U.S. patent application number 09/766722 was filed with the patent office on 2001-08-23 for phenylacetonitrilealkylaminoalkyl-ortho-substituted aryl compounds as immunosuppressives.
This patent application is currently assigned to G.D. Searle & Co.. Invention is credited to Farah, John M. JR., Liang, Chi-Dean, McKearn, John P., Mueller, Richard A..
Application Number | 20010016602 09/766722 |
Document ID | / |
Family ID | 27504026 |
Filed Date | 2001-08-23 |
United States Patent
Application |
20010016602 |
Kind Code |
A1 |
Liang, Chi-Dean ; et
al. |
August 23, 2001 |
Phenylacetonitrilealkylaminoalkyl-ortho-substituted aryl compounds
as immunosuppressives
Abstract
A class of substituted
phenylacetonitrile-alkylaminoalkyl-ortho-substitute- d aryl
compounds having immunosuppressive properties is described.
Compounds of this class would be useful in reducing recipient
rejection of transplanted organs and for treatment of autoimmune or
inflammatory diseases. Compounds of particular interest are of the
formula 1 wherein m is one or two; wherein n is a number selected
from one to five, inclusive; wherein R.sup.1 is selected from
hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
alkoxyalkyl, alkenyl and alkynyl; wherein R.sup.6 is selected from
loweralkyl; wherein each of R.sup.8, R.sup.9, R.sup.10 and R.sup.12
through R.sup.16 is independently selected from hydrido, hydroxy,
alkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, alkylcarbonyl,
alkoxycarbonyl, alkylcarbonylalkenyl, alkylaminocarbonyl and
alkoxyalkyl; with the proviso that at least one of R.sup.12 and
R.sup.16 must be selected from hydroxy, alkyl, hydroxyalkyl,
alkoxy, alkenyl, alkynyl, alkylcarbonyl, alkoxycarbonyl,
alkylcarbonylalkenyl, alkylaminocarbonyl and alkoxyalkyl; or a
tautomer thereof or a pharmaceutically-acceptable salt thereof.
Inventors: |
Liang, Chi-Dean; (Glenview,
IL) ; McKearn, John P.; (Pacific, MO) ; Farah,
John M. JR.; (St. Louis, MO) ; Mueller, Richard
A.; (Glencoe, IL) |
Correspondence
Address: |
Pharmacia Corporation
Corporate Patent Department
P.O. Box 5110
Chicago
IL
60680
US
|
Assignee: |
G.D. Searle & Co.,
P.O. Box 5110
Chicago
IL
|
Family ID: |
27504026 |
Appl. No.: |
09/766722 |
Filed: |
January 22, 2001 |
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09766722 |
Jan 22, 2001 |
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09499555 |
Feb 7, 2000 |
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09499555 |
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09076698 |
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09076698 |
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08851762 |
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08589131 |
Jan 22, 1996 |
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08589131 |
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08204121 |
Mar 1, 1994 |
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5486539 |
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08204121 |
Mar 1, 1994 |
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07926732 |
Aug 6, 1992 |
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07926732 |
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07623596 |
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5162569 |
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07623596 |
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07609145 |
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07609145 |
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07456004 |
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Current U.S.
Class: |
514/520 ;
514/390; 558/390 |
Current CPC
Class: |
C07C 255/43
20130101 |
Class at
Publication: |
514/520 ;
514/390; 558/390 |
International
Class: |
A61K 031/275; C07C
255/32 |
Claims
What is claimed is:
1. A compound of Formula I: 29wherein m is one or two; wherein n is
a number selected from one to ten, inclusive; wherein R.sup.1 is
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, aralkyl, aryl, aroylalkyl, alkoxyalkyl,
alkylcarbonylalkyl, alkoxycarbonylalkyl, alkylaryloxycarbonylalkyl,
alkenyl, cycloalkenyl, aralkoxycarbonylalkyl, alkynyl,
alkylthiocarbonylalkyl, alkylthiothiocarbonylalkyl,
arylthiocarbonylalkyl, arylthiothiocarbonylalkyl,
aralkylthiocarbonylalky- l, alkylarylthiocarbonylalkyl,
alkylsulfonyl, aralkylsulfonyl and arylsulfonyl; wherein each of
R.sup.2 and R.sup.3 is independently selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, aroyl,
aryloxy, aryloxyalkyl, alkoxyalkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkylthiocarbonyl, alkylthiothiocarbonyl,
arylthiocarbonyl, arylthiothiocarbonyl, aralkylthiocarbonyl and
alkylthiocarbonylalkyl; wherein each of R.sup.4, R.sup.5 and
R.sup.7 through R.sup.16 is independently selected from hydrido,
hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy,
aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy,
alkylthiocarbonylthio, alkylthiothiocarbonyl,
alkylthiothiocarbonylthio, arylthio, aryithiocarbonyl,
arylcarbonylthio, aryithiocarbonyloxy, arylthiocarbonylthio,
arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio,
aralkylithiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy,
aralkylthiocarbonylthio, alkylthiocarbonylalkyl,
aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl,
aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, and
wherein each of R.sup.2 through R.sup.5 and R.sup.7 through
R.sup.16 may be further independently selected from radicals of the
formula 30 with the proviso that at least one of R.sup.12 and
R.sup.16 must be selected from hydroxy, alkyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy,
aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl,
alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl,
cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl,
mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio,
cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio,
alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl,
alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl,
arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio,
arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio,
aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy,
aralkylthiocarbonylthio, alkylthiocarbonylalkyl,
aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl,
aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, and
radicals of the formula 31wherein A is selected from divalent
alkyl, alkenyl and alkynyl groups; wherein X is oxygen atom or
sulfur atom; wherein each r is a number independently selected from
zero to six, inclusive; wherein each of R.sup.17 through R.sup.29
is independently selected from hydrido, alkyl, cycloalkyl,
cycloalkylalkyl, aralkyl and aryl; wherein R.sup.6 is selected from
hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkyloxy, alkoxy, aralkyl, aroyl, aryloxy, aryloxyalkyl,
aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl,
alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro,
carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy,
alkylthiocarbonylthio, alkylthiothiocarbonyl,
alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl,
arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio,
arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio,
aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy,
aralkylthiocarbonylthio, alkylthiocarbonylalkyl,
aralkylthiocarbonylthio, alkylsulfinyl, alkylsulfonyl,
aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl and arylsulfonyl;
and wherein any of the foregoing A and R.sup.1 through R.sup.29
groups having a substitutable position may be substituted by one or
more groups independently selected from alkyl, alkenyl, alkynyl,
aralkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aroylalkyl, cycloalkenyl, cyanoamino,
alkylcarbonylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
carboxylalkyl, alkylthiocarbonylalkyl and alkylsulfonylalkyl; or a
tautomer thereof or a pharmaceutically-acceptable salt thereof.
2. Compound of claim 1 wherein m is one or two; wherein n is a
number selected from one to nine, inclusive; wherein R.sup.1 is
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, aralkyl, aryl, aroylalkyl, alkoxyalkyl,
alkylcarbonylalkyl, alkoxycarbonylalkyl, alkylaryloxycarbonylalkyl,
alkenyl, cycloalkenyl, aralkoxycarbonylalkyl and alkynyl; wherein
each of R.sup.2 and R.sup.3 is independently selected from hydrido,
alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl,
aroyl, aryloxy, aryloxyalkyl, alkoxyalkyl, alkylcarbonylalkyl,
alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl,
carboxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl,
and mercaptoalkyl; wherein each of R.sup.4, R.sup.5 and R.sup.7
through R.sup.16 is independently selected from hydrido, hydroxy,
alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy,
formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl,
aralkoxy, alkoxyalkyl, alkylcarbonylalkyl, alkenyl, cycloalkenyl,
alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
arylthio, mercapto, and wherein each of R.sup.2 through R.sup.5 and
R.sup.7 through R.sup.16 may be further independently selected from
radicals of the formula 32 with the proviso that at least one of
R.sup.12 and R.sup.16 must be selected from hydroxy, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl,
alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy,
alkoxyalkyl, alkylcarbonylalkyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
arylthio, mercapto, and radicals of the formula 33wherein A is
selected from divalent alkyl, alkenyl and alkynyl groups; wherein X
is oxygen atom or sulfur atom; wherein each r is a number
independently selected from zero to five, inclusive; wherein each
of R.sup.17 through R.sup.27 is independently selected from
hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl;
wherein R.sup.6 is selected from hydrido, alkyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, aralkyl, aroyl,
aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptoalkyl, alkoxycarbonyloxy,
alkylthio, cycloalkylthio, and wherein any of the foregoing A and
R.sup.1 through R.sup.27 groups having a substitutable position may
be substituted by one or more groups independently selected from
alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, cyano, alkoxyalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aroylalkyl, cycloalkenyl,
cyanoamino, alkylcarbonylalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl and carboxylalkyl; or a tautomer thereof or a
pharmaceutically-acceptable salt thereof.
3. Compound of claim 2 wherein m is one or two; wherein n is a
number selected from one to eight, inclusive; wherein R.sup.1 is
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, aralkyl, aryl, aroylalkyl, alkoxyalkyl,
alkylcarbonylalkyl, alkoxycarbonylalkyl, alkenyl and alkynyl,
wherein each of R.sup.2 and R.sup.3 is independently selected from
hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl,
aryl, aroyl, aryloxy, aryloxyalkyl, alkoxyalkyl,
alkylcarbonylalkyl, alkenyl, alkynyl, cyano, nitro, carboxyl,
carboxyalkyl, alkylcarbonyloxyalkyl and alkoxycarbonylalkyl;
wherein each of R.sup.4, R.sup.5 and R.sup.7 through R.sup.16 is
independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy,
aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl,
alkylcarbonylalkyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro,
carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, alkoxycarbonyloxy, and wherein each of
R.sup.2 through R.sup.5 and R.sup.7 through R.sup.16 may be further
independently selected from radicals of the formula 34 with the
proviso that at least one of R.sup.12 and R.sup.16 must be selected
from hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy,
aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonylalkyl, alkenyl,
cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl,
mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, and
radicals of the formula 35wherein A is selected from divalent
alkyl, alkenyl and alkynyl groups; wherein X is oxygen atom or
sulfur atom; wherein each r is a number independently selected from
zero to four, inclusive; wherein each of R.sup.17 through R.sup.24
is independently selected from hydrido, alkyl, cycloalkyl,
cycloalkylalkyl, aralkyl and aryl; wherein R.sup.6 is selected from
hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkyloxy, alkoxy, aralkyl, aroyl, aryloxy, aryloxyalkyl,
aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl,
alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro,
carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptoalkyl, and alkoxycarbonyloxy; and
wherein any of the foregoing A and R.sup.1 through R.sup.24 groups
having a substitutable position may be substituted by one or more
groups independently selected from alkyl, alkenyl, alkynyl,
aralkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aroylalkyl, cyanoamino, alkylcarbonylalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl and carboxylalkyl; or a
tautomer thereof or a pharmaceutically-acceptable salt thereof.
4. Compound of claim 3 wherein m is one or two; wherein n is a
number selected from one to seven, inclusive; wherein R.sup.1 is
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, alkoxyalkyl, alkylcarbonylalkyl,
alkoxycarbonylalkyl, alkenyl and alkynyl; wherein each of R.sup.2
and R.sup.3 is independently selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl, phenyl,
benzoyl, phenoxy, phenoxyalkyl, alkoxyalkyl, alkylcarbonylalkyl,
alkenyl, alkynyl, carboxyl, carboxyalkyl, alkylcarbonyloxyalkyl and
alkoxycarbonylalkyl; wherein each of R.sup.4, R.sup.5 and R.sup.7
through R.sup.16 is independently selected from hydrido, hydroxy,
alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy,
alkoxy, phenylalkyl, phenyl, benzoyl, phenoxy, phenoxyalkyl,
alkoxyalkyl, alkylcarbonylalkyl, alkynyl, carboxyl, carboxyalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
alkoxycarbonyloxy, and wherein each of R.sup.2 through R.sup.5 and
R.sup.7 through R.sup.16 may be further independently selected from
radicals of the formula 36 with the proviso that at least one of
R.sup.12 and R.sup.16 must be selected from hydroxy, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl,
alkoxy, phenylalkyl, phenyl, benzoyl, phenoxy, phenoxyalkyl,
phenalkoxy, alkoxyalkyl, alkylcarbonylalkyl, alkenyl, alkynyl,
carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, alkoxycarbonyloxy, and radicals of the formula
37wherein A is selected from divalent alkyl, alkenyl and alkynyl
groups; wherein each r is a number independently selected from zero
to four, inclusive; wherein each of R.sup.17 through R.sup.24 is
independently selected from hydrido, alkyl, cycloalkyl,
cycloalkylalkyl, phenylalkyl and phenyl; wherein R.sup.6 is
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkyloxy, alkoxy, phenylalkyl, benzoyl,
phenoxy, phenoxyalkyl, phenalkoxy, alkoxyalkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, alkynyl, carboxyl,
carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, mercaptoalkyl and alkoxycarbonyloxy; and
wherein any of the foregoing A and R.sup.1 through R.sup.24 groups
having a substitutable position may be substituted by one or more
groups independently selected from alkyl, alkenyl, alkynyl,
phenylalkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, phenyl, alkylcarbonylalkyl, alkoxycarbonylalkyl
and carboxylalkyl; or a tautomer thereof or a
pharmaceutically-acceptable salt thereof.
5. Compound of claim 4 selected from compounds of Formula II:
38wherein m is one or two; wherein n is a number selected from one
to six, inclusive; wherein R.sup.1 is selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, alkenyl and
alkynyl; wherein each of R.sup.8, R.sup.9, R.sup.10 and R.sup.12
through R.sup.16 is independently selected from hydrido, hydroxy,
alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy,
alkoxy, phenoxy, benzyloxy, and radicals of the formula 39 with the
proviso that at least one of R.sup.12 and R.sup.16 must be selected
from hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkyloxy, alkoxy, phenoxy, phenalkoxy, and radicals of the
formula 40wherein A is a spacer group independently selected from
one or more groups of the formula 41wherein each of R.sup.30 and
R.sup.31 is independently selected from hydrido, alkyl, cycloalkyl,
phenyl, benzyl, hydroxy, hydroxyalkyl, alkoxy, phenoxy,
alkoxyalkyl, benzyloxy, cyano, alkanoyl, 42wherein each of
R.sup.36, R.sup.37, R.sup.38 and R.sup.39 is independently selected
from hydrido, alkyl and phenyl; wherein R.sup.30 and R.sup.31 may
be taken together to form oxo or exomethylene; wherein each of
R.sup.32, R.sup.33, R.sup.34 and R.sup.35 is independently selected
from hydrido, alkyl, hydroxyalkyl and alkoxyalkyl; wherein each of
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21f R.sup.22,
R.sup.23 and R.sup.24 is independently selected from hydrido,
alkyl, cycloalkyl, cycloalkylalkyl and phenalkyl; wherein each r is
a number independently selected from zero to four, inclusive;
wherein R.sup.6 is selected from hydrido, alkyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, benzyl, alkenyl and alkynyl; and
wherein any of the foregoing A and R.sup.1, R.sup.6, R.sup.8,
R.sup.9, R.sup.10, R.sup.12 through R.sup.24 and R.sup.30 through
R.sup.39 groups having a substitutable position may be substituted
by one or more groups independently selected from alkyl, alkenyl,
alkynyl, benzyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl and phenyl; or a tautomer thereof or a
pharmaceutically-acceptable salt thereof.
6. Compound of claim 5 wherein m is one or two; wherein n is a
number selected from one to five, inclusive; wherein R.sup.1 is
selected from hydrido, alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl
and alkynyl; wherein each of R.sup.8, R.sup.9, R.sup.10 and
R.sup.12 through R.sup.16 is independently selected from hydrido,
hydroxy, alkyl, hydroxyalkyl, alkoxy, and radicals of the formula
43 with the proviso that at least one of R.sup.12 and R.sup.16 must
be selected from hydroxy, alkyl, hydroxyalkyl, alkoxy, and radicals
of the formula 44wherein A is a spacer group independently selected
from one or more groups of the formula 45wherein each of R.sup.30
and R.sup.31 is independently selected from hydrido, alkyl,
cycloalkyl, phenyl, benzyl, hydroxy, hydroxyalkyl, alkoxy and
alkoxy and alkoxyalkyl; wherein each of R.sup.32, R.sup.33,
R.sup.34 and R.sup.35 is independently selected from hydrido,
alkyl, hydroxyalkyl and alkoxyalkyl; wherein each of R.sup.17,
R.sup.18, R.sup.21 and R.sup.22 is independently selected from
hydrido and alkyl; wherein each r is a number independently
selected from zero to four, inclusive; wherein R.sup.6 is selected
from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
benzyl, alkenyl and alkynyl; and wherein any of the foregoing A and
R.sup.1, R.sup.6, R.sup.8, R.sup.9, R.sup.10, R.sup.12 through
R.sup.18, R.sup.21, R22 and R.sup.30 through R.sup.35 groups having
a substitutable position may be substituted by one or more groups
independently selected from alkyl, alkenyl, alkynyl, hydroxyalkyl
and alkoxyalkyl; or a tautomer thereof or a
pharmaceutically-acceptable salt thereof.
7. Compound of claim 6 wherein m is one or two; wherein n is a
number selected from one to five, inclusive; wherein R.sup.1 is
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, alkoxyalkyl, alkenyl and alkynyl; wherein R.sup.6
is selected from loweralkyl; wherein each of R.sup.8, R.sup.9,
R.sup.10 and R.sup.12 through R.sup.16 is independently selected
from hydrido, hydroxy, alkyl, hydroxyalkyl, alkoxy, alkenyl,
alkynyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylalkenyl,
alkylaminocarbonyl and alkoxyalkyl; with the proviso that at least
one of R.sup.12 and R.sup.16 must be selected from hydroxy, alkyl,
hydroxyalkyl, alkoxy, alkenyl, alkynyl, alkylcarbonyl,
alkoxycarbonyl, alkylcarbonylalkenyl, alkylaminocarbonyl and
alkoxyalkyl; or a tautomer thereof or a pharmaceutically-acceptable
salt thereof.
8. Compound of claim 7 selected from compounds and their
pharmaceutically-acceptable salts of the group consisting of methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-4-
,5-dimethoxybenzoate; ethyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methy-
lhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate; n-propyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-4-
,5-dimethoxybenzoate; n-butyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-met-
hylhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate; n-hexyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-4-
,5-dimethoxybenzoate;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl-
]methylamino]ethyl]-N-(1,1-dimethylethyl)-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-(1,1-dimethylethyl)-N-methyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-(1,1-dimethylethyl)-N-ethyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-(1,1-dimethylethyl)-N-propyl-4,5-dimethoxybenzamide;
2-[2-[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N--
(1,1-dimethylethyl)-N-butyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-(1,1-dimethylethyl)-N-pentyl--4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]
-N-ethyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-
-methylhexyl]methylamino]ethyl]-N-methyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-propyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-m-
ethylhexyl]methylamino]ethyl]-N-butyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-pentyl-4,5-dimethoxybenzamide;
.alpha.-[3-[[2-(4,5-dimethoxy-2-methylphen-
yl)ethyl]methylamino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzenea-
cetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-ethylphenyl)ethyl]methylamino-
]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-propylphenyl)ethyl]methylamino]propyl]-3,-
4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-butylphenyl)ethyl]methylamino]propyl]-3,4-
-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-pentylphenyl)ethyl]methylamino]propyl]-3,-
4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-methylphenyl)ethyl]methylamino]propyl]-3,-
4,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-ethylphenyl)ethyl]methylamino]propyl]-3,4-
,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-propylphenyl)ethyl]methylamino]propyl]-3,-
4,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-butylphenyl)ethyl]methylamino]propyl]-3,4-
,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-pentylphenyl)ethyl]methylamino]propyl]-3,-
4,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E-butenyl)
phenyl]ethyl]methylamino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)ben-
zeneacetonitrile;
.alpha.-[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E-pentenyl)
phenyl]ethyl]methylamino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)ben-
zeneacetonitrile;
.alpha.-[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E-butanyl)
phenyl]ethyl]methylamino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)ben-
zeneacetonitrile;
.alpha.-[3-[[2-[2-(hydroxymethyl)-4,5-dimethoxyphenyl]et-
hyl]methylamino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)
benzeneacetonitrile; and 1-methylethyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphe-
nyl)-5-methylhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate.
9. Compound of claim 8 which is methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphen-
yl)-5-methylhexyl]methylamino]-ethyl]-4,5-dimethoxybenzoate.
10. Compound of claim 8 which is methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphe-
nyl)-5-methylhexyl]methylamino]-ethyl]-4,5-dimethoxybenzoate,
2-hydroxy-1,2,3-propanetricarboxylic acid salt.
11. Compound of claim 8 which is methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphe-
nyl)-5-methylhexyl]methylamino]-ethyl]-4,5-dimethoxybenzoate,
2,3-dihydroxybutanedioic acid salt.
12. Compound of claim 8 which is
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5--
methylhexyl]methylamino]ethyl]-N-(1,1-dimethylethyl)-4,5-dimethoxybenzamid-
e, 2-hydroxy-1,2,3-propanetricarboxylic acid salt.
13. Compound of claim 8 which is
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5--
methylhexyl]methylamino]ethyl]-N-ethyl-4,5-dimethoxybenzamide,
2,3-dihydroxybutanedioic acid salt.
14. Compound of claim 8 which is
a-[3-[[2-(4,5-dimethoxy-2-methylphenyl)et-
hyl]methylamino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneaceton-
itrile, 2,3-dihydroxybutanedioic acid salt.
15. Compound of claim 8 which is
a-[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E-buten-
yl)phenyl]ethyl]methylamino]-propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)-
benzeneacetonitrile.
16. Compound of claim 8 which is
a-[3-[[2-[2-(hydroxymethyl)-4,5-dimethoxy-
phenyl]ethyl]methylamino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benz-
eneacetonitrile, 2-hydroxy-1,2,3-propanetricarboxylic acid
salt.
17. Compound of claim 8 which is 1-methylethyl
2-[2-[[4-cyano-4-(3,4-dimet-
hoxyphenyl)-5-methylhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate.
18. A composition comprising a therapeutically-effective amount of
an immunosuppressive compound and a pharmaceutically acceptable
carrier or diluent, said immunosuppressive compound selected from
compounds of Formula I: 46wherein m is one or two; wherein n is a
number selected from one to ten, inclusive; wherein R.sup.1 is
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, aralkyl, aryl, aroylalkyl, alkoxyalkyl,
alkylcarbonylalkyl, alkoxycarbonylalkyl, alkylaryloxycarbonylalkyl,
alkenyl, cycloalkenyl, aralkoxycarbonylalkyl, alkynyl,
alkylthiocarbonylalkyl, alkylthiothiocarbonylalkyl,
arylthiocarbonylalkyl, arylthiothiocarbonylalkyl,
aralkylthiocarbonylalky- l, alkylarylthiocarbonylalkyl,
alkylsulfonyl, aralkylsulfonyl and arylsulfonyl; wherein each of
R.sup.2 and R.sup.3 is independently selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, aroyl,
aryloxy, aryloxyalkyl, alkoxyalkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkylthiocarbonyl, alkylthiothiocarbonyl,
arylthiocarbonyl, arylthiothiocarbonyl, aralkylthiocarbonyl and
alkylthiocarbonylalkyl; wherein each of R.sup.4, R.sup.5 and
R.sup.7 through R.sup.16 is independently selected from hydrido,
hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy,
aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy,
alkylthiocarbonylthio, alkylthiothiocarbonyl,
alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl,
arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio,
arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio,
aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy,
aralkylthiocarbonylthio, alkylthiocarbonylalkyl,
aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl,
aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, and
wherein each of R.sup.2 through R.sup.5 and R.sup.7 through
R.sup.16 may be further independently selected from radicals of the
formula 47 with the proviso that at least one of R.sup.12 and
R.sup.16 must be selected from hydroxy, alkyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy,
aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl,
alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl,
cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl,
mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio,
cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio,
alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl,
alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl,
arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio,
arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio,
aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy,
aralkylthiocarbonylthio, alkylthiocarbonylalkyl,
aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl,
aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, and
radicals of the formula 48wherein A is selected from divalent
alkyl, alkenyl and alkynyl groups; wherein X is oxygen atom or
sulfur atom; wherein each r is a number independently selected from
zero to six, inclusive; wherein each of R.sup.17 through R.sup.29
is independently selected from hydrido, alkyl, cycloalkyl,
cycloalkylalkyl, aralkyl and aryl; wherein R.sup.6 is selected from
hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkyloxy, alkoxy, aralkyl, aroyl, aryloxy, aryloxyalkyl,
aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl,
alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro,
carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy,
alkylthiocarbonylthio, alkylthiothiocarbonyl,
alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl,
arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio,
arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio,
aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy,
aralkylthiocarbonylthio, alkylthiocarbonylalkyl,
aralkylthiocarbonylthio, alkylsulfinyl, alkylsulfonyl,
aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl and arylsulfonyl;
and wherein any of the foregoing A and R.sup.1 through R.sup.29
groups having a substitutable position may be substituted by one or
more groups independently selected from alkyl, alkenyl, alkynyl,
aralkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aroylalkyl, cycloalkenyl, cyanoamino,
alkylcarbonylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
carboxylalkyl, alkylthiocarbonylalkyl and alkylsulfonylalkyl; or a
tautomer thereof or a pharmaceutically-acceptable salt thereof.
19. The composition of claim 18 wherein m is one or two; wherein n
is a number selected from one to nine, inclusive; wherein R.sup.1
is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, aralkyl, aryl, aroylalkyl, alkoxyalkyl,
alkylcarbonylalkyl, alkoxycarbonylalkyl, alkylaryloxycarbonylalkyl,
alkenyl, cycloalkenyl, aralkoxycarbonylalkyl and alkynyl; wherein
each of R.sup.2 and R.sup.3 is independently selected from hydrido,
alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl,
aroyl, aryloxy, aryloxyalkyl, alkoxyalkyl, alkylcarbonylalkyl,
alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl,
carboxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl,
and mercaptoalkyl; wherein each of R.sup.4, R.sup.5 and R.sup.7
through R.sup.16 is independently selected from hydrido, hydroxy,
alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy,
formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl,
aralkoxy, alkoxyalkyl, alkylcarbonylalkyl, alkenyl, cycloalkenyl,
alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
arylthio, mercapto, and wherein each of R.sup.2 through R.sup.5 and
R.sup.7 through R.sup.16 may be further independently selected from
radicals of the formula 49 with the proviso that at least one of
R.sup.12 and R.sup.16 must be selected from hydroxy, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl,
alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy,
alkoxyalkyl, alkylcarbonylalkyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
arylthio, mercapto, and radicals of the formula 50wherein A is
selected from divalent alkyl, alkenyl and alkynyl groups; wherein X
is oxygen atom or sulfur atom; wherein each r is a number
independently selected from zero to five, inclusive; wherein each
of R.sup.17 through R.sup.27 is independently selected from
hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl;
wherein R.sup.6 is selected from hydrido, alkyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, aralkyl, aroyl,
aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptoalkyl, alkoxycarbonyloxy,
alkylthio, cycloalkylthio, and wherein any of the foregoing A and
R.sup.1 through R.sup.27 groups having a substitutable position may
be substituted by one or more groups independently selected from
alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, cyano, alkoxyalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aroylalkyl, cycloalkenyl,
cyanoamino, alkylcarbonylalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl and carboxylalkyl; or a tautomer thereof or a
pharmaceutically-acceptable salt thereof.
20. The composition of claim 19 wherein m is one or two; wherein n
is a number selected from one to eight, inclusive; wherein R.sup.1
is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, aralkyl, aryl, aroylalkyl, alkoxyalkyl,
alkylcarbonylalkyl, alkoxycarbonylalkyl, alkenyl and alkynyl,
wherein each of R.sup.2 and R.sup.3 is independently selected from
hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl,
aryl, aroyl, aryloxy, aryloxyalkyl, alkoxyalkyl,
alkylcarbonylalkyl, alkenyl, alkynyl, cyano, nitro, carboxyl,
carboxyalkyl, alkylcarbonyloxyalkyl and alkoxycarbonylalkyl,;
wherein each of R.sup.4, R.sup.5 and R.sup.7 through R.sup.16 is
independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy,
aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl,
alkylcarbonylalkyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro,
carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, alkoxycarbonyloxy, and wherein each of
R.sup.2 through R.sup.5 and R.sup.7 through R.sup.16 may be further
independently selected from radicals of the formula 51 with the
proviso that at least one of R.sup.12 and R.sup.16 must be selected
from hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy,
aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonylalkyl, alkenyl,
cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl,
mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, and
radicals of the formula 52wherein A is selected from divalent
alkyl, alkenyl and alkynyl groups; wherein X is oxygen atom or
sulfur atom; wherein each r is a number independently selected from
zero to four, inclusive; wherein each of R.sup.17 through R.sup.24
is independently selected from hydrido, alkyl, cycloalkyl,
cycloalkylalkyl, aralkyl and aryl; wherein R.sup.6 is selected from
hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkyloxy, alkoxy, aralkyl, aroyl, aryloxy, aryloxyalkyl,
aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl,
alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro,
carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptoalkyl, and alkoxycarbonyloxy; and
wherein any of the foregoing A and R.sup.1 through R.sup.24 groups
having a substitutable position may be substituted by one or more
groups independently selected from alkyl, alkenyl, alkynyl,
aralkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aroylalkyl, cyanoamino, alkylcarbonylalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl and carboxylalkyl; or a
tautomer thereof or a pharmaceutically-acceptable salt thereof.
21. The composition of claim 20 wherein m is one or two; wherein n
is a number selected from one to seven, inclusive; wherein R.sup.1
is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, alkoxyalkyl, alkylcarbonylalkyl,
alkoxycarbonylalkyl, alkenyl and alkynyl; wherein each of R.sup.2
and R.sup.3 is independently selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl, phenyl,
benzoyl, phenoxy, phenoxyalkyl, alkoxyalkyl, alkylcarbonylalkyl,
alkenyl, alkynyl, carboxyl, carboxyalkyl, alkylcarbonyloxyalkyl and
alkoxycarbonylalkyl; wherein each of R.sup.4, R.sup.5 and R.sup.7
through R.sup.16 is independently selected from hydrido, hydroxy,
alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy,
alkoxy, phenylalkyl, phenyl, benzoyl, phenoxy, phenoxyalkyl,
alkoxyalkyl, alkylcarbonylalkyl, alkynyl, carboxyl, carboxyalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
alkoxycarbonyloxy, and wherein each of R.sup.2 through R.sup.5 and
R.sup.7 through R.sup.16 may be further independently selected from
radicals of the formula 53 with the proviso that at least one of
R.sup.12 and R.sup.16 must be selected from hydroxy, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl,
alkoxy, phenylalkyl, phenyl, benzoyl, phenoxy, phenoxyalkyl,
phenalkoxy, alkoxyalkyl, alkylcarbonylalkyl, alkenyl, alkynyl,
carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, alkoxycarbonyloxy, and radicals of the formula
54wherein A is selected from divalent alkyl, alkenyl and alkynyl
groups; wherein each r is a number independently selected from zero
to four, inclusive; wherein each of R.sup.17 through R.sup.24 is
independently selected from hydrido, alkyl, cycloalkyl,
cycloalkylalkyl, phenylalkyl and phenyl; wherein R.sup.6 is
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkyloxy, alkoxy, phenylalkyl, benzoyl,
phenoxy, phenoxyalkyl, phenalkoxy, alkoxyalkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, alkynyl, carboxyl,
carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, mercaptoalkyl and alkoxycarbonyloxy; and
wherein any of the foregoing A and R.sup.1 through R.sup.24 groups
having a substitutable position may be substituted by one or more
groups independently selected from alkyl, alkenyl, alkynyl,
phenylalkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, phenyl, alkylcarbonylalkyl, alkoxycarbonylalkyl
and carboxylalkyl; or a tautomer thereof or a
pharmaceutically-acceptable salt thereof.
22. The composition of claim 21 wherein said immunosuppressant
compound is selected from compounds of Formula II: 55wherein m is
one or two; wherein n is a number selected from one to six,
inclusive; wherein R.sup.1 is selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, alkenyl and
alkynyl; wherein each of R.sup.8, R.sup.9, R.sup.10 and R.sup.12
through R.sup.16 is independently selected from hydrido, hydroxy,
alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy,
alkoxy, phenoxy, benzyloxy, and radicals of the formula 56 with the
proviso that at least one of R.sup.12 and R.sup.16 must be selected
from hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkyloxy, alkoxy, phenoxy, phenalkoxy, and radicals of the
formula 57wherein A is a spacer group independently selected from
one or more groups of the formula 58wherein each of R.sup.30 and
R.sup.31 is independently selected from hydrido, alkyl, cycloalkyl,
phenyl, benzyl, hydroxy, hydroxyalkyl, alkoxy, phenoxy,
alkoxyalkyl, benzyloxy, cyano, alkanoyl, 59wherein each of
R.sup.36, R.sup.37, R.sup.38 and R.sup.39 is independently selected
from hydrido, alkyl and phenyl; wherein R.sup.30 and R.sup.31 may
be taken together to form oxo or exomethylene; wherein each of
R.sup.32, R.sup.33, R.sup.34 and R.sup.35 is independently selected
from hydrido, alkyl, hydroxyalkyl and alkoxyalkyl; wherein each of
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22,
R.sup.23 and R.sup.24 is independently selected from hydrido,
alkyl, cycloalkyl, cycloalkylalkyl and phenalkyl; wherein each r is
a number independently selected from zero to four, inclusive;
wherein R.sup.6 is selected from hydrido, alkyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, benzyl, alkenyl and alkynyl; and
wherein any of the foregoing A and R.sup.1, R.sup.6.sub.1
R.sup.8.sub.1 R.sup.9.sub.1 R.sup.10, R.sup.12 through R.sup.24 and
R.sup.30 through R.sup.39 groups having a substitutable position
may be substituted by one or more groups independently selected
from alkyl, alkenyl, alkynyl, benzyl, hydroxyalkyl, alkoxyalkyl,
cycloalkyl, cycloalkylalkyl and phenyl; or a tautomer thereof or a
pharmaceutically-acceptable salt thereof.
23. The composition of claim 22 wherein m is one or two; wherein n
is a number selected from one to five, inclusive; wherein R.sup.1
is selected from hydrido, alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl
and alkynyl; wherein each of R.sup.8, R.sup.9, R.sup.10 and
R.sup.12 through R.sup.16 is independently selected from hydrido,
hydroxy, alkyl, hydroxyalkyl, alkoxy, and radicals of the formula
60 with the proviso that at least one of R.sup.12 and R.sup.16 must
be selected from hydroxy, alkyl, hydroxyalkyl, alkoxy, and radicals
of the formula 61wherein A is a spacer group independently selected
from one or more groups of the formula 62wherein each of R.sup.30
and R.sup.31 is independently selected from hydrido, alkyl,
cycloalkyl, phenyl, benzyl, hydroxy, hydroxyalkyl, alkoxy and
alkoxy and alkoxyalkyl; wherein each of R.sup.32, R.sup.33,
R.sup.34 and R.sup.35 is independently selected from hydrido,
alkyl, hydroxyalkyl and alkoxyalkyl; wherein each of R.sup.17,
R.sup.18, R.sup.21 and R.sup.22 is independently selected from
hydrido and alkyl; wherein each r is a number independently
selected from zero to four, inclusive; wherein R.sup.6 is selected
from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
benzyl, alkenyl and alkynyl; and wherein any of the foregoing A and
R.sup.1, R.sup.6, R.sup.8, R.sup.9, R.sup.10, R.sup.12 through
R.sup.18, R.sup.21, R.sup.22 and R.sup.30 through R.sup.35 groups
having a substitutable position may be substituted by one or more
groups independently selected from alkyl, alkenyl, alkynyl,
hydroxyalkyl and alkoxyalkyl; or a tautomer thereof or a
pharmaceutically-acceptable salt thereof.
24. The composition of claim 23 wherein m is one or two; wherein n
is a number selected from one to five, inclusive; wherein R.sup.1
is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, alkoxyalkyl, alkenyl and alkynyl; wherein R.sup.6
is selected from loweralkyl; wherein each of R.sup.8, R.sup.9,
R.sup.10 and R.sup.12 through R.sup.16 is independently selected
from hydrido, hydroxy, alkyl, hydroxyalkyl, alkoxy, alkenyl,
alkynyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylalkenyl,
alkylaminocarbonyl and alkoxyalkyl; with the proviso that at least
one of R.sup.12 and R.sup.16 must be selected from hydroxy, alkyl,
hydroxyalkyl, alkoxy, alkenyl, alkynyl, alkylcarbonyl,
alkoxycarbonyl, alkylcarbonylalkenyl, alkylaminocarbonyl and
alkoxyalkyl; or a tautomer thereof or a pharmaceutically-acceptable
salt thereof.
25. The composition of claim 24 wherein said immunosuppressant
compound is selected from compounds and their
pharmaceutically-acceptable salts of the group consisting of methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-m-
ethylhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate; ethyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-4-
,5-dimethoxybenzoate; n-propyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-me-
thylhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate; n-butyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-4-
,5-dimethoxybenzoate; n-hexyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-met-
hylhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate;
2-[2-[[4-cyano-4-(3,4-d-
imethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-(1,1-dimethylethyl)-4,5-
-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]-
methylamino]ethyl]-N-(1,1-dimethylethyl)-N-methyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-(1,1-dimethylethyl)-N-ethyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-(1,1-dimethylethyl)-N-propyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-(1,1-dimethylethyl)-N-butyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-(1,1-dimethylethyl)-N-pentyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-ethyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-me-
thylhexyl]methylamino]ethyl]-N-methyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-propyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-m-
ethylhexyl]methylamino]ethyl]-N-butyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-pentyl-4,5-dimethoxybenzamide;
.alpha.-[3-[[2-(4,5-dimethoxy-2-methylphen-
yl)ethyl]methylamino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzenea-
cetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-ethylphenyl)ethyl]methylamino-
]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-propylphenyl)ethyl]methylamino]propyl]-3,-
4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-butylphenyl)ethyl]methylamino]propyl]-3,4-
-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-pentylphenyl)ethyl]methylamino]propyl]-3,-
4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-methylphenyl)ethyl]methylamino]propyl]-3,-
4,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-ethylphenyl)ethyl]methylamino]propyl]-3,4-
,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-propylphenyl)ethyl]methylamino]propyl]-3,-
4,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.--[3-[[2-(4,5-dimethoxy-2-butylphenyl)ethyl]methylamino]propyl]-3,-
4,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-pentylphenyl)ethyl]methylamino]propyl]-3,-
4,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E-butenyl)phenyl]ethyl]-methylami-
no]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E-pentenyl)phenyl]ethyl]-methylam-
ino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E-butanyl)phenyl]ethyl]-methylami-
no]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-[2-(hydroxymethyl)-4,5-dimethoxyphenyl]ethyl]-methylamino]-
propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
and 1-methylethyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methyl-
amino]ethyl]-4,5-dimethoxybenzoate.
26. The composition of claim 25 wherein said immunosuppressant
compound is selected from compounds and their
pharmaceutically-acceptable salts of the group consisting of methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-m-
ethylhexyl]methylamino]-ethyl]-4,5-dimethoxybenzoate; methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]-ethyl]--
4,5-dimethoxybenzoate, 2-hydroxy-1,2,3-propanetricarboxylic acid
salt; methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]--
ethyl]-4,5-dimethoxybenzoate, 2,3-dihydroxybutanedioic acid salt;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-(1,1-dimethylethyl)-4,5-dimethoxybenzamide,
2-hydroxy-1,2,3-propanetricar- boxylic acid salt;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]me-
thylamino]ethyl]-N-ethyl-4,5-dimethoxybenzamide,
2,3-dihydroxybutanedioic acid salt;
.alpha.-[3-[[2-(4,5-dimethoxy-2-methylphenyl)ethyl]methylamino-
]propyl]-3,4-dimethoxy-.alpha.(1-methylethyl)benzeneacetonitrile,
2,3-dihydroxybutanedioic acid salt;
.alpha.-[3-[[2-[4,5-dimethoxy-2-(3-ox-
o-1E)butenyl)phenyl]ethyl]-methylamino]-propyl]-3,4-dimethoxy-.alpha.-(1-m-
ethylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-[2-(hydroxymethyl)-4,5-dime-
thoxyphenyl]ethyl]-methylamino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethy-
l)benzeneacetonitrile, 2-hydroxy-1,2,3-propanetricarboxylic acid
salt; and 1-methylethyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methyl-
amino]ethyl]-4,5-dimethoxybenzoate.
27. A method to suppress immune response in a subject, said method
comprising administering to said subject a
therapeutically-effective amount of an immunosuppressive compound
of Formula I: 63wherein m is one or two; wherein n is a number
selected from one to ten, inclusive; wherein R.sup.1 is selected
from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
aralkyl, aryl, aroylalkyl, alkoxyalkyl, alkylcarbonylalkyl,
alkoxycarbonylalkyl, alkylaryloxycarbonylalkyl, alkenyl,
cycloalkenyl, aralkoxycarbonylalkyl, alkynyl,
alkylthiocarbonylalkyl, alkylthiothiocarbonylalkyl,
arylthiocarbonylalkyl, arylthiothiocarbonylalkyl,
aralkylthiocarbonylalky- l, alkylarylthiocarbonylalkyl,
alkylsulfonyl, aralkylsulfonyl and arylsulfonyl; wherein each of
R.sup.2 and R.sup.3 is independently selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, aroyl,
aryloxy, aryloxyalkyl, alkoxyalkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkylthiocarbonyl, alkylthiothiocarbonyl,
arylthiocarbonyl, arylthiothiocarbonyl, aralkylthiocarbonyl and
alkylthiocarbonylalkyl; wherein each of R.sup.4, R.sup.5 and
R.sup.7 through R.sup.16 is independently selected from hydrido,
hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy,
aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy,
alkylthiocarbonylthio, alkylthiothiocarbonyl,
alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl,
arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio,
arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio,
aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy,
aralkylthiocarbonylthio, alkylthiocarbonylalkyl,
aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl,
aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, and
wherein each of R.sup.2 through R.sup.5 and R.sup.7 through
R.sup.16 may be further independently selected from radicals of the
formula 64 with the proviso that at least one of R.sup.12 and
R.sup.16 must be selected from hydroxy, alkyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy,
aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl,
alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl,
cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl,
mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio,
cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio,
alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl,
alkylthiothiocarbonylthio, arylthio, aryithiocarbonyl,
arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio,
arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio,
aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy,
aralkylthiocarbonylthio, alkylthiocarbonylalkyl,
aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl,
aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, and
radicals of the formula 65wherein A is selected from divalent
alkyl, alkenyl and alkynyl groups; wherein X is oxygen atom or
sulfur atom; wherein each r is a number independently selected from
zero to six, inclusive; wherein each of R.sup.17 through R.sup.29
is independently selected from hydrido, alkyl, cycloalkyl,
cycloalkylalkyl, aralkyl and aryl; wherein R.sup.6 is selected from
hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkyloxy, alkoxy, aralkyl, aroyl, aryloxy, aryloxyalkyl,
aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl,
alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro,
carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy,
alkylthiocarbonylthio, alkylthiothiocarbonyl,
alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl,
arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio,
arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio,
aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy,
aralkylthiocarbonylthio, alkylthiocarbonylalkyl,
aralkylthiocarbonylthio, alkylsulfinyl, alkylsulfonyl,
aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl and arylsulfonyl;
and wherein any of the foregoing A and R.sup.1 through R.sup.29
groups having a substitutable position may be substituted by one or
more groups independently selected from alkyl, alkenyl, alkynyl,
aralkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aroylalkyl, cycloalkenyl, cyanoamino,
alkylcarbonylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
carboxylalkyl, alkylthiocarbonylalkyl and alkylsulfonylalkyl; or a
tautomer thereof or a pharmaceutically-acceptable salt thereof.
28. The method of claim 27 wherein m is one or two; wherein n is a
number selected from one to nine, inclusive; wherein R.sup.1 is
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, aralkyl, aryl, aroylalkyl, alkoxyalkyl,
alkylcarbonylalkyl, alkoxycarbonylalkyl, alkylaryloxycarbonylalkyl,
alkenyl, cycloalkenyl, aralkoxycarbonylalkyl and alkynyl; wherein
each of R.sup.2 and R.sup.3 is independently selected from hydrido,
alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl,
aroyl, aryloxy, aryloxyalkyl, alkoxyalkyl, alkylcarbonylalkyl,
alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl,
carboxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl,
and mercaptoalkyl; wherein each of R.sup.4, R.sup.5 and R.sup.7
through R.sup.16 is independently selected from hydrido, hydroxy,
alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy,
formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl,
aralkoxy, alkoxyalkyl, alkylcarbonylalkyl, alkenyl, cycloalkenyl,
alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
arylthio, mercapto, and wherein each of R.sup.2 through R.sup.5 and
R.sup.7 through R.sup.16 may be further independently selected from
radicals of the formula 66 with the proviso that at least one of
R.sup.12 and R.sup.16 must be selected from hydroxy, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl,
alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy,
alkoxyalkyl, alkylcarbonylalkyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
arylthio, mercapto, and radicals of the formula 67wherein A is
selected from divalent alkyl, alkenyl and alkynyl groups; wherein X
is oxygen atom or sulfur atom; wherein each r is a number
independently selected from zero to five, inclusive; wherein each
of R.sup.17 through R.sup.27 is independently selected from
hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl;
wherein R.sup.6 is selected from hydrido, alkyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, aralkyl, aroyl,
aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptoalkyl, alkoxycarbonyloxy,
alkylthio, cycloalkylthio, and wherein any of the foregoing A and
R.sup.1 through R.sup.27 groups having a substitutable position may
be substituted by one or more groups independently selected from
alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, cyano, alkoxyalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aroylalkyl, cycloalkenyl,
cyanoamino, alkylcarbonylalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl and carboxylalkyl; or a tautomer thereof or a
pharmaceutically-acceptable salt thereof.
29. The method of claim 28 wherein m is one or two; wherein n is a
number selected from one to eight, inclusive; wherein R.sup.1 is
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, aralkyl, aryl, aroylalkyl, alkoxyalkyl,
alkylcarbonylalkyl, alkoxycarbonylalkyl, alkenyl and alkynyl,
wherein each of R.sup.2 and R.sup.3 is independently selected from
hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl,
aryl, aroyl, aryloxy, aryloxyalkyl, alkoxyalkyl,
alkylcarbonylalkyl, alkenyl, alkynyl, cyano, nitro, carboxyl,
carboxyalkyl, alkylcarbonyloxyalkyl and alkoxycarbonylalkyl,;
wherein each of R.sup.4, R.sup.5 and R.sup.7 through R.sup.16 is
independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy,
aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl,
alkylcarbonylalkyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro,
carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, alkoxycarbonyloxy, and wherein each of
R.sup.2 through R.sup.5 and R.sup.7 through R.sup.16 may be further
independently selected from radicals of the formula 68 with the
proviso that at least one of R.sup.12 and R.sup.16 must be selected
from hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy,
aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonylalkyl, alkenyl,
cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl,
mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, and
radicals of the formula 69wherein A is selected from divalent
alkyl, alkenyl and alkynyl groups; wherein X is oxygen atom or
sulfur atom; wherein each r is a number independently selected from
zero to four, inclusive; wherein each of R.sup.17 through R.sup.24
is independently selected from hydrido, alkyl, cycloalkyl,
cycloalkylalkyl, aralkyl and aryl; wherein R.sup.6 is selected from
hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkyloxy, alkoxy, aralkyl, aroyl, aryloxy, aryloxyalkyl,
aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl,
alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro,
carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptoalkyl, and alkoxycarbonyloxy; and
wherein any of the foregoing A and R.sup.1 through R.sup.24 groups
having a substitutable position may be substituted by one or more
groups independently selected from alkyl, alkenyl, alkynyl,
aralkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aroylalkyl, cyanoamino, alkylcarbonylalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl and carboxylalkyl; or a
tautomer thereof or a pharmaceutically-acceptable salt thereof.
30. The method of claim 29 wherein m is one or two; wherein n is a
number selected from one to seven, inclusive; wherein R.sup.1 is
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, alkoxyalkyl, alkylcarbonylalkyl,
alkoxycarbonylalkyl, alkenyl and alkynyl; wherein each of R.sup.2
and R.sup.3 is independently selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl, phenyl,
benzoyl, phenoxy, phenoxyalkyl, alkoxyalkyl, alkylcarbonylalkyl,
alkenyl, alkynyl, carboxyl, carboxyalkyl, alkylcarbonyloxyalkyl and
alkoxycarbonylalkyl; wherein each of R.sup.4, R.sup.5 and R.sup.7
through R.sup.16 is independently selected from hydrido, hydroxy,
alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy,
alkoxy, phenylalkyl, phenyl, benzoyl, phenoxy, phenoxyalkyl,
alkoxyalkyl, alkylcarbonylalkyl, alkynyl, carboxyl, carboxyalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
alkoxycarbonyloxy, and wherein each of R.sup.2 through R.sup.5 and
R.sup.7 through R.sup.16 may be further independently selected from
radicals of the formula 70 with the proviso that at least one of
R.sup.12 and R.sup.16 must be selected from hydroxy, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl,
alkoxy, phenylalkyl, phenyl, benzoyl, phenoxy, phenoxyalkyl,
phenalkoxy, alkoxyalkyl, alkylcarbonylalkyl, alkenyl, alkynyl,
carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, alkoxycarbonyloxy, and radicals of the formula
71wherein A is selected from divalent alkyl, alkenyl and alkynyl
groups; wherein each r is a number independently selected from zero
to four, inclusive; wherein each of R.sup.17 through R.sup.24 is
independently selected from hydrido, alkyl, cycloalkyl,
cycloalkylalkyl, phenylalkyl and phenyl; wherein R.sup.6 is
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkyloxy, alkoxy, phenylalkyl, benzoyl,
phenoxy, phenoxyalkyl, phenalkoxy, alkoxyalkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, alkynyl, carboxyl,
carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, mercaptoalkyl and alkoxycarbonyloxy; and
wherein any of the foregoing A and R.sup.1 through R.sup.24 groups
having a substitutable position may be substituted by one or more
groups independently selected from alkyl, alkenyl, alkynyl,
phenylalkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, phenyl, alkylcarbonylalkyl, alkoxycarbonylalkyl
and carboxylalkyl; or a tautomer thereof or a
pharmaceutically-acceptable salt thereof.
31. The method of claim 30 wherein said immunosuppressant compound
is selected from compounds of Formula II: 72wherein m is one or
two; wherein n is a number selected from one to six, inclusive;
wherein R.sup.1 is selected from hydrido, alkyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, alkoxyalkyl, alkenyl and alkynyl;
wherein each of R.sup.8, R.sup.9, R.sup.10 and R.sup.12 through
R.sup.16 is independently selected from hydrido, hydroxy, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy,
phenoxy, benzyloxy, and radicals of the formula 73 with the proviso
that at least one of R.sup.12 and R.sup.16 must be selected from
hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkyloxy, alkoxy, phenoxy, phenalkoxy, and radicals of the
formula 74wherein A is a spacer group independently selected from
one or more groups of the formula 75wherein each of R.sup.30 and
R.sup.31 is independently selected from hydrido, alkyl, cycloalkyl,
phenyl, benzyl, hydroxy, hydroxyalkyl, alkoxy, phenoxy,
alkoxyalkyl, benzyloxy, cyano, alkanoyl, 76wherein each of
R.sup.36, R.sup.37, R.sup.38 and R.sup.39 is independently selected
from hydrido, alkyl and phenyl; wherein R.sup.30 and R.sup.31 may
be taken together to form oxo or exomethylene; wherein each of
R.sup.32, R.sup.33, R.sup.34 and R.sup.35 is independently selected
from hydrido, alkyl, hydroxyalkyl and alkoxyalkyl; wherein each of
R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22,
R.sup.23 and R.sup.24 is independently selected from hydrido,
alkyl, cycloalkyl, cycloalkylalkyl and phenalkyl; wherein each r is
a number independently selected from zero to four, inclusive;
wherein R.sup.6 is selected from hydrido, alkyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, benzyl, alkenyl and alkynyl; and
wherein any of the foregoing A and R.sup.1, R.sup.6.sub.1 R.sup.8,
R.sup.9, R.sup.10, R.sup.12 through R.sup.24 and R.sup.30 through
R.sup.39 groups having a substitutable position may be substituted
by one or more groups independently selected from alkyl, alkenyl,
alkynyl, benzyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl and phenyl; or a tautomer thereof or a
pharmaceutically-acceptable salt thereof.
32. The method of claim 31 wherein m is one or two; wherein n is a
number selected from one to five, inclusive; wherein R.sup.1 is
selected from hydrido, alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl
and alkynyl; wherein each of R.sup.8, R.sup.9, R.sup.10 and
R.sup.12 through R.sup.16 is independently selected from hydrido,
hydroxy, alkyl, hydroxyalkyl, alkoxy, and radicals of the formula
77 with the proviso that at least one of R.sup.12 and R.sup.16 must
be selected from hydroxy, alkyl, hydroxyalkyl, alkoxy, and radicals
of the formula 78wherein A is a spacer group independently selected
from one or more groups of the formula 79wherein each of R.sup.30
and R.sup.31 is independently selected from hydrido, alkyl,
cycloalkyl, phenyl, benzyl, hydroxy, hydroxyalkyl, alkoxy and
alkoxy and alkoxyalkyl; wherein each of R.sup.32, R.sup.33,
R.sup.34 and R.sup.35 is independently selected from hydrido,
alkyl, hydroxyalkyl and alkoxyalkyl; wherein each of R.sup.17,
R.sup.18, R.sup.21 and R.sup.22 is independently selected from
hydrido and alkyl; wherein each r is a number independently
selected from zero to four, inclusive; wherein R.sup.6 is selected
from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
benzyl, alkenyl and alkynyl; and wherein any of the foregoing A and
R.sup.1, R.sup.6, R.sup.8, R.sup.9, R.sup.10, R.sup.12 through
R.sup.18, R.sup.21, R.sup.22 and R.sup.30 through R.sup.35 groups
having a substitutable position may be substituted by one or more
groups independently selected from alkyl, alkenyl, alkynyl,
hydroxyalkyl and alkoxyalkyl; or a tautomer thereof or a
pharmaceutically-acceptable salt thereof.
33. The method of claim 32 wherein m is one or two; wherein n is a
number selected from one to five, inclusive; wherein R.sup.1 is
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, alkoxyalkyl, alkenyl and alkynyl; wherein R.sup.6
is selected from loweralkyl; wherein each of R.sup.8, R.sup.9,
R.sup.10 and R.sup.12 through R.sup.16 is independently selected
from hydrido, hydroxy, alkyl, hydroxyalkyl, alkoxy, alkenyl,
alkynyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylalkenyl,
alkylaminocarbonyl and alkoxyalkyl; with the proviso that at least
one of R.sup.12 and R.sup.16 must be selected from hydroxy, alkyl,
hydroxyalkyl, alkoxy, alkenyl, alkynyl, alkylcarbonyl,
alkoxycarbonyl, alkylcarbonylalkenyl, alkylaminocarbonyl and
alkoxyalkyl; or a tautomer thereof or a pharmaceutically-acceptable
salt thereof.
34. The method of claim 33 wherein said immunosuppressant compound
is selected from compounds and their pharmaceutically-acceptable
salts of the group consisting of methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-m-
ethylhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate; ethyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-4-
,5-dimethoxybenzoate; n-propyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-me-
thylhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate; n-butyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-4-
,5-dimethoxybenzoate; n-hexyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-met-
hylhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate;
2-[2-[[4-cyano-4-(3,4-d-
imethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-(1,1-dimethylethyl)-4,5-
-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]-
methylamino]ethyl]-N-(1,1-dimethylethyl)-N-methyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-(1,1-dimethylethyl)-N-ethyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-(1,1-dimethylethyl)-N-propyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-(1,1-dimethylethyl)-N-butyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-(1,1-dimethylethyl)-N-pentyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-ethyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-me-
thylhexyl]methylamino]ethyl]-N-methyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-propyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-m-
ethylhexyl]methylamino]ethyl]-N-butyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-pentyl-4,5-dimethoxybenzamide;
.alpha.-[3-[[2-(4,5-dimethoxy-2-methylphen-
yl)ethyl]methylamino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzenea-
cetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-ethylphenyl)ethyl]methylamino-
]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-propylphenyl)ethyl]methylamino]propyl]-3,-
4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-butylphenyl)ethyl]methylamino]propyl]-3,4-
-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-pentylphenyl)ethyl]methylamino]propyl]-3,-
4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-methylphenyl)ethyl]methylamino]propyl]-3,-
4,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-ethylphenyl)ethyl]methylamino]propyl]-3,4-
,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-propylphenyl)ethyl]methylamino]propyl]-3,-
4,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-butylphenyl)ethyl]methylamino]propyl]-3,4-
,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-(4,5-dimethoxy-2-pentylphenyl)ethyl]methylamino]propyl]-3,-
4,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E)butenyl)phenyl]ethyl]-methylami-
no]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E)pentenyl)phenyl]ethyl]-methylam-
ino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E)butanyl)phenyl]ethyl]-methylami-
no]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-[2-(hydroxymethyl)-4,5-dimethoxyphenyl]ethyl]-methylamino]-
propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
and 1-methylethyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methyl-
amino]ethyl]-4,5-dimethoxybenzoate.
35. The method of claim 34 wherein said immunosuppressant compound
is selected from compounds and their pharmaceutically-acceptable
salts of the group consisting of methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-m-
ethylhexyl]methylamino]-ethyl]-4,5-dimethoxybenzoate; methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]-ethyl]--
4,5-dimethoxybenzoate, 2-hydroxy-1,2,3-propanetricarboxylic acid
salt; methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]--
ethyl]-4,5-dimethoxybenzoate, 2,3-dihydroxybutanedioic acid salt;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-
-(1,1-dimethylethyl)-4,5-dimethoxybenzamide,
2-hydroxy-1,2,3-propanetricar- boxylic acid salt;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]me-
thylamino]ethyl]-N-ethyl-4,5-dimethoxybenzamide,
2,3-dihydroxybutanedioic acid salt;
.alpha.-[3-[[2-(4,5-dimethoxy-2-methylphenyl)ethyl]methylamino-
]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile,
2,3-dihydroxybutanedioic acid salt;
.alpha.-[3-[[2-[4,5-dimethoxy-2-(3-ox-
o-1E)butenyl)phenyl]ethyl]-methylamino]-propyl]-3,4-dimethoxy-.alpha.-(1-m-
ethylethyl)benzeneacetonitrile;
.alpha.-[3-[[2-[2-(hydroxymethyl)-4,5-dime-
thoxyphenyl]ethyl]-methylamino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethy-
l)benzeneacetonitrile, 2-hydroxy-1,2,3-propanetricarboxylic acid
salt; and 1-methylethyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methyl-
-amino]ethyl]-4,5-dimethoxybenzoate.
36. The method of claim 27 further characterized by suppressing
immune response in a subject to prevent rejection of an organ
transplanted to said subject.
37. The method of claim 27 further characterized by suppressing
immune response in a subject susceptible to or afflicted with an
autoimmune or inflammatory disease.
38. The method of claim 37, wherein said autoimmune or inflammatory
disease is systemic lupus erythematosis.
39. The method of claim 37, wherein said autoimmune or inflammatory
disease is multiple sclerosis.
40. The method of claim 37, wherein said autoimmune or inflammatory
disease is insulin dependent diabetes mellitus.
41. The method of claim 37, wherein said autoimmune or inflammatory
disease is rheumatoid arthritis.
42. The method of claim 37, wherein said autoimmune or inflammatory
disease is psoriasis.
43. The method of claim 37, wherein said autoimmune or inflammatory
disease is inflammatory bowel disease.
44. The method of claim 37, wherein said autoimmune or inflammatory
disease is Crohn's Disease.
45. The method of claim 27 further characterized by suppressing
immune response in a subject susceptible to or afflicted with an
allergy.
46. The method of claim 27 further characterized by suppressing
immune response in a subject susceptible to or afflicted with
asthma.
47. The method of claim 27 further characterized by suppressing
immune response in a subject susceptible to or afflicted with
airway hypersensitivity.
48. The method of claim 27 further characterized by suppressing
immune response in a subject susceptible to or afflicted with
septic shock.
Description
RELATED APPLICATIONS
[0001] This is a continuation-in-part of U.S. Ser. No. 07/609,145
filed Nov. 6, 1990, which is a continuation of U.S. Ser. No.
07/456,004 filed Dec. 21, 1989.
FIELD OF THE INVENTION
[0002] This invention is in the field of clinical immunology and
relates to compounds having immunosuppressive properties. Of
particular interest is a family of
phenylacetonitrilealkylaminoalkyl-o-substituted aryl compounds for
reducing recipient rejection of transplanted organs, and for
treatment of autoimmune or inflammatory diseases, allergic or
asthmatic reactions and septic shock.
BACKGROUND OF THE INVENTION
[0003] Successful organ transplantation requires effective
physiological and pharmacological intervention of the immune system
of an organ recipient. Immunologic mechanisms are universal among
the human species. But histocompatibility variations between donor
and recipient lead inevitably to rejection of donor tissue by
stimulation of the recipient's immune system except, perhaps, in
donor-recipient pairing of the monozygotic type. One approach to
intervention of immune response in an organ transplant recipient,
especially a recipient targeted for an allogenic or homologous
graft, is by the use of immunosuppressive drugs. These drugs have
been used to prolong survival of transplanted organs in recipients
in cases involving, for example, transplants of kidney, liver,
heart, bone marrow and pancreas.
[0004] There are several types of immunosuppressive drugs available
for use in reducing organ rejection in transplantation. Such drugs
fall within three major classes, namely: antiproliferative agents,
antiinflammatory-acting compounds and inhibitors of lymphocyte
activation.
[0005] Examples of the class of antiproliferative agents are
azathioprine, cyclophosphamide and methotrexate. The compound
azathioprine acts by interrupting DNA synthesis through inhibition
of purine metabolism. The compound cyclophosphamide is an
alkylating agent which interferes with enzyme actions and
nucleotide cross-linking. The compound methotrexate is a folic acid
antagonist which interferes with nucleotide synthesis. While drugs
of the antiproliferative class may be effective immunosuppressives
in organ transplant recipients by limiting cell proliferation,
these drugs which mediate mitosis and cell division have severe
side effects on normal cell populations which have a high turn-over
rate, such as bone marrow cells and cells of the gastrointestinal
(GI) tract lining. Accordingly, such drugs often have severe side
effects, particularly, bone marrow depression, liver damage, hair
loss and GI tract disturbances.
[0006] A second class of immunosuppressive drugs for use in
transplantation is provided by compounds having antiinflammatory
action. Representatives of this drug class are generally known as
adrenal corticosteroids and have the advantage of not exerting
globally systemic cytotoxic effects. These compounds usually act by
inhibiting T-cell proliferation, or by reducing IL-2 production, or
by reducing chemotaxis, or by reducing neutrophil or macrophage
activity. Typical examples of adrenal corticosteroids are
prednisone and prednisolone. Compounds of this class are sometimes
used in combination with cytotoxic agents, such as compounds of the
antiproliferative class because the corticosteroids are
significantly less toxic. But the adrenal corticosteroids lack
specificity of effect and can exert a broad range of metabolic,
antiinflammatory and auto-immune effects. Typical side effects of
this class include increased organ-recipient infections and
interference with wound healing, as well as disturbing hemodynamic
balance, carbohydrate and bone metabolism and mineral
regulation.
[0007] A third class of immunosuppressive drugs for use in organ
transplantation is provided by compounds which generally prevent or
inhibit lymphocyte activation. Such compounds usually act by
blocking activated T-cell proliferation, or by inhibiting IL-2
production, or by inhibiting lymphokine production which depresses
B-cell and macrophage actions. The cyclosporin family of compounds
is the leading example of drugs in this class. Such compounds are
fungal metabolites which have been found to be very effective in
suppressing helper T cells so as to reduce both cellular and
humoral responses to newly-encountered antigens. Cyclosporins alter
macrophage and lymphocyte activity by reducing lymphokine secretion
and, in particular, by interfering with activation of
antigen-specific CD-4 cells, by preventing IL-2 secretion and
secretion of many T-cell products, as well as by interfering with
expression of receptors for these lymphokines. Cyclosporin A, in
particular, has been used extensively as an immunosuppressor agent
in organ transplantation. Other microbial metabolites include
cyclosporins such as cyclosporin B and cyclosporin G, and another
microbial product known as FK-506. Cyclosporin A suppresses humoral
immunity as well as cell-mediated reactions. Cyclosporin A is
indicated for organ rejection in kidney, liver, heart, pancreas,
bone-marrow and heart-lung transplants. Cyclosporin A is also
useful in the treatment of autoimmune and inflammatory diseases,
including rheumatoid arthritis, Crohn's disease, Graves
ophthalmopathy, severe psoriasis, aplastic anemia,
multiple-sclerosis, alopecia areata, penphigus and penphigoid,
dermatomyositis, polymyositis, Behcet's disease, uveitis, pulmonary
sarcocidiosis, biliary cirrhosis, myasthenia gravis and atopic
dermatitis.
[0008] Cyclosporins do possess several significant disadvantages.
Firstly, while cyclosporins have provided significant benefits in
organ transplantation, cyclosporins are non-specific
immunosuppressives. Thus, immunologic reactions to transplanted
tissue are not totally impeded, and desirable immune reactions may
be reduced against other foreign antigens. Secondly, cyclosporins
can produce severe side effects in many organ recipients. And
cyclosporins show host-variable effects on the liver, the CNS and
GI tract. Significant among the adverse side effects are damage to
the kidney and hyperplasia of gum tissue.
[0009] Thus, the need remains for efficacious, selective
immunosuppressive drugs in organ transplantation, especially for
grafts between less-than-perfectly matched donor-recipient
pairs.
[0010] Phenylacetonitrile compounds are known for use in treatment
of cardiovascular diseases. For example, U.S. Pat. No. 3,261,859
describes phenylacetonitrile compounds, including the well-known
compound verapamil, for use as coronary dilators. U.S. Pat. No.
4,593,042 describes certain bicycloamino-substituted
phenylacetonitrilealkyl compounds, including several specific
compounds having an isopropyl group attached to the alkylene alpha
carbon of the phenylacetonitrile nucleus. Such compounds are
characterized as calcium ion blockers for use in treatment of
hypertension. U.S. Pat. No. 4,681,970 describes
bicycloamino-substituted phenylacetonitrilealkyl compounds, several
specific compounds of which have a long chain alkyl group (i.e.,
twelve carbons) attached to the alkylene alpha carbon of the
phenylacetonitrile nucleus. These compounds are characterized as
calcium channel blockers for treatment of hypertension.
[0011] Phenylacetonitrile compounds have been investigated for
other pharmaceutical purposes. For example, certain calcium channel
blocking agents, including verapamil, have been investigated for
antiproliferative effects on T-cell mitogenesis [G. Walz et al,
Transplantation, 47, 33-334 (1989)]. Various calcium channel
blockers, including verapamil and nifedipine, have been studied for
interaction with stimulated T-lymphocytes [A. Nell et al, Scan. J.
Immunology, 24, 283-290 (1986)]. German Offen. 3826796 published
Feb. 8, 1990 describes substituted phenylacetonitrile compounds for
use in overcoming resistance to antimalarial or anticancer agents.
The calcium antagonists verapamil, nifedipine and nicardipine were
compared and found to produce dose-dependent acute and chronic
antiinflammatory effects [W. R. Chen et al, Acta. Pharmacologica
Sinica, 11(3), 281-285 (1990)].
DESCRIPTION OF INVENTION
[0012] Reduction in recipient rejection of a transplanted organ, or
treatment of an autoimmune or inflammatory disease, or an allergic
reaction or asthmatic condition, or treatment of septic shock may
be accomplished by a method to suppress immune response in a
recipient or treatment subject, which method comprises
administering to the subject a therapeutically-effective amount of
an immunosuppressive compound of Formula I: 2
[0013] wherein m is one or two; wherein n is a number selected from
one to ten, inclusive;
[0014] wherein R.sup.1 is selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl,
aroylalkyl, alkoxyalkyl, alkylcarbonylalkyl, alkoxycarbonylalkyl,
alkylaryloxycarbonylalkyl, alkenyl, cycloalkenyl,
aralkoxycarbonylalkyl, alkynyl, alkylthiocarbonylalkyl,
alkylthiothiocarbonylalkyl, arylthiocarbonylalkyl,
arylthiothiocarbonylalkyl, aralkylthiocarbonylalky- l,
alkylarylthiocarbonylalkyl, alkylsulfonyl, aralkylsulfonyl and
arylsulfonyl;
[0015] wherein each of R.sup.2 and R.sup.3 is independently
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl,
alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,
alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl,
carboxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl,
mercaptothiocarbonyl, mercaptoalkyl, alkylthiocarbonyl,
alkylthiothiocarbonyl, arylthiocarbonyl, arylthiothiocarbonyl,
aralkylthiocarbonyl and alkylthiocarbonylalkyl;
[0016] wherein each of R.sup.4, R.sup.5 and R.sup.7 through
R.sup.16 is independently selected from hydrido, hydroxy, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl,
alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy,
alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,
alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl,
carboxyalkyl, alkylcarbonyloxy alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy,
alkylthiocarbonylthio, alkylthiothiocarbonyl,
alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl,
arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio,
arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio,
aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy,
aralkylthiocarbonylthio, alkylthiocarbonylalkyl,
aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl,
aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, and
wherein each of R.sup.2 through R.sup.5 and R.sup.7 through
R.sup.16 may be further independently selected from radicals of the
formula 3
[0017] with the proviso that at least one of R.sup.12 and R.sup.16
must be selected from hydroxy, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, aralkyl, aryl,
aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl,
alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy,
alkylthiocarbonylthio, alkylthiothiocarbonyl,
alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl,
arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio,
arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio,
aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy,
aralkylthiocarbonylthio, alkylthiocarbonylalkyl,
aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl,
aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, and
radicals of the formula 4
[0018] wherein A is selected from divalent alkyl, alkenyl and
alkynyl groups; wherein X is oxygen atom or sulfur atom; wherein
each r is a number independently selected from zero to six,
inclusive; wherein each of R.sup.17 through R.sup.29 is
independently selected from hydrido, alkyl, cycloalkyl,
cycloalkylalkyl, aralkyl and aryl;
[0019] wherein R.sup.6 is selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy,
aralkyl, aroyl, aryloxy, aryloxyalkyl, aralkoxy,. alkoxyalkyl,
alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl,
cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl,
mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio,
cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio,
alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl,
alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl,
arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio,
arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio,
aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy,
aralkylthiocarbonylthio, alkylthiocarbonylalkyl,
aralkylthiocarbonylthio, alkylsulfinyl, alkylsulfonyl,
aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl and
arylsulfonyl;
[0020] and wherein any of the foregoing A and R.sup.1 through
R.sup.29 groups having a substitutable position may be substituted
by one or more groups independently selected from alkyl, alkenyl,
alkynyl, aralkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aroylalkyl, cycloalkenyl, cyanoamino,
alkylcarbonylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
carboxylalkyl, alkylthiocarbonylalkyl and alkylsulfonylalkyl;
[0021] or a tautomer thereof or a pharmaceutically-acceptable salt
thereof.
[0022] A preferred class consists of compounds within Formula I
wherein m is one or two; wherein n is a number selected from one to
nine, inclusive;
[0023] wherein R.sup.1 is selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl,
aroylalkyl, alkoxyalkyl, alkylcarbonylalkyl, alkoxycarbonylalkyl,
alkylaryloxycarbonylalkyl, alkenyl, cycloalkenyl,
aralkoxycarbonylalkyl and alkynyl;
[0024] wherein each of R.sup.2 and R.sup.3 is independently
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl,
alkoxyalkyl, alkylcarbonylalkyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, and mercaptoalkyl;
[0025] wherein each of R.sup.4, R.sup.5 and R.sup.7 through
R.sup.16 is independently selected from hydrido, hydroxy, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl,
alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy,
alkoxyalkyl, alkylcarbonylalkyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
arylthio, mercapto, and wherein each of R.sup.2 through R.sup.5 and
R.sup.7 through R.sup.16 may be further independently selected from
radicals of the formula 5
[0026] with the proviso that at least one of R.sup.12 and R.sup.16
must be selected from hydroxy, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, aralkyl, aryl,
aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl,
alkylcarbonylalkyl(alkenyl, cycloalkenyl, alkynyl, cyano, nitro,
carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
arylthio, mercapto, and radicals of the formula 6
[0027] wherein A is selected from divalent alkyl, alkenyl and
alkynyl groups; wherein X is oxygen atom or sulfur atom; wherein
each r is a number independently selected from zero to five,
inclusive; wherein each of R.sup.17 through R.sup.27 is
independently selected from hydrido, alkyl, cycloalkyl,
cycloalkylalkyl, aralkyl and aryl;
[0028] wherein R.sup.6 is selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy,
aralkyl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl,
alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl,
cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptoalkyl,
alkoxycarbonyloxy, alkylthio, cycloalkylthio,
[0029] and wherein any of the foregoing A and R.sup.1 through
R.sup.27 groups having a substitutable position may be substituted
by one or more groups independently selected from alkyl, alkenyl,
alkynyl, aralkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aroylalkyl, cycloalkenyl, cyanoamino,
alkylcarbonylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl and
carboxylalkyl;
[0030] or a tautomer thereof or a pharmaceutically-acceptable salt
thereof.
[0031] A more preferred class consists of compounds within Formula
I wherein m is one or two; wherein n is a number selected from one
to eight, inclusive;
[0032] wherein R.sup.1 is selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl,
aroylalkyl, alkoxyalkyl, alkylcarbonylalkyl, alkoxycarbonylalkyl,
alkenyl and alkynyl, wherein each of R.sup.2 and R.sup.3 is
independently selected from hydrido, alkyl, hydroxyalkyl,
cycloalkyl, cycloalkylalkyl, aralkyl, aryl, aroyl, aryloxy,
aryloxyalkyl, alkoxyalkyl, alkylcarbonylalkyl, alkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxyalkyl and
alkoxycarbonylalkyl,;
[0033] wherein each of R.sup.4, R.sup.5 and R.sup.7 through
R.sup.16 is independently selected from hydrido, hydroxy, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl,
alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy,
alkoxyalkyl, alkylcarbonylalkyl, alkenyl, cycloalkenyl, alkynyl,
cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, alkoxycarbonyloxy, and wherein each of
R.sup.2 through R.sup.5 and R.sup.7 through R.sup.16 may be further
independently selected from radicals of the formula 7
[0034] with the proviso that at least one of R.sup.12 and R.sup.16
must be selected from hydroxy, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, aralkyl, aryl,
aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl,
alkylcarbonylalkyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro,
carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl,
aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl,
mercaptoalkyl, alkoxycarbonyloxy, and radicals of the formula 8
[0035] wherein A is selected from divalent alkyl, alkenyl and
alkynyl groups; wherein X is oxygen atom or sulfur atom; wherein
each r is a number independently selected from zero to four,
inclusive; wherein each of R.sup.17 through R.sup.24 is
independently selected from hydrido, alkyl, cycloalkyl,
cycloalkylalkyl, aralkyl and aryl;
[0036] wherein R.sup.6 is selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy,
aralkyl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl,
alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl,
cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptoalkyl, and
alkoxycarbonyloxy;
[0037] and wherein any of the foregoing A and R.sup.1 through
R.sup.24 groups having a substitutable position may be substituted
by one or more groups independently selected from alkyl, alkenyl,
alkynyl, aralkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, aryl, aroylalkyl, cyanoamino, alkylcarbonylalkyl,
alkoxycarbonylalkyl, aralkoxycarbonylalkyl and carboxylalkyl;
[0038] or a tautomer thereof or a pharmaceutically-acceptable salt
thereof.
[0039] An even more preferred class consists of compounds within
Formula I wherein m is one or two; wherein n is a number selected
from one to seven, inclusive;
[0040] wherein R.sup.1 is selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl,
alkylcarbonylalkyl, alkoxycarbonylalkyl, alkenyl and alkynyl;
[0041] wherein each of R.sup.2 and R.sup.3 is independently
selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, phenylalkyl, phenyl, benzoyl, phenoxy,
phenoxyalkyl, alkoxyalkyl, alkylcarbonylalkyl, alkenyl, alkynyl,
carboxyl, carboxyalkyl, alkylcarbonyloxyalkyl and
alkoxycarbonylalkyl;
[0042] wherein each of R.sup.4, R.sup.5 and R.sup.7 through
R.sup.16 is independently selected from hydrido, hydroxy, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy,
phenylalkyl, phenyl, benzoyl, phenoxy, phenoxyalkyl, alkoxyalkyl,
alkylcarbonylalkyl, alkynyl, carboxyl, carboxyalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
alkoxycarbonyloxy, and wherein each of R.sup.2 through R.sup.5 and
R.sup.7 through R.sup.16 may be further independently selected from
radicals of the formula 9
[0043] with the proviso that at least one of R.sup.12 and R.sup.16
must be selected from hydroxy, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, phenylalkyl,
phenyl, benzoyl, phenoxy, phenoxyalkyl, phenalkoxy, alkoxyalkyl,
alkylcarbonylalkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl,
alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl,
alkoxycarbonyloxy, and radicals of the formula 10
[0044] wherein A is selected from divalent alkyl, alkenyl and
alkynyl groups; wherein each r is a number independently selected
from zero to four, inclusive; wherein each of R.sup.17 through
R.sup.24 is independently selected from hydrido, alkyl, cycloalkyl,
cycloalkylalkyl, phenylalkyl and phenyl;
[0045] wherein R.sup.6 is selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy,
phenylalkyl, benzoyl, phenoxy, phenoxyalkyl, phenalkoxy,
alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,
alkenyl, alkynyl, carboxyl, carboxyalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, mercaptoalkyl and
alkoxycarbonyloxy; and wherein any of the foregoing A and R.sup.1
through R.sup.24 groups having a substitutable position may be
substituted by one or more groups independently selected from
alkyl, alkenyl, alkynyl, phenylalkyl, hydroxyalkyl, cyano,
alkoxyalkyl, cycloalkyl, cycloalkylalkyl, phenyl,
alkylcarbonylalkyl, alkoxycarbonylalkyl and carboxylalkyl;
[0046] or a tautomer thereof or a pharmaceutically-acceptable salt
thereof.
[0047] An even more highly preferred class consists of compounds
within Formula I selected from compounds of Formula II: 11
[0048] wherein m is one or two; wherein n is a number selected from
one to six, inclusive; wherein R.sup.1 is selected from hydrido,
alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl,
alkenyl and alkynyl;
[0049] wherein each of R.sup.8, R.sup.9, R.sup.10 and R.sup.12
through R.sup.16 is independently selected from hydrido, hydroxy,
alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy,
alkoxy, phenoxy, benzyloxy, and radicals of the formula 12
[0050] with the proviso that at least one of R.sup.12 and R.sup.16
must be selected from hydroxy, alkyl, hydroxyalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkyloxy, alkoxy, phenoxy, phenalkoxy, and
radicals of the formula 13
[0051] wherein A is a spacer group independently selected from one
or more groups of the formula 14
[0052] wherein each of R.sup.30 and R.sup.31 is independently
selected from hydrido, alkyl, cycloalkyl, phenyl, benzyl, hydroxy,
hydroxyalkyl, alkoxy, phenoxy, alkoxyalkyl, benzyloxy, cyano,
alkanoyl, 15
[0053] wherein each of R.sup.36, R.sup.37, R.sup.38 and R3.sup.9 is
independently selected from hydrido, alkyl and phenyl; wherein
R.sup.30 and R.sup.31 may be taken together to form oxo or
exomethylene; wherein each of R.sup.32, R.sup.33, R.sup.34 and
R.sup.35 is independently selected from hydrido, alkyl,
hydroxyalkyl and alkoxyalkyl;
[0054] wherein each of R.sup.17, R.sup.18, R.sup.19, R.sup.20,
R.sup.21, R.sup.22, R.sup.23 and R.sup.24 is independently selected
from hydrido, alkyl, cycloalkyl, cycloalkylalkyl and phenalkyl;
[0055] wherein each r is a number independently selected from zero
to four, inclusive;
[0056] wherein R.sup.6 is selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, benzyl, alkenyl and
alkynyl;
[0057] and wherein any of the foregoing A and R.sup.1, R.sup.6,
R.sup.8, R.sup.9, R.sup.10, R.sup.12 through R.sup.24 and R.sup.30
through R.sup.39 groups having a substitutable position may be
substituted by one or more groups independently selected from
alkyl, alkenyl, alkynyl, benzyl, hydroxyalkyl, alkoxyalkyl,
cycloalkyl, cycloalkylalkyl and phenyl;
[0058] or a tautomer thereof or a pharmaceutically-acceptable salt
thereof.
[0059] A more highly preferred class consists of compounds within
Formula I wherein m is one or two; wherein n is a number selected
from one to five, inclusive;
[0060] wherein R.sup.1 is selected from hydrido, alkyl,
hydroxyalkyl, alkoxyalkyl, alkenyl and alkynyl;
[0061] wherein each of R.sup.8, R.sup.9, R.sup.10 and R.sup.12
through R.sup.16 is independently selected from hydrido, hydroxy,
alkyl, hydroxyalkyl, alkoxy, and radicals of the formula 16
[0062] with the proviso that at least one of R.sup.12 and R.sup.16
must be selected from hydroxy, alkyl, hydroxyalkyl, alkoxy, and
radicals of the formula 17
[0063] wherein A is a spacer group independently selected from one
or more groups of the formula 18
[0064] wherein each of R.sup.30 and R.sup.31 is independently
selected from hydrido, alkyl, cycloalkyl, phenyl, benzyl, hydroxy,
hydroxyalkyl, alkoxy and alkoxy and alkoxyalkyl;
[0065] wherein each of R.sup.32, R R.sup.34 and R.sup.35 is
independently selected from hydrido, alkyl, hydroxyalkyl and
alkoxyalkyl; wherein each of R.sup.17, R.sup.18, R.sup.21 and
R.sup.22 is independently selected from hydrido and alkyl;
[0066] wherein each r is a number independently selected from zero
to four, inclusive;
[0067] wherein R.sup.6 is selected from hydrido, alkyl,
hydroxyalkyl, cycloalkyl, cycloalkylalkyl, benzyl, alkenyl and
alkynyl;
[0068] and wherein any of the foregoing A and R.sup.1, R.sup.6,
R.sup.8, R.sup.9, R.sup.10, R.sup.12 through R.sup.18, R.sup.21,
R.sup.22 and R.sup.30 through R.sup.35 groups having a
substitutable position may be substituted by one or more groups
independently selected from alkyl, alkenyl, alkynyl, hydroxyalkyl
and alkoxyalkyl;
[0069] or a tautomer thereof or a pharmaceutically-acceptable salt
thereof.
[0070] An even more highly preferred class consists of compounds
within Formula II wherein m is one or two; wherein n is a number
selected from one to five, inclusive; wherein R.sup.1 is selected
from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,
alkoxyalkyl, alkenyl and alkynyl; wherein R.sup.6 is selected from
loweralkyl; wherein each of R.sup.8, R.sup.9, R.sup.10 and R.sup.12
through R.sup.16 is independently selected from hydrido, hydroxy,
alkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, alkylcarbonyl,
alkoxycarbonyl, alkylcarbonylalkenyl, alkylaminocarbonyl and
alkoxyalkyl; with the proviso that at least one of R.sup.12 and
R.sup.16 must be selected from hydroxy, alkyl, hydroxyalkyl,
alkoxy, alkenyl, alkynyl, alkylcarbonyl, alkoxycarbonyl,
alkylcarbonylalkenyl, alkylaminocarbonyl and alkoxyalkyl; or a
tautomer thereof or a pharmaceutically-acceptable salt thereof.
[0071] A family of compounds of specific interest within Formula I
consists of the following compounds and pharmaceutically-acceptable
salts thereof, as follows:
[0072] methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methyla-
mino]ethyl]-4,5-dimethoxybenzoate;
[0073] ethyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylam-
ino]ethyl]-4,5-dimethoxybenzoate;
[0074] n-propyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methy-
lamino]ethyl]-4,5-dimethoxybenzoate;
[0075] n-butyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methyl-
amino]ethyl]-4,5-dimethoxybenzoate;
[0076] n-hexyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methyl-
amino]ethyl]-4,5-dimethoxybenzoate;
[0077] 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]
methylamino]ethyl]-N-(1,1-dimethylethyl)-4,5-dimethoxybenzamide;
[0078] 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]
methylamino]ethyl]-N-(1,1-dimethylethyl)-N-methyl-4,5-dimethoxybenzamide;
[0079] 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]
methylamino]ethyl]-N-(1,1-dimethylethyl)-N-ethyl-4,5-dimethoxybenzamide;
[0080] 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]
methylamino]ethyl]-N-(1,1-dimethylethyl)-N-propyl-4,5-dimethoxybenzamide;
[0081] 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]
methylamino]ethyl]-N-(1,1-dimethylethyl)-N-butyl-4,5-dimethoxybenzamide;
[0082] 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]
methylaminolethyl]-N-(1,1-dimethylethyl)-N-pentyl--4,5-dimethoxybenzamide-
;
[0083] 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]
methylamino]ethyl]-N-ethyl-4,5-dimethoxybenzamide;
[0084] 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]
methylamino]ethyl]-N-methyl-4, 5-dimethoxybenzamide;
[0085] 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]
methylamino]ethyl]-N-propyl-4,5-dimethoxybenzamide;
[0086] 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]
methylaminolethyl]-N-butyl-4,5-dimethoxybenzamide;
[0087] 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]
methylamino]ethyl]-N-pentyl-4,5-dimethoxybenzamide;
[0088]
.alpha.-[3-[[2-(4,5-dimethoxy-2-methylphenyl)ethyl]methylamino]prop-
yl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
[0089]
.alpha.-[3-[[2-(4,5-dimethoxy-2-ethylphenyl)ethyl]methylamino]propy-
l]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
[0090]
.alpha.-[3-[[2-(4,5-dimethoxy-2-propylphenyl)ethyl]methylamino]prop-
yl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
[0091]
.alpha.-[3-[[2-(4,5-dimethoxy-2-butylphenyl)ethyl]methylamino]propy-
l]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
[0092]
.alpha.-[3-[[2-(4,5-dimethoxy-2-pentylphenyl)ethyl]methylamino]prop-
yl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
[0093]
.alpha.-[3-[[2-(4,5-dimethoxy-2-methylphenyl)ethyl]methylamino]prop-
yl]-3,4,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
[0094]
.alpha.-[3-[[2-(4,5-dimethoxy-2-ethylphenyl)ethyl]methylamino]propy-
l]-3,4,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
[0095]
.alpha.-[3-[[2-(4,5-dimethoxy-2-propylphenyl)ethyl]methylamino]prop-
yl]-3,4,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
[0096]
.alpha.-[3-[[2-(4,5-dimethoxy-2-butylphenyl)ethyl]methylamino]propy-
l]-3,4,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
[0097]
.alpha.-[3-[[2-(4,5-dimethoxy-2-pentylphenyl)ethyl]methylamino]prop-
yl]-3,4,5-trimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile;
[0098] .alpha.-[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E-butenyl)
phenyl]ethyl]methylamino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)ben-
zeneacetonitrile;
[0099] .alpha.-[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E-pentenyl)
phenyl]ethyl]methylamino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)ben-
zeneacetonitrile;
[0100] .alpha.[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E-butanyl)
phenyl]ethyl]methylamino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)ben-
zeneacetonitrile;
[0101]
.alpha.-[3-[[2-[2-(hydroxymethyl)-4,5-dimethoxyphenyl]ethyl]methyla-
mino]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)
benzeneacetonitrile; and
[0102] 1-methylethyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]-
methylamino]ethyl]-4,5-dimethoxybenzoate.
[0103] The term "hydrido" denotes a single hydrogen atom (H). This
hydrido group may be attached, for example, to a oxygen atom to
form a hydroxyl group; or, as another example, two hydrido groups
may be attached to a carbon atom to form a --CH.sub.2-- group.
Where the term "alkyl" is used, either alone or within other terms
such as "hydroxyalkyl", the term "alkyl" embraces linear or
branched radicals having one to about twenty carbon atoms or,
preferably, one to about fifteen carbon atoms. For some
substituents, more preferred alkyl radicals are "lower alkyl", that
is, radicals having one to about ten carbon atoms. For some
substituents, most preferred alkyl radicals are lower alkyl
radicals having one to about five carbon atoms. The term
"cycloalkyl" embraces cyclic radicals having three to about ten
ring carbon atoms, preferably three to about six carbon atoms, such
as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The terms
"alkylol" and "hydroxyalkyl" embrace linear or branched alkyl
groups having one to about ten carbon atoms any one of which may be
substituted with one or more hydroxyl groups. The term "alkenyl"
embraces linear or branched radicals having two to about twenty
carbon atoms, preferably three to about ten carbon atoms, and
containing at least one carbon-carbon double bond, which
carbon-carbon double bond may have either cis or trans geometry
within the alkenyl moiety. The term "alkynyl" embraces linear or
branched radicals having two to about twenty carbon atoms,
preferably two to about ten carbon atoms, and containing at least
one carbon-carbon triple bond. The term "cycloalkenyl" embraces
cyclic radicals having three to about ten ring carbon atoms
including one or more double bonds involving adjacent ring carbons.
The terms "alkoxy" and "alkoxyalkyl" embrace linear or branched
oxy-containing radicals each having alkyl portions of one to about
ten carbon atoms, such as methoxy group. The term "alkoxyalkyl"
also embraces alkyl radicals having two or more alkoxy groups
attached to the alkyl radical, that is, to form monoalkoxyalkyl and
dialkoxyalkyl groups. The term "alkylthio" embraces radicals
containing a linear or branched alkyl group, of one to about ten
carbon atoms attached to a divalent sulfur atom, such as a
methythio group. The term "aryl" embraces aromatic radicals such as
phenyl, naphthyl and biphenyl. The term "aralkyl" embraces
aryl-substituted alkyl radicals such as benzyl, diphenylmethyl,
triphenylmethyl, phenylethyl, phenylbutyl and diphenylethyl. The
terms "benzyl" and "phenylmethyl" are interchangeable. The terms
"aryloxy" and "arylthio" denote, respectively, aryl groups having
an oxygen or sulfur atom through which the radical is attached to a
nucleus, examples of which are phenoxy and phenylthio. The terms
"sulfinyl" and "sulfonyl", whether used alone or linked to other
terms, denotes respectively divalent radicals SO and SO.sub.2. The
term "aralkoxy", alone or within another term, embraces an aryl
group attached to an alkoxy group to form, for example, benzyloxy.
The term "acyl" whether used alone, or within a term such as
acyloxy, denotes a radical provided by the residue after removal of
hydroxyl from an organic acid, examples of such radical being
acetyl and benzoyl. "Lower alkanoyl" is an example of a more
preferred sub-class of acyl. The term "amido" denotes a radical
consisting of nitrogen atom attached to a carbonyl group, which
radical may be further substituted in the manner described herein.
The amido radical can be attached to the nucleus of a compound of
the invention through the carbonyl moiety or through the nitrogen
atom of the amido radical. The term "alkenylalkyl" denotes a
radical having a double-bond unsaturation site between two carbons,
and which radical may consist of only two carbons or may be further
substituted with alkyl groups which may optionally contain
additional double-bond unsaturation. The term "heteroaryl" embraces
aromatic ring systems containing one or two hetero atoms selected
from oxygen, nitrogen and sulfur in a ring system having five or
six ring members, examples of which are thienyl, furanyl,
pyridinyl, thiazolyl, pyrimidyl and isoxazolyl. Such heteroaryl may
be attached as a substituent through a carbon atom of the
heteroaryl ring system, or may be attached through a carbon atom of
a moiety substituted on a heteroaryl ring-member carbon atom, for
example, through the methylene substituent of imidazolemethyl
moiety. Also, such heteroaryl may be attached through a ring
nitrogen atom as long as aromaticity of the heteroaryl moiety is
preserved after attachment.
[0104] Specific examples of alkyl groups are methyl, ethyl,
n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,
n-pentyl, isopentyl, methylbutyl, dimethylbutyl, neopentyl,
n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,
n-tridecyl, n-tetradecyl and n-hexadecyl. Typical alkenyl and
alkynyl groups may have one unsaturated bond, such as an allyl
group, or may have a plurality of unsaturated bonds, with such
plurality of bonds either adjacent, such as allene-type structures,
or in conjugation, or separated by several saturated carbons.
[0105] It is preferred that certain selections of radicals for
R.sup.1 be avoided. Radicals for R.sup.1 which should preferably be
avoided are alkyl, alkenyl and alkynyl moieties having a hydroxy,
alkoxy or double or triple bond attached to the alpha carbon of the
moiety, that is, the carbon attached to the nitrogen atom of
Formula I on which R.sup.1 is substituted. It is also preferred
that certain selections of radicals for R.sup.6 be avoided.
Radicals for R.sup.4 which should preferably be avoided are
sulfhydryl, amino and mono- and di-substituted amino.
[0106] Also included in the family of compounds of Formulas I are
isomeric forms including diastereoisomers, regioisomers and the
pharmaceutically-acceptable salts thereof. The term
"pharmaceutically-acceptable salts" embraces salts commonly used to
form alkali metal salts and to form addition salts of free acids or
free bases, including quaternary ammonium salts. The nature of the
salt is not critical, provided that it is
pharmaceutically-acceptable. Suitable pharmaceutically-acceptable
acid addition salts of compounds of Formulas I may be prepared from
an inorganic acid or from an organic acid. Examples of such
inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric,
carbonic, sulfuric and phosphoric acid. Appropriate organic acids
may be selected from aliphatic, cycloaliphatic, aromatic,
araliphatic, heterocyclic, carboxylic and sulfonic classes of
organic acids, example of which are formic, acetic, propionic,
succinic, glycolic, gluconic, lactic, malic, tartaric, citric,
ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic,
benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic,
mandelic, embonic (pamoic), methansulfonic, ethanesulfonic,
2-hydroxyethanesulfonic- , pantothenic, benzenesulfonic,
toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic,
stearic, algenic, .beta.-hydroxybutyric, malonic, galactaric and
galacturonic acid. Suitable pharmaceutically-acceptable base
addition salts of compounds of Formulas I include metallic salts
made from aluminium, calcium, lithium, magnesium, potassium, sodium
and zinc or organic salts made from N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine) and procaine. All of these salts may be
prepared by conventional means from the corresponding compound of
Formula I by reacting, for example, the appropriate acid or base
with the compound of Formula I.
[0107] Compounds of general Formula I can possess one or more
asymmetric carbon atoms and are thus capable of existing in the
form of optical isomers as well as in the form of racemic or
nonracemic mixtures thereof. The optical isomers can be obtained by
resolution of the racemic mixtures according to conventional
processes, for example by formation of diastereoisomeric salts by
treatment with an optically active acid or base. Examples of
appropriate acids are tartaric, diacetyltartaric,
dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and
then separation of the mixture of diastereoisomers by
crystallization followed by liberation of the optically active
bases from these salts. A different process for separation of
optical isomers involves the use of a chiral chromatography column
optimally chosen to maximize the separation of the enantiomers.
Still another available method involves synthesis of covalent
diastereoisomeric molecules by reacting compounds of Formula I with
an optically pure acid in an activated form or an optically pure
isocyanate. The synthesized diastereoisomers can be separated by
conventional means such as chromatography, distillation,
crystallization or sublimation, and then hydrolyzed to deliver the
enantiomerically pure compound. The optically active compounds of
Formula I can likewise be obtained by utilizing optically active
starting materials. These isomers may be in the form of a free
acid, a free base, an ester or a salt.
GENERAL SYNTHETIC PROCEDURES
[0108] Compounds embraced by Formula I may be prepared in
accordance with Scheme I, which follows, wherein each of the R
substituents are as defined in Formula I above, except where
further noted.
[0109] Synthesis of the compounds of Formula I can be achieved by
the reaction of bis-electrophile, sequentially, with two
nucleophiles (Scheme I). The bis-electrophile can be, for example,
an alkyl chain, substituted at the desired positions with a halogen
or a sulfonic acid ester or the like or by a group that can be
transformed into such an electrophile. It may be convenient, upon
treatment with a nucleophile, that the two electrophilic groups
have a differential reactivity toward nucleophilic substitution,
e.g., a chloro group and a bromo group. Examples of
bis-electrophiles are 3-bromo-chloropropane, 4-bromo-chlorobutane,
4-bromobutane-1-para-toluenesulfonate, 5-chloro-1-methyl-butane
trifluoromethanesulfonate and the like. Examples of nucleophiles
that can be reacted with the above bis-electrophiles are the anions
of aryl-propionitriles, prepared using non-nucleophilic bases, and
primary or secondary amines. Non-nucleophilic bases are, for
example, sodium hydride, potassium hydride, lithium di-iso-propyl
amide (LDA, the salt of a sterically hindered amine) and the like.
Electrophilic groups are indicated in Scheme I by E.sub.1 and
E.sub.2. 19
[0110] The following Examples 1-9 are detailed descriptions of the
methods of preparation of compounds of Formula I. These detailed
preparations fall within the scope of, and serve to exemplify, the
above described Generic Procedures which form part of the
invention. These Examples 1-9 are presented for illustrative
purposes only and are not intended as a restriction on the scope of
the invention. All parts are by weight unless otherwise
indicated.
EXAMPLE 1
[0111] 20
[0112] methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methyla-
mino]ethyl]-4,5-dimethoxybenzoate
[0113] To verapamil (4.8 g) in 110 ml benzene was added 1 eq. of
palladium acetate (2.6 g) and the mixture was stirred at r.t. for
three days. This mixture was then transferred to a gasometric
apparatus [R. F. Heck, J.A.C.S., 83, 1097 (1961)] and flushed with
carbon monoxide. To the mixture was then added methanol and after
four hours 1.5 eq. triethylamine was added. The reaction mixture
was filtered and the solvent was removed. The product was purified
on a silica gel column and 2.2 g of product was obtained. [TLC: 5%
MeOH/CHCl.sub.3; R.sub.f: 0.45, Verapamil 0.5;
C.sub.29H.sub.40N.sub.2O.sub.6; M.W. 512.65; structure was
confirmed by .sup.1HNMR; IR 1718 cm.sup.-1]
1 Calc'd. Found C 67.95 67.01 H 7.86 8.12 N 5.46 5.24
EXAMPLE 2
[0114] 21
[0115] methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methyla-
mino]ethyl]-4,5-dimethoxybenzoate,
2-hydroxy-1,2,3-propanetricarboxylic acid salt
[0116] A saturated solution of citric acid in ether was added
dropwise to the product compound of Example 1 (300 mg) in 10 ml of
ethyl ether until the resulting solution became slightly acidic.
The resulting precipitate was filtered and was washed with 5 ml of
ether twice. The precipitate when dried provided 402 mg of the
title compound (95% yield)
[0117] [m.p. 112-117.degree. C. dec.;
C.sub.35H.sub.48N.sub.2O.sub.13; M.W. 704.77].
2 Calc'd. Found C 59.65 60.11 H 6.86 7.10 N 3.97 3.99
EXAMPLE 3
[0118] 22
[0119] methyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methyla-
mino]ethyl]-4,5-dimethoxybenzoate, 2,3-dihydroxybutanedioic acid
salt;
[0120] To the product compound of Example 1 (500 mg) in 20 ml ethyl
ether was added to a saturated solution of L-tartaric acid in ether
until the resulting solution became slightly acid. The resulting
precipitate was filtered and when dried yielded 0.6 g of the title
compound [C.sub.33H.sub.46N.sub.2O.sub.12; M.W. 662.73].
3 Calc'd. Found C 59.81 60.35 H 7.00 7.01 N 4.23 4.33
EXAMPLE 4
[0121] 23
[0122]
2-[2-[]4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]et-
hyl]-N-(1,1-dimethylethyl)-4,5-dimethoxybenzamide,
2-hydroxy-1,2,3-propane- tricarboxylic acid salt
[0123] To verapamil (4.8 g in 110 ml benzene) was added 1 eq. of
palladium acetate (2.6 g). The mixture was stirred at r.t. for 3
days. The mixture was then transferred to a gasometric apparatus
and flushed with carbon monoxide. To this mixture was then added
t-butylamine. This mixture was stirred at r.t. for 4 hrs. The
mixture was then filtered and solvent was removed. The product was
purified on a silica gel column which provided 1.6 g (32% yield)
[TLC: 40:60:2 EtOAc:toluene:Et.sub.3N; R.sub.f: Verapamil, 0.4;
title compound, 0.3; IR: 1715 cm.sup.-1, 1640 cm.sup.-1, 2210
cm.sup.-1]. Then, a saturated solution of citric acid in ether was
added to 1.2 g of the free base of the title compound in 20 ml
ethyl ether until the resulting solution became slightly acidic.
The precipitate was filtered and washed with ether to provide 1.6 g
(98% yield) of title compound [m.p. 85-115.degree. C.;
C.sub.38H.sub.55N.sub.3- 0.sub.12; structure vwas confirmed by
.sup.1HNMR].
4 Cal'd. Found C 61.2 62.72 H 7.38 7.46 N 5.63 6.08
EXAMPLE 5
[0124] 24
[0125]
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]et-
hyl]-N-ethyl-4,5-dimethoxybenzamide, 2,3-dihydroxybutanedioic acid
salt
[0126] To verapamil (4.8 g in 110 ml benzene) was added 1 eq. of
palladium acetate (2.6 g). The mixture was stirred at r.t. for
three days. The mixture was then transferred to a gasometric
apparatus and flushed with carbon monoxide. To this mixture was
then added ethylamine and the mixture was stirred for four hours.
The mixture was filtered and organic solvent was removed [TLC:
40:60:2/SKB:EtOAc:Et.sub.3N; Verapamil R.sub.f 0.25, Product 0.1].
This product compound was purified on a silica gel column and was
obtained in 3.8 g 84% yield. The product compound (1.2 g) was
dissolved in 40 ml ethyl ether and a saturated solution of
L-tartaric acid was added until the resulting solution became
slightly acidic. The precipitate, when filtered and dried, yielded
1.4 g of the title compound [structure was confirmed by
.sup.1HNMR].
5 Cal'd. Found C 60.43 61.01 H 7.31 7.42 N 6.22 6.29
EXAMPLE 6
[0127] 25
[0128]
.alpha.-[3-[[2-(4,5-dimethoxy-2-methylphenyl)ethyl]methylamino]prop-
yl]-3,4-dimethoxy-.alpha.-(1-methylethyl)benzeneacetonitrile,
2,3-dihydroxybutanedioic acid salt
[0129] To verapamil (4.8 g in 110 ml benzene) was added 1 eq.
palladium acetate (2.6 g) and the mixture was stirred at r.t. for
three days. Saturated aqueous NaCl (200 ml) and acetone (20 ml)
were added to the reaction mixture which was stirred at r.t. for 15
min. The organic phase was separated and the aqueous phase was
extracted with 50 ml CH.sub.2Cl.sub.2 three times. The organic
phases were combined and the mixture was concentrated n vacuo to
about 100 ml to remove water. To the mixture was then added 10.5 g
of triphenylphosphine and the mixture was stirred at r.t. for
one-half hour. Then, the mixture was cooled to 4.degree. C., 15
mmole (1.5 eq.) of methylmagnesiumchloride was added, the mixture
was stirred at r.t. for one hour and then cooled to 4.degree. C. To
this mixture was added 10 ml of saturated aq. NH.sub.4Cl solution
dropwise. After one-half hour at r.t., the organic phase was
separated and the resulting solid dried. The desired product was
separated from verapamil by reverse phase column chromatography as
follows:
[0130] Mobile Phase: 60-40 TEAA/CH.sub.3CN Retention Time:
Verapamil 9 min. title compound, 10.4 min. A yield of 25% (1.2 g)
of the free base of the title compound was obtained. To the free
base dissolved in 50 ml ethyl ester was added a saturated solution
of tartaric acid in ether until the resulting solution was slightly
acidic. The resulting precipitate was filtered and found to have
the following analysis: [Calculated for
C.sub.28H.sub.40N.sub.2O.sub.4.C.sub.4H.sub.6O.sub.6.H.su-
b.2O]
6 Calculated Found C 60.36 60.98 H 7.60 7.40 N 4.40 4.30
[0131] NMR(CD.sub.3OD), .delta.(ppm); 0.78(d, 3H, J=6.6H.sub.2),
1.22(d, 3H, J=6.6 Hz), 1.42(m,1H), 2.10-2.30(m, 4H), 2.18(S, 3H),
2.79(S, 3H), 2.8-3.3(m, 6H), 3.76(S, 6H), 3.80(S, 3H), 3.82(S, 3H),
6.73(S, 1H), 6.75(S, 1H), 6.92-7.1(m, 1H), .sup.13CNMR(CD.sub.3OD),
.delta.(ppm); 18.8, 18.98, 19.4
EXAMPLE 7
[0132] 26
[0133] .alpha.-[3-[[2-[4.5-dimethoxy-2-(3-oxo-1E-butenyl)
phenyl]ethyl]methylaminol-propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)be-
nzeneacetonitrile
[0134] To 4 g verapamil (8.8 mmole) in 100 ml of benzene was added
to 2.2 g of palladium acetate. The mixture was stirred for four
days at room temperature. A saturated solution of NaCl in 100 ml of
water and 96 ml of acetone was added to the resulting mixture,
which was stirred at room temperature for 15 minutes. Solvent was
then removed under reduced pressure. Then, there was added to the
mixture 100 ml of toluene, 25 ml of triethylamine and 10 mmol of
methylvinylketone. The mixture was heated at 120.degree. C. for 2
hours, and then allowed to cool to room temperature. The organic
phase was filtered, washed with water, dried, filtered again and
solvent was removed. After separation by chromatography, the title
compound was obtained (3.2 g, 80%) [m.p. 119-121, from ether].
7 Calculated Found C 71.24 71.57 H 8.10 8.30 N 5.36 5.25
[0135] NMR (ppm), 0.79(d, 3H, J=6.6H), 1.18(d, 3H, J=6.6H) 2.22 (S,
3H), 2.36 (S, 3H), 6.56 (d, 1H, J=15H) 6.68(S, 1H), 6.80-6.92(m,
2H), 6.36(S, 1H) 7.08(S, 1H), 7.76(d, 1H, J=15H) 3.87(S, 3H),
3.88(S, 3H), 4.00(S, 3H), 4.01(S, 3H)
[0136] IR 3410 cm.sup.-1, 2150 cm.sup.1, 1659 cm.sup.-1, 1639
cm.sup.-1, 1593 cm.sup.-1, 1509 cm.sup.-1
EXAMPLE 8
[0137] 27
[0138]
.alpha.-[3-[[2-[2-(hydroxymethyl)-4,5-dimethoxyphenyl]ethyl]methyla-
minol]propyl]-3,4-dimethoxy-.alpha.-(1-methylethyl)
benzeneacetonitrile, 2-hydroxy-1,2,3-propanetricarboxylic acid
salt
[0139] The compound of Example 1 (471 mg, 0.92 mmole) in 3 ml of
ether was added to LiAlH.sub.4 (21.3 mg, 56 mmole) dropwise during
a 10 minute period. This mixture was stirred at r.t. for one-half
hour. Five drops of H.sub.2O was added to the mixture followed by
the addition of five drops of 15% NaOH. Finally, 12 drops of
H.sub.2O was added to this mixture and the granular precipitate was
filtered. The organic material was extracted with ethyl ether (30
ml) and was dried [TLC: 70:5:20/EtOAc: Et.sub.3N:toluene; Example 1
compound, R.sub.f 0.5, free base of title compound, R.sub.f 0.2].
The free base of the title compound was separated and purified to
provide 260 mg product (yield: 55%). This product compound was then
dissolved in 10 ml ethyl ether, a saturated solution of citric acid
was added, and then the precipitate was collected and dried
[C.sub.34H.sub.48N.sub.2O.sub.12; the assigned structure was
supported by NMR].
8 Calculated Found C 60.34 61.21 H 7.15 7.24 N 4.14 4.13
EXAMPLE 9
[0140] 28
[0141] 1-methylethyl
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]-
methylamino]ethyl]-4,5-dimethoxybenzoate
[0142] To verapamil (4.8 g in 110 ml benzene) was added 1 eq. of
palladium acetate (2.6 g). This mixture was stirred at r.t. for 3
days and then transferred to a gasometric apparatus and flushed
with carbon monoxide. To this mixture was then added 1 eq. of
isopropanol, and this mixture was stirred at r.t. for 4 hrs. Then,
1.5 eq. of trielthylamine was added to the mixture, the resulting
precipitate was filtered and the organic lager was concentrated to
dryness. The product was purified on a silica gel column using
CF.sub.3CCl.sub.3:isopropanol: NH.sub.4OH/92.5:7:05 as eluent. The
title compound was obtained as an oil [1.55 g, 60% yield, the
structure was confirmed by .sup.1HNMR analysis].
9 Calculated Found C 68.86 68.34 H 8.20 8.32 N 5.18 4.91
BIOLOGICAL EVALUATION
[0143] Assay A: Suppression of Mitogen-Stimulated Proliferation
(Murine)
[0144] It is known that lymphocyte activation can be polyclonally
stimulated by plant lectins and other mitogens that induce blast
transformation and mitosis. Certain mitogens like Concanavalin A
(ConA), preferentially activate T-lymphocytes. Exposure to ConA
results in polyclonal activation of T-cells and can be used as an
in vitro index for general immunomodulation of pan T-cell activity.
In this assay spleen cells harvested from female Balb/c mice were
incubated at 37.degree. C., in 95% air/5% CO.sub.2 atmosphere in 96
well microtiter plates (105 cells/well) for 5 days with Iscove's
modified Dulbecco's medium [25 mM HEPES 2 mM L-glutamine, 5% fetal
bovine serum and 2-mercaptoethanol (40 .mu.M)] (100 .mu.l/well),
concanavalin A (ConA) alone (Sigma, St. Louis, Mo.; 1.0 .mu.g/ml)
or ConA in the presence of test compounds (0.001-25 .mu.M).
Inhibition of ConA-stimulated proliferation was measured by
calorimetric indicator of growth and proliferation, MTT
(3-(4,5-dimethylthiazol-2-yl)-2 diphenyl tetrazolium bromide; (100
.mu.l/well, 1 mg/ml) Sigma) [Mosmann, T., J. of Immunological
Methods, 65, 55-63, 1988]. After four hours, plates were
centrifuged (1200 rpm) media supernatants aspirated and dye loaded
cells were solubilized in isopropanol (150 .mu.l/well). The
absorbance was measured on an ELISA plate reader with a test
wavelength of 570 nm and a reference of 630 nm. The IC.sub.50
values for active immunosuppressant compounds were calculated by
four parameter logistic regression analysis of the results [Delean
et al, Am. J. Physiol., 2, 397 (1978)]. Results are shown in Table
I.
[0145] Assay B: Suppression of Human Mitogen Stimulation Assay
[0146] Normal human donor peripheral blood mononuclear cells (PMNC)
were isolated by density centrifugation using Ficoll-Paque(Pharacia
LKB, Uppsala Sweden, 350 RCF 45 minutes). Cells were washed and
incubated at 37.degree. C. in 95%air/5% CO.sub.2 atmosphere in 96
well microtiter plates (2.times.10.sup.5 cells/well) for 96hrs with
RPMI 1640 medium containing 5% fetal bovine serum and
2-mercaptoethanol (40M), Phytohemagglutinin (Difco, Detroit, MI 10
.mu.g/ml) in the presence or absence of test compounds. Inhibition
of PHA stimulated proliferation was measured by reduced
incorporation of .sup.3H-thymidine (0.5 .mu.Ci/well, added during
the last 24 hours of the assay). When possible, the IC.sub.50
values for active immunosuppressant compounds were calculated by
four parameter logistic regression analysis of the results [Delean
et al, DE ]. Results are shown in Table I.
[0147] Assay C: One-Way Mixed Lymphocyte Reaction (Human)
[0148] The mixed lymphocyte reaction (MLR) is an assay that
measures T-cell blast cell transformation and mitosis which occurs
when lymphocytes from different major and minor histocompatibility
complex (MHC) haplotypes are cocultured. This response is
considered a "one-way MLR" when stimulator cells are made
unresponsive by inhibition of DNA synthesis (treatment with
mitomycin-C or gamma-irradiation) prior to coculture with responder
cells. This assay can be used as an indicator of the cellular
immunomodulation mechanisms involved in transplant rejection. In
this assay, human peripheral blood mononuclear cells(PMNC) were
used as the responder cell population and were isolated from normal
donor blood as follows: Blood samples were collected in
LeucoPREP.TM. tubes (Becton Dickinson, Lincoln Park, N.J.) and the
mononuclear cell preparation was obtained by following the
manufacturers procedures. Isolated mononuclear cells were
co-incubated at 6.times.10.sup.4 cells/well with a stimulator cell
line at 2.times.10.sup.4 cells/well in RPMI 1640 medium containing
5% fetal bovine serum and 2-mercaptoethanol (40 .mu.M). The
stimulator cell line, Raji, which was derived from a human Burkitt
lymphoma (American Type Culture Collection, Rockville Md.) was
previously inactivated by mitomycin-C treatment (Sigma, St. Louis
Mo., 25 .mu.g/ml, 370 for 30 minutes). After repeated washings of
mitomycin-C from the stimulator cell line, cocultures were
incubated in 96 well microtiter plates at 37.degree. C., in 95%
air/5% CO.sub.2 atmosphere for 120 hours in the presence or absence
of test compounds (0.1-25 .mu.M). Inhibition of proliferation was
measured by reduced incorporation of .sup.3H-thymidine (0.5
.mu.Ci/well, added during the last 24 hours of the assay). The
IC.sub.50 values for the immunosuppressant compounds were
calculated by four parameter logistic regression analysis of the
results [Delean et al, Dab] Results are shown in Table I.
10TABLE I In Vitro Suppression of Immune Response Test Compound
Assay A.sup.1 Assay B.sup.2 Assay C.sup.3 of Example # IC.sub.50
(.mu.M) IC.sub.50 (.mu.M) IC.sub.50 (.mu.M) 1 NT NT NT 2 7.1 5.4
4.3 3 8.7 5.3 NT 4 13.3 9.9 8.9 5 >25 >25 20.2 6 NT NT NT 7
7.9 NT 15.5 8 NT NT NT 9 NT NT NT NT = Not Tested .sup.1Assay A:
Suppression of Mitogen-Stimulated Proliferation (Murine)
.sup.2Assay B: Suppression of Human Mitogen Stimulation .sup.3Assay
C: One-Way Mixed Lymphocyte Reaction (Human)
[0149] Assay D: Calcium Flux Assay
[0150] One of the earliest requirements of lymphocyte activation
involves the rapid mobilization of intracellular calcium and the
sustained influx of extracellular calcium. These cellular responses
to lymphocyte activators can be measured by calcium-binding
fluorescent dyes such as Indo-1 [P. S. Rabinovitch, et al J.
Immunol, 137, 952 (1986)]. The rapid and sustained changes in
intracellular calcium can be used to discriminate classes of
immunomodulatory compounds which alter early events in lymphocyte
activation. Human mononuclear cells or the human Jurkat T-cell line
(ATCC, Rockville Md.) were loaded with the calcium-sensitive dye,
Indo-1 (5 .mu.M), washed and incubated for 2-5 minutes in the
presence or absence of test compounds. Calcium flux was initiated
in lymphocytes by the binding of crosslinked antibody to the T cell
receptor(.alpha.CD3 at 250 ng/ml followed by goat-anti-mouse IgG)
or the lectin Phytohemagglutinin (PHA, 100 ug/ml). Jurkat cell
activation was initiated by the addition of purified antibody to
the T cell receptor (.alpha.CD3, 250 ng/ml). Subsequent changes in
the concentration if intracellular calcium was monitored over time
(6 min) by flow cytometry (Epics 753, Coulter Electronics, Hialeah
Fla.) to determine modulation of the initial calcium-mediated
activation of the cells [P. S. Rabinovitch, et al, E]. Jurkat cells
were incubated in the presence of compounds of Ex. #2, #4 and #5 at
1 to 10 times the IC.sub.50 values of Assay A listed in Table I for
5 minutes prior to flow cytometry. Tested compounds within this
group inhibited the plateau phase of intracellular calcium levels
induced by stimulation at 5 to 10 times the IC.sub.50 values of
Assay A. Human mononuclear cells were incubated in the presence of
the compound of Ex. #2, #4 and #5 at 2.times., 5.times. and
10.times. values of Assay A the IC.sub.50 listed in Table I. The
compounds of Ex. #2, #4 and #5 inhibited calcium flux in a dose
dependent manner.
[0151] Assay E: Combinations of Invention Compound with Cyclosporin
A (CsA) in Inhibiting Mitogen Induced T-cell Proliferation
[0152] PHA stimulated PBM cells were cultured in a constant dose of
a compound of Formula I and with decreasing doses of CsA, starting
with the minimum dose of CsA that totally blocks proliferation (125
ng/ml). CsA doses as low as 6 ng/ml were utilized. The
concentration of the compound of Example #3 was kept constant at 5
uM, whereas the concentrations of the compounds of Example #4 and
Example #5 were kept at 25 uM. Synergism was evidenced by a
super-additive inhibition of the mitogen-induced T-cell
proliferation, by the antiproliferative effects mediated by CsA and
the compounds of the present invention. Addition of the compounds
of Formula I shifted the IC.sub.50 of CsA by 3 to 4-fold.
[0153] Assay F: Calcium Antagonist Effects
[0154] An excised aortic segment was mounted in a tissue bath
containing modified Krebs solution. After depolarization of the
tissue with K.sup.+ (100 mM), Ca.sup.++, in cumulative
concentrations of 10.sup.-3M, 3.2.times.10.sup.-3M and 10.sup.-2M,
was injected into the bath to produce vascular smooth muscle
contraction. The developed tension (g) was measured and control
dose-response values are obtained. After 1 hr incubation with a
test compound at 10.sup.-6M concentration, the same doses of
Ca.sup.++ are repeated. The log dose-response curves of control and
after treatment were analyzed by linear regression.
11 Compound Example # pA.sub.2 1 6.81 4 6.56
[0155] Assay G: Calcium Channel Blocker Effects
[0156] Under ether anesthesia, the jugular vein, femoral artery and
left ventricle of adult male SHR were cannulated. After a 3-5 hour
recovery period, animals ere treated with either test compound or
placebo. Ten minutes was allowed for steady state conditions to be
reached. Arterial pressure was then monitored via the femoral
cannula. Immediately after this measurement, the reference blood
sample was taken and radioactively-labeled microspheres were
injected into the left ventricle. Rats were then sacrificed; organs
were removed, weighed and counted. Cardiac output was computed.
Percent cardiac output distribution per gram tissue, flow per gram
tissue, and resistance times gram tissue were calculated fro the
following organs: brain, heart, kidneys, splanchnic organs (liver
plus pancreas, spleen and G. I. tract), skeletal muscle and skill.
The tested compound was administered as an I.V. bolus of 1.0 mg/kg.
Differences in mean values between treatment and control groups
were analyzed by a one-way one variable analysis and least
significant difference test. The Example #6 compound caused a
decrease of vascular resistance as follows:
12 In the brain: Compound Example #6 149 mm Hg min. g/ml Control
(DMSO) 240 mm Hg min. g/ml p < 1.05
[0157]
13 In the kidneys: Compound Example #6 22.4 mm Hg min. g/ml Control
(DMSO) 37.6 mm Hg min. g/ml p < 0.05
[0158] Assay H: Blood Pressure Reducing Effects
[0159] Systemic blood pressure effects were assessed in vivo in an
anesthetized spontaneously hypertensive rat. The test compound was
administered intragastrically at 10.sup.-3M. Initial mean arterial
blood pressure (MAP) was measured directly via a previously
implanted arterial catheter immediately before administration of
the compound. Blood pressure readings were made 1, 2, 3, and 4
hours after administration of the test compound.
14 Compound Example # Decrease in MAP (mm Hg) 4 18 5 20
[0160] Also embraced within this invention is a class of
pharmaceutical compositions comprising one or more compounds of
Formula I in association with one or more non-toxic,
pharmaceutically-acceptable carriers and/or diluents and/or
adjuvants (collectively referred to herein as "carrier" materials)
and, if desired, other active ingredients. The compounds of the
present invention may be administered to a mammalian subject, such
as a human subject, by any suitable route, preferably in the form
of a pharmaceutical composition adapted to such a route, and in a
dose effective for the treatment intended.
Therapeutically-effective doses of the compounds of the present
invention required to prevent or arrest the progress of the medical
condition are readily ascertained by one of ordinary skill in the
art. The compounds and composition may, for example, be
administered by various routes including oral, nasal, topical,
buccal and sublingual, or by parenteral administration such as
subcutaneous, intramuscular, intravenous and intradermal
routes.
[0161] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are tablets or capsules.
These may with advantage contain an amount of active ingredient
from about 1 to 250 mg, preferably from about 25 to 150 mg. A
suitable daily dose for a mammal may vary widely depending on the
condition of the patient and other factors. However, a dose of from
about 0.1 to 300 mg/kg body weight, particularly from about 1 to
100 mg/kg body weight, may be appropriate.
[0162] The active ingredient may also be administered by injection
as a composition wherein, for example, saline, dextrose or water
may be used as a suitable carrier. A suitable daily dose is from
about 0.1 to 100 mg/kg body weight injected per day in multiple
doses depending on the disease being treated. A preferred daily
dose would be from about 1 to 30 mg/kg body weight. Compounds
indicated for prophylactic therapy will preferably be administered
in a daily dose generally in a range from about 0.1 mg to about 100
mg per kilogram of body weight per day. A more preferred dosage
will be a range from about 1 mg to about 100 mg per kilogram of
body weight. Most preferred is a dosage in a range from about 1 to
about 50 mg per kilogram of body weight per day. A suitable dose
can be administered, in multiple sub-doses per day. These sub-doses
may be administered in unit dosage forms. Typically, a dose or
sub-dose may contain from about 1 mg to about 100 mg of active
compound per unit dosage form. A more preferred dosage will contain
from about 2 mg to about 50 mg of active compound per unit dosage
form. Most preferred is a dosage form containing from about 3 mg to
about 25 mg of active compound per unit dose.
[0163] The dosage regimen for treating a disease condition with the
compounds and/or compositions of this invention is selected in
accordance with a variety of factors, including the type, age,
weight, sex and medical condition of the patient, the severity of
the disease, the route of administration, and the particular
compound employed, and thus may vary widely.
[0164] For therapeutic purposes, the compounds of this invention
are ordinarily combined with one or more adjuvants appropriate to
the indicated route of administration. If administered pe Da, the
compounds may be admixed with lactose, sucrose, starch powder,
cellulose esters of alkanoic acids, cellulose alkyl esters, talc,
stearic acid, magnesium stearate, magnesium oxide, sodium and
calcium salts of phosphoric and sulfuric acids, gelatin, acacia
gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl
alcohol, and then tableted or encapsulated for convenient
administration. Such capsules or tablets may contain a
controlled-release formulation as may be provided in a dispersion
of active compound in hydroxypropylmethyl cellulose. Formulations
for parenteral administration may be in the form of aqueous or
non-aqueous isotonic sterile injection solutions or suspensions.
These solutions and suspensions may be prepared from sterile
powders or granules having one or more of the carriers or diluents
mentioned for use in the formulations for oral administration. The
compounds may be dissolved in water, polyethylene glycol, propylene
glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,
benzyl alcohol, sodium chloride, and/or various buffers. Other
adjuvants and modes of administration are well and widely known in
the pharmaceutical art.
[0165] Although this invention has been described with respect to
specific embodiments, the details of these embodiments are not to
be construed as limitations. Various equivalents, changes and
modifications may be made without departing from the spirit and
scope of this invention, and it is understood that such equivalent
embodiments are part of this invention.
* * * * *