U.S. patent number RE39,197 [Application Number 10/356,794] was granted by the patent office on 2006-07-18 for cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds.
This patent grant is currently assigned to Abbott Laboratories. Invention is credited to James T. Link, Gang Liu, Zhonghua Pei, Tom von Geldern, Martin Winn, Zhili Xin.
United States Patent |
RE39,197 |
Link , et al. |
July 18, 2006 |
**Please see images for:
( Certificate of Correction ) ** |
Cell adhesion-inhibiting antiinflammatory and immune-suppressive
compounds
Abstract
The present invention relates to novel cinnamide compounds that
are useful for treating inflammatory and immune diseases, to
pharmaceutical compositions comprising these compounds, and to
methods of inhibiting inflammation or suppressing immune response
in a mammal.
Inventors: |
Link; James T. (Evanston,
IL), Liu; Gang (Gurnee, IL), Pei; Zhonghua
(Libertyville, IL), von Geldern; Tom (Richmond, IL),
Winn; Martin (Deerfield, IL), Xin; Zhili (Lake Bluff,
IL) |
Assignee: |
Abbott Laboratories (Abbott
Park, IL)
|
Family
ID: |
22832440 |
Appl.
No.: |
10/356,794 |
Filed: |
August 29, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
09222491 |
Dec 29, 1998 |
06110922 |
Aug 29, 2000 |
|
|
Current U.S.
Class: |
514/266.3;
514/712; 514/415; 548/306.4; 549/469; 568/58; 549/362; 544/282;
544/253; 514/395 |
Current CPC
Class: |
C07D
471/10 (20130101); C07D 239/42 (20130101); C07D
235/26 (20130101); C07D 295/32 (20130101); C07D
401/04 (20130101); C07D 487/08 (20130101); C07D
265/30 (20130101); C07D 211/22 (20130101); C07D
211/26 (20130101); C07D 317/58 (20130101); C07D
241/04 (20130101); C07D 213/81 (20130101); C07D
211/54 (20130101); C07D 405/12 (20130101); C07D
405/14 (20130101); C07D 207/14 (20130101); C07D
295/13 (20130101); C07D 243/08 (20130101); C07D
491/10 (20130101); C07D 209/18 (20130101); C07D
295/185 (20130101); C07D 295/215 (20130101); A61P
29/00 (20180101); C07D 209/08 (20130101); C07D
217/06 (20130101); C07D 401/12 (20130101); C07D
295/205 (20130101); C07D 319/18 (20130101); C07D
211/60 (20130101); C07D 211/62 (20130101); C07C
323/62 (20130101); C07D 307/52 (20130101); C07D
317/62 (20130101); A61P 37/00 (20180101); A61P
37/02 (20180101); A61P 37/06 (20180101); C07D
307/68 (20130101); C07D 401/06 (20130101); C07D
207/27 (20130101); C07D 207/20 (20130101); C07D
207/22 (20130101); C07D 207/26 (20130101); C07D
319/20 (20130101); C07D 241/24 (20130101); C07D
403/12 (20130101); C07D 207/09 (20130101); C07D
211/42 (20130101); C07D 211/46 (20130101); C07D
213/74 (20130101); C07D 213/75 (20130101); C07D
215/36 (20130101); C07D 295/26 (20130101); C07D
413/14 (20130101); A61P 19/00 (20180101); C07D
413/04 (20130101); C07D 211/74 (20130101); C07C
2601/02 (20170501); C07C 2601/04 (20170501); C07C
2601/08 (20170501) |
Current International
Class: |
A61K
31/505 (20060101); A61K 31/405 (20060101); C07D
239/70 (20060101); C07D 319/00 (20060101); C07D
319/14 (20060101) |
Field of
Search: |
;514/259,395,415,712
;544/253,282 ;548/306.4 ;549/362,469 ;568/58 |
References Cited
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Disubstituted 2,3-Di[trifluoromethyl] benzenes, Organic Letters
(2000) 2(21):3345. cited by other .
International Search Report for PCT Application No. PCT US
99/31162. cited by other .
International Search Report for PCT Application No. PCT US
00/08895. cited by other.
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Primary Examiner: Shameem; Golam M. M.
Attorney, Agent or Firm: Finnegan, Henderson, Farabow,
Garrett & Dunner LLP
Claims
What is claimed is:
1. A compound of .[.the.]. formula .Iadd.I:.Iaddend. ##STR00013##
or a pharmaceutically-acceptable salt or
.Iadd.pharmaceutically-acceptable .Iaddend.prodrug .[.thereof.].
.Iadd.of a compound of formula I.Iaddend., wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are independently selected
from a. hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f.
cyano, g. nitro, .Iadd.and .Iaddend. h. carboxaldehyde, .[.and.].
with the proviso that at least one of R.sub.1 .[.or.]. .Iadd.and
.Iaddend.R.sub.3 is a "cis-cinnamide" or a "trans-cinnamide",
defined as ##STR00014## wherein R.sub.8 and R.sub.9 are .Iadd.each
.Iaddend.independently selected from a. hydrogen, and b. alkyl, c.
carboxy.[. .]. alkyl, d. alkylaminocarbonyl.[. .]. alkyl, and e.
dialkylaminocarbonyl.[. .]. alkyl, and R.sub.10 and R.sub.11 are
.Iadd.each .Iaddend.independently selected from a. hydrogen, b.
alkyl, c. cycloalkyl, d. alkoxycarbonylalkyl, e. hydroxyalkyl, and
f. heterocyclylalkyl, or where .[.NR.sub.10R.sub.11 is.].
.Iadd.R.sub.10 and R.sub.11 are taken together with the N to form
an unsubstituted .Iaddend.heterocyclyl .Iadd.group, .Iaddend.or
.Iadd.a .Iaddend.substituted heterocyclyl, .Iadd.where the
substituted heterocyclyl group is substituted by one or more than
one substituent, .Iaddend.where .Iadd.the .Iaddend.substituents are
.Iadd.each .Iaddend.independently selected from 1) alkyl, 2)
alkoxy, 3) alkoxyalkyl, 4) cycloalkyl, 5) aryl, 6) heterocyclyl, 7)
heterocyclylcarbonyl, 8) heterocyclylalkylaminocarbonyl, 9)
hydroxy, 10) hydroxyalkyl, 11) hydroxyalkoxyalkyl, 12) carboxy, 13)
carboxycarbonyl, 14) carboxaldehyde, 15) alkoxycarbonyl, 16)
arylalkoxycarbonyl, 17) aminoalkanoyl, 18) carboxamido, 19)
alkoxycarbonylalkyl, 20) carboxamidoalkyl, 21) alkanoyl, 22)
hydroxyalkanoyl, 23) alkanoyloxy, 24) alkanoylamino, 25)
alkanoyloxyalkyl, and 26) alkylsulfonyl, and wherein Ar is .Iadd.an
unsubstituted aryl group, an unsubstituted heteroaryl group,
.Iaddend.a substituted aryl .Iadd.group, .Iaddend.or .Iadd.a
.Iaddend.substituted heteroaryl group, .Iadd.where the substituted
aryl group and the substituted heteroaryl group are substituted by
one or more than one substituent, .Iaddend.where
.[.substitutions.]. .Iadd.the substituents .Iaddend.are .Iadd.each
.Iaddend.independently selected from .[.a. hydrogen,.]. .[.b.].
.Iadd.a.Iaddend.. halogen, .[.c.]. .Iadd.b.Iaddend.. alkyl, .[.d.].
.Iadd.c.Iaddend.. aryl, .[.e.]. .Iadd.d.Iaddend.. haloalkyl,
.[.f.]. .Iadd.e.Iaddend.. hydroxy, .[.g.]. .Iadd.f.Iaddend..
alkoxy, .[.h.]. .Iadd.g.Iaddend.. alkoxycarbonyl, .[.i.].
.Iadd.h.Iaddend.. alkoxyalkoxy, .[.j.]. .Iadd.i.Iaddend..
hydroxyalkyl, .[.k.]. .Iadd.j.Iaddend.. aminoalkyl, .[.l.].
.Iadd.k.Iaddend.. alkyl(alkoxycarbonylalkyl)aminoalkyl, .[.m.].
.Iadd.l.Iaddend.. .Iadd.unsubstituted .Iaddend.heterocyclylalkyl,
.[.n.]. .Iadd.m.Iaddend.. substituted heterocyclylalkyl, .[.o.].
.Iadd.n.Iaddend.. carboxaldehyde, .[.p.]. .Iadd.o.Iaddend..
carboxaldehyde hydrazone, .[.q.]. .Iadd.p.Iaddend.. carboxamide,
.[.r.]. .Iadd.q.Iaddend.. alkoxycarbonyl.[. .]. alkyl, .[.s.].
.Iadd.r.Iaddend.. hydroxycarbonylalkyl (carboxyalkyl), .[.t.].
.Iadd.s.Iaddend.. cyano, .[.u.]. .Iadd.t.Iaddend.. amino, .[.v.].
.Iadd.u.Iaddend.. heterocyclylalkylamino, and .[.w.].
.Iadd.v.Iaddend.. "trans-cinnamide", .[.or a
pharmaceutically-acceptable salt or prodrug thereof..].
.Iadd.subject to the proviso that when R.sub.3 is a "cis-cinnamide"
or a "trans-cinnamide," as defined above, one or more than one of
the following conditions is fulfilled: (A) Ar is an unsubstituted
heteroaryl group, a substituted heteroaryl group, or a substituted
aryl group wherein when Ar is a pyridyl group, Ar is substituted
and Ar is not substituted by only one alkyl group; (B) one or more
than one of R.sub.1, R.sub.2, R.sub.4, and R.sub.5, as defined
above, are other than hydrogen; and (C) R.sub.10 and R.sub.11 are
taken together with N to form a substituted or unsubstituted
heterocyclyl group, as defined above..Iaddend.
2. A compound according to claim 1 wherein R.sub.1 is a
"cis-cinnamide" or a "trans-cinnamide", and R.sub.3 is
hydrogen.
3. A compound according to claim 1 wherein R.sub.3 is a
"cis-cinnamide" or a "trans-cinnamide".[., and R.sub.1 is
hydrogen.]. .
4. A compound according to claim 1 wherein R.sub.3 is a
"cis-cinnamide" or a "trans-cinnamide", and .Iadd.one or more than
one of .Iaddend.R.sub.1, R.sub.8, and R.sub.9 are .Iadd.each
.Iaddend.hydrogen.
5. A compound according to claim 4 wherein R.sub.3 is a
"cis-cinnamide".
6. A compound according to claim 4 wherein R.sub.3 is a
"trans-cinnamide".
7. A compound according to claim 1 wherein R.sub.3 is a
"cis-cinnamide" or a "trans-cinnamide", and R.sub.1, R.sub.2, and
R.sub.4 are each independently hydrogen or alkyl; and R.sub.5 is
selected from halogen, haloalkyl, and nitro.
8. A compound according to claim 4 wherein Ar is .[.aryl,.].
.Iadd.a .Iaddend.substituted aryl .Iadd.group.Iaddend., .Iadd.an
unsubstituted .Iaddend.heteroaryl .Iadd.group.Iaddend., or .Iadd.a
.Iaddend.substituted heteroaryl .Iadd.group.Iaddend..
9. A compound according to claim 4 wherein .Iadd.one or both of
.Iaddend.R.sub.10 and R.sub.11 are each independently selected from
hydrogen, alkyl, cycloalkyl, alkoxycarbonylalkyl, hydroxyalkyl, and
heterocyclylalkyl.
10. A compound according to claim 4 wherein .[.NR.sub.10R.sub.11
is.]. .Iadd.R.sub.10 and R.sub.11 are taken together with N to form
an unsubstituted .Iaddend.heterocyclyl .Iadd.group .Iaddend.or
.Iadd.a .Iaddend.substituted heterocyclyl .Iadd.group.Iaddend..
11. A compound according to claim .[.8.]. .Iadd.4 .Iaddend.wherein
Ar is selected from substituted phenyl, 1,3-benzimidazol-2-one,
1,4-benzodioxane, 1,3-benzodioxole, 1-benzopyr-2-en-4-one, indole,
isatin, 1,3-quinazolin-4-one, and quinoline.
12. A compound according to claim 11 wherein R.sub.3 is a
"trans-cinnamide".[.; and Ar is selected from
1,3-benzimidazol-2-one, 1,4-benzodioxane, 1,3-benzodioxole,
1-benzopyr-2-en-4-one, indole, isatin, phenyl,
1,3-quinazolin-4-one, and quinoline.]. .
13. A compound according to claim 12 wherein .Iadd.one or both of
.Iaddend.R.sub.10 and R.sub.11 are .Iadd.each
.Iaddend.independently selected from hydrogen, alkyl, cycloalkyl,
alkoxycarbonylalkyl, hydroxyalkyl, and heterocyclylalkyl.
14. A compound according to claim 12 wherein .[.NR.sub.10R.sub.11
is.]. .Iadd.R.sub.10 and R.sub.11 are taken together with N to form
an unsubstituted .Iaddend.heterocyclyl .Iadd.group .Iaddend.or
.Iadd.a .Iaddend.substituted heterocyclyl .[.as described above.].
.Iadd.group.Iaddend..
15. A composition comprising a compound .[.of.]. .Iadd.according to
.Iaddend.claim 1 .[.in.]. .Iadd.and .Iaddend.a
pharmaceutically-acceptable carrier.
16. A method of inhibiting inflammation comprising the
administration of a compound of .[.claim 1.]. .Iadd.formula I
.Iaddend.to a patient.Iadd.: .Iaddend. ##STR00015## .Iadd.or a
pharmaceutically-acceptable salt or pharmaceutically-acceptable
prodrug of a compound of formula I, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, and R.sub.5 are independently selected from a.
hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano,
g. nitro, and h. carboxaldehyde, with the proviso that at least one
of R.sub.1 and R.sub.3 is a "cis-cinnamide" or a "trans-cinnamide",
defined as .Iaddend. ##STR00016## .Iadd.where R.sub.8 and R.sub.9
are each independently selected from a. hydrogen, b. alkyl, c.
carboxyalkyl, d. alkylaminocarbonylalkyl, and e.
dialkylaminocarbonylalkyl, R.sub.10 and R.sub.11 are each
independently selected from a. hydrogen, b. alkyl, c. cycloalkyl,
d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl,
or R.sub.10 and R.sub.11 are taken together with the N to form an
unsubstituted heterocyclyl group, or a substituted heterocyclyl
group, where the substituted heterocyclyl group is substituted by
one or more than one substituent, where the substituents are each
independently selected from 1) alkyl, 2) alkoxy, 3) alkoxyalkyl, 4)
cycloalkyl, 5) aryl, 6) heterocyclyl, 7) heterocyclylcarbonyl, 8)
heterocyclylalkylaminocarbonyl, 9) hydroxy, 10) hydroxyalkyl, 11)
hydroxyalkoxyalkyl, 12) carboxy, 13) carboxycarbonyl, 14)
carboxaldehyde, 15) alkoxycarbonyl, 16) arylalkoxycarbonyl, 17)
aminoalkanoyl, 18) carboxamido, 19) alkoxycarbonylalkyl, 20)
carboxamidoalkyl, 21) alkanoyl, 22) hydroxyalkanoyl, 23)
alkanoyloxy, 24) alkanoylamino, 25) alkanoyloxyalkyl, and 26)
alkylsulfonyl, and Ar is an unsubstituted aryl group, an
unsubstituted heteroaryl group, a substituted aryl group, or a
substituted heteroaryl group, where the substituted aryl group and
the substituted heteroaryl group are substituted by one or more
than one substituent, where the substituents, are each
independently selected from a. halogen, b. alkyl, c. aryl, d.
haloalkyl, e. hydroxy, f. alkoxy, g. alkoxycarbonyl, h.
alkoxyalkoxy, i. hydroxyalkyl, j. aminoalkyl, k.
alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted
heterocyclylalkyl, m. substituted heterocyclylalkyl, n.
carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q.
alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s.
cyano, t. amino, u. heterocyclylalkylamino, and v.
"trans-cinnamide".Iaddend..
17. A method of inhibiting inflammation comprising the
administration of a composition .Iadd.comprising a compound
.Iaddend.of .[.claim 15.]. .Iadd.formula I .Iaddend.to a
patient.Iadd.: .Iaddend. ##STR00017## .Iadd.or a
pharmaceutically-acceptable salt or pharmaceutically-acceptable
prodrug of a compound of formula I, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, and R.sub.5 are independently selected from a.
hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano,
g. nitro, and h. carboxaldehyde, with the proviso that at least one
of R.sub.1 and R.sub.3 is a "cis-cinnamide" or a "trans-cinnamide",
defined as .Iaddend. ##STR00018## .Iadd.where R.sub.8 and R.sub.9
are each independently selected from a. hydrogen, b. alkyl, c.
carboxyalkyl, d. alkylaminocarbonylalkyl, and e.
dialkylaminocarbonylalkyl, R.sub.10 and R.sub.11 are each
independently selected from a. hydrogen, b. alkyl, c. cycloalkyl,
d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl,
or R.sub.10 and R.sub.11 are taken together with the N to form an
unsubstituted heterocyclyl group, or a substituted heterocyclyl
group, where the substituted heterocyclyl group is substituted by
one or more than one substituent, where the substituents are each
independently selected from 1) alkyl, 2) alkoxy, 3) alkoxyalkyl, 4)
cycloalkyl, 5) aryl, 6) heterocyclyl, 7) heterocyclylcarbonyl, 8)
heterocyclylalkylaminocarbonyl, 9) hydroxy, 10) hydroxyalkyl, 11)
hydroxyalkoxyalkyl, 12) carboxy, 13) carboxycarbonyl, 14)
carboxaldehyde, 15) alkoxycarbonyl, 16) arylalkoxycarbonyl, 17)
aminoalkanoyl, 18) carboxamido, 19) alkoxycarbonylalkyl, 20)
carboxamidoalkyl, 21) alkanoyl, 22) hydroxyalkanoyl, 23)
alkanoyloxy, 24) alkanoylamino, 25) alkanoyloxyalkyl, and 26)
alkylsulfonyl, and Ar is an unsubstituted aryl group, an
unsubstituted heteroaryl group, a substituted aryl group, or a
substituted heteroaryl group, where the substituted aryl group and
the substituted heteroaryl group are substituted by one or more
than one substituent, where the substituents, are each
independently selected from a. halogen, b. alkyl, c. aryl, d.
haloalkyl, e. hydroxy, f. alkoxy, g. alkoxycarbonyl, h.
alkoxyalkoxy, i. hydroxyalkyl, j. aminoalkyl, k.
alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted
heterocyclylalkyl, m. substituted heterocyclylalkyl, n.
carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q.
alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s.
cyano, t. amino, u. heterocyclylalkylamino, and v.
"trans-cinnamide" and a pharmaceutically-acceptable
carrier.Iaddend..
18. A method of suppressing immune response comprising the
administration of a compound of .[.claim 1.]. .Iadd.formula I
.Iaddend.to a patient.Iadd.: .Iaddend. ##STR00019## .Iadd.or a
pharmaceutically-acceptable salt or pharmaceutically-acceptable
prodrug of a compound of formula I, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, and R.sub.5 are independently selected from a.
hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano,
g. nitro, and h. carboxaldehyde, with the proviso that at least one
of R.sub.1 and R.sub.3 is a "cis-cinnamide" or a "trans-cinnamide",
defined as .Iaddend. ##STR00020## .Iadd.where R.sub.8 and R.sub.9
are each independently selected from a. hydrogen, b. alkyl, c.
carboxyalkyl, d. alkylaminocarbonylalkyl, and e.
dialkylaminocarbonylalkyl, R.sub.10 and R.sub.11 are each
independently selected from a. hydrogen, b. alkyl, c. cycloalkyl,
d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl,
or R.sub.10 and R.sub.11 are taken together with the N to form an
unsubstituted heterocyclyl group, or a substituted heterocyclyl
group, where the substituted heterocyclyl group is substituted by
one or more than one substituent, where the substituents are each
independently selected from 1) alkyl, 2) alkoxy, 3) alkoxyalkyl, 4)
cycloalkyl, 5) aryl, 6) heterocyclyl, 7) heterocyclylcarbonyl, 8)
heterocyclylalkylaminocarbonyl, 9) hydroxy, 10) hydroxyalkyl, 11)
hydroxyalkoxyalkyl, 12) carboxy, 13) carboxycarbonyl, 14)
carboxaldehyde, 15) alkoxycarbonyl, 16) arylalkoxycarbonyl, 17)
aminoalkanoyl, 18) carboxamido, 19) alkoxycarbonylalkyl, 20)
carboxamidoalkyl, 21) alkanoyl, 22) hydroxyalkanoyl, 23)
alkanoyloxy, 24) alkanoylamino, 25) alkanoyloxyalkyl, and 26)
alkylsulfonyl, and Ar is an unsubstituted aryl group, an
unsubstituted heteroaryl group, a substituted aryl group, or a
substituted heteroaryl group, where the substituted aryl group and
the substituted heteroaryl group are substituted by one or more
than one substituent, where the substituents, are each
independently selected from a. halogen, b. alkyl, c. aryl, d.
haloalkyl, e. hydroxy, f. alkoxy, g. alkoxycarbonyl, h.
alkoxyalkoxy, i. hydroxyalkyl, j. aminoalkyl, k.
alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted
heterocyclylalkyl, m. substituted heterocyclylalkyl, n.
carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q.
alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s.
cyano, t. amino, u. heterocyclylalkylamino, and v.
"trans-cinnamide".Iaddend..
19. A method of suppressing immune response comprising the
administration of a composition .Iadd.comprising a compound
.Iaddend.of .[.claim 15.]. .Iadd.formula I .Iaddend.to a
patient.Iadd.: .Iaddend. ##STR00021## .Iadd.or a
pharmaceutically-acceptable salt or pharmaceutically-acceptable
prodrug of a compound of formula I, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, and R.sub.5 are independently selected from a.
hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano,
g. nitro, and h. carboxaldehyde, with the proviso that at least one
of R.sub.1 and R.sub.3 is a "cis-cinnamide" or a "trans-cinnamide",
defined as .Iaddend. ##STR00022## .Iadd.where R.sub.8 and R.sub.9
are each independently selected from a. hydrogen, b. alkyl, c.
carboxyalkyl, d. alkylaminocarbonylalkyl, and e.
dialkylaminocarbonylalkyl, R.sub.10 and R.sub.11 are each
independently selected from a. hydrogen, b. alkyl, c. cycloalkyl,
d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl,
or R.sub.10 and R.sub.11 are taken together with the N to form an
unsubstituted heterocyclyl group, or a substituted heterocyclyl
group, where the substituted heterocyclyl group is substituted by
one or more than one substituent, where the substituents are each
independently selected from 1) alkyl, 2) alkoxy, 3) alkoxyalkyl, 4)
cycloalkyl, 5) aryl, 6) heterocyclyl, 7) heterocyclylcarbonyl, 8)
heterocyclylalkylaminocarbonyl, 9) hydroxy, 10) hydroxyalkyl, 11)
hydroxyalkoxyalkyl, 12) carboxy, 13) carboxycarbonyl, 14)
carboxaldehyde, 15) alkoxycarbonyl, 16) arylalkoxycarbonyl, 17)
aminoalkanoyl, 18) carboxamido, 19) alkoxycarbonylalkyl, 20)
carboxamidoalkyl, 21) alkanoyl, 22) hydroxyalkanoyl, 23)
alkanoyloxy, 24) alkanoylamino, 25) alkanoyloxyalkyl, and 26)
alkylsulfonyl, and Ar is an unsubstituted aryl group, an
unsubstituted heteroaryl group, a substituted aryl group, or a
substituted heteroaryl group, where the substituted aryl group and
the substituted heteroaryl group are substituted by one or more
than one substituent, where the substituents, are each
independently selected from a. halogen, b. alkyl, c. aryl, d.
haloalkyl, e. hydroxy, f. alkoxy, g. alkoxycarbonyl, h.
alkoxyalkoxy, i. hydroxyalkyl, j. aminoalkyl, k.
alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted
heterocyclylalkyl, m. substituted heterocyclylalkyl, n.
carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q.
alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s.
cyano, t. amino, u. heterocyclylalkylamino, and v.
"trans-cinnamide" and a pharmaceutically-acceptable
carrier.Iaddend..
.Iadd.20. A compound according to claim 1 selected from:
(2,4-Dichlorophenyl)[2-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]s-
ulfide;
(2,4-Dichlorophenyl)[2-(E-((3-(1-imidazolyl)propylamino)carbonyl)-
ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((2-hydroxyethylamino)carbonyl)ethenyl-
)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((6-hydroxyhexylamino)carbonyl)ethenyl-
)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((bis-(2-hydroxyethyl)ainino)carbonyl)-
ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-(2-oxopyrrolidin-1-yl)propylamino)-
carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)pheny-
l]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-methylpiperazin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-pyridyl)piperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide; (2-(Hydroxymethyl)phenyl)
(2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sul-
fide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-hydroxyethyl)piperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-hydroxyethoxyethyl)piperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((3-(hydroxymethyl)piperidin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((2-(hydroxymethyl)piperidin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((3-acetamidopyrrolidin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((4-(hydroxypiperidin-1-yl)carbonyl)ethenyl-
)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((piperidin-1-yl)carbonyl)ethenyl)phenyl]su-
lfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((4-acetylhomopiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((thiomorpholin-1-yl)carbonyl)ethenyl)pheny-
l]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((4-(2-oxo,-2,3-dihydro-1H-benzimidazol-1-y-
l)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((2-tetrahydroisoquinolinyl)carbonyl)etheny-
l)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)-
phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((2-(1-morpholinyl)ethylamino)car-
bonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-phenylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((3-(2-oxopyrrolidin-1-yl)propyla-
mino)carbonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((cyclopropylamino)carbonyl)ethen-
yl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(2,4-Dichlorophenyl)2-nitro-4-(E-((3-(2-oxopyrrolidin-1-yl)propylamino)ca-
rbonyl)ethenyl)phenyl]sulfide;
(2,3-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(4-Bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide;
(4-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-butoxycarbonyl)piperazin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(2-furoylcarbonyl)piperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(methanesulfonyl)piperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonylmethyl)piperaz-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonyl)piperazin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dichlorophenyl)
(2-nitro-4-(E-((4-(carboxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl-
]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxymethyl)piperazin--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide;
(2-Chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide;
(2-Aminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide;
(2-Hydroxymethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)et-
henyl)phenyl]sulfide;
(2-Ethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide;
(2-iso-Propylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(2-tert-Butylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(2-Chlorophenyl)[2-chloro-4-(E-((4-acetylpiperain-1-yl)carbonyl))2-propen-
yl)phenyl]sulfide;
(2-(1-Morpholinylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)et-
henyl)phenyl]sulfide;
(2-(4-(1,3-Benzodioxolyl-5-methyl)piperazin-1-ylmethyl)phenyl)[2-chloro-4-
-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-(4-(iso-Propylaminocarbonylmethyl)piperazin-1-ylmethyl)phenyl)[2-chlor-
o-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-((N-Ethoxycarbonylmethyl-N-methyl)aminomethyl)phenyl)[2-chloro-4-(E-((-
1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]su-
lfide;
(2-(4-Formylpiperazin-1-ylmethyl)phenyl)[2-chloro-4-(E-((1-morphol-
inyl)carbonyl)ethenyl)phenyl]sulfide;
(2-(E-((1-Morpholinyl)carbonyl)ethenyl)phenyl)[2-chloro-4-(E-((1-morpholi-
nyl)carbonyl)ethenyl)phenyl]sulfide;
(2-Formylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide;
(2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]su-
lfide, N,N-dimethyl hydrazone;
(2-((3-(1-Morpholinyl)propyl)-1-amino)phenyl)[2-chloro-4-(E-((1-morpholin-
yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-bromo-4-(E-((3-(2-oxopyrrolidin-1-yl)propylamino)c-
arbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-formyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)pheny-
l]sulfide; and
(2-Chloro-6-formylphenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide..Iaddend.
.Iadd.21. A compound of formula I: .Iaddend. ##STR00023## .Iadd.or
a pharmaceutically-acceptable salt or pharmaceutically-acceptable
prodrug of a compound of formula I, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, and R.sub.5 are independently selected from a.
hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano,
g. nitro, and h. carboxaldehyde, with the proviso that at least one
of R.sub.1 and R.sub.3 is a "cis-cinnamide" or a "trans-cinnamide",
defined as .Iaddend. ##STR00024## .Iadd.where R.sub.8 and R.sub.9
are each independently selected from a. hydrogen, b. alkyl, c.
carboxyalkyl, d. alkylaminocarbonylalkyl, and e.
dialkylaminocarbonylalkyl, R.sub.10 and R.sub.11 are each
independently selected from a. hydrogen, b. alkyl, c. cycloalkyl,
d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl,
or R.sub.10 and R.sub.11 are taken together with the N to form an
unsubstituted heterocyclyl group, or a substituted heterocyclyl
group, where the substituted heterocyclyl group is substituted by
one or more than one substituent, where the substituents are each
independently selected from 1) alkyl, 2) alkoxy, 3) alkoxyalkyl, 4)
cycloalkyl, 5) aryl, 6) heterocyclyl, 7) heterocyclylcarbonyl, 8)
heterocyclylalkylaminocarbonyl, 9) hydroxy, 10) hydroxyalkyl, 11)
hydroxyalkoxyalkyl, 12) carboxy, 13) carboxycarbonyl, 14)
carboxaldehyde, 15) alkoxycarbonyl, 16) arylalkoxycarbonyl, 17)
aminoalkanoyl, 18) carboxamido, 19) alkoxycarbonylalkyl, 20)
carboxamidoalkyl, 21) alkanoyl, 22) hydroxyalkanoyl, 23)
alkanoyloxy, 24) alkanoylamino, 25) alkanoyloxyalkyl, and 26)
alkylsulfonyl, and Ar is an unsubstituted aryl group, an
unsubstituted heteroaryl group, a substituted aryl group, or a
substituted heteroaryl group, where the substituted aryl group and
the substituted heteroaryl group are substituted by one or more
than one substituent, where the substituents are each independently
selected from a. halogen, b. alkyl, c. aryl, d. haloalkyl, e.
hydroxy, f. alkoxy, g. alkoxycarbonyl, h. alkoxyalkoxy, i.
hydroxyalkyl, j. aminoalkyl, k.
alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted
heterocyclylalkyl, m. substituted heterocyclylalkyl, n.
carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q.
alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s.
cyano, t. amino, u. heterocyclylalkylamino, and v.
"trans-cinnamide", subject to the proviso that when R.sub.3 is a
"cis-cinnamide" or a "trans-cinnamide," as defined above, one or
more than one of the following conditions is fulfilled: (A)
R.sub.1, as defined above, is other than hydrogen; (B) R.sub.8 and
R.sub.9 are both hydrogen and Ar is not pyridyl; and (C) R.sub.10
and R.sub.11 are taken together with N to form a substituted or
unsubstituted heterocyclyl group, as defined above..Iaddend.
.Iadd.22. A compound of formula I: .Iaddend. ##STR00025## .Iadd.or
a pharmaceutically-acceptable salt or pharmaceutically-acceptable
prodrug of a compound of formula I, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4, and R.sub.5 are independently selected from a.
hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano,
g. nitro, and h. carboxaldehyde, with the proviso that at least one
of R.sub.1 and R.sub.3 is a "cis-cinnamide" or a "trans-cinnamide",
defined as .Iaddend. ##STR00026## .Iadd.where R.sub.8 and R.sub.9
are each independently selected from a. hydrogen, b. alkyl, c.
carboxyalkyl, d. alkylaminocarbonylalkyl, and e.
dialkylaminocarbonylalkyl, R.sub.10 and R.sub.11 are each
independently selected from a. hydrogen, b. alkyl, c. cycloalkyl,
d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl,
or R.sub.10 and R.sub.11 are taken together with the N to form an
unsubstituted heterocyclyl group, or a substituted heterocyclyl
group, where the substituted heterocyclyl group is substituted by
one or more than one substituent, where the substituents are each
independently selected from 1) alkyl, 2) alkoxy, 3) alkoxyalkyl, 4)
cycloalkyl, 5) aryl, 6) heterocyclyl, 7) heterocyclylcarbonyl, 8)
heterocyclylalkylaminocarbonyl, 9) hydroxy, 10) hydroxyalkyl, 11)
hydroxyalkoxyalkyl, 12) carboxy, 13) carboxycarbonyl, 14)
carboxaldehyde, 15) alkoxycarbonyl, 16) arylalkoxycarbonyl, 17)
aminoalkanoyl, 18) carboxamido, 19) alkoxycarbonylalkyl, 20)
carboxamidoalkyl, 21) alkanoyl, 22) hydroxyalkanoyl, 23)
alkanoyloxy, 24) alkanoylamino, 25) alkanoyloxyalkyl, and 26)
alkylsulfonyl, and Ar is an unsubstituted aryl group, an
unsubstituted heteroaryl group, a substituted aryl group, or a
substituted heteroaryl group, where the substituted aryl group and
the substituted heteroaryl group are substituted by one or more
than one substituent, where the substituents are each independently
selected from a. halogen, b. alkyl, c. aryl, d. haloalkyl, e.
hydroxy, f. alkoxy, g. alkoxycarbonyl, h. alkoxyalkoxy, i.
hydroxyalkyl, j. aminoalkyl, k.
alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted
heterocyclylalkyl, m. substituted heterocyclylalkyl, n.
carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q.
alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s.
cyano, t. amino, u. heterocyclylalkylamino, and v.
"trans-cinnamide", subject to the proviso that one or more than one
of the following conditions is fulfilled: (A) Ar is an
unsubstituted heteroaryl group, a substituted heteroaryl group, or
a substituted aryl group; (B) two or more than two of R.sub.1,
R.sub.2, R.sub.3, R.sub.4, and R.sub.5, as defined above, are other
than hydrogen; and (C) R.sub.10 and R.sub.11 are taken together
with N to form a substituted or unsubstituted heterocyclyl group,
as defined above..Iaddend.
.Iadd.23. A compound of formula I: .Iaddend. ##STR00027## .Iadd.or
a pharmaceutically-acceptable salt or pharmaceutically-acceptable
prodrug of a compound of formula I, wherein R.sub.1, R.sub.2,
R.sub.4, and R.sub.5 are independently selected from a. hydrogen,
b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano, g. nitro,
and h. carboxaldehyde, where R.sub.3 is a "cis-cinnamide" or
"trans-cinnamide", defined as .Iaddend. ##STR00028## .Iadd.where
R.sub.8 and R.sub.9 are each independently selected from a.
hydrogen, b. alkyl, c. carboxyalkyl, d. alkylaminocarbonylalkyl,
and e. dialkylaminocarbonylalkyl, R.sub.10 and R.sub.11 are each
independently selected from a. hydrogen, b. alkyl, c. cycloalkyl,
d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl,
or R.sub.10 and R.sub.11 are taken together with the N to form an
unsubstituted heterocyclyl group, or a substituted heterocyclyl
group, where the substituted heterocyclyl group is substituted by
one or more than one substituent, where the substituents are each
independently selected from 1) alkyl, 2) alkoxy, 3) alkoxyalkyl, 4)
cycloalkyl, 5) aryl, 6) heterocyclyl, 7) heterocyclylcarbonyl, 8)
heterocyclylalkylaminocarbonyl, 9) hydroxy, 10) hydroxyalkyl, 11)
hydroxyalkoxyalkyl, 12) carboxy, 13) carboxycarbonyl, 14)
carboxaldehyde, 15) alkoxycarbonyl, 16) arylalkoxycarbonyl, 17)
aminoalkanoyl, 18) carboxamido, 19) alkoxycarbonylalkyl, 20)
carboxamidoalkyl, 21) alkanoyl, 22) hydroxyalkanoyl, 23)
alkanoyloxy, 24) alkanoylamino, 25) alkanoyloxyalkyl, and 26)
alkylsulfonyl, and Ar is an unsubstituted heteroaryl group, a
substituted aryl group, or a substituted heteroaryl group, where
the substituted aryl group and the substituted heteroaryl group are
substituted by one or more than one substituent, where the
substituents are each independently selected from a. halogen, b.
alkyl, c. aryl, d. haloalkyl, e. hydroxy, f. alkoxy, g.
alkoxycarbonyl, h. alkoxyalkoxy, i. hydroxyalkyl, j. aminoalkyl, k.
alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted
heterocyclylalkyl, m. substituted heterocyclylalkyl, n.
carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q.
alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s.
cyano, t. amino, u. heterocyclylalkylamino, and v.
"trans-cinnamide", wherein when Ar is pyridyl, Ar is substituted by
two or more than two substituents..Iaddend.
.Iadd.24. A compound according to claim 23 where one or more than
one of R.sub.1, R.sub.2, R.sub.4, and R.sub.5 are other than
hydrogen..Iaddend.
.Iadd.25. A compound according to claim 23 where R.sub.10 and
R.sub.11 are taken together with N to form a substituted or
unsubstituted heterocyclyl group..Iaddend.
.Iadd.26. A compound of formula I: .Iaddend. ##STR00029## .Iadd.or
a pharmaceutically-acceptable salt or pharmaceutically-acceptable
prodrug of a compound of formula I, wherein R.sub.1, R.sub.2,
R.sub.4, and R.sub.5 are independently selected from a. hydrogen,
b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano, g. nitro,
and h. carboxaldehyde, subject to the proviso that one or more than
one of R.sub.1, R.sub.2, R.sub.4, and R.sub.5 are other than
hydrogen, where R.sub.3 is a "cis-cinnamide" or "trans-cinnamide",
defined as .Iaddend. ##STR00030## .Iadd.where R.sub.8 and R.sub.9
are each independently selected from a. hydrogen, b. alkyl, c.
carboxyalkyl, d. alkylaminocarbonylalkyl, and e.
dialkylaminocarbonylalkyl, R.sub.10 and R.sub.11 are each
independently selected from a. hydrogen, b. alkyl, c. cycloalkyl,
d. alkoxycarbonylalkyl, e. hydroxyalkyl, and f. heterocyclylalkyl,
or R.sub.10 and R.sub.11 are taken together with the N to form an
unsubstituted heterocyclyl group, or a substituted heterocyclyl
group, where the substituted heterocyclyl group is substituted by
one or more than one substituent, where the substituents are each
independently selected from 1) alkyl, 2) alkoxy, 3) alkoxyalkyl, 4)
cycloalkyl, 5) aryl, 6) heterocyclyl, 7) heterocyclylcarbonyl, 8)
heterocyclylalkylaminocarbonyl, 9) hydroxy, 10) hydroxyalkyl, 11)
hydroxyalkoxyalkyl, 12) carboxy, 13) carboxycarbonyl, 14)
carboxaldehyde, 15) alkoxycarbonyl, 16) arylalkoxycarbonyl, 17)
aminoalkanoyl, 18) carboxamido, 19) alkoxycarbonylalkyl, 20)
carboxamidoalkyl, 21) alkanoyl, 22) hydroxyalkanoyl, 23)
alkanoyloxy, 24) alkanoylamino, 25) alkanoyloxyalkyl, and 26)
alkylsulfonyl, and Ar is an unsubstituted aryl group, an
unsubstituted heteroaryl group, a substituted aryl group, or a
substituted heteroaryl group, where the substituted aryl group and
the substituted heteroaryl group are substituted by one or more
than one substituent, where the substituents are each independently
selected from a. halogen, b. alkyl, c. aryl, d. haloalkyl, e.
hydroxy, f. alkoxy, g. alkoxycarbonyl, h. alkoxyalkoxy, i.
hydroxyalkyl, j. aminoalkyl, k.
alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted
heterocyclylalkyl, m. substituted heterocyclylalkyl, n.
carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q.
alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s.
cyano, t. amino, u. heterocyclylalkylamino, and v.
"trans-cinnamide"..Iaddend.
.Iadd.27. A compound according to claim 26 where R.sub.10 and
R.sub.11 are taken together with N to form a substituted
heterocyclyl group or an unsubstituted heterocyclyl
group..Iaddend.
.Iadd.28. A compound of formula I: .Iaddend. ##STR00031## .Iadd.or
a pharmaceutically-acceptable salt or pharmaceutically-acceptable
prodrug of a compound of formula I, wherein R.sub.1, R.sub.2,
R.sub.4, and R.sub.5 are each independently selected from a.
hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano,
g. nitro, and h. carboxaldehyde, where R.sub.3 is a "cis-cinnamide"
or "trans-cinnamide", defined as .Iaddend. ##STR00032## .Iadd.where
R.sub.8 and R.sub.9 are each independently selected from a.
hydrogen, b. alkyl, c. carboxyalkyl, d. alkylaminocarbonylalkyl,
and e. dialkylaminocarbonylalkyl, R.sub.10 and R.sub.11 are taken
together with the N to form an unsubstituted heterocyclyl group, or
a substituted heterocyclyl group, where the substituted
heterocyclyl group is substituted by one or more than one
substituent, where the substituents are each independently selected
from 1) alkyl, 2) alkoxy, 3) alkoxyalkyl, 4) cycloalkyl, 5) aryl,
6) heterocyclyl, 7) heterocyclylcarbonyl, 8)
heterocyclylalkylaminocarbonyl, 9) hydroxy, 10) hydroxyalkyl, 11)
hydroxyalkoxyalkyl, 12) carboxy, 13) carboxycarbonyl, 14)
carboxaldehyde, 15) alkoxycarbonyl, 16) arylalkoxycarbonyl, 17)
aminoalkanoyl, 18) carboxamido, 19) alkoxycarbonylalkyl, 20)
carboxamidoalkyl, 21) alkanoyl, 22) hydroxyalkanoyl, 23)
alkanoyloxy, 24) alkanoylamino, 25) alkanoyloxyalkyl, and 26)
alkylsulfonyl, and Ar is an unsubstituted aryl group, an
unsubstituted heteroaryl group, a substituted aryl group, or a
substituted heteroaryl group, where the substituted aryl group and
the substituted heteroaryl group are substituted by one or more
than one substituent, where the substituents are each independently
selected from a. halogen, b. alkyl, c. aryl, d. haloalkyl, e.
hydroxy, f. alkoxy, g. alkoxycarbonyl, h. alkoxyalkoxy, i.
hydroxyalkyl, j. aminoalkyl, k.
alkyl(alkoxycarbonylalkyl)aminoalkyl, l. unsubstituted
heterocyclylalkyl, m. substituted heterocyclylalkyl, n.
carboxaldehyde, o. carboxaldehyde hydrazone, p. carboxamide, q.
alkoxycarbonylalkyl, r. hydroxycarbonylalkyl(carboxyalkyl), s.
cyano, t. amino, u. heterocyclylalkylamino, and v.
"trans-cinnamide"..Iaddend.
.Iadd.29. A compound according to claim 1 wherein Ar is an
unsubstituted heteroaryl group or a substituted heteroaryl group
and wherein the heteroaryl group is selected from benzimidazolyl,
benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl,
dihydroindolyl, furyl, imidazolyl, indolyl, isoquinolyl,
isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyrimidinyl, pyrimidyl, pyrrolyl,
quinolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl,
thiadiazolyl, thiazolyl, thienyl, and compounds of the formula:
.Iaddend. ##STR00033## .Iadd.wherein X* and Z* are independently
selected from --CH.sub.2--, --CH.sub.2NH--, --CH.sub.2O--, --NH--,
and --O-- with the proviso that at least one of X* and Z* is not
--CH.sub.2--, and Y* is selected from --C(O)-- and
--(C(R'').sub.2).sub.v-- where R' is hydrogen or C.sub.1-4 alkyl
and v is 1-3..Iaddend.
.Iadd.30. A compound according to claim 21, wherein Ar is an
unsubstituted heteroaryl group or a substituted heteroaryl group
and wherein the heteroaryl group is selected from benzimidazolyl,
benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl,
dihydroindolyl, furyl, imidazolyl, indolyl, isoquinolyl,
isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyrimidinyl, pyrimidyl, pyrrolyl,
quinolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl,
thiadiazolyl, thiazolyl, thienyl, and compounds of the formula:
.Iaddend. ##STR00034## .Iadd.wherein X* and Z* are independently
selected from --CH.sub.2--, --CH.sub.2NH--, --CH.sub.2O--, --NH--,
and --O-- with the proviso that at least one of X* and Z* is not
--CH.sub.2--, and Y* is selected from --C(O)-- and
--(C(R'').sub.2).sub.v-- where R' is hydrogen or C.sub.1-4 alkyl
and v is 1-3..Iaddend.
.Iadd.31. A compound according to claim 22 wherein Ar is an
unsubstituted heteroaryl group or a substituted heteroaryl group
and wherein the heteroaryl group is selected from benzimidazolyl,
benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl,
dihydroindolyl, furyl, imidazolyl, indolyl, isoquinolyl,
isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyrimidinyl, pyrimidyl, pyrrolyl,
quinolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl,
thiadiazolyl, thiazolyl, thienyl, and compounds of the formula:
.Iaddend. ##STR00035## .Iadd.wherein X* and Z* are independently
selected from --CH.sub.2--, --CH.sub.2NH--, --CH.sub.2O--, --NH--,
and --O-- with the proviso that at least one of X* and Z* is not
--CH.sub.2--, and Y* is selected from --C(O)-- and
--(C(R'').sub.2).sub.v-- where R' is hydrogen or C.sub.1-4 alkyl
and v is 1-3..Iaddend.
.Iadd.32. A compound according to claim 23 wherein Ar is an
unsubstituted heteroaryl group or a substituted heteroaryl group
and wherein the heteroaryl group is selected from benzimidazolyl,
benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl,
dihydroindolyl, furyl, imidazolyl, indolyl, isoquinolyl,
isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyrimidinyl, pyrimidyl, pyrrolyl,
quinolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl,
thiadiazolyl, thiazolyl, thienyl, and compounds of the formula:
.Iaddend. ##STR00036## .Iadd.wherein X* and Z* are independently
selected from --CH.sub.2--, --CH.sub.2NH--, --CH.sub.2O--, --NH--,
and --O-- with the proviso that at least one of X* and Z* is not
--CH.sub.2--, and Y* is selected from --C(O)-- and
--(C(R'').sub.2).sub.v-- where R' is hydrogen or C.sub.1-4 alkyl
and v is 1-3..Iaddend.
.Iadd.33. A compound according to claim 26 wherein Ar is an
unsubstituted heteroaryl group or a substituted heteroaryl group
and wherein the heteroaryl group is selected from benzimidazolyl,
benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl,
dihydroindolyl, furyl, imidazolyl, indolyl, isoquinolyl,
isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyrimidinyl, pyrimidyl, pyrrolyl,
quinolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl,
thiadiazolyl, thiazolyl, thienyl, and compounds of the formula:
.Iaddend. ##STR00037## .Iadd.wherein X* and Z* are independently
selected from --CH.sub.2--, --CH.sub.2NH--, --CH.sub.2O--, --NH--,
and --O-- with the proviso that at least one of X* and Z* is not
--CH.sub.2--, and Y* is selected from --C(O)-- and
--(C(R'').sub.2).sub.v-- where R' is hydrogen or C.sub.1-4 alkyl
and v is 1-3..Iaddend.
.Iadd.34. A compound according to claim 27 wherein Ar is an
unsubstituted heteroaryl group or a substituted heteroaryl group
and wherein the heteroaryl group is selected from benzimidazolyl,
benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl,
dihydroindolyl, furyl, imidazolyl, indolyl, isoquinolyl,
isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyrimidinyl, pyrimidyl, pyrrolyl,
quinolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl,
thiadiazolyl, thiazolyl, thienyl, and compounds of the formula:
.Iaddend. ##STR00038## .Iadd.wherein X* and Z* are independently
selected from --CH.sub.2--, --CH.sub.2NH--, --CH.sub.2O--, --NH--,
and --O-- with the proviso that at least one of X* and Z* is not
--CH.sub.2--, and Y* is selected from --C(O)-- and
--(C(R'').sub.2).sub.v-- where R' is hydrogen or C.sub.1-4 alkyl
and v is 1-3..Iaddend.
.Iadd.35. A compound according to claim 28 wherein Ar is an
unsubstituted heteroaryl group or a substituted heteroaryl group
and wherein the heteroaryl group is selected from benzimidazolyl,
benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl,
dihydroindolyl, furyl, imidazolyl, indolyl, isoquinolyl,
isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyrimidinyl, pyrimidyl, pyrrolyl,
quinolinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl,
thiadiazolyl, thiazolyl, thienyl, and compounds of the formula:
.Iaddend. ##STR00039## .Iadd.wherein X* and Z* are independently
selected from --CH.sub.2--, --CH.sub.2NH--, --CH.sub.2O--, --NH--,
and --O-- with the proviso that at least one of X* and Z* is not
--CH.sub.2--, and Y* is selected from --C(O)-- and
--(C(R'').sub.2).sub.v-- where R' is hydrogen or C.sub.1-4 alkyl
and v is 1-3..Iaddend.
Description
TECHNICAL FIELD
The present invention relates to compounds that are useful for
treating inflammatory and immune diseases, to pharmaceutical
compositions comprising these compounds, and to methods of
inhibiting inflammation or suppressing immune response in a
mammal.
BACKGROUND OF THE INVENTION
Inflammation results from a cascade of events that includes
vasodilation accompanied by increased vascular permeability and
exudation of fluid and plasma proteins. This disruption of vascular
integrity precedes or coincides with an infiltration of
inflammatory cells. Inflammatory mediators generated at the site of
the initial lesion serve to recruit inflammatory cells to the site
of injury. These mediators (chemokines such as IL-8, MCP1, MIP-1,
and RANTES, complement fragments and lipid mediators) have
chemotactic activity for leukocytes and attract the inflammatory
cells to the inflamed lesion. These chemotactic mediators which
cause circulating leukocytes to localize at the site of
inflammation require the cells to cross the vascular endothelium at
a precise location. This leukocyte recruitment is accomplished by a
process called cell adhesion.
Cell adhesion occurs through a coordinately regulated series of
steps that allow the leukocytes to first adhere to a specific
region of the vascular endothelium and then cross the endothelial
barrier to migrate to the inflamed tissue (Springer, T. A.,
.[.1994,.]. .Iadd.".Iaddend.Traffic Signals for Lymphocyte
Recirculation and Leukocyte Emigration: The Multistep Paradigm,
.[.Cell.]. .Iadd." Cell (1994) .Iaddend.76:301-314; Lawrence, M.
B., and Springer, T. A., .[.1991,.].
.Iadd.".Iaddend.Leukocytes.[.'.]. Roll on a Selectin at Physiologic
Flow Rates: Distinction from and Prerequisite for Adhesion Through
Integrins, .[.Cell..]. .Iadd." Cell (1991) .Iaddend.65:859-873; Von
Adrian, U., Chambers, J. D., McEnvoy, L. M., Bargatze, R. F.,
Arfos, K. E. and Butcher, E. C., .[.1991,.].
.Iadd.".Iaddend.Two-Step Model of Leukocyte-Endothelial Cell
Interactions in Inflammation, .[.Proc. Natl. Acad. Sci. USA.].
.Iadd." Proc. Natl. Acad. Sci. USA (1991) .Iaddend.88: 7538-7542;
and Ley, K., Gaehtgens, P., Fennie, C., Singer, M. S., Lasky, L. H.
and Rosen, S. D., .[.1991,.]. .Iadd.".Iaddend.Lectin-Like Cell
Adhesion Molecule 1 Mediates Rolling in Mesenteric Venules .[.in
vivo, Blood.]. .Iadd.In Vivo," Blood (1991) .Iaddend.77:
2553-2555). These steps are mediated by families of adhesion
molecules such as integrins, Ig supergene family members, and
selectins which are expressed on the surface of the circulating
leukocytes and on the vascular endothelial cells. The first step
consists of leukocytes rolling along the vascular endothelial cell
lining in the region of inflammation. The rolling step is mediated
by an interaction between a leukocyte surface oligosaccharide, such
as Sialylated Lewis-X antigen (Slex), and a selectin molecule
expressed on the surface of the endothelial cell in the region of
inflammation. The selectin molecule is not normally expressed on
the surface of endothelial cells but rather is induced by the
action of inflammatory mediators such as TNF-.alpha. and
interleukin-1. Rolling decreases the velocity of the circulating
leukocyte.Iadd.s .Iaddend.in the region of inflammation and allos
the cells to more firmly adhere to the endothelial cell. The firm
adhesion is accomplished by the interaction of integrin molecules
that are present on the surface of the rolling leukocytes and their
counter-receptors (the Ig superfamily molecules) on the surface of
the endothelial cell. The Ig superfamily molecules or CAMs (Cell
Adhesion Molecules) are either not expressed or are expressed at
low levels on normal vascular endothelial cells. The .[.CAM's.].
.Iadd.CAMs.Iaddend., like the selectins, are induced by the action
of inflammatory mediators like TNF-alpha and IL-1. The final event
in the adhesion process is the extravasation of leukocytes through
the endothelial cell barrier and their migration along a
chemotactic gradient to the site of inflammation. This
transmigration is mediated by the conversion of the leukocyte
integrin from a low avidity state to a high avidity state. The
adhesion process relies on the induced expression of selectins and
.[.CAM's.]. .Iadd.CAMs .Iaddend.on the surface of vascular
endothelial cells to mediate the rolling and firm adhesion of
leukocytes to the vascular endothelium.
The interaction of the intercellular adhesion molecule ICAM-1
(cd54) on endothelial cells with the integrin LFA-1 on leukocytes
plays an important role in endothelial-leukocyte contact.
Leukocytes bearing high-affinity LFA-1 adhere to endothelial cells
through interaction with ICAM-1, initiating the process of
extravasation from the vasculature into the surrounding tissues.
Thus, an agent which blocks the ICAM-1/LFA-1 interaction suppresses
these early steps in the inflammatory response. Consistent with
this background, ICAM-1 knockout mice have numerous abnormalities
in their inflammatory responses.
The present .[.invention.]. .Iadd.application .Iaddend.discloses
compounds which bind to the interaction-domain .[.(1-domain).].
.Iadd.(I-domain) .Iaddend.of LFA-1, thus interrupting endothelial
cell-leukocyte adhesion by blocking the interaction of LFA-1 with
ICAM-1, ICAM-3, and other adhesion molecules. These compounds are
useful for the treatment of prophylaxis of diseases in which
leukocyte trafficking plays a role, notably acute and chronic
inflammatory diseases, autoimmune diseases, tumor metastasis,
allograft rejection, and reperfusion injury. The compounds of this
invention are diaryl sulfides, which are substituted with a
cinnamide moiety. The cinnamide functionality may be placed either
ortho- or para- to the linking sulfur atom, although
para-substitution is preferable. Appropriate substitution of both
aromatic rings is tolerated, and can be used to modulate a variety
of biochemical, physicochemical and pharmacokinetic properties. In
particular the amide moiety is readily modified; a variety of
secondary and tertiary amides are active, and alternatively a
heterocyclic ring may be attached at this position. Modifications
of this amide functionality are particularly useful in modulating
physico-chemical and pharmacokinetic properties.
SUMMARY OF THE INVENTION
In one embodiment of the present invention are disclosed compounds
represented by structural Formula I, below, ##STR00001## or a
pharmaceutically-acceptable salt or
.Iadd.pharmaceutically-acceptable .Iaddend.prodrug .[.thereof.].
.Iadd.of a compound of Formula I.Iaddend., .[.wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are independently selected
from a. hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f.
cyano, g. nitro, h. carboxaldehyde, and.]. .[.with the proviso that
at least.]. .Iadd.where .Iaddend.one .Iadd.or both .Iaddend.of
R.sub.1 .[.or.]. .Iadd.and .Iaddend.R.sub.3.Iadd., which may be the
same or different, .Iaddend.is a "cis-cinnamide" or a
"trans-cinnamide", defined as ##STR00002## .[.wherein.].
.Iadd.where .Iaddend.R.sub.8 and R.sub.9 are .Iadd.each
.Iaddend.independently selected from a. hydrogen, .[.and.]. b.
alkyl, c. carboxy.[. .]. alkyl, d. .[.alkylaminocarbonyl alkyl.].
.Iadd.monoalkylaminocarbonylalkyl.Iaddend., and e.
dialkylaminocarbonyl.[. .]. alkyl, and R.sub.10 and R.sub.11 are
.Iadd.each .Iaddend.independently selected from a. hydrogen, b.
alkyl, c. cycloalkyl, d. alkoxycarbonylalkyl, e. hydroxyalkyl, and
f. heterocyclylalkyl, or .[.where NR.sub.10R.sub.11 is.].
.Iadd.R.sub.10 and R.sub.11 are taken together with the N to form
an unsubstituted .Iaddend.heterocyclyl .Iadd.group, .Iaddend.or
.Iadd.a .Iaddend.substituted heterocyclyl .Iadd.group, where the
substituted heterocyclyl group is substituted by one or more than
one substituent.Iaddend., where .Iadd.the .Iaddend.substituents are
.Iadd.each .Iaddend.independently selected from 1) alkyl, 2)
alkoxy, 3) alkoxyalkyl, 4) cycloalkyl, 5) aryl, 6) heterocyclyl, 7)
heterocyclylcarbonyl, 8) heterocyclylalkylaminocarbonyl, 9)
hydroxy, 10) hydroxyalkyl, 11) hydroxyalkoxyalkyl, 12) carboxy, 13)
carboxycarbonyl, 14) carboxaldehyde, 15) alkoxycarbonyl, 16)
arylalkoxycarbonyl, 17) aminoalkanoyl, 18) carboxamido, 19)
alkoxycarbonylalkyl, 20) carboxamidoalkyl, 21) alkanoyl, 22)
hydroxyalkanoyl, 23) alkanoyloxy, 24) alkanoylamino, 25)
alkanoyloxyalkyl, and 26) alkylsulfonyl, .Iadd.R.sub.1, if it is
not "cis-cinnamide" or "trans-cinnamide", as defined above,
R.sub.3, if it is not "cis-cinnamide" or "trans-cinnamide", as
defined above, R.sub.2, R.sub.4, and R.sub.5, are each
independently selected from a. hydrogen, b. halogen, c. alkyl, d.
haloalkyl, e. alkoxy, f. cyano, g. nitro, and h.
carboxaldehyde,.Iaddend. and .[.wherein.]. Ar is .Iadd.an
unsubstituted aryl group, an unsubstituted heteroaryl group,
.Iaddend.a substituted aryl .Iadd.group, .Iaddend.or .Iadd.a
.Iaddend.substituted heteroaryl group, .Iadd.where the substituted
aryl group and the substituted heteroaryl group are substituted by
one or more than one substituent, .Iaddend.where
.[.substitutions.]. .Iadd.the substituents .Iaddend.are .Iadd.each
.Iaddend.independently selected from .[.a. hydrogen,.]. .[.b..].
.Iadd.a. .Iaddend.halogen, .[.c..]. .Iadd.b. .Iaddend.alkyl,
.[.d..]. .Iadd.c. .Iaddend.aryl, .[.e..]. .Iadd.d.
.Iaddend.haloalkyl, .[.f..]. .Iadd.e. .Iaddend.hydroxy, .[.g..].
.Iadd.f. .Iaddend.alkoxy, .[.h..]. .Iadd.g.
.Iaddend.alkoxycarbonyl, .[.i..]. .Iadd.h. .Iaddend.alkoxyalkoxy,
.[.j..]. .Iadd.i. .Iaddend.hydroxyalkyl, .[.k..]. .Iadd.j.
.Iaddend.aminoalkyl, .[.l..]. .Iadd.k.
.Iaddend.alkyl(alkoxycarbonylalkyl)aminoalkyl, .[.m..]. .Iadd.l.
unsubstituted .Iaddend.heterocyclylalkyl, .[.n..]. .Iadd.m.
.Iaddend.substituted heterocyclylalkyl, .[.o..]. .Iadd.n.
.Iaddend.carboxaldehyde, .[.p..]. .Iadd.o. .Iaddend.carboxaldehyde
hydrazone, .[.q..]. .Iadd.p. .Iaddend.carboxamide, .[.r..].
.Iadd.q. .Iaddend.alkoxycarbonyl.[. .]. alkyl, .[.s..]. .Iadd.r.
.Iaddend.hydroxycarbonylalkyl.[. .]. (carboxyalkyl), .[.t..].
.Iadd.s. .Iaddend.cyano, .[.u..]. .Iadd.t. .Iaddend.amino, .[.v..].
.Iadd.u. .Iaddend.heterocyclylalkylamino, and .[.w..]. .Iadd.v.
.Iaddend."trans-cinnamide".[...]. .Iadd., subject to the proviso
that when R.sub.3 is a "cis-cinnamide" or a "trans-cinnamide," as
defined above, one or more than one of the following conditions is
fulfilled: (A) Ar is an unsubstituted heteroaryl group, a
substituted heteroaryl group, or a substituted aryl group; (B) one
or more than one of R.sub.1, R.sub.2, R.sub.4, and R.sub.5, as
defined above, are other than hydrogen; and (C) R.sub.10 and
R.sub.11 are taken together with N to form a substituted or
unsubstituted heterocyclyl group, as defined above..Iaddend.
In another embodiment of the invention are disclosed compounds
represented by structural Formula I, above, when prepared by
synthetic processes or by metabolic processes. Preparation of the
compounds of the present invention by metabolic processes include
those occurring in the human or animal body (in vivo) or by
processes occurring in vitro.
In another embodiment of the invention are disclosed methods of
treatment or prophylaxis in which the inhibition of inflammation or
suppression of immune response is desired, comprising administering
an effective amount of a compound having Formula I.
In yet another embodiment of the invention are disclosed
pharmaceutical compositions containing compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms
The term "alkanoyl" as used herein refers to an alkyl group
attached to the parent molecular group through a carbonyl
group.
The term "alkanoylamino" as used herein refers to an alkanoyl group
attached to the parent molecular group though an amino group.
The term "alkanoyloxy" as used herein refers to an alkanoyl group
attached to the parent molecular group through an oxygen
radical.
The term "alkanoyloxyalkyl" as used herein refers to an alkanoyloxy
group attached to the parent molecular group through an alkyl
group.
The term "alkoxy" as used herein refers to an alkyl group attached
to the parent molecular group through an oxygen atom.
The term "alkoxyalkoxy" as used herein refers to an alkoxy group
attached to the parent molecular group through an alkoxy group.
The term "alkoxyalkyl" as used herein refers to an alkoxy group
attached to the parent molecular group through an alkyl group.
The term "alkoxycarbonyl" as used herein refers to an alkoxy group
attached to the parent molecular group through a carbonyl
group.
The term "alkoxycarbonylalkyl" as used herein refers to an
alkoxycarbonyl group attached to the parent molecular group through
an alkyl group.
The term "alkyl" as used herein refers to a saturated straight or
branched chain .Iadd.radical .Iaddend.group of 1-10 carbon atoms
derived from an alkane by the removal of one hydrogen atom.
The term "alkyl(alkoxycarbonylalkyl)amino" as used herein refers to
an amino group substituted with one alkyl group and one
alkoxycarbonylalkyl group.
The term "alkyl(alkoxycarbonylalkyl)aminoalkyl" as used herein
refers to an alkyl(alkoxycarbonylalkyl)amino group attached to the
parent molecular group through an alkyl group.
The term "alkylene" as used herein refers to a divalent group of
1-10 carbon atoms derived from a straight or branched chain alkane
by the removal of two hydrogen atoms.
The term "alkylsulfonyl" as used herein refers to an alkyl radical
attached to the parent molecular group through an --SO.sub.2--
group.
The term "amino" as used herein refers to a radical of the form
--NR.sub.18R.sub.19, or to to a radical of the form --NR.sub.18--,
where R.sub.18 and R.sub.19 are independently selected from
hydrogen, alkyl or cycloalkyl.
The term "aminoalkanoyl" as used herein refers to to an amino group
attached to the parent molecular group through an alkanoyl
group.
The term "aminoalkyl" as used herein refers to an amino group
attached to the parent molecular group through an alkyl group.
The term "aryl" as used herein refers to a mono- or bicyclic
carbocyclic ring system having one or two aromatic rings. The aryl
group can also be fused to a cyclohexane, cyclohexene, cyclopentane
or cyclopentene ring. The aryl groups of this invention can be
optionally substituted with alkyl, halogen, hydroxy, or alkoxy
substituents.
The term "arylalkoxy" as used herein refers to an aryl group
attached to the parent molecular group through an alkoxy group.
The term "arylalkoxycarbonyl" as used herein refers to an
arylalkoxy group attached to the parent molecular group through a
carbonyl group.
The term "carboxaldehyde" as used herein refers to the radical
--CHO.
The term "carboxaldehyde hydrazone" as used herein refers to the
radical --CH.dbd.N--NR.sub.20R.sub.21, where R.sub.20 and R.sub.21
are independently selected from hydrogen, alkyl or cycloalkyl.
The terms "carboxamide" or "carboxamido" as used herein refer to an
amino group attached to the parent molecular group through a
carbonyl group.
The term "carboxamidoalkyl" as used herein refers to a carboxamido
group attached to the parent molecular group through an alkyl
group.
The term "carboxy" as used herein refers to the radical --COOH.
The term "carboxycarbonyl" as used herein refers to a carboxy group
attached to the parent molecular group through a carbonyl
group.
The term "cyano" as used herein refers to the radical --CN.
The term "cycloalkyl" as used herein refers to a monovalent
saturated cyclic or bicyclic hydrocarbon group of 3-12 carbons
derived from a cycloalkane by the removal of a single hydrogen
atom. Cycloalkyl groups may be optionally substituted with alkyl,
alkoxy, halo, or hydroxy substituents.
The terms "halo" or "halogen" as used herein refers to F, Cl, Br,
or I.
The term "haloalkyl" as used herein refers to an alkyl group
substituted with one or more halogen atoms.
The terms "heterocycle" or "heterocyclyl" represent a 4-, 5-, 6- or
7-membered ring containing one, two or three heteroatoms
independently selected from the group consisting of nitrogen,
oxygen and sulfur. The 4- and 5-membered rings have zero to two
double bonds and the 6- and 7-membered rings have zero to three
double bonds. The term "heterocycle" or "heterocyclic" as used
herein additionally refers to bicyclic, tricyclic and tetracyclic
groups in which any of the above heterocyclic rings is fused to one
or two rings independently selected from an aryl ring, a
cyclohexane ring, a cyclohexane ring, a cyclopentane ring, a
cyclopenetene ring or another monocyclic heterocyclic ring.
Heterocycles include acridinyl, benzimidazolyl, benzofuryl,
benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl,
dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl,
dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl,
imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl,
isoxazolidinyl, isoxazolyl, morpholinyl, oxadizolyl, oxazolidinyl,
oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl,
pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl,
pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl,
pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl,
tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl,
thiadiazolyl, thiazolidinyl, thiazolyl, thienyl,
thiomorpholinyl,triazolyl, and the like.
Heterocyclics also include bridged bicyclic groups where a
monocyclic heterocyclic group is bridged by an alkylene group such
as ##STR00003## and the like.
Heterocyclics also include compounds of the formula ##STR00004##
where X* and Z* are independently selected from --CH.sub.2--,
--CH.sub.2NH--, --CH.sub.2O--, --NH-- and --O--, with the proviso
that at least one of X* and Z* is not --CH.sub.2--, and Y* is
selected from --C(O)-- and --(C(R'').sub.2).sub.v--, where R'' is
hydrogen or alkyl of one to four carbons, and v is 1-3. These
heterocycles include 1,3-benzodioxolyl, 1,4-benzodioxanyl,
1,3-benzimidazol-2-one and the like. The heterocycle groups of this
invention can be optionally substituted with alkyl, halogen,
hydroxy or alkoxy substituents.
The term "heterocyclylalkyl" as used herein refers to an
heterocyclic group attached to the parent molecular group through
an alkyl group.
The term "heterocyclylalkylamino" as used herein refers to an
heterocyclylalkyl group attached to the parent molecular group
through an amino group.
The term "heterocyclylalkylaminocarbonyl" as used herein refers to
a heterocyclylalkylamino group attached to the parent molecular
group through a carbonyl group.
The term "heterocyclylcarbonyl" as used herein refers to a
heterocyclyl group attached to the parent molecular group through a
carbonyl group.
The term "hydroxyalkanoyl" as used herein refers to an hydroxy
radical attached to the parent molecular group through an alkanoyl
group.
The term "hydroxyalkoxy" as used herein refers to an hydroxy
radical attached to the parent molecular group through an alkoxy
group.
The term "hydroxyalkoxyalkyl" as used herein refers to an
hydroxyalkoxy group attached to the parent molecular group through
an alkyl group.
The term "hydroxyalkyl" as used herein refers to an hydroxy radical
attached to the parent molecular group through an alkyl group.
The term "perfluoroalkyl" as used herein refers to an alkyl group
in which all of the hydrogen atoms have been replaced by fluoride
atoms.
The term "phenyl" as used herein refers to a monocyclic carbocyclic
ring system having one aromatic ring. The phenyl group can also be
fused to a cyclohexane or cyclopentane ring. The phenyl groups of
this invention can be optionally substituted with alkyl, halogen,
hydroxy or alkoxy substituents.
The term "pharmaceutically-acceptable prodrugs" as used herein
represents those prodrugs of the compounds of the present invention
which are, within the scope of sound medical judgment, suitable for
use in contact with the tissues of humans and lower animals
.[.with.]. .Iadd.without .Iaddend.undue toxicity, irritation,
allergic response, and the like, commensurate with a reasonable
benefit/risk ratio, and effective for their intended use, as well
as the zwitterionic forms, where possible, of the compounds of the
invention.
The term "prodrug", as used herein, represents compounds which are
rapidly transformed in vivo to the parent compound of the above
formula, for example, by hydrolysis in blood. A thorough discussion
is provided in T. Higuchi and V. Stella, Pro-drugs as Novel
Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in
Edward B. Roche, ed., Bioreversible Carriers in Drug Design,
American Pharmaceutical Association and Pergamon Press, 1987, both
of which are incorporated herein by reference.
The term "thioalkoxy" as used herein refers to an alkyl group
attached to the parent molecular group through a sulfur atom.
Compounds of the present invention can exist as stereoisomers
wherein asymmetric or chiral centers are present. These compounds
are designated by the symbols "R" or "S," depending on the
configuration of substituents around the chiral carbon atom. The
present invention contemplates various stereoisomers and mixtures
thereof. Stereoisomers include enantiomers and diastereomers, and
mixtures of enantiomers or diastereomers are designated (.+-.).
Individual stereoisomers of compounds of the present invention can
be prepared synthetically from commercially available starting
materials which contain asymmetric or chiral centers or by
preparation of racemic mixtures followed by resolution well-known
to those of ordinary skill in the art. These methods of resolution
are exemplified by (1) attachment of a mixture of enantiomers to a
chiral auxiliary, separation of the resulting mixture of
diastereomers by recrystallization or chromatography and liberation
of the optically pure product from the auxiliary, (2) salt
formation employing an optically active resolving agent, or (3)
direct separation of the mixture of optical enantiomers on chiral
chromatographic columns.
Geometric isomers can also exist in the compounds of the present
invention. The present invention contemplates the various geometric
isomers and mixtures thereof resulting from the arrangement of
substituents around a carbon-carbon double bond or arrangement of
substituents around a carbocyclic ring. Substituents around a
carbon-carbon double bond are designated as being in the Z.sup.j or
E configuration wherein the term "Z" represents substituents on the
same side of the carbon-carbon double bond and the term "E"
represents substituents on opposite sides of the carbon-carbon
double bond. The arrangement of substituents around a carbocyclic
ring are designated as cis or trans wherein the term "cis"
represents substituents on the same side of the plane of the ring
and the term "trans" represents substituents on opposite sides of
the plane of the ring. Mixtures of compounds wherein the
substituents are disposed on both the same and opposite sides of
plane of the ring are designated cis/trans.
As is apparent from the foregoing descriptions, the compounds of
Formula I are useful in a variety of forms, i.e., with various
substitutions as identified. Examples of particularly desirable
compounds are quite diverse, and many are mentioned herein.
Included are compounds in which R.sub.1 is a "cis-cinnamide" or a
"trans-cinnamide", and R.sub.3 is hydrogen; or where R.sub.3 is a
"cis-cinnamide" or a "trans-cinnamide", and R.sub.1 is hydrogen, or
R.sub.1, R.sub.2, and R.sub.4 are each independently hydrogen or
alkyl, and R.sub.5 is halogen, haloalkyl or nitro. Further
preferred compounds include those as above wherein R.sub.10 and
R.sub.11 are each in dependently hydrogen, alkyl, cycloalkyl,
alkoxycarbonylaalkyl, hydroxyalkyl, or heterocyclylalkyl, or where
NR.sub.10R.sub.11, is heterocyclyl or substituted heterocyclyl, and
where Ar is aryl, substituted aryl, heteroaryl, or substituted
heteroaryl.
Compounds of the present invention include, but are not limited to:
(2,4-Dichlorophenyl)[2-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]s-
ulfide;
(2,4-Dichlorophenyl)[2-E-((3-(1-imidazolyl)propylamino)carbonyl)et-
henyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((2-hydroxyethylamino)carbonyl)ethenyl-
)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((6-hydroxyhexylamino)carbonyl)ethenyl-
)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((bis-(2-hydroxyethyl)amino)carbonyl)e-
thenyl)phenyl]sulfide;
.[.(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-(1-pyrrolidin-2-only)propylamin-
o)carbonyl)ethenyl)phenyl]sulfide;.].
.Iadd.(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-(2-oxopyrrolidin-1-yl)propyl-
amino)carbonyl)ethenyl)phenyl]sulfide;.Iaddend.
(2,4-Dichlorophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)pheny-
l]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-methylpiperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-pyridyl)piperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
(2-(Hydroxymethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)-
phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sul-
fide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-hydroxyethyl)piperazin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-hydroxyethoxyethyl)piperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((3-(hydroxymethyl)piperidin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((2-(hydroxymethyl)piperidin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((3-acetamidopyrrolidin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((4-(hydroxypiperidin-1-yl)carbonyl)ethenyl-
)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((piperidin-1-yl)carbonyl)ethenyl)phenyl]su-
lfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((4-acetylhomopiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((thiomorpholin-1-yl)carbonyl)ethenyl)pheny-
l]sulfide;
.[.(2-Bromophenyl)[2-chloro-4-(E-((4-(1-benzimidazol-2-only)pip-
eridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;.].
.Iadd.(2-Bromophenyl)2-chloro-4-(E-((4-(2-oxo-2,3-dihydro-1H-benzimidazol-
-1-yl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;.Iaddend.
(2-Bromophenyl)[2-chloro-4-(E-((2-tetrahydroisoquinolinyl)carbonyl)etheny-
l)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)-
phenyl]sulfide;
.[.(2-Methyliphenyl)[2-trifluoromethyl-4-(E-((2-(-morpholinyl)ethylamino)-
carbonyl)ethenyl)phenyl]sulfide;.].
.Iadd.(2-Methylphenyl)[2-trifluoromethyl-4-(E-((2-(1-morpholinyl)ethylami-
no)carbonyl)ethenyl)phenyl]sulfide;.Iaddend.
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-phenylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
.[.(2-Methylphenyl)[2-trifluoromethyl-4-(E-((3-(1-pyrrolidin-2-only)propy-
lamino)carbonyl)ethenyl)phenyl]sulfide;.].
.Iadd.(2-Methylphenyl)[2-trifluoromethyl-4-(E-((3-(2-oxopyrrolidin-1-yl)p-
ropylamino)carbonyl)ethenyl)phenyl]sulfide;.Iaddend.
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((cyclopropylamino)carbonyl)ethen-
yl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
.[.(2,4-Dichlorophenyl)[2-nitro-4-(E-((3-(1-pyrrolidin-2-only)propylamino-
)carbonyl)ethenyl)phenyl]sulfide;.].
.Iadd.(2,4-Dichlorophenyl)2-nitro-4-(E-((3-(2-oxopyrrolidin-1-yl)propylam-
ino)carbonyl)ethenyl)phenyl]sulfide;.Iaddend.
(2,3-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(4-Bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide;
(4-Methylphenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)-
phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-butoxycarbonyl)piperazin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(2-furoylcarbonyl)piperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(methanesulfonyl)piperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonylmethyl)piperaz-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonyl)piperazin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-tert-butoxycarbonylmethyl)piperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxycarbonyl)piperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxymethyl)piperazin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide;
(2-Chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide;
(2-Aminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide;
(2-Hydroxymethyl)phenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide;
(2-Ethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide;
(2-iso-Propylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(2-tert-Butylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(2-Chlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl))2-prope-
nyl)phenyl]sulfide;
(2-(1-Morpholinylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)et-
henyl)phenyl]sulfide;
(2-(4-(1,3-Benzodioxolyl-5-methyl)piperazin-1-ylmethyl)phenyl)[2-chloro-4-
-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-(4-(iso-Propylaminocarbonylmethyl)piperazin-1-ylmethyl)phenyl)[2-chlor-
o-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-((N-Ethoxycarbonylmethyl-N-methyl)aminomethyl)phenyl)[2-chloro-4-(E-((-
1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]su-
lfide;
(2-(4-Formylpiperazin-1-ylmethyl)phenyl)[2-chloro-4-(E-((1-morpholi-
nyl)carbonyl)ethenyl)phenyl]sulfide;
(2-(E-((1-Morpholinyl)carbonyl)ethenyl)phenyl)[2-chloro-4-(E-((1-morpholi-
nyl)carbonyl)ethenyl)phenyl]sulfide;
(2-Formylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide;
(2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]su-
lfide, N,N-dimethyl hydrazone;
(2-((3-(1-Morpholinyl)propyl)-1-amino)phenyl)[2-chloro-4-(E-((1-morpholin-
yl)carbonyl)ethenyl)phenyl]sulfide;
.[.(2,4-Dichlorophenyl)[2-bromo-4-(E-((3-(1-pyrrolidin-2-only)propylamino-
)carbonyl)ethenyl)phenyl]sulfide;.].
.Iadd.(2,4-Dichlorophenyl)[2-bromo-4-(E-((3-(2-oxopyrrolidin-1-yl)propyla-
mino)carbonyl)ethenyl)phenyl]sulfide;.Iaddend.
(2,4-Dichlorophenyl)[2-formyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)pheny-
l]sulfide; and
(2-Chloro-6-formylphenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide. Pharmaceutical Compositions and Methods of
Treatment
The present invention also provides pharmaceutical compositions
which comprise compounds of the present invention formulated
together with one or more pharmaceutically-acceptable carriers.The
pharmaceutical compositions may be specially formulated for oral
administration in solid or liquid form, for parenteral injection,
or for rectal administration.
The pharmaceutical compositions of this invention can be
administered to humans and other animals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments, or drops), bucally, or as an
oral or nasal spray. The term "parenteral" administration as used
herein refers to modes of administration which include intravenous,
intramuscular, intraperitoneal, intrasternal, subcutaneous and
intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral
injection comprise pharmaceutically-acceptable sterile aqueous or
nonaqueous solutions, dispersions, suspensions or emulsions as well
as sterile powders for reconstitution into sterile injectable
solutions or dispersions just prior to use. Examples of suitable
aqueous and nonaqueous carriers, diluents, solvents or vehicles
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils (such as olive oil), and injectable organic
esters such as ethyl oleate. Proper fluidity can be maintained, for
example, by the use of coating materials such as lecithin, by the
maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as
.[.preservative.]. .Iadd.preservatives.Iaddend., wetting agents,
emulsifying agents, and dispersing agents. Prevention of the action
of microorganisms may be ensured by the inclusion of various
antibacterial and antifungal agents, for example, paraben,
chlorobutanol, phenol sorbic acid, and the like. It may also be
desirable to include isotonic agents such as sugars, sodium
chloride, and the like.[.,.]. .Iadd.. .Iaddend.Prolonged absorption
of the injectable pharmaceutical form may be brought about by the
inclusion of agents which delay absorption such as aluminum
monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This may be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices
of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly (orthoesters) and poly(anhydrides). Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
The injectable formulations can be sterilized, for example, by
filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically-acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or (a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
(b) binders such as, for example, carboxymethylcellulose,
alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c)
humectants such as glycerol, (d) disintegrating agents such as
agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain silicates, and sodium carbonate, (e) solution
retarding agents such as paraffin, (f) absorption accelerators such
as quaternary ammonium compounds, (g) wetting agents such as, for
example, cetyl alcohol and glycerol monostearate, (h) absorbents
such as kaolin and bentonite clay, and (.[.I.]. .Iadd.i.Iaddend.)
lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and
granules can be prepared with coatings and shells such as enteric
coatings and other coatings well known in the pharmaceutical
formulating art. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions which can be used include polymeric
substances and waxes.
The active compounds can also be in micro-encapsulated form, if
appropriate, with one or more of the above-mentioned
excipients.
Liquid dosage forms for oral administration include
pharmaceutically-acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid
dosage forms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents
and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures
thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifing and suspending agents,
sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain
suspending agents as, for example, ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol and sorbitan esters, microcrystalline
cellulose, aluminum metahydroxide, bentonite, agar-agar, and
tragacanth, and mixtures thereof.
Compositions for rectal or vaginal administration are preferably
suppositories which can be prepared by mixing the compounds of this
invention with suitable non-irritating excipients or carriers sucha
s cocoa butter, polyethylene glycol or a suppository wax which are
solid at room temperature but liquid at body temperature and
therefore melt in the rectum or vaginal cavity and release the
active compound.
Compounds of the present invention can also be administered in the
form of liposomes. As is known in the art, liposomes are generally
derived from phospholipids or other lipid substances. Liposomes are
formed by mono- or multi-lamellar hydrated liquid crystals that are
dispersed in an aqueous medium. Any non-toxic,
physiologically-acceptable and metabolizable lipid capable of
forming liposomes can be used. The present compositions in liposome
form can contain, in addition to a compound of the present
invention, stabilizers, preservatives, excipients, and the like.
The preferred lipids are the phospholipids and the phosphatidyl
cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example,
Prescott, Ed., Methods in Cell Biology Volume XIV, Academic Press,
New York, N.Y. (1976), p. 33 et seq.
The compounds of the present invention may be used in the form of
pharmaceutically-acceptable salts derived from inorganic or organic
acids. By "pharmaceutically-acceptable salt" is meant those salts
which are, within the scope of sound medical judgment, suitable for
use in contact with the tissues of humans and lower animals without
undue toxicity, irritation, allergic response and the like, and are
commensurate with a reasonable benefit/risk ratio.
Pharmaceutically-acceptable salts are well-known in the art. For
example, S. M. Berge, et al. .[.Describe.]. .Iadd., describe
.Iaddend.pharmaceutically-acceptable salts in detail in .[.J.
Pharmaceutical Sciences.]. , .Iadd.J. Pharmaceutical Sciences
(1977) .Iaddend..[.1977,.]. 66; 1 et seq. The salts may be prepared
.[.in situ.]. .Iadd.in situ .Iaddend.during the final isolation and
purification of the compounds of the invention or separately by
reacting a free base function with a suitable acid. Representative
acid addition salts include, but are not limited to acetate,
adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,
glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate
(isethionate), lactate, maleate, methanesulfonate, nicotinate,
2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, phosphate, glutamate, bicarbonate,
p-toluenesulfonate and undecanoate. Also, the basic
nitrogen-containing groups can be quaternized with such agents as
lower alkyl halides such as methyl, ethyl, propyl, and butyl
chlorides, bromides and iodides; dialkyl sulfates like dimethyl,
diethyl, dibutyl and diamyl sulfates; long chain halides such as
decyl, lauryl, myristyl and stearyl chlorides, bromides and
iodides; arylalkyl halides like benzyl and phenethyl bromides and
others. .[.Water.]. .Iadd.Water-soluble, .Iaddend.or
oil-soluble.Iadd., .Iaddend.or dispersible products are thereby
obtained. Examples of acids which may be employed to form
pharmaceutically acceptable acid addition salts include such
inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric
acid and phosphoric acid and such organic acids as oxalic acid,
maleic acid, succinic acid and citric acid.
Basic addition salts can be prepared .[.in situ.]. .Iadd.in situ
.Iaddend.during the final isolation and purification of compounds
of this invention by reacting a carboxylic acid-containing moiety
with a suitable base such as the hydroxide, carbonate or
bicarbonate of a pharmaceutically acceptable metal cation or with
ammonia or an organic primary, secondary or tertiary amine.
Pharmaceutically-acceptable basic addition salts include, but are
not limited to, cations based on alkali metals or alkaline earth
metals such as lithium, sodium, potassium, calcium, magnesium
.[.and.]. .Iadd., .Iaddend.aluminum .[.salts.]. and the like and
nontoxic quaternary ammonia and amine cations including ammonium,
tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, diethylamine,
ethylamine and the like. Other representative organic amines useful
for the formation of base addition salts include ethylenediamine,
ethanolamine, diethanolamine, piperidine, piperazine and the
like.
Dosage forms for topical administration of a compound of this
invention include powders, sprays, ointments and inhalants. The
active compound is mixed under sterile conditions with a
pharmaceutically-acceptable carrier and any needed preservatives,
buffers, or propellants which may be required. Opthalmic
formulations, eye ointments, powders and solutions are also
contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical
compositions of this invention may be varied so as to obtain an
amount of the active compound(s) that is effective to achieve the
desired therapeutic response for a particular patient,
compositions, and mode of administration. The selected dosage level
will depend upon the activity of the particular compound, the route
of administration, the severity of the condition being treated, and
the condition and prior medical history of the patient being
treated. However, it is within the skill of the art to start doses
of the compound at levels lower than required for to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved.
Generally dosage levels of about 0.1 to about 50 mg, more
preferably of about 5 to about 20 mg of active compound per
kilogram of body weight per day are administered orally or
intravenously to a mammalian patient. If desired, the effective
daily dose may be divided into multiple doses for purposes of
administration, e.g. two to four separate doses per day.
Preparation of Compounds of this Invention
The compounds and processes of the present invention may be better
understood in connection with the following synthetic schemes which
illustrate the methods by which the compounds of the invention can
be prepared. ##STR00005## ##STR00006##
Scheme 1 describes the synthesis of a typical cinnamide-substituted
diaryl sulfide 4 through an aldehyde intermediate 2. Aldehyde 2 is
prepared by reaction of a thiophenol (for example
2,4-dichlorothiophenol, 2-bromothiophenol, or the like) with
halo-substituted benzaldehyde derivative 1 (e.g.
2-chlorobenzaldehyde, 3-chloro,4-fluorobenzaldehyde, or the like)
in the presence of base (e.g. sodium carbonate, triethylamine, or
the like) and a polar solvent (e.g. dimethylformamide,
dimethylsulfoxide, or the like). The aldehyde group is homologated
to the corresponding cinnamic acid 3, using an acetate equivalent
(for example, malonic acid, triethoxyphosphonoacetate, or the like)
in the presence of an appropriate base and solvent. In some cases,
it may be necessary to hydrolyze an intermediate ester (for example
using sodium hydroxide in alcohol). The acid group is activated
(for example using thionyl chloride, or dicyclohexylcarbodiimide
and N-hydroxysuccinimide, or the like) and reacted with a primary
or secondary amine (for example, 6-aminohexanol,
pyrrolidone-3-propylamine, or the like) to provide the desired
analog 4. In one variant, a haloacetophenone can replace
benzaldehyde 2; the resultant cinnamides 4 are substituted with a
methyl group at the 3-position. ##STR00007## ##STR00008##
Alternatively, the order of these coupling steps may be reversed
(Scheme 2). A substituted halocinnamic acid 5 (e.g.
3-chloro,2-nitrocinnamic acid or the like) may be coupled with a
primary or secondary amine (e.g. N-acetylpiperazine or the like) as
described above to give the corresponding amide 6. The halo-group
can then be displaced with a substituted thiophenol in the presence
of base to provide the product 7. ##STR00009##
A number of the compounds described herein may be prepared from
intermediate benzylic alcohols like 8 (Scheme 3) Activation of the
alcohol moiety (for example, using phosphorus tribromide or
methanesulfonyl chloride and lithium halide in dimethylformamide)
and displacement with a primary or secondary amine (e.g.
morpholine, N-formylpiperazine or the like) provides analogs with
structures related to 9. Alternatively the alcohol may be oxidized
(for example using TPAP or PCC or the like) to give aldehyde 10.
##STR00010##
Cinnamides like 13 may be prepared from halo-substituted
derivatives 11 by palladium-mediated coupling [e.g. using tetrakis
(o-tolyl phosphine) palladium (0), Pd.sub.2 (dba).sub.3, or the
like] with acrylamide derivatives 12 (Scheme 4). In similar manner,
anilino-cinnamides like 16 can be prepared by palladium-mediated
coupling of amines 15 with halo-cinnamides 14. ##STR00011##
In some cases, functional groups on the aromatic rings can be
modified to produce new analogs (Scheme 5). For example, a nitro
group in compounds like 17 may be reduced (for example, with
tin(II) chloride, or by catalytic hydrogenation, or the like) to
the corresponding amine 18. This amine may then itself be converted
to a halogen, for example by diazotization using nitrous acid or
t-butyl nitrite in the presence of a metal halide salt like cupric
bromide, providing analog 19. ##STR00012##
It is also possible to assemble cinnamide-substituted diaryl
sulfides in a "reverse" sense (Scheme 6). Thus, for example,
compound 20, prepared as described in Scheme 1, may be deprotected
by treatment with base (e.g. potassium t-butoxide or the like) to
provide thiolate anion 21, which may be reacted with an activated
haloarene (e.g. 2,3-dichlorobenzaldehyde,
3-chloro,4-fluorobenzaldehyde or the like) to provide the
corresponding product 22.
The compounds and processes of the present invention will be better
understood in connection with the following examples which are
intended as an illustration of and not a limitation upon the scope
of the invention.
EXAMPLE 1
(2,4-Dichlorophenyl)[2-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]su-
lfide
EXAMPLE 1A
2-[(2,4-Dichlorophenyl)thio]benzaldehyde
To a stirred solution of 2,4-dichlorothiophenol (2.0 g, 11.2 mmol)
in 25 mL of anhydrous DMF was added potassium carbonate (3.09 g,
22.4 mmol), followed by 2-chlorobenzaldehyde (1.26 mL, 11.3 mmol).
The mixture was then heated under nitrogen atmosphere at 70.degree.
C. for 5 hours. The reaction mixture was then allowed to cool to
room temperature and partitioned between ether and water. The
aqueous layer was extracted with ether once and the combined
organic layer was washed with water and brine, dried over sodium
sulfate and condensed in vacuo. The crude product was purified via
silica gel flash chromatography, eluting with 5-10% ether/hexanes,
to give 2.62 g (9.25 mmol, 83%) of the desired aldehyde as a
colorless oil, which solidified slowly upon standing at room
temperature.
EXAMPLE 1B
trans-2-[(2,4-Dichlorophenyl)thio]cinnamic acid
A mixture of the aldehyde (1.50 g, 5.3 mmol) from Example 1A,
malonic acid (1.21 g, 11.6 mmol), piperidine (78.6 .mu.L, 0.80
mmol) in 8.0 mL of anhydrous pyridine was heated at 110.degree. C.
for 2 hours. Gas evolution ceased during this period. Pyridine was
then removed under vacuum. Water and 3N aq. HCl were then added
with stirring. The desired cinnamic acid was then collected through
filtration, washed with cold water and dried in a vacuum oven
overnight to give 1.56 g (4.8 mmol, 91%) of white solid.
EXAMPLE 1C
(2,4-Dichlorophenyl)[2-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]su-
lfide
A suspension of the acid (284 mg, 0.87 mmol) from Example 1B in 5
mL of methylene chloride was stirred with (COCl).sub.2 (84 .mu.L,
0.97 mmol), and one drop of DMF under nitrogen atmosphere for 90
minutes. The solvent was then removed under vacuum. The residue
(COCl).sub.2 was removed with benzene (2.times.) in vacuo. To a
separate flask, previously filled with 6-amino-1-hexanol (12 mg,
0.10 mmol), Hunig's base (22.8 .mu.L, 0.13 mmol) and DMAP (1.1 mg,
0.008 mmol) in 2.0 mL of CH.sub.2Cl.sub.2, the acid chloride (30
mg, 0.087 mmol) in 1.0 mL of CH.sub.2Cl.sub.2 was then dropped in
slowly. After 30 minutes, the reaction mixture was poured into 3N
HCl and extracted with ethyl aceetate (EtOAc). The organic layer
was washed with brine, dried with Na.sub.2SO.sub.4, condensed under
reduced pressure. The crude product was purified by preparative TLC
to give 21.0 mg (90%) of the title compound as a colorless oil.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.31-1.48 (m, 4H),
1.48-1.70 (m, 4H), 3.37 (q, J=6.7 Hz, 2H), 3.65 (t, J=6.3 Hz, 2H),
5.63 (br s, 1H), 6.36 (d, J=15.9 Hz, 1H), 6.71 (d, J=9.3 Hz, 1H),
7.95 (dd, J=2.4, 8.7 Hz, 1H), 7.31-7.49 (m, 4H), 7.65 (dd, J=2.1,
7.5 Hz, 1H), 7.99 (d, J=15.9 Hz, 1H). MS (DSI/NH.sub.3)
(M+NH.sub.4).sup.+ at m/z 441, 443, 445.
EXAMPLE 2
(2,4-Dichlorophenyl)[2-(E-((3-(1-imidazolyl)propylamino)carbonyl)ethenyl)p-
henyl]sulfide
The title compound was prepared by the procedures described in
Example 1C substituting 6-amino-1-hexanol with
1-(3-aminopropyl)imidazole. White powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.88 (p, J=7.7 Hz, 2H), 3.11 (q,
J=7.7 Hz, 2H), 3.97 (t, J=7.7 Hz, 2H), 6.63 (d, J=15.9 Hz, 1H),
6.70 (d, J=8.7 Hz, 1H), 6.89 (d, J=0.9 Hz, 1H), 7.17 (d, J=0.9 Hz,
1H), 7.33 (dd, J=2.7, 8.7 Hz, 1H), 7.46-7.65 (m, 4H), 7.72 (d,
J=2.7 Hz, 1H), 7.78 (d, J=15.9 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H),
8.24 (t, J=5.9 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 448,
450, 452. Analysis calculated for
C.sub.21H.sub.19N.sub.3O.sub.1Cl.sub.3S.sub.1.0.87H.sub.2O: C,
56.30; H, 4.67; N, 9.38. Found: C, 56.30; H, 4.56; N, 9.27.
EXAMPLE 3
(2,4-Dichlorophenyl)[2-chloro-4-(E-((2-hydroxyethylamino)carbonyl)ethenyl)-
phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with ethanolamine. Colorless oil; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 3.57 (q, J=7.65 Hz, 2H), 3.71 (q,
J=7.65 Hz, 2H), 6.06 (br s, 1H), 6.40 (d, J=15.3 Hz, 1H), 6.96 (d,
J=8.7 Hz, 1H), 7.22-7.30 (m, 4H), 7.49-7.60 (m, 1H), 7.55 (d,
J=15.3 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z 402, 404, 406, 408.
Analysis calculated for
C.sub.17H.sub.14N.sub.1O.sub.2Cl.sub.3S.sub.1.0.25H.sub.2O: C,
50.14; H, 3.59; N, 3.44. Found: C, 50.16; H, 3.62; N, 3.29.
EXAMPLE 4
(2,4-Dichlorophenyl)[2-chloro-4-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)-
phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend.. Colorless oil;
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.42 (m, 4H), 1.58 (m,
4H), 3.40 (q, J=6.7 Hz, 2H), 3.65 (br m, 2H), 5.60 (br t, 1H), 6.35
(d, J=15.3 Hz, 1H), 6.98 (d, J=8.7 Hz, 1H), 7.22-7.30 (m, 4H),
7.49-7.60 (m, 1H), 7.55 (d, J=15.3 Hz, 1H). MS (APCI) (M+H).sup.+
at m/z 458, 460, 462, 464. Analysis calculated for
C.sub.21H.sub.22N.sub.1O.sub.2Cl.sub.3S.sub.1.0.27H.sub.2O: C,
54.39; H, 4.90; N, 3.02. Found: C, 54.40; H, 4.85; N, 2.71.
EXAMPLE 5
(2,4-Dichlorophenyl)[2-chloro-4-(E-((bis-(2-hydroxyethyl)amino)carbonyl)et-
henyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with diethanolamine. Colorless oil; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 2.99 (br s, 2H), 3.67 (br m, 4H),
3.88 (t, J=5.1 Hz, 2H), 3.94 (t, J=5.1 Hz, 2H), 6.94 (d, J=1.53 Hz,
1H), 6.97 (d, J=8.7 Hz, 1H), 7.21-7.32 (m, 3H), 7.50-7.54 (m, 1H),
7.58 (d, J=2.4 Hz, 1H), 7.58 (d, J=15.3 Hz, 1H). MS (APCI)
(M+H).sup.+ at m/z 446, 448, 450, 452. Analysis calculated for
C.sub.19H.sub.18N.sub.1O.sub.3Cl.sub.3S.sub.1.1.09H.sub.2O: C,
48.93; H, 4.36; N, 3.00. Found: C, 48.88; H, 4.00; N, 3.01.
EXAMPLE 6
.[.(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-(1-pyrrolidin-2-only)propylamino-
)carbonyl)ethenyl)phenyl]sulfide.].
.Iadd.(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-(2-oxopyrrolidin-1-yl)propyl-
amino)carbonyl)ethenyl)phenyl]sulfide.Iaddend.
The title compound was prepared by the procedures described in
Example 1 substituting 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with 1-(3-aminopropyl)-2-pyrrolidinone. Colorless
oil; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.74 (qu, J=6.0 Hz,
2H), 2.09 (qu, J=7.5 Hz, 2H), 2.45 (t, J=8.25 Hz, 2H), 3.33 (q,
J=6.0 Hz, 2H), 3.42 (q, J=8.25 Hz, 4H), 6.46 (d, J=15.6 Hz, 1H),
7.02 (d, J=8.7 Hz, 1H), 7.14-7.23 (m, 2H), 7.30 (dd, J=2.4, 8.7 Hz,
1H), 7.51 (d, J=2.4 Hz, 1H). 7.51 (d, J=15.6 Hz, 1H), 7.60 (d,
J=2.1 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 483, 485, 487,
489. Analysis calculated for
C.sub.22H.sub.21N.sub.2O.sub.2Cl.sub.3S.sub.1.0.57H.sub.2O: C,
53.48; H, 4.52; N, 5.67. Found: C, 53.49; H, 4.60; N, 5.65.
EXAMPLE 7
(2,4-Dichlorophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl-
]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with morpholine. White solid; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 3.59-3.80 (m, 8H), 6.83 (d, J=15.6
Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 7.16-7.32 (m, 3H), 7.49-753 (m,
1H), 7.59 (d, J=2.4 Hz, 1H), 7.59 (d, J=15.6 Hz, 1H). MS
(DCI/NH.sub.3) (M+H).sup.+ at m/z 428, 430, 432, 434. Analysis
calculated for
C.sub.19H.sub.16N.sub.1O.sub.2Cl.sub.3S.sub.1.0.46H.sub.2O: C,
52.22; H, 3.90; N, 3.20. Found: C, 52.20; H, 3.76; N, 3.12.
EXAMPLE 8
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-methylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with 1-methylpiperazine. Colorless oil; .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta. 2.37 (s, 3H), 2.51 (br m, 4H),
3.64-3.87 (br m, 4H), 6.85 (d, J=15.6 Hz, 1H), 6.98 (d, J=8.7 Hz,
1H), 7.19-7.25 (m, 2H), 7.27 (dd, J=2.1, 8.7 Hz, 1H), 7.52 (t,
J=0.9 Hz, 1H), 7.57 (d, J=15.6 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H). MS
(DCI/NH.sub.3) (M+H).sup.+ at m/z 441, 443, 445, 447. Analysis
calculated for
C.sub.20H.sub.19N.sub.2O.sub.1Cl.sub.3S.sub.1.0.45H.sub.2O: C,
53.39; H, 4.46; N, 6.23. Found: C, 53.37; H, 4.46; N, 6.07.
EXAMPLE 9
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with 1-acetylpiperazine. White solid; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 2.15 (s, 3H), 3.50-3.58 (m, 2H),
3.58-3.85 (m, 6H), 6.85 (d, J=15.3 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H),
7.24-7.36 (m, 3H), 7.54 (dd, J=2.4 Hz, 1H), 7.61 (d, J=15.3 Hz,
1H), 7.61 (d, J=2.1 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z
486, 488, 490, 492. Analysis calculated for
C.sub.21H.sub.19N.sub.2O.sub.2Cl.sub.3S.sub.1.0.85H.sub.2O: C,
51.99; H, 4.30; N, 5.77. Found: C, 52.03; H, 4.27; N, 5.67.
EXAMPLE 10
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-pyridyl)piperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with 1-(2-pyridyl)piperazine. White solid;
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 3.59 (br m, 2H), 3.69 (br
m, 2H), 3.78 (br m, 2H), 3.86 (br m, 2H), 6.64-6.72 (m, 2H), 6.90
(d, J=15.6 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 7.22-7.25 (m, 2H), 7.31
(dd, J=2.4, 8.7 Hz, 1H), 7.49-7.57 (m, 2H), 7.61 (d, J=15.6 Hz,
1H), 7.62 (d, J=2.4 Hz, 1H), 8.19-8.24 (m, 1H). MS (DCI/NH.sub.3)
(M+H).sup.+ at m/z 504, 506, 508, 510. Analysis calculated for
C.sub.24H.sub.20N.sub.3O.sub.1Cl.sub.3S.sub.1: C, 57.10; H, 3.99;
N, 8.32. Found: C, 57.12; H, 4.06; N, 8.29.
EXAMPLE 11
(2-(Hydroxymethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)p-
henyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with 2-mercaptobenzyl
alcohol, 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with morpholine. White solid; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 3.50-3.62 (br m, 6H), 3.65-3.74 (br
m, 2H), 4.54 (d, J=5.7 Hz, 2H), 5.33 (t, J=5.7 Hz, 1H), 6.62 (d,
J=8.7 Hz, 1H), 7.28 (d, J=15.0 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H),
7.42 (d, J=15.0 Hz, 1H), 7.43 (dd, J=1.8, 8.7 Hz, 1H), 7.50 (dd,
J=2.1, 8.7 Hz, 1H), 7.55 (dd, J=2.1, 7.8 Hz, 1H), 7.68 (dd, J=1.5,
8.1 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+
at m/z 390, 392. Analysis calculated for
C.sub.20H.sub.20N.sub.1O.sub.3Cl.sub.1S.sub.1.0.09H.sub.2O: C,
61.35; H, 5.20; N, 3.58. Found: C, 61.37; H, 5.48; N, 3.81.
EXAMPLE 12
(2-(Bromophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sul-
fide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with morpholine. White solid; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 3.50-3.66 (br m, 6H), 3.66-3.79 (br
m, 2H), 7.05 (d, J=8.7 Hz, 1H), 7.26 (dd, J=2.1, 8.1 Hz, 1H), 7.33
(dd, J=2.1, 8.1 Hz, 1H), 7.36 (d, J=15.6 Hz, 1H), 7.39 (dd, J=1.8,
12.0 Hz, 1H), 7.45 (dd, J=1.8, 6.3 Hz, 1H), 7.48 (d, J=15.6 Hz,
1H), 7.64 (dd, J=2.1, 8.7 Hz, 1H), 7.80 (dd, J=2.8, 8.7 Hz, 1H),
8.09 (d, J=2.1 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 438,
440, 442.
EXAMPLE 13
(2,4-Dichlorophenyl)[2-chloro-4-(E-((2-hydroxyethyl)piperazin-1-yl)carbony-
l)ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with 1-hydroxyethylpiperazine. Colorless oil;
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 2.85-3.20 (br m, 6H),
3.84-4.29 (m, 6H), 6.80 (d, J=15.3 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H),
7.72-7.38 (m, 3H), 7.50-7.56 (m, 1H), 7.56-7.62 (m, 1H), 7.60 (d,
J=15.3 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 471, 473, 475,
477.
EXAMPLE 14
(2,4-Dichlorophenyl)[2-chloro-4-(E-((2-hydroxyethoxyethyl)piperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with 1-[2-(2-hydroxyethoxy)ethyl]piperazine.
Colorless oil; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 2.73 (br
m, 6H), 3.58-3.68 (m, 2H), 3.68-4.00 (m, 8H), 6.84 (d, J=15.3 Hz,
1H), 6.97 (d, J=8.7 Hz, 1H), 7.20-7.34 (m, 3H), 7.54 (d, J=7.5 Hz,
1H), 7.58 (d, J=15.3 Hz, 1H), 7.58-7.65 (overlapping d, 1H). MS
(DCIINH.sub.3) (M+H).sup.+ at m/z 515, 517, 519, 521.
EXAMPLE 15
(2-(Bromophenl)[2-chloro-4-(E-((3-hydroxymethyl)piperidin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with 3-hydroxymethylpiperidine. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 8.07 (d, J=17.7 Hz, 1H), 7.80 (d,
J=7.7 Hz, 1H), 7.63 (br d, J=7.7 Hz, 1H), 7.44 (d, J=7.0 Hz, 1H),
7.40 (br s, 2H), 7.35 (m, 1H), 7.25 (dd 7.7, 1.5, 1H), 7.06 (dd,
J=8.1 2.9, 1H), 4.57 (m, 1H), 4.45 (m, 1H), 4.16 (br m, 2H),
1.2-1.8 (m, 8H). HRMS calculated for
C.sub.21H.sub.21N.sub.1O.sub.2S.sub.1Br.sub.1Cl.sub.1: 466.0243.
Observed: 466.0247.
EXAMPLE 16
(2-(Bromophenyl)[2-chloro-4-(E-((2-hydroxymethyl)piperidin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with 2-hydroxymethylpiperidine. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 8.03 (m, 1H), 7.79 (d, J=7.8 Hz,
1H), 7.61 (m, 1H), 7.30-7.45 (m, 4H), 7.23 (m, 1H), 7.07 (m, 1H),
4.79 (m, 2H), 4.61 (m, 2H), 4.10 (m, 1H), 1.50 (m, 6H). HRMS
calculated for
C.sub.21H.sub.21N.sub.1O.sub.2S.sub.1Br.sub.1Cl.sub.1: 466.0243.
Observed: 466.0247.
EXAMPLE 17
(2-(Bromophenl)[2-chloro-4-(E-((3-acetamidopyrrolidin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with 3-acetamidopyrrolidine. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 8.14 (m, 1H), 8.07 (dd, J=9.8, 1.7
Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.64 (dd, J=8.1, 1.7 Hz, 1H),
7.25-7.47 (m, 4H), 7.10 (t, J=7.8 Hz, 1H), 7.03 (dd, J=8.1, 1.7 Hz,
1H), 3.45-4.34 (m, 6H), 2.02 (m, 2H), 1.81 (ap d, J=1.4 Hz, 1H),
HRMS calculated for
C.sub.21H.sub.20N.sub.2O.sub.2S.sub.1Br.sub.1Cl.sub.1: 479.0196.
Observed: 479.0183.
EXAMPLE 18
(2-(Bromophenyl)[2-chloro-4-(E-((4-hydroxypiperidin-1-yl)carbonyl)ethenyl)-
phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with 4-hydroxypiperidine. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 8.08 (d, J=1.7 Hz, 1H), 7.80 (dd,
J=8.0, 1.5 Hz, 1H), 7.63 (dd, J=8.3, 1.9 Hz, 1H), 7.44 (ap dd,
J=7.5, 1.4 Hz, 2H), 7.40 (ap d, J=3.7 Hz 2H), 7.34 (dt, J=7.6, 1.8
Hz, 1H), 7.25 (dd, J=7.5, 1.7 Hz 1H), 7.05 (d, J=8.1 Hz, 1H), 4.76
(br s, 1H), 4.01 (m, 2H), 3.72 (m, 1H), 3.12 (m, 1H), 1.75 (m, 2H),
1.32 (m, 2H). HRMS calculated for
C.sub.20H.sub.19N.sub.1O.sub.2S.sub.1Br.sub.1Cl.sub.1: 452.0087.
Observed: 452.0076.
EXAMPLE 19
(2-(Bromophenyl)[2-chloro-4-(E-((piperidin-1-yl)carbonyl)ethenyl)phenyl]su-
lfide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with piperidine. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 8.08 (d, J=1.7 Hz, 1H), 7.80 (dd, J=8.1, 1.4 Hz, 1H),
7.63 (dd, J=8.1, 1.7 Hz, 1H), 7.44 (ap dd, J=7.6, 1.5 Hz, 1H), 7.39
(ap d, J=4.8 Hz, 2H), 7.34 (dt, J=7.5, 1.6, 1H), 7.24 (dd, J=7.5,
1.7, 1H), 7.05 (d, J=8.1 Hz, 1H), 3.65 (br m, 2H), 3.53 (br m, 2H),
1.62 (br m, 2H), 1.50 (br m, 4H). HRMS calculated for
C.sub.20H.sub.19N.sub.1O.sub.1S.sub.1Br.sub.1Cl.sub.1: 436.0130.
Observed: 436.0122.
EXAMPLE 20
(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with nipecotic acid. Colorless oil; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.44-1.68 (br m, 1H), 1.68-2.00 (br
m, 2H), 2.51-2.67 (br m, 1H), 3.13-3.37 (br m, 1H), 3.80-4.12 (br
m, 1H), 4.30-5.00 (br m, 3H), 6.86 (d, J=15.3 Hz, 1H), 6.99 (d,
J=8.7 Hz, 1H), 7.16-7.24 (m, 2H), 7.29 (d, J=8.7 Hz, 1H), 7.47-7.55
(m, 1H), 7.55 (d, J=15.3 Hz, 1H), 7.60 (br d, 1H). MS (APCI)
(M+H).sup.+ at m/z 470, 472, 474, 476.
EXAMPLE 21
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-4-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with isonipecotic acid. Colorless oil; .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta. 1.68-1.85 (m, 2H), 1.98-2.09 (m,
2H), 2.60-2.72 (m, 1H), 2.90-3.13 (br m, 1H), 3.17-3.38 (br, m,
1H), 3.93-4.12 (br m, 1H), 4.38-4.59 (br m, 1H), 6.86 (d, J=15.3
Hz, 1H), 6.99 (dd, J=8.7 Hz, 1H), 7.20-7.25 (m, 2H), 7.28 (dd,
J=1.8,8.7 Hz, 1H), 7.49-7.53 (m, 1H), 7.56 (d, J=15.3 Hz, 1H), 7.60
(d, J=1.8 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z 470, 472, 474,
476.
EXAMPLE 22
(2-Bromophenyl)[2-chloro-4-(E-((4-acetylhomopiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-3-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with 4-acetylhomopiperazine. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 8.10 (m, 1H), 7.81 (d, J=7.7 Hz,
1H), 7.64 (m, 1H), 7.24-7.51 (m, 5H), 7.05 (m, 1H), 3.39-3.77 (m,
8H), 1.97 (m, 3H), 1.68 (m, 2H). HRMS calculated for
C.sub.22H.sub.22N.sub.2O.sub.2S.sub.1Br.sub.1Cl.sub.1: 493.0352.
Observed: 493.0352.
EXAMPLE 23
(2-Bromophenyl)[2-chloro-4-(E-((thiomorpholin-1-yl)carbonyl)ethenyl)phenyl-
]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-3-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with thiomorpholine. .sup.1H NMR (DMSO-d.sub.6,
300 MHz) 68.10 (d, J=1.5 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.64 (dd,
J=8.1, 1.5 Hz, 1H), 7.31-7.48 (m, 4H), 7.36 (m, 1H), 7.26 (dd,
J=8.1, 1.8 Hz, 1H), 7.05 (d J=8.1 Hz, 1H), 3.96 (m, 2H), 3.82 (m,
2H), 2.62 (m, 4H). HRMS calculated for
C.sub.19H.sub.17N.sub.1O.sub.1S.sub.2Br.sub.1Cl.sub.1: 455.9681.
Observed: 455.9676.
EXAMPLE 24
.[.(2-Bromophenyl)[2-chloro-4-(E-((4-(1-benzimidazol-2-only)piperidin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide.].
.Iadd.(2-Bromophenyl)[2-chloro-4-(E-((4-([2-oxo-2,3-dihydro-1H-benzimidaz-
ol-1-yl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2.Iaddend.-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-3-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with .[.4-(1-benzimidazol-2-only)piperidine.].
.Iadd.4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine.Iaddend..
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.14 (d, J=1.5 Hz, 1H),
7.80 (dd, J=7.9, 1.3 Hz, 1H), 7.67 (dd, J=8.1, 1.8 Hz, 1H), 7.48
(ap s, 2H), 7.44 (dt, J=7.5, 1.2, 1H), 7.34 (dt, J=7.6, 1.6, 1H),
7.26 (dd, J=7.7, 1.8 Hz, 1H), 7.22 (m, 1H), 7.06 (d, J=8.1, 1H),
6.97 (ap d, J=2.6, 3H), 4.64 (m, 1H), 4.48 (m, 2H), 2.79 (m, 2H),
2.29 (m, 2H), 1.78 (m, 2H). HRMS calculated for
C.sub.27H.sub.23N.sub.3O.sub.2SBr.sub.1Cl.sub.1: 568.0461.
Observed: 568.0477.
EXAMPLE 25
.[.(2-Bromophenyl)[2-chloro-4-(E-((2-tetrahydroisoguinolinyl)carbonyl
ethenyl)phenyl]sulfide.].
.Iadd.(2-Bromophenyl)[2-chloro-4-(E-((2-tetrahydroisoquinolinyl)carbonyl)-
ethenyl)phenyl]sulfide.Iaddend.
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
.[.3-chloro-4-fluoro-benzadehyde.].
.Iadd.3-chloro-3-fluoro-benzaldehyde.Iaddend., and
6-amino-1-hexanol with tetrahydroisoquinoline. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 8.12 (d, J=7.4 Hz, 1H), 7.81 (dd,
J=7.7. 1.1 Hz, 1H), 7.67 (dd, J=8.3, 1.3 Hz, 1H), 7.47 (m, 2H),
7.43 (dd, J=7.5, 1.3 Hz, 2H), 7.34 (dt, J=7.6, 1.7 Hz, 1H), 7.27 (d
7.7 Hz, 1H), 7.19 (m, 4H), 7.05 (d, J=8.1 Hz, 1H), 4.92 (s, 1H),
4.72 (s, 1H), 3.95 (t, J=5.9 Hz, 1H), 3.78 (t, J=5.7 Hz, 1H), 2.89
(t, J=5.3 HZ, 1H), 2.83 (t, J=3.7, 1H). HRMS calculated for
C.sub.24H.sub.19N.sub.1O.sub.2S.sub.1Br.sub.1Cl.sub.1: 484.0138.
Observed: 484.0128.
EXAMPLE 26
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)carbonyl
ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-methylthiophenol, 2-chlorobenzaldehyde with
.[.4-fluoro-3-trifluoromethylbenzadehyde.].
.Iadd.4-fluoro-3-trifluoromethylbenzaldehyde.Iaddend., and
6-amino-1-hexanol with 1-acetylpiperazine. .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 7.79 (s, 1H); 7.63 (d, J=15.4 Hz, 1H); 7.51 (d,
J=6.8 Hz, 1H); 7.41-7.33 (m, 3H); 7.28 (m, 1H); 6.83 (d, J=15.4 Hz,
1H); 6.79 (d, J=6.8 Hz, 1H); 3.80-3.60 (m, 6H); 3.57-3.50 (m, 2H);
2.34 (s, 3H); 2.14 (s, 3H). MS (ESI) m/z 919 (2M+Na).sup.+, 897
(2M+H).sup.+, 471 (M+Na).sup.+, 449 (M+H).sup.+.
EXAMPLE 27
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)p-
henyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-methylthiophenol, 2-chlorobenzaldehyde with
.[.4-fluoro-3-trifluoromethylbenzadehyde.].
.Iadd.4-fluoro-3-trifluoromethylbenzaldehyde.Iaddend., and
6-amino-1-hexanol with morpholine. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 7.79 (s, 1H); 7.63 (d, J=14.0 Hz, 1H); 7.52 (d, J=7.6
Hz, 1H); 7.40-7.30 (m, 3H); 7.28 (m, 1H); 6.87 (d, J=14.0 Hz, 1H);
6.84 (d, J=7.6 Hz, 1H); 3.73 (br s, 8H); 2.34 (s, 3H). MS (ESI) m/z
837 (2M+Na).sup.+, 815 (2M+H).sup.+, 408 (M+H).sup.+.
EXAMPLE 28
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((2-(1-morpholinyl)ethylamino)carb-
onyl)ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-methylthiophenol, 2-chlorobenzaldehyde with
.[.4-fluoro-3-trifluoromethylbenzadehyde.].
.Iadd.4-fluoro-3-trifluoromethylbenzaldehyde.Iaddend., and
6-amino-1-hexanol with 2-(1-morpholinyl)ethylamine. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 7.80 (s, 1H); 7.56 (d, J=15.8 Hz,
1H); 7.50 (d, J=8.1 Hz, 1H); 7.40-7.32 (m, 3H); 7.28 (m, 1H); 6.79
(d, J=15.8 Hz, 1H); 6.40 (d, J=8.1 Hz, 1H); 3.75 (t, J=4.6 Hz, 4H);
3.51 (q, J=5.5 Hz, 2H), 2.57 (t, J=5.8 Hz, 2H); 2.55-2.48 (m, 4H);
2.34 (s, 3H ). MS (ESI) m/z 923 (2M+Na).sup.+, 473 (M+Na).sup.+,
451 (M+H).sup.+.
EXAMPLE 29
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-phenylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-methylthiophenol, 2-chlorobenzaldehyde with
.[.4-fluoro-3-trifluoromethylbenzadehyde.].
.Iadd.4-fluoro-3-trifluoromethylbenzaldehyde.Iaddend., and
6-amino-1-hexanol with 4-phenylpiperazine. .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 7.81 (s, 1H); 7.64 (d, J=16.0 Hz, 1H); 7.51 (d,
J=8.2 Hz, 1H); 7.40-7.27 (m, 6H); 6.98-6.90 (m, 4H); 6.80 (d, J=8.2
Hz, 1H); 3.88 (br s, 4H); 2.23 (br s, 4H); 2.34 (s, 3H). MS (ESI)
m/z 987 (2M+Na).sup.+, 965 (2M+H).sup.+, 505 (M+Na).sup.+, 483
(M+H).sup.+, 451.
EXAMPLE 30
.[.(2-Methylphenyl)[2-trifluoromethyl-4-(E-((3-(1-pyrrolidin-2-only)propyl-
amino)carbonyl)ethenyl)phenyl]sulfide.].
.Iadd.(2-Methylphenyl)[2-trifluoromethyl-4-(E-((3-(2-oxopyrrolidin-1-yl)p-
ropylamino)carbonyl)ethenyl)phenyl]sulfide.Iaddend.
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-methylthiophenol, 2-chlorobenzaldehyde with
.[.4-fluoro-3-trifluoromethylbenzadehyde.].
.Iadd.4-fluoro-3-trifluoromethylbenzaldehyde.Iaddend., and
6-amino-1-hexanol with .[.1-pyrrolidin-2-only)propylamine.].
.Iadd.3-(2-oxopyrrolidin-1-yl)propylamine.Iaddend.. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 7.78 (s, 1H); 7.53 (d, J=15.6 Hz,
1H); 7.49 (d, J=7.2 Hz, 1H); 7.40-7.33 (m, 3H); 7.14 (m, 1H); 6.80
(d, J=8.2 Hz, 1H); 6.43 (d, J=15.6 Hz, 1H); 3.41 (m, 4H); 3.32 (q,
J=6.1 Hz, 2H); 2.43 (t, J=6.6 Hz, 2H); 2.34 (s, 3H), 2.08 (m, 2H),
1.75 (m, 2H). MS (ESI) m/z 947 (2M+Na).sup.+, 925 (2M+H).sup.+,
4.85 (M+Na).sup.+, 463 (M+H).sup.+.
EXAMPLE 31
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((cyclopropylamino)carbonyl)etheny-
l)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with
2-methylthiophenol, 2-chlorobenzaldehyde with
.[.4-fluoro-3-trifluoromethylbenzadehyde.].
.Iadd.4-fluoro-3-trifluoromethylbenzaldehyde.Iaddend., and
6-amino-1-hexanol with cyclopropylamine. .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 7.76 (s, 1H); 7.56 (d, J=15.4 Hz, 1H); 7.50 (d,
J=8.4 Hz, 1H); 7.40-7.30 (m, 3H); 7.28 (m, 1H); 6.88 (d, J=8.4 Hz,
1H); 6.30 (d, J=15.4 Hz, 1H); 5.70 (br s, 1H), 2.95 (m, 1H); 2.34
(s, 3H); 0.85 (m, 2H); 0.57 (m, 2H). MS (ESI) m/z 777
(2M+Na).sup.+, 755 (2M+H).sup.+, 400 (M+Na).sup.+, 378
(M+H).sup.+.
EXAMPLE 32
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
EXAMPLE 32A
1-Chloro-2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)benzene
To a stirred solution of trans-4-chloro-3-nitrocinnamic acid (1.50
g, 6.59 mmol) and 1-acetylpiperazine (0.89 g, 6.94 mmol) in 20 mL
of DMF at room temperature was added EDAC (1.4 g, 7.30 mmol). The
mixture was then stirred at room temperature for 2 hours. TLC
indicated the complete consumption of the acid. Water was then
added to quench the reaction and to precipitate out the product.
Cinnamide was then collected through filtration and washed with
cold water. The light yellow product was dried in .Iadd.a
.Iaddend.vacuum oven overnight at 40.degree. C.[...]. to give 2.04
g (6.03 mmol, 91.6%) of the title compound.
EXAMPLE 32B
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
To a stirred solution of 4-chloro-3-nitro-cinnamide (275 mg, 0.814
mmol) from Example 32A in 1.0 mL of DMF was added potassium
carbonate (169 mg, 1.22 mmol), followed by the dropwise addition of
2,4-dichlorothiophenol (146 mg, 0.815 mmol). The mixture was then
stirred at room temperature for 60 minutes. Completion of the
reaction was indicated by the TLC. Water was then added to
precipitate the product. Filtration, washing with cold water, and
drying in a vacuum oven afforded 350 mg (0.728 mmol, 89%) of the
.[.titled.]. .Iadd.title .Iaddend.compound as .Iadd.a
.Iaddend.light yellow solid. .sup.1H NMR (d.sup.6-DMSO, 300 MHz)
.delta. 2.05 (s, 3H), 3.42-3.50 (br m, 4H), 3.50-3.64 (br m, 2H),
3.64-3.79 (br m, 2H), 6.83 (d, J=8.7 Hz, 1H), 7.44 (d, J=15.3 Hz,
1H), 7.55 (d, J=15.3 Hz, 1H), 7.63 (dd, J=2.7, 8.7 Hz, 1H), 7.83
(d, J=8.7 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H),
8.69 (d, J=1.8 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 497,
499, 501. Analysis calculated for
C.sub.21H.sub.19N.sub.3O.sub.4Cl.sub.2S.sub.1.0.82H.sub.2O: C,
50.94; H, 4.20; N, 8.49. Found: C, 50.91; H, 4.21; N, 8.69.
EXAMPLE 33
.[.(2,4-Dichlorophenyl)[2-nitro-4-(E-((3-(1-pyrrolidin-2-only)propylamino)-
carbonyl)ethenyl)phenyl]sulfide.].
.Iadd.(2,4-Dichlorophenyl)[2-nitro-4-(E-((3-(2-oxopyrrolidin-1-yl)propyla-
mino)carbonyl)ethenyl)phenyl]sulfide.Iaddend.
The title compound was prepared by the procedures described in
Example 32 substituting 1-acetylpiperazine with
1-(3-aminopropyl)-2-pyrrolidinone. Light-yellow powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.64 (p, J=7.1 Hz, 2H), 1.91 (p,
J=7.5 Hz, 2H), 2.21 (t, J=8.3 Hz, 2H), 3.15 (q, J=6.3 Hz, 2H), 3.21
(dd, J=9.9, 17.7 Hz, 2H), 3.32 (overlapping t, J=8.4 Hz, 2H), 6.72
(d, J=15.6 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 7.46 (d, J=15.6 Hz,
1H), 7.63 (dd, J=2.4, 8.1 Hz, 1H), 7.79 (dd, J=2.4, 8.7 Hz, 1H),
7.84 (d, J=8.7 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 8.18 (t, J=6.0 Hz,
1H), 8.46 (d, J=2.1 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z
494, 496.
EXAMPLE 34
(2,3-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 32B substituting 2,4-dichlorothiophenol with
2,3-dichlorothiophenol. Light-yellow powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 2.04 (s, 3H), 3.42-3.50 (br m, 4H),
3.50-3.64 (br m, 2H), 3.64-3.79 (br m, 2H), 6.88 (d, J=8.7 Hz, 1H),
7.45 (d, J=15.6 Hz, 1H), 7.55 (t, J=7.65 Hz, 1H), 7.57 (d, J=15.6
Hz, 1H), 7.78 (dd, J=1.8, 8.1 Hz, 1H), 7.87 (dd, J=1.8, 8.1 Hz,
1H), 7.95 (dd, J=2.7, 9.0 Hz, 1H), 8.69 (d, J=1.8 Hz, 1H). MS
(DCI/NH.sub.3) (M+H).sup.+ at m/z 497, 499, 501.
EXAMPLE 35
(4-Bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phe-
nyl]sulfide
The title compound was prepared by the procedures described in
Example 32 substituting 2,4-dichlorothiophenol with
4-bromothiophenol. Light-yellow powder; .sup.1H NMR (d.sup.6-DMSO,
300 MHz) .delta. 2.04 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H),
3.60 (br m, 1H), 3.68 (br m, 1H), 3.74 (br m, 1H), 6.90 (d, J=8.7
Hz, 1H), 7.43 (d, J=15.0 Hz, 1H), 7.54 (d, J=15.0 Hz, 1H), 7.58 (d,
J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.92 (dd, J=2.1, 9.0 Hz,
1H), 8.65 (d, J=2.1 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z
507, 509.
EXAMPLE 36
(4-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide
The title compound was prepared by the procedures described in
Example 32 substituting 2,4-dichlorothiophenol with p-thiocresol.
Light-yellow powder; .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta.
2.04 (s, 3H), 2.39 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.60
(br m, 1H), 3.68 (br m, 1H), 6.89 (d, J=8.7 Hz, 1H), 7.20 (d, J=8.1
Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.40 (d, J=15.0 Hz, 1H), 7.53 (d,
J=15.0 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.89 (dd, J=2.1, 8.7 Hz,
1H), 8.64 (d, J=2.1 Hz, 1H). MS (DCI/NH.sub.3) (M+NH.sub.4).sup.+
at m/z 443.
EXAMPLE 37
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-butoxycarbonyl)piperazin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 32 substituting 1-acetylpiperazine with tert-butyl
piperazine carboxylate. Light-yellow powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.42 (s, 9H), 3.36 (overlapping m,
4H), 3.55 (br m, 2H), 3.70 (br m, 2H), 6.83 (d, J=8.7 Hz, 1H), 7.42
(d, J=15.6 Hz, 1H), 7.54 (d, J=15.6 Hz, 1H), 7.63 (dd, J=2.4, 8.4
Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.92 (dd, J=2.4, 8.7 Hz, 1H), 7.96
(d, J=2.7 Hz, 1H), 8.68 (d, J=2.4 Hz, 1H). MS (APCI) (M+H).sup.+ at
m/z 538, 540, 542.
EXAMPLE 38
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(2-furoylcarbonyl)piperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide
EXAMPLE 38A
2,4-Dichlorophenyl[2-nitro-4-(E-((piperazin-1-yl)carbonyl)ethenyl)phenyl]s-
ulfide
Trifluoroacetic Acid Salt
The compound (100 mg, 0.186 mmol) from Example 37 was dissolved in
0.5 mL of neat trifluoroacetic acid (TFA). The mixture was stirred
at room temperature for 1 hour. The TFA was then removed under
vacuum to give the title compound (105 mg) as a yellow solid.
EXAMPLE 38B
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(2-furoylcarbonyl)piperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide
To a stirred solution of piperazine TFA salt (35 mg, 0.067 mmol)
from Example 38A in 2.0 mL of CH.sub.2Cl.sub.2 was added Et.sub.3N
(23 .mu.L, 0.17 mmol), 4-dimethylaminopyridine (DMAP) (1.0 mg,
0.0082 mmol), and furyl chloride (8.0 .mu.L, 0.080 mmol). The
mixture was then stirred at room temperature for 30 minutes before
the solvent was removed. The crude product was purified with Gilson
HPLC system, YMC C-18 column, 75.times.30 mm I.D., S-5 .mu.M, 120
.ANG., and a flow rate of 25 mL/min, .lamda.=214, 245 nm; mobile
phase A, 0.05 M .[.NH.sub.4Oac.]. .Iadd.NH.sub.4OAc.Iaddend., and
B, CH.sub.3CN; linear gradient 20-100% of B in 20 minutes to give
the title compound (24 mg, 67%) as .Iadd.a .Iaddend.light-yellow
powder; .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 3.62-3.87 (br
m, 8H), 6.66 (q, J=2.1 Hz, 1H), 6.84 (d, J=8.7 Hz, 1H), 7.04 (d,
J=3.3 Hz, 1H), 7.44 (d, J=15.3 Hz, 1H), 7.56 (d, J=15.3 Hz, 1H),
7.63 (dd, J=2.4, 8.1 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.87 (d,
J=2.1 Hz, 1H), 7.92 (dd, J=2.1, 12.0 Hz, 1H), 7.96 (d, J=2.1 Hz,
1H), 8.70 (d, J=2.1 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z 532, 534,
536.
EXAMPLE 39
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(methanesulfonyl)piperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 38B substituting furoyl chloride with methanesulfonyl
chloride. Light-yellow powder; .sup.1H NMR (d.sup.6-DMSO, 300 MHz)
.delta. 2.90 (s, 3H), 3.25 (br m, 4H), 3.68 (br m, 2H), 3.83 (br m,
2H), 6.84 (d, J=9.0 Hz, 1H), 7.45 (d, J=15.6 Hz, 1H), 7.56 (d,
J=15.6 Hz, 1H), 7.63 (dd, J=2.4, 8.7 Hz, 1H), 7.83 (d, J=9.0 Hz,
1H), 7.93 (dd, J=2.1, 9.0 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H), 8.70 (d,
J=2.1 Hz, 1H). MS (ESI) (M+H).sup.+ at m/z 516, 518, 520.
EXAMPLE 40
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonylmethyl)piperazi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 38B substituting furoyl chloride with
2-chloro-N,N-diethylacetamide. Light-yellow powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.01 (t, J=7.2 Hz, 3H), 1.13 (t,
J=7.2 Hz, 3H), 2.46 (br m, 4H), 3.16 (s, 2H), 3.24 (q, J=7.2 Hz,
2H), 3.37 (q, J=7.2 Hz, 2H), 3.56 (br m, 2H), 3.69 (br m, 2H), 6.83
(d, J=9.0 Hz, 1H), 7.46 (d, J=15.3 Hz, 1H), 7.52 (d, J=15.3 Hz,
1H), 7.62 (dd, J=2.4, 8.7 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.92
(dd, J=2.1, 9.0 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H), 8.67 (d, J=2.1 Hz,
1H). MS (ESI) (M+NH.sub.4).sup.+ at m/z 573, 575, 577.
EXAMPLE 41
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonyl)piperazin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 38B substituting furoyl chloride with N,N-diethylcarbamyl
chloride. Light-yellow powder; .sup.1H NMR (d.sup.6-DMSO, 300 MHz)
.delta. 1.06 (t, J=6.9 Hz, 6H), 3.12 (br m, 4H), 3.15 (q, J=6.9 Hz,
4H), 3.58 (br m, 2H), 3.72 (br m, 2H), 6.83 (d, J=8.7 Hz, 1H), 7.42
(d, J=15.6 Hz, 1H), 7.53 (d, J=15.6 Hz, 1H), 7.63 (dd, J=2.7, 9.0
Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.92 (dd, J=2.4, 8.7 Hz, 1H), 7.95
(d, J=2.7 Hz, 1H), 8.68 (d, J=2.1 Hz, 1H). MS (APCI) (M+H).sup.+ at
m/z 537, 539, 541.
EXAMPLE 42
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-butoxycarbonylmethyl)piperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 38B substituting CH.sub.2CL.sub.2 with CH.sub.3CN as
solvent, and furoyl chloride with tert-butyl bromoacetate.
Light-yellow powder; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.47
(s, 9H), 2.70 (br m, 4H), 3.21 (s, 2H), 3.74 (br m, 2H), 3.82 (br
m, 2H), 6.73 (d, J=8.7 Hz, 1H), 6.92 (d, J=15.0 Hz, 1H), 7.39 (dd,
J=2.4, 8.7 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.61 (d, J=15.0 Hz,
1H), 7.62 (d, J=2.4 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H), 8.43 (br d,
1H). MS (APCI) (M+H).sup.+ at m/z 552, 554, 556.
EXAMPLE 43
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxycarbonyl)piperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
EXAMPLE 43A
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-carbethoxycarbonyl)piperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 38B substituting furoyl chloride with ethyl oxalyl
chloride.
EXAMPLE 43B
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxycarbonyl)piperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
To a stirred solution of the ethyl ester (40 mg, 0.074 mmol) from
Example 43A in 2 mL of ethanol was added saturated LiOH (0.25 mL).
The mixture was then stirred at room temperature for 2 hours. Water
(2 mL) was then added to the reaction mixture, which was then
acidified to pH=2 with concentrated HCl. The precipitates were
collected through filtration, washed with cold water, dried under
vacuum to give the .[.titled.]. .Iadd.title .Iaddend.compound (30
mg, 79%) as .Iadd.a .Iaddend.light yellow solid. .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 3.52 (br m, 4H), 3.62 (br m, 2H),
3.76 (br m, 2H), 6.84 (d, J=9.0 Hz, 1H), 7.46 (d, J=15.3 Hz, 1H),
7.56 (d, J=15.3 Hz, 1H), 7.63 (dd, J=2.7, 8.7 Hz, 1H), 7.83 (d,
J=9.0 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.96 (d, J=2.7 Hz, 1H), 8.70
(br d, 1H). MS (APCI) (M--COO).sup.+ at m/z 466, 468, 470.
EXAMPLE 44
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxymethyl)piperazin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 38A substituting compound from Example 37 with compound
from Example 42. Light-yellow powder; .sup.1H NMR (d.sup.6-DMSO,
300 MHz) .delta. 3.14 (s, 2H), 3.40 (overlapping br m, 4H), 3.44
(br m, 1H), 3.51 (br m, 1H), 3.57 (br m, 1H), 3.71 (br m, 1H), 6.82
(d, J=8.7 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.52 (d, J=15.6 Hz,
1H), 7.63 (dd, J=2.4, 8.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.92
(dd, J=2.4, 8.7 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 8.68 (d, J=2.4 Hz,
1H). MS (APCI) (M+H).sup.+ at m/z 496, 498, 500.
EXAMPLE 45
(2-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide
The title compound was prepared by the procedures described in
Example 32 substituting 2,4-dichlorothiophenol with o-thiocresol.
Light-yellow powder; .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta.
2.03 (s, 3H), 2.29 (s, 3H), 3.47 (br m, 4H), 3.53 (br m, 1H), 3.60
(br m, 1H), 3.67 (br m, 1H), 3.83 (br m, 1H), 6.64 (d, J=8.7 Hz,
1H), 7.40 (d, J=15.0 Hz, 1H), 7.36-7.42 (m, 1H), 7.46-7.57 (m, 3H),
7.63 (d, J=6.9 Hz, 1H), 7.89 (dd, J=2.4, 9.0 Hz, 1H), 8.66 (d,
J=2.4 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z 426.
EXAMPLE 46
(2-Chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide
The title compound was prepared by the procedures described in
Example 32 substituting 2,4-dichlorothiophenol with
2-chlorothiophenol. Light-yellow powder; .sup.1H NMR (d.sup.6-DMSO,
300 MHz) .delta. 2.04 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H),
3.60 (br m, 1H), 3.68 (br m, 1H), 3.73 (br m, 1H), 6.75 (d, J=9.0
Hz, 1H), 7.43 (d, J=15.3 Hz, 1H), 7.54 (d, J=15.3 Hz, 1H), 7.55
(dd, J=1.8, 8.1 Hz, 1H), 7.64 (t, J=1.8, 8.1 Hz, 1H), 7.76 (d,
J=1.8, 8.1 Hz, 1H), 7.82 (d, J=1.8, 8.1 Hz, 1H), 7.93 (dd, J=2.4,
9.0 Hz, 1H), 8.68 (d, J=2.4 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z
446, 448, 450.
EXAMPLE 47
(2-Aminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phe-
nyl]sulfide
The title compound was prepared by the procedures described in
Example 32 substituting 2,4-dichlorothiophenol with
2-aminothiophenol. Light-yellow powder; .sup.1H NMR (d.sup.6-DMSO,
300 MHz) .delta. 2.04 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H),
3.60 (br m, 1H), 3.68 (br m, 1H), 3.74 (br m, 1H), 5.58 (s, 2H),
6.65 (td, J=1.5, 15.0 Hz, 1H), 6.72 (dd, J=1.5, 8.7 Hz, 1H), 7.00
(dd, J=1.8, 8.7 Hz, 1H), 7.27 (t, J=1.5, 8.6 Hz, 1H), 7.36 (dd,
J=1.5, 8.7 Hz, 1H), 7.39 (d, J=15.3 Hz, 1H), 7.53 (d, J=15.3 Hz,
1H), 7.89 (dd, J=1.8, 8.7 Hz, 1H), 8/64 (d, J=1.8 Hz, 1H). MS
(APCI) (M+H).sup.+ at m/z 427.
EXAMPLE 48
(2-Hydroxymethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 32 substituting 2,4-dichlorothiophenol with
2-mercaptobenzyl alcohol. Light-yellow powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 2.03 (s, 3H), 3.47 (br m, 4H), 3.52
(br m, 1H), 3.60 (br m, 1H), 3.67 (br m, 1H), 3.73 (br m, 1H), 4.53
(d, J=5.7 Hz, 1H), 5.34 (t, J=5.7 Hz, 1H), 6.65 (d, J=8.7 Hz, 1H),
7.40 (d, J=15.3 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.53 (d, J=15.3
Hz, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.87 (dd,
J=2.1, 8.7 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H). MS (APCI)
(M+NH.sub.4).sup.+ at m/z 459.
EXAMPLE 49
(2-Ethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phe-
nyl]sulfide
The title compound was prepared by the procedures described in
Example 32 substituting 2,4-dichlorothiophenol with
2-ethylthiophenol. Light-yellow powder; .sup.1H NMR (d.sup.6-DMSO,
300 MHz) .delta. 1.01 (t, J=7.65 Hz, 3H), 2.04 (s, 3H), 2.69 (q,
J=7.65 Hz, 2H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.59 (br m, 1H),
3.67 (br m, 1H), 3.73 (br m, 1H), 6.64 (d, J=8.7 Hz, 1H), 7.38 (dd,
J=2.4, 7.5 Hz, 1H), 7.40 (d, J=15.6 Hz, 1H), 7.50-7.61 (m, 3H),
7.53 (d, J=15.6 Hz, 1H), 7.89 (dd, J=2.4, 8.7 Hz, 1H), 8.64 (d,
J=2.4 Hz, 1H). MS (APCI) (M+Cl).sup.- at m/z 474, 476.
EXAMPLE 50
(2-iso-Propylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 32 substituting 2,4-dichlorothiophenol with
2-isopropylthiophenol. Light-yellow powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.05 (d, J=6.9 Hz, 6H), 2.04 (s,
3H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.67 (br m,
1H), 3.72 (br m, 1H), 6.64 (d, J=8.4 Hz, 1H), 7.34-7.41 (m, 2H),
7.39 (d, J=15.3 Hz, 1H), 7.52 (d, J=15.3 Hz, 1H), 7.56-7.73 (m,
2H), 7.90 (dd, J=2.1, 8.7 Hz, 1H), 8.64 (d, J=2.1 Hz, 1H). MS
(APCI) (M+NH.sub.4).sup.30 at m/z 471. Analysis calculated for
C.sub.24H.sub.27N.sub.3O.sub.4S.sub.1.0.21H.sub.2O: C, 63.03; H,
5.96; N, 9.13. Found: C, 63.03; H, 6.04; N, 9.19.
EXAMPLE 51
(2-tert-Butylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 32 substituting 2,4-dichlorothiophenol with
2-tert-butylthiophenol. Light-yellow powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.46 (s, 9H), 2.04 (s, 3H), 3.47
(br m, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.67 (br m, 1H), 3.73
(br m, 1H), 6.68 (d, J=8.7 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.39
(d, J=15.3 Hz, 1H), 7.45-7.57 (m, 2H), 7.50 (d, J=15.3 Hz, 1H),
7.65 (d, J=8.1 Hz, 1H), 7.88 (dd, J=2.4, 8.7 Hz, 1H), 8.64 (d,
J=2.4 Hz, 1H). MS (APCI) (M+NH.sub.4).sup.+ at m/z 485.
EXAMPLE 52
(2-Chlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl))2-propen-
yl)phenyl]sulfide
EXAMPLE 52A
3'-Chloro-4'-[(2-chlorophenyl)thio]acetophenone
The title compound was prepared by the procedures described in
Example 1A substituting 2,4-dichlorothiophenol with
2-chlorothiophenol, and 2-chlorobenzaldehyde with
4'-fluoro-3'-chloroacetophenone.
EXAMPLE 52B
(2-Chlorophenyl)[2-chloro-4-(E-(1-ethoxycarbonyl)2-propenyl)phenyl]sulfide
To a stirred suspension of NaH (60% in mineral oil, 121 mg, 3.03
mmol) in 20 mL of anhydrous THF under nitrogen atmosphere was added
triethyl phosphonoacetate dropwise. After 20 minutes, the
acetophenone (600 mg, 2.02 mmol) from Example 52A in THF (5 mL) was
added in one portion. The resulting clear solution was then stirred
at room temperature for 7 hours. Reaction was then stopped, most of
the solvent was evaporated, and the residue was partitioned between
EtOAc (2.times.20 mL) and water. The combined organic layer was
washed with water and brine, dried over Na.sub.2SO.sub.4,
concentrated in vacuo. The crude product was purified using silica
gel flash column chromatography eluting with 5-10% Et.sub.2O in
hexanes to give the (E)-isomer of the cinnamate (500 mg, 68%) as a
white solid.
EXAMPLE 52C
(2-Chlorophenyl)[2-chloro-4-(E-(1-carboxy)2-propenyl)phenyl]sulfide
A mixture of the cinnamate (500 mg, 1.37 mmol) from Example 52B in
5 mL of EtOH/THF (4:1) was stirred with sat. LiOH solution (0.50
mL) at 50.degree. C.[...]. for 2 hours. The mixture was then
acidified with 3N HCl and extracted with CH.sub.2Cl.sub.2
(3.times.10 mL). The combined organic layer was dried over
MgSO.sub.4, concentrated under reduced pressure to give the
.[.titled.]. .Iadd.title .Iaddend.compound (450 mg, 97%) as a white
solid.
EXAMPLE 52D
(2-Chlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl))2-propen-
yl)phenyl]sulfide
The title compound was prepared using the cinnamic acid from
Example 52C by the procedures described in Example 1C substituting
6-amino-1-hexanol with 1-acetylpiperazine. White solid; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 2.10-2.20 (m, 3H), 2.25 (s, 3H),
3.40-3.80 (m, 8H), 6.28 (s, 1H), 7.00 (d, J=8.7 Hz, 1H), 7.19-7.36
(m, 4H), 7.46-7.56 (m, 2H). MS (APCI) (M+NH.sub.4).sup.+ at m/z
466, 468, 470.
EXAMPLE 53
(2-(1-Morpholinylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)eth-
enyl)phenyl]sulfide
EXAMPLE 53A
(2-(1-Bromomethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)p-
henyl]sulfide
To a stirred solution of benzyl alcohol (195 mg, 0.32 mmol) from
Example 11 in 2.0 mL of anhydrous DMF was added LiBr (48 mg, 0.35
mmol). The mixture was then cooled in an ice-water bath, and
PBr.sub.3 (60 .mu.L, 0.40 mmol) was dropped in slowly. The ice bath
was then removed and the mixture was stirred at room temperature
for 1 hour. Water was then added, the mixture was then partitioned
between EtOAc and aqueous NaHCO.sub.3. The aqueous layer was
extracted with EtOAc once. The combined organic layer was washed
with water and brine, dried over Na.sub.2SO.sub.4, concentrated on
a rotavap. The crude bromide (230 mg) was used directly for the
alkylation without purification.
EXAMPLE 53B
(2-(1-Morpholinylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)eth-
enyl)phenyl]sulfide
To a stirred solution of morpholine (10 .mu.L, 0.11 mmol) in 0.5 mL
of CH.sub.3CN was added Hunig base (23.7 .mu.L, 0.14 mmol),
followed by the bromide (40 mg, 0.091 mmol). The mixture was then
stirred at room temperature for 2 hours. Solvent was then removed
and the crude product was purified with Gilson Preparative HPLC as
described in Example 38B to give the .[.titled.]. .Iadd.title
.Iaddend.compound as a white solid. .sup.1H NMR (d.sup.6-DMSO, 300
MHz) .delta. 2.33 (br t, 4H), 3.45 (br t, 4H), 3.50-3.65 (m, 6H),
3.56 (s, 2H), 3.65-3.80 (br m, 2H), 6.74 (d, J=8.7 Hz, 1H), 7.30
(d, J=15.3 Hz, 1H), 7.35-7.41 (m, 2H), 7.43 (d, J=15.3 Hz, 1H),
7.46 (td, J=2.4, 8.1 Hz, 1H), 7.52 (dd, J=2.1, 8.7 Hz, 1H), 7.56
(d, J=8.1 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H). MS (DCI/NH.sub.3)
(M+H).sup.+ at m/z 459, 461.
EXAMPLE 54
(2-(4-(1,3-Benzodioxolyl-5-methyl)piperazin-1-ylmethyl)phenyl)[2-chloro-4--
(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 53B substituting morpholine with 1-piperonylpiperazine.
White solid; .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 2.13-2.40
(br m, 8H), 3.28 (s, 2H), 3.49-3.64 (br m, 6H), 3.54 (s, 2H), 3.70
(br m, 2H), 5.97 (s, 2H), 6.69 (dd, J=1.8, 8.1 Hz, 1H), 6.74 (d,
J=8.7 Hz, 1H), 6.79 (d, J=1.8 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 7.39
(d, J=15.3 Hz, 1H), 7.33-7.38 (m, 2H), 7.38-7.50 (m, 2H), 7.43 (d,
J=15.3 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 8.00 (d, J=2.1 Hz, 1H). MS
(DCI/NH.sub.3) (M+H).sup.+ at m/z 592, 594.
EXAMPLE 55
(2-(4-(iso-Propylaminocarbonylmethyl)piperazin-1-ylmethyl)phenyl)[2-chloro-
-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 53B substituting morpholine with
N-isopropyl-1-piperazineacetamide. White solid; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.04 (d, J=6.3 Hz, 6H), 2.20-2.42
(br m, 8H), 2.78 (s, 2H), 3.47-3.64 (br m, 6H), 3.56 (s, 2H),
3.64-3.76 (br m, 2H), 3.85 (qd, J=6.3, 8.1 Hz, 1H), 6.73 (d, J=8.7
Hz, 1H), 7.29 (d, J=15.6 Hz, 1H), 7.31-7.39 (m, 2H), 7.43 (d,
J=15.6 Hz, 1H), 7.45 (td, J=2.7, 6.3 Hz, 1H), 7.50 (dd, J=2.1, 8.7
Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 8.00 (d, J=2.1 Hz, 1H). MS
(DCI/NH.sub.3) (M+H).sup.+ at m/z 557, 559.
EXAMPLE 56
(2-((N-Ethoxycarbonylmethyl-N-methyl)aminomethyl)phenyl)[2-chloro-4-(E-((1-
-morpholinyl)carbonyl)ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 53B substituting morpholine with ethyl sarcosinate
hydrochloride. White solid; .sup.1H NMR (d.sup.6-DMSO, 300 MHz)
.delta. 1.16 (t, J=7.2 Hz, 3H), 2.27 (s, 2H), 3.30 (s, 2H),
3.51-3.66 (br m, 6H), 3.66-3.75 (br m, 2H), 3.78 (s, 2H), 4.05 (q,
J=7.2 Hz, 2H), 6.75 (d, J=8.7 Hz, 1H), 7.30 (d, J=15.3 Hz, 1H),
7.33-7.38 (m, 2H), 7.42-7.50 (m, 2H), 7.43 (d, J=15.3 Hz, 1H), 7.53
(dd, J=2.1, 8.7 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 8.02 (d, J=2.1 Hz,
1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 489, 491.
EXAMPLE 57
(2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sul-
fide
To a stirred solution of the alcohol (368 mg, 0.94 mmol) from
Example 11 in 5 mL of anhydrous acetonitrile was added activated 4
.ANG. molecular sieves, TPAP (3.3 mg, 0.0094 mmol), and NMO (110
mg, 1.03 mmol). The mixture was then stirred at room temperature
for 3 hours. The reaction mixture was then quenched with dimethyl
sulfide (100 .mu.L). The crude product was filtered through celite,
washed with acetonitrile, .Iadd.and .Iaddend.condensed in vacuo.
The .[.titled.]. .Iadd.title .Iaddend.compound was purified by
silica gel column chromatography to give a white solid (216 mg,
59%). .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 3.60 (br m, 6H),
3.73 (br m, 2H), 7.00 (d, J=8.4 Hz, 1H), 7.40 (d, J=15.3 Hz, 1H),
7.42 (d, J=8.4 Hz, 1H), 7.51 (d, J=15.3 Hz, 1H), 7.52 (td, J=1.8,
8.1 Hz, 1H), 7.61 (td, J=1.8, 8.1 Hz, 1H), 7.71 (dd, J=2.1, 8.4 Hz,
1H), 8.02 (dd, J=2.1, 8.4 Hz, 1H), 8.14 (d, J=2.1 Hz, 1H). MS
(DCI/NH.sub.3) (M+H).sup.+ at m/z 388, 390.
EXAMPLE 58
(2-(4-Formylpiperazin-1-ylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)car-
bonyl)ethenyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 53B substituting morpholine with 1-formyl piperazine. White
solid; .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 2.20-2.32 (m,
6H), 2.74 (br m, 2H), 3.48 (s, 2H), 3.59 (m, 6H), 3.70 (br m, 2H),
6.74 (d, J=8.7 Hz, 1H), 7.29 (d, J=15.6 Hz, 1H), 7.35-7.41 (m, 2H),
7.42 (d, J=15.6 Hz, 1H), 7.45-7.52 (m, 3H), 7.98 (d, J=2.1, 1H). MS
(DCI/NH.sub.3) (M+H).sup.+ at m/z 486, 488.
EXAMPLE 59
(2-(E-((1-Morpholinyl)carbonyl)ethenyl)phenyl)[2-chloro-4-(E-((1-morpholin-
yl)carbonyl)ethenyl)phenyl]sulfide
A mixture of bromide (80 mg, 0.18 mmol) from Example 12,
acryloylmorpholine (33 mg, 0.23 mmol), Pd(Oac).sub.2 (2.0 mg, 0.009
mmol), P(o-tolyl).sub.3 (17 mg, 0.056 mmol), Et.sub.3N (39 .mu.L,
0.27 mmol), and anhydrous DMF (1.0 mL) in a pressure tube was
flushed with nitrogen for 5 minutes before it .Iadd.was
.Iaddend.capped and heated at 110.degree. C.[.. over night.].
.Iadd.overnight.Iaddend.. TLC indicated almost complete consumption
of the starting bromide. The reaction mixture was then allowed to
cool .[.down.]. to room temperature.[.,.]. .Iadd.and
.Iaddend.partitioned between EtOAc and water. The aqueous layer was
extracted once with EtOAc. The combined organic layer was washed
with water and brine, dried over Na.sub.2SO.sub.4.[.,.]. .Iadd.and
.Iaddend.condensed under reduced pressure. The crude product was
purified with Gilson Preparative HPLC as described in Example 38B
to give the .[.titled.]. .Iadd.title .Iaddend.compound as a
light-brown solid (35 mg, 39%). .sup.1H NMR (d.sup.6-DMSO, 300 MHz)
.delta. 3.43-3.88 (m, 16H), 6.58 (d, J=8.7 Hz, 1H), 7.30 (d, J=15.3
Hz, 2H), 7.43 (d, J=15.3 Hz, 1H), 7.47-7.64 (m, 4H), 7.86 (d,
J=15.3 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H). MS
(DCI/NH.sub.3) (M+NH.sub.4).sup.+ m/z 516, 518. Analysis calculated
for C.sub.26H.sub.27N.sub.2O.sub.4Cl.sub.1S.sub.1.0.46H.sub.2O: C,
61.56; H, 5.55; N, 5.21. Found: C, 61.56; H, 5.50; N, 5.43.
EXAMPLE 60
(2-Formylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide
The title compound was prepared by the procedures described in
Example 57 substituting compound from Example 11 with compound from
Example 48. Yellow solid; .sup.1H NMR (d.sup.6-DMSO, 300 MHz)
.delta. 2.04 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.60 (br m,
1H), 3.68 (br m, 1H), 3.74 (br m, 1H), 6.85 (d, J=8.4 Hz, 1H), 7.44
(d, J=15.6 Hz, 1H), 7.55 (d, J=15.6 Hz, 1H), 7.61 (d, J=7.5 Hz,
1H), 7.73 (t, J=7.5 Hz, 1H), 7.80 (td, J=2.4, 7.5 Hz, 1H), 7.92
(dd, J=2.1, 9.0 Hz, 1H), 8.04 (dd, J=2.4, 7.5 Hz, 1H), 8.66 (d,
J=2.1 Hz, 1H), 10.29 (s, 1H). MS (APCI) (M+Cl).sup.- at m/z 474,
476.
EXAMPLE 61
(2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sul-
fide, N,N-dimethyl hydrazone
A mixture of the aldehyde (20 mg, 0.052 mmol) from Example 57,
1,1-dimethyl hydrazine (3.9 .mu.L, 0.052 mmol) in 0.5 mL of EtOH
with a tiny amount of AcOH was stirred at room temperature .[.over
night.]. .Iadd.overnight.Iaddend.. The solvent was then removed and
the product was purified by preparative TLC to give the
.[.titled.]. .Iadd.title .Iaddend.compound (20 mg, 90%) as a white
solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 2.91 (s, 6H),
3.55-3.82 (br m, 8H), 6.64 (d, J=8.7 Hz, 1H), 6.76 (d, J=15.3 Hz,
1H), 7.05 (dd, J=1.8, 8.7 Hz, 1H), 7.26 (td, J=1.8, 7.8 Hz, 1H),
7.43 (t, J=7.8 Hz, 1H), 7.47-7.57 (m, 2H), 7.54 (m, 2H), 8.04 (dd,
J=1.8, 8.7 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 430, 432,
434, 436.
EXAMPLE 62
(2-((3-(1-Morpholinyl)propyl)-1-amino)phenyl)[2-chloro-4-(E-((1-morpholiny-
l)carbonyl)ethenyl)phenyl]sulfide
A mixture of bromide (60 mg, 0.14 mmol) from Example 12,
aminopropylmorpholine (24 .mu.L, 0.17 mmol), Pd.sub.2(dba).sub.3
(1.2 mg, 0.0013 mmol), BINAP (2.5 mg, 0.004 mmol), NaOt-Bu (19 mg,
0.20 mmol), 18-crown-6 (50 mg, 0.20 mmol), and anhydrous toluene (1
mL) in a pressure tube was flushed with nitrogen for 3 minutes
before it was capped and heated at 80.degree. C.[.. over night.].
.Iadd.overnight.Iaddend.. The reaction was then stopped, and
allowed to cool .[.down.]. to room temperature. The reaction
mixture was partitioned between EtOAc and water, and the aqueous
layer was extracted once with EtOAc. The combined organic layer was
then washed with water and brine, dried over Na.sub.2SO.sub.4,
.Iadd.and .Iaddend.condensed under reduced pressure. The crude
product was purified with Gilson Preparative HPLC as described in
Example 38B to give the .[.titled.]. .Iadd.title .Iaddend.compound
as a light-brown oil (30 mg, 44%). .sup.1H NMR (d.sup.6-DMSO, 300
MHz) .delta. 1.62 (quintet, J=6.5 Hz, 2H), 2.15-2.26 (m, 8H), 3.17
(q, J=6.5 Hz, 2H), 3.22-3.76 (m, 12H), 3.50 (t, J=6.5 Hz, 2H), 5.72
(t, J=5.7 Hz, 1H), 6.47 (d, J=8.7 Hz, 1H), 6.68 (t, J=7.2 Hz, 1H),
6.81 (d, J=8.4 Hz, 1H), 7.26 (d, J=15.6 Hz, 1H), 7.35-7.42 (m, 2H),
7.43 (d, J=15.6 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz,
1H), 8.00 (d, J=2.1 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z 502,
504.
EXAMPLE 63
.[.(2,4-Dichlorophenyl)[2-bromo-4-(E-((3-(1-pyrrolidin-2-only)propylamino)-
carbonyl)ethenyl)phenyl]sulfide.].
.Iadd.(2,4-Dichlorophenyl)[2-bromo-4-(E-((3-(2-oxopyrrolidin-1-yl)propyla-
mino)carbonyl)ethenyl)phenyl]sulfide.Iaddend.
EXAMPLE 63A
.[.(2,4-Dichlorophenyl)[2-amino-4-(E-((3-(1-pyrrolidin-2-only)propylamino)-
carbonyl ethenyl)phenyl]sulfide.].
.Iadd.(2,4-Dichlorophenyl)[2-amino-4-(E-((3-(2-oxopyrrolidin-1-yl)propyla-
mino)carbonyl)ethenyl)phenyl]sulfide.Iaddend.
A mixture of nitro compound (780 mg, 1.58 mmol) from Example 33,
SnCl.sub.2 (1.50 g, 7.91 mmol) in 25 mL of anhydrous EtOH was
refluxed under nitrogen atmosphere for 90 minutes. The reaction was
then allowed to cool .[.down.]. to room temperature, quenched with
sat. NaHCO.sub.3, .Iadd.and .Iaddend.extracted with EtOAc
(2.times.50 mL). The combined organic layer was washed with water
and brine, dried over Na.sub.2SO.sub.4, .Iadd.and
.Iaddend.condensed in vacuo to give the crude aniline as .Iadd.a
.Iaddend.yellowish brown solid, which was converted to the bromide
without purification.
EXAMPLE 63B
.[.(2,4-Dichlorophenyl)[2-bromo4-(E-((3-(1-pyrrolidin-2-only)propylamino)c-
arbonyl)ethenyl)phenyl]sulfide.].
.Iadd.(2,4-Dichlorophenyl)[2-bromo-4-(E-((3-(2-oxopyrrolidin-1-yl)propyla-
mino)carbonyl)ethenyl)phenyl]sulfide.Iaddend.
To a stirred solution of t-butyl nitrite (57 .mu.L, 0.48 mmol),
CrBr.sub.2 (87 mg, 0.39 mmol) in 2.0 mL of CH.sub.3CN at room
temperature was added a solution of aniline from Example 63A (150
mg, 0.323 mmol) in 1.0 mL of CH.sub.3CN. The dark green solution
was then heated at 65.degree. C.[...]. under nitrogen atmosphere
for 90 minutes. The reaction mixture was then allowed to cool
.[.down.]. to room temperature, .Iadd.and .Iaddend.partitioned
between EtOAc and 3N HCl. The organic layer was then washed with
brine, dried over Na.sub.2SO.sub.4, .Iadd.and .Iaddend.condensed in
vacuo. The crude product was then purified with Gilson Preparative
HPLC as described in Example 38B to give the .[.titled.].
.Iadd.title .Iaddend.compound as a light-brown solid (50 mg, 29%).
Colorless oil; .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 1.63
(quintet, J=7.2 Hz, 2H), 1.91 (quintet, J=8.4 Hz, 2H), 2.22 (t,
J=8.4 Hz, 2H), 3.09-3.47 (m, 6H), 6.67 (d, J=15.3 Hz, 1H), 7.07 (d,
J=8.4 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.38 (d, J=15.3 Hz, 1H),
7.50 (dd, J=2.4, 8.7 Hz, 1H), 7.57 (dd, J=2.1, 8.4 Hz, 1H), 7.86
(d, J=2.4 Hz, 1H), 7.96 (d, J=2.1 Hz, 1H), 8.13 (t, J=6.0 Hz, 1H).
MS (ESI) (M+H).sup.+ at m/z 527, 529, 531, 533.
EXAMPLE 64
(2,4-Dichlorophenyl)[2-bromo-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]-
sulfide
EXAMPLE 64A
[1-Fluoro-2-formyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)benzene
The title compound was prepared by the procedures described in
Example 59 substituting the bromide from Example 12 with
2-fluoro-5-bromobenzaldehyde.
EXAMPLE 64B
(2,4-Dichlorophenyl)[2-bromo-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]-
sulfide
The title compound was prepared by the procedures described in
Example 32 substituting 4-chloro-3-nitro-cinnamide with the
compound from Example 64A. White solid: .sup.1H NMR (d.sup.6-DMSO,
300 MHz) .delta. 3.60 (br m, 6H), 3.71 (br m, 2H), 6.82 (d, J=8.7
Hz, 1H), 7.35 (d, J=15.6 Hz, 1H), 7.54 (d, J=15.6 Hz, 1H), 7.55
(dd, J=2.4, 8.7 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.86 (dd, J=2.4,
8.4 Hz, 1H), 7.91 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.1 Hz, 1H), 10.19
(s, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 422, 424, 426,
428.
EXAMPLE 65
(2-Chloro-6-formylphenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
EXAMPLE 65A
(2-Carbomethoxyethyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide
The title compound was prepared by the procedures described in
Example 1 substituting 2,4-dichlorothiophenol with methyl
3-mercaptopropionate, and 6-amino-1-hexanol with 1-acetyl
piperazine.
EXAMPLE 65B
(2-Chloro-6-formylphenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
To a stirred solution of the compound (105 mg, 0.26 mmol) from
Example 65A in 2 mL of THF under nitrogen atmosphere at 0.degree.
C.[...]. was added t-BuOK solution (1.0M, 281 .mu.L, 0.29 mmol).
Light orange precipitates appeared immediately. After completion of
the addition, the reaction mixture was stirred at room temperature
for 1 hour before the solvent was removed on a rotavap under
reduced pressure.
The yellow thiolate thus obtained was dissolved in 0.5 mL of DMF,
and 2,3-dichlorobenzaldehyde was then added. The mixture was then
heated at 80.degree. C.[...]. under nitrogen for 2 hours. Reaction
was then stopped and the solvent was removed under vacuum. The
crude product was purified with Gilson Preparative HPLC as
described in Example 38B to give the .[.titled.]. .Iadd.title
.Iaddend.compound as a white solid (25 mg, 21%). .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 2.05 (s, 3H), 3.48-3.58 (m, 2H),
3.58-3.84 (m, 6H), 6.53 (d, J=8.7 Hz, 1H), 6.80 (d, J=15.3 Hz, 1H),
7.19 (dd, J=1.8, 8.7 Hz, 1H), 7.51-7.62 (m, 2H), 7.60 (d, J=15.3
Hz, 1H), 7.84 (dd, J=1.8, 8.4 Hz, 1H), 7.99 (dd, J=1.8, 8.4 Hz,
1H). MS (APCI) (M+NH.sub.4).sup.+ at m/z 480, 482, 484.
Compounds that antagonize the interaction between ICAM-1 and LFA-1
can be identified, and their activities quantitated, using both
biochemical and cell-based adhesion assays. A primary biochemical
assay measures the ability of the compound in question to block the
interaction between the integrin LFA-1 and its adhesion partner
ICAM-1, as described below:
ICAM-1/LFA-1 Biochemical Interaction Assay
In the biochemical assay, 100 .mu.L of anti-LFA-1 antibody (ICOS
Corporation) at a concentration of 5 .mu.g/.[.ml.]. .Iadd.mL
.Iaddend.in Dulbecco's phosphate-buffered saaline (D-PBS) is used
to coat wells of a 96-well microtiter plate overnight at 4.degree.
C. The wells .[.are.]. .Iadd.were .Iaddend.then washed twice with
wash buffer (D-PBS w/o Ca.sup.++ or Mg.sup.++, 0.05% Tween 20) and
blocked by addition of 200 .mu.L of D-PBS, 5% fish skin gelatin.
Recombinant LFA-1 (100 .mu.L of 0.7 .mu.g/.[.ml.].
.Iadd.mL.Iaddend., ICOS Corporation) in D-PBS .[.is.]. .Iadd.was
.Iaddend.then added to each well. Incubation .[.continues.].
.Iadd.continued .Iaddend.for 1 hour at room temperature and the
wells .[.are.]. .Iadd.were .Iaddend.washed twice with wash buffer.
Serial dilutions of compounds being assayed as ICAM-1/LFA-1
antagonists, .Iadd.were .Iaddend.prepared as 10 mM stock solutions
in dimethyl sulfoxide (DMSO), .[.are.]. .Iadd.were .Iaddend.diluted
in D-PBS, 2 mM MgCl.sub.2, 1% fish skin gelatin and 50 .mu.L of
each dilution .Iadd.was .Iaddend.added to duplicate wells. This
.[.is.]. .Iadd.was .Iaddend.followed by .Iadd.the .Iaddend.addition
of 50 .mu.L of 0.8 .mu.g/.[.ml.]. .Iadd.mL .Iaddend.biotinylated
recombinant ICAM-1/Ig (ICOS Corporation) to the wells and the
plates .[.are.]. .Iadd.were .Iaddend.incubated at room temperature
for 1 hour. The wells .[.are.]. .Iadd.were .Iaddend.then washed
twice with wash buffer and 100 .mu.L of Europium-labeled
Streptavidin (Wallac Oy) diluted 1:100 in Delfia assay buffer
(Wallac Oy).Iadd., .Iaddend..[.are.]. .Iadd.was then .Iaddend.added
to the wells. Incubation .[.proceeds.]. .Iadd.proceeded
.Iaddend.for 1 hour at room temperature. The wells .[.are.].
.Iadd.were .Iaddend.washed eight times with wash buffer and 100
.mu.L of enhancement solution (Wallac Oy, cat. No. 1244-105)
.[.are.]. .Iadd.was .Iaddend.added to each well. Incubation
.[.proceeds.]. .Iadd.proceeded .Iaddend.for 5 minutes with constant
mixing. Time-resolved fluorimetry measurements .[.are.]. .Iadd.were
.Iaddend.made using .[.the.]. .Iadd.a .Iaddend.Victor 1420
Multilabel Counter (Wallac Oy) and the percent inhibition of each
candidate compound .[.is.]. .Iadd.was .Iaddend.calculated using the
following equation: .times. ##EQU00001## where "background" refers
to wells that .[.are.]. .Iadd.were .Iaddend.not coated with
anti-LFA-1 antibody.
Compounds of the present invention .[.exhibit.]. .Iadd.exhibited
.Iaddend.inhibitory activity in the above assay as follows:
TABLE-US-00001 Compound % inhibition of Example @ 4 .mu.M 1 75 2 73
3 75 4 72 5 73 6 85 7 87 8 74 9 93 10 79 11 87 12 90 13 79 14 82 15
88 16 86 17 84 18 86 19 93 20 82 21 80 22 90 23 90 24 80 25 82 26
94 27 94 28 87 29 84 30 93 31 92 32 92 33 91 34 91 35 89 36 90 37
91 38 91 39 86 40 90 41 83 42 56 43 82 44 78 45 88 46 87 47 82 48
89 49 93 50 94 51 84 52 86 53 87 54 86 55 82 56 83 57 90 58 80 59
92 60 95 61 88 62 92 63 82 64 81 65 86
Biological relevant activity of the compounds in this invention is
confirmed using a cell-based adhesion assay, which measures their
ability to block the adherence of JY-8 cells (a human
EBV-trasformed B cell line expressing LFA-1 on its surface) to
immobilized ICAM-1, as follows:
ICAM-1/JT-8 Cell Adhesion Assay
For .[.measurment.]. .Iadd.measurement .Iaddend.of .[.inhibotory.].
.Iadd.inhibitory .Iaddend.activity in the cell-based adhesion
assay, 96-well microtiter plates .[.are.]. .Iadd.were
.Iaddend.coated with 70 .mu.L of .[.recombinat.]. .Iadd.recombinant
.Iaddend.ICAM-1/Ig (ICOS Corporation) at a concentration of 5
.mu.g/mL in D-PBS .[.w/o.]. .Iadd.without .Iaddend.Ca.sup.++ .[.or
Mg++.]. .Iadd.or Mg.sup.++ .Iaddend.overnight at 4.degree. C. The
wells .[.are.]. .Iadd.were .Iaddend.then washed twice with D-PBS
and blocked by addition of 200 .mu.L of D-PBS, 5% fish skin gelatin
by incubation for 1 hour at room temperature. Fluorescent tagged
JY-8 cells (a human EBV-transformed B cell line .[.expresing.].
.Iadd.expressing .Iaddend.LFA-1 on its surface; 50 .mu.L at
2.times.10.sup.6 cells/.[.ml.]. .Iadd.mL .Iaddend.in RPMI 1640/1%
fetal .[.bovene.]. .Iadd.bovine .Iaddend.serum) .[.are.].
.Iadd.were .Iaddend.added to the wells. For fluorescent
.[.labelind.]. .Iadd.labelling .Iaddend.of JY-8 cells,
5.times.10.sup.6 cells washed once in RPMI 1640 .[.are.].
.Iadd.were .Iaddend.resuspended in 1 mL of RPMI 1640 containing 2
.mu.M Calceiun AM (Molecular.Iadd. .Iaddend.Probes), .[.are.].
.Iadd.were .Iaddend.incubated at 37.degree. C.[...]. for 30
minutes.Iadd., .Iaddend.and washed once with RPMI-1640/1% fetal
bovine serum. Dilutions of compounds to be assayed for ICAM-1/LFA-1
antagonistic activity .[.are.]. .Iadd.were .Iaddend.prepared in
RPMI-1640/1% fetal bovine serum from 10 mM stock solutions in DMSO
and 50 .mu.L .[.are.]. .Iadd.were .Iaddend.added to duplicate
wells. Microtiter plates .[.are.]. .Iadd.were .Iaddend.incubated
for 45 minutes at room temperature and the wells .[.are.].
.Iadd.were .Iaddend.washed gently once with RPMI-1640/1% fetal
bovine serum. Fluorescent intensity .[.is.]. .Iadd.was
.Iaddend.measured in a fluorescent plate reader with an excitation
wavelength at 485 nM and an emission wavelength at 530 nM. The
percent inhibition of a candidate compound at a given concentration
.[.is.]. .Iadd.was .Iaddend.calculated using the following
equation: .times. ##EQU00002## and these concentration/inhibition
data .[.are.]. .Iadd.were .Iaddend.used to generate does response
curves, from which IC.sub.50 values .[.are.]. .Iadd.were
.Iaddend.derived. Compounds of the present invention .[.exhibit.].
.Iadd.exhibited .Iaddend.blocking activity in the above assay as
follows:
TABLE-US-00002 Compound of Example IC.sub.50 nM 1 2,100 2 13,000 3
2,500 4 680 5 2,900 6 660 7 1,200 8 2,900 9 130 10 1,500 11 260 12
360 13 1,100 14 790 15 140 16 300 17 5,800 18 130 19 450 20 3,300
21 520 22 200 23 600 24 8,000 25 11,000 26 110 27 160 28 370 29 160
30 250 32 190 32 45 33 300 34 70 35 430 36 320 37 140 38 250 39 250
40 280 41 110 42 520 43 100 44 70 45 50 46 60 47 370 48 200 49 20
50 10 51 690 52 420 53 700 54 360 55 100 56 510 57 220 58 1,600 59
200 60 30 61 540 62 340 63 850 65 1,200
Compounds of the present invention have been demonstrated to act
via interaction with the integrin LFA-1, specifically by binding to
the interaction domain (I-domain), which is known to be critical
for the adhesion of LFA-1 to a variety of cell adhesion molecules.
As such, it is expected that these compounds should block the
interaction of LFA-1 with other CAM's. This has in fact been
demonstrated for the case of ICAM-3. Compounds of the present
invention may be evaluated for their ability to block the adhesion
of JY-8 cells (a human EBV-transformed B cell line expressing LFA-1
on its surface) to immobilized ICAM-3, as follows:
ICAM-3/JY-8 Cell Adhesion Assay
For measurement of inhibitory activity in the cell-based adhesion
assay, 96-well microtiter plates .[.are.]. .Iadd.were
.Iaddend.coated with 50 .mu.L of recombinant ICAM-3/Ig (ICOS
Corporation) at a concentration of 10 .mu.g/mL in D-PBS .[.w/o.].
.Iadd.without .Iaddend.Ca.sup.++ or Mg.sup.++ overnight at
4.degree. C. The wells .[.are.]. .Iadd.were .Iaddend.then washed
twice with D-PBS, blocked by addition of 100 .mu.L of D-PBS, 1%
bovine serum albumin (BSA) by incubation for 1 hour at room
temperature, and washed once with RPMI-1640/5% heat-inactivated
fetal bovine serum (adhesion buffer). Dilutions of compounds to be
assayed for ICAM-3/LFA-1 antagonistic activity .[.are.]. .Iadd.were
.Iaddend.prepared in adhesion buffer from 10 mM stock solutions in
DMSO and 100 .mu.L .[.are.]. .Iadd.were .Iaddend.added to duplicate
wells. JY-8 cells (a human EBV-transformed B cell line expressing
LFA-1 on its surface; 100 .mu.L at 0.75.times.10.sup.6
cells/.[.ml.]. .Iadd.mL .Iaddend.in adhesion buffer) .[.are.].
.Iadd.were .Iaddend.then added to the wells. Microtiter plates
.[.are.]. .Iadd.were .Iaddend.incubated for 30 minutes at room
temperature; the adherent cells .[.are.]. .Iadd.were .Iaddend.then
fixed with 50 .mu.L of 14% glutaraldehyde/D-PBS and .Iadd.were
.Iaddend.incubated for an additional 90 minutes. The wells
.[.are.]. .Iadd.were .Iaddend.washed gently with dH.sub.2O; 50
.mu.L of dH.sub.2O .[.is.]. .Iadd.was .Iaddend.added,
.[.following.]. .Iadd.followed .Iaddend.by 50 .mu.L of 1% crystal
violet. After 5 minutes the plates .[.are.]. .Iadd.were
.Iaddend.washed 3.[..times..]. .Iadd.times .Iaddend.with dH.sub.2O;
75 .mu.L of dH.sub.2O and 225 .mu.L of 95% EtOH .[.are.].
.Iadd.were .Iaddend.added to each well to extract the crystal
violet from the cells. Absorbance .[.is.]. .Iadd.was
.Iaddend.measured at 570 nM in an ELISA plate reader. The percent
inhibition of a candidate compound .[.is.]. .Iadd.was
.Iaddend.calculated using the following equation. .times.
##EQU00003## Compounds of the present invention .[.exhibit.].
.Iadd.exhibited .Iaddend.blocking activity in the above assay as
follows.[...]. .Iadd.:.Iaddend.
TABLE-US-00003 Compound % inhibition Of Example @ 0.6 .mu.M 9 100
12 100 15 100 16 100 17 100 18 100 26 100 27 100 30 100 32 100 34
100 35 100 41 100 45 100 46 100 49 100 50 100 54 100 59 100 60 100
62 100
The ability of the compounds of this invention to treat arthritis
can be demonstrated in a murine collagen-induced arthritis model
according to the method of Kakimoto, et al., Cell Immunol 142:
326-337, 1992, in a rat collagen-induced arthritis model according
to the method of Knoerzer, et al., Toxicol Pathol 25:13-19, 1997,
in a rat adjuvant arthritis model according to the method of
Halloran, et al., .[.Arthitis.]. .Iadd.Arthritis .Iaddend.Rheum 39:
810-819, 1996, in a rat streptococcal cell wall-induced arthritis
model according to the method of Schimmer, et al., J. Immunol 160:
1466-1477, 1998, or in a SCID-mouse human rheumatoid arthritis
model according to the method of Oppenheimer-Marks et al., J Clin.
Invest 101: 1261-1272, 1998.
The ability of the compounds of this invention to treat Lyme
arthritis can be demonstrated according to the method of Gross et
al., Science 281, 703-706, 1998.
The ability of compounds of this invention to treat asthma can be
demonstrated in a murine allergic asthma model according to the
method of Wegner et al., Science 247:456-459, 1990, or in a murine
non-allergic asthma model according to the method of Bloemen et
al., Am J Respir Crit Care Med 153:521-529, 1996.
The ability of compounds of this invention to treat inflammatory
lung injury can be demonstrated in a murine oxygen-induced lung
injury model according to the method of Wegner et al., Lung
170:267-279, 1992, in a murine immune complex-induced lung injury
model according to the method of Mulligan et al., J Immunol
154:1350-1363, 1995, or in a murine acid-induced lung injury model
according to the method of Nagase, et al., Am J Respir Crit Care
Med 154:504-510, 1996.
The ability of compounds of this invention to treat inflammatory
bowel disease can be demonstrated in a rabbit chemical-induced
colitis model according to the method of Bennet et al., J Pharmacol
Exp Ther 280:988-1000, 1997.
The ability of compounds of this invention to treat autoimmune
diabetes can be demonstrated in an NOD mouse model according to the
method of Hasagawa et al., Int Immunol 6:831-838, 1994, or in a
murine streptozotocin-induced diabetes model according to the
method of Herrold et al., Cell Immunol 157:489-500, 1994.
The ability of compounds of this invention to treat inflammatory
liver injury can be demonstrated in a murine liver injury model
according to the method of Tanaka et al., J Immunol 151:5088-5095,
1993.
The ability of compounds of this invention to treat inflammatory
glomerular injury can be demonstrated in a rat nephrotoxic serum
nephritis model according to the method of Kawasaki, et al., J
Immunol 150:1074-1083, 1993.
The ability of compounds of this invention to treat
radiation-induced enteritis can be demonstrated in a rat abdominal
irradiation model according to the method of Panes et al.,
Gastroenterology 108:1761-1769, 1995.
The ability of compounds of this invention to treat radiation
pneumonitis can be demonstrated in a murine pulmonary irradiation
model according to the method of Hallahan et al., Proc Natl Acad
Sci USA 94:6432-6437, 1997.
The ability of compounds of this invention to treat reperfusion
injury can be demonstrated in the isolated rat heart according to
the method of Tamiya et al., Immunopharmacology 29(1): 53-63, 1995,
or in the anesthetized dog according to the model of Hartman et
al., Cardiovasc Res 30(1): 47-54, 1995.
The ability of compounds of this invention to treat pulmonary
reperfusion injury can be demonstrated in a rat lung allograft
reperfusion injury model according to the method of DeMeester et
al., Transplantation 62(10): 1477-1485, 1996, or in a rabbit
pulmonary edema model according to the method of Horgan et al., Am
J Physiol 261(5): H1578-H1584, 1991.
The ability of compounds of this invention to treat stroke can be
demonstrated in a rabbit cerebral embolism stroke model according
the method of Bowes et al., Exp Neurol 119(2): 215-219, 1993, in a
rat middle cerebral artery ischemia-reperfusion model according to
the method of Chopp et al., Stroke 25(4): 869-875, 1994, or in a
rabbit reversible spinal cord ischemia model according to the
method of Clark et al., Neurosurg 75(4): 623-627, 1991.
The ability of compounds of this invention to treat peripheral
artery occlusion can be demonstrated in a rat skeletal muscle
ischemia/reperfusion model according to the method of Gute et al.,
Mol Cell Biochem 179: 169-187, 1998.
The ability of compounds of this invention to treat graft rejection
can be demonstrated in a murine cardiac allograft rejection model
according to the method of Isobe et al., Science 255: 1125-1127,
1992, in a murine thyroid gland kidney capsule model according to
the method of Talento et al., Transplantation 55: 418-422, 1993, in
a cynomolgus monkey renal allograft model according to the method
of Cosimi et al., J Immunol 144: 4604-4612, 1990, in a rat nerve
allograft model according to the method of Nakao et al., Muscle
Nerve 18: 93-102, 1995, in a murine skin allograft model according
to the method of Gorczynski and Wojcik, J Immunol 152: 2011-2019,
1994, in a murine corneal allograft model according to the method
of He et al., Opthalmol Vis Sci 35: 3218-3225, 1994, or in a
xenogeneic pancreatic islet cell transplantation model according to
the method of Zeng et al., Transplantation 58:681-689, 1994.
The ability of compounds of this invention to treat graft-vs.-host
disease (GVHD) can be demonstrated in a murine lethal GVHD model
according to the method of Haming et al., Transplantation
52:842-845, 1991.
The ability of compounds of this invention to treat cancers can be
demonstrated in a human lymphoma metastasis model (in mice)
according to the method of Aoudjit et al., J Immunol 161:2333-2338,
1998.
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