.
A number of compounds according to the present invention were made
using the above procedure, starting with the appropriate starting
amine of formula 1 R.sup.a=H and the appropriate aldehyde
reagent.
Furthermore, pharmaceutically acceptable salts of the compounds
described above can be prepared as follows. To a stirring solution
of compounds of the general formula 1 (prepared as described above,
1.0 equiv) in a suitable solvent such as methyl ethyl ketone,
dichloromethane/methanol (1:1) or methanol (0.1 m) at room
temperature was added the appropriate acid, such as citric acid,
p-toluenesulfonic acid, methanesulfonic acid or benzene sulfonic
acid (1.0 equiv) in one portion. The resulting mixture was stirred
at room temperature for up to 18 h, during which time a precipitate
formed. Filtration of the solid and drying under reduced pressure
afforded the desired salts. ##STR00022##
Alternative General Procedure for the Preparation of Compounds of
Formula 1.
To a stirring solution of 1.0 equiv of a compound of formula 1
where R.sup.a=H in anhydrous THF (0.1 M) at room temperature, was
added Et.sub.3N (5.0 equiv) or pyridine (5.0 equiv) and an
appropriately substituted acid chloride (2.0 equiv). After stirring
up to 24 h, the reaction was quenched by the addition of water and
diluted with methylene chloride. The layers were separated, the
aqueous layer was extracted with methylene chloride and the
combined organic layers were dried over anhydrous Na.sub.2SO.sub.4
and concentrated. The resulting crude material was purified through
flash chromatography, then carried onto the next step.
To a stirring solution of 1.0 equiv of the amide prepared above in
THF (0.2M) at room temperature was added lithium aluminum hydride
(4.0 equiv). The resulting mixture was stirred at room temperature
until judged complete by TLC. The reaction was cooled to 0.degree.
C. then carefully quenched by the slow addition of water (1.0 equiv
by mass relative to LAH), 10% NaOH (1.0 equiv by mass relative to
LAH) then water (3.0 equiv by mass relative to LAH). The resulting
slurry was stirred at room temperature for up to 16 hours. The
slurry was filtered and washed with THF. The resulting solution was
concentrated to yield crude material that was purified by flash
chromatography to afford the desired tertiary amines of formula
1.
The following compound was made using the above procedure, starting
with the appropriate starting amine of formula 1 and the
appropriate acid chloride reagent.
Furthermore, pharmaceutically acceptable salts of the compounds
listed below can be prepared as follows. To a stirring solution of
compounds of the general formula 1 (prepared as described above,
1.0 equiv.) in a suitable solvent such as methyl ethyl ketone,
methylene chloride/methanol (1:1) or methanol (0.1 M) at room
temperature was added the appropriate acid, such as citric acid,
p-toluenesulfonic acid, methansulfonic acid or benzene sulfonic
acid (1.0 equiv) in one portion. The resulting mixture was stirred
at room temperature for up to 18 h, during which time a precipitate
formed. Filtration of the solid and drying under reduced pressure
afforded the desired salts.
* * * * *