U.S. patent application number 09/761833 was filed with the patent office on 2001-09-13 for novel compounds with analgesic effect.
This patent application is currently assigned to Astra Pharma Inc.. Invention is credited to Delorme, Daniel, Roberts, Edward, Wei, Zhongyong.
Application Number | 20010021715 09/761833 |
Document ID | / |
Family ID | 26662830 |
Filed Date | 2001-09-13 |
United States Patent
Application |
20010021715 |
Kind Code |
A1 |
Delorme, Daniel ; et
al. |
September 13, 2001 |
Novel compounds with analgesic effect
Abstract
Compounds of general formula (I) 1 are disclosed and claimed in
the present application, as well as their pharmaceutically
acceptable salts, pharmaceutical compositions comprising the novel
compounds and their use in therapy, in particular in the management
of pain.
Inventors: |
Delorme, Daniel; (St.
Lazare, CA) ; Roberts, Edward; (St. Lazare de
Vaudreuil, CA) ; Wei, Zhongyong; (Pierrefonds,
CA) |
Correspondence
Address: |
Michael A. Sanzo
Pillsbury Winthrop LLP
East Tower, 9th Floor
1100 New York Ave. , N.W.
Washington
DC
20005-3918
US
|
Assignee: |
Astra Pharma Inc.
|
Family ID: |
26662830 |
Appl. No.: |
09/761833 |
Filed: |
January 18, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09761833 |
Jan 18, 2001 |
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09029633 |
Mar 5, 1998 |
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6187792 |
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09029633 |
Mar 5, 1998 |
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PCT/SE97/02050 |
Dec 9, 1997 |
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Current U.S.
Class: |
514/326 ;
514/317; 546/196; 546/205; 546/207 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 25/04 20180101; C07D 405/06 20130101; C07D 211/70 20130101;
C07D 401/06 20130101; C07D 211/46 20130101; A61P 25/00 20180101;
A61P 1/04 20180101; A61P 19/08 20180101 |
Class at
Publication: |
514/326 ;
514/317; 546/196; 546/207; 546/205 |
International
Class: |
A61K 031/445; C07D
211/06; C07D 401/00; C07D 405/00; C07D 411/00 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 20, 1996 |
SE |
9604785-7 |
Jul 1, 1997 |
SE |
9702535-7 |
Claims
1. A compound of the general formula (I) 70R.sup.1 is selected from
hydrogen, a branched or straight C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkenyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.4-C.sub.8(alkyl-cycloalkyl) wherein alkyl is C.sub.1-C.sub.2
alkyl and cycloalkyl is C.sub.3-C.sub.6 cycloalkyl;
C.sub.6-C.sub.10 aryl; or heteroaryl having from 5 to 10 atoms
selected from any of C, S, N and O; wherein the aryl and heteroaryl
may optionally and independently be substituted by 1 or 2
substituents independently selected from any of hydrogen, CH.sub.3,
--(CH.sub.2).sub.pCF.sub.3, halogen, --CONR.sup.5R.sup.4,
--COOR.sup.5, --COR.sup.5, --(CH.sub.2).sub.pNR.sup.5R.sup.4,
--(CH.sub.2).sub.pCH.sub.- 3(CH.sub.2).sub.pSOR.sup.5R.sup.4,
--(CH.sub.2).sub.pSO.sub.2R.sup.5, and
--(CH.sub.2).sub.pSO.sub.2NR.sup.5, wherein R.sup.4 and R.sup.5 is
each and independently as defined for R.sup.1 above and p is 0, 1
or 2; (C.sub.1-C.sub.2 alkyl)-(C.sub.6-C.sub.10 aryl); or
(C.sub.1-C.sub.2 alkyl)heteroaryl, the heteroaryl moieties having
from 5 to 10 atoms selected from any of C, S, N and O, and where
the aryl or heteroaryl may optionally and independently be
substituted by 1 or 2 substituents independently selected from any
of hydrogen, CH.sub.3, --(CH.sub.2).sub.qCF.sub.3, halogen,
--CONR.sup.5R.sup.4, --COOR.sup.5, --COR.sup.5,
--(CH.sub.2).sub.qNR.sup.5R.sup.4, --(CH.sub.2).sub.qCH.sub.-
3(CH.sub.2).sub.qSOR.sup.5R.sup.4,
--(CH.sub.2).sub.qSO.sub.2R.sup.5,
--(CH.sub.2).sub.qSO.sub.2NR.sup.5 and --(CH.sub.2).sub.pOR.sup.5,
wherein R.sup.4 and R.sup.5 is each and independently as defined
for R.sup.1 above and q is 0, 1 or 2; and 71wherein R.sup.18,
R.sup.19, R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24 and
R.sup.25 is each and independently hydrogen, C.sub.1-C.sub.6 alkyl
or C.sub.1-C.sub.6 alkenyl; R.sup.2 and R.sup.3 is each and
independently hydrogen or C.sub.1-C.sub.6 alkyl; A is selected from
72wherein R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13,
R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is each and independently
as defined for R.sup.1 above, and wherein the phenyl ring of each A
substituent may be optionally and independently substituted at any
position of the phenyl ring by 1 or 2 substituents Z.sup.1 and
Z.sup.2 which are each and independently selected from hydrogen,
CH.sub.3, --(CH.sub.2).sub.qCF.sub.3, halogen, --CONR.sup.6R.sup.7,
--COOR6, --COR.sup.6, --(CH.sub.2).sub.rNR.sup.6R.su- p.7,
--(CH.sub.2).sub.rCH.sub.3(CH.sub.2).sub.rSOR.sup.6,
--(CH.sub.2).sub.rSO.sub.2R.sup.6 and
--(CH.sub.2).sub.rSO.sub.2NR.sup.6R- .sup.7 wherein R.sup.6 and
R.sup.7 is each and independently as defined for R.sup.1 above and
r is 0, 1, or 2; Q is C.sub.5-C.sub.6 hydroaryl or
heterohydroaromatic having 5 or 6 atoms selected from anyone of C,
S, N and O; C.sub.5-C.sub.6 cykloalkyl, or heterocycloalkyl having
5 or 6 atoms selected from anyone of C, N, O and S; and where each
Q may optionally be substituted by a substituent Z.sup.1 and
Z.sup.2 as defined above; B is a substituted or unsubstituted
aromatic, heteroaromatic, hydroaromatic or heterohydroaromatic
moiety having from 5 to 10 atoms selected from any of C, S, N and
O, optionally and independently substituted by 1 or 2 substituents
independently selected from hydrogen, CH.sub.3,
--(CH.sub.2).sub.tCF.sub.3, halogen, --(CH.sub.2).sub.tCONR.sup-
.5R.sup.4, --(CH.sub.2).sub.tNR.sup.5R.sup.4,
--(CH.sub.2).sub.tCOR.sup.5, --(CH.sub.2).sub.tCOOR.sup.5,
--OR.sup.5, --(CH.sub.2).sub.tSOR.sup.5,
--(CH.sub.2).sub.tSO.sub.2R.sup.5, and
--(CH.sub.2)tSO.sub.2NR.sup.5R.sup- .4, wherein R.sup.4and R.sup.5
is each and independently as defined for R.sup.1 above, and t is 0,
1, 2 or 3; R.sup.4 and R.sup.5 is each and independently as defined
for R.sup.1 above; as well as pharmaceutically acceptable salts of
the compounds of the formula (I), and isomers, hydrates, isoforms
and prodrugs thereof.
2. A compound of the formula (I) according to claim 1, wherein A is
selected from 73wherein R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is
each and independently as defined for R.sup.1 above, and wherein
the phenyl ring of each A substituent may be optionally and
independently substituted at any position of the phenyl ring by 1
or 2 substituents Z.sup.1 and Z.sup.2 which are each and
independently selected from hydrogen, CH.sub.3,
--(CH.sub.2).sub.qCF.sub.3, halogen, --CONR.sup.6R.sup.7,
--COOR.sup.6, --COR.sup.6, --(CH.sub.2).sub.rNR.sup.6R.sup.7,
--(CH.sub.2).sub.rCH.sub.3(CH.sub.2).sub.rSOR.sup.6,
--(CH.sub.2).sub.rSO.sub.2R.sup.6 and
--(CH.sub.2).sub.rSO.sub.2NR.sup.6R- .sup.7 wherein R.sup.6 and
R.sup.7 is each and independently as defined for R.sup.1 above, and
r is 0, 1, or 2; Q is selected from morpholine, piperidine and
pyrrolidine; R.sup.1, R.sup.4, and R.sup.5 is each and
independently selected from hydrogen, a branched or straight
C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl, C.sub.4-C.sub.8
(alkyl-cycloalkyl) wherein alkyl is C.sub.1-C.sub.2 alkyl and
cycloalkyl is C.sub.3-C.sub.6 cycloalkyl; C.sub.6-C.sub.10 aryl;
and heteroaryl having from 5 to 6 atoms selected from any of C, S,
N and O; and where the aryl or heteroaryl may optionally and
independently be substituted by 1 or 2 substituents independently
selected from any of hydrogen, CH.sub.3,
--(CH.sub.2).sub.pCF.sub.3, halogen, --CONR.sup.5R.sup.4,
--COOR.sup.5, --COR.sup.5, --(CH.sub.2).sub.pNR.sup.5R.sup.4,
--(CH.sub.2).sub.pCH.sub.3(CH.sub.2).sub.pSOR.sup.5R.sup.4,
--(CH.sub.2).sub.pSO.sub.2R.sup.5, and
--(CH.sub.2).sub.pSO.sub.2NR.sup.5- , wherein R.sup.4 and R.sup.5
is each and independently as defined for R.sup.1 above and p is 0,
1 or 2; B is selected from phenyl, naphthyl, indolyl, benzofuranyl,
dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl,
isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl,
cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl,
tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl,
pyrrolidinyl, and indazolinyl, each optionally and independently
substituted by 1 or 2 substituents independently selected from
hydrogen, CH.sub.3, CF.sub.3, halogen,
--(CH.sub.2).sub.qCONR.sup.5R.sup.4,
--(CH.sub.2).sub.qNR.sup.5R.sup.4, --(CH.sub.2).sub.qCOR.sup.5,
--(CH.sub.2).sub.qCO.sub.2R.sub.5, and --OR.sup.5, wherein q is 0
or 1, and wherein R.sup.4 and R.sup.5 are as defined above; R.sup.2
and R.sup.3 is each and independently hydrogen or methyl.
3. A compound of the formula (I) according to claim 2, wherein
74wherein R.sup.8 and R.sup.9 are both ethyl, and where the phenyl
ring optionally and independently may be substituted at any
position of the phenyl ring by 1 or 2 substituents Z.sup.1 and
Z.sup.2 which are each and independently selected from hydrogen,
CH.sub.3, --(CH.sub.2).sub.qCF.sub.- 3, halogen,
--CONR.sup.6R.sup.7, --COOR.sup.6, --COR.sup.6,
--(CH.sub.2).sub.rNR.sup.6R.sup.7,
--(CH.sub.2).sub.rCH.sub.3(CH.sub.2).s- ub.rSOR.sup.6,
--(CH.sub.2).sub.rSO.sub.2R.sup.6 and
--(CH.sub.2).sub.rSO.sub.2NR.sup.6R.sup.7 wherein R.sup.6 and
R.sup.7 is each and independently as defined for R.sup.1 above and
r is 0, 1, or 2; R.sup.1 is selected from hydrogen, methyl, ethyl,
--CH.sub.2CH.dbd.CH.sub- .2, --CH.sub.2-cyclopropyl,
--CH.sub.2-aryl, or CH.sub.2-heteroaryl, the heteroaryl moieties
having from 5 to 6 atoms selected from any of C, S, N and O; B is
selected from phenyl, naphthyl, indolyl, benzofuranyl,
dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl,
isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl,
cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl,
tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, and
indazolinyl, each optionally and independently substituted by 1 or
2 substituents independently selected from hydrogen, CH.sub.3,
CF.sub.3, halogen, --(CH.sub.2).sub.qCONR.sup.5R.sup.4,
--(CH.sub.2).sub.qNR.sup.5R.sup.4, --(CH.sub.2).sub.qCOR.sup.5,
--(CH.sub.2).sub.qCO.sub.2R.sup.5, and --OR.sup.5, wherein q is 0
or 1, and wherein R.sup.4 and R.sup.5 are as defined above; and
R.sup.2 and R.sup.3 is each and independently hydrogen or
methyl.
4. A compound of the formula (I) according to claim 1, which
compound is any of 75
5. A compound according to claim 1, which is selected from 76
6. A compound according to any of the preceding claims, in form of
its hydrochloride, sulfate, tartrate or citrate salts.
7. A compound according to any of claims 1-6 for use in
therapy.
8. A compound according to claim 7, wherein the therapy is pain
management.
9. A compound according to claim 7, wherein the therapy is directed
towards gastrointestinal disorders.
10. A compound according to claim 7, wherein the therapy is
directed towards spinal injuries.
11. A compound according to claim 7, wherein the therapy is
directed to disorders of the sympathetic nervous system.
12. Use of a compound according to formula (I) of claim 1 for the
manufacture of a medicament for use in the treatment of pain.
13. Use of a compound according to formula (I) of claim 1 for the
manufacture of a medicament for use in the treatment of
gastrointestinal disorders.
14. Use of a compound according to formula (I) of claim 1 for the
manufacture of a medicament for use in the treatment of spinal
injuries.
15. A compound according to any of claim 1-7, further characterised
in that it is isotopically labelled.
16. Use of a compound according to claim 15 as a diagnostic
agent.
17. An isotopically labelled compound of the formula (I) of claim
1.
18. A diagnostic agent comprising a compound of the formula (I) of
claim 1.
19. A pharmaceutical composition comprising a compound of the
formula (I) according to claim 1 as an active ingredient, together
with a pharmacologically and pharmaceutically acceptable
carrier.
20. A process for the preparation of a compound of the formula (I)
according to claim 1, whereby a) a ketone of the formula (I)
77wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in formula
(I) of claim 1, and X is a leaving group, is reacted with an
organometallic reagent of the formula (j) or (k) 78wherein A and B
are as defined in formula (I) of claim 1, and M is a metal group;
and wherein the reaction is optionally performed in the presence of
a solvent, giving a compound of the formula (h) 79wherein A, B,
R.sup.1, R.sup.2 and R.sup.3 are as defined in formula (I) of claim
1, and wherein R1 also may be tert-butoxycarbonyl; b) the compound
of the formula (h) is dehydrated, giving a compound of the formula
(I) of claim 1.
21. A compound of the formula 80wherein A, B, R.sup.2 and R.sup.3
are as defined in formula (I) of claim 1.
22. A compound of the formula (h) according to step a) of claim 20,
wherein 81wherein R.sup.8 and R.sup.9 are both an ethyl group, and
Z.sup.1 andd Z.sup.2 are as defined in claim 1.
23. A compound according to claim 22, which compound is any of
82
24. A method for the treatment of pain, whereby an effective amount
of a compound of the formula (I) according to claim 1 is
administered to a subject in need of pain management.
25. A method for the treatment of gastrointestinal disorders,
whereby an effective amount of a compound of the formula (I)
according to claim 1, is administered to a subject suffering from
said gastrointestinal disorder.
26. A method for the treatment of spinal injuries, whereby an
effective amount of a compound of the formula (I) according to
claim 1, is administered to a subject suffering from said spinal
injury.
Description
FIELD OF THE INVENTION
[0001] The present invention is related to novel compounds, to a
process for their preparation, their use and pharmaceutical
compositions comprising the novel compounds. The novel compounds
are useful in therapy, and in particular for the treatment of
pain.
BACKGROUND AND PRIOR ART
[0002] The .delta. receptor has been identified as having a role in
many bodily functions such as circulatory and pain systems. Ligands
for the .delta. receptor may therefore find potential use as
analgesics, and/or as antihypertensive agents. Ligands for the
.delta. receptor have also been shown to possess immunomodulatory
activities.
[0003] The identification of at least three different populations
of opioid receptors (.mu., .delta. and .kappa.) is now well
established and all three are apparent in both central and
peripheral nervous systems of many species including man. Analgesia
has been observed in various animal models when one or more of
these receptors has been activated.
[0004] With few exceptions, currently available selective opioid
.delta. ligands are peptidic in nature and are unsuitable for
administration by systemic routes. Some non-peptidic .delta.
antagonists have been available for some time (see Takemori and
Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32: 239-269. for
review). These compounds, e.g. naltrindole, suffer from rather poor
(i.e., <10-fold) selectivity for the .delta. receptor vs. .mu.
receptor binding and exhibit no analgesic activity, a fact which
underscores the need for the development of highly selective
non-peptidic .delta. ligands.
[0005] Thus, the problem underlying the present invention was to
find new compounds having improved analgesic effects, but also with
an improved side-effect profile over current .mu. agonists and
potential oral efficacy.
[0006] Analgesics that have been identified and are existing in the
prior art have many disadvantages such as that they suffer from
poor pharmacokinetics and are not analgesic when administered by
systemic routes. Also, it has been documented that preferred
compounds, described within the prior art, show significant
convulsive effects when administered systemically.
[0007] The problem mentioned above has been solved by developing
novel compounds which possess a piperidine ring with an exocyclic
double bond, as will be described below.
OUTLINE OF THE INVENTION
[0008] The novel compounds according to the present invention are
defined by the general formula (I) 2
[0009] wherein
[0010] R.sup.1 is selected from hydrogen, a branched or straight
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkenyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.4-C.sub.8(alkyl-cycloalkyl) wherein alkyl is
C.sub.1-C.sub.2 alkyl and cycloalkyl is C.sub.3-C.sub.6
cycloalkyl;
[0011] C.sub.6-C.sub.10 aryl; or heteroaryl having from 5 to 10
atoms selected from any of C, S, N and O; wherein the aryl and
heteroaryl may optionally and independently be substituted by 1 or
2 substituents independently selected from any of hydrogen,
CH.sub.3, --(CH.sub.2).sub.pCF.sub.3, halogen, --CONR.sup.5R.sup.4,
--COOR.sup.5, --COR.sup.5, --(CH.sub.2).sub.pNR.sup.5R.sup.4,
--(CH.sub.2).sub.pCH.sub.- 3(CH.sub.2).sub.pSOR.sup.5R.sup.4,
--(CH.sub.2).sub.pSO.sub.2R.sub.5, and
--(CH.sub.2).sub.pSO.sub.2NR.sup.5, wherein R.sup.4 and R.sup.5 is
each and independently as defined for R.sup.1 above and p is 0, 1
or 2;
[0012] (C.sub.1-C.sub.2 alkyl)-(C.sub.6-C.sub.10 aryl); or
(C.sub.1-C.sub.2 alkyl)heteroaryl, the heteroaryl moieties having
from 5 to 10 atoms selected from any of C, S, N and O, and where
the aryl or heteroaryl may optionally and independently be
substituted by 1 or 2 substituents independently selected from any
of hydrogen, CH.sub.3, --(CH.sub.2).sub.qCF.sub.3, halogen,
--CONR.sup.5R.sup.4, --COOR.sup.5, --COR.sup.5,
--(CH.sub.2).sub.qNR.sup.5R.sup.4, --(CH.sub.2).sub.qCH.sub.-
3(CH.sub.2).sub.qSOR.sup.5R.sup.4,
--(CH.sub.2).sub.qSO.sub.2R.sup.5,
--(CH.sub.2).sub.qSO.sub.2NR.sup.5 and --(CH.sub.2).sub.pOR.sup.5,
wherein R.sup.4 and R.sup.5 is each and independently as defined
for R.sup.1 above and q is 0, 1 or 2; and 3
[0013] wherein R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22,
R.sup.23, R.sup.24 and R.sup.25 is each and independently hydrogen,
C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkenyl;
[0014] R.sup.2 and R.sup.3 is each and independently hydrogen or
C.sub.1-C.sub.6 alkyl;
[0015] A is selected from 4
[0016] wherein R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is each and
independently as defined for R.sup.1 above, and wherein the phenyl
ring of each A substituent may be optionally and independently
substituted at any position of the phenyl ring by 1 or 2
substituents Z.sup.1 and Z.sup.2 which are each and independently
selected from hydrogen, CH.sub.3, --(CH.sub.2).sub.qCF.sub.3,
halogen, --CONR.sup.6R.sup.7, --COOR6, --COR.sup.6,
--(CH.sub.2).sub.rNR.sup.6R.sup.7, --CH.sub.2).sub.rCH.sub.3-
(CH.sub.2).sub.rSOR.sup.6, --(CH.sub.2).sub.rSO.sub.2R.sup.6 and
--(CH.sub.2).sub.rSO.sub.2NR.sup.6R.sup.7 wherein R.sup.6 and
R.sup.7 is each and independently as defined for R.sup.1 above and
r is 0, 1, or 2;
[0017] Q is C.sub.5-C.sub.6 hydroaryl or heterohydroaromatic having
5 or 6 atoms selected from anyone of C, S, N and O; C.sub.5
-C.sub.6 cykloalkyl, or heterocycloalkyl having 5 or 6 atoms
selected from anyone of C, N, O and S; and where each Q may
optionally be substituted by a substituent Z.sup.1 and Z.sup.2 as
defined above;
[0018] B is a substituted or unsubstituted aromatic,
heteroaromatic, hydroaromatic or heterohydroaromatic moiety having
from 5 to 10 atoms selected from any of C, S, N and O, optionally
and independently substituted by 1 or 2 substituents independently
selected from hydrogen, CH.sub.3, --(CH.sub.2).sub.tCF.sub.3,
halogen, --(CH.sub.2).sub.tCONR.sup- .5R.sup.4,
--(CH.sub.2).sub.tNR.sup.5R.sup.4, --(CH.sub.2).sub.tCOR.sup.5,
--(CH.sub.2).sub.tCOOR.sup.5, --OR.sup.5,
--(CH.sub.2).sub.tSOR.sup.5, --(CH.sub.2).sub.tSO.sub.2R.sup.5, and
--(CH.sub.2)tSO.sub.2NR.sup.5R.sup- .4, wherein R.sup.4 and R.sup.5
is each and independently as defined for R.sup.1 above, and t is 0,
1, 2 or 3; and
[0019] R.sup.4 and R.sup.5 is each and independently as defined for
R.sup.1 above.
[0020] Within the scope of the invention are also pharmaceutically
acceptable salts of the compounds of the formula (I), as well as
isomers, hydrates, isoforms and prodrugs thereof.
[0021] Preferred compounds according to the invention are compounds
of the formula (I) wherein
[0022] A is selected from 5
[0023] wherein R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.17 is each and
independently as defined for R.sup.1 above, and wherein the phenyl
ring of each A substituent may be optionally and independently
substituted at any position of the phenyl ring by 1 or 2
substituents Z.sup.1 and Z.sup.2 which are each and independently
selected from hydrogen, CH.sub.3, --(CH.sub.2).sub.qCF.sub.3,
halogen, --CONR.sup.6R.sup.7, --COOR.sup.6, --COR.sup.6,
--(CH.sub.2).sub.rNR.sup.6R.sup.7, --(CH.sub.2).sub.rCH.sub.-
3(CH.sub.2).sub.rSOR.sup.6, --(CH.sub.2).sub.rSO.sub.2R.sup.6 and
--(CH.sub.2).sub.rSO.sub.2NR.sup.6R.sup.7 wherein R.sup.6 and
R.sup.7 is each and independently as defined for R.sup.1 above, and
r is 0, 1, or 2;
[0024] Q is selected from morpholine, piperidine and
pyrrolidine;
[0025] R.sup.1, R.sup.4, and R.sup.5 is each and independently
selected from hydrogen, a branched or straight C.sub.1-C.sub.4
alkyl, C.sub.3-C.sub.5 cycloalkyl, C.sub.4-C.sub.8
(alkyl-cycloalkyl) wherein alkyl is C.sub.1-C.sub.2 alkyl and
cycloalkyl is C.sub.3-C.sub.6 cycloalkyl; C.sub.6-C.sub.10 aryl;
and heteroaryl having from 5 to 6 atoms selected from any of C, S,
N and O; and where the aryl or heteroaryl may optionally and
independently be substituted by 1 or 2 substituents independently
selected from any of hydrogen, CH.sub.3,
--(CH.sub.2).sub.pCF.sub.3, halogen, --CONR.sup.5R.sup.4,
--COOR.sup.5, --COR.sup.5, --(CH.sub.2).sub.pNR.sup.5R.sup.4,
--(CH.sub.2).sub.pCH.sub.- 3(CH.sub.2).sub.pSOR.sup.5R.sup.4,
--(CH.sub.2).sub.pSO.sub.2R.sup.5, and
--(CH.sub.2).sub.pSO.sub.2NR.sup.5, wherein R.sup.4 and R.sup.5 is
each and independently as defined for R.sup.1 above and p is 0, 1
or 2;
[0026] B is selected from phenyl, naphthyl, indolyl, benzofuranyl,
dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl,
isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl,
cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl,
tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl,
pyrrolidinyl, and indazolinyl, each optionally and independently
substituted by 1 or 2 substituents independently selected from
hydrogen, CH.sub.3, CF.sub.3, halogen,
--(CH.sub.2).sub.qCONR.sup.5R.sup.4, --(CH.sub.2).sub.qNR.sup.5R-
.sup.4, --(CH.sub.2).sub.qCOR.sup.5,
--(CH.sub.2).sub.qCO.sub.2R.sup.5, and --OR.sup.5, wherein q is 0
or 1, and wherein R.sup.4 and R.sup.5 are as defined above;
[0027] R.sup.2 and R.sup.3 is each and independently hydrogen or
methyl.
[0028] Especially preferred compounds according to the invention
are compounds of the formula (I) wherein
[0029] A is 6
[0030] wherein R.sup.8 and R.sup.9 are both ethyl, and where the
phenyl ring optionally and independently may be substituted at any
position of the phenyl ring by 1 or 2 substituents Z.sup.1 and
Z.sup.2 which are each and independently selected from hydrogen,
CH.sub.3, --(CH.sub.2).sub.qCF.sub.3, halogen,
--(CONR.sup.6R.sup.7, --COOR.sup.6, --COR.sup.6,
--(CH.sub.2).sub.rNR.sup.6R.sup.7, --(CH.sub.2).sub.rCH.sub.-
3(CH.sub.2).sub.rSOR.sup.6, --(CH.sub.2).sub.rSO.sub.2R.sup.6 and
--(CH.sub.2).sub.rSO.sub.2NR.sup.6R.sup.7 wherein R.sup.6 and
R.sup.7 is each and independently as defined for R.sup.1 above and
r is 0, 1, or 2;
[0031] R.sup.1 is selected from hydrogen, methyl, ethyl,
--CH.sub.2CH.dbd.CH.sub.2, --CH.sub.2-cyclopropyl, --CH.sub.2-aryl,
or CH.sub.2-heteroaryl, the heteroaryl moieties having from 5 to 6
atoms selected from any of C, S, N and O;
[0032] B is selected from phenyl, naphthyl, indolyl, benzofuranyl,
dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl,
isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl,
cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl,
tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, and
indazolinyl, each optionally and independently substituted by 1 or
2 substituents independently selected from hydrogen, CH.sub.3,
CF.sub.3, halogen, --(CH.sub.2).sub.qCONR.sup.5R.sup.4,
--(CH.sub.2).sub.qNR.sup.5R.sup.4, --(CH.sub.2).sub.qCOR.sup.5,
--(CH.sub.2).sub.qCO.sub.2R.sup.5, and --OR.sup.5, wherein q is 0
or 1, and wherein R.sup.4 and R.sup.5 are as defined above;
[0033] R.sup.2 and R.sup.3 is each and independently hydrogen or
methyl.
[0034] The substituents A and B respectively, may optionally be
substituted at any position of the ring.
[0035] By "halogen" we mean chloro, fluoro, bromo and iodo.
[0036] By "aryl" we mean an aromatic ring having from 6 to 10
carbon atoms, such as phenyl and naphtyl.
[0037] By "heteroaryl" we mean an aromatic ring in which one or
more of the from 5-10 atoms in the ring are elements other than
carbon, such as N, S and O.
[0038] By "hydroaromatic" we mean a partly or fully saturated
aromatic ring structure having 5-10 carbon atoms in the ring.
[0039] By "heterohydroaromatic" we mean a partly or fully saturated
aromatic ring structure in which one or more of the 5-10 atoms in
the ring are elements other than carbon, such as N, S and O.
[0040] By "isomers" we mean compounds of the formula (I), which
differ by the position of their functional group and/or
orientation. By "orientation" we mean stereoisomers,
diastereoisomers, regioisomers and enantiomers.
[0041] By "isoforms" we mean compounds of the formula (I) which
differ by their crystal lattice, such as crystalline compound and
amorphous compounds.
[0042] By "prodrug" we mean pharmacologically acceptable
derivatives, e.g. esters and amides, such that the resulting
biotransformation product of the derivative is the active drug. The
reference by Goodman and Gilmans, The Pharmacological basis of
Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992,
"Biotransformation of Drugs, p. 13-15, describing prodrugs
generally, is hereby incorporated.
[0043] The novel compounds of the present invention are useful in
therapy, especially for the treatment of various pain conditions
such as chronic pain, acute pain, cancer pain, pain caused by
rheumatoid arthritis, migraine, visceral pain etc. This list should
however not be interpreted as exhaustive.
[0044] Compounds of the invention are useful as inmmunomodulators,
especially for autoimmune diseases, such as arthritis, for skin
grafts, organ transplants and similar surgical needs, for collagen
diseases, various allergies, for use as anti-tumour agents and anti
viral agents.
[0045] Compounds of the invention are useful in disease states
where degeneration or dysfunction of opioid receptors is present or
implicated in that paradigm. This may involve the use of
isotopically labelled versions of the compounds of the invention in
diagnostic techniques and imaging applications such as positron
emission tomography (PET).
[0046] Compounds of the invention are useful for the treatment of
diarrhoea, depression, urinary incontinence, various mental
illnesses, cough, lung oedema, various gastro-intestinal disorders,
spinal injury and drug addiction, including the treatment of
alcohol, nicotine, opioid and other drug abuse and for disorders of
the sympathetic nervous system for example hypertension.
[0047] Compounds of the invention are useful as an analgesic agent
for use during general anaesthesia and monitored anaesthesia care.
Combinations of agents with different properties are often used to
achieve a balance of effects needed to maintain the anaesthetic
state (e.g. Amnesia, analgesia, muscle relaxation and sedation).
Included in this combination are inhaled anaesthetics, hypnotica,
anxiolytics, neuromuscular blockers and opioids.
[0048] The compounds of the present invention in isotopically
labelled form are useful as a diagnostic agent.
[0049] Also within the scope of the invention is the use of any of
the compounds according to the formula (I) above, for the
manufacture of a medicament for the treatment of any of the
conditions discussed above.
[0050] A further aspect of the invention is a method for the
treatment of a subject suffering from any of the conditions
discussed above, whereby an effective amount of a compound
according to the formula (I) above, is administered to a patient in
need of such treatment.
Methods of Preparation
[0051] The compounds of the present invention may be prepared as
described in the following. 7 8 9 10
[0052] As shown in SCHEME I & II above, compounds of the
formula (I) above, may be obtained by dehydration of hydroxy
compounds (g) or (h), wherein R.sup.1, R.sup.2, R.sup.3, A and B
are as defined in formula (I) above. Subsequent dehydration of
hydroxyl compounds (g) or (h), wherein R.sup.1, R.sup.2, R.sup.3, A
and B are as defined in formula (I), may be performed without
solvents or in a solvent such as water, alcohols, esters, HMPA,
dichloromethane, toluene, ethers, ketones, carboxylic acids or in a
solvent mixture in the presence of Br.o slashed.nstedt or Lewis
acids such as sulphuric acid, hydrochloric acid, trifluoroacetic
acid, aluminium trichloride, ZnCl.sub.2 or the like, or in the
presence of metallic oxides such as Al.sub.2O.sub.3,
Cr.sub.2O.sub.3, TiO.sub.2, WO.sub.3, P.sub.2O.sub.5 or the like,
or in the presence of other dehydrating agents such as I.sub.2,
dimethyl sulfoxide, KHSO.sub.4, CuSO.sub.4, phthalic anhydride or
the like.
[0053] The substituents R.sup.1, R.sup.2 and R.sup.3 and the
substituents on A and B of compound (I), as defined above, may be
modified by methods known in the art and exemplfied in the
literature, see e.g. Protecting groups by Green, or Modern
Synthetic Reactions by House, which are well known to a person
skilled in the art, after or during the preparation of (I) from (g)
and (h).
[0054] As shown the route a of SCHEME I, compounds of formula (g),
as described above, may be obtained by a reaction between a ketone
of formula (c) wherein R.sup.1, R.sup.2 and R.sup.3 are as defined
in formula (I), and a compound of formula (e) wherein A and B are
as defined in formula (I), and X is a suitable group such as H, Cl,
Br, I, OSO.sub.2R or the like.
[0055] The reaction may be performed without solvents, or in an
organic solvent such as THF, toluene, ethers, dimethylsulfoxide, or
in solvent mixtures by treatment with an appropriate metal such as
magnesium, lithium, zinc, copper, cerium or the like, or by
treatment with a metal halide such as SmI.sub.2, CrCl.sub.2 or the
like, or by treatment with an organometallic agents such as
alkylmagnesium halides, alkyllithium or the like.
[0056] R.sup.1, R.sup.2 and R.sup.3 and the substituents on A and B
of compounds (g), as defined above, may be modified, by methods
known in the art, after or during the organometallic reactions
(March, J., Advanced Organic Chemistry, 4.sup.th Ed, John Wiley
& Sons, 1992).
[0057] Compounds of formula (c) and (e) may be commercially
available, or prepared by methods known in the art (March, J.,
Advanced Organic Chemistry, 4.sup.th Ed, John Wiley & Sons,
1992).
[0058] As shown in route b of SCHEME II, compounds of formula (h),
as described above, may be obtained by a reaction between a ketone
of formula (i) wherein R.sup.1, R.sup.2 and R.sup.3, and B are as
defined in formula (I), and an organometallic reagent of formula
(j) wherein A is as defined in formula (I), and M is an appropriate
metal group such as magnesium, lithium, zinc, copper, cerium or the
like. The reaction may be performed without solvents, or in an
organic solvent such as THF, toluene, ethers, dimethylsulfoxide, or
in solvent mixtures.
[0059] As shown in route c of SCHEME II, compounds of formula (h)
may also be obtained by reactions among a carbonyl compound of
formula (I), wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in
formula (I), and X is an appropriate leaving group such as Cl, Br,
OH, OR, SR, NR.sub.2, N(OR')R or the like, and organometallic
reagents of formula (j) and (k), wherein A and B are as defined in
formula (I), and M is an appropriate metal group such as magnesium,
lithium, zinc, copper, cerium or the like. The reactions may be
performed without solvents or in solvents such as THF, toluene,
ethers, dimethyl formamide, dioxane, dimethylsulfoxide, or in
solvent mixtures.
[0060] R.sup.1, R.sup.2 and R.sup.3 and the substituents on A and B
of compounds (h), as defined above, may be modified, by methods
known in the art and exemplfied in the literature, see e.g.
Protecting groups by Green, or Modern Synthetic Reactions by House,
which are well known to a person skilled in the art, after or
during the organometallic reactions.
[0061] Compounds of formula (i), (j), (k) and (l) may be
commercially available, or prepared by methods known in the art
(March, J., Advanced Organic Chemistry, 4.sup.th Ed, John Wiley
& Sons, 1992).
[0062] As shown in SCHEME III above, compounds of the formula (I)
above, may be obtained from the Suzuki coupling of vinylic halide
(o) (X=Br, I) with a boronic acid, boronate ester (p), in the
presence of a base such as Na.sub.2CO.sub.3, K.sub.2CO.sub.3,
K.sub.3PO.sub.4, triethylamine, CsF, NaOH or alkoxides and
palladium catalyst such as (PPh.sub.3).sub.4Pd,
Bis(dibenzylideneacetone)Pd(0), Pd on carbon with PPh.sub.3; Pd(II)
species may also be used as a catalyst including:
(PPh.sub.3).sub.2PdCl.sub.2,
1,4-Bis(diphenylphosphinobutane)palladium(II- ) chloride, Palladium
acetate, Bis(acetonitrile)palladium(II) chloride,
dichloro[1,1'-bis(diphenylphosphino)ferrocene] palladium(II) and
palladium acetate-tri(0-tolyl)phosphine, wherein R.sup.1, R.sup.2,
R.sup.3, A and B are as defined in formula (I) above. The Suzuki
coupling may be performed in toluene, xylene, anisole, DMF, THF,
alcohols, ethers, water or in a solvent mixture.
[0063] Compounds or formula (p), where B is as defined in formula
(I) and Z is B(OH).sub.2, may be commercially available or prepared
from the hydrolysis of a boronate ester. Compounds or formula (p),
where B is as defined in formula (I) and Z is B(OR).sub.2 (R=Me,
Et), may be prepared from the reaction of a compound of formula B-M
and B(OR).sub.3 where R=Me or Et, and M is an appropriate metal
group such as lithium or magnesium or the like. Compounds of
formula (p) where B is as defined in formula (I) and Z is
9-borabicyclo[3.3.1]nonane (9-BBN) may be prepared from the
reaction of an alk-1-yne with borabicyclo[3.3.1]nonane.
[0064] The substituents R.sup.1, R.sup.2, R.sup.3 and the
substituents on A and B of compound (I) as defined above, may be
modified by methods known in the art and exemplified in the
literature, see e.g. Protecting groups by Green or Modern Synthetic
Reactions by House, which are well known to a person skilled in the
art, after or during the preparation of (I) from (o) and (p).
[0065] As shown in SCHEME III, compounds of formula (o) wherein X
is Br or I, may be prepared from the halogenation and elimination
of an alkene of formula (n) wherein R.sup.1, R.sup.2, R.sup.3 and A
are as defined in formula (I). The halogenation may be performed in
a solvent such as dichloromethane, chloroform, carbon
tetrachloride, dichloroethane, or acetic acid using molecular
bromine or iodine as halogenation agent. The subsequent elimination
step is accomplished in a solvent such as water, alcohols, DMF, or
ethers using a base such as sodium hydroxide, potassium hydroxide,
metal alkoxides, or triethylamine.
[0066] As shown in SCHEME III, compounds of formula (n), as
described above, may be prepared from the Wittig reaction of a
ketone of formula (c), where R.sup.1, R.sup.2 and R.sup.3 are as
defined in formula (I), and a reagent of formula (m) where A is as
defined in formula (I) and Y is an appropriate phosphonate or
phosphonium salt. The Wittig reaction may be carried out under a
variety of conditions known in the art and exemplified in the
literature (March, J., Advanced Organic Chemistry, 4.sup.th Ed.,
John Wiley & Sons, 1992).
[0067] Reagents of formula (c) and (m) may be commercially
available, or prepared by methods known in the art (March, J.,
Advanced Organic Chemistry, 4.sup.th Ed., John Wiley & Sons,
1992).
[0068] As shown in SCHEME IV above, compounds of formula (u) may be
obtained by dehydration of hydroxy compound (t) wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.12, R.sup.13 and B are as defined above.
Dehydration step may be performed without solvent or in a solvent
such as water, alcohols, esters, HMPA, dichloromethane, toluene,
ethers, ketones, carboxylic acids, or in a solvent mixture in the
presence of Bronstedt or Lewis acids such as sulfuric acid,
hydrochloric acid, trifluoroacetic acid, aluminium trichloride,
ZnCl.sub.2, or the like, or in the presence of metallic oxides such
as Al.sub.2O.sub.3, Cr.sub.2O.sub.3, TiO.sub.2, WO.sub.3,
P.sub.2O.sub.5 or the like, or in the presence of other dehydrating
agents such as I.sub.2, dimethylsulfoxide, KHSO.sub.4, CuSo.sub.4,
phthalic anhydride or the like.
[0069] The substituents R.sup.1, R.sup.2 and R.sup.3 and the
substituent B of compound (u) as defined above may be modified by
methods known in the art and exemplified in the literature, see
e.g. Protecting Groups by Green, or Modern Synthetic Reactions by
House, which are well known to a person skilled in the art, after
or during the preparation of (u) from (t).
[0070] As shown in SCHEME IV above, compounds of formula (t) may be
obtained from compound (s) wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.13 and B are as defined above using alkylation reaction with
alkyl halide such as MeI in presence of a base such as sodium
hydroxide and a phase transfer agent such as Bu.sub.4NHSO.sub.4.
Compounds of formula (s) may be prepared by a reaction between a
ketone of formula (r) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.13
are as defined above and an organometallic reagent of formula (k)
wherein B is defined in formula (I) and M is an appropriate metal
group such as magnesium, lithium, zinc, copper, cerium, or the
like. The reaction may be performed without solvent or in solvents
such as THF, toluene, ethers, dimethylformamide, dioxane,
dimethylsufoxide, or in solvent mixtures.
[0071] The substituents R.sup.1, R.sup.2, R.sup.3, R.sup.13 of
compound (s) as defined above may be modified by methods known in
the art and exemplified in the literature, see e.g. Protecting
Groups by Green, or Modern Synthetic Reactions by House, which are
well known to a person skilled in the art, after or during the
preparation of (s) from (r) and (k).
[0072] As shown in SCHEME IV, a compound of formula (r) may be
obtained by reactions among a carbonyl compound of formula (l)
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in formula (I)
and X is an appropriate leaving group such as Cl, Br, OH, OR, SR,
NR.sub.2, N(OR')R or the like and organometallic reagent obtained
by first base treatment such as NaH on compound (q) wherein
R.sup.13 is as defined above followed by subsequent
transmetallation using alkyl lithium such as Buli. The reaction may
be performed in solvents such as THF, toluene, ethers,
dimethylformamide, dioxane, or in solvent mixtures. The
substituents R.sup.1, R.sup.2, R.sup.3, R.sup.13 of compound (r) as
defined above may be modified by methods known in the art and
exemplified in the literature, see e.g. Protecting Groups by Green,
or Modern Synthetic Reactions by House, which are well known to a
person skilled in the art, after or during the preparation of (r)
from (q) and (l).
[0073] As shown in SCHEME IV, compounds of formula (q) may be
obtained by acylation of 4-iodoaniline using either acylanhydride
or acylchloride in an organic solvent such as dichloromethane. The
substituent R.sup.13 of compound (q) is as defined above.
[0074] The invention will now be described in more detail by way of
the following Examples, which are not to be construed as limiting
the invention in any way.
A) Synthetic Scheme For the Preparation of the Compounds of
Examples 1-7
[0075] The compounds of Examples 1-7 were prepared by following the
procedure as is shown in Scheme 1 below. 11
[0076] (i) Preparation of N-t-Butoxylcarbonyl
N'-methyl-N'-methoxyl-isonip- ecotamide (Compound 2)
[0077] A mixture of ethyl isonipecotate (compound 1) (4.71 g, 30.0
mmol), di-tert-butyl dicarbonate (6.55 g, 30.0 mmol) and
Na.sub.2CO.sub.3 (4.77 g, 45 mmol) in H.sub.2O-THF (90/10 mL) was
refluxed for 2 h. The reaction mixture was extracted with ethyl
acetate (150 mL). The organic layer was washed with brine, dried
over MgSO.sub.4. Removal of solvents gave N-t-butoxylcarbonyl ethyl
isonipecotate (7.67 g):
[0078] .delta..sub.H (400 MHz, CDCl.sub.3) 1.25 (t, J=7.2 Hz, 3H),
1.45 (s, 9H), 1.62 (m, 2H), 1.87 (m, 2H), 2.43 (m, 1H), 2.84 (m,
2H), 4.02 (m, 2H), 4.13 (q, J=7.2 Hz, 2H); .delta..sub.C-13 (100
MHz, CDCl.sub.3) .delta.: 14.0, 27.8, 28.2, 40.9, 42.9, 60.2, 79.2,
154.4, 174.2.
[0079] The above N-t-butoxylcarbonyl ethyl isonipecotate was
dissolved in dry THF (60 mL) and mixed with NHMe(OMe) HCl (4.39 g,
45.0 mmol). The mixture was treated with i-PrMgCl (2.0 M in THF, 45
ml, 90 mmol) at -20 C. and the resulting solution was stirred for 1
hr at -5.degree. C. and then quenched with aqueous NH.sub.4Cl
solution and extracted with ethyl acetate (2.times.100 mL). The
combined organic layers were washed with brine, dried over
MgSO.sub.4. Removal of solvents gave N-t-butoxylcarbonyl
N'-methyl-N'-methoxyl-isonipecotamide (compound 2) (8.0 g,
98%):
[0080] .delta..sub.H (400 MHz, CDCl.sub.3) 1.30 (s, 9H), 1.54 (m,
4H), 2.65 (m, 3H), 3.02 (s, 3H), 3.56 (s, 3H), 3.99 (brs, 2H);
.delta..sub.C-13 (100 MHz, CDCl.sub.3) .delta.: 27.7, 28.1, 32.0,
37.8, 43.1, 61.3, 79.1, 154.4, 176.0.
[0081] (ii) Preperation of
4-(4'-N',N'-Diethylaminocarbonylbenzoyl)-N-t-bu-
toxylcarbonylpiperidine (Compound 3)
[0082] To a solution of 4-iodo-N,N-diethylbenzamide (9.09 g, 30.0
mmol) and TMEDA (6.96 g, 60.0 mmol) in dry THF (60 mL) was added
t-butyllithium (35.0 mL, 1.7 M, 60.0 mmol) at -78.degree. C. After
30 min, N-t-butoxylcarbonyl N'-methyl-N'-methoxyl-isonipecotamide
(compound 2) (8.0 g, 29.4 mmol) in THF (10 mL) was dropwise added.
The reaction mixture was warmed to r.t. and then quenched with
aqueous NH.sub.4Cl solution, neutralized with hydrochloric acid
(concentrated, 20 mL) at .degree. C., and extracted with ethyl
acetate (2.times.100 mL). The combined organic layers were washed
with brine, dried over MgSO.sub.4. Removal of solvents gave a crude
product, which was purified by silica gel column eluting with
MeOH-CH.sub.2Cl.sub.2 (2:98) to provide
4-(4'-N',N'-diethylaminocarbonylbenzoyl)-N-t-butoxylcarbonylpiperidine
(compound 3) (3.15 g, 28%):
[0083] .delta..sub.H (400 MHz, CDCl.sub.3) 1.08 (brs, 3H), 1.23
(brs, 3H), 1.43 (s, 9H), 1.61 (m, 2H), 1.80 (m, 2H), 2.89 (m, 2H),
3.20 (brs, 2H), 3.40 (m, 1H), 3.53 (brs, 2H), 4.11 (brs, 2H), 7.44
(d, J=8.0 Hz, 2H), 7.94 (d, J=8.0 Hz, 2H).
[0084] (iii) Preparation of
4-(.alpha.-Hydroxyl-.alpha.-(4-N-t-butoxylcarb-
onylpiperidinyl)-.alpha.-(1-naphthyl)-methyl)-N,N-diethylbenzamide
(Compound 4)
[0085] To a solution of 1-bromonaphthalene (0.52 g, 2.5 mmol) in
dry THF (10 mL) was added n-butyllithium (1.1 mL, 2.5 M, 2.75 mmol)
at -78.degree. C. After 30 min,
4-(4'-N',N'-diethylaminocarbonylbenzoyl)-N-t-
-butoxylcarbonylpiperidine (compound 3) (776 mg, 2.0 mmol) in THF
(2 mL) was dropwise added. The reaction mixture was warmed to r.t.
and then quenched with aqueous NH.sub.4Cl solution, and extracted
with ethyl acetate (2.times.50 mL). The combined organic layers
were washed with brine, dried over MgSO.sub.4. Removal of solvents
gave a crude product, which was purified by silica gel column
eluting with MeOH-CH.sub.2Cl.sub.2 (0.5:99.5.fwdarw.5:95) to
provide
4-(.alpha.-hydroxyl-.alpha.-(4-N-t-butoxylcarbonylpiperidinyl)-.alpha.-(1-
-naphthyl)-methyl)-N,N-diethylbenzanide (compound 4) (760 mg,
74%):
[0086] m.p. 121-124.degree. C. (CH.sub.2Cl.sub.2); .nu..sub.max
(KBr) cm.sup.-1 3402, 2960, 1685, 1626, 1425, 1283, 1160;
Anal.Calcd.for C.sub.32H.sub.40N.sub.2O.sub.4.0.50H.sub.2O: C,
73.11; H, 7.86; N, 5.33. Found: C, 72.86; H, 7.64; N, 5.26;
.delta..sub.H (400 MHz, CDCl.sub.3) 1.03 (brs, 3H), 1.16 (brs, 3H),
1.18-1.35 (m, 3H), 1.95 (m, 1H), 2.60 (m, 2H), 2.75 (brs, 2H), 3.15
(brs, 2H), 3.42 (brs, 2H), 4.10 (brs, 2H), 7.10-7.50 (m, 7H), 7.75
(m, 3H), 8.27 (brs, 1H); .delta..sub.C-13 (100 MHz, CDCl.sub.3)
.delta.: 12.8, 14.1, 27.1, 27.2, 28.4, 39.2, 43.3, 45.4, 79.3,
80.4, 124.1, 124.9, 125.2, 125.3, 126.0, 127.3, 128.8, 129.2,
131.4, 135.0, 135.2, 139.4, 146.5, 154.6, 171.0.
[0087] (iv) Preparation of
4-(.alpha.-Hydroxyl-.alpha.-(4-N-t-butoxylcarbo-
nylpiperidinyl)-2,6-dimethylbenzyl)-N,N-diethylbenzamide (Compound
5)
[0088] Method as described for compund 4, except using
2-bromo-m-xylene; (749 mg, 76%):
[0089] m.p. 92-96.degree. C. (CH.sub.2Cl.sub.2); .nu..sub.max (KBr)
cm.sup.-1 3451, 2970, 1690, 1631, 1425, 1165; Anal.Calcd.for
C.sub.30H.sub.42N.sub.2O.sub.4.0.50H.sub.2O: C, 71.54; H, 8.61; N,
5.56. Found: C, 71.70; H, 8.34; N, 5.62; .delta..sub.H (400 MHz,
CDCl.sub.3) 1.10 (brs, 3H), 1.21 (brs, 3H), 1.32 (m, 2H), 1.43 (s,
9H), 1.69 (m, 1H), 1.77 (m, 1H), 2.32 (s, 6H), 2.47 (s, 1H), 2.75
(m, 3H), 3.25 (brs, 2H), 3.51 (brs, 2H), 4.13 (brs, 2H), 6.91 (m,
2H), 7.00 (m, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H);
.delta..sub.C-13 (100 MHz, CDCl.sub.3) .delta.: 12.6, 14.0, 25.0,
27.7, 28.2, 39.1, 42.9, 43.1, 44.4, 53.3, 79.1, 83.0, 125.8, 126.3,
127.2, 131.2, 135.3, 136.7, 142.9, 147.8, 154.5, 170.7.
EXAMPLE 1
Preparation of
N,N-Diethyl-4-(phenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 6)
[0090] To a solution of
4-(.alpha.-hydroxyl-.alpha.-(4-N-t-butoxylcarbonyl-
piperidinyl)-benzyl)-N,N-diethylbenzamide (932 mg, 2.0 mmol) in dry
dichloromethane (10 mL) was added trifluoroacetic acid (10.0 mL) at
r.t. The reaction mixture was stirred for 16 h at r.t., and then
condensed. The residue was dissolved in AcOEt (100 ml). The
resulting solution was washed with 1 N NaOH solution, aqueous
NH.sub.4Cl solution and brine, dried over MgSO.sub.4. Removal of
solvents gave a crude product, which was purified by silica gel
column eluting with MeOH-CH.sub.2Cl.sub.2 (20:80) to provide
(.alpha.-phenyl-.alpha.-(4-N',N'-diethylaminocarbonylp-
henyl))-4-methylene-piperidine (compound 6), (632 mg, 91%):
[0091] .delta..sub.H (400 MHz, CDCl.sub.3) 1.08 (brs, 3H), 1.17
(brs, 3H), 2.29 (m, 4H), 2.86 (m, 4H), 2.94 (brs, 1H), 3.24 (brs,
2H), 3.47 (brs, 2H), 7.09 (m, 4H), 7.15 (m, 1H), 7.24 (m, 4H);
.delta..sub.C-13 (100 MHz, CDCl.sub.3) .delta.: 12.6, 14.1, 32.7,
32.8, 39.1, 43.2, 47.9, 126.0, 126.4, 127.9, 129.6, 134.9, 135.4,
135.9, 141.7, 143.2, 171.1.
[0092] HCl salt: m.p. 110-120.degree.
C.(AcOEt-Ether-CH.sub.2Cl.sub.2); .nu..sub.max (KBr) cm.sup.-1
3440, 2970, 1617, 1438, 1289; Anal.Calcd.for
C.sub.23H.sub.28N.sub.2O.1.0 HCl. 0.50CH.sub.2Cl.sub.2.
0.25H.sub.2O: C, 65.35; H, 7.12; N, 6.49. Found: C, 65.14; H, 7.08;
N, 6.55.
EXAMPLE 2
Preparation of
N,N-Diethyl4-(1-naphtyl-piperidin-4-ylidene-methyl)-benzami- de
(Compound 7)
[0093] Method as described for Example 1, using compound 4;(226 mg,
71%):
[0094] m.p. 80-85.degree. C. (MeOH-CH.sub.2Cl.sub.2); .nu..sub.max
(KBr) cm.sup.-1 3052, 2970, 1628, 1431, 1286; Anal.Calcd.for
C.sub.27H.sub.30N.sub.2O . 0.20CH.sub.2Cl.sub.2: C, 78.62; H, 7.37;
N, 6.74. Found: C, 78.63; H, 7.07; N, 6.54; .delta..sub.H (400 MHz,
CDCl.sub.3) 1.06 (brs, 3H), 1.16 (brs, 3H), 2.00 (m, 2H), 2.53 (m,
2H), 2.64 (brs, NH), 2.77 (m, 2H), 2.97 (m, 2H), 3.20 (brs, 2H),
3.47 (brs, 2H), 7.26 (m, 5H), 7.43 (m, 3H), 7.74 (m, 2H), 8.0 (m,
1H); .delta..sub.C-13 (100 MHz, CDCl.sub.3) .delta.: 12.8, 14.1,
32.6, 33.5, 39.1, 43.2, 47.9, 48.2, 125.5, 125.7, 125.8, 126.1,
127.1, 127.2, 129.1, 131.9, 132.5, 133.8, 135.1, 138.3, 139.8,
142.6, 171.1.
EXAMPLE 3
Preparation of
N,N-Diethyl-4-(2,6-dimethylphenyl-piperidin-4-ylidene-methy-
l)-benzamide (Compound 8)
[0095] Method as described for Example 1, using compound 5 (242 mg,
80%).
[0096] Its HCl salt: Dec..gtoreq.115.degree. C.
(AcOEt-Ether-CH.sub.2Cl.su- b.2); .nu..sub.max (KBr) cm.sup.-1
2970, 2725, 1590, 1464, 1290, 1101; Anal.Calcd.for
C.sub.25H.sub.32N.sub.2O. 1.0 HCl. 0.50CH.sub.2Cl.sub.2.
0.5H.sub.2O: C, 65.94; H, 7.60; N, 6.03. Found: C, 65.98; H, 7.37;
N, 5.81.
EXAMPLE 4
Preparation of
N,N-Diethyl-4-(1-naphtyl-N-allyl-piperidin-4-ylidene-methyl-
)-benzamide (Compound 9)
[0097] A mixture of
(.alpha.-(1-Naphthyl)-.alpha.-(4-N',N'-diethylaminocar-
bonylphenyl))-4-methylene-piperidine (compound 7) (125 mg), allyl
bromide (90 mg) and K.sub.2CO.sub.3 (138 mg) in MeCN (10 mL) was
stirred for 14 hr at r.t., and then quenched with 1 N NH.sub.4OH
solution, extracted with AcOEt (100 ml). The organic phase was
washed with aqueous NH.sub.4Cl solution and brine, dried over
MgSO.sub.4. Removal of solvents gave a crude product, which was
purified by silica gel column eluting with MeOH-CH.sub.2Cl.sub.2
(2:98) to provide (.alpha.-(1-naphthyl)-.alpha.-(4--
N',N'-diethylaminocarbonylphenyl))-4-methylene-N-allylpiperidine
(50 mg, 36%):
[0098] .delta..sub.H (400 MHz, CDCl.sub.3) 1.08 (brs, 3H), 1.19
(brs, 3H), 2.08 (m, 2H), 2.39 (m, 2H), 2.61 (m, 4H), 3.01 (m, 2H),
3.24 (brs, 2H), 3.52 (brs, 2H), 5.13 (m, 2H), 5.90 (m, 1H), 7.27
(m, 5H), 7.45 (m, 3H), 7.80 (m, 2H), 8.04 (m, 1H); .delta..sub.C-13
(100 MHz, CDCl.sub.3) .delta.: 12.8, 14.1, 30.9, 32.0, 39.1, 43.2,
54.7, 54.9, 61.5, 117.8, 125.4, 125.6, 125.8, 126.0, 127.1, 128.2,
129.1, 131.8, 132.4, 133.7, 135.0, 138.0, 139.8, 142.6, 171.1.
[0099] Its HCl salt: m.p. 110-120.degree. C.
(AcOEt-Ether-CH.sub.2Cl.sub.2- ); .nu..sub.max (KBr) cm.sup.-1
3416, 2961, 1620, 1430, 1288; Anal.Calcd.for
C.sub.30H.sub.34N.sub.2O. 1.0 HCl. 0.50CH.sub.2Cl.sub.2,
0.25H.sub.2O; C, 70.17; H, 7.05; N, 5.37. Found: C, 70.15; H, 6.92;
N, 5.24.
EXAMPLE 5
Preparation of
N,N-Diethyl-4-(phenyl-N-benzyl-piperidin-4-ylidene-methyl)--
benzamide (Compound 10)
[0100] Method as described for Example 4, using compound 6 and
benzyl bromide (215 mg, 98%);
[0101] .delta..sub.H (400 MHz, CDCl.sub.3) 1.09 (brs, 3H), 1.19
(brs, 3H), 2.37 (m, 4H), 2.47 (m, 4H), 3.25 (brs, 2H), 3.50 (brs,
4H), 7.0-7.30 (m, 14 H); .delta..sub.C-13 (100 MHz, CDCl.sub.3)
.delta.: 12.7, 14.0, 31.6, 39.1, 43.1, 54.9, 55.0, 62.8, 125.9,
126.2, 126.8, 127.8, 128.0, 128.9, 129.6, 129.7, 134.9, 135.0,
136.3, 138.2, 141.9, 143.3, 171.0.
[0102] Its HCl salt: m.p. 230-245.degree. C.
(AcOEt-Ether-CH.sub.2Cl.sub.2- ); .nu..sub.max (KBr) cm.sup.-1
3423, 2976, 1624, 1434, 1288; Anal.Calcd.for
C.sub.30H.sub.34N.sub.2O. 1.0 HCl. 0.25CH.sub.2Cl.sub.2.
0.25H.sub.2O: C, 72.55; H, 7.25; N, 5.59. Found: C, 72.38; H, 7.16;
N, 5.50.
EXAMPLE 6
Preparation of
N,N-Diethyl-4-(N-2,3-epoxypropyy-phenyl-piperidin-4-ylidene-
-methyl)-benzamide (Compound 11)
[0103] Method as described for Example 4, using compound 6 and
epibromohydrin (102 mg, 84%):
[0104] .delta..sub.H (400 MHz, CDCl.sub.3) 1.10 (brs, 3H), 1.20
(brs, 3H), 2.28 (m, 1H), 2.39 (m, 4H), 2.45 (m, 1H), 2.54 (m, 2H),
2.61 (m, 2H), 2.74 (m, 2H), 3.09 (m, 1H), 3.26 (brs, 2H), 3.50
(brs, 2H), 7.10 (m, 4H), 7.15 (m, 1H), 7.25 (m, 4H);
.delta..sub.C-13 (100 MHz, CDCl.sub.3) .delta.: 12.8, 14.1, 31.4,
39.1, 43.2, 44.9, 50.1, 55.5, 60.8, 126.0, 126.4, 127.9, 129.6,
129.7, 135.0, 135.3, 135.7, 141.8, 143.2, 171.1.
EXAMPLE 7
Preparation of
N,N-Diethyl-4-(1-cyclopropylmethyl-phenyl-piperidin-4-ylide-
ne-methyl)-benzamide (Compound 12)
[0105] Method as described for Example 4, using compound 6 and
cyclopropylmethyl chloride (104 mg, 86%):
[0106] .delta..sub.H (400 MHz, CDCl.sub.3) 0.20 (m, 2H), 0.59 (m,
2H), 1.04 (m, 1H), 1.14 brs, 3H), 1.24 (brs, 3H), 2.48 (d, J=6.4
Hz, 2H), 2.56 (brs, 4H), 2.80 (brs, 4H), 3.29 (brs, 2H), 3.53 (brs,
2H), 7.14 (m, 4H), 7.22 (m, 1H), 7.27 (m, 4H); .delta..sub.C-13
(100 MHz, CDCl.sub.3) .delta.: 4.18, 7.3, 12.8, 14.1, 30.3, 39.2,
43.2, 54.3, 62.7, 126.2, 126.6, 128.0, 129.5, 129.6, 134.1, 135.3,
136.3, 141.5, 142.9, 171.0.
[0107] Its HCl salt: Dec..gtoreq.100.degree.
C.(AcOEt-Ether-CH.sub.2Cl.sub- .2); .nu..sub.max (KBr) cm.sup.-1
3027, 2359, 1620, 1439, 958; Anal.Calcd.for
C.sub.27H.sub.34N.sub.2O. 1.0 HCl. 0.50CH.sub.2Cl.sub.2.
0.75H.sub.2O: C, 66.73; H, 7.64; N, 5.66. Found: C, 66.60; H, 7.45;
N, 5.78.
B) Synthetic Scheme For the Preparation of the Compound of Example
8
[0108] The compound of Example 8 was prepared by following the
procedure as is shown in Scheme 2 below. 12
[0109] (i) Preparation of
4-(2-Benzofuroyl)-N-t-butoxylcarbonylpiperidine (Compound 13)
[0110] To a solution of 2,3-benzofuran (295 mg, 2.5 mmol) in dry
THF (10 mL) was added t-butyllithium (1.5 mL, 1.7 M, 2.5 mmol) at
-78.degree. C. After 30 min, N-t-butoxylcarbonyl
N-methyl-N-methoxyl-isonipecotamide (544 mg, 2.0 mmol) in THF (2
mL) was dropwise added. the reaction mixture was warmed to r.t. and
then quenched with aqueous NH.sub.4Cl solution, and extracted with
ethyl acetate (2.times.50 mL). The combined organic layers were
washed with brine, dried over MgSO.sub.4. Removal of solvents gave
a crude product, which was purified by silica gel column eluting
with MeOH-CH.sub.2Cl.sub.2 (5:95) to provide
4-(2-benzofuroyl)-N-t-butoxy- lcarbonylpiperidine (13) (456 mg,
69%):
[0111] .delta..sub.H (400 MHz, CDCl.sub.3) 1.46 (s, 9H), 1.75 (m,
2H), 1.91 (m, 2H), 2.91 (m, 2H), 3.37 (m, 1H), 4.20 (brs, 2H), 7.29
(m, 1H), 7.46 (m, 1H), 7.53 (s, 1H), 7.56 (m, 1H), 7.69 (m, 1H);
.delta..sub.C-13 (100 MHz, CDCl.sub.3) .delta.: 27.8, 28.3, 43.1,
44.4, 79.5, 112.3, 112.9, 123.1, 123.8, 126.9, 128.2, 151.8, 154.5,
155.5, 192.8.
[0112] (ii) Preparation of
4-(.alpha.-Hydroxy-.alpha.-(4-N-t-butoxylcarbon-
ylpiperidinyl)-2-benzofuryl)-N,N-diethylbenzamide (Compound 14)
[0113] Method as described for compound 4, using
4-iodo-N,N-diethylbenzami- de (425 mg, 61%):
[0114] m.p. 102-106.degree. C. (CH.sub.2Cl.sub.2);
[0115] .nu..sub.max (KBr) cm.sup.-1 3362, 2970, 1690, 1617, 1425,
1288, 1160; .delta..sub.H (400 MHz, CDCl.sub.3) 1.06 (brs, 3H),
1.20 (brs, 3H), 1.24 (m, 2H), 1.46 (m, 11H), 2.42 (m, 1H), 2.58
(brs, 2H), 3.20 (brs, 2H), 3.50 (brs, 2H), 4.05 (brs, 2H), 4.37 (s,
1H), 6.70 (s, 1H), 7.16 (m, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.41 (d,
J=7.6 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.58 (d, J=8.0 Hz, 2H);
.delta..sub.C-13 (100 MHz, CDCl.sub.3) .delta.: 12.6, 13.9, 25.5,
26.3, 28.2, 39.0, 43.1, 44.9, 77.3, 79.0, 103.3, 110.9, 120.6,
122.5, 123.5, 125.6, 125.8, 127.9, 135.3, 144.0, 154.4, 154.5,
160.5, 170.9.
EXAMPLE 8
Preparation of
N,N-Diethyl-4-(2-benzofuryl-piperidin-4-ylidene-methyl)-ben- zamide
(Compound 15)
[0116] Method as described for Example 1, using compound 14 (135
mg, 88%):
[0117] .delta..sub.H (400 MHz, CDCl.sub.3) 1.20 (brs, 3H), 1.24
(brs, 3H), 2.36 (brs, 2H), 3.00 (brs, 4H), 3.15 (brs, 2H), 3.33
(brs, 2H), 3.56 (brs, 2H), 4.45 (brs, 1H), 6.25 (s, 1H), 7.24 (m,
4H), 7.41 (m, 4H); .delta..sub.C-13 (100 MHz, CDCl.sub.3) .delta.:
12.9, 14.2, 29.6, 32.0, 32.4, 39.3, 43.4, 47.2, 107.4, 111.0,
120.7, 122.7, 124.2, 126.0, 126.5, 128.2, 129.9, 136.1, 139.5,
140.5, 154.4, 156.2, 171.0.
[0118] Its HCl salt: Dec..gtoreq.120.degree.
C.(AcOEt-Ether-CH.sub.2Cl.sub- .2); .nu..sub.max (KBr) cm.sup.-1
2977, 2801, 1586, 1449, 1257.
C) Synthetic Scheme For the Preparation of the Compounds of
Examples 9-10
[0119] The compounds of Examples 9 and 10 were prepared by
following the procedure of Scheme 3 below. 13
[0120] (i) Preparation of
4-(4-Fluorobenzoyl)-N-t-butoxylcarbonylpiperidin- e (Compound
18)
[0121] A mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride
(compound 16) (2.44 g, 10 0 mmol), Di-tert-butyl dicarbonate (2.18
g, 10.0 mmol) and Na.sub.2CO.sub.3 (1.59 g, 15 mmol) in H2O-THF
(50/5 mL) was refluxed for 1 h. The reaction mixture was extracted
with ethyl acetate (2.times.100 mL). The combined organic layers
were washed with brine, dried over MgSO.sub.4. Removal of solvents
gave 4-(4-fluorobenzoyl)-N-t-b- utoxylcarbonylpiperidine (OB
701-31, 2.28 g, 74%);
[0122] m.p. 80-83.degree. C. (CH.sub.2Cl.sub.2); .nu..sub.max (KBr)
cm.sup.-1 2980, 2842, 1680, 1587, 1416, 1160; .delta..sub.H (400
MHz, CDCl.sub.3) 1.44 (s, 9H), 1.69 (m, 2H), 1.79 (m, 2H), 2.87 (m,
2H), 3.34 (m, 1H), 4.13 (brs, 2H), 7.12 (m, 2H), 7.95 (m, 2H);
.delta..sub.C-13 (100 MHz, CDCl.sub.3) .delta.: 27.4, 28.4, 43.2,
43.4, 79.6, 115.8, 115.9, 130.8, 130.9, 132.2, 154.6, 164.4, 166.9,
200.4.
[0123] (ii) Preparation of
4-(4-Chlorobenzoyl)-N-t-butoxylcarbonylpiperidi- ne (Compound
19)
[0124] Method as described for compound 18, using compound 17 (1.23
g, 85%):
[0125] m.p. 122-125.degree. C. (CH.sub.2Cl.sub.2); .nu..sub.max
(KBr) cm.sup.-1 2970, 2842, 1680, 1582, 1420, 1200; .delta..sub.H
(400 MHz, CDCl.sub.3) 1.47(s, 9H), 1.69 (m, 2H), 1.81 (m, 2H), 2.90
(m, 2H), 3.36 (m, 1H), 4.18 (brs, 2H), 7.44 (m, 2H), 7.88 (m, 2H);
.delta..sub.C-13 (100 MHz, CDCl.sub.3) .delta.: 28.3, 28.4, 43.2,
43.4, 79.6, 129.0, 129.6, 134.1, 139.4, 154.6, 200.7.
[0126] (iii) Preparation of
4-(.alpha.-Hydroxy-.alpha.-(4-N-t-butoxylcarbo-
nylpiperidinyl)-4-fluorobenzyl)-N,N-diethylbenzamide (Compound
20)
[0127] Method as described for compound 4, using compound 18 and
4-iodo-N,N-diethylbenzamide (454 mg, 47%):
[0128] m.p. 84-86.degree. C. (CH.sub.2Cl.sub.2); .nu..sub.max (KBr)
cm.sup.-1 3421, 2970, 1685, 1612, 1430, 1288, 1165; .delta..sub.H
(400 MHz, CDCl.sub.3) 1.13 (brs, 3H), 1.23 (brs, 3H), 1.32 (m, 4H),
1.44 (s, 9H), 2.48 (m, 1H), 2.68 (brs, 2H), 3.26 (brs, 2H), 3.54
(brs, 2H), 3.57 (s, 1H), 4.11 (brs, 2H), 6.96 (m, 2H), 7.27 (d,
J=8.0 Hz, 2H), 7.44 (m, 2H), 7.47 (d, J=8.0 Hz, 2H);
.delta..sub.C-13 (100 MHz, CDCl.sub.3) .delta.: 12.9, 14.0, 26.2,
28.2, 39.1, 43.2, 43.6, 44.3, 78.9, 79.1, 114.5, 114.7, 125.7,
126.1, 127.5, 127.6, 135.0, 141.2, 146.9, 154.5, 160.0, 162.5,
170.9.
[0129] (iv) Preparation of
4-(.alpha.-Hydroxy-.alpha.-(4-N-t-butoxylcarbon-
ylpiperidinyl)-4-chlorobenzyl)-N,N-diethylbenzamide (Compound
21)
[0130] Method as described for compound 4, using compound 19 and
4-iodo-N,N-diethylbenzamide (626 mg, 63%):
[0131] m.p. 100-105.degree. C. (CH.sub.2Cl.sub.2); .nu..sub.max
(KBr) cm.sup.-1 3411, 2970, 1685, 1617, 1425, 1288, 1165, 1092;
.delta..sub.H (400 MHz, CDCl.sub.3) 1.08 (brs, 3H), 1.20 (brs, 3H),
1.33 (m, 4H), 1.41 (s, 9H), 2.44 (m, 1H), 2.63 (brs, 2H), 3.22
(brs, 2H), 3.49 (brs, 2H), 3.99 (s, 1H), 4.05 (m, 2H), 7.20 (m,
4H), 7.39 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H);
.delta..sub.C-13 (100 MHz, CDCl.sub.3) .delta.: 12.5, 13.9, 25.9,
28.1, 39.0, 43.0, 44.1, 78.7, 79.0, 125.6, 126.0, 127.2, 127.8,
131.9, 134.8, 144.1, 146.6, 154.3, 170.7.
EXAMPLE 9
Preparation of
N,N-Diethyl-4-(4-fluorophenyl-piperidin-4-ylidene-methyl)-b-
enzamide (Compound 22)
[0132] Method as described for Example 1 (compound 6), using
compound 20.
[0133] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.12 (3H, br m,
C+E,uns H.sub.3CH.sub.2--), 1.24 (3H, br m, C+E,uns
H.sub.3CH.sub.2--), 2.32 (4H, m, piperidine C+E,uns H--), 2.54 (1H,
br m, N+E,uns H), 2.91 (4H, m. piperidine C+E,uns H--), 3.27 (2H,
br m, C+E,uns H.sub.2N--), 3.52 (2H, br m, C+E,uns H.sub.2N--),
7.00 (2H, m, Ar+E,uns H, 7.09 (2H, m, Ar+E,uns H), 7.11 (2H, d,
J=8.0 Hz, Ar+E,uns H), 7.29 (2H, d, J=8.0 Hz, Ar+E,uns H).
EXAMPLE 10
Preparation of
N,N-Diethyl-4-(4-chlorophenyl-piperidin-4-ylidene-methyl)-b-
enzamide (Compound 23)
[0134] Method as described for Example 1 (compound 6), using
compound 21.
[0135] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.13 (3H, br m,
C+E,uns H.sub.3CH.sub.2--), 1.22 (3H, br m, C+E,uns
H.sub.3CH.sub.2--), 2.02 (1H, br m, N+E,uns H), 2.30 (4H, m,
piperidine C+E,uns H--), 2.90 (4H, m, piperidine C+E,uns H--), 3.28
(2H, br m, C+E,uns H.sub.2N--), 3.53 (2H, br m, C+E,uns
H.sub.2N--), 7.04 (2H, d, J=8.0 Hz, Ar+E,uns H), 7.11 (2H, d, J=8.0
Hz, Ar+E,uns H), 7.25 (2H, d, J=8.0 Hz, Ar+E,uns H), 7.30 (2H, d,
J=8.0 Hz, Ar+E,uns H).
[0136] Its HCl salt: m.p. 115-120.degree. C.
(H.sub.2O-CH.sub.2Cl.sub.2); IR (KBr) 3337, 2973, 1618, 1431, 1290,
1092 cm.sup.-1; Anal. Calcd. for
C.sub.23H.sub.27ClN.sub.2O.1.0OHCl.1.20H.sub.2O: C, 62.64%; H,
6.95%; N, 6.35%; Found: C, 62.53%; H, 6.91%; N, 6.30%.
D) Synthetic Scheme For the Preparation of the Compound of Example
11
[0137] 14
EXAMPLE 11
Preparation of
N,N-Diethyl-4-(phenyl-N-allyl-piperidin-4-ylidene-methyl)-b-
enzamide (Compound 25)
[0138]
4-(.alpha.-hydroxy-.alpha.-(4-N-allylpiperidinyl)-benzyl)-N,N-dieth-
ylbenzamide (compound 24) (81 mg) was dissolved in CH.sub.2Cl.sub.2
(10 ml) and was treated with thionyl chloride (2 ml) at r.t. The
reaction mixture was refluxed for 2 hrs, and then condensed. The
residue was dissolved in ethyl acetate (50 mL) and the resulting
solution was washed with NH.sub.4OH (1 N), aqueous NH.sub.4Cl
solution and brine, dried over MgSO.sub.4. Removal of solvents gave
a crude product, which was purified by silica gel column eluting
with MeOH-CH.sub.2Cl.sub.2 (1:99.fwdarw.5:95) to provide
(.alpha.-phenyl-.alpha.-(4-N',N'-diethylami-
nocarbonylphenyl))-4-methylene-N-allylpiperidine (compound 25;
Example 11) (32 mg, 40%):
[0139] .delta..sub.H(400 MHz, CDCl.sub.3) 1.12 (brs, 3H), 1.21
(brs, 3H), 2.43 (m, 4H), 2.55 (m, 4H), 3.08 (d, J=6.8 Hz, 2H), 3.25
(brs, 2H), 3.53 (brs, 2H), 5.18 (m, 2H), 5.86 (m, 1H), 7.12 (m,
4H), 7.20 (m, 1H), 7.27 (m, 4H).
[0140] Its HCl salt: m.p. 85-95.degree. C.
(AcOEt-CH.sub.2Cl.sub.2); .nu..sub.max (KBr) cm.sup.-1 3491, 2971,
1624, 1428, 1289, 1096; Anal.Calcd.for
C.sub.26H.sub.32N.sub.2O.HCl. 0.25 H.sub.2O. 0.25CH.sub.2Cl.sub.2:
C, 69.95; H, 7.60; N, 6.21. Found: C, 70.00; H, 7.73; N, 6.07.
EXAMPLE 12
Preparation of
N,N-Diethyl-4-(4-chlorophenyl-N-benzyl-piperdin-4-ylidene-m-
ethyl)-benzamide (Compound 26)
[0141] 15
[0142] Method as described for Example 4, using compound 23 (96 mg)
and benzyl bromide (43 mg) provided
N,N-diethyl-4-(4-chlorophenyl-N-benzyl-pi-
peridin-4-ylidene-methyl)-benzamide (110 mg, 93%):
[0143] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.13 (3H, br m,
C+E,uns H.sub.3CH.sub.2--), 1.23 (3H, br m, C+E,uns
H.sub.3CH.sub.2--), 2.37 (4H, m, piperidine C+E,uns H--), 2.49 (4H,
m, piperidine C+E,uns H--), 3.28 (2H, br m, CH.sub.3C+E,uns
H.sub.2N--), 3.53 (4H, br m, PhC+E,uns H.sub.2N and CH.sub.3C+E,uns
H.sub.2N--), 7.04 (2H, d, J=8.0 Hz, Ar+E,uns H), 7.11 (2H, d, J=8.0
Hz, Ar+E,uns H), 7.25 (2H, d, J=8.0 Hz, Ar+E,uns H), 7.29 (7H, m,
Ar+E,uns H).
[0144] Its (CHOHCO.sub.2H).sub.2 salt: m.p. 100-110.degree. C.
(MeOH); IR (KBr) 3368, 2977, 1728, 1603, 1433, 1290, 1087
cm.sup.-1; Anal.Calcd.for
C.sub.34H.sub.39ClN.sub.2O.sub.7.1.50H.sub.2O: C, 62.81%; H, 6.51%;
N, 4.31%; Found: C, 62.85%; H, 6.17%; N, 4.21%.
EXAMPLE 13
Preparation of
N,N-Diethyl-4-[(N-3-methyl-2-butenyl)-phenyl-piperidin-4-yl-
idene-methyl]-benzamide (Compound 27)
[0145] 16
[0146] Method as described for example 4, using
1-Bromo-3-methyl-2-butene as the alkylating reagent.
[0147] IR (NaCl Film): HCl salt .nu.=3432, 2976, 1623, 1434,
cm.sup.-1.
[0148] .sup.1H NMR: (Base) (CDCl.sub.3, TMS) .delta.:
1.10.about.1.30 (6H, br, OCNCH.sub.2C+E,uns H.sub.3), 1.64 (3H, s,
.dbd.CC+E,uns H.sub.3), 1.73 (3H, s, .dbd.CC+E,uns H.sub.3), 2.40
(4H, m, NC+E,uns H.sub.2CH.sub.2), 2.52 (4H, m, .dbd.CC+E,uns
H.sub.2), 3.0 (2H, d, J=7.6 Hz, NC+E,uns H.sub.2CH.dbd.C),
3.20.about.3.60 (4H, br, OCNC+E,uns H.sub.2CH.sub.3),. 5.28 (1H, m,
NCH+E,uns .sub.2C+E,uns H.dbd.C), 7.16.about.7.45(9H, m,
Ar)ppm.
[0149] ANALYSIS: (%) Anal.Calcd.for:: C.sub.28H.sub.36N.sub.2O.
1.8HCl: C, 69.74; H, 7.90; N, 5.81. Found: C, 69.71; H, 7.48; N,
5.58.
EXAMPLE 14
Preparation of
N,N-diethyl-4-[(1-Cyclohexyl-piperidin-4-ylidene)-phenyl-me-
thyl]-benzamide (Compound 28)
[0150] 17
[0151] A mixture of compound 6 (100 mg, 0.29 mmol), cyclohexanone
(36 ul, 0.35 mmol) and Ti(OPr-i).sub.4 (0.17 ml, 0.58 mmol) was
ultrasonicated for 1 hr and then stirred at rt overnight under a
nitrogen atmosphere. The mixture was diluted with ethanol (5 ml)
and followed by addition of NaBH.sub.4 (33 mg, 0.87 mmol). The
resulting mixture was stirred for 12 hr at rt. 2N NH.sub.3.H.sub.2O
was added to quench the reaction and the mixture filtered through
celite. The filtrate was extracted with ethyl acetate several times
and the combined organic phases washed with water and brine, and
dried over Na.sub.2SO.sub.4. Concentration in vacuo and MPLC
purification (0::100 to 100:0 EtOAc:Heptane eluting on silcal gel
60) gave the title compound (24 mg, 20%).
[0152] m.p. (HCl salt): 105-109.degree. C. IR (HCl salt, film)
.nu.: 3394 (NH), 1620 (CONEt.sub.2)cm.sup.-1.
[0153] .sup.1H NMR (free amine, 400 MHz, CDCl.sub.3) .delta.:
1.00-1.25 (17H, m, NCH+E,uns
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2, 2.times.+E,uns CH.sub.3
and +E,uns CH(CH)C.dbd.C), 1.60 (1H, m, +E,uns CH(CH)C.dbd.C), 1.75
(1H, m, +E,uns CH(CH)C.dbd.C), 1.80 (1H, m, +E,uns CH(CH)C.dbd.C),
2.30 (3H, m, N+E,uns CH.sub.2 and N+E,uns CH), 2.60 (2H, m, N+E,uns
CH.sub.2), 3.20 (2H, bs, N+E,uns CH.sub.2CH.sub.3), 3.50 (2H, bs,
N+E,uns CH.sub.2CH.sub.3), 7.00-7.30 (9H, m, +E,uns Ar).
[0154] .sup.13C NMR (free amine, 100 MHz, CDCl.sub.3) .delta.:
12.7, 14.1, 25.9, 28.7, 32.0, 39.1, 43.2, 50.7, 50.8, 63.6, 126.0,
126.3, 127.9, 129.7, 129.8, 134.7, 134.9, 136.9, 142.0, 143.4,
171.2. Elemental analysis: Calcd.for
C.sub.29H.sub.40N.sub.2OCl.sub.2: C, 69.17; H, 8.01; N, 5.56.
Found: C, 69.17; H, 7.82; N, 5.18.
EXAMPLE 15
Preparation of
N,N-Diethyl-4-[(N-butyl)-phenyl-piperidin-4-ylidene-methyl]-
-benzamide (Compound 29)
[0155] 18
[0156] Method as described for Example 4, using 1-Iodobutane as the
alkylating reagent. IR (NaCl Film):(HCl salt) .nu.=3430, 2967,
2499, 1622, 1433 cm.sup.-1
[0157] .sup.1H NMR: (CDCl.sub.3, TMS) .delta.: 0.92 (3H, t, J=7.2
Hz, CH.sub.2C+E,uns H.sub.3), 1.10.about.1.26 (6H, br,
OCNCH.sub.2C+E,uns H.sub.3), 1.32 (2H, m, C+E,uns H2CH3), 1.53 (2H,
m, CH2C+E,uns H2CH2), 2.42 (6H, m NC+E,uns H2), 2.55 (4H, m,
.dbd.CCH2), 3.20.about.3.60 (4H, br, OCNC+E,uns H.sub.2CH.sub.3),
7.10.about.7.31 (9H, m Ar)ppm. ANALYSIS: (%) Anal.Calcd.for:
C.sub.27H.sub.36N.sub.2O.HCl.0.4CH.sub.2Cl.sub.2.0.4H- .sub.2O: C,
68.24; H, 8.07; N, 5.81. Found: C, 68.24; H, 8.12; N, 5.89.
EXAMPLE 16
Preparation of
N,N-Diethyl-4-[(N-4-methoxybenzyl)-phenyl-piperidin-4-ylide-
ne-methyl]-benzamide (Compound 30)
[0158] 19
[0159] Method as described for Example 4, using compound 6 (174 mg)
and 4-methoxybenzyl chloride (78 mg) provided
N,N-diethyl-4-[(N-4-methoxybenz-
yl)-phenyl-piperidin-4-ylidene-methyl]-benzamide (160 mg, 68%):
[0160] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.11 (3H, br,
C+E,uns H.sub.3CH.sub.2N--), 1.20 (3H, br, C+E,uns
H.sub.3CH.sub.2N--), 2.38 (4H, m, CC+E,uns H.sub.2C), 2.46 (4H, m,
NC+E,uns H.sub.2--), 3.26 (2H, m, NC+E,uns H.sub.2--), 3.47 (2H, s,
C+E,uns H.sub.2N--), 3.49 (2H, br, CH.sub.3C+E,uns H.sub.2N--),
3.77 (3H, s, OC+E,uns H.sub.3), 6.83 (2H, d, J=8.0 Hz, Ar+E,uns H),
7.05-7.30 (11H, m, Ar+E,uns H).
[0161] Its HCl salt: m.p. 100-110.degree. C. (CH.sub.2Cl.sub.2); IR
(KBr) 3425, 2974, 1618, 1515, 1434, 1255 cm.sup.-1; Anal.Calcd.for
C.sub.31H.sub.36N.sub.2O.sub.2.1.0HCl 0.35CH.sub.2Cl.sub.2: C,
70.41%; H, 7.11%; N, 5.24%; Found: C, 70.46%; H, 7.10%; N,
5.21%.
EXAMPLE 17
Preparation of
N,N-Diethyl-4-[(N-2,4-dichlorobenzyl)-phenyl-piperidin-4-yl-
idene-methyl]-benzamide (Compound 31)
[0162] 20
[0163] Method as described for Example 4, using compound 6 (174 mg)
and .alpha.,2,4-trichlorotoluene(98 mg) provided
N,N-diethyl-4-[(N-2,4-dichlo-
robenzyl)-phenyl-piperidin-4-ylidene-methyl]-benzamide (206 mg,
81%):
[0164] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.12 (3H, br,
C+E,uns H.sub.3CH.sub.2N--), 1.21 (3H, br, C+E,uns
H.sub.3CH.sub.2N--), 2.39 (4H, m, CC+E,uns H.sub.2C), 2.52 (4H, m,
NC+E,uns H.sub.2--), 3.28 (2H, m, NC+E,uns H.sub.2--), 3.53 (2H,
br, CH.sub.3C+E,uns H.sub.2N--), 3.57 (2H, m, NC+E,uns H.sub.2--),
7.05-7.48 (12H, m, Ar+E,uns H).
[0165] Its HCl salt: m.p. 95-110.degree. C. (CH.sub.2Cl.sub.2); IR
(KBr) 3408, 2976, 1620, 1472, 1436, 1288, 1101 cm.sup.-1;
Anal.Calcd.for C.sub.30H.sub.32N.sub.2OCl.sub.2.1.0HCl
0.30CH.sub.2Cl.sub.2: C, 63.91%; H, 5.95%; N, 4.92%, Found: C,
63.81%; H, 6.03%; N, 4.84%.
EXAMPLE 18
Preparation of
N,N-Diethyl-4-[(1-methyl-piperidin-4-ylidene)-phenyl-methyl-
]-benzamide (Compound 32)
[0166] 21
[0167]
N,N-Diethyl-4-[(piperidin-4-ylidene)-phenyl-methyl]-benzamide (0.34
g, 1.0 mmol) was disolved in acetonitrile (5 mL). Potassium
carbonate (0.14 g, 1.0 mmol) and methyl iodide (63 .mu.L, 1.0 mmol)
was added with stirring at 25.degree. C. After 30 min., the
reaction mixture was evaporated and put onto silica gel for
purification by chromatography using 0 to 10% MeOH(10% NH.sub.4OH)
in CH.sub.2Cl.sub.2 to give 48 mg of the final product (28% of
converted starting material), which was converted to the
hydrochloride salt by treatment with HCl in ether.
[0168] Mp: 110.degree. C. (dec.). IR (KBr) (cm-1): 2361, 1695,
1487, 1289. MS(free amine): 362, 318, 219, 189, 165, 144. .sup.1H
NMR: (amine, CDCl.sub.3): .delta.=1.1(m, 6H, amide-Me), 2.40 (s,
3H, MeN), 2.49, 2.60 (2m, 8H, piperazine-H), 3.40 (m, 4H,
amide-CH.sub.2) 7.08-7.34 (m, 9H, Ar-H).
C.sub.24H.sub.30N.sub.2O.times.0.1 H.sub.2O.times.3.1 HCl,
requires: C:60.39, H:7.03, N:5.87. Found C:60.43, H:6.84,
N:5.45.
EXAMPLE 19
Preparation of
N,N-Diethyl-4-[(N-tert-butoxycarbonyl-piperidin-4-yl)-8-qui-
nolinyl-hydroxy-methyl]-benzamide (Compound 33)
[0169] 22
[0170] To a solution of 4-iodo-N,N-diethylbenzamide (1.52 g, 5.0
mmol) and 8-bromoquinoline (1.0 g) in dry THF (30 mL) was added
n-butyllithium (7.0 mL, 2.5 M, 17.5 mmol) at -78.degree. C. After
10 min, N-t-butoxylcarbonyl ethyl isonipecotate (2) (0.77 g, 3.0
mmol) in THF (5 mL) was dropwise added. The reaction mixture was
warmed to .degree. C., and then quenched with aqueous NH.sub.4Cl
solution, and extracted with ethyl acetate (2.times.100 mL). The
combined organic layers were washed with brine, dried over
MgSO.sub.4. Removal of solvents gave a crude product, which was
purified by silica gel column eluting with MeOH-CH.sub.2Cl.sub.2
(2:98) to MTL 0599 (145 mg, 9%):
[0171] m.p. 100-105.degree. C.; IR (NaCl) 2971, 1686, 1625, 1426,
1167 cm.sup.-1; Anal.Calcd.for
C.sub.31H.sub.39N.sub.3O.sub.4.0.20H.sub.2O: C, 71.43%; H, 7.62%.
Found: C, 71.50%; H, 7.75%; .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 1.07 (3H, br, C+E,uns H.sub.3CH.sub.2N--), 1.19 (3H, br,
C+E,uns H.sub.3CH.sub.2N--), 1.24 (1H, m, piperidine C+E,uns H--),
1.43 (9H, s, C+E,uns H.sub.3C), 1.65 (1H, m, piperidine C+E,uns
H--), 1.89 (2H, m, piperidine C+E,uns H--), 2.52 (1H, m, piperidine
C+E,uns H--), 2.64 (1H, br, piperidine C+E,uns H--), 2.78 (1H, br,
piperidine C+E,uns H--), 3.22 (2H, br, CH.sub.3C+E,uns H.sub.2N--),
3.49 (2H, br, CH.sub.3C+E,uns H.sub.2N--), 4.16 (2H, br, piperidine
C+E,uns H--), 7.24 (2H, d, J=8.0 Hz, Ar+E,uns H), 7.35 (1H, dd,
J=8.0, 4.4 Hz, Ar+E,uns H), 7.55 (2H, d, J=8.0 Hz, Ar+E,uns H),
7.58 (1H, d, J=8.0 Hz, Ar+E,uns H), 7.71 (1H, d, J=8.0 Hz, Ar+E,uns
H), 7.80 (1H, d, J=8.0 Hz, Ar+E,uns H), 8.14 (1H, d, J=8.0 Hz,
Ar+E,uns H), 8.69 (1H, m, Ar+E,uns H), 9.80 (1H, s, O+E,uns H).
EXAMPLE 20
Preparation of
N,N-Diethyl-4-(8-quinolinyl-piperidin-4-ylidene-methyl)-ben- zamide
(Compound 34)
[0172] 23
[0173] A mixture of the compound of Example 19 (45 mg),
trifluoroacetic acid (1.0 mL) and trifluoromethanesulforic acid (1
mL) was refluxed for 8 hrs., and then condensed. The residue was
dissolved in AcOEt (50 ml). The resulting solution was washed with
1 N NaOH solution, aqueous NH.sub.4Cl solution and brine, dried
over Na.sub.2SO.sub.4. Removal of solvents gave a crude product,
which was purified by silica gel column eluting with NH.sub.4OH
(1N)-MeOH-CH.sub.2Cl.sub.2 (2.5:17.5:80) to provide
N,N-diethyl-4-(8-quinolinyl-piperidin-4-ylidene-methyl)-benzamide
(29 mg, 84%):
[0174] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.07 (3H, br m,
C+E,uns H.sub.3CH.sub.2--), 1.20 (3H, br m, C+E,uns
H.sub.3CH.sub.2--), 2.00 (2H, m, piperidine C+E,uns H--), 2.46 (1H,
s, N+E,uns H), 2.52 (2H, m, piperidine C+E,uns H--), 2.75 (1H, m,
piperidine C+E,uns H--), 2.92 (2H, m, piperidine C+E,uns H--), 3.05
(1H, m, piperidine C+E,uns H--), 3.22 (2H, m, C+E,uns H.sub.2N--),
3.49 (2H, m, C+E,uns H.sub.2N--), 7.23 (2H, m, Ar+E,uns H), 7.32
(2H, m, Ar+E,uns H), 7.36 (1H, m, Ar+E,uns H), 7.49 (2H, m,
Ar+E,uns H), 7.72 (1H, dd, J=6.4, 3.2 Hz, Ar+E,uns H), 8.11 (1H,
dd, J=8.4, 1.6 Hz, Ar+E,uns H), 8.91 (1H, dd, J=4.0, 1.6 Hz,
Ar+E,uns H).
[0175] Its HCl salt: m.p.>170.degree. C. (Dec.); IR (KBr) 3410,
2973, 1614, 1551, 1436, 1284 cm.sup.-1; Anal.Calcd.for
C.sub.26H.sub.29N.sub.3O- . 2.0 HCl. 0.50 CH.sub.2Cl.sub.2. 0.75
H.sub.2O: C, 60.23%; H, 6.39%; Found: C, 60.27%; H, 6.42%.
EXAMPLE 21
Preparation of
N,N-Diethyl-4-[(N-tert-butoxycarbonyl-piperidin-4-yl)-3-met-
hoxyphenyl-hydroxy-methyl]-benzamide (Compound 35)
[0176] 24
[0177] Method as for Example 19 using 3-bromoanisole provided the
title compound (226 mg, 23%):
[0178] m.p.95-103.degree. C.; IR (NaCl) 3422, 2973, 1684, 1614,
1429, 1289 cm.sup.-1; Anal.Calcd.for
C.sub.29H.sub.40N.sub.2O.sub.5.0.60H.sub.2O: C, 68.64%; H, 8.18%;
N, 5.52%. Found: C, 68.66%; H, 7.98%; N, 5.64%; .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 1.07 (3H, br, C+E,uns H.sub.3CH.sub.2N--),
1.19 (3H, br, C+E,uns H.sub.3CH.sub.2N--), 1.31 (4H, m, piperidine
C+E,uns H--), 1.41 (9H, s, C+E,uns H,C), 2.46 (1H, m, piperidine
C+E,uns H--), 2.64 (2H, br, piperidine C+E,uns H--), 3.22 (2H, br,
CH.sub.3C+E,uns H.sub.2N--), 3.49 (2H, br, CH.sub.3C+E,uns
H.sub.2N--), 3.65 (1H, s, O+E,uns H), 3.72 (3H, s, OC+E,uns
H.sub.3), 4.06 (2H, br, piperidine C+E,uns H--), 6.69 (1H, m,
Ar+E,uns H), 7.01 (1H, d, J=7.6 Hz, Ar+E,uns H), 7.08 (1H, s,
Ar+E,uns H), 7.17 (1H, d, J=8.0 Hz, Ar+E,uns H), 7.21 (2H, d, J=8.0
Hz, Ar+E,uns H), 7.48 (2H, d, J=8.0 Hz, Ar+E,uns H).
EXAMPLE 22
Preparation of
N,N-Diethyl-4-(3-methoxyphenyl-piperidin-4-ylidene-methyl)--
benzamide (Compound 36)
[0179] 25
[0180] Method as described for Example 1, using the compound of
Example 21 (100 mg) provided
N,N-diethyl-4-(3-methoxyphenyl-piperidin-4-ylidene-meth-
yl)-benzamide (75 mg, 98%):
[0181] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.12 (3H, br,
C+E,uns H.sub.3CH.sub.2N--), 1.23 (3H, br, C+E,uns
H.sub.3CH.sub.2N--), 2.34 (4H, m, piperidine C+E,uns H--), 2.91
(4H, br, piperidine C+E,uns H--), 3.17 (1H, s, N+E,uns H), 3.27
(2H, br, CH.sub.3C+E,uns H.sub.2N--), 3.52 (2H, br, CH.sub.3C+E,uns
H.sub.2N--), 3.76 (3H, s, OC+E,uns H.sub.3), 6.64 (1H, s, Ar+E,uns
H), 6.70 (1H, d, J=8.0 Hz, Ar+E,uns H), 6.76 (1H, d, J=7.6 Hz,
Ar+E,uns H), 7.15 (2H, d, J=8.0 Hz, Ar+E,uns H), 7.22 (1H, m,
Ar+E,uns H), 7.29 (2H, d, J=8.0 Hz, Ar+E,uns H).
[0182] Its HCl salt: m.p.>90.degree. C. (Dec); IR (NaCl) 2970,
1621, 1430, 1287 cm.sup.-1; Anal.Calcd.for
C.sub.24H.sub.30N.sub.2O.sub.2.HCl.1- .70H.sub.2O: C, 64.69%; H,
7.78%; N, 6.29%; Found: C, 64.82%; H, 7.60%; N, 6.08%
EXAMPLE 23
Preparation of
N,N-Diethyl-4-[(N-benzyl)-3-methoxyphenyl-piperidin-4-ylide-
ne-methyl]-benzamide (Compound 37)
[0183] 26
[0184] Method as for Example 4, using the compound of Example 22
(38 mg) provided
N,N-diethyl-4-[(N-benzyl)-3-methoxyphenyl-piperidin-4-ylidene-me-
thyl]-benzamide (46 mg, 98%):
[0185] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.12 (3H, br,
C+E,uns H.sub.3CH.sub.2N--), 1.25 (3H, br, C+E,uns
H.sub.3CH.sub.2N--), 2.38 (4H, m, piperidine C+E,uns H--), 2.48
(4H, br, piperidine C+E,uns H--), 3.27 (2H, br, CH.sub.3C+E,uns
H.sub.2N--), 3.52 (2H, s, Ph C+E,uns H.sub.2N), 3.53 (2H, br,
CH.sub.3C+E,uns H.sub.2N--), 3.75 (3H, s, OC+E,uns H.sub.3), 6.65
(1H, s, Ar+E,uns H), 6.69 (1H, d, J=8.0 Hz, Ar+E,uns H), 6.74 (1H,
d, J=7.6 Hz, Ar+E,uns H), 7.13 (2H, d, J=8.0 Hz, Ar+E,uns H),
7.13-7.32 (8H, m, Ar+E,uns H).
[0186] Its HCl salt: m.p. 100-110.degree. C. (CH.sub.2Cl.sub.2); IR
(NaCl) 3421, 2972, 1619, 1430, 1287 cm.sup.-1; Anal.Calcd.for
C.sub.31H.sub.36N.sub.2O.sub.2.HCl.0.40CH.sub.2Cl.sub.2: C, 69.96%;
H, 7.07%; N, 5.20%; Found: C, 69.94%; H, 7.06%; N, 5.15%.
EXAMPLE 24
Preparation of
N,N-Diethyl-4-[(N-tert-butoxycarbonyl-piperidin-4-yl)-3-flu-
orophenyl-hydroxy-methyl]-benzamide (Compound 38)
[0187] 27
[0188] Method as for Example 19 using 3-bromofluorobenzene provided
the title compound (257 mg, 27%):
[0189] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.03 (3H, br,
C+E,uns H.sub.3CH.sub.2N--), 1.15 (3H, br, C+E,uns
H.sub.3CH.sub.2N--), 1.19-1.29 (4H, m, piperidine C+E,uns H--),
1.35 (9H, s, C+E,uns H.sub.3C), 2.39 (1H, m, piperidine C+E,uns
H--), 2.59 (2H, br, piperidine C+E,uns H--), 3.17 (2H, br,
CH.sub.3C+E,uns HN--), 3.28 (1H, s, O+E,uns H), 3.45 (2H, br,
CH.sub.3C+E,uns H.sub.2N--), 4.02 (2H, br, piperidine C+E,uns H--),
6.80 (1H, m, Ar+E,uns H), 7.15 (3H, m, Ar+E,uns H), 7.18 (2H, d,
J=8.0 Hz, Ar+E,uns H), 7.39 (2H, d, J=8.0 Hz, Ar+E,uns H).
EXAMPLE 25
Preparation of
N,N-Diethyl-4-(3-fluorophenyl-piperidin-4-ylidene-methyl)-b-
enzamide (Compound 39)
[0190] 28
[0191] Method as for Example 20 using the compound of Example 24
(165 mg) provided
N,N-Diethyl-4-(3-fluorophenyl-piperidin-4-ylidene-methyl)-benzam-
ide (108 mg, 87%):
[0192] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.08 (3H, br,
C+E,uns H.sub.3CH.sub.2N--), 1.19 (3H, br, C+E,uns
H.sub.3CH.sub.2N--), 2.09 (1H, s, N+E,uns H), 2.25 (4H, m,
piperidine C+E,uns H--), 2.84 (4H, br, piperidine C+E,uns H--),
3.23 (2H, br, CH.sub.3C+E,uns H.sub.2N--), 3.47 (2H, br,
CH.sub.3C+E,uns H.sub.2N--), 6.74 (1H, m, Ar+E,uns H), 6.86 (2H, m,
Ar+E,uns H), 7.06 (2H, d, J=8.0 Hz, Ar+E,uns H), 7.18 (1H, m,
Ar+E,uns H), 7.24 (2H, d, J=8.0 Hz, Ar+E,uns H).
[0193] Its HCl salt: m.p.>70.degree. C. (Dec.); IR (NaCl) 2978,
1605, 1478, 1432, 1290 cm.sup.-1; Anal.Calcd.for
C.sub.23H.sub.27N.sub.2OF.HCl.- 0.25 CH.sub.2Cl.sub.2.1.50
H.sub.2O: C, 61.89%; H, 7.04%; N, 6.21%; Found: C, 61.97%; H,
6.95%; N, 6.22%.
E) Synthetic Scheme For the Preparation of the Compound of Example
26
[0194] The compound of Example 26 was prepared by following the
procedure as is shown in Scheme 5 below. 29
[0195] (i) Preparation of Preparation of 4'-Iodo-acetanilide
(Compound 40)
[0196] To a solution of 4-Iodo-aniline (15 g, 69 mmol) in dry
CH.sub.2Cl.sub.2 (100 ml) was added acetic anhydride(14.09 g, 138
mmol) at room temperature, the reaction mixture was then stirred
for 2 hr. The gray color precipitate formed during the reaction was
filtered, washed with ether and collected, the mother solution was
concentrated to dryness and AcOEt was added, the resulting
precipitate was filtered, washed with ether and combined with the
previous solid as the desired product (15.95 g, 88.7%).
[0197] .sup.1H NMR: (CDCl.sub.3) .delta.: 2.19 (3H, s, COC+E,uns
H.sub.3), 7.2 (1H, s, br, --N+E,uns H), 7.23 (2H, m, Ar), 7.61 (2H,
m, Ar)
[0198] (ii) Preparation of
4-(4-acetamidobenzoyl)-N-t-butoxylcarbonylpiper- idine (Compound
41)
[0199] To a solution of 4'-iodo-acetanilide (11.7 g, 45 mmol) in
dry THF (200 ml) was added NaH (1.62 g, 67.5 mmol) at 0.degree. C.,
the reaction mixture was stirred for 30 min while temperature was
warming up to room temperature, following by the slow addition of
n-BuLi (1.6 M in Heptane, 54 mmol) at -78.degree. C. The mixture
was stirred for 15 min then N-t-Butoxylcarbonyl
N'-methyl-N'methoxyl-isonipecotamide(6.15 g, 30 mmol) in THF (10
ml) was added dropwise via syringe. The reaction mixture was warmed
up to r.t. and then quenched with aqueous NH.sub.4Cl solution, and
extracted with ethyl acetate (2.times.100 ml) The organic layer was
washed with saturated (aq)NH.sub.4Cl, brine, dried over MgSO.sub.4
and concentrated to give a crude product, which was further
purified by silica gel column chromatography using
MeOH-CH.sub.2Cl.sub.2 (0:100.about.5:95) to provide the desired
product (9.02 g, 87%).
[0200] .sup.1H NMR: (CDCl.sub.3) .delta.: 1.47 (9H, s
(CH.sub.3).sub.3), 1.6-1.8 (4H, m, piperidine), 2.21 (3H, s,
COCH.sub.3), 2.9 (2H, m, piperidine), 3.37 (1H, m, COCH-), 4.15
(2H, m, piperidine), 7.64 (2H, m, Ar), 7.86 (1H, s, br, --CON+E,uns
H), 7.91 (2H, m, Ar).
[0201] (iii) Preparation of
4-((.alpha.-Hydroxy-.alpha.-(4-N-t-butoxylcarb-
onylpiperidinyl)-3-Fluorobenzyl) acetanilide (Compound 42)
[0202] Method as described for the preparation of compound 4 but
substituting 3-fluoro-1-iodobenzene for 1-bromonaphthalene to give
the title compound. (93%)
[0203] .sup.1H NMR: (DMSO-D.sub.6) .delta.: 1.2-1.3 (4H, m,
piperidine), 1.37 (9H, s, (CH.sub.3).sub.3), 2.0 (3H, s,
COCH.sub.3), 2.65 (3H, br, piperidine), 3.95 (2H, m, piperidine),
6.98 (1H, m, Ar), 7.21-7.50 (7H, m, Ar), 9.85 (1H, s, OC-N+E,uns
H)
[0204] (iv) Preparation of
N-methyl-4-(.alpha.-Hydroxy-.alpha.-(4-N-t-buto-
xylcarbonylpiperidinyl)-3-Fluorobenzyl) acetanilide (Compound
43)
[0205] To a 2M (aq)NaOH solution (10 ml), tetrabutylammonium
hydrogen sulphate(1.35 g, 3.97 mmol) was added, followed by the
addition of
4-(.alpha.-Hydroxy-)-.alpha.-(4-N-t-butoxylcarbonylpiperidinyl)-3-fluorob-
enzyl)acetanilide (825 mg, 1.86 mmol) and methyl iodide (769 mg,
5.4 mmol) in 10 ml of dichloromethane. The reaction mixture was
then refluxed for 1 hr, cooled down to r.t. The dichloromethane
layer was collected and evaporated to .about.1 ml. Ethyl acetate
was added and the precipitate was filtered out. The organic phase
was washed with brine and dried over MgSO4, concentrated to give a
solid which was further purified by MPLC using
MeOH-CH.sub.2Cl.sub.2 (5:95) as to give the pure titled compound
(770 mg, 93%).
[0206] .sup.1H NMR: (CDCl.sub.3) .delta.:1.2-1.5 (4H, m,
piperidin), 1.42 (9H, s, (CH.sub.3).sub.3), 1.83 (3H, s, COC+E,uns
H.sub.3), 2.52 (1H, m, --C+E,uns H--C--OH), 2.70 (2H, m,
piperidine), 2.86 (1H, s, br, --OH), 3.21 (3H, s, NC+E,uns
H.sub.3), 4.15 (2H, s, br, piperidine), 6.90 (1H, m, Ar), 7.12-7.60
(7H, m, Ar).
EXAMPLE 26
Preparation of
N-methyl-4-(3-Fluorophenyl-piperidin-4-ylidenemethyl)acetan- ilide
(Compound 44)
[0207] To a solution of
N-methyl-4-(.alpha.-Hydroxy-.alpha.-(4-N-t-butoxyl-
carbonylpiperidinyl)-3-fluorobenzyl) acetanilide (300 mg, 0.657
mmol) in dry dichloromethane (5 mL) was added trifluoroacetic acid
(5.0 mL) at r.t. The reaction mixture was refluxed for 4 hr., and
then condensed. The residue was dissolved in AcOEt (50 ml). The
resulting solution was washed with 2 N (aq)NaOH, (aq) NH.sub.4Cl
and brine, dried over MgSO.sub.4. Removal of solvents gave a crude
product, which was purified by MPLC eluting with
MeOH-CH.sub.2Cl.sub.2-NH.sub.4OH (5:95:1) to provide the pure
product (176 mg, 79%). mp. 235.about.237.degree. C. dec.
[0208] IR (NaCl Film): (HCl salt) .nu.(max.)=2961, 2722, 2480,
1658, 1608, 1580, 1507, 1429, 1381 cm.sup.-1.
[0209] .sup.1H NMR: (CDCl.sub.3) .delta.: 1.89 (3H, s, COC+E,uns
H.sub.3), 1.95 (1H, s, --N+E,uns H), 2.32(4H, m, piperazine), 2.92
(4H, m, piperazine), 3.26 (3H, s, N--C+E,uns H.sub.3), 6.81-7.28
(8H, m, Ar) .sup.13C NMR:(CDCl.sub.3) .delta.: 22.4, 33.2, 33.3,
37.0, 48.3, 113.3(m, C--F), 116.5(m, C--F), 125.4, 126.6, 129.5,
129.6, 130.9, 133.7, 137.7, 141.2, 142.8, 144.2, 161.3, 163.8,
170.4. ANALYSIS: (%) Anal.Calcd.for: C.sub.21H.sub.23N.sub.2FO.HCl:
C, 67.28; H, 6.45; N, 7.47. Found: C, 66.88; H, 6.44; N, 7.16.
F) Synthetic Scheme For the Preparation of the Compound of Example
27
[0210] The compound of Example 27 was prepared by following the
procedure as is shown in Scheme 6 below. 30
[0211] (i) Preparation of N-tert-Butoxylcarbonyl-4-piperidone
(Compound 46)
[0212] A mixture of compound 45 (50 g, 0.325 mol) and di-tert-butyl
dicarbonate (71 g, 0.325 mol) in 300 mL of dichloromethane were
stirred at 0.degree. C. while triethylamine (133 g, 1.32 mol) was
added dropwise. The mixture was allowed to warm to room temperature
and was stirred for 12 hrs. The solvent was evaporated and the
crude product was partitioned between water (400 mL) and diethyl
ether (400 mL). The aqueous phase was washed with an additional
portion of diethyl ether (400 mL). The combined ether was washed
with water (400 mL) and brine (400 mL) dried over MgSO.sub.4.
Removal of solvent gave compound 46 as a pale yellow solid. (55.3
g, 85%):
[0213] .delta..sub.H(400 MHz, CDCl.sub.3) 1.50 (s, 9H), 2.45 (t,
4H, J=6.1 Hz), 3.72 (t, 4H, J=6.1 Hz)
[0214] (ii) Preparation of
4-(4-Methoxycarbonyl-benzylidene)-piperidine-1-- carboxylic acid
tert-butyl ester (Compound 49)
[0215] Methyl 4-(bromomethyl) benzoate (compound 47) (11.2 g, 49
mmol) was dissolved in 25 mL trimethyl phosphite and refluxed under
N.sub.2 for 5 hrs. Excess trimethyl phosphite was removed by
co-distillation with toluene to give crude
4-(Dimethoxy-phosphorylmethyl)-benzoic acid methyl ester (compound
48).
[0216] .delta..sub.H(400 MHz, CDCl.sub.3) 3.20 (d, 2H, J=22 Hz),
3.68 (d, 3H 10.8 Hz), 3.78 (d, 3H, 11.2 Hz), 3.91 (s, 3H), 7.38 (m,
2H), 8.00 (d, 2H, J=8 Hz.
[0217] The crude product (compound 48) was dissolved in dry THF
(200 mL) under N.sub.2 and cooled to -78.degree. C. Lithium
diisopropylamide (32.7 mL 1.5 M in hexanes, 49 mmol) was added
dropwise. The solution was allowed to warm to room temperature. A
solution of compound 46 (9.76 g, 49 mmol in 100 mL dry THF) was
added to the reaction dropwise and was stirred under N.sub.2 for 12
hrs. Water (300 mL) and ethyl acetate (300 mL) were added to the
reaction mixture and extracted. The aqueous phase was washed with
ethyl acetate (2.times.300 mL). The combined ethyl acetate was
dried over MgSO.sub.4 and evaporated to give a crude product, which
was purified by silica gel chromatography (0-33% ethyl acetate in
hexanes) to provide compound 49 as a white solid (5.64 g, 35%).
[0218] .delta..sub.H(400 MHz, CDCl.sub.3) 1.44 (s, 1H), 2.31 (t,
J=5.5 Hz, 2H), 2.42 (t, J=5.5 Hz, 2H), 3.37 (t, J=5.5 Hz, 2H), 3.48
(t, J=5.5 Hz, 2H), 3.87(s, 3H), 6.33 (s, 1H), 7.20 (d J=6.7 Hz,
2H), 7.94 (d, J=6.7 Hz, 2H). .delta..sub.c-13 (CDCl.sub.3) 28.3,
29.2, 36.19, 51.9, 123.7, 127.8, 128.7, 129.4, 140.5, 142.1, 154.6,
166.8 ppm. .nu..sub.max (NaCl) cm.sup.-1 3424, 2974, 2855, 1718,
1688, 1606, 1427, 1362, 1276.
[0219] Analysis calculated for C.sub.19H.sub.25NO.sub.4: C 68.86%,
H 7.60%, N 4.23%; actual: C 69.1%, H7.69%, N 4.25%.
[0220] (iii) Preparation of
4-Bromo-4-[bromo-(4-methoxycarbonyl-phenyl)-me-
thyl]-piperidine-1-carboxylic acid tert-butyl ester (Compound
50)
[0221] To a solution of compound 49 (5.2 g, 16 mmol) in dry
dichloromethane (200 mL) was added K.sub.2CO.sub.3 (1.0 g). A
bromine solution (2.9 g, 18 mmol in 30 mL DCM) was then added
dropwise at 0.degree. C. and stirred for 1.5 hrs at room
temperature. The K.sub.2CO.sub.3 was removed by filtration and the
solvent was evaporated to dryness. The crude product was dissolved
in ethyl acetate (200 mL) and washed with water (200 mL), 0.5 M HCl
(200 mL) and brine (200 mL), dried over MgSO.sub.4. The solvent was
evaporated to give crude product which was recrystallized from
methanol to give compound 50 as a white solid (6.07 g, 78%).
[0222] .delta..sub.H (400 MHz, CDCl.sub.3) 1.28 (s, 9H), 1.75 (m,
2H), 1.90 (m, 2H), 2.1 (m, 4H), 3.08 (br, 4H), 3.90 (s, 3H), 4.08
(br, 4H), 5.14 (s, 1H), 7.57 (d, J=8.4 Hz, 2H) 7.98 (d, J=8.4 Hz,
2H). .delta..sub.c-13 (400 MHz, CDCl.sub.3) 28.3, 36.6, 38.3, 40.3,
52.1, 63.2, 72.9, 129.0, 130.3, 130.4, 141.9, 154.4, 166.3 ppm.
.nu..sub.max (NaCl) cm.sup.-1 3425, 2969, 1725, 1669, 1426, 1365,
1279, 1243.
[0223] Analysis calculated for: C.sub.19H.sub.25Br.sub.2NO.sub.4:
V46.6%, H 5.13%, N 2.85%; actual: 46.64%, H 5.16%, N 2.89%.
[0224] (iv) Preparation of
4-[Bromo-(4-caboxy-phenyl)-methylene]-piperidin- e-1-carboxylic
acid tert-butyl ester (Compound 51)
[0225] To a solution of compound 50 (5.4 g 11 mmol) in methanol
(300 mL) at 40.degree. C. was added 2.0 M NaOH (100 mL). The
reaction was stirred for 3 hrs at 40.degree. C. The crude salt was
isolated by filtration. The solid was dried overnight en vacuo. The
dry salt was dissolved in 40% acetonitrile/water and the pH was
adjusted to 2 using concentrated HCl. The desired product (7) (3.8
g, 87%) was isolated as a white powder by filtration.
[0226] .delta..sub.H (400 MHz, CDCl.sub.3) 1.45 (s, 9H), 2.22 (dd,
J=5.5 Hz, 6.1 Hz, 2H), 2.64 (dd, J=5.5 Hz, 6.1 Hz, 2H), 3.34 (dd,
J=5.5 Hz, 6.1 Hz, 2H), 3.54 (dd, J=5.5 Hz, 6.1 Hz, 2H), 7.35 (d,
J=6.7 Hz, 2H), 8.08 (d, J=6.7 Hz, 2H). .delta..sub.c-13 (400 MHz,
CDCl.sub.3) 28.3, 31.5, 34.2, 44.0, 115.3, 128.7, 129.4, 130.2,
137.7, 145.2, 154.6, 170.3.
[0227] Analysis calculated for: C.sub.18H.sub.22BrNO.sub.4: C
54.56%, H 5.60%, N 3.53%; actual: C 54.66%, H 5.68%, N 3.59%.
[0228] (v) Preparation of
4-[Bromo-(4-diethylcarbamoyl-phenyl)-methylene]--
piperidine-1-carboxylic acid tert-butyl ester (Compound 52)
[0229] To a solution of compound 51 (1.0 g, 2.5 mmol) in dry
dichloromethane (10 mL) at -20.degree. C. was added
iso-butylchloroformate (450 mg, 3.3 mmol). After 20 min at
-20.degree. C. diethylamine (4 mL) was added and the reaction was
allowed to warm to room temperature. After 1.5 hrs the solvent was
evaporated and the reaction mixture was partitioned between ethyl
acetate and water. The ethyl acetate was washed with water and
brine and dried over MgSO.sub.4 and removed by evaporation. The
crude product was purified by silica gel chromatography (0-60%
ethyl acetate in heptanes) to give the product (compound 52) as
white needles (800 mg, 73%).
[0230] .delta..sub.H(400 MHz, CDCl3) 1.13 (br, 3H), 1.22 (br, 3H),
1.44 (s, 9H), 2.22 (t, J=5.5 Hz, 2H). 2.62 (t, J=5.5 Hz, 2H), 3.31
(t, J=5.5 Hz, 2H), 3.52 (t, J=5.5 Hz, 2H), 7.27 (d, J=7.9 Hz. 2H),
7.33 (d, J=7.9 Hz, 2H). .delta..sub.c-13 (400 MHz, CDCl.sub.3)
12.71, 14.13, 28.3, 31.5, 34.2, 39.1, 43.2, 79.7, 115.9, 126.3,
129.3, 136.8, 137.1, 140.6, 154.6, 170.5.
[0231] Analysis calculated for: C.sub.22H.sub.31BrN.sub.2O.sub.3: C
58.3%, H 6.92%, N6.21%; actual: C 58.62%, 6.89%, 6.21%.
EXAMPLE 27
Preparation of
N,N-Diethyl-4-[piperidin-4-ylidene(3-trifluoromethyl-phenyl-
)-methyl]-benzamide (Compound 54,
Ar=3-Trifluoromethylphenyl)(general procedure)
[0232] The Suzuki coupling of compound 52 with a variety of boronic
acids and the subsequent deprotection were performed on a small
scale in parallel. The reactions and liquid-liquid extractions were
carried out in 25.times.150 mm culture tubes. The protocol for a
typical reaction is outlined below.
[0233] To a solution of compound 52 (25 mg, 57 .mu.mol) and
Tetrakis(triphenyl phosphine) palladium(0) (5 mg, 4.3 .mu.mol) in
xylenes (degassed, 0.5 mL) was added 3-Trifluorophenyl boronic acid
(28.5 mg, 150 .mu.mol) in ethanol (degassed, 0.5 mL) followed by
150 .mu.L of 2M Na.sub.2CO.sub.3 (aq) (300 .mu.mol). The reaction
was allowed to procede at 80.degree. C. for 1.5 hrs under Ar. The
reaction was diluted with water (1 mL) and diethyl ether (1 mL) and
vortexed. The organic phase was isolated and evaporated to give a
crude product (compound 9, Ar=3-Trifluoromethylphenyl).
[0234] The Boc group was removed by treating the crude product with
1 mL of TFA. After 30 minutes at room temperature the TFA was
evaporated to give the crude TFA salt. The salt was neutralized
with 1 M NH.sub.4OH(1.0M) and extracted into diethyl ether
(2.times.1 mL). The ether phase was acidified with 4.0 M HCl in
dioxane (200 .mu.L) and the HCl salt was extracted into water
(2.times.1 mL). The aqueous salt solution was washed with diethyl
ether (2.times.1 mL) and lyophilized to yield the product (compound
54, Ar=3-Trifluoromethylphenyl) as a white powder (10 mg, 39%).
[0235] .sup.1H NMR (CDCl.sub.3) (base) .delta. 1.11 (br, 3H), 1.20
(br, 3H), 2.26 (t, J=5.6 Hz, 2H), 2.31 (t, J=5.6 Hz, 2H), 2.88-2.91
(m, 4H), 3.27 (br, 2H), 3.52 (br, 2H), 7.10-7.47 (m, *H).
[0236] Analysis calculated for:
C.sub.24H.sub.28N.sub.2OF.sub.3Cl.times.1.- 80 H.sub.2O: C, 59.39;
H, 6.56; N, 5.77; Actual: C, 59.39; H, 5.90; N, 5.77.
EXAMPLES 28-52
[0237] By following the same procedure as described for compound 54
of Example 27 but substituting the respective boronic acids for
3-trifluoromethylphenylboronic acid, the following compounds were
also prepared.
EXAMPLE 28
N,N-Diethyl-4-(3-nitrophenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 55)
[0238] 3-nitrophenylboronic acid was used. 31
[0239] 1H NMR (CDCl3) (base) .delta. 1.11 (br, 3H), 1.21 (br, 3H),
2.27-2.34 (m, 4H), 2.92 (t, J=6.0 Hz, 4H), 3.26 (br, 2H), 3.52 (br,
2H), 7.10 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.40-7.50 (m,
2H), 7.95-8.08 (m, 2H)
EXAMPLE 29
N,N-Diethyl-4-(4-toluyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 56)
[0240] p-toluylboronic acid was used. 32
[0241] 1H NMR (CDCl.sub.3) (base) .delta. 1.10 (br, 3H), 1.19 (br,
3H), 2.29 (s, 3H), 2.26-2.31 (m, 4H), 2.86-2.88 (m, 4H), 3.25 (br,
2H), 3.49 (br, 2H), 6.95-7.28 (m, 8H)
EXAMPLE 30
N,N-Diethyl-4-(4-formylphenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 57)
[0242] 4-formylphenylboronic acid was used. 33
[0243] 1H NMR (CDCl3) (base) .delta. 1.10 (br, 3H), 1.20 (br, 3H),
2.28-2.33 (m, 4H), 2.89-2.92 (m, 4H), 3.25 (br, 2H), 3.50 (br, 2H),
7.08-7.79 (m, 8H), 9.95 (s, 1H)
EXAMPLE 31
N,N-Diethyl-4-(3-chloro-4-fluorophenyl-piperidin-4-ylidene-methyl)-benzami-
de (Compound 58)
[0244] 3-chloro-4-fluorophenylboronic acid was used. 34
[0245] 1H NMR (CDCl3) (base) .delta. 1.10 (br, 3H), 1.20 (br, 3H),
2.26-2.30 (m, 4H), 2.86-2.91 (m, 4H), 3.25 (br, 2H), 3.50 (br, 2H),
6.93-7.30 (m, 7H)
EXAMPLE 32
N,N-Diethyl-4-(4-fluorophenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 59)
[0246] 4-fluorophenylboronic acid was used. 35
[0247] 1 HNMR (CDCl3) (base) .delta. 1.11 (br, 3H), 1.16 (br, 3H),
2.25 (s, 4H), 2.84 (s, 4H), 3.20 (br, 2H), 3.47 (br, 2H), 6.92 (m,
2H), 7.01 (m, 4H), 7.23 (d, J=8.8 Hz, 2H)
EXAMPLE 33
N,N-Diethyl-4-(2-fluorophenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 60)
[0248] 2-fluorophenylboronic acid was used. 36
[0249] 1H NMR (CDCl3) (base) .delta. 1.11 (br, 3H), 1.15 (br, 3H),
2.10 (t, J=5.2 Hz, 2H), 2.27 (t, J=5.2 Hz, 2H), 2.83(m, 4H), 3.20
(br, 2H), 3.45 (br, 2H), 6.94-7.03 (m, 3H), 7.10-7.23 (m, 5H)
EXAMPLE 34
N,N-Diethyl-4-(2,4-dichlorophenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 61)
[0250] 2,4-dichlorophenylboronic acid was used. 37
[0251] 1H NMR (DMSO) (HCl salt) .delta. 1.07 (br, 6H), 2.24 (t,
2H), 2.50 (t, 2H), 3.10 (t, 2H), 3.30 (t, 2H), 3.31 (br, 2H), 3.43
(br, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.43 (d,
J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.68 (s, 1H), 9.20 (br,
2H)
EXAMPLE 35
N,N-Diethyl-4-(3,5-dichlorophenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 62)
[0252] 3,5-dichlorophenylboronic acid was used. 38
[0253] 1H NMR (DMSO) (HCl salt) .delta. 1.03 (br, 6H), 2.36-2.38
(m, 4H), 3.0-3.2 (m, 4H), 3.2 (br, 2H), 3.38 (br, 2H), 7.19 (s,
1H), 7.21 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 7.49 (s, 2H),
9.10 (br, 2H)
EXAMPLE 36
N,N-Diethyl-4-(3-acetylphenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 63)
[0254] 3-acetylphenylboronic acid was used. 39
[0255] 1H NMR (CDCl3) (base) .delta. 1.11 (br, 3H), 1.20 (br, 3H),
2.26 (t, J=5.6 Hz, 2H), 2.32 (t, J=5.6 Hz, 2H), 2.55 (s, 3H),
2.92-2.88 (m, 4H), 3.26 (br, 2H), 3.51 (br, 2H), 7.11 (d, J=8.0 Hz,
2H), 7.29 (d, J=8.0 Hz, 2H), 7.29 (d, J=7.2 Hz, 1H), 7.37 (t, J=8.0
Hz, 1H), 7.70 (s, 1H), 7.79 (d, J=7.2 Hz, 1H)
EXAMPLE 37
N,N-Diethyl-4-(3,5-trifluoromethylphenyl-piperidin-4-ylidene-methyl)-benza-
mide (Compound 64)
[0256] 3,5-trifluoromethylphenylboronic acid was used. 40
[0257] 1H NMR (DMSO) (HCl salt) .delta. 1.06 (br, 3H), 1.08 (br,
3H), 2.33 (br, 2H), 2.41 (br, 2H), 3.12 (br, 6H), 3.38 (br, 2H),
7.24 (d, J=7.6 Hz, 2H), 7.30 (d, J=7.6 Hz, 2H), 7.84 (s, 2H), 8.00
(s, 2H), 8.9 (br, 2H)
EXAMPLE 38
N,N-Diethyl-4-(3-thiophenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 65)
[0258] 3-thiophenylboronic acid was used. 41
[0259] 1 HNMR (DMSO) (HCl salt) .delta. 1.10 (br, 6H), 2.44 (t,
2H), 2.58 (t, 2H), 3.10-3.15 (m, 4H), 3.21 (br, 2H), 3.44 (br, 2H),
6.86 (d, J=4.8 Hz, 1H), 7.20 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz,
2H), 7.33 (s, 1H), 7.52 (d, J=4.8 Hz, 1H)
EXAMPLE 39
N,N-Diethyl-4-(2-thiophenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 66)
[0260] 2-thiophenylboronic acid was used. 42
[0261] 1H NMR (CDCl3) (base) .delta. 1.12 (br, 3H), 1.20 (br, 3H),
2.24 (t, J=5.2 Hz, 2H), 2.50 (t, J=5.2 Hz, 2H), 2.85 (t, J=5.6 Hz,
2H), 2.92 (t, J=5.6 Hz, 2H), 3.27 (br, 2H), 3.51 (br, 2H), 6.75 (d,
J=3.6 Hz, 1H), 6.93 (t, J=3.6 Hz, 1H), 7.16 (d, J=7.2 Hz, 2H), 7.21
(d, J=3.6 Hz, 1H), 7.30 (d, J=7.2 Hz, 2H)
EXAMPLE 40
N,N-Diethyl-4-(4-methylthiophenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 67)
[0262] 4-methylthiophenylboronic acid was used. 43
[0263] 1H NMR (CDCl3) (base) .delta. 1.11 (br, 3H), 1.20 (br, 3H),
2.32-2.75 (m, 4H), 2.45 (s, 3H), 2.90-2.87 (m, 4H), 3.26 (br, 2H),
3.51 (br, 2H), 7.01 (d, J=6.0 Hz, 2H), 7,10 (d, J=6.0 Hz, 2H), 7.15
(d, J=6.8 Hz, 2H), 7.27 (d, J=6.8 Hz, 2H)
EXAMPLE 41
N,N-Diethyl-4-(3-aminophenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 68)
[0264] 3-aminophenylboronic acid was used. 44
[0265] 1H NMR (CDCl3) (base) .delta. 1.11 (br, 3H), 1.20 (br, 3H),
2.27-2.33 (m, 4H), 2.86-2.90 (m, 4H), 3.27 (br, 2H), 3.51 (br, 2H),
3.57 (br, 2H), 3.68 (s, 1H), 6.39 (s, 1H), 6.52 (dd, J=1.6 Hz,
J=7.6 Hz, 2H), 7.06 (t, J=8.0 Hz, 1H), 7.12 (d, J=6.4 Hz, 2H), 7.26
(d, J=6.4 Hz, 2H)
EXAMPLE 42
N,N-Diethyl-4-(4-trifluoromethylphenyl-piperidin-4-ylidene-methyl)-benzami-
de (Compound 69)
[0266] 4-trifluoromethylphenylboronic acid was used. 45
[0267] 1H NMR (DMSO) (HCl salt) .delta. 1.05 (br, 6H), 2.35 (t,
2H), 2.40 (t, 2H), 3.09 (m, 6H), 3.35 (b,r, 2H), 7.17 (d, J=8.0 Hz,
2H), 7.28 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.67 (d, J=8.0
Hz, 2H), 8.71 (br, 2H)
EXAMPLE 43
N,N-Diethyl-4-(4-methoxyphenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 70)
[0268] 4-methoxyphenylboronic acid was used. 46
[0269] 1H NMR (CDCl3) (base) .delta. 1.12 (br, 3H), 1.19 (br, 3H),
2.29 (m, 4H), 2.87 (m, 4H), 3.27 (br, 2H), 3.51 (br, 2H), 3.77 (s,
3H), 6.80 (m, 2H), 7.00 (m, 2H), 7.10 (d, J=8.4 Hz, 2H), 7.26 (d,
J=8.4 Hz)
EXAMPLE 44
N,N-Diethyl-4-(3,4-dichlorophenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 71)
[0270] 3,4-dichlorophenylboronic acid was used. 47
[0271] 1 H NMR (CDCl3) (base) .delta. 1.12 (br, 3H), 1.20 (br, 3H),
2.28 (t, J=5.6 Hz, 4H), 2.89 (m, 4H), 3.27 (br, 2H), 3.52 (br, 2H),
6.8-7.4 (m, 7H)
EXAMPLE 45
N,N-Diethyl-4-(2-trifluoromethylphenyl-piperdine-4-ylidene-methyl)-benzami-
de (Compound 72)
[0272] 2-trifluoromethylphenylboronic acid was used. 48
[0273] 1H NMR (CDCl3) (base) .delta. 1.05 (br, 3H), 1.16 (br, 3H),
1.95 (m, 2H), 2.35-2.41 (m, 2H), 2.7-2.9 (m, 4H), 3.20 (br, 2H),
3.48 (br, 2H), 7.2-7.6 (m, 8H)
EXAMPLE 46
N,N-Diethyl-4-(3-toluyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 73)
[0274] m-tolylboronic acid was used. 49
[0275] 1H NMR (CDCl3) (base) .delta. 1.11 (br, 3H), 1.19 (br, 3H),
2.28 (s, 3H), 2.29 (m, 4H), 2.89 (m, 4H), 3.27 (br, 2H), 3.51 (br,
2H), 6.8-7.3 (m, 8H)
EXAMPLE 47
N,N-Diethyl-4-(2-methoxyphenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 74)
[0276] 2-methoxyphenylboronic acid was used. 50
[0277] 1H NMR (CDCl3) (base) .delta. 1.09 (br, 3H), 1.18 (br, 3H),
2.10 (q, J=4.8 Hz, 2H), 2.31 (q, J=4.8 Hz, 2H), 2.8-2.9 (m, 4H),
3.25 (br, 2H), 3.50 (br, 2H), 3.68 (s, 3H), 6.83-6.90 (m, 2H), 7.0
(d, 1H), 7.15-7.25 (m, 5H)
EXAMPLE 48
N,N-Diethyl-4-(3-formylphenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 75)
[0278] 3-formylphenylboronic acid was used. 51
[0279] 1H NMR (CDCl3) (base) .delta. 1.15 (br, 3H), 1.20 (br, 3H),
2.26-2.34 (m, 4H), 2.90-2.92 (m, 4H, 3.28 (br, 2H), 3.2 (br, 2H),
7.11-7.31 (m, 8H), 9.96 (s, 1H)
EXAMPLE 49
N,N-Diethyl-4-(2-naphtyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 76)
[0280] 2-naphtylboronic acid was used. 52
[0281] 1H NMR (CDCl3) (base) .delta. 1.11 (br, 3H), 1.20 (br, 3H),
2.35-2.39 (m, 4H), 2.91-2.96 (m, 4H), 3.27 (br, 2H), 3.51 (br, 2H),
7.16-7.40 (m, 5H), 7.42-7.44 (m, 2H), 7.57 (s, 1H), 7.72-7.79 (m,
2H)
EXAMPLE 50
N,N-Diethyl-4-(2-formylphenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 77)
[0282] 2-formylphenylboronic acid was used. 53
[0283] 1H NMR (CDCl3) (base) .delta. 1.09 (br, 3H), 1.18 (br, 3H),
1.70-2.10 (m, 2H), 2.40-2.49 (m, 2H), 2.76-2.84 (m, 2H), 2.85-2.97
(m, 2H), 3.23 (br, 2H), 3.48 (br, 2H), 7.13-7.40 (m, 6H), 7.53-7.55
(m, 1H), 7.90 (d, J=7.6 Hz,1H), 10.27 (s, 1H)
EXAMPLE 51
N,N-Diethyl-4-(4-acetylphenyl-piperidin-4-ylidene-methyl)-benzamide
(Compound 78)
[0284] 4-acetylphenylboronic acid was used. 54
[0285] 1H NMR (CDCl3) (base) .delta. 1.11 (br, 3H), 1.20 (br, 3H),
2.30-2.35 (m, 4H), 2.56 (s, 3H), 2.92 (m, 4H), 3.27 (br, 2H), 3.52
(br, 2H), 7.10-7.30 (m, 6H), 7.87 (d, J=7.2 Hz, 2H)
EXAMPLE 52
N,N-Diethyl-4-(3-trifluoromethylphenyl-piperdin-4-ylidene-methyl)-benzamid-
e (Compound 79)
[0286] 3-trifluoromethylphenylboronic acid was used. 55
[0287] 1H NMR (CDCl3) (base) .delta. 1.11 (br, 3H), 1.20 (br, 3H),
2.26 (t, J=5.6 Hz, 2H), 2.31 (t, J=5.6 Hz, 2H), 2.88-2.91 (m, 4H),
3.27 (br, 2H), 3.52 (br, 2H), 7.10-7.47 (m, 8H)
EXAMPLE 53
Preparation of
N,N-Diethyl-4-([1-(2,6-Diamino-hexanoyl)-piperidin-4-yliden-
e]-phenyl-methyl)-benzamide (Compound 80).
[0288] 56
[0289] L-Boc-Lysine(Cbz) (0.38 g, 1.0 mmol) was dissolved in dry
tetrahydrofuran (5 mL) under nitrogen at -15.degree. C.
N-Methylmorpholine (0.11 mL, 1.0 mmol) then isobutyl chloroformate
(0.13 mL, 1 mmol) was added. After stirring 10 minutes,
N,N-Diethyl-4-(phenyl-p- iperidin-4-ylidene-methyl)-benzamide
(compound 6) (0.35 g, 1.0 mmol) was added in tetrahydrofuran (1 mL)
and the temperature was allowed to rise to 25.degree. C. for 2 h.
The reaction mixture was evaporated onto silica gel. MPLC on silica
gel (0 to 100% ethyl acetate in heptane) gave 0.4 g.
[0290] The product (0.40 g, 0.56 mmol) was dissolved in methylene
chloride (10 mL) and treated with trifluoroacetic acid (3 mL) for
30 min, then the volatiles were evaporated. The residue was
dissolved in acetic acid (25 mL) and subjected to hydrogenolysis
1.5 h with hydrogen (1 atm) over palladium on carbon (10%, 0.10 g).
The solvent was evaporated and the residue purified by
chromatography on a short reverse phase (RP-18) column, eluting
with 0 to 30% acetonitrile in water. The free amine was extracted
with 5% potassium carbonate/methylene chloride to give 123 mg and
then treated with two equivalents of hydrochloric acid in
methanol/water. Lyophilization gave the dihydrochloride salt.
[0291] .sup.1H NMR: (free amine, CD.sub.3OD): .delta.=1.0-1.7(m,
16H, amide-Me, piperidine-H, lysine-H), 2.3-2.7 and 3.0-4.5 (m,
11H, amide-H, piperidine-H, lysine-H),4.8 (s, 4H, 2 NH.sub.2),
7.10-7.50 (m, 9H, Ar-H). C.sub.29H.sub.40N.sub.4O.sub.2.times.2.4
H.sub.2O.times.2 HCl, requires: C:58.76,H:7.96, N:9.43. Found
C:58.70, H:7.51, N:9.33.
EXAMPLE 54
Preparation of
4-[(4-Diethylcarbamoyl-phenyl)-phenyl-methylene]-piperidine-
-1-carboxylic acid phosphono-oxymethyl ester Compound 81)
[0292] 57
[0293] N,N-Diethyl-4-(phenyl-piperidin-4-ylidene-methyl)-benzamide
(compound 6) (0.62 g, 1.8 mmol) was dissolved in methylene chloride
(10 mL) and 1,8-bisdiaminonaphtalene (0.42 g, 2.0 mmol) was added.
The solution was cooled to 0.degree. C. and chloromethyl
chloroformate (0.25 g, 2.0 mmol) added dropwise in methylene
chloride (1 mL). After 2 h at 25.degree. C., a further portion of
first 1,8-bisdiaminonaphtalene (0.21 g, 1.0 mmol), then
chloromethyl chloroformate (0.12 g,1.0 mmol) was added. After a
total of 4 hours, the solution was washed with 1 M HCl, brine and
dried (MgSO.sub.4) and evaporation gave 0.62 g. The residue was
dissolved in toluene (25 mL), silver dibenzylphosphate (0.81 g, 2.1
mmol) was added and the mixture was heated 3 h at 80.degree. C. The
solution was filtered, then washed with 5% potassium carbonate
solution, brine, dried (K.sub.2CO.sub.3) and evaporated. MPLC on
silica gel (0 to 100% ethyl acetate in heptane) gave 0.66 g (0.96
mmol, 54%). The residue was dissolved in ethyl acetate (50 mL) and
subjected to hydrogenolysis (1 atm hydrogen) with palladium on
carbon (10%, 0.3 g) for 2 h. After filtration and evaporation of
the solvent, the product was treated with two equivalents of sodium
hydroxide in methanol/water. Lyophilization gave the disodium salt
of the product as a white solid.
[0294] .sup.1H NMR: (D.sub.2O): .delta.=1.03, 1.20 (2 m, 6H,
amide-Me), 2.34 (m, 4H, piperidine-H), 3.19-3.61 (m, 8H,
amide-CH.sub.2, piperidine-H), 5.44 (d, J=13 Hz, 2H, OCH.sub.2O),
7.18-7.36 (m, 9H, Ar-H).
[0295] Compounds 80 and 81 respectively, are suitable prodrugs of
the compounds of the general formula (I).
G) Synthetic Scheme For the Preparation of the Compounds of
Examples 55-57
[0296] The compounds of Examples 55, 56 and 57 were prepared by
following the procedure of Scheme 7 below. 58
[0297] (i) Preparation of
tert-butyl-4-{bromo[4-(morpholinocarbonyl)phenyl-
]methylene}-1-piperidinecarboxylate (Compound 82)
[0298] To a solution of compound 51, prepared according to scheme
6, (0.25 g, 0.625 mmole) and freshly distilled triethylamine (0.5
mL)in dichloromethane (12 mL), was added oxalyl chloride (0.38 mL
2.0 M, 0.75 mmole) dropwise at room temperature. The solution was
stirred for 10 minutes at room temperature and the solvent and
excess reagents were removed in vacuo to give the acid chloride as
a crude product which was used in the next step without further
purification.
[0299] Morpholine (56 mg, 0.65 mmole) was added to a solution of
the acid chloride (0.65 mmole) and triethylamine (0.5 mL) in
dichloromethane (5 mL). The reaction was allowed to proceed for one
hour at room temperature. The solvent was then removed in vacuo.
The crude product was partitioned between ethyl acetate (25 mL) and
water (25 mL). The water was washed with ethyl acetate and the
combined ethyl acetate was washed with 2M NaOH (2.times.25 mL), (2M
HCl (2.times.25 mL), brine (1.times.25 mL) and dried over magnesium
sulfate. The solvent was removed in vacuo to give the product
(compound 82) (294 mg, 97% yield).
[0300] .sup.1H nmr CDCl.sub.3 (400 MHz) 1.44 (s, 9H), 2.21 (t,
J=5.6 Hz, 2H), 2.62 (t, J=5.6 Hz, 2H), 3.31 (t, J=5.6 Hz, 2H), 3.52
(t, J=5.6 Hz, 2H), 3.69 (br, 8H), 7.31 (d, J=6.4 Hz, 2H), 7.37 (d,
J=6.4 Hz, 2H).
[0301] (ii) Preparation of
tert-butyl-4-{bromo[4-(piperidinocarbonyl)pheny-
l]methylene}-1-piperidinecarboxylate (Compound 83)
[0302] Same procedure as described for the preparation of compound
82, but using piperidine in place of morpholine.
[0303] .sup.1H nmr CDCl.sub.3 (400 MHz) 1.44 (s, 9H), 1.51 (br,
2H), 1.66 (br, 4H), 2.21 (t, J=5.6 Hz, 2H), 2.62 (t, J=5.6 Hz, 2H),
3.31 (t, J=5.6 Hz, 2H), 3.33(br, 2H), 3.52 (t, J=5.6 Hz, 2H), 3.68
(br, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H)
[0304] (iii) Preparation of
tert-butyl-4-{bromo[4-(tetrahydro-1H-1-pyrroly-
lcarbonyl)phenyl]methylene}-1-piperidinecarboxylate (Compound
84)
[0305] Same procedure as described for the preparation of compound
82, but using pyrrolidine in place of morpholine.
[0306] .sup.1H nmr CDCl.sub.3 (400 MHz) 1.44 (s, 9H), 1.87 (q,
J=6.8 Hz, 2H), 1.95 (q, J=6.8 Hz, 2H), 2.20 (t, J=5.6 Hz, 2H), 2.62
(t, J=5.6 Hz, 2H), 3.31 (t, J=5.6 Hz, 2H), 3.43 (t, J=6.8 Hz, 2H),
3.52 (t, J=5.6 Hz, 2H), 3.63 (t, J=6.8 Hz, 2H), 7.27 (d, J=8.0 Hz,
2H), 7.47 (d, J=8.0 Hz, 2H)
EXAMPLE 55
Preparation of
4-[(3-fluorophenyl)-piperidin-4-yl-methyl]-phenyl-morpholin-
-4-yl-methanone (Compound 85)
[0307] To a solution of compound 82 (37 mg, 0.082 mmol) and
tetrakis(triphenyl phosphine) palladium(0) (5 mg, 0.0043 mmol) in
xylenes (degassed, 0.5 mL) was added 3-fluorophenyl boronic acid
(25 mg, 0.18 mmol) in ethanol (degassed, 0.5 mL) followed by 150
.mu.L 2M Na.sub.2CO.sub.3 (aq) (300 .mu.mol). The reaction was
allowed to proceed at 80.degree. C. for 2 hrs under argon. The
reaction was diluted with water (1 mL) and diethyl ether (1 mL) and
vortexed. The organic phase was isolated and evaporated to give a
crude product which was used without further purification.
[0308] The Boc group was removed by treating the crude product with
1 mL of TFA. After 30 minutes at room temperature the TFA was
evaporated to give the crude TFA salt. The salt was neutralized
with 1 M NH.sub.4OH (1.0 M) and extracted into diethyl ether
(2.times.1 mL). The ether phase was acidified with 4.0 M HCl in
dioxane (200 .mu.L) and the HCl salt was extracted into water
(2.times.1 mL). The aqueous salt solution was washed with diethyl
ether (2.times.1 mL) and lyophilized to yield the product as a
white powder.
[0309] .sup.1H NMR CDCl.sub.3 (400 MHz) .delta. 2.67 (m, 4H), 3.19
(m, 4H), 3.45 (br, 2H), 3.68 (br, 6H), 6.75 (d, J=9.6 Hz, 1H), 6.85
(d, J=8.0 Hz, 1H), 6.95 (m, 1H), 7.11 (d, J=7.6 Hz, 2H), 7.25 (s,
1H), 7.35 (d, J=7.6 Hz, 2H).
EXAMPLE 56
Preparation of
4-[(3-fluorophenyl)-piperidin-4-yl-methyl]-phenyl-piperidin-
-1-yl-methanone (Compound 86)
[0310] Same procedure as described for the preparation of compound
85, but using compound 83 as starting material.
[0311] .sup.1H NMR CDCl.sub.3 (400 MHz) .delta. 1.51 (br, 2H), 1.65
(br, 4H), 2.60 (br, 4H), 3.14 (br, 4H), 3.33 (br, 2H), 3.68 (br,
2H), 6.76 (d, J=8.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.93 (t, J=8.0
Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.25 (s, 1H), 7.32 (d, J=8.4 Hz,
2H).
EXAMPLE 57
Preparation of
4-[(3-fluorophenyl)-piperidin-4-yl-methyl]-phenyl-pyrolidin-
-1-yl-methanone (Compound 87)
[0312] Same procedure as for the preparation of compound 85, but
using compound 84 as starting material.
[0313] .sup.1H NMR CDCl.sub.3 (400 MHz) .delta. 1.84-1.89 (m, 2H),
1.90-1.98 (m, 2H), 2.60-2.63 (m, 4H), 3.13-3.17 (m, 4H), 3.41 (t,
J=6.8 Hz, 2H), 3.62 (t, J=6.8 Hz), 6.73 (d, J=8.8 Hz, 1H), 6.86 (d,
J=7.2 Hz, 1H), 6.93 (m, 1H), 7.10 (d, J=8.0 Hz, 2H), 7.25 (s, 1H),
7.45 (d, J=8.0 Hz, 2H).
H) Synthetic Scheme For the Preparation of the Compounds of
Examples 58-68
[0314] The compounds of Examples 58-68 were prepared by following
the procedure of Scheme 8 (a)-(c) below. 59 60 61
[0315] (i) Preparation of
4-[Bromo-(4-ethoxycarbonylamino-phenyl)-methyl]--
piperidine-1-carboxylic acid tert-butyl ester (Compound 88)
[0316] To a mixture of compound 51, prepared according to Scheme 6,
(0.25 g, 0.625 mmole) in toluene (5 mL), was added
diphenylphosphorylazide (0.192 g, 0.70 mmole) and triethylamine
(0.1 mL, 0.7 mmole). After stirring the mixture under argon at
95.degree. C. for two hours an excess of anhydrous ethanol (2 mL)
and triethylamine (0.1 mL) were added and the solution was stirred
at 95.degree. C. for an additional 5 hours. After cooling to room
temperature the reaction mixture was partitioned between water and
diethyl ether. The ether was washed with water, dried over
magnesium sulfate and removed in vacuo to give the product
(compound 88) as a tan foam (300 mg, 99% yield).
[0317] .sup.1H NMR (400 MHz) (CDCl.sub.3) 1.30 (t, J=7.2 Hz, 3H),
1.44 (s, 9H), 2.22 (t, J=6.0 Hz, 2H), 2.60 (t, J=6.0 Hz, 2H), 3.31
(t, J=6.0 Hz, 2H), 3.51 (t, J=6.0 Hz, 2H), 4.21 (q, J=7.2 Hz, 2H),
6.58 (s, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H).
[0318] (ii) Preparation of
4-[(4-ethoxycarbonylaminophenyl)-(3-fluoropheny-
l)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (Compound
92)
[0319] The Suzuki coupling of the four vinyl bromides (compounds
88-91) with 3-fluorophenyl boronic acid was performed in parallel.
The reactions and liquid-liquid extractions were carried out in 25
mm.times.150 mm culture tubes. The protocol for a typical reaction
is outlined below.
[0320] To a solution of compound 88 (0.30 g, 0.625 mmoles) and
tetrakis(triphenyl phosphine), palladium(0) (50 mg) in toluene
(degassed, 5 mL) was added 3-fluorophenyl boronic acid (0.182 g,
1.3 mmoles) in ethanol (degassed, 5 mL) followed by 0.75 mL 2M
Na.sub.2CO.sub.3 (aq) (1.5 mmoles). The reaction was allowed to
proceed at 80.degree. C. for 3 hrs under argon. The reaction was
diluted with water and diethyl ether and vortexed. The organic
phase was isolated and evaporated to give a crude product. The
crude product was purified by silica gel chromatography (0-50%
EtOAc in hexanes) to give the product (compound 92) as a white
powder (0.166 g, 58% yield).
[0321] .sup.1H NMR (400 MHz) (CDCl.sub.3) .delta. 1.25 (t, J=7.2
Hz, 3H), 1.44 (s, 9H), 2.27-2.33 (m, 4H), 3.41-3.44 (m, 4H), 4.20
(q, J=7.2 Hz, 2H), 6.52 (s, 1H), 6.76 (d, J=10 Hz, 2H), 6.85-6.89
(m, 2H), 7.01 (d, J=8.8 Hz, 2H), 7.19-7.23 (m, 1H), 7.28 (d, J=8.8
Hz, 2H)
EXAMPLE 58
Preparation of
4-[(3-fluorophenyl)-piperidin-4-yl-methyl]-phenyl-carbamic Acid
Ethyl Ester (Compound 96)
[0322] The removal of the BOC protecting group was performed on a
small scale in parallel in test tubes (13 mm.times.100 mm). A
typical procedure is described below. The BOC group was removed by
treating compound 92 (50 mg, 0.11 mmole) with HCl in dioxane (4.0
M, 2 mL). The mixture was stirred at room temperature for 30
minutes. The solvent and HCl were removed in vacuo to yield the
product compound 96 as a white powder after lyophilization (40 mg,
99% yield).
[0323] .sup.1H NMR (400 MHz) (CDCl.sub.3) .delta. 1.28 (t, J=7.2
Hz, 3H), 2.27-2.31 (m, 4H), 2.85-2.91 (m, 4H), 4.19 (q, J=7.2 Hz,
2H), 6.50 (s, 1H), 6.76 d, J=10 Hz, 1H), 6.85-6.89 (m, 2H), 7.01
(d, J=8.8 Hz, 2H), 7.19-7.23 (m, 1H), 7.28 (d, J=8.8 Hz, 2H).
EXAMPLE 59
Preparation of
4-[(3-fluorophenyl)-piperidin-4-yl-methyl]-phenyl-methyl Carbamic
Acid Ethyl Ester (Compound 100)
[0324] The alkylation of the amide nitrogen was performed on a
small scale in parallel in test tubes (13 mm.times.100 mm). A
typical procedure is outline below.
[0325] To a solution of compound 92 (50 mg, 0.11 mmoles) in
dichloromethane (1.5 mL) was added methyl iodide (31 mg, 0.22
mmoles), aqueous sodium hydroxide (1.0 mL, 2M) and
tetrabutylammonium sulfate (44 mg, 0.13 mmoles). The solution was
refluxed for one hour. After cooling to room temperature the
dichloromethane was separated and evaporated. Ether was added to
the residue and the white tetrabutylammonium iodide was removed by
filtration. The ether was removed in vacuo to give the crude
product compound 100 as a clear oil. The BOC group was removed by
treatment with HCl in dioxane as described above to give the
product as a white powder after lyophilization (17 mg, 42%
yield).
[0326] .sup.1H NMR (400 MHz) (CDCl.sub.3) .delta. 1.23 (t, J=7.2
Hz, 3H), 2.27-2.33 (m, 4H), 2.85-2.91 (m, 4H), 3.26 (s, 3H), 4.15
(q, J=7.2 Hz, 2H), 6.78 (d, J=10 Hz, 1H), 6.85-6.89 (m, 2H), 7.05
(d, J=8.0 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H) 7.19-7.23 (m, 1H).
EXAMPLE 60
Preparation of
4-[(1-benzylpiperidin-4-yl)-(3-fluorophenyl)-methyl]-phenyl-
-carbamic Acid Ethyl Ester (Compound 116)
[0327] The benzylation of compound 100 was performed on a small
scale in parallel in test tubes (13 mm.times.100 mm). A typical
procedure is outline below.
[0328] The free base form of compound 100 was obtained by addition
of ammonium hydroxide (1M, 0.5 mL) to an aqueous solution of
compound 100 (0.046 mmoles) and extracted into ether. The ether was
removed in vacuo to give an oil which was dissolved in
dichloromethane and treated with benzyl bromide (0.14 mL of 0.5 M
in dichloromethane and triethylamine (0.05 mL). The solution was
stirred at room temperature for 5 hours. The solvent was removed in
vacuo. The product was dissolved in water/acetonitrile/HCl (2:1:0.5
M) and lyophilized to give the product compound 108 as a white
powder.
[0329] .sup.1H NMR (400 MHz) (CDCl.sub.3) .delta. 1.28 (t, J=7.2
Hz, 3H), 2.33-2.36 (m, 4H), 2.38-2.46 (m, 4H), 3.51 (s, 2H), 4.19
(q, J=7.2 Hz, 2H), 6.50 (s, 1H), 6.78 d, J=10 Hz, 1H), 6.85-6.89
(m, 2H), 7.05 (d, J=8.0 Hz, 2H), 7.19-7.30 (m, 7H).
EXAMPLES 61-68
[0330] The following compounds were also made by following the
synthesis routes described in Schemes 8 (a)-(c).
1TABLE 1 Characterization data [.sup.1HNMR; 400 MHz Example
Compound Chemical structure (CDCl.sub.3)] Scheme 61 108 62
.delta.1.17(t, J=7.6Hz, 3H), 2.28-2.35(m, 4H), 2.40-2.45 (m, 4H),
3.21(s, 3H), 3.50(s, 2H), 4.10(q, J=7.2Hz, 2H), 6.73(d, J=8.7Hz,
1H), 6.85 (m, 2H), 7.01(d, J=8.8 Hz, 2H), 7.2-7.3(m, 8H) 8 (c) 62
103 63 .delta.1.21(d, J=6.8Hz, 6H), 2.28(t, J=5.6Hz, 2H), 2.31 (t,
J=5.6Hz, 2H), 2.88(t, J=5.6Hz, 4H), 3.25(s, 3H), 4.93(quin,
J=6.0Hz, 1H), 6.78(d, 1H), 6.87(d, 2H), 7.04(d, 2H), 7.14(d, 2H),
7.15-7.29(m, 2H) 8 (b) 63 107 64 .delta.1.14(t, J=7.2Hz, 3H),
1.20(d, J=6.4Hz, 6H), 2.92 (t, J=5.2Hz, 2H), 2.33(t, J=5.2Hz, 2H),
2.90(t, 3=5.2 Hz, 4H), 3.66(q, J=7.6Hz, 2H), 4.93(quin, J=6.0Hz,
1H), 6.79(d, 1H), 6.88(d, 2H), 7.02(d, 2H), 7.15(d, 2H),
7.18-7.25(m, 2H) 8 (b) 64 102 65 .delta.2.27-2.33(m, 4H),
2.88-2.90(m, 4H), 3.27(s, 3H), 3.70(s, 3H), 6.79(d, 10Hz,1H),
6.88-6.90(m, 2H), 7.06 (d, 3=8.4Hz, 2H), 7.13(d, J=8.4Hz, 2H),
7.20-7.25(m, 1H) 8 (b) 65 106 66 .delta.1.13(t, J=6.8Hz, 3H),
2.27-2.33(m, 4H), 2.88-2.90(m, 4H), 3.67(s, 3H), 3.68(q, J=6.8Hz,
2H), 6.79 (d, 10Hz, 1H), 6.88-6.90 (m, 2H), 7.06(d, J=8.4Hz, 2H),
7.13(d, J=8.4Hz, 2H), 7.20-7.25(m, 1H) 8 (b) 66 104 67
.delta.1.13(t, J=6.8Hz, 3H), 1.21(t, J=7.2Hz, 3H), 2.30-2.36(m,
4H), 2.91-2.93(m, 4H), 3.67(q, J=6.8 Hz, 2H), 4.13(q, J=6.8Hz, 2H),
6.79(d, 10Hz, 1H), 6.88-6.90(m, 2H), 7.06(d, J=8.4Hz, 2H), 7.13(d,
J=8.4Hz, 2H), 7.20-7.25 (m, 1H) 8 (b) 67 99 68 .delta.1.26(d,
J=6.0Hz, 6H), 2.27-2.32(m, 4H, 2.87-2.89(m, 4H), 4.95-5.02(m, 1H),
6.56(s, 1H), 6.79(d, 10Hz, 1H), 6.88-6.90(m, 2H), 7.01(d, J =8.4Hz,
2H), 7.20-7.25(m, 1H), 7.27(d, J=8.4Hz, 2H) 8 (b) 68 98 69
.delta.2.27-2.31(m, 4H), 2.86-2.89(m, 4H), 3.75(s, 3H), 6.64(s,
1H), 6.76-6.80(m, 1H), 6.85-7.00(m, 2H), 7.02(d, J=8.8Hz, 2H),
7.18-7.22(m, 1H), 7.28(d, J=8.8Hz, 2H) 8 (b)
[0331] The best mode of performing the invention known at present,
is to use the compounds 6, 7, 9, 10, 12, 26. 27, 34, 39, 44, 58,
59, 62, 69, 71, 104, 106, and 109.
Pharmaceutical Compositions
[0332] The novel compounds according to the present invention may
be administered orally, intramuscularly, subcutaneously, topically,
intranasally, intraperitoneally, intrathoracially, intravenously,
epidurally, intrathecally, intracerebroventricularly and by
injection into the joints.
[0333] A preferred route of administration is orally, intravenously
or intramuscularly.
[0334] The dosage will depend on the route of administration, the
severity of the disease, age and weight of the patient and other
factors normally considered by the attending physician, when
determining the individual regimen and dosage level at the most
appropriate for a particular patient.
[0335] For preparing pharmaceutical compositions from the compounds
of this invention, inert, pharmaceutically acceptable carriers can
be either solid or liquid. Solid form preparations include powders,
tablets, dispersible granules, capsules, cachets, and
suppositories.
[0336] A solid carrier can be one or more substances which may also
act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, or tablet disintegrating agents; it can
also be an encapsulating material.
[0337] In powders, the carrier is a finely divided solid which is
in a mixture with the finely divided active component. In tablets,
the active component is mixed with the carrier having the necessary
binding properties in suitable proportions and compacted in the
shape and size desired.
[0338] For preparing suppository compositions, a low-melting wax
such as a mixture of fatty acid glycerides and cocoa butter is
first melted and the active ingredient is dispersed therein by, for
example, stirring. The molten homogeneous mixture is then poured
into convenient sized molds and allowed to cool and solidify.
[0339] Suitable carriers are magnesium carbonate, magnesium
stearate, talc, lactose, sugar, pectin, dextrin, starch,
tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a
low-melting wax, cocoa butter, and the like.
[0340] Pharmaceutically acceptable salts are acetate,
benzenesulfonate, benzoate, bicarbonate. bitartrate, bromide,
calcium acetate, camsylate, carbonate, chloride, citrate,
dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,
glucaptate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
hydroxynaphthoate, iodide, isethionate, lactate, lactobionate,
malate, maleate, mandelate mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, pamoate (embonate),
pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,
stearate, subacetate, succinate, sulfate, tannate, tartrate,
teoclate, triethiodide, benzathine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine, procaine, aluminium,
calcium, lithium, magnesium, potassium, sodium, and zinc.
[0341] Preferred pharmaceutically acceptable salts are the
hydrochlorides and citrates.
[0342] The term composition is intended to include the formulation
of the active component with encapsulating material as a carrier
providing a capsule in which the active component (with or without
other carriers) is surrounded by a carrier which is thus in
association with it. Similarly, cachets are included.
[0343] Tablets, powders, cachets, and capsules can be used as solid
dosage forms suitable for oral administration.
[0344] Liquid from compositions include solutions, suspensions, and
emulsions. Sterile water or water-propylene glycol solutions of the
active compounds may be mentioned as an example of liquid
preparations suitable for parenteral administration. Liquid
compositions can also be formulated in solution in aqueous
polyethylene glycol solution.
[0345] Aqueous solutions for oral administration can be prepared by
dissolving the active component in water and adding suitable
colorants, flavoring agents, stabilizers, and thickening agents as
desired. Aqueous suspensions for oral use can be made by dispersing
the finely divided active component in water together with a
viscous material such as natural synthetic gums, resins, methyl
cellulose, sodium carboxymethyl cellulose, and other suspending
agents known to the pharmaceutical formulation art.
[0346] Preferably the pharmaceutical compositions is in unit dosage
form. In such form, the composition is divided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of the preparations, for example, packeted
tablets, capsules, and powders in vials or ampoules. The unit
dosage form can also be a capsule, cachet, or tablet itself, or it
can be the appropriate number of any of these packaged forms.
BIOLOGICAL EVALUATION
A) IN VITRO MODEL
[0347] Cell Culture
[0348] Human 293S cells expressing cloned human .mu., .delta., and
.kappa. receptors and neomycin resistance were grown in suspension
at 37.degree. C. and 5% CO.sub.2 in shaker flasks containing
calcium-free DMEM 10% FBS, 5% BCS, 0.1% Pluronic F-68, and 600
.mu.g/ml geneticin.
[0349] Membrane Preparation
[0350] Cells were pelleted and resuspended in lysis buffer (50 mM
Tris, pH 7.0, 2.5 mM EDTA, with PMSF added just prior to use to 0.1
mM from a 0.1 M stock in ethanol), incubated on ice for 15 min,
then homogenized with a polytron for 30 sec. The suspension was
spun at 1000 g (max) for 10 min at 4.degree. C. The supernatant was
saved on ice and the pellets resuspended and spun as before. The
supernatants from both spins were combined and spun at 46,000
g(max) for 30 min. The pellets were resuspended in cold Tris buffer
(50 mM Tris/Cl, pH 7.0) and spun again. The final pellets were
resuspended in membrane buffer (50 mM Tris, 0.32 M sucrose, pH
7.0). Aliquots (1 ml) in polypropylene tubes were frozen in dry
ice/ethanol and stored at -70.degree. C. until use. The protein
concentrations were determined by a modified Lowry assay with
SDS.
[0351] Binding Assays
[0352] Membranes were thawed at 37.degree. C., cooled on ice,
passed 3 times through a 25-gauge needle, and diluted into binding
buffer (50 mM Tris, 3 mM MgCl.sub.2, 1 mg/ml BSA (Sigma A-7888), pH
7.4, which was stored at 4.degree. C. after filtration through a
0.22 m filter, and to which had been freshly added 5 .mu.g/ml
aprotinin, 10 .mu.M bestatin, 10 .mu.M diprotin A, no DTT).
Aliquots of 100 .mu.l (for .mu.g protein, see Table 1) were added
to iced 12.times.75 mm polypropylene tubes containing 100 .mu.l of
the appropriate radioligand (see Table 1) and 100 .mu.l of test
peptides at various concentrations. Total (TB) and nonspecific (NS)
binding were determined in the absence and presence of 10 .mu.M
naloxone respectively. The tubes were vortexed and incubated at
25.degree. C. for 60-75 min, after which time the contents are
rapidly vacuum-filtered and washed with about 12 mil/tube iced wash
buffer (50 mM Tris, pH 7.0, 3 mM MgCl.sub.2) through GF/B filters
(Whatman) presoaked for at least 2 h in 0.1% polyethyleneimine. The
radioactivity (dpm) retained on the filters was measured with a
beta counter after soaking the filters for at least 12 h in
minivials containing 6-7 ml scintillation fluid. If the assay is
set up in 96-place deep well plates, the filtration is over
96-place PEI-soaked unifilters, which were washed with 3.times.1 ml
wash buffer, and dried in an oven at 55.degree. C. for 2 h. The
filter plates were counted in a TopCount (Packard) after adding 50
.mu.l MS-20 scintillation fluid/well.
[0353] Data Analysis
[0354] The specific binding (SB) was calculated as TB-NS, and the
SB in the presence of various test peptides was expressed as
percentage of control SB. Values of IC.sub.50 and Hill coefficient
(n.sub.H) for ligands in displacing specifically bound radioligand
were calculated from logit plots or curve fitting programs such as
Ligand, GraphPad Prism, SigmaPlot, or ReceptorFit. Values of
K.sub.i were calculated from the Cheng-Prussoff equation.
Mean.+-.S.E.M. values of IC.sub.50, K.sub.i and n.sub.H were
reported for ligands tested in at least three displacement
curves.
[0355] Receptor Saturation Experiments
[0356] Radioligand K.sub..delta. values were determined by
performing the binding assays on cell membranes with the
appropriate radioligands at concentrations ranging from 0.2 to 5
times the estimated K.sub..delta. (up to 10 times if amounts of
radioligand required are feasable). The specific radioligand
binding was expressed as pmole/mg membrane protein. Values of
K.sub..delta. and B.sub.max from individual experiments were
obtained from nonlinear fits of specifically bound (B) vs. nM free
(F) radioligand from individual according to a one-site model.
B) BIOLOGICAL MODEL (IN VIVO MODEL)
FREUND'S COMPLETE ADJUVANT (FCA), AND SCIATIC NERVE CUFF INDUCED
MECHANO-ALLODYNIA IN RAT
[0357] Animals
[0358] Male Sprague-Dawley rats (Charles River, St-Constant,
Canada) weighing 175-200 g at the time of surgery were used. They
were housed in groups of three in rooms thermostatically maintained
at 20.degree. C. with a 12:12 hr light/dark cycle, and with free
access to food and water. After arrival, the animals were allowed
to acclimatize for at least 2 days before surgery. The experiments
were approved by the appropriate Medical Ethical Committee for
animal studies.
EXPERIMENTAL PROCEDURE
FREUND'S COMPLETE ADJUVANT
[0359] The rats were first anesthetized in a Halothane chamber
after which 10 .mu.l of FCA was injected s.c. into the dorsal
region of the left foot, between the second and third external
digits. The animals were then allowed to recover from anesthesia
under observation in their home cage.
SCIATIC NERVE CUFF
[0360] The animals were prepared according to the method described
by Mosconi and Kruger (1996). Rats were anesthetized with a mixture
of Ketamine/Xylazine i.p. (2 ml/kg) and placed on their right side
and an incision made over, and along the axis of, the lateral
aspect of the left femur. The muscles of the upper quadriceps were
teased apart to reveal the sciatic nerve on which a plastic cuff
(PE-60 tubing, 2 mm long) was placed around. The wound was then
closed in two layers with 3-0 vicryl and silk sutures.
DETERMINATION OF MECHANO-ALLODYNIA USING VON FREY TESTING
[0361] Testing was performed between 08:00 and 16:00 h using the
method described by Chaplan et al. (1994). Rats were placed in
Plexiglas cages on top of a wire mesh bottom which allowed access
to the paw, and were left to habituate for 10-15 min. The area
tested was the mid-plantar left hind paw, avoiding the less
sensitive foot pads. The paw was touched with a series of 8 Von
Frey hairs with logarithmically incremental stiffness (0.41, 0.69,
1.20, 2.04, 3.63, 5.50, 8.51, and 15.14 grams; Stoelting, Ill.,
USA). The von Frey hair was applied from underneath the mesh floor
perpendicular to the plantar surface with sufficient force to cause
a slight buckling against the paw, and held for approximately 6-8
seconds. A positive response was noted if the paw was sharply
withdrawn. Flinching immediately upon removal of the hair was also
considered a positive response. Ambulation was considered an
ambiguous response, and in such cases the stimulus was
repeated.
TESTING PROTOCOL
[0362] The animals were tested on postoperative day 1 for the
FCA-treated group and on post-operative day 7 for the Sciatic Nerve
Cuff group. The 50% withdrawal threshold was determined using the
up-down method of Dixon (1980). Testing was started with the 2.04 g
hair, in the middle of the series. Stimuli were always presented in
a consecutive way, whether ascending or descending. In the absence
of a paw withdrawal response to the initially selected hair, a
stronger stimulus was presented; in the event of paw withdrawal,
the next weaker stimulus was chosen. Optimal threshold calculation
by this method requires 6 responses in the immediate vicinity of
the 50% threshold, and counting of these 6 responses began when the
first change in response occurred, e.g. the threshold was first
crossed. In cases where thresholds fell outside the range of
stimuli, values of 15.14 (normal sensitivity) or 0.41 (maximally
allodynic) were respectively assigned. The resulting pattern of
positive and negative responses was tabulated using the convention,
X=no withdrawal; O=withdrawal, and the 50% withdrawal threshold was
interpolated using the formula:
50% g threshold=10.sup.(Xf+k.delta.)/10,000
[0363] where Xf=value of the last von Frey hair used (log units);
k=tabular value (from Chaplan et al. (1994)) for the pattern of
positive/negative responses; and .delta.=mean difference between
stimuli (log units). Here .delta.=0.224.
[0364] Von Frey thresholds were converted to percent of maximum
possible effect (% MPE), according to Chaplan et al. 1994. The
following equation was used to compute % MPE:
% MPE=Drug treated threshold (g)-allodynia threshold (g).times.100
Control threshold (g)-allodynia threshold (g)
ADMINISTRATION OF TEST SUBSTANCE
[0365] Rats were injected (subcutaneously, intraperitoneally, or
orally) with a test substance prior to von Frey testing, the time
between administration of test compound and the von Frey test
varied depending upon the nature of the test compound.
Definitions
[0366] The following abbreviations have the indicated meanings:
[0367] Ac=acetyl
[0368] Ar=aryl
[0369] t-BOC=tertiary-butoxycarbonyl
[0370] t-Bu=tertiary-butyl
[0371] Et=ethyl
[0372] iPr=isopropyl
[0373] Me=methyl
[0374] Ph=phenyl
[0375] Pr=propyl
[0376] r.t.=room temperature
[0377] TFA=trifluoroacetic acid
[0378] THF=tetrahydrofuran
[0379] TMEDA=N,N,N',N'-tetramethylethylenediamine
* * * * *