U.S. patent application number 10/877967 was filed with the patent office on 2005-02-10 for novel compounds useful in pain management.
This patent application is currently assigned to AstraZeneca Canada Inc.. Invention is credited to Delorme, Daniel, Gregor, Vlad, Roberts, Edward, Sun, Eric.
Application Number | 20050032789 10/877967 |
Document ID | / |
Family ID | 20411787 |
Filed Date | 2005-02-10 |
United States Patent
Application |
20050032789 |
Kind Code |
A1 |
Delorme, Daniel ; et
al. |
February 10, 2005 |
Novel compounds useful in pain management
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; (Quebec,
CA) ; Gregor, Vlad; (San Diego, CA) ; Roberts,
Edward; (Solothurn, CH) ; Sun, Eric; (San
Diego, CA) |
Correspondence
Address: |
FITCH, EVEN, TABIN & FLANNERY
P. O. BOX 65973
WASHINGTON
DC
20035
US
|
Assignee: |
AstraZeneca Canada Inc.
|
Family ID: |
20411787 |
Appl. No.: |
10/877967 |
Filed: |
June 28, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10877967 |
Jun 28, 2004 |
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09555575 |
Jun 1, 2000 |
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6777561 |
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09555575 |
Jun 1, 2000 |
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PCT/SE99/01075 |
Jun 16, 1999 |
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Current U.S.
Class: |
514/227.5 ;
514/232.2; 514/252.12; 514/317; 514/595; 544/159; 544/399; 544/59;
546/231; 564/47 |
Current CPC
Class: |
C07C 273/1854 20130101;
C07C 275/28 20130101; A61K 51/0406 20130101; A61K 51/0446
20130101 |
Class at
Publication: |
514/227.5 ;
514/232.2; 514/252.12; 514/317; 514/595; 544/059; 544/159; 544/399;
546/231; 564/047 |
International
Class: |
A61K 031/54; A61K
031/537; A61K 031/495; A61K 031/445; A61K 031/17 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 22, 1998 |
SE |
9802209-8 |
Claims
1. A compound according to formula I 34wherein m and n is each and
independently an integer of from 1-3, and one or more of the
hydrogens in such an alkylene-chain may optionally be substituted
by anyone of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, or
hydroxy; or one or more of the methylene groups may optionally be
substituted by a heteroatom such as O, N or S; R.sup.1 is selected
from hydrogen, a branched or straight C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.4-C.sub.8(alkyl-cycloalkyl) wherein the alkyl is
C.sub.1-C.sub.2 alkyl and the cycloalkyl is C.sub.3-C.sub.6
cycloalkyl; R.sup.2 is selected from any of (i) hydrogen; (ii) a
straight or branched C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl
or C.sub.2-C.sub.6 alkynyl; (iii) --[(CH.sub.2).sub.q-aryl]; (iv)
--[(CH.sub.2).sub.r-hetero- aryl] where the heteroaryl has from 5
to 10 atoms and the heteroatom being selected from any of S, N and
O; and wherein the aryl and heteroaryl may optionally and
independently be substituted by 1 or 2 substituents Y where each Y
is as defined below; and wherein q and r is each and independently
an integer of from 0 to 3; (v) C.sub.3-C.sub.10 cycloalkyl,
optionally comprising one or more unsaturations and optionally
susbtituted by one or more heteroaryl(s) where the heteroaryl has
from 5 to 10 atoms and the heteroatom being selected from any of S,
N and O; and wherein the aryl and heteroaryl may optionally and
independently be substituted by 1 or 2 substituents Y where each Y
is as defined below; (vi) C.sub.6-C.sub.10 aryl, optionally and
independently substituted by one or more heteroaryl(s) having from
5 to 10 atoms and the heteroatom(s) being selected from any of S, N
and O and wherein the heteroaryl may optionally and independently
be substituted by 1 or 2 substituents Y wherein each Y is as
defined below; (vii) heteroaryl having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; wherein the aryl
and heteroaryl may optionally and independently be substituted by 1
or 2 substituents Y wherein each Y is as defined below; or R.sup.1
and R.sup.2 may optionally form a heterocyclic ring; R.sup.3 is
selected from anyone of (i) hydrogen; (ii) a straight or branched
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6
alkynyl; (iii) --[(CH.sub.2).sub.q-aryl] wherein q is an integer of
from 0 to 3, and wherein the aryl may optionally be substituted by
one or more heteroaryl(s) having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y wherein each Y is as defined below; (iv)
heteoaryl-(C.sub.5-C.sub.10 alkyl), where the heteroaryl has from 5
to 10 atoms and the heteroatom being selected from any of S, N and
O, and wherein the aryl and heteroaryl may optionally and
independently be substituted by 1 or 2 substituents Y where each Y
is as defined below; (v) C.sub.3-C.sub.10 cycloalkyl, optionally
comprising one or more unsaturations and optionally substituted by
one or more heteroaryl(s) having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O, and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y where each Y is as defined below; (vi)
--[(C.sub.3-C.sub.6 cycloalkyl)-(CH.sub.2).sub.q] wherein q is an
integer of from 1 to 3; R.sup.4 is selected from (i) hydrogen; (ii)
a straight or branched C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl or C.sub.2-C.sub.6 alkynyl; (iii) --[(CH.sub.2).sub.q-aryl]
wherein q is an integer of from 0 to 3, and wherein the aryl may
optionally be substituted by one or more heteroaryl(s) having from
5 to 10 atoms and the heteroatom being selected from any of S, N
and O; and wherein the aryl and heteroaryl may optionally and
independently be substituted by 1 or 2 substituents Y wherein each
Y is as defined below; (iv) heteoaryl-(C.sub.5-C.sub.10 alkyl),
where the heteroaryl has from 5 to 10 atoms and the heteroatom
being selected from any of S, N and O, and wherein the aryl and
heteroaryl may optionally and independently be substituted by 1 or
2 substituents Y where each Y is as defined below; (v)
C.sub.3-C.sub.10 cycloalkyl, optionally comprising one or more
unsaturations and optionally susbtituted by one or more
heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y where each Y is as defined below; (vi)
C.sub.6-C.sub.10 aryl, optionally and independently substituted by
one or more heteroaryl(s) having from 5 to 10 atoms and the
heteroatom(s) being selected from any of S, N and O and wherein the
heteroaryl may optionally and independently be substituted by 1 or
2 substituents Y wherein each Y is as defined below; (vii)
heteroaryl having from 5 to 10 atoms and the heteroatom being
selected from any of S, N and O; wherein the aryl and heteroaryl
may optionally and independently be substituted by 1 or 2
substituents Y wherein each Y is as defined below; R.sup.5 is
selected from anyone of (i) hydrogen; (ii) a straight or branched
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6
alkynyl; (iii) --[(CH.sub.2).sub.q-aryl] wherein q is an integer of
from 0 to 3, and wherein the aryl may optionally be substituted by
one or more heteroaryl(s) having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y wherein each Y is as defined below; (iv)
heteoaryl-(C.sub.5-C.sub.10 alkyl), where the heteroaryl has from 5
to 10 atoms and the heteroatom being selected from any of S, N and
O, and wherein the aryl and heteroaryl may optionally and
independently be substituted by 1 or 2 substituents Y where each Y
is as defined below; (v) C.sub.3-C.sub.10 cycloalkyl, optionally
comprising one or more unsaturations and optionally substituted by
one or more heteroaryl(s) having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O, and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y where each Y is as defined below; 35
wherein R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 is each
and independently selected from (a) hydrogen; (b) a straight or
branched C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl or
C.sub.2-C.sub.6 alkynyl; (c) --[(CH.sub.2).sub.q-aryl] wherein q is
an integer of from 0 to 3, and wherein the aryl may optionally be
substituted by one or more heteroaryl(s) having from 5 to 10 atoms
and the heteroatom being selected from any of S, N and O; and
wherein the aryl and heteroaryl may optionally and independently be
substituted by 1 or 2 substituents Y wherein each Y is as defined
below; (d) heteoaryl-(C.sub.5-C.sub.10 alkyl), where the heteroaryl
has from 5 to 10 atoms and the heteroatom being selected from any
of S, N and O, and wherein the aryl and heteroaryl may optionally
and independently be substituted by 1 or 2 substituents Y where
each Y is as defined below; (e) C.sub.3-C.sub.10 cycloalkyl,
optionally comprising one or more unsaturations and optionally
susbtituted by one or more heteroaryl(s) where the heteroaryl has
from 5 to 10 atoms and the heteroatom being selected from any of S,
N and O; and wherein the aryl and heteroaryl may optionally and
independently be substituted by 1 or 2 substituents Y where each Y
is as defined below; (f) C.sub.6-C.sub.10 aryl, optionally and
independently substituted by one or more heteroaryl(s) having from
5 to 10 atoms and the heteroatom(s) being selected from any of S, N
and O and wherein the heteroaryl may optionally and independently
be substituted by 1 or 2 substituents Y wherein each Y is as
defined below; or R.sup.4 and R.sup.5 may optionally form a
heterocyclic ring; Y is each and independently selected from any of
hydrogen, CH.sub.3; --(CH.sub.2).sub.p1CF.sub.3; halogen;
C.sub.1-C.sub.3 alkoxy; hydroxy; --NO.sub.2; --OCF.sub.3;
--CONR.sup.aR.sup.b; --COOR.sup.a; --COR.sup.a;
--CH.sub.2).sub.p2NR.sup.- aR.sup.b; --(CH.sub.2).sub.p3CH.sub.3,
(CH.sub.2).sub.p4SOR.sup.aR.sup.b;
--(CH.sub.2).sub.p5SO.sub.2R.sup.a;
--(CH.sub.2).sub.p6SO.sub.2NR.sup.a;
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; 1 or 2
heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being
selected from any of S, N and O; and oxides such as N-oxides or
sulfoxides; and wherein R.sup.a and R.sup.b is each and
independently 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; and wherein p.sup.1, p.sup.2, p.sup.3, p.sup.4, p.sup.5
and p.sup.6 is each and independently 0, 1 or 2; as well as
pharmaceutically acceptable salts, isomers, hydrates, isoforms and
prodrugs thereof.
2. A compound according to formula I of claim 1,
whereinm=n=1R.sup.1 is selected from (i) hydrogen; (ii) a branched
or straight C.sub.1-C.sub.6 alkyl; or (iii) C.sub.3-C.sub.8
cycloalkyl; R.sup.2 is selected from any of (i) hydrogen; (ii) a
straight or branched C.sub.1-C.sub.6 alkyl; (iii)
--[(CH.sub.2).sub.q-aryl]; (iv) --[(CH.sub.2).sub.r-heteroaryl]
where the heteroaryl has from 5 to 10 atoms and the heteroatom
being selected from any of S, N and O; and wherein the aryl and
heteroaryl may optionally and independently be substituted by 1 or
2 substituents Y where each Y is as defined in claim 1; and wherein
q and r is each and independently an integer of from 0 to 3; (v)
C.sub.3-C.sub.6 cycloalkyl, optionally comprising one or more
unsaturations and optionally susbtituted by one or more
heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y where each Y is as defined above; (vi)
C.sub.6-C.sub.10 aryl, optionally and independently be substituted
by 1 or 2 substituents Y wherein each Y is as defined in claim 1;
(vii) heteroaryl having from 5 to 10 atoms and the heteroatom being
selected from any of S, N and O; wherein the aryl and heteroaryl
may optionally and independently be substituted by 1 or 2
substituents Y wherein each Y is as defined in claim 1; or R.sup.1
and R.sup.2 may optionally form a heterocyclic ring; R.sup.3 is
selected from anyone of (i) hydrogen; (ii) a straight or branched
C.sub.1-C.sub.6 alkyl; (iii) --[(CH.sub.2).sub.q-aryl] wherein q is
an integer of from 0 to 3, and wherein the aryl may optionally be
substituted by one or more heteroaryl(s) having from 5 to 10 atoms
and the heteroatom being selected from any of S, N and O; and
wherein the aryl and heteroaryl may optionally and independently be
substituted by 1 or 2 substituents Y wherein each Y is as defined
in claim 1; (iv) heteoaryl-(C.sub.5-C.sub.10 alkyl), where the
heteroaryl has from 5 to 10 atoms and the heteroatom being selected
from any of S, N and O, and wherein the aryl and heteroaryl may
optionally and independently be substituted by 1 or 2 substituents
Y where each Y is as defined in claim 1; (v) C.sub.3-C.sub.10
cycloalkyl, optionally comprising one or more unsaturations and
optionally substituted by one or more heteroaryl(s) having from 5
to 10 atoms and the heteroatom being selected from any of S, N and
O, and wherein the aryl and heteroaryl may optionally and
independently be substituted by 1 or 2 substituents Y where each Y
is as defined in claim 1; (vi) --[(C.sub.3-C.sub.6
cycloalkyl)-(CH.sub.2)q] wherein q is an integer of from 1 to 3;
R.sup.4 is selected from (i) hydrogen; (ii) a straight or branched
C.sub.1-C.sub.6 alkyl; (iii) --[(CH.sub.2).sub.q-aryl] wherein q is
an integer of from 0 to 3, and wherein the aryl may optionally be
substituted by one or more heteroaryl(s) having from 5 to 10 atoms
and the heteroatom being selected from any of S, N and O; and
wherein the aryl and heteroaryl may optionally and independently be
substituted by 1 or 2 substituents Y wherein each Y is as defined
in claim 1; (iv) heteoaryl-(C.sub.5-C.sub.10 alkyl), where the
heteroaryl has from 5 to 10 atoms and the heteroatom being selected
from any of S, N and O, and wherein the aryl and heteroaryl may
optionally and independently be substituted by 1 or 2 substituents
Y where each Y is as defined in claim 1; (v) C.sub.6-C.sub.10 aryl,
optionally and independently substituted by one or more
heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being
selected from any of S, N and O and wherein the heteroaryl may
optionally and independently be substituted by 1 or 2 substituents
Y wherein each Y is as defined in claim 1; R.sup.5 is selected from
anyone of (i) hydrogen; (ii) a straight or branched C.sub.1-C.sub.6
alkyl; (iii) --[(CH.sub.2).sub.q-aryl] wherein q is 0 or 1, and
wherein the aryl may optionally be substituted by one or more
heteroaryl(s) having from 5 to 10 atoms and the heteroatom being
selected from any of S, N and O; and wherein the aryl and
heteroaryl may optionally and independently be substituted by 1 or
2 substituents Y wherein each Y is as defined in claim 1; (iv)
heteoaryl-(C.sub.5-C.sub.10 alkyl), where the heteroaryl has from 5
to 10 atoms and the heteroatom being selected from any of S, N and
O, and wherein the aryl and heteroaryl may optionally and
independently be substituted by 1 or 2 substituents Y where each Y
is as defined in claim 1; (v) C.sub.3-C.sub.6 cycloalkyl,
optionally comprising one or more unsaturations and optionally
substituted by one or more heteroaryl(s) having from 5 to 10 atoms
and the heteroatom being selected from any of S, N and O, and
wherein the aryl and heteroaryl may optionally and independently be
substituted by 1 or 2 substituents Y where each Y is as defined
claim 1; 36 wherein R.sup.7, R.sup.8, R.sup.9, R.sup.10 and
R.sup.11 is each and independently selected from (a) hydrogen; (b)
a straight or branched C.sub.1-C.sub.6 alkyl or C.sub.2-C.sub.6
alkenyl; (c) --[(CH.sub.2).sub.q-aryl] wherein q is an integer of
from 0 to 3, and wherein the aryl may optionally be substituted by
one or more heteroaryl(s) having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y wherein each Y is as defined in claim 1;
(d) heteoaryl-(C.sub.5-C.sub.10 alkyl), where the heteroaryl has
from 5 to 10 atoms and the heteroatom being selected from any of S,
N and O, and wherein the aryl and heteroaryl may optionally and
independently be substituted by 1 or 2 substituents Y where each Y
is as defined in claim 1; (e) C.sub.3-C.sub.10 cycloalkyl,
optionally comprising one or more unsaturations and optionally
susbtituted by one or more heteroaryl(s) where the heteroaryl has
from 5 to 10 atoms and the heteroatom being selected from any of S,
N and O; and wherein the aryl and heteroaryl may optionally and
independently be substituted by 1 or 2 substituents Y where each Y
is as defined in claim 1; (f) C.sub.6-C.sub.10 aryl, optionally and
independently substituted by one or more heteroaryl(s) having from
5 to 10 atoms and the heteroatom(s) being selected from any of S, N
and O and wherein the heteroaryl may optionally and independently
be substituted by 1 or 2 substituents Y wherein each Y is as
defined in claim 1; or R.sup.4 and R.sup.5 may form a heterocyclic
ring which may optionally and independently be substituted by 1 or
2 substituents Y wherein each Y is as defined in claim 1.
3. A compound according to claim 2, whereinm=n=1R.sup.1 is selected
from (i) a straight or branched C.sub.1-C.sub.6 alkyl; or (ii)
C.sub.3-C.sub.8 cycloalkyl; R.sup.2 is selected from (i) methyl; or
(ii) phenyl optionally substituted by 1 or 2 substituents Y wherein
each Y is as defined in claim 1; R.sup.3 is selected from (i)
--CH.sub.2-phenyl, optionally substituted by 1 or 2 subtituents Y
where Y is as defined in claim 1; (ii) --CH.sub.2-cyclohexyl or
--CH.sub.2-cyclopentyl; R.sup.4 is selected from (i) hydrogen; or
(ii) methyl; R.sup.5 is selected from (i) hydrogen; (ii) methyl; or
37R.sup.4 and R.sup.5 together form a heterocyclic ring, optionally
substituted by 1 or 2 substituents Y, where Y is as defined in
claim 1.
4. A compound according to claim 1, which compound is anyone
selected from 38394041
5. A compound according to any of the preceding claims, in form of
its hydrochloride, sulfate, tartrate or citrate salts.
6. A compound according to any of claims 1-5 for use in
therapy.
7. A compound according to claim 6, wherein the therapy is pain
management.
8. A compound according to claim 6, wherein the therapy is directed
towards gastrointestinal disorders.
9. A compound according to claim 6, wherein the therapy is directed
towards spinal injuries.
10. A compound according to claim 6, wherein the therapy is
directed to disorders of the sympathetic nervous system.
11. Use of a compound according to formula I of claim 1 for the
manufacture of a medicament for use in the treatment of pain.
12. 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.
13. 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.
14. A compound according to any of claims 1-10, further
characterised in that it is isotopically labelled.
15. Use of a compound according to claim 14 as a diagnostic
agent.
16. An isotopically labelled compound of the formula I of claim
1.
17. A diagnostic agent comprising a compound of the formula I of
claim 1.
18. 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.
19. A process for the preparation of a compound of the formula I
according to claim 1, whereby A) (i) bis-amino xylylene of the
formula 42 is converted into mono-(diBoc)-guanidinomethyl of the
formula (II) 43 which thereafter is reacted with an aldehyde,
providing a secondary amine of the general formula IV 44 wherein
R.sup.3 is as defined in formula I of claim 1; (ii) compound IV is
subjected to an urea formation, providing a compound of the formula
(VI) 45 which finally is deprotected, providing a compound of the
general formula VII 46 wherein R.sup.1, R.sup.2 and R.sup.3 are as
defined in formula I of claim 1; or B) (i) a compound of the
formula (VIII). 47 wherein X is CN and Y is CHO, is subjected to a
reductive amination using a primary amine R.sup.3NH.sub.2 wherein
R.sup.3 is as defined in formula I of claim 1, providing a compound
of the formula (IX) 48 wherein R.sup.3 is as defined in formula I
of claim 1, which thereafter is subjected to an urea reaction by
using a chloroformate of the formula (V) 49 which finally is
reduced, providing a compound of the formula (XI) 50(ii) compound
(VIII) wherein X is CH.sub.2Br and Y is CN, is reacted with an
amine R.sup.4R.sup.5NH wherein R.sup.4 and R.sup.5 are as defined
in formula I of claim 1, providing a compound of the formula (XII)
51 which is reduced and reacted with an aldehyde R.sup.3CHO wherein
R3 is as defined in formula I of claim 1, and finally subjected to
an urea action with a chloroformate (V) as in step (i), providing a
compound of the formula (XV) 52 is wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are as defined in formula I of claim
1.
20. 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.
21. 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.
22. 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 analgesics 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 in 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 now been solved by
developing novel 1,4-substituted phenyl compounds, as will be
described below.
[0008] The novel compounds according to the present invention are
defined by the general formula I 2
[0009] wherein
[0010] m and n is each and independently an integer of from 1-3,
and one or more of the hydrogens in such an alkylene-chain may
optionally be substituted by anyone of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, or hydroxy; or
[0011] one or more of the methylene groups may optionally be
substituted by a heteroatom such as O, N or S;
[0012] R.sup.1 is selected from hydrogen, a branched or straight
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.4-C.sub.8(alkyl-cycloalkyl) wherein the alkyl is
C.sub.1-C.sub.2 alkyl and the cycloalkyl is C.sub.3-C.sub.6
cycloalkyl;
[0013] R.sup.2 is selected from any of
[0014] (i) hydrogen;
[0015] (ii) a straight or branched C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6 alkynyl;
[0016] (iii) --[(CH.sub.2).sub.q-aryl];
[0017] (iv) --[(CH.sub.2).sub.r-heteroaryl] where the heteroaryl
has from 5 to 10 atoms and the heteroatom being selected from any
of S, N and O;
[0018] and wherein the aryl and heteroaryl may optionally and
independently be substituted by 1 or 2 substituents Y where each Y
is as defined below; and wherein q and r is each and independently
an integer of from 0 to 3;
[0019] (v) C.sub.3-C.sub.10 cycloalkyl, optionally comprising one
or more unsaturations and optionally susbtituted by one or more
heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O;
[0020] and wherein the aryl and heteroaryl may optionally and
independently be substituted by 1 or 2 substituents Y where each Y
is as defined below;
[0021] (vi) C.sub.6-C.sub.10 aryl, optionally and independently
substituted by one or more heteroaryl(s) having from 5 to 10 atoms
and the heteroatom(s) being selected from any of S, N and O and
wherein the heteroaryl may optionally and independently be
substituted by 1 or 2 substituents Y wherein each Y is as defined
below;
[0022] (vii) heteroaryl having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; wherein the aryl
and heteroaryl may optionally and independently be substituted by 1
or 2 substituents Y wherein each Y is as defined below; or
[0023] R.sup.1 and R.sup.2 may optionally form a heterocyclic
ring;
[0024] R.sup.3 is selected from anyone of
[0025] (i) hydrogen;
[0026] (ii) a straight or branched C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6 alkynyl;
[0027] (iii) --[(CH.sub.2).sub.q-aryl] wherein q is an integer of
from 0 to 3, and wherein the aryl may optionally be substituted by
one or more heteroaryl(s) having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y wherein each Y is as defined below;
[0028] (iv) heteoaryl-(C.sub.5-C.sub.10 alkyl), where the
heteroaryl has from 5 to 10 atoms and the heteroatom being selected
from any of S, N and O, and wherein the aryl and heteroaryl may
optionally and independently be substituted by 1 or 2 substituents
Y where each Y is as defined below;
[0029] (v) C.sub.3-C.sub.10 cycloalkyl, optionally comprising one
or more unsaturations and optionally substituted by one or more
heteroaryl(s) having from 5 to 10 atoms and the heteroatom being
selected from any of S, N and O, and wherein the aryl and
heteroaryl may optionally and independently be substituted by 1 or
2 substituents Y where each Y is as defined below;
[0030] (vi) --[(C.sub.3-C.sub.6 cycloalkyl)-(CH.sub.2).sub.q]
wherein q is an integer of from 1 to 3;
[0031] R.sup.4 is selected from
[0032] (i) hydrogen;
[0033] (ii) a straight or branched C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6 alkynyl;
[0034] (iii) --[(CH.sub.2).sub.q-aryl] wherein q is an integer of
from 0 to 3, and wherein the aryl may optionally be substituted by
one or more heteroaryl(s) having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y wherein each Y is as defined below;
[0035] (iv) heteoaryl-(C.sub.5-C.sub.10 alkyl), where the
heteroaryl has from 5 to 10 atoms and the heteroatom being selected
from any of S, N and O, and wherein the aryl and heteroaryl may
optionally and independently be substituted by 1 or 2 substituents
Y where each Y is as defined below;
[0036] (v) C.sub.3-C.sub.10 cycloalkyl, optionally comprising one
or more unsaturations and optionally susbtituted by one or more
heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O;
[0037] and wherein the aryl and heteroaryl may optionally and
independently be substituted by 1 or 2 substituents Y where each Y
is as defined below;
[0038] (vi) C.sub.6-C.sub.10 aryl, optionally and independently
substituted by one or more heteroaryl(s) having from 5 to 10 atoms
and the heteroatom(s) being selected from any of S, N and O and
wherein the heteroaryl may optionally and independently be
substituted by 1 or 2 substituents Y wherein each Y is as defined
below;
[0039] (vii) heteroaryl having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; wherein the aryl
and heteroaryl may optionally and independently be substituted by 1
or 2 substituents Y wherein each Y is as defined below;
[0040] R.sup.5 is selected from anyone of
[0041] (i) hydrogen;
[0042] (ii) a straight or branched C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6 alkynyl;
[0043] (iii) --[(CH.sub.2).sub.q-aryl] wherein q is an integer of
from 0 to 3, and wherein the aryl may optionally be substituted by
one or more heteroaryl(s) having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y wherein each Y is as defined below;
[0044] (iv) heteoaryl-(C.sub.5-C.sub.10 alkyl), where the
heteroaryl has from 5 to 10 atoms and the heteroatom being selected
from any of S, N and O, and wherein the aryl and heteroaryl may
optionally and independently be substituted by 1 or 2 substituents
Y where each Y is as defined below;
[0045] (v) C.sub.3-C.sub.10 cycloalkyl, optionally comprising one
or more unsaturations and optionally substituted by one or more
heteroaryl(s) having from 5 to 10 atoms and the heteroatom being
selected from any of S, N and O, and wherein the aryl and
heteroaryl may optionally and independently be substituted by 1 or
2 substituents Y where each Y is as defined below; 3
[0046] wherein
[0047] R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 is each and
independently selected from
[0048] (a) hydrogen;
[0049] (b) a straight or branched C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6 alkynyl;
[0050] (c) --[(CH.sub.2).sub.q-aryl] wherein q is an integer of
from 0 to 3, and wherein the aryl may optionally be substituted by
one or more heteroaryl(s) having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y wherein each Y is as defined below;
[0051] (d) heteoaryl-(C.sub.5-C.sub.10 alkyl), where the heteroaryl
has from 5 to 10 atoms and the heteroatom being selected from any
of S, N and O, and wherein the aryl and heteroaryl may optionally
and independently be substituted by 1 or 2 substituents Y where
each Y is as defined below;
[0052] (e) C.sub.3-C.sub.10 cycloalkyl, optionally comprising one
or more unsaturations and optionally susbtituted by one or more
heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y where each Y is as defined below;
[0053] (f) C.sub.6-C.sub.10 aryl, optionally and independently
substituted by one or more heteroaryl(s) having from 5 to 10 atoms
and the heteroatom(s) being selected from any of S, N and O and
wherein the heteroaryl may optionally and independently be
substituted by 1 or 2 substituents Y wherein each Y is as defined
below; or
[0054] R.sup.4 and R.sup.5 may optionally form a heterocyclic
ring;
[0055] Y is each and independently selected from any of hydrogen,
CH.sub.3; --(CH.sub.2).sub.p1CF.sub.3; halogen; C.sub.1-C.sub.3
alkoxy; hydroxy; --NO.sub.2; --OCF.sub.3; --CONR.sup.aR.sup.b;
--COOR.sup.a; --COR.sup.a; --CH.sub.2).sub.p2NR.sup.aR.sup.b;
--(CH.sub.2).sub.p3CH.sub- .3, (CH.sub.2).sub.p4SOR.sup.aR.sup.b;
--(CH.sub.2).sub.p5SO.sub.2R.sup.a;
--(CH.sub.2).sub.p6SO.sub.2NR.sup.a;
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; 1 or 2
heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being
selected from any of S, N and O; and oxides such as N-oxides or
sulfoxides; and wherein
[0056] R.sup.a and R.sup.b is each and independently 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; and
wherein
[0057] p.sup.1, p.sup.2, p.sup.3, p.sup.4, p.sup.5 and p.sup.6 is
each and independently 0, 1 or 2.
[0058] 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.
[0059] Examples of heterocyclic ring systems which may be formed by
R.sup.2 and R.sup.3 together include but are not limited to
azeridine, pyrrolidine, piperidine, azepine, azocine, their
hydrogenated or dehydrogenated derivatives, their aminoderivatives
and other aza-heterocycle moieties and their derivatives, such as
dihydroimidazoles, di-, tetra- and hexahydropyrimidines and the
like.
[0060] Preferred compounds according to the invention are compounds
of the formula I wherein
m=n=1
[0061] R.sup.1 is selected from
[0062] (i) hydrogen;
[0063] (ii) a branched or straight C.sub.1-C.sub.6 alkyl; or
[0064] (iii) C.sub.3-C.sub.8 cycloalkyl;
[0065] R.sup.2 is selected from any of
[0066] (i) hydrogen;
[0067] (ii) a straight or branched C.sub.1-C.sub.6 alkyl;
[0068] (iii) --[(CH.sub.2).sub.q-aryl];
[0069] (iv) --[(CH.sub.2).sub.r-heteroaryl] where the heteroaryl
has from 5 to 10 atoms and the heteroatom being selected from any
of S, N and O;
[0070] and wherein the aryl and heteroaryl may optionally and
independently be substituted by 1 or 2 substituents Y where each Y
is as defined above; and wherein q and r is each and independently
an integer of from 0 to 3;
[0071] (v) C.sub.3-C.sub.6 cycloalkyl, optionally comprising one or
more unsaturations and optionally susbtituted by one or more
heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O;
[0072] and wherein the aryl and heteroaryl may optionally and
independently be substituted by 1 or 2 substituents Y where each Y
is as defined above;
[0073] (vi) C.sub.6-C.sub.10 aryl, optionally and independently be
substituted by 1 or 2 substituents Y wherein each Y is as defined
above;
[0074] (vii) heteroaryl having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; wherein the aryl
and heteroaryl may optionally and independently be substituted by 1
or 2 substituents Y wherein each Y is as defined above; or
[0075] R.sup.1 and R.sup.2 may optionally form a heterocyclic
ring;
[0076] R.sup.3 is selected from anyone of
[0077] (i) hydrogen;
[0078] (ii) a straight or branched C.sub.1-C.sub.6 alkyl;
[0079] (iii) --[(CH.sub.2).sub.q-aryl] wherein q is an integer of
from 0 to 3, and wherein the aryl may optionally be substituted by
one or more heteroaryl(s) having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y wherein each Y is as defined above;
[0080] (iv) heteoaryl-(C.sub.5-C.sub.10 alkyl), where the
heteroaryl has from 5 to 10 atoms and the heteroatom being selected
from any of S, N and O, and wherein the aryl and heteroaryl may
optionally and independently be substituted by 1 or 2 substituents
Y where each Y is as defined above;
[0081] (v) C.sub.3-C.sub.10 cycloalkyl, optionally comprising one
or more unsaturations and optionally substituted by one or more
heteroaryl(s) having from 5 to 10 atoms and the heteroatom being
selected from any of S, N and O, and wherein the aryl and
heteroaryl may optionally and independently be substituted by 1 or
2 substituents Y where each Y is as defined above;
[0082] (vi) --[(C.sub.3-C.sub.6 cycloalkyl)-(CH.sub.2)q] wherein q
is an integer of from 1 to 3;
[0083] R.sup.4 is selected from
[0084] (i) hydrogen;
[0085] (ii) a straight or branched C.sub.1-C.sub.6 alkyl;
[0086] (iii) --[(CH.sub.2).sub.q-aryl] wherein q is an integer of
from 0 to 3, and wherein the aryl may optionally be substituted by
one or more heteroaryl(s) having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y wherein each Y is as defined above;
[0087] (iv) heteoaryl-(C.sub.5-C.sub.10 alkyl), where the
heteroaryl has from 5 to 10 atoms and the heteroatom being selected
from any of S, N and O, and wherein the aryl and heteroaryl may
optionally and independently be substituted by 1 or 2 substituents
Y where each Y is as defined below;
[0088] (v) C.sub.6-C.sub.10 aryl, optionally and independently
substituted by one or more heteroaryl(s) having from 5 to 10 atoms
and the heteroatom(s) being selected from any of S, N and O and
wherein the heteroaryl may optionally and independently be
substituted by 1 or 2 substituents Y wherein each Y is as defined
above;
[0089] R.sup.5 is selected from anyone of
[0090] (i) hydrogen;
[0091] (ii) a straight or branched C.sub.1-C.sub.6 alkyl;
[0092] (iii) --[(CH.sub.2).sub.q-aryl] wherein q is 0 or 1, and
wherein the aryl may optionally be substituted by one or more
heteroaryl(s) having from 5 to 10 atoms and the heteroatom being
selected from any of S, N and O; and wherein the aryl and
heteroaryl may optionally and independently be substituted by 1 or
2 substituents Y wherein each Y is as defined above;
[0093] (iv) heteoaryl-(C.sub.5-C.sub.10 alkyl), where the
heteroaryl has from 5 to 10 atoms and the heteroatom being selected
from any of S, N and O, and wherein the aryl and heteroaryl may
optionally and independently be substituted by 1 or 2 substituents
Y where each Y is as defined above;
[0094] (v) C.sub.3-C.sub.6 cycloalkyl, optionally comprising one or
more unsaturations and optionally substituted by one or more
heteroaryl(s) having from 5 to 10 atoms and the heteroatom being
selected from any of S, N and O, and wherein the aryl and
heteroaryl may optionally and independently be substituted by 1 or
2 substituents Y where each Y is as defined above; 4
[0095] wherein
[0096] R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 is each and
independently selected from
[0097] (a) hydrogen;
[0098] (b) a straight or branched C.sub.1-C.sub.6 alkyl or
C.sub.2-C.sub.6 alkenyl;
[0099] (c) --[(CH.sub.2).sub.q-aryl] wherein q is an integer of
from 0 to 3, and wherein the aryl may optionally be substituted by
one or more heteroaryl(s) having from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y wherein each Y is as defined above;
[0100] (d) heteoaryl-(C.sub.5-C.sub.10 alkyl), where the heteroaryl
has from 5 to 10 atoms and the heteroatom being selected from any
of S, N and O, and wherein the aryl and heteroaryl may optionally
and independently be substituted by 1 or 2 substituents Y where
each Y is as defined above;
[0101] (e) C.sub.3-C.sub.10 cycloalkyl, optionally comprising one
or more unsaturations and optionally susbtituted by one or more
heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the
heteroatom being selected from any of S, N and O; and wherein the
aryl and heteroaryl may optionally and independently be substituted
by 1 or 2 substituents Y where each Y is as defined above;
[0102] (f) C.sub.6-C.sub.10 aryl, optionally and independently
substituted by one or more heteroaryl(s) having from 5 to 10 atoms
and the heteroatom(s) being selected from any of S, N and O and
wherein the heteroaryl may optionally and independently be
substituted by 1 or 2 substituents Y wherein each Y is as defined
above; or
[0103] R.sup.4 and R.sup.5 may form a heterocyclic ring which may
optionally and independently be substituted by 1 or 2 substituents
Y wherein each Y is as defined above.
[0104] Particularly preferred compounds according to the invention
are compounds of the formula I wherein
m=n=1
[0105] R.sup.1 is selected from
[0106] (i) a straight or branched C.sub.1-C.sub.6 alkyl; or
[0107] (ii) C.sub.3-C.sub.8 cycloalkyl;
[0108] R.sup.2 is selected from
[0109] (i) methyl; or
[0110] (ii) phenyl optionally substituted by 1 or 2 substituents Y
wherein each Y is as defined above;
[0111] R.sup.3 is selected from
[0112] (i) --CH.sub.2-phenyl, optionally substituted by 1 or 2
subtituents Y where Y is as defined above;
[0113] (ii) --CH.sub.2-cyclohexyl or --CH.sub.2-cyclopentyl;
[0114] R.sup.4 is selected from
[0115] (i) hydrogen; or
[0116] (ii) methyl;
[0117] R.sup.5 is selected from
[0118] (i) hydrogen;
[0119] (ii) methyl; or 5
[0120] R.sup.4 and R.sup.5 together form a heterocyclic ring,
optionally substituted by 1 or 2 substituents Y, where Y is as
defined above.
[0121] By "halogen" we mean chloro, fluoro, bromo and iodo.
[0122] By "aryl" we mean an aromatic ring having 6 or 10 carbon
atoms, such as phenyl and naphthyl.
[0123] 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.
[0124] 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.
[0125] By "isoforms" we mean compounds of the formula I which
differ in the relative physical arrangement of molecules by crystal
lattice, such that isoforms refer to various crystalline compounds
and amorphous compounds.
[0126] By "prodrug" we mean pharmacologically acceptable
derivatives, e.g. esters and amides, such that the resulting
biotransformation product of the derivative is an active form of
the 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 by reference.
[0127] 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.
[0128] Compounds of the invention are useful as immunomodulators,
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.
[0129] 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).
[0130] 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.
[0131] 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 (eg. Amnesia, analgesia, muscle relaxation and sedation).
Included in this combination are inhaled anaesthetics, hypnotica,
anxiolytics, neuromuscular blockers and opioids.
[0132] The compounds of the present invention in isotopically
labelled form are useful as a diagnostic agent.
[0133] 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.
[0134] 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 (1) above, is administered to a patient in
need of such treatment.
[0135] The best mode of performing the invention known at present,
is to use the compounds according to Example 1 (compound 12) and
Example 2 (compound 13). The numbering of the compounds is in
accordance with the numbering in the Schemes presented in the
following.
[0136] Methods of Preparation
[0137] The compounds of the present invention may be prepared as
described in Scheme 1 below.
[0138] General Procedure for the Preparation of 1,4 or
1,3-guanidinomethyl aminomethyl xylylene 6
[0139] As shown in Scheme 1 above, compounds of the formula VI may
be obtained from commercially available bis-amino
xylylene.(compound 1).
[0140] Compound 1 is converted into mono-(diBoc)-guanidinomethyl
derivative 2 using a protected guanylating reagent such as
1-H-pyrazole-1-(N,N-bis (tert-butoxycarbonyl) carboxamidine in an
organic solvent such as THF.
[0141] The secondary amine of the formula III may be generated
using a reductive amination step, where compound 2 is reacted with
an aldehyde II in the presence of an acid such as acetic acid or a
Lewis acid such as ZnCl.sub.2, in a protic solvent such as methanol
or ethanol in the presence of a reducing agent such as sodium
cyanobrohydride.
[0142] Compounds of the formula V may be obtained by performing an
urea formation using compound III with a chloroformate of the
formula IV in a solvent such as methylene chloride and in the
presence of a tertiary amine as base, such as triethylamine.
[0143] Finally, a compound of the formula VI may be obtained by
cleavage of the Boc protecting group with an acid such as aqueous
hydrochloric acid or by using organic acid such as trifluoroacetic
acid in a solvent such a methylene chloride.
[0144] 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.
[0145] Step 1(a)
[0146] Preparation of 1-(diBoc)-guanidinomethyl-4-aminomethyl
benzene (compound 2)
[0147] Part A
[0148] 1-H-pyrazole-1-carboxamidine was prepared according to
Benatowicz et.al., J. Org. Chem. 1992, 57, pp. 2497-2502, and
protected with di-tert-butyl dicarbonate to give
1-H-pyrazole-1-N,N-bis(tert-butoxycarbo- nyl)carboxamidine
(compound 1) according to Drake et. al, Synth 1994. pp.
579-582.
[0149] Part B
[0150] To a solution of p-xylylenediamine (compound 1) (30.8 g,
0.226 mol) in THF (300 mL) was added a solution of
1-H-Pyrazole-1-(N,N-bis(tert-buto- xycarbonyl)carboxamidine (35.0
g, 0.113 mol) in THF (100 mL). The solution was stirred at room
temperature for 3 h. The solvent was removed under reduced
pressure. Water was added to the residue and the aqueous mixture
was extracted with ethyl acetate. The organic layer was washed with
brine, dried over MgSO.sub.4 and concentrated. The product
(compound 2) was purified by column chromatography on silica gel
using a mixture of methylene chloride:methanol as the eluent to
give 24.3 g (57% yield) of 1-(diBoc)-guanidinomethyl-4-aminomethyl
benzene (compound 2 where NH.sub.2 is in 4-position).
[0151] .sup.1H NMR (CDCl.sub.3) .delta. 8.5 (broad s, 1H), 7.32 (s,
4H), 4.65 (d, 2H), 3.89 (s, 2H), 1.5 (s, 9H), 1.48 (s, 9H).
[0152] Step 1(b)
[0153] Preparation of 1-(diBoc)guanidinomethyl-3-aminomethyl
benzene
[0154] 1-(diBoc)-guanidinomethyl-3-aminomethyl benzene was prepared
in a similar fashion from m-xylylenediamine and of
1-H-Pyrazole-1-(NN-bis(tert- -butoxycarbonyl)carboxamidine.
[0155] .sup.1H NMR (CDCl.sub.3) .delta. 8.52 (broad s, 1H),
7.28-7.08 (m, 4H), 4.56 (d, 2H), 3.81 (s, 2H), 1.42 (s, 9H), 1.39
(s, 9H).
[0156] Step 2
[0157] Reductive amination: Preparation of
1-(diBoc)-guanidinomethyl-4-[N-- (cyclohexylmethyl)]benzene
(compound 2 where NH.sub.2 is in 3-position)
[0158] To a methanolic solution (15 ml) of compound 2 where the
amino group is in 4-position) (341 mg, 0.90 mmol) and
cyclohexanecarboxaldehyde (111.17 mg, 0.99 mmol) was added zinc
chloride (122.79 mg, 0.90 mmol) and sodium cyanoborohydride (67.93
mg, 1.08 mmol). The mixture was stirred over night under nitrogen,
wherafter the mixture was diluted with saturated aqueous sodium
bicarbonate, and extracted with methylene chloride. The organic
phase was washed with brine, dried over MgSO.sub.4 and
concentrated. This crude product was further purified by silica gel
chromatography using CH.sub.2Cl.sub.2/MeOH (95:5) as the solvent,
to give 164 mg of the pure desired product (compound 2 where
NH.sub.2 is in 3-position).
[0159] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 0.83 (2H, m,
cyclohexane ring); 1.10 (3 H, m, cyclohexane ring); 1.42 (9H, s,
boc), 1.46 (9H, s, boc), 1.65 (6H, m, cyclohexane ring), 2.41 (2H,
d, J=6.8 Hz, C.sub.6H.sub.11--CH.sub.2), 3.72 (2H, s,
C.sub.6H.sub.4--CH.sub.2), 4.54 (2H, d, J=5.6 Hz,
NNCNH--CH.sub.2--C.sub.6H.sub.4), 7.18.about.7.25 (4H, m, Ar), 8.50
(1H, br, NH--CNN) ppm.
[0160] Specific examples illustrating the preparation of secondary
amines, i.e. intermediates of the formula III, are provided in
Table 1 below.
1TABLE 1 Inter- Intermediate mediate of the formula III Aldehyde
Characterization no. and chemical name [R.sup.3CHO] data 3 7
cyclohexane carboxaldehyde .sup.1H NMR (CDCl.sub.3) .delta. (ppm):
0.83 (2H, m, cyclohexane ring); 1.42 (9H, s, boc), 1.46 (9H, s,
boc), 1.65 (6H, m, cyclohexane ring), 2.41 (2H, d, J=6.8 Hz,
C.sub.6H.sub.11--CH.sub.2), 3.72 (2H, s, C.sub.6H.sub.4--CH.sub.2),
#4.54 (2H, d, J=5.6 Hz, NNCNH--CH.sub.2--C.sub.6H.sub.4), 7.18
.about. 7.25 (4H, m, Ar), 8.50 (1H, br, NH--CNN) ppm. 4
81-(diBoc)-guanidino methyl-4-[N-(2,2- diphenylethyl)aminom ethyl]
benzene Diphenyl- benzaldehyde .sup.1H (CDCl.sub.3) .delta. 8.5
(broad s, 1H), 7.23-7.14 (m, 14H), 4.58 (d, 2H), 4.18 (t, 1H), 3.78
(s, 2H), 3.22 (d, 2H), 1.50 (s, 9H), 1.47 (s, 9H). MS(FAB+): 559 (M
+ H), 359. 5 91-(diBoc)-guanidino- methyl-4-[N-(4- chlorobenzyl)
aminomethyl] benzene 4-chloro- benzaldehyde .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.6 (broad t, 1H), 7.42-7.1 (m, 10H), 4.52
(t, 2H), 3.7 (s, 2H), 3.2 (s, 2H), 1.5 (s, 9H), 1.45 (s, 9H).
MS(FAB+): 503 (M + H), 403, 303. 6 101-(diBoc)-guanidino-
methyl-4-[N-(benzyl) aminomethyl] benzene Benzaldehyde .sup.1H NMR
(CDCl.sub.3) .delta. 7.2 (m, 9H), 4.5 (s, 2H), 4.15 (t, 2H), 3.7
(s, 2H), 1.5 (s, 18H). 7 111-(diBoc)-guanidino- methyl-4-[N-(2-
chloro- benzyl)aminomethyl]benzene 2-chloro- benzaldehyde .sup.1H
NMR (CDCl.sub.3) .delta. 8.62 (broad s, 1H), 7.48-7.1 (m, 8H), 4.62
(d, 2H), 3.95 (s, 2H), 3.85 (s, 2H), 1.53 (s, 9H), 1.5 (s, 9H). 8
121-(diBoc)-guanidino- methyl-4-[N-(3- chloro-
benzyl)aminomethyl]benzene 3-chlorobenz- aldehyde .sup.1H NMR
(CDCl.sub.3) .delta. 8.56 (broad t, 1H), 7.4-7.15 (m, 8H), 4.6 (d,
2H), 3.8 (s, 4H), 1.56 (s, 9H), 1.52 (s, 9H). MS(APCI): 503 (M +
H), 403, 303. 9 131-(diBoc)-guanidino- methyl-3-[N-(2,2-
diphenylethyl) aminomethyl]benzene Diphenylacet- aldehyde MS(ES+):
559 (M + H), 459, 359. 10 141-(diBoc)-guanidino- methyl-3-[N-(4-
chloro-benzyl) aminomethyl] benzene 4-chlorobenz- aldehyde .sup.1H
NMR (CDCl.sub.3) .delta. 8.48 (broad s, 1H), 7.3-6.96 (m, 8H),
4.68-4.32 (m, 4H), 3.78-3.6 (m, 2H).
[0161] 1516
[0162] Alternatively, as shown in Scheme 2, compounds of the
formula (XI) may be obtained by using compounds of the formula
(VIII) wherein X=CN and Y=CHO, as a starting material.
[0163] A reductive amination using a primary amine with compound
(VIII) in the presence of an acid such as acetic acid, and in the
presence of a reducing agent such as sodium cyanoborohydride in a
solvent such as methanol or ethanol, provides a compound of the
formula (IX).
[0164] Compounds of the formula (X) may be obtained by performing
an urea reaction using compounds of the formula (IX) with a
chloroformate of the formula (V) in a solvent such as methylene
chloride and in the presence of a tertiary amine as base, such as
triethylamine.
[0165] Compounds of the formula (XI) may be prepared by a reduction
of the nitrile function in formula (X), using a reduction agent
such as borane-THF complex in a solvent such as THF.
[0166] Compounds of the formula (XV) may be prepared by reacting
compounds of the formula (VIII) wherein X=CH.sub.2Br and Y=CN, with
an amine in a solvent such as acetonitrile, providing a compound of
the formula (XII). A reduction of the nitrile function using a
reducing agent such as borane-THF complex in a solvent such as THF,
provides the primary amine of the formula (XIII).
[0167] A reductive amination step of (XIII) as described above,
provides a compound of the formula (XIV). Finally, urea formation
of the secondary amine (XIV) as described above, provides a
compound of the formula (XV).
[0168] Alternatively, compounds of the formula (XV) may be prepared
by using a monoprotected dialdehyde such as a compound of the
formula (VIII) wherein X=CH(OEt).sub.2 and Y=CHO, and a reductive
amination in the presence of a reducing agent such as sodium
cyanoborohydride in a solvent such as methanol or ethanol. Urea
formation as described above provides a compound of the formula
(XVII). Hydrolysis of the diethyl acetal function in compound
(XVII) using an acid such as TFA in a solvent such as methylene
chloride, provides the corresponding aldehyde (XVIII).
[0169] Finally, a reductive amination as described before, provides
compounds of the formula (XV).
[0170] The invention will now be described in more detail by the
following Examples, which are not to be construed as limiting the
invention.
EXAMPLE 1
Preparation of
1-N-(cyclohexylmethyl)-N-(N-methyl-N-phenylcarbamoyl)-amino-
methyl-4-guanidinomethyl-benzene (Compound 12)
[0171] Compound 12 of the present Example was prepared by following
the synthetic route described in Scheme 2 below. 1718
[0172] To a solution of compound 3 (164 mg, 0.35 mmol) in methylene
chloride (10 ml) was added N-methyl-N-phenyl carbamoylchloride
(120.78 mg, 0.71 mmol) and triethylamine (71.90 mg, 0.71 mmol). The
mixture was stirred at room temperature for 3 h, washed with a
saturated NH.sub.4Cl aqueous solution and brine, dried over
MgSO.sub.4 and concentrated to give the crude product (compound
11). This crude compound was used directly without purification for
the preparation of compound 12. It was dissolved in dry methylene
chloride (3 ml), 1.5 ml of TFA was added and the reaction mixture
was stirred at room temperature for 1 hour. The excess of solvent
and TFA was evaporated, the residue was purified by reverse phase
preparative HPLC to give the pure desired product (100 mg, 71% in 2
steps).
[0173] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 0.70 (2H, m,
cyclohexane ring); 1.10 (3H, m, cyclohexane ring); 1.41 (3H, m,
cyclohexane ring); 1.53 (3H, m, cyclohexane ring); 2.72 (2H, d,
J=6.4 Hz, C.sub.6H.sub.7--CH.sub.2), 3.00 (3H, s, N--CH.sub.3),
4.13 (2H, S, C.sub.6H.sub.4--CH.sub.2), 4.24 (2H, d, J=4.8 Hz,
NH--CH.sub.2-Ph), 6.93.about.7.25 (9H, m, Ar), 8.13 (1H, br,
NH--C.dbd.N). MS Observed (CI): 408.45 (MH+).
[0174] The following specific compounds were prepared by following
the synthesis description described above.
EXAMPLES 2-7
[0175] The following compounds were prepared by using the same
procedure as described in Example 1, but using the intermediate and
acid chloride indicated in Table 2 below.
2TABLE 2 Inter Carbamoyl Structure and Medi- Chloride or Physical
Ex. chemical name ate Isocyanate Characterization 2
191-N-[(4-chlorobenzyl)-N- (N-methyl-N-phenyl-
carbamoyl)]-aminomethyl- 4-guanidino-benzene 5 N-methyl-N-phenl
carbamoyl chloride .sup.1H NMR (DMSO-d.sub.6) .delta. 8.0 (t, 1H),
8.6-8.2 (m, 14H), 4.4 (d, 2H), 4.2 (d, 4H), 3.1 (s, 3H). 3
201-N-[(4-chlorobenzyl)-N- (N,N-dimethyl carbamoyl)]-aminomethyl-
4-guanidinomethyl- benzene 5 Dimethylcarba- molychloride .sup.1H
NMR (DMSO-d.sub.6) .delta. 8.1 (broad, 1H), 7.4 (d, 2H), 7.25 (d,
2H), 7.15 (m, 4H), 4.35 (d, 2H), 4.15 (d, 4H), 2.85 (s, 6H).
MS(APCI): 374 (M + H). 4 211-N-[(4-chlorobenzyl)-N-
(N-methyl-N-phenyl- carbamoyl)]-aminomethyl- 3-guanidinomethyl-
benzene 10 N-methyl-N-phenyl carbamoyl chloride .sup.1H NMR
(CDCl.sub.3) .delta. 7.05-7.5 (m, 13H), 4.4 (broad s, 2H), 4.15 (s,
2H), 3.35 (s, 3H), 3.05 (d, 2H). MS(APCI): 436 (M + H) 5
221-N-[(4-chlorobenzyl)-N- (3- nitrophenylcarbamoyl)]-
aminomethyl-4- guanidinomethyl-benzene 5 3-nitrophenyl- isocyanate
.sup.1H NMR (DMSO-d.sub.6) .delta. 9.2 (s, 1H), 8.6 (s, 1H), 8.1
(broad, 1H), 8.0 (d, 1H), 7.7 (d, 1H), 7.55 (t, 1H), 7.4 (d, 1H),
7.2 (m, 6H), 4.7 (d, 4H), 4.3 (d, 2H). #MS(APCI): 466 (M + H) 6
231-N-[(4-chlorobenzyl)-N- (4-phenoxycarbamoyl)]-
aminomethyl-4-guanidino- methyl-benzene 5 4-phenoxy- phenyl-
isocyanate .sup.1H NMR (DMSO-d.sub.6) .delta. 8.8 (s, 1H), 7.8-7.5
(m, 12H), 7.1 (t, 1H), 6.9 (d, 4H), 4.5 (d, 4H), 4.3 (d, 2H).
MS(APCI): 514. (M + H) 7 241-N-[(2-chlorobenzyl)-N-
(N-methyl-N-phenyl- carbamoyl)]-aminomethyl-
4-guanidinomethyl-benzene 7 N-methyl-N- Phenylcarbamoyl- chloride
.sup.1H NMR (DMSO-d.sub.6) .delta. 8.2 (broad, 1H), 7.4-6.95 (m,
13H), 4.5 (s, 2H), 4.2 (d, 4H), 3.1 (s, 3H). MS(APCI): 436. (M +
H). 8 251-N-[(3-chlorobenzyl)-N- (N-methyl-N-phenyl-
carbamoyl)]-aminomethyl-4- guanidinomethyl-benzene 8 N-methyl-N-
phenylcarbamoyl chloride .sup.1H NMR (DMSO-d.sub.6) .delta. 8.2
(broad, 1H), 7.4-7.1 (m, 13H), 4.35 (d, 2H), 4.15 (s, 4H), 3.1 (s,
3H). MS(APCI): 436. (M + H). 9 261-N-[(benzyl)-N-(N-methy- l-
N-phenylcarbamoyl)]- aminomethyl-4-guanidino- methyl-benzene 6
N-methyl-N- phenylcarbamoyl- chloride .sup.1H NMR (DMSO-d.sub.6)
.delta. 8.1 (t, 1H), 7.3 (m, 8H), 7.05 (m, 6H), 4.45 (d, 2H), 4.05
(d, 4H), 3.15 (s, 3H).
EXAMPLE 10
Preparation of
1-N-[(2,4-dichlorobenzyl)-N-(N-methyl-N-phenylcarbamoyl)]-a-
minomethyl-4-guanidinomethyl-benzene (Compound 21)
[0176] 27
[0177] Following the same procedure as described in Example 1, step
2 but substituting 2,4-dichlorobenzaldehyde for
cyclohexanecarboxaldehyde, the title compound 21 was obtained.
[0178] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.2 (broad, 1H), 7.5-7.1
(m, 12H), 4.5 (d, 2H), 4.2 (s, 4H), 3.1 (s, 3H). MS(APCI): 469.95
(M+H).
EXAMPLE 11
Preparation of
1-N-[(4-chlorobenzyl)-N-(N-methyl-N-phenylcarbamoyl)]-amino-
methyl-4-aminomethyl-benzene (Compound 25)
[0179] Compound 25 of the present Example was prepared by following
the procedure described in Scheme 3 below. 28
Step 1
Preparation of N-(4-chlorobenzyl)-4-cyanobenzyl amine (Compound
22)
[0180] To a methanolic solution (20 mL) of 4-chlorobenzylamine
(1.02 g, 7.2 mmol) was added successively ZnCl2 (0.981 g, 7.2
mmol), 4-cyanobenzaldehyde (1.007 g, 7.3 mmol), and NaCNBH.sub.3
(0.452 g, 7.2 mmol). The reaction mixture was stirred at r.t. for 2
days. It was diluted with aq. sodium bicarbonate and the reaction
mixture was extracted with methylene chloride. The combined organic
extracts were washed with brine, dried over magnesium sulfate and
concentrated. The product (compound 22) was purified by silica gel
chromatography: 1.43 g (77%).
[0181] .sup.1H NMR (CDCl.sub.3) .delta. 7.45 (d, 2H), 7.28 (d, 2H),
7.10 (s, 4H), 3.68 (s, 2H), 3.58 (s, 2H).
Step 2
Preparation of
1-N-[(4-chlorobenzyl)-N-(N-methyl-N-phenylcarbamoyl)]-amino-
methyl-4-cyanobenzene (Compound 24)
[0182] To a solution of N-(4-chlorobenzyl)-4-cyanobenzyl amine
(compound 22)(1.43 g, 5.57 mmol) in dioxane (20 mL) was added
N-methyl-N-phenyl carbamoyl chloride (compound 23) (1.039 g, 6.12
mmol) and triethylamine (0.853 mL, 6.12 mmol). The reaction mixture
was stirred at r.t. for 1 day, then it was diluted with ethyl
acetate and washed with 10% HCl, saturated sodium bicarbonate,
water, brine, dried over MgSO.sub.4 and concentrated to give
compound 24: 1.95 g (89%).
Step 3
Preparation of
1-N-[(4-chlorobenzyl)-N-(N-methyl-N-phenylcarbamoyl)]-amino-
methyl-4-aminomethyl-benzene (Compound 25)
[0183] To a THF (6 mL) solution of
1-N-[(4-chlorobenzyl)-N',N'-(methyl,
phenyl)carbamoyl]-aminomethyl-4-cyanobenzene (compound 24) (0.39 g,
1 mmol) was added a 1M BH.sub.3.THF complex (2.2 mL). The mixture
was heated at 90.degree. C. overnight. Then a 2.55 M HCl in
methanol (3 mL) was added and the reaction mixture was heated at
reflux for 1 h. The mixture was diluted with water and extracted
with ethyl acetate. The organic layer was dried over MgSO.sub.4 and
concentrated. The product (compound 25) was purified by preparative
TLC using methanol/methylene chloride/ammonium hydroxide as the
eluent.
[0184] .sup.1H NMR (CDCl.sub.3) .delta. 7.20-6.84 (m, 13H), 4.00
(s, 4H), 3.70 (s, 2H), 3.05 (s, 3H), 2.05 (broad s, 2H). MS: 394.
(M+H).
EXAMPLE 12
Preparation of
1-N-[4-chlorobenzyl)-N-(N-methyl-N-phenylcarbamoyl)]-aminom-
ethyl-4-(N-pyrrolidinomethyl)-benzene (Compound 32)
[0185] The compound 32 of Example 11 was prepared by following the
procedure described in Scheme 4 below. 2930
Step 1
Preparation of 4-cyano-1-N-pyrrolinomethyl benzene (Compound
28)
[0186] 4-cyano benzyl bromide (compound 26) (20.0 g, 0.102 mol) was
dissolved in acetonitrile(100 mL) and added to a cooled (0.degree.
C.) solution of pyrrolidine (compound 27) (8.5 g, 0.12 mol) in
acetonitrile. The mixture was stirred at RT for 3 days. The
reaction mixture was acidified with 4N HCl and washed with ethyl
acetate. The aqueous layer was basified with 20% sodium hydroxide
and extracted with ethyl acetate. The organic layer was
concentrated to give product (compound 28)(11.0 g, 58%) which was
carried on to the next step with no further purification.
[0187] .sup.1H NMR (CDCl.sub.3) .delta.; 7.6 (d, 2H), 8.4 (d, 2H),
3.55 (s, 2H), 2.55 (t, 2H), 1.7 (t, 2H). MS: 187. (M+H)
Step 2
Preparation of 4-N-aminomethyl-1-N-pyrrolinomethyl benzene
(Compound 29)
[0188] 4-cyanomethyl-1-N-pyrrolinomethyl benzene (compound 28) (11
g, 59 mmol) was dissolved in dry THF(20 mL). To this solution was
added a 1M solution of borane complex (180 mL). The mixture was
refluxed overnight. The solution was then cooled to r.t. and a
solution of 3N HCl in methanol (120 mL) was added dropwise. The
mixture was again refluxed overnight. After cooling to room
temperature, the product (compound 29) fell out of solution as
white precipitate and was collected and washed with THF: 11.6
g.
[0189] .sup.1H NMR (CDCl.sub.3) .delta. 8.8 (broad, 1H), 7.6 (d,
2H), 7.4 (d, 2H), 4.4 (s, 2H), 4.0 (s, 2H), 3.3 (t, 2H), 3.0(t,
21H), 2.0 (t, 4H). MS: 191. (M+H)
Step 3
Preparation of
N-(4chlorobenzyl)-1-(1-N-pyrrolidinomethyl)-benzylamine (Compound
31)
[0190] Following the same procedure as described for Example 10,
step 1, but substituting 4-chlorobenzylamine for compound 29 and
4-cyanobenzaldehyde for 4-chlorobenzaldehyde, the title compound
was obtained.
[0191] MS: 357 (M+H)
Step 4
Preparation of
1-N-[(4-chlorobenzyl)-N-(N-methyl-N-phenylcarbamoyl)]-amino-
methyl-4-(1-N-pyrrolidinomethyl)benzene (Compound 32)
[0192] Following the procedure described in Example 10, step 2, but
substituting compound 22 for compound 31, the title compound was
obtained.
[0193] .sup.1H NMR (CDCl.sub.3) .delta. 7.55 (d, 2H), 7.45 (d, 2H),
7.4(d, 2H), 7.2 (d, 2H), 7.0 (d, 2H), 6.95 (d, 2H), 4.3 (d, 4H),
4.1 (s, 2H), 3.25 (s, 3H), 3.1 (t, 4H), 2.05 (t, 4H). MS 448.
(M+H)
EXAMPLE 13
Preparation of
1-N-[(4-chlorobenzyl)-N-(N-methyl-N-phenylcarbamoyl)]-amino-
methyl-4-(N,N-dimethyl)-aminomethyl-benzene (Compound 35)
[0194] The compound 35 of Example 12 was prepared by following the
procedure described in Scheme 5 below. 31
Step 1
Preparation of 1-N-(4chlorobenzyl)-4-(N,N-dimethyl)aminomethyl
benzyl amine (Compound 34)
[0195] A round bottom flask was charged with
1-N-aminomethyl-4-N,N-dimethy- laminomethyl benzene hydrochloride
(compound 33) (2.36 g, 10 mmol), 4-chlorobenzaldehyde (compound 30)
(1.51 g, 11 mmol, 97% pure), and methanol (40 mL). The mixture was
stirred at r.t. for 20 minutes, then solid NaCNBH.sub.3 was added
and the reaction mixture was stirred at r.t. overnight. It was
diluted with aqueous sodium bicarbonate, and extracted with ethyl
acetate. The combined organic extracts were washed with brine,
dried over MgSO.sub.4 and concentrated to give 1.29 g of (compound
34)as an oily residue.
Step 2
Preparation of
1-N-[(4-chlorobenzyl)-N-(N-methyl-N-phenylcarbamoyl)]-amino-
methyl-4-(N,N-dimethyl)-aminomethyl-benzene (Compound 35)
[0196] To a solution of
1-N-(4-chlorobenzyl)-4-(N,N-dimethyl)aminomethyl benzyl amine
(compound 34) (0.562 g, 1.95 mmol)) in dioxane (8 mL) was added
triethylamine (0.326 mL, 2.34 mmol)) and N-methyl,N-phenyl
carbamoyl chloride (compound 23) (0.395 g, 2.34 mmol). The mixture
was stirred at r.t. overnight, then diluted with aqueous sodium
bicarbonate and extracted with ethyl acetate. The organic extracts
were washed with brine, dried over MgSO.sub.4 and concentrated to a
colorless oil. The product (compound 35) was purified by silica gel
chromatography using methanol/ethyl acetate/ammonium hydroxide as
the eluent.
[0197] .sup.1H NMR (CDCl.sub.3) .delta. 7.40-6.95 (m, 13H), 4.20
(s, 4H), 3.42 (s, 2H), 3.25 (s, 3H), 2.32 (s, 6H). MS: 422.
(M+H).
EXAMPLE 14
Preparation of
1-N-[(4-chlorobenzyl)-N-(N-methyl-N-phenylcarbamoyl)]-amino-
methyl-4-(N-methyl)-aminomethyl-benzene (Compound 40)
[0198] The compound 40 of Example 13 was prepared by following the
procedure described in Scheme 6 below. 3233
Step 1
Preparation of 1-diethyl acetal-4-N-(4-chlorobenzyl) benzyl amine
(Compound 37)
[0199] To a solution of tere-phthalaldehyde mono-(diethyl acetal)
(compound 36) (0.416 g, 2 mmol) and 4-chlorobenzylamine (compound
21) (0.283 g, 2 mmol) in methanol (5 mL, containing 1% glacial
acetic acid v/v). was added solid NaCNBH.sub.3. The reaction
mixture was stirred at r.t. overnight. It was diluted with aqueous
sodium bicarbonate and extracted with ethyl acetate. The combined
organic extracts were washed with brine, dried over MgSO.sub.4 and
concentrated to an oil, (compound 37): 0.61 g (91%). MS: 334.02
(M+H).
Step 2
Preparation of
1-N-[(4-chlorobenzyl)-N-(N-methyl-N-phenylcarbamoyl)]-amino-
methyl-4-carboxaldehyde (Compound 39)
[0200] To a solution of 1-diethyl acetal-4-N-(4-chlorobenzyl)
benzyl amine (compound 37) (0.60 g, 1.8 mmol) in dioxane (5 mL) was
added triethylamine (0.279 mL, 2 mmol) and N-methyl,N-phenyl
carbamoyl chloride (compound 23) (0.336 g, 1.98 mmol). The mixture
was stirred at r.t. overnight, then diluted with aqueous sodium
bicarbonate and extracted with ethyl acetate. The organic extracts
were washed with brine, dried over MgSO.sub.4 and concentrated to
give (compound 38): 0.69 g.
[0201] The acetal (compound 38) (0.67 g, 1.42 mmol) was dissolved
in 50% trifluoroacetic acid/methylene chloride (5 mL) and stirred
at r.t. for 3.5 h. The mixture was concentrated to an oily residue
which was redissolved in CH.sub.2Cl.sub.2 and washed with sodium
bicarbonate, brine, dried over MgSO.sub.4 and concentrated to an
oil, (compound 39): 0.504 g.
[0202] .sup.1H NMR (CDCl.sub.3) .delta. 9.80 (s, 1H), 7.72-6.68 (m,
13H), 4.10 (s, 2H), 3.97 (s, 2H), 3.10 (s, 3H).
Step 3
Preparation of
1-N-[(4-chlorobenzyl)-N-(N-methyl-N-phenylcarbamoyl)]-amino-
methyl-4-(N-methyl)-aminomethyl-benzene (Compound 40)
[0203] To a methanolic solution (5 mL) of compound 39 (0.50 g, 1.28
mmol) was added a solution of 2M methylamine in methanol (0.7 mL,
1.40 mmol), and glacial acetic acid (0.05 mL). Solid NaCNBH.sub.3
(0.08 g, 1.28 mmol) was then added and the mixture was stirred at
r.t. overnight. It was diluted with aqueous sodium bicarbonate and
extracted with ethyl acetate. The organic extracts were washed with
brine, dried and concentrated. The product (compound 40) was
purified by silica gel chromatography, using a mixture of
methanol/methylene chloride/ammonium hydroxide as the eluent.
[0204] .sup.1H NMR (CDCl.sub.3) .delta. 7.40-6.95 (m, 13H), 4.19
(s, 2H), 4.16 (s, 2H), 3.82 (s, 2H), 3.19 (s, 3H), 2.46 (s, 3H).
MS: 408.03. (M+H).
[0205] Pharmaceutical Compositions
[0206] 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.
[0207] A preferred route of administration is orally, intravenously
or intramuscularly.
[0208] 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 as the most
appropriate for a particular patient.
[0209] 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.
[0210] 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.
[0211] 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.
[0212] 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.
[0213] 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.
[0214] 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.
[0215] Preferred pharmaceutically acceptable salts are the
hydrochlorides, trifluoroacetates and bitartrates.
[0216] 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.
[0217] Tablets, powders, cachets, and capsules can be used as solid
dosage forms suitable for oral administration.
[0218] 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.
[0219] 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.
[0220] 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
[0221] A) In Vitro Model
[0222] Cell Culture
[0223] 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 DMEM10% FBS, 5% BCS, 0.1% Pluronic F-68, and 600
.mu.g/ml geneticin.
[0224] Membrane Preparation
[0225] 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.
[0226] Binding assays
[0227] 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 ml/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.
[0228] Data Analysis
[0229] 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.
[0230] Receptor Saturation Experiments
[0231] 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.
[0232] B) Biological Model (In Vivo Model)
[0233] Freund's Complete Adjuvant (FCA), and Sciatic Nerve Cuff
Induced Mechano-Allodynia in Rat
[0234] Animals
[0235] 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
[0236] Freund's Complete Adjuvant
[0237] 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.
[0238] Sciatic Nerve Cuff
[0239] 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.
[0240] Determination of Mechano-Allodynia Using Von Frey
Testing
[0241] 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.
[0242] Testing Protocol
[0243] 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
[0244] 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.
[0245] 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: 1 % MPE = Drug
treated threshold ( g ) - allodynia threshold ( g ) Control
threshold ( g ) - allodynia threshold ( g ) .times. 100
[0246] Administration of Test Substance
[0247] 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.
* * * * *