U.S. patent application number 11/555914 was filed with the patent office on 2007-03-08 for novel substituted diamine derivatives useful as motilin agonists.
Invention is credited to Sigmond G. Johnson, Ralph A. Rivero.
Application Number | 20070054888 11/555914 |
Document ID | / |
Family ID | 22748615 |
Filed Date | 2007-03-08 |
United States Patent
Application |
20070054888 |
Kind Code |
A1 |
Johnson; Sigmond G. ; et
al. |
March 8, 2007 |
NOVEL SUBSTITUTED DIAMINE DERIVATIVES USEFUL AS MOTILIN
AGONISTS
Abstract
The present invention relates to novel substituted diamine
derivatives for the formula ##STR1## wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, X.sup.1, X.sup.2, X.sup.3, X.sup.4, A, Y and n
are as described in the specification, pharmaceutical compositions
containing them and intermediates used in their manufacture. More
particularly, the compounds of the invention are motilin receptor
antagonists useful for the treatment of associated conditions and
disorders such as gastrointestinal reflux disorders, eating
disorders leading to obesity and irritable bowel syndrome.
Inventors: |
Johnson; Sigmond G.;
(Flemington, NJ) ; Rivero; Ralph A.; (North Wales,
PA) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
22748615 |
Appl. No.: |
11/555914 |
Filed: |
November 2, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11386960 |
Apr 26, 2006 |
7166601 |
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11555914 |
Nov 2, 2006 |
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11066202 |
Feb 25, 2005 |
7112586 |
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11386960 |
Apr 26, 2006 |
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10291133 |
Nov 8, 2002 |
6967199 |
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11066202 |
Feb 25, 2005 |
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09829767 |
Apr 10, 2001 |
6511980 |
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10291133 |
Nov 8, 2002 |
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60202131 |
May 5, 2000 |
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Current U.S.
Class: |
514/183 ;
514/357; 514/408; 540/474; 546/329; 548/577 |
Current CPC
Class: |
C07C 233/75 20130101;
C07D 209/48 20130101; A61P 1/04 20180101; C07D 471/08 20130101;
C07D 211/40 20130101; C07D 207/27 20130101; A61P 1/00 20180101;
C07D 209/66 20130101; C07D 217/06 20130101; A61P 3/00 20180101;
C07D 209/54 20130101; C07D 333/20 20130101; C07D 207/08 20130101;
A61P 3/04 20180101; A61P 43/00 20180101; C07D 307/68 20130101; C07D
213/74 20130101; C07D 295/185 20130101; C07D 295/088 20130101; C07D
213/40 20130101; C07C 233/25 20130101; C07D 295/13 20130101; C07D
213/89 20130101; C07D 221/04 20130101 |
Class at
Publication: |
514/183 ;
514/357; 514/408; 540/474; 548/577; 546/329 |
International
Class: |
A61K 31/4433 20070101
A61K031/4433; A61K 31/44 20070101 A61K031/44; A61K 31/40 20070101
A61K031/40; A61K 31/397 20070101 A61K031/397; C07D 207/04 20060101
C07D207/04; C07D 257/02 20060101 C07D257/02 |
Claims
1. A compound of formula (I): ##STR57## wherein: R.sup.1 is
selected from the group consisting of hydrogen, aryl, aralkyl,
heterocyclyl, diarylalkyl, heterocyclyl-alkyl, and lower alkyl;
wherein the alkyl, aryl or heterocyclyl moieties in the foregoing
groups may be substituted with one or more substituents
independently selected from halogen, hydroxy, nitro, carboxy,
cyano, amino, dialkylamino, lower alkoxy, lower alkyl,
tri-halomethyl, alkylamino, carboxy and alkoxycarbonyl; R.sup.2 is
selected from the group consisting of aryl, aralkyl, cycloalkyl,
cycloalkyl-alkyl heterocyclyl, heterocyclyl-alkyl, diarylalkyl,
aminoalkyl, tri-halomethyl, arylamino and lower alkyl; wherein the
alkyl, aryl, heterocyclyl-alkyl, heterocyclyl, or amino moieties in
the foregoing groups may be substituted with one or more
substituents independently selected from halogen, hydroxy, nitro,
cyano, amino, dialkylamino, lower alkoxy, lower alkyl,
tri-halomethyl, alkylamino, phenyl, carboxy, carboxyalkyl and
alkoxycarbonyl; X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are
independently absent or selected from the group consisting of CO
and SO.sub.2; provided that at least one of X.sup.1 or X.sup.2 and
at least one of X.sup.3 or X.sup.4 is CO or SO.sub.2; alternatively
R.sup.1, R.sup.2 and X.sup.1 can be taken together (with the amine
nitrogen) to form a monocyclic or fused bicyclic or tricyclic
secondary amine ring structure; wherein the monocyclic or fused
bicyclic or tricyclic secondary amine ring structure may be
optionally substituted with one or more substituents independently
selected from halogen, oxo, nitro, cyano, amino, alkylamino,
dialkylamino, trialkylamino, lower alkoxy, lower alkyl,
tri-halomethyl, carboxy, acetyloxy, alkoxycarbonyl, aryl, aralkyl
and heterocyclyl; A is selected from the group consisting of lower
alkyl, lower alkenyl, cycloalkyl, cycloalkyl-alkyl,
alkyl-cycloalkyl, cycloalkenyl, cycloalkenyl-alkyl,
alkyl-cycloalkenyl, alkyl-cycloalkyl-alkyl; alkyl-aryl-alkyl,
alkyl-aryl, aryl-alkyl and phenyl; where, in each case, the A group
may optionally be substituted with one or more substituents
selected from R.sup.7; where R.sup.7 is selected from alkyl,
tri-halomethyl, cycloalkyl, aryl, aralkyl, heterocyclyl,
heterocyclyl-alkyl, diarylalkyl, aminoalkyl, or arylamino; wherein
the alkyl, aryl, heterocyclyl-alkyl, heterocyclyl, or amino
moieties in the foregoing groups may be substituted with one or
more substituents independently selected from halogen, hydroxy,
nitro, cyano, amino, dialkylamino, lower alkoxy, lower alkyl,
tri-halomethyl, alkylamino, phenyl, carboxy and alkoxycarbonyl;
provided that A is not -1,3-cyclopentyl-1-ene-alkyl; R.sup.3 is
selected from the group consisting of hydrogen, aryl, heterocyclyl,
aralkyl, diarylalkyl, heterocyclo-alkyl, tri-halomethyl,
alkylamino, arylamino and lower alkyl; wherein the aryl,
heterocyclyl, aralkyl, diarylalkyl, heterocyclyl-alkyl, alkylamino,
arylamino or lower alkyl group may be substituted with one or more
substituents independently selected from halogen, nitro, cyano,
amino, dialkylamino, lower alkoxy, lower alkyl, tri-halomethyl,
carboxy and alkoxycarbonyl; Y is selected from the group consisting
of --O--, --NH--, --S-- and --SO.sub.2--; n is an integer from 0 to
5; R.sup.4 is selected from the group consisting of hydrogen,
amino, alkylamino, dialkylamino, N-alkyl-N-aralkyl-amino,
trialkylamino, dialkylaminoalkoxyalkyl, heterocyclyl,
heterocyclyl-alkyl, oxo-substituted heterocyclyl and lower alkyl
substituted heterocyclyl; R.sup.5 is selected from the group
consisting of hydrogen, halogen, nitro, cyano, amino, alkylamino,
dialkylamino, trialkylamino, lower alkoxy, lower alkyl,
tri-halomethyl, carboxy and alkoxycarbonyl; and the
pharmaceutically acceptable salts, esters and pro-drug forms
thereof.
2. A compound as in claim 1 wherein R.sup.1 is benzyl, R.sup.2 is
benzyl, A is 1,3-cyclohexyl-methyl, X.sup.1 is absent, X.sup.2 is
absent, X.sup.3 is absent, X.sup.4 is C(O), R.sup.3 is
4-fluorophenyl, Y is 3-O--, n is 2, R.sup.4 is 1-pyrrolidinyl and
R.sup.5 is hydrogen and pharmaceutically acceptable salts, esters
and pro-drug forms thereof.
3. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound of claim 1.
4. A pharmaceutical composition made by mixing a compound of claim
1 and a pharmaceutically acceptable carrier.
5. A process for making a pharmaceutical composition comprising
mixing a compound of claim 1 and a pharmaceutically acceptable
carrier.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This is a divisional application of and claims priority to
U.S. application Ser. No. 11/386,960 filed Apr. 26, 2006, which is
a divisional application of and claims priority to U.S. application
Ser. No. 11/066,202 filed Feb. 25, 2005, which is a divisional
application of and claims priority to U.S. application Ser. No.
10/291,133, filed Nov. 8, 2002, now issued as U.S. Pat. No.
6,967,199, which is a divisional application of U.S. application
Ser. No. 09/829,767, filed Apr. 10, 2001, now issued as U.S. Pat.
No. 6,511,980, which claims priority from U.S. provisional
application Ser. No. 60/202,131, filed May 5, 2000, the contents of
each are hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to novel substituted diamine
derivatives, pharmaceutical compositions containing them and
intermediates used in their manufacture. More particularly, the
compounds of the invention are motilin receptor antagonists useful
for the treatment of associated conditions and disorders such as
gastrointestinal reflux disorders, eating disorders leading to
obesity and irritable bowel syndrome.
BACKGROUND OF THE INVENTION
[0003] In mammals, the digestion of nutrients and the elimination
of waste are controlled by the gastrointestinal system. Within this
system, there are a number of natural peptides, ligands, enzymes,
and receptors which play a vital role and are potential targets for
drug discovery. Modifying the production of, or responses to these
endogenous substances can have an effect upon the physiological
responses such as diarrhea, nausea, and abdominal cramping. One
example of an endogenous substance which affects the
gastrointestinal system is motilin.
[0004] Motilin is a peptide of 22 amino acids which is produced in
the gastrointestinal system of a number of species. Although the
sequence of the peptide varies from species to species, there are a
great deal of similarities. For example, human motilin and porcine
motilin are identical; while motilin isolated from the dog and the
rabbit differ by five and four amino acids respectively. Motilin
induces smooth muscle contractions in the stomach tissue of dogs,
rabbits, and humans as well as in the colon of rabbits. Apart from
local gastrointestinal intestinal tissues, motilin and its
receptors have been found in other areas. For example motilin has
been found in circulating plasma, where a rise in the concentration
of motilin has been associated with gastric effects which occur
during fasting in dogs and humans. Itoh, Z. et al. Scand. J.
Gastroenterol. 11:93-110, (1976); Vantrappen, G. et al. Dig. Dis
Sci 24, 497-500 (1979). In addition, when motilin was intravenously
administered to humans it was found to increase gastric emptying
and gut hormone release. Christofides, N. D. et al.
Gastroenterology 76:903-907, 1979.
[0005] Aside from motilin itself, there are other substances which
are agonists of the motilin receptor and which elicit
gastrointestinal emptying. One of those agents is the antibiotic
erythromycin. Even though erythromycin is a useful drug, a great
number of patients are affected by the drug's gastrointestinal side
effects. Studies have shown that erythromycin elicits biological
responses that are comparable to motilin itself and therefore may
be useful in the treatment of diseases such as chronic idiopathic
intestinal pseudo-obstruction and gastroparesis. Weber, F. et al.,
The American Journal of Gastroenterology, 88:4, 485-90 (1993).
[0006] Although motilin and erythromycin are agonists of the
motilin receptor, there is a need for antagonists of this receptor
as well. The nausea, abdominal cramping, and diarrhea which are
associated with motilin agonists are unwelcome physiological
events. The increased gut motility induced by motilin has been
implicated in diseases such as Irritable Bowel Syndrome and
esophageal reflux. Therefore researchers have been searching for
motilin antagonists.
[0007] One such antagonist is OHM-11526. This is a peptide derived
from porcine motilin which competes with both motilin and
erythromycin for the motilin receptor in a number of species,
including rabbits and humans. In addition, this peptide is an
antagonist of the contractile smooth muscle response to both
erythromycin and motilin in an in vitro rabbit model. Depoortere,
I. et al., European Journal of Pharmacology, 286, 241-47, (1995).
Although this substance is potent in that model (IC.sub.50 1.0 nM)
it is a peptide and as such offers little hope as an oral drug
since it is susceptible to the enzymes of the digestive tract. Zen
Itoh, Motilin, xvi (1990). Therefore it is desirable to find other
non-peptidic agents which act as motilin antagonists. The compounds
of this invention are such agents.
[0008] The compounds of this invention are non-peptidyl motilin
antagonists with potencies and activities comparable to known
peptidyl motilin antagonists. These compounds compete with motilin
and erythromycin for the motilin receptor site in vitro. In
addition, these compounds suppress smooth muscle contractions
induced by motilin and erythromycin with activities and potencies
comparable to OHM 11526 in an in vitro model.
SUMMARY OF THE INVENTION
[0009] The present invention is directed to compounds of the
formula (I): ##STR2##
[0010] wherein
[0011] R.sup.1 is selected from the group consisting of hydrogen,
aryl, aralkyl, heterocyclyl, diarylalkyl, heterocyclyl-alkyl, and
lower alkyl; wherein the alkyl, aryl or heterocyclyl moieties in
the foregoing groups may be substituted with one or more
substituents independently selected from halogen, hydroxy, nitro,
carboxy, cyano, amino, dialkylamino, lower alkoxy, lower alkyl,
tri-halomethyl, alkylamino, carboxy and alkoxycarbonyl;
[0012] R.sup.2 is selected from the group consisting of aryl,
aralkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,
heterocyclyl-alkyl, diarylalkyl, aminoalkyl, tri-halomethyl,
arylamino and lower alkyl; wherein the alkyl, aryl,
heterocyclyl-alkyl, heterocyclyl, or amino moieties in the
foregoing groups may be substituted with one or more substituents
independently selected from halogen, hydroxy, nitro, cyano, amino,
dialkylamino, lower alkoxy, lower alkyl, tri-halomethyl,
alkylamino, phenyl, carboxy, carboxyalkyl and alkoxycarbonyl;
[0013] X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are independently
absent or selected from the group consisting of CO and SO.sub.2;
provided that at least one of X.sup.1 or X.sup.2 and at least one
of X.sup.3 or X.sup.4 is CO or SO.sub.2;
[0014] alternatively R.sup.1, R.sup.2 and X.sup.1 can be taken
together (with the amine nitrogen) to form a monocyclic or fused
bicyclic or tricyclic secondary amine ring structure; wherein the
monocyclic or fused bicyclic or tricyclic secondary amine ring
structure may be optionally substituted with one or more
substituents independently selected from halogen, oxo, nitro,
cyano, amino, alkylamino, dialkylamino, trialkylamino, lower
alkoxy, lower alkyl, tri-halomethyl, carboxy, acetyloxy,
alkoxycarbonyl, aryl, aralkyl andr heterocyclyl;
[0015] A is selected from the group consisting of lower alkyl,
lower alkenyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl,
cycloalkenyl, cycloalkenyl-alkyl, alkyl-cycloalkenyl,
alkyl-cycloalkyl-alkyl; alkyl-aryl-alkyl, alkyl-aryl, aryl-alkyl
and phenyl; where, in each case, the A group may optionally be
substituted with one or more substituents selected from
R.sup.7;
[0016] where R.sup.7 is selected from alkyl, tri-halomethyl,
cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclyl-alkyl,
diarylalkyl, aminoalkyl, or arylamino; wherein the alkyl, aryl,
heterocyclyl-alkyl, heterocyclyl, or amino moieties in the
foregoing groups may be substituted with one or more substituents
independently selected from halogen, hydroxy, nitro, cyano, amino,
dialkylamino, lower alkoxy, lower alkyl, tri-halomethyl,
alkylamino, phenyl, carboxy and alkoxycarbonyl;
[0017] provided that A is not -1,3-cyclopentyl-1-ene-alkyl;
[0018] R.sup.3 is selected from the group consisting of hydrogen,
aryl, heterocyclyl, aralkyl, diarylalkyl, heterocyclo-alkyl,
tri-halomethyl, alkylamino, arylamino and lower alkyl; wherein the
aryl, heterocyclyl, aralkyl, diarylalkyl, heterocyclyl-alkyl,
alkylamino, arylamino or lower alkyl group may be substituted with
one or more substituents independently selected from halogen,
nitro, cyano, amino, dialkylamino, lower alkoxy, lower alkyl,
tri-halomethyl, carboxy and alkoxycarbonyl;
[0019] Y is selected from the group consisting of --O--, --NH--,
--S-- and --SO.sub.2--;
[0020] n is an integer from 0 to 5;
[0021] R.sup.4 is selected from the group consisting of hydrogen,
amino, alkylamino, dialkylamino, N-alkyl-N-aralkyl-amino,
trialkylamino, dialkylaminoalkoxyalkyl, heterocyclyl,
heterocyclyl-alkyl, oxo-substituted heterocyclyl and lower
alkyl-substituted heterocyclyl;
[0022] R.sup.5 is selected from the group consisting of hydrogen,
halogen, nitro, cyano, amino, alkylamino, dialkylamino,
trialkylamino, lower alkoxy, lower alkyl, tri-halomethyl, carboxy
and alkoxycarbonyl;
[0023] and the pharmaceutically acceptable salts, esters and
pro-drug forms thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0024] Relative to the above generic description, certain compounds
of the general formula are preferred. ##STR3## where p and t are
integers from 1-6. More preferably, R.sup.4 is selected from the
group consisting of hydrogen, 4-morpholinyl, 1-pyrrolidinyl,
2-oxo-pyrrolidin-1-yl, 2-(1-methylpyrrolidinyl), 1-piperazinyl,
1-piperidinyl, di(methyl)aminoethyloxyethyl,
N-methyl-N-benzyl-amino, di(methyl)amino and diethylamino. More
preferably still, R.sup.4 is selected from the group consisting of
hydrogen, 4-morpholinyl, 1-pyrrolidinyl, 1-piperazinyl,
1-piperidinyl, di(methyl)amino and di(ethyl)amino. More referably
still, R.sup.4 is selected from the group consisting of hydrogen,
4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl and di(methyl)amino.
Most preferably, R.sup.4 is selected from the group consisting of
hydrogen, 4-morpholinyl, 1-pyrrolidinyl and 1-piperidinyl;
[0025] Preferably R.sup.5 is selected from the group consisting of
hydrogen and lower alkyl. More preferably R.sup.5 is selected from
the group consisting of hydrogen and methyl.
[0026] In a preferred embodiment of the present invention are those
compounds of general formula (I) wherein:
[0027] R.sup.1 is selected from the group consisting of hydrogen,
aralkyl, heterocyclyl and heterocyclyl-alkyl; where the aralkyl,
heterocyclyl or heterocyclyl-alkyl may be substituted with one or
more substituents independently selected from halogen, lower alkyl,
lower alkoxy, tri-halomethyl, hydroxy or nitro;
[0028] R.sup.2 is selected from the group consisting of alkyl,
tri-halomethyl, aryl, aralkyl, arylamino, biphenyl, cycloalkyl,
cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl; where the
aryl, aralkyl or heterocyclyl group may be substituted with one or
more substituents independently selected from halogen, lower
alkoxy, nitro, carboxy, carboxyalkyl, hydroxy, phenyl,
diphenylmethyl, tri-halomethyl or trihaloalkylacetyl;
[0029] X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are independently
absent or selected from the group consisting of CO and SO.sub.2;
such that at least one of X.sup.1 or X.sup.2 and at least one of
X.sup.3 or X.sup.4 is CO or SO.sub.2;
[0030] A is selected from the group consisting of lower alkyl,
alkyl-cycloalkyl, cycloalkyl-alkyl, -cycloalkyl, -cycloalkenyl-,
cycloalkenyl-alkyl- and -aryl-alkyl-; where the alkyl moiety in the
foregoing groups may be substituted with one or more substituents
independently selected from aralkyl or cycloalkyl;
[0031] provided that A is not -1,3-cyclopentyl-1-ene-alkyl;
[0032] R.sup.3 is selected from the group consisting of hydrogen,
aryl, aralkyl and arylamino; where the aryl or aralkyl group may be
substituted with one or more substituents independently selected
from halogen, lower alkyl, lower alkoxy or tri-halomethyl;
[0033] Y is --O--;
[0034] n is an integer from 0 to 3;
[0035] R.sup.4 is selected from the group consisting of hydrogen,
heterocyclyl, oxo-substituted heterocyclyl, lower alkyl-substituted
heterocyclyl, di(lower alkyl)amino, N-lower alkyl-N-aralkyl-amino
and di(lower alkyl)amino alkoxy alkyl;
[0036] R.sup.5 is selected from the group consisting of hydrogen
and lower alkyl;
[0037] and the pharmaceutically acceptable salts, esters and
pro-drug forms thereof.
[0038] In a preferred embodiment are compounds of the general
formula (I) wherein:
[0039] R.sup.1 is selected from the group consisting of hydrogen,
phenyl(C.sub.1-C.sub.6) alkyl-, naphthyl(C.sub.1-6)alkyl and
heterocyclyl(C.sub.1-C.sub.6)alkyl- where the heterocyclyl group is
selected from pyridyl and where the phenyl, naphthyl or
heterocyclyl moiety is optionally substituted with one to three
substituents selected from halogen, lower alkyl, lower alkoxy,
tri-halomethyl, hydroxy and nitro;
[0040] R.sup.2 is selected from the group consisting of
(C.sub.1-C.sub.6) branched or unbranched alkyl, phenyl,
phenyl(C.sub.1-C.sub.6)alkyl-, tri-halomethyl, phenylamino-,
biphenyl, diphenyl(C.sub.1-C.sub.6)alkyl-, C.sub.5-8cycloalkyl,
C.sub.5-8cycloalkyl-alkyl, heterocyclyl and
heterocyclyl(C.sub.1-C.sub.6)alkyl- wherein the heterocyclyl moiety
is selected from naphthyl, furyl, pyridyl, pyrrolidinyl and thienyl
and wherein the phenyl or heterocyclyl group may be substituted
with one to four substitutuents selected from halogen, lower
alkoxy, nitro, carboxy, carboxy(C.sub.1-4)alkyl, hydroxy, phenyl,
diphenylmethyl, trihalomethyl and trihaloalkylacetyl;
[0041] X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are independently
absent or selected from the group consisting of CO and SO.sub.2;
such that at least one of X.sup.1 or X.sup.2 and at least one of
X.sup.3 or X.sup.4 is CO or SO.sub.2;
[0042] A is selected from the group consisting of lower alkyl,
loweralkyl-cycloalkyl, cycloalkyl-loweralkyl, -cycloalkyl,
-cycloalkenyl-, cycloalkenyl-loweralkyl- and -phenyl-loweralkyl-
and -benzyl-loweralkyl, provided that A is not
-1,3-cyclopentyl-1-ene-alkyl;
[0043] R.sup.3 is selected from the group consisting of hydrogen,
phenyl, benzyl and phenylamino-; where the phenyl or benzyl
moieties may be substituted with one to three substituents selected
from halogen, lower alkyl, lower alkoxy and trihalomethyl;
[0044] Y is -0-;
[0045] n is an integer from 0 to 3;
[0046] R.sup.4 is selected from the group consisting of hydrogen,
heterocyclyl, oxo substituted heterocyclyl, lower alkyl-substituted
heterocyclyl, di(loweralkyl)amino, N-lower alkyl-N-aralkyl-amino
and a moiety of the formula: ##STR4##
[0047] where p and t are integers from 1-6;
[0048] R.sup.5 is selected from hydrogen and lower alkyl;
[0049] and the pharmaceutically acceptable salts esters and
pro-drug forms thereof.
[0050] In a more preferred embodiment of the present invention are
compounds of the general formula (I) wherein
[0051] R.sup.1 is selected from the group consisting of hydrogen,
benzyl, 2-(phenyl)ethyl, 4-methylbenzyl, 3-methoxybenzyl,
3-nitrobenzyl, 3-chlorobenzyl, 3-fluorobenzyl, 4-chlorobenzyl,
2,3-dichlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl,
3,4-difluorobenzyl, 3-trifluoromethylbenzyl, 1-naphthyl-methyl,
2-pyridyl-methyl and 4-(1-hydroxy)pyridyl;
[0052] R.sup.2 is selected from the group consisting of methyl,
ethyl, t-butyl, 2,2-dimethylpropyl, benzyl, 2-(phenyl)ethyl,
3-(phenyl)propyl, 1-(phenyl)propyl, 3-carboxy-n-propyl,
3-carboxy-3-methyl-n-butyl, 2,2-dimethyl-3-carboxy-n-propyl,
trichloromethyl, trifluoromethyl, 2-naphthyl, phenylamino,
3-methoxyphenyl, 3-hydroxyphenyl, 4-fluorobenzyl, 3-carboxybenzyl,
3-methoxybenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl,
2-(4-methoxyphenyl)ethyl, 4-fluorophenyl, 2-(4-chlorophenyl)ethyl,
3-nitrophenyl, 3,5-di(trifluoromethyl)phenyl,
3,3,3-trifluoropropan-2-oyl, diphenylmethyl, 4-biphenyl,
3-carboxymethyl-1,2,2-tri methyl-cyclopentyl, cyclopentylethyl,
(1-carboxymethyl-cyclopentyl)-methyl, 2-furyl, 2-pyridyl-(2-ethyl),
1-pyrrolidinyl-(2-ethyl), 2-theinylmethyl and 2-thienylethyl;
[0053] X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are independently
absent or selected from the group consisting of CO and SO.sub.2;
such that one of X.sup.1 or X.sup.2 and one of X.sup.3 or X.sup.4
is CO or SO.sub.2;
[0054] A is selected from the group consisting of 1,2-ethyl,
1,3-propyl, 1,4-butyl, 2-methyl-1,3-propyl,
1,1,-dimethyl-(1,3-propyl), 2-cyclopentyl-1,3-n-propyl,
1S,3R-cyclopentyl-methyl, 1,2-cyclopent-1-enyl,
1,4-cyclopentyl-2-ene-methyl, methyl -1,3-cyclohexyl,
1,2-cyclohexyl-methyl-, 1,3-cyclohexyl-methyl-,
1S,3R-cyclohexyl-methyl-, 1R,3S-cyclohexyl-methyl,
1,4-cyclohexyl-methyl-, 1,2-cyclohex-4-enyl, 1,3-phenyl-methyl and
1-benzyl-methyl-;
[0055] R.sup.3 is selected from the group consisting of hydrogen,
phenylamino, 4-methylphenyl, 4-fluorophenyl, 2-fluorobenzyl,
3-fluorobenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-methoxybenzyl and
4-trifluoromethylbenzyl;
[0056] Y is selected from the group consisting of -3-O-- and
-4-O--;
[0057] n is an integer selected from 0, 2 or 3;
[0058] R.sup.4 is selected from the group consisting of hydrogen,
4-morpholinyl, 1-pyrrolidinyl, 2-oxo-pyrrolidin-1-yl,
2-(1-methylpyrrolidinyl), 1-piperazinyl, 1-piperidinyl,
di(methyl)aminoethyloxyethyl, N-methyl-N-benzyl-amino,
di(methyl)amino and diethylamino;
[0059] R.sup.5 is selected from the group consisting of hydrogen,
2-methyl and 6-methyl;
[0060] and the pharmaceutically acceptable salts, esters and
pro-drug forms thereof.
[0061] In another preferred embodiment of the present invention are
compounds of the formula (I) wherein R.sup.1, R.sup.2 and X.sup.1
are taken together (with the amine nitrogen) to form an optionally
substituted, monocyclic or fused bicyclic or tricyclic secondary
amine ring structure selected from the group consisting of
1-phenyl-1,2,3,4-tetrahydroisoquinolinyl,
4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl,
2-[1-benzyl-6-methoxy-1,2,3,4-tetrahydro]naphthyl,
isoindole-1,3-dione, 5-t-butyl-isoindole-1,3-dione,
5-fluoro-isoindole-1,3-dione, 5-methyl-isoindole-1,3-dione,
5,6-dichloro-isoindole-1,3-dione, 4,7-dichloro-isoindole-1,3-dione,
5-bromo-isoindole -1,3-dione, 5-acetyloxy-isoindole-1,3-dione,
benzo[e]isoindole-1,3-dione, 8-fluorobenzo[e]isoindole-1,3-dione,
4,4-dimethyl-piperidine-2,6-dione,
3-aza-bicyclo[3.1.0]hexane-2,6-dione and
8-aza-spiro[4.5]decane-7,9-dione; and the pharmaceutically
acceptable salts, esters and pro-drug forms thereof.
[0062] In a particularly preferred embodiment R.sup.1, R.sup.2 and
X.sup.1 are taken together (with the amine nitrogen) to form
1-phenyl-1,2,3,4-tetrahydroisquinolinyl, X.sup.2 is C(O), A is
1,3-propyl, X.sup.3 is C(O), R.sup.3 is 4-fluorobenzyl, Y is 3-O--,
n is 2 and R.sup.4 is 4-morpholinyl.
[0063] In another preferred embodiment R.sup.1, R.sup.2 and X.sup.1
are taken together (with the amine nitrogen) to form
4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl, X.sup.2 is C(O), A
is 1,3-n-propyl, X.sup.3 is absent, R.sup.3 is 4-fluorophenyl,
X.sup.4 is C(O), Y is 3-O--, n is 2 and R.sup.4 is
4-morpholinyl.
[0064] In still another preferred embodiment, R.sup.1, R.sup.2 and
X.sup.1 are taken together (with the amine nitrogen) to form
2-[1-benzyl-6-methoxy-1,2,3,4-tetrahydro]-naphthyl, X.sup.2 is
C(O), A is 1,3-n-propyl, X.sup.3 is absent, R.sup.3 is
4-fluorophenyl, X.sup.4 is C(O), Y is 3-O--, n is 2 and R.sup.4 is
4-morpholinyl.
[0065] In a class of the invention are compounds of the formula (I)
wherein
[0066] R.sup.1 is selected from the group consisting of benzyl,
2-(phenyl)ethyl, 3-nitrobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl,
3,4-difluorobenzyl, 3,5-dichlorobenzyl, 3-trifluoromethylbenzyl and
2-pyridyl-methyl;
[0067] R.sup.2 is selected from the group consisting of t-butyl,
2-(phenyl)ethyl, trichloromethyl, 3-carboxybenzyl, 3-methoxybenzyl,
2-(4-methoxyphenyl)ethyl, 2-(4-chlorophenyl)ethyl, diphenylmethyl,
2-(2-pyridyl)ethyl, 2-(1-pyrrolidinyl)ethyl and
2-(2-thienyl)ethyl;
[0068] X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are independently
absent or CO; such that one of X.sup.1 or X.sup.2 and one of
X.sup.3 or X.sup.4 is CO;
[0069] A is selected from the group consisting of 1,2-ethyl,
1,3-propyl, 2-methyl-1,3-propyl, 1,1,-dimethyl-(1,3-propyl),
2-cyclopentyl-1,3-n-propyl, 1S,3R-cyclopentyl-methyl,
1,3-cyclohexyl-methyl, 1S,3R-cyclohexyl-methyl- and
1R,3S-cyclohexyl-methyl-;
[0070] R.sup.3 is selected from the group consisting of
phenylamino, 4-fluorophenyl, 3-fluorobenzyl, 2-fluorobenzyl,
4-fluorobenzyl, 4-chlorobenzyl, 4-methoxybenzyl and
4-trifluoromethylbenzyl;
[0071] Y is selected from the group consisting of -3-O-- and
-4-O--;
[0072] n is an integer selected from 2 or 3;
[0073] R.sup.4 is selected from the group consisting of hydrogen,
4-morpholinyl, 1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl,
di(methyl)amino and di(ethyl)amino;
[0074] R.sup.5 is selected from the group consisting of hydrogen,
2-methyl and 6-methyl;
[0075] and the pharmaceutically acceptable salts, esters and
pro-drug forms thereof.
[0076] In another class of the invention are compounds of the
formula (I) wherein
[0077] R.sup.1 is selected from the group consisting of benzyl,
2-(phenyl)ethyl, 3-nitrobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl,
3,4-difluorobenzyl, 3,5-dichlorobenzyl and
3-trifluoromethylbenzyl;
[0078] R.sup.2 is selected from the group consisting of t-butyl,
2-(phenyl)ethyl, trichloromethyl, 3-carboxybenzyl, 3-methoxybenzyl,
2-(2-pyridyl)ethyl and 2-(2-thienyl)ethyl;
[0079] X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are independently
absent or CO; such that one of X.sup.1 or X.sup.2 and one of
X.sup.3 or X.sup.4 is CO;
[0080] A is selected from the group consisting of 1,3-propyl,
1S,3R-cyclopentyl-methyl, 1,3-cyclohexyl-methyl-,
1S,3R-cyclohexyl-methyl- and 1R,3S-cyclohexyl-methyl-;
[0081] R.sup.3 is selected from the group consisting of
phenylamino, 4-fluorophenyl, 3-fluorobenzyl and 4-fluorobenzyl;
[0082] Y is -3-O--;
[0083] n is 2;
[0084] R.sup.4 is selected from the group consisting of hydrogen,
4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl and
di(methyl)amino;
[0085] R.sup.5 is selected from the group consisting of hydrogen,
2-methyl and 6-methyl;
[0086] and the pharmaceutically acceptable salts, esters and
pro-drug forms thereof.
[0087] Particularly preferred are compounds of the formula (I)
wherein
[0088] R.sup.1 is selected from the group consisting of benzyl,
3-nitrobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl,
3,4-difluorobenzyl and 3-trifluoromethylbenzyl;
[0089] R.sup.2 is selected from the group consisting of t-butyl,
2-(phenyl)ethyl, trichloromethyl, 2-(2-pyridyl)ethyl and
2-(2-thienyl)ethyl;
[0090] X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are independently
absent or CO; such that one of X.sup.1 or X.sup.2 and one of
X.sup.3 or X.sup.4 is CO;
[0091] A is selected from the group consisting of 1,3-propyl,
1S,3R-cyclopentyl-methyl, 1,3-cyclohexyl-methyl-,
1S,3R-cyclohexyl-methyl- and 1R,3S-cyclohexyl-methyl-;
[0092] R.sup.3 is selected from the group consisting of
phenylamino, 4-fluorophenyl, 3-fluorobenzyl and 4-fluorobenzyl;
[0093] Y is -3-O--;
[0094] n is 2;
[0095] R.sup.4 is selected from the group consisting of hydrogen,
4-morpholinyl, 1-pyrrolidinyl and 1-piperidinyl; [0096] R.sup.5 is
selected from the group consisting of hydrogen and 2-methyl;
[0097] and the pharmaceutically acceptable salts, esters and
pro-drug forms thereof.
[0098] In still another particularly preferred embodiment of the
present invention are compounds of the formula (I) wherein R.sup.1
is 3-chlorobenzyl, R.sup.2 is trichloromethyl, X.sup.1 is CO,
X.sup.2 is absent, X.sup.3 is absent, X.sup.4 is CO, A is
1S,3R-cyclohexyl-methyl-, R.sup.3 is 4-fluorophenyl, Y is -3-O--, n
is 2, R.sup.4 is 1-piperidinyl, R.sup.5 is hydrogen and the
pharmaceutically acceptable salts, esters and pro-drug forms
thereof.
[0099] In still another particularly preferred embodiment of the
present invention are compounds of the formula (I) wherein R.sup.1
is 3-chlorobenzyl, R.sup.2 is trichloromethyl, X.sup.1 is CO,
X.sup.2 is absent, X.sup.3 is absent, X.sup.4 is CO, A is
1R,3S-cyclohexyl-methyl-, R.sup.3 is 4-fluorophenyl, Y is -3-O--, n
is 2, R.sup.4 is 1-piperidinyl, R.sup.5 is hydrogen and the
pharmaceutically acceptable salts, esters and pro-drug forms
thereof.
[0100] Listed in Tables 1-16 are specific compounds of the present
invention. TABLE-US-00001 TABLE 1 ##STR5## ID # R.sup.1 R.sup.2
R.sup.3 128 benzyl 2-(phenyl)ethyl 4-fluorobenzyl 163
3-chlorobenzyl 2-(phenyl)ethyl 4-fluorobenzyl 164 benzyl
2-(phenyl)ethyl 3-fluorobenzyl 165 benzyl 2-(phenyl)ethyl
2-fluorobenzyl 166 benzyl 2-(phenyl)ethyl 4-methoxybenzyl 167
benzyl 2-(phenyl)ethyl 4-trifluoromethylbenzyl 168 benzyl
2-(phenyl)ethyl 4-chlorobenzyl
[0101] TABLE-US-00002 TABLE 2 ##STR6## ID R.sup.1 R.sup.2 R.sup.3 Y
n R.sup.4 R.sup.5 129 benzyl 2-(phenyl)ethyl 4-fluoro 3-O 2 4- H
benzyl morpholinyl 159 benzyl 3- 4-fluoro 3-O 2 4- H (phenyl)propyl
benzyl morpholinyl 162 3-chloro 2-(phenyl)ethyl 4-fluoro 3-O 2 4- H
benzyl benzyl morpholinyl 169 benzyl 2-(phenyl) 3-fluoro 3-O 2 4- H
ethyl benzyl morpholinyl 170 benzyl 2-(phenyl) 2-fluoro 3-O 2 4- H
ethyl benzyl morpholinyl 171 benzyl 2-(phenyl) 4-methoxy 3-O 2 4- H
ethyl benzyl morpholinyl 172 benzyl 2-(phenyl) 4-trifluoro 3-O 2 4-
H ethyl methyl benzyl morpholinyl 173 benzyl 2-(phenyl) 4-chloro
3-O 2 4- H ethyl benzyl morpholinyl 175 benzyl 2-(phenyl) 4-fluoro
3- 0 H H ethyl benzyl O-- 176 benzyl 2-(phenyl) 4-fluoro 3-O 2
2-oxo- H ethyl benzyl pyrrolidin-1-yl 177 benzyl 2-(phenyl)
4-fluoro 3-O 2 dimethyl amino H ethyl benzyl ethyloxy ethyl 178
benzyl 2-(phenyl) 4-fluoro 3-O 2 diethyl H ethyl benzyl amino 179
benzyl 2-(phenyl) 4-fluoro 3-O 2 1-piperazinyl H ethyl benzyl 180
benzyl 2-(phenyl) 4-fluoro 3-O 2 1-pyrrolidinyl H ethyl benzyl 181
benzyl 2-(phenyl) 4-fluoro 3-O 2 dimethyl H ethyl benzyl amino 182
benzyl 2-(phenyl) 4-fluoro 3-O 2 1-piperidinyl H ethyl benzyl 187
benzyl 2-(phenyl) 4-fluoro 3-O 3 dimethyl H ethyl benzyl amino 188
benzyl 2-(phenyl) 4-fluoro 3-O 3 1-piperidinyl H ethyl benzyl 191
benzyl 2-(phenyl) 4-fluoro 4-O 2 1-pyrrolidinyl H ethyl benzyl 192
benzyl 2-(phenyl) 4-fluoro 4-O 2 4- H ethyl benzyl morpholinyl 193
benzyl 2-(phenyl) 4-fluoro 4-O 3 1-piperidinyl H ethyl benzyl 194
benzyl 2-(phenyl) 4-fluoro 4-O 2 dimethyl H ethyl benzyl amino 195
benzyl 2-(phenyl) 4-fluoro 4-O 2 diethyl H ethyl benzyl amino 196
benzyl 2-(phenyl) 4-fluoro 3-O 2 1-pyrrolidinyl 2- ethyl benzyl
methyl 197 3-nitro 2-(phenyl) 4-fluoro 3-O 2 1-pyrrolidinyl H
benzyl ethyl benzyl 198 3-chloro 3-methoxy 4-fluoro 3-O 2
1-pyrrolidinyl H benzyl benzyl benzyl 199 3,5- 2-(phenyl) 4-fluoro
3-O 2 1-pyrrolidinyl H dichloro benzyl ethyl benzyl 200 3-trifluoro
2-(phenyl) 4-fluoro 3-O 2 1-pyrrolidinyl H methyl benzyl ethyl
benzyl 201 3-chloro 2-(2- 4-fluoro 3-O 2 1-pyrrolidinyl H benzyl
pyridyl)ethyl benzyl 202 3-chloro 2-(4-chloro 4-fluoro 3-O 2
1-pyrrolidinyl H benzyl phenyl) ethyl benzyl 203 3-chloro 2-(1-
4-fluoro 3-O 2 1-pyrrolidinyl H benzyl pyrrolidinyl)ethyl benzyl
204 3-chloro 2-(2-thienyl) 4-fluoro 3-O 2 1-pyrrolidinyl H benzyl
ethyl benzyl 205 3-nitro 2-(phenyl) 4-fluoro 3-O 2 4- H benzyl
ethyl benzyl morpholinyl 206 3-chloro 3-methoxy 4-fluoro 3-O 2 4- H
benzyl benzyl benzyl morpholinyl 207 benzyl 2-(phenyl) 4-fluoro 3-O
2 1-pyrrolidinyl 6- ethyl benzyl methyl 215 2-(phenyl) 3-carboxy
4-fluoro 3-O 2 1-pyrrolidinyl 2- ethyl benzyl benzyl methyl 234
benzyl 2-(phenyl) 4-fluoro 3-O 2 4- 2- ethyl benzyl morpholinyl
methyl
[0102] TABLE-US-00003 TABLE 3 ##STR7## ID R.sup.1 R.sup.2 A R.sup.3
154 benzyl 2-(phenyl)ethyl 2-cyclopentyl-1,3-n- 4-fluorobenzyl
propyl 155 benzyl 2-(phenyl)ethyl cis-1,2-cyclohex-4-
4-fluorobenzyl enyl 156 benzyl 2-(phenyl)ethyl 1,2-cylopentenyl H
160 benzyl 2-(phenyl)ethyl 1,3-n-butyl 4-fluorobenzyl 189 benzyl
2-(phenyl)ethyl 2-methyl-(1,3-propyl) 4-fluorobenzyl 190 benzyl
2-(phenyl)ethyl 1,1-dimethyl-(1,3- 4-fluorobenzyl propyl)
[0103] TABLE-US-00004 TABLE 4 ##STR8## ID R.sup.1 R.sup.2 X.sup.4
R.sup.3 5 benzyl 2-(phenyl)ethyl CO phenylamino 6 benzyl
2-(phenyl)ethyl CO 4-methylphenyl 7 benzyl 2-(phenyl)ethyl CO
4-fluorophenyl 12 benzyl ethyl SO.sub.2 4-methylphenyl 13 benzyl
ethyl CO 4-methylphenyl 14 benzyl ethyl CO 4-fluorophenyl 19 benzyl
methyl CO phenylamino 20 benzyl methyl SO.sub.2 4-methylphenyl 21
benzyl methyl CO 4-methylphenyl 22 benzyl methyl CO 4-fluorophenyl
26 benzyl benzyl CO phenylamino 27 benzyl benzyl SO.sub.2
4-methylphenyl 28 benzyl benzyl CO 4-methylphenyl 29 benzyl benzyl
CO 4-fluorophenyl 34 4-methylbenzyl ethyl CO phenylamino 35
4-methylbenzyl ethyl SO.sub.2 4-methylphenyl 36 4-methylbenzyl
ethyl CO 4-methylphenyl 37 4-methylbenzyl ethyl CO
4-fluorophenyl
[0104] TABLE-US-00005 TABLE 5 ##STR9## ID R.sup.1 R.sup.2 X.sup.4
R.sup.3 1 benzyl 2-(phenyl)ethyl CO phenylamino 2 benzyl
2-(phenyl)ethyl SO.sub.2 4-methylphenyl 3 benzyl 2-(phenyl)ethyl CO
4-methylphenyl 4 benzyl 2-(phenyl)ethyl CO 4-fluorophenyl 8 benzyl
ethyl CO phenylamino 9 benzyl ethyl SO.sub.2 4-methylphenyl 10
benzyl ethyl CO 4-methylphenyl 11 benzyl ethyl CO 4-fluorophenyl 15
benzyl methyl CO phenylamino 16 benzyl methyl SO.sub.2
4-methylphenyl 17 benzyl methyl CO 4-methylphenyl 18 benzyl methyl
CO 4-fluorophenyl 23 benzyl benzyl CO phenylamino 24 benzyl benzyl
SO.sub.2 4-methylphenyl 25 benzyl benzyl CO 4-methylphenyl 30
4-methylbenzyl ethyl CO phenylamino 31 4-methylbenzyl ethyl
SO.sub.2 4-methylphenyl 32 4-methylbenzyl ethyl CO 4-methylphenyl
33 4-methylbenzyl ethyl CO 4-fluorophenyl 143 H diphenylmethyl CO
4-fluorophenyl 144 benzyl 3-(phenyl)propyl CO 4-fluorophenyl 145
benzyl 2,2-dimethylpropyl CO 4-fluorophenyl 146 benzyl
2-(4-methoxyphenyl) CO 4-fluorophenyl ethyl 147 3-chlorobenzyl
2-(4-methoxyphenyl) CO 4-fluorophenyl ethyl
[0105] TABLE-US-00006 TABLE 6 ##STR10## ID R.sup.1 R.sup.2
Stereo.sup.# R.sup.3 R.sup.4 232 3-chlorobenzyl t-butyl cis
4-fluorophenyl N-methyl-N- racemate benzyl-amino 233 3-chlorobenzyl
t-butyl cis 4-fluorophenyl di(ethyl)amino racemate 235
3-chlorobenzyl t-butyl cis 4-fluorophenyl 2-(1-methyl) acemate
pyrrolidinyl 236 3-chlorobenzyl trichloro cis 4-fluorophenyl
2-(1-methyl) methyl racemate pyrrolidinyl 237 3-chlorobenzyl
t-butyl cis 4-fluorophenyl 1-piperidinyl racemate 238
3-chlorobenzyl trichloro cis 4-fluorophenyl 1-piperidinyl methyl
racemate .sup. 239.sup.a 3-chlorobenzyl trichloro 1S, 3R
4-fluorophenyl 1-piperidinyl methyl .sup. 240.sup.b 3-chlorobenzyl
trichloro 1R, 3S 4-fluorophenyl 1-piperidinyl methyl 264 hydrogen
3-carboxy- cis 4-fluorophenyl 1-piperidinyl n-propyl racemate 265
hydrogen 3-carboxy- cis 4-fluorophenyl 1-piperidinyl
1,2,2-trimethyl- racemate cyclopentyl 266 hydrogen 3-methyl- cis
4-fluorophenyl 1-piperidinyl 3-carboxy-n-butyl racemate 267
hydrogen (1-carboxy methyl- cis 4-fluorophenyl 1-piperidinyl
cyclopentyl)-methyl racemate 268 hydrogen 3-carboxy- cis
4-fluorophenyl 1-piperidinyl 2,2-dimethyl-n-propyl racemate
.sup.#The term "cis racemate" denotes a mixture of four possible
diastereomers, with the two cis diastereomers predominately
present.
[0106] TABLE-US-00007 TABLE 7 ##STR11## ID R.sup.1 X.sup.1 R.sup.2
R.sup.3 40 benzyl CO phenylamino phenylamino 41 benzyl CO
3-methoxyphenyl phenylamino 42 benzyl CO t-butyl phenylamino 43
benzyl CO 2-(phenyl)ethyl phenylamino 44 benzyl CO 2-naphthyl
phenylamino 45 benzyl CO 3-nitrophenyl phenylamino 46 benzyl CO
diphenylmethyl phenylamino 47 3-chlorobenzyl CO trichloromethyl
phenylamino 48 benzyl CO 2-furyl phenylamino 49 3-chlorobenzyl CO
3,5-di-trifluoro phenylamino methylphenyl 50 3-chlorobenzyl CO
4-biphenyl phenylamino 51 3-chlorobenzyl CO 3-methoxy phenylamino
phenyl 52 3-chlorobenzyl CO t-butyl phenylamino 53 3-chlorobenzyl
CO 2-(phenyl)ethyl phenylamino 54 3-chlorobenzyl CO 2-naphthyl
phenylamino 55 3-chlorobenzyl CO 3-nitrophenyl phenylamino 56
3-chlorobenzyl CO diphenyl methyl phenylamino 57 benzyl SO.sub.2
2-naphthyl phenylamino 58 3-fluorobenzyl CO trichloromethyl
phenylamino 59 3,4-dichloro CO trichloromethyl phenylamino benzyl
60 3,5-dichloro CO trichloromethyl phenylamino benzyl 61
3-methoxybenzyl CO trichloromethyl phenylamino 62 3-trifluoromethyl
CO trichloromethyl phenylamino benzyl 63 4-chlorobenzyl CO
trichloromethyl phenylamino 64 1-naphthyl-methyl CO trichloromethyl
phenylamino 65 3-nitrobenzyl CO trichloromethyl phenylamino 66
2,3-dichloro CO trichloromethyl phenylamino benzyl 67 benzyl CO
trichloromethyl phenylamino 68 2-pyridyl-methyl CO trichloromethyl
phenylamino 69 H CO phenynamino phenylamino 70 H CO 2-furyl
phenylamino 71 H SO.sub.2 2-naphthyl phenylamino 72 H CO
trichloromethyl phenylamino 73 H CO trifluoromethyl phenylamino 74
H CO 3,5-di-trifluoro phenylamino methylphenyl 75 H CO 4-biphenyl
phenylamino 76 H CO 3-methoxyphenyl phenylamino 77 H CO t-butyl
phenylamino 78 H CO 2-(phenyl)ethyl phenylamino 79 H CO 2-naphthyl
phenylamino 80 H CO 3-nitrophenyl phenylamino 81 H CO
diphenylmethyl phenylamino 82 benzyl CO 3,5-di(trifluoro
phenylamino methyl)phenyl 83 benzyl CO 4-biphenyl phenylamino 86
3-chlorobenzyl CO 3-hydroxyphenyl phenylamino 90 2-pyridyl-methyl
CO trichloromethyl 4-fluorophenyl 91 H CO trichloromethyl
4-fluorophenyl 92 2,3-dichloro CO trichloromethyl 4-fluorophenyl
benzyl 93 3-nitrobenzyl CO trichloromethyl 4-fluorophenyl 94
1-naphthyl-methyl CO trichloromethyl 4-fluorophenyl 95
4-chlorobenzyl CO trichloromethyl 4-fluorophenyl 96
3-trifluoromethyl CO trichloromethyl 4-fluorophenyl benzyl 97
3-methoxybenzyl CO trichloromethyl 4-fluorophenyl 98 3,5-dichloro
CO trichloromethyl 4-fluorophenyl benzyl 99 3,4-dichloro CO
trichloromethyl 4-fluorophenyl benzyl 100 3-fluorobenzyl CO
trichloromethyl 4-fluorophenyl 101 3-chlorobenzyl CO diphenylmethyl
4-fluorophenyl 102 3-chlorobenzyl CO 3-nitrophenyl 4-fluorophenyl
103 3-chlorobenzyl CO 2-naphthyl 4-fluorophenyl 104 3-chlorobenzyl
CO 2-(phenyl)ethyl 4-fluorophenyl 105 3-chlorobenzyl CO t-butyl
4-fluorophenyl 106 3-chlorobenzyl CO 3-methoxyphenyl 4-fluorophenyl
107 3-chlorobenzyl CO 3,5-di-trifluoro 4-fluorophenyl methylphenyl
108 3-chlorobenzyl CO trifluoromethyl 4-fluorophenyl 109
3-chlorobenzyl CO 4-biphenyl 4-fluorophenyl 110 3-chlorobenzyl CO
3,3,3-trifluoro 4-fluorophenyl propan-2-onyl 111 3-chlorobenzyl CO
trichloromethyl 4-fluorophenyl 112 benzyl CO diphenylmethyl
4-fluorophenyl 113 benzyl CO 3-nitrophenyl 4-fluorophenyl 114
benzyl CO 2-naphthyl 4-fluorophenyl 115 benzyl CO 2-(phenyl)ethyl
4-fluorophenyl 116 benzyl CO t-butyl 4-fluorophenyl 117 benzyl CO
3-methoxyphenyl 4-fluorophenyl 118 benzyl CO 4-biphenyl
4-fluorophenyl 119 benzyl CO 3,5-ditrifluoro 4-fluorophenyl
methylphenyl 120 benzyl CO trifluoromethyl 4-fluorophenyl 121
benzyl CO 3,3,3-trifluoro 4-fluorophenyl propan-2-onyl 122 benzyl
CO trichloromethyl 4-fluorophenyl 123 benzyl SO.sub.2 2-naphthyl
4-fluorophenyl 124 benzyl CO 2-furyl 4-fluorophenyl 125 benzyl CO
phenylamino 4-fluorophenyl 241 3-chlorobenzyl CO 3-methoxybenzyl
4-fluorophenyl 242 3-chlorobenzyl CO 2- 4-fluorophenyl
cyclopentylethyl 243 3-chlorobenzyl CO 4-methoxybenzyl
4-fluorophenyl 244 3-chlorobenzyl CO Benzyl 4-fluorophenyl 245
3-chlorobenzyl CO 3,4- 4-fluorophenyl dimethoxybenzyl 246
3-chlorobenzyl CO t-butylmethyl 4-fluorophenyl 247 3-chlorobenzyl
CO 1(1-phenyl) 4-fluorophenyl propyl 248 3-chlorobenzyl CO
2-thienylmethyl 4-fluorophenyl 249 3-chlorobenzyl CO 4-fluorobenzyl
4-fluorophenyl
[0107] TABLE-US-00008 TABLE 8 ##STR12## ID R.sup.1 R.sup.2 R.sup.3
158 H trichloromethyl 4-fluorophenyl 161 3-chlorobenzyl t-butyl
4-fluorophenyl 157 benzyl trifluoromethyl 4-fluorophenyl
[0108] TABLE-US-00009 TABLE 9 ##STR13## ID R.sup.1 R.sup.2
Stereo.sup.# R.sup.3 R.sup.5 208 3-nitrobenzyl trichloromethyl 1S,
3R 4-fluorophenyl CH.sub.3 209 3-chlorobenzyl trichloromethyl 1S,
3R 4-fluorophenyl CH.sub.3 210 benzyl trichloromethyl 1S, 3R
4-fluorophenyl CH.sub.3 223 3-chlorobenzyl trichloromethyl cis
phenylamino H race- mate 224 benzyl trichloromethyl cis phenylamino
H race- mate 225 benzyl t-butyl cis phenylamino H race- mate 226
3-chlorobenzyl t-butyl cis 4-fluorophenyl H race- mate 227 3,4-
t-butyl cis 4-fluorophenyl H dichlorobenzyl race- mate 228 3,4-
t-butyl cis 4-fluorophenyl H difluorobenzyl race- mate 229 benzyl
t-butyl 1S, 3R 4-fluorophenyl H 230 benzyl t-butyl 1R, 3S
4-fluorophenyl H 211 3-nitrobenzyl trichloromethyl cis
4-fluorophenyl H race- mate 212 3-chlorobenzyl trichloromethyl cis
4-fluorophenyl H race- mate 213 benzyl trichloromethyl cis
4-fluorophenyl H race- mate 214 benzyl t-butyl cis 4-fluorophenyl H
race- mate .sup.#The term "cis racemate" denotes a mixture of four
possible diastereomers, with the two cis diastereomers
predominately present.
[0109] TABLE-US-00010 TABLE 10 ##STR14## Cyclohexyl Relative
Conformation is CIS ID R.sup.1 R.sup.2 R.sup.3 174 2-pyridylmethyl
trichloromethyl 4-fluorophenyl 183 benzyl benzyl phenylamino 184
3-chlorobenzyl 3-methoxyphenyl phenylamino 185 3-chlorobenzyl
2-furyl phenylamino 186 3-nitrobenzyl 3-methoxyphenyl
phenylamino
[0110] TABLE-US-00011 TABLE 11 ##STR15## ID R.sup.1 R.sup.2 Stereo
R.sup.3 216 benzyl t-butyl 1S, 3R 4-fluorophenyl 217 3-chlorobenzyl
t-butyl 1S, 3R 4-fluorophenyl 218 benzyl trichloromethyl 1S, 3R
4-fluorophenyl 219 3-nitrobenzyl trichloromethyl 1S, 3R
4-fluorophenyl 220 3,4-difluorobenzyl t-butyl 1S, 3R 4-fluorophenyl
231 benzyl trichloromethyl 1R, 3S 4-fluorophenyl
[0111] TABLE-US-00012 TABLE 12 ##STR16## ID R.sup.1 X.sup.1 R.sup.2
130 H CO 2-(phenyl)ethyl 131 H CO trichloromethyl 132 H CO
4-biphenyl 133 H CO diphenylmethyl 134 H CO 3-methoxybenzyl 135 H
SO.sub.2 4-biphenyl 151 benzyl CO trichloromethyl 152 benzyl CO
2-(phenyl)ethyl
[0112] TABLE-US-00013 TABLE 13 ##STR17## ID R.sup.1 R.sup.2 136
benzyl 2-(phenyl)ethyl 137 H diphenylmethyl 138 H 2-(phenyl)ethyl
139 benzyl 3-(phenyl)propyl 140 benzyl 2,2-dimethylpropyl 141
3-chlorobenzyl 2,2-dimethylpropyl
[0113] TABLE-US-00014 TABLE 14 ##STR18## R.sup.1, R.sup.2 and
X.sup.1 Taken Together with the ID amine nitrogen) A X.sup.3
X.sup.4 R.sup.3 142 1-phenyl-1,2,3,4- 1,3-phenyl- absent CO
4-fluoro tetrahydroisoquinolin-2-yl methyl phenyl 148
1-phenyl-1,2,3,4- 1,3-n-propyl absent CO 4-fluoro
tetrahydroisoquinolin-2-yl phenyl 149 4-[(4- 1,3-n-propyl absent CO
4-fluoro chlorophenyl)phenylmethyl]- phenyl piperazin-1-yl 150
2-[1-benzyl-6-methoxy- 1,3-n-propyl absent CO 4-fluoro
1,2,3,4-tetrahydro]-naphthyl phenyl 153 1-phenyl-1,2,3,4-
1,3-n-propyl CO absent 4-fluoro tetrahydroisoquinolinyl benzyl
[0114] TABLE-US-00015 TABLE 15 ##STR19## ID R.sup.1 R.sup.2 A
R.sup.3 R.sup.4 39 3-chloro trichloro methyl-1,3- phenyl
4-morpholinyl benzyl methyl cyclopentyl amino 221 benzyl t-butyl
1,4-cyclopentyl- 4-fluoro 1-pyrrolidinyl 2-ene-methyl phenyl
[0115] TABLE-US-00016 TABLE 16 ##STR20## R.sup.1, R.sup.2 and
X.sup.1 Taken Together ID (with the amine nitrogen) 250
5-t-butyl-isoindole-1,3-dione 251 5-fluoro-isoindole-1,3-dione 252
benzo[e]isoindole-1,3-dione 253 5-methyl-isoindole-1,3-dione 254
8-aza-spiro[4.5]decane-7,9-dione 255
5,6-dichloro-isoindole-1,3-dione 256 5-methyl-isoindole-1,3-dione
257 isoindole-1,3-dione 258 4,4-dimethyl-piperidine-2,6-dione 259
5-bromo-isoindole-1,3-dione 260 5-acetyloxy-isoindole-1,3-dione 261
8-fluoro-benzo[e]isoindole-1,3-dione 262
3-aza-bicyclo[3.1.0]hexane-2,4-dione 263
4,7-dichloro-isoindole-1,3-dione
[0116] TABLE-US-00017 TABLE 17 ##STR21## ID # R.sup.1 R.sup.2
R.sup.3 R.sup.4 84 benzyl H phenylamino 4-morpholino 85
3-chlorobenzyl H phenylamino 4-morpholino 87 3,5-dichlorobenzyl H
phenylamino 4-morpholino 88 1-naphthylmethyl H phenylamino
4-morpholino 89 4-(1-hydroxy)-pyridyl H phenylamino 4-morpholino
222 benzyl benzyl 4-fluorophenyl 1-pyrrolidinyl
[0117] Illustrative of the invention is a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and
any of the compounds described above. Illustrating the invention is
a pharmaceutical composition made by mixing any of the compounds
described above and a pharmaceutically acceptable carrier. A
further illustration of the invention is a process for making a
pharmaceutical composition comprising mixing any of the compounds
described above and a pharmaceutically acceptable carrier.
[0118] Included in the invention is the use of any of the compounds
described above for the preparation of a medicament for treating a
disorder mediated by the motilin receptor, in a subject in need
thereof.
[0119] Also included in the invention is the use of any of the
compounds described above for the preparation of a medicament for
treating a condition selected from gastrointestinal reflux
disorders, eating disorders leading to obesity and irritable bowel
syndrome in a subject in need thereof.
[0120] Exemplifying the invention are methods of treating a
disorder mediated by the motilin receptor, in a subject in need
thereof, comprising administering to the subject a therapeutically
effective amount of any of the compounds or pharmaceutical
compositions described above.
[0121] An example of the invention is a method for treating a
condition selected from gastrointestinal reflux disorders, eating
disorders leading to obesity and irritable bowel syndrome in a
subject in need thereof, comprising administering to the subject an
effective amount of any of the compounds or pharmaceutical
compositions described above.
[0122] Another example of the invention is the use of any of the
compounds described above in the preparation of a medicament for:
(a) treating gastrointestinal reflux disorders, (b) treating
irritable bowel syndrome, (c) treating eating disorders leading to
obesity, in a subject in need thereof.
[0123] Listed below are definitions of various terms used to
describe this invention. These definitions apply to the terms as
they are used throughout this specification, unless otherwise
limited in specific instances, either individually or as part of a
larger group.
[0124] The term "halogen" or "halo" refers to fluorine, chlorine,
bromine and iodine.
[0125] The term "alkyl", unless otherwise specified, refers to
straight or branched chain unsubstituted hydrocarbon groups of 1 to
20 carbon atoms, preferably 1 to 8 carbon atoms. The expression
"lower alkyl" refers to straight or branched chain unsubstituted
alkyl groups of 1 to 6 carbon atoms. For example, alkyl radicals
include, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-pentyl,
2-methylpropyl, 2-methylbutyl, 3,3-dimethylpropyl, neo-pentyl,
n-hexyl, 2-hexyl and 2-methylpentyl. Similarly, the term "alkenyl",
unless otherwise specified, refers to straight or branched chain
alkene groups of 2 to 10 carbon atoms. The term "lower alkenyl"
refers to straight or branched chain alkene groups of 2 to 6 carbon
atoms.
[0126] The term "substituted alkyl", unless otherwise specified,
refers to an alkyl group substituted by, for example, one to four
substituents, such as, halo, trifluoromethyl, trifluoromethoxy,
hydroxy, alkoxy, cycloalkyoxy, heterocyclyloxy, oxo, alkanoyl,
aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino,
cycloalkylamino, heterocycloamino, disubstituted amines in which
the amino substituents are independently selected from alkyl, aryl
or aralkyl, alkanoylamine, aroylamino, aralkanoylamino, substituted
alkanoylamino, substituted arylamino, substituted aralkanoylamino,
thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio,
heterocyclothio, alkylthiono, arylthiono, aralkylthiono,
alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g.
SO.sub.2NH.sub.2), substituted sulfonamido, nitro, cyano, carboxy,
carbamyl (e.g. CONH.sub.2) substituted carbamyl (e.g. CONH alkyl,
CONH aryl, CONH aralkyl or cases where there are two substituents
on the nitrogen selected from alkyl, aryl or aralkyl),
alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos,
such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl,
pyridyl, pyrimidyl and the like.
[0127] The term "cycloalkyl", unless otherwise specified, refers to
saturated unsubstituted cyclic hydrocarbon ring systems, preferably
containing 1 to 3 rings and 3 to 8 carbon atoms per ring. For
example, cycloalkyl radicals include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, and the like. Similarly, the
term "cycloalkenyl" refers to partially unsaturated, unsubstituted
cyclic hydrocarbon groups of 3 to 20 carbon atoms, preferably 3 to
8 carbon atoms. Suitable examples of cycloalkenyl groups include
cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclooctyl, cyclodecyl,
cyclododecyl, adamantyl, and the like.
[0128] The term "alkoxy", unless otherwise specified, refers to
oxygen ether radical of the above described straight or branched
chain alkyl groups. The expression "lower alkoxy" refers to
unsubstituted alkoxy groups of 1 to 6 carbon atoms. Suitable
examples of alkoxy groups include methoxy, ethoxy, n-propoxy,
sec-butoxy, t-butoxy, n-hexyloxy and the like.
[0129] The term "aryl", unless otherwise specified, refers to
monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12
carbon atoms in the ring portion, such as phenyl, naphthyl,
biphenyl and diphenyl, each of which may be optionally
substituted.
[0130] The term "aralkyl", unless otherwise specified, refers to an
aryl group bonded directly through an alkyl group, such as benzyl,
2-(phenyl)ethyl, 3-(phenyl)propyl, naphthyl-methyl and the
like.
[0131] The term "substituted aryl" refers to an aryl group
substituted by, for example, one to five substituents such as
alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl,
hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl,
alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino,
heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio,
cycloalkylthio, heterocyclothio, ureido nitro, cyano, carboxy,
carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono,
alkysulfonyl, sulfonamido, aryloxy and the like.
[0132] The term "diarylalkyl", unless otherwise specified, refers
to an alkyl group substituted with two independently selected aryl
groups. Suitable examples include diphenylmethyl,
1,1-diphenylethyl, and the like.
[0133] The term "heteroatom" shall include oxygen, sulfur and
nitrogen.
[0134] The terms "heterocyclyl", "heterocyclic" and "heterocyclo",
unless otherwise specified, refer to a saturated, unsaturated,
partially unsaturated, aromatic, partially aromatic or non-aromatic
cyclic group. Such a group, for example, can be a 4 to 7 membered
monocyclic or a 7 to 11 bicyclic ring system which contains at
least one heteroatom in at least one carbon atom containing ring.
Each ring of the heterocyclic group containing a heteroatom may
have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen
atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms
may also optionally be oxidized and where the nitrogen heteroatoms
may also optionally be quaternized. The heterocyclic group may be
attached at any heteroatom or carbon atom.
[0135] Exemplary monocyclic heterocyclic groups include
pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl,
imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,
isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,
isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl,
oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl,
4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, tetrahydropryanyl, tetrahydrothiopyranyl,
tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl,
thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane,
tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl,
thiiranyl, triazinyl, triazolyl, tetrazolyl and the like.
[0136] Exemplary bicyclic heterocyclic groups include
benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl,
quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl,
isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl,
benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl,
indazolyl, pyrrolopyridyl, furopyridinyl (such as
furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl, or
furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such
as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl,
benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl,
benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl,
dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl,
isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl,
piperonyl, purinyl, pyridopyridyl, quinazolinyl,
tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl,
and the like.
[0137] The term "monocyclic or fused bicyclic or tricyclic
secondary amine ring structure" shall mean any 4 to 8 monocyclic or
7 to 11 fused bicyclic or 13 to 14 tricyclic ring structure;
wherein the ring structure is saturated, partially unsaturated or
benzo-fuzed; wherein the ring structure contains at least one
nitrogen atom through which the ring structure is bound directly to
the other portions of the compound; and wherein the ring structure
may optionally containing one to three additional heteroatoms
selected from nitrogen, oxygen or sulfur.
[0138] Suitable examples include 1,2,3,4-tetrahydroisoquinolinyl,
1-piperazinyl, 1,2,3,4-tetrahydronaphthyl, isoindolyl,
benzo[e]isoindolyl, 8-aza-spiro[4.5]decane,
3-aza-bicyclo[3.1.o]hexane, and the like.
[0139] The monocylic, bicyclic or tricyclic secondary amine ring
structure may optionally be substituted with one to five
substituents independently selected from alkyl, substituted alkyl,
halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy,
cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino,
alkylamino, aralkylamino, cycloalkylamino, heterocycloamino,
dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio,
heterocyclothio, ureido nitro, cyano, oxo, carboxy, carboxyalkyl,
carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl,
sulfonamido, aryloxy, aryl, aralkyl, heterocyclyl, and the
like.
[0140] The term "tri-halomethyl" refers to trichloromethyl,
trifluoromethyl, tribromomethyl and triiodomethyl.
[0141] Under standard nomenclature used throughout this disclosure,
the terminal portion of the designated side chain is described
first, followed by the adjacent functionality toward the point of
attachment. Thus, for example, a "phenyl(alkyl)amido(alkyl)"
substituent refers to a group of the formula ##STR22##
[0142] Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers.
Where the compounds possess two or more chiral centers, they may
additionally exist as diastereomers. It is to be understood that
all such isomers and mixtures thereof are encompassed within the
scope of the present invention. Furthermore, some of the
crystalline forms for the compounds may exist as polymorphs and as
such are intended to be included in the present invention. In
addition, some of the compounds may form solvates with water (i.e.,
hydrates) or common organic solvents, and such solvates are also
intended to be encompassed within the scope of this invention.
[0143] As used herein, the term "cis racemate" indicates a mixture
of four possible diastereomers, more particularly, two cis
diastereomers and two trans diastereomers, with the two cis
diastereomers present in a amount equal to greater than about 75%,
preferably in an amount greater than about 90%, more preferably in
an amount greater than about 95%.
[0144] When a particular group is "substituted" (e.g., aryl,
heteroaryl, heterocyclyl), that group may have one or more
substituents, preferably from one to five substituents, more
preferably from one to three substituents, most preferably from one
to two substituents, independently selected from the list of
substituents. Where the group has a plurality of moieties, such as
"alkylamino" or "heterocyclyl-alkyl" the substitution may be on any
or all of the moieties independently, e.g. in the case of
"alkylamino" the substitution may be on the alkyl or amino moiety,
or both.
[0145] It is intended that the definition of any substituent or
variable at a particular location in a molecule be independent of
its definitions elsewhere in that molecule. It is understood that
substituents and substitution patterns on the compounds of this
invention can be selected by one of ordinary skill in the art to
provide compounds that are chemically stable and that can be
readily synthesized by techniques known in the art as well as those
methods set forth herein.
[0146] Suitable protecting groups as referred to within this
specification include the standard hydroxy and amino protecting
groups, as applicable. The terms "hydroxy protecting group" and
"amino protecting group" as used herein mean any of the known
protecting groups used in the art of organic synthesis, for example
as described in Protective Groups in Organic Synthesis, 2.sup.nd
Ed., T. W. Greene and P. G. M. Wuts, John Wiley & Sons, New
York, 1991, hereby incorporated by reference.
[0147] Examples of hydroxy-protecting groups P, include, but are
not limited to, methyl, benzyl, tetrahydropyranyl,
tri(C.sub.1-C.sub.6)alkylsilyl such as t-butyldimethylsilyl,
t-butyl, 2-methoxyethoxymethyl (MEM), 4-dimethylcarbamoylbenzyl and
O-phenoxyacetyl ethers. The hydroxy-protecting group selected is
preferably one that is easily removable in the reaction
process.
[0148] Examples of suitable amino protecting groups include, but
are not limited to, acetyl(Ac), benzoyl(Bz), trifluoroacetyl(Tfa),
toluenesulfonyl(Tos), benzyl (Bn), triphenylmethyl(Trt),
o-nitrophenyl-sulfenyl(Nps), benzyloxycarbonyl(Cbz or Z),
t-butoxycarbonyl(Boc), allyloxycarbonyl(alloc),
9-fluorenylmethyloxycarbonyl(Fmoc), 2-bromo-benzyloxycarbonyl
(2-Br-Z), 2-chloro-benzyloxycarbonyl (2-Cl-Z),
t-butyl-dimethylsilyloxycarbonyl,
[2-(3,5-dimethoxyphenyl)-propyl-2-oxycarbonyl] (Ddz),
2,2,2-trichloroethyloxycarbonyl (Troc),
biphenylylisopropyloxycarbonyl(Bpoc), and
o-nitrobenzyloxycarbonyl.
[0149] Throughout this specification, certain abbreviations are
employed having the following meanings, unless specifically
indicated otherwise. [0150] AcOH=Acetic Acid [0151]
ADDP=1,1'-(azodicarbonyl)dipiperidine [0152] BSA=Bovine Serum
Albumin [0153] DCM=Dichloromethane [0154] DEAD=Diethyl
azodicarboxylate [0155] DIEA=Diisopropylethylamine [0156]
DMAP=Di(methyl)aminopyridine [0157] DMF=N,N-dimethylformamide
[0158] DMSO=Dimethylsulfoxide [0159] EA=Ethyl acetate [0160]
EDCI=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide [0161]
EDTA=Ethylenediamine tetraacetic acid [0162] EGTA=Ethylene
glycol-bis(.beta.-aminoethyl ether)-N,N,N',N'-tetraacetic acid
[0163] Et.sub.2O=Diethyl ether [0164] EtOAc=Ethyl acetate [0165]
EtOH=Ethanol [0166] Et.sub.3N=Triethylamine [0167]
HEPES=N-(2-hydroxyethyl)piperazine-N-ethanesulfonic acid [0168]
LAH=Lithium Aluminum Hydride [0169] MeOH=Methanol [0170] MeI=Methyl
Iodide [0171] Oms=Mesylate [0172] Otos=Tosylate [0173] Phe=Phenyl
[0174] Pt=Protecting Group [0175]
PyBOP=Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium
hexafluorophosphate [0176] TBAF=Tetrabutylammonium fluoride [0177]
TEA=Triethylamine [0178] TFA=Trifluoroacetic Acid [0179]
THF=Tetrahydrofuran [0180] Tris-HCl=Tris[hydroxymethyl]aminomethyl
hydrochloride
[0181] The synthesis of substituted N-benzyl-m-anisidines,
compounds of formula (II), intermediates used in the synthetic
route for select compounds of the invention, are known in the art.
##STR23##
[0182] Routes for synthesis of substituted N-benzyl-m-anisidines
include alkylation (Hoerlein; Chem. Ber.; 87; 1954; 463, 467, 468),
reductive amination (Nussbaumer, P.; et. al.; J Med. Chem.; 37; 24;
1994; 4079-4084) and reduction of the corresponding
N-benzoyl-m-anisidine (Pratt; McGovern; J. Org. Chem.; 29; 1964;
1540, 1542). Additionally, N-benzyl-N-phenyl-malonamic acid methyl
ester, a compound of formula (III) below, is a known compound, a
variant of one of the intermediates elucidated in the synthesis
that follows (Wee, A.; Tetrahedron, 50; 3; 1994; 609-626).
##STR24##
[0183] Routes to the synthesis of
4-phenyl-1,2,3,4-tetrahydroisoquinolines are also known in the
literature (Maryanoff, B., et. al., J. Org. Chem., 46, 1981, 355
360; Schwan, T. et. al., J. Heterocycl. Chem., 1974, 11, 807; and
references therein).
[0184] Schemes 1-8 below depict synthesis routes for producing
compounds of the formula (I).
[0185] Compounds of formula (I) wherein X.sup.2 and X.sup.3 are
each carbonyl, X.sup.1 and X.sup.4 are each absent and R.sup.3 is
--CH.sub.2--R.sup.6, may be produced according to the process
outlined in Scheme 1. The process of Scheme 1 is particularly
preferred for preparation of compounds of formula (I) wherein A is
incorporated into the molecule via reaction with a suitably
selected unsymmetrically substituted anhydride; wherein A is a
substituted alkyl; and wherein it is desired to have the
substituent closer to the R.sup.1X.sup.1R.sup.2N portion of the
compound of formula (I). ##STR25##
[0186] More specifically, a protected aniline derivative of formula
(IV), wherein Pt represents a protecting group, a known compound or
compound prepared by known methods, is reacted with a suitably
substituted aldehyde of the formula (V), wherein R.sup.3A is
selected from hydrogen, aryl, heterocyclyl, aralkyl, diarylalkyl,
heterocyclo-alkyl, tri-halomethyl, alkylamino, dialkylamino,
alkylaminoalkyl, arylamino, diarylamino or lower alkyl; in the
presence of a reducing agent such as sodium cyanoborohydride,
sodium triacetoxyborohydride, and the like, under dehydrating
conditions, for example, in an acid alcohol solution such as acidic
methanol or in a solution of titanium tetraisopropoxide in DCM, to
produce the corresponding secondary aniline derivative of formula
(VI).
[0187] The secondary aniline derivative of formula (VI) is coupled
with a suitably selected, protected dicarboxylic acid of formula
(VII), wherein Pt' is a protecting group or with an anhydride of
the desired substituent A, to produce the corresponding acid-amide
of formula (VIII).
[0188] When the secondary aniline derivative of formula (VI) is
coupled with a cyclic anhydride of the desired substituent A, such
as glutaric anhydride and the like, the anhydride ring is subjected
to ring opening, preferably at a temperature between about room
temperature and about 110.degree. C., in an organic solvent such as
chloroform, toluene, and the like.
[0189] When the secondary aniline derivative of formula (VI) is
coupled with a protected dicarboxylic acid of formula (VII), the
protecting group is then removed by hydrolysis, using an inorganic
base such as lithium hydroxide, sodium hydroxide, potassium
hydroxide, and the like, in an alcohol or in an organic
solvent/water mixture such as methanol, ethanol, THF/water,
preferably lithium hydroxide in THF/water.
[0190] The acid-amide compound of formula (VIII) is activated using
a known coupling agent, such as EDCI and the like, and coupled with
a suitably substituted amine of formula (IX), in an organic base
such as TEA, DIEA, and the like, in the presence of an organic
solvent such as THF, DMF, DCM and the like, to produce the
corresponding diamide of formula (X).
[0191] Alternatively, the acid-amine compound of formula (VIII) may
be converted to the corresponding acid chloride with a reagent such
thionyl chloride, oxalyl chloride, and the like, and then coupled
to the substituted amine of formula (IX) to produce the diamide of
formula (X).
[0192] The compound of formula (X) is deprotected by known methods
[for example, when the protecting group is methyl ether, the methyl
group is removed with boron tribromide in dichloromethane at
-78.degree. C.; when the protecting group is
t-butyldimethylsilylether, the silyl group is removed with
tetrabutylammonium fluoride in THF] to produce the corresponding
compound of formula (XI).
[0193] The compound of formula (XI) is reacted with a suitably
substituted compound of formula (XII), wherein W represents a
leaving group such as halogen, OMS, OTos, and the like, in the
presence of a base such as sodium hydride, potassium carbonate, and
the like, in an organic solvent such as DMF, THF, and the like, to
produce the corresponding compound of formula (Ia). Alternatively,
when W is OH, the compound of formula (XI) may be reacted directly,
under Mitsunobu conditions, to a suitably substituted compound of
formula (XII).
[0194] Compounds of formula (I) wherein X.sup.2 and X.sup.3 are
each carbonyl, X.sup.1 and X.sup.4 are each absent and R.sup.3 is
--CH.sub.2--R.sup.6 may alternatively be prepared according to the
process outlined in Scheme 2. ##STR26##
[0195] Accordingly, a suitably substituted nitrobenzene of formula
(XIII), a compound prepared by known methods, is reacted with a
suitably substituted compound of formula (XII), wherein W
represents a leaving group such as halogen, OMS, OTos, and the
like, in the presence of a base such as sodium hydride,
triethylamine, and the like, in an organic solvent such as DMF,
THF, and the like, to produce the corresponding compound of formula
(XIV).
[0196] The nitro group on the compound of formula (XIV) is reduced
by known methods, for example by hydrogenation over palladium on
carbon in ethyl acetate, to produce the corresponding compound of
formula (XV).
[0197] The compound of formula (XV) is reacted with a suitably
substituted aldehyde of formula (V), wherein R.sup.3A is as
previously defined, in the presence of a reducing agent such as
sodium cyanoborohydride, sodium triacetoxyborohydride, and the
like, under dehydrating conditions, for example, in an acid alcohol
solution such as acidic methanol or in a solution of titanium
tetraisopropoxide in DCM, to produce the corresponding compound of
formula (XVI).
[0198] The compound of formula (XVI) is reacted with a suitably
selected anhydride of the desired A substituent, optionally in an
organic solvent such as THF, DMF, DCM, and the like, to produce the
corresponding compound of formula (XVII). When reacting with a
cyclic anhydride of the desired substituent A, such as glutaric
anhydride and the like, the anhydride ring is subjected to ring
opening, preferably at a temperature between about room temperature
and about 110.degree. C., in an organic solvent such as chloroform,
toluene, and the like.
[0199] The compound of formula (XVII) is coupled with a suitably
substituted amine of formula (IX), in the presence of a coupling
agent, such as PyBOP, and the like, in an organic solvent such as
THF, DMF, DCM, and the like, to produce the corresponding compound
of formula (Ib).
[0200] Compounds of formula (I) wherein X.sup.2 and X.sup.3 are
each carbonyl, X.sup.1 and X.sup.4 are each absent and R.sup.3 is
--CH.sub.2--R.sup.6, may alternatively be prepared according to the
process outlined in Scheme 3. This process is particularly
preferred for preparation of compounds of formula (I) wherein A is
incorporated into the molecule via reaction with a suitably
selected, unsymmetrically substituted anhydride; wherein A is a
substituted alkyl; and wherein it is desired to have the
substituent distal to the R.sup.1X.sup.1R.sup.2N portion of the
compound of formula (I). ##STR27##
[0201] More specifically, a suitably substituted amine of formula
(IX) is reacted with a suitably selected anhydride of the desired A
substituent, in an organic solvent such as THF, DMF, DCM, and the
like, to produce the corresponding compound of formula (XVIII).
When the compound of formula (IX) is coupled with a cyclic
anhydride of the desired A substituent, such as glutaric anhydride
and the like, the anhydride ring is subjected to ring opening,
preferably at a temperature between about room temperature and
about 110.degree. C., in an organic solvent such as chloroform,
toluene, and the like.
[0202] The compound of formula (XVIII) is coupled with a suitably
substituted compound of formula (XVI), prepared as in Scheme 2
above, in an organic solvent such as THF, DMF, DCM and the like,
after conversion of the compound of formula (XVIII) to the
corresponding acid chloride using a reagent such as thionyl
chloride, oxalyl chloride, and the like, to produce the
corresponding compound of formula (Ib).
[0203] Alternatively, the compound of formula (XVIII) may be
coupled directly with a suitably substituted compound of formula
(XVI), optionally in the presence of a coupling agent such as
PyBrop, and the like, in an organic solvent such as THF, DMF, DCM,
and the like.
[0204] Compounds of formula (I) wherein X.sup.1 and X.sup.3 are
each absent, X.sup.2 is carbonyl, and X.sup.4 is carbonyl or
sulfonyl, may be prepared according to the process outlined in
Scheme 4. ##STR28##
[0205] More specifically, an anhydride of the desired substituent A
is reacted with a suitably substituted compound of formula (XIV),
prepared as outlined in scheme 2, in an organic solvent such as
THF, DMF, DCM and the like, to produce the corresponding compound
of formula (XIX).
[0206] The compound of formula (XIX) is coupled with a suitably
substituted amine of formula (IX), in the presence of a coupling
agent, such as PyBOP, and the like, in an organic solvent such as
THF, DMF, DCM and the like, to produce the corresponding compound
of formula (XX).
[0207] The compound of formula (XX) is selectively reduced, by
known methods, for example, by reacting with sodium
cyanoborohydride in AcOH (Tetrahedron Letters, 10, 763-66, 1976),
to produce the corresponding compound of formula (XXI).
[0208] The compound of formula (XXI) is reacted with an
appropriately selected and suitably substituted isocyanate of
formula (XXII), wherein R.sup.3A is a previously defined, or a
sulfonyl chloride of formula (XXIII) or a carbonyl chloride of
formula (XXIV), in an organic solvent such as THF, DMF, DCM and the
like, to produce the corresponding compound of formula (Ic).
[0209] Compounds of formula (I) wherein X.sup.1 and X.sup.4 are
each carbonyl or sulfonyl and X.sup.2 and X.sup.3 are each absent,
may be prepared according to the process outlined in Scheme 5. This
process is particularly preferred for the preparation of compounds
of formula (I) wherein A is -cyclohexyl-methyl-,
-cyclopentyl-methyl and -cyclopentenyl-methyl-. ##STR29##
##STR30##
[0210] Accordingly, a trityl-protected compound of formula (XXV),
wherein A.sup.1 is cycloalkyl, cycloalkenyl, alkyl-cycloalkyl, aryl
or alkyl-aryl, a known compound or compound prepared by known
methods, [for example by the method disclosed in K. Barlos, D.
Theodoropoulos, and D. Papaioannou in J. Org. Chem. 1982, 47,
1324-1326], is coupled to a suitably substituted compound of
formula (XIV), prepared according to Scheme 2 above, using a
coupling agent such as PyBOP, and the like, to produce the
corresponding compound of formula (XXVI).
[0211] The compound of formula (XXVI) is subjected to reduction of
the carbonyl group using known reducing agents, for example borane
dimethylsulfide at reflux, lithium aluminum hydride in THF, and the
like, to produce the corresponding compound of formula (XXVII).
[0212] The compound of formula (XXVII) is reacted with an
appropriately selected and suitably substituted isocyanate of
formula (XXII), wherein R.sup.3A is as previously defined, sulfonyl
chloride of formula (XXIII) or carbonyl chloride of formula (XXIV),
in an organic solvent such as DCM, toluene, chloroform, and the
like, to produce the corresponding compound of formula
(XXVIII).
[0213] The compound of formula (XXVIII) is deprotected by removal
of the trityl protecting group, using a solution of trifluoroacetic
acid in dichloromethane, to produce the corresponding compound of
formula (XXIX).
[0214] The compound of formula (XXIX) is reacted with a suitably
substituted aldehyde of formula (XXX), wherein R.sup.1A is selected
from the group consisting of hydrogen, aryl, aralkyl, heterocyclyl,
diarylalkyl, heterocyclyl-alkyl, and lower alkyl; wherein the
alkyl, aryl, heterocyclyl or amino group may be substituted with
one or more substituents independently selected from halogen,
hydroxy, nitro, carboxy, cyano, amino, dialkylamino, lower alkoxy,
lower alkyl, tri-halomethyl, alkylamino, carboxy or alkoxycarbonyl;
by known methods, [for example by reductive amination or by the
method of R. Mattson, et. al., in J. Org. Chem. 1990, 55, 2552-2554
using stepwise addition of titanium tetraisopropoxide neat or in a
dichloromethane, followed by addition of methanol and
sodiumcyanoborohydride], to produce the corresponding compound of
formula (XXXI).
[0215] The compound of formula (XXXI) is reacted with an
appropriately selected and suitably substituted isocyanate of
formula (XXXII), wherein R.sup.2A is selected from aryl, aralkyl,
heterocyclyl, heterocyclyl-alkyl, diarylalkyl, tri-halomethyl,
arylamino or lower alkyl, or a sulfonyl chloride of formula
(XXXIII) or a carbonyl chloride of formula (XXXIV), or an anhydride
of formula (XXXXVII) in an organic solvent such as DCM, toluene,
and the like, to produce the corresponding compound of formula
(Id). When the compound of formula (XXXI) is reacted with a
sulfonyl chloride of formula (XXXIII) or a carbonyl chloride of
formula (XXXIV), the reaction is carried out with further addition
of an organic base such as TEA, DIPEA, and the like.
[0216] Compounds of formula (I) wherein A is a substituted alkyl
may alternatively be prepared according to the process outlined in
Scheme 6. ##STR31##
[0217] More specifically, a suitably substituted compound of
formula (XVI), prepared as described in Scheme 2 above, is coupled
with an appropriately selected, Fmoc protected compound of formula
(XXXV), in an organic solvent such as DCM, DMF, and the like, to
produce the corresponding compound of formula (XXXVI).
[0218] The compound of formula (XXXVI) is deprotected by removal of
the Fmoc protecting group by known methods [for example by treating
with piperidine in DM F], to produce the corresponding compound of
formula (XXXVII).
[0219] The compound of formula (XXXVII) is reacted with a suitably
substituted aldehyde of formula (XXX), wherein R.sup.1A is as
previously defined, in the presence of a reducing agent such as
sodium cyanoborohydride, and the like, under dehydrating
conditions, for example in an acid alcohol solution such as acidic
methanol or in a solution of titanium tetraisopropoxide in DCM,
followed by addition of methanol and sodium cyanoborohydride, to
produce the corresponding compound of formula (XXXVIII).
[0220] The compound of formula (XXXVIII) is coupled with an
appropriately selected and suitably substituted isocyanate of
formula (XXXII), wherein R.sup.2A is as previously defined,
sulfonyl chloride of formula (XXXIII) or carbonyl chloride of
formula (XXXIV), in an organic solvent such as DCM, and the like,
in the presence of an organic base such as TEA, DIEA, and the like,
to produce the corresponding compound of formula (Ie).
[0221] Optionally, the compound of formula (XXXVIII) may be further
reacted with a second equivalent of the compound of formula (XXX)
to yield a derivative of the compound of formula (XXXVIII), wherein
the leftmost amine nitrogen is di-substituted with the
--CH.sub.2--R.sup.1A group, wherein R.sup.1A is as previously
defined.
[0222] Compounds of formula (I), particularly those wherein X.sup.1
and X.sup.3 are each absent, X.sup.2 is carbonyl and X.sup.4 is
carbonyl or sulfonyl may be prepared according to the process
outlined in Scheme 7. This process is particularly preferred for
preparation of compounds of formula (I) wherein A is contains a
non-hydrogen substituent alpha to the right-hand most amine
nitrogen. ##STR32##
[0223] Accordingly, a suitably substituted compound of formula
(XV), prepared as in Scheme 2 above, is alkylated with an
appropriately selected compound of formula (XXXIX), ins an organic
solvent such as DCM, chloroform, and the like, to produce the
corresponding compound of formula (XXXX).
[0224] The compound of formula (XXXX) is coupled with an
appropriately selected and suitably substituted isocyanate of
formula (XXII), wherein R.sup.3A is as previously defined, sulfonyl
chloride of formula (XXIII) or carbonyl chloride of formula (XXIV),
in an organic solvent such as DCM, and the like, to produce the
corresponding compound of formula (XXXXI). When the compound of
formula (XXXX) is reacted with a sulfonyl chloride of formula (XXXI
II) or a carbonyl chloride of formula (XXXIV), the reaction is run
in the presence of an organic base such as TEA, DIEA, and the
like.
[0225] The compound of formula (XXXXI) is subjected to hydrolysis
of the methyl ester, in the presence of an inorganic base such as
sodium hydroxide, and the like, to produce the corresponding
compound of formula (XXXXII).
[0226] The compound of formula (XXXXII) is coupled with a suitably
substituted amine of formula (IX), in the presence of a coupling
agent such as PyBOP, and the like, in an organic solvent such as
DCM, and the like, to produce the corresponding compound of formula
(If).
[0227] Compounds of formula (I), particularly those wherein X.sup.1
and X.sup.4 are each carbonyl or sulfonyl and X.sup.2 and X.sup.3
are each absent may be prepared according to the process outlined
in Scheme 8 ##STR33##
[0228] Accordingly, wherein A.sup.1 is an oxo and cyano substituted
cycloalkyl, an oxo and cyano substituted cycloalkenyl, an oxo and
cyano substituted cycloalkyl-alkyl, an oxo-alkyl and cyano
substituted aryl or an oxo-alkyl and cyano-alkyl substituted
aryl-alkyl, a known compound or compound prepared by known methods,
is reacted with a compound of formula (XV), prepared as outlined in
Scheme 2, in the presence of a reducing agent such as sodium
cyanoborohydride, and the like, under dehydrating conditions, for
example in an acid alcohol solution such as acidic methanol, to
produce the corresponding compound of formula (XXXXIII).
[0229] The compound of formula (XXXXIII) is reacted with an
appropriately selected and suitably substituted isocyanate of
formula (XXII), wherein R.sup.3A is as previously defined, sulfonyl
chloride of formula (XXIII) or carbonyl chloride of formula (XXIV),
in an organic solvent such as DCM, and the like, to produce the
corresponding compound of formula (XXXXIV). When the compound of
formula (XXXXIII) is reacted with a sulfonyl chloride of formula
(XXIII) or a carbonyl chloride of formula (XXIV), the reaction is
run in the presence of an organic base such as TEA, DIEA, and the
like.
[0230] The cyano functional group on the compound of formula
(XXXXIV) is reduced by known methods, for example by treatment with
lithium aluminum hydride, in an organic solvent such as THF, and
the like, to produce the corresponding compound of formula
(XXXXV).
[0231] The compound of formula (XXXXV) is reacted with a suitably
substituted aldehyde of formula (XXX), wherein R.sup.1A is as
previously defined, in the presence of a reducing agent such as
sodium cyanoborohydride, and the like, under dehydrating
conditions, for example in an acid alcohol solution such as acidic
methanol or in a solution of titanium tetraisopropoxide in DCM,
followed by addition of methanol and sodium cyanoborohydride, to
produce the corresponding compound of formula (XXXXVI).
[0232] The compound of formula (XXXXVI) is reacted with an
appropriately selected and suitably substituted isocyanate of
formula (XXXII), wherein R.sup.2A is as previously defined,
sulfonyl chloride of formula (XXXI II), or carbonyl chloride of
formula (XXXIV), in an organic solvent such as DCM, and the like,
to produce the corresponding compound of formula (Ig). When the
compound of formula (XXXXVI) is reacted with a sulfonyl chloride of
formula (XXXIII) or a carbonyl chloride of formula (XXXIV), the
reaction is run in the presence of an organic base such as TEA,
DIEA, and the like.
[0233] Compounds of formula (I) wherein R.sup.1, X.sup.1 and
R.sup.2 are taken together (with the amine nitrogen) to form an oxo
substituted heterocyclyl group, may be prepared according to the
process outlined in Scheme 9. ##STR34##
[0234] More particularly, the compound of formula (XXIX), prepared
as in Scheme 5, is reacted with a suitably substituted symmetric or
asymmetric anhydride, a compound of formula (XXXXVII), preferably a
symmetric anhydride, in an organic solvent such as toluene, DCM,
and the like, to yield the corresponding compound of formula
(XXXXVIII).
[0235] The compound of formula (XXXXVIII) is heated at an elevated
temperature in the range of about 40-180.degree. C., or treated
with addition of an anhydride such as acetic anhydride,
trifluoroacetic anhydride, and the like, in an organic solvent such
as methylene chloride, toluene, 1,2-dichlorobenzene, and the like,
to yield the corresponding compound of formula (Ih), wherein
##STR35## represents the group wherein R.sup.1, R.sup.2 and X.sup.1
are taken together (with the amine nitrogen) to form a cyclic oxo
substituted heterocyclyl.
[0236] Wherein the compound of formula (XXXXVII) is an asymmetric
anhydride, (a compound of the formula
R.sup.2'-C(O)--C(O)--R.sup.2'', wherein R.sup.2' and R.sup.2'' are
different), the R.sup.2 group which is coupled onto the compound of
formula (XXIX) may be readily determined by one skilled in the art,
based on the relative reactivities of the carbonyl groups adjacent
to the R.sup.2' and R.sup.2'' groups.
[0237] It is generally preferred that the respective product of
each process step be separated from other components of the
reaction mixture and subjected to purification before its use as a
starting material in a subsequent step. Separation techniques
typically include evaporation, extraction, precipitation and
filtration. Purification techniques typically include column
chromatography (Still, W. C. et. al., J. Org. Chem. 1978, 43,
2921), thin-layer chromatography, HPLC, acid-base extraction,
crystallization and distillation.
[0238] Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers.
Where the compounds possess two or more chiral centers, they may
additionally exist as diastereomers. It is to be understood that
all such isomers and mixtures thereof are encompassed within the
scope of the present invention.
[0239] Where the processes for the preparation of the compounds
according to the invention give rise to mixture of stereoisomers,
these isomers may be separated by conventional techniques such as
preparative chromatography. The compounds may be prepared in
racemic form, or individual enantiomers may be prepared either by
enantiospecific synthesis or by resolution. The compounds may, for
example, be resolved into their component enantiomers by standard
techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active acid, such as
(-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-I-tartaric
acid followed by fractional crystallization and regeneration of the
free base. The compounds may also be resolved by formation of
diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the
compounds may be resolved by enzymatic resolution or by using a
chiral HPLC column.
[0240] To prepare the pharmaceutical compositions of this
invention, one or more compounds or salts thereof, as the active
ingredient, is intimately admixed with a pharmaceutical carrier
according to conventional pharmaceutical compounding techniques,
which carrier may take a wide variety of forms depending on the
form of preparation desired for administration, e.g., oral or
parenteral. In preparing the compositions in oral dosage form, any
of the usual pharmaceutical media may be employed. Thus for liquid
oral preparations, such as for example, suspensions, elixirs and
solutions, suitable carriers and additives include water, glycols,
oils, alcohols, flavoring agents, preservatives, coloring agents
and the like; for solid oral preparations such as, for example,
powders, capsules and tablets, suitable carriers and additives
include starches, sugars, diluents, granulating agents, lubricants,
binders, disintegrating agents and the like. Because of their ease
in administration, tablets and capsules represent the most
advantageous oral dosage form, in which case solid pharmaceutical
carriers are obviously employed. If desired, tablets may be sugar
coated or enteric coated by standard techniques. For parenterals,
the carrier will usually comprise sterile water, though other
ingredients, for example, for purposes such as aiding solubility or
for preservation, may be included. Injectable suspensions may also
be prepared, in which case appropriate liquid carriers, suspending
agents and the like may be employed. The pharmaceutical
compositions herein will preferably contain per dosage unit, e.g.,
tablet, capsule, powder, injection, teaspoonful and the like, from
about 5 to about 500 mg of the active ingredient, although other
unit dosages may be employed.
[0241] In therapeutic use for treating disorders of the
gastrointestinal system in mammals, the compounds of this invention
may be administered in an amount of from about 0.5 to 100 mg/kg 1-2
times per day orally. In addition the compounds may be administered
via injection at 0.1-10 mg/kg per day. Determination of optimum
dosages for a particular situation is within the capabilities of
formulators.
[0242] In order to illustrate the invention, the following examples
are included. These examples do not limit the invention. They are
meant to illustrate and suggest a method of practicing the
invention. Although there are other methods of practicing this
invention, those methods are deemed to be within the scope of this
invention.
EXAMPLE 1
N-trityl-cis-3-aminocyclohexanecarboxylic acid
[0243] Adapting the method of K. Barlos, D. Papaioannou and D.
Theodoropoulos, JOC, 1982, 47, 1324-1326,
cis-3-aminocyclohexanecarboxylic acid was protected as the N-trityl
derivative.
[0244] TMSCI (26.1 ml, 0.205 mmol) was added to a suspension of
cis-3-aminocyclohexanecarboxylic acid (29.4 g, 0.205 mmol)
suspended in a 5:1 solution of CH.sub.2Cl.sub.2-CH.sub.3CN (500 ml)
at room temperature. The mixture was heated at reflux for 2 hours
and then allowed to cool to ambient temperature. TEA (57.2 ml,
0.410 mmol) was added dropwise to the mixture, followed immediately
by portionwise addition of triphenylmethyl chloride (57.2 g, 0.205
mmol). After stirring for 18 h, MeOH was added to the mixture to
give a homogeneous solution. The mixture was evaporated down to
dryness and the resultant residue partitioned between Et.sub.2O and
10% citric acid (1:1, 800 ml total). The ether layer was collected
and combined with an ether extraction (150 ml) of the citric acid
layer. The combined ether fractions were then extracted with 2 M
NaOH (3.times.250 ml) and water (1.times.100 ml). The aqueous
layers were washed with ether (2.times.150 ml). After cooling to
0.degree. C., the aqueous layer was acidified to pH 7 with
concentrated HCl and extracted with ethyl acetate (3.times.200 ml).
The combined extracts were dried over MgSO.sub.4 and evaporated
down to give a white foam, 67.4 g, 85% yield.
[0245] MS 384 (M.sup.-)
[0246] .sup.1H NMR (CDCl.sub.3) .delta. 0.44-0.95 (br m, 3H),
0.97-1.22 (br m, 2H), 1.30-1.48 (br m, 1H), 1.53-1.79 (br m, 2H),
1.8-2.04 (br m, 1H), 2.10-2.29 (br m, 1H), 6.95-7.24 (m, 9H),
7.36-7.59 (m, 6H).
EXAMPLE 2
1-(2-(3-nitrophenoxy)ethyl)pyrrolidine
[0247] Following the procedure disclosed in GB 924961; 1959; Chem.
Abstr.; 59; 9883b; 1963.
[0248] 3-nitrophenol (3.29 g, 23.7 mmol) in DMF (20 ml) was added
dropwise to 60% NaH (2.65 g, 66.2 mmol) in 30 ml DMF at 0.degree.
C., under nitrogen. The reaction was stirred until H.sub.2(g)
evolution ceased. 1-(2-chloroethyl)pyrrolidine hydrochloride (5.63
g, 33.1 mmol) was then added portionwise. The mixture was stirred
at room temperature for 18 h. The reaction mixture was quenched
with 2N NaOH (50 ml) and the desired product extracted into ether
(3.times.50 ml). The combined ether layers were washed (2.times.50
ml) with water, dried over MgSO.sub.4, and evaporated to dryness in
vacuo. The residue was purified through a silica gel plug using 10%
ethyl acetate/hexane to remove the impurities and then the desired
product was eluted off with 40% ethyl acetate/hexane containing 2%
Et.sub.3N to yield a pale yellow oil.
[0249] MS 237 (MH.sup.+)
[0250] .sup.1H NMR (CDCl.sub.3) .delta.1.78-1.88 (m, 4H), 2.55-2.66
(m, 4H), 2.94 (t, J=5.8 Hz, 2H), 4.18 (t, J=5.8 Hz, 2H), 7.23-7.28
(m, 1H), 7.42 (virtual t, J=8.2 Hz, 1H), 7.75-7.76 (m, 1H),
7.80-7.83 (m, 1H).
EXAMPLE 2B
2-(2-(3-aminophenoxy)ethyl)-1-methylpyrrolidine
[0251] 3-aminophenol (0.74 g, 6.8 mmol) in DMF (10 ml) was added
dropwise to 95% NaH (0.49 g, 20.4 mmol) in 10 ml DMF at 0.degree.
C., under nitrogen. The reaction was stirred until H.sub.2(g)
evolution ceased. 2-(2-chloroethyl)-1-methylpyrrolidine
hydrochloride (1.25 g, 6.8 mmol) was then added portionwise. The
mixture was stirred at room temperature for 18 h. The reaction
mixture was quenched with 1N NaOH (50 ml) and the desired product
extracted into ether (3.times.50 ml). The combined ether layers
were washed (2.times.50 ml) with water, dried over MgSO.sub.4, and
evaporated to dryness in vacuo. The residue was purified on silica
gel by flash chromatography using 2% TEA in ethyl acetate to give
an oil.
[0252] MS 221 (MH.sup.+)
[0253] .sup.1H NMR (CDCl.sub.3) .delta.1.46-2.31 (m, 8H), 2.34 (s,
3H), 3.08 (ddd, J=8.3, 7.6, 2.4 Hz, 1H), 3.64 (br s, 2H), 3.89-4.08
(m, 2H), 6.20-6.36 (m, 3H), 7.04 (t, J=8.0 Hz, 1H).
EXAMPLE 2C
1-(2-(3-aminophenoxy)ethyl)piperidine
[0254] Following the procedure as described in Example 2B, 19.9 g
(0.182 mol) of 3-aminophenol was converted into the title compound
as a light yellow oil.
[0255] MS 221 (MH.sup.+)
[0256] .sup.1H NMR (CDCl.sub.3) .delta.1.38-1.50 (m, 2H), 1.52-1.66
(m, 4H), 2.43-2.56 (m, 4H), 2.75 (t, J=6.1 Hz, 2H), 3.65 (s br, 2H)
4.07 (t, J=6.1 Hz, 2H), 6.22-6.35 (m, 3H), 7.04 (t, J=7.9 Hz,
1H).
EXAMPLE 3
1-(2-(3-aminophenoxy)ethyl)pyrrolidine
[0257] A mixture of 1-(2-(3-nitrophenoxy)ethyl)pyrrolidine (3.49 g,
14.8 mmol), 10% palladium on carbon (400 mg) and ethyl acetate (20
ml) was reduced under 50 psi hydrogen for 10 h. The reaction
mixture was filtered through Celite 545 and the product extracted
into 1M HCl (3.times.20 ml). The acidic layer was washed with ether
(2.times.20 ml) and then the pH adjusted to >10 with 2M NaOH.
The aqueous layer was extracted with ether (3.times.20 ml), dried
over MgSO.sub.4 and concentrated in vacuo. The product was eluted
through a silica gel pad (75% ethyl acetate/hexane/1% Et.sub.3N) to
yield the product as a pale yellow oil.
[0258] MS 207 (MH.sup.+)
[0259] .sup.1H NMR (CDCl.sub.3) .delta.1.72-1.80 (m, 2H), 2.54-2.71
(m, 2H), 2.88 (t, J=8.2 Hz, 2H), 3.48-3.79 (br s, 2H), 4.07 (t,
J=8.2 Hz, 2H), 6.22-6.39 (m, 3H), 7.05 (virtual t, J=9.1 Hz,
1H).
EXAMPLE 4
N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-cis-3-(triphenylmethylamino)cycloh-
exylcarboxamide
[0260] Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium
hexafluorophosphate (PyBop) (4.8 g, 9.3 mmol) was added to a
mixture of N-trityl-cis-3-aminocyclohexanecarboxylic acid (3.3 g,
8.4 mmol), 1-(2-(3-aminophenoxy)ethyl)pyrrolidine (1.4 g, 7.0
mmol), DIEA (1.6 ml, 9.3 mmol) and dichloromethane (30 ml). After
stirring overnight, the crude mixture was evaporated onto silica
gel and purified by flash chromatography (20% EtOAc/2%
Et.sub.3N/hexane, then 60% EtOAc/2% Et.sub.3N/hexane). The title
compound was isolated as a white foam upon evaporation.
[0261] Yield: 3.2 g, 78%
[0262] MS 596 (MNa.sup.+), 574 (MH.sup.+), 332 (MH.sup.+-trt), 243
(trt.sup.+).
EXAMPLE 5
N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-cis-3-(triphenylmethylamino)cycl-
ohexylmethylamine
[0263] LAH (220 mg, 5.8 mmol) was added to
N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-cis-(3-(triphenylmethyl)amino)cyc-
lohexylmethyl-carboxamide (2.1 g, 3.7 mmol) in THF (10 ml) under
nitrogen at ambient temperature. The reaction was refluxed for 8 h,
cooled to room temperature and quenched with a saturated solution
of Rochelle's salt (potassium sodium tartrate). The precipitate was
filtered away through Celite 545 leaving the crude product as an
oil upon evaporation. The residue was dissolved in EtOAc (20 ml),
washed with water (2.times.20 ml) and dried over MgSO.sub.4.
Evaporation of the solvent yielded the product as a white foam.
[0264] MS 582 (MNa.sup.+), 560 (MH.sup.+), 318 (MH.sup.+-trt), 243
(trt.sup.+).
EXAMPLE 6
N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-[cis-3-(triphenylmethylamino)cyc-
lohexylmethyl]-4-fluorophenylcarboxamide
[0265] 4-fluorobenzoyl chloride (0.34 ml, 2.9 mmol) in
dichloromethane (5 ml) was added dropwise to a solution of
N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-cis-3-(triphenylmethylamino)cyc-
lohexylmethylamine (1.4 g, 2.6 mmol), triethylamine (0.40 ml, 2.9
mmol) and dichloromethane (10 ml). After 3 h the reaction was
quenched with 2M NaOH (3 ml) and extracted with DCM (3.times.20
ml). The organic layers were combined, dried over MgSO.sub.4 and
evaporated onto silica gel in vacuo. The product was purified by
chromatography on a silica gel column, preconditioned with
Et.sub.3N, using 50% EtOAc/2% Et.sub.3N/hexane. The product was
isolated as a white foam.
[0266] MS 682 (MH.sup.+), 440 (MH.sup.+-trt), 243 (trt.sup.+).
EXAMPLE 7
N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-[cis-(3-aminocyclohexyl)methyl]--
4-fluorophenylcarboxamide
[0267] 10% TFA/1% triethylsilane/DCM (35 ml) was added to
N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-[cis-3-(triphenylmethylamino)cy-
clohexylmethyl]-4-fluorophenylcarboxamide (1.75 g, 2.57 mmol). Upon
completion, after 3 h, the desired product was extracted into 1 M
HCl (3.times.20 ml). The extracts were washed with DCM (2.times.20
ml) and the aqueous layer (cooled to 0 C) made basic with NaOH.
Extraction of the aqueous layer with EtOAc (3.times.20 ml) yielded,
upon drying (MgSO.sub.4) and evaporation, the product as a pale
yellow oil.
[0268] MS 462 (MNa.sup.+), 440 (MH.sup.+).
EXAMPLE 8
[0269] ##STR36##
[0270] To a stirred solution of
N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-(cis-3-amino-cyclohexyl)methyl--
4-fluorophenylcarboxamide (1.0 g, 2.3 mmol) and benzaldehyde (0.26
ml, 2.5 mmol) in toluene (4 ml) was added titanium(IV) isopropoxide
(0.82 ml, 2.8 mmol) under nitrogen. After 18 h, EtOH (0.8 ml) was
added followed by portionwise addition of sodium
triacetoxyborohydride (0.63 g, 2.8 mmol). After an additional 4 h
of stirring, the reaction was quenched with 2M NaOH. The
precipitate was filtered off through Celite 545, then dried over
MgSO.sub.4 and evaporated in vacuo to yield crude
N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-(cis-3-(benzylamino)cyclohexyl)-
methyl-4-fluorophenylcarboxamide.
[0271] The crude residue (1.2 g) was taken up in DCM (4 ml),
followed by addition of trimethylacetyl chloride (0.31 ml, 2.5
mmol). The reaction was complete in less than 2 h. The reaction was
neutralized with a saturated solution of NaHCO.sub.3, extracted
with DCM (3.times.10 ml), dried over MgSO.sub.4 and evaporated onto
silica gel. The product was purified by flash chromatography (50%
EtOAc/1% Et.sub.3N/hexane) to yield a white foam (690 mg). Addition
of 1M HCl (1.2 ml, 1.2 mmol) in ether to the free base in ether (5
ml) yielded the product.
[0272] MS 614 (MH.sup.+); HPLC (RT 4.11 min.)
EXAMPLE 9
N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-(cis-3-(triphenylmethylamino)cyc-
lohexyl)methyl-N'-phenylurea
[0273] Phenylisocyanate (0.31 ml, 2.9 mmol) was added dropwise to a
solution of
N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-(cis-3-(triphenylmethylamino)-c-
yclohexyl)methylamine (1.4 g, 2.6 mmol) in dichloromethane (5 ml).
After stirring for 18 h, the reaction mixture was evaporated onto
silica gel. The title product was isolated by chromatography (50%
EtOAc/hexane, then 60% EtOAc/2% Et.sub.3N/hexane) as a white
foam.
[0274] MS 679 (MH.sup.+), 437 (MH.sup.+-trt), 243 (trt.sup.+).
EXAMPLE 10
[0275] ##STR37##
[0276] By the method of example 7 and 8,
N-(3-(2-(1-pyrrolidino)ethyloxy)phenyl)-N-(cis-3-(triphenylmethyl)aminocy-
clohexyl)methyl-N'-phenylurea, benzaldehyde and trimethylaacetyl
chloride were reacted to yield the title compound.
[0277] MS 437 (MH.sup.+).
EXAMPLE 11
N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-[(cis-3-(3-nitrobenzyl)aminocyclo-
hexylmethyl]-4-fluorophenylcarboxamide
[0278] To a stirred solution of
N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-(cis-3-aminocyclohexyl)methyl-4--
fluorophenylcarboxamide (5.3 g, 12 mmol) and 3-nitrobenzaldehyde
(2.0 g, 13 mmol) in DCM (30 ml) was added titanium(IV) isopropoxide
(4.6 ml, 16 mmol) under nitrogen. After 3 h, EtOH (20 ml) was added
followed by portionwise addition of sodium cyanoborohydride (1.0 g,
16 mmol). The reaction was stirred overnight, then quenched with 2M
NaOH. The resulting precipitate was filtered off through Celite
545, the filtrate was dried over MgSO.sub.4 and evaporated in vacuo
to yield crude product. MS 591 (MH.sup.+).
EXAMPLE 12
[0279] ##STR38##
[0280] Trichloroacetyl chloride (0.93 ml, 8.3 mmol) was added to
crude
N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-[(cis-3-(3-nitrobenzyl)aminocycl-
ohexylmethyl]4-fluorophenylcarboxamide (4.9 g, 8.3 mmol) taken up
in DCM (20 ml). The reaction was complete in less than 2 h. The
reaction was neutralized with a saturated solution of NaHCO.sub.3,
extracted into DCM (3.times.15 ml), dried over MgSO.sub.4 and
evaporated onto silica gel. The product was purified by
chromatography (50% EtOAc/2% Et.sub.3N/hexane) to yield the title
compound as a white foam.
[0281] MS 736 (MH.sup.+); HPLC (RT 4.11 min.).
EXAMPLE 13
N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-{(cis3-(benzylamino)cyclohexyl)me-
thyl}-N'-phenylurea
[0282] By the method of example 11,
N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-(cis
-3-aminocyclohexyl)methyl-N'-phenylurea and benzaldehyde were
converted into the title compound.
[0283] MS 543 (MH.sup.+).
EXAMPLE 14
[0284] ##STR39##
[0285] By the method of example 9,
N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-{(cis-3-(benzylamino)cyclohexyl)-
methyl}-N'-phenylurea and phenylisocyanate were converted into the
title compound.
[0286] MS 662 (MH.sup.+); HPLC (RT 4.38 min.).
EXAMPLE 15
[0287] ##STR40##
[0288] By the method of example 12,
N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-{(cis-3-(benzylamino)cyclohexyl)-
methyl}-N'-phenylurea and 2-naphthalenesulfonyl chloride were
converted into the title compound.
[0289] MS 733 (MH.sup.+); HPLC (RT 4.97 min.).
EXAMPLE 16
[0290] ##STR41##
[0291] By the method of example 12,
N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-cis
-3-(aminocyclohexyl)methyl}-N'-phenylurea and trichloroacetyl
chloride were converted into the title compound.
[0292] MS 599 (MH.sup.+); HPLC (RT 3.59 min.).
EXAMPLE 17
1-(2-(3-amino-2-methylphenoxy)ethyl)pyrrolidine
[0293] By the method of examples 2 and
3,1-(2-chloroethyl)pyrrolidine hydrochloride and
2-methyl-3-nitrophenol were converted into the title compound.
[0294] MS 221 (MH.sup.+)
[0295] .sup.1H NMR (CDCl.sub.3) .delta.1.75-1.86 (m, 4H), 2.05 (s,
3H), 2.62-2.67 (m, 4H), 2.92 (t, J=6.0 Hz, 2H), 3.60 (br s, 2H),
4.09 (t, J=6.0 Hz, 2H), 6.33 (virtual d, J=8.1 Hz, 2H), 6.95
(virtual t, J=9.1 Hz, 1H).
EXAMPLE 18
4-(2-(3-aminophenoxy)ethyl)morpholine
[0296] By the method of examples 2 and
3,4-(2-chloroethyl)morpholine hydrochloride and 3-nitrophenol were
converted into the title compound.
[0297] MS 223 (MH.sup.+)
EXAMPLE 19
N-(4-fluorophenylmethyl)-4-(2-(3-aminophenoxy)ethyl)morpholine
[0298] 4-fluorobenzaldehyde (1.3 ml, 12 mmol) was added to a
stirred solution of 4-(2-(3-aminophenoxy)ethyl)morpholine (2.2 g,
10 mmol) in 2% AcOH/MeOH (40 ml). After 1 h, sodium
cyanoborohydride (0.50 g, 12 mmol) was added portionwise to the
mixture. After an additional 2 h, 2M NaOH (20 ml) was added and the
mixture evaporated to give a tan residue. The residue was
partitioned between 1N HCl and ether. The acid layer was washed
2.times.40 ml with ether and then adjusted to a pH>10 with NaOH.
The product was extracted into ethyl acetate (3.times.50 ml), dried
over magnesium sulfate and evaporated down to yield the title
compound as a brown oil.
[0299] MS 331 (MH.sup.+)
[0300] .sup.1H NMR (CDCl.sub.3) .delta. 2.50-2.65 (m, 4H), 2.76 (t,
J=5.8 Hz, 2H), 3.68-3.82 (m, 4H), 4.01-4.16 (m, 3H), 4.29 (d, J=5.3
Hz, 2H), 6.18 (s, 1H), 6.22-6.33 (m, 2H), 6.97-7.13 (m, 3H),
7.29-7.40 (m, 2H).
EXAMPLE 20
[0301] ##STR42##
[0302]
N-(4-fluorophenylmethyl)-4-(2-(3-amino-phenoxy)ethyl)morpholine
(260 mg, 0.79 mmol) and glutaric anhydride (95 mg, 0.79 mmol) were
combined and refluxed in chloroform (3 ml) overnight. To the
organic solution at ambient temperature was added,
N-benzylphenethylamine (170 mg, 0.79 mmol), DIEA (0.28 ml, 1.6
mmol) and PyBOP (420 mg, 0.80 mmol). The sample was concentrated
down upon completion (<3 h). Chromatography on silica gel with
1% MeOH in ethyl acetate provided the title compound.
[0303] MS 638 (MH.sup.+); HPLC (RT 4.32 min.)
[0304] .sup.1H NMR (CDCl.sub.3) (approximately 1:1 mixture of
rotomers) .delta. 1.85-2.01 (m, 2H), 2.08-2.22 (m, 2H), 2.26-2.43
(m, 2H), 2.78 (t, J=7.4 Hz, 2H), 2.9-3.13 (m, 2H), 3.32-3.74 (m,
6H), 3.88-4.05 (m, 4H), 4.24-4.42 (m, 3H), 4.54 (s, 1H), 4.75-4.88
(m, 2H), 6.45 (s, 1H), 6.59 (t, J=6.2 Hz, 1H), 6.78-7.00 (m, 3H),
7.03-7.39 (m, 13H).
EXAMPLE 21
N-(3-nitrophenyl)methyl)phenethylamine
[0305] Sodium cyanoborohydride (0.18 g, 2.7 mmol) was added to a
preformed imine of phenethylamine (0.28 g, 2.3 mmol) and
3-nitrobenzaldehyde (0.38 g, 2.5 mmol) in 2% AcOH-MeOH. The
reaction was quenched after 4 h with a saturated solution of sodium
bicarbonate and the solvent removed in vacuo. The resultant residue
was partitioned between water and dichloromethane (20 ml total).
The aqueous layer extracted with DCM (3.times.20 ml), the organic
extracts were combined and dried over sodium sulfate. The crude
material was used without further purification.
[0306] MS 257 (MH.sup.+).
EXAMPLE 22
N-(4-fluorophenyl)methyl)-N-[3-(2-(1-pyrrolidino)ethyloxy)-2-methylphenyl]-
-N'-(2-phenethyl)-1,5-pentyldiamide
[0307] A solution of
N-(4-fluorophenylmethyl)-1-(2-(3-amino-2-methylphenoxy)-ethyl)pyrrolidine
(4.85 g, 14.8 mmol) and glutaric anhydride (2.02 g, 17.7 mmol) in
toluene (30 ml) was heated to reflux. After 12 h the reaction was
concentrated in vacuo. PyBop (430 mg, 0.81 mmol) was added to the
solution of crude
N-(4-fluorophenylmethyl)-N-3-(2-(1-pyrrolidino)ethyloxy)-2-methylphenylca-
rboxamidopentyric acid (330 mg, 0.74 mmol) and phenethylamine (90
mg, 0.74 mmol) in DMF (2 ml). The reaction mixture was stirred
overnight, diluted with 2 M NaOH and then extracted with ether
(3.times.20 ml). The combined extracts were washed with a brine
solution and dried over MgSO.sub.4. The crude material was purified
by flash chromatography on silica gel using 80% ethyl acetate/2%
Et.sub.3N/hexane as eluent to yield the title compound as a brown
oil. MS 546 (MH.sup.+).
EXAMPLE 23
[0308] ##STR43##
[0309] 60% sodium hydride (.about.3 mg, 0.07 mmol) was added to
N-(4-fluorophenyl)methyl)-N-[3-(2-(1-pyrrolidino)ethyloxy)-2-methylphenyl-
]-N'-(2-phenethyl)-1,5-pentyldiamide (30 mg, 0.06 mmol) in DMF (1
ml). After 10 min, methyl-3-(bromomethyl)benzoate (16 mg, 0.07
mmol) was added to the stirred solution. The reaction was quenched
with sodium bicarbonate after 18 h and then extracted (3.times.15
ml) into ether. The title product was isolated by semi-prep HPLC
(C-18 column, 30% CH.sub.3CN/water/0.1% TFA to 60%
CH.sub.3CN/water/0.1% TFA). Note: the methyl ester was hydrolyzed
under the acidic mobile phase conditions.
[0310] MS 680 (MH.sup.+); HPLC (RT 3.53 min.)
EXAMPLE 24
[0311] N-(3-tert-butyldimethylsiloxyphenyl)-4-fluorobenzylamine
[0312] By the method of example 19, 4-fluorobenzaldehyde (4.41 g,
35.5 mmol) and 3-aminophenol (3.60 g, 32.3 mmol) were reacted to
yield a clear oil (6.75 g) upon silica gel purification (15% ethyl
acetate/hexane).
[0313] MS 218 (MH.sup.+).
[0314] The resultant N-3-hydroxyphenyl-4-fluorobenzylamine (4.25 g,
19.6 mmol) and imidazole (1.33 g, 19.6 mmol) were combined in DMF
(20 ml) and treated with tetrabutyldimethylsilyl chloride (3.05 g,
19.6 mmol). After 5 h, the reaction was diluted with saturated
NaHCO.sub.3 and extracted with ether. The ether layers were
combined, washed with water and dried over MgSO.sub.4. The title
product was isolated by flash chromatography (15% EA/hexane) as a
clear oil (3.75 g, 58%).
[0315] MS 332 (MH.sup.+)
[0316] .sup.1H NMR (CDCl.sub.3) .delta. 0.12 (s, 6H), 0.81 (s, 9H),
3.84 (br s, 1H), 4.12 (s, 2H), 5.96 (t, J=2.2 Hz, 1H), 6.10 (td,
J=8.0, 2.2 Hz, 2H), 6.84-6.91 (m, 3H), 7.16-7.21 (m, 2H).
EXAMPLE 25
N-((4-fluorophenyl)methyl)-N-(3-hydroxyphenyl)-N'-(2-phenethyl)-N'-benzyl--
1,5-pentyldiamide (#175)
[0317]
N-(4-fluorophenyl)methyl)-N-(3-tert-butyldimethylsiloxyphenyl)-N'--
(2-phenethyl)-N'-benzyl-1,5-pentyldiamide (4.2 g, 6.6 mmol),
prepared by method of example 20, in THF (10 ml) was treated with 1
M TBAF (7.3 ml, 7.3 mmol). The reaction, complete in less than 15
h, was quenched with 0.1 M HCl. The aqueous layer was extracted
with ethyl acetate (3.times.30 ml) and the organic layers dried
over MgSO.sub.4. The crude material was purified by flash
chromatography using 50% ethyl acetate/hexane as eluent. The title
compound was recovered as a clear oil.
[0318] MS 525 (MH.sup.+)
[0319] .sup.1H NMR (CDCl.sub.3) (approximately 1:1 mixture of
rotomers) .delta. 1.84-2.02 (m, 2H), 2.08-2.21 (m, 2H), 2.25 (t,
J=7.3 Hz, 1H), 2.34 (t, J=7.3 Hz, 1H), 2.72-2.86 (m, 2H), 3.38-3.59
(m, 2H), 4.37 (s, 1H), 4.55 (s, 1H), 4.76 (s, 1H), 4.78 (s, 1H),
6.40 (t, J=7.7 Hz, 1H), 6.52 (m, 1H), 6.77-6.93 (m, 3H), 7.03-7.39
(m, 13H), 8.41 (s, 1H).
EXAMPLE 26
[0320] ##STR44##
[0321] To
N-(4-fluorophenyl)methyl)-N-(3-hydroxyphenyl)-N'-(2-phenethyl)--
N'-benzyl-1,5-pentyldiamide (75 mg, 0.14 mmol) in THF (1 ml) was
added 1-(2-hydroxyethyl)piperazine (22 mg, 0.17 mmol),
tri-n-butylphosphine (0.14 ml, 0.57 mmol), and ADDP (86 mg, 0.34
mmol). After 18 h the reaction was diluted with a solution of
saturated sodium bicarbonate and then extracted into ethyl acetate
(3.times.15 ml). The combined organic layers were dried over
MgSO.sub.4 and evaporated down to an oil. The title product was
isolated by semi-prep HPLC (C-18 column, 30% CH.sub.3CN/water/0.1%
TFA to 60% CH.sub.3CN/water/0.1% TFA).
[0322] MS 637 (MH.sup.+); HPLC (RT 3.34 min.).
EXAMPLE 27
N-[3-(2-(4-morpholino)ethoxy)phenyl]-N'-(2-phenethyl)-N'-benzyl-1,4-butyld-
iamide
[0323] Applying the procedure used in Example 20, with substitution
of 4-(2-(3-aminophenoxyethyl)morpholine and succinic anhydride for
N-(4-fluorophenylmethyl)-4-(2-(3-aminophenoxy)ethyl)morpholine and
glutaric anhydride respectively, yielded the title compound as a
white solid.
[0324] MS 516 (MH.sup.+)
EXAMPLE 28
[0325] ##STR45##
[0326]
N-[3-(2-(4-morpholino)ethoxy)phenyl]-N'-(2-phenethyl)-N'-benzyl-1,-
4-butyldiamide (0.39 g, 0.75 mmol) was dissolved in a solution of
sodium borohydride (0.14 g, 3.8 mmol) in THF (4 mL). Acetic acid
(0.22 ml, 3.75 mmol) was slowly added to the reaction mixture at
0.degree. C. After 18 h, the reaction was quenched with 1N HCl,
neutralized with saturated sodium bicarbonate and the THF layer
collected. The organic layer was dried over MgSO.sub.4, filtered
and then treated with phenyl isocyanate (0.080 ml, 0.75 mmol) to
yield crude solid product. The crude material was purified by flash
chromatography using 50% ethyl acetate/hexane as eluent. The title
compound was recovered as a clear oil.
[0327] MS 621 (MH.sup.+);
[0328] .sup.1H NMR (CD.sub.3OD) (approximately 1:1 mixture of
rotomers) .delta. 1.72-1.97 (m, 2H), 2.25 (t, J=6.8 Hz, 1H), 2.45
(t, J=6.8 Hz, 1H), 2.73-2.94 (m, 2H), 3.18-3.42 (m, 2H), 3.48-3.91
(m, 10H), 3.97-4.15 (m, 2H), 4.40 (t, J=4.9 Hz, 2H), 4.49 (s, 1H),
4.63 (s, 1H), 6.89-7.06 (m, 4H), 7.09-7.48 (m, 15H).
EXAMPLE 29
2,2-dimethylpropylbenzylamine
Step A: N-3-chlorobenzyltrimethylacetamide
[0329] 3-chlorobenzylamine (3.54 g, 25 mmol) was added dropwise to
trimethylacetyl chloride (2.65 ml, 21.5 mmol) and Et.sub.3N (3.5
ml, 25 mmol) in DCM (25 ml). After two hours, the reaction mixture
was washed with 1N HCl and the organic layer collected and dried
over MgSO.sub.4. N-3-chlorobenzyltrimethylacetamide was
precipitated from DCM/hexane as a white solid, 3.95 g,
[0330] MS 192 (MH.sup.+).
Step B:
[0331] N-benzyltrimethylacetamide (2.35 g, 12.3 mmol) in THF (10
ml) was refluxed with 1M borane-tetrahydrofuran (13.5 ml) for 15
hours. The reaction was quenched with 1N HCl, washed with ether,
and the aqueous layer adjusted to a pH>10. The aqueous layer was
extracted with EtOAc and the organic layers combined and dried over
MgSO.sub.4.
[0332] The title compound may be alternatively be prepared
according to the procedure described in Overman, Larry E.; Burk,
Robert M.; TELEAY; Tetrahedron Lett.; 25; 16; 1984; 1635-1638
EXAMPLE 30
[0333] ##STR46##
[0334] EDCI-MeI (0.33 g, 1.1 mmol) was added to
N-(4-fluorophenylmethyl)-4-(2-(3-aminophenoxy)ethyl)morpholine
(0.27 g, 0.83 mmol) (Prepared in Example 19), and Fmoc-L-Phe-OH
(0.39 g, 1.0 mmol) in CHCl.sub.3 (15 mL). After 8 h, the reaction
was diluted with a saturated solution of NaHCO.sub.3, extracted
with DCM and dried over MgSO.sub.4. The desired product was
isolated by flash chromatography (50-100% EA/hexane) to yield a
white solid.
[0335] MH+700.
EXAMPLE 31
[0336] ##STR47##
#152
[0337] The product prepared in Example 29, (31 mg, 0.044 mmol) was
dissolved in DCM (1 mL) and deprotected with piperidine (7.4 .mu.l,
0.082 mmol) to yield a white solid upon evaporation.
[0338] MH+478.
[0339] The crude product was then dissolved along with benzaldehyde
(16 .mu.l, 0.16 mmol) in 2% AcOH/MeOH (1 ml). To this solution was
added NaBH.sub.3CN (20 mg, 0.32 mmol) in two portions. After 1 h,
the solvent was evaporated and the residue partitioned between 1N
HCl and ether. The aqueous layer was washed with ether, adjusted to
pH .about.10 with 2N NaOH and extracted with DCM. The organic layer
was dried over MgSO.sub.4 and evaporated down. Hydrocinnamoyl
chloride (12 .mu.l, 0.08 mmol) was then added to the residue
dissolved in DCM (2 ml) and DIEA (16 .mu.l, 0.09 mmol). The title
compound was isolated by semi-prep HPLC as the TFA salt.
[0340] MH+700; HPLC (RT 5.16 mins).
EXAMPLE 32
[0341] ##STR48##
[0342] 4-(2-(3-amino-phenoxy)ethyl)morpholine (389 mg, 1.75 mmol)
and methyl 3-bromomethylbenzoate (482 mg, 2.1 mmol) were reacted in
CHCl.sub.3 (5 mL), that contained Et.sub.3N (293 .mu.l, 2.1 mmol).
The reaction was refluxed for 16 h, until completion, as evidenced
by disappearance of the starting aniline derivative on TLC (Rf 0.5
for product, ethyl acetate eluent)).
[0343] MS (MH.sup.+) 371
[0344] The reaction mixture was cooled and then treated with
Et.sub.3N (293 .mu.l, 2.1 mmol) and 4-fluorobenzoyl chloride (207
.mu.l, 1.75 mmol). Upon completion, the reaction mixture was
quenched with 1N NaOH and extracted 3 times with DCM. The organic
layer was dried over MgSO.sub.4 and evaporated down onto silica
gel.
[0345] The title compound was isolated by flash chromatography
(gradient from 80% EA/hexane to 100% EA) to yield a white
solid.
[0346] MS (MH.sup.+) 493
EXAMPLE 33
[0347] ##STR49##
[0348] The compound prepared in Example 31 (375 mg, 0.82 mmol) was
refluxed in a mixture of 10% NaOH/EtOH (30 ml). After 2 h, the EtOH
was evaporated under vacuum. The residue was diluted with 2N NaOH
and washed with ether. The aqueous layer was then acidified to pH 1
with concentrated HCl and extracted with DCM. The organic layer was
dried over MgSO4 and evaporated down. The residue was dissolved in
DCM (10 mL) and partitioned into ten aliquots. One aliquot was
treated with phenethylamine (12 mg, 0.10 mmol) and EDCI-MeI (29 mg,
0.10 mmol). After 16 h, the reaction mixture was washed 2.times.
with water and evaporated down to yield a brown residue. The title
compound was isolated by semi-prep HPLC (reverse phase, C-18) as
the TFA salt.
[0349] MH+582; HPLC (RT 3.41 mins).
EXAMPLE 34
N-3-cyanocyclopentyl-4-(2-(3-amino-phenoxy)ethyl)morpholine
[0350] 4-(2-(3-aminophenoxy)ethyl)morpholine (2.15 g, 9.67 mmol)
and 3-cyanocyclopentanone (1.06 g, 9.67 mmol) (prepared according
to the process decsribed by Della, E.; Knill, A.; Aust. J. Chem.;
47; 10; 1994; 1833-1842) were combined in 1% AcOH/MeOH (50 ml). To
this solution was added NaBH.sub.3CN (925 mg, 14.5 mmol) in
portions. After 12 h, the solvent was evaporated off and the
residue partitioned between saturated NaHCO.sub.3 and ethyl
acetate. The aqueous layer was extracted with ethyl acetate, the
combined organic layers were dried over MgSO.sub.4 and evaporated
down. The title compound was purified by flash chromatography with
ethyl acetate as the eluent, 2.1 g
[0351] MS (MH.sup.+) 316.
EXAMPLE 35
[0352] ##STR50##
[0353] Phenylisocyanate (0.65 ml, 5.9 mmol) was added to
N-3-cyanocyclopentyl-4-(2-(3-amino-phenoxy)ethyl)morpholine (1.88
g, 5.95 mmol) partially dissolved in THF (25 ml) at room
temperature. After 15 h, crude material was placed on a silica gel
column and eluted with ethyl acetate to give 680 mg of a yellow
oil.
[0354] MS (MH.sup.+) 435.
EXAMPLE 36
[0355] ##STR51##
[0356] The product prepared in Example 34 (0.65 g, 1.5 mmol)
dissolved in THF (10 ml) was added to 1M LAH (4.5 ml) at
-78.degree. C. and allowed to warm to room temperature. After 15 h,
the reaction was quenched with a saturated solution of Rochelle's
salt (potassium sodium tartrate). The precipitate was filtered away
through Celite 545 to yield the crude product as an oil upon
evaporation. The residue was dissolved in EtOAc, washed with water
and dried over MgSO.sub.4. Evaporation of the solvent yielded the
product as an oil.
[0357] (MH.sup.+) 439
EXAMPLE 37
[0358] ##STR52##
[0359] Sodium cyanoborohydride (34 mg, 0.54 mmol) was added to the
product prepared in Example 35 (78 mg, 0.18 mmol) and
3-chlorobenzaldehyde (40 .mu.l, 0.36 mmol) in 1% AcOH/MeOH (2 ml).
After 6 hours the reaction was acidified with 1N HCl, then
neutralized with 2N NaOH and extracted into dichloromethane.
[0360] (MH.sup.+) 563.
[0361] The organic layer was dried over MgSO.sub.4, cooled to
0.degree. C. and then treated with trichloroacetyl chloride (20
.mu.l, 0.18 mmol). The final product was isolated by flash
chromatography (ethyl acetate).
[0362] (MH.sup.+) 707
EXAMPLE 38
[0363] ##STR53##
[0364] N-trityl-cis-3-aminocyclohexanecarboxylic acid (13.1 g, 34
mmol) was added to a solution of PyBop (17.7 g, 34 mmol) and DIEA
(11.8 ml, 68 mmol) in DCM (70 mL) and stirred for 10 minutes.
1-(2-(3-aminophenoxy)ethyl)piperidine (6.8 g, 30.9 mmol) in DCM (30
mL) was added to the reaction mixture over the course of 20 mins.
The coupled product was purified by flash chromatography (25% ethyl
acetate/1% Et.sub.3N/hexane) and evaporated down to yield a white
foam.
[0365] The foam was dissolved in THF (100 mL), treated with LAH
(1.3 g, 34 mmol) and refluxed for 7 hrs. Upon cooling, the reaction
mixture was alternately quenched with NaOH and water to yield a
granular solid. The heterogenous reaction mixture was then filtered
through Celite 545. The reduced product was extracted into ether
from water. The combined organic layers were dried over MgSO.sub.4
and evaporated to dryness.
[0366] The crude product and Et.sub.3N (4.7 ml, 34 mmol) were
dissolved in DCM (100 mL). 4-fluorobenzoyl chloride (4.0 ml, 34
mmol) of was added dropwise to this solution. After 2 hours the
reaction mixture was evaporated onto silica gel and then purified
by flash chromatography (20% ethyl acetate/1% Et.sub.3N/hexane) to
yield the title compound.
EXAMPLE 39
[0367] ##STR54##
[0368] The compound prepared as in Example 38, was dissolved in 20%
TFA/1% TES/DCM and stirred for 1 hr. The reaction mixture was
evaporated down to dryness. The crude material was partitioned
between ether and 1N HCl. The aqueous solution was washed twice
with ether, cooled to 0.degree. C. and the pH adjusted to 12 with
NaOH. The deprotected amine was extracted into DCM and dried over
MgSO.sub.4.
[0369] Following the procedure as described in Example 8, the
deprotected amine, 3-chlorobenzaldehyde and trichloroacetyl
chloride were reacted to yield the title compound. The enantiomers
were separated using a Chiralpak AD HPLC column.
EXAMPLE 40
[0370] ##STR55##
[0371]
N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-(cis-3-aminocyclohexyl)me-
thyl-4-fluorophenylcarboxamide (83 mg, 0.18 mmol) and
3,3-dimethylglutaric anhydride (28 mg, 0.20 mmol) were combined and
heated at 90.degree. C. in toluene (2 mL) for two hours. The
reaction mixture was concentrated in vacuo and purified by
semi-prep HPLC (C18 column, acetonitrile/water/0.1% TFA) to yield
the title compound.
EXAMPLE 41
[0372] ##STR56##
[0373]
N-(3-(2-(4-morpholino)ethyloxy)phenyl)-N-(cis-3-aminocyclohexyl)me-
thyl-4-fluorophenylcarboxamide (83 mg, 0.18 mmol) and phthalic
anhydride (30 mg, 0.20 mmol) were dissolved in toluene (2 mL). The
reaction was heated at 90.degree. C. for two hours. To the reaction
was then added acetic anhydride (0.2 ml, 2.1 mmol) and the reaction
refluxed for an additional 15 hours. The reaction mixture was
concentrated in vacuo and purified by semi-prep HPLC (C18 column,
acetonitrile/water/0.1% TFA) to yield the title compound as a white
solid.
EXAMPLE 42
In Vitro Testing
Motilin Receptor Binding
[0374] Rabbit colon was removed, dissected free from the mucosa and
serosa, and diced into small pieces. The muscle tissue was
homogenized in 10 volumes of 50 mM Tris-Cl, 10 mM MgCl.sub.2, 0.1
mg/ml bacitracin, and 0.25 mM Peflabloc, at pH 7.5 in a Polytron
(29000 rpm, 4.times.15 seconds). The homogenate was centrifuged at
1000.times.g for 15 minutes and the supernatant discarded. The
pellet was washed twice before being suspended in homogenizing
buffer. The crude homogenate was resuspended through a 23 gauge
needle before storing at -80.degree. C. In a total volume of 0.5
ml, the binding assay contained the following components: buffer
(50 mM Tris-Cl, 10 mM MgCl.sub.2, 1 mM EDTA, 15 mg/ml BSA, 5 mg/ml
of pepstatin, leupeptin, aprotinin, and 0.15 mg/ml bacitracin),
I.sup.125 radio-labeled porcine motilin (50000-70000 cpm; specific
activity 2000 Ci/mmole), test compound, and membrane protein. After
60 minutes at 30.degree. C., the samples were cooled in ice,
centrifuged in the cold at 13000.times.g for 1 minute. The pellet
was washed twice with 1 ml of cold saline, the supernatant was
aspirated, and the pellet at the bottom of the tube counted in a
gamma counter. Non-specific binding was determined by the inclusion
of 1 mM of unlabeled motilin. IC.sub.50 values were determined from
Kaleidograph curves.
EXAMPLE 43
In Vitro Testing
Human Antrum Tissue
[0375] Human antrum tissue from Analytical Biological Services
(Wilmington, Del.) was prepared as a motilin receptor preparation
in the following manner. The muscle tissue was homogenized in 10
volumes of 50 mM Tris-Cl, 10 mM MgCl.sub.2, 0.1 mg/ml bacitracin,
and 0.25 mM Peflabloc, pH 7.5) in a Polytron (29000 rpm, 4.times.15
seconds). The homogenate was centrifuged at 1000.times.g for 15
minutes and the supernatant discarded. The pellet was washed twice
before being suspended in homogenizing buffer. The crude homogenate
was resuspended through a 23 gauge needle before aliquoting and
storing at -80.degree. C. The human cloned receptor was prepared
from HEK 293 cells overexpressed with the motilin receptor. Cell
pellets were thawed and resuspended in 2-3 volumes of homogenizing
buffer (10 mM Tris-Cl, 0.2 mM MgCl.sub.2, 5 mM KCl, 5 .mu.g/ml
aprotinin, leupeptin, and pepstatin A, and 50 .mu.g/ml bacitracin,
pH 7.5) and allowed to sit on ice for 15-20 minutes. The suspension
was homogenized on ice in a Dounce type homogenizer using 15
strokes. Sucrose and EDTA were added to a final concentration of
0.25M and 1 mM, respectively, and mixed with a few additional
strokes. The material was centrifuged at 400.times.g for 5 minutes,
and the supernatant saved. The pellet was re-resuspended twice with
5 ml homogenizing buffer and rehomogenized as before, and the
supernatants combined. The supernatant was centrifuged at
100000.times.g for 1 hour. The pellet is retained and resuspended
with 5 ml of homogenizing buffer through a 19 g and 25 g needle.
The suspension is aliquoted and stored at -80.degree. C. until
used. The binding assay contains the following components (50 mM
HEPES, 5 mM MgCl.sub.2, and 1 mM EGTA, pH 7.0, 15 mg/ml BSA, 10
.mu.g/ml aprotinin, leupeptin, and pepstatin A, 0.25 mg/ml
bacitracin, and 10 mM benzamidine), 125I-radiolabelled porcine
motilin (50000-70000 cpm; specific activity 2000 Ci/mmol), test
compound, and membrane protein. After 60 minutes at 30.degree. C.,
the samples are placed on ice and centrifuged for 1 minute at
13000.times.g. The pellet is washed twice with 1 ml cold saline,
and after removal of the final supernatant, the pellet at the
bottom of the tube is counted in a gamma counter. Non-specific
binding is measured by the inclusion of 1 .mu.M unlabelled motilin.
IC.sub.50 values were determined from Kaleidograph curves.
[0376] 125I-Motilin Binding to Human Antral Stomach Membranes and
the Human Cloned Receptor: TABLE-US-00018 Human Antrum IC.sub.50
(nM) 1.0 .+-. 0.1 Human Cloned Receptor IC.sub.50 (nM) 3.55 .+-.
0.05
EXAMPLE 44
In Vivo Testing
Rabbit Tissue Bath Procedure
[0377] One New Zealand White rabbit (Covance) of either sex was
euthanized with an IV injection of Sleepaway. The duodenum was
quickly excised, the lumen rinsed with saline to clean, and the
tissue placed in cold, aerated (95% O.sub.2-5% CO.sub.2) Tyrodes
buffer (NaCl 136.9 mM, KCl 2.7 mM, CaCl.sub.2 1.8 mM,
MgCl.sub.21.04 mM, NaH.sub.2PO.sub.4 0.42 mM, NaHCO.sub.3 11.9 mM,
Glucose 5.55 mM, pH 7.4). The duodenum, being kept moist at all
times, was cleaned of any excess mesenteric tissue, and then cut
into 3 cm segments starting at the proximal end. Sixteen tissue
segments were usually prepared from each duodenum. These segments
were tied on both ends with 3-0 silk suture (Ethicon). One end of
the tissue was attached to an S-hook on a custom made glass support
rod (Crown Glass Co., Somerville) and the rod plus tissue were
placed in a 15 ml isolated tissue bath (Radnoti). The other end of
the glass rod was attached to a Grass Force Displacement Transducer
FT03. The tissue was maintained in room temperature Tyrodes buffer
pH 7.4 and continually gassed with 95% O.sub.2-5% CO.sub.2. The
tissues were adjusted to 1.0 g resting tension and maintained at
that tension throughout the equilibration period. An MI2 Tissue
Bath Computer was used to record and analyze data.
[0378] The tissues were washed twice during a 30 minute
equilibration period and readjusted to 1 g resting tension as
necessary. After equilibration the tissues were challenged with 3
.mu.M Carbachol (Carbamoylcholine Chloride-Sigma). After maximal
contraction was attained, the tissues were washed 3 times with
Tyrodes. The tissues were allowed a 20 minute resting/equilibration
period, during which time they were washed once and readjusted to 1
g resting tension. The tissues were challenged a second time with 3
.mu.M Carbachol, and this contraction was considered as maximal, or
100% contraction. The tissues were washed 3 times, equilibrated for
10 minutes, washed again and readjusted to 1 g resting tension.
Vehicle or test compound in 30% DMSO-50 mM HEPES was added directly
to the bath and the tissues were incubated for 20 minutes. Test
compounds and vehicle were run in duplicate. The tissues were then
challenged with 3 nM Porcine Motilin (Bachem) and when maximum
contraction was attained another 3 .mu.M aliquot of Carbachol was
added to see if the test compound inhibited this contraction.
[0379] The percent inhibition by test compound of the motilin
induced contraction was calculated by first determining the ratio
of the vehicle contractions with Motilin compared to the Carbachol
contractions. This Tissue Adjustment Factor (TAF) was used to
determine the value for the potential uninhibited contraction with
Motilin for each tissue. The percent inhibition was then determined
by dividing the actual Motilin contraction in treated tissues by
the potential uninhibited contraction and subtracting this number
from 1. IC.sub.50 values were determined by graphing results with
Kaleidograph graphing program.
[0380] Tables 18 and 19 below list molecular weight, % Inhibition
and IC.sub.50 values measured for select compounds of the present
invention. TABLE-US-00019 TABLE 18 Rabbit Colon Human Antrum Mol.
Wt.* % Inh IC.sub.50 % Inh Tissues ID Cal'd (MH.sup.+) @1 mM
(.mu.M) @1 .mu.M IC.sub.50 (.mu.M) IC.sub.50 (.mu.M) 1 621 621 35 2
656 656 9 3 620 620 35 4 624 624 75 0.69 5 635 635 40 6 634 634 24
7 638 638 42 8 545 545 18 9 580 580 27 10 544 544 29 11 548 548 0
12 594 594 4 13 558 558 21 14 562 562 25 15 531 531 21 16 566 566
21 17 530 530 12 18 534 534 0 19 545 545 5 20 580 580 8 21 544 544
34 22 548 548 23 23 607 607 48 24 642 642 6 25 606 606 23 26 621
621 22 27 656 656 22 28 620 620 13 29 624 624 18 30 559 559 17 31
594 594 39 32 558 558 12 33 562 562 16 34 573 573 7 35 608 608 17
36 572 572 32 37 576 576 11 39 709 707 4 40 662 662 11 41 677 677
58 42 627 627 50 43 675 675 74 0.73 44 697 697 4 45 692 692 67 1.16
46 737 737 32 47 723 721 23 48 637 637 67 0.656 49 817 817 37 50
757 757 32 51 711 711 73 0.65 52 661 661 45 53 709 709 52 54 731
731 42 55 726 726 48 56 771 771 27 57 733 733 15 58 706 705 38 59
757 755 23 60 757 755 65 0.66 61 718 717 55 62 756 755 58 63 723
721 55 64 738 737 32 65 733 732 80 0.035 0.027 66 757 755 39 67 688
687 75 0.957 68 689 688 73 0.66 69 572 572 0 70 547 547 0 71 643
643 43 72 598 597 40 73 549 549 25 74 693 693 29 75 633 633 19 76
587 587 26 77 537 537 19 78 585 585 10 79 607 607 39 80 602 602 34
81 647 647 56 82 783 783 0 83 723 723 3 86 697 697 16 90 692 691 95
0.49 >0.3 91 601 600 36 92 760 758 80 93 736 735 100 0.09 0.0205
94 741 740 28 95 726 724 51 96 759 758 71 1.68 >.03 97 721 720
56 98 760 758 75 0.76 99 760 758 62 0.572 100 709 708 78 101 774
774 59 102 729 729 47 103 734 734 2 104 712 712 30 105 664 664 80
0.39 0.03 106 714 714 69 1.05 107 820 820 29 108 676 676 70 0.815
109 760 760 27 110 718 718 35 111 726 724 72 0.88 112 740 740 70
0.48 113 695 695 51 114 700 700 49 115 678 678 26 116 630 630 61
0.772 117 680 680 17 118 726 726 58 119 786 786 22 120 642 642 69
0.954 121 684 684 37 122 691 690 64 0.84 123 736 736 8 124 640 640
70 0.904 125 665 665 25 128 624 624 75 0.23 129 638 638 90 0.058
130 610 610 8 131 623 622 19 132 658 658 10 133 672 672 6 134 626
626 0 135 694 694 8 136 672 672 43 137 644 644 30 138 582 582 36
139 586 586 13 140 638 638 45 141 672 672 21 142 670 670 17 143 596
596 0 144 638 638 54 145 590 590 35 146 654 654 32 147 688 688 61
0.49 148 622 622 19 149 699 699 27 150 680 680 0 151 713 712 1 152
700 700 0 153 636 636 89 0.081 0.03 154 692 692 62 0.41 155 676 676
34 156 554 554 18 157 642 642 16 158 601 600 37 159 652 652 83
0.275 160 652 652 61 0.96 161 664 664 22 162 672 672 85 0.178 0.021
163 658 658 85 0.174 0.019 164 624 624 84 0.194 0.048 165 624 624
63 0.55 166 636 636 23 167 674 674 42 168 640 640 36 169 638 638 97
0.046 0.24 170 638 638 81 0.163 0.185 171 650 650 63 0.462 0.23 172
688 688 40 173 654 654 84 0.29 0.28 174 692 691 0 175 525 525 0 176
636 636 32 177 640 640 52 >1.0 178 624 624 100 0.07 0.015 179
637 637 85 0.24 0.023 180 622 622 99 0.014 0.011 181 596 596 100
0.093 0.012 182 636 636 94 0.022 0.053 183 661 661 2 184 711 711 6
185 671 671 0 186 722 722 0 187 610 610 100 0.229 188 650 650 100
0.247 0.092 189 652 652 70 0.3 190 666 666 99 0.2 0.067 191 622 622
27 192 638 638 15 193 650 650 7 194 596 596 23 195 624 624 62 196
636 636 100 0.006 0.004 197 667 667 85 0.009 0.0076 198 672 672 100
0.107 199 691 690 91 0.1 200 690 690 92 0.041 201 657 657 93 0.057
0.0168 202 691 690 100 0.33 0.23 203 649 649 98 0.24 204 662 662 89
0.029 0.003 205 683 683 76 0.1 206 688 688 60 0.77 207 636 636 87
0.064 208 734 733 91 0.009 0.048 209 724 722 84 0.059 0.021 210 689
688 90 0.086 0.024 211 720 719 100 0.014 0.072 212 710 708 89 0.058
0.036 213 675 674 84 0.058 0.027 214 614 614 95 0.029 0.024 215 680
680 100 0.084 216 600 600 100 217 634 634 98 218 661 660 98 0.024
0.035 219 706 705 98 0.0076 220 636 636 92 0.042 221 598 598 94 223
707 705 100 0.041 224 672 671 98 0.039 225 611 611 93 0.021 226 648
648 100 0.032 0.009 227 683 682 100 0.025 228 650 650 100 0.025 229
614 614 100 0.01 230 614 614 100 0.072 231 661 660 88 0.13 232 698
698 62 233 650 650 89 0.17 234 652 652 86 0.218 235 662 61 236 724
53 237 662 96 0.168 238 724 98 0.097 239 724 0.073 240 724 >0.70
241 728 14 242 704 36 243 728 35 244 698 42 245 758 40 246 678 73
247 726 41 248 704 86 0.760
249 716 22 250 642 0 251 604 0 252 636 15 253 600 30 254 606 25 255
655 22 256 600 27 257 586 0 258 580 34 259 665 17 260 644 30 261
654 0 262 550 18 263 655 11 264 570 6 265 638 67 266 598 5 267 624
21 268 598 17 *For compounds containing chlorine, listed Mol. Wt.
values are provided for the most abundant isotope.
[0381] TABLE-US-00020 TABLE 19 Cal'd Mol. % Inh @1 mM % Inh @1 mM
ID Wt. MW (MH.sup.+) (Rabbit colon) (Human antrum) 38 577.4 576 22
84 542.7 543 12 85 577.2 577 28 87 611.6 611 22 88 592.8 593 0 89
561.7 562 3 222 619.8 620 83 83
[0382] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *