U.S. patent application number 09/828783 was filed with the patent office on 2001-10-18 for heteroaryl amidines, methylamidines and guanidines and use thereof as protease inhibitors.
Invention is credited to Hoffman, James B., Illig, Carl R., Marugan, Juan J., Rudolph, M. Jonathan, Subasinghe, Nalin L., Wilson, Kenneth J..
Application Number | 20010031781 09/828783 |
Document ID | / |
Family ID | 26755264 |
Filed Date | 2001-10-18 |
United States Patent
Application |
20010031781 |
Kind Code |
A1 |
Illig, Carl R. ; et
al. |
October 18, 2001 |
Heteroaryl amidines, methylamidines and guanidines and use thereof
as protease inhibitors
Abstract
The present invention is directed to compounds of Formula I:
wherein X is O, S or NR.sup.7 and R.sup.1-R.sup.7, Y and Z are set
forth in the specification, as well as hydrates, solvates or
pharmaceutically acceptable salts thereof. Also described are
methods for preparing the compounds of Formula I. The novel
compounds of the present invention are potent inhibitors of
proteases, especially trypsin-like serine proteases, such as
chymotrypsin, trypsin, plasmin and urokinase. Certain of the
compounds exhibit direct, selective inhibition of urokinase, or are
intermediates useful for forming compounds having such
activity.
Inventors: |
Illig, Carl R.;
(Phoenixville, PA) ; Subasinghe, Nalin L.; (West
Chester, PA) ; Hoffman, James B.; (Ardmore, PA)
; Wilson, Kenneth J.; (Exton, PA) ; Rudolph, M.
Jonathan; (Doylestown, PA) ; Marugan, Juan J.;
(Exton, PA) |
Correspondence
Address: |
STERNE, KESSLER, GOLDSTEIN & FOX PLLC
1100 NEW YORK AVENUE, N.W., SUITE 600
WASHINGTON
DC
20005-3934
US
|
Family ID: |
26755264 |
Appl. No.: |
09/828783 |
Filed: |
April 10, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09828783 |
Apr 10, 2001 |
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09372748 |
Aug 11, 1999 |
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09372748 |
Aug 11, 1999 |
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09247062 |
Feb 9, 1999 |
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60074110 |
Feb 9, 1998 |
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Current U.S.
Class: |
514/426 ;
514/447; 514/472; 548/557; 549/480; 549/68 |
Current CPC
Class: |
C07D 417/14 20130101;
C07D 413/04 20130101; C07D 409/04 20130101; C07D 417/12 20130101;
C07D 333/38 20130101; C07D 409/12 20130101; C07D 417/04
20130101 |
Class at
Publication: |
514/426 ;
514/447; 514/472; 549/480; 549/68; 548/557 |
International
Class: |
A61K 031/40; A61K
031/381; A61K 031/34 |
Claims
What is claimed is:
1. A compound of Formula I: 37or a solvate, hydrate or
pharmaceutically-acceptable salt thereof, wherein: X is O, S or
NR.sup.7, where R.sup.7 is hydrogen, alkyl, aralkyl,
hydroxy(C.sub.2-4)alkyl, or alkoxy(C.sub.2-4)alkyl; Y is a direct
covalent bond, CH.sub.2 or NH; Z is NR.sup.5R.sup.6, hydrogen or
alkyl, provided that Y is NH whenever Z is hydrogen or alkyl;
R.sup.1 is hydrogen, amino, hydroxy, halogen, cyano, C.sub.1-4
alkyl or --CH.sub.2R, where R is hydroxy, amino or C.sub.1-3
alkoxy; R.sup.2 and R.sup.3 are independently: i. hydrogen; ii.
halogen; iii. hydroxy; iv. nitro; v. cyano; vi. amino,
monoalkylamino, dialkylamino, monoarylamino, diarylamino,
monoalkylmonoarylamino, monoaralkylamino, diaralkylamino,
monoalkylmonoaralkylamino, monoheterocycleamino,
diheterocycleamino, monoalkylmonoheterocycleamino,
alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino,
alkylsulfonylamino, aralkylsulfonylamino, aralkenylsulfonylamino,
arylsulfonylamino, heteroarylsulfonylamino,
di(aralkylsulfonyl)amino, di(aralkenylsulfonyl)amino,
di(arylsulfonyl)amino, or di-(heteroarylsulfonyl)amino,
formylamino, alkanoylamino, alkenoylamino, alkynoylamino,
aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino,
heteroaralkanoylamino, H(S)CNH--, or thioacylamino, wherein any of
the aryl or heteroaryl containing groups can be optionally
substituted on the aromatic ring and wherein any of the heterocycle
containing groups can be optionally ring substituted; vii.
aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl,
aminoacyl, monoarylaminocarbonyl, diarylaminocarbonyl or
monoalkylmonoarylaminocarbo- nyl; viii. aminothiocarbonyl,
monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, thioacyl or
aminothioacyl; ix. aninocarbonylamino, mono- and
dialkylaminocarbonylamino, mono- and diarylaminocarbonylamino, or
mono- and diaralkylaminocarbonylamino; x. aminocarbonyloxy, mono-
and dialkylaminocarbonyloxy, mono- and diarylaminocarbonyloxy,
mono- and diaralkylaminocarbonyloxy; xi. aminosulfonyl, mono- and
dialkylaminosulfonyl, mono- and diarylaminosulfonyl, or mono- and
diaralkylaminosulfonyl; xii. alkoxy, or alkylthio, wherein the
alkyl portion of each group may be optionally substituted, xiii.
aralkoxy, aryloxy, heteroaryloxy, aralkylthio, arylthio, or
heteroarylthio, wherein the aryl portion of each group can be
optionally substituted; xiv. alkylsulfonyl, wherein the alkyl
portion can be optionally substituted; xv. aralkylsulfonyl,
aralkenylsulfonyl, arylsulfonyl or heteroarylsulfonyl, wherein the
aryl portion of each group can be optionally substituted; xvi.
alkenyl, or alkynyl; xvii. optionally substituted aryl; xviii.
optionally substituted alkyl; xix. optionally substituted aralkyl;
xx. optionally substituted heterocycle; or xxi. optionally
substituted cycloalkyl; and R.sup.4, R.sup.5 and R.sup.6 are
independently hydrogen, C.sub.1-4 alkyl, aryl, hydroxyalkyl,
aminoalkyl, monoalkylamino(C.sub.2-10)alkyl,
dialkylamino(C.sub.2-10)alky- l, carboxyalkyl, cyano, amino,
alkoxy, or hydroxy, or --CO.sub.2R.sup.w, where R.sup.w is alkyl,
cycloalkyl, phenyl, benzyl, 38where R.sup.d and R.sup.e are
independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or
phenyl, R.sup.f is hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or
phenyl, R.sup.g is hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or
phenyl, and R.sup.h is aralkyl or C.sub.1-6 alkyl; provided that at
least one of R.sup.2 or R.sup.3 is selected from the group
consisting of: (a) an optionally substituted alkyl group,
preferably C.sub.1-C.sub.6 alkyl, more preferably C.sub.1-C.sub.3;
(b) alkoxy, aryloxy, alkylthio or arylthio, any of which is
optionally substituted; (c) optionally substituted
C.sub.6-C.sub.14aryl, or optionally substituted aralkyl, except
that R.sup.3 is not nitrophenyl or aminophenyl, when R.sup.1 and
R.sup.2 are both hydrogen or methyl; (d) optionally substituted
heterocycle; and (e) optionally substituted cycloalkyl.
2. A compound of claim 1, wherein R.sup.2 or R.sup.3 is alkyl,
cycloalkyl, alkoxy, alkylthio or alkylsulfonyl, and the alkyl
portion of said alkyl, cycloalkyl, alkoxy, alkylthio or
alkylsulfonyl is optionally substituted with 1 to 4 substituents
selected from the group consisting of halogen, hydroxy, thiol,
amino, monoalkylamino, dialkylamino, formylamino, acylamino,
aminoacyl, monoalkylaminocarbonyl, dialkylaminocarbonyl,
thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy,
aryloxy, aminocarbonyloxy, monoalkylaminocarbonyloxy,
dialkylnaminocarbonyloxy, monoarylaminocarbonyloxy,
diarylaaminocarbonyloxy, monoaralkylaminocarbonyloxy,
diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl,
aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino,
aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,
aryloxycarbonylamino, monoalkylaminothiocarbonyl,
dialkylaminothiocarbony- l, aralkoxy, carboxy, carboxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl,
alkylthio and arylthio.
3. A compound of claim 1, wherein R.sup.3 is optionally substituted
alkyl or alkylthio.
4. A compound of claim 2, wherein said 1 to 4 substituents are
selected from the group consisting of chloro, hydroxy, amino,
mono(C.sub.1-4)alkylamino, di(CI4)alkylamino, formylamino,
C.sub.2-6 acylamino, aminocarbonyl, C.sub.2-8 aminoacyl, C.sub.2-6
thioacylamino, aminothiocarbonyl, C.sub.2-8 aminothioacyl,
C.sub.1-6 alkoxy, C.sub.6-14 aryloxy, carboxy,
carboxy(C.sub.1-6)alkyl, C.sub.2-8 alkoxycarbonyl, nitro, cyano,
trifluoromethyl, C.sub.1-6 alkylthio, C.sub.6-14 arylthio,
C.sub.1-6 aralkylsulfonylamino, C.sub.1-6 arylsulfonylamino,
monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy,
mono(C.sub.6-10)arylaminocarbonyloxy,
di(C.sub.6-lo)arylaminocarbonyloxy, monoaralkylcarbonyloxy,
diaralkylcarbonyloxy, C.sub.1-6 alkoxycarbonylamino,
C.sub.7-C.sub.15 aralkoxycarbonylamino, and C.sub.6-C.sub.10
aryloxycarbonylamino.
5. A compound of claim 1, wherein at least one of R.sup.2 and
R.sup.3 is aryl, aralkoxy, arylthio, aralkyl, aryloxy, aralkylthio,
aralkylsulfonyl, arylsulfonyl, heterocycle or heterocycloalkyl
optionally substituted with 1 to 4 substituents selected from the
group consisting of halogen, hydroxy, thiol, amino, monoalkylamino,
dialkylamino, formylamino, acylamino, amninoacyl, mono
alkylaminocarbonyl, dialkylaminocarbonyl, thiocarbonylamino,
thioacylamino, aminothiocarbonyl, alkoxy, aryloxy,
aminocarbonyloxy, mono alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, monoarylaminocarbonyloxy,
diarylaminocarbonyloxy, monoaralkylaminocarbony- loxy,
diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl,
aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino,
aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,
aryloxycarbonylamino, mono alkylaminothiocarbonyl,
dialkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl,
alkylthio and arylthio.
6. A compound of claim 5, wherein said 1 to 4 substitutents are
selected from the group consisting of chloro, hydroxy, amino,
mono(C.sub.1-4)alkylamino, di(C.sub.1-4)alkylamino, formylamino,
C.sub.2-6 acylamino, aminocarbonyl, C.sub.2-8 aminoacyl, C.sub.3-7
cycloalkyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.6-14 aryloxy,
carboxy, carboxy(C.sub.1-6)alkyl, C.sub.2-8 alkoxycarbonyl, nitro,
cyano, trifluoromethyl, C.sub.1-6 alkylthio, C.sub.6-14 arylthio,
C.sub.6-14 aryl, tetrazolyl, thienyl, 3,4-methylenedioxy,
3,4-ethylenedioxy, 3,4-propylenedioxy, C.sub.1-6
alkylsulfonylamino, C.sub.1-6 aralkylsulfonylamino, C.sub.1-6
arylsulfonylamino, mono- or dialkylaminocarbonyloxy, mono- or di-
C.sub.6-10 arylaminocarbonyloxy, mono- or diaralkylcarbonyloxy,
C.sub.1-6 alkoxycarbonylamino, C.sub.7-C.sub.15
aralkoxycarbonylamino, C.sub.6-C.sub.10 aryloxycarbonylamino,
C.sub.2-6 thioacylamino, aminothiocarbonyl, and C.sub.2-8
aminothioacyl.
7. A compound of claim 1, wherein X is sulfur or oxygen; Y is a
covalent bond or --NH--; R is hydrogen, amino, hydroxy or halogen;
one of R.sup.2 or R.sup.3 is hydrogen, C.sub.1-6 alkylthio,
C.sub.1-6 alkyl, or C.sub.1-6 alkoxy, and the other of R.sup.2 or
R.sup.3 is aminoacyl, acylamino, aminosulfonyl, sulfonylamino,
aminocarbonylamino, alkoxycarbonylamino, optionally substituted
oxazolyl, optionally substituted isoxazolyl, optionally substituted
benzothienyl, optionally substituted furanyl, optionally
substituted pyrazolyl or optionally substituted pyridyl.
8. A compound of claim 7, wherein R.sup.4, R.sup.5 and R.sup.6 are
hydrogen.
9. A compound of claim 1, wherein X is sulfur or oxygen; Y is a
covalent bond or --NH--; Z is NR.sup.5R.sup.6; R is hydrogen,
amino, hydroxy or halogen; one of R.sup.2 and R.sup.3 is hydrogen,
C.sub.1-6 alkylthio, C.sub.1-6 alkyl or C.sub.1-6 alkoxy, and the
other of R.sup.2 and R.sup.3 is 39where Ar is phenyl, thiazolyl,
thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, furanyl,
imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, tetrazolyl,
pyrrolyl, pyrazolyl, oxadiazolyl, oxazolinyl, isoxazolinyl,
imidazolinyl, triazolyl, pyrrolinyl, benzothiazolyl, benzothienyl,
benzimidazolyl, 1,3-oxazolidin-2-onyl, and imidazolin-2-onyl;
R.sup.8 and R.sup.9 are independently selected from the group
consisting of hydrogen, halogen, amino, mono(C.sub.1-4)alkylami-
no, arylamino, mono C.sub.6-14 arylamino, di(C.sub.6-14)arylamino,
mono(C.sub.6-14)ar(C.sub.1-6)alkylamino,
di(C.sub.6-14)ar(C.sub.1-6)alkyl- amino, di(C.sub.1-4)alkylamino,
formylamino, C.sub.2-6 acylamino, aminocarbonyl, C.sub.2-8
aminoacyl, C.sub.2-6 thioacylamino, aminothiocarbonyl, C.sub.2-8
aminothioacyl, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-6
alkoxy, carboxy, carboxy(C.sub.1-6)alkyl, C.sub.2-8 alkoxycarbonyl,
nitro, cyano, trifluoromethyl, tetrazolyl, thienyl, C.sub.6-14
aryloxy, C.sub.1-6 alkylthio, C.sub.6-14 arylthio, C.sub.6-14 aryl,
and C.sub.6-14 ar(C.sub.1-6)alkyl, wherein the aryl portions of any
of said groups may be optionally substituted with 1 to 3
substituents independently selected from the group consisting of
halogen, hydroxy, amino, mono(C.sub.1-4)alkylamino,
di(C.sub.1-.sub.4)alkylamino, formylamino, C.sub.1-4acylamino,
C.sub.1-4aminoacyl, mono(C.sub.1-.sub.4)alkylaminocarbonyl,
di(C.sub.1-4)alkylaminocarbonyl, thiocarbonylamino,
C.sub.1-4thioacylamino, aminothiocarbonyl, C.sub.1-4 alkoxy,
C.sub.6-10-aryloxy, aminocarbonyloxy, mono(C.sub.1-4)alkylaminoca-
rbonyloxy, di(C.sub.1-4) alkylaminocarbonyloxy,
mono(C.sub.6-10)arylaminoc- arbonyloxy, di(C.sub.6
IO)arylaminocarbonyloxy, mono(C.sub.4-12)aralkylami- nocarbonyloxy,
di(C.sub.4-12)aralkylaminocarbonyloxy, C.sub.1-4alkylsulfonyl,
C.sub.6-10arylsulfonyl, (C.sub.7-12) aralkylsulfonyl,
C.sub.1-4alkylsulfonylamino, C.sub.6-10arylsulfonylamino- ,
(C.sub.7-12) aralkylsulfonylamino, C.sub.1-4alkoxycarbonylamino,
C.sub.7-12aralkoxycarbonylamino, C.sub.6-10aryloxycarbonylamino,
mono(C.sub.1-4)alkylaminothiocarbonyl,
di(C.sub.1-.sub.4)alkylaminothioca- rbonyl, C.sub.7-,.sub.2
aralkoxy, carboxy, carboxy(C.sub.1-4)alkyl,
C.sub.1-4alkoxycarbonyl, C.sub.1-4alkoxycarbonylalkyl, nitro,
cyano, trifluoromethyl, C.sub.1-4alkylthio, C.sub.6-10arylthio,
3,4-methylenedioxy, 3,4-ethylenedioxy, and 3,4-propylenedioxy; and
R.sup.4, R.sup.5, R.sup.6 are independently hydrogen,
C.sub.1-4alkyl, amino, C.sub.1-4 alkoxy or hydroxy.
10. A compound of claim 9, wherein X is sulfur; Y is a covalent
bond; Z is NR.sup.5R.sup.6; R is hydrogen; R.sup.2is 40where Ar is
phenyl, thiazolyl, oxazolyl, pyridyl or imidazolyl; R.sup.8 and
R.sup.9 are independently selected from the group consisting of
hydrogen and C.sub.6-10 aryl optionally substituted with 1 to 3
substituents independently selected from the group consisting of
chloro, hydroxy, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-4
alkoxy, amino, carboxy, phenyl, napthyl, biphenyl, hydroxyphenyl,
methoxyphenyl, chlorophenyl, dichlorophenyl, aminophenyl,
carboxyphenyl, nitrophenyl, 3,4-ethylenedioxy, 3,4-methylenedioxy,
and 3,4-propylenedioxy; R.sup.3 is methylthio or methyl; and
R.sup.4, R.sup.5, R.sup.6 are hydrogen.
11. A compound of claim 1, wherein X is sulfur; Y is a direct
covalent bond; Z is NR.sup.5R.sup.6; R is hydrogen; R.sup.2 is
alkyl, ar(alkyl), alkylsulfonyl, --SO.sub.2-alkyl, amido, amidino,
or 41where Ar is an aromatic or heteroaromatic group selected from
the group consisting of phenyl, thiazolyl, oxazolyl, imidazolyl and
pyridyl; R.sup.8 and R.sup.9 are independently selected from the
group consisting of hydrogen, carboxy, phenyl, naphthyl, alkyl,
pyridyl, oxazolyl, furanyl, cycloalkyl and amino, any of which may
be optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halogen, alkyl, haloalkyl,
alkaryl, heteroaryl, phenyl, naphthyl, alkoxy, aryloxy, hydroxy,
amino nitro, thiophenyl, benzothiophenyl, fluorenyl,
3,4-ethylenedioxy, 3,4-methylenedioxy, 3,4-propylenedioxy,
arylsulfonamido, alkylsulfonamido and aryloxy, each of said 1 to 3
substituents may be further optionally substituted with one or more
groups selected from alkoxy, haloalkyl, halogen, alkyl, amino,
acetyl, hydroxy, dialkylamino, dialkylamino acyl,
monoalkylaminoacyl, --SO.sub.2-heteroaryl, --SO.sub.2-aryl, or
aryl; R.sup.3 is --SO.sub.2-alkyl, trifluoromethyl, S(O)-alkyl,
hydrogen, alkoxy, alkylthio, alkyl, aralkyl]thio; and R.sup.4,
R.sup.5, R.sup.6 are hydrogen.
12. A compound of claim 11, wherein Ar is thiazolyl and at least
one of R.sup.7 and R.sup.8 is phenyl.
13. A compound of claim 11 or 12, wherein said thiazolyl is
thiazol-2-yl.
14. A compound of claim 13, wherein R.sup.2 is a
4-phenylthiazol-2-yl group, wherein said phenyl is further
optionally substituted.
15. A compound of claim 11 or 12, wherein said thiazolyl is
thiazol-4-yl.
16. A compound of claim 15, wherein R.sup.2 is a
2-aminothiazol-4-yl group.
17. A compound of claim 11, wherein said oxazolyl is
oxazol-2-yl.
18. A compound of claim 11, wherein said oxazolyl is
oxazol-4-yl.
19. A compound of claim 11, wherein R.sup.3 is methylthio.
20. A compound of Formula I 42or a solvate, hydrate or
pharmaceutically acceptable salt thereof, wherein X is sulfur; Y is
a covalent bond; Z is NR.sup.5R.sup.6; R is hydrogen; R.sup.2is
43where Ar is phenyl, thiazolyl, or oxazolyl; R.sup.8 and R.sup.9
are independently selected from the group consisting of hydrogen
and C.sub.6-10 aryl optionally substituted with 1 to 3 substituents
independently selected from the group consisting of chloro,
hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, phenyl,
3,4-ethylenedioxy, 3,4-methylenedioxy, and 3,4-propylenedioxy;
R.sup.3 is methylthio; and R.sup.4, R.sup.5, R.sup.6 are
hydrogen.
21. A compound of Formula I 44or a solvate, hydrate or
pharmaceutically acceptable salt thereof, wherein X is sulfur; Y is
a covalent bond; R is hydrogen; R.sup.2 is 45where Ar is thiazolyl;
R.sup.8 and R.sup.9 are independently selected from the group
consisting of hydrogen and C.sub.6-10 aryl substituted with a
sulfonamide group; R.sup.3 is methylthio; and R.sup.4, R.sup.5, R6
are hydrogen.
22. A compound of claim 21, wherein said sulfonamide group is a
C.sub.6-10 arylsulfonamide, alkylsulfonamide, alkoxysulfonamide or
heteroarylsulfonamide.
23. A compound of claim 22, wherein said sulfonamide group is
selected from the group consisting of 4-methylphenylsulfonamide,
methylsulfonamide, phenylsulfonamide, trifluoromethylsulfonamide,
4-fluorophenylsulfonamide, 4-chlorophenylsulfonamide,
3-chlor-chorophenylsulfonamide, 4-methoxysulfonamide,
2,4-difluorophenylsulfonamide, 2-(thiophene)sulfonamide,
2-(5-chlorothiophene) sulfonamide, butylsulfonamide, and
isopropylsulfonamide.
24. A compound of Formula I 46or a solvate, hydrate or
pharmaceutically acceptable salt thereof, wherein X is sulfur; Y is
a covalent bond; Z is NR.sup.5R.sup.6; R.sup.1 is hydrogen; R.sup.2
is 47where Ar is thiazolyl; R.sup.8 and R.sup.9 are independently
selected from the group consisting of hydrogen and C.sub.6-10 aryl
substituted with a group selected from --OCH.sub.2C(O)-alkoxy,
--OCH.sub.2C(O)-amino, --OCH.sub.2C(O)--NH--alkyl or
--OCH.sub.2C(O)-N(alkyl).sub.2; R.sup.3 is methylthio; and R.sup.4,
R.sup.5, R.sup.6 are hydrogen.
25. A compound of Formula III, 48or a salt thereof, wherein A is
methylthio or methyl; G.sup.1 is --O--, --S--, --NH--, or a
covalent bond; n is an integer from 1-10; m is an integer from 0-1;
and R' and R" are independently selected from hydrogen, alkyl, aryl
or aralkyl, or R' and R" taken together with the N atom to which
they are attached form a 3-8 membered heterocyclic ring optionally
containing an additional O, N, or S atom.
26. A compound according to claim 25, wherein said 3-8 membered
heterocyclic ring contains an additional N atom, said additional N
atom optionally substituted by hydrogen, C.sub.1-4alkyl,
C.sub.6-10aryl, C.sub.6-10ar(C.sub.1-4)alkyl, C.sub.1-6alkoxy,
alkoxycarbonyl or benzyloxycarbonyl.
27. A compound according to claim 25, wherein said 3-8 membered
heterocyclic ring is piperazinyl, pyrrolidinyl, piperidinyl or
morpholinyl, which is further optionally substituted by 1-4
substituents selected from halogen, hydroxy, amino, monoalkylamino,
dialkylamino, formylamino, acylamino, aminoacyl,
monoalkylaminocarbonyl, dialkylaminocarbonyl, thiocarbonylamino,
thioacylamnino, aminothiocarbonyl, alkoxy, aryloxy,
aminocarbonyloxy, monoaikylaminocarbonyloxy,
dialkylaminocarbonyloxy, monoarylaminocarbonyloxy,
diarylaminocarbonyloxy, monoarakylaminocarbonyl- oxy,
diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl,
aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino,
arakylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,
aryloxycarbonylamino, mono alkylaminothiocarbonyl,
dialkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl,
alkylthio and arylthio.
28. A compound of claim 11, wherein Ar is thiazolyl; and one of
R.sup.8 and R.sup.9 is hydrogen and the other of R.sup.8 and
R.sup.9 is amino, said amino group optionally substituted with
halogen, hydroxy, amino, monoalkylamino, dialkylamino, formylamino,
acylamino, aminoacyl, monoalkylaminocarbonyl, dialkylaminocarbonyl,
thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy,
aryloxy, aminocarbonyloxy, monoalkylaminocarbonyloxy,
dialkylaminocarbonyloxy, monoarylaminocarbonyloxy,
diarylaminocarbonyloxy, monoaralkylaminocarbony- loxy,
diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl,
aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino,
aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,
aryloxycarbonylamino, monoalkylaminothiocarbonyl,
dialkylaminothiocarbony- l, aralkoxy, carboxy, carboxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl,
alkylthio and arylthio.
29. A compound of Formula IV 49wherein A is methylthio or methyl;
and R'" is hydrogen, C.sub.6-14 aryl, C.sub.1-6 alkyl, alkoxy
(C.sub.6-14)arYl amno(C.sub.6-14)arll
monoalkylamino(C.sub.6-14)arl, dialkylamno(C.sub.6-14)arl
C.sub.6-10ar(C.sub.1-6)akyl C.sub.1-6 alk(C.sub.6-14)aryl,
amino(C.sub.1-6)alkyl, monoalkylamino (C.sub.1-6)alkyl,
dialkylamino (C.sub.1-6)alkyl, hydroxy(C.sub.6-14)aryl, or
hydroxy(C.sub.1-6)alkyl, any of which is further optionally
substituted by 1-4 non-hydrogen substituents selected from halogen,
hydroxy, amino, monoalkylamino, dialkylamino, formylamino,
acylamino, aminoacyl, mono- or di- alkylaminocarbonyl,
thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy,
aryloxy, amiinocarbonyloxy, mono- or di-alkylaminocarbonyloxy,
mono- or diarylaminocarbonyloxy, mono- or diarakylaminocarbonyloxy,
alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino,
arylsulfonylamino, arakylsulfonylamino, alkoxycarbonylamino,
aralkoxycarbonylamino, aryloxycarbonylamino, mono- or di-
alkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl,
alkylthio and arylthio.
30. A compound of claim 29 which is one of:
4-{2-[(3-methoxyphenyl)amino](-
1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,
4-{2-[(4-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2--
carboxamidine, 4-(2-{[4-(dimethylamino)phenyl]amino
}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine,
4-{2-[(4-chloro-2-methylthiothiophene-2-carboxamidine]4-{2-[(diphenylmeth-
yl)amino}(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidine,
5-methylthio-4-{2-[(3-phenylpropyl)amino](1,3-thiazol-4-yl)}thiophene-2-c-
arboxamidine,
5-methylthio-4-{2-[(2,4,5-trimethylphenyl)amino](1,3-thiazol-
-4-yl)}thiophene-2-carboxamidine,
4-{2-[(2-fluorophenyl)amino]methylthioth- iophene-2-carboxamidine,
4-}2-[(3-chloro-2-methylphenyl)amino](1,3-thiazol-
-4-yl)-5-methylthiothiophene-2-carboxamidine,
4-(2-{[2-(methylethyl)phenyl-
]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine,
5-methylthio-4-(2-{[4-(phenylmethoxy)phenyl]amino
}(1,3-thiazol-4-yl))thi- ophene-2-carboxamidine,
4-{2-[(2-bromophenyl)amino](1,3-thiazol-4-yl)}-5-m-
ethylthiothiophene-2-carboxamidine,
4-{2-[(2,6-dichlorophenyl)amino](1,3-t-
hiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,
4-{2-[(2-bromo-4-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiop-
hene-2-carboxamidine, 5-methylthio-4-{2-[(2-morpholin-4-ylethyl)
thiazol-4-yl)}thiophene-2-carboxamidine,
4-{2-[(2,3-dichlorophenyl)amino]-
(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine,
5-methylthio-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiop-
hene-2-carboxamidine,
5-methylthio-4-{2-[(2-piperidylethyl)amino](1,3-thia-
zol-4-yl)}thiophene-2-carboxamidine,
4-(2-{[(4-methylphenyl)methyl]amino
}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine,
4-(2-{[4-(4-chlorophenoxy)phenyl]amino
}(1,3-thiazol-4-yl))-5-methylthiot- hiophene-2-carboxamnidine
4-(2-{[4-phenoxyphenyl]amino }methylthiothiophene-2-carboxanmidine,
5-methylthio-4-(2-{[4-(phenylamino-
)phenyl]amino)}(1,3-thiazol-4-yl))thiophene-2-carboxamidine,
5-methylthio-4-(2-{[4-benzylphenyl]amino}(1,3-thiazol-4-yl))thiophene-2-c-
arboxamidine,
5-methylthio-4-(2-{[4-(piperidylsulfonyl)phenyl]aamino
}(1,3-thiazol-4-yl))thiophene-2-carboxamidine
5-methylthio-quinolylamino)
(1,3-thiazol-4-yl)]thiophene-2-carboxamidine,
5-methylthio-4-[2-(2-naphth- ylamino)
(1,3-thiazol-4-yl)]thiophene-2-carboxamidine,
4-[2-(2H-benzo[3,4-d]1,3-dioxolan-5-ylamino)
(1,3-thiazol-4-yl)]-5-methyl- thiothiophene-2-carboxamidine,
4-{2-[(7-bromofluoren-2-yl)amino](1,3-thiaz-
ol-4-yl)}-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiop-
hene-2-carboxamidine,
5-methylthio-4-(2-{[4-(phenyldiazenyl)phenyl]amino
}(1,3-thiazol-4-yl))thiophene-2-carboxamidine, 5-methylthio
4-(2-{[3-(hydroxymethyl)phenyl]amino
}(1,3-thiazol-4-yl))-thiophene-2-car- boxamidine,
4-[2-({3-[(3-methylpiperidyl)methyl]phenyl }amino)
(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidine,
4-{2-[(3-hydroxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2--
carboxamidine, 4-(2-{[4-(carbamoylmethoxy)phenyl]amino
}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine,
5-methyl-4-{2-25 4-yl)}thiophene-2-carboxamidine,
5-methyl-4-{2-[(4-pheno-
xyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine,
5-methyl-4-[2-(phenylamino)
(1,3-thiazol-4-yl)]thiophene-2-carboxamidine,
4-(4-isoxazol-5-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidi-
ne.
31. A compound of claim 1 which is one of:
4-[4-(4-chlorophenyl)thiazol-2--
yl]-5-methylthiothiophene-2-carboxamidine;
4-phenyl-5-methylthiothiophene-- 2-carboxamidine;
4-[4-(2,4-dichlorophenyl)thiazol-2-yl]-5-methylthiothioph-
ene-2-carboxamidine;
4-(4-methylthiazol-2-yl)-5-methylthiothiophene-2-carb- oxamidine;
4-[4-(3-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-car-
boxamidine;
4-[4-(3-hydroxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-ca-
rboxamidine;
4-(4-phenylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidin- e;
4-[4-(4-nitrophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine-
;
4-[4-(3,4-ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carb-
oxamidine;
4-[4-(3,4-propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothioph-
ene-2-carboxamidine;
4-[4-(4-(naphth-2-yl)thiazol-2-yl]-5-methylthiothioph-
ene-2-carboxamidine; and
4-isopropylsulfonyl-5-methylthiothiophene-2-carbo- xamidine; or a
hydrate, solvate or pharmaceutically acceptable salt thereof.
32. A compound of claim 11, which is one of:
4-phenyl-5-methylthiothiophen- e-2-carboxamidine;
4-[4-(4-chlorophenyl)thiazol-2-yl]-5-methylthiothiophen-
e-2-carboxamidine;
4-[4-(4-phenylphenyl)thiazol-2-yl]-5-methylthiothiophen-
e-2-carboxamidine;
4-[4-(3-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophe-
ne-2-carboxaniidine;
4-[4-(3-hydroxyphenyl)thiazol-2-yl]-5-methylthiothiop-
hene-2-carboxamidine;
4-(4-phenylthiazol--2-yl)-5-methylthiothiophene-2-ca- rboxamidine;
4-[4-(4-nitrophenyl)thiazol-2-yl]-5-methylthiothiophene-2-car-
boxamidine;
4-[4-(3,4-ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothioph-
ene-2-carboxamidine;
4-[4-(4-methoxyphenyl)thiazol-2-yl]-5-methylthiothiop-
hene-2-carboxamidine;
4-[4-(3,4-propylenedioxyphenyl)thiazol-2-yl]-5-methy-
lthiothiophene-2-carboxamidine;
4-isopropylsulfonyl-5-methylthiothiophene-- 2-carboxamidine;
4-(4-methylthiazol-2-yl)-5-methylthiothiophene-2-carboxam- idine;
4-[4-(2,4-dichlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carb-
oxamidine;
4-(2-naphthylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidin- e;
4-[4-(4-chloro-3-methylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-car-
boxamidine;
4-(5-methyl-4-phenylthiazol-2-yl)-5-methylthiothiophene-2-carb-
oxamidine;
4-[4-(4-chloro-3-nitrophenyl)thiazol-2-yl]-5-methylthiothiophen-
e-2-carboxamidine;
4-(5-phenyloxazol-2-yl)-5-methylthiothiophene-2-carboxa- midine;
4-[4-(3-fluoro-5-trifluoromethylphenyl)-5-methylthiazol-2-yl]-5-me-
thylthiothiophene-2-carboxamidine;
4-[4-(3,5-bis(trifluoromethyl)phenyl)-5-
-methyl-thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3-fluoro-5-trifluoromethylphenyl)thiazol-2-yl]-5-methylthiothiophen-
e-2-carboxamidine;
4-[4-(3-bromophenyl)thiazol-2-yl]-5-methylthiothiophene-
-2-carboxamidine;
4-[4-(3,4-methylenedioxyphenyl)thiazol-2-yl]-5-methylthi-
othiophene-2-carboxamidine;
4-[4-(4-methylphenyl)thiazol-2-yl]-5-methylthi-
othiophene-2-carboxamidine;
4-[4-(3,5-bis(trifluoromethyl)phenyl)thiazol-2-
-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(2-methoxyphenyl)thiazol--
2-yl]-5-methylthiothiophene-2-carboxamidine;
4-(4-phenylimidazol-2-yl)-5-m- ethylthiothiophene-2-carboxamidine;
4-[4-(2,4-dimethoxyphenyl)thiazol-2-yl-
]-5-methylthiothiophene-2-carboxamnidine;
4-(4-benzylthiazol-2-yl)-5-methy- lthiothiophene-2-carboxamidine;
4-[4-(3,4-dichlorophenyl)thiazol-2-yl]-5-m-
ethylthiothiophene-2-carboxamidine;
4-[4-(3-methylphenyl)thiazol-2-yl]-5-m-
ethylthiothiophene-2-carboxamidine;
4-[4-(3,5-dimethoxyphenyl)thiazol-2-yl-
]-5-methylthiothiophene-2-carboxamidine;
4-[4-(2-methylphenyl)thiazol-2-yl-
]-5-methylthiothiophene-2-carboxamidine;
4-[4-(2,5-dimethoxyphenyl)thiazol-
-2-yl]-5-methylthiothiophene-2-carboxamnidine;
4-(4,5-diphenyl)thiazol-2-y-
l-5-methylthiothiophene-2-carboxamidine;
4-(2-phenyl)thiazol-4-yl-5-methyl- thiothiophene-2-carboxamidine;
4-[4-(2-chloro-3-pyridyl)thiazol-2-yl]-5-me-
thylthiothiophene-2-carboxamidine; 4-[4-(phexylthiazol
-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(4-chlophenyl)thiazol--
2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4(4-chcloohenylthiazol-2-y-
l]-5-methylthiothiophene-2-carboxamidine;
4-[4-(2-chydroxphenyl)thiazol-2--
yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3-trifluoromethoxyphenyl)- thiazol
-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(2-chloro-4-pyrid yl)thiazol-2-yl]-5-methylthiothiophene-2-230
carboxamidine;
4-(5-phenyl-2-py.dyl)-5-methylthiothiophene-2-carboxamidin- e;
4-[2-(2-chlorophenylamino)thiazol-4-yl]-5-methylthiothiophene-2-carboxa-
midine;
4-[2-(3-methoxyphenylamino)thiazol-4-yl]-5-methylthiothiophene-2-c-
arboxamidine; 4-[2-( phenylamino)thiazol-4-yl
]-5-methylthiothiophene-2-ca- rboxamidine;
4-[2-(2,5-dimethoxyphenylamnino)thiazol-4-yl]-5-methylthiothi-
ophene-2-carboxamidine;
4-(2-aminothiazol-4-yl)-5-methylthiothiophene-2-ca- rboxamidine;
4-[2-(4-chloro-2-methylphenylamino)thiazol-4-yl]-5-methylthio-
thiophene-2-carboxamidine;
4-[2-(4-dimethylaminophenylamino)thiazol-4-yl]--
5-methylthiothiophene-2-carboxamidine;
4-[2-(4-methoxyphenylamino)thiazol--
4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(4-hydroxy-3-methoxyphen-
yl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3-hydroxy-4-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-car-
boxamidine;
4-[2-(2-fluorophenylamino)thiazol-4-yl]-5-methylthiothiophene--
2-carboxamidine;
4-[2-(2,4,5-trimethylphenyl)aminothiazol-4-yl]-5-methylth-
iothiophene-2-carboxamidine;
4-[2-(3-chloro-2-methylphenyl)aminothiazol-4--
yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(2-isopropylphenyl)aminoth-
iazol-4-yl]-5-methylthiothiophene-2-carboxa-dine;
4-[2-(4-benzyloxyphenyl)-
aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(2-bromophenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamni-
dine;
4-[2-(2,5-dich-orophenyl)aminothiazol-4-yl]-5-methythiothiophene-2-c-
arboxamidine; 4-[2-(2-bromo-4mtyphenyl)aminothiazol
-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(2,3-dichlorophenyl)am-
inothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(3,4,5-trimethoxyphenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-c-
arboxamidine;
4-[2-(2-piperidinylethyl)aminothiazol-4yl]-5-methylthiothiop-
hene-2-carboxamidine;
4-[2-(4-methylphenyl)aminothiazol-4-yl]-5-methylthio-
thiophene-2-carboxamidine;
4-(4-phenyloxazol-2-yl)-5-methylthiothiophene-2- -carboxamidine;
4-[2-(diphenylmethyl)aminothiazol-4-yl]-5-methylthiothioph-
ene-2-carboxamidine;
4-[2-(3-phenylpropyl)aminothiazol-4-yl]-5-methylthiot-
hiophene-2-carboxamidine; or a solvate, hydrate or pharmaceutically
acceptable salt hereof.
33. A method of treating a disease selected from benign prostatic
hypertrophy, prostatic carcinoma, tumor metastisis, restenosis and
psoriasis, comprising administering to a patient in need of such
treatment an effective amount of a compound of Formula I: 50or a
solvate, hydrate or pharmaceutically-acceptable salt thereof,
wherein: X is oxygen, sulfur or NR.sup.7; R.sup.7 is hydrogen,
alkyl, aralkyl, hydroxy(C.sub.3-4)alkyl, alkoxy(C.sub.3-4)alkyl; Y
is a covalent bond, CH.sub.2 or NH; Z is NR.sup.5R.sup.6; R is a
hydrogen, amino, hydroxy, halogen, cyano, C.sub.1-4 alkyl,
--CH.sub.2R where R is hydroxyamino, or C.sub.1-3 alkoxy; R.sup.2
and R.sup.3 are independently: i. hydrogen; ii. halogen; iii.
hydroxy; iv. nitro; v. cyano; vi. amino, monoalkylamino,
dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino,
monoaralkylamino, diaralkylamino, alkarylamino,
alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino,
alkylsulfonylamino, aralkylsulfonylamino, arylsulfonylamino,
formylamino, acylamino, H(S)CNH--, or thioacylamino; vii.
aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl,
arylaminocarbonyl, or aminoacyl; viii. aminothiocarbonyl,
monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, thioacyl, or
aminothioacyl; ix. aminocarbonylamino, monoalkylaminocarbonylamino,
dialkylaminocarbonylamino, monoarylaminocarbonylamino,
diarylaminocarbonyl-amino, monoaralkylaminocarbonylamino, or
diaralkylaminocarbonylamino, x. aminocarbonyloxy,
monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy,
monoarylaminocarbonyloxy, diarylaminocarbonyloxy,
monoaralkylaminocarbony- loxy, or diaralkylaminocarbonyloxy, xi.
aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl,
monoarylaminosulfonyl, diarylaminosulfonyl, or
monoaralkylaminosulfonyl, or diaralkylaminosulfonyl, xii. alkoxy or
alkylthio, wherein said alkyl portion of said alkoxy or alkylthio
group may be optionally substituted; xiii. aralkoxy, aryloxy,
aralkylthio, or arylthio, wherein the aryl portion of said
aralkoxy, aryloxy, aralkylthio or arylthio group may be optionally
substituted; xiv. alkylsulfonyl, wherein the alkyl portion may be
optionally substituted; xv. aralkylsulfonyl, or arylsulfonyl,
wherein the aryl portion of each group can be optionally
substituted, xvi. alkenyl or alkynyl; xvii. optionally substituted
aryl; xviii. optionally substituted alkyl; xix. optionally
substituted aralkyl; xx. optionally substituted heterocycle; or
xxi. optionally substituted cycloalkyl; and R.sup.4, R.sup.5 and
R.sup.6 are independently hydrogen, C.sub.1-4alkyl, aryl,
hydroxyalkyl, aminoalkyl, monoalkylamino(C.sub.2-10)alkyl,
dialkylamino(C.sub.2-10)alkyl, carboxyalkyl, cyano, amino, alkoxy,
or hydroxy.
34. A method according to claim 33, wherein said effective amount
is between about 0.01 and about 50 milligrams per kilogram per
day.
35. A method according to claim 34, wherein said effective amount
is between about 0.1 and about 20 milligrams per kilogram per
day.
36. A pharmaceutical composition comprising a compound according to
claim 1 or claim 11, or a pharmaceutically acceptable ester, salt
or ether thereof, and a pharmaceutically acceptable carrier.
37. A pharmaceutical composition according to claim 36, wherein
said compound is present in an amount between 0.01 and 100
milligrams.
38. A method of inhibiting a protease selected from the group
consisting of leukocyte neutrophil elastase, chymotrypsin, trypsin,
pancreatic elastase, cathepsin G, thrombin, urokinase, factor Xa,
plasmin, thermolysin, C-1 esterase, C-3 convertase, acrosin,
thrombin, kallikreins, and pepsin, comprising contacting said
protease with a compound according to claim 1 or claim 11.
39. A method according to claim 38 wherein said protease is
trypsin, chymotrypsin, plasmin or urokinase.
40. A method of treating adult respiratory distress syndrome, wound
healing, gout, rheumatoid arthritis, reperfusion damage,
atherosclerosis, restenosis, neoplasia, metastasis, emphysema,
Alzheimer's disease, pancreatitis, benign prostatic hypertrophy,
prostatic carcinoma, psoriasis or Parkinson's disease, comprising
administering to a patient in need of such treatment an effective
amount of a compound according to claim 1 or claim 11.
41. A pharmaceutical composition according to claim 36, suitable
for parenteral, oral, subcutaneous, intravenous, intramuscular,
intraperitoneal, transdermal, buccal or ocular administration.
42. A process for forming a compound of Formula I 51or a solvate,
hydrate or pharmaceutically-acceptable salt thereof, wherein: X is
oxygen, sulfur or NR.sup.7; R.sup.7 is hydrogen, alkyl, aralkyl,
hydroxy(C.sub.2-4)alkyl- , or alkoxy(C.sub.2-4)alkyl; Y is a
covalent bond, CH.sub.2or NH; R.sup.1 is a hydrogen, amino,
hydroxy, halogen, cyano, C.sub.1-4 alkyl or --CH.sub.2R where R is
hydroxyamino or C.sub.1-3 alkoxy; R.sup.2 and R.sup.3 are
independently: i. hydrogen; ii. halogen; iii. hydroxy; iv. nitro;
v. cyano; vi. amino, monoalkylamino, dialkylamino, monoarylamnino,
diarylamino, monoalkylmonoarylamino, monoaralkylamino,
diaralkylamino, alkarylamino, alkoxycarbonylamino,
aralkoxycarbonylamnino, aryloxycarbonylamino, alkylsulfonylamino,
aralkylsulfonylamino, arylsulfonylamino, formylamino, acylamino,
H(S)CNH--, or thioacylamino; vii. aminocarbonyl,
monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl,
arylaminocarbonyl, or aminoacyl; viii. aminothiocarbonyl,
monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, thioacyl, or
aminothioacyl; ix. aminocarbonylamino, monoalkylaminocarbonylamino,
dialkylaminocarbonylamino, monoarylaminocarbonylamino,
diarylaminocarbonylamino, monoaralkylaminocarbonylamino, or
diaralkylaminocarbonylamino, x. aminocarbonyloxy,
monoalkyla.inocarbonylo- xy, dialkylaminocarbonyloxy,
monoarylaminocarbonyloxy, diarylaminocarbonyloxy,
monoaralkylaminocarbonyloxy, or diaralkylaminocarbonyloxy, xi.
aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl,
monoarylaminosulfonyl, diarylaminosulfonyl, or
monoaralkylaminosulfonyl, or diaralkylaminosulfonyl, xii. alkoxy or
alkylthio, wherein said alkyl portion of said alkoxy or alkylthio
group may be optionally substituted; xiii. aralkoxy, aryloxy,
aralkylthio, or arylthio, wherein the aryl portion of said
aralkoxy, aryloxy, aralkylthio or arylthio group may be optionally
substituted; xiv. alkylsulfonyl, wherein the alkyl portion may be
optionally substituted; xv. aralkylsulfonyl, or arylsulfonyl,
wherein the aryl portion of each group can be optionally
substituted, xvi. alkenyl or alkynyl; xvii. optionally substituted
aryl; xviii. optionally substituted alkyl; xix. optionally
substituted aralkyl; xx. optionally substituted heterocycle; or
xxi. optionally substituted cycloalkyl; and R.sup.4, R.sup.5 and
R.sup.6 are independently hydrogen, C.sub.1-4 alkyl, aryl,
hydroxyalkyl, aminoalkyl, monoalkylamino(C.sub.2-10)alkyl,
dialkylamino(C.sub.2-10)alkyl, carboxyalkyl, cyano, amino, alkoxy,
hydroxy or hydrazino; said process comprising: (a) adding a Lewis
acid to a suspension of anhydrous ammonium chloride in an aprotic
solvent stirred under an inert atmosphere at a temperature near
0.degree. C. to form a mixture; (b) allowing said mixture to warm
to room temperature with stirring and thereafter stirring said
mixture until substantially all of the solid has dissolved; (c)
adding to said mixture a compound of formula V 52wherein
R.sup.1-R.sup.3, R.sup.7, X and Y are as defined above; and R.sup.8
is selected from alkyl and aryl; (d) heating said mixture at reflux
for a predetermined period of time and thereafter allowing said
mixture to cool to room temperature.
43. A process according to claim 42, wherein said Lewis acid is
trimethylaluminum or triethylaluminum.
44. A process according to claim 42, wherein said aprotic solvent
is selected from toluene, benzene, xylene, or mesitylene.
45. A pharmaceutical composition suitable for oral administration
according to claim 41, wherein said compound is present in an
amount between 25 milligrams and 100 milligrams.
46. A pharmaceutical composition suitable for parenteral
administration according to claim 41, wherein said compound is
present in an amount between 0.5 milligrams and 10 milligrams.
47. A compound of claim 1, wherein X is sulfur.
48. A compound of claim 1, wherein Y is a covalent bond.
49. A compound of claim 1, wherein R.sup.1 is hydrogen.
50. A compound of claim 1, wherein R.sup.4, R.sup.5 and R.sup.6 are
all hydrogen.
51. A compound of claim 1, wherein R.sup.3 is methylthio or
methyl.
52. A compound of claim 1, wherein the aryl portion of R.sup.2 is
optionally substituted with 1 to 4 substituents selected from the
group consisting of halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
hydroxy, nitro, trifluoromethyl, C.sub.6-10 aryl, C.sub.6-10
aryloxy, C.sub.6-10 arylmethoxy, C.sub.1-6 aminoalkyl, carboxy,
3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino,
mono(C.sub.6-10)arylamino, di(C.sub.6-10)arylamino, C.sub.1-6
alkylsulfonylamino, C.sub.6-10 arylsulfonylamino,
C.sub.1-8acylamino, C.sub.1-8 alkoxycarbonyl, C.sub.1-6
alkanoylamino, C.sub.6-14 aroylamino, C.sub.1-6 hydroxyalkyl,
methylsulfonyl, phenylsulfonyl, thienyl and tetrazole.
53. A compound of claim 52, wherein any of said C.sub.6-10 aryl,
C.sub.6-10 aryloxy, C.sub.6-10 arylmethoxy is further substituted
by one or two of chloro, halogen, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, phenyl, hydroxy, nitro, trifluoromethyl, carboxy,
3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy or
amino.
54. A compound of claim 52, wherein said optional substituent is
thienyl further substituted by one or two of chloro, amino, methyl,
methoxy or hydroxy.
55. A compound of claim 1, wherein R.sup.2 is C.sub.1-6
alkylsulfonylamino, C.sub.6-10ar(C.sub.1-6)alkylsulfonylamino,
C.sub.6-10ar(C.sub.2-6)alkenylsulfonylamino, C.sub.6-10
arylsullfonylamino, heteroarylsulfonylamino,
di(C.sub.6-10ar(C.sub.1-6)al- kylsulfonyl)amino,
di(C.sub.6-10(ar(C.sub.2-6)alkenylsulfonyl)amino,
di(C.sub.6-uoarylsulfonyl)amino or di-(heteroarylsulfonyl)amino,
wherein any of the aryl or heteroaryl containing groups is
optionally substituted on the aromatic ring.
56. A compound of claim 55, wherein R.sup.2 is C.sub.6-10
arylsullfonylamino, di(C.sub.6-10arylsulfonyl)amino,
C.sub.6-10ar(C.sub.1-3) alkylsulfonylamino,
di(C.sub.6-10ar(C.sub.1-3)alk- ylsulfonyl)amino or
thienylsulfonylamino, wherein any of the aryl or thienyl containing
groups is further optionally substituted.
57. A compound of claim 1, wherein R.sup.2 is
biphenylsulfonylamino, bis(biphenylsulfonyl)amino,
naphth-2-ylsulfonylamino, di(naphth-2-ylsulfonyl)amino,
6-bromonaphth-2-ylsulfonylamino,
di(6-bromonaphth-2-ylsulfonyl)amino, naphth-1-ylsulfonylamino,
di(naphth- I -ylsulfonyl)amino, 2-methylphenylsulfonylamino,
di-(2-methylphenylsulfo- nyl)amino, 3-25 methylphenylsulfonylamino,
di-(3-methylphenylsulfonyl)amin- o, 4-methylphenylsulfonylamino,
di-(4-methylphenylsulfonyl)amino, benzylsulfonylamino,
4-methoxyphenylsulfonylamino, di-(4-methoxyphenylsulfonyl)amino,
4-iodophenylsulfonylamino, di-(4-iodophenylsulfonyl)amino,
3,4-dimethoxyphenylsulfonylamino,
bis-(3,4-dimethoxyphenylsulfonyl)amino,
2-chlorophenylsulfonylamino, di-(2-chlorophenylsulfonyl)amino,
3-chlorophenylsulfonylamino, di-(3-chlorophenylsulfonyl)amino,
4-chlorophenylsulfonylamino, di-(4-chlorophenylsulfonyl)amino,
phenylsulfonylamino, di-(phenyl 4-tert-butylphenylsulfonylamino,
di-(4-tert-butylphenylsulfonyl)amino, 2-phenylethenylsulfonylamino
or 4-(phenylsulfonyl)thien-2-ylsulfonylamino- .
58. A compound of claim 1, wherein R2 is amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino,
mono(C.sub.6-10)arylamino, di(C.sub.6-10)arylamino,
mono(C.sub.1-6)alkylmono(C.sub.6-10)arylamino,
monoar(C.sub.1-6)alkylamino, di(C.sub.6-10)ar(C.sub.1-6)alkylamino,
mono(C.sub.1-6)alkylmono(C.sub.6-10)ar(C.sub.1-6)alkylamino,
monoheteroarylamino, diheteroarylamino,
mono(C.sub.1-6)alkylmonoheteroary- lamino, wherein any of the aryl
or heteroaryl 15 containing groups is optionally substituted on the
aromatic ring.
59. A compound of claim 58, wherein R.sup.2 is
mono(C.sub.6-10)arylamino,
mono(C.sub.1-6)alkylmono(C.sub.6-10)arylamino,
mono(C.sub.6-10)ar(C.sub.1- -3)alkylamino,
mono(C.sub.1-6)alkylmono(C.sub.6-10)ar(C.sub.1-3)alkylamino- ,
monoheteroarylamino or mono(C.sub.1-6)alkylmonoheteroarylamino.
60. A compound of claim 59, wherein R.sup.2 is
1,3-thiazol-2-ylamino, imidazol-4-ylamino, quinolin-2-ylamino or
quinolin-6-ylamino.
61. A compound of claim 58, wherein R.sup.2 is anilino,
naphtha-2-ylamino, naphth-1-ylamino, 4-(biphenyl)thiazol-2-ylamino,
4-(phenyl)thiazol-2-ylam- ino, 4-phenyl-5-methylthiazol-2-ylamino,
4-hydroxy-4-trifluoromethylthiazo- l-2-ylamino,
3-phenylphenylamino, pyrimidin-2-ylamino, 4-isopropylphenylamino,
3-isopropylphenylamino, 4-phenylphenylamino,
3-fluoro-4-phenylphenylamino, 3,4-methylenedioxyphenylamino,
n-butylphenylamino, N-methyl-N-(2-methylphenyl)amino,
3-nitrophenylamino, 4-methoxyphenylamino, 3-methoxyphenylamino,
2-methoxyphenylamino, 2-methylphenylamino, 3-methylphenylamino,
3,4-dimethylphenylamino, 3-chlorophenylamino, 4-chlorophenylamino,
4-(3-fluoro-4-methylphenyl)amin- o, 4-(indan-5-yl)amino,
benzylamino, indanylmethylamino,
2,3-dihydrobenzofuranylmethylamino, 2-phenylimidazol-5-ylamino,
3-hydroxybenzylamino, 3-phenoxyphenylamino, 4-phenoxyphenylamino,
3-benzyloxyphenylamino, 4-benzyloxyphenylamino, quinolin-6-ylamino,
quinolin-3-ylamino, 4-(phenylamino)phenylamino,
4-(4-ethylphenyl)phenylam- ino, 4-(dimethylamino)phenylamino,
4-cyclohexylphenylamino, 4-(9-ethylcarbazol-3-yl)amino,
4-(t-butyl)phenylamino or 4-methylthiophenylamino.
62. A compound of claim 1, wherein R.sup.2 is alkanoylamino,
alkenoylamino, aroylamino, aralkanoylamino, aralkenoylamino,
heteroaroylamino, or heteroarylalkanoylamino, any of which is
optionally substituted on the aromatic ring.
63. A compound of claim 62, wherein R.sup.2 is
(C.sub.6-10)arylcarbonylafn- ino,
C.sub.6-10ar(C.sub.1-3)alkylcarbonylamino,
C.sub.6-10ar(C.sub.2-3)alk- enylcarbonylamino, C.sub.6-10
aryloxy(C.sub.1-3)alkylcarbonylamino,
C.sub.3-8cycloalkylcarbonylamino, C.sub.1-6 alkylcarbonylamino or
heteroarylcarbonylamino.
64. A compound of claim 63, wherein R.sup.2 is
furanylcarbonylamino, and quinolinylcarbonylamino.
65. A compound of claim 63, wherein R.sup.2 is
3-hydroxyphenylcarbonylamin- o, 2-phenylethenylcarbonylamino,
phenylcarbonylamino, cyclohexylcarbonylamino,
4-methyl-3-nitrophenylcarbonylamino, furan-2-ylcarbonylamino,
tert-butylcarbonylamino, 5-(3,5-dichlorophenoxy)-
furan-2-ylcarbonylamino, naphth-1-ylcarbonylamino,
quinolin-2-ylcarbonylam- ino, 4-ethoxyphenylcarbonylamino,
phenoxymethylcarbonylamino or 3-methylphenylcarbonylamino.
66. A compound of claim 1, wherein R.sup.2 is C.sub.6-10 aryloxy,
C.sub.6-10 ar(C.sub.1-6)alkoxy, C.sub.6-10 arylsulfonyl, C.sub.6-l0
ar(C.sub.1-6)alkylsulfonyl or C.sub.6-10
ar(C.sub.2-6)alkenylsulfonyl, any of which is optionally
substituted on the aromatic ring.
67. A compound of claim 66, wherein R.sup.2 is C.sub.6-10 aryloxy
or C.sub.6-10 arylsulfonyl.
68. A compound of claim 67, wherein R.sup.2 is phenoxy,
naphthyloxy, phenylsulfonyl or naphthylsulfonyl.
69. A compound of claim 1, which is one of:
methylthio-4-(6-quinolylamino)- thiophene-2-carboxamidine;
5-methylthio-4-[(3-phenylphenyl)amino]thiophene- -2-carboxamidine;
5-methylthio-4-(3-quinolyln amino)thiophene-2-carboxamid- ine;
5-methylthio-4-(pyrimidin-2-ylamino)thiophene-2-carboxamidine;
4-[(4-cyclohexylphenyl)amino]-5-methylthiothiophene-2-carboxamidine;
methyl 4-amino-5-methylthiothiophene-2-carboxylate; methyl
4-[(aminothioxomethyl)amnino]-5-methylthiothiophene-2-carboxylate;
5-methylthio-4-[(4-phenyl(1,3-thiazol-2-yl))amino]thiophene-2-carboxamidi-
ne; 5-methylthio-4-{[4-(4-phenylphenyl) (1,3-thiazol-2-yl)]amino
}thiophene-2-carboxamidine;
4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl))amino-
]-5-methylthiothiophene-2-carboxamidine;
4-{[4-hydroxy-4-(trifluoromethyl) (1,3-thiazolin-2-yl)]amino
}-5-methylthiothiophene-2-carboxamidine;
5-methylthio-4-(2-naphthylamino)thiophene-2-carboxamidine;
4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine;
4-[(3-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine;
4-[(3-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine;
4-{[3-(methylethyl)phenyl]amino
}-5-methylthiothiophene-2-carboxamidine;
5-methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxamidine;
4-{[4-(methylethyl)phenyl]amino
}-5-methylthiothiophene-2-carboxamidine;
4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine;
5-methylthio-4-[(4-phenylphenyl)amino]thiophene-2-carboxamidine;
4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxamidine;
4-(2H-benzo[d]1,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-carboxamidi-
ne; 4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxamidine;
5-methylthio-4-[benzylamino]thiophene-2-carboxamidine;
4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine;
4-(2,3-dihydrobenzo[b]furan-5-ylamino)-5-methylthiothiophene-2-carboxamid-
ine;
5-methylthio-4-[(2-phenylimidazol-4-yl)amino]thiophene-2-carboxamidin-
e;
5-methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxamidine;
4-{[(3-hydroxyphenyl)methyl]amino}-5-methylthiothiophene-2-carboxamidine;
5-methylthio-4-(phenylcarbonylamino)thiophene-2-carboxamidine;
4-((2E)-3-phenylprop-2-enoylamino)-5-methylthiothiophene-2-carboxamidine;
4-[(4-chlorophenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine;
4-(cyclohexylcarbonylamino)-5-methylthiothiophene-2-carboxamidine;
methyl
4-[(4-methyl-3-nitrophenyl)carbonylamino]-5-methylthiothiophene-2-carboxy-
late;
4-(2-furylcarbonylamino)-5-methylthiothiophene-2-carboxamidine;
4-(2,2-dimethylpropanoylamino)-5-methylthiothiophene-2-carboxamidine;
4-{[5-(3,5-dichlorophenoxy) (2-furyl)]carbonylamino }
-5-methylthiothiophene-2-carboxamidine;
5-methylthio-4-(naphthylcarbonyla- mino)-thiophene-2-carboxamidine;
5-methylthio-4-(2-quinolylcarbonyl-amino)-
thiophene-2-carboxamidine; 4-
[(3-methoxyphenyl)carbonylamino]-5-methylthi-
othiophene-2-carboxamidine;
4-[2-(2-hydroxy-5-methoxyphenyl)acetylamino]-5-
-methylthiothiophene-2-carboxamidine; 4-
[(4-ethoxyphenyl)carbonylamino]-5-
-methylthiothiophene-2-carboxamidine;
5-methylthio-4-(2-phenoxyacetylamino- )-thiophene-2-carboxamidine;
4- [(3-methylphenyl)carbonylamino]
-5-methylthiothiophene-2-carboxamidine;
5-methylthio-4-{[3-(phenylmethoxy- )phenyl]amino }
thiophene-2-carboxamidine; 5-methylthio-4-[(3-phenoxypheny-
l)amino]thiophene-2-carboxamidine;
5-methylthio-4-[(4-phenoxyphenyl)amino]- thiophene-2-carboxamidine;
4-[(2-methoxyphenyl)amino]-5-methylthiothiophen- e-2-carboxamidine;
4-[(2-methylphenyl)amino]-5-methylthiothiophene-2-carbo- xamidine;
4-[(3-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine;
4-(methylphenylamino)-5-methylthiothiophene-2-carboxamidine;
5-methyl-4-(phenylamino)thiophene -2-carboxamidine;
4-{[4-(dimethylamino)phenyl]amino}-5-methylthiothiophene-2-carboxamidine;
4-[(4-ethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine;
5-methylthio-4-{[4-(phenylmethoxy)phenyl] amino }
thiophene-2-carboxamidi- ne;
5-methylthio-4-{[4-(phenylamino)phenyl]amino
}thiophene-2-carboxamidin- e;
4-[(4-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine;
4-[(3-fluoro-4-methylphenyl)amino]
-5-methylthiothiophene-2-carboxamidine- ;
4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine;
4-[(9-ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxamidine;
5-methylthio-4-{[(4-phenylphenyl)sulfonyl]amino }
thiophene-2-carboxamidi- ne; 4-{bis[(4-phenylphenyl)sulfonyl]amino
} -5-methylthiothiophene-2-carbo- xamidine;
5-methylthio-4-[(2-naphthylsulfonyl)-amino]thiophene-2-carboxami-
dine; 4-
[bis(2-naphthylsulfonyl)amino]--methylthiothiophene-2-carboxamidi-
ne; 4-{[(6-bromo(2-naphthyl))sulfonyl]amino
}-5-methylthiothiophene-2-carb- oxamidine; 4-{
bis[(6-bromo(2-naphthyl))sulfonyl] amino }
-5-methylthiothiophene-2-carboxamidine;
5-methylthio-4-[(naphthylsulfonyl-
)-amino]thiophene-2-carboxamidine;
4-[bis(naphthylsulfonyl)amino]-5-methyl-
thiothiophene-2-carboxamidine; 4-{[(2-methylphenyl)sulfonyl] amino
} -5-methylthiothiophene-2-carboxamidine; 4-{
bis[(2-methylphenyl)sulfonyl]- amino }
-5-methylthiothiophene-2-carboxamidine; 4-{[(3-methylphenyl)sulfon-
yl]amino } -5-methylthiothiophene-2-carboxamidine; 4-{
bis[(3-methylphenyl)sulfonyl]aamino
}-5-methylthiothiophene-2-carboxamidi- ne;
4-{[(4-methylphenyl)sulfonyl] amino } -5-methylthiothiophene-2-2$
carboxamidine; 4-{ bis [(4-methylphenyl)sulfonyl] amino }
-5-methylthiothiophene-2-carboxamidine;
5-methylthio-4-{[benzylsulfonyl] amino }
-thiophene-2-carboxamidine; 5-methylthio-4-phenoxythiophene-2-car-
boxamidine; or
5-methylthio-4-(phenylsulfonyl)thiophene-2-carboxamidine; or a
salt, solvate, hydrate or prodrug thereof.
70. A compound of Formula I: 53or a solvate, hydrate or
pharmaceutically-acceptable salt thereof, wherein: X is oxygen or
sulfur; Y is a covalent bond or NH; Z is NR.sup.5R.sup.6; R.sup.1
is a hydrogen, amino, hydroxy or halogen; R.sup.2 is
alkylsulfonylamino, aralkylsulfonyla-ino, aralkenylsulfonylamino ,
arylsulfonylamino, heteroarylsulfonylamino,
di(aralkylsulfonyl)a.ino, di(aralkenylsulfonyl)amino,
di(arylsulfonyl)amino, or di(heteroarylsulfonyl)amrino, wherein any
of the aryl or heteroaryl containing groups are optionally
substituted on the aromatic ring; or amino, monoalkylamino,
dialkylamino, monoarylamino, diarylamiino, monoalkylmonoarylamino,
monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino,
monoheterocycleamino, diheterocycleamino,
monoalkylmonoheterocycleamino, wherein any of the aryl or
heterocycle containing groups is optionally substituted; or
alkanoylamino, alkenoylamino, alkynoylamino, aroylamino,
aralkanoylamino, aralkenoylamino, heteroaroylamino,
heteroarylalkanoylamino, any of which is optionally substituted on
the aromatic ring; or alkoxy, alkylthio, aryloxy, aralkoxy,
arylthio, aralkylthio, arylsulfonyl, aralkylsulfonyl,
aralkenylsulfonyl, any of which is optionally substituted; or
alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino,
wherein any of the aryl containing groups is optionally substituted
on the aromatic ring; or formylamino, H(S)CNH--, or thioacylamino;
R.sup.3 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkyl optionally
substituted with OH, NH.sub.2, COOH, aminocarbonyl, or C.sub.1-6
alkoxy.
71. A pharmaceutical composition comprising a compound according to
claim 70, or a pharmaceutically acceptable ester, salt or ether
thereof, and a pharmaceutically acceptable carrier.
72. A pharmaceutical composition according to claim 71, wherein
said compound is present in an amount between 0.01 and 100
milligrams.
73. A method of inhibiting a protease selected from the group
consisting of leukocyte neutrophil elastase, chymotrypsin, trypsin,
pancreatic elastase, cathepsin G, thrombin, urokinase, factor Xa,
plasmin, thermolysin, C-1 esterase, C-3 convertase, acrosin,
thrombin, kallikreins, and pepsin, comprising contacting said
protease with a compound according to 70.
74. A method according to claim 73 wherein said protease is
trypsin, chymotrypsin, plasmin or urokinase.
75. A method of treating adult respiratory distress syndrome, wound
healing, gout, rheumatoid arthritis, reperfusion damage,
atherosclerosis, restenosis, neoplasia, metastasis, emphysema,
Alzheimer's disease, pancreatitis, benign prostatic hypertrophy,
prostatic carcinoma, psoriasis or Parkinson's disease, comprising
administering to a patient in need of such treatment an effective
amount of a compound according to claim 70.
76. A compound of claim 70, which is one of:
5-methylthio-4-(6-quinolylami- no)thiophene-2-carboxamidine
5-methylthio-4-[(3-phenylphenyl)amino]thiophe- ne-2-carboxamidine
5-methylthio-4-(3-quinolylamino)thiophene-2-carboxamidi- ne
5-methylthio-4-(pyrimidin-2-ylamino)thiophene-2-carboxamidine
4-[(4-cyclohexylphenyl)amnino]-5-methylthiothiophene-2-carboxamidine
methyl 4-amino-5-methylthiothiophene-2-carboxylate methyl
4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylate
5-methylthio-4-[(4-phenyl(1,3-thiazol-2-yl))amino]thiophene-2-carboxamidi-
ne 5-methylthio-4-{[4-(4-phenylphenyl) ( 1,3-thiazol-2-yl)] amino }
thiophene-2-carboxamidine 4-[(5-methyl-4-phenyl(
1,3-thiazol-2-yl))amino]- -5-methylthiothiophene-2-carboxamidine
4-{[4-hydroxy-4-(trifluoromethyl) ( 1,3-thiazolin-2-yl)] amino }
-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-(2-naphthylamino)thiophene-2-carboxamidine
4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine
4-[(3-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine 4-
[(3-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine
4-{[3-(methylethyl)phenyl]amino }
-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxamidine
4-{[4-(methylethyl)phenyl] amino }
-5-methylthiothiophene-2-carboxamidine
4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
5-methylthio-4- [(4-phenylphenyl)amino]thiophene-2-carboxamidine
4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
4-(2H-benzo[d]
1,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-carboxamid- ine
4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
5-methylthio-4- [benzylamino]thiophene-2-carboxamnidine
4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine
4-(2,3-dihydrobenzo[b]
furan-5-ylamino)-5-methylthiothiophene-2-carboxami- dine
5-methylthio-4-[(2-phenylimidazol-4-yl)amino]thiophene-2-carboxamidin-
e 5-methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxamidine
4-{[(3-hydroxyphenyl)methyl]amino }
-5-methylthiothiophene-2-carboxamidin- e
5-methylthio-4-(phenylcarbonylamino)thiophene-2-carboxamidine
4-((2E)-3-phenylprop-2-enoylamino)-5-methylthiothiophene-2-carboxamidine
4-
[(4-chlorophenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine
4-(cyclohexylcarbonylamino)-5-methylthiothiophene-2-carboxamidine
methyl
4-[(4-methyl-3-nitrophenyl)carbonylamino]-5-methylthiothiophene-2-carboxy-
late 4-(2-furylcarbonylamino)-5-methylthiothiophene-2-carboxamidine
4-(2,2-dimethylpropanoylamino)-5-methylthiothiophene-2-carboxamidine
4-{[5-(3,5-dichlorophenoxy) (2-furyl)]carbonylamino }
-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-(naphthylcarbonylam- ino)-thiophene-2-carboxamidine
5-methylthio-4-(2-quinolylcarbonyl-amino)th-
iophene-2-carboxamidine 4-
[(3-methoxyphenyl)carbonylamino]-5-methylthioth-
iophene-2-carboxamidine 4-
[2-(2-hydroxy-5-methoxyphenyl)acetylamino]-5-me-
thylthiothiophene-2-carboxamidine
4-[(4-ethoxyphenyl)carbonylamino]-5-meth-
ylthiothiophene-2-carboxamidine
5-methylthio-4-(2-phenoxyacetylamino)-thio- phene-2-carboxamidine
4-[(3-methylphenyl)carbonylamino]-5-methylthiothioph-
ene-2-carboxamidine 5-methylthio-4-{[3-(phenylmethoxy)phenyl]amino
}thiophene-2-carboxamidine
5-methylthio-4-[(3-phenoxyphenyl)amino]thiophe- ne-2-carboxamidine
5-methylthio-4-[(4-phenoxyphenyl)amino]thiophene-2-carb- oxamidine
4- [(2-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidin- e
4- [(2-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
4-[(3-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine
4-(methylphenylamino)-5-methylthiothiophene-2-carboxamidine
5-methyl-4-(phenylamino)thiophene-2-carboxamidine
4-{[4-(dimethylamino)ph- enyl] amino }
-5-methylthiothiophene-2-carboxamidine 4-[(4-ethylphenyl)amnino]
-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-{[4-(phenylmethoxy)phenyl] amino
}thiophene-2-carboxamidin- e
5-methylthio-4-{[4-(phenylamino)phenyl] amino }
thiophene-2-carboxamidin- e 4-[(4-methoxyphenyl)amino]
-5-methylthiothiophene-2-carboxamidine
4-[(3-fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine
4-[(9-ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-{[(4-phenylphenyl)sulfonyl] amino }
thiophene-2-carboxamidine 4-{ bis[(4-phenylphenyl)sulfonyl] amino }
-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-[(2-naphthylsulfony-
l)-amino]thiophene-2-carboxamidine
4-[bis(2-naphthylsulfonyl)amino]-5-meth-
ylthiothiophene-2-carboxamidine 4-{[(6-bromo(2-naphthyl))sulfonyl]
amino } -5-methylthiothiophene-2-carboxamidine
4-{bis[(6-bromo(2-naphthyl))sulfon- yl]aamino }
-5-methylthiothiophene-2-carboxamidine 5-methylthio-4-
[(naphthylsulfonyl)-amnino]thiophene-2-carboxamidine
4-[bis(naphthylsulfonyl)amino]-5-methylthiothiophene-2-carboxamidine
4-{[ (2-methylphenyl) sulfonyl] amino } -5
-methylthiothiophene-2-carboxamidin- e 4-{ bis
[(2-methylphenyl)sulfonyl]amino } -5-methylthiothiophene-2-carbo-
xamidine 319-4-{[(3-methylphenyl)sulfonyl] amino }
-5-methylthiothiophene-- 2-carboxamidine 4-{ bis
[(3-methylphenyl)sulfonyl] amino }
-5-methylthiothiophene-2-carboxamidine
4-{[(4-methylphenyl)sulfonyl] amino }
-5-methylthiothiophene-2-carboxamidine 4-{
bis[(4-methylphenyl)sulfonyl]amino }
-5-methylthiothiophene-2-carboxamidi- ne
5-methylthio-4-{[benzylsulfonyl] amino } -thiophene-2-carboxamidine
5-methylthio-4-phenoxythiophene-2-carboxamidine
5-methylthio-4-(phenylsul- fonyl)thiophene-2-carboxamidine or salts
or prodrugs thereof.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 09/372,748, filed Aug. 11, 1999, which application is a
continuation-in-part of U.S. application Ser. No. 09/247,062, filed
Feb. 9, 1999, which application claims benefit under 35 U.S.C.
.sctn. 119(e) of U.S. Provisional Application No. 60/074,110, filed
Feb. 9, 1998, each of which is herein incorporated by
reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to novel heteroaryl compounds
that function as enzyme inhibitors, and particularly to a new class
of non-peptidic inhibitors of proteolytic enzymes such as urokinase
(uPa).
[0004] 2. Related Art
[0005] Proteases are enzymes that cleave proteins at single,
specific peptide bonds. Proteases can be classified into four
generic classes: serine, thiol or cysteinyl, acid or aspartyl, and
metalloproteases (Cuypers et al., J. Biol. Chem. 257:7086 (1982)).
Proteases are essential to a variety of biological activities, such
as digestion, formation and dissolution of blood clots,
reproduction and the immune reaction to foreign cells and
organisms. Aberrant proteolysis is associated with a number of
disease states in man and other mammals. The human neutrophil
proteases, elastase and cathepsin G, have been implicated as
contributing to disease states marked by tissue destruction. These
disease states include emphysema, rheumatoid arthritis, corneal
ulcers and glomerular nephritis. (Barret, in Enzyme Inhibitors as
Drugs, Sandler, ed., University Park Press, Baltimore, (1980)).
Additional proteases such as plasmin, C-1 esterase, C-3 convertase,
urokinase and tissue-type plasminogen activators, acrosin, and
kallikreins play key roles in normal biological functions of
mammals. In many instances, it is beneficial to disrupt the
function of one or more proteolytic enzymes in the course of
therapeutically treating a mammal.
[0006] Serine proteases include such enzymes as elastase (human
leukocyte), cathepsin G, plasmin, C-1 esterase, C-3 convertase,
urokinase and tissue-type plasminogen activators, acrosin,
chymotrypsin, trypsin, thrombin, factor Xa and kallikreins.
[0007] Human leukocyte elastase is released by polymorphonuclear
leukocytes at sites of inflammation and thus is a contributing
cause for a number of disease states. Cathepsin G is another human
neutrophil serine protease. Compounds with the ability to inhibit
the activity of these enzymes are expected to have an
anti-inflammatory effect useful in the treatment of gout,
rheumatoid arthritis and other inflammatory diseases, and in the
treatment of emphysema. Chymotrypsin and trypsin are digestive
enzymes. Inhibitors of these enzymes are useful in treating
pancreatitis. Inhibitors of urokinase plasminogen activator are
useful in treating excessive cell growth disease states, such as
benign prostatic hypertrophy, prostatic carcinoma and
psoriasis.
[0008] Urokinase (urinary-type plasminogen activator or uPA;
International Union of Biochemistry Classification Number:
EC3.4.21.31) is a proteolytic enzyme which is highly specific for a
single peptide bond in plasminogen. It is a multidomain serine
protease, having a catalytic B chain (amino acids (aa) 144-411),
and an amino-terminal fragment ("ATF", aa 1-143) consisting of a
growth factor-like domain (4-43) and a Kringle domain (aa 47-135).
The uPA Kringle domain appears to bind heparin, but not fibrin,
lysine, or aminohexanoic acid. The growth factor-like domain bears
some similarity to the structure of epidermal growth factor (EGF)
and is thus also referred to as "EGF-like" domain. The single chain
pro-uPA is activated by plasmin, cleaving the chain into a
two-chain active form that is stabilized by a disulfide bond.
[0009] Cleavage of the peptide bond in plasminogen by urokinase
(plasminogen activation) results in the formation of a potent
general protease, plasmin. Many cell types use urokinase as a key
initiator of plasmin-mediated proteolytic degradation or
modification of extracellular support structures (e.g., the
extracellular matrix (ECM) and the basement membrane (BM)). Cells
exist, move, and interact with each other in tissues and organs
within the physical framework provided by the ECM and BM. Movement
of cells within the ECM or across the BM requires local proteolytic
degradation or modification of these structures, allowing cells to
invade into adjacent areas that were previously unavailable.
[0010] Central to the ability of urokinase to mediate cellular
migration and invasiveness is the existence of specific high
affinity urokinase receptors (uPARs) which concentrate urokinase on
the cell surface, leading to the generation of locally high plasmin
concentrations between cells and ECM or BM (Blasi, F., et al., Cell
Biol. 104:801-804 (1987); Roldan, A. L., et al., EMBO J. 9:467-74
(1990)). The binding interaction is apparently mediated by the
EGF-like domain (Rabbani, S. A., et al., J. Biol. Chem.
267:14151-56 (1992)). Cleavage of pro-uPA into active uPA is
accelerated when pro-uPA and plasminogen are receptor-bound. Thus,
plasmin activates pro-uPA, which in turn activates more plasmin by
cleaving plasminogen. This positive feedback cycle is apparently
limited to the receptor-based proteolysis on the cell surface,
since a large excess of protease inhibitors is found in plasma,
including .alpha..sub.2 antiplasmin, PAI-1 and PAI-2. High plasmin
concentrations between invasive cells and ECM or BM are necessary
in order to overcome inhibitory effect of these ubiquitous plasmin
inhibitors. Thus, it is cell surface receptor-bound urokinase, and
not simply free urokinase secreted by cells, which plays the
predominant role in initiating cellular invasiveness.
[0011] Plasmin can activate or degrade extracellular proteins such
as fibrinogen, fibronectin, and zymogens, including matrix
metalloproteinases. Plasminogen activators thus can regulate
extracellular proteolysis, fibrin clot lysis, tissue remodeling,
developmental cell and smooth muscle cell migration, inflammation,
and metastasis. Cellular invasiveness initiated by urokinase is
central to a wide variety of normal and disease-state physiological
processes (reviewed in Blasi, F., et al., J. Cell Biol. 104:801-804
(1987); Dan.o slashed., K., et al., Adv. Cancer Res. 44:139-266
(1985); Littlefield, B. A., Ann. N.Y. Acad. Sci. 622:167-175
(1991); Saksela, O., Biochim. Biophys. Acta 823:35-65 (1985);
Testa, J. E., and Quigley, J. P., Cancer Metast. Rev. 9:353-367
(1990)). Such processes include, but are not limited to,
angiogenesis (neovascularization), bone restructuring, embryo
implantation in the uterus, infiltration of immune cells into
inflammatory sites, ovulation, spermatogenesis, tissue remodeling
during wound repair, restenosis and organ differentiation,
fibrosis, local invasion of tumors into adjacent areas, metastatic
spread of tumor cells from primary to secondary sites, and tissue
destruction in arthritis. Inhibitors of urokinase therefore have
mechanism-based anti-angiogenic, anti-arthritic, anti-inflammatory,
anti-restenotic, anti-invasive, anti-metastatic, anti-osteoporotic,
anti-retinopathic (for angiogenesis-dependent retinopathies),
contraceptive, and tumoristatic activities. Inhibitors of urokinase
are useful agents in the treatment of a variety of disease states,
including but not limited to, benign prostatic hypertrophy,
prostatic carcinoma and psoriasis.
[0012] Beneficial effects of urokinase inhibitors have been
reported using anti-urokinase monoclonal antibodies and certain
other known urokinase inhibitors. For instance, anti-urokinase
monoclonal antibodies have been reported to block tumor cell
invasiveness in vitro (Hollas, W., et al., Cancer Res.
51:3690-3695, (1991); Meissauer, A., et al., Exp. Cell Res.
192:453-459 (1991)), tumor metastasis and invasion in vivo
(Ossowski, L., J. Cell Biol. 107:2437-2445 (1988); Ossowski, L., et
al., J. Cancer Res. 51:274-81 (1991)), and angiogenesis in vivo
(Jerdan, J. A., et al., J. Cell Biol. 115[3 Pt 2]:402a (1991)). In
addition, amiloride, a known urokinase inhibitor of only moderate
potency, has been reported to inhibit tumor metastasis in vivo
(Kellen, J. A., et al., Anticancer Res. 8:1373-1376 (1988)) and
angiogenesis/capillary network information in vitro (Alliegro, M.
A., et al., J. Cell Biol. 115[3 Pt 2]:402a (1991)).
[0013] Urokinase plays a significant role in vascular wound healing
and arterial neointima formation after injury, most likely
affecting cellular migration. Urokinase mediates plasmin
proteolysis, which in turn promotes vascular wound-healing and
associated neointima formation (Carmeliet et al., Circ. Res.
81:829-839 (Nov. 1997), Lupu et al., Fibrinolysis 10 Supp 2:33-35
(1996)). A viral serine proteinase inhibitor, SERP-1, has been
employed to reduce plaque formation after primary balloon
angioplasty in rabbits. This activity has been attributed to the
inhibition by SERP-1 of cellular proteinases, such as plasmin or
urokinase (Lucas et al., Circulation 94:2890-2900 (1996)).
[0014] A need continues for non-peptidic compounds that are potent
and selective urokinase inhibitors, and which possess greater
bioavailability and fewer side-effects than currently available
urokinase inhibitors. Accordingly, new classes of potent urokinase
inhibitors, characterized by potent inhibitory capacity and low
toxicity, are potentially valuable therapeutic agents for a variety
of conditions.
SUMMARY OF THE INVENTION
[0015] The present invention is broadly directed to the use of
heteroaryl amidines, methylamidines and guanidines having Formula I
(below) as protease inhibitors, preferably as urokinase
inhibitors.
[0016] Compounds of the present invention exhibit anti-urokinase
activity via direct, selective inhibition of urokinase, or are
intermediates useful for forming compounds having such activity.
Compounds of the present invention inhibit urokinase and are,
therefore, useful anti-angiogenic, anti-arthritic,
anti-inflammatory, anti-restenotic, anti-invasive, anti-metastatic,
anti-osteoporotic, anti-retinopathic (for angiogenesis-dependent
retinopathies), contraceptive, and tumoristatic treatment agents.
For example, such treatment agents are useful in the treatment of a
variety of disease states, including but not limited to, benign
prostatic hypertrophy, prostatic carcinoma, tumor metastasis and
psoriasis.
[0017] Also provided are methods to inhibit extracellular
proteolysis, methods to treat benign prostatic hypertrophy,
prostatic carcinoma, tumor metastasis, psoriasis, and other
conditions by administering the compound of Formula I.
[0018] A number of the heteroaryl compounds described herein are
novel compounds. Therefore, the present invention is also directed
to novel compounds of Formula I.
[0019] Further provided are pharmaceutical compositions comprising
a compound of Formula I and one or more pharmaceutically acceptable
carriers or diluents and said pharmaceutical compositions further
comprising a thrombolytic agent such as tissue plasminogen
activator and streptokinase.
[0020] Further provided are methods of synthesizing compounds of
Formula I.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0021] The present invention is broadly directed to a method of
inhibiting proteases, particularly serine proteases, by contacting
a serine protease with a compound of the general Formula I: 1
[0022] or a solvate, hydrate or pharmaceutically acceptable salt
thereof; wherein:
[0023] X is O, S or NR.sup.7, where R.sup.7 is hydrogen, alkyl,
aralkyl, hydroxy(C.sub.2-4)alkyl, or alkoxy(C.sub.2-4)alkyl;
[0024] Y is a direct covalent bond, CH.sub.2 or NH;
[0025] Z is NR.sup.5R.sup.6, hydrogen or alkyl, provided that Y is
NH whenever Z is hydrogen or alkyl;
[0026] R is hydrogen, amino, hydroxy, halogen, cyano, C.sub.1-4
alkyl or --CH.sub.2R, where R is hydroxy, amino or C.sub.1-3
alkoxy;
[0027] R.sup.2 and R.sup.3 are independently:
[0028] i. hydrogen;
[0029] ii. halogen;
[0030] iii. hydroxy;
[0031] iv. nitro;
[0032] v. cyano;
[0033] vi. amino, monoalkylamino, dialkylamino, monoarylamino,
diarylamino, monoalkylmonoarylamino, monoaralkylamino,
diaralkylamino, monoalkylmonoaralkylamino, monoheterocycleamino,
diheterocycleamino, monoalkylmonoheterocycleamino,
alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino,
alkylsulfonylamino, aralkylsulfonylamino, aralkenylsulfonylamino,
arylsulfonylamino, heteroarylsulfonylamino,
di(aralkylsulfonyl)amino, di(aralkenylsulfonyl)amino,
di(arylsulfonyl)amino, or di-(heteroarylsulfonyl)amino,
formylamino, alkanoylamino, alkenoylamino, alkynoylamino,
aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino,
heteroaralkanoylamino, H(S)CNH--, or thioacylamino, wherein any of
the aryl or heteroaryl containing groups can be optionally
substituted on the aromatic ring and wherein any of the heterocycle
containing groups can be optionally ring substituted;
[0034] vii. aminocarbonyl, monoalkylaminocarbonyl,
dialkylaminocarbonyl, acyl, aminoacyl, monoarylaminocarbonyl,
diarylaminocarbonyl or monoalkylmonoarylaminocarbonyl;
[0035] viii. aminothiocarbonyl, monoalkylaminothiocarbonyl,
dialkylaminothiocarbonyl, thioacyl or aminothioacyl;
[0036] ix. aminocarbonylamino, mono- and dialkylaminocarbonylamino,
mono- and diarylaminocarbonylamino, or mono- and
diaralkylaminocarbonylamino;
[0037] x. aminocarbonyloxy, mono- and dialkylaminocarbonyloxy,
mono- and diarylaminocarbonyloxy, mono- and
diaralkylaminocarbonyloxy;
[0038] xi. aminosulfonyl, mono- and dialkylaminosulfonyl, mono- and
diarylaminosulfonyl, or mono- and diaralkylaminosulfonyl;
[0039] xii. alkoxy, or alkylthio, wherein the alkyl portion of each
group may be optionally substituted,
[0040] xiii. aralkoxy, aryloxy, heteroaryloxy, aralkylthio,
arylthio, or heteroarylthio, wherein the aryl portion of each group
can be optionally substituted;
[0041] xiv. alkylsulfonyl, wherein the alkyl portion can be
optionally substituted;
[0042] xv. aralkylsulfonyl, aralkenylsulfonyl, arylsulfonyl or
heteroarylsulfonyl, wherein the aryl portion of each group can be
optionally substituted;
[0043] xvi. alkenyl, or alkynyl;
[0044] xvii. optionally substituted aryl;
[0045] xviii. optionally substituted alkyl;
[0046] xix. optionally substituted aralkyl;
[0047] xx. optionally substituted heterocycle; or
[0048] xxi. optionally substituted cycloalkyl; and
[0049] R.sup.4, R.sup.5 and R.sup.6 are independently hydrogen,
C.sub.1-4 alkyl, aryl, hydroxyalkyl, aminoalkyl,
monoalkylamino(C.sub.2-10)alkyl, dialkylamino(C.sub.2-10)alkyl,
carboxyalkyl, cyano, amino, alkoxy, or hydroxy, or
--CO.sub.2R.sup.w, where
[0050] R.sup.w is alkyl, cycloalkyl, phenyl, benzyl, 2
[0051] where R.sup.d and R.sup.e are independently hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl or phenyl, R.sup.f is hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl or phenyl, R.sup.g is hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl or phenyl, and R.sup.h is
aralkyl or C.sub.1-6 alkyl.
[0052] The present invention is also directed to novel compounds of
Formula I, where X, Y and R.sup.1-R.sup.6 are as defined above;
provided that at least one of R.sup.2 or R.sup.3 is selected from
the group consisting of:
[0053] (a) an optionally substituted alkyl group, preferably
C.sub.1-C.sub.6 alkyl, more preferably C.sub.1-C.sub.3;
[0054] (b) alkoxy, aryloxy, alkylthio or arylthio, any of which is
optionally substituted;
[0055] (c) optionally substituted C.sub.6-C.sub.14 aryl, or
optionally substituted aralkyl, except that R.sup.3 is not
nitrophenyl or aminophenyl, when R.sup.1 and R.sup.2 are both
hydrogen or methyl;
[0056] (d) optionally substituted heterocycle; and
[0057] (e) optionally substituted cycloalkyl.
[0058] When an alkyl-containing group, heterocyclic-containing
group or aryl-containing group of R.sup.2 or R.sup.3 is optionally
substituted, the optional substituents can be 1 to 4 non-hydrogen
substituents, provided that the resulting compound is stable.
Values of optional substituents on alkyl groups are halogen,
hydroxy, thiol, amino, monoalkylamino, dialkylamino, formylamino,
aminoiminomethyl, acylamino, aminoacyl, mono- or
di-alkylaminocarbonyl, thiocarbonylamino, thioacylamino,
aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, mono- or
di-alkylaminocarbonyloxy, mono- or diarylaminocarbonyloxy, mono- or
diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl,
aralkylsulfonyl, alkylsulfonylamino, arylsulfonylamino,
aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,
aryloxycarbonylamino, mono- or di-alkylaminothiocarbonyl, aralkoxy,
carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro,
cyano, trifluoromethyl, alkylthio and arylthio.
[0059] Preferred values of optional substituents on an alkyl group
are chloro, hydroxy, amino, mono(C.sub.1-4)alkylamino,
di(C.sub.1-4)alkylamino, formylamino, C.sub.2-6 acylamino,
aminocarbonyl, C.sub.2-8 aminoacyl, C.sub.1-6 alkoxy, C.sub.6-14
aryloxy, carboxy, carboxy(C.sub.1-6)alkyl, C.sub.2-8
alkoxycarbonyl, nitro, cyano, trifluoromethyl, C.sub.1-6 alkylthio,
C.sub.6-14 arylthio, C.sub.1-6 alkylsulfonylamino, C.sub.7-15
aralkylsulfonylamino, C.sub.6-10 arylsulfonylamino, mono- or
di(C.sub.1-6)alkylaminocarbonyloxy, mono- or
di-(C.sub.6-10)arylaminocarbonyloxy, mono- or
di(C.sub.7-15)aralkylcarbon- yloxy, C.sub.1-6 alkoxycarbonylamino,
C.sub.7-C.sub.15 aralkoxycarbonylamino, and C.sub.6-C.sub.10
aryloxycarbonylamino.
[0060] Preferred values of optional substituents on aryl-containing
and heterocyclic-containing groups include chloro, hydroxy, amino,
mono(C.sub.1-4) alkylamino, di(C.sub.1-4)alkylamino, formylamino,
C.sub.2-6 acylamino, aminocarbonyl, C.sub.2-8 aminoacyl, C.sub.3-7
cycloalkyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.6-14 aryloxy,
carboxy, carboxy(C.sub.1-6)alkyl, C.sub.2-8 alkoxycarbonyl, nitro,
cyano, trifluoromethyl, C.sub.1-6 alkylthio, C.sub.6-14 arylthio,
C.sub.6-14 aryl, substituted phenyl, tetrazolyl, thienyl (further
optionally substituted by one, two or three of chloro, hydroxy,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, amino or carboxy),
3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy,
C.sub.1-6 alkylsulfonylamino, C.sub.7-15 aralkylsulfonylamino,
C.sub.1-6 arylsulfonylamino, C.sub.1-6 alkyl/sulfonyl, C.sub.6-10
arylsulfonyl, mono- or di(C.sub.1-6)alkylamino- carbonyloxy, mono-
or di- C.sub.6-10 arylaminocarbonyloxy, mono- or
di-(C.sub.7-15)aralkylcarbonyloxy, C.sub.1-6 alkoxycarbonylamino,
C.sub.7-C.sub.15 aralkoxycarbonylamino, C.sub.6-C.sub.10
aryloxycarbonylamino, C.sub.2-6 thioacylamino, aminothiocarbonyl,
and C.sub.2-8 aminothioacyl.
[0061] Preferred values of R include hydrogen, amino, hydroxy and
fluoro.
[0062] A preferred value of R.sup.2 is Formula II: 3
[0063] where Ar is phenyl, thiazolyl, thiazolinyl, oxazolyl,
isothiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl,
pyrazinyl, thienyl (thiophenyl), pyrrolyl, oxazolinyl and
benzothienyl.
[0064] Preferred values of R.sup.3 include C.sub.1-4 alkyl
(optionally substituted), halogen, amino, acylamino, C.sub.1-6
alkylthio (such as methylthio or ethylthio), C.sub.1-6 alkoxy (such
as methoxy and ethoxy), trifluoromethyl, methylsulfonyl, and
benzylthio.
[0065] A preferred value of X is divalent sulfur (S).
[0066] Preferred values of Y are a covalent bond or --NH--, most
preferably a covalent bond.
[0067] Preferred values of R.sup.4, R.sup.5 and R.sup.6 in Formula
I are hydrogen, hydroxy, cyano, C.sub.1-6 alkyl, or C.sub.1-6
alkoxy. Suitable values of R.sup.4, R.sup.5 and R.sup.6 include
hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, and
ethoxy. In the most preferred embodiments, R.sup.4, R.sup.5 and
R.sup.6 are each hydrogen.
[0068] Preferred values of R.sup.4, R.sup.5 and R.sup.6 in Formula
I also include prodrugs such as --CO.sub.2R.sup.w, where R.sup.w,
in each instance, is preferably one of C.sub.1-4 alkyl,
C.sub.4-7cycloalkyl or benzyloxycarbonyl. Suitable values of
R.sup.4, R.sup.5 and R.sup.6 include hydrogen, methyl, ethyl,
propyl, n-butyl, hydroxy, methoxy, ethoxy, cyano,
--CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3 and
--CO.sub.2CH.sub.2CH.sub.2CH.sub.3. In the most preferred
embodiments, R.sup.4, R.sup.5 and R.sup.6 are each hydrogen.
[0069] Also preferred at R.sup.4, R.sup.5 and R.sup.6 is the group
--CO.sub.2R.sup.w, where R.sup.w is one of 4
[0070] where R.sup.d-R.sup.h are defined as above. When R.sup.4,
R.sup.5 and R.sup.6 are --CO.sub.2R.sup.w, where R.sup.w is one of
one of these moieties, the resulting compounds are prodrugs that
possess desirable formulation and bioavailability characteristics.
A preferred value for each of R.sup.d, R.sup.e and R.sup.g is
hydrogen, R.sup.f is methyl, and preferred values for R.sup.h
include benzyl and tert-butyl.
[0071] Preferred values of R.sup.7 include hydrogen, C.sub.1-6
alkyl, C.sub.6-10 ar(C.sub.1-4)alkyl, and C.sub.2-6 hydroxyalkyl.
Suitable values are hydrogen, methyl, ethyl, and benzyl.
[0072] The term alkyl as employed herein by itself or as part of
another group refers to both straight and branched chain radicals
of up to 12 carbons, such as methyl, ethyl, propyl, isopropyl,
butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl,
4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl,
undecyl, dodecyl.
[0073] The term "alkenyl" is used herein to mean a straight or
branched chain radical of 2-20 carbon atoms, unless the chain
length is limited thereto, including, but not limited to, ethenyl,
1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl,
and the like. Preferably, the alkenyl chain is 2 to 10 carbon atoms
in length, more preferably, 2 to 8 carbon atoms in length most
preferably from 2 to 4 carbon atoms in length.
[0074] The term "alkynyl" is used herein to mean a straight or
branched chain radical of 2-20 carbon atoms, unless the chain
length is limited thereto, wherein there is at least one triple
bond between two of the carbon atoms in the chain, including, but
not limited to, acetylene, 1-propylene, 2-propylene, and the like.
Preferably, the alkynyl chain is 2 to 10 carbon atoms in length,
more preferably, 2 to 8 carbon atoms in length, most preferably
from 2 to 4 carbon atoms in length.
[0075] In all instances herein where there is an alkenyl or alkynyl
moiety as a substituent group, the unsaturated linkage, i.e., the
vinylene or acetylene linkage is preferably not directly attached
to a nitrogen, oxygen or sulfur moiety.
[0076] The term "alkylthio" as employed herein by itself or as part
of another group refers to a straight or branched chain radical of
1 to 20 carbon atoms, unless the chain length is limited thereto,
bonded to a sulfur atom, including, but not limited to, methylthio,
ethylthio, n-propylthio, isopropylthio, and the like. Preferably
the alkylthio chain is 1 to 10 carbon atoms in length, more
preferably 1 to 8 carbon atoms in length.
[0077] The term "alkoxy" as employed herein by itself or as part of
another group refers to a straight or branched chain radical of 1
to 20 carbon atoms, unless the chain length is limited thereto,
bonded to an oxygen atom, including, but not limited to, methoxy,
ethoxy, n-propoxy, isopropoxy, and the like. Preferably the alkoxy
chain is 1 to 10 carbon atoms in length, more preferably 1 to 8
carbon atoms in length.
[0078] The term "cycloalkyl" as employed herein by itself or as
part of another group refers to cycloalkyl groups containing 3 to 9
carbon atoms. Typical examples are cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and
cyclononyl.
[0079] The term "halogen" or "halo" as employed herein by itself or
as part of another group refers to chlorine, bromine, fluorine or
iodine with chlorine being preferred.
[0080] The term "acyl" as employed herein by itself or as part of
another group refers to the group --C(O)R.sup.g where R.sup.g is
alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, heteroaryl,
heteroarylalkyl or heteroarylalkenyl. Preferred acyl groups are
alkanoyl, aralkanoyl and aroyl groups (--C(O)R.sup.g where R.sup.g
is C.sub.1-8 alkyl, C.sub.6-10 aryl(C.sub.1-4 )alkyl or C.sub.6-10
aryl).
[0081] The term "thioacyl" as employed herein by itself or as part
of another group refers to the group --C(S)R.sup.g where R.sup.g is
alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, heteroaryl,
heteroarylalkyl or heteroarylalkenyl, preferably C.sub.1-.sub.8
alkyl.
[0082] The term "thiocarbonyl" as employed herein by itself or as
part of another group refers to the group --C(S)--.
[0083] The term "monoalkylamine" as employed herein by itself or as
part of another group refers to an amino group which is substituted
with one alkyl group having from 1 to 6 carbon atoms.
[0084] The term "dialkylamine" as employed herein by itself or as
part of another group refers to an amino group which is substituted
with two alkyl groups, each having from 1 to 6 carbon atoms
[0085] The term "aryl" as employed herein by itself or as part of
another group refers to monocyclic or bicyclic aromatic groups
containing from 6 to 14 carbons in the ring portion, preferably
6-10 carbons in the ring portion, such as phenyl, naphthyl or
tetrahydronaphthyl.
[0086] The term "aralkyl or arylalkyl" as employed herein by itself
or as part of another group refers to C.sub.1-6alkyl groups as
discussed above having an aryl substituent, such as benzyl,
phenylethyl or 2-naphthylmethyl.
[0087] The terms "heterocyclic," "heterocyclo" or "heterocycle" as
employed herein by themselves or as part of larger groups refers to
a saturated or wholly or partially unsaturated 3-7 membered
monocyclic, or 7-10 membered bicyclic ring system, which consists
of carbon atoms and from one to four heteroatoms independently
selected from the group consisting of O, N, and S, wherein the
nitrogen and sulfur heteroatoms can be optionally oxidized, the
nitrogen can be optionally quaternized, and including any bicyclic
group in which any of the above-defined heterocyclic rings is fused
to a benzene ring, and wherein the heterocyclic ring can be
substituted on carbon or on a nitrogen atom if the resulting
compound is stable. Especially useful are rings containing one
oxygen or sulfur, one to three nitrogen atoms, or one oxygen or
sulfur combined with one or two nitrogen atoms. Examples of such
heterocyclic groups include piperidinyl, piperazinyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl,
2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl,
pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl,
pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,
oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl,
indolyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl,
thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl,
tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl
sulfone, and oxadiazolyl. Morpholino is the same as
morpholinyl.
[0088] The term "heteroatom" is used herein to mean an oxygen atom
("O"), a sulfur atom ("S") or a nitrogen atom ("N"). It will be
recognized that when the heteroatom is nitrogen, it may form an
NR.sup.yR.sup.z moiety, wherein R.sup.y and R.sup.z are,
independently from one another, hydrogen or C.sub.1 to C.sub.8
alkyl, or together with the nitrogen to which they are bound, form
a saturated or unsaturated 5-, 6-, or 7-membered ring.
[0089] The term "heteroaryl" as employed herein refers to groups
having 5 to 14 ring atoms; 6, 10 or 14 electrons shared in a cyclic
array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen
or sulfur heteroatoms (where examples of heteroaryl groups are:
thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl,
furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl,
xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl,
pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,
4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl,
naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl,
4.alpha.H-carbazolyl, carbazolyl, .beta.-carbolinyl,
phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl,
phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and
phenoxazinyl groups).
[0090] The expression prodrug denotes a derivative of a known
direct acting drug, which derivative has enhanced delivery
characteristics and therapeutic value as compared to the drug, and
is transformed into the active drug by an enzymatic or chemical
process. Useful prodrugs are those where R.sup.4, R.sup.5 and/or
R.sup.6 are --CO.sub.2R.sup.w, where R.sup.w is defined above. See,
U.S. Pat. No. 5,466,811 and Saulnier et al., Bioorg. Med. Chem.
Lett. 4:1985-1990 (1994).
[0091] The term "substituted", as used herein, means that one or
more hydrogens of the designated moiety are replaced with a
selection from the indicated group, provided that no atoms normal
valency is exceeded, and that the substitution results in a stable
compound. When a substituent is keto (i.e., .dbd.O), then 2
hydrogens attached to an atom of the moiety are replaced.
[0092] By stable compound or stable formula is meant herein a
compound that is sufficiently robust to survive isolation to a
useful degree of purity from a reaction mixture and formulation
into an efficacious therapeutic agent.
[0093] A first preferred group of compounds falling within the
scope of the present invention include compounds of Formula I
wherein X is sulfur or oxygen; Y is a covalent bond or --NH--;
R.sup.1 is hydrogen, amino, hydroxy or halogen; R.sup.4, R.sup.5
and R.sup.6 are independently hydrogen, C.sub.1-4alkyl, amino,
cyano, C.sub.1-4alkoxy or hydroxy, and are preferably all hydrogen;
one of R.sup.2 or R.sup.3 is hydrogen, C.sub.1-6 alkyl (optionally
substituted with hydroxy, amino, carboxy or aminocarbonyl),
C.sub.1-6 alkylthio or C.sub.1-6 alkoxy; and the other of R.sup.2
or R.sup.3 is aminoacyl, acylamino, aminosulfonyl, sulfonylamino,
aminocarbonylamino, alkoxycarbonylamino, optionally substituted
oxazolyl, optionally substituted isoxazolyl, optionally substituted
benzothienyl, optionally substituted furanyl, optionally
substituted pyrazolyl or optionally substituted pyridyl.
[0094] Specific compounds within the scope of the invention include
the compounds described in the Examples, such as the following:
[0095]
4-[4-(4-chlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxam-
idine;
[0096] 4-phenyl-5-methylthiothiophene-2-carboxamidine;
[0097]
4-[4-(2,4-dichlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carb-
oxamidine;
[0098]
4-(4-methylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
[0099] methyl
4-[4-(4-phenylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-c-
arboxylate;
[0100]
4-[4-(3-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxa-
midine,
[0101]
4-[4-(3-hydroxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxa-
midine,
[0102]
4-(4-phenylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine,
[0103]
4-[4-(4-nitrophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxami-
dine,
[0104]
4-[4-(3,4-ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-
-carboxamidine,
[0105] 4-[4- (3,4-propylenedioxyphenyl)thiazol-2-yl]-5
-methylthiothiophene-2-carboxamidine,
[0106]
4-[4-(4-(naphth-2-yl)thiazol-2-yl]-5-methylthiothiophene-2-carboxam-
idine,
[0107]
4-isopropylsulfonyl-5-methylthiothiophene-2-carboxamidine;
[0108] 4-phenyl-5-methylthiothiophene-2-carboxamidine;
[0109]
4-[4-(4-chlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxam-
idine;
[0110]
4-[4-(4-phenylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxam-
idine;
[0111]
4-[4-(4-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxa-
midine;
[0112]
4-(2-naphthylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
[0113]
4-[4-(4-chloro-3-methylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-
-carboxamidine;
[0114]
4-(5-methyl-4-phenylthiazol-2-yl)-5-methylthiothiophene-2-carboxami-
dine;
[0115]
4-[4-(4-chloro-3-nitrophenyl)thiazol-2-yl]-5-methylthiothiophene-2--
carboxamidine;
[0116]
4-(5-phenyloxazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
[0117] 4
4-[4-(3-fluoro-5-trifluoromethylphenyl)-5-methylthiazol-2-yl]-5-m-
ethylthiothiophene-2-carboxamidine;
[0118]
4-[4-(3,5-bis(trifluoromethyl)phenyl)-5-methyl-thiazol-2-yl]-5-meth-
ylthiothiophene-2-carboxamidine;
[0119]
4-[4-(3-fluoro-5-trifluoromethylphenyl)thiazol-2-yl]-5-methylthioth-
iophene-2-carboxamidine;
[0120]
4-[4-(3-bromophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxami-
dine;
[0121]
4-[4-(3,4-methylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene--
2-carboxamidine;
[0122]
4-[4-(4-methylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxam-
idine;
[0123]
4-[4-(3,5-bis(trifluoromethyl)phenyl)thiazol-2-yl]-5-methylthiothio-
phene-2-carboxamidine;
[0124]
4-[4-(2-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxa-
midine;
[0125]
4-(4-phenylimidazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
[0126]
4-[4-(2,4-dimethoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-car-
boxamidine;
[0127]
4-(4-benzylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
[0128]
4-[4-(3,4-dichlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carb-
oxamidine;
[0129]
4-[4-(3-methylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxam-
idine;
[0130]
4-[4-(3,5-dimethoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-car-
boxamidine;
[0131]
4-[4-(2-methylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxam-
idine;
[0132]
4-[4-(2,5-dimethoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-car-
boxamidine;
[0133]
4-(4,5-diphenylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
[0134]
4-(2-phenyl)thiazol-4-yl-5-methylthiothiophene-2-carboxamidine;
[0135] 4-[4-(2-chloro-3-pyridyl)thiazol
-2-yl]-5-methylthiothiophene-2-car- boxamidine;
[0136]
4-[4-(phenoxymethyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxami-
dine;
[0137]
4-(4-cyclohexylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
[0138]
4-[4-(4-chorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxami-
dine;
[0139]
4-[4-(2-hydroxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxa-
midine;
[0140]
4-[4-(3-trifluoromethoxyphenyl)thiazol-2-yl]-5-methylthiothiophene--
2-carboxamidine;
[0141]
4-[4-(2-chloro-4pyriyl)thiazol-2-yl]-5-methylthiothiophene-2-carbox-
aniidine;
[0142]
4-(5-phenyl-2-pyridyl)-5-methylthiothiophene-2-carboxamidine;
[0143]
4-[2-(2-chlorophenylamino)thiazol-4-yl]-5-methylthiothiophene-2-car-
boxamnidine;
[0144]
4-[2-(3-methoxyphenylamino)thiazol-4-yl]-5-methylthiothiophene-2-ca-
rboxamidine;
[0145]
4-[2-(phenylamino)thiazol-4-yl]-5-methylthiothiophene-2-carboxamidi-
ne;
[0146]
4-[2-(2,5-dimethoxyphenylamino)thiazol-4-yl]-5-methylthiothiophene--
2-carboxamidine;
[0147]
4-(2-aminothiazol-4-yl)-5-methylthiothiophene-2-carboxamidine;
[0148]
4-[2-(4-chloro-2-methylphenylamino)thiazol-4-yl]-5-methylthiothioph-
ene-2-carboxamidine;
[0149]
4-[2-(4-dimethylaminophenylamino)thiazol-4-yl]-5-methylthiothiophen-
e-2-carboxamidine;
[0150]
4-[2-(4-methoxyphenylamino)thiazol-4-yl]-5-methylthiothiophene-2-ca-
rboxamidine;
[0151]
4-[4-(4-hydroxy-3-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-
-2-carboxamidine;
[0152]
4-[4-(3-hydroxy-4-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-
-2-carboxamidine;
[0153]
4-[2-(2-fluorophenylamino)thiazol-4-yl]-5-methylthiothiophene-2-car-
boxamidine;
[0154]
4-[2-(2,4,5-trimethylphenyl)aminothiazol-4-yl]-5-methylthiothiophen-
e-2-carboxamidine;
[0155]
4-[2-(3-chloro-2-methylphenyl)aminothiazol-4-yl]-5-methylthiothioph-
ene-2-carboxamidine;
[0156]
4-[2-(2-isopropylphenyl)aminothiazol-4-yl]-5-methylthiothiophene-2--
carboxamidine;
[0157]
4-[2-(4-benzyloxyphenyl)aminothiazol-4-yl]-5-methylthiothiophene-2--
carboxamidine;
[0158]
4-[2-(2-bromophenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carb-
oxamidine;
[0159]
4-[2-(2,5-dichlorophenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-
-carboxamidine;
[0160]
4-[2-(2-bromo-4-methylphenyl)aminothiazol-4-yl]-5-methylthiothiophe-
ne-2-carboxamnidine;
[0161]
4-[2-(2,3-dichlorophenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-
-carboxamidine;
[0162]
4-[2-(3,4,5-trimethoxyphenyl)aminothiazol-4-yl]-5-methylthiothiophe-
ne-2-carboxamidine;
[0163]
4-[2-(2-piperidinylethyl)aminothiazol-4yl]-5-methylthiothiophene-2--
carboxamidine;
[0164]
4-[2-(4-methylphenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-car-
boxamidine;
[0165]
4-[4-phenyloxazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
[0166]
4-[2-(diphenylmethyl)aminothiazol-4-yl]-5-methylthiothiophene-2-car-
boxamidine; and
[0167]
4-[2-(3-phenylpropyl)aminothiazol-4-yl]-5-methylthiothiophene-2-car-
boxamidine,
[0168] as well as pharmaceutically acceptable salts thereof, for
example the hydrochloride, hydrobromide and acetate salts thereof,
or a prodrug thereof.
[0169] A second preferred group of compounds falling within the
scope of the present invention include compounds of Formula I
wherein X is sulfur or oxygen; Y is a covalent bond or --NH--; Z is
NR.sup.5R.sup.6; R.sup.1 is hydrogen, amino, hydroxy or halogen;
R.sup.4, R.sup.5 and R.sup.6 are independently hydrogen, C.sub.1-4
alkyl, amino, C.sub.1-4 alkoxy or hydroxy, and are preferably all
hydrogen; one of R.sup.2 or R.sup.3 is hydrogen, C.sub.1-6
alkylthio, C.sub.1-6 alkyl optionally substituted with OH,
NH.sub.2, COOH or aminocarbonyl, or C.sub.1-6 alkoxy; and the other
of R.sup.2 or R.sup.3 is: 5
[0170] where:
[0171] Ar is a group selected from the group consisting of phenyl,
thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl,
furanyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl
(thiophenyl), tetrazolyl, pyrrolyl, pyrazolyl, oxadiazolyl,
oxazolinyl, isoxazolinyl, imidazolinyl, triazolyl, pyrrolinyl,
benzothiazolyl, benzothienyl, benzimidazolyl,
1,3-oxazolidin-2-onyl, imidazolin-2-onyl (preferably phenyl,
thiazolyl, thiazolinyl, oxazolinyl, isothiazolyl, isoxazolyl,
imidazolyl, pyridyl, pyrimidinyl, thienyl, pyrrolyl, oxazolinyl and
benzothienyl), any of which can optionally include an exocyclic=O
(keto) or .dbd.NR.sup.V (imino) group, where R.sup.V is alkyl,
aryl, aralkyl, alkylamino, arylimino or aralkylimino; and
[0172] R.sup.8 and R.sup.9 are independently selected from the
group consisting of hydrogen, halogen, amino,
mono(C.sub.1-4)alkylamino, di(C.sub.1-4)alkylamino, arylamino,
mono- and di- (C.sub.6-14)arylamino, mono- and
di-(C.sub.6-14)ar(C.sub.1-6)alkylamino, formylamino, C.sub.2-6
acylamino, aminocarbonyl, C.sub.2-8 aminoacyl, C.sub.2-6
thioacylamino, aminothiocarbonyl, C.sub.2-8 aminothioacyl,
C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.1-6 alkoxy, carboxy,
carboxy(C.sub.1-6)alkyl, C.sub.2-8 alkoxycarbonyl, nitro, cyano,
trifluoromethyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl,
isoxazolyl, furanyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl,
thienyl (thiophenyl), tetrazolyl, pyrrolyl, pyrazolyl, oxadiazolyl,
oxazolinyl, isoxazolinyl, imidazolinyl, triazolyl, pyrrolinyl,
benzothiazolyl, benzothienyl, benzimidazolyl,
1,3-oxazolidin-2-onyl, imidazolin-2-onyl, C.sub.6-14 aryloxy,
C.sub.1-6 alkylthio, C.sub.6-14 arylthio, C.sub.6-14 aryl, or
C.sub.6-14 ar(C.sub.1-6)alkyl, wherein the aforementioned
heteroaryl groups and the aryl portions of C.sub.6-14 aryloxy,
mono- and di C.sub.6-14 aryl amino, mono- and di- C.sub.6-14
ar(C.sub.1-6)alkylamino, C.sub.6-14 arylthio, C.sub.6-14
ar(C.sub.1-6)alkyl, and C.sub.6-14 aryl can be further optionally
substituted, preferably by one, two or three of halogen, hydroxy,
amino, mono(C.sub.1-4)alkylamino, di(C.sub.1-4)alkylamino,
formylamino, C.sub.1-4acylamino, C.sub.1-4 aminoacyl, mono- or
di-(C.sub.1-4)alkylaminocarbonyl, thiocarbonylamino,
C.sub.1-4thioacylamino, aminothiocarbonyl, C.sub.1-4 alkoxy,
C.sub.6-10aryloxy, aminocarbonyloxy, mono- or
di(C.sub.1-4)alkylaminocarb- onyloxy, mono- or
di(C.sub.6-10)arylaminocarbonyloxy, mono- or
di(C.sub.7-15)aralkylaminocarbonyloxy, C.sub.1-4alkylsulfonyl,
C.sub.6-10arylsulfonyl, (C.sub.7-15)aralkylsulfonyl,
C.sub.1-4alkylsulfonylamino, C.sub.6-10arylsulfonylamino,
(C.sub.7-15)aralkylsulfonylamino, aminosulfonyl, mono- and
di-alkylaminosulfonyl, mono- and di-arylaminosulfonyl, mono- and
di-aralkylaminosulfonyl, C.sub.1-4alkoxycarbonylamino,
C.sub.7-15aralkoxycarbonylamino, C.sub.6-10aryloxycarbonylamino,
mono- or di-(C.sub.1-4)alkylaminothiocarbonyl, C.sub.7-15aralkoxy,
carboxy, carboxy(C.sub.1-4)alkyl, C.sub.1-4 alkoxycarbonyl,
C.sub.1-4alkoxycarbonylalkyl, carboxy(C.sub.1-4)alkoxy,
alkoxycarbonylalkoxy, nitro, cyano, trifluoromethyl,
C.sub.1-4alkylthio and C.sub.6-10arylthio, or by
3,4-methylenedioxy, 3,4-ethylenedioxy, and 3,4-propylenedioxy.
[0173] Preferred values of R.sup.8 and R.sup.9 are halogen,
C.sub.1-6 alkyl, C 1.sub.6 alkoxy, hydroxy, nitro, trifluoromethyl,
C.sub.6-10 aryl (further optionally substituted by one or two of
chloro, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, nitro,
trifluoromethyl, carboxy, 3,4-methylenedioxy, 3,4-ethylenedioxy,
3,4-propylenedioxy, or amino), 4-phenylphenyl (biphenyl), C.sub.1-6
aminoalkyl, carboxy, C.sub.1-6 alkyl, 3,4-methylenedioxy,
3,4-ethylenedioxy, 3,4-propylenedioxy, amino, C.sub.1-6
alkanoylamino, C.sub.6-14 aroylamino, C.sub.1-6 hydroxyalkyl,
thienyl (further optionally substituted by one or two of chloro,
amino, methyl, methoxy, or hydroxy) and tetrazolyl. More
preferably, R.sup.2 is thienyl, oxazolyl, or thiazolyl, optionally
substituted by any of the aforementioned groups.
[0174] Examples of preferred R.sup.8 and R.sup.9 groups include
4-chlorophenyl, 2,4-dichlorophenyl, methyl, 4-nitrophenyl,
3-nitrophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl,
3-(2,4-dimethylthien-5-yl)phenyl, 3-hydroxyphenyl,
5-(carboxymethyl)thien-2-yl, phenyl, 3,4-ethylenedioxyphenyl,
3,4-propylenedioxyphenyl, naphth-2-yl,
3-phenyl-4-(tetrazol-5-yl)phenyl, 2,4-dichlorophenyl),
4-phenylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-phenylphenyl,
phenylthiomethyl, 2-chloro-4,5-dimethoxyphenyl,
4-chloro-3-methylphenyl, 5-methyl-4-phenyl, 4-chloro-3-nitrophenyl,
3-fluoro-5-trifluoromethylphenyl, 3,5-bis(trifluoromethyl),
3-fluoro-5-trifluoromethylphenyl, 3-bromophenol,
3,4-methylenedioxyphenyl- , 4-methylphenyl, 3-methylphenyl,
3,5-bis(trifluoromethyl)phenyl, 2-methoxyphenyl,
6-phenyl-2-pyridyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl,
benzyl, 3,4-dichlorophenyl, 3-methylphenyl, 3,5-dimethoxyphenyl,
2-methylphenyl, 2,5-dimethoxyphenyl, 2-chloro-3-pyridyl,
phenoxymethyl, cyclohexyl, 2-hydroxyphenyl,
3-trifluoromethoxyphenyl, 2-chloro-4-pyridyl, 3-chloro-4-pyridyl,
2-chlorophenylamino, 3-methoxyphenylamino, phenylamino,
2,5-dimethoxyphenylamino, amino, 4-chloro-2-methylphenylamino,
4-dimethylaminophenylamino, 4-methoxyphenylamino,
4-hydroxy-3-methoxyphen- yl, 3-hydroxy-4-methoxyphenyl,
2-fluorophenylamino, 2,4,5-trimethylphenylamino,
3-chloro-2-methylphenylamino, 2-isopropylphenylamino,
4-benzyloxyphenylamino, 2-bromophenylamino,
2,5-dichlorophenylamino, 2-bromo-4-methylphenylamino,
2,3-dichlorophenylamino, 3,4,5-trimethoxyphenylamino,
2-piperidinylethylamino, 4-methylphenylamino, 2-thienyl,
2-5,6,7,8-tetrahydronaphthyl, 3-(2-phenoxyacetic acid)phenyl,
2-(2-phenoxyacetic acid)phenyl, diphenylmethylamino,
3-phenylpropylamino, 3-phenylphenyl, phenylthiomethyl,
2-chloro-4,5-dimethoxyphenyl, and isopropyl.
[0175] A third preferred group of compounds are those of Formula I
wherein:
[0176] X is sulfur;
[0177] Y is a covalent bond;
[0178] Z is NR.sup.5R.sup.6;
[0179] R is hydrogen;
[0180] R.sup.3 is methylthio or methyl;
[0181] R.sup.4, R.sup.5 and R.sup.6 are all hydrogen; and
[0182] R.sup.2 is Formula II, where Ar is phenyl, thiazolyl,
oxazolyl, benzothienyl, pyridyl, or imidazolyl; and R.sup.8 and
R.sup.9 are independently hydrogen, or C.sub.6-10 aryl or
heterocycle, optionally substituted by one, two or three of chloro,
hydroxy, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkoxy,
amino, carboxy, phenyl, naphthyl, biphenyl, hydroxyphenyl,
methoxyphenyl, dimethoxyphenyl, carboxyalkoxyphenyl,
alkoxycarbonylalkoxy, carboxyethoxy, alkylsulfonylaminophenyl,
arylsulfonylaminophenyl, acylsulfonylaminophenyl,
aralkylsulfonylaminophenyl, heteroarylsulfonylaminophenyl where the
heteroaryl portion is optionally halo or C.sub.1-6alkyl
substituted, chlorophenyl, dichlorophenyl, aminophenyl,
carboxyphenyl, nitrophenyl, or by 3,4-methylenedioxy,
3,4-ethylenedioxy, and 3,4-propylenedioxy.
[0183] A fourth preferred group of compounds are those of Formula I
wherein:
[0184] X is sulfur;
[0185] Y is a direct covalent bond;
[0186] Z is NR.sup.5R.sup.6;
[0187] R is hydrogen;
[0188] R.sup.2 is alkyl, ar(alkyl), alkylsulfonyl,
--SO.sub.2-alkyl, amido, amidino, or 6
[0189] where
[0190] Ar is an aromatic or heteroaromatic group selected from the
group consisting of phenyl, thiazolyl, oxazolyl, imidazolyl and
pyridyl;
[0191] R.sup.8 and R.sup.9 are independently selected from the
group consisting of hydrogen, carboxy, phenyl, naphthyl, alkyl,
pyridyl, oxazolyl, furanyl, cycloalkyl and amino, any of which may
be optionally substituted with 1 to 3 substituents independently
selected from the group consisting of halogen, alkyl, haloalkyl,
alkaryl, heteroaryl, phenyl, naphthyl, alkoxy, aryloxy, hydroxy,
amino nitro, thiophenyl, benzothiophenyl, fluorenyl,
3,4-ethylenedioxy, 3,4-methylenedioxy, 3,4-propylenedioxy,
arylsulfonamido, alkylsulfonamido and aryloxy, each of said 1 to 3
substituents may be further optionally substituted with one or more
groups selected from alkoxy, haloalkyl, halogen, alkyl, amino,
acetyl, hydroxy, dialkylamino, dialkylamino acyl,
monoalkylaminoacyl, --SO.sub.2-heteroaryl, --SO.sub.2-aryl, or
aryl;
[0192] R.sup.3 is --SO.sub.2-alkyl, trifluoromethyl, S(O)-alkyl,
hydrogen, alkoxy, alkylthio, alkyl, aralkylthio; and
[0193] R.sup.4, R.sup.5, R.sup.6 are hydrogen.
[0194] Preferred compounds of this embodiment are those where Ar is
a thiazolyl, preferably thiazol-2-yl or thiazol-4-yl, and at least
one of R.sup.8 and R.sup.9 is substituted phenyl, most preferably
on the 4-position of the thiazol-2-yl group. Also preferred are
compounds where R.sup.2 is a 4-phenylthiazol-2-yl group wherein
said phenyl is further optionally substituted. and R.sup.3 is
methylthio.
[0195] A fifth preferred group of compounds are those of Formula
III: 7
[0196] or a pharmaceutically acceptable salt or prodrug thereof,
where
[0197] A is methylthio or methyl;
[0198] G is --O--, --S--, --NH--, or a covalent bond;
[0199] n is an integer from 1-10, preferably from 1-6;
[0200] m is an integer from 0-1; and
[0201] R' and R" are independently selected from hydrogen, alkyl,
aryl or aralkyl, or R' and R" are taken together with the N atom to
which they are attached form a 3-8 membered heterocyclic ring,
optionally containing an additional O, N, or S atom, and when said
3-8 membered heterocyclic ring contains an additional N atom, said
additional N atom is optionally substituted by hydrogen,
C.sub.1-4alkyl, C.sub.6-10aryl, C.sub.6-10ar(C.sub.1-4)alkyl, acyl,
alkoxycarbonyl or benzyloxycarbonyl.
[0202] Most preferred compounds of Formula III are those for which
R' and R", taken together with the N atom to which they are
attached, form a ring selected from piperazinyl, pyrrolidinyl,
piperidinyl or morpholinyl, which are further optionally
substituted with 1 to 4 non-hydrogen substituents selected from
halogen, hydroxy, amino, monoalkylamino, dialkylamino, formylamino,
acylamino, aminoacyl, mono- or di- alkylaminocarbonyl,
thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy,
aryloxy, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, mono-
or diarylaminocarbonyloxy, mono- or diarakylaminocarbonyloxy,
alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino,
arylsulfonylamino, arakylsulfonylamino, alkoxycarbonylamino,
aralkoxycarbonylamino, aryloxycarbonylamino, mono- or di-
alkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl,
alkylthio and arylthio, where each of these substituents has the
preferred values set forth for Formulae I and II above.
[0203] Examples of preferred compounds of Formula III include:
[0204] 5-methylthio-4-[4-(3-{[N
-(2-morpholin-4-ylethyl)carbamoyl]methoxy }phenyl)
(1,3-thiazol-2-yl)]thiophene-2-carboxamidine,
[0205]
5-methylthio-4-{4-[3-(2-morpholin-4-yl-2-oxoethoxy)phenyl](1,3-thia-
zol-2-yl)}thiophene-2-carboxamidine,
[0206]
5-methylthio-4-{4-[3-(2-oxo-2-piperazinylethoxy)phenyl](1,3-thiazol-
-2-yl)}thiophene-2-carboxamidine,
[0207] 4-[4-(3-{[N-(2-aminoethyl)carbamoyl]methoxy}phenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine,
[0208] 4-(4-{3-[2-(4-acetylpiperazinyl)-2-oxoethoxy]phenyl
}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,
[0209] 4-(4-{3-[2-(4-methylpiperazinyl)-2-oxoethoxy]phenyl
}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine, the
compound described in Example 151,
[0210]
5-methylthio-4-[4-(3-{2-oxo-2-[4-benzylpiperazinyl]ethoxy}phenyl)
(1,3-thiazol-2-yl)]thiophene-2-carboxamidine,
[0211] (D,L)-4-(4-{3-[2-(3-aminopyrrolidinyl)-2-oxoethoxy]phenyl
}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,
[0212]
5-methylthio-4-{4-[3-(2-oxo-2-piperidylethoxy)phenyl](1,3-thiazol-2-
-yl)}thiophene-2-carboxamidine,
[0213] (D,L)-ethyl
1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiaz-
ol-4-yl]phenoxy }acetyl)piperidine-2-carboxylate,
[0214]
5-methylthio-4-{4-[3-(2-oxo-2-pyrrolidinylethoxy)phenyl](1,3-thiazo-
l-2-yl)}thiophene-2-carboxamidine,
[0215] 5-methylthio-4-[4-(3-{2-oxo-2-[4-benzylpiperidyl]ethoxy
}phenyl) (1,3-thiazol-2-yl)]thiophene-2-carboxamidine,
[0216] (D,L)-4-(4-{3-[2-(3-methylpiperidyl)-2-oxoethoxy]phenyl
}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,
[0217] 4-(4-{3-[2-(4-methylpiperidyl)-2-oxoethoxy]phenyl
}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,
[0218] 4-(4-{3-[2-(2-azabicyclo[4.4.0]dec-2-yl)-2-oxoethoxy]phenyl
}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,
[0219] (D,L)-ethyl
1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiaz-
ol-4-yl]phenoxy }acetyl)piperidine-3-carboxylate,
[0220]
5-methylthio-4-{4-[3-(2-oxo-2-(1,2,3,4-tetrahydroquinolyl)ethoxy)ph-
enyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine,
[0221] ethyl
1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-y-
l]phenoxy }acetyl)piperidine-4-carboxylate,
[0222] 4-(4-{.3-[2-((3R)-3-hydroxypiperidyl)-2-oxoethoxy]phenyl
}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamnidine,
[0223] D,L-4-(4-{3-[2-(2-ethylpiperidyl)-2-oxoethoxy]phenyl
}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamnidine,
[0224] 4-4-(4-{3-[2-((3S)-3-hydroxypyrrolidinyl)-2-oxoethoxy]phenyl
}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine,
[0225]
D,L-4-[4-(3-{2-[3-(hydroxymethyl)piperidyl]-2-oxoethoxy}phenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine,
[0226] 4-{4-[3-(2-{(2R)-2-[(phenylamino)methyl]pyrrolidinyl
}-2-oxoethoxy)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxam-
idine,
[0227]
4-[4-(3-{2-[(3R)-3-(methoxymethyl)pyrrolidinyl]-2-oxoethoxy}phenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine,
[0228]
1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phen-
oxy }acetyl)piperidine-3-carboxamide, and
[0229] 2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl
}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy }acetic acid;
[0230] or pharmaceutically acceptable salts or prodrugs
thereof.
[0231] A sixth preferred group of compounds are those of Formula
IV: 8
[0232] or a pharmaceutically acceptable salt or prodrug thereof,
where
[0233] A is methylthio or methyl; and
[0234] R'" is hydrogen, C.sub.6-14aryl, C.sub.1-6 alkyl, C.sub.1-6
alkoxy (C.sub.6-14)aryl, amino(C.sub.6-14)aryl,
monoalkylamino(C.sub.6-14)aryl, dialkylamino(C.sub.6-14)aryl,
C.sub.6-10ar(C.sub.1-6)alkyl, heterocycle(C.sub.2-6)alkyl such as
morpholinoalkyl, piperazinylalkyl and the like,
C.sub.1-6alk(C.sub.6-14)aryl, amino(C.sub.1-6)alkyl,
mono(C.sub.1-6)alkylamino(C.sub.1-6)alkyl,
di(C.sub.1-6)alkylamino(C.sub.- 1-6)alkyl, hydroxy(C.sub.6-14)aryl,
or hydroxy(C.sub.1-6)alkyl, where the aryl and heterocyclic rings
can be further optionally substituted by 1-4 non-hydrogen
substituents selected from halogen, hydroxy, amino,
mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, formylamino,
(C.sub.1-6)acylamino, amino(C.sub.1-6)acyl, mono- or
di-(C.sub.1-6)alkylaminocarbonyl, thiocarbonylamino,
(C.sub.1-6)thioacylamino, aminothiocarbonyl, (C.sub.1-6)alkoxy,
(C.sub.6-10)aryloxy, aminocarbonyloxy, mono- or
di-(C.sub.1-6)alkylaminoc- arbonyloxy, mono- or
di-(C.sub.6-10)arylaminocarbonyloxy, mono- or
di(C.sub.6-10)ar(C.sub.1-6)alkylaminocarbonyloxy,
(C.sub.1-6)alkylsulfony- l, (C.sub.6-10)arylsulfonyl,
(C.sub.6-10)ar(C.sub.1-6)alkylsulfonyl, (C.sub.1-6)
alkylsulfonylamino, C.sub.6-10 arylsulfonylamino,
(C.sub.6-10)ar(C.sub.1-6)alkylsulfonylamino,(C.sub.1-6)alkoxycarbonylamin-
o, (C.sub.6-10)ar(C.sub.1-6)alkoxycarbonylamino,
C.sub.6-10aryloxycarbonyl- amino, mono- or
di-(C.sub.1-6)alkylaminothiocarbonyl,
(C.sub.6-10)ar(C.sub.1-6)alkoxy, carboxy, (C.sub.1-6)carboxyalkyl,
C.sub.1-6alkoxycarbonyl, (C.sub.1-6)alkoxycarbonyl(C.sub.1-6)alkyl,
nitro, cyano, trifluoromethyl, (C.sub.1-6)alkylthio and
C.sub.6-10arylthio.
[0235] Examples of preferred compounds of Formula IV include:
[0236]
4-{2-[(3-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothioph-
ene-2-carboxamidine,
[0237]
4-{2-[(4-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothioph-
ene-2-carboxamidine,
[0238] 4-{2-{[4-(dimethylamino)phenyl]amino
}(1,3-thiazol-4-yl))-5-methylt- hiothiophene-2-carboxamidine,
[0239]
4-{2-[(4-chloro-2-methylphenyl)amino](1,3-thiazol-4-y1)}-5-methylth-
iothiophene-2-carboxamidine,
[0240]
4-{2-[(diphenylmethyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophe-
ne-2-carboxamidine,
[0241]
5-methylthio-4-{2-[(3-phenylpropyl)amino](1,3-thiazol-4-yl)}thiophe-
ne-2-carboxamidine,
[0242]
5-methylthio-4-{2-[(2,4,5-trimethylphenyl)amino](1,3-thiazol-4-yl)}-
thiophene-2-carboxamidine,
[0243]
4-{2-[(2-fluorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophe-
ne-2-carboxamidine,
[0244] 4-{2-[(3-chloro-2-methylphenyl) amino](1,3-thiazol -4-yl
)}5-methylthiothiophene-2-carboxamidine,
[0245] 4-(2-{[2-(methylethyl)phenyl]amino
}(1,3-thiazol-4-yl))-5-methylthi- othiophene-2-carboxamidine,
[0246] 5-methylthio-4-(2-{[4-(phenylmethoxy)phenyl]amino
}(1,3-thiazol-4-yl))thiophene-2-carboxamidine,
[0247]
4-{2-[(2-bromophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophen-
e-2-carboxamidine,
[0248]
4-{2-[(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothi-
ophene-2-carboxamidine,
[0249]
.sup.4-{2-[(2-bromo-4-methylphenyl)amino](1,3-thiazol-4-yl)}-5-meth-
ylthiothiophene-2-carboxamidine,
[0250] 5-methylthio-4-{2-[(2-morpholin-4-ylethyl)amino](1
,.sup.3-thiazol-4-yl)}thiophene-2-carboxamidine,
[0251]
4-{2-[(2,3-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothi-
ophene-2-carboxamidine,
[0252]
5-methylthio-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)-
}thiophene-2-carboxamidine,
[0253]
5-methylthio-4-{2-[(2-piperidylethyl)amino](1,3-thiazol-4-yl)}thiop-
hene-2-carboxamidine,
[0254] 4-(2-{[(4-methylphenyl)methyl]amino
}(1,3-thiazol-4-yl))-5-methylth- iothiophene-2-carboxamidine,
[0255] 4-(2-{[4-(4-chlorophenoxy)phenyl]amino
}(1,3-thiazol-4-yl))-5-methy- lthiothiophene-2-carboxamidine,
[0256] 4-(2-{[4-phenoxyphenyl]amino
}(1,3-thiazol-4-yl))-5-methylthiothiop- hene-2-carboxamidine,
[0257] 5-methylthio-4-(2-{[4-(phenylamino)phenyl]amino
}(1,3-thiazol-4-yl))thiophene-2-carboxamidine,
[0258] 5-methylthio-4-(2-{[4-benzylphenyl]amino
}(1,3-thiazol-4-yl))thioph- ene-2-carboxamidine,
[0259] 5-methylthio-4-(2-{[4-(piperidylsulfonyl)phenyl]amino
}(1,3-thiazol-4-yl))thiophene-2-carboxamidine,
[0260] 5-methylthio-4-[2-(3-quinolylamino)
(1,3-thiazol-4-yl)]thiophene-2-- 02 carboxamidine,
[0261] 5-methylthio-4-[2-(2-naphthylamino)
(1,3-thiazol-4-yl)]thiophene-2-- carboxamidine,
[0262] 4-[2-(2H-benzo[3,4-d]1,3-dioxolan-5-ylamino)
(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidine,
[0263]
4-{2-[(7-bromofluoren-2-yl)amino](1,3-thiazol-4-yl)}-5-methylthioth-
iophene-2-carboxamidine,
[0264]
4-{2-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothi-
ophene-2-carboxamidine,
[0265] 5-methylthio-4-(2-{[4-(phenyldiazenyl)phenyl]amino
}(1,3-thiazol-4-yl))thiophene-2-carboxamidine,
[0266] 5-methylthio 4-(2-{[3-(hydroxymethyl)phenyl]amino
}(1,3-thiazol-4-yl))-thiophene-2-carboxamidine,
[0267] 4-[2-({3-[(3-methylpiperidyl)methyl]phenyl }amino)
(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidine,
[0268]
4-{2-[(3-hydroxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothioph-
ene-2-carboxamidine,
[0269] 4-(2-{[4-(carbamoylmethoxy)phenyl]amino
}(1,3-thiazol-4-yl))-5-meth- ylthiothiophene-2-carboxamidine,
[0270]
5-methyl-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thi-
ophene-2-carboxamidine,
[0271]
5-methyl-4-{2-[(4-phenoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene--
2-carboxamidine,
[0272] 5-methyl-4-[2-(phenylamino)
(1,3-thiazol-4-yl)]thiophene-2-carboxam- idine, and
[0273]
4-(4-isoxazol-5-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carbo-
xamidine;
[0274] as well as pharmaceutically acceptable salts and prodrugs
thereof.
[0275] A seventh preferred group of compounds are compounds of
Formula I, or a pharmaceutically acceptable salt or prodrug
thereof, wherein:
[0276] X is sulfur or oxygen, preferably sulfur;
[0277] Y is a covalent bond or --NH--, preferably a covalent
bond;
[0278] Z is NR.sup.5R.sup.6;
[0279] R is hydrogen, amino, hydroxy or halogen, preferably
hydrogen;
[0280] R.sup.4, R.sup.5 and R.sup.6 are independently hydrogen,
C.sub.1-4 alkyl, amino, C.sub.1-4 alkoxy or hydroxy, and are
preferably all hydrogen;
[0281] R.sup.3 is hydrogen, C.sub.1-6 alkylthio, C.sub.1-6 alkyl
optionally substituted with OH, NH.sub.2, COOH or aminocarbonyl, or
C.sub.1-6 alkoxy, preferably methylthio or methyl; and
[0282] R.sup.2 is
[0283] alkylsulfonylamino, aralkylsulfonylamino,
aralkenylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,
di(aralkylsulfonyl)amino, di(aralkenylsulfonyl)amino,
di(arylsulfonyl)amino, or di-(heteroarylsulfonyl)amino, wherein any
of the aryl or heteroaryl containing groups can be optionally
substituted on the aromatic ring; or
[0284] amino, monoalkylamino, dialkylamino, monoarylamino,
diarylamino, monoalkylmonoarylamino, monoaralkylamino,
diaralkylamino, monoalkylmonoaralkylamino, monoheterocycleamino,
diheterocycleamino, monoalkylmonoheterocycleamino, wherein any of
the aryl or heteroaryl containing groups can be optionally
substituted on the aromatic ring and wherein any of the heterocycle
containing groups can be optionally ring substituted; or
[0285] alkanoylamino, alkenoylamino, alkynoylamino, aroylamino,
aralkanoylamino, aralkenoylamino, heteroaroylamino,
heteroarylalkanoylamino, any of which is optionally substituted on
the aromatic ring; or
[0286] alkoxy and alkylthio, either of which is optionally
substituted, or aryloxy, aralkoxy, arylthio, aralkylthio,
arylsulfonyl, aralkylsulfonyl, aralkenylsulfonyl, any of which is
optionally substituted on the aromatic ring; or
[0287] alkoxycarbonylamino, aralkoxycarbonylamino,
aryloxycarbonylamino, wherein any of the aryl containing groups can
be optionally substituted on the aromatic ring; or
[0288] formylamino, H(S)CNH--, or thioacylamino.
[0289] Preferred optional substituents are halogen, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, hydroxy, nitro, trifluoromethyl,
C.sub.6-10 aryl, C.sub.6-10 aryloxy, C.sub.6-10 arylmethoxy
(wherein the aryl groups on these aryl-containing substituents are
further optionally substituted by one or two of chloro, halogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, phenyl, hydroxy, nitro,
trifluoromethyl, carboxy, 3,4-methylenedioxy, 3,4-ethylenedioxy,
3,4-propylenedioxy, or amino), C.sub.1-6 aminoalkyl, carboxy,
alkyl, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy,
amino, mono- or di-(C.sub.1-6)alkylamino, mono- or di- C.sub.6-10
arylamino, C.sub.1-6 alkylsulfonylamino,
C.sub.6-10arylsulfonylamino, C.sub.1-8 acylamino, C.sub.1-8
alkoxycarbonyl, C.sub.1-6 alkanoylamino, C.sub.6-14 aroylamino,
C.sub.1-6 hydroxyalkyl, methylsulfonyl, phenylsulfonyl, thienyl
(further optionally substituted by one or two of chloro, amino,
methyl, methoxy, or hydroxy) and tetrazolyl.
[0290] In one aspect of this embodiment, R.sup.2 is preferably
C.sub.1-6 alkylsulfonylamino, C.sub.6-10
ar(C.sub.1-6)alkylsulfonylamino, C.sub.6-10
ar(C.sub.2-6)alkenylsulfonylamino, C.sub.6-10 arylsulfonylamino,
heteroarylsulfonylamino, di(C.sub.6-10
ar(C.sub.1-6)alkylsulfonyl)amino, di(C.sub.6-10
ar(C.sub.2-6)alkenylsulfo- nyl)amino, di(C.sub.6-10
arylsulfonyl)amino, or di-(heteroarylsulfonyl)ami- no, wherein any
of the aryl or heteroaryl containing groups can be optionally
substituted on the aromatic ring.
[0291] Especially preferred R.sup.2 groups in this embodiment of
the invention include C.sub.6-10 arylsulfonylamino, di-(C.sub.6-10
arylsulfonyl)amino, C.sub.6-10 ar(C.sub.1-3)alkylsulfonylamino,
di-(C.sub.6-10 ar(C.sub.1-3)alkylsulfonyl)amino,
thienylsulfonylamino, any of which is optionally substituted on the
aromatic ring.
[0292] Useful values of R.sup.2, when R.sup.2 is a substituted
sulfonylamino group include biphenylsulfonylamino,
bis(biphenylsulfonyl)amino, naphth-2-ylsulfonylamino,
di(naphth-2-ylsulfonyl)amino, 6-bromonaphth-2-ylsulfonylamino,
di(6-bromonaphth-2-ylsulfonyl)amino, naphth-1-ylsulfonylamino,
di(naphth-1-ylsulfonyl)amino, 2-methylphenylsulfonylamino,
di-(2-methylphenylsulfonyl) amino, 3-methylphenylsulfonylamino,
di-(3-methylphenylsulfonyl) amino, 4-methylphenylsulfonylamino,
di-(4-methylphenylsulfonyl)amino, benzylsulfonylamino,
4-methoxyphenylsulfonylamino, di-(4-methoxyphenylsulfonyl)amino,
4-iodophenylsulfonylamino, di-(4-iodophenylsulfonyl)amino,
3,4-dimethoxyphenylsulfonylamino,
bis-(3,4-dimethoxyphenylsulfonyl)amino,
2-chlorophenylsulfonylamino, di-(2-chlorophenylsulfonyl)amino,
3-chlorophenylsulfonylamino, di-(3-chlorophenylsulfonyl)amino,
4-chlorophenylsulfonylamino, di-(4-chlorophenylsulfonyl)amino,
phenylsulfonylamino, di-(phenylsulfonyl)amino,
4-tert-butylphenylsulfonyl- amino,
di-(4-tert-butylphenylsulfonyl)amino, 2-phenylethenylsulfonylamino,
and 4-(phenylsulfonyl)thien-2-ylsulfonylamino.
[0293] In another aspect of this embodiment, R.sup.2 is preferably
amino, mono(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino,
mono(C.sub.6-10)arylamino, di(C.sub.6-10)arylamino,
mono(C.sub.1-6)alkylmono(C.sub.6-10)arylamino,
monoar(C.sub.1-6)alkylamin- o,
di(C.sub.6-10)ar(C.sub.1-6)alkylamino,
mono(C.sub.1-6)alkylmono(C.sub.6- -10)ar(C.sub.1-6)alkylamino,
monoheteroarylamino, diheteroarylamino,
mono(C.sub.1-6)alkylmonoheteroarylamino, wherein any of the aryl or
heteroaryl containing groups can be optionally substituted on the
aromatic ring.
[0294] Especially preferred R.sup.2 groups in this embodiment of
the invention include mono(C.sub.6-10)arylamino,
mono(C.sub.1-6)alkylmono(C.s- ub.6-10)arylamino,
mono(C.sub.6-10)ar(C.sub.1-3)alkylamino,
mono(C.sub.1-6)alkylmono(C.sub.6-10)ar(C.sub.1- 3)alkylamino,
monoheteroarylamino, and mono(C.sub.1-6)alkylmonoheteroarylamino.
Examples of suitable heteroarylamino groups include
1,3-thiazol-2-ylamino, imidazol-4-ylamino, quinolin-2-ylamino and
quinolin-6-ylamino.
[0295] Useful values of R.sup.2, when R.sup.2 is a substituted
amino group include anilino, naphth-2-ylamino, naphth-1-ylamino,
4-(biphenyl)thiazol-2-ylamino, 4-(phenyl)thiazol-2-ylamino,
4-phenyl-5-methylthiazol-2-ylamino,
4-hydroxy-4-trifluoromethylthiazol-2-- ylamino,
3-phenylphenylamino, pyrimidin-2-ylamino, 4-isopropylphenylamino,
3-isopropylphenylamino, 4-phenylphenylamino,
3-fluoro-4-phenylphenylamino- , 3,4-methylenedioxyphenylamino,
n-butylphenylamino, N-methyl-N-(2-methylphenyl)amino,
3-nitrophenylamino, 4-methoxyphenylamino, 3-methoxyphenylamino,
2-methoxyphenylamino, 2-methylphenylamino, 3-methylphenylamino,
3,4-dimethylphenylamino, 3-chlorophenylamino, 4-chlorophenylamino,
4-(3-fluoro-4-meth 4-(indan-5-yl)amino, benzylamino,
indanylmethylamino, 2,3-dihydrobenzofuranylmethyl,
2-phenylimidazol-5-yl, 3-hydroxybenzyl, 3-phenoxyphenylamino,
4-phenoxyphenylamino, 3-benzyloxyphenylamnino,
4-benzyloxyphenylamino, quinolin-6-ylamino, quinolin-3-ylamino,
4-(phenylamino)phenylamino, 4-(4-ethylphenyl)phenylamino,
4-(dimethylamino)phenylamino, 4-cyclohexylphenylamino,
4-(9-ethylcarbazol-3yl)amino, 4-(t-butyl)phenylamino, and
4-methylthiophenyl amino.
[0296] In another aspect of this embodiment, R.sup.2 is preferably
an acylamino group, such as alkanoylamino, alkenoylamino,
aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino,
heteroarylalkanoylamino, any of which is optionally substituted on
the aromatic ring.
[0297] Especially preferred R.sup.2 groups in this embodiment of
the invention include (C.sub.6-10)arylcarbonylamino, C.sub.6-10
ar(C.sub.1-3)alkylcarbonylamino, C.sub.6-10)
ar(C.sub.2-3)alkenylcarbonyl- amino, C.sub.6-10
aryloxy(C.sub.1-3)alkylcarbonylamino, C.sub.3-8
cycloalkylcarbonylamino, C.sub.1-6 alkylcarbonylamino, and
heteroarylcarbonylamino, such as furanylcarbonylamino, and
quinolinylcarbonylamino.
[0298] Useful values of R.sup.2, when R.sup.2 is an acylamino group
include 3-hydroxyphenylcarbonylamino, 2-phenylethenylcarbonylamino,
phenylcarbonylamino, cyclohexylcarbonylamino,
4-methyl-3-nitrophenylcarbo- nylamino, furan-2-ylcarbonylamino,
tert-butylcarbonylamino,
5-(3,5-dichlorophenoxy)furan-2-ylcarbonylamino,
naphth-1-ylcarbonylamino, quinolin-2-ylcarbonylamino,
4-ethoxyphenylcarbonylamino, phenoxymethylcarbonylamino, and
3-methylphenylcarbonylamino.
[0299] In another aspect of this embodiment, R.sup.2 is preferably
C.sub.6-10 aryloxy, C.sub.6-10 ar(C.sub.1-6)alkoxy, C.sub.6-10
arylsulfonyl, C.sub.6-10 ar(C.sub.1-6)alkylsulfonyl, or C.sub.6-10
ar(C.sub.2-6)alkenylsulfonyl, any of which is optionally
substituted on the aromatic ring. Especially preferred R.sup.2
groups in this embodiment of the invention include C.sub.6-10
aryloxy, and C.sub.6-10 arylsulfonyl.
[0300] Useful values of R.sup.2, when R.sup.2 is an aryloxy or
arylsulfonyl group include phenoxy, naphthyloxy, phenylsulfonyl,
and naphthylsulfonyl.
[0301] Representative compounds within the scope of this seventh
embodiment of the invention include:
[0302]
5-methylthio-4-(6-quinolylamino)thiophene-2-carboxamidine
[0303]
5-methylthio-4-[(3-phenylphenyl)amino]thiophene-2-carboxamidine
[0304]
5-methylthio-4-(3-quinolylamino)thiophene-2-carboxamidine
[0305]
5-methylthio-4-(pyrimidin-2-ylamino)thiophene-2-carboxamidine
[0306]
4-[(4-cyclohexylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
[0307] methyl 4-amino-5-methylthiothiophene-2-carboxylate
[0308] methyl
4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxy-
late
[0309]
5-methylthio-4-[(4-phenyl(1,3-thiazol-2-yl))amino]thiophene-2-carbo-
xamidine
[0310] 5-methylthio-4-{[4-(4-phenylphenyl) (1,3-thiazol-2-yl)]amino
}thiophene-2-carboxamidine
[0311]
4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl))amino]-5-methylthiothiophen-
e-2-carboxamidine
[0312] 4-{[4-hydroxy-4-(trifluoromethyl)
(1,3-thiazolin-2-yl)]amino}-5-met-
hylthiothiiophene-2-carboxamidine
[0313]
5-methylthio-4-(2-naphthylamino)thiophene-2-carboxamidine
[0314]
4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine
[0315]
4-[(3-methylphenyl),no]-5-methylthiothiophene-2-carboxamidine
[0316]
4-[(3-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine
[0317] 5-[4-{[3-(methylethyl)phenyl]amino
]-5-methylthiothiophene-2-carbox- amidine
[0318]
5-methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxamidine
[0319] 4-{[4-(methylethyl)phenyl]amino
}-5-methylthiothiophene-2-carboxami- dine
[0320]
4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
[0321]
5-methylthio-4-[(4-phenylphenyl)amino]thiophene-2-carboxamidine
[0322]
4-[(3-fluoro-4-phenylphenyl)]amino]-5-methylthiothiophene-2-carboxa-
midine
[0323]
4-(2H-benzo[d]1,3-dioxolen-5-ylano)-5-methylthiothiophene-2-carboxa-
midine
[0324]
4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
[0325] 5-methylthio-4-[benzylamino]thiophene-2-carboxamidine
[0326]
4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine
[0327]
4-(2,3-dihydrobenzo[b)]furan-5-ylamino)-5-methylthiothiophene-2-car-
boxamidine
[0328]
5-methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxamidine
[0329] 4-{[(3-hydroxyphenyl)methyl]amino
}-5-methylthiothiophene-2-carboxa- midine
[0330]
5-methylthio-4-(phenylcarbonylamino)thiophene-2-carboxamidine
[0331]
4-[((2E)-3-phenylprop-2-enoylamino]-5-methylthiothiophene-2-carboxa-
midine
[0332]
4-[(4-chlorophenyl)carbonylamino]-5-methylthiothiophene-2-carboxami-
dine
[0333]
4-(cyclohexylcarbonylamino)-5-methylthiothiophene-2-carboxamidine
[0334] methyl
4-[(4-methyl-3-nitrophenyl)carbonylamino]-5-methylthiothioph-
ene-2-carboxylate
[0335]
4-(2-furylcarbonylamino)-5-methylthiothiophene-2-carboxamidine
[0336]
4-(2,2-dimethylpropanoylamino)-5-methylthiothiophene-2-carboxamidin-
e
[0337] 4-{[5-(3,5-dichlorophenoxy) (2-furyl)]carbonylamino
}-5-methylthiothiophene-2-carboxamidine
[0338]
5-methylthio-4-(naphthylcarbonylamino)-thiophene-2-carboxamidine
[0339]
5-methylthio-4-(2-quinolylcarbonyl-amino)thiophene-2-carboxamidine
[0340]
4-[(3-methoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxam-
idine
[0341]
4-[2-(2-hydroxy-5-methoxyphenyl)acetylamino]-5-methylthiothiophene--
2-carboxamidine
[0342]
4-[(4-ethoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxami-
dine
[0343]
5-methylthio-4-(2-phenoxyacetylamino)-thiophene-2-carboxamidine
[0344]
4-[(3-methylphenyl)carbonylamino]-5-methylthiothiophene-2-carboxami-
dine
[0345] 5-methylthio-4-,[3-(phenylmethoxy)phenyl]amino
}thiophene-2-carboxamidine
[0346]
5-methylthio-4-[(3-phenoxyphenyl)amino]thiophene-2-carboxamidine
[0347]
5-methylthio-4-[(4-phenoxyphenyl)amino]thiophene-2-carboxamidine
[0348]
4-[(2-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine
[0349]
4-[(2-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
[0350]
4-[(3-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine
[0351]
4-(methylphenylamino)-5-methylthiothiophene-2-carboxamidine
[0352] 5-methyl-4-(phenylamino) thiophene-2-carboxamidine
[0353] 4-[4-(dimethylamino)phenyl]amino -5-
methylthiothiophene-2-carboxam- idine
[0354] 4-[(4-ethylphenyl)amino
l]-5-methylthiothiophene-2-carboxamidine
[0355] 5-methylthio-4-[4-(phenylmethoxy)phenyl]amino
}thiophene-2-carboxamidine
[0356] 5-methylthio-4-{[4-(phenylamino)phenyl]amino
}thiophene-2-carboxamidine
[0357] 4-[(4-methoxy
phenyl)amino]-5-methylthiothiophene-2-carboxamidine
[0358]
4-[(3-fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxam-
idine
[0359]
4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine
[0360]
4-[(9-ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxamidi-
ne
[0361]
5-methylthio-4-{[(4-phenylphenyl)sulfonyl]amino}thiophene-2-carboxa-
midine
[0362] 4-{bis [(4-phenylphenyl)sulfonyl]amino
}-5-methylthiothiophene-2-ca- rboxamidine
[0363]
5-methylthio-4-[(2-naphthylsulfonyl)-amino]thiophene-2-carboxamidin-
e
[0364]
4-[bis(2-naphthylsulfonyl)amino]-5-methylthiothiophene-2-carboxamid-
ine
[0365] 4-{[(6-bromo(2-naphthyl))sulfonyl]amino
}-5-methylthiothiophene-2-c- arboxamidine
[0366] 4-{bis [(6-bromo(2-naphthyl))sulfonyl]amino
}-5-methylthiothiophene- -2-carboxamidine
[0367]
5-methylthio-4-[(naphthylsulfonyl)-amino]thiophene-2-carboxamidine
[0368]
4-[bis(naphthylsulfonyl)amino]-5-methylthiothiophene-2-carboxamidin-
e
[0369] 4-{[(2-methylphenyl)sulfonyl]amino
}-5-methylthiothiophene-2-carbox- amidine
[0370] 4-{bis [(2-methylphenyl)sulfonyl]amino
}-5-methylthiothiophene-2-ca- rboxamidine
[0371] 4-{[(3-methylphenyl)sulfonyl]amino
}-5-methylthiothiophene-2-carbox- amidine
[0372] 4-{bis[(3-methylphenyl)sulfonyl]amino
}-5-methylthiothiophene-2-car- boxamidine
[0373] 4-{[(4-methylphenyl)sulfonyl]amino
}-5-methylthiothiophene-2-carbox- amidine
[0374] 4-{bis [(4-methylphenyl)sulfonyl]amino
}-5-methylthiothiophene-2-ca- rboxamidine
[0375] 5-methylthio-4-{[benzylsulfonyl]amino
}-thiophene-2-carboxamidine
[0376] 5-methylthio-4-phenoxythiophene-2-carboxamidine
[0377] 5-methylthio-4-(phenylsulfonyl)thiophene-2-carboxamidine
[0378] as well as salts thereof, such as hydrochloride or
trifluoracetate salts and prodrugs thereof.
[0379] Methods of Use and Pharmaceutical Compositions
[0380] For medicinal use, the pharmaceutically acceptable acid
addition salts, those salts in which the anion does not contribute
significantly to toxicity or pharmacological activity of the
organic cation, are preferred. The acid addition salts are obtained
either by reaction of an organic base of Formula I with an organic
or inorganic acid, preferably by contact in solution, or by any of
the standard methods detailed in the literature available to any
practitioner skilled in the art. Examples of useful organic acids
are carboxylic acids such as maleic acid, acetic acid, tartaric
acid, propionic acid, fumaric acid, isethionic acid, succinic acid,
cyclamic acid, pivalic acid and the like; useful inorganic acids
are hydrohalide acids such as HCl, HBr, HI; sulfuric acid;
phosphoric acid and the like. Preferred acids for forming acid
addition salts include HCl and acetic acid.
[0381] The compounds of the present invention represent a novel
class of potent inhibitors of metallo, acid, thiol and serine
proteases. Examples of the serine proteases inhibited by compounds
within the scope of the invention include leukocyte neutrophil
elastase, a proteolytic enzyme implicated in the pathogenesis of
emphysema; chymotrypsin and trypsin, digestive enzymes; pancreatic
elastase, and cathepsin G, a chymotrypsin-like protease also
associated with leukocytes; thrombin and factor Xa, proteolytic
enzymes in the blood coagulation pathway. Inhibition of
thermolysin, a metalloprotease, and pepsin, an acid protease, are
also contemplated uses of compounds of the present invention. The
compounds of the present invention are preferably employed to
inhibit trypsin-like proteases.
[0382] Compounds of the present invention that inhibit urokinase
plasminogen activator are potentially useful in treating excessive
cell growth disease state. Compounds of the present that inhibit
urokinase are, therefore, useful as anti-angiogenic,
anti-arthritic, anti-inflammatory, anti-invasive, anti-metastatic,
anti-restenotic, anti-osteoporotic, anti-retinopathic (for
angiogenesis-dependent retinopathies), contraceptive, and
tumoristatic treatment agents. For example, such treatment agents
are useful in the treatment of a variety of disease states,
including but not limited to, benign prostatic hypertrophy,
prostatic carcinoma, tumor metastasis, restenosis and psoriasis.
Also provided are methods to inhibit extracellular proteolysis,
methods to treat benign prostatic hypertrophy, prostatic carcinoma,
tumor metastasis, restenosis and psoriasis by administering the
compound of Formula I. For their end-use application, the potency
and other biochemical parameters of the enzyme inhibiting
characteristics of compounds of the present invention are readily
ascertained by standard biochemical techniques well known in the
art. Actual dose ranges for this application will depend upon the
nature and severity of the disease state of the patient or animal
to be treated as determined by the attending diagnostician. It is
to be expected that a general dose range will be about 0.01 to 50
mg, preferably 0.1 to about 20 mg per kg per day for an effective
therapeutic effect.
[0383] An end use application of the compounds that inhibit
chymotrypsin and trypsin is in the treatment of pancreatitis. For
their end-use application, the potency and other biochemical
parameters of the enzyme-inhibiting characteristics of the
compounds of the present invention is readily ascertained by
standard biochemical techniques well known in the art. Actual dose
ranges for their specific end-use application will, of course,
depend upon the nature and severity of the disease state of the
patient or animal to be treated, as determined by the attending
diagnostician. It is expected that a useful dose range will be
about 0.01 to about 50 mg, preferably about 0.1 to about 20 mg per
kg per day for an effective therapeutic effect.
[0384] Compounds of the present invention that are distinguished by
their ability to inhibit either factor Xa or thrombin may be
employed for a number of therapeutic purposes. As factor Xa or
thrombin inhibitors, compounds of the present invention inhibit
thrombin production. Therefore, these compounds are useful for the
treatment or prophylaxis of states characterized by abnormal venous
or arterial thrombosis involving either thrombin production or
action. These states include, but are not limited to, deep vein
thrombosis; disseminated intravascular coagulopathy which occurs
during septic shock, viral infections and cancer; myocardial
infarction; stroke; coronary artery bypass; fibrin formation in the
eye; hip replacement; and thrombus formation resulting from either
thrombolytic therapy or percutaneous transluminal coronary
angioplasty (PCTA).
[0385] By virtue of the effects of both factor Xa and thrombin on a
host of cell types, such as smooth muscle cells, endothelial cells
and neutrophils, the compounds of the present invention find
additional use in the treatment or prophylaxis of adult respiratory
distress syndrome; inflammatory responses; wound healing;
reperfusion damage; atherosclerosis; and restenosis following an
injury such as balloon angioplasty, atherectomy, and arterial stent
placement. The compounds of the present invention may be useful in
treating neoplasia and metastasis as well as neurodegenerative
diseases, such as Alzheimer's disease and Parkinson's disease.
[0386] When employed as thrombin or factor Xa inhibitors, the
compounds of the present invention may be administered in an
effective amount within the dosage range of about 0.1 to about 500
mg/kg, preferably between 0.1 to 30 mg/kg body weight, on a regimen
in single or 2-4 divided daily doses.
[0387] Human leucocyte elastase is released by polymorphonuclear
leukocytes at sites of inflammation and thus is a contributing
cause for a number of disease states. Compounds of the present
invention are expected to have an anti-inflammatory effect useful
in the treatment of gout, rheumatoid arthritis and other
inflammatory diseases, and in the treatment of emphysema. The
leucocyte elastase inhibitory properties of compounds of the
present invention are determined by the method described below.
Cathepsin G has also been implicated in the disease states of
arthritis, gout and emphysema, and in addition, glomerulonephritis
and lung infestations caused by infections in the lung. In their
end-use application the enzyme inhibitory properties of the
compounds of Formula I is readily ascertained by standard
biochemical techniques that are well-known in the art.
[0388] The Cathepsin G inhibitory properties of compounds within
the scope of the present invention are determined by the following
method. A preparation of partially purified human Cathepsin G is
obtained by the procedure of Baugh et al., Biochemistry 15: 836
(1979). Leukocyte granules are a major source for the preparation
of leukocyte elastase and cathepsin G (chymotrypsin-like activity).
Leukocytes are lysed and granules are isolated. The leukocyte
granules are extracted with 0.20 M sodium acetate, pH 4.0, and
extracts are dialyzed against 0.05 M Tris buffer, pH 8.0 containing
0.05 M NaCl overnight at 4.degree. C. A protein fraction
precipitates during dialysis and is isolated by centrifugation.
This fraction contains most of the chymotrypsin-like activity of
leukocyte granules. Specific substrates are prepared for each
enzyme, namely N-Suc-Ala-Ala-Pro-Val-p-nitroanilide and
Suc-Ala-Ala-Pro-Phe-p-nit- roanilide. The latter is not hydrolyzed
by leukocyte elastase. Enzyme preparations are assayed in 2.00 mL
of 0.10 M Hepes buffer, pH 7.5, containing 0.50 M NaCl, 10%
dimethylsulfoxide and 0.0020 M Suc-Ala-Ala-Pro-Phe-p-nitroanilide
as a substrate. Hydrolysis of the p-nitroanilide substrate is
monitored at 405 nm and at 25.degree. C.
[0389] Useful dose range for the application of compounds of the
present invention as neutrophil elastase inhibitors and as
Cathepsin G inhibitors depend upon the nature and severity of the
disease state, as determined by the attending diagnostician, with a
range of 0.01 to 10 mg/kg body weight, per day, being useful for
the aforementioned disease states.
[0390] Additional uses for compounds of the present invention
include analysis of commercial reagent enzymes for active site
concentration. For example, chymotrypsin is supplied as a standard
reagent for use in clinical quantitation of chymotrypsin activity
in pancreatic juices and feces. Such assays are diagnostic for
gastrointestinal and pancreatic disorders. Pancreatic elastase is
also supplied commercially as a reagent for quantitation of
.alpha..sub.1-antitrypsin in plasma. Plasma
.alpha..sub.1-antitrypsin increases in concentration during the
course of several inflammatory diseases, and
.alpha..sub.1-antitrypsin deficiencies are associated with
increased incidence of lung disease. Compounds of the present
invention can be used to enhance the accuracy and reproducibility
of these assays by titrametric standardization of the commercial
elastase supplied as a reagent. See, U.S. Pat. No. 4,499,082.
[0391] Protease activity in certain protein extracts during
purification of particular proteins is a recurring problem which
can complicate and compromise the results of protein isolation
procedures. Certain proteases present in such extracts can be
inhibited during purification steps by compounds of the present
invention, which bind tightly to various proteolytic enzymes.
[0392] The pharmaceutical compositions of the invention can be
administered to any animal that can experience the beneficial
effects of the compounds of the invention. Foremost among such
animals are humans, although the invention is not intended to be so
limited.
[0393] The pharmaceutical compositions of the present invention can
be administered by any means that achieve their intended purpose.
For example, administration can be by parenteral, subcutaneous,
intravenous, intramuscular, intraperitoneal, transdermal, buccal,
or ocular routes. Alternatively, or concurrently, administration
can be by the oral route. The dosage administered will be dependent
upon the age, health, and weight of the recipient, kind of
concurrent treatment, if any, frequency of treatment, and the
nature of the effect desired.
[0394] In addition to the pharmacologically active compounds, the
new pharmaceutical preparations can contain suitable
pharmaceutically acceptable carriers comprising excipients and
auxiliaries that facilitate processing of the active compounds into
preparations that can be used pharmaceutically.
[0395] The pharmaceutical preparations of the present invention are
manufactured in a manner that is, itself, known, for example, by
means of conventional mixing, granulating, dragee-making,
dissolving, or lyophilizing processes. Thus, pharmaceutical
preparations for oral use can be obtained by combining the active
compounds with solid excipients, optionally grinding the resulting
mixture and processing the mixture of granules, after adding
suitable auxiliaries, if desired or necessary, to obtain tablets or
dragee cores.
[0396] Suitable excipients are, in particular, fillers such as
saccharides, for example, lactose or sucrose, mannitol or sorbitol,
cellulose preparations and/or calcium phosphates, for example,
tricalcium phosphate or calcium hydrogen phosphate, as well as
binders, such as, starch paste, using, for example, maize starch,
wheat starch, rice starch, potato starch, gelatin, tragacanth,
methyl cellulose, hydroxypropylmethylcellulose, sodium
carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,
disintegrating agents can be added, such as, the above-mentioned
starches and also carboxymethyl-starch, cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof, such as,
sodium alginate. Auxiliaries are, above all, flow-regulating agents
and lubricants, for example, silica, talc, stearic acid or salts
thereof, such as, magnesium stearate or calcium stearate, and/or
polyethylene glycol. Dragee cores are provided with suitable
coatings that, if desired, are resistant to gastric juices. For
this purpose, concentrated saccharide solutions can be used, which
may optionally contain gum arabic, talc, polyvinyl pyrrolidone,
polyethylene glycol, and/or titanium dioxide, lacquer solutions and
suitable organic solvents or solvent mixtures. In order to produce
coatings resistant to gastric juices, solutions of suitable
cellulose preparations, such as, acetylcellulose phthalate or
hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or
pigments can be added to the tablets or dragee coatings, for
example, for identification or in order to characterize
combinations of active compound doses.
[0397] Other pharmaceutical preparations which can be used orally
include push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer, such as, glycerol or
sorbitol. The push-fit capsules can contain the active compounds in
the form of granules that may be mixed with fillers such as
lactose, binders such as starches, and/or lubricants such as talc
or magnesium stearate and, optionally, stabilizers. In soft
capsules, the active compounds are preferably dissolved or
suspended in suitable liquids, such as, fatty oils or liquid
paraffin. In addition, stabilizers may be added.
[0398] Suitable formulations for parenteral administration include
aqueous solutions of the active compounds in water-soluble form,
for example, water-soluble salts, alkaline solutions and
cyclodextrin inclusion complexes. Especially preferred salts are
hydrochloride and acetate salts. One or more modified or unmodified
cyclodextrins can be employed to stabilize and increase the water
solubility of compounds of the present invention. Useful
cyclodextrins for this purpose are disclosed in U.S. Pat. Nos.
4,727,064, 4,764,604, and 5,024,998.
[0399] In addition, suspensions of the active compounds as
appropriate oily injection suspensions can be administered.
Suitable lipophilic solvents or vehicles include fatty oils, for
example, sesame oil, or synthetic fatty acid esters, for example,
ethyl oleate or triglycerides or polyethylene glycol-400 (the
compounds are soluble in PEG-400). Aqueous injection suspensions
can contain substances that increase the viscosity of the
suspension, for example, sodium carboxymethyl cellulose, sorbitol,
and/or dextran. Optionally, the suspension may also contain
stabilizers.
[0400] Methods of Making
[0401] Many synthetic methods used to form compounds of the present
invention generally involve the formation of an amidine from a
carboxylic acid derivative, such as an ester or a nitrile. In the
process a Lewis acid, such as trimethylaluminum, is added to a
source of ammonia, such as ammonium chloride in an aprotic solvent,
such as a toluene, under an inert atmosphere (e.g., under an
atmosphere of nitrogen or argon gas) at a temperature between
-15.degree. C. and 5.degree. C., preferably at 0.degree. C. An
appropriate carboxylic acid derivative is added to the mixture and
the mixture is heated at reflux for a predetermined period of time,
preferably between 1 hr. and 24 hrs., and most preferably between 1
hr. and 4 hrs. The resulting solution is allowed to cool to room
temperature and the amidine product isolated by known methods.
[0402] Description of Syntheses
[0403] The chemical schemes appear after the description of the
schemes.
Scheme 1a
[0404] Scheme 1a illustrates a general approach to compounds of
Formula I where X.dbd.O or S, R.sup.3=alkylthio, aralkylthio,
arylthio, alkyloxy, aralkyloxy or aryloxy, Y=bond and
Z.dbd.NR.sup.5R.sup.6. When R.sup.22 and R.sup.21 of compounds 2
and 3 are retained in the final product, they correspond to R.sup.2
and R.sup.3 of Formula I, respectively. Otherwise R.sup.22 and
R.sup.21 represent groups which, after further transformations,
will become R.sup.2 and R.sup.3 of Formula I.
[0405] Starting with the heterocycle where X.dbd.O or S
appropriately substituted by two leaving groups, the leaving groups
can be sequentially displaced by appropriate nucleophiles
(preferably the anion of the group R.sup.21 or R.sup.22 to be
substituted) to produce the mono- or disubstituted heterocycles.
ages Examples of leaving groups include halogens (chlorine, bromine
or iodine), sulfonates (methanesulfonate, toluenesulfonate or
trifluoromethanesulfonate) or sulfones (methylsulfonyl). Preferable
nucleophiles include anions of thiols or alcohols having as the
counterion an alkali or alkali earth metal such as sodium, lithium,
potassium, magnesium or cesium, or in some cases, a transition
group metal such as zinc, copper or nickel. In certain cases where
the nucleophile used contains an anion on carbon, catalysis of the
displacement may be useful for this transformation. Examples of
catalysts would include compounds containing palladium, silver or
Ni salts.
Scheme 1b
[0406] Scheme 1b illustrates approaches to providing the
functionality of Y(CNR.sup.4)Z in compounds of Formula I where
X.dbd.N, O or S, R.sup.22 and R.sup.21 are defined as in Scheme 1a.
Depending on the nature of the group W in 3, several methods may be
employed in the transformation of W to Y(CNR.sup.4)Z.
[0407] When W in 3 is a cyano group (CN), primary amide
(CONH.sub.2) or ester (CO.sub.2R.sup.23), direct conversion to an
unsubstituted amidine 5 (i.e. Formula I where Y=bond,
Z.dbd.NR.sup.5R.sup.6 and R.sup.4, R.sup.5, R.sup.6=H) can be
effected by treatment with a reagent consisting of a Lewis acid
complexed to ammonia. This complex is produced by treatment of
ammonia or an ammonium salt, preferably an ammonium halide and most
preferably ammonium chloride or bromide, with an appropriate Lewis
acid, preferably a trialkylaluminum and most preferably trimethyl-
or triethylaluminum in a solvent inert to the Lewis acid employed.
For example, when a trialkylaluminum Lewis acid is employed with an
ammonium halide, reaction occurs with loss of one equivalent of
alkane to produce the dialkylhaloaluminum complex of ammonia (see
for example Sidler, D. R., et al, J. Org. Chem., 59:1231 (1994)).
Examples of suitable solvents include unsaturated hydrocarbons such
as benzene, toluene, xylenes, or mesitylene, preferably toluene, or
halogenated hydrocarbons such as dichloroethane, chlorobenzene or
dichlorobenzene. The amidination reaction is generally carried out
at elevated temperatures, preferably 40-200.degree. C., more
preferably 80-140.degree. C., and most preferably at the reflux
temperature of a solvent in the range of 80-120.degree. C.
[0408] When W is a cyano group (CN), direct conversion to a mono-
or disubstituted amidine 5 (R.sup.4, R.sup.5, R.sup.6=H) is also
possible by treatment with a reagent consisting of a Lewis acid,
preferably a trialkylaluminum, complexed to a mono- or
disubstituted amine H.sub.2NR.sup.5 or HNR5R.sup.6 (Garigipati, R.,
Tetrahedron Lett. 31: 1969 (1990)). Alternatively the same addition
of a mono- or disubstituted amine may catalyzed by a copper salt
such as Cu(I) chloride (Rousselet, G., et al, Tetrahedron Lett. 34:
6395 (1993)).
[0409] When W in 3 is a carboxyl group (CO.sub.2H), indirect
conversion to an unsubstituted amidine 5 can be carried out by
initial esterification to 4 by any of a number of well-known
dehydrating agents (for example, dicyclohexylcarbodiimide) with an
alcohol (R.sup.23OH). More preferably 4 can be made by initial
formation of an acid chloride by treatment of 3 with any of a
number of anhydrides of HCl and another acid, such as thionyl
chloride, POCl.sub.3, PCl.sub.3, PCl.sub.5, or more preferably
oxalyl chloride, with or without an added catalyst such as
N,N-dimethylformamide (DMF), followed by the alcohol R.sup.23OH.
Conversion to the unsubstituted amidine 5 (R.sup.4, R.sup.5,
R.sup.6=H) can be carried out by treatment with a Lewis acid
complexed to ammonia.
[0410] Amidines 5 also can be produced indirectly by conversion of
3 (W.dbd.CN) to iminoethers 6 by exposure to a strong acid such as
a hydrogen halide, HBF.sub.4 or other non-nucleophilic acid,
preferably gaseous HCl in the presence of an alcohol R.sup.23 OH
(R.sup.23=alkyl, branched alkyl or cycloalkyl, preferably Me or Et)
and most preferably with the alcohol as solvent. Alternatively when
W.dbd.CONH.sub.2, conversion to an iminoether can be carried out by
treatment with a trialkyloxonium salt (Meerwein's salts). In either
case, treatment of the iminoether 6 with ammonia (R.sup.5,
R.sup.6=H) or a mono- or disubstituted amine (HNR.sup.5R.sup.6)
provides the corresponding unsubstituted or substituted amidines 5
(i.e. via classical Pinner synthesis: Pinner, A., Die Iminoaether
und ihre Derivate, Verlag R. Oppenheim, Berlin (1892)).
[0411] When W.dbd.NH.sub.2 in 3, treatment with a reagent
Z(CNR.sup.4)L where Z=alkyl and L is a leaving group such as
O-alkyl and preferably OMe, provides the subclass of amidines 135
(Z=alkyl ) which are isomeric to 5 (Formula I, where Y.dbd.NH,
Z.dbd.H or alkyl). Examples of reagents for this reaction include
methyl or ethyl acetimidate hydrochloride. Alternatively treatment
of 3 (W.dbd.NH.sub.2) with a trialkyl orthoformate ester,
preferably trimethyl- or triethyl orthoformate, followed by an
amine R.sup.4NH.sub.2 affords the corresponding formidines 135
(Z.dbd.H) (Formula I, where Y.dbd.NH, Z.dbd.H).
[0412] Also, when W.dbd.NH.sub.2, 3 can be treated with a reagent
Z(CNR.sup.4)L where R.sub.4=H and Z.dbd.NR.sup.5R6 and L is a
leaving group such as pyrazole, methylpyrazole, SO.sub.3H, S-alkyl,
S-aryl, trifluoromethanesulfonate (OTf) or
trifluoromethanesulfonamide (NHTf), preferably pyrazole, SO.sub.3H
or trifluoromethanesulfonamide (NHTf). Examples of these reagents
include aminoiminosulfonic acid (Miller, A. E. and Bischoff, J. J.,
Synthesis, 777 (1986) and 1H-pyrazole-1-carboxamidin- e
hydrochloride (Bernatowicz, M. S., et al., J. Org. Chem. 57:2497
(1992)). Such treatment provides guanidines 136 directly (Formula I
where Y.dbd.NH, Z.dbd.NR.sup.5R.sup.6). Alternatively a reagent
Z(CNP)L may be also used where Z.dbd.NHP.sup.2 and L again a
leaving group such as pyrazole, methylpyrazole, SO.sub.3H, S-alkyl,
S-aryl, trifluoromethanesulfonate (OTf) or
trifluoromethanesulfonamide (NHTf), to provide protected guanidines
(p, p.sup.2=alkoxylcarbonyl, aralkoxycarbonyl or polymer-bound
alkoxylcarbonyl similar to those described below in Scheme 4a)
where the protecting groups P.sup.1 and P.sup.2 can then be removed
to give unsubstituted 136 (R.sup.4, R.sup.5 and R.sup.6=H).
Protected guanidines are advantageous when further transformations
are required after introduction of the guanidine functionality
where an unprotected guanidine would not be stable. Examples of
these protected reagents include reagents such as
N,N'-bis(tert-butoxycarbonyl)-S-methylthiourea (Bergeron, R. J. and
McManis, J. S, J. Org. Chem. 52:1700 (1987)),
N,N'-bis(benzyloxycarbonyl)- -1 H-pyrazole-1-carboxamidine or
N,N'-bis(tert-butoxycarbonyl)-1 H-pyrazole-1-carboxamidine
(Bernatowicz, M. S., et al., Tetrahedron Letters, 34: 3389 (1993)),
N,N'-bis(benzyloxycarbonyl)-N-trifluoromethane- sulfonylguanidine,
and N,N'-bis(bis(tert-butoxycarbonyl)-N-trifluoromethan-
esulfonylguanidine (Feichtinger, K., et al, J. Org. Chem. 63:3804
(1998)). Detailed descriptions and examples of these protecting
groups and their use as protection for amidines are further
outlined in Schemes 4a, 4b and 5.
[0413] When W in 3 is an ester (CO.sub.2R.sup.23) or carboxyl group
(CO.sub.2H), indirect conversion to an N-substituted or
unsubstituted methylamidine (Formula I where Y.dbd.CH.sub.2,
Z.dbd.NR.sup.5R.sup.6) can be carried out by initial reduction of
the ester or carboxyl by any of a number of well-known reducing
agents. When W in 3 is an ester (CO.sub.2R.sup.23), examples of
reducing agents include reducing agents such lithium aluminum
hydride (LAH) and lithium borohydride. When W in 3 is a carboxyl
group (CO.sub.2H), examples of reducing agents include LAH and
borane complexed to THF, dimethyl sulfide, dimethylamine or
pyridine. The resulting hydroxymethyl derivative (W.dbd.CH.sub.2OH)
is converted to a cyanomethyl derivative (W.dbd.CH.sub.2CN) by
initial formation of a leaving group (W.dbd.CH.sub.2L) where the
leaving group L is a halogen (chlorine, bromine or iodine) or
sulfonate ester (for example methanesulfonate, toluenesulfonate or
trifluoromethanesulfonate). Displacement of L by cyanide can then
be performed by treatment with a metal cyanide such as LiCN, NaCN,
KCN or CuCN in a polar solvent such as DMF and with or without a
catalyst such as a crown ether, to afford the cyanomethyl
derivative (see for example Mizuno, Y., et al, Synthesis, 1008
(1980)). More preferably, the conversion of W.dbd.CH.sub.2OH to
W.dbd.CH.sub.2CN may be effected by a Mitsunobu reaction
(Mitsunobu, O., Synthesis, 1 (1981)) using an azodicarboxylate
ester such as diethyl azodicarboxylate or diisopropyl
azodicarboxylate, Ph.sub.3P and a source of cyanide such as HCN or
more preferably acetone cyanohydrin (Wilk, B. Synthetic Commun.
23:2481(1993)). Treatment of the resulting cyanomethyl intermediate
(W.dbd.CH.sub.2CN) under the conditions described for the
conversion of 3 (W.dbd.CN) to 5 (either directly or indirectly via
6) provides the corresponding amidinomethyl products.
Scheme 1c
[0414] When not commercially available, alkylthiothiophenes (3,
X.dbd.S, R.dbd.OH or NH.sub.2, R.sup.21=SR.sup.54, W.dbd.CN,
C.sub.0.sub.2R.sup.23, CONH.sub.2) can be synthesized by the
methods illustrated in Scheme 1c. Condensation of carbon disulfide
and a malonic acid derivative (R .sup.2CH.sub.2R.sup.22) in the
presence of two alkylating agents R.sup.54L and WCH.sub.2L and a
base in a suitable medium provide 3 (Dolman, H., European Patent
Application No. 0 234 622 Al (1987)). When
R.sup.22=R.sup.52.dbd.CN, the resulting R will be NH.sub.2; when
R.sup.22=R.sup.52=C.sub.0.sub.2R.sup.23, the resulting R will be
OH; and when R.sup.22 and R.sup.52=CN, C.sub.0.sub.2R.sup.23, the
resulting R can be selected to be OH or NH.sub.2 (and R.sup.22=CN
or CO.sub.2R.sup.23) depending on the reaction conditions and order
of reagent addition. Examples of malonic acid derivatives suitable
for this transformation include but are not limited to malonate
diesters such as dimethyl malonate or diethyl malonate (R.sup.52,
R.sup.22=CO.sub.2R.sup.2- 3, R.sup.23=Me or Et), malononitrile
(R.sup.52, R.sup.22=CN), or methyl or ethyl cyanoacetate
(R.sup.52=C.sub.0.sub.2R.sup.23, R.sup.22=CN, R.sup.23=Me or Et).
Leaving groups L include halides such as chloride, bromide or
iodide, preferably bromide or iodide, or sulfonates such as
toluenesulfonate, benzenesulfonate, methanesulfonate or
trifluoromethanesulfonate. Examples of alkylating agent R.sup.54L
include primary or secondary alkyl, allyl or aralkyl halides or
sulfonates, such as methyl iodide, isopropyl bromide, allyl
bromide, benzyl chloride or methyl trifluoromethanesulfonate, or a
2-haloacetate ester such as tert-butyl 2-bromoacetate. Examples of
alkylating agents WCH.sub.2L include 2-chloroacetonitrile, methyl
2-bromoacetate or 2-bromoacetamide. Suitable media are generally
polar aprotic solvents, for example, NAN-dimethylformamide (DMF),
N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP) or
dimethylsulfoxide (DMSO), preferably DMF.
[0415] Alternatively compounds 3 (R.sup.22=CN) can be synthesized
from precursors 138 (derived from malononitrile, R.sup.4L and
carbon disulfide), a thioglycolate WCHSH and a base in a suitable
polar solvent, preferably methanol (Tominaga, Y., et al, J.
Heterocyclic Chem. 31:771 (1994)).
[0416] When 3 contains an amino group at R, it can be diazotized
with subsequent loss of nitrogen to give 3, R.sup.1=H by treatment
with a nitrosating agent in suitable solvent. Nitrosating agents
include nitrosonium tetrafluoroborate, nitrous acid or, more
preferably and alkyl nitrite ester such as tert-butyl nitrite.
Suitable solvents are those which are stable to the nitrosating
agents, preferably DMF, benzene or toluene.
[0417] Scheme 1d
[0418] When not commercially available, heterocyclic precursors 1
or 2 (X.dbd.O, S; W.dbd.C.sub.0.sub.2R.sup.23, COOH; L=halogen)
used in Scheme la can be synthesized by the methods illustrated in
Scheme1d. Depending on the conditions used, treatment of compounds
such as 139 with elemental halogen (Cl.sub.2, Br.sub.2 or 12,
preferably Br.sub.2) or an N-halosuccinimide reagent, preferably
N-bromosuccinimide (NBS), affords either 1 or 2 directly.
Description of suitable solvents and conditions to selectively
produce 1 or 2 are found in Karminski-Zamola, G. et al,
Heterocycles 38:759 (1994); Divald, S., et al, J. Org. Chem.
41:2835 (1976); and Bury, P., et al, Tetrahedron 50:8793
(1994).
Scheme 2a
[0419] Scheme 2a illustrates the synthesis of compounds 12
representing the subclass of compounds for which R.sup.2 is Formula
II, where Ar=2-thiazolyl, Y=bond and Z.dbd.NR.sup.5R.sup.6.
Starting with compound 1 (L.dbd.Br) and using the sequential
displacement methodology discussed for Scheme la, R.sup.21 can be
first introduced to give 7. This is followed by a second
displacement with a metal cyanide such as copper (I) cyanide,
sodium cyanide or lithium cyanide and most preferably copper (I)
cyanide at a temperature of 80-200.degree. C. and preferably at
100-140.degree. C., in a polar aprotic solvent, preferably DMF or
DMSO, to give 8. After esterification by any of the means described
for the conversion of 3 to 4, conversion to the thioamide is
carried out by treatment of the nitrile with any of the methods
well known in the art (see for example Ren, W., et al., J.
Heterocyclic Chem. 23:1757 (1986) and Paventi, M. and Edward, J.
T., Can. J. Chem. 65:282 (1987)). A preferable method is treatment
of the nitrile with hydrogen sulfide in the presence of a base such
as a trialkyl or heterocyclic amine, preferably triethylamine or
pyridine, in a polar solvent such as acetone, methanol or DMF and
preferably methanol. Conversion to the thiazole can be executed by
classical Hantzsch thiazole synthesis followed by amidine formation
as discussed in Scheme 1b.
Scheme 2b
[0420] Scheme 2b illustrates the synthesis of compounds
representing the subclass of compounds for which R.sup.2 is Formula
II where, in addition to being an alternate route to Ar=2-thiazolyl
(20) (see 12, Scheme 2a) also provide compounds of Formula II where
Ar=2-oxazolyl (16) or 2-imidazolyl (18) (Y=bond and
Z.dbd.NR.sup.5R.sup.6). Starting with compound 9, a selective
hydrolysis of the nitrile with a tetrahalophthalic acid, preferably
tetrafluoro- or tetrachlorophthalic acid, can be used to give 7
according to the method of Gribble, G. W. et al., Tetrahedron Lett.
29: 6557 (1988). Conversion to the acid chloride can be
accomplished using the procedures discussed for conversion of 3 to
4, preferably with oxalyl chloride in dichloromethane in the
presence of a catalytic amount of DMF. Coupling of the acid
chloride to an aminoketone (R.sup.26COCH(R.sup.27)NH.sub.2) can be
performed in the presence of an acid scavenger, preferably
N,N-diisopropylethylamine (DIEA) or pyridine in a suitable solvent
such as DMF, dichloromethane or tetrahydrofuran (THF) to afford the
common intermediate 14. Alternatively coupling of the acid chloride
to a less-substituted aminoketone (R.sup.26COCH.sub.2NH.sub.2) can
be used followed by optional alkylation with alkylating agent R
.sup.27L in the presence of a base, preferably NaH or t-BuOK.
Transformation of 14 to the corresponding 2-oxazolyl (15),
2-imidazolyl (17) or 2-thiazolyl (19) esters can carried out by the
methodology of Suzuki, M., et al., Chem. Pharm. Bull. 34:3111
(1986) followed by amidination according to Scheme 1b. In addition,
direct conversion of ketoamide 14 to imidazolyl derivative 18 is
possible under the same conditions for conversion of 17 to 18 when
conducted for extended periods, preferably greater than 2 h.
Scheme 2c
[0421] Scheme 2c describes a general route to the synthesis of
oxazoles, imidazoles and thiazoles of structure 27, 29 and 31
respectively. Acid 2 (see Scheme la) is converted to the ester by
methods that are well known in the art (Theodora W. Greene and
Peter G. M. Wuts, John Wiley and Sons, Inc. 1991). For example
methyl ester 21 is formed by treating the acid in an appropriate
solvent such as methanol with trimethylsilyldiazomethane.
Alternatively the acid is treated with oxalyl chloride and
catalytic amounts of dimethylformamide (DMF) in an appropriate
solvent such as dichloromethane to form the acid chloride, which is
then treated with methanol to give the methyl ester. Ester 21 is
treated with a palladium (0) catalyst such as palladium
tetrakistriphenylphosphine, and an alkylstannane such as
hexa-n-butyldistannane or tri-n-butyltin chloride in an appropriate
solvent such as DMF at elevated temperatures (50.degree. C.
-120.degree. C.) to give the arylstannane of general structure 22
(Stille, J. K., Angew. Chem. Int. Ed. Engl. 25:508-524 (1986)). The
stannane 22 is then treated with acid chlorides in the presence of
a palladium(0) catalyst to give ketone 23. The ketone is treated
with ammonia/ammonium chloride to give amine 24. Alternatively the
ketone is reacted with an azide such as sodium azide in a suitable
solvent such as DMF, and the resulting azidoketone is reduced to
amine 23 with a suitable reducing agent such as catalytic
hydrogenation in the presence of palladium on carbon and an acid
such as HCl (Chem. Pharm. Bull. 33:509-514 (1985)). Ketoamides 25
are formed by coupling the ketoamine 24 with a variety of suitably
functionalized acid chlorides. Alternatively amide coupling may be
performed using any of a number of peptide coupling reagents such
as 1,3-dicyclohexylcarbodiimide (Sheehan, J. C. et al., J. Am.
Chem. Soc., 77:1067 (1955)) or Castro's reagent (BOP, Castro, B.,
et al., Synthesis 413 (1976)). In another approach, amides 25 are
formed directly from ketones 23 by reacting with various amide
salts in an appropriate solvent such as DMF. The amide salts are
generated by treating the amides with a suitable base such as
sodium hydride (NaH). For example acetamide is treated with NaH in
DMF at 0.degree. C. to give sodium acetamide. Keto amide 25 is
cyclized to the oxazole 26, imidazole 28 and thiazole 30 using
procedures similar to that shown in scheme 2b. Oxazole 26,
imidazole 28 and thiazole 30 are treated with trimethylaluminum and
ammonium chloride in refluxing toluene to give the amidines 27, 29
and 31 respectively.
Scheme 2d
[0422] Scheme 2d illustrates to the preparation of compounds of
Examples 42-43, where R.sup.2and R.sup.43 correspond in Formula I
to groups R.sup.3 and R.sup.2, respectively. The acids 2 can be
converted to the stannane by treatment with base, such as n-butyl
lithium or sec-butyl lithium, followed by trimethyltin chloride.
The resulting acid can be then converted to the ester 22 by methods
that are well known in the art (Theodora W. Greene and Peter G. M.
Wuts, Protective Groups in Organic Chemistry, John Wiley and Sons,
Inc. 1991). For example the methyl ester can be made by treating
the acid 2 in a suitable solvent such as methanol with
trimethylsilyldiazomethane. The stannane 22 can be reacted with
suitable halides in the presence of catalytic amounts of a
palladium catalyst, such as palladium tetrakistriphenylphosphine,
to give the esters 32 (Stille, J. K., Angew. Chem. Int. Ed. Engl.
25:508-524 (1986)). These esters are then treated with
trimethylaluminum and ammonium chloride in refluxing toluene to
give the amidines 33. In the case where R.sup.43L.sub.n (n=2), this
can be cross-coupled to an aryl, heteroaryl or vinyl boronic acid
or ester to give compounds 34 (Miyaura, N. and Suzuki, A., Chem.
Rev. 95:2457-2483 (1995)). This can usually be done in the presence
of catalytic amounts of a palladium (0) catalyst such as
tetrakistriphenylphosphine palladium and a base such as potassium
carbonate in DMF at 90.degree. C. Similar cross-coupling reactions
can also be achieved by using aryl, heteroaryl and vinyl stannanes
instead of boronic acids or esters. These esters are converted to
the amidines 35 in the manner previously described.
Scheme 2e
[0423] Scheme 2e represents a modification to the methodology
outlined in Scheme 2b which allows synthesis of compounds of
Formula II where Ar=2-thiazolyl, 2-oxazolyl or 2-imidazolyl (Y=bond
and Z.dbd.NR.sup.5R.sup.6) but which are regioisomeric to 16, 18 or
20 in the relative positions of substituents R.sup.26 and R.sup.27.
This is illustrated in Scheme 2b by the synthesis of 2-oxazolyl
derivative 39. Thus, acid 13 can be coupled to an
hydroxy-containing amine R.sup.27CH(NH.sub.2)CH(R.sup.26)OH to give
amide 36 by any of a number of amide coupling reagents well known
in the art (see Bodanszky, M. and Bodanszky, A., The Practice of
Peptide Synthesis, Springer-Verlag, New York (1984)). More
preferably 13 can be converted to the corresponding acid chloride
using any of the procedures mentioned for conversion of 3 to 4
followed by treatment with the R.sup.27CH(NH.sub.2)CH(R.sup.26)OH
in the presence of an acid scavenger, preferably
N,N-diisopropylethylamine (DIEA) or pyridine in a suitable solvent
such as DMF, dichloromethane or tetrahydrofuran (THF) to give 36.
Oxidation of the alcohol 36 to the aldehyde 37 (R.sup.26=H) or
ketone 37 (R.sup.26=alkyl, aryl, aralkyl, heterocycle) can be
effected by any of a number of common methods known in the art (see
for example F. Carey, F. A., Sundberg, R. J. Advanced Organic
Chemistry, Part B: Reactions and Synthesis, 3rd Edition, Plenum
Press, New York (1990)), preferably by a mild Moffatt-type
oxidation such as a Swern oxidation (Mancuso, A. J., Huang, S. L.
and Swern, D., J. Org. Chem. 3329 (1976)) or more preferably using
Dess-Martin reagent (Dess, D. B. and Martin, J. C., J. Org. Chem.
48:4155 (1983)). Conversion to the heterocycle (in this case the
oxazole) is effected with any of a number of reagents including
phosphorus oxychloride, P.sub.2O.sub.5 or thionyl chloride (see
Moriya, T., et al., J. Med. Chem. 31:1197 (1988) and references
therein). Alternatively closure of 37 with either Burgess reagent
or under Mitsunobu conditions affords the corresponding oxazolinyl
derivatives (Wipf, P. and Miller, C. P., Tetrahedron Lett. 3: 907
(1992)). Final amidination to 39 as in Scheme 1b completes the
synthesis.
Scheme 2f
[0424] Scheme 2f illustrates a general approach to the synthesis of
thiazoles of structure 43 (Formula II, X.dbd.S, Ar=thiazolyl).
Nitriles of structure 40 can be treated with hydrogen sulfide
(H.sub.2S) in a suitable solvent such as methanol, or pyridine in
the presence of a base such as triethylamine to give thioamides 41
(Ren, W. et al., J. Heterocyclic Chem. 23:1757-1763 (1986)).
Thioamides 41 can be then treated with various haloketones 42
preferably bromoketones under suitable reaction conditions such as
refluxing acetone or DMF heated to 50.degree. C. -80.degree. C. to
form the thiazoles 43 (Hantzsch, A. R. et al., Ber. 20:3118
(1887)).
Scheme 2 g
[0425] Scheme 2 g illustrates one synthetic route to 2-haloketones
of structure 42 which are employed in the synthesis of thiazolyl
derivatives as in Schemes 2a and 2f. 2-Bromoketones 42 (L.dbd.Br)
are prepared by treating the ketone 44 with a suitable brominating
agent such as Br.sub.2 or N-bromosuccinimide in a suitable solvent
such as chloroform or acetic acid (EP 0393936 Al). Alternatively,
the ketone 44 is treated with a polymer-supported brominating agent
such as poly(4-vinyl)pyridinium bromide resin (Sket, B., et al.,
Synthetic Communications 19:2481-2487 (1989)) to give bromoketones
42. In a similar fashion 2-chloroketones are obtained by treating
44 with copper (II) chloride in a suitable solvent such as
chloroform (Kosower, E. M., et al., J. Org. Chem. 28:630
(1963)).
Scheme 2h
[0426] Scheme 2h illustrates another synthetic route to
2-haloketones of structure 42 which is particularly useful in that
it employs acids 45 or activated carbonyl compounds such as 46 as
precursors which are more readily available than the ketones 44.
The acid 45 is converted to the acid halide 46 (L.dbd.Cl, Br or
OCOR.sup.39) by treating with a suitable halogenating reagent. For
example, an acid chloride is formed by treating 45 with oxalyl
chloride and catalytic amounts of DMF in dichloromethane. The acid
chloride is converted to a diazoketone by treatment with
trimethysilyldiazomethane (Aoyama, T. et al., Tetrahedron Lett.
21:4461-4462 (1980)). The resulting diazoketone is converted to a
2-haloketone of structure 42 by treatment with a suitable mineral
acid. For example a bromoketone is formed by treating the
diazoketone in a suitable solvent such as acetonitrile (CH.sub.3CN)
with a solution of 30% hydrogen bromide (HBr) in acetic acid
(Organic Synthesis Collective Vol III, 119, John Wiley and Sons,
New York, Ed. Horning E. C.). In an alternative approach the acid
45 is converted to the mixed-anhydride 46 by treatment with a
suitable chloroformate such as isobutyl chloroformate or tert-butyl
chloroformate in a suitable solvent, such as tetrahydrofuran or
dichloromethane, in the presence of a base such as
N-methylmorpholine. The mixed anhydride 46 is converted to a
diazoketone by treatment with trimethylsilyldiazomethane and the
resulting diazoketone is converted to a haloketone in the manner
described above.
Scheme 2i
[0427] When amide coupling as described in Scheme 2e is followed
directly by amidination, compounds of Formula I where R.sup.2 or
R.sup.3 is aminoacyl or aminoiminomethyl can be derived. Thus,
coupling of acid 13 (or the corresponding acid chloride as
previously described) with an amine R.sup.5R.sup.52NH can afford
130 which can be carried on to the amidine 131. Upon either longer
or more vigorous additional treatment (for example, higher
temperatures) with a Lewis acid-ammonia reagent as described in
Scheme 1b, the amide group can be converted to an aminoiminomethyl
group to give a bisamidine compound 132.
Scheme 3a
[0428] Acid 13 can also be converted to an amine 47 from which
sulfonamides, ureas and urethanes can be formed (Formula I where
R.sup.2 or R.sup.3=NR.sup.32SO.sub.2R.sup.3, NHCONR.sup.51R.sup.52
or NHCOR.sup.31, respectively). Scheme 3a illustrates this
methodology for introduction of these three groups at R.sup.2 of
Formula I. Conversion of the acid 13 to an intermediate acyl azide
can be followed by heating of such azide in the presence of an
alcohol under Curtius rearrangement conditions to form the
carbamate ester of the alcohol. Subsequent carbamate ester
hydrolysis yields amine 47. The intermediate acyl azide may be
synthesized by coupling the acid 13 to hydrazine through the acid
chloride or by any of the amide coupling procedures discussed for
Scheme 2e followed by nitrosation of the resulting hydrazide by any
of the nitrosating agents discussed for conversion of 3
(R.sup.1=NH.sub.2) to 3 (R.sup.1=H) in Scheme 1c. More preferably
conversion of 13 to 47 is carried out through treatment of acid 13
with diphenylphosphoryl azide in the presence of an alcohol,
preferably tert-butanol, and a base, preferably triethylamine or
DEEA, as shown in Scheme 3a, to give a tert-butylcarbamate that is
readily decomposed to the salt of amine 47 on exposure to an acid,
preferably HCl or trifluoroacetic acid in a suitable solvent such
as CH.sub.2Cl.sub.2. Further treatment with a base such as NaOH or
preferably K.sub.2CO.sub.3 or NaHCO.sub.3 provides the free base
47. Treatment of amine 47 with a sulfonyl chloride
R.sup.3SO.sub.2C.sub.1 in the presence of an acid scavenger, such
as pyridine or DIEA, followed by optional alkylation on nitrogen
with an alkylating agent R.sup.32L in the presence of a base such
as K.sub.2CO.sub.3, DIEA or more preferably sodium hydride, in a
solvent such as THF, MeCN or CU.sub.2Cl.sub.2 affords the
sulfonylamine functionality at R.sup.2 (48). When necessary, this
transformation can be catalyzed by the presence of
4-dimethylaminopyridine for less reactive sulfonyl chlorides.
Similar treatment of amine 47 with an isocyanate R.sup.5NCO or
carbamyl chloride R.sup.5R.sup.52COCl affords the
aminocarbonylamine functionality at R.sup.2 (50). Similar treatment
of amine 47 with an acid chloride R.sup.31COCl affords the
carbonylamine functionality at R.sup.2 (52). Conversion of the
esters in 48, 50 and 52 to amidines as previously mentioned gives
the products 49, 51 and 53. Further conversion of the acylamino
group of 53 as discussed for synthesis of 132 also provides access
to the iminomethylamino group at R.sup.2 (54).
Scheme 3b
[0429] Introduction of an aminosulfonyl group (including
monoalkylaminosulfonyl and dialkylaminosulfonyl groups) for R.sup.2
of Formula I can be carried out starting from amine such as 47 as
well. Conversion to a sulfonyl chloride by the method of Gengnagel,
et al. (U.S. Pat. No. 3,947,512 (1976)) and treatment with an amine
R.sup.34NH.sub.2 followed by optional alkylation on nitrogen with
R.sup.35L (under the sulfonylation and alkylation conditions
described in Scheme 3a) provides 56 which is further converted to
amidines 57 as previously described.
Scheme 3c
[0430] In addition to the synthesis outlined in Scheme 3a, amine 47
may also be produced as illustrated in Scheme 3c. A nitrothienyl
ester 122 (Dell'Erba, C. and Spinelli, D., Tetrahedron, 21: 1061
(1965), Dell'Erba, C. et al., J. Chem. Soc, Perkin Trans 2, 1779
(1989)) with a suitable leaving group L may be substituted with an
anion of R.sup.21 to give intermediate 123. Amine 47 is then
derived from reduction of the nitro group. Appropriate reagents to
effect reduction of the nitro functionality include hydrogen gas in
the presence of a catalyst such as palladium or platinum metal
deposited on carbon or barium sulfate in any of a number of
solvents such as methanol, ethanol, ethyl acetate, DMF or THF. More
preferably, tin (II) chloride may be employed as a reductant in
solvents such as DMF or THF, or in the presence of HCl in a solvent
such as methanol or ethanol. Alternatively, metals such as zinc or
iron (Stanetty, P. and Kremslehner, M., Heterocycles 48: 259
(1998)) may also be used.
Scheme 4a
[0431] Scheme 4a illustrates the preparation of the compounds of
Formula III and Examples 48-59 and 61-77. The amidine moiety of
compounds of structure 60 can be protected with a protecting group
P.sup.1 that can be readily removed from 62 and 64 using methods
known to those skilled in the art (Theodora W. Greene and Peter G.
M. Wuts, John Wiley and Sons, Inc. 1991). For example, a
tert-butoxycarbonyl (BOC) protecting group can be removed by
exposure to strongly acidic medium such as hydrogen chloride in a
suitable solvent such as dioxane, or by trifluoroacetic acid in a
suitable solvent such as methylene chloride. Benzyloxycarbonyl
(Cbz) protecting groups can be removed by catalytic hydrogenation
using palladium on carbon as a catalyst in solvents such as ethanol
or tetrahydrofuran.
[0432] In some cases, P can be a solid support such as polystyrene
or polyethyleneglycol-grafted polystyrene which can be attached to
the amidine moiety via a cleavable linker such as
4-(benzyloxy)benzyloxy-carb- onyl (using carbonate Wang resin).
Attaching an amidine to a solid support can be achieved by treating
a solid support having a linker containing an appropriately
activated functional group with the amidine under suitable
conditions. For example, an amidine can be attached to Wang resin
by treating para-nitrophenylcarbonate Wang resin with the amidine
and a suitable base such as DBU in a suitable solvent such as DMF.
When D is OH or SH the protected amidines 61 can be alkylated with
carboxy-protected (protecting group is R.sup.36) haloaliphatic
acids, such as bromoacetic acid or bromopropionic acid in the
presence of a suitable base such as cesium carbonate or DIEA, in a
suitable solvent such as DMF with heating when necessary to give
compounds of structure 62. When D is NO.sub.2, the nitro group can
be reduced prior to alkylation using an appropriate reducing agent,
such as tin (II) chloride, in a suitable solvent such as DMF, or by
catalytic hydrogenation using palladium on carbon as a catalyst in
solvents such as ethanol or tetrahydrofuran. Other useful carboxy
protecting groups are well known in the art (Theodora W. Greene and
Peter G. M. Wuts, Protective Groups in Organic Chemistry, John
Wiley and Sons, Inc. 1991). For example, tert-butyl ester can be
removed by exposure to strongly acidic medium such as hydrogen
chloride in a suitable solvent such as dioxane, or such as
trifluoroacetic acid in a suitable solvent such as methylene
chloride. Benzyl ester can be removed by catalytic hydrogenation
using palladium on carbon as a catalyst in solvents such as ethanol
or tetrahydrofuran or by base hydrolysis.
[0433] When protecting groups P.sup.1 and R.sup.36 in compounds 62
are orthogonal (as defined by the ability to remove one protecting
group preferentially in the presence of the other), R.sup.36 can be
preferentially removed to give acids 63. For example when P.sup.1
is BOC and R.sup.36 is OMe, the methyl ester can be removed by
treating with a base such as sodium hydroxide in a suitable solvent
such as aqueous tetrahydrofuran leaving the BOC group intact. When
protecting groups p and R.sup.36 in compounds 62 are not
orthogonal, both protecting groups are removed, and the amidine can
be protected with a suitable protecting group such as BOC or a
suitably functionalized resin. The protected amidine 63 can be
treated with various amines under suitable amide coupling
conditions, such as in the presence 1-hydroxy-7-azabenzotriazole
(HOAt), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU) and DIEA to form amides of structure 64.
The amidine protecting group can be then removed, for example by
treating with an acid, such as trifluoroacetic acid in a suitable
solvent such as methylene chloride, when a BOC protecting group is
employed, to give amidines 65.
Scheme 4b
[0434] Scheme 4b illustrates a specific example which utilizes the
method described in Scheme 4a. The amidine moiety of 66 can be
monoprotected with a tert-butyloxycarbonyl group. The monoprotected
phenoxyamidine 67 can be alkylated on the phenolic hydroxy group
with an ester of 2-bromoacetic acid to give 68. In the case where
the ester can be removed by base, it can be hydrolyzed with aqueous
base, such as NaOH, to give the acid 69. This acid can be treated
with various amines in the presence of 1-hydroxy-7-azabenzotriazole
(HOAt), O-(7-azabenzotriazol-1-yl)-1,1,3,- 3-tetramethyluronium
hexafluorophosphate (HATU) and DIEA to form amides of structure 70.
The amines are unsubstituted, di- or mono-substituted aliphatic or
aromatic amines. In some cases the amines are cyclic-amines such as
piperazine and piperidine. The amides 70 are then treated with
trifluoroacetic acid to give the amidines 71. In the case where the
ester 68 is acid-labile, it can be treated with trifluoroacetic
acid to give the amidino-acid 72. This amidine can be loaded on to
an insoluble support, such as polystyrene or
polyethyleneglycol-grafted polystyrene via a cleavable linker, such
as Wang, which is functionalized as an activated carbonate such as
p-nitrophenylcarbonate or succinimidyl carbonate. Generally this
can be done by treating the activated carbonate resin with the
amidine and a suitable base such as DBU in a suitable solvent such
as DMF. The support-bound acid 73 can be treated with various
amines in the presence of 1-hydroxy-7-azabenzotriazole (HOAt),
O-(7-azabenzotriazol-1-yl)- ,1,3 ,3-tetramethyluronium
hexafluorophosphate (HATU) and DIEA to form amides. These amides
are then cleaved from the solid support by treating with
trifluoroacetic acid to give compounds of structure 71.
Scheme 5
[0435] Scheme 5 illustrates a synthetic route to amidines
containing di-substituted thiazoles represented by compounds for
which R.sup.2 is Formula II and both R and R.sup.9 are non-hydrogen
substituents . The ketoamide 74 can be converted to the
mono-bromoketoamide by treating with bromine in acetic acid.
Thiazoles 76 are formed by reacting the bromoketoamide with 10
under suitable conditions, preferably by heating the mixture in DMF
or acetone. Amidines 77 are formed by heating 76 in toluene with
trimethylaluminum and ammonium chloride. The amidines 77 are
treated with strong acid such as HCl to give the acids 78. The
amidines 78 are in one route protected with a suitable protecting
group such as BOC to give 79. The protected amidines 79 are treated
with various amines under suitable coupling conditions, such as in
the presence of HOAt, HATU, and DIEA to form various amides. The
amidine protecting group can be then removed, for example by
treating with trifluoroacetic acid in a suitable solvent such as
methylene chloride, when a BOC protecting group is employed to give
amidines 80. In a second route, the amidines 78 can be loaded onto
an insoluble support, such as polystyrene or
polyethyleneglycol-grafted polystyrene via a cleaveable linker,
such as Wang resin, which is functionalized as an activated
carbonate ester, such as p-nitrophenylcarbonate or succinimidyl
carbonate, to give a resin-bound scaffold 81. The resin-bound acid
81 can be treated with various amines under suitable coupling
conditions such as in the presence of HOAT, HATU and DEA to form
amides. These amides are then cleaved from the solid support by
treating with trifluoroacetic acid to give amidines 80.
Scheme 6a
[0436] Scheme 6a illustrates the preparation of compounds of
Examples 144, 145, 146, 147, 148, 149, 150 and 151. Compounds of
this invention correspond to those of Formula I where R.sup.2 is
Formula II and where Ar is thiazole and R.sup.37 and R.sup.38
(R.sup.8 and R.sup.9 of Formula II) are phenyl, which can be
additionally substituted. Starting from 2,5-dibromothiophene 90,
treatment with lithium diisopropylamide followed by R.sup.21L,
where L is a leaving group, preferably a halogen, mesylate,
tosylate, or methyl sulfate, and more preferably iodomethane or
methyl sulfate, according to the procedure of Kano, et al.,
Heterocycles 20(10):2035 (1983), gives 91. Compound 91 can be
treated with an appropriate base, preferably a lithium alkyl like
n-butyllithium, sec-butyllithium, or t-butyllithium, and more
preferably n-butyllithium, followed by carbon dioxide gas and
conversion of the resulting carboxylate salt to the free acid with
a mineral acid, preferably hydrochloric acid. Conversion to ester
21 can be carried out by preparation of the acid chloride using
oxalyl chloride and treatment of this intermediate acid chloride
with an alcohol R.sup.23 in an appropriate solvent, preferably
dichloromethane, with an appropriate base, preferably pyridine.
Compound 21 can be treated with copper (I) cyanide in refluxing
dimethylformamide to give compound 9. Compound 9 can be treated
with hydrogen sulfide gas in an appropriate solvent, preferably
methanol, containing an appropriate base, preferably triethylamine
to give compound 10. Compound 10 can be treated with an appropriate
ketone where L is a leaving group, preferably halogen, mesyl, or
tosyl, and most preferably bromo, refluxing in a suitable solvent,
preferably, acetone, dimethylformamide, dimethyl acetamide, methyl
ethyl ketone, or other polar aprotic solvents, and most preferably
acetone to give compound 92. Compound 92 is treated with an
appropriate reagent, preferably the aluminum amide reagent to give
amidine 93.
Scheme 6b
[0437] Scheme 6b illustrates the preparation of the compound of
Example 144, which corresponds to a compound for which R.sup.2 is
Formula II, and where Ar is thiazole and R.sup.8 and R.sup.9
(R.sup.37 and R.sup.38 in Scheme 6b) are phenyl, which can be
optionally substituted. Starting from 2,5-dibromothiophene 90,
treatment with n-butyllithium produces an anion which undergoes a
rearrangement (Kano, S., et al, Heterocycles 20:2035 (1983)).
Quenching with carbon dioxide gas and conversion of the resulting
carboxylate salt to the free acid with a mineral acid, preferably
hydrochloric acid, gives acid 94. Conversion to ester 95 can be
carried out by preparation of the acid chloride using oxalyl
chloride and treatment of this intermediate acid chloride with an
alcohol R.sup.23-OH in an appropriate solvent, preferably
dichloromethane, with an appropriate base, preferably pyridine.
Compound 95 can be treated with copper (I) cyanide in refluxing
dimethylformamide to give compound 96. Compound 96 can be treated
with hydrogen sulfide gas in an appropriate solvent, preferably
methanol, containing an appropriate base, preferably triethylamine
to give compound 97. Compound 97 can be treated with an appropriate
ketone where L is a leaving group, preferably halogen, mesyl, or
tosyl, and most preferably bromo, refluxing in a suitable solvent,
preferably, acetone, dimethylformamide, dimethyl acetamide, methyl
ethyl ketone, or other polar aprotic solvents, and most preferably
acetone to give compound 98. Compound 98 is treated with an
appropriate reagent, preferably the aluminum amide reagent
(Al(CH.sub.3).sub.3/NH.sub.4Cl) to give amidine 99.
Scheme 7a
[0438] Scheme 7a illustrates the preparation of compounds for which
R.sup.2 is Formula II and Ar is thiazol-4-yl. As illustrated, the
acids 13 can be converted to their acid chlorides by treatment with
oxalyl chloride with dimethylformamide catalysis in methylene
chloride, or by using thionyl chloride, either neat or in an
organic solvent, at ambient or elevated temperature. Compounds are
then homologated to the desired a-haloketones 100 by sequential
treatment with trimethylsilyldiazomethane and hydrogen bromide. An
alternative would be to substitute diazomethane (generated from
Diazald.RTM., Aldrich Chemical Co., Milwaukee, Wis.) for the
trimethylsilyldiazomethane. Also, the conversion of 13 to 100 can
be effected using the procedure derived for the synthesis of
compound 42 from compound 46.
[0439] The alpha-haloketones 100 are then allowed to react with the
appropriate thiourea (Scheme 7b) or thioamide derivative in an
organic solvent, preferably acetone or dimethylformamide at
70.degree. C. to give 2-aminothiazoles or thiazoles 101.
[0440] The thiazoles 101 can be treated with the aluminum amine
reagent (Al(CH.sub.3).sub.3/NH.sub.4Cl) formed at ambient
temperature by the reaction of trimethylaluminum with ammonium
chloride in an organic solvent, preferably toluene. The ester can
then be converted to the amidines 102 at elevated temperatures,
preferably higher than 80.degree. C.
Scheme 7b
[0441] As shown in Scheme 7b, amines 110 (or their hydrochloride
salts) can be converted to their respective mono-substituted
thioureas (methan-1-thiones) 112 by treatment with thiophosgene to
form the intermediate isothiocyanates 111. Preferred conditions
include treating the amine with thiophosgene in a biphasic solvent
system composed of a halogenated solvent such as chloroform and an
aqueous phase of saturated sodium bicarbonate. Alternatively, the
reaction may be effected by treatment of 110 with a hindered amine
and thiophosgene such as triethylamine or diisopropylethylamine in
an organic solvent such as tetrahydrofuran or methylene chloride.
Another alternative to forming isothiocyanates 111 is the direct
treatment of primary amines and carbon disulfide in pyridine with
dicyclohexylcarbodiimide (Jochims, Chem. Ber. 101:1746 (1968)).
[0442] Isothiocyanates 111 can be converted to thioureas 112 by
treatment with an ammonia-alcohol solution, preferably a 2M ammonia
in methanol or ethanol solution, at room temperature or elevated
temperatures (>70.degree. C.). Alternatively, the thioureas 112
can be prepared directly form the appropriate urea (or thioamide
from the appropriate amide when R.sup.8=alkyl or aryl)) by
treatment with Lawesson's reagent (Lawesson, S. -O., et. al. Bull.
Soc. Chim. Belg. 87:223, 293 (1978)).
Scheme 8
[0443] Scheme 8 illustrates the preparation of compounds of this
invention where R.sup.2 is Formula II and Ar is thiazole and
R.sup.37 and R.sup.38 are phenyl which is further substituted by a
sulfonylamino or carbonylamino group. Starting from thioamide 10,
treatment with a nitro substituted 2-halo-acetophenone, where the
halogen is chloro, bromo, or iodo, preferably bromo, refluxing in a
suitable solvent, preferably acetone, dimethylformamide, dimethyl
acetamide, methyl ethyl ketone, or other polar aprotic solvents,
and most preferably acetone. The reduction of nitroaryl compound
113 can be carried out with a suitable reducing agent, preferably
tin (II) chloride, titanium (II) chloride, iron (III) chloride,
lithium metal, sodium metal, catalytic hydrogenation over platinum
or palladium catalyst, and most preferably 20% aqueous solution of
titanium (III) chloride. The acylation of aniline 114 can be
carried out with an appropriate acyl compound R.sup.42L where L is
a halogen, preferably chloro, in an appropriate solvent, preferably
dichloromethane, containing a base, preferably pyridine,
N-methylmorpholine, or diisopropylethylamine. Alternatively, the
acylation of aniline 114 is carried out with an activated
carboxylic acid compound R.sup.42COL where L is hydroxy activated
with dicyclohexylcarbodiimide,
ethyl-3-(diethylamino)propylcarbodiimide (EDAC),
O-(7-azabenzotriazol-1-y- l)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), or pentafluorophenyl. The sulfonylation
of aniline 114 can be carried out with and appropriate sulfonyl
chloride compound R.sup.41SO.sub.2L in an appropriate solvent,
preferably dichloromethane, containing a base, preferably N-methyl
morpholine, diisopropylethylamine, or pyridine, most preferably
N-methyl morpholine, with or without a condensation catalyst,
preferable dimethylaminopyridine (DMAP). The amidinylation of
compounds 115 and 117 can be carried out with an appropriate
reagent, preferably the aluminum amide reagent
(Al(CH.sub.3).sub.3/NH.sub.4Cl).
Scheme 9
[0444] Scheme 9 illustrates the preparation of compounds of Formula
I, for which one of R and R.sup.6 is a non-hydrogen substituent.
The amidines 5 are converted to the amidoximes 119 by heating with
hydroxylamine in a suitable solvent such as ethanol. The
cyanoamidines 120 are prepared by heating the amidines 5 with
cyanamide in a suitable solvent such as ethanol. (Huffman, K. R.
and Schaeffer, F., J. Amer. Chem. Soc. 28:1812 (1963).
Alternatively 5 can be heated with an amine such as methylamine to
give the N-alkylated amidines 121.
Scheme 10
[0445] Scheme 10 illustrates an approach to compounds of Formula I
where X.dbd.S or O, R.sup.2=arylamino, R.sup.3=alkylthio,
aralkylthio, arylthio, alkyloxy, aralkyloxy, aryloxy, alkylamino,
dialkylamino, aralkylamino, diaralkylamino, arylamino or
diarylamino, Y=bond and Z.dbd.NR.sup.5R.sup.6.
[0446] Aminothiophenes 47 (Formula I where X.dbd.S, or O;
R.sup.2=NH.sub.2) can be reacted with an arylboronic acid
(R.sup.56B(OR.sup.58).sub.2, R.sup.8=H) or arylboronic ester
(R.sup.56B (OR.sup.58).sub.2, R.sup.58=alkyl) in the presence of a
copper catalyst, preferably copper (II) acetate, and an amine base
such as triethylamine or pyridine (Chan, D. M. T. et al.,
Tetrahedron Lett 39: 2933 (1998)) to give a thienylarylamine 124.
Conversion of the ester to amidine 125 is carried out in the manner
previously described in Scheme 1b.
Scheme 11
[0447] Another route to compounds of this invention, where
R.sup.2=arylamino or alkylarylamino and alkylamino and where
R.sup.3, Y and Z are as described in Scheme 10, is shown in Scheme
11 where intermediate 2 (R.sup.21=R.sup.3, L=leaving group) is
aminated using conditions well known in the art. (See for example:
Ahman, J. and Buchwald, S. L., Tetrahedron Lett. 38: 6363 (1997)
and Wolfe, J. P. and Buchwald, S. L., Tetrahedron Lett. 38: 6359
(1997). For reviews see: Frost, C. G and Mendonca, P., J. Chem.
Soc, Perkin Trans 1: 2615 (1998) and Wolfe, J. P. et al., Acc.
Chem. Res. 31: 805 (1998).) Thus, 2 may be treated with an aniline
R.sup.56R.sup.57NH (R.sup.56=aryl, R.sup.57=H or alkyl) in the
presence of a palladium catalyst, a suitable palladium ligand and a
base to give 127. Suitable catalysts include any of a number of
Pd(0) or Pd(II) salts, such as tetrakis(triphenylphosphino)
palladium (0), dichlorobis(acetonitrile)palladium (II) or
preferably palladium (II) acetate or
tris(dibenzylideneacetone)dipalladium. The most appropriate ligands
for any given reaction are often compound-dependent and are
discussed in detail in the aforementioned references but may
include 1,1-bis(diphenylphosphino)ferrocene (DPPF),
1-[2-(diphenylphosphino)ferro- cenyl]ethyl methyl ether (PPF-OMe),
or preferably 2,2-bis(diphenylphosphin- o)-1,1-binaphthyl (BINAP).
Appropriate bases include sodium t-butoxide or preferably cesium
carbonate or potassium phoshate. Useful solvents include DMF,
dioxane, dimethoxyethane or preferably toluene. Conversion of the
ester to amidine 128 is carried out in the manner previously
described in Scheme 1b.
Scheme 12
[0448] The corresponding compounds of Formula I where
R.sup.2=alkylamino and R.sup.3, Y and Z are as described in Scheme
10 are produced as shown in Scheme 12 by initial reductive
alkylation of amine 47 with an aldehyde R.sup.59CHO or ketone
R.sup.59COR.sup.60 in the presence of any of a number of suitable
reducing agents including sodium borohydride, sodium
cyanoborohydride or, more preferably, sodium or tetraalkylammonium
salts of triacetoxyborohydride to give 129. Depending on the
reducing agent employed, suitable solvents may include an alcohol,
such as methanol, ethanol or isopropanol, or solvents such as THF
or dichloromethane. Conversion of the ester to the amidine 130 is
again carried out in the manner previously described in Scheme
1b.
Scheme 13
[0449] Scheme 13 illustrates an approach to compounds of Formula I
where R.sup.2 is a 2-thiazolylamino and R.sup.3, Y and Z are as
described in Scheme 10. In this method, amine 47 can be first
converted to a thiourea 131 using the various procedures outlined
in Scheme 7b. Further reaction of the thiourea with a leaving
group-substituted ketone R.sup.37COCH(L)R.sup.38, preferably a
2-haloketone as described in Schemes 2f, 2 g or 2h, can provide
thiazolylaminothiophenes 132 which are then converted to the
corresponding amidines 133 by the previously described methodology
of Scheme 1b. 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
27 28 29 30 31 32 33 34 35 36
EXAMPLE 1
[0450] 4-[4-(4-chlorophenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-c- arboxamidine
[0451] Trimethylaluminum (2.0 M in toluene, 2 mL) was added
dropwise over 10 min to a suspension of ammonium chloride (216 mg)
in toluene (2 mL), stirred under N.sub.2 at 0.degree. C. When gas
evolution moderated, the mixture was stirred at 25.degree. C. for
30 min, when most of the solid had dissolved, methyl
4-[4-(4-chlorophenyl) (1,3-thiazol-2-yl)]-5-methylt-
hiothiophene-2-carboxylate (100 mg, Maybridge Chemical Co.,
Cornwall, U.K.) was added in one portion. This solution was heated
to reflux in stages over 1 h. After 2.5 h of reflux, the reaction
mixture was allowed to cool to 25.degree. C., and was poured on to
a vigorously stirred slurry of silica gel (2 g) in CHCl.sub.3 (20
mL). After 20 min the solids were collected by suction filtration,
and washed with MeOH (3.times.10 mL). The combined filtrates were
evaporated to dryness, and the residual yellow solid was subjected
to preparative thin-layer chromatography to obtain 77 mg of
4-[(4-chlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2--
carboxamidine as a yellow solid. .sup.1H-NMR (DMSO-d.sub.6; 300
MHz) .delta. 2.80 (s, 3H), 7.55-7.59 (m, 1H), 8.04-8.13 (m, 1H),
8.31 (s, 1H), 8.69 (s, 1 H),), 9.2 (broad s, 4H). Mass spectrum
(MALDI-TOF, m/z): Calcd. for C.sub.15H.sub.12ClN.sub.3S.sub.3,
365.9 (M+H), found 366.9.
EXAMPLE 2
[0452] 5-Methylthiothiophene-2-carboxamidine
[0453] 5-(Methylthio)thiophene-2-carbonitrile (100 mg, Maybridge
Chemical Company, Cornwall, UK) was taken in a dry 2 dram vial. To
this a solution of saturated HCl in anhydrous MeOH (4 mL) was
added. The vial was tightly capped and the mixture was stirred for
24 h. The vial was cooled in an ice bath, uncapped and N.sub.2 was
bubbled through the solution to remove dissolved HCl. The solvent
was removed under reduced pressure and the resulting residue was
dried under high vacuum for 24 h. A solution of methanolic ammonia
(2M NH.sub.3 in MeOH) was added to the vial, and the mixture was
stirred for 3 days. Methanol was removed under vacuum and the
resulting residue was subjected to preparative thin-layer
chromatography to obtain 5-(methylthio)thiophene-2-carboxamidine as
a yellow solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 2.64
(s, 3H), 7.22 (d, J=3.8 Hz, 1H), 7.95 (broad d, J=3.33 Hz, 1H), 9.4
(broad s, 4H). Mass spectrum (MALDI-TOF, m/z): Calcd. for
C.sub.6H.sub.8N.sub.2S.sub.2, 172.3 (M+H), found 173.0.
EXAMPLE 3
[0454] 5-Methylthio-4-phenylthiophene-2-carboxamidine
[0455] Methyl 5-methylthio-4-phenylthiophene-2-carboxylate (100 mg,
Maybridge Chemical Company, Cornwall, UK) was treated in a manner
similar to that for Example 1, to give 50 mg of
4-phenyl-5-methylthiothiophene-2-- carboxamidine as an off-white
solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 2.65 (s, 3H),
7.39-7.60 (m, 5H), 8.27 (s, 1H), 9.2 (broad s, 4H). Mass spectrum
(MALDI-TOF, m/z): Calcd. for C.sub.12H.sub.12N.sub.2S.sub.2- ,
248.4 (M+H), found 249.0.
EXAMPLE 4
[0456] 4-[4-(2,4-Dichlorophenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene- -2-carboxamidine
[0457] Methyl 4-[4-(2,4-dichlorophenyl)
(1,3-thiazol-2-yl)]-5-methylthioth- iophene-2-carboxylate (100 mg,
Maybridge Chemical Company, Cornwall, UK) was treated in a manner
similar to that for Example 1, to give 60 mg of
4-[4-(2,4-dichlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamid-
ine as a yellow solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta.
2.77 (s, 3H), 7.6 (dd, J=2.2 and 8.5 Hz, 1H), 7.79 (d, J=2.2 Hz,
1H), 8.09 (d, J=8.5 Hz, 1H), 8.3 (s, 1H), 8.6 (s, 1H). Mass
spectrum (MALDI-TOF, m/z): Calcd. for
C.sub.15H.sub.11N.sub.3S.sub.3Cl.sub.2, 400.0 (M+H), found
400.1.
EXAMPLE 5
[0458]
4(4-Methyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine
[0459] Methyl
4-(4-methyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carbo-
xylate (100 mg, Maybridge Chemical Company, Cornwall, UK) was
treated in a manner similar to that for Example 1, to give 40 mg of
4-(4-methylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine as a
yellow solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 2.43 (s,
3H), 2.7 (s, 3H), 7.38 (s, 1H), 8.28 (s, 1H). Mass spectrum
(MALDI-TOF, m/z): Calcd. for C.sub.10H.sub.11N.sub.3S.sub.3, 270.0
(M+H), found 270.1.
EXAMPLE 6
[0460] a) Methyl 5-methylthio-4-(4-(2-naphthyl)
(1,3-thiazol-2-yl))thiophe- ne-2-carboxylate: Methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-car- boxylate
[0461] (40 mg, Maybridge Chemical Company, Cornwall, UK) was
reacted with 2-bromo-2-acetonaphthone (1.1 eq) in a manner similar
to Example 13 step (a) to give 40 mg of methyl
5-methylthio-4-(4-(2-naphthyl)
(1,3-thiazol-2-yl))thiophene-2-carboxylate. .sup.1H-NMR
(CDCl.sub.3/CD.sub.3OD; 300 MHz) .delta. 3.71 (s, 3H), 3.94 (s,
3H), 7.47-7.55 (m, 2H), 7.67 (s, 1H), 7.84-7.99 (m, 3H), 8.08 (dd,
J=1.75 Hz and 8.6 Hz, 1H), 8.3 (s, 1H), 8.5 (s, 1H).
[0462] b) 5-Methylthio-4-(4-(2-naphthyl)
(1,3-thiazol-2-yl))thiophene-2-ca- rboxamidine:
[0463] Methyl 5-methylthio-4-(4-(2-naphthyl)
(1,3-thiazol-2-yl))thiophene-- 2-carboxylate, (40 mg) as prepared
in the previous step was treated in a manner similar to that for
Example 1, to give 30 mg of
4-[4-(naphth-2-yl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine.
.sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 2.83 (s, 3H), 7.52-7.69
(m, 2H), 7.95-8.01 (m, 2H), 8.05 (d, J=8.6 Hz, 1H), 8.24 (dd,
J=1.69 Hz and 8.6 Hz, 1H), 8.4 (s, 1H), 8.65 (s, 1H), 8.74 (s, 1H).
Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.19H.sub.15N.sub.3S.sub.3, 382.1 (M+H), found 382.0.
EXAMPLE 7
[0464] 5-Methylthio-4-[4-(4-phenylphenyl)
(1,3-thiazol-2-yl)]thiophene-2-c- arboxamidine hydrochloride
[0465] a) Methyl 5-methylthio-4-[4-(4-phenylphenyl)
(1,3-thiazol-2-yl)]thiophene-2-carboxylate: 27 mg (0.109 mmol) of
methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 2 mL
of reagent grade acetone. 4-Phenyl-2-bromoacetophenone (33 mg;
0.120 mmol; Aldrich Chemical Co., Milwaukee, Wis.) was added and
the solution was allowed to reflux for 2.5 h. The solution was
allowed to cool and solid was filtered and washed with methanol and
dried in vacuo to afford 30 mg (65% yield) of methyl
5-methylthio-4-[4-(4-phenylphenyl) (l ,3-thiazol-2-yl)]thiophen-
e-2-carboxylate. .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.28
(s, 1H), 8.24 (s, 1H), 8.17 (d, J=8.5 Hz, 2H), 7.8 (d, J=8.5Hz,
2H), 7.74-7.77 (m, 2H), 7.48-7.53 (m, 2H), 7.40 (m, 1H), 2.78 (s,
3H). Mass Spectrum (MALDI-TOF, CHCA matrix, m/z) Calcd. for
C.sub.22H.sub.16NO.sub.2S.sub.3: 423.0 (M+H), found 424.4.
[0466] b) 5-Methylthio-4-[4-(4-phenylphenyl)
(1,3-thiazol-2-yl)]thiophene-- 2-carboxamidine hydrochloride: To a
stirred suspension of 0.473 mmol (25 mg) of ammonium chloride
(Fisher Scientific Pittsburgh, Pa.) in 2 mL of anhydrous toluene
(Aldrich Chemical Co.) placed under nitrogen atmosphere at
0.degree. C., 237 .mu.L (0.473 mmol) of 2M trimethylaluminum in
toluene (Aldrich Chemical Co.) was added via syringe over 10 min
and then let stir at 0.degree. C. for 30 min after which 20 mg
(0.0473 mmol) of methyl 5-methylthio-4-[4-(4-phenylphenyl)
(1,3-thiazol-2-yl)]thiophene-2-- carboxylate was added to solution
and allowed to reflux for 2.5 h. The reaction mixture was quenched
by pouring over a slurry of 500 mg of silica in 10 mL of
chloroform. The silica was poured onto a sintered glass funnel and
washed with a 10% methanol/CH.sub.2Cl.sub.2 solution and
concentrated. The crude product was purified on a 1 mm silica prep
plate eluting with 10% methanol/CH.sub.2C.sub.2 to afford 10 mg
(53% yield) of 5-methylthio-4-[4-(4-phenylphenyl)
(1,3-thiazol-2-yl)]thiophene-2-carboxa- midine hydrochloride. Mass
Spectrum (MALDI-TOF, CHCA matrix, m/z) Calcd. for
C.sub.21H.sub.17N.sub.3S.sub.3: 408.1 (M+H), found 408.0.
EXAMPLES 8 & 9
[0467] 4-[4-(3-Methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-- carboxamidine
hydrochloride and 4-[4-(3-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine
hydrochloride
[0468] a) Methyl 4-[4-(3-methoxyphenyl)
(1,3-thiazol-2-yl)J-5-methylthioth- iophene-2-carboxylate: 32 mg
(0.133 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 2 mL
of reagent grade acetone. 3-Methoxy-2-bromo acetophenone (0.155
mmol; 36 mg; Aldrich Chemical Co.) was added and the solution was
allowed to reflux for 2.5 h The solution was allowed to cool and a
solid was filtered and washed with methanol and dried in vacuo. The
solid was purified on 1 mm silica plate eluting with 25% ethyl
acetate/hexane to afford 31 mg (63% yield) of methyl
4-[4-(3-methoxyphenyl) (1,3-thiazol-2-yl)]-5-methylthiothiophene-2-
-carboxylate.
[0469] b) 4-{4-(3-Methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene- -2-carboxamidine
hydrochloride and 4-[4-(3-4-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine
hydrochloride: To a stirred suspension of 0.821 mmol (44 mg) of
ammonium chloride (Fisher Scientific) in 2 mL of anhydrous toluene
(Aldrich Chemical Co.) placed under nitrogen atmosphere at
0.degree. C., was added 411 .mu.L (0.821 mmol) of 2M
trimethylaluminum in toluene (Aldrich Chemical Co.) via syringe
over 10 min and then let stir at 0.degree. C. for 30 min after
which 31 mg (0.0821 mmol) of methyl 4-[4-(3-methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate was added
to solution and allowed to reflux for 2.5 h. The reaction mixture
was quenched by pouring over a slurry of 500 mg of silica in 10 mL
of chloroform. The silica was poured onto a sintered glass funnel
and washed with a 10% methanol/CH.sub.2Cl.sub.2 solution and
concentrated. The crude product was purified on a 1 mm silica prep
plate eluting with 10% methanol/CH.sub.2C.sub.2-to afford 4.4 mg
(15% yield) of 4-[4-(3-methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carbox- amidine
hydrochloride and 4.2 mg (15% yield) of 4-[4-(3-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine
hydrochloride. 4-[4-(3-methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carbox- amidine
hydrochloride: .sup.1H-NMR (CD.sub.3300 MHz) .delta. 8.5 (s, 1H),
7.9 (s, 1H), 7. 59-7.65 (m, 2H), 7.33-7.38 (m, 1H), 6.91-6.95 (m,
1H), 3.87 (s, 1H), 2.8 (s, 3H) Mass Spectrum (MALDI-TOF, CHCA
matrix, m/z) Calcd. for C.sub.16H.sub.15N.sub.3OS.sub.3:
361.5(M+H), found 362.2. 4-[4-(3-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carbox- amidine
hydrochloride: .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.50 (s,
1H), 7.81 (s, 1H), 7.26-7.51 (m, 2H), 7.24 (m, 1H), 6.79 (m, 1H),
2.8 (s, 3H) Mass Spectrum (MALDI-TOF, CHCA matrix, m/z) Calcd. for
C.sub.15H.sub.13N.sub.3OS.sub.3: 347.5(M+H), found 348.0.
EXAMPLE 10
5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine
hydrochloride
[0470] a) Methyl
5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-ca-
rboxylate: 33 mg (0.133 mmol) methyl
4-(aminothioxomethyl)-5-methylthiothi- ophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 2 mL
of reagent grade acetone. 2-Bromoacetophenone (0.133 mmol; 27 mg;
Aldrich Chemical Co.) was added and the solution was allowed to
reflux for 2.5 h. The solution was allowed to cool and the solid
was filtered and washed with methanol and dried in vacuo. The solid
was purified on 1 mm silica plate eluting with 25% ethyl
acetate/hexane mixture to afford 46 mg (90% yield) of methyl
5-methylthio-4-(4-phenyl(1,-
3-thiazol-2-yl))thiophene-2-carboxylate.
[0471] b)
5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxami-
dine hydrochloride: To a stirred suspension of 1.32 mmol (71 mg) of
ammonium chloride (Fisher Scientific) in 2 mL of anhydrous toluene
(Aldrich Chemical Co.) placed under nitrogen atmosphere at
0.degree. C., 662 .mu.L (1.32 mmol) of 2M trimethylaluminum in
toluene (Aldrich Chemical Co.) was added via syringe over 10 min
and then let stir at 0.degree. C. for 30 min after which 46 mg
(0.133 mmol) of methyl
5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate
was added to solution and allowed to reflux for 2.5 h. The reaction
mixture was quenched by pouring over a slurry of 500 mg of silica
in 10 mL of chloroform. The silica was poured onto a sintered glass
funnel and washed with a 10% methanol/CH.sub.2Cl.sub.2 solution and
concentrated. The crude product was purified on a 2 g silica silica
SPE column eluting with 10% methanol/CH.sub.2Cl.sub.2 to afford
32.5 mg (75% yield) of
5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine
hydrochloride. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 8.70 (s,
1H), 8.25 (s, 1H), 8.07-8.11 (m, 2H), 7.37-7.53 (m, 3H), 2.8 (s,
3H). Mass Spectrum (MALDI-TOF, CHCA matrix, m/z) Calcd. for
C.sub.15H.sub.13N.sub.3- S.sub.3: 331.5(M+H), found 332.1.
EXAMPLE 11
[0472] 5-Methylthio-4-[4-(4-nitrophenyl)
(1,3-thiazol-2-yl)]thiophene-2-ca- rboxamidine hydrochloride
[0473] a) Methyl 5-methylthio-4-[4-(4-nitrophenyl)
(1,3-thiazol-2-yl)]thio- phene-2-carboxylate: 38 mg (0.141 mmol) of
methyl 4-(aminothioxomethyl)-5-- methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 2 mL
of reagent grade acetone. 2-Bromo-4-nitroacetophenone (0.155 mmol;
38 mg; Aldrich Chemical Co.) was added and the solution was allowed
to reflux for 2.5 h. The solution was allowed to cool and a solid
was filtered and washed with methanol and dried in vacuo. The crude
product was dissolved in CH.sub.2Cl.sub.2 and 0.141 mmol of
N-(2-mercapto)aminoethyl polystyrene resin (Calbiochem, San Diego,
Calif.; 1.28mmol/g; 110 mg) was added and allowed to stir
overnight. The solution was filtered, concentrated and dried to
afford 60 mg (90% yield) of crude methyl
5-methylthio-4-[4-(4-nitrophenyl)
(1,3-thiazol-2-yl)]thiophene-2-carboxylate.
[0474] b) 5-Methylthio-4-[4-(4-nitrophenyl)
(1,3-thiazol-2-yl)]thiophene-2- -carboxamidine hydrochloride: To a
stirred suspension of 1.66 mmol (90 mg) of ammonium chloride
(Fisher Scientific) in 2 mL of anhydrous toluene (Aldrich Chemical
Co.) placed under nitrogen atmosphere at 0.degree. C., 830 .mu.L
(1.66 mmol) of 2M trimethylaluminum in toluene (Aldrich Chemical
Co.) was added via syringe over 10 min and then let stir at
0.degree. C. for 30 min after which 60 mg (0.166 mmol) of
5-methylthio-4-[4-(4-nitrophenyl)
(1,3-thiazol-2-yl)]thiophene-2-carboxyl- ate was added to solution
and allowed to reflux for 2.5 h. The reaction mixture was quenched
by pouring over a slurry of 500 mg of silica in 10 mL of
chloroform. The silica was poured onto a sintered-glass funnel and
washed with a 10% methanol/CH.sub.2C.sub.2 solution and
concentrated. The crude product was purified on a 1 mm silica prep
plate eluting with 10% methanol/CH.sub.2Cl.sub.2 to afford 12 mg
(19% yield) of 5-methylthio-4-[4-(4-nitrophenyl)
(1,3-thiazol-2-yl)]thiophene-2-carboxam- idine hydrochloride.
.sup.1H-NMR (CD.sub.3OD, 300 MHz) .delta. 8.58 (s, 1H), 8.32-8.33
(m, 4H), 8.24 (s, 1H), 2.83 (s, 3H). Mass Spectrum (MALDI-TOF, CHCA
matrix, m/z) Calcd. for C.sub.15Hl.sub.2N.sub.4O.sub.2S.- sub.3:
376.5(M+H), found 377.3.
EXAMPLE 12
[0475]
4-[4-(3,4-Ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-
-carboxamidine hydrochloride
[0476] a) Methyl 4-(4-(2H,3H-benzo[3,4-e]l,4-dioxin-6-yl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate: 40 mg
(0.162 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 2 mL
of reagent grade acetone.
1-(2H,3H-benzo[e]1,4-dioxin-6-yl)-2-bromoethan-1-o- ne (0.162 mmol;
42 mg; Maybridge Chemical Co. LTD., Cornwall, U.K.) was added and
the solution was allowed to reflux for 3 h. The solution was
allowed to cool and allowed to stir for 2 days after which the
reaction solution was concentrated in vacuo. The crude product was
dissolved in 50 mL of CH.sub.2Cl.sub.2 and partitioned between 50
mL of 1 N NaOH (aq.). The organic layer was obtained and dried over
sodium sulfate and concentrated to afford 60 mg (90% yield) of
methyl
4-[4-(3,4-ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carbo-
xylate.
[0477] b)
4-[4(3,4-Ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-
-2-carboxamidine hydrochloride: To a stirred suspension of 1.62
mmol (86 mg) of ammonium chloride (Fisher Scientific) in 2 mL of
anhydrous toluene (Aldrich Chemical Co.) placed under nitrogen
atmosphere at 0.degree. C., 810 .mu.L (1.62 mmol) of 2M
trimethylaluminum in toluene (Aldrich Chemical Co.) was added via
syringe over 10 min and then let stir at 0.degree. C. for 30 min
after which 60 mg (0.162 mmol) of methyl
4-[4-(3,4-ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carbo-
xylate was added to solution and allowed to reflux for 2.5 h. The
reaction mixture was quenched by pouring over a slurry of 500 mg of
silica in 10 mL of chloroform. The silica was poured onto a
sintered glass funnel and washed with a 10%
methanol/CH.sub.2Cl.sub.2 solution and concentrated. The crude
product was purified on a 1 mm silica prep plate eluting with 10%
methanol/CH.sub.2Cl.sub.2 to afford 47 mg (75% yield) of
4-[4-(3,4-ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carbo-
xamidine hydrochloride. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta.
8.53 (s, 1H), 7.73 (s, 1H), 7.56 (d, J=2Hz, 1H), 7.50 (dd, J=2.1 Hz
and 8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.28 (s, 4H), 2.8 (s, 3H).
Mass Spectrum (MALDI-TOF, CHCA matrix, m/z) Calcd. for
C.sub.17H.sub.15N.sub.3O.sub.2S.- sub.3: 389.5(M+H), found
390.1.
EXAMPLE 13
[0478] 4-[4-(4-Methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-- carboxamidine
hydrochloride
[0479] a) Methyl 4-[4-(4-methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthioth- iophene-2-carboxylate: 30 mg
(0.122 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 1.2
mL of reagent grade acetone. 2-bromo-4-methoxy acetophenone (0.146
mmol; 28 mg; Aldrich Chemical Co.) was added and the solution was
allowed to reflux for 3 h. The solution was allowed to cool and a
solid was filtered and washed with methanol and dried in vacuo to
afford 46 mg (90% yield) of methyl 4-[4-(4-methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carbox- ylate.
[0480] b) 4-[4-(4-Methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene- -2-carboxamidine
hydrochloride: To a stirred suspension of 1.22 mmol (66 mg) of
ammonium chloride (Fisher Scientific) in 2 mL of anhydrous toluene
(Aldrich Chemical Co.) placed under nitrogen atmosphere at
0.degree. C., 612 .mu.L (1.22 mmol) of 2M trimethylaluminum in
toluene (Aldrich Chemical Co.) was added via syringe over 10 min
and then let stir at 0.degree. C. for 30 min after which 46 mg
(0.122 mmol) of 4-[4-(4-methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carbox- ylate was added
to solution and allowed to reflux for 2.5 h. The reaction mixture
was quenched by pouring over a slurry of 500 mg of silica in 10 mL
of chloroform. The silica was poured onto a sintered glass funnel
and washed with a 10% methanol/CH.sub.2Cl.sub.2 solution and
concentrated. The crude product was purified on a 1 mm silica prep
plate eluting with 10% methanol/CH.sub.2Cl.sub.2 to afford 32 mg
(73% yield) of 4-[4-(4-methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carbox- amidine
hydrochloride. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.53 (s,
1H), 7.98 (d, J=7 Hz, 2H), 7.75 (s, 1H), 7.01 (d, J=5 Hz, 2H), 3.9
(s, 3H), 2.8 (s, 3H). Mass Spectrum (MALDI-TOF, CHCA matrix, m/z)
Calcd. for C.sub.16H.sub.15N.sub.3OS.sub.3: 362.0 (M+H), found
362.2.
EXAMPLE 14
[0481]
4-[4-(3,4-Propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene--
2-carboxamidine hydrochloride
[0482] a) Methyl
4-[4(3,4-propylenedioxyphenyl)thiazol-2-yl]-5-methylthiot-
hiophene-2-carboxylate: 42 mg (0.170 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL
of reagent grade acetone. 3,4-Propylenedioxy-2-bromoacetophenone
(0.170 mmol; 28 mg; Maybridge Chemical Co. LTD., Cornwall, U.K.)
was added and the solution was allowed to reflux for 3 h. The
solution was allowed to cool and a solid was filtered and purified
on a 1 mm silica prep plate eluting with 20% ethyl acetate/hexane
and dried in vacuo to afford 42 mg (59% yield) of methyl
4-[4-(3,4-propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothioph-
ene-2-carboxylate.
[0483] b)
4-[4(3,4-Propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophen-
e-2-carboxamidine hydrochloride: To a stirred suspension of 1.01
mmol (54 mg) of ammonium chloride (Fisher Scientific) in 2 mL of
anhydrous toluene (Aldrich Chemical Co.) placed under nitrogen
atmosphere at 0.degree. C., 510 .mu.L (1.01 mmol) of 2M
trimethylaluminum in toluene (Aldrich Chemical Co.) was added via
syringe over 10 min and then let stir at 0.degree. C. for 30 min
after which 42 mg (0.101 mmol) of methyl
4-[4-(3,4-propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carb-
oxylate was added to solution and allowed to reflux for 3 h. The
reaction mixture was quenched by pouring over a slurry of 500 mg of
silica in 20 mL of chloroform. The silica was poured onto a
sintered glass funnel and washed with a 10%
methanol/CH.sub.2Cl.sub.2 solution and concentrated to afford 20 mg
(50% yield) of 4-[4-(3,4-propylenedioxyphenyl)thiazol-2-yl]--
5-methylthiothiophene-2-carboxamidine hydrochloride. .sup.1H-NMR
(CD.sub.3OD; 300 MHz) .delta. 8.53 (s, 1H), 7.78 (s, 1H), 7.68
(d,J=2.2 Hz, 1H), 7.60 (dd, J=2.2 Hz and 8.4 Hz, 1H), 7.00 (d,
J=8.3 Hz; 1H), 4.19-4.28 (m, 4H), 2.77 (s, 3H), 2.18-2.23 (m, 2H).
Mass Spectrum (MALDI-TOF, CHCA matrix, m/z) Calcd. for
C.sub.18H.sub.17N.sub.3O.sub.2S.- sub.3: 404.1 (M+H), found
404.1.
EXAMPLE 15
[0484] 5-Methylthio-4(4-(2-thienyl)
(1,3-thiazol-2-yl))thiophene-2-carboxa- midine acetate
[0485] a) 2-Bromo-1-(2-thienyl)ethan-1-one: To a solution of 500 mg
(3.96 mmol) of 2-acetyl thiophene (Aldrich Chemical Co.) dissolved
in 20 mL of CHCl.sub.3, was added 1 drop of 30% HBr/CH.sub.3COOH
(Aldrich Chemical Co.) followed by 3.96 mmol (633 mg; 204 .mu.L) of
bromine (Aldrich Chemical Co.) added dropwise over 30 min. The
reaction was allowed to stir for 1 h. The solution was concentrated
to an oil and dried in vacuo. The crude product was purified on 1
mm silica prep plates eluting with neat CH.sub.2Cl.sub.2 to obtain
300 mg (37% yield) of 2-bromo-1-(2-thienyl)ethan-1-one. .sup.1H-NMR
(CDCl.sub.3; 300 MHz) .delta. 7.80 (m, 2H), 7.18 (m, 1H), 4.37 (s,
2H).
[0486] b) Methyl 5-methylthio-4-(4-(2-thienyl)
(1,3-thiazol-2-yl))thiophen- e-2-carboxylate: 44 mg (0.176 mmol) of
methyl 4-(aminothioxomethyl)-5-meth- ylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 3 mL
of reagent grade acetone. 2-Bromo-1-(2-thienyl)ethan-1-one (0.176
mmol; 36 mg) was added and the solution was allowed to reflux for 3
h. The solution was allowed to cool and was concentrated. The crude
product was dissolved in 20 mL of CH.sub.2Cl.sub.2 and washed with
20 mL of 1N HCl (aq.). The organic layer was obtained and dried
over sodium sulfate to afford 115 mg (80% yield) of crude methyl
5-methylthio-4-(4-(2-thienyl) (l,3-thiazol-2-yl))thiophen-
e-2-carboxylate.
[0487] c) 5-Methylthio-4-(4-(2-thienyl)
(1,3-thiazol-2-yl))thiophene-2-car- boxamidine acetate: To a
stirred suspension of 2.80 mmol (150 mg) of ammonium chloride
(Fisher Scientific) in 5 mL of anhydrous toluene (Aldrich Chemical
Co.) placed under nitrogen atmosphere at 0.degree. C., 1.5 mL (2.8
mmol) was added 2M trimethylaluminum in toluene (Aldrich Chemical
Co.) via syringe over 15 min and then let stir at 0.degree. C. for
25 min. after which 115 mg (0.280 mmol) of methyl
5-methylthio-4-(4-(2-thienyl)
(1,3-thiazol-2-yl))thiophene-2-carboxylate in 5 mL of anhydrous
toluene was added to solution and allowed to reflux for 1.5 h. The
reaction mixture was quenched by pouring over a slurry of silica in
CH.sub.2Cl.sub.2. The silica was poured onto a sintered glass
funnel and washed with a 10% methanol/CH.sub.2Cl.sub.2 solution and
concentrated. The crude product was purified on a 1 mm silica prep
plate eluting with 10% methanol/CH.sub.2Cl.sub.2 with 1%
CH.sub.3COOH to afford 40 mg (43% yield) of
5-methylthio-4-(4-(2-thienyl)
(1,3-thiazol-2-yl))thiophene-2-carboxamidine acetate. .sup.1H-NMR
(CD.sub.3OD; 300 MHz) .delta. 8.52 (s, 1H), 7.74 (s, 1H), 7.59 (dd,
J=2 Hz and 5 Hz, 1H), 7.42 (dd, J=2 Hz and 5 Hz, 1H), 7.11 (m, 1H),
2.79 (s, 3H). Mass Spectrum (MALDI-TOF, CHCA matrix, m/z) Calcd.
for C.sub.13H.sub.11N.sub.3S.sub.4: 338.0 (M+H), found 337.9.
EXAMPLE 16
[0488] 4-[4-(3-Bromophenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-ca- rboxamidine
hydrochloride
[0489] a) Methyl 4-[4-(3-bromophenyl)
(1,3-thiazol-2-yl)]-5-methylthiothio- phene-2-carboxylate: 99 mg
(0.400 mmol) of methyl 4-(aminothioxomethyl)-5--
methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD.,
Cornwall, U.K.) was dissolved in 25 mL of reagent grade acetone.
2-Bromo-3-bromo acetophenone (0.4 mmol; 111 mg) was added and the
solution was allowed to reflux for 3 h. The solution was allowed to
cool and a solid was filtered and dissolved in 5 mL of hot
tetrahydrofuran (THF), (Aldrich Chemical Co.) and purified on a 1
mm silica prep plate eluting with 20% ethyl acetate/hexane and
dried in vacuo to afford 66 mg (40% yield) of methyl
4-[4-(3-bromophenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxyl- ate.
[0490] b) 4-[4-(3-Bromophenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2- -carboxamidine
hydrochloride: To a stirred suspension of 1.55 mmol (83 mg) of
ammonium chloride (Fisher Scientific) in 10 mL of anhydrous toluene
(Aldrich Chemical Co.) placed under nitrogen atmosphere at
0.degree. C., 774 .mu.L (1.55 mmol) of 2M trimethylaluminum in
toluene (Aldrich Chemical Co.) was added via syringe over 10 min
and then let stir at 25.degree. C. for 20 min after which 66 mg
(0.155 mmol) of 4-[4-(3-bromophenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxyl- ate was added
to solution and allowed to reflux for 3 h. The reaction mixture was
quenched by pouring over a slurry of 5 g of silica in 25 mL of
chloroform. The silica was poured onto a sintered glass funnel and
washed with a 10% methanol/CH.sub.2Cl.sub.2 solution and
concentrated. The crude product was purified on 1 mm silica plates
eluting with 10% methanol/CH.sub.2Cl.sub.2 to afford 63 mg (90%
yield) of 4-[4-(3-bromophenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxam- idine
hydrochloride. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.49 (s,
1H), 8.21 (m, 1H), 7.96 (m, 2H), 7.50 (m, 1H), 7.5 (m, 1H), 7.34
(m, 1H), 2.8 (s, 3H). Mass Spectrum (MALDI-TOF, CHCA matrix, m/z)
Calcd. for C.sub.15H.sub.12BrN.sub.3S.sub.3: 411.9 (M+H), found
411.9.
EXAMPLE 17
[0491] 4-[4-(4-Chloro-3-nitrophenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiop- hene-2-carboxamidine
hydrochloride
[0492] a) Methyl 4-[4-(4-chloro-3-nitrophenyl)
(1,3-thiazol-2-yl)]-5-methy- lthiothiophene-2-carboxylate: 50 mg
(0.202 mmol ) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 10
mL of reagent grade acetone. 2-Bromo-4-chloro-3-nitroacetophenone
(0.212 mmol; 59 mg) was added and the solution was allowed to
reflux for 3 h. The solution was allowed to cool and a solid was
filtered and dissolved in hot tetrahydrofuran (THF) and purified on
a 1 mm silica prep plate eluting with 20% ethyl acetate/hexane and
dried in vacuo to afford 60 mg (70% yield) of methyl
4-[4-(4-chloro-3-nitrophenyl) (1,3-thiazol-2-yl)]-5-meth-
ylthiothiophene-2-carboxylate.
[0493] b) 4-[4-(4-Chloro-3-nitrophenyl)
(1,3-thiazol-2-yl)]-5-methylthioth- iophene-2-carboxamidine
hydrochloride: To a stirred suspension of 1.40 mmol (75 mg) of
ammonium chloride (Fisher Scientific) in 10 mL of anhydrous toluene
(Aldrich Chemical Co.) placed under nitrogen atmosphere at
0.degree. C., 700 .mu.L (1.40 mmol) of 2M trimethylaluminum in
toluene (Aldrich Chemical Co.) was added via syringe over 10 min
and then let stir for 20 min after which 60 mg (0.140 mmol) of
4-[4-(4-chloro-3-nitrop- henyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate was added
to solution and allowed to reflux for 3 h. The reaction mixture was
quenched by pouring over a slurry of 5 g of silica in 50 mL of
chloroform. The silica was poured onto a sintered glass funnel and
washed with a 10% methanol/CH.sub.2Cl.sub.2 solution and
concentrated. The crude product was purified on 1 mm silica plates
eluting with 10% methanol/CH.sub.2Cl.sub.2 to afford 17 mg (32%
yield) of 4-[4-(4-chloro-3-nitrophenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2- -carboxamidine
hydrochloride. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.53-8.58
(m, 2H), 8.26 (dd, J=2.2 Hz and 8.5 Hz, 1H), 8.16 (s, 1H), 7.72 (d,
J=8.5 Hz, 1H), 2.80 (s, 3H).
EXAMPLE 18
[0494] 4-[4-(4-Chloro-3-methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothio- phene-2-carboxamidine
hydrochloride
[0495] a) Methyl 4-[4-(4-chloro-3-methylphenyl)
(1,3-thiazol-2-yl)]-5-meth- ylthiothiophene-2-carboxylate: 155 mg
(0.627 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 10
mL of reagent grade acetone.
2-Bromo-1-(4-chloro-3-methylphenyl)ethan-1-one (0.658 mmol; 163 mg)
was added and the solution was allowed to reflux for 3 h. The
solution was allowed to cool and the reaction mixture was
concentrated and dissolved in 50 mL of CH.sub.2Cl.sub.2. The
organic layer was washed with 50 mL of 1N HCl (aq.), dried over
sodium sulfate and concentrated. The crude product was purified on
a 1 mm silica plate eluting with 20% ethyl acetate/ hexane to
afford 168 mg (68% yield) of methyl 4-[4-(4-chloro-3-methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothi- ophene-2-carboxylate.
[0496] b) 4-[4-(4-Chloro-3-methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiot- hiophene-2-carboxamidine
hydrochloride: To a stirred suspension of 4.24 mmol (227 mg) of
ammonium chloride (Fisher Scientific) in 15 mL of anhydrous toluene
(Aldrich Chemical Co.) placed under nitrogen atmosphere at
0.degree. C., 2.2 mL (4.24 mmol) of 2M trimethylaluminum in toluene
(Aldrich Chemical Co.) was added via syringe over 10 min and then
let stir for 20 min at 25.degree. C. after which 168 mg (0.424
mmol) of methyl 4-[4-(4-chloro-3-methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothi- ophene-2-carboxylate was added
to solution and allowed to reflux for 2.5 h. The reaction mixture
was quenched by pouring over a slurry of 5 g silica in chloroform.
The silica was poured onto a sintered glass funnel and washed with
a 10% methanol/CH.sub.2Cl.sub.2 solution and concentrated to afford
117 mg (73% yield) of 4-[4-(4-chloro-3-methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine
hydrochloride. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.53 (s,
1H), 8.03 (dd, J=1.2 Hz and 2.7 Hz, 1H), 7.9 (s, 1H), 7.85 (dd, J=2
Hz and 8.5 Hz 1H), 7.38 (dd, J=8.3 Hz and 17.4 Hz, 1H), 2.8 (s, 3H)
2.45 (s, 3H). Mass Spectrum (MALDI-TOF, CHCA matrix, m/z) Calcd.
for C.sub.16H.sub.14ClN.sub.3S.sub.3- : 380.0 (M+H), found
380.3.
EXAMPLE 19
[0497]
4-(5-Methyl-4-phenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-car-
boxamidine hydrochloride
[0498] a) Methyl
4-(5-methyl-4-phenyl(1,3-thiazol-2-yl))-5-methylthiothiop-
hene-2-carboxylate: 48 mg (0.194 mmol) of methyl
4-(aminothioxomethyl)-5-m- ethylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL
of reagent grade acetone. 2-Bromo-1-phenylpropan-1-one (0.223 mmol;
48 mg) was added and the solution was allowed to reflux for 5 h.
The solution was allowed to cool and the reaction mixture was
concentrated and dissolved in 50 mL of CH.sub.2Cl.sub.2. The
organic layer was washed with 50 mL of 1NHCl (aq.), dried over
sodium sulfate and concentrated. The crude product was purified on
a 1 mm silica plate eluting with 20% ethyl acetate/ hexane to
afford 53 mg (76% yield) of methyl
4-(5-methyl-4-phenyl(1,3-thiazol-2-yl)-
)-5-methylthiothiophene-2-carboxylate.
[0499] b)
4(5-Methyl-4-phenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-c-
arboxamidine hydrochloride: To a stirred suspension of 1.47 mmol
(78 mg) of ammonium chloride (Fisher Scientific) in 5 mL of
anhydrous toluene (Aldrich Chemical Co.) placed under nitrogen
atmosphere at 0.degree. C., 735 .mu.L (1.47 mmol) of 2M
trimethylaluminum in toluene (Aldrich Chemical Co.) was added via
syringe over 10 min and then let stir for 20 min at 25.degree. C.
then, 53 mg (0.147 mmol) of methyl
4-(5-methyl-4-phenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxyla-
te were added to solution and allowed to reflux for 2.5 h. The
reaction mixture was quenched by pouring over a slurry of 5 g
silica in chloroform. The silica was poured onto a sintered glass
funnel and washed with a 10% methanol/CH.sub.2Cl.sub.2 solution and
concentrated to afford 26 mg (51% yield) of
4-(5-methyl-4-phenyl(1,3-thiazol-2-yl))-5-methylthio-
thiophene-2-carboxamidine hydrochloride. .sup.1H-NMR (CD.sub.3OD;
300 MHz) 6 8.45 (s, 1H), 7.74-7.77 (mn, 2H), 7.44-7.50 (m, 2H),
7.38-7.41 (mn, 1H), 2.8 (s, 3H) 2.6 (s, 3H). Mass Spectrum
(MALDI-TOF, CHCA matrix, m/z) Calcd. for
C.sub.16H.sub.15N.sub.3S.sub.3: 346.0 (M+H), found 345.6.
EXAMPLE 20
[0500] 4-[4-(4-Methylphenyl)
(1,3-thiazol-2-yl)l-5-methylthiothiophene-2-c- arboxamidine
trifluoroacetate
[0501] a) Methyl 4-{4-(4-methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothi- ophene-2-carboxylate: 103 mg
(0.416 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL
of reagent grade acetone. 2-Bromo-4-methyl acetophenone (0.416
mmol; 89 mg) was added and the solution was allowed to reflux for 3
h. The solution was allowed to cool and crude product was filtered
and washed two times with acetone and purified on a 1 mm silica
plate eluting with 20% ethyl acetate/ hexane to afford 104 mg (69%
yield) of methyl 4-[4-(4-methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
[0502] b) 4-[4-(4-Methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-- 2-carboxamidine
trifluoroacetate: To a stirred suspension of 2.87 mmol (154 mg) of
ammonium chloride (Fisher Scientific) in 10 mL of anhydrous toluene
(Aldrich Chemical Co.) placed under nitrogen atmosphere at
0.degree. C., 144 .mu.L (2.87 mmol) of 2M trimethylaluminum in
toluene (Aldrich Chemical Co.) was added via syringe over 10 min
and then let stirred for 20 min at 25.degree. C. after which 104 mg
(0.287 mmol) of 4-[4-(4-methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxy- late was added
to solution and allowed to reflux for 3 h. The reaction mixture was
quenched by pouring over a slurry of 5 g of silica in 50 mL of
chloroform. The silica was poured onto a sintered glass funnel and
washed with a 10% methanol/CH.sub.2C.sub.2 solution and
concentrated. The crude product was then purified on a 1 mm silica
prep plate eluting with 10% methanol/CH.sub.2Cl.sub.2 with 1%
CH.sub.3COOH. The product was then basified with aq. NaOH and
extracted with CHCl.sub.3 and concentrated. TFA was added and the
product was crystallized from methanol as 4-[4-(4-methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxa- midine
trifluoroacetate (20 mg; 30% yield). .sup.1H-NMR (DMSO-d.sub.6; 300
MHz) .delta. 8.62 (s, 1H), 8.12 (s, 1H), 7.98 (d, 1H, J=8.1 Hz)
7.31 (d, 1H, J=8.1 Hz), 2.8 (s, 3H) 2.5 (s, 3H). Mass Spectrum
(MALDI-TOF, CHCA Matrix, m/z) Calcd. for
C.sub.16H.sub.15N.sub.3S.sub.3: 346.0 (M+H), found 346.1.
EXAMPLE 21
[0503] 4-[4(2-methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-c- arboxamidine
hydrochloride
[0504] a) Methyl 4-[4-(2-methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthioth- iophene-2-carboxylate: 105 mg
(0.424 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL
of reagent grade acetone. 2-Bromo-2-methoxy acetophenone (0.467
mmol; 110 mg) was added and the solution was allowed to reflux for
3 h. The solution was allowed to cool and the solution
concentrated. The crude product was dissolved in 100 mL of
CH.sub.2Cl.sub.2 and washed one time with 50 mL of 1N NaOH. The
organic layer was obtained, dried over sodium sulfate, concentrated
and purified on a 1 mm silica plate eluting with 20% ethyl acetate/
hexane to afford 160 mg (95% yield) of methyl
4-[4-(2-methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
[0505] b) 4-[4-(2-Methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene- -2-carboxamidine
hydrochloride: To a stirred suspension of 4.23 mmol (227 mg) of
ammonium chloride (Fisher Scientific) in 10 mL of anhydrous toluene
placed under nitrogen atmosphere at 0.degree. C., 2.12 mL (4.23
mmol) of 2M trimethylaluminum in toluene (Aldrich Chemical Co.) was
added via syringe over 10 min and then let stir for 20 min at
25.degree. C. after which 160 mg (0.287 mmol) of methyl
4-[4-(2-methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate in a
solution of 5 mL of anhydrous toluene was added to solution and
allowed to reflux for 3 h. The reaction mixture was quenched by
pouring over a slurry of 5 g of silica in 30 mL of chloroform. The
silica was poured onto a sintered glass funnel and washed with a
10% methanol/CH.sub.2Cl.sub.2 solution and concentrated. The crude
product was then purified on a 2 mm silica prep plate eluting with
10% methanol/CH.sub.2Cl.sub.2 with 1% NH.sub.4OH. The product was
then dissolved in 2 mL of 4N HCl/dioxane and concentrated to afford
45 mg (29% yield) of 4-[4-(2-methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine
hydrochloride. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 8.68 (s,
1H), 8.36 (dd, J=1.6 Hz and 7.74 Hz, 1H), 8.21 (s, 1H), 7.36-7.42
(m, 1H), 7.05-7.22 (m, 3 H), 3.97 (s, 3H), 2.8 (s, 3H). Mass
Spectrum (MALDI-TOF, CHCA Matrix, m/z) Calcd. for
C.sub.16H.sub.15N.sub.3OS.sub.3: 362.0 (M+H), found 361.7.
EXAMPLE 22
[0506] 4-[4-(2,4-Dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophen- e-2-carboxamidine
hydrochloride
[0507] a) Methyl 4-[4-(2,4dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthi- othiophene-2-carboxylate: 99 mg
(0.424 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL
of reagent grade acetone. 2-Bromo-2,4-dimethoxyacetophenone (0.440
mmol; 114 mg) was added and the solution was allowed to reflux for
2.5 h. The solution was allowed to cool and the crude product was
collected as a solid and washed with methanol and dried yielding 91
mg (56% yield) of methyl 4-[4-(2,4-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-ca- rboxylate.
[0508] b) 4-[4-(2,4-Dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiop- hene-2-carboxamidine
hydrochloride: To a stirred suspension of 2.23 mmol (119 mg) of
ammonium chloride (Fisher Scientific) in 10 mL of anhydrous toluene
placed under nitrogen atmosphere at 0.degree. C., 1.1 mL (2.23
mmol) of 2M trimethylaluminum in toluene was added via syringe over
10 min and then let stirred for 20 min at 25.degree. C. after which
81 mg (0.223 mmol) of methyl 4-[4-(2,4-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-m- ethylthiothiophene-2-carboxylate was added
to solution and allowed to reflux for 2.5 h. The reaction mixture
was quenched by pouring over a slurry of silica in chloroform. The
silica was poured onto a sintered glass funnel and washed with a
10% methanol/CH.sub.2Cl.sub.2 solution and concentrated. The crude
product was then purified on a 0.5 mm silica prep plate eluting
with 10% methanol/CH.sub.2Cl.sub.2 to afford 32 mg (37% yield) of
4-[4-(2,4-dimethoxyphenyl) (1,3-thiazol-2-yl)]-5-methylthiothio-
phene-2-carboxamidine hydrochloride. .sup.1H-NMR (CD.sub.3OD; 300
MHz) .delta. 8.49 (s, 1H), 8.31 (d, J=8.5 Hz, 1H), 7.93 (s, 1H),
6.64 (m, 2H), 3.97 (s, 3 H), 3.85 (s, 3H), 2.79 (s, 3H). Mass
Spectrum (MALDI-TOF, CHCA Matrix, m/z) Calcd. for
C.sub.17H.sub.17N.sub.3O.sub.2S.sub.3: 392.1(M+H), found 392.4.
EXAMPLE 23
[0509] 4-[4-(3,4-Dichlorophenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene- -2-carboxamidine
hydrochloride
[0510] a) Methyl 4-[4-(3,4-dichlorophenyl)
(1,3-thiazol-2-yl)]-5-methylthi- othiophene-2-carboxylate: 176 mg
(0.712 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with
2-bromo-3,4-dichloroacetophenone (0.854 mmol; 330 mg) in a manner
similar to Example 22, step (a) to afford 270 mg (91% yield) of
methyl 4-[4-(3,4-dichlorophenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-car- boxylate.
[0511] b) 4-[4-(3,4-Dichlorophenyl)
(1,3-thiazol-2-yl)]-5-methylthiothioph- ene-2-carboxamidine
hydrochloride: 270 mg (0.648 mmol) of methyl
4-[4-(3,4-dichlorophenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-car- boxylate was
treated in a manner similar to Example 22, step (b) to afford 135
mg (52% yield) of 4-[4-(3,4-dichlorophenyl)
(1,3-thiazol-2-yl)]-5-met- hylthiothiophene-2-carboxamidine
hydrochloride. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.54 (s,
1H), 8.22 (d, J=2 Hz, 1H), 8.02 (s, 1H), 7.94 (dd, J=2 Hz and 8.4
Hz, 1H), 7.58 (d, J=8.5 Hz, 1 H), 2.79 (s, 3H). Mass Spectrum
(MALDI-TOF, CHCA Matrix, m/z) Calcd. for C.sub.15H.sub.11C.sub.1-
2N.sub.3S.sub.3: 400.0 (M+H), found 400.6.
EXAMPLE 24
[0512] 4-[4-(3-Methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-c- arboxamidine
hydrochloride
[0513] a) Methyl 4-[4-(3-methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothi- ophene-2-carboxylate: Methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2- -carboxylate, 106 mg
(0.428 mmol) (Maybridge Chemical Co. LTD., Cornwall, U.K.) was
reacted with 2-bromo-3methylacetophenone (0.428 mmol, 91 mg) in a
manner similar to Example 22, step (a) to afford 98 mg (63% yield)
of methyl 4-[4-(3-methylphenyl)
(1.3-thiazol-2-yl)]-5-methylthiothiophene-2-- carboxylate.
[0514] b) 4-[4-(3-Methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-- 2-carboxamidine
hydrochloride: 4-[4-(3-methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate, (98 mg,
0.271 mmol) was treated in a similar manner to Example 22, step (b)
to afford 75 mg (80% yield) of 4-[4-(3-methylphenyl)
(1,3-thiazol-2-yl)]-5-methylth- iothiophene-2-carboxamidine
hydrochloride. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.56 (s,
1H), 7.88 (s, 1H), 7.86 (d, J=14 Hz, 2H), 7.33 (m, 1H), 7.19 (m, I
H), 2.79 (s, 3H), 2.42 (s, 3H). Mass Spectrum (MALDI-TOF, CHCA
Matrix, m/z) Calcd. for C.sub.16H.sub.15N.sub.3S.sub.3: 346.0
(M+H), found 346.7
EXAMPLE 25
[0515] 5-Methylthio-4-(4-(2-5,6, 7,8-tetrahydronaphthyl)
(1,3-thiazol-2-yl))thiophene-2-carboxamidine hydrochloride
[0516] a) Methyl 5-methylthio-4-(4-(2-5,6, 7,8-tetrahydronaphthyl)
(1,3-thiazol-2-yl))thiophene-2-carboxylate: Methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate, (160 mg,
0.647 mmol) (Maybridge Chemical Co. LTD., Cornwall, U.K.) was
reacted with 2-bromo-1-(2-5,6,7,8-tetrahydronaphthyl)ethan-1-one
(0.712 mmol; 180 mg) in a manner similar to Example 22, step (a) to
afford 106 mg (41% yield) of methyl
5-methylthio-4-(4-(2-5,6,7,8-tetrahydronaphthyl)
(1,3-thiazol-2-yl))thiophene-2-carboxylate.
[0517] b) 5-Methylthio-4-(4-(2-5,6,7,8-tetrahydronaphthyl)
(1,3-thiazol-2-yl))thiophene-2-carboxamidine hydrochloride: 106 mg
(0.264 mmol) of methyl
5-methylthio-4-(4-(2-5,6,7,8-tetrahydronaphthyl)
(1,3-thiazol-2-yl))thiophene-2-carboxylate was treated in a similar
manner to Example 22, step (b) to afford 88 mg (80% yield) of
5-methylthio-4-(4-(2-5,6,7,8-tetrahydronaphthyl)
(1,3-thiazol-2-yl))thiop- hene-2-carboxamidine hydrochloride.
.sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.49 (s, 1H), 7.78 (s,
1H), 7.73 (m, 2H), 7.11 (m, 1 H), 2.79 (m, 7H), 1.82-1.86 (m, 4H).
Mass Spectrum (MALDI-TOF, CHCA Matrix, m/z) Calcd. for
C.sub.19H.sub.19N.sub.3S.sub.3: 386.1 (M+H), found 386.2
EXAMPLE 26
[0518] 4-[4-(3,5-Dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophen- e-2-carboxamidine
hydrochloride
[0519] a) Methyl 4-[4-(3,5-dimethoxyphenyl)
(1,3-thiazol-2-yl)l-5-methylth- iothiophene-2-carboxylate: 100 mg
(0.404 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with
2-bromo-3,5-dimethoxyacetophenone (0.444 mmol) in a manner similar
to Example 22, step (a) to afford 44 mg (27% yield) of methyl
4-[4-(3,5-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-ca- rboxylate.
[0520] b) 4-[4(3,5-Dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothioph- ene-2-carboxamidine
hydrochloride: 44 mg (0.108 mmol) of methyl
4-[4-(3,5-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-ca- rboxylate was
treated in a manner similar to Example 22, step (b) to afford 25 mg
(60% yield) of 4-[4-(3,5-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine
hydrochloride. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.52 (s,
1H), 7.91 (s, 1H), 7.23 (d, J=2.2 Hz, 1H), 6.50 (t, 1H), 3.85 (s, 6
H), 2.89 (s, 3H). Mass Spectrum (MALDI-TOF, CHCA Matrix, m/z)
Calcd. for C.sub.17H.sub.11N.sub.3- O.sub.2S.sub.3: 392.11 (M+H),
found 392.4.
EXAMPLE 27
[0521] 4-[4-(2-Methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-c- arboxamidine
hydrochloride
[0522] a) Methyl 4-[4(2-methylphenyl)
(1,3-thiazol-2-yl)l-5-methylthiothio- phene-2-carboxylate: 160 mg
(0.647 mmol) of methyl 4-(aminothioxomethyl)-5-
-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD.,
Cornwall, U.K.) was reacted with 2-bromo-2-methyl acetophenone
(0.711 mmol, 152 mg) in a manner similar to Example 22, step (a) to
afford 124 mg (53% yield) of methyl 4-[4-(2-methylphenyl) (l
,3-thiazol-2-yl)]-5-methylthiothiophen- e-2-carboxylate.
[0523] b) 4-[4-(2-Methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-- 2-carboxamidine
hydrochloride: 124 mg (0.343 mmol) of methyl 4-[4-(2-methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxy- late was
treated in a manner similar to Example 22, step (b) to afford 60 mg
(50% yield) of 4-[4-(2-methylphenyl)
(1,3-thiazol-2-yl)]-5-methylthiot- hiophene-2-carboxamidine
hydrochloride. .sup.1H-NMR (CD.sub.3OD; 300 MHz) 6 8.50 (s, 1H),
7.65 (m, 2H), 7.22-7.32 (m, 3H), 2.79 (s, 3H), 2.51 (s, 3H). Mass
Spectrum (MALDI-TOF, CHCA Matrix, m/z) Calcd. for
C.sub.16H.sub.15N.sub.3S.sub.3: 346.0 (M+H), found 346.2.
EXAMPLE 28
[0524] 4-[4-(2,5-Dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophen- e-2-carboxamidine
hydrochloride
[0525] a) Methyl 4-[4-(2,5-dimethoxyphenyl)
(1,3-thiazol-2-yl)l-5-methylth- iothiophene-2-carboxylate: 132 mg
(0.534 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with
2-bromo-2,5-dimethoxy acetophenone (0.587 mmol; 152 mg) in a manner
similar to Example 22, step (a) to afford 97 mg (45% yield) of
methyl 4-[4-(2,5-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
[0526] b) 4-[4-(2,5-Dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiop- hene-2-carboxamidine
hydrochloride: 97 mg (0.238 mmol) of methyl
4-[4-(2,5-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-ca- rboxylate was
treated in a manner similar to Example 22, step (b) to afford 30 mg
(32% yield) of 4-[4-(2,5-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine
hydrochloride. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.46 (s,
1H), 8.10 (s, 1H), 7.99 (d, J=3.2 Hz, 1H), 7.05 (d, J=9 Hz, 1H),
6.93 (d,J=3.2 Hz, 1H), 6.90 (d,J=3.2 Hz, 1H), 3.94 (s, 3H), 3.83
(s, 3H), 2.51 (s, 3H). Mass Spectrum (MALDI-TOF, CHCA Matrix, m/z)
Calcd. for C.sub.17H.sub.17N.sub.3O.sub.2S.- sub.3: 392.1 (M+H),
found 392.1.
EXAMPLE 29
[0527] 4-[4-(4-Chloro(3-pyridyl))
(1,3-thiazol-2-yl)]-5-methylthiothiophen- e-2-carboxamidine
hydrochloride
[0528] a) Methyl 4-[4-(4-chloro(3-pyridyl))
(1,3-thiazol-2-yl)]-5-methylth- iothiophene-2-carboxylate: 240 mg
(0.970 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with
2-bromo-1-(4-chloro(3-pyridyl))ethan-1-one (1.06 mmol; 250 mg) in a
manner similar to Example 22, step (a) to afford 286 mg (77% yield)
of methyl 4-[4-(4-chloro(3-pyridyl))
(1,3-thiazol-2-yl)]-5-methylthiothiophe- ne-2-carboxylate.
[0529] b) 4-[4-(4-Chloro(3-pyridyl))
(1,3-thiazol-2-yl)]-5-methylthiothiop- hene-2-carboxamidine
hydrochloride: 286 mg (0.747 mmol) of methyl
4-[4-(4-chloro(3-pyridyl))
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-ca- rboxylate was
treated in a manner similar to Example 22, step (b) to afford 134
mg (49% yield) of 4-[4-(4-chloro(3-pyridyl))
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine
hydrochloride. Mass Spectrum (MALDI-TOF, CHCA Matrix, m/z) Calcd.
for C.sub.14H.sub.11N.sub.4ClS.sub.3: 366.9 (M+H), found 366.6
EXAMPLE 30
[0530] 4-(4-(2H-Benzo[d]1,3-dioxolen-5-yl)
(1,3-thiazol-2-yl))-5-methylthi- othiophene-2-carboxamidine
hydrochloride
[0531] a) 1-(2H-Benzo[3,4-d/1,3-dioxolen-5-yl)-2-bromoethan-i-one:
To a solution of 2.5 g (15.23 mmol) of 3,4-methylenedioxy
acetophenone in 200 mL of anhydrous methanol was added 61 mmol (20
g) of poly (4-vinylpyridinium tribromide), Aldrich Chemical Co.,
and allowed to reflux for 2.5 h. The solution was filtered and
concentrated.
1-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-2-bromoethan-1-one (1.4 g, 38%
yield) was obtained methylene chloride/hexanes as off-white
crystals. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 8.20 (s, 1H),
8.07 (s, 1H), 7.63 (m, 2H), 7.03 (dd, J=1.2 Hz and 7.1 Hz, 1H),
6.09 (s, 2H), 3.86 (s, 3H), 2.75 (s, 3H).
[0532] b) Methyl 4-(4-(2H-benzo[d]1,3-dioxolen-5-yl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate: 1.4 g
(5.66 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted
1-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-2-bromoethan-1-one (5.66 mmol,
1.37 g) in a manner similar to Example 22, step (a) to afford 1.55
g (70% yield) of methyl 4-(4-(2H-benzo[d]1,3-dioxolen-5-yl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate.
[0533] c) 4-(4-(2H-Benzo[d]1,3-dioxolen-5-yl)
(1,3-thiazol-2-yl))-5-methyl- thiothiophene-2-carboxamidine
hydrochloride: 1.55 g (3.95 mmol) of methyl
4-(4-(2H-benzo[d]1,3-dioxolen-5-yl)
(1,3-thiazol-2-yl))-5-methylthiothiop- hene-2-carboxylate was
treated in a manner similar to Example 22, step (b) to afford 130
mg (9% yield) of 4-(4-(2H-benzo[d]1,3-dioxolen-5-yl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine
hydrochloride. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.51 (s,
1H), 7.73 (s, 1H), 7.58 (m, 2H), 6.89 (d, J-8 Hz, 1H), 6.00 (s,
2H), 2.79 (s, 3H). Mass Spectrum (MALDI-TOF, CHCA Matrix, m/z)
Calcd. for C.sub.16H.sub.13N.sub.3- O.sub.2S.sub.3: 376.0 (M+H),
found 376.1.
EXAMPLE 31
[0534] 4-[4-(3,4-Dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophen- e-2-carboxamidine
hydrochloride
[0535] a) 1-(3,4-Dimethoxyphenyl)-2-bromoethan-1-one: 2 g of
1-(3,4-dimethoxyphenyl)ethan-1-one (11. I mmol) was reacted in a
manner similar to Example 15 step (a), to yield 1.2 g (42% yield)
of 1-(3,4-dimethoxyphenyl)-2-bromoethan-1-one.
[0536] b) Methyl .sup.4-[4-(3,4-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-met- hylthiothiophene-2-carboxylate: 105 mg
(0.424 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with
1-(3,4-dimethoxyphenyl)-2-bromoethan-1-one (0.467 mmol; 120 mg) in
a manner similar to Example 22, step (a) to afford 148 mg (85%
yield) of methyl 4-[4-(3,4-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophe- ne-2-carboxylate.
[0537] c) 4-J4-(3,4-Dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiop- hene-2-carboxamidine
hydrochloride: 148 mg (0.363 mmol) of methyl
4-[4-(3,4-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-ca- rboxylate was
reacted in a manner similar to Example 22, step (b) to afford 70 mg
(50% yield) of 4-[4-(3,4-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine
hydrochloride. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.50 (s,
1H), 7.76 (s, 1H), 7.61 (m, 2H), 7.31 (m, 1H), 7.01 (d, J=8 Hz,
1H), 3.9 (s, 3H) 3.86 (s, 3H), 2.78 (s, 3H). Mass Spectrum
(MALDI-TOF, CHCA Matrix, m/z) Calcd. for
C.sub.17H.sub.17N.sub.3O.sub.2S.sub.3: 392.1 (M+H), found
392.4.
EXAMPLE 32
[0538] 4-[4-(2-Chloro(3-pyridyl))
(1,3-thiazol-2-yl)]-5-methylthiothiophen- e-2-carboxamidine
[0539] a) Methyl 4-[4-(2-chloro(3-pyridyl))
(1,3-thiazol-2-yl)]-5-methylth- iothiophene-2-carboxylate:
2-Chloropyridine-3-carbonyl chloride (300 mg, 1.7 mmol) was
dissolved in anhydrous CH.sub.3CN (4 mL). While stirring well with
a magnetic stirrer, trimethylsilyldiazomethane (4 mL, 2M solution
in hexane, 8 mmol) was dripped into the reaction mixture. The
resulting yellow solution was stirred for 2h at room temperature,
at which time the mixture was cooled in an ice bath. To the cold
solution, 30% HBr in acetic acid (2 mL) was added dropwise with
vigorous evolution of gas. This solution was stirred for I h during
which time 2-bromo-1-(2-chloro(3-pyridyl))ethan-1-one precipitated.
This solid was collected by filtration and dried under vacuum. The
dry solid (142 mg, 0.6 mmol) was dissolved in acetone (10 ml). To
this solution
5-(methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide (100
mg, 0.4 mmol, Maybridge Chemical Company, Cornwall, UK) was added
and heated at reflux for 5 h. At this point the solid that
precipitated was filtered off and washed with methanol and dried
under vacuum to give 110 mg (71%) of methyl
4-[4-(2-chloro(3-pyridyl)) (1,3-thiazol-2-yl)]-5-methylthiothio-
phene-.sup.2-carboxylate. .sup.1H-NMR (CDCl.sub.3; 300 MHz) .delta.
2.70 (s, 3H), 3.92 (s, 3H), 7.39 (dd, J=4.7 and 7.7 Hz, 1H), 8.11
(s, 1H), 8.22 (s, 1H), 8.38 (dd, J=1.9 and 4.7 Hz, 1H), 8.62 (dd,
J=1.9 and 7.7 Hz, 1H).
[0540] b) 4-[4-(2-Chloro(3-pyridyl))
(1,3-thiazol-2-yl)]-5-methylthiothiop- hene-2-carboxamidine: Methyl
4-[4-(2-chloro(3-pyridyl))
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate (100 mg,
0.26 mmol) as prepared in previous step was treated in a manner
similar to that for Example 1, to give 50 mg (52%) of
4-[4-(2-chloro(3-pyridyl))
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine as a
solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 2.79 (s, 3H),
7.62 (dd, J=4.9 and 7.4 Hz, 1H), 8.41 (s, 1H), 8.49 (m, 2H), 8.69
(s, 1H), 9.1 (broad s, 2H), 9.4 (broad s, 2H). Mass spectrum (ESI,
m/z): Calcd. for C.sub.14H.sub.11N.sub.4S.sub.3C.sub.1: 367.0
(M+H), found 369.0.
EXAMPLE 33
[0541]
4-(4-Cyclohexyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxam-
idine
[0542] a)
Methyl-4-(4-cyclohexyl(1,3-thiazol-2-yl))-5-methylthiothiophene--
2-carboxylate: Cyclohexanecarbonyl chloride (300 mg, 2.0 mmol) was
treated in a manner similar to that for Example 32 to give
2-bromo-1-cyclohexylethan-1-one. The dry solid (125 mg) was
dissolved in acetone (10 ml). To this solution
5-(methoxycarbonyl)-2-(methylthio)-thio- phene-3-thiocarboxamide
(100 mg, 0.4 mmol, Maybridge Chemical Company, Cornwall, UK) was
added and heated at reflux for 5 h. At this point the solid that
precipitated was filtered off and washed with methanol and dried
under vacuum to give 100 mg (70%) of methyl
4-(4-cyclohexyl(1,3-thi-
azol-2-yl))-5-methylthiothiophene-2-carboxylate which was used
without further purification in the following step.
[0543] b)
4-(4-Cyclohexyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carbo-
xamidine: Methyl
4-(4-cyclohexyl(1,3-thiazol-2-yl))-5-methylthiothiophene--
2-carboxylate (100 mg, 0.28 mmol) as prepared in previous step was
treated in a manner similar to that for Example 1, to give 60 mg
(63%) of
4-(4-cyclohexyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine
as a solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 1.21-1.53
(m, 5H), 1.61-1.78 (m, 3H), 2.05 (m, 2H), 2.7 (s, 3H), 2.74 (m,
1H), 7.33 (s, 1H), 8.32 (s, 1H). Mass spectrum (MALDI-TOF, m/z):
Calcd. for C.sub.15H.sub.19N.sub.3S.sub.3, 338.1 (M+H), found
338.1.
EXAMPLE 34
[0544] 4-Phenyl-5-(trifluoromethyl)thiophene-2-carboxamidine
[0545] Methyl 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylate
(100 mg, 0.37 mmol, Maybridge Chemical Company, Cornwall, UK) was
treated in a manner similar to that for Example 1 to give 80 mg
(85%) of 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxamidine as a
solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 7.45-7.52 (m,
5H), 7.79 (d, J=1.4 Hz, 1H). Mass spectrum (MALDI-TOF, m/z): Calcd.
for C.sub.12H.sub.9F.sub.3N.sub.2S, 271.1 (M+H), found 271.2.
EXAMPLE 35
[0546]
5-Methylthio-4-(2-phenyl(l,3-thiazol-4-yl))thiophene-2-carboxamidin-
e
[0547] a) Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate:
5-(Methoxycarbonyl)-2-methylthiothiophene-3-carboxylic acid (200
mg, 0.86 mmol) as prepared in Example 95 was taken in a round
bottomed flask and anhydrous CH.sub.2Cl.sub.2 (10 mL) was
introduced to the flask. This solution was cooled in an ice bath
under an argon atmosphere. To this mixture oxalyl chloride (328 mg,
2.6 mmol) was added followed by anhydrous DMF (500 .mu.L). The
resulting solution was stirred at 4.degree. C. for 30 min and then
allowed to warm up to room temperature, while monitoring for the
disappearance of the acid by TLC. After 2 h solvents were removed
under vacuum and the residual oxalyl chloride was removed
azeotropically with toluene. The resulting residue was dried under
high-vacuum to give the acid chloride as a gray solid. This solid
was dissolved in anhydrous CH.sub.3CN (8 mL). While stirring well
with a magnetic stirrer trimethylsilyldiazomethane (4 mL, 8 mmol,
2M solution in hexane) was dripped into the reaction mixture. The
resulting yellow solution was stirred for 2h at room temperature,
at which time the mixture was cooled in an ice bath. To the cold
solution 30% HBr in acetic acid (2 mL) was added dropwise, with
vigorous evolution of gas. This solution was stirred for 1 h,
during which methyl 4-(2-bromoacetyl)-5-met-
hylthiothiophene-2-carboxylate precipitates. This solid was
collected by filtration and dried under vacuum to give 120 mg
(45%). .sup.1H-NMR (CDCl.sub.3; 300 MHz) .delta. 2.64 (s, 3H), 3.91
(s, 3H), 4.27 (s, 2H), 8.10 (s, 1H).
[0548] b) Methyl
5-methylthio-4-(2-phenyl(1,3-thiazol-4-yl))thiophene-2-ca-
rboxylate:
5-(Methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide (100
mg, 0.4 mmol, Maybridge Chemical Company, Cornwall, UK) was
dissolved in acetone (20 ml). To this solution, methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (112 mg) as
prepared in previous step was added and heated at reflux for 3 h.
At this point the solid that precipitated was filtered off and
washed with acetone and dried under vacuum to give 82 mg (65%) of
methyl
5-methylthio-4-(2-phenyl(1,3-thiazol-4-yl))thiophene-2-carboxylate.
.sup.1H-NMR (CDCl.sub.3; 300 MHz) .delta. 2.67 (s, 3H), 3.91 (s,
3H), 7.44-7.49 (m, 3H), 7.61 (s, 1H), 8.03-8.06 (m, 2H), 8.28 (s,
1H).
[0549] c)
5-Methylthio-4-(2-phenyl(,3-thiazol-4-yl))thiophene-2-carboxamid-
ine: Methyl
5-methylthio-4-(2-phenyl(1,3-thiazol-4-yl))thiophene-2-carboxy-
late (80 mg) as prepared in previous step was treated in a manner
similar to that for Example 1, to give 50 mg of
5-methylthio-4-(2-phenyl(1,3-thia-
zol-4-yl))thiophene-2-carboxamidine as a solid. .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) .delta. 2.75 (s, 3H), 7.51-7.60 (m, 3H),
8.02 (s, 1H), 8.06 (m, 2H), 8.70 (s, 1H), 9.06 (broad s, 2H), 9.38
(broad s, 2H). Mass spectrum (MALDI-TOF, m/z): Calcd. for
C.sub.15H.sub.13N.sub.3S.sub.3, 332.0 (M+H), found 332.1.
EXAMPLE 36
[0550] 4-[4-(2-Chloro(4-pyridyl))
(1,3-thiazol-2-yl)]-5-methylthiothiophen- e-2-carboxamidine
[0551] a) Methyl-4-[4-(2-chloro(4-pyridyl))
(1,3-thiazol-2-yl)]-5-methylth- iothiophene-2-carboxylate:
2-Chloropyridine-4-carbonyl chloride (300 mg, 1.7 mmol) was
dissolved in anhydrous CH.sub.3CN (4 mL). While stirring well with
a magnetic stirrer trimethylsilyldiazomethane (4 mL, 8 mmol, 2M
solution in hexane) was dripped into the reaction mixture. The
resulting yellow solution was stirred for 2 h at room temperature,
at which time the mixture was cooled in an ice bath. To the cold
solution 30% HBr in acetic acid (2 mL) was added dropwise, with
vigorous evolution of gas. This solution was stirred for 1 h,
during which time 2-bromo- 1-(2-chloro(4-pyridyl))ethan-1-one
precipitates. This solid was collected by filtration and dried
under vacuum. The dry solid (142 mg, 0.6 mmol) was dissolved in
acetone (10 ml). To this solution
5-(methoxycarbonyl)-2-(methylthio)-thiophene-.sup.3-thiocarboxamide
(100 mg, 0.4 mmol, Maybridge Chemical Company, Cornwall, UK) was
added and heated at reflux for 5 h. At this point the solid that
precipitated was filtered off and washed with methanol and dried
under vacuum to give 100 mg of methyl 4-[4-(2-chloro(4-pyridyl))
(1,3-thiazol-2-yl)]-5-methylthiot- hiophene-2-carboxylate.
.sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 2.73 (s, 3H), 3.94 (s,
3H, overlapping H.sub.2O peak), 7.92-7.99 (m, 2H), 8.05 (s, 1H),
8.24 (s, 2H), 8.48 (m, 1H).
[0552] b) 4-[4-(2-Chloro(4-pyridyl))
(1,3-thiazol-2-yl)I-5-methylthiothiop- hene-2-carboxamidine: Methyl
4-[4-(2-chloro(4-pyridyl))
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate (100 mg,
0.26 mmol) as prepared in previous step was treated in a manner
similar to that for Example 1, to give 50 mg of
4-[4-(2-chloro(4-pyridyl))
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine as a
solid. .sup.1H-NMR (CDCl.sub.3/CD.sub.3OD; 300 MHz) .delta. 2.82
(s, 3H), 7.95 (dd, J=1.4 and 5.3 Hz, 1H), 8.08 (d, J=I.0 Hz, 1H),
8.23 (s, 1H), 8.42 (d, J=5.3 Hz, 1H), 8.56 (s, 1H). Mass spectrum
(MALDI-TOF, m/z): Calcd. for C.sub.14H.sub.11N.sub.4S.sub.3Cl,
367.0 (M+H), found 367.1.
EXAMPLE 37
[0553] 4-[4-(4-Chlorophenyl)
(1,3-thiazol-2-yl)]-5-(methylsulfonyl)thiophe-
ne-2-carboxamidine
[0554] 4-[4-(4-Chlorophenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-c- arboxamidine (35 mg,
0.1 mmol) prepared according to Example I was dissolved in a
mixture of MeOH and CH.sub.2Cl.sub.2 (1:1, 6 mL). While stirring
well, m-chloroperoxybenzoic acid (100 mg) was added in portions to
this solution over a 3h period. The mixture was stirred for a
further 2 h and the solvents were removed under vacuum. The
resulting residue was dissolved in MeOH (8 m-L). Strong anion
exchange resin (AG 1-X8, 5 ml, 1.4 meq/mL) was packed into a
disposable chromatography column and washed with H.sub.2O
(5.times.5 mL) and MeOH (3.times.5 mL). The methanolic solution
from the reaction was slowly introduced into this column, and the
column effluent was collected. The column was washed with MeOH
(2.times.5 mL) and these washings were also collected. The combined
effluents were evaporated under vacuum and the residue was
subjected to preparative thin layer chromatography (silica gel, 10%
MeOH in CH.sub.2Cl.sub.2 with 2% acetic acid). The major band was
isolated and suspended in CH.sub.2Cl.sub.2 and filtered. The
filtrate was collected and the residue was washed with 10% MeOH in
CH.sub.2Cl.sub.2 saturated with NH.sub.3. The washings were
combined with the original filtrate and the solvents were removed
under vacuum. The resulting solid was dissolved in 10% MeOH in
CHCl.sub.3 and filtered through a 0.45 micron filter. The filtrate
was collected and evaporated under vacuum to give 20 mg (53%) of an
off-white solid. .sup.1H-NMR (CDCl.sub.3/CD.sub.3OD; 300 MHz)
.delta. 3.78 (s, 3H), 7.47 (d, J=8.7 Hz, 2H), 7.96 (d, J=8.7 Hz,
1H), 8.00 (s, 1H), 8.35 (s, 1H). Mass spectrum (MALDI-TOF, m/z):
Calcd. for C.sub.15H.sub.12O.sub.2N.sub.3S.sub.3C.sub.1, 398.0
(M+H), found 398.0.
EXAMPLE 38
[0555] Hydrazino[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))
(2-thienyl)]methanimine
[0556] a)
5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxami-
de: Liquid ammonia (5 mL) was condensed into a cold (-78.degree.
C.) Teflon-lined steel bomb. Methyl
5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl-
))thiophene-2-carboxylate (0.6 g, 1.7 mmol) as prepared in Example
10 step (a) was introduced in one portion and the bomb was sealed
and heated in an oil bath at 80.degree. C. for 48h. The bomb was
cooled to -78.degree. C., opened and the ammonia was allowed to
evaporate at room temperature. The residual solid was collected and
dried under vacuum to give 0.5 g (88%) of
5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxami-
de. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 2.75 (s, 3H), 7.38
(m, 1H), 7.40-7.51 (m, 2H), 8.04-8.18 (m, 2H), 8.19 (s, 1H), 8.20
(s, 1H).
[0557] b)
5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carbonitr-
ile: A slurry of P.sub.2O.sub.5 (2.7 g, 19 mmol) and
hexamethyldisiloxane (6.7 mL) in dichloroethane (13 mL) was heated
to 90.degree. C., while stirring under a N.sub.2 atmosphere. After
stirring for 2 h, the resulting clear solution was allowed to cool
to 40.degree. C.
5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamide
(0.9 g, 2.7 mmol) as prepared in previous step was added to this
solution and the mixture was heated at 75.degree. C. for 5h. This
solution was cooled to room temperature and stirred with aqueous
NaCl (6 M, 100 mL) for 10 min. As the aqueous solution is added a
yellow solid precipitated. After 10 min this solid was separated by
filtration, and dried under vacuum to give (0.5 g, 59%) of
5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-
-2-carbonitrile as a yellow solid. .sup.1H-NMR(DMSO-d.sub.6; 300
MHz) .delta. 2.76 (s, 3H), 7.38 (m, 1H), 7.48 (m, 2H), 8.07 (m,
2H), 8.22 (s, 1H), 8.51 (s, 1H).
[0558] c) Hydrazino[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))
(2-thienyl)]methanimine:
5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiop-
hene-2-carbonitrile (100 mg, 0.32 mmol) as prepared in previous
step was dissolved in EtOH (10 mL). To this solution hydrazine
monohydrate (10 eq) was added and the mixture was heated at reflux
for 3h. The EtOH solution was concentrated down to 1 mL and water
(2 mL) was added to this solution. This resulted in the formation
of a white solid. The solid was collected by filtration washed with
a small amount of water and dried under vacuum to give 50 mg (45%)
of hydrazino[5-methylthio-4-(4-phenyl(1,- 3-thiazol-2-yl))
(2-thienyl)]methanimine. .sup.1H-NMR (CD.sub.3OD/CDCl.sub.3; 300
MHz) .delta. 2.69 (s, 3H), 7.39 (m, 1H), 7.47 (m, 2H), 7.52 (s,
1H), 7.98 (m, 2H), 8.10 (s, 1H). Mass spectrum (ESI, m/z): Calcd.
for C.sub.15H.sub.14N.sub.4S.sub.3, 347.04 (M+H), found 347.1.
EXAMPLE 39
[0559] {Imino[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))
(2-thienyl)]methyl]methylamine
[0560]
5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidin-
e (20 mg, 0.06 mmol) as prepared in Example 10 step (b) was
dissolved in MeOH, and to this solution methylamine (0.6 mL, 2M
solution in tetrahydrofuran) was added. This solution was refluxed
for 6h, at which time the solvents were removed under vacuum to
give a solid. This solid was dissolved in a small amount of MeOH.
H.sub.2O was added dropwise to the methanolic solution until a
precipitate was formed. This solid was isolated, washed with a
small amount of water and dried under vacuum to give 15 mg (72%) of
{imino[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))
(2-thienyl)]methyl}methylamine. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz)
.delta. 2.77 (s, 3H), 3.00 (s, 3H), 7.36-7.42 (m, 1H), 7.47-7.52
(m, 2H), 8.07-8.10 (m, 2H), 8.23 (s, 1H), 8.55 (s, 1H). Mass
spectrum (ESI, m/z): Calcd. for C.sub.16H.sub.15N.sub.3S.sub.3,
346.5 (M+H), found 346.2.
EXAMPLE 40
[0561]
2-{3-[2-(5-Amidino-2-methylthio-3-thienyl)-c,3-thiazol-4-yl]phenoxy-
tacetic acid
[0562] a) 2-Bromo-1-(3-hydroxyphenyl)ethan-1-one:
2-Bromo-1-(3-methoxyphen- yl)ethan- 1-one (2 g, 8.7 mmol) was taken
in a round bottomed flask equipped with magnetic stir bar. The
flask was put under a N.sub.2 atmosphere and CH.sub.2Cl.sub.2 was
introduced into the flask. The resulting solution was cooled in a
dry ice-acetone bath and BBr.sub.3 (27 mL, 1M in CH.sub.2Cl.sub.2)
was introduced dropwise. The resulting solution was allowed to warm
up to room temperature overnight. The solvents were removed under
vacuum and the residue was purified by passing through a short pad
of silica gel (50 g) to give 1.3 g (69%) of
2-bromo-1-(3-hydroxyphenyl)ethan-1-one as an oil. .sup.1H-NMR
(CDCl.sub.3; 300 MHz) .delta. 4.47 (s, 2H), 6.21 (s, 1H), 7.14 (m,
1H), 7.35 (m, 1H), 7.52-7.82 (m, 2H).
[0563] b) Methyl-4-[4-(3-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthioth- iophene-2-carboxylate:
2-Bromo-1-(3-hydroxyphenyl)ethan-1-one (229 mg, 1.1 mmol) as
prepared in previous step was treated in a manner similar to that
of Example 13, step (a) to give 225 mg (61%) of methyl
4-[4-(3-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carbox- ylate as a
solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 2.76 (s, 3H),
3.86 (s, 3H), 6.87 (m, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.49 (m, 2H),
8.12 (s, 1H), 8.20 (s, 1H).
[0564] c) (tert-Butoxy)-N-([4-[4-(3-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-m-
ethylthio(2-thienyl)]iminomethyl)carboxamide:
4-[4-(3-Hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine (2 g, 5.8
mmol), prepared by treating methyl 4-[4-(3-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate in a manner
similar to that f DMF (10 mL). To this solution di-tert-butyl
dicarbonate (1.38 g, 6.3 mmol) and DIEA (2 mL, 11.5 mmol) was
added, and the mixture was stirred at room temperature for 18 h.
DMF was removed under vacuum and the residue was purified by silica
gel column chromatography to give 1.8 g (70%) of
(tert-butoxy)-N-({4-[4-(3-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthio(2-thienyl)}iminomethyl)carboxamide
as an oil. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 1.58 (s,
9H), 2.81 (s, 3H), 6.81 (m, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.49-7.52
(m, 2H), 8.09 (s, 1H), 8.71 (s, 1H).
[0565] d) tert-Butyl
2-[3-[2-(5-[[(tert-butoxy)carbonylamino]iminomethyl]--
2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate:
(tert-Butoxy)-N-( {4-[4-(3-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthi-
o(2-thienyl)}iminomethyl)carboxamide (23 mg, 0.05 mmol) as prepared
in previous step was dissolved in anhydrous DMF (1 mL). To this
solution tert-butyl 2-bromoacetate (20 mg, 0.1 mmol),
Cs.sub.2CO.sub.3 (33.5 mg, 0.1 mmol) and KI (5 mg) was added and
the mixture was heated at 70.degree. C. for 18 h. The solvents were
removed under vacuum and the residue was purified by preparative
silica gel thin-layer chromatography to give 12 mg (42%) of
tert-butyl 2-{3-[2-(5-{[(tert-butoxy)carbonylamino-
]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy
acetate which was used in the following step.
[0566] e)
2-{3-[2-(5-Amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phen-
oxy}acetic acid: tert-Butyl
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminom-
ethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate (12
mg, 0.02 mmol) as prepared in previous step was dissolved in 1 ml
50% TFA in CH.sub.2Cl.sub.2 containing 2% H.sub.2O and stirred for
4h. The solvents were removed under vacuum. The residual TFA was
removed by azeotroping with toluene to give 8.7 mg (100%) of
2-{3-[2-(5-amidino-2-methylthio-3-t-
hienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid as a buff colored
solid. .sup.1H-NMR (CD.sub.3OD/CDCl.sub.3; 300 MHz) 5 2.77 (s, 3H),
4.74 (S, 2H), 6.93 (m, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.62 (m, 1H),
7.68 (M, 1H), 7.84 (s, 1H), 8.46 (s, 1H). Mass spectrum (ESI, m/z):
Calcd. for C.sub.17H.sub.15N.sub.3O.sub.3S.sub.3, 406.5 (M+H),
found 406.3.
EXAMPLE 41
[0567]
2-[2-[2-(5-Amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy-
}acetic acid
[0568] a) tert-Butyl
2-{2-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl]--
2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy]acetate:
4-[4-(2-Hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carbox- amidine (100
mg, 0.29 mmol) as prepared in Example 196 step (b) was treated in a
manner similar to that shown in Example 40 step (c) to give 100 mg
(0.22 mmol, 77%) of (tert-butoxy)-N-( {4-[4-(2-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthio(2-thienyl)}iminomethyl)carboxamide.
This compound was treated in a manner similar to that shown in
Example 40, step (d) to give 63 mg (50%) of tert-butyl
2-{2-[2-(5-{[(tert-butoxy)carb-
onylamino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}ac-
etate. .sup.1H-NMR (CDCl.sub.3; 300 MHz) .delta. 1.55 (s, 9H), 1.56
(s, 9H), 2.69 (s, 3H), 4.66 (s, 2H), 6.88 (dd, J=0.8 and 8.3 Hz,
1H), 7.14 (dt, J=1.0 and 7.6 Hz, 1H), 7.30 (m, 1H), 8.08 (s, 1H),
8.48 (dd, J=1.8 and 7.8 Hz, 1H), 8.51 (s, 1H).
[0569] b)
2-{2-[2-(5-Amidino-2-methylthio-3-thienyl)-I,3-thiazol-4-yl]phen-
oxy}acetic acid: tert-Butyl
2-{2-[2-(5-{[(tert-butoxy)carbonylamino]iminom-
ethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate (60
mg, 0.12 mmol) as prepared in previous step was treated in a manner
similar to that shown in Example 40, step (e) to give 22 mg (50%)
of
2-{2-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy
}acetic acid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 2.80 (s,
3H), 4.90 (s, 2H), 7.17 (m, 2H), 7.36 (m, 1H), 8.41 (d, J=6.3 Hz,
1H), 8.60 (s, 1H), 8.62 (s, 1H), 9.00 (broad s, 2H), 9.37 (broad s,
2H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.17H.sub.15N.sub.3O.sub.3S.sub.3, 406.5 (M+H), Found
406.1.
EXAMPLE 42
[0570]
5-Methylthio-4-(6-phenyl(2-pyridyl))thiophene-2-carboxamidine
[0571] a) Methyl
4-(1,1-dimethyl-1-stannaethyl)-5-methylthiothiophene-2-ca-
rboxylate: 4-Bromo-5-methylthiothiophene-2-carboxylic acid (EP
0676395 A2) (4.67 g, 18.4 mmol) was dissolved in anhydrous THF (30
mL), taken in a round bottomed flask and cooled to -78.degree. C.
under a N.sub.2 atmosphere. To this solution n-butyllithium (20.3
mL, 40.6 mmol, 2M in cyclohexane) was introduced in a dropwise
manner. The resulting solution was stirred at -78.degree. C. for 45
min and then allowed to warm up to -60.degree. C. To this solution
trimethyltin chloride (40.6 mL, 40.6 mmol, 1M in THF) was added
dropwise. This solution was stirred at -60.degree. C. for 30 min
and then allowed to warm up to room temperature. The THF was
removed under vacuum and the residue was treated with H.sub.2O and
extracted with hexane. The hexane layer was evaporated and the
residue was dissolved in Et.sub.2O. The Et.sub.2O solution was
washed with 10% HCl , saturated NaCl and dried over anhydrous
MgSO.sub.4. Et.sub.2O was removed under vacuum and the residue was
taken in MeOH. The MeOH solution was treated with
trimethylsilyldiazomethane (18.5 mL, 2M in hexane) and stirred at
room temperature for 1 h. The solvents were removed under vacuum to
give 2 g (31%) of methyl 4-(1,1-dimethyl-1-stanna-
ethyl)-5-methylthiothiophene-2-carboxylate as an oil. .sup.1H-NMR
(CDCl.sub.3; 300 MHz) .delta. 0.31 (s, 9H), 2.57 (s, 3H), 3.86 (s,
3H), 6.98 (s, 1H).
[0572] b)
Methyl-4-(6-bromo(2-pyridyl))-5-methylthiothiophene-2-carboxylat-
e: Methyl
4-(1,1-dimethyl-1-stannaethyl)-5-methylthiothiophene-2-carboxyla-
te (195 mg, 0.56 mmol) as prepared in previous step, and
2,6-dibromopyridine (398 mg, 1.7 mmol) were taken in anhydrous DMF
(2 mL). To this mixture tetrakistriphenylphosphine-palladium (20
mg) was added and heated at 120.degree. C. for 24 h. DMF was
removed under vacuum and the residue was purified by preparative
silica gel thin -layer chromatography to give 78 mg (41%) of methyl
4-(6-bromo(2-pyridyl))-5-met- hylthiothiophene-2-carboxylate as a
solid. .sup.1H-NMR (CDCl.sub.3; 300 MHz) .delta. 2.60 (s, 3H), 3.78
(s, 3H), 7.19 (s, 1H), 7.47 (dd, J=1.l and 7.7 Hz, 1H)), 7.58 (t,
J=7.7, 1H), 7.65 (dd, J=1.1 and 7.4 Hz, 1H).
[0573] c) Methyl
5-methylthio-4-(6-phenyl(2-pyridyl))thiophene-2-carboxyla- te:
Methyl 4-(6-bromo(2-pyridyl))-5-methylthiothiophene-2-carboxylate
(78 mg, 0.23 mmol) as prepared in previous step, phenylboronic acid
(33 mg, 0.27 mmol) and tetrakistriphenylphosphine-palladium (10 mg)
were taken in DMF (1 mL). To this solution K.sub.2CO.sub.3 (75 mg,
0.54 mmol) and H.sub.2O (0.3 mL) were added and the mixture was
stirred and heated at 90.degree. C. for 18h. Solvents were removed
under vacuum and the residue was dissolved in EtOAc and extracted
with H.sub.2O, washed with saturated NaCl and dried over anhydrous
Na.sub.2SO.sub.4. Thin-layer chromatography of the aqueous layer
indicated the presence of some hydrolyzed product. Therefore the
aqueous layer was separated acidified with 10% HCl and extracted
with EtOAc. The EtOAc layer was washed with saturated NaCl and
dried over anhydrous Na.sub.2SO.sub.4. This second EtOAc fraction
was evaporated and the residue was dissolved in MeOH and treated
with trimethylsilyldiazomethane (1.2 eq). This methanolic solution
and the first EtOAc fraction were combined and evaporated. The
residue was subjected to preparative thin-layer chromatography (10%
EtOAc in Hexane) to give 40 mg (51%) of methyl
5-methylthio-4-(6-phenyl(2-pyridyl))thiophe- ne-2-carboxylate which
was used directly in the next step.
[0574] d)
5-Methylthio-4-(6-phenyl(2-pyridyl))thiophene-2-carboxamidine:
Methyl 5-methylthio-4-(6-phenyl(2-pyridyl))thiophene-2-carboxylate
(40 mg, 0.12 mmol) as prepared in previous step was treated in a
manner similar to that for Example 1, to give 10 mg of
5-methylthio-4-(6-phenyl(- 2-pyridyl))thiophene-2-carboxamidine as
a solid. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 2.69 (s, 3H),
7.45-7.60 (m, 3H), 7.62 (s, 1H), 7.79 (dd, J=0.9 and 7.8 Hz, 1H),
7.96 (dd, J=0.9 and 8.0 Hz, 1H), 8.03-8.12 (m, 3H). Mass spectrum
(ESI, m/z): Calcd. for C.sub.17H.sub.15N.sub.3S.sub.2, 326.1 (M+H),
found 326.1.
EXAMPLE 43
[0575] 5-Methylthio-4-(3-phenylphenyl)thiophene-2-carboxamidine
[0576] a) Methyl
5-methylthio-4-(3-phenylphenyl)thiophene-2-carboxylate: Methyl
4-(1,1-dimethyl-1-stannaethyl)-5-methylthiothiophene-2-carboxylate
(200 mg, 0.57 mmol, as prepared in Example 42, step a) and
1-bromo-3-phenylbenzene (266 mg, 1.14 mmol) were taken in anhydrous
DMF (2 mL). To this mixture tetrakistriphenylphosphine-palladium
(20 mg) was added and heated at 120.degree. C. for 24 h. DMF was
removed under vacuum and the residue was purified by preparative
silica gel thin -layer chromatography to give 39 mg (20%) methyl
5-methylthio-4-(3-phenylphenyl)- thiophene-2-carboxylate as a
solid. .sup.1H-NMR (CD.sub.3OD; 300 MHz)6 2.60 (s, 3H), 3.75 (s,
3H), 7.3-7.5 (m, 6H), 7.60-7.66 (m, 4H).
[0577] b) 5-Methylthio-4-(3-phenylphenyl)thiophene-2-carboxamidine:
Methyl 5-methylthio-4-(3-phenylphenyl)thiophene-2-carboxylate (35
mg, 0.1 mmol) as prepared in previous step was treated in a manner
similar to that for Example 1, to give 17 mg of
5-methylthio-4-(3-phenylphenyl)thiophene-2-ca- rboxamidine as a
solid. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 2.60 (s, 3H),
7.3-7.6 (m, 10H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.18H.sub.16N.sub.2S.sub.2, 325.4 (M+H), found 325.2.
EXAMPLE 44
[0578] 5-Methylthio-4-[4-(phenylthiomethyl)
(1,3-thiazol-2-yl)]thiophene-2- -carboxamidine
[0579] a) Methyl 5-methylthio-4-[4-(phenylthiomethyl)
(1,3-thiazol-2-yl)]thiophene-2-carboxylate: 2-Phenylthioacetyl
chloride (1.0 g, 5.4 mmol) was treated in a manner similar to that
for Example 32 step (a) to give
2-bromo-1-phenylthiomethylethan-1-one. The dry solid (1.3 g, 5.3
mmol) was dissolved in acetone (25 ml). To this solution
5-(methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide
(1.32 g, 5.3 mmol, Maybridge Chemical Co.) was added and heated at
reflux for 5 h. At this point the solid that precipitated was
filtered off and washed with acetone and dried under vacuum to give
1.5 g (71%) of methyl 5-methylthio-4-[4-(phenylthiomethyl)
(1,3-thiazol-2-yl)]thiophene-2-carbo- xylate which was used without
further purification in the following step.
[0580] b) 5-Methylthio-4-[4-phenylthiomethyl)
(1,3-thiazol-2-yl)]thiophene- -2-carboxamidine: Methyl
5-methylthio-4-[4-(phenylthiomethyl)
(1,3-thiazol-2-yl)]thiophene-2-carboxylate (1.5 g, 3.8 mmol) as
prepared in previous step was treated in a manner similar to that
for Example 1, however the product was purified by crystallizing
from methanol to give 0.86 g (60%)
5-methylthio-4-[4-(phenylthiomethyl) (1,3-thiazol-2-yl)]thio-
phene-2-carboxamidine as a solid. .sup.1H-NMR (DMSO-d.sub.6; 300
MHz) .delta. 2.72 (s, 3H), 4.38 (s, 2H), 7.18-7.39 (m, 5H), 7.57
(s, 1H), 8.46 (s, 1H). Mass spectrum (MALDI-TOF, m/z): Calcd. for
C.sub.16H.sub.15N.sub.3S.sub.4, 378.0 (M+H), found 378.1.
EXAMPLE 45
[0581] 4-[4-(2-Chloro-4,5-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthi- othiophene-2-carboxamidine
[0582] a) Methyl-4-[4-(2-chloro-4,5-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate:
2-Chloro-4,5-dimethoxybenzoic acid (0.5 g, 2.3 mmol) and
PC.sub.1.sub.5 (0.54 g, 2.6 mmol) were placed in a round bottomed
flask fitted with a reflux condenser. The mixture was heated in an
oil bath at 120.degree. C. for 70 min. The mixture was allowed to
cool and the formed phosphorus oxychloride was removed under vacuum
to give 0.52 g (96%) of 2-chloro-4,5-dimethoxybenzoyl chloride as a
solid. 2-Chloro-4,5-dimethoxybenzoyl chloride (0.52 g, 2.2 mmol)
was treated in a manner similar to that for Example 32 step (a) to
give 2-bromo-1-(2-chloro-4,5-dimethoxyphenyl) ethan-1-one. The dry
solid (0.65 g, 2.2 mmol) was dissolved in acetone (25 ml). To this
solution
5-(methoxycarbonyl)-2-(methylthio)-thiophene-3-thiocarboxamide
(0.55 g, 2.2 mmol) was added and heated at reflux for 5 h. At this
point the solid that precipitated was filtered off and washed with
acetone and dried under vacuum to give 0.53 g (54%) of methyl
4-[4-(2-chloro-4,5-dimethoxyp- henyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
.sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 2.73 (s, 3H), 3.83 (s,
3H), 3.84 (s, 3H), 3.85 (s, 3H), 7.13 (s, 1H), 7.69 (s, 1H), 8.13
(s, 1H), 8.17 (s, 1H).
[0583] b) 4-[4-(2-Chloro-4,5-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methyl- thiothiophene-2-carboxamidine: Methyl
4-[4-(2-chloro-4,5-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate (0.53 g,
1.2 mmol) as prepared in previous step was treated in a manner
similar to that for Example 1, however the product was purified by
crystallizing from methanol to give to give 0.3 g (60%)
4-[4-(2-chloro-4,5-dimethoxyphe- nyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine as a
solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 2.77 (s, 3H),
3.84 (s, 6H), 7.13 (s, 1H), 7.71 (s, 1H), 8.17 (s, 1H), 8.69 (s,
1H), 9.16 (broad s, 2H), 9.48 (broad s, 2H). Mass spectrum
(MALDI-TOF, m/z): Calcd. for
C.sub.17H.sub.16N.sub.3O.sub.2S.sub.3C.sub.1, 426.0 (M+H), found
426.6.
EXAMPLE 46
[0584]
4-[(Methylethyl)sulfonyl]-5-methylthiothiophene-2-carboxamidine
[0585] Methyl
4-[(methylethyl)sulfonyl]-5-methylthiothiophene-2-carboxylat- e
(100 mg, Maybridge Chemical Company, Cornwall, UK) was treated in a
manner similar to that for Example 1, to give 50 mg of
4-[(methylethyl)sulfonyl]-5-methylthiothiophene-2-carboxamidine.
.sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 1.21 (d, J=6.77 Hz,
6H), 2.66 (s, 3H), 3.55 (m, 1H), 7.85 (s, 1H). Mass spectrum
(MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.9H.sub.14N.sub.2O.sub.2S.sub.3, 279.0 (M+H), found 279.3.
EXAMPLE 47
[0586] Methyl
2-[3-[2-(5-amidino-2-methylthio-3-thienyl)-2,3-thiazol-4-yl2-
phenoxy-2acetate trifluoroacetate
[0587] To a solution of 42 mg (0.094 mmol) of
(tert-butoxy)-N-({4-[4-(3-hy- droxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthio(2-thienyl)}iminomethyl)carbo-
xamide, prepared in a manner similar to Example 40, step (c), in 2
mL of anhydrous N-dimethylformamide (DMF) was added potassium
iodide (0.006 mmol, 1 mg, Aldrich Chemical Co.), cesium carbonate
(0.187 mmol, 61 mg, Aldrich Chemical Co.), and methyl bromoacetate
(0.187 mmol, 18 .mu.L, Aldrich Chemical Co.) and heated to
60.degree. C. overnight. The reaction solution was concentrated and
purified on a 1 mm silica prep plate eluting with 3%
methanol/CH.sub.2Cl.sub.2 to afford 11 mg (23% yield) of methyl
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methylthio--
3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate which was then
subjected to a solution of 50% trifluoracetic acid/CH.sub.2Cl.sub.2
for 1 h then concentrated and triturated with diethyl ether and
dried to afford 7 mg (77% yield) of methyl
2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thia-
zol-4-yl]phenoxyacetate trifluoroacetate. .sup.1H-NMR (CD.sub.3OD;
300 MHz) .delta. 8.51 (s, 1H), 7.92 (s, 1H), 7.66 (m, 2H),
7.34-7.39 (t, 1H), 6.93 (m, 1H), 4.8 (s, 2H) 3.80 (s, 3H), 2.78 (s,
3H). Mass Spectrum (LC-Q ESI, m/z) Calcd. for
C.sub.18H.sub.17N.sub.3O.sub.3S.sub.3: 419.5 (M+H), found
420.3.
EXAMPLE 48
[0588] 5-Methylthio-4-[4-(3-[[N-benzylcarbamoyl]methoxy}phenyl)
(1,3-thiazol-2-yl)]thiophene-2-carboxamidine trifluoroacetate
[0589] 100 mg (0.197 mmol) of
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]imin-
omethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic
acid, as prepared in the previous step, were dissolved in 1 mL of
anhydrous DMF and PyBOP (0.396 mmol, 206 mg), benzylamine (0.396
mmol, 42 mg), and diisopropylethylamine (0.494 mmol; 86 .mu.L) were
added to the solution and stirred for 18 hrs after which the
solution was concentrated and purified on a 2 g silica SPE column
and deprotected with 50% trifluoroacetic acid/ methylene chloride
to afford 60 mg (67% yield) of
5-methylthio-4-[4-(3-{[N-benzylcarbamoyl]methoxy}phenyl)(1,3-thiazol-2-yl-
)]thiophene-2-carboxamidine trifluoroacetate. .sup.1H-NMR
(CDCl.sub.3,TFA-d; 300 MHz) .delta. 8.97 (s, 1H), 7.86 (s, 1H),
7.53 (t, 1H), 7.33 (m, 7H), 7.17 (d, 1H), 4.79 (s, 2H) 4.59 (s,
2H), 2.95 (s, 3H). Mass Spectrum (ESI, m/z) Calcd. for
C.sub.24H.sub.22N.sub.4O.sub.2S.sub.3- : 494.6 (M+H), found
495.2.
EXAMPLE 49
[0590] 2-yl)}-5-methylthiothiophene-2-carboxamidine
trifluoroacetate
[0591] Dissolved 100 mg (0.197 mmol) of
2-{3-[2-(5-{[(tert-butoxy)carbonyl-
amino]iminomethyl]-2-methylthio-3-thienyl)-I1,3-thiazol-4-yl]phenoxy}aceti-
c acid, prepared in a manner similar to Example 48, step (c), in 1
mL of anhydrous DMF and added PyBOP (0.396 mmol, 206 mg),
3,4-dimethoxybenzylamine (0.396 mmol,66 mg), and
diisopropylethylamine (0.494 mmol; 86 .mu.L) and let stir for 18
hrs after which solution was concentrated and purified on a 2 g
silica SPE column and deprotected with 50% trifluoroacetic acid/
methylene chloride to afford 45 mg (41% yield)
4-{4-[3-({N-[(3,4-dimethoxyphenyl)methyl]carbamoyl]methoxy)phenyl](1,3-th-
iazol-2-yl)}-5-methylthiothiophene-2-carboxamidine
trifluoroacetate. .sup.1H-NMR (CDCl3/TFA-d; 300 MHz) .delta. 8.48
(s, 1H), 7.78 (s, 1H), 7.72 (m, 1H), 7.66 (d, 1H), 7.39 (t, 1H),
7.02 (d, 1H) 4.68 (s, 2H), 4.43 (s, 2H), 3.75 (s, 3H). 3.56 (s,
3H). 2.78 (s, 3H). Mass Spectrum (LC-Q ESI, m/z) Calcd. for
C.sub.26H.sub.26N.sub.4O.sub.4S.sub.3: 554.6 (M+H), found 555.2
EXAMPLE 50
[0592]
5-Methylthio-4-[4-[3-({N-[2-phenylamino)ethyl]carbamoyl]methoxy)phe-
nyl(1,3-thiazol-2-yl)}thiophene-2-carboxamidine
trifluoroacetate
[0593] Dissolved 100 mg (0.197 mmol) of
2-{3-[2-(5-{[(tert-butoxy)carbonyl-
amino]iminomethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic
acid, prepared in a manner similar to Example 48, step (c), in 1 mL
of anhydrous DMF and added PyBOP (0.396 mmol, 206 mg),
N-phenylethylenediamine (0.396 mmol, 54 mg), and
diisopropylethylamine (0.494 mmol; 86 .mu.L) and let stir for 18
hrs after which solution was concentrated and purified on a 2 g
silica SPE column and deprotected with 50% trifluoroacetic acid/
methylene chloride to afford 65 mg (63% yield)
5-methylthio-4-{4-[3-(
{N-[2-(phenylamino)ethyl]carbamoyl}methoxy)phenyl]-
(1,3-thiazol-2-yl)}thiophene-2-carboxamidine
trifluoroacetate.sup.1H-NMR (CDCl.sub.3/TFA-d; 300 MHz) .delta.
8.50 (s, 1H), 7.82 (s, 1H), 7.77 (s, 1H), 7.66 (d, 1H), 7.39
(t,1H), 7.02 (d, 1H) 4.68 (s, 2H), 4.43 (s, 2H), 3.75 (s, 3H). 3.56
(s, 3H). 2.78 (s, 3H). Mass Spectrum (LC-Q ESI, m/z) Calcd. for
C.sub.25H.sub.25N.sub.5O.sub.2S.sub.3: 523.6 (M+H), found 524.1
EXAMPLE 51
[0594]
5-Methylthio-4-[4(3-[[N-(2-morpholin-4-ylethyl)carbamoyl(methoxy(ph-
enyl) (1,3-thiazol-2-yl)]thiophene-2-carboxamidine
trifluoroacetate
[0595] 83 mg (0.164 mmol) of
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]imino-
methyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic
acid, prepared in a manner similar to Example 40, step (c), was
reacted with 2-morpholin-4-ylethylamine (0.328 mmol, 43 .mu.L) in a
manner similar to Example 48 to afford 46 mg (54% yield) of
5-methylthio-4-[4-(3-{[N-(2-mor-
pholin-4-ylethyl)carbamoyl]methoxy}phenyl)
(1,3-thiazol-2-yl)]thiophene-2-- carboxamidine trifluoroacetate.
.sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 9.38 (bs, 2H), 9.08
(bs, 2H), 8.61 (s, 1H), 8.45 (t, 1H), 8.27 (s, 1H), 7.72 (m, 2H)
7.45 (t, 1H), 7.02 (d, J=8 Hz, 1H), 4.62 (s, 2H), 3.53-3.64 (m,
5H), 3.24-3.38 (m, 5H), 2.80 (s, 3H), 1.1 (t, 2H). Mass Spectrum
(ESI, m/z) Calcd. for C.sub.23H.sub.27N.sub.5O.sub.3S.sub.3: 517.6
(M+H), found 518.2.
EXAMPLE 52
[0596]
5-Methylthio-4-[4-[3-(2-morpholin-4-yl-2-oxoethoxy)phenyl(1,3-thiaz-
ol-2-yl)}thiophene-2-carboxamidine trifluoroacetate
[0597] 73 mg (0.144 mmol) of
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]imino-
methyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic
acid, prepared in a manner similar to Example 48, step (c), was
reacted with morpholine (0.288 mmol; 25 .mu.L) in a manner similar
to Example 48 step (b) to afford 50 mg (75% yield)
5-methylthio-4-{4-[3-(2-morpholin-4-yl-2--
oxoethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine
trifluoroacetate. .sup.1H-NMR (DMSO-d.sub.6/TFA-d; 300 MHz) .delta.
9.38 (bs, 1H), 9.08 (bs, 2H), 8.66 (s, 1H), 8.22 (s, 1H), 7.72 (m,
2H) 7.42 (t, 1H), 6.98-7.00 (dd, J=2.3 Hz and 8.2 Hz, 1H), 4.95 (s,
2H), 3.53-3.67 (m, 8H), 2.82 (s, 3H). Mass Spectrum (ESI, m/z)
Calcd. for C.sub.21H.sub.22N.sub.4O.sub.3S.sub.3: 474.6 (M+H),
found 475.2.
EXAMPLE 53
[0598]
5-Methylthio-4-4-[3-(2-oxo-2-piperazinylethoxy)phenyl](1,3-thiazol--
2-yl)]thiophene-2-carboxamidine trifluoroacetate
[0599] 100 mg (0.198 mmol) of
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]imin-
omethyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic
acid, prepared in a manner similar to Example 48, step (c), was
reacted with tert-butyl piperazinecarboxylate (0.396 mmol; 74 mg)
in a manner similar to Example 48, step (b) to afford 40 mg (43%
yield) of
5-methylthio-4-{4-[3-(2-oxo-2-piperazinylethoxy)phenyl](1,3-thiazol-2-yl)-
}thiophene-2-carboxamidine trifluoroacetate. .sup.1H-NMR
(DMSO-d.sub.6/TFA-d; 300 MHz) .delta. 8.68 (s, 1H), 8.20(s, 1H),
7.75 (m, 2H) 7.43 (t, 1H), 7.01 (dd, J=2.3 Hz and 8.1 Hz, 1H), 5.02
(s, 2H), 3.76 (bs, 4H), 3.17-3.26 (m, 4H). 2.82 (s, 3H). Mass
Spectrum (LC-Q ESI, m/z) Calcd. for
C.sub.21H.sub.23N.sub.5O.sub.2S.sub.3: 473.6 (M+H), found
474.2.
EXAMPLE 54
[0600] 51 mg (0.101 mmol) of
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]imino-
methyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic
acid, prepared in a manner similar to Example 48, step (c), was
reacted with N-(2-aminoethyl) (tert-butoxy)carboxamide (0.202 mmol;
32 mg) in a manner similar to Example 48, step (b) to afford 80 mg
(80% yield) of
4-(4-{3-[(N-{2-[(tert-butoxy)carbonylamino]ethyl}carbamoyl)methoxy]phenyl-
}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine which
was then deprotected with 4N HCl in dioxane to afford 36 mg (68%
yield) of 4-[4-(3-{[N-(2-aminoethyl)carbamoyl]methoxy}phenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine
hydrochloride. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.55 (s,
1H), 7.95 (s, 1H), 7.73 (m, 2H) 7.41 (t, 1H), 7.05 (m, 1H), 4.80
(s, 2H), 3.51 (m, 2H), 3.13-3.31 (m, 2H), 2.83 (s, 3H). Mass
Spectrum (ESI, m/z) Calcd. for
C.sub.19H.sub.21N.sub.5O.sub.2S.sub.3: 447.5 (M+H), found
448.2.
EXAMPLE 55
[0601] 4-(4-[3-[2-(4-Acetylpiperazinyl)-2-oxoethoxy]phenyl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine
trifluoroacetate
[0602] 52 mg (0.103 mmol) of
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]imino-
methyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic
acid, prepared in a manner similar to Example 48, step (c), was
reacted with 1-acetyl piperazine (0.154 mmol, 20 mg), I
-hydroxy-7-azabenzotriazole (HOAt)) (0.154 mmol, 21 mg),
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetrameth- yluronium
hexafluorophosphate) HATU (0.154 mmol, 58 mg) and
diisopropylethylamine (0.258 mmol, 44 .mu.L) in DMF to afford crude
product which was then purified on 1 mm silica prep plates eluting
with 3% methanol/methylene chloride to afford 28 mg (53% yield) of
N-{[4-(4-{3-[2-(4-acetylpiperazinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl-
))-5-methylthio(2-thienyl)]iminomethyl}(tert-butoxy)carboxamide.
This was subsequently reacted with a solution of trifluoroacetic
acid: methylene chloride: water (47.5%: 47.5%: 2.5%) for 1 hour,
concentrated and purified on a silica SPE column eluting with 15%
methanol/methylene chloride to afford 20 mg (80% yield) of
4-(4-{3-[2-(4-acetylpiperazinyl)--
2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidi-
ne trifluoroacetate. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.48
(s, 1H), 7.91 (s, 1H), 7.69 (m, 2H) 7.38 (t, 1H), 6.99 (dd, J=2 Hz
and 8.1 Hz, 1H), 4.93 (s, 2H), 3.52-3.67 (m, 8H), 2.78 (s, 3H),
2.12 (s, 3H). Mass Spectrum (ESI, m/z) Calcd. for
C.sub.23H.sub.25N.sub.5O.sub.3S.sub.3- : 515.6 (M+H), found
516.2.
EXAMPLE 56
[0603] 4-(4-3-[2-(4-Methylpiperazinyl)-2-oxoethoxy]phenyl)
(1,3-thiazol-2-y1))-5-methylthiothiophene-2-carboxamidine
trifluoroacetate
[0604] 54 mg (0.107 mmol) of
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]imino-
methyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic
acid, prepared in a manner similar to Example 48, step (c), was
reacted with N-methyl piperazine (0.128 mmol, 14 .mu.L),
1-hydroxy-7-azabenzotriazole (HOAt) (0.128 mmol, 17 mg),
O-(7-azabenzotriazol- I -yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) HATU (0.128 mmol, 49 mg) and
diisopropylethylamine (0.268 mmol, 56 AL) in DMF to afford crude
product which was then partitioned between methylene chloride and
1N NaOH and washed. The organic layer was obtained and similarly
washed with 10% citric acid and saturated aq. sodium chloride,
dried over sodium sulfate and concentrated to a yellow oil. The oil
was then purified on 1 mm silica prep plates eluting with 5%
methanol/methylene chloride to afford
(tert-butoxy)-N-{imino[4-(4-{3-[2-(4-methylpiperazinyl)-2-oxoethoxy]pheny-
l}(1,3-thiazol-2-yl))-5-methylthio(2-thienyl)]methyl}carboxamide.
This was subsequently reacted with a solution of trifluoroacetic
acid: methylene chloride: water (47.5%: 47.5%: 2.5%) for 1 hour,
concentrated and purified on a silica SPE column eluting with
10-15% methanol/methylene chloride to afford 17 mg (33% yield) of
4-(4-f{3-[2-(4-methylpiperazinyl)-
-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamid-
ine trifluoroacetate. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta.
8.52 (s, 1H), 7.91 (s, 1H), 7.69 (m, 2H), 7.38 (t, 1H), 6.98 (dd,
J=2.0 Hz and 8.1 Hz, 1H), 4.90 (s, 2H), 3.66 (t, 4H), 2.78 (s, 3H),
2.49-2.57 (m, 4H), 2.35 (s, 3H). Mass Spectrum (ESI, m/z) Calcd.
for C.sub.22H.sub.25N.sub.5- O.sub.2S.sub.3: 487.6 (M+H), found
488.2
EXAMPLE 57
[0605]
5-Methylthio-4-[4-(3-[2-oxo-2-[4-benzylpiperazinyl]ethoxy]phenyl)
(1,3-thiazol-2-yl)]thiophene-2-carboxamidine trifluoroacetate
[0606] 54 mg (0.107 mmol) of
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]imino-
methyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic
acid, prepared in a manner similar to Example 48, step (c), was
reacted with N-benzylpiperazine (0.128 mmol, 22 .mu.L),
1-hydroxy-7-azabenzotriazole (HOAt) (0.128 mmol, 17 mg),
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethy- luronium
hexafluorophosphate) HATU (0.128 mmol, 48 mg) and
diisopropylethylamine (0.267 mmol, 50 .mu.L) in DMF to afford crude
product which was then partitioned between methylene chloride and
1N NaOH and washed. The organic layer was obtained and similarly
washed with 10% citric acid and saturated aq. sodium chloride,
dried over sodium sulfate and concentrated to a yellow oil. The oil
was then purified on 1 mm silica prep plates eluting with 5%
methanol/methylene chloride to afford (tert-butoxy)-N-(imino
{5-methylthio-4-[4-(3-{2-oxo-2-[4-benzylpiperaziny-
l]ethoxy}phenyl) (1,3-thiazol-2-yl)](2-thienyl)}methyl)carboxamide.
This was subsequently reacted with a solution of trifluoroacetic
acid: methylene chloride: water (47.5%: 47.5%: 2.5%) for 1 hour,
concentrated and purified on a 5 g silica SPE column eluting with
10-15% methanol/methylene chloride to afford 36 mg (60% yield) of
5-methylthio-4-[4-(3-{2-oxo-2-[4-benzylpiperazinyl]ethoxy}phenyl)
(1,3-thiazol-2-yl)]thiophene-2-carboxamidine trifluoroacetate.
.sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.54 (s, 1H), 7.93 (s,
1H), 7.71 (m, 2H), 7.50 (s, 5H) 7.39 (t, 1H), 6.99 (dd, J=2 Hz and
8.1 Hz, 1H), 4.94 (s, 2H), 4.37 (s, 2H), 3.3 (m, 4H), 2.81 (s, 3H),
2.49-2.57 (m, 4H), 2.35 (s, 3H). Mass (ESI, m/z) Calcd. for
C.sub.29H.sub.29N.sub.5O.su- b.2S.sub.3: 563.7 (M+H), found
564.3.
EXAMPLE 58
[0607] (D,L)-4-(4-[3-[2-(3-Aminopyrrolidinyl)-2-oxoethoxy]phenyl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine
trifluoroacetate
[0608] 41 mg (0.081 mmol) of
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]imino-
methyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic
acid, prepared in a manner similar to Example 48, step (c), was
reacted with (D,L) (tert-butoxy)-N-pyrrolidin-3-ylcarboxamide
(0.122 mmol, 23 mg),
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) HATU (0.122 mmol, 46 mg),
1-hydroxy-7-azabenzotriazo- le (HOAt) (0.122 mmol, 17 mg) and
diisopropylethylamine (0.203 mmol, 35,.mu.L) in a manner similar to
Example 56 to afford 20 mg (53% yield) of
(D,L)-4-(4-{3-[2-(3-aminopyrrolidinyl)-2-oxoethoxy]phenyl
}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine
trifluoroacetate. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.54
(s, 1H), 7.94 (s, 1H), 7.71 (m, 2H), 7.39 (t, 1H), 6.99 (dd, J=2.0
Hz and 8.1 Hz, 1H), 4.85 (s, 2H), 4.37 (s, 2H), 3.60-4.01 (m, 5H),
2.81 (s, 3H), 2.15-2.71 (m, 2H). Mass Spectrum (ESI, m/z) Calcd.
for C.sub.21H.sub.23N.sub.5O.sub.2S.sub.3: 473.6 (M+H), found
474.3.
EXAMPLE 59
[0609]
5-Methylthio-4-4-[3-(2-oxo-2-piperidylethoxy)phenyl(1,3-thiazol-2-y-
l))thiophene-2-carboxamidine trifluoroacetate
[0610] 33 mg (0.065 mmol) of
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]imino-
methyl}-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic
acid, prepared in a manner similar to Example 40, step (c), was
reacted with piperidine (0.078 mmol, 8 EL),
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetrame- thyluronium
hexafluorophosphate) HATU (0.078 mmol, 30 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.078 mmol, 11 mg) and
diisopropylethylamine (0.163 mmol, 56 .mu.L) in a manner similar to
Example 57 to afford 15 mg (41% yield) of
5-methylthio-4-{4-[3-(2-oxo-2-p-
iperidylethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine
trifluoroacetate. .sup.1H-NMR (CD.sub.3OD; 300 MHz) .delta. 8.54
(s, 1H), 7.92 (s, 1H), 7.69 (m, 2H), 7.35-7.40 (t, 1H), 6.98 (dd,
J=2 Hz and 8.1 Hz. 1H), 4.95 (s, 2H), 3.52-3.60 (m, 4H), 2.80 (s,
3H), 1.57-1.70 (m, 6H). Mass Spectrum (ESI, m/z) Calcd. for
C.sub.22H.sub.24N.sub.4O.sub.2S.- sub.3: 472.6 (M+H), found
473.2.
EXAMPLE 60
[0611] 2-(3-[2-[5-(Imino
{[(4-polystyrloxyphenyl)methoxy}carbonylaminometh-
yl)-2-methylthio-3-thienyl -1,3-thiazol-4-yl]phenoxy)acetic
acid
[0612] 2 g (1.86 mmol) of p-nitrophenyl carbonate Wang resin (0.93
mmol/g) (Calbiochem-Novabiochem, San Diego, Calif.) was suspended
in 9 mL of a 2:1 mixture of anhydrous DMSO:DMF. 2 g (4.93 mmol) of
2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceti-
c acid was added to suspension followed by the addition of 1 mL of
1,8-diazabicyclo[5.4.0]undec-7-ene, (DBU, 6.69 mmol) and let shake
vigorously for 5 days after which resin was washed thoroughly with
DMF, MeOH, and diethyl ether and dried in vacuo to afford 2 g of
resin-bound
2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}aceti-
c acid.
EXAMPLE 61
[0613] (D,L)-Ethyl
1-(2-[3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiaz-
ol-4-yl]phenoxy]acetyl)piperidine-2-carboxylate
trifluoroacetate
[0614] 100 mg (0.093 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio--
3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was suspended 1 mL of
anhydrous DMF.
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) HATU (0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M; 68 mg), ethyl
piperidine-2-carboxylate (0.5 M; 78 .mu.L) and
diisopropylethylamine (0.233 mmol, 40 [.mu.L) were added and
allowed to shake vigorously for 18 hrs, after which the resin was
washed thoroughly with DMF, methanol, methylene chloride, and
diethyl ether. After drying, crude product was removed from resin
by reaction with a solution of trifluoroacetic acid: methylene
chloride: water (47.5%: 47.5%: 2.5%) for 1 hour. The solution was
filtered and concentrated to a yellow oil. After purification on a
2 g silica SPE column, eluting with a gradient of 3%-10%
MeOH/methylene chloride, 15 mg (30% yield) of (D,L)-ethyl
1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-y-
l]phenoxy}acetyl)piperidine-2-carboxylate trifluoroacetate was
obtained. Mass Spectrum (ESI, m/z) Calcd. for
C.sub.25H.sub.28N.sub.4O.sub.4S.sub.3- : 544.70 (M+H), found
545.2
EXAMPLE 62
[0615]
5-Methylthio-4-[4-[3-(2-oxo-2-pyrrolidinylethoxy)phenyl](1,3-thiazo-
l-2-yl)}thiophene-2-carboxamidine trifluoroacetate
[0616] 100 mg (0.093 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio--
3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was suspended 1 mL of
anhydrous DMF.
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) HATU (0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M; 68 mg), pyrrolidine
(0.5 M; 42 .mu.L) and diisopropylethylamine (0.233 mmol, 40 [L)
were added and allowed to shake vigorously for 18 hours, after
which the resin was washed thoroughly with DMF, methanol, methylene
chloride, and diethyl ether. After drying, crude product was
removed from resin by reaction with a solution of trifluoroacetic
acid: methylene chloride: water (47.5%: 47.5%: 2.5%) for I hour.
After trituration with diethyl ether and drying, 18 mg (42% yield)
of 5-methylthio-4-{4-[3-(2-oxo-2-pyrrolidinylethoxy)phenyl](1,3-th-
iazol-2-yl)}thiophene-2-carboxamidine trifluoroacetate was
obtained. Mass Spectrum (ESI, m/z) Calcd. for
C.sub.21H.sub.22N.sub.4O.sub.2S.sub.3: 458.6 (M+H), found 459.2
EXAMPLE 63
[0617] 5
S-Methylthio-4-[4-(3-[2-oxo-2-[4-benzylpiperidyl]ethoxy}phenyl)
(1,3-thiazol-2-yl)]thiophene-2-carboxamidine trifluoroacetate
[0618] 80 mg (0.074 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio-3-
-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was suspended in 1 mL
of anhydrous DMF.
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) HATU (0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M; 68 mg), 4-benzyl
piperidine (0.5 M; 88 .mu.L) and diisopropylethylamine (0.185 mmol,
32 .mu.L) were added and allowed to shake vigorously for 18 hrs,
after which the resin was washed thoroughly with DMF, methanol,
methylene chloride, and diethyl ether. After drying, crude product
was removed from resin by reaction with a solution of
trifluoroacetic acid: methylene chloride: water (47.5%: 47.5%:
2.5%) for 1 hour. After trituration with diethyl ether and drying,
17 mg (40% yield) of
5-methylthio-4-[4-(3-{2-oxo-2-[4-benzylpiperidyl]ethoxy}phenyl)
(1,3-thiazol-2-yl)]thiophene-2-carboxamidine trifluoroacetate was
obtained. Mass Spectrum (ESI, m/z) Calcd. for
C.sub.29H.sub.30N.sub.4O.su- b.2S.sub.3: 562.7 (M+H), found
563.3.
EXAMPLE 64
[0619] (D,L)-4-(43-[2-(3-Methylpiperidyl)
-2-oxoethoxy]phenyl}(1,3-thiazol-
-2-yl))-5-methylthiothiophene-2-carboxamidine trifluoroacetate
[0620] 80 mg (0.074 mmol) of resin-bound
2-f{3-[2-(5-amidino-2-methylthio--
3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was reacted with
(+/-)-3-methyl piperidine (0.5 M, 59 .mu.L) and
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetra- methyluronium
hexafluorophosphate) HATU (0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M; 68 mg) and
diisopropylethylamine (0.185 mmol, 32 .mu.L) in 1 mL of anhydrous
DMF in a manner similar to Example 63 to afford 10 mg (28% yield)
of
4-(4-{3-[2-(3-methylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5-m-
ethylthiothiophene-2-carboxamidine trifluoroacetate. Mass Spectrum
(ESI, m/z) Calcd. for C.sub.23H.sub.26N.sub.4O.sub.2S.sub.3: 486.6
(M+H), found 487.3.
EXAMPLE 65
[0621]
4-(4-[3-[2-(4-Methylpiperidyl)-2-oxoethoxy]phenyl(1,3-thiazol-2-yl)-
)-5-methylthiothiophene-2-carboxamidine trifluoroacetate
[0622] 80 mg (0.074 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio-3-
-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was reacted with
4-methyl piperidine (0.5 M, 59 .mu.L) and
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroni- um
hexafluorophosphate) HATU (0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M; 68 mg) and
diisopropylethylamine (0.185 mmol, 32 .mu.L) in 1 mL of anhydrous
DMF in a manner similar to Example 63 to afford 12 mg (33% yield)
of 4-(4-{3-[2-(4-methylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thi-
azol-2-yl))-5-methylthiothiophene-2-carboxamidine trifluoroacetate.
Mass Spectrum (ESI, m/z) Calcd. for
C.sub.23H.sub.26N.sub.4O.sub.2S.sub.3: 486.6 (M+H), found
487.3.
EXAMPLE 66
[0623]
4-(4-[3-[2-(2-Azabicyclo[4.4.]dec-2-yl)-2-oxoethoxy]phenyl](1,3-thi-
azol-2-yl))-5-methylthiothiophene-2-carboxamidine
trifluoroacetate
[0624] 80 mg (0.074 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio-3-
-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was reacted with
decahydroquinoline (0.5 M, 75 .mu.L) and
O-(7-azabenzotriazol-1-yl)-]-1,1,3,3-tetramethyluro- nium
hexafluorophosphate) HATU (0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazo- le (HOAt) (0.5 M; 68 mg) and
diisopropylethylamine (0.185 mmol, 32 .mu.L) in 1 mL of anhydrous
DMF in a manner similar to Example 63 to afford 16 mg (41% yield)
of 4-(4-{3-[2-(2-azabicyclo[4.4.0]dec-2-yl)-2-oxoethoxy]ph-
enyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine
trifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for
C.sub.26H.sub.30N.sub.4O.sub.2S.sub.3: 526.7 (M+H), found
527.2.
EXAMPLE 67
[0625] (D,L)-Ethyl
1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiaz-
ol-4-yl]phenoxy]acetyl)piperidine-3-carboxylate
trifluoroacetate
[0626] 80 mg (0.074 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio-3-
-thienyl)-1,3-thiazol-4-yl]phenoxy)acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was reacted with ethyl
nipecotate (0.5 M, 78 .mu.L) and O-(7-azabenzotriazol-1-yl)-1,1,3,3
tetramethyluronium hexafluorophosphate) HATU (0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M, 68 mg) and
diisopropylethylamine (0.185 mmol, 32 .mu.L) in 1 mL of anhydrous
DMF in a manner similar to Example 63 to afford 18 mg (45% yield)
of ethyl 1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-th-
iazol-4-yl]phenoxy}acetyl)piperidine-3-carboxylate
trifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for
C.sub.28H.sub.28N.sub.4O.sub.4S.sub.3: 545.7 (M+H), found
545.2.
EXAMPLE 68
[0627]
5-Methylthio-4-[4-[3-(2-oxo-2-(I,2,3,4-tetrahydroquinolyl)ethoxy)ph-
enyl](1,3-thiazol-2-yl)]thiophene-2-carboxamidine
trifluoroacetate
[0628] 100 mg (0.093 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio--
3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was reacted with
1,2,3,4-tetrahydroisoquinoline (0.5M) and
O-(7-azabenzotriazol-1-yl)-1,1,- 3,3-tetramethyluronium
hexafluorophosphate) HATU (0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M; 68 mg) and
diisopropylethylamine (0.233 mmol, 40 .mu.L) in 1 mL of anhydrous
DMF in a manner similar to Example 63 to afford 20 mg (42% yield)
of
5-methylthio-4-{4-[3-(2-oxo-2-(1,2,3,4-tetrahydroquinolyl)ethoxy)phenyl](-
1,3-thiazol-2-yl)}thiophene-2-carboxamidine trifluoroacetate. Mass
Spectrum (ESI, m/z) Calcd. for
C.sub.26H.sub.24N.sub.4O.sub.2S.sub.3: 520.7 (M+H), found
521.2.
EXAMPLE 69
[0629] Ethyl
1-(2-(3-J2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-y-
l]phenoxy}ethyl)piperidine-4-carboxylate trifluoroacetate
[0630] 100 mg (0.093 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio--
3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was reacted with ethyl
isonipecotate (0.5 M, 77 mg) and
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) HATU (0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M; 68 mg) and
diisopropylethylamine (0.233 mmol, 40 [.mu.L) in 1 mL of anhydrous
DMF in a manner similar to Example 63 to afford 21 mg (42% yield)
of ethyl 1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-
-thiazol-4-yl]phenoxy}acetyl)piperidine-4-carboxylate
trifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for
C.sub.25H.sub.28N.sub.4O.sub.4S.sub.3- : 545.7 (M+H), found
545.3.
EXAMPLE 70
[0631] 4-(4-[3-[2-((3R)-3-Hydroxypiperidyl)-2-oxoethoxy]phenyl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine
trifluoroacetate
[0632] 100 mg (0.093 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio--
3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was reacted with
R-(+)-3-hydroxy piperidine (0.5 M, 69 mg) and
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramet- hyluronium
hexafluorophosphate) HATU (0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5M; 68 mg) and
diisopropylethylamine (0.233 mmol, 40 .mu.L) in 1 mL of anhydrous
DMF in a manner similar to Example 63 to afford 16 mg (36% yield)
of
4-(4-{3-[2-((3R)-3-hydroxypiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl-
))-5-methylthiothiophene-2-carboxamidine trifluoroacetate. Mass
Spectrum (ESI, m/z) Calcd. for
C.sub.22H.sub.23N.sub.4O.sub.3S.sub.3: 489.7 (M+H), found
489.2.
EXAMPLE 71
[0633]
D,L-4-(4-[3-[2-(2-Ethylpiperidyl)-2-oxoethoxy]phenyl]l(1,3-thiazol--
2-yl))-5-methylthiothiophene-2-carboxamidine trifluoroacetate
[0634] 100 mg (0.093 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio--
3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was reacted with
2-ethyl piperidine (0.5M) and
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) HATU (0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5M; 68 mg) and
diisopropylethylamine (0.233 mmol, 40 L) in 1 mL of anhydrous DMF
in a manner similar to Example 63 to afford 11 mg (23% yield) of
D,L-4-(4-{3-[2-(2-ethylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiaz-
ol-2-yl))-5-methylthiothiophene-2-carboxamidine trifluoroacetate.
Mass Spectrum (ESI, m/z) Calcd. for
C.sub.24H.sub.27N.sub.4O.sub.2S.sub.3: 501.4 (M+H), found
501.4.
EXAMPLE 72
[0635]
4(4-[3-[2-((3S)-3-Hydroxypyrrolidinyl)-2-oxoethoxy]phenyl}(1,3-thia-
zol-2-yl))-5-methylthiothiophene-2-carboxamidine
trifluoroacetate
[0636] 100 mg (0.093 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio--
3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was reacted with
R-(-)-3-pyrrolidinol (0.5 M, 62 mg) and
0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) (HATU, 0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5M; 68 mg) and
diisopropylethylamine (0.233 mmol, 40 .mu.L) in 1 mL of anhydrous
DMF in a manner similar to Example 63 to afford 10 mg (23% yield)
of 4-(4-{3-[2-((3S)-3-hydroxypyrrolidinyl)-2-oxoethoxy]phenyl
}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine
trifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for
C.sub.21H.sub.22N.sub.4O.sub.3S.sub.3: 475.2 (M+H), found
475.2.
EXAMPLE 73
[0637]
5-Methylthio-4-(4-[3-[(N-(5,6,7,8-tetrahydronaphthyl)carbamoyl)meth-
oxy]phenyl}(1,3-thiazol-2-yl))thiophene-2-carboxamidine
trifluoroacetate
[0638] 100 mg (0.093 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio--
3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was reacted with
5,6,7,8-tetrahydro-1-naphthylamine (0.5 M, 73 mg) and
0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) (HATU, 0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M; 68 mg) and
diisopropylethylamine (0.233 mmol, 40 [.mu.L) in 1 mL of anhydrous
DMF in a manner similar to Example 63 to afford 15 mg (30% yield)
of 5-methylthio-4-(4-{3-[(N-(5,6,7,8-tetrahydronaphthyl)ca-
rbamoyl)methoxy]phenyl
}(1,3-thiazol-2-yl))thiophene-2-carboxamidine trifluoroacetate.
Mass Spectrum (ESI, m/z) Calcd. for
C.sub.27H.sub.26N.sub.4O.sub.2S.sub.3: 535.2 (M+H), found
535.3.
EXAMPLE 74
[0639]
D,L-4-[4-(3-[2-[3-(Hydroxymethyl)piperidyl]-2-oxoethoxy}phenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine
trifluoroacetate
[0640] 100 mg (0.093 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio--
3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was reacted with
3-piperidine methanol (0.5 M, 58 mg) and
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) (HATU, 0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5M; 68 mg) and
diisopropylethylamine (0.233 mmol, 40 .mu.L in 1 mL of anhydrous
DMF in a manner similar to Example 40 to afford to 19 mg (40%
yield) of
D,L-4-[4-(3-{2-[3-(hydroxymethyl)piperidyl]-2-oxoethoxy}ph- enyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine
trifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for
C.sub.23H.sub.25N.sub.4O.sub.3S.sub.3: 503.2 (M+H), found
503.2.
EXAMPLE 75
[0641]
4{4-4-[3-(2-[(2R)-2-[(Phenylamino)methyl]pyrrolidinyl}-2-oxoethoxy)-
phenyl](1,3-thiazol-2-yl)J-5-methylthiothiophene-2-carboxamidine
trifluoroacetate
[0642] 100 mg (0.093 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio--
3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was reacted with
(S)-(+)-2-anilino methyl pyrrolidine (0.5 M, 88 mg) and
O-(7-azabenzotriazol-1-yl)-1,1,3,3-- tetramethyluronium
hexafluorophosphate) (HATU, 0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5M; 68 mg) and
diisopropylethylamine (0.233 mmol, 40 .mu.L) in 1 mL of anhydrous
DMF in a manner similar to Example 63 to afford 13 mg (25% yield)
of
4-{4-[3-(2-{(2R)-2-[(phenylamino)methyl]pyrrolidinyl}-2-oxoethoxy)phenyl]-
(1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidine
trifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for
C.sub.28H.sub.28N.sub.5O.sub.2S.sub.3: 563.8 (M+H), found
564.2.
EXAMPLE 76
[0643] 4-[4-(3-[2-[(3R)-3-(Methoxymethyl)pyrrolidinyl]-2-oxoethoxy
phenyl) (1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine
trifluoroacetate
[0644] 100 mg (0.093 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio--
3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was reacted with
(S)-(+)-2-methoxymethyl pyrrolidine (0.5 M, 58 mg) and
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) (HATU, 0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5M; 68 mg) and
diisopropylethylamine (0.233 mmol, 40 .mu.L) in 1 mL of anhydrous
DMF in a manner similar to Example 63 to afford 16 mg (35% yield)
of 4-[4-(3-{2-[(3R)-3-(methoxymethyl)pyrrolidinyl]-2-oxoethox-
y}phenyl) (1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine
trifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for
C.sub.23H.sub.26N.sub.4O.sub.3S.sub.3: 503.2 (M+H), found
503.3.
EXAMPLE 77
[0645]
1-(2-[3-[2-(5-Amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phen-
oxy]acetyl)piperidine-3-carboxamide trifluoroacetate
[0646] 100 mg (0.093 mmol) of resin-bound
2-{3-[2-(5-amidino-2-methylthio--
3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as
prepared in a manner similar to Example 60, was reacted with
nipecotamide (0.5 M, 64 mg) and
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate) (HATU, 0.5 M, 190 mg),
1-hydroxy-7-azabenzotriazole (HOAt) (0.5M; 68 mg) and
diisopropylethylamine (0.233 mmol, 40 .mu.L) in 1 mL of anhydrous
DMF in a manner similar to Example 63 to afford 11 mg (23% yield)
1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-y-
l]phenoxy}acetyl)piperidine-3-carboxamide trifluoroacetate. Mass
Spectrum (ESI, m/z) Calcd. for
C.sub.23H.sub.25N.sub.4O.sub.3S.sub.3: 516.2 (M+H), found
516.3.
EXAMPLE 78
[0647]
5-Methylthio-4-[4-[3-(trifluoromethoxy)phenyl](1,3-thiazol-2-yl)]th-
iophene-2-carboxamidine hydrochloride
[0648] a) Methyl
S-methylthio-4-(4-[3-(trifluoromethoxy)phenyl](1,3-thiazo-
l-2-yl)]thiophene-2-carboxylate: 435 mg (1.76 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate was
dissolved in 10 mL of reagent grade acetone.
2-bromo-3-trifluoromethoxy acetophenone, prepared in a manner
similar to Example 95, step (a), (1.76 mmol; 497 mg) was added and
the solution was allowed to reflux for 3 h. The solution was
allowed to cool and concentrated to an oil which was then dissolved
in 150 mL of methylene chloride and washed with 50 mL of 10% HCl
(aq.) and 50 mL of 2N NaOH (aq.). The organic layer was obtained
and dried over magnesium sulfate and concentrated affording 877 mg
(90% yield) of a
methyl-5-methylthio-4-{4-[3-(trifluoromethoxy)phenyl](1,3-thi-
azol-2-yl)}thiophene-2-carboxylate.
[0649] b)
5-Methylthio-4-[4-[3-(trifluoromethoxy)phenyl](1,3-thiazol-2-yl)-
]thiophene-2-carboxamidine hydrochloride: To a stirred suspension
of 19.4 mmol (1.04 g) of ammonium chloride (Fisher Scientific) in
20 mL of anhydrous toluene (Aldrich Chemical Co.) placed under
nitrogen atmosphere at 0.degree. C., 9.7 mL (19.4 mmol) of 2M
trimethylaluminum in toluene (Aldrich Chemical Co.) was added via
syringe over 15 min and then let stir at 0.degree. C. for 30 min
after which 837 mg (1.94 mmol) of
methyl-5-methylthio-4-{4-[3-(trifluoromethoxy)phenyl](1,3-thiazol-2-yl)}t-
hiophene-2-carboxylate was added to solution and allowed to reflux
for 3 h. The reaction mixture was quenched by pouring over a slurry
of 10 g of silica in 50 mL of chloroform. The silica was poured
onto a sintered glass funnel and washed with ethyl acetate and
eluting with a 15% methanol/CH,Cl.sub.2 solution and concentrated.
The crude product was purified on 1 mm silica prep plates eluting
with 15% methanol/CH.sub.2Cl.sub.2 and treated with 4N HCl/dioxane
to afford 37 mg (5% yield) of
5-methylthio-4-{4-[3-(trifluoromethoxy)phenyl](1,3-thiazol--
2-yl)}thiophene-2-carboxamidine hydrochloride. .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) .delta. 9.43 (bs, 1.9 H), 9.05 (bs, 1.9 H),
8.67 (s, 1H), 8.43 (s, 1H), 8.10 (m, 2H), 7.65 (t, 1H), 7.40 (m,
1H), 2.8 (s, 3H). Mass Spectrum (LCQ-ESI, m/z) Calcd. for
C.sub.16H.sub.12F.sub.3N.sub.3OS.sub.3- : 415.5(M+H), found
416.2.
EXAMPLE 79
[0650]
5-Methylthio-4-(5-phenyl(1,3-oxazol-2-yl))thiophene-2-carboxamidine
hydrochloride
[0651] a) Methyl
5-methylthio-4-[N-(2-oxo-2-phenylethyl)carbamoyl]thiophen-
e-2-carboxylate: To a stirred suspension of 300 mg (1.29 mmol) of
5-(methoxycarbonyl)-2-methylthiothiophene-3-carboxylic acid (as
prepared in Example 95) in 10 mL of anhyd CH.sub.2Cl.sub.2 (under a
CaSO.sub.4 drying tube) was added 135 mL (1.55 mmol) of oxalyl
chloride followed by 30 mL of anhyd DMF. After stirring for 2 h at
room temperature, the mixture was concentrated in vacuo. The
resulting yellow solid was dissolved in 10 mL of anhyd
CH.sub.2Cl.sub.2, cooled (0.degree. C.) and 266 mg (1.55 mmol) of
2-aminoacetophenone was added. N,N-diisopropylethylamine (DIEA)
(756 mL, 4.34 mmol) was added dropwise over 3 min and the mixture
stirred for 1 h at room temperature. The mixture was concentrated
to an oil and partitioned between 125 mL of EtOAc and 80 mL of 1 M
HCl. The aqueous layer was extracted with ethyl acetate (2.times.30
mL) and the combined organic phases were washed with 1 M HCl (60
mL), saturated NaHCO.sub.3 (120 mL), and brine (120 mL) and dried
over NaSO.sub.4. After removing the solvent in vacuo, the residue
was recrystallized from MeOH to afford the title compound as a
cream-colored powder (314 mg, 70%). .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.82 (t, 1H, J=6 Hz), 8.43 (s, 1H), 8.02 (d,
2H, J=7 Hz), 7.69 (t, 1H, J=7 Hz), 7.57 (t, 2H, J=7 Hz), 4.72 (d,
2H, J=6 Hz), 3.84 (s, 3H) and 2.57 (s, 3H). Mass spectrum
(MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for
C.sub.16H.sub.15NO.sub.4S.sub.2: 372.0 (M+Na). Found: 372.1.
[0652] b) Methyl
5-methylthio-4-(5-phenyl(1,3-oxazol-2-yl))thiophene-2-car-
boxylate: To a cooled (0.degree. C.) solution of 80.1 mg (0.229
mmol) of methyl
5-methylthio-4-[N-(2-oxo-2-phenylethyl)carbamoyl]thiophene-2-carbo-
xylate (as prepared in the previous step) in 2 mL of anhyd DMF was
added 26.7 mL (0.286 mmol) of phosphorus oxychloride. After
stirring for 20 h at room temperature, the mixture was concentrated
in vacuo. The resulting yellow solid was recrystallized twice from
MeOH to afford the title compound as a beige powder (48.8 mg, 64%).
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 8.26 (s, 1H), 7.88 (s,
1H), 7.86 (d, 2H, J=7 Hz), 7.51 (m, 2H), 7.40 (m, 1H), 3.86 (s,
3H), and 2.79 (s, 3H). Mass spectrum (MALDI-TOF,
a-cyano-4-hydroxycinnamic acid matrix) calcd. for
C.sub.16H.sub.13NO.sub.3S.sub.2: 332.0 (M+H). Found: 331.9.
[0653] c)
5-Methylthio-4(5-phenyl(1,3-oxazol-2-yl))thiophene-2-carboxamidi-
ne hydrochloride: Methyl
5-methylthio-4-(5-phenyl(1,3-oxazol-2-yl))thiophe- ne-2-carboxylate
(37.0 mg, 0.112 mmol, as prepared in the previous step) was treated
according to the procedure in Example 10, step (b) using 59.9 mg
(1.12 mmol) of ammonium chloride in 0.50 mL of toluene and 0.560 mL
(1.12 mmol) of 2 M trimethylaluminum in toluene. The resulting
residue was chromatographed on a 5 g silica SPE column (Waters
Sep-Pak) with 10% MeOH--CH.sub.2Cl.sub.2 to elute an impurity
followed by 20% MeOH--CH.sub.2Cl.sub.2 to give 39 mg of a light
yellow glass. Crystallization from MeOH--MeCN afforded the title
compound as a cream-colored solid (33.4 mg, 85%). .sup.1H-NMR (300
MHz, DMSO-d.sub.6) .delta. 9.45 (broad s, 2H), 9.13 (broad s, 2H),
8.72 (s, 1H), 7.93 (s, 1H), 7.84 (d, 2H, J=7 Hz), 7.53 (t, 2H, J=7
Hz), 7.42 (t, 1H, J=7 Hz), and 2.80 (s, 3H). Mass spectrum
(MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for
C.sub.15H.sub.13N.sub.3OS.sub.2: 316.1 (M+H). Found: 316.5.
EXAMPLES 80 and 81
[0654]
5-Methylthio-4-(4-phenylimidazol-2-yl)thiophene-2-carboxamidine
trifluoroacetate and
5-Methylthio-4-[N-(2-oxo-2-phenylethyl)carbamoyl]thi-
ophene-2-carboxamidine trifluoroacetate
[0655] Methyl
5-methylthio-4-[N-(2-oxo-2-phenylethyl)carbamoyl]thiophene-2-
-carboxylate (39.4 mg, 0.100 mmol, as prepared in Example 79, step
(a)) was treated according to the procedure in Example 10, step (b)
using 64.2 mg (1.20 mmol) of ammonium chloride in 0.2 mL of toluene
and 0.600 mL (1.20 mmol) of 2 M trimethylaluminum in toluene. The
resulting residue was chromatographed on a 5-g silica SPE column
(Waters Sep-Pak) with a gradient of 5-20% MeOH--CH.sub.2Cl.sub.2 to
elute an impurity followed by 20% MeOH--CH.sub.2C.sub.2 to give a
yellow resin. Crystallization from MeOH-Et.sub.2O-MeCN afforded 16
mg of a yellow solid consisting of two products by.sup.1H-NMR
spectra. A portion of the mixture (11 mg) was purified by
reverse-phase HPLC (5m C.sub.8 column, 4.6.times.100 mm, gradient
5-100% solvent B over 15 min, solvent A=0.1% TFA/H.sub.2O, solvent
B=0.1%TFA/MeCN, detection at 215 nm) to afford 6 mg of
5-methylthio-4-(4-phenylimidazol-2-yl)thiophene-2-carboxamidine
trifluoroacetate as a colorless glass. .sup.1H-NMR (300 MHz,
CD.sub.3OD) .delta. 8.23 (s, 1H), 7.80 (s, 1H), 7.79 (d, 2H, J=7
Hz), 7.48 (m, 2H), 7.39 (m, 1H), and 2.78 (s, 3H). Mass spectrum
(electrospray ionization) calcd. for
C.sub.15H.sub.14N.sub.4S.sub.2: 315.1 (M+H). Found: 315.3. Also
isolated was 4 mg of
5-methylthio-4-[N-(2-oxo-2-phenylethyl)carbamoy-
l]-thiophene-2-carboxamidine trifluoroacetate as a colorless glass.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.30 (broad s, 2H),
8.86 (broad s, 2H), 8.68 (t, 1H, J=5.4 Hz), 8.43 (s, 1H), 8.04 (d,
2H, J=7 Hz), 7.70 (t, 1H, J=7 Hz), 7.58 (t, 2H, J=7 Hz), 4.78 (d,
2H, J=5.4 Hz), and 2.63 (s, 3H). Mass spectrum (electrospray
ionization) calcd. for C.sub.15H.sub.15N.sub.3O.sub.2S.sub.2: 334.1
(M+H). Found: 334.3.
EXAMPLE 82
[0656] 4-(4-Phenyl-1,3-thiazol-2-yl)thiophene-2-carboxamidine
hydrochloride
[0657] a) 4-Bromothiophene-2-carboxylic acid: To a cooled
(0.degree. C.) solution of 10.0 g (47.1 mmol based on 90% purity)
of 4-bromothiophene-2-carbaldehyde (Aldrich Chemical Company,
Milwaukee, Wis.) in 200 mL of t-butanol was added 100 mL of 20 %
(w/v) NaH.sub.2PO.sub.4 followed by 60 mL (0.566 mol) of
2-methyl-2-butene. Sodium chlorite (70.8 mmol based on 80% purity)
in 60 mL of water was added with stirring. After stirring the
two-phase mixture vigorously for 16 h at room temperature, the pH
of the aqueous layer was adjusted to 1-2 with 20% HCl. The layers
were separated and the aqueous layer extracted with EtOAc
(2.times.120 mL). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to afford 9.8 g of an
off-white solid. Recrystallization from a minimum of MeCN (three
crops) gave the title compound as a white solid (9.02 g, 93%).
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.79 (d, 1H, J=1.5 Hz),
and 7.55 (d, 1H, J=1.5 Hz).
[0658] b) Methyl 4-bromothiophene-2-carboxylate: To a cooled
(-20.degree. C.) solution of 6.02 g (29.1 mmol) of
4-bromothiophene-2-carboxylic acid (as prepared in the previous
step) in 100 mL of anhyd MeOH under nitrogen was added 2.55 mL
(34.9 mmol) of thionyl chloride dropwise at a rate to keep the
temperature below -5.degree. C. (ca. 8-10 min). After stirring for
1 h at room temperature, the mixture was refluxed for 8 h, cooled,
and concentrated in vacuo. The resulting 6.7 g of pale amber oil
was passed through a 150 g pad of silica gel with ca. 600 mL of
CH.sub.2Cl.sub.2 (discarding the first 120 mL which contained a
minor impurity) to afford, after concentration in vacuo, the title
compound as a colorless oil (6.11 g, 95%). .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta. 7.69 (d, 1H, J=1.5 Hz), 7.45 (d, 1H, J=1.5 Hz),
and 3.90 (s, 3H).
[0659] c) Methyl 4-cyanothiophene-2-carboxylate: To a solution of
3.82 g (17.3 mmol) methyl 4-bromothiophene-2-carboxylate (as
prepared in the previous step) in 10 mL of anhyd DMF was added 3.10
g (34.6 mmol) of copper (I) cyanide. The mixture was heated to
reflux with stirring for 18 h, cooled and poured into 100 mL of 10%
(w/v) KCN. The mixture was extracted with EtOAc (3.times.60 mL) and
the combined extracts were washed with 150 mL each of water and
brine. The dark solution was dried over Na2SO.sub.4, treated with
decolorizing carbon, filtered and the resulting colorless solution
concentrated in vacuo. The resulting light yellow solid was
recrystallized from MeOH to afford the title compound as a
cream-colored solid (1.67 g, 58%). .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta. 8.09 (d, 1H, J=1.4 Hz), 7.93 (d, 1H, J=1.4 Hz),
and 3.93 (s, 3H). IR (film): 2235 and 1712 cm.sup.-1.
[0660] d) Methyl 4-(aminothioxomethyl)thiophene-2-carboxylate: A
solution of 1.32 g (7.89 mmol) of methyl
4-cyanothiophene-2-carboxylate (as prepared in the previous step)
in 200 mL of reagent grade MeOH was degassed with nitrogen through
a fritted gas dispersion tube for 10 min. Triethylamine (5.50 mL,
39.5 mmol) was added and hydrogen sulfide gas was bubbled into the
solution at a vigorous rate for 5 min and then at a minimal rate
(as measured through an outlet oil bubbler) for 5 h with stirring.
The gas introduction was stopped and the mixture was capped and
stirred for 19 h at room temperature. The mixture was concentrated
in vacuo to a yellow solid which was suspended in 10 mL of EtOH,
cooled to -20.degree. C., and filtered washing with 5 mL of cold
(-20.degree. C.) EtOH. The resulting solid was dried under suction
followed by high vacuum to afford the title compound as a beige
solid (1.31 g, 82%). .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.
9.85 (broad s, 1H), 9.51 (broad s, 1H), 8.50 (d, 1H, J=1.5 Hz),
8.28 (d, 1H, J=1.5 Hz), and 3.84 (s, 3H).
[0661] e) Methyl
4-(4-phenyl-1,3-thiazol-2-yl)thiophene-2-carboxylate: To a solution
of 150 mg (0.745 mmol) of methyl 4-(aminothioxomethyl)-thiophe-
ne-2-carboxylate (as prepared in the previous step) in 6 mL of
acetone was added 148 mg (0.745 mmol) of 2-bromoacetophenone. After
refluxing for 2 h, the mixture was concentrated by boiling to a
volume of ca. 2 mL. The resulting mixture was cooled (-10.degree.
C.) and filtered washing with cold acetone (2.times.0.5 mL). A
second crop was obtained from the mother liquors and the combined
crops dried to afford the title compound as a beige solid (202 mg,
90%). .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 8.56 (d, 1H,
J=1.5 Hz), 8.25 (d, 1H, J=1.5 Hz), 8.18 (s, 1H), 8.04 (d, 2H, J=7
Hz), 7.48 (t, 2H, J=7 Hz), 7.38 (t, 1H, J=7 Hz), and 3.89 (s, 3H).
Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix)
calcd. for C.sub.15H.sub.11NO.sub.2S.sub.2: 302.0 (M+H). Found:
301.8.
[0662] f) 4-(4-Phenyl-l,3-thiazol-2-yl)thiophene-2-carboxamidine
hydrochloride: Methyl
4-(4-phenyl-1,3-thiazol-2-yl)thiophene-2-carboxylat- e (160 mg,
0.531 mmol, as prepared in the previous step) was treated according
to the procedure in Example 10, step (b) using 284 mg (5.31 mmol)
of ammonium chloride in 2.6 mL of toluene and 2.65 mL (5.30 mmol)
of 2 M trimethylaluminum in toluene. The resulting light yellow
solid was chromatographed on a 10 g silica SPE column (Waters
Sep-Pak) with a gradient of 5-20% MeOH--CH.sub.2Cl.sub.2 The
resulting pale amber glass was triturated with
CH.sub.2Cl.sub.2-MeCN and concentrated in vacuo to afford the title
compound as a beige solid (68 mg, 45%). .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) .delta. 9.51 (broad s, 2H), 9.09 (broad s, 2H), 8.71
(d, 1H, J=1.5 Hz), 8.61 (d, 1H, J=1.5 Hz), 8.21 (s, 1H), 8.05 (d,
2H, J=7 Hz), 7.50 (t, 2H, J=7 Hz), and 7.40 (t, 1H, J=7 Hz). Mass
spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd.
for C.sub.14H.sub.11N.sub.3S.sub.2: 286.0 (M+H). Found: 286.3.
EXAMPLE 83
[0663]
5-Methylthio-4-[4-benzyl(1,3-thiazol-2-yl)]thiophene-2-carboxamidin-
e hydrochloride
[0664] a) Bromo-3-phenylacetone: To a solution of 132 mL (1.00
mmol) of phenylacetyl chloride in 1.0 mL of anhyd MeCN was added
1.05 mL (2.10 mmol) of a 2 M solution of trimethylsilyldiazomethane
in hexane. After stirring 1 h at room temperature, the mixture was
cooled (0.degree. C.) and 300 mL (1.50 mmol) of 30 wt % HBr in
acetic acid was added dropwise (gas evolution). After stirring 15
min, the mixture was concentrated in vacuo and rapidly
chromatographed on a 2 g silica SPE column (Waters Sep-Pak) with
50% CH.sub.2Cl.sub.2-hexane to afford the title compound as a pale
yellow oil (201 mg, 94%). .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.
7.2-7.4 (m, SH), 3.95 (s, 2H), 3.92 (s, 2H).
[0665] b) Methyl
5-methylthio-4-[4-benzyl(1,3-thiazol-2-yl)]thiophene-2-ca-
rboxylate: Using a procedure similar to that of Example 10 with 171
mg (0.690 mmol) of methyl
.sup.4-(aminothioxomethyl)-5-methylthiothiophene-2- -carboxylate
(as prepared in Example 82, step (e)) in 4 mL of acetone and 147 mg
(0.690 mmol) of I -bromo-3-phenylacetone (as prepared in the
previous step) afforded the title compound as a light tan powder
(236 mg, 95%). .sup.1H-NMR (300 MHz, DMSO -d.sub.6) .delta. 8.11
(s, 1H), 7.2-7.4 (m, 5H), 4.11 (s, 2H), 3.84 (s, 3H), and 2.72 (s,
3H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid
matrix) calcd. for C.sub.17H.sub.15NO.sub.2S.sub.3: 362.0 (M+H).
Found: 362.3.
[0666] c)
5-Methylthio-4-[4-benzyl(1,3-thiazol-2-yl)]thiophene-2-carboxami-
dine hydrochloride: Methyl
5-methylthio-4-[4-benzyl(1,3-thiazol-2-yl)]thio-
phene-2-carboxylate (60 mg, 0.166 mmol, as prepared in the previous
step) was treated according to the procedure in Example 10, step
(b) using 88.8 mg (1.66 mmol) of ammonium chloride in 0.5 mL of
toluene and 0.830 mL (5.30 mmol) of 2 M trimethylaluminum in
toluene to afford, after trituration from MeOH with Et2O, the title
compound as a yellow solid (38.2 mg, 60%). .sup.1H-NMR (300 MHz,
CD.sub.3OD) .delta. 8.43 (s, 1H), 7.16-7.33 (m, 5H), 4.15 (s, 2H),
and 2.75 (s, 3H). Mass spectrum (MALDI-TOF,
a-cyano-4-hydroxycinnamic acid matrix) calcd. for
C.sub.16H.sub.15N.sub.3S.sub.3: 346.0 (M+H). Found: 346.0.
EXAMPLE 84
[0667]
5-Methylthio-4-(4-phenyl(1,3-oxazol-2-yl))thiophene-2-carboxamidine
hydrochloride
[0668] a) Methyl
4-[N-(2-hydroxy-1-phenylethyl)carbamoyl]-5-methylthiothio-
phene-2-carboxylate: To a stirred suspension of 1.23 g (5.29 mmol)
of 5-(methoxycarbonyl)-2-methylthiothiophene-3-carboxylic acid (as
prepared in Example 79, step (a)) in 20 mL of anhyd
CH.sub.2Cl.sub.2 (under a CaSO.sub.4 drying tube) was added 1.85 mL
(21.2 mmol) of oxalyl chloride followed by 30 mL of anhyd DMF.
After stirring for 2 h at room temperature, the mixture was
concentrated in vacuo. The resulting yellow solid was dissolved in
20 mL of anhyd CH.sub.2Cl.sub.2, cooled (0.degree. C.) and 1.85 mL
of N,N-diisopropylethylamine (10.6 mmol) and 1.02 g (7.41 mmol) of
phenylglycinol was added and the mixture stirred for 1 h at room
temperature. The mixture was concentrated to an oil and partitioned
between 200 mL of EtOAc and 200 mL of saturated NaHCO.sub.3. The
organic phase was washed with saturated NaHCO.sub.3 (200 mL), 10%
(w/v) citric acid, and brine (200 mL), and dried over
Na.sub.2SO.sub.4. After removing the solvent in vacuo, the residue
was chromatographed on a 10 g silica SPE column (Waters Sep-Pak)
with a gradient of 0-20% EtOAc--CH.sub.2Cl.sub.2 to afford the
title compound as a light yellow solid (1.26 g, 68%). .sup.1H-NMR
(300 MHz, CDCl.sub.3) .delta. 8.00 (s, 1H), 7.30-7.42 (m, 5H), 7.08
(d, 1H, J=7.2 Hz), 5.26 (m, 1H), 3.99 (t, 2H, J=5.4 Hz), 3.89 (s,
3H), 2.60 (s, 3H), and 2.33 (t, 1H, J=6.1 Hz). Mass spectrum
(electrospray ionization) calcd. for
C.sub.16H.sub.17NO.sub.4S.sub.2: 352.1 (M+H). Found: 352.0.
[0669] b) Methyl
5-methylthio-4-[N-(2-oxo-1-phenylethyl)carbamoyl]thiophen-
e-2-carboxylate: To a solution of 505 mg (1.44 mmol) methyl
4-[N-(2-hydroxy-1-phenylethyl)carbamoyl]-5-methylthiothiophene-2-carboxyl-
ate (as prepared in the previous step) in 20 .mu.L of anhydrous
CH.sub.2Cl.sub.2 was added 856 mg (2.02 mmol) of Dess Martin
reagent (Omega Chemical Company, Inc., Levis (Qc) Canada). After
stirring in an open flask for 1.5 h at room temperature, the
mixture was concentrated in vacuo. to ca. 10% volume and
partitioned between 50 mL of EtOAc and 50 mL of saturated
NaHCO.sub.3-brine (1:1). The organic phase were washed with brine
(200 mL), dried over Na2SO.sub.4 and concentrated in vacuo.
Concentrated again from CH.sub.2Cl.sub.2 followed by high vacuum
afforded the title compound as a light yellow foam (495 mg, 98%)
which was used in the next step without further purification.
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 9.64 (s, 1H), 8.04 (s,
1H), 7.59 (d, 1H, J=5 Hz), 7.36-7.46 (m, 5H), 5.76 (d, 1H, J=5 Hz),
3.90 (s, 3H), and 2.62 (s, 3H).
[0670] c) Methyl
5-methylthio-4-(4-phenyl(1,3-oxazol-2-yl))thiophene-2-car-
boxylate: To a cooled (0.degree. C.) solution of 465 mg (1.33 mmol)
methyl
5-methylthio-4-[N-(2-oxo-1-phenylethyl)carbamoyl]thiophene-2-carboxylate
(as prepared in the previous step) in 6 mL of anhyd DMF was added
186 mL (2.00 mmol) of phosphorus oxychloride. After stirring for 14
h at room temperature, the mixture was treated with 10 mL of
saturated NaHCO.sub.3 and concentrated to dryness under high
vacuum. The resulting residue was partitioned between 80 mL of
EtOAc and 60 mL of water. The aqueous layer was extracted with
EtOAc (2.times.10 mL) and the combined organic phases washed with
brine (60 mL), and dried over Na.sub.2SO.sub.4. The resulting 406
mg of amber-colored solid was recrystallized from
CH.sub.2Cl.sub.2-Et.sub.2O to remove the majority of a polar
impurity as a cream-colored solid. The remaining mother liquors
were chromatographed on a 10 g silica SPE column (Waters Sep-Pak)
with a gradient of 40-100% CH.sub.2Cl.sub.2-hexane and the
resulting residue triturated with Et.sub.2O-hexane (2:1)) to afford
the title compound as a light beige solid (114 mg, 26%).
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.24 (s, 1H), 7.93 (s,
1H), 7.83 (m, 2H), 7.43 (m, 2H), 7.33 (m, 1H), 3.91 (s, 3H), and
2.72 (s, 3H). Mass spectrum (ESI) calcd. for
C.sub.16H.sub.13NO.sub.3S.sub.2: 332.0 (M+H). Found: 332.2.
[0671] d)
5-Methylthio-4-(4-phenyl(1,3-oxazol-2-yl))thiophene-2-carboxamid-
ine hydrochloride: Methyl
5-methylthio-4-(4-phenyl(1,3-oxazol-2-yl))thioph- ene-2-carboxylate
(80.3 mg, 0.242 mmol, as prepared in the previous step) was treated
according to the procedure in Example 10, step (b) using 155 mg
(2.90 mmol) of ammonium chloride in 1.45 mL of toluene and 1.45 mL
(2.90 mmol) of 2 M trimethylaluminum in toluene. The resulting
light yellow solid was chromatographed on a 5 g silica SPE column
(Waters Sep-Pak) with 10% MeOH--CH.sub.2Cl.sub.2 to give a light
yellow resin. Crystallization from MeOH- Et.sub.2O (ca. 1:3)
afforded the title compound as a yellow solid (62.2 mg, 82%).
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.39 (broad s, 2H),
8.97 (broad s, 2H), 8.78 (s, 1H), 8.60 (s, 1H), 7.89 (d, 2H, J=7
Hz), 7.49 (t, 2H, J=7 Hz), 7.38 (t, 1H, J=7 Hz), and 2.80 (s, 3H).
Mass spectrum (ESI) calcd. for C.sub.15H.sub.13N.sub.3OS.sub.2:
316.1 (M+H). Found: 316.2.
EXAMPLE 85
[0672] 4-[4-(4-hydroxy-3-methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthioth- iophene-2-carboxamidine
hydrochloride
[0673] a) 4-(Chlorocarbonyl)-2-methoxyphenyl acetate: To a stirred
suspension of 1.00 g (4.76 mmol) of 4-acetoxy-3-methoxybenzoic acid
(Pfaltz and Bauer, Inc.) in 4 mL of anhyd CH.sub.2Cl.sub.2 (under a
CaSO.sub.4 drying tube) was added 4.15 mL (47.6 mmol) of oxalyl
chloride followed by 25 mL of anhyd DMF. After stirring for 4 h at
room temperature, the mixture was concentrated in vacuo to afford
the title compound as light yellow crystals (1.12 g, 103%).
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.81 (dd, 1H, J=8.4, 2.1
Hz), 7.66 (d, 1H, 2.1 Hz), 7.19 (d, 1H, 8.4 Hz), 3.91 (s, 3H), and
2.35 (s, 3H).
[0674] b) 4-(2-Bromoacetyl)-2-methoxyphenyl acetate: To a solution
of 1.09 g (4.6 mmol) of 4-(chlorocarbonyl)-2-methoxyphenyl acetate
(as prepared in the precious step) in 10 mL of anhyd
CH.sub.2Cl.sub.2 was added 10.0 mL (20.0 mmol) of a 2 M solution of
trimethylsilyldiazomethane in hexane. After stirring 2 h at room
temperature, the mixture was cooled (0.degree. C.) and 3.20 mL
(16.0 mmol) of 30 wt % HBr in acetic acid was added dropwise (gas
evolution). After stirring 5 min, the mixture was concentrated in
vacuo and rapidly chromatographed on a 10-g silica SPE column
(Waters Sep-Pak) with CH.sub.2Cl.sub.2 to afford the title compound
as a light yellow crystalline solid (1.28 g, 97%). .sup.1H-NMR (300
MHz, CDCl.sub.3) .delta. 7.63 (d, 1H, 1.9 Hz), 7.59 (dd, 1H, J=8.2,
1.9 Hz), 7.16 (d, 1H, 8.2 Hz), 4.43 (s, 2H), 3.91 (s, 3H), and 2.35
(s, 3H).
[0675] c)
2-Methoxy-4-{2-[5-(methoxycarbonyl)-2-methylthio(3-thienyl)
(1,3-thiazol-4-yl)]phenyl acetate: Using a procedure similar to
that of Example 82, step (e) with 1.00 g (4.04 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Company, Cornwall, UK) in 15 .mu.L of reagent
acetone and 1.16 g (4.04 mmol) of 4-(2-bromoacetyl)-2-methoxyphenyl
acetate (as prepared in the previous step) afforded the title
compound as 1.42 g of a yellow solid which, according to the
.sup.1H-NMR spectrum, consisted of a ca. 1 :1 mixture of the title
compound and the corresponding compound resulting from partial loss
of the acetate. .sup.1H-NMR (300 MHz, DMSO -d.sub.6) .delta. 8.27
(s, 1H), 8.22 (s, 1H), 8.19 (s, 1H), 8.00 (s, 1 H), 7.78 (d, 1H,
1.9 Hz), 7.67 (dd, 1H, J=8.2, 1.9 Hz), 7.61 (d, 1H, 1.9 Hz), 7.51
(dd, 1H, J=8.2, 1.9 Hz), 7.19 (d, 1H, 8.2 Hz), 6.86 (d, 1H, 8.2
Hz), 8.87 (m, 12H), 2.76 (s, 3H), 2.75 (s, 3H), and 2.28 (s, 3H).
Mass spectrum (ESI) calcd. for C.sub.19H.sub.17NO.sub.5S.sub.3 and
C.sub.17H.sub.15NO.sub.3S.sub.3 436.0 (M+H) and 394.1 (M+H). Found:
436.1 and 394.2. The mixture was used without further purification
in the following step where formation of the amidine involves
concomitant removal of the acetate.
[0676] d) 4-[4-(4-hydroxy-3-methoxyphenyl)
(1,3-thiazol-2-yl)I-5-methylthi- othiophene-2-carboxamidine
hydrochloride: A portion of the mixture (500 mg, ca. 1.21 mmol as
based on the .sup.1H-NMR integration) containing the
2-methoxy-4-{2-[5-(methoxycarbonyl)-2-methylthio(3-thienyl)](1,3-thiazol--
4-yl)}phenyl acetate (as prepared in the previous step) was treated
according to the procedure in Example 10, step (b) using 610 mg
(11.4 mmol) of ammonium chloride in 5.7 mL of toluene and 5.70 mL
(11.4 mmol) of 2 M trimethylaluminum in toluene. After
chromatography of the resulting residue on a 10 g silica SPE column
(Waters Sep-Pak) with a gradient of 5-20% MeOH--CH.sub.2Cl.sub.2 to
obtain a yellow glass which was recrystallized from
MeOH--CH.sub.2Cl.sub.2 to afford the title compound as a pale
yellow solid (192 mg, 42%). .sup.1H-NMR (300 MHz, DMSO-d.sub.6)
.delta. 9.35 (broad s, 2H), 9.27 (s, 1H), 8.97 (broad s, 2H), 8.62
(s, 1H), 8.04 (s, 1H), 7.62 (s, 1H), 7.54 (d, 1H J=8.2 Hz), 6.88
(d, 1H, J=8.2 Hz), 3.87 (s, 3H), and 2.79 (s, 3H). Mass spectrum
(ESI) calcd. for C.sub.16H.sub.15N.sub.3O.sub.2S.sub.3: 378.0(M+H).
Found: 378.1.
EXAMPLE 86
[0677] 4-[4-(3-Hydroxy-4-methoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthioth- iophene-2-carboxamidine
hydrochloride
[0678] a) 3-Acetyloxy-4-methoxybenzoic acid: To a suspension of 600
mg (3.57 mmol) of 3-hydroxy-4-methoxybenzoic acid (Aldrich Chemical
Company, Milwaukee, Wis.) in 5 mL of anhyd CH.sub.2Cl.sub.2 was
added 1.31 mL (7.50 mmol) of N. N-diisopropylethylamine and the
mixture stirred until homogeneous (ca. 5 min). Acetyl chloride (305
mL, 4.28 mmol) was added dropwise over 2 min followed by 2.0 mg
((0.016 mmol) of 4-dimethylaminopyridine. After stirring at room
temperature for 1 h, the mixture was poured into 50 mL of EtOAc and
washed with 1 M HCl (3.times.25 mL). The organic phase was
extracted with saturated NaHCO.sub.3 (6.times.15 mL) and the
combined extracts saturated with solid NaCl and acidified to pH 2
with conc HCl. The resulting suspension was extracted with EtOAc
(3.times.20 mL) and the combined extracts were dried over
Na.sub.2SO.sub.4 and concentrated in vacuo to afford the title
compound as a light beige powder (463 mg, 62%). .sup.1H-NMR (300
MHz, CDCl.sub.3) .delta. 8.00 (dd, 1H, J=8.7, 2.0 Hz), 7.79 (d, 1H,
2.0 Hz), 7.00 (d, 1H, 8.7 Hz), 3.91 (s, 3H), and 2.34 (s, 3H).
[0679] b) 3-(Chlorocarbonyl)-6-methoxyphenyl acetate: Using the
procedure in Example 85, step (a), 400 mg (1.90 mmol) of
3-acetyloxy-4-methoxybenzo- ic acid (as prepared in the previous
step) was treated with 663 mL (7.60 mmol) of oxalyl chloride and 25
mL of anhyd DMF for 2 h to afford, after workup, the title compound
as a beige crystalline solid which was used in the following step
without further purification.
[0680] c) 5-(2-Bromoacetyl)-2-methoxyphenyl acetate: Using the
procedure in Example 85, step (b), the entire sample of
3-(chlorocarbonyl)-6-methox- yphenyl acetate (as prepared in the
previous step) in 5 mL of anhyd CH.sub.2Cl.sub.2 was treated with
2.09 mL (4.18 mmol) of a 2 M solution of trimethylsilyldiazomethane
in hexane and 456 mL (2.28 mmol) of 30 wt % HBr in acetic acid.
Chromatography as in Example 85, step (b) followed by
recrystallization from CH.sub.2Cl.sub.2-hexane afforded the title
compound as a faintly yellow solid (366 mg, 67%). .sup.1H-NMR (300
MHz, CDCl.sub.3) .delta. 7.79 (dd, 1H, J=8.6, 2.2 Hz), 7.70 (d, 1H,
2.2 Hz), 7.03 (d, 1H, 8.6 Hz), 4.38 (s, 2H), 3.92 (s, 3H), and 2.34
(s, 3H).
[0681] d)
2-Methoxy-5-[2-[5-(methoxycarbonyl)-2-methylthio(3-thienyl)
(1,3-thiazol-4-yl)]phenyl acetate: Using a procedure similar to
that of Example 82, step (e) with 282 mg (1.14 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Company, Cornwall, UK) in 4 mL of acetone and
3.27 mg (1.14 mmol) of 5-(2-bromoacetyl)-2-methoxyphenyl acetate
(as prepared in the previous step) afforded a yellow solid (374 mg)
which, according to the.sup.1H-NMR spectrum, consisted of a 3:7
mixture of the title compound and the corresponding compound
resulting from partial loss of the acetate. Mass spectrum (ESI)
calcd. for C.sub.19H.sub.17NO.sub.5S.sub.3 and
C.sub.17H.sub.15NO.sub.3S.sub.3 436.0 (M+H) and 394.1 (M+H). Found:
436.0 and 394.0. The mixture was used without further purification
in the following step where formation of the amidine involves
concomitant removal of the acetate.
[0682] e) 4-[4-(3-Hydroxy-4-methoxyphenyl)
(1,3-thiazol-2-yl)J-5-methylthi- othiophene-2-carboxamidine
hydrochloride: A portion of the mixture (320 mg, ca. 0.788 mmol as-
based on the.sup.1H-NMR spectrum) containing the 2-methoxy-5-.
2-[5-(methoxycarbonyl)-2-methylthio(3-thienyl)](1,3-thiazol-
-4-yl)}phenyl acetate (as prepared in the previous step) was
treated according to the procedure in Example 10, step (b), using
415 mg (7.76 mmol) of ammonium chloride in 3.5 mL of toluene and
3.88 mL (7.66 mmol) of 2 M trimethylaluminum in toluene. After
chromatography of the resulting residue on a 10 g silica SPE column
(Waters Sep-Pak) with 10-40% MeOH--CH.sub.2Cl.sub.2, a light yellow
solid was obtained which was dissolved in 45 mL of DMF and filtered
to remove silica gel. Concentration under high vacuum and
recrystallization from MeOH-Et.sub.2O afforded the title compound
as a light tan solid (132 mg, 44%). .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) .delta. 9.49 (broad s, 2H), 9.16 (broad s, 2H), 8.67
(s, 1H), 7.98 (s, 1H), 7.5 (obscured m, 3H), 7.00 (obscured d, 1H,
J=8.3 Hz), 3.82 (s, 3H), and 2.79 (s, 3H). Mass spectrum (ESI)
calcd. for C.sub.16H.sub.15N.sub.3O.sub.2S.sub.3: 378.0 (M+H).
Found: 378.1.
EXAMPLE 87
[0683] 5-Methylthio-4-(N-phenylcarbamoyl)thiophene-2-carboxamidine
hydrochloride
[0684] a) Methyl
5-methylthio-4-(N-phenylcarbamoyl)thiophene-2-carboxylate- : To 182
mg (0.785 mmol) of 5-(methoxycarbonyl)-2-methylthiothiophene-3-ca-
rboxylic acid (as prepared in Example 95) in 4 mL of anhyd
CH.sub.2Cl.sub.2 was treated with 275 mL (3.15 mmol) of oxalyl
chloride and 6 mL of anhyd DMF for 2 h similar to Example 79, step
(a); followed by 206 .mu.L (1.18 mmol) of N,N-diisopropylethylamine
and 85.9 mL (0.942 mmol) of aniline in 3 mL of anhyd
CH.sub.2Cl.sub.2 for 20 min. The mixture was poured into 25 mL of
EtOAc and washed with 1 M HCl (2.times.25 mL), saturated
NaHCO.sub.3 (2.times.25 mL), and brine (25 mL), and dried over
Na.sub.2SO.sub.4. Removal of the solvent in vacuo, afforded the
pure title compound as a light yellow solid (163 mg, 68%).
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.23 (broad s, 1H), 8.10
(s, 1H), 7.63 (d, 2H, J=7 Hz), 7.36 (t, 2H, J=7 Hz), 7.15 (t, 2H,
J=7 Hz), 3.90 (s, 3H), and 2.64 (s, 3H).
[0685] b)
5-Methylthio-4-(N-phenylcarbamoyl)thiophene-2-carboxamidine
hydrochloride: Methyl
5-methylthio-4-(N-phenylcarbamoyl)thiophene-2-carbo- xylate (60.0
mg, 0.195 mmol , as prepared in the previous step) was treated
similarly to the procedure in Example 10, step (b) using 310 mg
(5.80 mmol) of ammonium chloride in 2 mL of toluene and 2.90 mL
(5.80 mmol) of 2 M trimethylaluminum in toluene for 6 h.
Chromatography of the resulting residue on a 2 g silica SPE column
(Waters Sep-Pak) with a gradient of 5-20% MeOH--CH.sub.2C.sub.2,
followed by crystallization from MeOH-Et.sub.2O afforded the title
compound as a beige solid (40.3 mg, 71%). .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) .delta. 10.24 (s, 1H), 9.34 (broad s, 2H), 9.05
(broad s, 2H), 8.75 (s, 1H), 7.73 (d, 2H, J=8 Hz), 7.36 (t, 2H, J=8
Hz), 7.11 (m, 1H), and 2.67 (s, 3H). Mass spectrum (ESI) calcd. for
C.sub.13H.sub.13N.sub.3OS.sub.2: 292.1 (M+H). Found: 292.4.
EXAMPLE 88 and 89
[0686]
5-Methylthio-4-[N-benzylcarbamoyl]thiophene-2-carboxamidinehydrochl-
oride and
4-Amino[benzylamino]methyl]-5-methylthiothiophene-2-carboxamidin- e
hydrochloride
[0687] a) Methyl
5-methylthio-4-[N-benzylcarbamoyl]thiophene-2-carboxylate- : The
identical procedure of Example 87, step (a) was used with 103 mL
(0.942 mmol) of benzylamine and the same amounts of all other
reagents to afford the title compound as a light yellow solid (167
mg, 66%). .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.93 (s, 1H),
7.28-7.38 (m, 5H), 6.58 (broad s, 1H), 4.62 (s, 2H, J=5.7 Hz), 3.87
(s, 3H), and 2.60 (s, 3H).
[0688] b)
5-Methylthio-4-[N-benzylcarbamoyl]thiophene-2-carboxamidinehydro-
chloride and
4-{Imino[benzylamino]methyl]-5-methylthiothiophene-2-carboxam-
idinehydrochloride: Methyl
5-methylthio-4-[N-benzylcarbamoyl]thiophene-2-c- arboxylate (62.7
mg, 0.195 mmol, as prepared in the previous step) was treated
similarly to the procedure in Example 10, step (b) using 310 mg
(5.80 mmol) of ammonium chloride in 2 mL of toluene and 2.90 mL
(5.80 mmol) of 2 M trimethylaluminum in toluene for 6 h.
[0689] Chromatography of the resulting residue on a 2 g silica SPE
column (Waters Sep-Pak) with a gradient of 5-20%
MeOH--CH.sub.2C.sub.2, followed by crystallization from
MeOH-Et.sub.2O afforded 5-methylthio-4-[N-benzylc-
arbamoyl]thiophene-2-carboxamidinehydrochloride as a beige solid
(21.1 mg, 35%). .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 7.93
(s, 1H), 7.28-7.38 (m, 5H), 6.58 (broad s, 1H), 4.62 (s, 2H, J=5.7
Hz), 3.87 (s, 3H), and 2.60 (s, 3H). Mass spectrum (ESI) calcd. for
C.sub.14H.sub.15N.sub.3OS.su- b.2: 306.1 (M+H). Found: 306.6.
[0690] Also isolated and crystallized from MeOH-Et.sub.2O was the
more polar
4-{imino[benzylamino]methyl}-5-methylthiothiophene-2-carboxamidineh-
ydrochloride as a beige solid (32.0 mg, 54%). .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) consistent with desired product as broad mixture of
rotomers. Mass spectrum (ESI) calcd. for
C.sub.14H.sub.16N.sub.4S.sub.2: 305.1 (M+H). Found: 305.8.
EXAMPLES 90 and 91
[0691]
4-[N-Methyl-N-benzylcarbamoyl]-5-methylthiothiophene-2-carboxamidin-
e hydrochloride and
4-[Imino[methylbenzylamino]methyl]-5-methylthiothiophe-
ne-2-carboxamidinehydrochloride
[0692] a) Methyl
4-[N-methyl-N-benzylcarbamoyl]-5-methylthiothiophene-2-ca-
rboxylate: The identical procedure of Example 87, step (a) was used
with 122 mL (0.942 mmol) of N-benzylmethylamine and the same
amounts of all other reagents to afford the title compound as a
light yellow solid (169 mg, 64%). .sup.1H-NMR (300 MHz, CDCl.sub.3)
.delta. 7.68 (s, 1H), 7.34 (m, 5H), 4.6 (broad m, 2H), 3.86 (s,
3H), 2.91 (m, 3H), and 2.60 (s, 3H).
[0693] b)
4-[N-Methyl-N-benzylcarbamoyl]-5-methylthiothiophene-2-carboxami-
dine hydrochloride and
4-[Imino[methylbenzylamino]methyl]-5-methylthiothio-
phene-2-carboxamidine hydrochloride: Methyl
4-[N-methyl-N-benzylcarbamoyl]-
-5-methylthiothiophene-2-carboxylate (65.4 mg, 0.195 mmol, as
prepared in the previous step) was treated similarly to the
procedure in Example 10, step (a) using 310 mg (5.80 mmol) of
ammonium chloride in 2 mL of toluene and 2.90 mL (5.80 mmol) of 2 M
trimethylaluminum in toluene for 6 h.
[0694] Chromatography of the resulting residue on a 2 g silica SPE
column (Waters Sep-Pak) with a gradient of 5-20%
MeOH--CH.sub.2Cl.sub.2 afforded
4-[N-methyl-N-benzylcarbamoyl]-5-methylthiothiophene-2-carboxamidine
hydrochloride as a amber-colored glass (34.3 mg, 55%). .sup.1H-NMR
(300 MHz, DMSO-d.sub.6) .delta. 9.32 (broad s, 2H), 9.06 (broad s,
2H), 8.11 (s, 1H), 7.36 (m, 5H), 4.66 (m, 2H), 2.88 (s, 3H) and
2.66 (s, 3H). Mass spectrum (ESI) calcd. for
C.sub.15H.sub.17N.sub.3OS.sub.2: 320.1 (M+H). Found: 320.4.
[0695] Also isolated and then crystallized from MeOH-Et.sub.2O was
the more polar 4-{imino [methylbenzylamino]methyl
}-5-methylthiothiophene-2-c- arboxamidine hydrochloride as a beige
solid (19.8 mg, 32%). .sup.1H-NMR (300 MHz, DMSO-d.sub.6)
consistent with desired product as broad mixture of rotomers. Mass
spectrum (ESI) calcd. for C.sub.15H.sub.11N.sub.4S.sub.- 2: 319.1
(M+H). Found: 319.6.
EXAMPLES 92 and 93
[0696]
5-Methylthio-4-[N-(2-phenylethyl)carbamoyl]thiophene-2-carboxamidin-
e hydrochloride and
4-{Imino[(2-phenylethyl)amino]methyl]-5-methylthiothio-
phene-2-carboxamidine hydrochloride
[0697] a) Methyl
5-methylthio-4-[N-(2-phenylethyl)carbamoyl]thiophene-2-ca-
rboxylate: The identical procedure of Example 87, step (a) was used
with 118 mL (0.942 mmol) of phenethylamine and the same amounts of
all other reagents to afford the title compound as a light yellow
solid (165 mg, 63%). .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 7.86
(s, 1H), 7.30-7.35 (m, 5H), 6.44 (m, 1H), 3.87 (s, 3H), 3.70 (q,
2H, J=7 Hz), 2.93 (t, 2H, J=7 Hz), and 2.53 (s, 3H).
[0698] b)
5-Methylthio-4-[N-(2-phenylethyl)carbamoyl]thiophene-2-carboxami-
dine hydrochloride and
4-[Imino[(2-phenylethyl)amino]methyl]-5-methylthiot-
hiophene-2-carboxamidine hydrochloride: Methyl
5-methylthio-4-N-(2-phenyle- thyl)carbamoyl]thiophene-2-carboxylate
(65.4 mg, 0.195 mmol, as prepared in the previous step) was treated
similarly to the procedure in Example 10, step (a) using 310 mg
(5.80 mmol) of ammonium chloride in 2 mL of toluene and 2.90 mL
(5.80 mmol) of 2 M trimethylaluminum in toluene for 6 h.
[0699] Chromatography of the resulting residue on a 2 g silica SPE
column (Waters Sep-Pak) with a gradient of 5-20%
MeOH--CH.sub.2Cl.sub.2, followed by crystallization from
MeOH-Et.sub.2O afforded
5-methylthio-4-[N-(2-phenylethyl)carbamoyl]thiophene-2-carboxamidine
hydrochloride as a beige solid (17.4 mg, 28%). .sup.1H-NMR (300
MHz, DMSO-d.sub.6) .delta. 8.8-9.3 (broad m, 4H), 8.48 (m, 1H),
8.35 (s, 1H), 7.26 (m, 5H), 3.44 (m, 2H), 2.82 (t, 3H, J=7.5 Hz),
and 2.61 (s, 3H). Mass spectrum (ESI) calcd. for
C.sub.15H.sub.17N.sub.3OS.sub.2: 320.1 (M+H). Found: 320.4.
[0700] Also isolated and crystallized from MeOH-Et.sub.2O was the
more polar
4-{imino[(2-phenylethyl)amino]methyl}-5-methylthiothiophene-2-carbo-
xamidine hydrochloride as a beige solid (19.1 mg, 31%). .sup.1H-NMR
(300 MHz, DMSO-d.sub.6) .delta. 8.37 (s, 1H), 7.2-7.4 (m, 5H), 3.70
(t, 2H, J=7.6 Hz), 2.96 (t, 2H, J=7.6 Hz), and 2.71 (s, 3H). Mass
spectrum (ESI) calcd. for C.sub.15H.sub.18N.sub.4S.sub.2: 319.1
(M+H). Found: 319.5.
EXAMPLE 94
[0701] 3-Amino-2-aza-3-[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))
(2-thienyl)]prop-2-enenitrile
[0702] To 100 mg (0.302 mmol) of
5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl-
))thiophene-2-carboxamidine (as prepared in Example 10, step b) in
3 mL of EtOH was added 29.6 mg (0.604 mmol) of cyanamide as a
solution in 0.3 mL of water. The mixture was heated to reflux and
0.302 mL (0.302 mmol) of 1 M aqueous KOH was added. After 3 h, the
mixture was cooled (0.degree. C.) and filtered washing with
ice-cold EtOH. The resulting solid was dried in vacuo to afford the
title compound as a light yellow powder (78.4 mg, 73%). .sup.1H-NMR
(300 MHz, DMSO-d.sub.6) .delta. 9.31 (broad s, 1H), 8.70 (broad s,
1H), 8.63 (s, 1H), 8.19 (s, 1H), 8.09 (d, 2H, J=7 Hz), 7.49 (t, 2H,
J=7 Hz), 7.39 (t, 1H, J=7 Hz), and 2.75 (s, 3H). Mass spectrum
(MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for
C.sub.16H.sub.12N.sub.4S.sub.3: 357.0 (M+H). Found: 357.1.
EXAMPLE 95
[0703] 5-(Methoxycarbonyl)-2-methylthiothiophene-3-carboxylic
acid
[0704] Methyl 4-cyano-5-methylthiothiophene-2-carboxylate (2.20 g,
10.3 mmol, Maybridge Chemical Company, Cornwall, UK) and
tetrafluorophthalic acid (2.45 g, 10.3 mmol) in an 8-.mu.L sealable
pressure tube (Ace Glass Company) with stir bar was heated to
160.degree. C. The molten mixture was stirred for 4 days, cooled
and the resulting residue broken up and extracted by refluxing with
80 mL chloroform. The mixture was cooled, decolorizing carbon (ca.
0.5 g) was added and the mixture filtered (Celite). The resulting
solution was extracted with saturated NaHCO.sub.3 (4.times.30 mL)
and the combined aqueous extracts acidified to pH 1-2 with conc HCl
and filtered to provide a light tan solid. After dissolving the
solid in a minimum of I M K.sub.2CO.sub.3 (35-40 mL) and filtering
(washing with 10-20 mL of water) to clarify the solution, it was
slowly acidified to pH 6.5-7.0 with stirring and filtered (Celite)
to remove a brown precipitate. The pH adjustment and filtration was
repeated and the resulting solution was saturated with solid NaCl
and acidified to pH 1-2 with conc HCl. The precipitate was
filtered, washed with water (3.times.10 mL) and dried over
P.sub.2O.sub.5 under high vacuum to afford the title compound as a
cream-colored powder (1.24 g, 52%). .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) .delta. 13.14 (broad s, 1H), 7.89 (s, 1H), 3.82 (s,
3H) and 2.64 (s, 3H). Mass spectrum (ESI, negative mode) calcd. for
C.sub.8H.sub.8O.sub.4S.sub.2: 232.0 (M-). Found: 231.7.
EXAMPLE 96
[0705] 5-Ethylthio-4-
{4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidin- e
hydrochloride 5
[0706] a) Methyl
4-(4-phenyl(1,3-thiazol-2-yl))-5-(methylsulfonyl)thiophen-
e-2-carboxylate: Using the procedure of Example 141, step (a) with
600 mg (1.73 mmol) of methyl
5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophen-
e-2-carboxylate as prepared in Example 10, step (a) afforded 642 mg
(98%) of the title compound as a light yellow powder. .sup.1H-NMR
(300 MHz, CDCl.sub.3) .delta. 7.93 (s, 1H), 7.90 (m, 2H), 7.63 (s,
1H), 7.47 (m, 2H), 7.39 (m, 1H), 3.98 (s, 3H) and 3.73 (s, 3H).
Mass spectrum (ESI, m/z): calcd. for
C.sub.16H.sub.13NO.sub.4S.sub.3 380.0 (M+H), found 380.2.
[0707] b) 4-(4-Phenyl)
(1,3-thiazol-2-yl))-5-(methylsulfonyl)thiophene-2-c- arboxamidine
hydrochloride: Using the procedure of Example 141, step (b) with
560 mg (1.48 mmol) methyl 4-[4-(4-chlorophenyl)
(1,3-thiazol-2-yl)]-5-(methylsulfonyl)thiophene-2-carboxylate as
prepared in the previous step afforded 392 mg (66%) of the title
compound as a off-white solid. .sup.1H-NMR (300 MHz, DMSO-d.sub.6)
.delta. 9.7 (broad s, 2H), 9.4 (broad s, 2H), 8.58 (s, 1H), 8.43
(s, 1H), 8.02 (d, 2H, J=7 Hz), 7.52 (t, 2H, J=7 Hz), 7.43 (t, 1H,
J=7 Hz), and 3.90 (s, 3H). Mass spectrum (ESI, m/z): calcd. for
C.sub.15H.sub.13N.sub.3O.sub.2S.sub.3 364.0 (M+H), found 364.1.
[0708] c)
5-Ethylthio-4(4-phenyl(,,3-thiazol-2-yl))thiophene-2-carboxamidi-
ne hydrochloride: Using the procedure of Example 141, step (c) with
23.1 mg (0.0578 mmol) of the 4-(4-phenyl)
(1,3-thiazol-2-yl))-5-(methylsulfony- l)thiophene-2-carboxamidine
hydrochloride (as prepared in the previous step), 64.1 mL(0.867
mmol) of ethanethiol (in 2 portions over 2 h) and 40.3 mL (0.231
mmol) of DIEA in 3 mL of methanol gave a yellow resin which was
chromatographed on a 2 g silica SPE column (Waters Sep-Pak) with a
gradient of 0-15% MeOH--CH.sub.2Cl.sub.2, followed by trituration
with CH.sub.2Cl.sub.2 to afford the title compound as an off-white
solid (21.7 mg, 98%). .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta.
9.45 (broad s, 2H), 9.07 (broad s, 2H), 8.68 (s, 1H), 8.28 (s, 1H),
8.09 (d, 2H, J=7 Hz), 7.51 (t, 2H, J=7 Hz), 7.40 (t, 1H, J=7 Hz),
3.23 (q, 2H, J=7 Hz) and 1.42 (t, 3H, J=7 Hz). Mass spectrum (ESI)
calcd. for C.sub.16H.sub.15N.sub.3S.sub.3: 346.1 (M+H). Found:
346.2.
EXAMPLE 97
[0709] 5-Methylthio-4-[4-phenoxymethyl)
(1,3-thiazol-2-yl)]thiophene-2-car- boxamidine hydrochloride
[0710] a) 3-Bromo-1-phenoxyacetone: To a solution of 6.c (0.050
mmol) of phenoxyacetyl chloride in 250 mL of anhyd MeCN in a 1-dram
short vial (Wheaton Glass) was added 50 mL (0.100 mmol) of a 2 M
solution of trimethylsilyldiazomethane in hexane and the vial
capped with a PTFE-lined cap. After stirring 1 h at room
temperature on a vortex shaker, the mixture was cooled (0.degree.
C.) and 21 mL (0.1105 mmol) of 30 wt % HBr in acetic acid was added
dropwise (gas evolution). After vortexing for 10 min, the mixture
was concentrated in vacuo on a vacuum centrifuge concentrator
(Speed-Vac, Savant Instruments, Inc.) to provide an amber-colored
oil which was used directly in the following step.
[0711] b) Methyl 5-methylthio-4-[4-(phenoxymethyl)
(1,3-thiazol-2-yl)]thio- phene-2-carboxylate: To the
3-bromo-1-phenoxyacetone (as prepared in the previous step in a
1-dram vial) was added 14.8 mg (0.060 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge Chemical Company, Cornwall, UK) as 1.48 mL of a 10 mg
/mL solution in acetone. The vial was tightly capped and placed on
a heated platform shaker (Innova model 4080, New Brunswick
Scientific Co., Inc.) and vortexed at 55.degree. C. and 250 rpm for
4 h. To the resulting mixture was added 50 mg (0.150 mmol) of
diethylaminomethyl-polystyrene resin (Fluka Chemika-Biochemika, 3.0
mmol / g) as 0.50 mL of a 100 mg / mL suspension in acetone and the
mixture vortexed briefly. Chloroacetylpolystyrene resin (30 mg,
0.150 mmol, Advanced ChemTech Inc., 5.0 mmol / g) was then added
followed by (0.750 mg, 0.005 mmol) NaI as 100 mL of a 7.5 mg / mL
solution in acetone. The mixture was again capped tightly and
placed on a heated platform shaker and vortexed at 55.degree. C.
and 250 rpm for 22 h. The mixture was filtered through a 2 mL
fritted column (BioRad Biospin minicolumn) washing with acetone
(2.times.0.5 mL) and MeOH (2.times.0.5 mL) into a 2 dram vial and
concentrated on a vacuum centrifuge concentrator to afford 21.0 mg
of the title compound as an off-white solid. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.17 (s, 1H), 7.82 (s, 1H), 7.13 (m, 2H),
7.07 (m, 2H), 6.96 (m, 1H), 5.22 (s, 2H), 3.85 (s, 3H), and 2.74
(s, 3H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid
matrix) calcd. for C.sub.17H.sub.15NO.sub.- 3S.sub.3: 378.0 (M+H).
Found: 378.3.
[0712] c) 5-Methylthio-4-[4-(phenoxymethyl)
(1,3-thiazol-2-yl)]thiophene-2- -carboxamidine hydrochloride: The
methyl 5-methylthio-4-[4-(phenoxymethyl)
(1,3-thiazol-2-yl)]thiophene-2-carboxylate (as prepared in the
previous step)under nitrogen in a 2 dram vial with a micro magnetic
stir bar) was capped with an open-top phenolic cap containing a
PTFE-backed silicone septum. A 1 M solution of the reagent freshly
prepared from trimethylaluminum and ammonium chloride in toluene
according to the procedure in Example 10, step b (0.750 mL, 0.750
mmol) was added by syringe by puncturing the septum once with the
needle to allow venting of gas followed by a second puncture to
inject the reagent. The vial was placed in an aluminum heating
block under nitrogen (Fisher Scientific Dry Bath Incubator fitted
with a custom-made nitrogen manifold cover). The manifold was
flushed with nitrogen and the reaction stirred by means of a large
magnetic stir motor placed inverted on top of the manifold. The
reaction was heated to 100.degree. C. for 4 h, and cooled to room
temperature over ca. 2 h. The contents of the vial were quenched
carefully into 0.5 g of silica gel in 2 mL of --CH.sub.2Cl.sub.2,
capped and shaken to homogeneity. The slurry was filtered through a
4-mL fritted column (Isolab microcolumn) into a 2-dram vial washing
with CH.sub.2Cl.sub.2 (2.times.1 mL), CH.sub.2Cl.sub.2-MeOH (1:1,
1.times.1 mL) and MeOH(2.times.1 mL) and the filtrate concentrated
on a vacuum centrifuge concentrator to a yellow solid. Filtration
through a 500 mg silica SPE column (Supelco LC-Si) with 10% MeOH
--CH.sub.2Cl.sub.2 afforded the title compound as a yellow solid
(14.8 mg). .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.45 (d, 2H,
J=8.2 Hz), 9.11 (d, 2H, J=8.2 Hz), 8.97 (broad s, 2H), 8.65 (s,
1H), 7.90 (s, 1H), 7.0-7.5 (m, 5H), 5.25 (s, 2H), and 2.79 (s, 3H).
Mass spectrum (MALDI-TOF, genetic acid matrix) calcd. for
C.sub.17H.sub.15NO.sub.3S.sub.3: 362.0 (M+H). Found: 361.7.
EXAMPLES 98-126
[0713] Examples 98-104 were carried out using the procedure of
Example 97, steps (b) and (c) using 0.050 mmol of the reagent
specified in the table. Examples 105-126 were carried out using the
procedure of Example 97, steps (a), (b) and (c) using 0.05 mmol of
reagent.
1 Mass Spectrum (ESI) Calcd Example Reagent Compound Formula (M +
H) Found 98 1-bromo- 4-[4-(tert-butyl)(1,3- C13 H17 N3 S3 312.1
312.2 pinacolone thiazol-2-yl)]-5- methylthiothiophene-2-
carboxamidine hydrochloride 99 4-fluoro- 4-[4-(4- C15 H12 F N3
350.0 350.2 phenacyl fluorophenyl)(1,3- S3 bromide
thiazol-2-yl)]-5- methylthiothiophene-2- carboxamidine
hydrochloride 100 4-cyano- 4-[4-(4- C16 H15 N5 S3 374.1 374.2
phenacyl amidinophenyl)(1,3- bromide thiazol-2-yl)]-5-
methylthiothiophene-2- carboxamidine hydrochloride 101 3-fluoro-
4-[4-(3- C15 H12 F N3 350.0 350.2 phenacyl fluorophenyl)(1,3- S3
bromide thiazol-2-yl)]-5- methylthiothiophene-2- carboxamidine
hydrochloride 102 4-(diethylamino)- 4-{4-[4-(diethylamino)- C19 H22
N4 S3 403.1 403.2 phenacyl phenyl](1,3-thiazol-2- bromide yl)}-5-
methylthiothiophene-2- carboxamidine hydrochloride 103 3-chloro-
4-[4-(3- C15 H12 Cl N3 366.0 366.1 phenacyl chlorophenyl)(1,3- S3
bromide thiazol-2-yl)]-5- methylthiothiophene-2- carboxamidine
hydrochloride 104 3,4-difluoro- 4-[4-(3,4- C15 H11 F2 N3 368.0
368.2 phenacyl difluorophenyl)(1,3- S3 bromide thiazol-2-yl)]-5-
methylthiothiophene-2- carboxamidine hydrochloride 105
2,6-difluoro- 4-[4-(2,6- C15 H11 F2 N3 368.0 368.2 benzoyl chloride
difluorophenyl)(1,3- S3 thiazol-2-yl)]-5- methylthiothiophene-2-
carboxamidine hydrochloride 106 4-ethoxy-benzoyl 4-[4-(4- C17 H17
N3 O 376.1 376.2 chloride ethoxyphenyl)(1,3- S3 thiazol-2-yl)]-5-
methylthiothiophene-2- carboxamidine hydrochloride 107 4-chloro-
4-{4-[(4- C16 H14 Cl N3 396.0 396.1 phenoxyacetyl chlorophenoxy)- O
S3 chloride methyl](1,3-thiazol-2- yl)}-5- methylthiothiophene-2-
carboxamidine hydrochloride 108 cyclopentane- 4-(4-cyclopentyl(1,3-
C14 H17 N3 S3 324.1 324.2 carbonyl chloride thiazol-2-yl))-5-
methylthiothiophene-2- carboxamidine hydrochloride 109 1-naphthoyl
5-methylthio-4-(4- C19 H15 N3 S3 382.1 382.2 chloride
naphthyl(1,3-thiazol-2- yl))thiophene-2- carboxamidine
hydrochloride 110 3,5-dichloro- 4-[4-(3,5- C15 H11 C12 N3 400.0
400.1 benzoyl chloride dichlorophenyl)(1,3- S3 thiazol-2-yl)]-5-
methylthiothiophene-2- carboxamidine hydrochloride 111 2,5-
4-[4-(2,5- C15 H11 F2 N3 368.0 368.2 difluorobenzoyl
difluorophenyl)(1,3- S3 chloride thiazol-2-yl)]-5-
methylthiothiophene-2- carboxamidine hydrochloride 112
9-fluorenone-4- 5-methylthio-4-[4-(9- C22 H15 N3 O 434.1 434.2
carbonyl chloride oxofluoren-4-yl)(1,3- S3 thiazol-2-yl)]thiophene-
2-carboxamidine hydrochloride 113 3- 4-{4-[(3- C17 H17 N3 O 376.1
376.2 methoxyphenyl- methoxyphenyl)methyl]( S3 acetyl chloride
1,3-thiazol-2-yl)}-5- methylthiothiophene-2- carboxamidine
hydrochloride 114 4-methyl valeroyl 4-[4-(3-methylbutyl)(1,3- C14
H19 N3 S3 326.1 326.2 chloride thiazol-2-yl)]-5-
methylthiothiophene-2- carboxamidine hydrochloride 115 3-(2-
4-{4-[3-(2- C19 H15 Cl N4 447.0 447.1 chlorophenyl)-5-
chlorophenyl)-5- O S3 methylisoxazole- methylisoxazol-4-yl](1,3-
4-carbonyl thiazol-2-yl)}-5- chloride methylthiothiophene-2-
carboxamidine hydrochloride 116 4-n-amyloxy- 5-methylthio-4-[4-(4-
C20 H23 N3 O 418.1 418.2 benzoyl chloride pentyloxyphenyl)(1,3- S3
thiazol-2-yl)]thiophene- 2-carboxamidine hydrochloride 117 1-(4-
4-{4-[(4-chlorophenyl)- C20 H20 Cl N3 434.1 434.3 chlorophenyl)-
1-cyclopentyl](1,3-thiazol- S3 cyclopentanecarb 2-yl)}-5-
onyl-chloride methylthiothiophene-2- carboxamidine hydrochloride
118 4-(trifluoro- 5-methylthio-4-{4-[4- C16 H12 F3 N3 416.0 416.1
methoxy)benzoyl (trifluoromethoxy)phenyl] O S3 chloride
(1,3-thiazol-2- yl)}thiophene-2- carboxamidine hydrochloride 119
3-chloro- 4-[4-(3- C17 H12 Cl N3 422.0 422.1 benzo[b]
chlorobenzo[b]thiophen- S4 thiophene-2- 2-yl)(1,3-thiazol-2-yl)]-
carbonyl chloride 5-methylthiothiophene-2- carboxamidine
hydrochloride 120 3-(2-chloro-6- 4-{4-[3-(6-chloro-2- C19 H14 Cl F
N4 465.0 465.1 fluorophenyl)-5- fluorophenyl)-5- O S3
methylisoxazole- methylisoxazol-4-yl](1,3- 4-carbonyl
thiazol-2-yl)}-5- chloride methylthiothiophene-2- carboxamidine
hydrochloride 121 3-cyanobenzoyl 4-[4-(3- C16 H15 N5 S3 374.1 374.7
chloride amidinophenyl)(1,3- thiazol-2-yl)]-5-
methylthiothiophene-2- carboxamidine hydrochloride 122 4- 4-{4-[(4-
C17 H17 N3 O 376.1 376.2 methoxyphenyl- methoxyphenyl)- S3 acetyl
chloride methyl](1,3-thiazol-2- yl)}-5- methylthiothiophene-2-
carboxamidine hydrochloride 123 3-(t-butyl)-1- 4-{4-[3-(tert- C16
H19 N5 S3 378.1 378.2 benzylpyrazole- butyl)pyrazol-5-yl](1,3- 5-
thiazol-2-yl)}-5- carbonyl methylthiothiophene-2- chloride
carboxamidine hydrochloride 124 3-(4- 5-methylthio-4-[4-(1- C12 H13
N3 S3 296.0 296.2 chlorophenyl)- methylvinyl)(1,3-thiazol-
2,2-dimethyl- 2-yl)]thiophene-2- propanoyl carboxamidine chloride
hydrochloride 125 n-(1- 5-methylthio-4-(4-{1- C27 H24 N4 O2 565.1
565.1 naphthalene- [(naphthylsulfonyl)amino]- S4 sulfonyl)-1-
2-phenylethyl}(1,3- phenylalanyl thiazol-2-yl))thiophene- chloride
2-carboxamidine hydrochloride 126 2-bromo-5- ,4-[4-(2-bromo-5- C16
H14 Br N3 440.0 440.2 methoxybenzoyl methoxyphenyl)(1,3- O S3
chloride thiazol-2-yl)]-5- methylthiothiophene-2- carboxamidine
hydrochloride
EXAMPLE 127
[0714] a) 1-[3,5-Bis(trifluoromethyl)phenyl]-2-bromoetlian-1-one: A
stirred suspension of 1 g (3.9 mmol) of
3,5-bis(trifluoromethyl)acetophen- one (Lancaster, Windham, N.H.,
USA) in dry methanol (20 mL) and 1 g (15 mmol, 2.6 eq) of
poly(4-vinyl pyridinium tribromide) (Aldrich, Milwaukee, Wis., USA)
was protected from moisture with dry nitrogen, and heated at reflux
for 70 min. The polymer was filtered from the cooled solution and
washed with methanol and twice with dichloromethane. The solvents
were removed in vacuo to give
1-[3,5-bis(trifluoromethyl)phenyl]-2-bromoethan-- 1-one (1.2 g,
92%). .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 8.43 (m, 2H),
8.12 (m, 1H), 4.46 (s, 3H).
[0715] b) Methyl
4-[4-[3,5-bis(trifluoromethyl)phenyl](1,3-thiazol-2-yl))--
5-methylthiothiophene-2-carboxylate: A solution of 75 mg (0.3 mmol)
of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge, Cornwall, UK) was reacted with 101 mg (0.3 mmol) of
1-[3,5-bis(trifluoromethyl)phenyl]-2-bromoethane-1-one in a manner
similar Example 8, step (a) to give methyl
4-{4-[3,5-bis(trifluoromethyl)-
phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate (7
mg, 5%) as a solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta.
8.75 (s, 1H), 8.73 (m, 2H), 8.29 (s, 1H), 8.13 (m, 1H), 3.87 (s,
3H), 2.79 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z):
Calcd. for C.sub.18H.sub.11NO.sub.2S.sub.3F.sub.6, 484.0 (M+H),
found 484.0.
[0716] c)
4-[4-[3,5-Bis(trifluoromethyl)phenyl](1,3-thiazol-2-yl)}-5-methy-
lthiothiophene-2-carboxamidine: Methyl
4-[4-3,5-bis(trifluoromethyl)phenyl-
](1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (7 mg,
14.5 mmol) was treated in a manner similar to that for Example 10,
step (b), to give
4-{4-[3,5-bis(trifluoromethyl)phenyl](1,3-thiazol-2-yl)}-5-methylthiothio-
phene-2-carboxamidine (6 mg, 89%) as a yellow solid. .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) 8.78 (s, 1H), 8.74 (s, 2H), 8.62 (s, 1H),
8.15 (s, 1H), 2.82 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix,
m/z): Calcd. for C.sub.17H.sub.11N.sub.3S.sub.3F.sub.6, 468.0
(M+H), found 468.0.
EXAMPLE 128
[0717] a)
2-Bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]etlian-1-one: A
stirred suspension of 1 g (4.5 mmol) of
3-fluoro-5-(trifluoromethyl)aceto- phenone (Lancaster, Windham, NH,
USA) was treated in a manner similar to that for Example 127, step
(a) to give of a 1:1 mixture of
2-bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethan]-one and
dibrominated product (1.6 g, 100%). .sup.1H-NMR (DMSO-d.sub.6; 300
MHz) .delta. 8.25-7.52 (m, 6H), 6.54 (s, 1H), 4.42 (s, 2H).
[0718] b) Methyl
4-{4-[3-fluoro-5-(trifluoromethyl)phenyl](1,3-thiazol-2-y-
l)]-5-methylthiothiophene-2-carboxylate: A solution of 75 mg (0.3
mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge. Cornwall, UK) was reacted with of 86 mg (0.3 mmol)
2-bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethan-1-one in a
manner similar to Example 8, step (a) to give, methyl
4-{4-[3-fluoro-5-(trifluor-
omethyl)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate
(41 mg, 31%) as a solid. .sup.1H-NMR (DMSO-d6; 300 MHz) .delta.
8.59 (s, 1H), 8.29 (m, 1H), 8.27 (s, 1H), 8.25 and 8.21 (m, 1H, 1:1
ratio conformers), 7.73 and 7.70 (m, 1 H, 1:1 ratio conformers).
Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.17H.sub.11NO.sub.2S.sub.3F.sub.4, 434.0 (M+H), found
434.0.
[0719] c)
4-{4-[3-Fluoro-5-(trifluoromethyl)phenyl(1,3-thiazol-2-yl))-5-me-
thylthiothiophene-2-carboxamidine: Methyl
4-{4-[3-fluoro-5-(trifluoromethy-
l)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate
(40 mg, 0.92 mmol) was treated in a manner similar to that for
Example 10, step (b), to give
4-{4-[3-fluoro-5-(trifluoromethyl)phenyl](1,3-thiazol-2-yl)}-
-5-methylthiothiophene-2-carboxamidine (31 mg, 81%) as a yellow
solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 9.36 (br s, 2H),
9.01 (br s, 2H), 8.68 (s, 1H), 8.63 (s, 1H), 8.30 (m, 1H), 8.25 and
8.22 (m, 1H, 1:1 ratio conformers), 7.75 and 7.73 (m, 1H, 1:1 ratio
conformers), 2.82 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix,
m/z): Calcd. for C.sub.16H.sub.11N.sub.3S.sub.3F.sub.4, 418.5
(M+H), found 418.0.
EXAMPLE 129
[0720] a)
2-Bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]propan-1-one: A
stirred suspension of 1 g (4.5 mmol) of
1-[3-fluoro-5-(trifluoromethyl)ph- enyl]propan-1-one (Lancaster,
Windham, N.H., USA) was treated in a manner similar to that for
Example 127, step (a) to give 2-bromo-1-[3-fluoro-5-(-
trifluoromethyl)phenyl]propan-1-one (1.33 g, 99%). .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) .delta. 8.07 (m, 1H), 7.92 and 7.89 (m, 1H,
1:1 ratio conformers), 7.57 and 7.55 (m, 1H, 1: I ratio
conformers), 5.20 (q, 1 H, J=6.6Hz), 1.93 (d, 3H, J=6.6 Hz).
[0721] b) Methyl
4-{4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-methyl(1,3-th-
iazol-2-yl)]-5-methylthiothiophene-2-carboxylate: A solution of 75
mg (0.3 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge, Cornwall, UK) was reacted with 90 mg (0.3 mmol) of
2-bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]propan-1-one in a
manner similar to Example 8, step (a) to give, methyl
4-{4-[3-fluoro-5-(trifluor-
omethyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carbox-
ylate (31.9 mg, 24%) as a solid. .sup.1H-NMR (DMSO-d.sub.6; 300
MHz) .delta. 8.17 (s, 1H), 7.98 (m, 1H), 7.95 and 7.92 (m, 1H, 1:1
ratio conformers), 7.77 and 7.74 (m, 1H, 1:1 ratio conformers),
3.87 (s, 3H), 2.75 (s, 3H), 2.70 (s, 3H). Mass spectrum (MALDI-TOF,
CHCA matrix, m/z): Calcd. for
C.sub.18H.sub.13NO.sub.2S.sub.3F.sub.4, 448.0 (M+H), found
448.0.
[0722] c)
4-4-[3-Fluoro-5-(trifluoromethyl)phenyl]-5-methyl(1,3-thiazol-2--
yl)l-5-methylthiothiophene-2-carboxamidine: Methyl
4-{4-[3-fluoro-5-(trifl-
uoromethyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}-5-methylthiothiophene-2-car-
boxylate (30 mg, 0.067 mmol) was treated in a manner similar to
that for Example 10, step (b), to give
4-{4-[3-fluoro-5-(trifluoromethyl)phenyl]-5-
-methyl(1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidine
(32 mg, quantitive yield) as a yellow solid. .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) .delta. 9.42 (br s, 2H), 9.03 (br s, 2H),
8.60 (s, 1H), 7.98 (m, 1H), 7.95 and 7.92 (m, 1H, 1:1 ratio
conformers), 7.79 and 7.76 (m, 1H, 1:1 ratio conformers), 2.78 (s,
3H), 2.71 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z):
Calcd. for C.sub.17H.sub.13N.sub.3S.sub.3F.sub.4, 432.0 (M+H),
found 432.6.
EXAMPLE 130
[0723] a) 1-[3,5-Bis(trifluoromethyl)phenyl]-2-bromopropan-1-one: A
stirred suspension of 1 g (3.7 mmol) of
1-[3,5-bis(trifluoromethyl)phenyl- ]-propan-1-one (Lancaster,
Windham, N.J., USA) treated in a manner similar to that for Example
127, step (a) to give 2-bromo-1-[3-fluoro-5-(trifluor-
omethyl)phenyl]propan-1-one (1.1 g, 86%). .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) .delta. 8.46 (m, 2H), 8.09 (m, 1), 5.26 (q,
1H, J=6.6Hz), 1.96 (d, 3H, J=6.5 Hz). Mass spectrum (MALDI-TOF,
CHCA matrix, m/z): Calcd. for C.sub.11H.sub.7OBrF.sub.6, 349.0
(M+H), found 348.9.
[0724] b) Methyl
4-{4-[3,5-bis(trifluoromethyl)phenyl]-5-methyl(,3-thiazol-
-2-yl))-5-methylthiothiophene-2-carboxylate: A solution of 75 mg
(0.3 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge, Cornwall, UK) was reacted with 105 mg
1-[3,5-Bis(trifluoromet- hyl)phenyl]-2-bromopropan-1-one in a
manner similar to Example 8, step (a) to give, after preparative
thin-layer chromatography purification, methyl
4-{4-[3,5-bis(trifluoromethyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}-5-methy-
lthiothiophene-2-carboxylate (16.2 mg, 11%) as a solid. .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) .delta. 8.41 (m, 2H), 8.18 (m, 2H), 3.86
(s, 3H), 2.75 (s, 3H), 2.71 (s, 3H). Mass spectrum (MALDI-TOF, CHCA
matrix, m/z): Calcd. for C.sub.19H.sub.13NO.sub.2S.sub.3F.sub.6,
498.0 (M+H), found 497.6.
[0725] c)
4-{4-[3,5-Bis(trifluoromethyl)phenyl]-5-methyl(1,3-thiazol-.sup.-
2-yl),-5-methylthiothiophene-2-carboxamidine: Methyl
4-{4-[3,5-bis(trifluoromethyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}-5-methy-
lthiothiophene-2-carboxylate (15 mg, 0.031 mmol) was treated in a
manner similar to that for Example 10, step (b), to give
4-{4-[3,5-bis(trifluoro-
methyl)phenyl]-5-methyl(1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxa-
midine (13 mg, 88%) as a yellow solid. .sup.1H-NMR (DMSO-d.sub.6;
300 MHz) .delta. 9.39 (br s, 2H), 8.94 (br s, 2H), 8.58 (s, 1H),
8.40 (m, 2H), 8.19 (m, 1H), 2.79 (s, 3H), 2.73 (s, 3H). Mass
spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for
C18H.sub.13N.sub.3S.sub.3F.sub.6, 482.0 (M+H), found 482.5.
EXAMPLE 131
[0726] a) 2-Bromo-1,2-diphenylethan-1-one: A stirred suspension of
0.2 g (1 mmol) of deoxybenzoin was treated in a manner similar to
that for Example 127, step (a) to give
2-bromo-1,2-diphenylethan-1-one (270 mg, 98%). .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) .delta. 8.10-8.06 (m, 2H), 7.95-7.31 (m,
8H), 7.21 (s, 1H).
[0727] b) Methyl
4-(4,5-diphenyl(1,3-thiazol-2-yl))-5-methylthiothiophene--
2-carboxylate: A solution of 75 mg (0.3 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge, Cornwall, UK) was reacted with 92 mg, 0.3 mmol) of
2-bromo-1,2-diphenylethan-1-one in a manner similar to Example 8,
step (a) to give, after preparative thin-layer chromatography
purification, methyl
4-(4,5-diphenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxy-
late (9 mg, 7%) as a solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz)
.delta. 8.94 (br s, 0.4H), 8.66 (s, 1H), 8.60 (br s, 0.3 H), 8.08
(s, 1H), 7.93 and 7.20 (AB quartet, 2H, J=8.7 Hz), 7.68 and 7.35
(AB quartet, 2H, J=8.2 Hz), 2.77 (s, 3H), ), 2.33 (s, 3H). Mass
spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.22H.sub.17NO.sub.2S.sub.3, 424.0 (M+H), found 424.3.
[0728] c)
4-(4,5-Diphenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carbo-
xamidine: Methyl
4-(4,5-diphenyl(1,3-thiazol-2-yl))-5-methylthiothiophene--
2-carboxylate (9 mg, 0.021 mmol) was treated in a manner similar to
that for Example 10, step (b), to give
4-(4,5-diphenyl(1,3-thiazol-2-yl))-5-me-
thylthiothiophene-2-carboxamidine (3 mg, 35%) as a brown oil. Mass
spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.22H.sub.17N.sub.3S.sub.3, 408.1 (M+H), found 408.0.
EXAMPLE 132
[0729] a) Methyl
4-(4-benzo[b]thiophen-2-yl(1,3-thiazol-2-yl))-5-methylthi-
othiophene-2-carboxylate: A solution of 75 mg (0.3 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate was
reacted with 77 mg (0.3 mmol) of 3-bromoacetylbenzo[b]thiophene
(Maybridge, Cornwall, UK) in a manner similar to Example 8, step
(a) to give, after preparative thin-layer chromatography
purification, methyl
4-(4-benzo[b]thiophen-2-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-car-
boxylate (28 mg, 23%) as a solid. .sup.1H-NMR (DMSO-d.sub.6; 300
MHz) .delta. 8.63 (d, 1H, J=7.4 Hz), 8.30 (s, 1H), 8.25 (s, 1H),
8.22 (s, 1H), 7.53-7.46 (m, 2H), 3.87 (s, 3H), 2.78 (s, 3H).
[0730] b)
4(4-Benzo[b]thiophen-2-y(1,3-thiazol-2-yl))-5-methylthiothiophen-
e-2-carboxamidine: Methyl
4-(4-benzo[b]thiophen-2-yl(1,3-thiazol-2-yl))-5--
methylthiothiophene-2-carboxylate (28 mg, 0.69 mmol) was treated in
a manner similar to that for Example 10, step (b), to give
4-(4-benzo[b]thiophen-2-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-car-
boxamidine (17 mg, 64%) as a brown solid. .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) .delta. 9.22 (br s, 4H), 8.68 (s, 1H), 8.66
(d, 1H, J=7.6 Hz), 8.30 (s, 1H), 8.25 (s, 1H), 8.10 (d, 1H, J=7.3
Hz), 7.55-7.45 (m, 2H), 2.81 (s, 3H). Mass spectrum (MALDI-TOF, GA
matrix, m/z): Calcd. for C.sub.17H.sub.13N.sub.3S4, 388.0 (M+H),
found 388.2.
EXAMPLE 133
[0731] a) Methyl
4-(4-benzo[d]benzo[3,4-b]furan-3-yl(1,3-thiazol-2-yl))-5--
methylthiothiophene-2-carboxylate: A solution of 75 mg (0.3 mmol)
of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge, Cornwall, UK) was reacted with 86 mg (0.3 mmol) of
2-(bromoacetyl)-dibenzofuran (Aldrich, Milwaukee, Wis., USA) in a
manner similar to Example 8, step (a) to give, after preparative
thin-layer chromatography purification, methyl
4-(4,5-diphenyl(1,3-thiazol-2-yl))-5--
methylthiothiophene-2-carboxylate (45 mg, 36%) as a solid.
.sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 8.83-7.44 (m, 7H), 8.29
(s, 1H), 8.27 (s, 1 H), 3.88 (s, 3H), 2.80 (s, 3H). Mass spectrum
(MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.22H.sub.15NO.sub.3S.sub.3, 438.0 (M+H), found 438.5.
[0732] b)
4-4-Benzo[d]benzo[3,4-bifuran-3-yl(1,3-thiazol-2-yl))-5-methylth-
iothiophene-2-carboxamidine: Methyl
4-(4-benzo[d]benzo[3,4-b]furan-3-yl(1,-
3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (45 mg, 0.11
mmol) was treated in a manner similar to that for Example 10, step
(b), to give
4-4-benzo[d]benzo[3,4-b]furan-3-yl(1,3-thiazol-2-yl))-5-methylthiothiophe-
ne-2-carboxamidine (16.8 mg, 36%) as a yellow solid. .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) .delta. 9.72-9.10 (m, 3H), 8.84-7.31 (m,
9H), 2.84 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z):
Calcd. for C.sub.21H.sub.15N.sub.3OS.sub.3, 422.0 (M+H), found
421.9.
EXAMPLE 134
[0733] a) Methyl 4-(4-(4-nitrophenyl)
(1,3-thiazol-2-yl))-5-methylthiothio- phene-2-carboxylate: A
solution of 1 g (4 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge, Cornwall, UK) was reacted with 987 mg (4 mmol) of
2-bromo-4-nitroacetophe- none in a manner similar to Example 8,
step (a) to give methyl 4-(4-(4-nitrophenyl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxyl- ate (1.7 g,
quantitive yield) as a brown solid. .sup.1H-NMR (DMSO-d.sub.6; 300
MHz) .delta. 8.57 (s, 1H), 8.34 (s, 4H), 8.25 (s, 1H), 3.94 (s,
3H), 3.81 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z):
Calcd. for C.sub.16H.sub.12N.sub.2O.sub.4S.sub.3 393.0 (M+H), found
392.8.
[0734] b) Methyl
4-(4-(4-aminophenyl),(1,3-thiazol-2-yl))-5-methylthiothio-
phene-2-carboxylate: Methyl 4-(4-(4-nitrophenyl)
(1,3-thiazol-2-yl))-5-met- hylthiothiophene-2-carboxylate (800 mg,
2 mmol) was dissolved in 150 mL tetrahydrofuran and treated with
20% titanium chloride solution (Fisher Scientific, Pittsburgh, PA,
USA) for 1 h. The mixture was poured into 2 M sodium hydroxide
solution (100 mL), extracted with dichloromethane (4.times.50 mL).
The combined organic layers were washed with saturated brine
solution and dried over anhydrous sodium sulfate. The solid was
filtered off, and the solvent removed in vacuo. This material was
purified by column chromatography on silica gel (30 g) eluting with
dichloromethane:methanol 98/2 (v:v) to give methyl
4-(4-(4-aminophenyl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (500 mg,
69%) as a solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 8.17
(s, 1H), 7.77 (s, 1H), 7.74 and 6.62 (AB quartet, 2H, J=8.6 Hz),
5.35 (s, 2H), 3.86 (s, 3H), 2.74 (s, 3H). ). Mass spectrum
(MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.16H.sub.14N.sub.2O.sub.2S.sub.3 363.0 (M+H), found 362.4.
[0735] c) Methyl 4-(4-t4-1(methy ul o yl)amino]phenyl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate: Methyl
4-(4-(4-aminophenyl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxyl- ate (200 mg,
0.55 mmol) was dissolved in dry dichloromethane (20 mL). To this,
N-methyl morpholine (150 .mu.L, 1.38 mmol) and
dimethylaminopyridine (6.1 mg, 0.055 mmol) were added, the mixture
was cooled on an ice bath, and methanesulfonyl chloride (43 .mu.L,
0.55 mmol) was added dropwise. The mixture was then stirred for 8
days at room temperature. The mixture was partitioned between
saturated sodium bicarbonate (50 mL) and dichloromethane (20 mL).
The aqueous layer was extracted with dichloromethane (3.times.20
mL), and the combined organic layers were washed with saturated
sodium bicarbonate (20 mL), brine (2.times.20 mL), and dried over
anhydrous sodium sulfate. The solvent was removed in vacuo. Column
chromatography on silica gel (100 g) eluting with
dichloromethane:methanol 99/1 (v:v), gave methyl
4-(4-{4-[(methylsulfonyl)amino]phenyl
}(1,3-thiazol-2-yl))-5-methylthioth- iophene-2-carboxylate (155 mg,
64%) as a solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 9.92
(s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 8.40 and 6.90 (AB quartet, 2H,
J=8.7 Hz), 3.87 (s, 3H), 3.05 (s, 3H), 2.76 (s, 3H). Mass spectrum
(MALDI-TOF, CHCA matrix m/z): Calcd. for
C.sub.17H.sub.16N.sub.2O.sub.4S.sub.4441.0 (M+H), found 441.2.
[0736] d)
4-(4-[4-[(Methylsulfonyl)amino]phenyl[(1,3-thiazol-2-yl))-5-meth-
ylthiothiophene-2-carboxamidine: Methyl
4-(4-{4-[(methylsulfonyl)amino]phe-
nyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (81 mg,
0.184 mmol) was treated in a manner similar to that for Example 10,
step (b), to give
4-(4-{4-[(methylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methy-
lthiothiophene-2-carboxamidine (24.9 mg, 32%) as a light brown
solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 10.0 (br s, 1H),
9.3 (br s, 2H), 8.98 (s, 1H), 8.65 (s, 1H), 8.21 (s, 1H), 7.98 and
7.5 (AB quartet, 2H, J=8.6 Hz), 3.05 (s, 3H), 2.79 (s, 3H). Mass
spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.16H.sub.16N.sub.4O.sub.2S.sub.4425.0 (M+H), found 425.1.
EXAMPLE 135
[0737] a) Methyl-4-(4-[4-[(phenylsulfonyl)amino]phenyl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate: Methyl
4-(4-(4-aminophenyl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxyl- ate (100 mg,
0.28 mmol) was dissolved in dry dichloromethane (10 .mu.L). To
this, N-methyl morpholine (46 .mu.L, 0.42 mmol) and
dimethylaminopyridine (3.4 mg, 0.028 mmol) were added, the mixture
was cooled on an ice bath, and benzenesulfonyl chloride 35 .mu.L,
0.28 mmol) was added dropwise. The mixture was then stirred for 24
h at room temperature. Workup was carried out as in Example 134,
step (c). Trituration with dichloromethane and methanol gave methyl
4-(4-{4-[(phenylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothi-
ophene-2-carboxylate (44 mg, 31%) as a crystalline solid.
.sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 10.46 (s, 1H), 8.19 (s,
1H), 8.05 (s, 1H), 7.91 and 7.19 (AB quartet, 2H, J=8.7 Hz), 7.81
(m, 2H), 7.64-7.54 (m, 3H) 3.85 (s, 3H), 2.74 (s, 3H). Mass
spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.22H.sub.18N.sub.2O.sub.4S.sub.4 504.2 (M+H), found 504.1
[0738] b) 4-(4-{4-[(Phenylsulfonyl)amino]phenyl)
(1,3-thiazol-2-yl))-5-met- hylthiothiophene-2-carboxamidine: Methyl
4-(4-{4-[(phenylsulfonyl)amino]ph-
enyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (30
mg, 0.060 mmol) was treated in a manner similar to that for Example
10, step (b), to give
4-(4-{4-[(phenylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methy-
lthiothiophene-2-carboxamidine (12.6 mg, 43%) as a yellow solid.
.sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 9.13 (br s, 3H), 8.60
(s, 1H), 8.08 (s, 1H) 7.93 and 7.20 (AB quartet, 2H, J=8.7 Hz),
7.82-7.79 (m, 2H), 7.65-7.53 (m, 3H) 3.85 (s, 3H), 2.74 (s, 3H).
Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.21H.sub.18N.sub.4O.sub.2S- .sub.4, 87.0 (M+H), found
487.7.
EXAMPLE 136
[0739] a) Methyl
4-(4-[4-[(trifluoromethysulfonyl)amino]phenyl](1,3-thiazo-
l-2-yl))-5-methylthiothiophene-2-carboxylate: Methyl
4-(4-(4-aminophenyl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (200 mg,
0.55 mmol) was dissolved in dry pyridine (20 mL). The mixture was
cooled on an ice bath, and trifluoromethanesulfonic anhydride (0.5
mL, 3 mmol) was added. The mixture was then stirred for 1.5 h at
room temperature. Workup was carried out as in Example 134, step
(c). Column chromatography on silica gel (30 g) eluting with
hexanes:ethyl acetate 7/3 (v:v), followed by preparative thin layer
chromatography eluting with dichloromethane:methanol 99/1 (v:v)
gave methyl 4-(4-{4-[(trifluoromethyl-
sulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxyl-
ate (160 mg, 59%) as a solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz)
.delta. 8.48 and 7.87(s, 3/2 ratio conformers, 1H), 8.23 (s, 1H),
8.21 (s, 1H1), 8.29 and 7.84 (AB quartet, 2H, 2/3 ratio conformers,
J=8.7 Hz), 8.10 and 7.37 (AB quartet, 2H, J=8.7 Hz), 3.87 and 3.86
(s, 2/3 ratio conformers, 3H), 2.77 and 2.76 (s, 2/3 ratio
conformers, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z):
Calcd. for C.sub.17H.sub.13N.sub.2O.sub.4S- .sub.4F.sub.4495.0
(M+H), found 495.6
[0740] b) 4-(4-[4-[(Trifluoromethylsulfonyl)amino]phenyl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine: Methyl
4-(4-{4-[(trifluoromethylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-meth-
ylthiothiophene-2-carboxylate (30 mg, 0.061 mmol) was treated in a
manner similar to that for Example 10, step (b), to give of
4-(4-{4-[(trifluoromethylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-meth-
ylthiothiophene-2-carboxamidine (21.6 mg, 74%) as a light brown
solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 9.39 (br s, 2H),
8.97 (br s, 2H), 8.64 (s, 1H), 8.24 (s, 1H), 8.12 and 7.39 (AB
quartet, 2H, J=8.7 Hz), 4.78 (br s, 1H), 2.79 (s, 3H). Mass
spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.16H.sub.13N.sub.4O.sub.2S.sub.4F.sub.3, 479.0 (M+H), found
479.5.
EXAMPLE 137
[0741] a) Methyl-4-(4-[4-[(toluenesulfonyl)amino]phenyl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate: Methyl
4-(4-(4-aminophenyl)
(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxyl- ate (33 mg,
0.09 mmol) was dissolved in dry dichloromethane (5 mL). To this,
N-methyl morpholine (10 .mu.L, 0.09 mmol) and p-toluenesulfonyl
chloride (17 mg, 0.09 mmol) was added and the mixture was stirred
at room temperature for 5 days. Workup was carried out as in
Example 134, step (c). Trituration with dichloromethane and
methanol gave methyl 4-(4-{4-[(toluenesulfonyl)amino]phenyl
}(1,3-thiazol-2-yl))-5-methylthiot- hiophene-2-carboxylate (20 mg,
43%) as a brown solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta.
10.39 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.91 and 7.18 (AB
quartet, 2H, J=8.7 Hz), 7.68 and 7.35 (AB quartet, 2H, J=8.2 Hz),
3.85 (s, 3H), 2.74 (s, 3H), 2.27 (s, 3H). Mass spectrum (MALDI-TOF,
CHCA matrix, m/z): Calcd. for C.sub.23H.sub.20N.sub.2O.sub.4S-
.sub.4, 517.2 (M+H), found 517.0.
[0742] b)
4-(4-[4-[(Toluenesulfonyl)amino]phenyl(1,3-thiazol-2-yl))-5-meth-
ylthiothiophene-2-carboxamidine: Methyl
4-(4-{4-[(toluenesulfonyl)amino]ph- enyl
}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (15 mg,
0.029 mmol) was treated in a manner similar to that for Example 10,
step (b), to give
4-(4-{4-[(toluenesulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-
-methylthiothiophene-2-carboxamidine (17.9 mg, 81%) as a light
brown solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 8.94 (br
s, 0.4H), 8.66 (s, 1H), 8.60 (br s, 0.3 H), 8.08 (s, 1H), 7.93 and
7.20 (AB quartet, 2H, J=8.7 Hz), 7.68 and 7.35 (AB quartet, 2H,
J=8.2 Hz), 2.77 (s, 3H), 2.33 (s, 3H). Mass spectrum (MALDI-TOF,
CHCA matrix, m/z): Calcd. for
C.sub.22H.sub.20N.sub.4O.sub.2S.sub.4: 501.1 (M+H), found
501.1.
EXAMPLE 138
[0743] a) Methyl-4-[4-(4-chlorophenyl)
(1,3-thiazol-2-yl)]-5-(methylsulfin- yl)thiophene-2-carboxylate: To
a stirred solution of 764 mg (2 mmol) of methyl
4-[4-(4-chlorophenyl) (1,3-thiazol-2-yl)]-5-methylthiothiophene-2--
carboxylate (Maybridge, Cornwall, UK) dissolved in
1,1,1,3,3,3-hexafluoroi- sopropanol (2.5 mL) was added 30% hydrogen
peroxide (0.45 mL, 4 mmol). This solution was stirred for 45 h at
room temperature. Dichloromethane (10 mL) was added after 2 hours.
Additional hydrogen peroxide (2.times.0.45 mL portions) was added
after 4 hours and 24 hours. The mixture was quenched with 10%
sodium sulfite in brine (4 mL). The organic layer was separated,
dried over anhydrous sodium sulfate, and the solvents removed in
vacuum. Column chromatography on silica gel (45 g), eluting with
dichloromethane:methanol 99/1 (v:v) gave methyl
4-[4-(4-chlorophenyl)
(1,3-thiazol-2-yl)]-5-(methylsulfinyl)thiophene-2-c- arboxylate
(720 mg, 90%) as a solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz)
.delta. 8.37 (s, 1H), 8.30 (s, 1H), 8.05 and 7.52 (AB quartet, 2H,
J=8.6 Hz), 3.91 (s, 3H), 3.16 (s, 3H). Mass spectrum (MALDI-TOF, GA
matrix, m/z): Calcd. for
C.sub.16H.sub.12NO.sub.3S.sub.3C.sub.1:398.0 (M+H), found
397.8.
[0744] b) 4-[4-(4-Chlorophenyl)
(13-thiazol-2-yl)]-5-(methylsulfinyl)thiop- hene-2-carboxamidine:
Methyl 4-[4-(4-chlorophenyl) (l,3-thiazol-2-yl)]-5-(-
methylsulfinyl)thiophene-2-carboxylate (100 mg, 0.25 mmol) was
treated in a manner similar to that for Example 10, step (b), to
give, after preparative thin layer chromatography purification
eluting with dichloromethane:methanol:acetic acid 9/1/0.5 (v:v:v),
4-[4-(4-chlorophenyl)
(1,3-thiazol-2-yl)]-5-(methylsulfinyl)thiophene-2-c- arboxamidine
(18.2 mg, 19%) as a solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz)
.delta. 8.33 (s, 1H), 8.22 (s, 1H), 8.05 and 7.57 (AB quartet, 2H,
J=8.6 Hz), 3.12 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix
m/z): Calcd. for C.sub.15H.sub.12N.sub.3OS.sub.3C.sub.1382.0 (M+H),
found 382.1.
EXAMPLE 139
[0745] a) Methyl 4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate:
To a stirred solution of (4.5 g, 21 mmol) of methyl
4-cyano-5-methylthiothioph- ene-2-carboxylate (Maybridge, Cornwall,
UK) was dissolved in dichloromethane (250 mL) and treated with
m-chloroperbenzoic acid (15.3 g, 90 mmol) at room temperature for
2.25 h. The mixture was filtered and the solid washed with
dichloromethane (2.times.50 mL). The filtrate was washed with
sodium bicarbonate (2.times.100 mL), sodium thiosulfate (100 mL),
sodium bicarbonate (100 mL), water (100 mL), brine (100 mL), and
dried over anhydrous sodium sulfate. The solvent was removed in
vacuo to give methyl
4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (4.91 g, 95%) as
a solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 8.44 (s, 1H),
3.91 (s, 3H), 3.58 (s, 3H).
[0746] b) Methyl 4-cyano-5-methoxythiophene-2-carboxylate: Methyl
4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (2 g, 8 mmol) was
refluxed with 0.5 M sodium methoxide in methanol (16 mL) for 15
minutes. The solution was cooled, the crystallized solid collected
on a Buchner funnel and washed with methanol (50 mL) to give methyl
4-cyano-5-methoxythiophene-2-carboxylate (1.145 g, 73%) as a solid.
.sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 8.87 (s, 1H) 4.19 (s,
3H), 3.82 (s, 3H).
[0747] c) Methyl
4-(aminothioxomethyl)-5-methoxythiophene-2-carboxylate: Methyl
4-cyano-5-methoxythiophene-2-carboxylate (1 g, 5 mmol) was
dissolved in dry methanol (150 mL) and triethylamine (3.5 mL, 25.4
mmol) was added. After degassing the solution with argon for 10
minutes, hydrogen sulfide gas was bubbled through the solution for
5 h. After stirring 18 h at room temperature, the solution was
degassed by bubbling argon (6 h), concentrated to 20 mL and acetone
(20 mL) was added. The dark solid was collected on a Buchner funnel
and washed with acetone. Recrystallize solid from hot ethanol (15
mL) to give methyl
4-(aminothioxomethyl)-5-methoxythiophene-2-carboxylate (683 mg,
59%) as a brown oil. Mass spectrum (MALDI-TOF, CHCA matrix, m/z):
Calcd. for C.sub.8H.sub.9NO.sub.3S.sub.2 232.0 (M+H), found
232.4
[0748] d) Methyl
5-methoxy-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carbo- xylate:
A solution of 400 mg (1.73 mmol) of methyl 4-(aminothioxomethyl)-5-
-methoxythiophene-2-carboxylate was reacted with 345 mg (1.73 mmol)
of 2-bromoacetophenone (Aldrich, Milwaukee, Wis., USA) in a manner
similar to Example 8, step (a) to give methyl
5-methoxy-4-(4-phenyl(1,3-thiazol-2- -yl))thiophene-2-carboxylate
(56 mg, 10%) as a solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz)
.delta. 8.22 (s, 1H), 8.14 (s, 1H), 8.05 (m, 2H), 7.47 (m, 2H),
7.36 (m, 1H), 4.26 (s, 3H), 3.85 (s, 3H).
[0749] e)
5-Methoxy-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidin-
e: Methyl
5-methoxy-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (55
mg, 0.16 mmol) was treated in a manner similar to that for Example
10, step (b), to give
5-methoxy-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2- -carboxamidine
(36 mg, 69%) as a yellow solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz)
.delta. 9.34 (br s, 2H), 8.94 (br s, 2H), 8.70 (s, 1H), 8.20 (s,
1H), 8.07 (m, 2H), 7.49 (m, 2H), 7.38 (m, 1H), 4.32 (s, 3H). Mass
spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.15H.sub.13N.sub.3OS.sub.2 316.5 (M+H), found 316.1
EXAMPLE 140
[0750] a) Methyl
4-cyano-5-[(4-methoxyphenyl)methylthiothiophene-2-carboxy- late: To
a stirred solution of 2.5 g (10 mmol) of methyl
4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (Example 139,
step (a)) in dry methanol (15 mL) was added
p-methoxybenzylmercaptan (3.8 mL, 28 mmol) and triethylamine (1.4
mL, 10 mmol). This solution was refluxed for 15 min and cooled. The
resulting solid was collected on a buchner funnel and washed with
methanol (2.times.25 mL) to methyl
4-cyano-5-[(4-methoxyphenyl)methylthiothiophene-2-carboxylate (2.84
g, 89%) as a solid.
[0751] b) Methyl
4-(aminothioxomethyl)-5-f(4-methoxyphenyl)methylthio]thio-
phene-2-carboxylate: Methyl
4-cyano-5-[(4-methoxyphenyl)methylthiothiophen- e-2-carboxylate
(2.5 g, 7.8 mmol) was treated as in Example 139, step (c) to give
methyl 4-(aminothioxomethyl)-5-[(4-methoxyphenyl)methylthiothioph-
ene-2-carboxylate (1.32 g, 48%) as a solid. .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) .delta. 9.64 (s, 1H), 9.28 (s, 1H), 8.08
(s, 1H), 7.35 and 6.92 (AB quartet, 2H, J=8.7 Hz), 4.27 (s, 2H),
3.82 (s, 3H), 3.75 (s, 3H).
[0752] c) Methyl
5-(methoxyphenylthio)-4-(4-phenyl(1,3-thiazol-2-yl))thiop-
hene-2-carboxylate: A solution of 1.2 g (3.4 mmol) of methyl
4-(aminothioxomethyl)-5-[(4-methoxyphenyl)methylthiothiophene-2-carboxyla-
te was reacted with 676 mg (3.4 mmol) of 2-bromoacetophenone
(Aldrich, Milwaukee, Wis., USA) in a manner similar to Example 8,
step (a) to give methyl
5-(methoxyphenylthio)-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-ca-
rboxylate (755 mg, 49%) as a solid. .sup.1H-NMR (DMSO-d.sub.6; 300
MHz) .delta. 8.26 (s, 1H), 8.22 (s, 1H), 8.04 (m, 2H), 7.48 (m,
2H), 7.38 (m, 1H), 7.33 and 6.89 (AB quartet, 2H, J=8.7 Hz), 4.40
(s, 2H), 3.86 (s, 3H), 3.72 (s, 3H).
[0753] d)
5-(Methoxyphenylthio)-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2--
carboxamidine: Methyl
5-(methoxyphenylthio)-4-(4-phenyl(1,3-thiazol-2-yl))-
thiophene-2-carboxylate (100 mg, 0.22 mmol) was treated in a manner
similar to that for Example 10, step (b), to give
5-methoxy-4-(4-phenyl(1- ,3-thiazol-2-yl))thiophene-2-carboxamidine
(94 mg, 91%) as an orange solid. .sup.1H-NMR (DMSO-d.sub.6; 300
MHz) .delta. 9.49 (br s, 2H), 9.15 (br s, 2H), 8.70 (s, 1H), 8.26
(s, 1H), 8.07 (m, 2H), 7.49 (m, 2H), 7.40 (m, 1H), 7.35 and 6.90
(AB quartet, 2H, J=8.7 Hz), 4.41 (s, 2H), 3.73 (s, 3H). Mass
spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.22H.sub.19N.sub.3OS.sub.3 438.5 (M+H), found 438.1.
EXAMPLE 141
[0754] a) Methyl-4-[4-(4-chlorophenyl)
(1,3-thiazol-2-yl)]-5-(methylsulfon- yl)thiophene-2-carboxylate: To
a stirred solution of 1 g (2.6 mmol) of methyl
4-[4-(4-chlorophenyl) (1,3-thiazol-2-yl)]-5-methylthiothiophene-2--
carboxylate (Maybridge, Cornwall, UK) was dissolved in dry
dichloromethane (50 mL) and treated with m-chloroperbenzoic acid
(1.94 g, 11.3 mmol) at room temperature for 1.5 h. The solution was
filtered and the solid washed with dichloromethane. The filtrate
was washed with sodium bicarbonate solution (2.times.20 mL), sodium
thiosulfate solution (20 mL), sodium bicarbonate solution (20 mL),
brine (20 mL), and dried over anhydrous sodium sulfate. The solvent
was removed in vacuo to give methyl 4-[4-(4-chlorophenyl)
(1,3-thiazol-2-yl)]-5-(methylsulfonyl)thiophene-2-c- arboxylate
(826 mg, 77%) as a tan solid. Mass spectrum (MALDI-TOF, CHCA
matrix, m/z): Calcd. for
C.sub.16H.sub.12NO.sub.4S.sub.3C.sub.1414.0 (M+H), found 414.8.
[0755] b) 4-[4-(4-Chlorophenyl)
(1,3-thiazol-2-yl)]-5-(methylsulfonyl)thio- phene-2-carboxamidine:
Methyl 4-[4-(4-chlorophenyl)
(1,3-thiazol-2-yl)]-5-(methylsulfonyl)thiophene-2-carboxylate (200
mg, 0.4 mmol) was treated in a manner similar to that for Example
10, step (b), to give 4-[4-(4-chlorophenyl)
(1,3-thiazol-2-yl)]-5-(methylsulfonyl)- thiophene-2-carboxamidine
(85 mg, 53%) as a yellow solid.
[0756] c) 4-[4-(4-Chlorophenyl)
(1,3-thiazol-2-yl)]-5-phenylmethylthio)thi- ophene-2-carboxamidine:
A stirred solution of 80 mg (0.2 mmol) of 4-[4-(4-chlorophenyl)
(1,3-thiazol-2-yl)]-5-(methylsulfonyl)thiophene-2-c- arboxamidine
benzyl mercaptan (115 .mu.L, 0.980 mmol) was treated in a manner
similar to that for Example 140, step (a) to give, after silica gel
column chromatography (20 g) eluting with
dichloromethane:methanol:ac- etic acid 9/1/0.5 (v:v:v),
4-[4-(4-chlorophenyl) (1,3-thiazol-2-yl)]-5-(ph-
enylmethylthio)thiophene-2-carboxamidine (75 mg, 85%) as a pale
orange solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 9.44 (br
s, 2H), 9.03 (br s, 2H), 8.67 (s, 1H), 8.33 (s, 1H), 8.08 and 7.56
(AB quartet, 2H, J=8.7 Hz), 7.54-7.17 (m, 5H), 4.45 (s, 2H). Mass
spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.21H.sub.16N.sub.3S.sub.3Cl 442.0 (M+H), found 442.7.
EXAMPLE 142
[0757] a) 1-[5-(tert-Butyl)-2-methyl(3-furyl)]-2-bromoethan-1-one:
A solution of 1 g (5 mmol) of
5-(tert-butyl)-2-methylfuran-3-carbonyl chloride (Maybridge,
Cornwall, UK) dissolved in dry acetonitrile (4 mL) and 6.25 mL
(12.5 mmol) of 2 M trimethylsilyldiazomethane in hexanes (Aldrich,
Milwaukee, Wis.) was stirred 1.75 h at room temperature and the
mixture was cooled on an ice bath for 5 min. To this, 30% hydrogen
bromide in acetic acid (2 mL, 10 mmol) was added dropwise over 10
min. This was stirred an additional 20 minutes on an ice bath.
Evaporation of the solvents gave
1-[5-(tert-butyl)-2-methyl(3-furyl)]-2-bromoethan-1-one (1 g, 77%)
as a brown oil. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 6.50
(s, 1H), 4.57(s, 2H), 2.52 (s, 1H), 1.24 (s, 9H). Mass spectrum
(LCA, m/z): Calcd. for C.sub.11H.sub.15O.sub.2Br, 259.1 and 261.1
(M+H), found 259.1 and 261.1.
[0758] b) Methyl 4-t4-[5-(tert-butyl)-2-methyl(3-fu 1)
(3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate: A solution
of 955 mg (3.86 mmol) of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-ca- rboxylate
(Maybridge, Cornwall, UK) was reacted with 1 g (3.86 mmol) of
1-[5-(tert-butyl)-2-methyl(3-furyl)]-2-bromoethan-1-one (1 g) in a
manner similar to Example 8, step (a) to give methyl
4-{4-[5-(tert-butyl)-2-meth-
yl(3-furyl)](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate
(999 mg, 64%) as a red-brown solid. .sup.1H-NMR (DMSO-d.sub.6; 300
MHz) .delta. 8.14 (s, 1H), 7.74 (s, 1H), 6.46 (s, 1H), 3.86 (s,
3H), 2.74 (s, 3H), 2.66 (s, 3H), 1.27 (s, 9H). Mass spectrum
(MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.19H.sub.21NO.sub.3S.sub.3, 408.1 (M+H), found 408.0.
[0759] c)
4-[4-[5-(tert-Butyl)-2-methyl(3-furyl)](I,3-thiazol-2-yl),]-5-me-
thylthiothiophene-2-carboxamidine: Methyl
4-{4-[5-(tert-butyl)-2-methyl(3--
furyl)](1,.sup.3-thiazol-.sup.2-yl)}-5-methylthiothiophene-2-carboxylate
(940 mg, 2.3 mmol) was treated in a manner similar to that for
Example 10, step (b) to give
4-{4-[5-(tert-butyl)-2-methyl(3-furyl)](1,3-thiazol--
2-yl)}-5-methylthiothiophene-2-carboxamidine (930 mg, quantitive
yield) as a yellow solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz)
.delta. 9.42 (br s, 2H), 9.03 (br s, 2H), 8.59 (s, 1H), 7.77 (s,
1H), 6.47 (s, 1H), 2.78 (s, 3H), 2.68 (s, 3H), 1.27 (s, 9H). Mass
spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.18H.sub.21N.sub.3OS.sub.3, 392.1 (M+H), found 392.1.
EXAMPLE 143
[0760] a)
1-[3-(tert-Butyl)-i-benzylpyrazol-5-yl]-2-bromoetlian-1-one: A
solution of 1 g (3.6 mmol) of
3-(tert-butyl)-1-benzylpyrazole-5-carbonyl chloride (Maybridge,
Cornwall, UK) was dissolved in dry acetonitrile (4 mL) and 4.5 mL
(9 mmol) of 2 M trimethylsilyldiazomethane in hexanes (Aldrich,
Milwaukee, Wis., USA) was added. After stirring 1 h 20 min at room
temperature, the mixture was cooled on an ice bath for 5 min. To
this, 30% hydrogen bromide in acetic acid (2 mL, 10 mmol) was added
dropwise over 15 min. This was stirred an additional 15 minutes on
an ice bath. Filtration of the precipitated solid and evaporation
of the solvents gave
1-[3-(tert-butyl)-1-benzylpyrazol-5-yl]-2-bromoethan-1-one (1.47 g,
quantitive yield) as an orange solid. .sup.1H-NMR (DMSO-d.sub.6;
300 MHz) .delta. 7.33-7.06 (m, 5H), 7.08 (s, 11H), 5.64 (s, 2H),
4.57 (s, 2H), 1.28 (s, 9H). Mass spectrum (MALDI-TOF, CHCA matrix,
m/z): Calcd. for C.sub.16H.sub.19N.sub.2OBr, 335.1 and 337.1 (M+H),
found 335.6 and 337.6.
[0761] b) Methyl
4-4-[3-(tert-Butyl)-1-benzylpyrazol-5-yl](1,3-thiazol-2-y-
l)]-5-methylthiothiophene-2-carboxylate: A solution of 823 mg (3.3
mmol of methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate
(Maybridge, Cornwall, UK) was reacted with 1.36 g (3.3 mmol) of
1-[3-(tert-butyl)-1-benzylpyrazol-5-yl]-2-bromoethan-1-one in a
manner similar to Example 8, step (a) to give methyl
4-{4-[3-(tert-butyl)-1-benz-
ylpyrazol-5-yl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate
(1.25 g, 79%) as a crystalline solid. .sup.1H-NMR (DMSO-d.sub.6;
300 MHz) .delta. 8.11 (s, 1H), 8.05 (s, 1H), 7.28-6.99 (m, 5H),
6.70 (s, 1H), 5.88 (s, 2H), 3.86 (s, 3H), 2.70 (s, 3H), 1.30 (s,
9H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.24H.sub.21N.sub.3O.sub.2S- .sub.3, 484.1 (M+H), found
483.9.
[0762] c)
4-[4-[3-(tert-Butyl)-1-benzylpyrazol-5-yl[(1,3-thiazol-2-yl))-5--
methylthiothiophene-2-carboxamidine: Methyl
4-{4-[3-(tert-butyl)-1-benzylp-
yrazol-5-yl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate
(1.2 mg, 2.6 mmol) was treated in a manner similar to that for
Example 10, step (b) to give
4-{4-[3-(tert-butyl)-1-benzylpyrazol-5-yl](1,3-thiazol-2-
-yl)}-5-methylthiothiophene-2-carboxamidine (1.21 g, quantitive
yield) as a yellow solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz)
.delta. 9.43 (br s, 1H), 9.07 (br s, 1H), 8.60 (s, 1H), 8.04 (s,
1H), 7.37-6.97 (m, 5H), 6.70 (s, 1H), 5.92 (s, 2H), 2.73 (s, 3H),
1.30 (s, 9H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd.
for C.sub.23H.sub.25N.sub.5S.sub.3, 468.1 (M+H), found 468.1.
EXAMPLE 144
[0763] a) 4-Bromo-5-methylthiophene-2-carboxylic acid: A stirred
solution of 1 g (3.9 mmol) of 2-methyl-3,5-dibromothiophene
(prepared by the method of Kano, S. et al., Heterocycles
20(10):2035, 1983) in dry tetrahydrofuran (10 mL) was cooled
to-78.degree. C. and 2 M n-butyllithium in cyclohexane (1.93 mL,
3.87 mmol) was added over 3 min. After stirring 3 min at
-78.degree. C., the mixture was added to tetrahydrofuran (100 mL)
with dry ice suspended. This mixture was allowed to stir and warm
to room temperature. To this, 6 N hydrochloric acid (50 mL) was
added carefully. Then, water (50 mL) was added and the layers were
separated. The aqueous layer was extracted with diethyl ether
(4.times.30 .mu.L). The combined organic layers were washed with
water, brine, and dried over anhydrous sodium sulfate. The solvents
were removed in vacuo to give an 85/15 mixture of
4-bromo-5-methylthiophene-2-carboxyl- ic acid and
5-bromothiophene-2-carboxylic acid (780 mg, 90%) as a tan solid.
.sup.1H-NMR (DMSO-d6; 300 MHz) .delta. 13.33 (br s, 1H), 7.62 (s,
1H), 7.56 and 7.34 (AB quartet, 0.35H, J=3.9 Hz), 2.41 (s, 3H). Gas
Chromatography/Mass spectroscopy (m/z): Calcd. for
C.sub.6H.sub.5O.sub.2SBr, 220.9 and 222.9 (M+H), found 221.3 and
223.3. Calcd. for C.sub.5H.sub.3O.sub.2SBr, 206.9 and 208.9 (M+H),
found 207.3 and 209.3.
[0764] b) Methyl 4-bromo-5-methylthiophene-2-carboxylate: A
solution of 780 mg (3.5 mmol) of an 85/15 mixture of
4-bromo-5-methylthiophene-2-carb- oxylic acid and
5-bromothiophene-2-carboxylic acid was dissolved in methanol (50
mL) and treated with 9 ml (18 mmol) 2 M trimethylsilyldiazomethane
in hexanes (Aldrich, Milwaukee, Wis., USA). Evaporation of the
solvents gave an 8/2 mixture of methyl
4-bromo-5-methylthiophene-2-carboxylate and methyl
5-bromothiophene-2-carboxylate (858 mg, quantitive yield) as a
brown oil. Gas Chromatography/Mass spectroscopy (m/z): Calcd. for
C.sub.7H.sub.7O.sub.2SBr, 234.9 and 236.9 (M+H), found 235.3 and
237.3. Calcd. for C.sub.6H.sub.4O.sub.2SBr, 220.9 and 222.9 (M+H),
found 221.3 and 223.3.
[0765] c) Methyl 4-cyano-5-methylthiophene-2-carboxylate: A
solution of an 8/2 mixture of 823 mg (3.5 mmol) of methyl
4-bromo-5-methylthiophene-2-ca- rboxylate and methyl
5-bromothiophene-2-carboxylate was dissolved in dry
dimethylformamide (5 mL) and refluxed with copper cyanide (345 mg,
3.9 mmol) for 7 hours. The cooled solution was poured into 0.1 M
aqueous sodium cyanide solution (200 mL) and extracted with diethyl
ether (5.times.30 mL). The organic layers were washed with brine
(2.times.30 mL), dried over anhydrous sodium sulfate, and the
solvents removed in vacuo. The resulting brown solid was purified
by column chromatography on silica gel eluting with hexanes:ethyl
acetate 9/1 (v:v) to give a 95/5 mixture of methyl
4-cyano-5-methylthiophene-2-carboxylate and methyl
5-methylthiophene-2-carboxylate (369 mg, 68%) as a yellow solid.
.sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 8.06 (s, 1H), 8.05 and
7.90 (2H, 0. I H, J=4.0 Hz, minor component), 3.87 (s, 3H, minor
component), 3.84 (s, 3H) 2.68 (s, 3H).
[0766] d) Methyl
4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate: A stirred
solution of 804 mg (4.4 mmol) of methyl 4-cyano-5-methylthiophene-
-2-carboxylate was treated in a manner similar to Example 139, step
(c) to give, after fractional crystallization ethanol of the
unreacted starting nitrile, a 2:3 ratio of methyl
4-(aminothioxomethyl)-5-methylthiophene-2-- carboxylate and methyl
4-cyano-5-methylthiophene-2-carboxylate (457 mg, 48%) as a light
brown solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 9.93 (br
s, 1H, minor), 9.34 (br s, 1H, minor), 8.06 (s, 1H, major), 7.77
(s, 1H, minor component), 3.84 (s, 3H, minor), 3.81 (s, 3H, major),
2.68 (s, 3H, major), 2.61 (s, 2H, minor). Mass spectrum (MALDI-TOF,
CHCA matrix, m/z): Calcd. for C.sub.8H.sub.9NO.sub.2S.sub.2 216.0
(M+H), found 216.4.
[0767] e) Methyl
5-methyl-4-(4-phenyl(,3-thiazol-2-yl))thiophene-2-carboxy- late: A
solution of 200 mg (0.93 mmol) of methyl 4-(aminothioxomethyl)-5-m-
ethylthiophene-2-carboxylate was reacted with 185 mg (0.93 mmol) of
2-bromoacetophenone in a manner similar to Example 8, step (a) to
give, after purification by preparative thin layer chromatography
eluting with hexanes:ethyl acetate 7/3 (v:v), a mixture of methyl
5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate and
methyl 4-cyano-5-methylthiophene-2-carboxylate (96 mg, 36%) as a
solid.
[0768] f) 5)
5-Methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamid- ine:
Methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (64
mg, 0.23 mmol) was treated in a manner similar to Example 10, step
(b) to give, after preparative high pressure liquid chromatography
(Dynamax C.sub.18 column, 300 A pore size, 10 Jim particle size,
40% to 100% acetonitrile over 30 minutes in 0.1% aqueous
trifluoroacetic acid)
5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine
(0.6 mg, 0.9%) as an an off-white solid. .sup.1H-NMR (CD.sub.3OD,
300 MHz) .delta. 8.44 (s, 1H), 8.02 (m, 2H), 7.92 (s, 1H), 7.45 (m,
2H), 7.36 (m, 1H), 2.96 (s, 3H). Mass spectrum (MALDI-TOF, CHCA
matrix, m/z): Calcd. for C.sub.15H.sub.13N.sub.3S.sub.2 300.1
(M+H), found 300.6.
[0769] g)
.sup.5-(4-Phenyl-1,.sup.3-thiazol-2-yl)thiophene-2-carboxamide:
From the HPLC purified mixture in the previous step was isolated
5-(4-phenyl-1,3-thiazol-2-yl)thiophene-2-carboxamide as an
off-white solid (2 mg). .sup.1H-NMR (Methanol-d.sub.4; 300 MHz)
.delta. 7.99 (m, 2H), 7.97 (s, 1H), 7.95 and 7.78 (AB quartet, 2H,
J=4.2 Hz), 7.48-7.35 (m, 3H). Mass spectrum (MALDI-TOF, CHCA
matrix, m/z): Calcd. for C.sub.14H.sub.11N.sub.3S.sub.2 286.0
(M+H), found 286.2.
EXAMPLE 145
[0770] a) Methyl 4-[4-(3,4-dimethoxyphenyl)
(1,3-thiazol-2-yl)/-5-methylth- iophene-2-carboxylate: A solution
of 257 mg (0.48 mmol, based on a mixture containing 60% nitrile) of
methyl 4-(aminothioxomethyl)-5-methylthiophene- -2-carboxylate was
reacted with 124 mg (0.48 mmol) of
2-bromo-(3,4-dimethoxy)-acetophenone (Example 31, step (a)) was
reacted in a manner similar to Example 8, step (a) to give 10
methyl 4-[4-(3,4-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiophene-2-carbox- ylate (95 mg, 53%)
as a solid. Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for
C.sub.18H.sub.17NO.sub.4S.sub.2 376.1 (M+H), found 376.3.
[0771] b) 4-J4-(3,4-Dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiophene- -2-carboxamide: Methyl
4-[4-(3,4-dimethoxyphenyl) (1,3-thiazol-2-yl)]-5-15
methylthiophene-2-carboxylate (95 mg, 0.25 mmol) was treated in a
manner similar to Example 10, step (b) to give
4-[4-(3,4-dimethoxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxamide (8 mg, 9%) as a
yellow solid. .sup.1H-NMR (Methanol-d.sub.4; 300 MHz) .delta. 8.42
(s, 1H), 7.81 (s, 1H), 7.61 (m, 2H), 7.03 (m, 1H), 3.92 (s, 3H),
3.88 (s, 3H), 2.95 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix,
m/z): Calcd. for CH.sub.17N.sub.3O.sub.2S.sub.2 360.1 (M+H), found
360.2.
EXAMPLE 146
[0772] a) 4-Bromo-5-methylthiophene-2-carboxylic acid: A solution
of 27.65 g (108 mmol) of 2-methyl-3,5-dibromothiophene (prepared by
the method of Kano, S. et 25 al., Heterocycles 20(10):2035, 1983)
was dissolved in dry tetrahydrofuran (280 mL), cooled to
-78.degree. C. and 2 M n-butyl lithium in cyclohexane (54 mL, 108
mmol) was added over 10 min. After stirring 20 min at -78.degree.
C., dry carbon dioxide gas was bubbled through the solution for 1.5
h as the mixture was allowed to warm to room temperature. To this 6
N hydrochloric acid (100 mL) was added carefully. The layers were
separated and the aqueous layer was extracted with diethyl ether
(4.times.50 mL). The combined organic layers were washed with
brine, and dried over anhydrous sodium sulfate. The solvents were
removed in vacuo to give 4-bromo-5-methylthiophene-2-carboxylic
acid (22.4 g, 94%) as an off-white solid. .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) .delta. 13.34 (br s, 1H), 7.61 (s, 1H),
2.41 (s, 3H).
[0773] b) Isopropyl 4-bromo-5-methylthiophene-2-carboxylate: A
solution of 5 g (22.6 mmol) of
4-bromo-5-methylthiophene-2-carboxylic acid was dissolved in dry
dichloromethane (200 mL) and reacted with oxalyl chloride (2 mL,
22.6 mmol) and dimethylformamide (100 .mu.L) stirring on an ice
bath for 30 min and then at room temperature for 2.5 h. The
solvents were removed in vacuo and the residue was passed through
silica gel, eluting off with hexanes:ethyl acetate 7/3 (v:v), ethyl
acetate, and dichloromethane. The solvents were removed in vacuo
and the resulting oil dissolved in dry dichloromethane (100 mL).
This solution was reacted with dry pyridine (9 mL, 113 mmol) and
dry isopropanol (40 mL, 522 mmol) for 88 h. The solvents were
removed in vacuo and the residue partitioned between sodium
bicarbonate (150 mL) and dichloromethane (75 mL). The aqueous
layers were extracted with dichloromethane (2.times.20 mL), and the
combined organic layers were washed with sodium bicarbonate (30
mL), brine (30 mL), and dried over anhydrous sodium sulfate. The
solvents were removed in vacuo. The residue was purified by column
chromatography eluting with hexanes:ethyl acetate 9/1 (v:v) to give
isopropyl 4-bromo-5-methylthiophene-2-carboxylate (1.91 g, 32%) as
a pale yellow oil. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 7.66
(s, 1H), 5.07 (septet, 1H, J=6.2 Hz), 2.42 (s, 3H), 1.29 (d, 6H,
J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for
C.sub.9H.sub.11O.sub.2SBr 264.2 (M+H), found 264.8.
[0774] c) Isopropyl 4-cyano-5-methylthiophene-2-carboxylate: A
stirred solution of 1.9 g (7.3 mmol) of isopropyl
4-bromo-5-methylthiophene-2-car- boxylate was dissolved in dry
dimethylformamide (30 mL) and refluxed with copper cyanide (785 mg,
8.8 mmol) for 16 hours. The cooled solution was poured into 0.1 M
aqueous sodium cyanide solution (300 mL) and extracted with diethyl
ether (4.times.40 mL). The organic layers were washed with brine
(2.times.40 mL), dried over anhydrous sodium sulfate, and the
solvents removed in vacuo. Column chromatography on silica gel
eluting with hexanes:ethyl acetate 9/1 (v:v), gave isopropyl
4-cyano-5-methylthiophene-2-carboxylate (960 mg, 63%) as a yellow
crystalline solid.sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 8.01
(s, 1H), 5.09 (septet, 1H, J=6.2 Hz), 2.67 (s, 3H), 1.29 (d, 6H,
J=6.2 Hz).
[0775] d) Isopropyl
4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate: A stirred
solution of 960 mg (4.59 mmol) of isopropyl
4-cyano-5-methylthiophene-2-carboxylate was treated in a manner
similar to Example 139, step (c) to give, after crystallization
from diethyl ether, isopropyl
4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate (623 mg, 56%)
as a solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 9.93 (br s,
1H), 9.34 (br s, 1H), 7.54 (s, 1H), 5.07 (septet, 1H, J=6.2 Hz),
2.60 (s, 3H), 1.29 (d, 6H, J=6.2 Hz). Mass spectrum (MALDI-TOF, GA
matrix, m/z): Calcd. for C10H.sub.13NO.sub.2S.sub.2 244.0 (M+H),
found 243.8.
[0776] e) Isopropyl
5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-car- boxylate: A
solution of 375 mg (1.54 mmol) of isopropyl
4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate was reacted
with 307 mg (1.54 mmol) of 2-bromoacetophenone (Aldrich, Milwaukee,
Wis., USA) in a manner similar to Example 8, step (a) to give,
after crystallization from methanol, isopropyl
5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene- -2-carboxylate
(347 mg, 66%) as light brown needles. .sup.1H-NMR (DMSO-d.sub.6;
300 MHz) .delta. 8.23 (s, 1H), 8.09 (s, 1H), 8.05 (m, 2H), 7.49 (m,
2H), 7.38 (m, 1H), 5.13 (septet, 1H, J=6.2 Hz), 2.86 (s, 3H), 1.33
(d, 6H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for
C.sub.19H.sub.17NO.sub.2S.sub.2 344.1 (M+H), found 344.1.
[0777] f)
5-Methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine- :
Isopropyl
5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (340
mg, 0.99 mmol) was treated in a manner similar to Example 10, step
(b) to give
5-methyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamid- ine
(360 mg, quantitive yield) as a yellow solid. This material was
dissolved in dry methanol (20 mL) and treated with 1 M HCl (g) in
diethyl ether. Evaporation of the solvents in vacuo and
recrystallization from methanol gave the hydrochloride salt of
5-methyl-4-(4-phenyl(l,3-thiazol-- 2-yl))thiophene-2-carboxamidine
(252 mg, 76%) as a light brown crystalline solid. .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) .delta. 9.45 (br s, 2H), 9.10 (br s, 2H),
8.56 (s, 1H), 8.27 (s, 1H), 8.06 (m, 2H), 7.50 (m, 2H), 7.40 (m,
1H), 2.93 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.15H.sub.13N.sub.3S.sub.2 300.1 (M+H), found 300.2.
EXAMPLE 147
[0778] a)
2-Methyl-5-[(methylethyl)oxycarbonyl]thiophene-3-carboxylic acid: A
stirred mixture of 500 mg (2.39 mmol) of isopropyl
2-methyl-3-cyanothiophene-5-carboxylate and tetrafluorophthalic
acid (570 mg, 2.39 mmol) was heated in a glass bomb at 160.degree.
C. for 66 hours. The cooled residue was digested in hot chloroform
(30 mL), treated with norite, and filtered through celite. The
celite was washed with hot chloroform (30 mL). The cooled
chloroform extracts were filtered and extracted with saturated
sodium bicarbonate (4.times.10 .mu.L). The basic extracts were
washed with chloroform, filtered through celite, and acidified to
pH 1 with concentrated hydrochloric acid. The solid was collected
by filtration and washed with water (3 x 10 mL) to give
2-methyl-5-[(methylethyl)oxycarbonyl]thiophene-3-carboxylic acid
(288 mg, 53%) as a light brown solid. .sup.1H-NMR (DMSO-d.sub.6;
300 MHz) .delta. 13.03 (br s, 1H), 7.85 (s, 1H), 5.08 (septet, 1H,
J=6.2 Hz), 2.71 (s, 3H), 1.29 (d, 6H. J=6.2 Hz). Mass spectrum
(ESI, m/z): Calcd. for C.sub.10H.sub.2O.sub.4S 229.1 (M+H), found
228.8
[0779] b) Isopropyl
4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate: A stirred
solution of 300 mg (1.3 mmol) of 2-methyl-5-[(methylethyl)oxycarb-
onyl]thiophene-3-carboxylic acid was dissolved in dry
dichloromethane (10 mL) and treated with oxalyl chloride (174
.mu.L, 2 mmol) and dimethylformamide (50 .mu.L). The mixture was
stirred at room temperature for 1.25 h, the solvents removed in
vacuo, and the residue passed through silica gel (1 inch in a 60
.mu.L sintered-glass Buchner funnel) and eluted off with
dichloromethane (150 mL). This material was treated in a manner
similar to Example 142, step (a) to give isopropyl
4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate (266 mg, 67%/o)
as a solid.
[0780] c) Isopropyl
4-(2-amino(1,3-thiazol-4-yl))-5-methylthiophene-2-carb- oxylate: A
solution of 260 mg (0.85 mmol) of isopropyl
4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate was reacted with
65 mg (0.85 mmol) of thiourea in a manner similar to Example 8,
step (a) to give isopropyl
4-(2-amino(l,3-thiazol-4-yl))-5-methylthiophene-2-carboxyl- ate
(257 mg, quantitive yield) as a white solid. .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) .delta. 7.90 (s, 1H), 6.93 (s, 1H), 5.09
(septet. 1H, J=6.2 Hz), 2.61 (s, 3H), 1.29 (d, 6H, J=6.2 Hz). Mass
spectrum (ESI, m/z): Calcd. for
C.sub.12H.sub.14N.sub.2O.sub.2S.sub.2 283.1 (M+H), found 283.1
[0781] d)
4-(2-Amino(1,3-thiazol-4-yl))-5-methylthiophene-2-carboxamidine:
Isopropyl
4-(2-amino(1,3-thiazol-4-yl))-5-methylthiophene-2-carboxylate (240
mg, 0.85 mmol) was treated in a manner similar to Example 10, step
(b) to give
4-(2-amino(1,3-thiazol-4-yl))-5-methylthiophene-2-carboxamidi- ne
(20 mg, 10%) as a solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz):
.delta. 9.30 (br s, 2H), 8.99 (bs, 2H), 8.28 (s, 1H), 6.78 (s, 1H),
2.71 (s, 3H); Mass Spectrum (ESI, m/z) calcd. for
C.sub.9H.sub.10N.sub.4S2, 238.8 (M+H), found 239.2.
EXAMPLE 148
[0782] a) 4-Bromo-5-ethylthiophene-2-carboxylic acid: A stirred
solution of 10 g (35 mmol) of 4,5-dibromothiophene-2-carboxylic
acid (Lancaster, Windham, NH, USA) in dry THF (100 mL) was cooled
to -78.degree. C. To this, 35 mL (70 mmol) of 2.0 M n-butyllithium
in cyclohexane (Aldrich, Milwaukee, Wis., USA) was added dropwise
over 15 min, and the reaction was allowed to stir for 15 min at
-78.degree. C. The mixture was quenched with ethyl iodide (2.8 mL,
35 mmol) and allowed to warm to room temperature. The mixture was
carefully poured into 6N hydrochloric acid (100 mL) and extracted
with diethyl ether (4.times.50 mL). The organic layers were washed
with water (2.times.50 mL), brine (50 mL), and dried over anhydrous
sodium sulfate. The solvents were removed in vacuo to give
2-ethyl-3-bromo-thiophene-5-carboxylate (7 g, 85%) as a dark solid.
.sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 13.25 (br s, 1H), 7.62
(s, 1H), 2.80 (q, 2H, J=7.5 Hz), 1.23 (t, 3H, J=7.5 Hz).
[0783] b) Isopropyl 4-bromo-5-ethylthiophene-2-carboxylate: A
solution of 7 g (30 mmol) of 4-bromo-5-ethylthiophene-2-carboxylic
acid was dissolved in dry dichloromethane (200 mL) and treated with
oxalyl chloride (3.2 mL, 36 mmol) and dimethylformamide (0.5 mL)
for 18.5 h. The solvents were removed in vacuo and the residual
brown oil was passed through silica gel (2 inches in a 350 mL
scintered-glass Buchner funnel) and eluted with 700 mL of
hexanes:ethyl acetate 9/1 (v:v). The elutate was concentrated in
vacuo and the oil dissolved in dry dichloromethane (200 mL). This
solution was treated with pyridine (12 mL, 150 mmol) and dry
isopropanol (60 mL, 750 mmol) for 4 h at room temperature. The
solvents were removed in vacuo and the residue partioned between
dichloromethane (100 mL) and water (200 mL). The aqueous layers
were extracted with dichloromethane (2.times.30 mL). The combined
organic layers were extracted with sodium bicarbonate (2.times.30
mL), brine (30 mL), and dried over anhydrous sodium sulfate. The
solvent was removed in vacuo. Purification by column chromatography
on silica gel (250 g) eluting with hexanes:ethyl acetate 95/5 (v:v)
gave isopropyl 2-ethyl-3-bromo-thiophene-5-carboxylate (4 g, 48%)
as a yellow oil. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 7.66
(s, 1H), 5.89 (septet, 1H, J=6.2 Hz), 2.80 (q, 2H, J=7.5 Hz), 1.29
(d, 6H, J=6.0 Hz), 1.24 (t, 3H, J=7.5 Hz).
[0784] c) Isopropyl 4-cyano-5-ethylthiophene-2-carboxylate: A
stirred solution of 4 g (14.4 mmol) of isopropyl
4-bromo-5-ethylthiophene-2-carbo- xylate was refluxed in dry
dimethylformamide (50 mL) with copper cyanide (1.94 g, 22 mmol) for
8 hours. The cooled mixture was poured into 0.1 M sodium cyanide
(500 mL) and extracted with diethyl ether (4.times.50 mL). The
organic layers were washed twice with brine (50 mL) and dried over
anhydrous sodium sulfate. The solvents were removed in vacuo.
Column chromatography on silica gel (400 g), eluting with
hexanes:ethyl acetate 9/1 (v:v) gave isopropyl
2-ethyl-3-cyano-thiophene-5-carboxylate (1.7 g, 53%) as a pale
yellow oil. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 8.03 (s,
1H), 5.10 (septet, 1H, J=6.2 Hz), 3.04 (q, 2H, J=7.5 Hz), 1.31 (t,
3H, J=7.5 Hz), 1.30 (d, 6H, J=6.2 Hz). Mass spectrum (ESI ml/z):
Calcd. for C.sub.11H.sub.13NO.sub.2S 224.1 (M+H), found 224.0.
[0785] d)
Isopropyl4-(aminothioxomethyl)-5-ethylthiophene-2-carboxylate: A
stirred solution of 1.7 g (7.6 mmol) of isopropyl
4-cyano-5-ethylthiophen- e-2-carboxylate was treated as in Example
139, step (c) to give isopropyl
5-ethyl-4-(aminothioxomethyl)-5-ethylthiophene-2-carboxylate (1.45
g, 74%) as a yellow solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz)
.delta. 9.93 (br s, 1H), 9.39 (br s, 1H), 8.04 (s, 1H), 5.08
(septet, 1H, J=6.2 Hz), 3.08 (q, 2H, J=7.5 Hz), 1.29 (d, 6H, J=6.2
Hz), 1.24 (t, 3H, J=7.5 Hz).
[0786] e) Isopropyl
5-ethyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carb- oxylate: A
solution of 450 mg (1.75 mmol) of isopropyl
5-ethyl-4-(aminothioxomethyl)-5-ethylthiophene-2-carboxylate was
reacted with 348 mg (1.75 mmol) of 2-bromoacetophenone (Aldrich,
Milwaukee, Wis., USA) in a manner similar to Example 8, step (a) to
give isopropyl
5-ethyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (303
mg, 49%) as an off-white solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz)
.delta. 8.22 (s, 1H), 8.07 (s, 1H), 8.03 (m, 2H), 7.49 (m, 2H),
7.38 (m, 1H), 5.13 (septet, 1H, J=6.2 Hz), 3.34 (q, 2H, J=7.4 Hz),
1.39 (t, 3H, J=7.4 Hz), 1.33 (d, 6H, J=6.2 Hz). Mass spectrum (ESI,
m/z): Calcd. for C.sub.19H.sub.19NO.sub.2S.sub.2 358.1 (M+H), found
358.1.
[0787] j)
5-Ethyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine:
Isopropyl
5-ethyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxylate (250
mg, 0.70 mmol) was treated in a manner similar to that for Example
10, step (b), to give
5-ethyl-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-c- arboxamidine
(148 mg, 67%) as a yellow solid. .sup.1H-NMR (DMSO-d.sub.6; 300
MHz) .delta. 9.44 (br s, 2H), 9.07 (br s, 2H), 8.54 (s, 1H), 8.26
(s, 1H), 8.05 (m, 2H), 7.50 (m, 2H), 8.70 (s, 1H), 7.40 (m, 1H),
3.44 (q, 2H, J=7.4 Hz), 1.42 (t, 3H, J=7.4 Hz). Mass spectrum (ESI,
m/z): Calcd. for C.sub.16H.sub.15N.sub.3S.sub.2 314.1 (M+H), found
314.2.
EXAMPLE 149
[0788] a) Isopropyl 4-[4-(3-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthi- ophene-2-carboxylate: A solution
of 1.97 g (8.1 mmol) of isopropyl
4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate was reacted
with 1.74 g (8.1 mmol) of 3-hydroxy-2-bromoacetophenone (Example
40, step (a)) were reacted in a manner similar to Example 8, step
(a) to give, after column chromatography on silica gel eluting with
hexane:ethyl acetate 7/3 (v:v), crystallization from acetonitrile,
and recrystallization from hexanes, isopropyl
4-[4-(3-hydroxyphenyl) (1,3-thiazol-2-yl)]-5-methylthi-
ophene-2-carboxylate (1.4 g, 48%) as brown solid. .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) .delta. 9.57 (br s, 1H), 8.14 (s, 1H), 8.08
(s, 1H), 7.46 (m, 2H), 7.26 (m, 1H),), 6.78 (m, 1H), 5.12 (septet,
1H, J=6.2 Hz), 2.85 (s, 3H), 1.33 (d, 6H, J=6.2 Hz). Mass spectrum
(ESI, m/z): Calcd. for C.sub.18H.sub.17NO.sub.3S.sub.2 360.1 (M+H),
found 360.1.
[0789] b) 4-[4-(3-Hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiophene-2-c- arboxamide: Isopropyl
4-[4-(3-hydroxyphenyl) (1,3-thiazol-2-yl)]-5-methylt-
hiophene-2-carboxylate (1.4 g, 3.89 mmol) was treated in a manner
similar to Example 10, step (b) to give 4-[4-(3-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxamide (360 mg, 31%)
as a brown solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 9.62
(br s, 1H), 9.45 (br s, 2H), 9.09 (br s, 2H), 8.53 (s, 1H), 8.16
(s, 1H), 7.47 (m, 2H), 7.27 (m, 1H), 6.80 (m, 1H), 2.93 (s, 3H).
Mass spectrum (ESI, m/z): Calcd. for C.sub.15H.sub.13N.sub.3
OS2316.1 (M+H), found 316.2.
EXAMPLE 150
[0790] a) (tert-Butoxy)-N-({4-[4-(3-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-m- ethyl(2-thienyl)]iminomethyl)carboxamide:
A stirred solution of 320 mg (1 mmol) of 4-[4-(3-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiophene-2-c- arboxamide was dissolved
in dry dimethylformamide (50 mL) and treated with 262 mg (1.2 mmol)
of di-tert-butyl-dicarbonate (Acros, Pittsburgh, PA, USA) and
diisopropylethylamine (261 .mu.L, 1.5 mmol) for 64 hours at room
temperature. The mixture was poured into sodium bicarbonate
solution (200 mL) and extracted with dichloromethane (6.times.30
mL). The organic extracts were washed twice with brine (50 mL) and
dried over anhydrous sodium sulfate. The solvents were in vacuo and
column chromatography on silica gel (100 g) eluting with
dichloromethane:methanol 95/5 (v:v) gave
(tert-butoxy)-N-({4-[4-(3-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methyl(2-t- hienyl)}iminomethyl)carboxamide
(247 mg, 59%) as a yellow oil. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz)
.delta. 9.56 (s, 1H), 9.12 (br s, 2H), 8.47 (s, 1H), 8.09 (s, 1H),
7.46 (m, 2H), 7.26 (m, 1H), 6.78 (m, 1H), 2.83 (s, 3H), 1.45 (s,
9H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.20H.sub.21N.sub.3O.sub.3S.sub.2 416.1 (M+H), found 415.7
[0791] b)
Methyl-2-{3-[2-(5-[[(tert-butoxy)carbonylamino]iminomethyl}-2-me-
thyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy]acetate: A stirred
solution of 247 mg (0.595 mmol) of
(tert-butoxy)-N-({4-[4-(3-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methyl(2-thienyl)}iminomethyl)carboxamide was
dissolved in dry dimethylformamide (4 mL) and treated with cesium
carbonate (291 mg, 0.89 mmol) and methyl bromoacetate (136 mg, 0.89
mmol) for 3 h at 60.degree. C. The mixture was poured into water
(50 mL) and extracted with dichloromethane (9.times.10 mL). The
organic extracts were washed with brine (10 mL) and dried over
anhydrous sodium sulfate. The solvents were removed in vacuo and
column chromatography on silica gel (50 g) eluting with
dichloromethane:methanol 98/2 (v:v) gave methyl
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)--
1,3-thiazol-4-yl]phenoxy}acetate (178 mg, 61%) as an oil. Mass
spectrum (ESI, m/z): Calcd. for C.sub.23H.sub.25N.sub.3OS.sub.2
488.1 (M+H), 388.1 ((M-BOC)+H), found 487.8, 388.2.
[0792] c)
Methyl-2-{3-[2-(5-amidino-2-methyl-3-thienyl)-1,3-thiazol-4-yl]p-
henoxyacetate: Methyl
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl
}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate (15 mg,
0.031 mmol) treated with dichloromethane:trifluoroacetic acid 1/1
(v:v) with 2.5% water added at room temperature for 1.5 h. Removal
of the solvents in vacuo gave methyl
2-{3-[2-(5-amidino-2-methyl-3-thienyl)-1,3-thiazol-4-
-yl]phenoxyacetate (8.1 mg, 52%) as a brown solid. .sup.1H-NMR
(DMSO-d.sub.6; 300 MHz) .delta. 9.38 (br s, 2H), 8.94 (br s, 2H),
8.51 (s, 1H), 8.31 (s, 1H), 7.62 (m, 2H), 7.41 (m, 1H), 6.96 (m,
1H), 4.89 (s, 2H), 3.72 (s, 3H), 2.92 (s, 3H). Mass spectrum (ESI,
m/z): Calcd. for C.sub.18H.sub.17N.sub.3O.sub.3S.sub.2 388.1 (M+H),
found 388.3.
EXAMPLE 151
[0793] a)
2-[3-[2-(5-[[(tert-Butoxy)carbonylamino]iminomethyl]-2-methyl-3--
thienyl)-J,3-thiazol-4-yl]phenoxy}acetic acid: A stirred solution
of 50 mg (0.11 mmol) of methyl
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl-
}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate was
dissolved in tetrahydrofuran (10 mL) and treated 2M aqueous sodium
hydroxide solution (2 mL) at room temperature for 1 h 10 min. The
solvents were removed in vacuo. Purification by passing the solid
through silica gel (1 inch in a 60 mL sintered-glass Buchner
funnel) eluting with dichloromethane:methano- l 8/2 (v:v) gave
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-me-
thyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (44 mg, 88%)
as a yellow solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta. 9.38
(br s, 2H), 8.94 (br s, 2H), 8.51 (s, 1H), 8.31 (s, 1H), 7.62 (m,
2H), 7.41 (m, 1H), 6.96 (m, 1H), 4.89 (s, 2H), 3.72 (s, 3H), 2.92
(s, 3H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.22H.sub.23N.sub.3O.sub.5S.sub.2 474.1 (M+H), 374.1
((M-BOC)+H) found 374.2, 473.7.
[0794] b)
2-[3-[2-(5-Amidino-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxya-
cetic acid: Methyl
2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2--
methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate (4 mg, 0.0084
mmol) was treated with dichloromethane:trifluoroacetic acid 1/1
(v:v) with 2.5% water added at room temperature for 2 h 35 min.
Removal of the solvents in vacuo gave
2-{3-[2-(5-amidino-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phe-
noxy}acetic acid (2.9 mg, 71%) as a solid. Mass spectrum (ESI,
m/z): Calcd. for C.sub.17H.sub.15N.sub.3O.sub.3S.sub.2 373.1 (M+H),
found 374.2.
[0795] c) tert-Butyl
4-(2-[3-[2-(5-[[(tert-butoxycarbonylamino]iminomethyl-
]-2-methyl-3-thienyl)-I,3-thiazol-4-yl]phenoxytacetyl)piperazinecarboxylat-
e: A stirred solution of 40 mg (0.084 mmol) of
2-{3-[2-(5-{[(tert-butoxy)c- arbonylamino]iminomethyl
}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxylac- etic acid
dissolved in dry dimnethylformamide (5 mL) was treated with
hydroxybenzotriazole (23 mg, 0.17 mmol), 32 mg (0.17 mmol) of
N-tert-butoxycarbonyl-piperazine (Lancaster, Windham, N.H., USA),
65 mg (0.17 mmol) of
O-(7-azabenzotriazol-1-yl)-N,N,,N-tetramethyluronium
hexafluorophosphate (HATU) at room temperature for 20 h. The
mixture was partitioned between dichloromethane (50 mL) and brine
(50 mL). The aqueous layers were extracted twice with
dichloromethane (50 mL) and the combined organic layers were washed
with brine (50 mL) and dried over anhydrous sodium sulfate. The
solvents were removed in vacuo. Purification preparative thin layer
chromatography eluting with dichloromethane:methanol 95/5 (v:v)
gave tert-butyl
4-(2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thieny-
l)-1,3-thiazol-4-yl]phenoxy}acetyl)piperazinecarboxylate (25 mg,
46%) as a white solid. .sup.1H-NMR (DMSO-d.sub.6; 300 MHz) .delta.
9.13 (br s, 2H), 8.50 (s, 1H), 8.20 (s, 1H), 7.63 (m, 2H), 7.39 (m,
1H), 6.95 (m, 1H), 4.93 (s, 2H), 3.47-3.34 (m, 8H), 2.82 (s, 3H),
1.45 (s, 9H), 1.42 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.31H.sub.39N.sub.5O.sub.6S- .sub.2 642.3 (M+H), 542.3
((M-BOC)+H), 442.3 ((M-2 BOC)+H), found 642.0, 542.2, 442.3.
[0796] d) 5-Methyl-4-[4-[3-(2-oxo-2-piperazinyletho
y)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine: tert-Butyl
4-(2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thieny-
l)-1,3-thiazol-4-yl]phenoxy}acetyl)piperazinecarboxylate (25 mg,
0.039 mmol) treated with dichloromethane:trifluoroacetic acid 1/1
(v:v) with 2.5% water added at room temperature for 2 h. Removal of
the solvents in vacuo gave
5-methyl-4-{4-[3-(2-oxo-2-piperazinylethoxy)phenyl](1,3-thiazo-
l-2-yl)}thiophene-2-carboxamidine (27.4 mg, quantitive yield) as an
off-white solid. .sup.1H-NMR (Methanol-d.sub.4; 300 MHz) .delta.
8.41 (s, 1H), 7.94 (s, 1H), 7.67 (m, 2H), 7.39 (m, 1H), 7.00 (m,
1H), 4.96 (s, 2H), 3.88 (m, 4H), 3.25 (m, 4H), 2.95 (s, 3H). Mass
spectrum (ESI, m/z): Calcd. for
C.sub.21H.sub.23N.sub.5O.sub.2S.sub.2 442.1 (M+H), found 442.4.
EXAMPLE 152
[0797] Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate
[0798] To a stirring slurry of
2-methylthio-(5-carbomethoxy)-thiophene-3-c- arboxylic acid (2.0 g,
8.61 mmol) in 28 mL of CH.sub.2Cl.sub.2 under N.sub.2 containing
0.8 mL DMF at 0.degree. C. was added oxalyl chloride (1.9 equiv,
16.3 mmol) slowly via syringe. The reaction was allowed to warm to
ambient temperature after 1 h, and then stirred an additional 1 h.
The reaction mixture was filtered through a 20 cm pad of silica gel
in a 30 mL sintered glass funnel wetted with 50% ethyl
acetate-hexanes and further eluted with the same solvent system
until the eluent showed no product by UV visualization. The solvent
was concentrated in vacuo, azeotroped with toluene (lx), and dried
under vacuum to afford the acid chloride (1.52 g) as a light yellow
solid. The acid chloride was dissolved in 20 mL of CH.sub.3CN,
cooled to 0.degree. C., and treated with TMSCHN.sub.2 (2.1 equiv,
6.3 mL, 2 M in hexanes) dropwise via syringe. The reaction was
allowed to warm to ambient temperature (0.5 h), cooled back to 5oC
and immediately treated with 30% HBr-acetic acid (0.66 mL) dropwise
via an addition funnel. After 15 min. at 0.degree. C., the reaction
diluted with 20 mL of ether, filtered and thoroughly washed with
ether (3.times.20 mL). The yellow solids were dried under vacuum to
afford methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate
(1.0 g, 37% yield) as a yellow powder. .sup.1H NMR (DMSO-d.sub.6,
300 MHz) .delta. 2.66 (s, 3H), 3.84 (s, 3H), 5.03 (s, 2H), 8.29 (s,
1H).
EXAMPLE 153
[0799]
Isopropyl-4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate
[0800] To a stirring slurry of
2-methyl-(5-carboisopropoxy)-thiophene-3-ca- rboxylic acid (0.40 g,
1.75 mmol) in 15 mL of CH.sub.2Cl.sub.2 under N.sub.2 containing
0.8 mL DMF at 0.degree. C. was added oxalyl chloride (1.9 equiv,
3.32 rnmol,) slowly via syringe. The reaction was allowed to warm
to ambient temperature after 1 h, and then stirred an additional 1
h. The solvent was concentrated in vacuo, azeotroped with toluene
(lx), and dried under vacuum to afford the acid chloride (0.397 g,
1.60 mmol) as a light yellow solid. The acid chloride was dissolved
in 7 mL of CH.sub.3CN, cooled to 0.degree. C., and treated with
TMSCHN.sub.2 (2.1 equiv, 1.68 mL, 2 M in hexanes) dropwise via
syringe. The reaction was allowed to warm to ambient temperature
(0.5 h), cooled back to 5.degree. C. and immediately treated with
30% HBr-acetic acid (0.5 mL) dropwise via an addition funnel. After
15 min. at 0.degree. C., the reaction mixture was filtered through
a IO cm pad of silica gel in a 15 mL sintered glass funnel wetted
with 50% ethyl acetate-hexanes and further eluted with the same
solvent system until the eluent showed no product by UV
visualization. The solvent was concentrated in vacuo dried under
vacuum to afford
isopropyl-4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate (0.329
g, 61% yield) as an oil which solidified upon standing to a tan
solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.31 (d, 6H,
J=6.3 Hz), 2.71 (s, 3H), 4.60 (s, 2H), 5.09 (m, 1H), 8.08 (s,
1H).
EXAMPLE 154
[0801] a) Metltyl
5-methylthio-4-[2-([henylamino)-(1,3-thiazol-4-yl)]-thio-
phene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothi- ophene-2-carboxylate (60.5 mg,
0.19 mmol) was slurried in 4 mL of acetone with phenyl thiourea (1
equiv, 30 mg) and heated to 70.degree. C. . After 3 h the reaction
was allowed to cool to room temperature, filtered, and dried in
vacuo to give 62.5 mg (69% yield) of methyl
5-methylthio-4-[2-(phenylamino)-(1,3-thiazol-4-yl)]-thiophene-2-carboxyla-
te hydrobromide. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.65
(s, 3H), 3.83 (s, 3H), 6.95-6.99 (m, 1H), 7.28-7.35 (m, 4H), 7.67
(d, 1H, J=1.4, 7.7 Hz), 8.06 (s, 1H), 10.54 (s, 1H); Mass Spectrum
(ESI) m/z calcd. for C.sub.16H.sub.14N.sub.2O.sub.2S.sub.3, 362.49
(M+H), found 363.7.
[0802] b) 5-Methylthio-4-[2-phenylamino)
(1,3-thiazol-4-yl)]thiophene-2-ca- rboxamidine hydrochloride: To a
flame-dried flask containing 57.8 mg (8 equiv, 1.08 mmol) of
NH.sub.4Cl under N.sub.2 was charged 1.3 mL of toluene. AlMe.sub.3
(8 equiv, 2M/hexanes, 0.54 mL) was added dropwise to the stirred
slurry over a 3 min. period, and allowed to stir another 5 min. At
this time methyl 5-methylthio-4-[2-(phenylamino)-(1,3-thiazol-4-y-
l)]-thiophene-2-carboxylate hydrobromide (1 equiv, 60 mg, 0.135
mmol) was quickly added in one portion and the resultant mixture
was immersed in a 120.degree. C. oil bath. After 2 h 10 min. at
this temperature, TLC (silica gel 60 F.sub.254, Merck KGaA,
Darmstadt, Germany, 9:1:0.5 CH.sub.2C.sub.2-MeOH-AcOH eluent)
indicated the reaction to be complete by disappearance of the
starting material. The reaction was allowed to cool to ambient
temperature, then added via pipette to a stirred slurry of 1.3 g of
SiO.sub.2 in 20 mL of CHCl.sub.3. The residual residue in the flask
was rinsed with 4 mL of MeOH, briefly sonicated and added to the
SiO.sub.2 slurry. The slurry was stirred for 10 min. and then
filtered through a 15-mL sintered glass funnel containing 20 cm of
SiO.sub.2 with 50% CHC.sub.3-MeOH. The yellow fraction was
collected, discarding the forerun. TLC indicated the product was
essentially pure. The solvent was removed in vacuo, and the residue
triturated with 10% MeOH--CH.sub.2Cl.sub.2. The solids were removed
by filtration. The solvent was concentrated in vacuo to give 30.1
mg (66% yield) of
5-methylthio-4-[2-(phenylamino)-(1,3-thiazol-4-yl)]thiophene-2-carboxamid-
ine hydrochloride as a red-brown powder. .sup.1H NMR (DMSO-d.sub.6,
300 MHz) .delta. 2.73 (s, 3H), 6.94-7.00 (m, 1H), 7.15 (s, 1H),
7.30-7.35 (m, 1H), 7.78 (d, 1H, J=8.7 Hz), 8.49 (s, 1H), 8.87 (bs,
2H), 9.31 (bs, 2H), 10.38 (s, 1H); Mass Spectrum (ESI) m/z calcd.
for C.sub.15H.sub.14N.sub.4- S.sub.3, 346.50 (M+H), found
347.2.
EXAMPLE 155
[0803] a) Methyl
4-[2-[(2-chlorophenyl)amino](1,3-thiazol-4-yl)I-5-methylt-
hiothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methyl- thiothiophene-2-carboxylate (50 mg) was
allowed to react with 2-chlorophenyl thiourea (26.7 mg) as
described in Example 154, step (a), to give 58 mg (75%) of methyl
4-{2-[(2-chlorophenyl)amino]-(1,3-thiazol-4-
-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 2.66 (s, 3H), 3.82 (s, 3H), 7.04
(m, 1H), 7.32-7.38 (m, 2H), 7.47 (dd, 1H,J=1.4, 8.7 Hz), 8.12 (s,
1H), 8.56 (dd, 1H, J=1.4, 8.3 Hz), 9.75 (s, 1H); Mass Spectrum
(ESI) m/z calcd. for C.sub.16H.sub.13ClN.sub.2O.sub.2S.sub.3,
396.94 (M+H), found 397.1.
[0804] b)
4-2-[(2-Chlorophenyl)amino(1,3-thiazol-4-yl)]-5-methyltltiothiop-
hene-2-carboxamidine hydrochloride: Methyl
4-{2-[(2-chlorophenyl)amino]-(1-
,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide
(40 mg, 0.08 mmol) was treated as described in Example 154, step
(b) to give 24 mg (71.8%)of
4-{2-[(2-chlorophenyl)amino]-(1,3-thiazol-4-yl)}-5-methylthi-
othiophene-2-carboxamidine hydrochloride. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 2.71 (s, 3H), 7.04 (td, 1H, J=1.4,
7.8 Hz), 7.21 (s, 1H), 7.35 (t, 1H, J=8.5 Hz), 8.42 (s, 1H), 8.57
(dd, 1H, J=1.3, 8.3 Hz), 8.80 (bs, 2H), 9.26 (bs, 2H), 9.79 (s,
1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.15H.sub.14N.sub.4S.sub.3C.sub.1, 380.94 (M+H), found
381.1.
EXAMPLE 156
[0805] a) Methyl
4-(2-amino(1,3-thiazol-4-yl))-5-methylthiothiophene-2-car- boxylate
hydrobromide: Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-ca-
rboxylate (50 mg, 0.16 mmol) was allowed to react with thiourea (12
mg) as described in Example 154, step (a), to give 54 mg (70%
yield) of methyl
4-(2-amino-(1,.sup.3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate
hydrobromide. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.69 (s,
3H), 3.83 (s, 3H), 7.00 (s, 1H), 8.05 (s, 1H); Mass Spectrum (ESI)
m/z calcd. for C.sub.10H.sub.10O.sub.2S.sub.3N.sub.2, 286.41 (M+H),
found 287.1;
[0806] b)
4-(2-Amino-(I,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxami-
dine hydrochloride: Methyl
4-(2-amino-(1,3-thiazol-4-yl))-5-methylthiothio-
phene-2-carboxylate hydrobromide (110 mg, 0.29 mmol) was treated as
described in Example 154, step (b). The resultant amidine (74 mg)
was stirred in 3 mL of dry methanol under N.sub.2 and treated with
ca. lmL of ether saturated with dry HCl gas. Dry ether (1.5 mL) was
then added and the result was allowed to sit for 2 h at ambient
temperature and then filtered to give 40 mg (45% yield) of
4-(.sup.2-amino-(1,3-thiazol-4-yl))-
-5-methylthiothiophene-2-carboxamidine hydrochloride. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 2.69 (s, 3H), 6.90 (s, 1H), 8.44
(s, 1H), 9.20, 9.42 (s, 4H, NH); Mass Spectrum (ESI) m/z
calcd.C.sub.9H.sub.10N.su- b.4S.sub.3, 270.4 (M+H), found
271.2.
EXAMPLE 157
[0807] a) Methyl 4-2-[(2,5-dimethoxyphenyl)amino (1,3-tli i
azol-4-yl)]-5-metiylthiothiophene-2-carboxylate hydrobromide:
Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (49.4
mg, 0.15 mmol) was allowed to react with 2,5-dimethoxy phenyl
thiourea (37.2 mg) as described in Example 154, step (a), to give
65.5 mg (87% yield) of methyl
4-{2-[(2,5-dimethoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiot-
hiophene-2-carboxylate hydrobromide. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 2.66 (s, 3H), 3.76 (s, 3H), 3.81 (s, 3H), 3.83 (s,
3H), 6.49 (dd, 1H, J=3.0, 8.8 Hz), 6.92 (d, 1H, J=8.9 Hz), 7.26 (s,
1H), 8.17 (s, 1H), 8.37 (d, 1H, J=3.1 Hz), 9.70 (s, 1H); Mass
Spectrum (ESI) m/z calcd. for
C.sub.18H.sub.18N.sub.2O.sub.4S.sub.3, 422.54 (M+H), found
423.1.
[0808] b)
4-(2-[(2,5-Dimethioxyphenyl)amino](1,3-thiazol-4-yl)]-5-methylth-
iothiophene-2-carboxamidine: Methyl
4-{2-[(2,5-dimethoxyphenyl)amino]-(1,3-
-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide
(45.5 mg, 0.09 mmol) was treated as described in Example 154, step
(b), followed by preparative thin layer chromatography (500 mm
silica gel plate, J. T. Baker, Phillipsburg, NJ,
10%-methanol--CH.sub.2Cl.sub.2-satd. NH.sub.3 eluent) to give 9.9
mg (27% yield of 4-{2-[(2,5-dimethoxyphenyl)amino](1,-
3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 2.60 (s, 3H), 3.73 (s, 3H), 3.81
(s, 3H), 6.48 (dd, 1H, J=3.1, 8.8 Hz), 6.92 (d, 1H, J=7.9 Hz), 7.05
(s, 1H), 7.5 (bs, 2H), 8.04 (s, 1H), 8.34 (d, 1H, J=1.0 Hz), 9.6
(bs, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.17H.sub.18N.sub.4O.sub.2S.sub.3, 406.55 (M+H), found
407.1.
EXAMPLE 158
[0809] a)
Methyl-4-[2-[(3-methoxyphenyl)amino(1,3-thiazol-4-yl)]-5-methylt-
hiothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methyl- thiothiophene-2-carboxylate (53.3 mg,
0.17 mmol) was allowed to react with 2-methoxy phenyl thiourea
(34.5 mg) as described in Example 154, step (a), to give 61 mg (76%
yield) of methyl 4-{2-[(3-methoxyphenyl)amino](1,-
3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.67 (s, 3H), 3.78 (s,
3H), 3.83 (s, 3H), 6.53 (d, 1H, J=6.8 Hz), 7.13-7.24 (m, 2H), 7.29
(s, 3H), 7.59 (m, 1H), 8.16 (s, 3H), 10.32 (s, 1H); Mass Spectrum
(ESI) m/z calcd. for C.sub.17H.sub.16N.sub.2O.sub.3S.sub.3, 392.52
(M+H), found 393.2.
[0810] b)
4-(2-[(3-Methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothi-
ophene-2-carboxamidine hydrochloride: Methyl
4-{2-[(3-methoxyphenyl)amino]-
-(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate
hydrobromide (54.6 mg, 0.11 mmol) was treated as described in
Example 154, step (b) to give 25.2 mg (56%) of
4-{2-[(3-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5--
methylthiothiophene-2-carboxamidine hydrochloride. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 2.71 (s, 3H), 3.77 (s, 3H), 6.54
(m, 1H), 7.15 (s, 3H), 7.19-7.28 (m, 2H), 7.47 (m, 1H), 8.46 (s,
1H), 8.86 (bs, 2H), 9.28 (bs, 2H), 10.36 (s, 1H); Mass Spectrum
(ESI) m/z calcd. for C.sub.16H.sub.16N.sub.4OS.sub.3, 376.52 (M+H),
found 377.2.
EXAMPLE 159
[0811] a) Methyl
4-[2-[(4-methoxyphenyl)amino(1,3-thiazol-4-yl)]-5-methylt-
hiothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methyl- thiothiophene-2-carboxylate (41.3 mg,
0.13 mmol) was allowed to react with 5-methoxy phenyl thiourea
(26.8 mg) as described in Example 154, step (a) to give 25 mg (41%
yield) of methyl 4-{2-[(4-methoxyphenyl)amino](1,3-thi-
azol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.64, 2.68 (s, 3H
rotomer) ), 3.72, 3.73 (s, 3H rotomer), 3.83 (s, 3H), 6.91 (dd, 2H,
J=6.7, 8.8 Hz), 7.21 (s, 1H), 7.59 (d, 1H, J=9.0 Hz), 7.67 (d, 1H,
J=9.0 Hz), 8.05, 8.13 (s, 1H rotomer), 10.16, 10.34 (bs, 1H,
rotomer); Mass Spectrum (ESI) m/z calcd. for
C.sub.17H.sub.16N.sub.2O.sub.2S.sub.3, 392.52 (M+H), found
393.1.
[0812] b)
4-{2-[(4-Methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothi-
ophene-2-carboxamidine hydrochloride: Methyl
4-{2-[(4-methoxyphenyl)amino]-
-(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate
hydrobromide (22 mg, 0.046 mmol) was treated as described in
Example 154, step (b) to give 11.5 mg (61% yield) of
4-{2-[(4-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-
-nmethylthiothiophene-2-carboxamidine hydrochloride. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 2.72 (s, 3H), 3.73 (s, 3H), 6.91
(d, 2H, J=9.0 Hz), 7.08 (s, 1H), 7.69 (d, 2H, J=9.1 Hz), 8.44 (s,
1H), 8.83 (bs, 2H), 9.28 (bs, 2H), 10.15 (s, 1H);Mass Spectrum
(ESI) m/z calcd. for C.sub.16H.sub.16N.sub.4OS.sub.3, 376.52 (M+H),
found 377.1.
EXAMPLE 160
[0813] a) Methyl
4-(2-{[4-(dimethylamino)phenyl]amino](1,3-thiazol-4-yl))--
5-methylthiothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (50 mg, 0.16
mmol) was allowed to react with 4-N,N-dimethylaminophenyl thiourea
(31.5 mg) as described in Example 154, step (a), to give 53.2 mg
(75% yield) of methyl
4-(2-{[4-(dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothio-
phene-2-carboxylate hydrobromide. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 2.69 (s, 3H), 3.15 (s, 6H), 3.83 (s, 3H), 7.36 (s,
1H), 7.55 (bs, 2H), 7.88 (d, 2H, J=8.3 Hz), 8.16 (s, 1H), 10.56
(bs, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.18H.sub.19N.sub.3O.sub.2S.sub.3, 405.56 (M+H), found
406.1.
[0814] b)
4-(2-([4-(Dimethylamino)phenyl]amino](1,3-thiazol-4-yl))-5-methy-
ltltiotltiophene-2-carboxamidine hydrochloride: Methyl
4-(2-{[4-(dimethylamino)phenyl]amino
}(1,3-thiazol-4-yl))-5-methylthiothi- ophene-2-carboxylate
hydrobromide (50 mg, 0.10 mmol) was treated as described in Example
154, step (b) to give 9.4 mg (22% yield) of
4-{2-[(4-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2--
carboxamidine hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 2.70 (s, 3H), 2.84 (s, 6H), 6.75 (d, 2H, J=9.2 Hz), 7.00
(s, 1H), 7.56 (d, 2H, J=9.1 Hz), 8.31 (s, 1H), 8.68 (bs, 3H), 9.92
(bs, 1H).
EXAMPLE 161
[0815] a) Methyl
4-2-[(4-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-
-methylthiothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (50 mg, 0.16
mmol) was allowed to react with 2-methyl-4-chlorophenyl thiourea
(32.1 mg) as described in Example 154, step (a), to give 62.2 mg
(79% yield) of methyl
4-{2-[(4-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothio-
phene-2-carboxylate hydrobromide. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 2.28, 2.29 (s, 3H rotomer), 2.62, 2.66 (s, 3H
rotomer), 3.82 (s, 3H), 7.21-7.29 (m, 3H), 8.04, 8.11 (s, 1 H
rotomer), 8.17 (d, 1H, J=8.8 Hz), 8.30 (d, 1H, J=8.4 Hz), 9.44 (s,
1H), 9.59 (s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.17H.sub.15C.sub.1N.sub.2O.sub.2S.sub.3, 410.96 (M+H), found
411.1.
[0816] b)
4-[2-[(4-Chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)J-5-methy-
lthiothiophene-2-carboxamidine hydrochloride: Methyl
4-{2-[(4-chloro-2-methylphenyl)amino]-(1,3-thiazol-4-yl)}-5-methylthiothi-
ophene-2-carboxylate hydrobromide (55 mg, 0.17 mmol) was treated as
described in Example 154, step (b) to give 16 mg (22% yield) of
4-{2-[(4-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothio-
phene-2-carboxamidine hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 2.30 (s, 3H), 2.70 (s, 3H), 7.15 (s, 1H), 7.23-7.29
(m, 2H), 8.34 (d, 1H, J=8.6 Hz), 8.44 (s, 1H), 8.86 (bs, 2H), 9.29
(bs, 2H), 9.47 (s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.16H.sub.15ClN.sub.4S.sub.3, 394.97 (M+H), found 395.1.
EXAMPLE 162
[0817] a) Methyl
4-[2-[(diphenylmethyl)amino(1,3-thiazol-4-yl)]-5-methylth-
iothophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylth- iothiophene-2-carboxylate (50 mg,
0.16 mmol) was allowed to react with diphenylmethane thiourea (38
mg) as described in Example 154, step (a), to give 145 mg (100%
yield) of methyl 4-{2-[(diphenylmethyl)amino](1,3-th-
iazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide after
removal of solvent in vacuo. .sup.1.sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 2.50 (s, 3H), 2.80 (s, 3H), 6.13, 6.18 (d, 1H rotomer,
J=7.9 Hz), 7.23-7.41 (m, I 1H), 8.00, 8.02 (s, 1H rotomer), 8.73,
8.86 (d, 1H, rotomer, J=8.0 Hz); Mass Spectrum (ESI) m/z calcd. for
C.sub.23H.sub.20N.sub.2O.sub.2S.sub.3, 452.62 (M+H), found
453.0.
[0818] b)
4-[2-[(Diphenylmethyl)amino](1,3-thiazol-4-yl))-5-methylthiothio-
phene-2-carboxamidine: Methyl
4-{2-[(diphenylmethyl)amino](1,3-thiazol-4-y-
l)}-5-methylthiothiophene-2-carboxylate hydrobromide. (96.3 mg.
0.18 mmol) was treated as described in Example 154, step (b) to
give 16 mg (20% yield) of
4-{2-[(diphenylmethyl)amino](1,3-thiazol-4-yl)}-5-methylthiothi-
ophene-2-carboxamidine hydrochloride. .sup.1H NMR (DMSO-d.sub.6,
300 MHz) .delta. 2.59 (s, 3H), 6.23 (d, 1H, J=7.9 Hz), 6.84 (s,
1H), 7.22-7.40 (m, 10 H), 8.09 (bs, 3H), 8.12 (s, 1H), 8.68 (d, 1H,
J=8.4 Hz); Mass Spectrum (ESI) m/z calcd. for
C.sub.22H.sub.20N.sub.4S.sub.3, 436.62 (M+H), found 437.1.
EXAMPLE 163
[0819] a) Methyl
5-methylthio-4-[2-[(3-phenylpropyl)amino](1,3-thiazol-4-y-
l)]thiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methyl- thiothiophene-2-carboxylate (131 mg,
0.42 mmol) was allowed to react with propylphenyl thiourea (82.3
mg) in DMF as described in Example 154, step (a), then filtered
through a 5 cm pad of silica gel in a 15 mL glass fritted funnel
with 10% methanol--CHCl.sub.3. Concentration of the solvent in
vacuo gave 203 mg (100% yield) of methyl
5-methylthio-4-{2-[(3-phenylpropyl)amino](1,3-thiazol-4-yl)}thiophene-2-c-
arboxylate hydrobromide. .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 1.89 (m, 2H), 2.62 (s, 3H), 2.63-2.71 (m, 2H), 3.27-3.39
(m, 2H), 3.82 (s, 3H), 6.97 (s, 1H), 7.15-7.31 (m, 5H), 8.06 (s,
1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.19H.sub.20N.sub.2O.sub.2S.sub.3, 404.57 (M+H), found
405.1.
[0820] b)
5-Methylthio-4-[2-[(3-phenylpropyl)amino](1,3-thiazol-4-yl)]thio-
phene-2-carboxamidine hydrochloride: Methyl
-5-methylthio-4-{2-[(3-phenylp-
ropyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylate hydrobromide
(112 mg, 0.23 mmol) was treated as described in Example 154, step
(b) to give 16 mg (16% yield) of
4-{2-[(diphenylmethyl)amino](1,3-thiazol-4-yl)}-5-me-
thylthiothiophene-2-carboxamidine hydrochloride, which was further
purified by preparative thin layer chromatography using
20%-methanol--CH.sub.2C.sub.2-satd. NH.sub.3 as eluent. .sup.1H NMR
(DMSO-d,, 300 MHz) .delta. 1.89 (m, 2H), 2.54 (s, 1H), 2.66 (at,
2H, J=7.3 Hz), 3.31 (m, 2H), 6.69 (bs, 3H), 6.76 (s, 1H), 7.15-7.31
(m, 5H), 7.69 (m, 1H), 7.84 (s, 1H); Mass Spectrum (ESI) m/z calcd.
for C.sub.18H.sub.20N.sub.4S.sub.3, 388.58 (M+H), found 389.2.
EXAMPLE 164
[0821] a) Methyl
5-methylthio-4-[2-[(2,4,5-trimethylphenyl)amino](1,3-thia-
zol-4-yl)]thiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.21
mmol) was allowed to react with 2,4,5-trimethylphenyl thiourea as
described in Example 154, step (a) to give 42.3 mg (41% yield) of
methyl
5-methylthio-4-{2-[(2,4,5-trimethylphenyl)amino](1,3-thiazol-4-yl)}thioph-
ene-2-carboxylate hydrobromide. .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 2.16 (s, 3H), 2.18 (s, 3H), 2.19 (s, 3H), 2.64 (s, 3H),
3.82 (s, 3H), 6.97 (s, 1H), 7.18 (s, 11H), 7.86 (s, 11H), 8.12 (s,
11H), 9.29 (s, 11H); Mass Spectrum (ESI) m/z calcd. for
C.sub.19H.sub.20N.sub.2O.sub.2S.- sub.3, 404.57 (M+H), found
405.1.
[0822] b)
5-Methylthio-4-[2-[(2,4,5-trimethylphenyl)amino](1,3-thiazol-4-y-
l)Jthiophene-2-carboxamidine hydrochloride: Methyl
-5-methylthio-4-{2-[(2,-
4,5-trimethylphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylate
hydrobromide (37.3 mg, 0.07 mmol) was treated as described in
Example 154, step (b) to give 28.3 mg (95% yield) of
5-methylthio-4-{2-[(2,4,5-tr-
imethylphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine
hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.16 (s,
3H), 2.19 (s, 3H), 2.20 (s, 3H), 2.68 (s, 3H), 6.97 (s, 1H), 7.03
(s, 1H), 7.84 (s, 1H), 8.41 (s, 1H), 8.84 (bs, 2H), 9.26 (bs, 3H);
Mass Spectrum (ESI) m/z calcd. for C.sub.18H.sub.20N.sub.4S.sub.3,
388.58 (M+H), found 389.2.
EXAMPLE 165
[0823] a) Methyl
4-[2-[(2-fluorophenyl)amino](1,3-thiazol-4-yl)]-5-methylt-
hiothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methyl- thiothiophene-2-carboxylate (60 mg,
0.19 mmol) was allowed to react with 2-fluorophenyl thiourea as
described in Example 154, step (a) to give 55.6 mg (70% yield) of
methyl 4-{2-[(2-fluorophenyl)amino](1,3-thiazol-4--
yl)}-5-methylthiothiophene-2-carboxylate hydrobromide.
.sup.1.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.68 (s, 3H),
3.83 (s, 3H), 6.96-7.04 (m, 1H), 7.14-7.29 (m, 3H), 7.35 (s, 1H),
8.06, 8.14 (s, 1H rotomer), 8.61 (td, 1H rotomer, J=1.5, 8.5 Hz),
10.14, 10.30 (s, 1H rotomer); Mass Spectrum (ESI) m/z calcd. for
C.sub.16H.sub.13FN.sub.2O.sub.2S.sub.3, 380.48 (M+H), found
381.1.
[0824] b)
4-[2-[(2-Fluorophenyl)amino](1,3-thiazol-4-yl)l-5-methylthiothio-
phene-2-carboxamidine hydrocltloride: Methyl
4-{2-[(2-fluorophenyl)amino](-
1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide
(55.6 mg, 0.13 mmol)) was treated as described in Example 154, step
(b) to give 12.4 mg (24%) of
4-{2-[(2-fluorophenyl)amino](1,3-thiazol-4-yl)}-5-methyl-
thiothiophene-2-carboxamidine hydrochloride. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz); .delta. 2.72 (s, 3H), 3.16 (s, 3H),
6.97-7.08 (m, 1H), 7.18-7.36 (m, 4H), 8.49 (s, 1H), 8.70 (td, 1H,
1.4, 8.4 Hz), 8.92 (bs, 2H), 9.32 (bs, 2H), 10.18 (d, 1H, J=1.6
Hz); Mass Spectrum (ESI) m/z calcd. for
C.sub.15H.sub.13FN.sub.4S.sub.3, 364.49 (M+H), found 365.1.
EXAMPLE 166
[0825] a) Methyl
4-[2-[(3-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)]--
5-methylthiothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19
mmol) was allowed to react with 2-methyl-3-chlorophenyl thiourea
(39 mg) as described in Example 154, step (a) to give 61.8 mg (66%
yield) of methyl
4-{2-[(3-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothio-
phene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd.
for C.sub.17H.sub.15ClN.sub.2O.sub.2S.sub.3, 410.96 (M+H), found
411.1.
[0826] b)
4-[2-[(3-Chloro-2-methylphenyl)amino](1,3-tlziazol-4-yl)]-5-metl-
hyltlziothiiophene-2-carboxamidine hydrochloride: Methyl
4-{2-[(3-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothio-
phene-2-carboxylate hydrobromide (61.8 mg, 0.12 mmol) was treated
as described in Example 154, step (b) to give 46.7 mg (90% yield)
of
4-{2-[(3-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothio-
phene-2-carboxamidine hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 2.34 (s, 3H), 2.69 (s, 3H), 7.15 (s, 1H), 7.18-7.26
(m, 2H), 8.12 (d, 1H, J=7.9 Hz), 8.41 (s, 1H), 8.84 (bs, 2H), 9.27
(bs, 2H), 9.61 (s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.16H.sub.15ClN.sub.4S.sub.3, 394.97 (M+H), found 395.1.
EXAMPLE 167
[0827] a) Methyl-4-(2-[[2-(methylethyl)phenyl]amino)
(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate
hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19
mmol) was allowed to react with 2-isopropyl phenyl thiourea (40 mg)
as described in Example 154, step (a) to give 33.1 mg (36% yield)
of methyl
4-(2-{[2-(methylethyl)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothioph-
ene-2-carboxylate hydrobromide. .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 1.17 (d, 6H, J=6.7 Hz), 2.60, 2.65 (s, 3H rotomer), 3.27
(s, 1H), 3.82 (s, 3H), 7.13 (s, 1H), 7.14-7.25 (m, 2H), 7.34-7.37
(m, 1H), 7.78 (m, 1H), 7.99, 8.08 (s, 1H rotomer), 9.52, 9.61 (bs,
1H rotomer); Mass Spectrum (ESI) m/z calcd. for
C.sub.19H.sub.20N.sub.2O.sub.2S.sub.3, 404.57 (M+H), found
405.1.
[0828] b) 4-(2-([2-(Methylethyl)phenyl]amino)
(1,3-thiazol-4-yl))-5-methyl- thiothiophene-2-carboxamidine
hydrochloride: Methyl 4-(2-{[2-(methylethyl)phenyl]amino
}(1,3-thiazol-4-yl))-5-methylthiothiop- hene-2-carboxylate
hydrobromide (33.1 mg, 0.06 mmol) was treated as described in
Example 154, step (b) to give 22.4 mg (88%) of
4-(2-{[2-(methylethyl)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothioph-
ene-2-carboxamidine hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 1.19 (d, 6H,J=6.8 Hz), 2.70 (s, 3H), 3.32 (m, 1H),
7.04 (s, 1H), 7.14-7.25 (m, 2H), 7.35 (dd, 1H, J=1.4, 7.5 Hz), 7.86
(dd, 1H, J=1.4, 7.9 Hz), 8.37 (s, 1H); Mass Spectrum (ESI) m/z
calcd. for C.sub.18H.sub.20N.sub.4S.sub.3, 388.58 (M+H), found
389.2.
EXAMPLE 168
[0829] a) Methyl
5-methylthio-4-(2-{[4-(phenylmethoxy)phenyl]amino](1,3-th-
iazol-4-yl))thiophene-2-carboxylate: Methyl
4-(2-bromoacetyl)-5-methylthio- thiophene-2-carboxylate (336.3 mg,
1.08 mmol) was allowed to react with 4-benzyloxyphenyl thiourea
(279 mg) as described in Example 154, step (a) to give 450 mg (76%
yield) of methyl 4-(2-{[4-phenylmethoxyphenyl]amino}(-
1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate
hydrobromide. Mass Spectrum (ESI) m/z calcd. for
C.sub.23H.sub.20N.sub.2O.sub.3S.sub.3, 468.61 (M+H), found
469.2.
[0830] b) S-Metiylthio-4-(2-([4-(phenylmethoxy)phenyl]amino)
(1,3-thiazol-4-yl))tl/iophene-2-carboxamidine hydrochloride: Methyl
4-(2-{[4-phenylmethoxyphenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothioph-
ene-2-carboxylate hydrobromide (100 mg, 0.18 mmol) was treated as
described in Example 154, step (b) to give 23.9 mg (27% yield)
5-methylthio-4-(2-{[4-(phenylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))thio-
phene-2-carboxamidine hydrochloride. .sup.1H NMR (DMSO-d6, 300 MHz)
.delta. 2.73 (s, 3H), 5.08 (s, 2H), 7.00 (d, 2H, J=8.2 Hz), 7.09
(s, 1H), 7.31-7.47 (m, 5H), 7.70 (d, 2H, J=8.0 Hz), 8.47 (s, 1H),
8.88 (bs, 2H), 9.30 (bs, 2H), 10.20 (s, 1H); Mass Spectrum (ESI)
m/z calcd. for C.sub.22H.sub.20N.sub.4OS.sub.3, 452.62 (M+H), found
453.1.
EXAMPLE 169
[0831] a) Methyl
4-[2-[(2-bromophenyl)amino](1,3-thiazol-4-yl))-5-methylth-
iothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylt- hiothiophene-2-carboxylate (60 mg,
0.19 mmol) was allowed to react with 2-bromophenyl thiourea (44 mg)
as described in Example 154, step (a) to give 63.1 mg (64% yield)
of methyl 4-{2-[(2-bromophenyl)amino](1,3-thiazo-
l-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.65 (s, 3H), 3.82 (s, 3H),
7.00 (m, 1H), 7.33 (s, 1H), 7.40 (m, 1H), 7.64 (dd, 1H, J=1.4, 7.9
Hz), 8.04, 8.11 (s, 1H rotomer), 8.27, 8.37 (dd, 1H 9.60, 9.80 (bs,
1H rotomer, J=1.5, 8.2 Hz), Mass Spectrum (ESI) m/z calcd. for
C.sub.16H.sub.13BrN.sub.2O.sub.2S- .sub.3, 441.39 (M+H), found
441.1.
[0832] b)
4-2-[(2-Bromophenyl)amino(1,3-thiazol-4-yl)]-5-methylthiothiophe-
ne-2-carboxamidine hydrochloride: Methyl
4-{2-[(2-bromophenyl)amino](1,3-t-
hiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide
(63.1 mg, 0.12 mmol) was treated as described in Example 154, step
(b) to give 47.9 mg (86% yield) of
4-{2-[(2-bromophenyl)amino](1,.sup.3-thiazol-4-yl)}-5-m-
ethylthiothiophene-2-carboxamidine hydrochloride. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 2.70 (s, 3H), 7.01 (m 1H), 7.20 (s,
11H), 7.40 (m, 11H), 7.65 (dd, 1H, J=1.5, 8.0), 8.38 (dd, 1H,
J=1.5, 8.3 Hz), 8.44 (s, 1H), 8.89 (bs, 2H), 9.30 (bs, 2H), 9.62
(s, 11H); Mass Spectrum (ESI) m/z calcd. for
C.sub.15H.sub.13BrN.sub.4S.sub.3, 425.39 (M+H), found 425.1.
EXAMPLE 170
[0833] a) Methyl
4-{2-(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl),-5-meth-
ylthiothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-met- hylthiothiophene-2-carboxylate (60 mg,
0.19 mmol) was allowed to react with 2,6-dichlorophenyl thiourea
(42 mg) as described in Example 154, step (a) to give 63.1 mg (65%
yield) of methyl 4-{2-[(2,6-dichlorophenyl)-
amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate
hydrobromide. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.59 (s,
3H), 3.8 (s, 3H), 7.15 (s, 1H), 7.36 (m, 1H), 7.61 (m, 2H), 7.97
(s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.16H.sub.12Cl.sub.2N.sub.2O.sub.2S.sub- .3, 431.38 (M+H),
found 431.0.
[0834] b)
4-[2-[(2,6-Dichlorophenyl)amino](1,3-thiazol-4-yl)J-5-methylthio-
thiophene-2-carboxamidine hydrochloride: Methyl
4-{2-[(2,6-dichlorophenyl)-
amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate
hydrobromide (43 mg, 0.08 mmol) was treated as described in Example
154, step (b) to give 14.5 mg (40% yield) of
4-{2-[(2,6-dichlorophenyl)amino](1,3-thiazol--
4-yl)}-5-methylthiothiophene-2-carboxamidine hydrochloride. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.69 (s, 3H), 7.15 (s, 1H),
7.18-7.26 (m, 2H), 8.13 (d, 1H, J=7.5 Hz), 8.41 (s, 1H), 8.84 (bs,
2H), 9.27 (bs, 2H), 9.61 (bs, 1H); Mass Spectrum (ESI) m/z calcd.
for C.sub.15H.sub.12C.sub.1- 2N.sub.4S.sub.3, 415.39 (M+H), found
415.1.
EXAMPLE 171
[0835] a) Methyl
4-[2-[(2-bromo-4-methylphenyl)amino](1,3-thiazol-4-yl)}-5-
-methylthiothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19
mmol) was allowed to react with 2-bromo-4-methylphenyl thiourea (47
mg) as described in Example 154, step (a) to give 62 mg (61% yield)
of methyl
4-{2-[(2-bromo-4-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiop-
hene-2-carboxylate hydrobromide. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 2.28 (s, 3H), 3.82 (s, 3H), 7.21 (m, 1H), 7.27 (s,
1H), 7.48 (m, 1H), 8.14, 8.17 (s, 1H rotomer), 9.52, 9.72 (bs, 1H
rotomer); Mass Spectrum (ESI) m/z calcd. for
C.sub.17H.sub.15BrN.sub.2O.sub.2S.sub.3, 455.42 (M+H), found
455.0.
[0836] b)
4-[2-[(2-Bromo-4-methylphenyl)amino](1,3-thiazol-4-yl)J-5-methyl-
thiothiophene-2-carboxamidine hydrochloride: Methyl
4-{2-[(2-bromo-4-methylpheny)amino](1,3-thiazol-4-yl)}-5-methylthiothioph-
ene-2-carboxylate hydrobromide (62 mg, 0.11 mmol) was treated as
described in Example 154, step (b) to give 26 mg (50% yield) of
4-{2-[(2-bromo-4-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiop-
hene-2-carboxamidine hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 2.28 (s, 3H), 2.70 (s, 3H), 7.14 (s, 1H), 7.21 (dd,
1H, J=1.6, 8.5 Hz), 7.49 (d, 1H, J=1.5 Hz), 8.16 (d, 1H, 8.3 Hz),
8.41 (s, 1H), 8.85 (bs, 2H), 9.28 (bs, 2H), 9.53 (s, 1H); Mass
Spectrum (ESI) m/z calcd. for C.sub.16H.sub.15BrN.sub.4S.sub.3,
439.42 (M+H), found 439.1.
EXAMPLE 172
[0837] a) Methyl
5-methylthio-4-[2-[(2-morpholin-4-ylethyl)amino](1,3-thia-
zol-4-yl)]thiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (100 mg, 0.32
mmol), was allowed to react with 1-ethylmorpholinothiourea (61.2
mg) as described in Example 154, step (a) to give 120.8 mg (79%
yield) methyl
5-methylthio-4-{2-[(2-morpholin-4-ylethyl)amino](1,3-thiazol-4-yl)}thioph-
ene-2-carboxylate hydrobromide. .sup.1H NMR (CD.sub.3OD, 300 MHz)
.delta. 2.64 (s, 3H), 3.43-3.52 (m, 5H), 3.83-3.86 (m, 1OH), 6.95
(s, 1H), 8.04 (s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.16H.sub.12N.sub.3O.sub.- 3S.sub.3, 399.55 (M+H), found
400.1.
[0838] b)
5-Methyltflio-4-[2-[(2-morpholin-4-ylethyl)amino](1,3-thiazol-4--
yl)]thiophene-2-carboxylate hydrochloride:
Methyl-5-methylthio-4-{2-[(2-mo-
rpholin-4-ylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylate
hydrobromide (62 mg, 0.12 mmol) was treated as described in Example
154, step (b) to give 26 mg (52% yield) of
5-methylthio-4-f{2-[(2-morpholin-4--
ylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylate
hydrochloride. .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 2.69 (s, 3H),
3.16-3.95 (m, 15H), 6.96 (s, 1H), 8.01 (bs, 1H), 8.49 (s, 1H), 8.84
(bs, 2H), 9.28 (bs, 2H), 10.49 (bs, 1H); Mass Spectrum (ESI) m/z
calcd. for C.sub.15H.sub.21N.sub.5OS.sub.3, 383.56 (M+H), found
384.2.
EXAMPLE 173
[0839] a)
Methyl-4-t2-[(2,3-dichlorophenyl)amino](1,3-thliazol-4-yl)]-5-me-
tlhyltltiothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19
mmol) was allowed to react with 2,3-dichlorophenylthiourea (42 mg)
as described in Example 154, step (a) to give 60.5 mg (62% yield)
methyl
4-{.sup.2-[(2,3-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothio-
phene-2-carboxylate hydrobromide. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 2.66 (s, 3H), 3.82 (s, 3H), 7.27 (dd, 1H, J=1.5, 6.5
Hz), 7.36 (d, 1H, J=8.2 Hz), 7.43 (s, 1H), 8.14 (s, 1H), 8.62 (dd,
1H, J=1.5, 8.4 Hz), 9.95 (bs, 1H); Mass Spectrum (ESI) m/z calcd.
for C.sub.16H.sub.12Cl.sub.2N.sub.2O.sub.2S.sub.3, 431.38 (M+H),
found 431.1.
[0840] b)
4-[2-[(2,3-Dichlorophenyl)amino](1,3-thiazol-4-yl)l-5-methylthio-
thiophene-2-carboxamidine hydrochloride: Methyl
4-{2-[(2,3-dichlorophenyl)-
amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate
hydrobromide (60.5 mg, 0.11 mmol) was treated as described in
Example 154, step (b) to give 15 mg (30% yield) of
4-{2-[(2,3-dichlorophenyl)amino](1,3-thiazol-4--
yl)}5-methylthiothiophene-2-carboxamidine hydrochloride. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.71 (s, 3H), 7.27-7.28-7.41
(m, 2H), 8.45 (s, 1H), 8.63 (dd, 1H, J=1.5, 8.4 Hz), 8.84 (bs, 2H),
9.29 (bs, 2H), 9.99 (s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.15H.sub.12Cl.sub.2- N.sub.4S.sub.3, 415.34 (M+H), found
415.1.
EXAMPLE 174
[0841] a) Methyl
5-methylthio-4-[2-[(3,4,5-trimethoxyphenyl)amino](1,3-thi-
azol-4-yl)]thiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19
mmol) was allowed to react with 2,3,4-trimethoxyphenylthiourea (46
mg) as described in Example 154, step (a) to give 61.8 mg (63%
yield) of methyl
5-methylthio-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiop-
hene-2-carboxylate hydrobromide. .sup.1.sup.1H NMR (DMSO-d.sub.6,
300 MHz) .delta. 2.67 (s, 3H), 3.81 (s, 6H), 3.82 (s, 3H), 7.11 (s,
2H), 7.25 (s, 1H), 8.19 (s, 1H), 10.25 (s, 1H); Mass Spectrum (ESI)
m/z calcd. for C.sub.18H.sub.20N.sub.4O.sub.3S.sub.3, 436.56 (M+H),
found 437.1.
[0842] b)
5-Methylthio-4-[2-[(3,4,5-trimethoxyphenyl)amino/(1,3-thiazol-4
yl)lthiophene-2-carboxamidine hydrochloride: Methyl
5-methylthio-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiop-
hene-2-carboxylate hydrobromide (61.8 mg, 0.11 mmol) was treated as
described in Example 154, step (b) to give 14 mg (27% yield) of
5-methylthio-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiop-
hene-2-carboxamidine hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 2.70 (s, 3H), 3.61 (s, 3H), 3.80 (s, 6H), 7.08 (s,
2H), 7.14 (s, 1H), 8.44 (s, 1H), 8.84 (bs, 2H), 9.26 (bs, 2H),
10.29 (s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.18H.sub.20N.sub.4O.sub.3S.sub.3, 436.56 (M+H), found
437.1.
EXAMPLE 175
[0843] a) Methyl
5-methylthio-4-[2-[(2-piperidylethyl)amino}(1,3-thiazol-4-
-yl)]thiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-meth- ylthiothiophene-2-carboxylate (100 mg,
0.32 mmol) was allowed to react with N-ethylpiperidylthiourea (60.6
mg) as described in Example 154, step (a) to give 90 mg (59% yield)
of methyl 5-methylthio-4-{2-[(2-piperidylet-
hyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylate hydrobromide.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.41 (m, 2H), 1.70-1.79
(m, 6H), 2.65 (s, 3H), 2.95 (m, 2H), 3.52 (m, 2H), 3.73 (m, 2H),
3.82 (s, 3H), 7.08 (s, 1H), 7.96 (at, 1H, J=5.3 Hz), 8.09 (s, 1H),
9.40 (bs, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.17H.sub.23N.sub.3O.sub.2S.sub.3, 397.6 (M+H), found
398.1.
[0844] b)
5-Methylthio-4-[2-[(2-piperidylethyl)amino(1,3-thiazol-4-yl)jthi-
ophene-2-carboxamidine hydrochloride: Methyl
5-methylthio-4-{2-[(2-piperid-
ylethyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylate
hydrobromide (72 mg, 0.15 mmol) was treated as described in Example
154, step (b) to give 26.8 mg (43% yield) of
5-methylthio-4-{2-[(2-piperidylethyl)amino](1,3-th-
iazol-4-yl)}thiophene-2-carboxamidine hydrochloride. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 1.40 (m, 2H), 1.72-1.79 (m, 6H),
2.69 (s, 3H), 2.96 (m, 2H), 3.51 (m, 2H), 3.76 (m, 2H), 6.97 (s,
1H), 8.08 (t, 1H, J=5.5 Hz), 8.60 (s, 1H), 8.95 (bs, 1H), 9.35 (bs,
2H), 10.25 (s, 11H); Mass Spectrum (ESI) m/z calcd. for
C.sub.16H.sub.23N.sub.5S.sub.3, 381.1 (M+H), found 382.2.
EXAMPLE 176
[0845] a) Methyl
4-(2-[[(4-metllylphenyl)methyl]amino}(1,3-thiazol-4-yl))--
S-methylthiothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (111 mg, 0.35
mmol) was allowed to react with 4-methylphenylmethylthiourea as
described in Example 154, step (a) to give 125 mg (81% yield) of
methyl
4-(2-{[(4-methylphenyl)methyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiop-
hene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd. for
C.sub.18H.sub.18N.sub.2O.sub.2S.sub.2, 358.5 (M+H), found
359.1.
[0846] b)
4-(2-[[(4-Methylphenyl)methyl]amino](1,3-thiazol-4-yl))-5-methyl-
thiothiophene-2-carboxamidine hydrochloride: Methyl
4-(2-{[(4-methylphenyl)methyl]amino
}(1,3-thiazol-4-yl))-5-methylthiothio- phene-2-carboxylate
hydrobromide (118 mg, 0.26 mmol) was treated as described in
Example 154, step (b) to give 58.2 mg (54% yield) of
4-(2-{[(4-methylphenyl)methyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiop-
hene-2-carboxamidine hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 2.27 (s, 3H), 2.66 (s, 3H), 4.49 (d, 2H, J=5.7 Hz),
6.88 (s, 1H), 7.13 (d, 2H, J=7.8 Hz), 7.27 (d, 2H, J=8.0 Hz), 8.20
(t, 1H, J=5.8 Hz), 8.42 (s, 1H), 8.90 (bs, 2H), 9.27 (bs, 2H); Mass
Spectrum (ESI) m/z calcd. for C.sub.17H.sub.18N.sub.4S.sub.3,
374.55 (M+H), found 375.2.
EXAMPLE 177
[0847] a) Aminof [4-(4-chlorophenoxy)phenyl]amino]methane-1-thione:
Unless otherwise indicated, all thioureas, isothiocyanates,
thioamides and amines were purchased from Maybridge Chemical Co.
Ltd.(Cornwall, U.K.), Transworld Chemical Co. (Rockville, Md.), or
Aldrich Chemical Co., (Milwaukee, Wis.). (i)
4-Amino-4-chlorodiphenylether (TCl America, Portland OR, 520 mg,
2.03 mmol) was slurried in 10 mL of ether and treated with ca. 1 mL
of ether saturated with HCl gas. After 5 min. the solvent was
removed in vacuo. To a stirring biphasic solution amine-HCl salt in
20 mL CHC.sub.1.sub.3-satd NaHCO.sub.3 (1:1, v/v) at ambient
temperature was added thiophosgene (1.2 equiv, 2.4 mmol) in 5 mL of
CHCl.sub.3 dropwise via an addition funnel. The reaction was
vigorously stirred for 1 h (TLC, 50% ethyl acetate-hexanes
indicates clean conversion to a higher R.sup.f spot), at which time
the layers were separated, the aqueous layer extracted with
CHCl.sub.3 (lx20 mL), and the combined organic layers washed with
brine (lx20 mL) and dried (Na.sub.2SO.sub.4). Concentration of the
solvent in vacuo yielded the crude
4-(4-chlorophenoxy)-phenylisothiocyanate (414 mg). (ii) The
4-(4-chlorophenoxy)-phenylisothiocyanate was transferred to an Ace
Glass pressure tube equipped with a Teflon coated stir bar and
treated with a 2.0 M solution of NH.sub.3 in 5 ml methanol (Aldrich
Chemical Co., Milwaukee, Wis.)). The tube was sealed and immersed
in a 80.degree. C. oil bath. After 2 h, the reaction was cooled to
0.degree. C. in an ice bath. The precipitates were filtered and
dried under vacuum to yield amino {[4-(4-chlorophenoxy)phenyl]amino
}methane-1-thione (328 mg, 79%). .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 7.02 (m, 4H), 7.41 (m, 4H), 9.65 (s, 1H); Mass
Spectrum (ESI) m/z calcd. for C.sub.13H.sub.11ClN.sub.- 2OS, 278.8
(M+H), found 279.4.
[0848] b)
Methyl-4-(2-([4-(4-chlorophenoxy)phenyl]amino(1,3-thiazol-4-yl))-
-5-methylthiothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (309 mg, 1.0
mmol) was allowed to react with aminof
[4-(4-chlorophenoxy)phenyl]amino}methane- -1-thione (297 mg) as
described in Example 154, step (a) to give 410 mg (72% yield) of
methyl 4-(2-{[4-(4-chlorophenoxy)phenyl]amino}(1,3-thiazol-
-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide. Mass
Spectrum (ESI) m/z calcd. for
C.sub.22H.sub.17ClN.sub.2O.sub.3S.sub.3, 489.1 (M+H), found
489.1.
[0849] c) 4-(2-[[4-(4-Chlorophenoxy)phenyl]amino)
(1,3-thiazol-4-yl))-5-me- thylthiothiophene-2-carboxamidine
hydrochloride: Methyl-4-(2-{[4-(4-chloro- phenoxy)phenyl]amino
}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxyl- ate
hydrobromide (300 mg, 0.52 mmol) was treated as described in
Example 154, step (b) to give 129.9 mg (49% yield) of
4-(2-{[4-(4-chlorophenoxy)p-
henyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine
hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.72 (s,
31H), 6.97 (m, 211), 7.07 (m, 2H), 7.15 (s, 1H), 7.40 (m, 2H), 7.85
(m, 2H), 8.46 (s, 1H), 8.82 (bs, 2H), 9.27 (bs, 2H), 10.43 (bss,
11H); Mass Spectrum (ESI) m/z calcd. for
C.sub.21H.sub.17ClN.sub.4OS.sub.3, 473.1 (M+H), found 473.2,
475.1.
EXAMPLE 178
[0850] a) Methyl 5-methylthio-4-[2-([4-[5-(trifluoromethyl)
(2-pyridyloxy)jphenylamino)
(1,3-thiazol-4-yl)]thiophene-2-carboxlate: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (70 mg, 0.23
mmol) was allowed to react with
4-[5-(trifluoromethyl)pyrid-2-yloxy]thiob- enzamide (50 mg) as
described in Example 154, step (a) to give 115 mg (98% yield) of
methyl 5-methylthio-4-[2-({4-[5-(trifluoromethyl)
(2-pyridyloxy)]phenyl }amino)
(1,3-thiazol-4-yl)]thiophene-2-carboxylate. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 2.70 (s, 31H), 3.85 (s, 31H), 7.38
(m, 31H), 8.10 (m, 11H), 8.18 (s, 11H), 8.28 (dd, 11H, -2.7, 8.8
Hz), 8.32 (s, 1H), 8.60 (m, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.22H.sub.15F.sub.3N.sub.2O.sub.3S.sub.3, 508.56 (M+H), found
509.2.
[0851] b) 5-Methiylthio-4-[2-({4-[5-(trifluoromethyl)
(2-pyridyloxy)Jphenyl]amino)
(1,3-thiazol-4-yl)jthiophene-2-carboxamidine hydrochloride: Methyl
5-methylthio-4-[2-( {4-[5-(trifluoromethyl)
(2-pyridyloxy)]phenyl}amino)
(1,3-thiazol-4-yl)]thiophene-2-carboxylate (95 mg, 0.18 mmol) was
treated as described in Example 154, step (b) to give 30.3 mg (32%
yield) of 5-methylthio-4-[2-({4-[5-(trifluoromethyl)
(2-pyridyloxy)Jphenyl }amino)
(1,3-thiazol-4-yl)]thiophene-2-carboxamidin- e hydrochloride.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.75 (s, 3H), 7.34 (d,
1H, J=8.7 Hz), 7.41 (m, 2H), 8.01 (s, 1H), 8.10-8.14 (m, 2H), 8.29
(dd, 1H, J=2.5, 8.4 Hz), 8.60 (m, 1H), 8.63 (s, 1H), 8.91 (bs, 2H),
9.31 (bs, 2H); Mass Spectrum (ESI) m/z calcd. for
C.sub.21H.sub.15F.sub.3- N.sub.4OS.sub.3, 492.6 (M+H), found
493.1.
EXAMPLE 179
[0852] a)
Methyl-4-(2-{[4-phenoxyphenyl]amino](1,3-thiazol-4-yl))-5-methyl-
thiothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methy- lthiothiophene-2-carboxylate (200 mg,
0.64 mmol) was allowed to react with 4-phenoxyphenylthiourea (158
mg) as described in Example 154, step (a) to give 300 mg (88%
yield) of methyl 4-(2-{[4-(phenoxy)phenyl]amino}(1,3-thi-
azol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide. Mass
Spectrum (ESI) m/z calcd. for
C.sub.22H.sub.18N.sub.2O.sub.3S.sub.3, 454.6 (M+H), found
455.2.
[0853] b)
4-(2-[[4-Phenoxyphenyl]amino](1,3-thiazol-4-yl))-5-methyltltiotl-
tiophene-2-carboxamidine hydrochloride:
Methyl-4-(2-{[4-(phenoxy)phenyl]am-
ino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate
hydrobromide (230 mg, 0.42 mmol) was treated as described in
Example 154, step (b) and purified by preparative thin layer
chromatography (20% methanol--CH.sub.2Cl.sub.2-satd. NH.sub.3, 500
mm silica gel plate, J. T. Baker, Phillipsburg, NJ) to give 86 mg
(47% yield) of the product. A 46 mg aliquot was dissolved in 1 mL
of methanol, treated with 3 drops of ether saturated with HCl gas,
and concentrated in vacuo with toluene (2.times.5mL) to give 42.3
mg (21% yield) of 4-(2-{[4-phenoxyphenyl]amino-
}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine
hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.71 (s,
3H), 6.97-7.11 (m, 4H), 7.15 (s, 1H), 7.36 (m, 2H), 7.72, 7.85 (d,
2H rotomer, J=8.7 Hz), 8.36, 8.55 (s, 1H rotomer), 9.00 (bs, 2H),
9.35 (bs, 2H), 10.49 (s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.22H.sub.18N.sub.4OS.sub.3, 438.6 (M+H), found 439.2.
EXAMPLE 180
[0854] a) Aminof [4-(phenylamino)phenyl]amino]methane-1-thione:
4-Aminodiphenylamine (500 mg, 2.71 mmol) was treated as described
in Example 177, step (a) and recrystallized from toluene to give
350 mg (53% yield) of aminof
[4-(phenylamino)phenyl]amino}methane-1-thione. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 6.80 (m, 1H), 7.01-7.24 (m, 8H),
8.15 (s, 1H), 9.45 (s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.13H.sub.13N.sub.3S, 243.33 (M+H), found 244.2.
[0855] b)
Methyl-5-methylthio-4-(2-([4-(phenylamino)phenyl]amino](1,3-thia-
zol-4-yl))thiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (90 mg, 0.28
mmol) was allowed to react with amino
{[4-(phenylamino)phenyl]amino}methane-l -thione (70.8 mg) as
described in Example 154, step (a) to give 71 mg (47% yield) of
methyl 5-methylthio-4-(2-{[4-(phenylamino)phenyl]amino}(1,-
3-thiazol-4-yl))thiophene-2-carboxylate hydrobromide. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 2.66 (s, 3H), 3.82 (s, 3H), 6.73
(m, 1 H), 6.96-7.24 (m, 9H), 7.63 (d, 1H, J=8.6 Hz), 8.12 (s, 1H),
10.13 (bs, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.22H.sub.19N.sub.3O.sub.2S.s- ub.3, 453.60 (M+H), found
454.2.
[0856] c) 5-Methylthio-4-(2-{[4-(phenylamino)phenyl]amino)
(1,3-thiazol-4-yl))thiophene-2-carboxamidine hydrochloride: Methyl
5-methylthio-4-(2-{[4-(phenylamino)phenyl]amino
}(1,3-thiazol-4-yl))thiop- hene-2-carboxylate hydrobromide (71 mg,
0.13 mmol) was treated as described in Example 154, step (b) to
give 23.3 mg (38% yield) of
5-methylthio-4-(2-{[4-(phenylamino)phenyl]amino
}(1,3-thiazol-4-yl))thiop- hene-2-carboxamidine hydrochloride.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.72 (s, 3H), 6.74 (t,
1H, J=7.3 Hz), 6.98 (d, 1H, J=7.6 Hz), 7.08 (m, 2H), 7,18 (m, 2H),
7.66 (d, 2H, J=8.9 Hz), 7.99 (s, 1H), 8.45 (s, 1H), 9.03 (bs, 4H),
10.17 (s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.21H.sub.19N.sub.5S.sub.3, 437.59 (M+H), found 438.2.
EXAMPLE 181
[0857] a) Aminof [4-benzylphenyl]amino]methane-1-thione:
4-Benzylphenylamine (500 mg, 2.73 mmol) was treated as described in
Example 177, step (a) to give 410 mg (62% yield) of aminof
[4-benzylphenyl]amino}methane-1-thione. .sup.1H NMR (DMSO-d.sub.6,
300 MHz) .delta. 3.89 (s, 2H), 7.14-7.28 (m, 9H), 9.59 (s, 1H);
Mass Spectrum (ESI) m/z calcd. for C.sub.14H.sub.14N.sub.2S.sub.3,
242.1 (M+H), found 243.2.
[0858] b) Methyl 5-methylthio-4-(2-([4-benzylphenyl]amino)
(1,3-thiazol-4-yl))thiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-5 methylthiothiophene-2-carboxylate (90 mg,
0.28 mmol) was allowed to react with aminof
[4-benzylphenyl]amino}methane-1-th- ione (70.5 mg) as described in
Example 154, step (a) to give 70.1 (47% yield) of methyl
5-methylthio-4-(2-{[4-benzylphenyl]amino}(1,3-thiazol-4--
yl))thiophene-2-carboxylate hydrobromide. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 2.66 (s, 3H), 3.82 (s, 3H), 3.87
(s, 2H), 7.14-7.30 (m, 8H), 7.66 (d, 2H, J=8.5 Hz), 8.12 (s, 1H),
10.23 (s, 1H); (Mass Spectrum (ESI) m/z calcd. for
C.sub.22H.sub.19N.sub.3O.sub.2S.sub.3, 453.6 (M+H), found
454.2.
[0859] c) 5-Methylthio-4-(2-[[4-he tzylphenyl]amino)
(1,3-thiazol-4-yl))thiophene-2-carboxamidine hydrochloride: Methyl
5-methylthio-4-(2-{[4-benzylphenyl]amino
}(1,3-thiazol-4-yl))thiophene-2-- carboxylate hydrobromide (82.2
mg, 0.15 mmol) was treated as described in Example 154, step (b) to
give 33.4 mg (47% yield) of
5-methylthio-4-(2-{[4-benzylphenyl]amino}(1,3-thiazol-4-y]))thiophene-2-c-
arboxamidine hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 2.72 (s, 3H), 3.89 (s, 2H), 7.12 (s, 1H), 7.16-7.29 (m,
7H), 7.69 (d, 2H, J=8.6 Hz), 8.43 (s, 1H), 9.02 (bs, 4H), 10.28 (s,
1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.22H.sub.20N.sub.4S.sub.3, 436.6 (M+H), found 437.2.
EXAMPLE 182
[0860] a) ({4-[(Aminothioxomethyl)amino]phenyl]sulfonyl)piperidine:
4-Aminophenylsulphonylpiperidine (500 mg, 2.08 mmol) was treated as
described in Example 177, step (a) to give 382 mg (61% yield) of
({4-[(aminothioxomethyl)amino]phenyl }sulfonyl)piperidine. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.34 (m, 2H), 1.53 (m, 4H),
2.85 (m, 4H), 7.62 (m, 2H), 7.78 (m, 2H), 10.10 (bs, 1H); Mass
Spectrum (ESI) m/z calcd. for
C.sub.12H.sub.17N.sub.3O.sub.2S.sub.2, 299.4 (M+H), found
300.2.
[0861] b)
Methyl-5-methylthio-4-(2-t[4-(piperidylsulfonyl)phenyl]amino](1,-
3-thiazol-4-yl))thiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (90 mg, 0.28
mmol) was allowed to react with
({4-[(aminothioxomethyl)amino]phenyl}sulfonyl)p- iperidine (87.1
mg) as described in Example 154, step (a) to give 105 mg (63%
yield) of methyl
5-methylthio-4-(2-{[4-(piperidylsulfonyl)phenyl]ami- no
}(1,3-thiazol-4-yl))thiophene-2-carboxylate hydrobromide. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.33 (m, 2H), 1.52 (m, 4H),
2.69 (s, 3H), 2.84 (m, 4H), 3.82 (s, 3H), 7.43 (s, 1H), 7.66 (m,
2H), 7.98 (m, 2H), 8.16 (s, 1H), 10.85 (s, 1H); (Mass Spectrum
(ESI) m/z calcd. for C.sub.21H.sub.23N.sub.3O.sub.4S.sub.4, 509.69
(M+H), found 510.2.
[0862] c) 5-Methylthio-4-(2-[[4-piperidy u o
yl)phenyl]amino](1,3-thiazol-- 4 yl))thiophene-2-carboxamidine
hydrochloride: Methyl
5-methylthio-4-(2-{[4-(piperidylsulfonyl)phenyl]amino
}(1,3-thiazol-4-yl))thiophene-2-carboxylate hydrobromide (105 mg,
0.17 mmol) was treated as described in Example 154, step (b) to
give 30.3 mg (34% yield) of
5-methylthio-4-(2-{[4-(piperidylsulfonyl)phenyl]amino}(1,3-
-thiazol-4-yl))thiophene-2-carboxamidine hydrochloride. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 1.36 (m, 2H), 1.54 (m, 4H), 2.76
(s, 3H), 2.86 (m, 4H), 7.30 (s, 1H), 7.68 (d, 2H, J=8.8 Hz), 8.03
(d, 2H, J=8.8 Hz), 8.51 (s, 1H), 8.84 (bs, 2H), 9.28 (bs, 2H),
10.94 (s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.20H.sub.23N.sub.5O.sub.2S.sub.5, 493.69 (M+H), found
494.2.
EXAMPLE 183
[0863] a) Amino(3-quinolylamino)methane-1-thione: 3-Aminoquinoline
(500 mg, 3.46 mmol) was treated as described in Example 177, step
(a) to give 285 mg (41% yield) of
amino(3-quinolylamino)methane-1-thione. .sup.1H NMR (DMSO-d.sub.6,
300 MHz) .delta. 7.57 (m, 1H), 7.67 (m, 1H), 7.94 (m, 2H), 8.41 (d,
1H, J=2.4 Hz), 8.85 (d, 1H, J=2.5 Hz), 10.03 (s, 1H); Mass Spectrum
(ESI) m/z calcd. for C.sub.10H.sub.9N.sub.3S, 203.3 (M+H), found
204.1.
[0864] b) Methyl 5-methylthio-4-[2-(3-quinolylamino)
(1,3-thiazol-4-yl)]thiophene-2-carboxylate: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (90 mg, 0.28
mmol) was allowed to react with
amino(3-quinolylamino)methane-1-thione (59.1 mg) as described in
Example 154, step (a) to give 107.5 mg (78% yield) of methyl
5-methylthio-4-[2-(3-quinolylamino) (1,3-thiazol-4-yl)]thiophene-2-
-carboxylate hydrobromide. .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 2.75 (s, 3H), 3.84 (s, 3H), 7.52 (s, 1H), 7.92-8.05 (m,
2H), 8.22 (s, 1H), 9.22 (m, 2H); Mass Spectrum (ESI) m/z calcd. for
C.sub.19H.sub.15N.sub.3O.sub.2S.sub.3, 413.54 (M+H), found
414.1.
[0865] c) 5-Methylthio-4-[2-(3-quinolylamino)
(1,3-thiazol-4-yl)]thiophene- -2-carboxamidine hydrochloride:
Methyl 5-methylthio-4-[2-(3-quinolylamino)
(1,3-tbiazol-4-yl)]thiophene-2-carboxylate hydrobromide (107.5 mg,
0.21 mmol) was treated as described in Example 154, step (b) to
give 4.5 mg (4.9% yield) of 5-methylthio-4-[2-(3-quinolylamino)
(1,3-thiazol-4-yl)]thiophene-2-carboxamidine hydrochloride. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.80 (s, 3H), 7.29 (s, 1H),
7.59 (m, 2H), 7.93 (m, 2H), 8.54 (s, 1H), 8.89 (bs, 2H), 8.91 (m,
1H), 9.16 (m, 1H), 9.29 (bs, 2H), 10.97 (s, 1H); Mass Spectrum
(ESI) m/z calcd. for C.sub.18H.sub.15N.sub.5S.sub.3, 397.5 (M+H),
found 398.1.
EXAMPLE 184
[0866] a) Methyl-5-methylthio-4-[2-(2-naphthylamitio)
(1,3-thiazol-4-yl)]thiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (65 mg, 0.21
mmol) was allowed react with 2-napthylthiourea (42.4 mg) as
described in Example 154, step (a) to give 82.5 mg (80% yield)of
methyl 5-methylthio-4-[2-(2-naphthylamino)
(1,3-thiazol-4-yl)]thiophene-2-carbox- ylate hydrobromide. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.67 (s, 3H), 3.83 (s, 3H),
7.31 (s, 1H), 7.50-7.67 (m, 4H), 7.93 (m, 1H), 8.15 (s, 1H),
8.31-8.35 (m, 1H), 8.46 (d, 1H, J=7.6), 10.22 (s, 1H)); Mass
Spectrum (ESI) m/z calcd. for
C.sub.20H.sub.16N.sub.2O.sub.2S.sub.3, 412.6 (M+H), found
413.1.
[0867] c) 5-Methylthio-4-[2-(2-naphthylamino)
(1,3-thiazol-4-yl)]thiophene- -2-carboxamidine hydrochloride:
Methyl 5-methylthio-4-[2-(2-naphthylamino)
(1,3-thiazol-4-yl)]thiophene-2-carboxylate hydrobromide (42.7 mg,
0.086 mmol) was treated as described in Example 154, step (b) to
give 5.8 m,, (16% yield) of 5-methylthio-4-[2-(2-naphthylamino)
(1,3-thiazol-4-yl)]thiophene-2-carboxamidine hydrochloride. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.72 (s, 3H), 7.12-7.27 (m,
3H), 7.50-7.68 (m, 3H), 7.94 (m, 1H), 8.32-8.35 (m, m, 1H), 8.51
(s, 1H), 8.97 (bs, 2H), 9.34 (bs, 2H), 10.26 (s, 1H); Mass Spectrum
(ESI) m/z calcd. for C.sub.19H.sub.16N.sub.4S.sub.3, 396.6 (M+H),
found 397.2.
EXAMPLE 185
[0868] a) Methyl-4-[2-(2H-benzo[3,4-dJl,3-dioxolan-5-ylamino)
(1,3-thiazol-4-yl)J-5-methylthiothiophene-2-carboxylate
hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (65 mg, 0.21
mmol) was allowed to react with 2,3-methylenedioxyphenylthiourea
(41.2 mg) as described in Example 154, step (a) to give 51 mg (50%
yield) of methyl 4-[2-(2H-benzo[3,4-d]1,3-dioxolan-5-ylamino)
(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxylate
hydrobromide. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.66 (s,
3H), 3.83 (s, 3H), 5.98 (s, 2H), 6.84-6.89 (m, 1H), 6.96, 7.04 (dd,
1H rotomer, J=2.2, 8.5 Hz), 7.25 (s, 1H), 7.46, 7.60 (d, 1H
rotomer, J=2.1 Hz), 8.05, 8.13 (s, 1H rotomer), 10.19, 10.34 (s,
1H, rotomer); Mass Spectrum (ESI) m/z calcd. for
C.sub.17H.sub.14N.sub.2O.sub.4S.sub.3, 406.5 (M+H), found
407.1.
[0869] b) 4-[2-(2H-Benzof 3,4-djl,3-dioxolan-5-ylamino)
(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidine
hydrochloride: Methyl 4-[2-(2H-benzo[3,4-d]1,3-dioxolan-5-ylamino)
(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxylate
hydrobromide (51 mg, 0.10 mmol) was treated as described in Example
154, step (b) to give 16.6 mg (39% yield) of
4-[2-(2H-benzo[3,4-d]1,3-dioxolan-5-ylamino)
(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidine
hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.71(s,
3H), 5.98 (s, 2H), 6.87 (d, 1H, J=8.2 Hz), 7.09-7.13 (m, 2H), 7.67
(d, 1H, J=2.4 Hz), 8.50 (s, 1H), 8.95 (bs, 2H), 9.33 (bs, 2H),
10.30 (s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.16H.sub.14N.sub.4O.sub.2S3, 390.51 (M+H), found 391.2;
EXAMPLE 186
[0870] a) Amino[(7-bromofluoren-2-yl)amino]methane-1-thione:
2-Amino-7-bromofluorene (500 mg, 1.90 mmol) was treated as
described in Example 177, step (a) to give 128 mg (21% yield) of
amino[(7-bromofluoren-2-yl)amino]methane-1-thione. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 3.35 (s, 2H), 7.35 (d, 11H, J=8.3
Hz), 7.54 (d, 1H, J=8.0 Hz), 7.66 (s, 1H), 7.77-7.87 (m, 3H), 9.80
(s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.14H.sub.11BrN.sub.2S, 319.2 (M+H), found 320.1, 321.1.
[0871] b)
Methyl-4-{2-[(7-bromofluoren-2-yl)amino](1,3-thiazol-4-yl)}-5-me-
thylthiothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (90 mg, 0.28
mmol) was allowed to react with
amino[(7-bromofluoren-2-yl)amino]methane-1-thio- ne (92.8 mg) as
described in Example 154, step (a) to give 141 mg (82% yield) of
methyl 4-{2-[(7-bromofluoren-2-yl)amino](1,3-thiazol-4-yl)}-5-m-
ethylthiothiophene-2-carboxylate hydrobromide. .sup.1.sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 2.70 (s, 3H), 3.83 (s, 3H), 3.93
(s, 2H), 7.33 (s, 1H), 7.51 (dd, 1H, J=1.9, 8.0 Hz), 7.65 (dd, 1H,
J=2.0, 8.4 Hz), 7.74 (ad, 2H, J=8.3 Hz), 7.83 (ad, 1H, J=8.4 Hz),
8.18 (s, 1H), 8.23 (d, 1H, J=1.4 Hz), 10.47 (s, 1H).
[0872] c)
4-[2-[(7-Bromofluoren-2-yl)amino](1,3-thiazol-4-yl)]-5-methylthi-
othiophene-2-carboxamidine hydrochloride:
Methyl-4-{2-[(7-bromofluoren-2-y-
l)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate
hydrobromide (100 mg, 0.15 mmol) was treated as described in
Example 154, step (b) to give 3.3 mg (4% yield) of
4-{2-[(7-bromofluoren-2-yl)amino](1-
,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine
hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.76 (s,
3H), 3.95 (s, 2H), 7.18 (s, 1H), 7.54 (dd, 1H, J=1.8, 10.0 Hz),
7.67-7.76 (m, 3H), 7.85 (d, 1H, J=8.2 Hz), 8.23 (s, 1H), 8.50 (s,
1H), 10.53 (s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.22H.sub.17BrN.sub.4S.sub.3, 513.5 (M+H), found 513.1,
515.1.
EXAMPLE 187
[0873] a)
Methyl-4-[2-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl)l-5-met-
hylthiothiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (65 mg, 0.21
mmol) was allowed to react with 4-cyclohexylphenylthiourea (49.2
mg) as described in Example 154, step (a) to give 45 mg (41% yield)
of methyl
4-{2-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-
-2-carboxylate hydrobromide. .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 1.23-1.39 (m, 5H), 1.71-1.79 (m, 5H), 2.68 (s, 3H), 3.83
(s, 3H), 7.16 (d, 2H,J=8.6 Hz), 7.26 (s, 1H), 7.65 (d, 2H, J=8.7
Hz), 8.14 (s, 1H), 10.19 (s, 1H); Mass Spectrum (ESI) m/z calcd.
for C.sub.22H.sub.24N.sub.2- O.sub.2S.sub.3, 444.64 (M+H), found
445.2.
[0874] b)
4-[2-[(4-Cyclohexylphenyl)amino](1,3-thiazol-4-yl)J-5-methylthio-
thiophene-2-carboxamidine hydrochloride: Methyl
4-{2-[(4-cyclohexylphenyl)-
amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate
hydrobromide (31.1 mg, 0.059 mmol) was treated as described in
Example 154, step (b) to give 12.8 mg (47% yield) of
4-{2-[(4-cyclohexylphenyl)amino](1,3-thiaz-
ol-4-yl)}-5-methylthiothiophene-2-carboxamidine hydrochloride.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.33-1.40 (m, 5H),
1.68-1.79 (m, 5H), 2.44 (m, 1H), 2.73 (s, 3H), 7.12 (s, 1H), 7.18
(d, 2H, J=8.7 Hz), 7.68 (d, 2H, J=8.7 Hz), 8.47 (s, 1H), 8.85 (bs,
2H), 9.32 (bs, 2H), 10.28 (s, 1H); Mass Spectrum (ESI) m/z calcd.
for C.sub.21H.sub.24N.sub.4S.sub.3, 428.64 (M+H), found 429.2.
EXAMPLE 188
[0875] a) Amino([4-(phenyldiazenyl)phenyl]amino]methane-1-thione:
4-Phenylazophenylisothiocyanate (314 mg, 1.30 mmol) was treated as
described in Example 177, step (a), part (ii), to give 295 mg (88%
yield) of aminof [4-(phenyldiazenyl)phenyl]amino}methane- 1-thione.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 6.84 (m, 1H), 7.57 (m,
2H), 7.73 (m, 2H), 7.85-7.89 (m, 4H), 10.04 (s, 1H); Mass Spectrum
(ESI) m/z calcd. for C.sub.13H.sub.12N.sub.4S, 256.3 (M+H), found
257.2.
[0876] b) Methyl 5-methylthio-4-(2-[14-(henyldiazenyl)phenyl]amino)
(1,3-thiazol-4-yl))thiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (65 mg, 0.21
mmol) was allowed to react with amino
{[4-(phenyldiazenyl)phenyl]amino}methane-- 1-thione (53.8 mg) as
described in Example 154, step (a) to give 80.6 mg (70% yield) of
methyl 5-methylthio-4-(2-{[4-(phenyldiazenyl)phenyl]amino}-
(1,3-thiazol-4-yl))thiophene-2-carboxylate hydrobromide. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.72 (s, 3H), 3.84 (s, 3H),
7.46 (s, 1H), 7.49-7.61 (m, 3H), 7.84 (m, 2H), 7.91-8.02 (m, 4H),
8.20 (s, 1H), 10.83 (s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.22H.sub.18N.sub.4O.sub.- 2S.sub.3, 466.6 (M+H), found
467.1.
[0877] c) 5-Methylthio-4-(2-{[4-(Phenyldiazenyl)phenyl]amino)
(1,3-thiazol-4 yl))thiophene-2-carboxamidine hydrochloride: Methyl
5-methylthio-4-(2-{[4-(phenyldiazenyl)phenyl]amino}(1,3-thiazol-4-yl))thi-
ophene-2-carboxylate hydrobromide (47.7 mg, 0.087 mmol) was treated
as described in Example 154, step (b) to give 32.8 mg (77% yield)
of 5-methylthio-4-(2-{[4-(phenyldiazenyl)phenyl]amino3
(1,3-thiazol-4-yl))thiophene-2-carboxamidine hydrochloride. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.78 (s, 3H), 7.26 (s, 1H),
7.49-7.63 (m, 3H), 7.66-7.74 (m, 3H), 7.84-8.08 (m, 3H), 8.60 (s,
1H), 11.02 (bs, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.21H.sub.18N.sub.6S.sub.3, 45 0.6 (M+H), found 451.1.
EXAMPLE 189
[0878] a) {3-[(Aminothioxomethyl)amino]phenyl]methan-1-ol:
3-Aminobenzyl alcohol (550 mg, 4.46 mmol) was treated as described
in Example 177, step (a) to give 618 mg (76% yield) of
{3-[(aminothioxomethyl)amino]phenyl}met- hanol. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 4.47 (d, 2H, J=5.6 Hz), 5.19 (t,
1H, J=5.7 Hz), 7.06 (d, 1H, J=6.2 Hz), 7.18-7.30 (m, 3H), 9.73 (s,
1Il).
[0879] b) Methyl-5-methylthio-4(2-t[3-(hydroxymethyl)phenyl]amino)
(1,3-thiazol-4-yl))-thiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (1.01 g, 3.26
mmol) was allowed to react with of
{3-[(aminothioxomethyl)amino]phenyl}methan-1- -ol as described in
Example 154, step (a) to give 1.42 g (92% yield) of
methyl-5-methylthio-4-(2-{[3-(hydroxymethyl)phenyl]amino
}(1,3-thiazol-4-yl))-thiophene-2-carboxylate hydrobromide. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.67 (s, 3H), 3.83 (s, 3H),
4.49 (s, 2H), 6.92 (m, 1H), 7.23-7.31 (m, 2H), 7.60 (m, 1H), 7.81
(bs, 1H), 8.17 (s, 1H), 10.29 (bs, 1H).
[0880] c) 5-Methylthio
4-(2-{[3-(hydroxymethyl)phenyl]amino}(1,3-thiazol-4-
-yl))-thiophene-2-carboxamidine hydrochloride:
Methyl-5-methylthio-4-(2-{[-
3-(hydroxymethyl)phenyl]amino}(1,3-thiazol-4-yl))-thiophene-2-carboxylate
hydrobromide (700 mg, 1.47 mmol) was treated as described in
Example 154, step (b) using 1:9:1 methanol--CH.sub.2Cl.sub.2-DMF as
eluent to give 195 mg (32% yield) of 5-methylthio
4-(2-{[3-(hydroxymethyl)phenyl]amino
}(1,3-thiazol-4-yl))-thiophene-2-carboxamidine hydrochloride.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.71 (s, 3H), 4.50 (s,
2H), 6.93 (d, 1H, J=7.6 Hz), 7.15 (s, 1H), 7.21-7.27 (m, 1H), 7.38
(bs, 1H), 7.65 (d, 1H, J=8.1 Hz), 7.80 (s, 1H), 8.53 (s, 1H), 8.94
(bs, 2H), 9.32 (bs, 2H), 10.37 (s, 1H); Mass Spectrum (ESI) m/z
calcd. for C.sub.16H.sub.16N.sub.4- OS.sub.3, 376.5 (M+H), found
377.2.
EXAMPLE 190
[0881] a)
(tert-Butoxy)-N-[(4-[2-[(3-hydroxymethylphenyl)amino](1,3-thiazo-
l-4 yl)}-5-methylthio(2-thienyl))iminomethylqarboxamide:
5-Methylthio
4-(2-{[3-(hydroxymethyl)phenyl]amino}(1,3-thiazol-4-yl))-thiophene-2-carb-
oxamidine (103 mg, 0.27 mmol) was slurried in THF (4 mL) and
treated with 0.5 mL of 0.5 N NaOH. tert-Butyldicarbonate (0.40
mmol) was added in one portion and the resulting mixture was
stirred overnight. The reaction was partitioned in CH.sub.2Cl.sub.2
and water. The organic layer was separated and washed with brine
(Ix20 mL) and dried (Na.sub.2SO.sub.4). Removal of the solvent in
vacuo, followed by purification on preparative thin layer
chromatography (500 mm silica gel plate, J. T. Baker, Phillipsburg,
NJ, 1% methanol-CH.sub.2Cl.sub.2), gave 45 mg (35% yield) of
((tert-Butoxy)-N-[(4-{2-[(3-hydroxymethylphenyl)amino](,3-thiazol-4-yl-
)}-5-methylthio(2-thienyl))iminomethyl]-carboxamide. l .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 1.44 (s, 9H), 2.66 (s, 3H), 4.49
(d, 2H, J=5.7 Hz), 5.15 (t, 1H, J=5.5 Hz), 6.92 (d, 1H, J=7.5 Hz),
6.96 (s, 1H), 7.26 (m, 1H), 7.66-7.75 (m, 2H), 8.38 (s, 1H), 8.98
(bs, 2H), 10.24 (s, 1H).
[0882] b) (tert-Butoxy)-N-(iminof
4-[2-([3-[(3-methylpiperidyl)methyl]phen- yl]amino)
(1,3-thiazol-4-yl)]-5-methylthio(2-thienyl)}methyl)carboxamide: To
a stirring solution of
((tert-butoxy)-N-[(4-{2-[(3-hydroxymethylphenyl-
)amino](1,3-thiazol-4-yl)}-5-methylthio(2-thienyl))iminomethyl]-carboxamid-
e (45 mg, 0.094 mmol) under N.sub.2 was added triethylamine (2
equiv, 26.3 tl), followed by methansulfonyl chloride (Aldrich
Chemical Co., Milwaukee, WI, 0.13 mmol, 10.2 Il ). The reaction was
stirred for 1 h, at which time the reaction was partitioned in
CH.sub.2Cl.sub.2-water. The organic layer was washed with brine (20
mL), filtered through a 5-cm pad of silica gel in a 15-mL fritted
glass funnel and dried (Na.sub.2SO.sub.4). Removal of the solvent
in vacuo afforded the crude mesylate (44 mg) which was used
immediately without further purification. To 25.3 mg (0.045 mmol)
of the mesylate in 0.5 mL of DMF was added 3-methyl piperidine
(0.18 mmol, 21.4 .mu.L) and the result was heated to 65.degree. C.
in an oil bath for 4 h. The reaction was concentrated in vacuo and
purified by preparative thin layer chromatography (250 mm silica
gel plate, 10% methanol--CH.sub.2Cl.sub.2, J. T. Baker,
Phillipsburg, N.J.) to give 8.2 mg (32% yield) of
(tert-butoxy)-N-(iminof 4-[2-({3-[(3-methylpiperidyl)methyl]phenyl
}amino)
(1,3-thiazol-4-yl)]-5-methylthio(2-thienyl)}methyl)carboxamide.
Mass Spectrum (ESI) m/z calcd. for
C.sub.27H.sub.35N.sub.5O.sub.2S.sub.3, 557.8 (M+H), found 557.9,
458.2 (--C(O)OC(CH.sub.3).sub.3.
[0883] c) 4-[2-([3-[(3-Methylpiperidyl)methyl]phenyl]amino)
(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidine
hydroclhloride: (tert-Butoxy)-N-(iminof
4-[2-({3-[(3-methylpiperidyl)methyl]phenyl}amino)
(1,3-thiazol-4-yl)]-5-methylthio(2-thienyl)}methyl)carboxamide (8.2
mg, 0.014 mmol) was stirred 2 mL of a 10% 3N HCl-ethyl acetate
solution at 0.degree. C. for 30 min., at which time the solvent was
removed in vacuo to give 8 mg (100% yield) of the
4-[2-({3-[(3-methylpiperidyl)methyl]phen- yl}amino)
(1,3-thiazol-4-yl)]-5-methylthiothiophene-2-carboxamidine
hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.83 (d,
3H, J=5.6 Hz), 1.54-2.48 (m, 5H), 2.52-2.63 (m, 4H), 2.66 (s, 3H),
4.23 (d, 2H, J=4.8 Hz), 7.15-7.23 (m, 2H), 7.41 (t, 1H, J=7.8 Hz),
7.86-7.92 (m, 2H), 8.63 (s, 1H), 9.01 (bs, 2H), 9.42 (bs, 2H),
10.63 (s, 1H); (Mass Spectrum (ESI) m/z calcd. for
C.sub.22H.sub.27N5S.sub.3, 457.7 (M+H), found 458.2.
EXAMPLE 191
[0884] a)
Methyl-5-methylthio-4-2-[(3-hydroxyphenyl)amino(1,3-thiazol-4-yl-
)]-thiophene-2-carboxylate hydrobromide: Methyl
4-(2-bromoacetyl)-5-methyl- thiothiophene-2-carboxylate (60 mg,
0.19 mmol) was allowed to react with 3-hydroxyphenylthiourea (32.6
mg) as described in Example 154, step (a) to give 80.2 mg (92%
yield) of methyl-5-methylthio-4-{2-[(3-hydroxyphenyl-
)amino](1,3-thiazol-4-yl)}-thiophene-2-carboxylate hydrobromide.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.67 (s, 3H), 3.83 (s,
3H), 6.38 (d, 1H, J=7.6 Hz), 7.06-7.12 (m, 2H), 7.20-7.29 (m, 2H),
8.14 (s, 1H), 10.17 (s, 1H).
[0885] b)
4-[2-[(3-Hydroxyphenyl)amino](1,3-thiazol-4-yl)]-5-methylthiothi-
ophene-2-carboxamidine hydrochloride:
Methyl-5-methylthio-4-{2-[(3-hydroxy-
phenyl)amino](1,3-thiazol-4-yl)}-thiophene-2-carboxylate
hydrobromide (460 mg, 1.0 mmol) was treated as described in Example
154, step (b) to give 215 mg (54% yield) of
4-{2-[(3-hydroxyphenyl)amino](1,3-thiazol-4-yl)}-5--
methylthiothiophene-2-carboxamidine hydrochloride. (Mass Spectrum
(ESI) m/z calcd. for C.sub.15H.sub.14N.sub.4OS.sub.3, 362.5 (M+H),
found 363.2.
[0886] c)
(tert-Butoxy)-N-[(4-[2-[(4-hydroxyphenyl)amino(1,3-thiazol-4-yl)-
)-5-methylthio(2-thienyl))iminomethyl]carboxamide: To a stirring
solution of
4-{2-[(3-hydroxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-
-2-carboxamidine hydrochloride (215 mg, 0.48 mmol) in 4 mL of
CH.sub.2C.sub.2-DMF (3: 1, v/v) was added di-isopropylethylamine
(1.2 equiv). Di-tert-butyl dicarbonate (1.2 equiv, 127 mg, Aldrich
Chemicals, Milwaukee, Wis.) was then added dropwise in 1 mL
CH.sub.2Cl.sub.2 via an addition funnel. The reaction was allowed
to stir overnight, partitioned in CH.sub.2Cl.sub.2-H.sub.2O, and
the layers separated. The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was
purified by flash chromatography (I % methanol--CH.sub.2Cl.sub.2)
to give 60 mg (27% yield) of
(tert-butoxy)-N-[(4-{2-[(4-hydroxyphenyl)amino](1,3--
thiazol-4-yl)}-5-methylthio(2-thienyl))iminomethyl]carboxamide.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.44 (s, 9H), 2.72 (s,
31H), 6.38 (m, 1H), 6.96 (s, 1H), 7.06-7.12 (m, 2H), 7.28 (m, 1H),
8.35 (s, 1H), 9.00 (bs, 2H), 9.28 (s, 1H), 10.11 (s, 1H); Mass
Spectrum (ESI) m/z calcd. for
C.sub.20H.sub.22N.sub.4O.sub.3S.sub.3, 462.6 (M+H), found 462.7,
363.2 [-C(O)OC(CH.sub.3).sub.3].
[0887] d)
(tert-Butoxy)-N-{[4-(2-[[3-(carbamoylmethoxy)phenyl]amino](1,3-t-
hiazol-4-yl))-5-methylthio(2-thienyl)liminomethyl]carboxamide: To
stirring solution of
(tert-butoxy)-N-[(4-{2-[(4-hydroxyphenyl)amino](1,3-thiazol-4-
-yl)}-5-methylthio(2-thienyl))iminomethyl]carboxamide (65 mg, 0.14
mmol) in 1.5 mL of DMF was added sequentially Cs.sub.2CO.sub.3 (1.5
equiv, 60.1 mg, Aldrich Chemicals, Milwaukee, Wis.), bromoacetamide
(1.2 equiv, 20.4 mg, Aldrich Chemicals, Milwaukee, Wis.), and a
catalytic amount of KI. The reaction was warmed to 58.degree. C. in
an oil bath, stirred for 48 h, at which time another 0.6 equiv of
bromoacetamide was added. Stirring was continued for another 24 h,
at which time the reaction was filtered and concentrated in vacuo.
The residue was purified by preparative thin layer chromatography
(50% ethyl acetate-hexanes) to give 9 mg (12% yield) of
(tert-butoxy)-N-{[4-(2-{[3-(carbamoylmethoxy)phenyl]amino}(1,3-thiazol-
-4-yl))-5-methylthio(2-thienyl)]iminomethyl}carboxamide. Mass
Spectrum (ESI) m/z calcd. for
C.sub.22H.sub.25N.sub.5O.sub.4S.sub.3, 519.7 (M+H), found 519.7,
420.7 [--C(O)OC(CH.sub.3).sub.3].
[0888] e) 4-(2-[[4-(Carbamoylmethoxy)phenyl]amino
](1,3-tltiazol-4-yl))-5-- methylthiothiophene-2carboxamidine
trifluoroacetate: To a stirring suspension
of(tert-butoxy)-N-{[4-(2-{[3-(carbamoylmethoxy)phenyl]amino
}(1,3-thiazol-4-yl))-5-methylthio(2-thienyl)]iminomethyl}carboxamide
(ca. 4 mg, 0.007 mmol) in CH.sub.2Cl.sub.2-DMF (4 mL, 3:1 v/v) at
0.degree. C. was added 1 mL of trifluoroacetic acid. The
homogeneous solution was stirred an additional 40 min. at this
temperature, warmed to ambient temperature over a 30 min. period
and concentrated in vacuo to give 4 mg (100% yield) of
4-(2-{[4-(carbamoylmethoxy)phenyl]amino}(1,3-thiazol-4-yl-
))-5-methylthiothiophene-2-carboxamidine trifluoroacetate. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.75 (s, 3H), 4.21(d, 2H,JJ=5.7
Hz), 6.64 (dd, 1H,J=2.4, 8.2 Hz), 6.97 (dd, 1H,J=1.1, 8.2 Hz), 7.16
(s, 1H), 7.22 (m, 1H), 7.60-7.63 (m, 1H), 7.69-7.72 (m, 1H), 7.88
(t, 1H, J=2.1 Hz), 8.42 (s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.17H.sub.17N50.sub.- 2S.sub.3, 419.6 (M+H), found 420.1.
EXAMPLE 192
[0889] a) Isopropyl
5-methyl-4-[2-[(3,4,5-trimethoxyphenyl)amino](1,3-thia-
zol-4-yl)}thiophene-2-carboxylate hydrobromide:
Isopropyl-4-(2-bromoacetyl- )-5-methylthiophene-2-carboxylate (84
mg, 0.27 mmol) was allowed to react with
3,4,5-trimethoxyphenylthiourea (66.5 mg) as described in Example
154, step (a) to give 68 mg (48% yield) of isopropyl
5-methyl-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-
-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd. For
C.sub.21H.sub.24N.sub.2O.sub.5S.sub.2, 448.56 (M+H), found
449.0.
[0890] b)
5-Methyl-4-(2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4
yl)Jthiophene-2-carboxamidinehydrochloride:
Isopropyl5-methyl-4-{2-[(3,4,-
5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylate
hydrobromide (59 mg, 0.11 mmol) was treated as described in Example
154, step (b) to give 24.4 mg (50% yield) of
5-methyl-4-{2-[(3,4,5-trimethoxyp-
henyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine
hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.81 (s,
3H), 3.61 (s, 3H), 3.77 (s, 6H), 7.04 (s, 2H), 7.09 (s, 1H), 8.40
(s, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.18H.sub.20N.sub.4O.sub.3S.sub.2, 404.5 (M+H), found
405.2.
EXAMPLE 193
[0891] a) Isopropyl
5-methyl-4-[2-[(4-phenoxyphenyl)amino](1,3-thiazol-4-y-
l)]thiophene-2-carboxylate hydrobromide:
Isopropyl-4-(2-bromoacetyl)-5-met- hylthiophene-2-carboxylate (91
mg, 0.29 mmol) was allowed to react with 4-phenoxyphenylthiourea
(72.6 mg) as described in Example 154, step (a) to give 115 mg (75%
yield) of isopropyl 5-methyl-4-{2-[(4-phenoxyphenyl)a-
mino](1,3-thiazol-4-yl)}thiophene-2-carboxylate hydrobromide.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.28 (d, 6H, J=6.2 Hz),
2.70 (s, 3H), 6.06 (quintet, 1 H, J=6.2 Hz), 6.92-7.09 (m, 5H),
7.15 (s, 1H), 7.30-7.37 (m, 2H), 7.56-7.70 (m, 2H), 7.98 (s, 1H);
Mass Spectrum (ESI) m/z calcd. for
C.sub.24H.sub.22N.sub.2O.sub.3S.sub.2, 450.6 (M+H), found 451.2,
409.2 [--CH(CH.sub.3).sub.2].
[0892] b)
5-Methyl-4-[2-f(4-phenoxyphenyl)amino](1,3-thiazol-4-yl)jthiophe-
ne-2-carboxamidine hydrochloride: Isopropyl
5-methyl-4-{2-[(4-phenoxypheny-
l)amino](1,3-thiazol-4-yl)}thiophene-2-carboxylate hydrobromide
(95.5 mg, 0.17 mmol) was treated as described in Example 154, step
(b) to give 23.8 mg (32% yield) of
5-methyl-4-{2-[(4-phenoxyphenyl)amino](1,3-thiazol-4-yl-
)}thiophene-2-carboxamidine hydrochloride. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 2.76 (s, 3H), 6.95-7.12 (m, 6H),
7.34-7.39 (m, 2H), 7.72-7.78 (m, 2H), 8.33 (s, 1H), 8.98 (bs, 3H),
10.29 (bs, 1H); Mass Spectrum (ESI) m/z calcd. for
C.sub.21H.sub.18N.sub.4O.sub.2S.sub.3, 406.5 (M+H), found
407.2.
EXAMPLE 194
[0893] a) Isopropyl 5-methyl-4-[2-(phenylamino)
(1,3-thiazol-4-yl)]-thioph- ene-2-carboxylate h ydrobromide:
Isopropyl 4-(2-bromoacetyl)-5-methylthiop- hene-2-carboxylate (64
mg, 0.21 mmol) was allowed to react with phenylthiourea (32.1 mg)
as described in Example 154, step (a) to give 80 mg (87% yield) of
isopropyl 5-methyl-4-[2-(phenylamino)
(1,3-thiazol-4-yl)]-thiophene-2-carboxylate hydrobromide. Mass
Spectrum (ESI) m/z calcd. for
C.sub.18H.sub.18N.sub.2O.sub.2S.sub.2, 358.5 (M+H), found
359.2.
[0894] b) 5-Methyl-4-[2-(phenylamino)
(1,3-thiazol-4-yl)]thiophene-2-carbo- xamidine hydrochloride:
Isopropyl 5-methyl-4-[2-(phenylamino)
(1,3-thiazol-4-yl)]-thiophene-2-carboxylate hydrobromide (74 mg,
0.16 mmol) was treated with phenylthiourea (24.3 mg) as described
in Example 154, step (b) to give 15 mg (28% yield) (of
5-methyl-4-[2-(phenylamino)
(1,3-thiazol-4-yl)]thiophene-2-carboxamidine hydrochloride, which
was fuirther purified by recrystallization from methanol-water.
.sup.1.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.79 (s, 3H),
6.96 (t, 1H, J=7.2 Hz), 7.09 (s, 1H), 7.33 (t, 2H, J=7.5 Hz), 7.71
(d, 2H, J=7.7 Hz), 8.39 (s, 1H), 8.95 (bs, 2H), 9.33 (bs, 2H),
10.37 (s, I H); Mass Spectrum (ESI) m/z calcd. for
C.sub.15H.sub.14N.sub.4S.sub.3, 314.4 (M+H), found 315.2.
EXAMPLE 195
[0895] a) Methyl
4-(4-isoxazol-5-yl(1,3-thiazol-2-yl))-5-methyltltiothioph-
ene-2-carboxylate: Methyl
4-(aminothioxomethyl)-5-methylthiothiophene-2-ca- rboxylate (872
mg, 2.51 mmol) was allowed to react with
2-bromo-1-isoxazol-5-ylethan-1-one (737 mg, prepared from from
isoxazole-5-carbonyl chloride [Maybridge Chemicals, Cornwall, UK]as
described in Example 177, step (a) as described in Example 154,
step (a) to give 704 mg (83% yield) of methyl
4-(4-isoxazol-5-yl(1,3-thiazol-2-yl)-
)-5-methylthiothiophene-2-carboxylate. .sup.1H NMR (DMSO-d.sub.6,
300 MHz) .delta. 2.75 (s, 3H), 3.85 (s, 3H), 6.93 (d, 1H, J=1.8
Hz), 8.22 (s, 1H), 8.38 (s, 1H), 8.70 (d, 1H, J=1.8 Hz).
[0896] b)
4-(4-Isoxazol-5-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-ca-
rboxamidine hydrochloride: Methyl
4-(4-isoxazol-5-yl(1,3-thiazol-2-yl))-5--
methylthiothiophene-2-carboxylate (350 mg, 1.03 mmol) was treated
as described in Example 154, step (b) to give 290 mg (78% yield) of
4-(4-isoxazol-5-yl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidi-
ne hydrochloride, of which an aliquot was further purified by
recrystallization from methanol-isopropanol-water (3:1:0.2, v/v/v).
.sup.1.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.79 (s, 3H),
6.93 (d, 1H, J=1.9 Hz), 8.45 (s, 1H), 8.74 (m, 2H), 9.23 (bs, 2H),
9.53 (bs, 2H); Mass Spectrum (MALDI-TOF, CHCA matrix) m/z calcd.
for C.sub.12H.sub.10N.sub.4OS.sub.3, 322.4 (M+H), found 323.3.
EXAMPLE 196
[0897] a) Methyl 4-[4-(2-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthioth- iophene-2-carboxylate: Methyl
4-(aminothioxomethyl)-5-methylthiothiophene-- 2-carboxylate (808
mg, 3.26 mmol) was allowed to react with
2-(2-bromoacetyl)hydroxybenzene (925 mg, prepared from
2-(chlorocarbonyl)phenyl acetate [Aldrich Chemicals, Milwaukee,
Wis.]as described in Example 177, step (a)) as described in Example
154, step (a) to give 433 mg (37% yield) of methyl
4-[4-(2-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate. .sup.1H
NMR(DMSO-d.sub.6, 300 MHz) .delta. 2.77 (s, 3H), 3.86 (s, 3H),
6.91-7.00 (m, 2H), 7.23 (m, 1H), 8.14-8.19 (m, 2H), 8.24 (s, 1H);
Mass Spectrun (ESI) m/z calcd. for C.sub.16H.sub.13NO.sub.3S.sub.3,
363.48 (M+H), found 364.2.
[0898] b) 4-[4-(2-Hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methyltltiothiophen- e-2-carboxamidine
hydrochloride: Methyl 4-[4-(2-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate (400 mg,
1.1 mmol) was treated as described in Example 154, step (b) to give
173 mg (41% yield) of 4-[4-(2-hydroxyphenyl)
(1,3-thiazol-2-yl)]-5-methylthiothi- ophene-2-carboxamidine
hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.81 (s,
3H), 6.92-7.02 (m, 2H), 7.22 (m, 1H), 8.20 (dd, 1H, J=1.7, 7.8 Hz),
8.27 (s, 1H), 8.65 (s, 1H), 9.00 (bs, 2H), 9.41 (bs, 2H), 10.58 (s,
1H); Mass Spectrum (ESI) m/z calcd. for C.sub.15H.sub.13N.sub.3-
OS.sub.3, 347.48 (M+H), found 348.2.
EXAMPLE 197
[0899] 5-Methylthio-4-(6-quinolylamino)thiophene-2-carboxamidine
hydrochloride
[0900] a) Methyl
5-methylthio-4-(6-quinolylamino)thiophene-2-carboxylate: To an
oven-dried glass vial with stir bar was added a mixture of 65.2 mg
(0.244 mmol) of methyl 4-bromo-5-methylthiothioplene-2-carboxylate
(as prepared in Example 241, step (a)), 5.2 mg (9.5 mol %) of
palladium (II) acetate, 22.2 mg (14.6 mol %) of
racemic-2,2-bis(diphenylphosphino)-1,1-b- inaphthyl (BINAP), 125 mg
(0.384 mmol) of cesium carbonate and 50.3 mg (0.349 mmol) of
6-aminoquinoline. The vial was transferred to a glove bag, flushed
with dry argon and anhydrous toluene (488 tiL) was added. The vial
was capped with a Teflon-lined screw cap and heated at 100IC for 48
h. To the cooled suspension was added ethyl acetate (4 mL), the
mixture filtered (Celite), washing with ethyl acetate (2.times.2
mL), and the solvents removed in vacuo. The resulting residue was
purified by chromatography on a 10-g silica SPE column with a
gradient of 5-12% ethyl acetate--CH.sub.2Cl.sub.2 to afford 53.3 mg
(66%) of the title compound as a pale yellow resin. .sup.1H-NMR
(CDCl.sub.3, 400 MHz) .delta. 8.77 (dd, 1H, J 4.2, 1.6 Hz), 8.04
(d, 1H, J=9.4 Hz), 8.02 (d, 1H, J=8.4 Hz), 7.90 (s, 1H), 7.41 (dd,
1H, J=9.0, 2.6 Hz), 7.36 (dd, 1H, J=8.3, 4.2 Hz), 7.27 (d, 1H,
J=2.6 Hz), 3.92 (s, 3H) and 2.45 (s, 3H). Mass spectrum (ESI, m/z):
Calcd. For C.sub.16H.sub.15N.sub.2O.sub.2S.sub.2, 331.1 (M+H),
found 331.2.
[0901] b) 5-Methylthio-4-(6-quinolylamino)thiophene-2-carboxamidine
hydrochloride: Trimethylaluminum (2.0 M in toluene, 0.76 rnL, 1.52
mmol) was added dropwise to a suspension of ammonium chloride (85.6
mg, 1.60 mmol) in anhydrous toluene (0.76 mL) under Ar at 0.degree.
C. The mixture was stirred at 25.degree. C. for 30 min and then
50.2 mg (0.152 mmol) of methyl
5-methylthio-4-(6-quinolylamino)thiophene-2-carboxylate (as
prepared in previous step) was added. The reaction mixture was
heated slowly to 100.degree. C. and stirred for 4 h. The cooled
mixture was added to a vigorously stirred slurry of silica gel (3
g) in chloroform (15 mL). The suspension was filtered (Celite)
washing with 25% MeOH--CH.sub.2Cl.sub.2 (2.times.5 mL), 50%
MeOH--CH.sub.2Cl.sub.2 (2.times.5 mL) and 75%
MeOH--CH.sub.2Cl.sub.2 (2.times.5 mL). The combined washings were
concentrated and the resulting residue was purified on a 5-g silica
SPE column with a gradient of 10-15% MeOH--CH.sub.2Cl.sub.2 to
afford 42.2 mg (79%) of the title compound as a yellow solid.
.sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 9.39 (br s, 2H), 9.12
(br s, 2H), 8.63 (dd, 1H, J=4.2, 1.6 Hz), 8.44 (s, 1H), 8.16 (m,
2H), 7.89 (d, 1H, J=8.5 Hz), 7.54 (dd, 1H, J=9.1, 2.6 Hz), 7.39
(dd, 1H, J=8.3, 4.2 Hz), 7.20 (d, 1H, J=2.5 Hz) and 2.55 (s, 3H).
Mass spectrum (ESI, m/z): Calcd. For
C.sub.15H.sub.14N.sub.4S.sub.2, 315.1 (M+H), found 315.2.
EXAMPLE 198
[0902]
5-Methylthio-4-[(3-phenylphenyl)amino]thiphene-2-carboxamidine
hydrochloride
[0903] a) Methyl
5-methylthio-4-[(3-phenylphenyl)amino}thiophene-2-carboxy- late:
The same procedure as in Example 197, step (a), was followed using
62.2 mg (0.233 mmol) of methyl
4-bromo-5-methylthiothiophene-2-carboxylat- e (as prepared in
Example 241, step (a)), 4.7 mg (9.0 mol %) of palladium (II)
acetate, 20.0 mg (13.8 mol %) of racemic-BINAP, 140 mg (0.430 mmol)
of cesium carbonate, 48.2 mg (0.285 mmol) of 3-aminobiphenyl and
466 .mu.L of toluene, and chromotographed as before using 20-40%
CH.sub.2Cl.sub.2-hexane to afford 52.3 mg (63%) of the title
compound as a yellow resin. .sup.1H-NMR (CDCl.sub.3, 400 MHz)
.delta. 7.81 (s, 1H), 7.61 (m, 2H), 7.46 (m, 2H), 7.38 (m, 2H),
7.21 (m, 2H), 7.03 (m, 1H), 6.22 (s, 1H), 3.90 (s, 31H), 2.43 (s,
3H). Mass spectrum (ESI, m/z): Calcd. For
C.sub.19H.sub.17NO.sub.2S.sub.2, 356.1 (M+H), found 356.2.
[0904] b)
5-Methylthio-4-[(3-phenylphenyl)amilzojthiophelle-2-carboxamidin- e
hydrochloride: The same procedure as in Example 197, step (b) was
followed using 46.4 mg (0.131 mmol) of methyl
5-methylthio-4-[(3-phenylph- enyl)amino}thiophene-2-carboxylate (as
prepared in previous step), 0.76 mL of trimethylaluminum (2.0 M in
toluene, 1.57 mmol), 87.7 mg of ammonium chloride (1.64 mmol) and
0.79 mL of toluene, and purified on a 5-g silica SPE column with
5-10% MeOH--CH.sub.2Cl.sub.2 to afford 46.8 mg (95%) of the title
compound as a yellow foam. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz)
.delta. 9.04 (br s, 4H), 8.10 (s, 1H), 8.06 (s, 1H), 7.62 (m, 2H),
7.46 (m, 2H), 7.35 (m, 2H), 7.19 (t, 1H, J=1.9Hz), 7.12 (d, 1H,
J=8.2Hz), 6.95 (dd, I1H, J=7.8, 1.9 Hz), 2.53 (s, 3H). Mass
spectrum (ESI, m/z): Calcd. For C.sub.18H.sub.17N.sub.3S.sub.2,
340.1 (M+H), found 340.2.
EXAMPLE 199
[0905] 5-Methylthio-4-(3-quinolylamino)thiophene-2-carboxamidine
hydrochloride
[0906] a) Methyl
5-methylthio-4-(3-quinolylamino)thiophene-2-carboxylate: The same
procedure as in Example 197, step (a) was followed using 104 mg
(0.389 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate
(as prepared in Example 241, step (a)), 7.1 mg (8.1 mol %) of
palladium (II) acetate, 29.3 mg (12.1 mol%) of racemic-BINAP, 192
mg (0.589 mmol) of cesium carbonate, 70.5 mg (0.489 mmol) of
3-aminoquinoline and 778 lL of toluene, and chromatographed as
before using 3-8% ethyl acetate--CH.sub.2Cl.sub.2 to afford 34.4 mg
(27%) of the title compound as a yellow resin. .sup.1H-NMR
(CDCl.sub.3, 400 MHz) .delta. 8.73 (d, 1H, J=2.5 Hz), 8.04 (d, 1H,
J=8.2 Hz), 7.85 (d, 1H, J=4.0 Hz), 7.71 (d, 1H, J=7.9 Hz), 7.62 (m,
1H), 7.56 (m, 2H), 6.34 (s, 1H), 3.93 (s, 3H) and 2.46 (s, 3H).
Mass spectrum (ESI, m/z): Calcd. For
C.sub.16H.sub.14N.sub.2O.sub.2S.sub.2, 331.1 (M+H), found
331.3.
[0907] b) 5-Methylthio-4-(3-quinolylamino)thiophene-2-carboxamidine
hydrochloride: The same procedures as in Example 197, step (b) was
followed using 32.3 mg (0.0977 mmol) of methyl
5-methylthio-4-(3-quinolyl- amino)thiophene-2-carboxylate (as
prepared in previous step), 0.586 mL of trimethylaluminum (2.0 M in
toluene, 1.17 mmol) and 65.8 mg of ammonium chloride (1.26 mmol)
and 0.59 mL of toluene and purified on a 5-g silica SPE column with
5-12% MeOH--CH.sub.2Cl.sub.2 to afford, after concentration once
from MeOH--MeCN (1:1), 17.3 mg (51%) of the title compound as a
light tan crystalline solid. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz)
.delta. 9.09 (br s, 4H), 8.79 (s, 1H), 8.56 (s, 1H), 8.12 (s, 1H),
7.89 (m, 1H), 7.79 (m, 1H), 7.56 (s, 1H), 7.50 (m, 2H) and 2.55 (s,
3H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.15H.sub.14N.sub.4S.sub.2, 315.1 (M+H), found 315.4.
EXAMPLE 200
[0908]
5-Methylthio-4-(pyrimidin-2-ylamino)thiophene-2-carboxamidine
hydrochloride
[0909] a) Methyl
5-methylthio-4-(pyrimidin-2-ylamino)thiophene-2-carboxyla- te: The
same procedure as in Example 197, step (a) was followed using 50.9
mg (0.191 mmol) of methyl
4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example
241, step (a)), 2.7 mg (6.3 mol %) of palladium (II) acetate, 11.3
mg (9.5 mol %) of racemic-BINAP, 101 mg (0.310 mmol) of cesium
carbonate, 25.9 mg (0.270 mmol) of 2-aminopyrimidine and 381 lL of
dioxane, and chromatographed as before using 5-10% ethyl
acetate-hexane to afford 16.7 mg (31%) of the title compound as a
yellow crystalline solid: .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta.
8.72 (s, 1H), 8.49 (d, 1H, J=4.8 Hz), 6.80 (t, 1H, J=4.8 Hz), 3.92
(s, 3H), 2.42 (s, 3H) and 1.28 (br s, 2H). Mass spectrum (ESI,
m/z): Calcd. for C.sub.11H.sub.11N.sub.3O.sub.2S.sub.2, 282.0
(M+H), found 282.3.
[0910] b)
5-Methylthio-4-(pyrimidin-2-ylamino)thiophene-2-carboxamidine
hydrochloride: The same procedure as in Example 197, step (b) was
followed using 15.2 mg (0.0540 mmol) of methyl
5-methylthio-4-(pyrimidin-- 2-ylamino)thiophene-2-carboxylate (as
prepared in previous step), 0.324 mL or trimethylaluminum (2.0 M in
toluene, 0.648 mmol) and 36.4 mg of ammonium chloride (0.680 mmol)
and 0.32 mL of toluene, and purified on a 2-g silica SPE column
with 5-15% MeOH--CH.sub.2Cl.sub.2 to afford, after concentration
once from MeOH--MeCN (1: 10), 11.4 mg (70%) of the title compound
as a light yellow crystalline solid. .sup.1H-NMR (DMSO-d.sub.6, 300
MHz) .delta. 9.24 (br s, 2H), 8.85 (br s, 2H), 8.45 (d, 1H, J=4.8
Hz), 8.25 (s, 1H), 6.87 (t, 1H, J=4.8 Hz) and 2.53 (s, 3H). Mass
spectrum (ESI, m/z): Calcd. for C.sub.10H.sub.11N.sub.5S.sub.2,
266.1 (M+H), found 266.2.
EXAMPLE 201
[0911]
4-[(4-Cyclohexylphenyl)amino-5-methylthiothiophene-2-carboxamidine
hydrochloride
[0912] a) Methyl
4-[(4-cyclohexylphenyl)amino]-5-methylthiothiophene-2-car-
boxylate: The same procedure as in Example 197, step (a) was
followed using 122 mg (0.457 mmol) of methyl
4-bromo-5-methylthiothiophene-2-30 carboxylate (as prepared in
Example 241, step (a)), 9.9 mg (9.7 mol %) of palladium (II)
acetate, 42.3 mg (14.9 mol %) of racemic-BINAP, 206 mg (0.632 mmol)
of cesium carbonate, 102 mg (0.582 mmol) of 4-cyclohexylaniline and
913 {tL of toluene, and chromatographed as before using 20-40%
CH.sub.2Cl.sub.2-hexane to afford 73.8 mg (45%) of the title
compound as a light green resin:.sup.1H-NMR (CDCl.sub.3, 400 MHz)
.delta. 7.74 (s, 1H), 7.15 (d, 2H, J=8.4 Hz), 6.98 (d, 2H, J=8.4
Hz), 6.12 (s, 1H), 3.88 (s, 3H), 2.48 (m, 1H), 2.39 (s, 3H), 1.87
(m, 4H), 1.76 (br d, 1H, J=12.5 Hz), 1.41 (m, 4H) and 1.28 (m, 1H).
Mass spectrum (ESI, m/z): Calcd. for
C.sub.19H.sub.23NO.sub.2S.sub.2, 362.1 (M+H), found 362.4.
[0913] b)
4-[(4-Cyclohexylphenyl)amino]-5-methylthiothiophene-2-carboxamid-
ine hydrochloride: The same procedure as in Example 197, step (b)
was followed using 70.2 mg (0.194 mmol) of methyl
4-[(4-cyclohexylphenyl)amin- o]-5-methylthiothiophene-2-carboxylate
(as prepared in previous step), 0.970 mL or trimethylaluminum (2.0
M in toluene, 1.94 mmol), 109 mg of ammonium chloride (2.04 mmol)
and 0.97 mL of toluene, and purified on a 10-g silica SPE column
with 4-8% MeOH--CH.sub.2Cl.sub.2 to afford 57.7 mg (78%) of the
title compound as a yellow foam. .sup.1H-NMR (DMSO-d.sub.6, 400
MHz) .delta. 8.45 (br s, 4H), 7.97 (s, 1H), 7.86 (s, 1H), 7.08 (d,
2H, J=8.5 Hz), 6.92 (d, 2H, J=8.5 Hz), 2.48 (s, 3H), 1.65-1.85 (m,
5H) and 1.35 (m, 5H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.18H.sub.23N.sub.3S.sub.2, 346.1 (M+H), found 346.4.
EXAMPLE 202
[0914] Methyl 4-amino-5-methylthiothiophene-2-carboxylate
[0915] To a pressure tube (Ace Glass, Vineland, N.J.) containing
1.0 g (4.30 mmol) of
5-(methoxycarbonyl)-2-methylthiothiophene-3-carboxylic acid (as
prepared in Example 95), 1.01 mL (1.1 equiv, 4.73 mmol) of
diphenylphosphoryl azide, and 1.57 mnL (2.1 equiv, 9.03 mmol) of
N,N-diisopropylethylamine was charged 7 mL of t-butanol. The
resultant mixture was sealed and heated to 80.degree. C. in an oil
bath for 6 h. The dark reaction mixture was cooled to ambient
temperature and concentrated in vacuo. The crude oil was dissolved
in 3 mL of CH.sub.2Cl.sub.2 and then treated with 2 mL of 1: I
CH.sub.2Cl.sub.2-trifluoroacetic acid followed by 0.5 mL H20. After
6 h, the mixture was concentrated in vacuo, dissolved in 50 mL of
CH.sub.2Cl.sub.2, washed with satd. NaHCO.sub.3, dried
(Na.sub.2SO4), and eluted through a pad of silica gel with 50%
ethyl acetate-hexanes. The solvent was concentrated in vacuo and
the crude amine was purified by preparative thin layer
chromatography (20% ethyl acetate-hexanes, 2000 pm SiO.sub.2 gel)
to yield 210 mg (24%) of metlhyl 4-amino-5-methylthiothiop-
hene-2-carboxylate as a honey-colored oil. I.sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 2.28 (s, 3H), 3.77 (s, 3H), 5.36
(bs, 2H), 7.24 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.7H.sub.9NO.sub.2S.sub.2, 204.02 (M+H), found 204.0.
EXAMPLE 203
[0916] Methyl
4-[(aminothioxometlhyl)amino]-5-methylthiothiophene-2-carbox-
ylate
[0917] To a stirring 5 mL biphasic CH.sub.2Cl.sub.2-NaHCO.sub.3 (1:
1, v/v) mixture of 98 mg (0.48 mmol) of methyl
4-amino-5-methylthiothiophene- -2-carboxylate was added 43 tiL (1.2
equiv, 0.57 mmol) of thiophosgene (Aldrich Chemical, Milwaukee,
Wis.). The reaction was stirred vigorously overnight, diluted with
CH.sub.2Cl.sub.2 (50 mL), and the layers separated. The organic
layer was washed with NaHCO.sub.3 (lxl 5mL), brine (lxl5mL), and
dried (Na.sub.2SO.sub.4). Concentration of the solvent in vacuo
yielded the crude isothiocyanate, which was dissolved in 5 mL of 2M
NH.sub.3 in MeOH and stirred overnight. The reaction was
concentrated to 12 volume and filtered. The filtered solids were
washed with acetone and dried, yielding 79.8 mg (63.4%) of methyl
4-[(aminothioxomethyl)amino]-5-- methylthiothiophene-2-carboxlyate
as a light tan solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
2.51 (s, 3H), 3.81 (s, 3H), 7.41 (bs, 2H), 8.03 (s, 1H) and 9.27
(bs, 1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.8H.sub.10N.sub.2O.sub.2S.sub.3, 263.00 (M+H), found
263.2.
EXAMPLE 204
[0918]
5-Methylthio-4-[(4-phenyl(1,3-thiazol-2-yl))amino}thiophene-2-carbo-
xamidine
[0919] a) Methyl
5-methylthio-4-[(4-phenyl(1,3-thiazol-2-yl)amino}thiophen-
e-2-carboxylate: To a 25-mL round bottom flask containing 40 mg
(0.15 mmol) of methyl
4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carb- oxylate
and 30.3 mg (1 equiv, 0.15 mmol) of bromoacetophenone was added 2
mL of acetone, and the resultant mixture was heated to reflux for
18 h. The reaction was cooled to room temperature and filtered to
give 50 mg (92%) of methyl
5-methylthio-4-[(4-phenyl(1,3-thiazol-2-yl))amino]thiophe-
ne-2-carboxylate, which was used without fiirther purification.
.sup.1.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.49 (s, 3H),
3.84 (s, 3H), 7.09 (s, 1H), 7.26-7.48 (m, 3H), 7.85 (m, 2H), 8.63
(s, 1H), 10.06 (bs, 1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.16H.sub.14N.sub.2O.s- ub.2S.sub.3, 363.03 (M+H), found
363.4.
[0920] b)
5-Methylthio-4-[(4-phenyl(1,3-thiazol-2-yl)amino]thiophene-2-car-
boxamidine: Using a procedure similar to that of Example 154, step
(b), 47 mg (0.13 mmol) of methyl
5-methylthio-4-[(4-phenyl(1,3-thiazol-2-yl))amin-
o]thiophene-2-carboxylate was allowed to react with 0.5 mL (8
equiv, 1.04 mmol) of the AlMe.sub.3/NH.sub.4Cl reagent and purified
by preparative thin layer chromatography (20%
MeOH--CHCl.sub.3-satd. NH.sub.3, 500 Jm SiO.sub.2 gel plate) to
give 19 mg (42%) of 5-methylthio-4-[(4-phenyl(1,3-
-thiazol-2-yl))amino]thiophene-2-carboxamidine as a yellow solid.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.43 (s, 3H), 7.27-7.42
(m, 4H), 7.90 (d, 2H, J=7.1 Hz), 8.41 (s, 1H). Mass spectrum (ESI,
m/z): Calcd. for C.sub.15H.sub.14N.sub.4S.sub.3, 347.05 (M+H),
found 347.1.
EXAMPLE 205
[0921] 5-Methylthio-4-[[4-(4-phenylphenyl)
(1,3-thiazol-2-yl)]aminot]thiop- hene-2-carboxamidine
[0922] a) Methyl 5-methylthio-4-[[4-(4-phenylphenyl)
(1,3-thiazol-2-yl)]amino]thiophene-2-carboxylate: Using a procedure
similar to Example 204, step (a) 53 mg (0.2 mmol) of methyl
4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylate
was allowed to react with 55.6 mg (0.2 mmol) of
4-phenyl-bromoacetophenone for 3 h to afford 57 mg (65%) of methyl
5-methylthio-4-{[4-(4-phenylpheny- l)
(1,3-thiazol-2-yl)]amino}thiophene-2-carboxylate. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 2.51 (s, 3H), 3.86 (s, 3H), 6.93
(s, 1H rotomer), 7.10 (s, 1H rotomer), 7.27 (s, 1H rotomer),
7.37-7.50 (m, 3H rotomer), 7.72-7.76 (m, 4H rotomer), 8.4 (d, 2H,
8.4 Hz), 8.66 (s, 1H rotomer), 10.10 (bs, 1H). Mass spectrum (ESI,
m/z): Calcd. for C.sub.22H.sub.18N.sub.2O.sub.2S.sub.3, 439.06
(M+H), found 439.2.
[0923] b)
5-Methylthio-4-{4-(4-phenylphenyl(1,3-thiazol-2-yl)}amino]thioph-
ene-2-carboxamidine: Using a procedure similar to that of Example
154, step (b), 57 mg (0.12 mmol) of methyl
5-methylthio-4-{[4-(4-phenylphenyl)
(1,3-thiazol-2-yl)]amino}thiophene-2-carboxylate was allowed to
react with 6.7 equiv (0.87 mmol) of the AlMe.sub.3/NH.sub.4Cl
reagent and purified by preparative thin layer chromatography (20%
MeOH--CHCl.sub.3-satd. NH.sub.3, 500 .mu.m SiO.sub.2 plate) to give
20.7 mg (40.7%) of 5-methylthio-4-{[4-(4-phenylphenyl)
(1,3-thiazol-2-yl)]amin- o }thiophene-2-carboxamidine. .sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. 2.51 (s, 3H), 6.93 (s, 1H), 7.10
(s, 1H), 7.27 (s, 1H), 7.35-7.50 (m, 4H), 7.72-7.76 (m, 4H),
7.94-7.96 (m, 2H), 8.66 (s, 11H), 10.11 (bs, 1H). Mass spectrum
(ESI, m/z): Calcd. for C.sub.21H.sub.18N.sub.4S.sub.3, 423.08
(M+H), found 423.2.
EXAMPLE 206
[0924]
4-[(5-Methyl-4-phenyl(1,3-thiazol-2-yl))amino]-5-methylthiothiophen-
e-2-carboxamidine
[0925] a)
Methyl-4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl)amino]-5-methiylth-
iothiophene-2-carboxylate: Using a procedure similar to Example
204, step (a), 51 mg (0.19 mmol) of methyl
4-[(aminothioxomethyl)amino]-5-methylthi- othiophene-2-carboxylate
was allowed to react with 41.4 mg (0.38 mmol) of
2-bromopropiophenone (Aldrich Chemical Co., Milwaukee, Wis.) in 2
mL of DMF for 4 h. Concentration in vacuo of the reaction mixture
afforded 73 mg (100%) of
methyl-4-[(5-methyl-4-phenyl(1,3-thiazpl-2-yl))amino]-5-meth-
ylthiothiophene-2-carboxylate. Mass spectrum (ESI, m/z): Calcd. for
C.sub.17H.sub.16N.sub.2O.sub.2S.sub.3, 377.05 (M+H), found
377.2.
[0926] b)
4-[(5-Methyl-4-phenyl(1,3-thiazol-2-yl))amino]-5-methylthiothiop-
hene-2-carboxamidine: Using a procedure similar to Example 154,
step (b), 73 mg (0.19 mmol) of
methyl-4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl))amino-
]-5-methylthiothiophene-2-carboxylate was allowed to react with 8
equiv (1.5 mmol) of the AlMe.sub.3/NH.sub.4Cl reagent and purified
by preparative thin layer chromatography
(20%-MeOH--CHCl.sub.3-satd. NH.sub.3, 500 pm SiO2 plate) to afford
17.9 mg (26%) of
4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl))amino]-5-methylthiothiophene-2-ca-
rboxamidine. H NMR (DMSO-d.sub.6, 300 MHz): .delta. 2.40 (s, 3H),
2.51 (s, 3H rotomer), 2.73 (s, 3H rotomer), 7.29-7.44 (m, 2H
rotomer), 7.64-7.73 (m, 3H rotomer), 7.95 (s, 1H rotomer), 8.06 (s,
1H rotomer). Mass spectrum (ESI, m/z): Calcd. for
C.sub.16H.sub.16N.sub.4S.sub.3, 361.06 (M+H), found 361.2.
EXAMPLE 207
[0927] 4-{[4-Hydroxy-4-(trifluoromethyl)
(1,3-thiazolin-2-yl)]amino}-5-met-
hylthiothiophene-2-carboxamidine
[0928] a) Methyl 4-{[4-hydroxy-4-(trifluoromethyl)
(1,3-tlliazolin-2-yl)]a- mino}-5-methylthiothiophene-2-carboxylate:
Using a procedure similar to Example 204, step (a), 56 mg (0.21
mmol) of methyl
4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylate
was allowed to react with 40 mg (0.21 mmol) of
bromotrifluoroacetone (Aldrich Chemical Co., Milwaukee, Wis.) to
afford 40.3 mg (54%) of methyl 4-{[4-hydroxy-4-(trifluoromethyl)
(1,3-thiazolin-2-yl)]amino}-5-methylthi- othiophene-2-carboxylate.
Mass spectrum (ESI, m/z): Calcd. for
C.sub.11H.sub.11F.sub.3N.sub.2O.sub.3S.sub.3, 373.00 (M+H), found
373.0.
[0929] b) 4-[[4-Hydroxy-4-(trifluoromethyl)
(1,3-thiazolin-2-yl)]amino]-5--
methylthiothiophene-2-carboxamidine: Using a procedure similar to
Example 154, step (b), 40 mg (0.11 mmol) of methyl
4-{[4-hydroxy-4-(trifluorometh- yl)
(1,3-thiazolin-2-yl)]amino}-5-methylthiothiophene-2-carboxylate was
allowed to react with 8 equiv (0.89 mmol) of the AlMe.sub.3/NH4Cl
reagent and purified by preparative thin layer chromatography
(20%-MeOH--CHCl.sub.3-satd. NH.sub.3, 500 [m SiO2 plate) to afford
11 mg (28%) of 4-{[4-hydroxy-4-(trifluoromethyl)
(1,3-thiazolin-2-yl)]amino}-5-- methylthiothiophene-2-carboxamidine
as a ca. 1:1 mixture of cyclized aminal and open imine tautomers.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.73 (s, 3H tautomer),
2.89 (s, 3H tautomer), 3.36 (d, 2H, J=6.5 Hz), 3.62 (d, 2H, J=7.2
Hz), 7.95 (s, 1H), 8.36 (bs, 2H), 9.79 (bs, 1H). Mass spectrum
(ESI, m/z): Calcd. for C.sub.10H.sub.11F.sub.3N.sub.4OS.sub- .3,
357.01 (M+H), found 357.2.
EXAMPLE 208
[0930]
5-Methylthio-4-(2-naphthylamino)thiophene-2-carboxamidine
[0931] a) Methzyl
5-methylthio-4-(2-naphthylamino)thiopheize-2-carboxylate- : To an
oven-dried round bottom flask equipped with Teflon-coated stir bar
and rubber septum was added 190 mg (0.93 mmol) of methyl
4-amino-5-methylthiothiophene-2-carboxylate, 320 mg (2 equiv, 1.86
mmol) of 2-napthalene boronic acid (Lancaster Synthesis, Windham,
NH), and 168 mg (1 equiv, 0.93 mmol) of Cu(OAc).sub.2 (Aldrich
Chemical Co., Milwaukee, Wis.). The flask was flushed with Ar, then
charged with 4 mL CH.sub.2Cl.sub.2 followed by 259 .mu.L (2 equiv,
1.86 mmol) of NEt.sub.3. The mixture was stirred vigorously for 48
h and then filtered through a small pad of SiO.sub.2, eluting with
50% ethyl acetate-hexanes. Concentration of the solvent in vacuo,
and purification of the residue by preparative thin layer
chromatography (25% ethyl acetate-hexanes, 1000 [M SiO.sub.2 plate)
afforded 170 mg (55%) of methyl 5-methylthio-4-(2-naphth-
ylamino)thiophene-2-carboxylate and 54 mg (28%) of recovered methyl
4-amino-5-methylthiothiophene-2-carboxylate. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 2.43 (s, 3H), 3.92 (s, 3H), 6.29 (s,
1H), 7.21 (dd, 1H, J=2.35, 8.7 Hz), 7.33-7.37 (m, 2H), 7.45 (m,
1H), 7.71 (d, 1H, J=8.2 Hz), 7.78 (m, 2H), 7.88 (s, 1H). Mass
spectrum (ESI, m/z): Calcd. for C.sub.17H.sub.15NO.sub.2S.sub.2,
330.06 (M+H), found 330.1.
[0932] b) 5-Methylthio-4-(2-naphthylamino)thiophene-2-carboxamidine
hydrochloride: Using a procedure similar to Example 154,
step(b),730 mg (2.21 mmol) of methyl
5-methylthio-4-(2-naphthylamino)thiophene-2-carboxy- late was
allowed to react with 8 equiv (17.7 mmol) of the
AlMe.sub.3/NH.sub.4Cl reagent and purified by preparative thin
layer chromatography (20%-MeOH--CHCl.sub.3-satd. NH.sub.3, 1000 [Lm
SiO2 plate) to afford
5-methylthio-4-(2-naphthylamino)thiophene-2-carboxamidine, which
was dissolved in 4 mL of dry MeOH, cooled to 0.degree. C. and
carefully treated with 1.6 mL(1.5 equiv, 3.31 mmol) of 2M HCl in
ether. The reaction was stored at 5.degree. C. overnight, then
concentrated in vacuo with toluene (3xlOmL) and then hexanes (2x 10
mL). The yellow solid was dried under vacuum to afford 415 mg
(53.6%) of
5-methylthio-4-(2-naphthylamino)thiophene-2-carboxamidine
hydrochloride. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.53 (s,
3H), 7.20 (d, 1H, J=2.2 Hz), 7.24-7.31 (m, 2H), 7.38 (m, 1H), 7.69
(d, 1H, 8.1 Hz), 7.75-7.79 (m, 2H), 8.13 (s, 1H), 8.24 (s, 1H),
9.06 (bs, 2H), 9.33 (bs, 2H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.16H.sub.15N.sub.3S.sub.2, 314.08 (M+H), found 314.5.
EXAMPLE 209
[0933]
4-[(4-Chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine
[0934] a) Methyl
4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxy- late:
Using a procedure similar to Example 208, step (a), 66.6 mg (0.32
mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was
allowed to react with 100 mg (2 equiv, 0.64 mmol) of 4-chlorophenyl
boronic acid to give 11.8 mg (11.7%) of methyl
4-[(4-chlorophenyl)amino]-5-methylthiot- hiophene-2-carboxylate and
21 mg (31.5%) of unreacted starting material. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 2.41 (s, 3H), 3.89 (s, 3H), 6.09 (bs,
1H), 6.94 (d, 2H, J=8.6 Hz), 7.25 (d, 2H, J=8.6 Hz), 7.70 (s, I
H).
[0935] b)
4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine
hydrochloride: Using a procedure similar to Example 154, step (b),
11.8 mg (0.037 mmol) of methyl
4-[(4-chlorophenyl)amino]-5-methylthiothiophene- -2-carboxylate was
allowed to react with 8 equiv (2.96 mmol) of the
AlMe.sub.3/NH.sub.4Cl reagent to afford 13 mg ( l00%) of
4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine.
.sup.1.sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.41 (s, 3H),
6.91-6.95 (m, 2H), 7.10-7.13 (m, 2H), 7.64 (s, 1H), 7.93 (s, 1H),
8.67 (bs, 2H), 9.11 (bs, 2H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.12H.sub.12ClN.sub.3S.sub.2, 298.02 (M+H), found 298.1.
EXAMPLE 210
[0936]
4-t(3-Methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
[0937] a) Methyl
4-[(3-metlylphenyl)amino]-5-nietltylthliothiophene-2 carboxylate:
Using a procedure similar to Example 208, step (a), 55.7 mg (0.27
mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was
allowed to react with 73.4 mg (2 equiv, 0.54 mmol) of
3-methylphenyl boronic acid to give 29.2 mg (36.8%) of methyl
4-[(3-methyl)amino]-5-meth- ylthiothiophene-2-carboxylate. .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 2.35 (s, 3H), 2.40 (s, 3H), 3.89
(s, 3H), 6.11 (bs, 1H), 6.80-6.86 (m, 3H), 7.20 (m, 1H), 7.77 (s,
1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.14H.sub.15NO.sub.2S.sub.2, 294.06 (M+H), found 294.1.
[0938] b)
4-[(3-Metlzylphenyl)amino]-5-methylthiothiophene-.sup.2-carboxam-
idine: Using a procedure similar to Example 154, step (b), 29.2 mg
(0.098 mmol) of methyl
4-[(3-methyl)amino]-5-methylthiothiophene-2-carboxylate was allowed
to react with 8 equiv (0.78 mmol) of the AlMe.sub.3/NH4Cl reagent
and purified by preparative thin layer chromatography
(20%-MeOH--CHCl.sub.3-satd. NH.sub.3, 500 [m SiO.sub.2 plate) to
afford 27 mg (100%) of
4-[(3-methylphenyl)amino]-5-methylthiothiophene-2-carboxa- midine.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.24 (s, 3H), 2.50 (s,
3H), 6.65 (d, 1H, J=7.3 Hz), 6.74-6.76 (m, 2H), 7.10 (m, 1H), 7.88
(s, 1H), 7.97 (s, 1H), 9.07 (bs, 3H). Mass spectrum (ESI, m/z):
Calcd. for C.sub.13H.sub.15N.sub.3S.sub.2, 278.08 (M+H), found
278.2.
EXAMPLE 211
[0939]
4-[(3-Methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine
[0940] a)
Methyl-4-[(3-methoxyphenyl)amino]-5-methylthiothiophene-2-carbox-
ylate: Using a procedure similar to Example 208, step (a), 73.2 mg
(0.35 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate
was allowed to react with 109 mg (2 equiv, 0.70 mmol) of
3-methoxyphenyl boronic acid to give 25.2 mg (23%) of methyl
4-[(3-methoxyphenyl)amino]-5-methylthioth- iophene-2-carboxylate.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.40 (s, 3H), 3.81 (s,
3H), 3.89 (s, 3H), 6.12 (s, 1H), 6.43-6.63 (m, 2H), 7.20 (m, 1H),
7.78 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.14H.sub.15NO.sub.3S.sub.2, 310.06 (M+H), found 310.1.
[0941] b)
4-[(3-Methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
hydrochloride: Using a procedure similar to Example 154, step (b),
25.2 mg (0.081 mmol) of methyl
4-[(3-methyl)amino]-5-methylthiothiophene-2-car- boxylate was
allowed to react with 8 equiv (0.64 mmol) of the
AlMe.sub.3/NH.sub.4Cl reagent to afford 27 mg (100%) of
4-[(3-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine.
.sup.1H NMR (DMSO, 400 MHz) .delta. 2.49 (s, 3H), 3.71 (s, 3H),
6.41 (dd, 1H,J=2.1, 8.0 Hz), 6.49 (m, 1H), 6.50-6.54 (m, 1H), 7.12
(m, 1H), 7.97 (s, 1H), 8.01 (s, 1H), 8.88 (bs, 2H), 9.23 (bs, 2H).
Mass spectrum (ESI, m/z): Calcd. for
C.sub.13H.sub.15N.sub.3OS.sub.2, 294.07 (M+H), found 294.1.
EXAMPLE 212
[0942]
4-[[3-(Methyletlzylsphenyl]amino]-5-methylthiothiophene-2-carboxami-
dine
[0943] a) Methyl 4-[J3-(methylethzyl)phenyl]amino
-5-methylthiothiophene-2- -carboxylate: Using a procedure similar
to Example 208, step (a), 74.4 mg (0.36 mmol) of methyl
4-amino-5-methylthiothiophene-2-carboxylate was allowed to react
with 118 mg (2 equiv, 0.72 mmol) of 3-isopropylphenyl boronic acid
to give 22.6 mg (19.5%) of methyl 4-[(3-methylethylphenyl)am-
ino]-5-methylthiothiophene-2-carboxylate. .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 1.27 (d, 6H, J=6.9 Hz), 2.40 (s, 3H), 2.89 (m,
1H), 3.88 (s, 3H), 6.15 (s, 1H), 6.86-6.89 (m, 3H), 7.24 (m, 1H),
7.77 (s, 1H).
[0944] b)
4-{13-(Methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxa-
midine: Using a procedure similar to Example 154, step (b), 22.6 mg
(0.07 mmol) of methyl
4-{[3-(methylethyl)phenyl]amino}-5-methylthiothiophene-2--
carboxylate was allowed to react with 8 equiv (0.56 mmol) of the
AlMe.sub.3/NH.sub.4Cl reagent to afford 18.9 mg (78.8%) of)
4-{[3-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxamidine.
.sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.18 (d, 6H, J=9.2 Hz),
2.51 (s, 3H), 2.81 (m, 1H), 6.71-6.77 (m, 2H), 6.85 (s, 1H), 7.14
(m, 1H), 7.98 (s, 1H), 8.32 (s, 1H), 8.88 (bs, 2H), 9.23 (bs, 2H).
Mass spectrum (ESI, m/z): Calcd. for
C.sub.15H.sub.19N.sub.3S.sub.2, 306.11 (M+H), found 306.2.
EXAMPLE 213
[0945]
5-Methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxamidine
[0946] a) Methyl
5-methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxyl- ate:
Using a procedure similar to Example 208, step (a), 74.4 mg (0.36
mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was
allowed to react with 120 mg (2 equiv, 0.72 mmol) of 3-nitrophenyl
boronic acid to give 14.5 mg (12.4%) of methyl
5-methylthio-4-[(3-nitrophenyl) amino]thiophene-2-carboxylate.
I.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.45 (s, 3H), 3.93 (s,
3H), 6.21 (s, 1H), 7.41-7.47 (m, 2H), 7.73-7.78 (m, 3H).
[0947] b)
5-Methylthio-4-1(3-nitrophenyl)amino]thliophlene-2-carboxamidine- :
Using a procedure similar to Example 154, step (b), 14.5 mg (0.04
mmol) of methyl
5-methylthio-4-[(3-nitrophenyl)amino]thiophene-.sup.2-carboxyla- te
was allowed to react with 8 equiv (0.35 mmol) of the
AlMe.sub.3/NH.sub.4Cl reagent to afford 4.3 mg (34.8%) of
5-methylthio-4-[(.sup.3-nitrophenyl)amino]thiophene-2-carboxamidine.
Mass spectrum (ESI, m/z): Calcd. for
C.sub.12H.sub.12N.sub.4O.sub.2S.sub.2, 309.05 (M+H), found
309.2.
EXAMPLE 214
[0948]
4-[[4-(Methyletlyl)phenyl]amino]-5-methylthiothiophene-2-carboxamid-
ine
[0949] a) Methyl
4-{[4-(methylethyl)phenyl]amino}-5-methylthiothiophene-2--
carboxylate: Using a procedure similar to Example 208, step (a),
74.4 mg (0.36 mmol) of methyl
4-amino-5-methylthiothiophene-2-carboxylate was allowed to react
with 118 mg (2 equiv, 0.72 mmol) of 4-isopropylphenyl boronic acid
to give 14.5 mg (12.5%) of methyl 4-[(4-methylethylphenyl)am-
ino]-5-methylthiothiophene-2-carboxylate. .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 1.26 (d, 6H, J=6.2 Hz), 2.39 (s, 3H), 2.89 (m,
1H), 3.89 (s, 3H), 6.98-7.01 (m, 2H), 7.17-7.19 (m, 2H), 7.73 (s,
1H).
[0950] b)
4-{[4-(Methylethyl)phenyl]amino]-5-methylthiothiophene-2-carboxa-
midine: Using a procedure similar to Example 154, step (b), 14.5 mg
(0.045 mmol) of methyl
4-{[4-(methylethyl)phenyl]amino}-5-methylthiothiophene-2--
carboxylate was allowed to react with 8 equiv (0.36 mmol) of the
AlMe.sub.3/NH4Cl reagent to afford 11.4 mg (74%) of
4-{[4-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxamidine.
.sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.17 (d, 6H, J=9.2 Hz),
2.51 (s, 3H), 2.81 (m, 1H), 6.92 (d, 2H, J=11.4Hz), 7.10 (d, 2H,
J=11.2 Hz), 7.88 (s, 1H), 7.96 (s, 1H), 8.89 (bs, 2H), 9.22 (bs,
2H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.15H.sub.19N.sub.3S.sub.2, 306.11 (M+H), found 306.2.
EXAMPLE 215
[0951]
4-[(3,4-Dimethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
[0952] a) Methyl
4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-car-
boxylate: Using a procedure similar to Example 208, step (a), 74.4
mg (0.36 mmol) of methyl
4-amino-5-methylthiothiophene-2-carboxylate was allowed to react
with 108 mg (2 equiv, 0.72 mmol) of 3, 4-dimethylphenyl boronic
acid to give 135.9 mg (32.4%) of methyl 4-[(3,4-dimethylphenyl)am-
ino]-5-methylthiothiophene-2-carboxylate. .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 2.24 (s, 3H), 2.26 (s, 3H), 2.38 (s, 3H), 3.88 (s,
3H), 6.11 (bs, 1H), 6.80-6.84 (m, 2H), 7.07 (d, 1H, J=7.9 Hz), 7.71
(s, 1H).
[0953] b)
4-[(3,4-Dimethylphenyl)amino]-5-methylthiothiophene-2-carboxamid-
ine: Using a procedure similar to Example 154, step (b), 35.6 mg
(0.116 mmol) of methyl
4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-car- boxylate
was allowed to react with 8 equiv (0.93 mmol) of the
AlMe.sub.3/NH4Cl reagent to afford 26.1 mg (68.5%) of
4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine.
1.sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.13 (s, 3H), 2.16 (s,
3H), 2.51 (s, 3H), 6.69-6.78 (m, 2H), 6.99 (d, 1H, J=10.8 Hz), 7.76
(s, 1H), 7.91 (s, 1H), 8.82 (bs, 2H), 9.17 (bs, 2H). Mass spectrum
(ESI, m/z): Calcd. for C.sub.14H.sub.17N.sub.3S.sub.2, 292.09
(M+H), found 292.2.
EXAMPLE 216
[0954]
5-Methylthio-4-[(4-phenylphenyl)amino]thiophene-2-carboxamidine
[0955] a) Methyl
5-methylthio-4-[(4-phenylphenyl)amino]thiophene-2-carboxy- late:
Using a procedure similar to Example 208, step (a), 74.4 mg (0.36
mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was
allowed to react with 142.5 mg (2 equiv, 0.72 mmol) of
4-phenylphenyl boronic acid to give 24.5 mg (19.1%) of methyl
4-[(4-phenylphenyl)amino]-5-methyl- thiothiophene-2-carboxylate.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.45 (s, 3H), 3.92 (s,
3H), 6.38 (bs, 1H), 7.08-7.14 (m, 2H), 7.33 (m, 1H), 7.43-7.46 (m,
2H), 7.54-7.60 (m, 4H), 7.82 (s, 1H).
[0956] b) 5-Methylthio-4-[(4-phenylphenyl)amino]th
iophene-2-carboxamidine- : Using a procedure similar to Example
154, step (b), 24.5 mg (0.07 mmol) of methyl
4-[(4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxylate was
allowed to react with 8 equiv (0.56 mmol) of the AlMe.sub.3/NH4Cl
reagent to afford 16.9 mg (64.1%) of
5-methylthio-4-[(4-phenylphenyl)amin- o]thiophene-2-carboxamidine.
.sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.51 (s, 3H), 7.03 (d,
2H, J=8.6 Hz), 7.26-7.61 (m, 7H), 8.04 (s, 1H), 8.15 (s, 1H), 8.88
(bs, 2H), 9.25 (bs, 2H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.18H.sub.17N.sub.3S.sub.2, 340.09 (M+H), found 340.2.
EXAMPLE 217
[0957]
4-[(3-Fluoro4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxami-
dine
[0958] a) Methyl
4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthiothiophene--
2-carboxylate: Using a procedure similar to Example 208, step (a),
74.4 mg (0.36 mmol) of methyl
4-amino-5-methylthiothiophene-2-carboxylate was allowed to react
with 155.5 mg (2 equiv, 0.72 mmol) of 3-fluoro-4-phenylphenyl
boronic acid to give 50.6 mg (41.6%) of methyl
4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxylate.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.44 (s, 3H), 3.91 (s,
3H), 6.19 (s, 1H), 6.78-6.86 (m, 2H), 7.32-7.39 (m, 2H), 7.73-7.47
(m, 2H), 7.55 (d, 1H, J=6.9 Hz), 7.82 (s, 1H).
[0959] b)
4-[(3-Fluoro-4-phenylphenyl)amino]-5-tnetlzylthiotltiophene-2-ca-
rboxamidine: Using a procedure similar to Example 154, step (b),
50.6 mg (0.13 mmol) of methyl
4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthiothio-
phene-2-carboxylate was allowed to react with 8 equiv (1.08 mmol)
of the AlMe.sub.3/NH4Cl reagent to afford 39 mg (76.1%) of
4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxamidine.
.sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.51 (s, 3H), 6.75-6.87
(m, 2H), 7.30-7.50 (m, 6H), 8.06 (s, 1H), 8.37 (s, 1H), 8.90 (bs,
2H), 9.27 (bs, 2H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.18H.sub.16FN.sub.3S.- sub.2, 358.08 (M+H), found 358.2.
EXAMPLE 218
[0960]
4-(2H-Benzo[d]1,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-carbo-
xamidine
[0961] a) Methyl
4-(2H-benzoldll,3-dioxolen-5-ylamino)-5-methylthiothiophe-
ne-2-carboxylate: Using a procedure similar to Example 208, step
(a), 74.4 mg (0.36 mmol) of methyl
4-amino-5-methylthiothiophene-2-carboxylate was allowed to react
with 119.4 mg (2 equiv, 0.72 mmol) of 3,4-methylenedioxyphenyl
boronic acid to give 24.4 mg (20.9%) of methyl
4-(2H-benzo[d]1,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-carboxylate-
. .sup.1.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 2.39 (s, 3H),
3.87 (s, 3H), 5.96 (s, 2H), 6.00 (bs, 1H), 6.52 (dd, 1H, J=2.3, 8.3
Hz), 6.63 (d, 1H, J=2.2 Hz), 6.76 (d, 1H, J=8.3 Hz), 7.59 (s,
1H).
[0962] b)
4-(2H-Benzofdll,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-ca-
rboxamidine: Using a procedure similar to Example 154, step (b),
24.4 mg (0.075 mmol) of methyl
4-(2H-benzo[d]1,3-dioxolen-5-ylamino)-5-methylthio-
thiophene-2-carboxylate was allowed to react with 8 equiv (0.6
mmol) of the AlMe.sub.3/NH.sub.4Cl reagent to afford 7.7 mg (29.7%)
4-(2H-benzo[d]1,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-carboxamidi-
ne. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.51 (s, 3H), 5.95
(s, 2H), 6.46 (dd, 1H, J=3.0, 11.2 Hz), 6.65 (d, 1H, J=2.8 Hz),
6.79 (d, 1H, J=11.0 Hz), 7.80 (s, 1H), 7.87 (s, 1H), 8.91 (bs, 2H),
9.24 (bs. 2H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.13H.sub.13N.sub.3O.sub.2S.sub.- 2, 308.05 (M+H), found
308.2.
EXAMPLE 219
[0963]
4-[(4-Butylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
[0964] a) Methyl
4-[(4-butylphenyl)aminoi-5-methylthiothiophene-2-carboxyl- ate:
Using a procedure similar to Example 208, step (a). 74.4 mg (0.36
mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was
allowed to react with 128 mg (2 equiv, 0.72 mmol) of 4-butylphenyl
boronic acid to give 22.2 mg (18.3%) of methyl
4-[(4-butylphenyl)amino]-5-methylthioth- iophene-2-carboxylate.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.97 (t, 2H, J=7.4 Hz),
1.38 (m, 2H), 1.59 (m, 2H obscured by water), 2.39 (s, 3H), 2.58
(t, 2H, J=7.6 Hz), 3.90 (s, 3H), 6.12 (bs, 1H), 6.97 (d, 2H, J=8.2
Hz), 7.12 (d, 2H, J=8.4 Hz), 7.73 (s, 1H).
[0965] b)
4-[(4-Butylphenyl)amino]-5-methyltltiothiophene-2-carboxamidine:
Using a procedure similar to Example 154, step (b), 22.2 mg (0.06
mmol) of methyl
4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxylate was
allowed to react with 8 equiv (0.52 mmol) of the
AlMe.sub.3/NH.sub.4Cl reagent to afford 18.9 mg (88%) of
4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxamidine.
.sup.1H NMR (DMSO-d.sub.6, 400 MHz) X 0.89 (t, 2H, J=9.7 Hz),
1.23-1.33 (m, 2H), 1.51 (m, 2H), 2.47-2.50 (m, 2H obscured by
DMSO-d.sub.6), 2.51 (s, 3H), 6.90 (d, 2H, J=11.3 Hz), 7.05 (d, 2H,
J=11.2 Hz), 7.86 (s, 1H), 7.94 (s, 1H), 8.78 (bs, 2H), 9.21 (bs,
2H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.16H.sub.21N.sub.3S.sub.2, 320.13 (M+H), found 320.2.
EXAMPLE 220
[0966] 5-Methylthio-4-[benzylamino]thiophene-2-carboxamidine
[0967] a)
Methyl-5-methylthio-4-[benzylamino]thiophene-2-carboxylate: To a
2-drarn vial equipped with a stir bar and septum cap was weighed 60
mg (0.29 mmol) of methyl
4-amino-5-methylthiothiophene-2-carboxylate and 30.7 mg (0.29 mmol)
of benzaldehyde. The vial was charged with 1 mL
CH.sub.2Cl.sub.2-DMF (2:1, v/v) and 135 mg (2.2 equiv, 0.63 mmol)
of NaHB(OAc).sub.3 was added. The reaction was flushed with Ar and
allowed to stir for 48 h. At this time 2 mL of CH.sub.3OH was
added, the reaction stirred an additional 15 min then diluted with
20 ml of CH.sub.2Cl.sub.2. The organic layer was washed with water
(2.times.20 mL), dried (Na.sub.2SO.sub.4), and concentrated in
vacuo into an oven-dried 2 dram vial to give the crude
methyl-5-methylthio-4-[benzylamino]thiophene-2-car- boxylate
together with unreduced imine. The crude reaction mixture was
converted to the amidine without further purification. Mass
spectrum (ESI, m/z): Calcd. for C.sub.14H.sub.15NO.sub.2S.sub.2,
294.06 (M+H), found 292.2 (imine), 294.2.
[0968] b) 5-Methylthio-4-[benzylamino]thiophene-2-carboxamidine: To
a 2-dram vial containing a stir bar and
methyl-5-methylthio-4-[benzylamino]- thiophene-2-carboxylate
(assume 0.29 mmol) was added 2 mL of toluene, followed by 8 equiv
(2.32 mmol) of the AlMe.sub.3/NH.sub.4Cl reagent. The resultant
yellow mixture was heated to 110.degree. C. for 3 h, cooled to
ambient temperature, and then added to a slurry of 1 g of SiO.sub.2
gel in 10 mL of CHC.sub.1.sub.3. After stirring for 15 min, the
slurry was eluted through a 15-mL sintered glass funnel containing
a pad of silica gel with 50% CHCl.sub.3--CH.sub.3OH. The solvent
was removed in vacuo and the residue was triturated with 10%
CH.sub.3OH -CHCl.sub.3 and filtered. Removal of the solvent in
vacuo gave the crude product which was purified by preparative thin
layer chromatography (500 JIm SiO.sub.2, 20%
CH.sub.3OH--CHCl.sub.3-satd. NH.sub.3) 14.8 mg (18.3% from methyl
4-amino-5-methylthiothiophene-2-carboxylate) of
5-methylthio-4-[benzylami- no]thiophene-2-carboxamidine. .sup.1H
NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.49 (s, 3H), 4.35 (d, 2H,
J=6.7 Hz), 5.91 (t, 1H, J=6.8 Hz), 7.20-7.38 (m, 6H). Mass spectrum
(ESI, m/z): Calcd. for C.sub.13H.sub.15N.sub.3S.su- b.2, 278.08
(M+H), found 278.3.
EXAMPLE 221
[0969]
4-(Indan-S-ylamino)-5-methylthiothiophene-2-carboxamidine
[0970] a) Methyl
4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxylate: Using the
procedure described in Example 220, step (a), 60 mg (0.29 mmol) of
methyl 4-amino-5-methylthiothiophene-2-carboxylate, 42.3 mg (0.29
mmol) of 5-indancarboxaldehyde, and 135 mg (2.2 equiv, 0.63 mmol)
of NaHB(OAc).sub.3 were allowed to react to give methyl
4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxylate. Mass
spectrum (ESI, m/z): Calcd. for C.sub.17H.sub.19NO.sub.2S.sub.2,
334.09 (M+H), found 332.3 (imine), 333.4.
[0971] b)
4-(lndan-5-ylamino}-5-methylthiothiophene-2-carboxamidine: Using
the procedure described in Example 220, step (b), 22.0 mg (27.3%
from methyl 4-amino-5-methylthiothiophene-2-carboxylate) of
4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine was
obtained. H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.94-2.01 (m, 2H),
2.49 (s, 3H), 2.77-2.82 (m, 4H), 4.29 (d, 2H, J=5.6 Hz), 5.78 (t,
1H, J=8.1 Hz), 7.08 (d, 1H, J=7.8 Hz), 7.14 (d, 1H, J=7.5 Hz), 7.20
(s, 1H), 7.23 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.16H.sub.19N.sub.3S.sub.2, 318.11 (M+H), found 318.3.
EXAMPLE 222
[0972]
4-(2,3-Dihydrobenzofbffuran-5-ylamino)-5-methylthiothiophene-2-carb-
oxamidine
[0973] a) Methyl
4-(2,3-dilhydrobenzo[bLfuran-5-ylamino)-5-methylthiothiop-
hene-2-carboxylate: Using the procedure described in Example 220,
step (a), 60 mg (0.29 mmol) of methyl
4-amino-5-methylthiothiophene-2-carboxyl- ate, 42.9 mg (0.29 mmol)
of 2,3-dihydrobenzo[b]furan-5-carboxaldehyde, and 135 mg (2.2
equiv, 0.63 mmol) of NaHB(OAc).sub.3 were allowed to react to give
methyl
4-(2,3-dihydrobenzo[b]furan-5-ylamino)-5-methylthiothiophene--
2-carboxylate. Mass spectrum (ESI, m/z): Calcd. for
C.sub.16H.sub.17NO.sub.3S.sub.2, 336.07 (M+H), found 334.3 (imine),
335.3.
[0974] b)
4-(2,3-Dihydrobenzo[bffuran-5-ylamino)-5-methylthiothiophene-2-c-
arboxamidine: Using the procedure described in Example 220, step
(b), 21.8 mg (23.5% from methyl
4-amino-5-methylthiothiophene-2-carboxylate) of
4-(2,3-dihydrobenzo[b]furan-5-ylamino)-5-methylthiothiophene-2-carboxamid-
ine was obtained. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.49
(s, 3H), 3.13 (t, 2H, J=:8.7 Hz), 4.24 (d, 2H, J=6.6 Hz), 4.48 (t,
2H, J=8.7Hz), 5.69 (t, 1H, J=6.7 Hz), 6.68 (d, 1H, J=12.4 Hz), 7.06
(d, 1H, J=7.4 Hz), 7.21 (s, 1H), 7.26 (s, 1H). Mass spectrum (ESI,
m/z): Calcd. for C.sub.15H.sub.17N.sub.3OS.sub.2, 320.09 (M+H),
found 320.3.
EXAMPLE 223
[0975]
5-Methylthio-4-[(2-phenylimidazol-4-yl)amino]thiophene-2-carboxamid-
ine
[0976] a) Methyl 5-methylthio-4-[(2-phenylimidazol-4-yl)
amino]thiophene-2-carboxylate: Using the procedure described in
Example 220, step (a), 60 mg (0.29 mmol) of methyl
4-amino-5-methylthiothiophene-- 2-carboxylate, 49.9 mg (0.29 mmol)
of 4-formyl-2-phenylimidazole, and 135 mg (2.2 equiv, 0.63 mmol) of
NaHB(OAc).sub.3 were allowed to react to give) methyl
5-methylthio-4-[(2-phenylimidazol-4-yl)amino]thiophene-2-car-
boxylate. Mass spectrum (ESI, m/z): Calcd. for
C.sub.17H.sub.17N.sub.3O.su- b.2S.sub.2, 360.08 (M+H), found
360.0.
[0977] b)
5-Methylthio-4-[(2-phenylimidazol-4-yl)amino]thiophene-2-carboxa-
midine: Using the procedure described in Example 220, step (b),
30.9 mg (30% from methyl
4-amino-5-methylthiothiophene-2-carboxylate) of
5-methylthio-4-[(2-phenylimidazol-4-yl)amino]thiophene-2-carboxamidine
was obtained. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.49 (s,
3H), 4.30-4.38 (m, 3H), 7.09 (bs, 1H), 7.32 (m, 1H), 7.40-7.44 (m,
3H), 7.90-7.95 (m, 3H), 8.43 (bs, 3H). Mass spectrum (ESI, m/z):
Calcd. for C.sub.16H.sub.17N.sub.5S.sub.2, 344.10 (M+H), found
344.2.
EXAMPLE 224
[0978]
5-Methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxamidine
[0979] a) Methyl
5-metlhylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carb- oxylate:
Using the procedure described in Example 220, step (a), 60 mg (0.29
mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 45.5
mg (0.29 mmol) of 2-quinolinecarboxaldehyde, and 135 mg (2.2 equiv,
0.63 mmol) of NaHB(OAc).sub.3 were allowed to react to give methyl
5-methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxylate.
Mass spectrum (ESI, m/z): Calcd. for
C.sub.17H.sub.16N.sub.2O.sub.2S.sub.2, 345.07 (M+H), found 343.3
(imine), 345.2.
[0980] b)
5-Methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxamidin-
e: Using the procedure described in Example 220, step (b), 2.5 mg
(2.6% from methyl 4-amino-5-methylthiothiophene-2-carboxylate) of
5-methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxamidine
was obtained. Mass spectrum (ESI, m/z): Calcd. for
C.sub.16H.sub.16N.sub.4S.s- ub.2, 329.09 (M+H), found 329.3.
EXAMPLE 225
[0981] 4-{[(3-Hydroxyphenyl)methyl]amino}-5-methylthiothioph
ene-2-carboxamidine
[0982] a) Methyl
4-[[(3-liydroxyphenyl)mzethyl]amino]-5-methylthiothiophen-
e-2-carboxylate: Using the procedure described in Example 220, step
(a), 61.6 mg (0.30 mmol) of methyl
4-amino-5-methylthiothiophene-2-carboxylate- , 49.5 mg (0.30 mmol)
of 3-acetoxybenzaldehyde, and 135 mg (2.2 equiv, 0.63 mmol) of
NaHB(OAc).sub.3 were allowed to react to give methyl
4-{[(3-hydroxyphenyl)methyl]amino}-5-methylthiothiophene-2-carboxylate.
Mass spectrum (ESI, m/z): Calcd. for
C.sub.14H.sub.16NO.sub.3S.sub.2, 352.07 (M+H), found, 350.2
(imine), 352.1.
[0983] b) Methyl 4-[[(3-hydroxyph
enyl)metlhyl]antitioj-5-methylthiothioph- ene-2-carboxylate: Using
the procedure described in Example 220, step (b), 7.9 mg (8.9% from
methyl 4-amino-5-methylthiothiophene-2-carboxylate) of methyl
4-{[(3-hydroxyphenyl) methyl]amino}-5-methylthiothiophene-2-carbox-
ylate; Mass spectrum (ESI, m/z): Calcd. for
C.sub.13H.sub.15N.sub.3OS.sub.- 2, 294.07 (M+H), found 294.3.
EXAMPLE 226
[0984]
5-Methylthio-4-(phenylcarbonylamino)thiophene-2-carboxamidine
[0985] a) Methyl
5-methylthio-4-(phenylcarbonylamino)thiophene-2-carboxyla- te: To a
stirring solution of 114 mg (0.55 mmol) of methyl
4-amino-5-methylthiothiophene-2-carboxylate in 4 mL of
CH.sub.2Cl.sub.2 at 0.degree. C. was added 142 SL (1.5 equiv, 0.82
mmol) of N,N-diisopropylethylamine via syringe, followed by 71.3 AL
(1.1 equiv, 0.61 mmol) of benzoyl chloride. The reaction was
allowed to warm to room temperature, and stirred an additional 4h.
At this time the reaction was partitioned in 40 InL of 1:1
CH.sub.2Cl.sub.2-satd. NaHCO.sub.3 (v/v) and the organic layer was
separated, washed with 20 mL of brine, dried (Na.sub.2SO.sub.4),
and concentrated in vacuo to afford 113 mg (66.8%) of methyl
5-methylthio-4-(phenylcarbonylamino)thiophene-2-carboxylate which
was used without further purification. .sup.1.sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. 2.55 (s, 3H), 3.83 (s, 3H),
7.47-7.56 (m, 2H), 7.64 (m, 1H), 7.88 (s, 1H), 7.93-7.99 (m, 2H),
10.12 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.14H.sub.13NO.sub.3S.sub.2, 308.04 (M+H), found 308.2.
[0986] b)
5-Methylthio-4-(phenylcarbonylamino)thiophene-2-carboxamidine:
Using a procedure similar to Example 154, step (b), 100 mg (0.32
mmol) of methyl
4-{[4-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxyla-
te was allowed to react with 8 equiv (2.58 mmol) of the
AlMe.sub.3/NH4Cl reagent to afford 95.4 mg (100%) of
5-methylthio-4-(phenylcarbonylamino)t- hiophene-2-carboxamidine. I
.sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.59 (s, 3H), 7.30-7.64
(m, 3H), 7.98-8.00 (m, 2H), 8.23 (s, 1H), 9.19 (bs, 2H), 9.41 (bs,
2H), 10.35 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.13H.sub.14N.sub.3OS.sub.2, 292.06 (M+H), found 292.2.
EXAMPLE 227-240
[0987] To each of a series of 2-dram vials equipped a with a stir
bar and Teflon septum was added between 0.3 and 0.6 mmol an acid
chloride (1 equiv), followed by 1 equiv of methyl
4-amino-5-methylthiothiophene-2-car- boxylate as a 1M
CH.sub.2Cl.sub.2 solution. An additional 2 mL of
CH.sub.2Cl.sub.2was charged into each vial, followed by 1.5 equiv
of N,N-diisopropylethylamine. Each vial was swept with Ar and
allowed to stir for 3 h. At this time 4 mL of satd. NaHCO.sub.3 was
added to each vial and stirring was continued for 5 min. The
aqueous layers were removed by pipette and Na.sub.2SO.sub.4 was
added to each vial. The vials were allowed to stand overnight, and
the contents then eluted through 5-g silica gel (SPE column)
cartridges with 0.5% MeOH--CH.sub.2Cl.sub.2. The amides were
concentrated in vacuo into pre-weighed 2-dram vials equipped with a
stir bar and Teflon septum for the subsequent amidination
reactions. The vials were purged with Ar and charged with 2 niL of
toluene, followed by 8 equiv of the AlMe.sub.3/NH.sub.4Cl reagent
as a 1M solution in toluene. The reactions were heated to 110C in a
heating block for 3 h. They were then cooled to ambient temperature
and each was added by pipette to a slurry of 1.5 g silica gel in 15
mL of CH.sub.2Cl.sub.2. Each slurry was vigorously stirred for 15
min, at which time they were filtered through a 15 mL sintered
glass funnel containing 20 cm of silica gel with 50%
CHCl.sub.3-MeOH. The yellow fractions were collected and
concentrated in vacuo. The solids were triturated with 10%
MeOH--CHC.sub.1.sub.3 and filtered. Concentration in vacuo yielded
the crude amidines, which were purified by preparative thin layer
chromatography (20% MeOH--CHCl.sub.3-satd. NH.sub.3, 500 um
SiO.sub.2) to afford the amidines as their respective free
bases.
2 Example Acid Chloride Amidine Product % Yield.sup.a 227 cinnamoyl
chloride 4-((2E)-3-phenylprop-2-enoylamino)- 15.3%
5-methylthiothiophene-2- carboxamidine 228 4-chlorobenzoyl chloride
4-[(4-chlorophenyl)carbonylamino]-5- 44.6%
methylthiothiophene-2-carboxamidine 229 cyclohexoyl chloride
4-(cyclohexylcarbonylamino)-5- 17.8% methylthiothiophene-2-carbo-
xamidine 230 3-nitro-4-methylbenzoyl methyl 4-[(4-methyl-3- 8.8%
chloride nitrophenyl)carbonylamino]-5-
methylthiothiophene-2-carboxylate 231 2-furoyl chloride
4-(2-furylcarbonylamino)-5- 13.3% methylthiothiophene-2-carboxam-
idine 232 2,2-dimethyl-propanoyl 4-(2,2-dimethylpropanoylamino)-5-
8.5% chloride methylthiothiophene-2-carboxamidine 233
5-(3,5-dichloro-4- 4-{[5-(3,5-dichlorophenoxy)(2- 22.9%
phenoxy)furan-2- furyl)]carbonylamino}-5- carbonyl chloride
methylthiothiophene-2-carboxamidine 234 1-napthoyl chloride
5-methylthio-4- 3.1% (naphthylcarbonylamino)-thiophene-2-
carboxamidine 235 2-quinolinyl chloride 5-methylthio-4-(2-quino-
lylcarbonyl- 6.8% amino)thiophene-2-carboxamidine 236
3-methoxybenzoyl 4-[(3-methoxyphenyl)carbonylamino]- 6.8% chloride
5-methylthiothiophene-2- carboxamidine 237 2-(2,5-
4-[2-(2-hydroxy-5- 18.3% dimethoxyphenyl)acetyl
methoxyphenyl)acetylamino]-5- chloride methylthiothiophene-2-carb-
oxamidine 238 4-ethoxybenzoyl 4-[(4-ethoxyphenyl)carbonylamino]-5-
34% chloride methylthiothiophene-2-carboxamidine 239
2-phenoxyacetyl 5-methylthio-4-(2- 10% chloride
phenoxyacetylamino)-thiophene-2- carboxamidine 240 3-methylbenzoyl
4-[(3-methylphenyl)carbonylamino]-5- 21.1% chloride
methylthiothiophene-2-carboxamidine .sup.aYield calculated from
starting methyl 4-amino-5-methylthiothiophene-2-carboxyla- te.
EXAMPLE 227
[0988]
4-((2E)-3-Phenylprop-2-enoylamino)-5-methyltlziothiopliene-2-carbox-
amidine
[0989] a) Methyl
4-((2E)-3-phenylprop-2-enoylamino)-5-methylthiothiophene--
2-carboxylate: yield: 100%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz)
.delta. 2.49 (s, 3H), 3.83 (s, 3H), 7.12 (d, 1H, J=15.7 Hz),
7.41-7.66 (m, 6H), 8.24 (s, 1H), 9.92 (s, 1H). Mass spectrum (ESI,
m/z): Calcd. for C.sub.16H.sub.15NO.sub.3S.sub.2, 334.06 (M+H),
334.1.
[0990] b)
4-((2E)-3-Phenylprop-2-enoylamino)-5-methyltlliothiophene-2-carb-
oxamidine: .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.54 (s,
3H). 7.13 (d, 1H, J=15.7 Hz), 7.41-7.51 (m, 3H), 7.59-7.66 (m, 2H),
8.40 (s, 1H), 8.81 (bs, 3H), 10.02 (bs, 1H). Mass spectrum (ESI,
m/z): Calcd. for C.sub.15H.sub.15N.sub.3OS.sub.2, 318.07 (M+H),
318.2.
EXAMPLE 228
[0991]
4-[(4-Chlorophenyl)carbonylamino]-S-methylthiothiopfhene-2-carboxam-
idine
[0992] a) Methyl
4-[(4-clilorophenyl)carbonylaminio/-5-methylthiothiophene-
-2-carboxylate: yield: 53%. .sup.1.sup.1H NMR (DMSO-d.sub.6, 400
MHz) .delta. 2.55 (s, 3H), 3.83 (s, 3H), 7.62 (d, 2H, J=8.5 Hz).
7.87 (s. 1H), 7.97 (d, 2H, J=8.5 Hz), 10.21 (s, 1H).
[0993] b)
4-[(4-Chlorophenyl)carbonylamino]-S-nietliylthiothiopheiie-2-car-
boxamidine: .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.59 (s,
3H). 7.63-7.66 (m, 2H), 7.98-8.01 (m, 2H), 8.99 (bs, 2H), 9.33 (bs,
2H) 10.39 (s. 1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.13H.sub.12ClN.sub.3OS- .sub.2, 326.02 (M+H), found 326.2.
EXAMPLE 229
[0994]
4-(Cyclohexylcarbonylamino)-5-methylthiothiophene-2-carboxamidine
[0995] a) Methyl
4-(cyclohexylcarbonylamino)-5-izethylthiothziopheze-2-car-
boxylate: yield: 69.9%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.
1.22-1.81 (m, 11H), 2.51 (s, 3H), 3.82 (s, 3H), 7.97 (s, 1H), 9.55
(s, 1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.14H.sub.19NO.sub.3S.sub.2- , 314.09 (M+H), found 314.2.
[0996] b)
4-(Cyclohexylcarbonylamino)-5-methylthiothiophene-2-carboxamidin-
e: .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.59
(s,3H),7.63-7.66 (m, 2H), 7.98-8.01 (m, 2H), 8.99 (bs, 2H), 9.33
(bs, 2H), 10.39 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.13H.sub.20N.sub.3OS.sub.2, 298.10 (M+H), found 298.2.
EXAMPLE 230
[0997] Methyl
4-[(4-methyl-3-nitrophenyl)carbonylamino]-5-methylthiothioph-
ene-2-carboxylate
[0998] a) Methyl
4-[(4-metzyl-3-nitrophenyl)carboinylamino]-5-methylthioth-
iophene-2-carboxylate: yield: 80%. .sup.1H NMR (DMSO-d.sub.6, 400
MHz) .delta. 2.56 (s, 3H), 2.61 (s, 3H), 3.82 (s, 3H), 7.70 (d, 1H,
J=8.1 Hz), 7.86 (s, 1H), 8.19 (dd, 1H, J=1.7, 8.0 Hz), 8.56 (d, 1H,
J=1.7 Hz), 10.41 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.15H.sub.14N.sub.2O.su- b.5S.sub.2, 367.42 (M+H), found
367.2.
[0999] b) Methyl
4-[(4-methyl-3-nitrophenyl)carbonylamino]-5-methylthiothi-
ophene-2-carboxylate: .sup.1H NMR (DMSO-d.sub.6. 400 MHz) .delta.
2.47 (s, 3H), 2.61 (s, 3H), 7.12 (bs, 3H), 7.69-7.73 (m, 2H), 8.20
(dd, 1H, J=1.6, 7.9 Hz), 8.57 (d, 1H, J=1.6 Hz). Mass spectrum
(ESI, m/z): Calcd. for C.sub.14H.sub.14N.sub.4O.sub.3S.sub.2,
351.06 (M+H), found 351.2.
EXAMPLE 231
[1000]
4-(2-Furylcarbonylamino)-5-methylthiothiophene-2-carboxamidine
[1001] a) Methyl
4-(2-furylcarbonylamino)-5-methylthiothiophene-2-carboxyl- ate:
yield: 100%; .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.54 (s,
3H), 3.83 (s, 3H), 6.71 (dd, 1H, J1.8, 3.4 Hz), 7.33 (d, 1H, J=3.5
Hz), 7.87 (s, 1H), 7.95 (m, 1H), 9.93 (s, 1H). Mass spectrum (ESI,
m/z): Calcd. for C.sub.12H.sub.11O.sub.4S.sub.2, 298.02 (M+H),
found 298.3.
[1002] b) 4-(2-Furylcarboiiylamino)-5-methylthiothiophene-2
carboxamidine: .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.51 (s,
3H), 6.71 (dd, 1H, J=1.8, 3.5 Hz), 7.18 (bs, 3H), 7.32 (d, 1H,
J=3.4 Hz), 7.79 (s, 1H), 7.96 (m, 1H). Mass spectrum (ESI, m/z):
Calcd. for C.sub.11H.sub.11N.sub.3O.su- b.2S.sub.2282.04 (M+H),
found 282.2.
EXAMPLE 232
[1003]
4-(2,2-Dimethylpropanoylamino)-5-methylthiothiophene-2-carboxamidin-
e
[1004] a) Methyl
4-(2,2-dimethylpropanoylamino)-5-methylthiothiophene-2-ca-
rboxylate: yield: 93.4%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz)
.delta. 1.23 (s, 9H), 2.51 (s, 3H), 3.81 (s, 3H), 7.74 (s, 1H),
9.04 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.12H.sub.17NO.sub.3S.sub.2, 288.07 (M+H), found 288.1.
[1005] b)
4-(2,2-Dimethylpropanoylamino)-5-methylthiothiophene-2-carboxami-
dine: .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.24 (s, 9H),
2.55 (s, 3H), 8.05 (s, 1H), 9.0 (bs, 3H), 9.1 (s, 1H). Mass
spectrum (ESI, m/z): Calcd. for C.sub.11H.sub.17N.sub.3OS.sub.2,
272.09 (M+H), found 272.2.
EXAMPLE 233
[1006] 4-{[5-(3,5-Dichlorophenoxy)
(2-furyl)}carbonylamino]-5-methylthioth-
iophene-2-carboxamidine
[1007] a) Methyl 4-[[5-(3, 5-diclilorophenoxy)
(2-furyl)lcarbonylamino]-5-- methylthiothiophene-2-carboxylate:
yield: 96.9%. Mass spectrum (ESI, m/z): Calcd. for
C.sub.18H.sub.13C.sub.12NO.sub.5S.sub.2, 457.97 (M+H), found
457.9.
[1008] b) 4-[[5-(3,5-D ichloroph enoxy) (2 furyl)lcarbon
ylamino]-5-methylthiothiophene-2-carboxamidine: y.sup.1H NMR
(DMSO-d.sub.6, 400 MHz) .delta. 2.53 (s, 3H), 6.12-6.17 (m, 1H),
6.79 (d, 1H, J=l.8 Hz), 7.40-7.43 (m, 2H), 7.70 (m, 1H), 8.13 (s,
1H), 8.92 (bs, 2H), 9.21 (bs, 1H), 10.06 (s, 1H). Mass spectrum
(ESI, m/z): Calcd. for
C.sub.17H.sub.14Cl.sub.2N.sub.35.sub.3S.sub.2, 7441.99 (M+H), found
442.2.
EXAMPLE 234
[1009] a) Methyl
5-methylthzio-4-(naphthiylcarbonylamino)tiiophene-2-carbo- xate
yield: 80.8%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.59-7.67
(m, 3H), 7.80 (d, 1H, J=6.8 Hz), 8.02-8.34 (m, 4H), 10.38 (s,
1H).
[1010] b) 5-Methyltio-4-(n aphthylcarbonylamino)thol )liiophene-2
carboxamidine:.sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.50 (s,
3H), 7.60 (m, 3H), 7.76 (d, 1H, J=6.7 Hz), 7.94 (s, 1H), 8.03 (d,
1H, J=6.8 Hz), 8.09 (d, 11H, 8.3 Hz), 8.30 (d, 1H, J=8.8 Hz). Mass
spectrum (ESI, m/z): Calcd. for C.sub.17H.sub.15N.sub.3OS.sub.2,
342.07 (M+H), found 342.2.
EXAMPLE 235
[1011]
5-Methylthio-4-(2-quinolylcarbonylamino)thiophene-2-carboxamidine
[1012] a) Methyl
5-methylthio-4-(2-quinolylcarbonylamino)thiophene-2-carbo- xylate:
yield: 80.9%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.59 (s,
3H), 3.86 (s, 3H), 8.03-8.06 (m, 3H), 8.24-8.29 (m, 3H), 9.58 (s,
1H), 10.63 (s, 1H).
[1013] b)
5-Methylthio-4-(2-quinolylcarbonylamino)thiophene-2-carboxamidin-
e: .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.53 (s, 3H), 7.21
(bs, 3H), 7.74 (s, 1H), 7.96-7.98 (m, 2H), 8.19-8.22 (m, 4H), 9.77
(s, 1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.16H.sub.14N.sub.4OS.sub.2, 343.45 (M+H), found 343.1.
EXAMPLE 236
[1014]
4-[(3-Methoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxam-
idine
[1015] a) Methyl
4-[(3-methoxyphenyl)carbonylamino]-5-methylthiothiophene--
2-carboxylate: yield: 90.3%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz)
.delta. 2.55 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H), 7.19 (m, 1H),
7.39-7.59 (m, 3H), 7.85 (s, 1H), 10.09 (s, 1H). Mass spectrum (ESI,
m/z): Calcd. for C.sub.15H.sub.15NO.sub.4S2, 338.05 (M+H), found
338.3.
[1016] b)
4-[(3-Methoxyphenyl)carbonylamino]-5-methylthiotlliophene-2-carb-
oxamidine: .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.58 (s,
3H), 3.84 (s, 3H), 7.19 (dd, 1H, J=2.1, 8.1 Hz), 7.45-7.57 (m, 3H),
8.15 (s, 1H), 9.11 (bs, 4H), 10.32 (bs, 1H). Mass spectrum (ESI,
m/z): Calcd. for C.sub.14H.sub.15N.sub.3O.sub.2S.sub.2, 322.07
(M+H), found 322.2.
EXAMPLE 237
[1017] 4-[2-(2,
5-Dimethoxyphenyl)acetylamino]-5-metlyltlziotlziophene-2-c-
arboxamidine
[1018] a) Methyl
4-[2-(2,5-dimethoxyphenyl)acetylamino]-5-methyltltiothiop-
hene-2-carboxylate: .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.
2.47 (s, 3H), 3.67 (s, 2H), 3.70 (s, 3H), 3.75 (s, 3H), 3.80 (s,
3H), 6.81 (dd, 1H, J=3.0, 8.8 Hz), 6.87 (d, 1H, J=3.0 Hz), 6.93 (d,
1H, J=8.9 Hz), 8.04 (s, 1H), 9.62 (s, 1H);
[1019] b) 4-[2-(2,5-Dimethoxyphenyl)acetylamino]-5-5
methylthiothiophene-2-carboxamidine: .sup.1H NMR (DMSO-d.sub.6, 400
MHz) .delta. 2.38 (s, 3H), 3.66 (s, 2H), 3.70 (s, 3H), 3.76 (s,
3H), 6.81 (dd, 1H, J=3.3, 8.0 Hz), 6.88-6.94 (m, 2H), 7.91 (s, 1H),
9.42 (bs, 1H).
EXAMPLE 238
[1020]
4-[(4-Ethoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxami-
dine
[1021] a) Methyl
4-[(4-ethoxyphenyl)carbonylamino]-5-methylthiothiophene-2-
-carboxylate: .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.36 (t,
3H, J=7.0 Hz), 2.54 (s, 3H), 3.83 (s, 3H), 4.13 (q, 2H, J=7.0 Hz),
7.05 (d, 2H, J=8.8 Hz), 7.87 (s, 1H), 7.93 (d, 2H, J=8.8 Hz), 9.93
(s, 1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.16HI.sub.7NO.sub.4S.sub.2, 352.07 (M+H), found 352.2.
[1022] b)
4-[(4-Ethoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carbox-
amidine: .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.36 (t, 3H,
J=7.0 Hz), 2.55 (s, 3H), 4.13 (q, 2H, J=7.0 Hz), 7.04-7.08 (m, 2H),
7.94-7.97 (m, 2H), 8.09 (s, 1H);8.73 (bs, 3H), 10.01 (bs, 1H). Mass
spectrum (ESI, niz): Calcd. for
C.sub.15H.sub.17N.sub.3O.sub.2S.sub.2, 336.08 (M+H), found
336.2.
EXAMPLE 239
[1023]
5-Methylthio-4-(2-phenoxyacetylamino)thiophene-2-carboxamidine
[1024] a) Methyl
5-methylthio-4-(2-phenoxyacetylamino)thiiophene-2-carboxy- late:
yield: 79%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.48 (s,
3H), 3.82 (s, 3H), 4.78 (s, 2H), 6.97-7.02 (m, 2H), 7.31-7.35 (m,
2H), 8.05 (s. 1H), 9.80 (s, 1H).
[1025] b)
5-Methylthio-4-(2-phenoxyacetylamino)thliopheie-2-carboxamidine:
.sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 2.52 (s, 3H), 4.81 (s,
2H), 6.97-7.04 (m, 3H), 7.31-7.35 (m, 2H), 8.26 (s, 1H), 8.84 (bs,
4H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.14H.sub.15N.sub.3O.sub.2S.sub.2, 322.43 (M+H), found
322.2.
EXAMPLE 240
[1026]
4-[(3-Methylphenyl)carbonylamino]-5-methylthiothiophene-2-carboxami-
dine
[1027] a) Methyl
4-[(3-methylphenyl)carbonylamino]-5-methylthiothiophene-2-
-carboxylate: yield: 79%. .sup.1H NMR (DMSO-d.sub.6, 400 MHz)
.delta. 2.40 (s, 3H), 2.55 (s, 3H), 3.83 (s, 3H), 4.78 (s, 2H),
7.42-7.43 (m, 2H), 7.47-7.77 (m, 2H), 7.86 (s, 1H), 10.06 (s, 1H).
Mass spectrum (ESI, m/z): Calcd. for
C.sub.15H.sub.15NO.sub.3S.sub.2, 322.06 (M+H), found 322.2.
[1028] b)
4-[(3-Methylphenyl)carbonylamino]-5-methylthiothiophene-2-carbox-
amidine: .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.40 (s, 3H),
2.55 (s, 3H), 7.43-7.44 (m, 2H), 7.75-7.78 (m, 2H), 8.05 (s, 1H),
8.52 (bs, 3H), 10.12 (bs, 1H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.14H.sub.15N.sub.3OS.sub.2, 306.07 (M+H), found 306.2.
EXAMPLE 241
[1029] a) Methyl 4-bromo-5-metlzylthiotltiophene-2-carboxylate: To
a stirred solution of 4-bromo-5-methylthiothiophene-2-carboxylic
acid (87 mmol), prepared according to the procedure of Kleemann, et
aL., EP 0676395A2, in dry methanol (750 mL) was added thionyl
chloride (7 mL, 96 mmol) dropwise. After stirring for 10 min at
room temperature, the solution was heated to reflux and stirred 7.5
h. The solution was cooled and the solvents were removed in vacuo.
The resulting solid was dissolved in dichloromethane (1500 mL) and
washed with saturated sodium bicarbonate (2.times.300 mL), water
(300 mL), saturated brine (300 mL), and dried over anhydrous sodium
sulfate. The solvents were removed in vacuo. The resulting solid
was recrystallized twice from hexane/ethyl acetate to give methyl
4-bromo-5-methylthiothiophene-2-carboxylate (4.4 g, 19%). H-NMR
(CDCl.sub.3, 400 MHz) .delta. 7.66 (s, 1H), 3.90 (s, 3H), 2.60 (s,
3H).
[1030] b) Methyl 5-methylthio-4-[[3-(plienylmetlhoxy)phenyl]amino)
thiophene-2-carboxylate: A dry mixture of 60 mg (0.225 mmol) of
methyl 4-bromo-5-methylthiothiophene-2-carboxylic acid, as prepared
in the previous step, 3.0 mg (6 mole %) of palladium (II) acetate
(Aldrich Chemical Co., Milwaukee, Wis.), 12.6 mg (9 mole %) of
racemic-2,2-bis(diphenylphosphino)- ,1-binaphthyl (Strem,
Newburyport, Mass.), 110 mg (0.34 rnmol, 1.5 eq) of cesium
carbonate (Aldrich Chemical Co., Milwaukee, Wis.), and 54 mg (0.29
mmol, 1.3 eq) of 3-benzyloxyaniline (Aldrich Chemical Co.,
Milwaukee, Wis.) was added to an oven-dried 1-dram glass vial. This
vial was flushed with dry argon in a glove bag, dry toluene (450
JIL, 0.5 M) was added, and the assembly was heated at 100.degree.
C. for 36 h. To the cooled suspension ethyl acetate (4 mL) was
added, the mixture passed through 1 inch of Celite, washed with
ethyl acetate (2.times.4 mL) and the solvents removed in vacuo.
Purification by preparative thin-layer chromatography (1: 1
dichloromethane/hexanes) gave 13 mg of the title compound (15%) as
a pale yellow solid. .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 7.77
(s, 1H), 7.47-6.59 (m, 9H), 6.11 (s, 1H), 5.07 (s, 2H), 3.89 (s,
3H), 2.47 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.20H.sub.19NO.sub.3S.sub.2- , 386.1 (M+H), found 386.3.
[1031] c) 5-Methymli io-4-t[3-(phenylmethoxy)phenyl]amino) thiophe
ne-2-carboxamidine: Trimethylaluminum (2.0 M in toluene, 2 mL) was
added dropwise over 10 min to a suspension of ammonium chloride
(216 mg) in toluene (2 mL), stirred under dry nitrogen at 0.degree.
C. After the mixture was stirred at 25.degree. C. for 30 min, when
most of the solid had dissolved, this mixture was taken up in a
syringe and added to 13 mg (0.03 mmol) of methyl
5-methylthio-4-{[3-(phenylmethoxy)phenyl]amino
}thiophene-2-carboxylate. The reaction mixture was heated to reflux
in stages and stirred for 2h 10 min. The cooled mixture was poured
in to a vigorously stirred slurry of silica gel (2 g) in chloroform
(20 mL). To this suspension methanol (50 mL) was added, the mixture
was passed through 1 inch of silica gel in a sintered glass Buchner
funnel, washed with methanol (50 mL), and the solvents removed in
vacuo. The crude product was purified on a 5 g silica gel SPE
column washing first with dichloromethane and then eluting the
product off with IO % methanol in dichloromethane. The product was
further purified by preparative High Pressure Liquid Chromatography
(HPLC) on a Dynamnax C 18 column, 60 A pore size, 10 M particle
size, 40 to 100% methanol over 30 min in 0.1% trifluoroacetic acid
to give 5.4 mg of the title compound (45%) as a yellow solid.
.sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.84 (s, 1H), 7.44-6.60
(m, 9H), 5.08 (s, 2H), 2.48 (s, 3H). Mass spectrum (ESI, m/z):
Calcd. for C.sub.19H.sub.19N.sub.3OS.sub.2, 370.1 (M+H), found
370.2.
EXAMPLE 242
[1032] a) Methyl
5-methylthio-4-[(3-phenoxyphenyl)amino]thiophene-2-carbox- ylate: A
stirred suspension of 80 mg (0.299 mmol) of methyl
4-bromo-5-methylthiothiophene-2-carboxylate and 72 mg (0.389 mmol,
1.3 eq) of 3-phenoxyaniline (Aldrich, Milwaukee, Wis.) was treated
as in Example 241, step (b). Further purification of the product by
preparative thin layer chromatography eluting with 10% ethyl
acetate in hexane gave 36 mg of the title compound (32%) as a
yellow oil. .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 7.76 (s, 1H),
7.40-6.65 (m, 9H), 6.26 (s, 1H), 3.89 (s, 3H), 2.40 (s, 3H). Mass
spectrum (ESI, m/z): Calcd. for C.sub.19H.sub.17NO.sub.3S.sub.2,
372.1 (M+H), found 372.2.
[1033] b)
5-Methylthio-4-[(3-phenoxyphenyl)amino]thiophene-2-carboxamidine- :
Methyl
5-methylthio-4-[(3-phenoxyphenyl)amino]thiophene-2-carboxylate (36
mg, 0.097 mmol) was treated as in Example 241, step (c), but
without HPLC purification to give 30 mg of the title compound (86%)
as an orange glass. .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 9.28
(s, 2H), 8.11 (s, 2H), 7.99 (s, 1H), 7.34-6.50 (m, 9H), 6.29 (s,
1H), 2.35 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.18H.sub.17N.sub.3OS.sub.2, 356.1 (M+H), found 356.2.
EXAMPLE 243
[1034] a)
5-Methylthio-4-[(4-phenoxyphenyl)amitiolthiophene-2-carboxamidin-
e: A stirred suspension of 80 mg (0.299 mmol) of methyl
4-bromo-5-methylthiothiophene-2-carboxylate and 72 mg (0.389 mmol,
1.3 eq) of 4-phenoxyaniline (Aldrich, Milwaukee, Wis.) was treated
as in Example 241, step (b). Further purification of the product by
preparative thin layer chromatography eluting with 10% ethyl
acetate in hexane gave 53 mg of the title compound (48%) as a
yellow oil. .sup.1H-NMR (CDC.sub.3. 400 MHz) .delta. 7.70 (s, 1H),
7.34-7.00 (m, 9H), 6.11 (s, 1H), 3.89 (s, 3H), 2.42 (s, 3H). Mass
spectrum (ESI, m/z): Calcd. for C.sub.19H.sub.17NO3S.sub.2, 372.1
(M+H), found 372.1.
[1035] b) 5-Methylthio-4-[(4-phenoxyphenyl)aminzolthiop
hene-2-carboxamidine: Methyl
5-methylthio-4-[(4-phenoxyphenyl)amino]thiop- hene-2-carboxylate
(53 mg, 0.14 mmol) was treated as in Example 241, step (c), but
without HPLC purification to give 58 mg of the title compound
(quantitative yield) as an orange glass. .sup.1H-NMR (CDCl.sub.3,
400 MHz) .delta. 8.89 (s, 2H), 8.59 (s, 2H), 8.00 (s, 1H),
7.25-6.87 (m, 9H), 6.20 (s, 1H), 2.27 (s, 3H). Mass spectrum (ESI,
m/z): Calcd. for C.sub.18H.sub.17N.sub.3OS.sub.2, 356.1 (M+H),
found 356.2.
EXAMPLE 244
[1036] a) Methyl
4-[(2-methoxyphlenyl)amino]-5-methylthiothiophene-2-carbo- xylate:
A stirred suspension of 103 mg (0.386 mmol) of methyl
4-bromo-5-methylthiothiophene-2-carboxylate and 57 mg (0.46 mmol,
1.2 eq) of 2-methoxyaniline (Aldrich, Milwaukee, Wis.) was treated
in a manner similar to Example 241, step (b) to give 78 mg the
title compound (65%) as a yellow oil. .sup.1H-NMR (CDCl.sub.3, 400
MHz) .delta. 7.82 (s, 1H), 7.12-6.52 (m, 4H), 6.52 (s, 1H), 3.92
(s, 3H), 3.87 (s, 3H), 2.40 (s, 3H). Mass spectrum (ESI, m/z):
Calcd. for C.sub.14H.sub.5NO.sub.3S.sub.2, 310.1 (M+H), found
310.2.
[1037] b)
4-[(2-Methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine- :
Methyl
4-[(2-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxylate (78
mg, 0.25 mmol) was treated as in Example 241, step (c), but without
HPLC purification to give 75 mg of the title compound (quantitative
yield) as an orange glass. .sup.1H-NMR (CD.sub.3OD, 400 MHz)
.delta. 7.91 (s, 1H), 7.15-6.93 (m, 4H), 3.93 (s, 3H), 2.48 (s,
3H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.13H.sub.15N.sub.3OS.sub.2, 294.1 (M+H), found 294.2.
EXAMPLE 245
[1038] a) Methyl
4-[(2-methylphenyl)amino]-5-metiylthiothiophene-2-carboxy- late: A
dry mixture of 100 mg (0.374 mmol) of methyl
4-bromo-5-methylthiothiophene-2-carboxylate, 51 mg (14.9 mole %) of
tris(dibenzylideneacetone)dipalladium (Lancaster, Pelham, NH), 52
mg (22.3 mole %) of
racemic-2,2-bis(diphenylphosphino)-1,1-binaphthyl (Strem,
Newburyport, Mass.), 183 mg of (0.56 mmol, 1.5 eq) cesium carbonate
(Aldrich Chemical Co., Milwaukee, Wis.), and 71 [tL (0.49 mmol, 1.3
eq) of 2- methylaniline (Aldrich Chemical Co., Milwaukee, Wis.) was
added to an oven- dried 1-dram glass vial. This vial was flushed
with dry argon in a glove bag, dry toluene (750 [L, 0.5 M) was
added, and the assembly was heated at 100.degree. C. for 40 h. To
the cooled suspension ethyl acetate (4 mL) was added, the mixture
passed through 1 inch of Celite, washed with ethyl acetate
(2.times.4 mL) and the solvents removed in vacuo. Purification by
preparative thin-layer chromatography (1 :1
dichloromethane/hexanes) gave 67 mg of the title compound (61%) as
a yellow oil. .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 7.64 (s,
1H), 7.23-6.94 (m, 4H), 5.91 (br s, 1H), 3.88 (s, 3H), 2.41 (s,
3H), 2.31 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.14H.sub.15NO.sub.2S.sub.2- , 294.1 (M+H), found 294.2.
[1039] b) 4-[(2-Methylphenyl)amino]-5-methylthiothiophene-2-
carboxamidine: Methyl
4-[(2-methylphenyl)amino]-5-methylthiothiophene- 2-carboxylate (67
mg, 0.23 mmol) was treated as in Example 241, step (c), but without
HPLC purification to give 20 mg of the title compound (30%) as a
yellow glass. .sup.1H-NMR (CD.sub.3OD; 400 MHz) .delta. 7.56 (s,
1H), 7.24-6.99 (m, 4H), 2.49 (s, 3H), 2.29 (s, 3H). Mass spectrum
(ESI, m/z): Calcd. for C.sub.13H.sub.15N.sub.3S.sub.2, 278.1 (M+H),
found 278.2.
EXAMPLE 246
[1040] a) Methyl 4-J(3-chlorophenyl)amino]-5-methylthiothiophene-2-
carboxylate: A stirred suspension of 80 mg (0.299 mmol) of methyl
4-bromo- 5-methylthiothiophene-2-carboxylate and 41 .mu.L (0.389
mol, 1.3 eq) of 3- chloroaniline (Aldrich, Milwaukee, Wis.) was
treated in a manner similar to Example 241, step (b) to give 47 mg
of the title compound (50%) as a yellow oil. .sup.1H-NMR
(CDCl.sub.3, 400 MHz) .delta. 7.75 (s, 1H), 7.23-6.89 (m, 41), 6.10
(s, 1H), 3.89 (s, 3H), 2.42 (s, 3H). Mass spectrum (ESI, m/z):
Calcd. for C.sub.13H.sub.12NO.sub.2S.sub.2- CI, 314.0 (M+H), found
314.1.
[1041] b) 4-[(3-Chlorophenyl)amino]-5-methylthiothiophene-2-
carboxamidine: Methyl
4-[(3-chlorophenyl)amino]-5-methylthiothiophene-2- carboxylate (47
mg, 0.15 mmol) was treated as in Example 241, step (c) to give 33
mg of the title compound (75%/o) as a light yellow solid.
.sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 9.22 (s, 2H), 8.81 (s,
2H), 8.22 (s, 11), 7.99 (s, 11H), 7.24-6.82 (m, 4H), 2.53 (s, 3H).
Mass spectrum (ESI, m/z): Calcd. for
C.sub.12H.sub.12N.sub.3S.sub.2Cl, 298.0 (M+H), found 298.3.
EXAMPLE 247
[1042] a) Methyl 4-(methylphenylamino)-5-methylthiothiophene-2-
carboxylate: A stirred suspension of 100 mg (0.374 mmol) of methyl
4- bromo-5-methylthiothiophene-2-carboxylate and 72 .mu.L (0.487
mmol, 1.3 eq) of N-methylaniline (Aldrich Chemical Co., Milwaukee,
Wis.) was treated in a manner similar to Example 245, step (a) to
give 23 mg of the title compound (21%) as a yellow oil. .sup.1H-NMR
(CDCl.sub.3, 400 MHz) .delta. 7.61 (s, 1H), 7.26-6.68 (m, 5H), 3.89
(s, 3H), 3.25 (s, 3H), 2.50 (s, 3H). Mass spectrum (ESI, m/z):
Calcd. for C.sub.14H.sub.15NO.sub.2S.s- ub.2, 294.1 (M+H), found
294.3.
[1043] b)
4-(Methylphenylamino)-5-methylthiothiophene-2-carboxamidine: Methyl
4-[(2-methylphenyl)amino]-5-methylthiothiophene-2-carboxylate (23
mg, 0.078 mmol) was treated as in Example 241, step (c), but
without HPLC purification to give 5.6 mg of the title compound
(26%) as a yellow glass. .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta.
7.83 (s, 1H), 7.24-6.71 (m, 4H), 3.27 (s, 3H), 2.57 (s, 3H). Mass
spectrum (ESI, m/z): Calcd. for
C.sub.1.sub.3H.sub.15N.sub.3S.sub.2, 278.1 (M+H), found 278.3.
EXAMPLE 248
[1044] a) Methyl 5-methyl-4-(phenylamino)thiophene-2-carboxylate: A
stirred suspension of 400 mg (1.7 mmol) methyl
5-methyl-4-bromo-thiophene- -2-carboxylate and 192 [L (2.1 mmol,
1.25 eq) of aniline (Aldrich, Milwaukee, Wis.) was treated in a
manner similar to Example 241, step (b) to give 66 mg of the title
compound (16%) as a brown glass. .sup.1H-NMR (DMSO-d.sub.6, 400
MHz) .delta. 7.70 (s, 1H), 7.56 (s, 1H), 7.17 (m, 2H), 6.72 (m,
3H), 3.79 (s, 3H), 2.31 (s, 3H). Mass spectrum (MALDI, ,genetic
acid matrix, m/z): Calcd. for C.sub.13H.sub.13NO.sub.2S, 248.1
(M+H), found 247.5.
[1045] b) 5-Methyl-4-(phenylamino)thiophene-2-carboxamidine: Methyl
4-(methylphenylamino)-5-methylthiothiophene-2-carboxylate (66 mg,
0.27 mmol) was treated as in Example 241, step (c), but without
HPLC purification to give 57 mg of the title compound (91%) as a
brown glass. H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 9.17 (s, 2H),
8.85 (s, 2H), 7.98 (s, 1H), 7.85 (s, 1H), 7.21-6.73 (m, 5H), 2.39
(s, 3H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.12H.sub.13N.sub.3S, 232.1 (M+H), found 232.2.
EXAMPLE 249
[1046] a) Methyl
4-([4-(dimethylamino)phenyl]amino]-5-met/rylfthiothiophen-
e-2-carboxylate: A stirred suspension of 100 mg (0.267 mmol) methyl
5-methyl-4-bromo-thiophene-2-carboxylate and 66 mg (0.35 mmol, 1.3
eq) of 4-amino-N,N-dimethylaniline (Fluka, Milwaukee, Wis.) was
treated in a manner similar to Example 241, step (b), but eluting
with 1:1 ethyl acetate/hexane for preparative thin-layer
chromatography purification, to give 86 mg of the title compound
(quantitative yield) as an orange glass. .sup.1H-NMR (CDCl.sub.3,
400 MHz) .delta. 7.53 (s, 1H), 7.16 and 6.62 (AB quartet, 4H, J=8.9
Hz), 5.99 (s, 1H), 3.86 (s, 3H), 2.94 (s, 6H), 2.39 (s, 3H). Mass
spectrum (ESI, m/z): Calcd. for C.sub.15H.sub.18N.sub.2O.su-
b.2S.sub.2, 323.1 (M+H), found 323.3.
[1047] b)
4-[[4-(Dimethylamino)phenyl]amino]-5-methylthiothiophene-2-carbo-
xamidine: Methyl
4-(methylphenylamino)-5-methylthiothiophene-2-carboxylate (86 mg,
0.267 mmol) was treated as in Example 241, step (c), but without
HPLC purification. This material was further purified by passing
through 1 inch of basic alumina and eluting with 10% methanol in
dichloromethane (15 mL) to give 62 mg of the title compound (76%)
as a brown glass. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.95
(s, 4H), 7.75 (s, 1H), 7.56 (s, 1H), 6.97 and 6.72 (AB quartet, 4H,
J=8.9 Hz), 2.83 (s, 6H), 2.44 (s, 3H). Mass spectrum (ESI, m/z):
Calcd. for C.sub.14H.sub.18N.sub.4S.sub.2, 307.1 (M+H), found
307.3.
EXAMPLE 250
[1048]
4-[(4-Ethylphenyl)amino]-5-methylthiothiopheize-2-carboxamidiize
hydrochloride
[1049] a) Methyl
4-[(4-ethylphenyl)amino]-5-nietliylthiothiophene-2-carbox- ylate:
To an oven-dried glass vial with stir bar was added a mixture of
100 mg (0.374 mmol) of methyl
4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example
241, step (a)), 5.8 mg (6.9 mol %) of palladium (II) acetate, 21.7
mg (9.3 mol %) of racemic-2,2-bis(diphenylphosphino)-1-
,1-binaphthyl, 171.5 mg (0.526 mmol) of cesium carbonate and 59 mg
(0.487 mmol) of 4-ethylaniline. The vial was transferred to a glove
bag, flushed with dry argon and anhydrous toluene (749 .mu.L) was
added. The vial was capped with a Teflon-lined screw cap and heated
at 100.degree. C. for 48 h. The cooled suspension was filtered
(Celite) washing with ethyl acetate (2.times.2 mL), and the
solvents removed in vacuo. The resulting residue was purified on 1
mm silica prep plates eluting with 40% methylene chloride-hexanes
to afford 14 mg (12%) of methyl 4-[(4-ethylphenyl)amino]-
-5-methylthiothiophene-2-carboxylate as a pale yellow resin which
was used directly in the following step.
[1050] b)
4-[(4-Ethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
hydrochloride: Trimethylaluminum (2.0 M in toluene, 0.182 mL, 0.363
mmol) was added dropwise to a suspension of ammonium chloride (19
mg, 0.363 mmol) in anhydrous toluene (1 mL) under Ar at 0C. The
mixture was stirred at 25.degree. C. for 30 min and then 14 mg
(0.036 mmol) of methyl
4-[(4-ethylphenyl)amino]-5-methylthiothiophene-2-carboxylate (as
prepared in previous step) was added. The reaction mixture was
heated slowly to 100 C and stirred for 4 h. The cooled mixture was
added to a vigorously stirred slurry of silica gel (1.3 g) in
chloroform (20 mL). The suspension was filtered (silica) washing
with 50% MeOH--CH.sub.2Cl.sub.2 (2.times.50 mL). The washings were
concentrated and the resulting residue was purified on a 0.5 mm
silica prep plate eluting with a 10% MeOH--CH.sub.2Cl.sub.2 to
afford 8 mg (67%) of 4-[(4-ethylphenyl)amino]-5-
-methylthiothiophene-2-carboxamidine hydrochloride as a yellow oil.
.sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.84 (s, 1H), 7.14 (d,
2H, 8 Hz), 7.01 (d, 2H, 8 Hz), 2.55 (q, 2H, 65.5 Hz), 2.48 (s, 3H),
1.23 (t, 3H, 15.2 Hz). Mass spectrum (ESI, m/z): Calcd. for
C.sub.14H.sub.17N.sub.3S.sub.2, 292.1 (M+H), found 292.5.
EXAMPLE 251
[1051] 5-Methylthio-4-[[4-phenylmethoxy)phenyl]amin
ojthiophene-2-carboxamidine hydrochloride
[1052] a) Methyl
S-methylthio-4-[[4-(phenylmethoxy)phenyl/amino]thiophene--
2-carboxylate: The same procedure as in Example 250, step a was
followed using 100 mg (0.374 mmol) of methyl
4-bromo-5-methylthiothiophene-2-carbo- xylate (as prepared in
Example 241, step (a)), 5.5 mg (6.5 mol %) of palladium (II)
acetate, 23.6 mg (10.1 mol %) of racemic-2,2-bis(diphenylp-
hosphino)-1,1-binaphthyl, 194 mg (0.595 mmol) of cesium carbonate,
97.3 mg (0.488 mmol) of 4-benzyloxyaniline and 749 PL of toluene,
and chromatographed as before using 40% CH.sub.2Cl.sub.2-hexane to
afford 7 mg (5%) of methyl
5-methylthio-4-{[4-(phenylmethoxy)phenyl]amino}thiophen-
e-2-carboxylate as a yellow resin which was used directly in the
following step.
[1053] b)
5-Methylthio-4-[[4-(henylmethoxy)pheenyl]amino]thiophene-2-carbo-
xamidine hydrochloride: The same procedure as in Example 250, step
(b) was followed using 7 mg (0.018 mmol) of methyl
5-methylthio-4-{[4-(phenylmeth-
oxy)phenyl]amino}thiophene-2-carboxylate (as prepared in previous
step), 0.091 mL of trimethylaluminum (2.0 M in toluene, 0.182
mmol), 10 mg of ammonium chloride (0.182 mmol) and 1 mL of toluene,
and purified on a 0.5 mm silica prep plate eluting with 10%
MeOH--CH.sub.2Cl.sub.2 to afford 3 mg (41%) of
5-methylthio-4-{[4-(phenylmethoxy)phenyl]amino}thiophene-2-ca-
rboxamidine hydrochloride as a yellow oil. .sup.1H-NMR (CD.sub.3OD,
400 MHz) .delta. 7.72 (s, 1H), 7.45 (d, 2H, 7 Hz), 7.39 (t, 2H, 9
Hz), 7.37 (d, 1H, 12 Hz), 7.06 (d, 2H, 12Hz), 6.97 (d, 2H, 12Hz),
5.08 (s, 2H), 2.46 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.19H.sub.19N.sub.3OS.sub.2, 370.1 (M+H), found 370.3.
EXAMPLE 252
[1054]
5-Methylthio-4-[[4-(phenylamino)phenyl]amino]thiophene-2-earboxamid-
ine hydrochloride
[1055] a) Methyl 5-methylthio-4-[[4-(phenylamii2o)phenyl]amino)
thiophene-2-carboxylate: The same procedure as in Example 250, step
(a) was followed using 100 mg (0.374 mmol) of methyl
4-bromo-5-methylthiothio- phene-2-carboxylate (as prepared in
Example 241, step a), 5.5 mg (6.5 mol %) of palladium (II) acetate,
21.6 mg (9.3 mol %) of
racemic-2,2-bis(diphenylphosphino)-l,l-binaphthyl, 173.7 mg (0.533
mmol) of cesium carbonate, 92.3 mg (0.500 mmol) of
N-phenyl-1,4-phenylenediamin- e, and 749 lL of toluene, and
chromatographed as before using 40% CH.sub.2Cl.sub.2-hexane to
afford 58 mg (42%) of methyl
5-methylthio-4-{[4-(phenylamino)phenyl]amino}thiophene-2-carboxylate
as a brown solid. H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.85 (s,
1H), 7.61 (s, 1H). 7.48 (s, 1H), 7.14 (t, 2H, 16 Hz), 6.99 (d, 2H,
16 Hz), 6.90 (q, 4H, 44 Hz), 6.70 (t, 2H, 4 Hz), 3.77 (s, 3H), 2.43
(s, 3H).
[1056] b)
5-Methylthio-4-[[4-(phenylamino)phenyl]amino]thiophene-2-carboxa-
midine hydrochloride: The same procedure as in Example 250, step
(b) was followed using 58 mg (0.156 mmol) of methyl
5-methylthio-4-{[4-(phenylami-
no)phenyl]amino}thiophene-2-carboxylate (as prepared in previous
step), 0.783 mL of trimethylaluminum (2.0 M in toluene, 1.56 mmol),
84 mg of ammonium chloride (1.56 mmol) and 10 mL of toluene, and
purified by passing through a pad of silica eluting with 50%
MeOH--CH.sub.2Cl.sub.2 to afford 50 mg (75%) of the
5-methylthio-4-{[4-(phenylamino)phenyl]amino-
}thiophene-2-carboxamidine hydrochloride as a brown solid.
.sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.91 (d, 2H, 12 Hz),
7.78 (s, 1H), 7.20 (t, 3H, 12 Hz), 7.04-6.94 (m, 5H), 6.71 (m, 1H),
2.47 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.18H.sub.18N.sub.4S.sub.2, 355.1 (M+H), found 355.4.
EXAMPLE 253
[1057]
4-[(4-Methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine
hydrochloride
[1058] a) Methyl
4-[(4-methoxyphenyl)amino/-5-methylthiothiophene-2-carbox- ylate:
To an oven-dried glass vial with stir bar was added a mixture of
120 mg (0.449 mmol) of methyl
4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example
241, step (a)), 7.1 mg (7 mol %) of palladium (II) acetate, 29.4 mg
(10.5 mol %) of racemic-2,2-bis(diphenylphosphino)--
1,1-binaphthyl, 205 mg (0.629 mmol) of cesium carbonate and 69.1 mg
(0.561 mmol) of p-anisidine. The vial was transferred to a glove
bag, flushed with dry argon and anhydrous toluene (0.9 mL) was
added. The vial was capped with a Teflon-lined screw cap and heated
at 100.degree. C. for 48 h. To the cooled suspension was added
ethyl acetate (4 mL), the mixture filtered (Celite) washing with
ethyl acetate (2.times.2 mL), and the solvents removed in vacuo.
The resulting residue was purified by silica gel preparative thin
layer chromatography (40% CH.sub.2Cl.sub.2 in hexane) to afford 83
mg (60%) of the title compound as a yellow oil. .sup.1H-NMR
(CDCl.sub.3, 400 MHz) .delta. 2.39 (s, 3H), 3.82 (s, 3H), 3.87 (s,
3H), 6.03 (s, 1H), 6.89 (m, 2H), 7.03 (m, 2H), 7.58 (s, 1H).
[1059] b)
4-[(4-Methoxyphenyl)amino]-5-metlyltlliothliophene-2-carboxamidi-
ne hydrochloride: Trimethylaluminum (2.0 M in toluene, 2 mL, 4
mmol) was added dropwise to a suspension of ammonium chloride (216
mg, 4 mmol) in anhydrous toluene (1 mL) under Ar at room
temperature. The mixture was stirred at 25.degree. C. for 30 min
and then 80 mg (0.259 mmol) of methyl
4-[(4-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxylate (as
prepared in previous step) in anhydrous toluene (1 mL) was added.
The reaction mixture was heated slowly to 100.degree. C. and
stirred for 2.5 h. The cooled mixture was added to a vigorously
stirred slurry of silica gel (3 g) in chloroform (20 mL). The
suspension was filtered washing with MeOH (4.times.5 mL) and 50%
MeOH--CH.sub.2Cl.sub.2 (4.times.5 mL). The combined washings were
concentrated and the resulting residue was purified on a 2-g silica
SPE column with 5% MeOH--CH.sub.2Cl.sub.2 to afford 50 mg (59%) of
the title compound as an orange solid. .sup.1H-NMR (DMSO-d.sub.6;
400 MHz) .delta. 2.44 (s, 3H), 3.69 (s, 3H), 6.84 (m, 2H), 6.98 (m,
2H), 7.73 (s, 1H), 7.84 (s, 1H), 9.01 (br s, 2H), 9.24 (br s, 2H).
Mass spectrum (ESI, m/z): Calcd. for
C.sub.13H.sub.15N.sub.3OS.sub.2- , 294.1 (M+H), found 294.2.
EXAMPLE 254
[1060]
4-[(3-Fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxam-
idine
[1061] a) Methyl
4-[(3-fluorofmethylphetzyl)amino]-5-methylthiothiophene-2-
-carboxylate: To an oven-dried glass vial with stir bar was added a
mixture of 120 mg (0.449 mmol) of methyl
4-bromo-5-methylthiothiophene-2-- carboxylate (as prepared in
Example 241, step (a), 41 mg (10 mol %) of
tris-(dibenzylidineacetone)dipalladium, 42 mg (15 mol %) of
racemic-2,2-bis(diphenylphosphino)-1,1-binaphthyl, 205 mg (0.629
mmol) of cesium carbonate and 70 mg (0.56 mmol) of
3-fluoro-4-methylaniline. The vial was transferred to a glove bag,
flushed with dry argon and anhydrous toluene (0.9 mL) was added.
The vial was capped with a Teflon-lined screw cap and heated at
100.degree. C. for 48 h. To the cooled suspension was added ethyl
acetate (4 irL), the mixture filtered (Celite) washing with ethyl
acetate (2.times.2 mL), and the solvents removed in vacuo. The
resulting residue was purified by silica gel preparative thin layer
chromatography (10% Et.sub.2O in hexane) to afford 103 mg (78%) of
the title compound as a yellow oil.sup.1H-NMR (CDCl.sub.3, 400 MHz)
.delta. 2.22 (d,3H, J=1.6 Hz), 2.40 (s, 3H), 3.89 (s, 3H), 6.09 (s,
1H), 6.68 (m, 1H), 6.71 (s, 1H), 7.08 (m, 1H), 7.72 (s, 1H).
[1062] b)
4-[(3-Fluoro-4-methylphenyl)amino]-5-methyltlziothiophlene-2-car-
boxamidine: The same procedure as in Example 253, step (b) was
followed using 103 mg (0.349 mmol) of methyl
4-[(3-fluoro-4-methylphenyl)amino]-5--
methylthiothiophene-2-carboxylate (as prepared in previous step), 2
mL of trimethylaluminum (2.0 M in toluene, 4 mmol), 216 mg of
ammonium chloride (4 mmol) and 2 mL of toluene, and purified on a
2-g silica SPE column with 5% MeOH--CH.sub.2Cl.sub.2 to afford 45
mg (44%) of the title compound as a yellow foamI.sup.1H-NMR
(DMSO-d.sub.6; 400 MHz) .delta. 2.13 (s, 3H), 2.50 (s, 3H ), 6.70
(m, 2H), 7.10 (m, 1H), 7.98 (s, 1H), 8.09 (s, 1H), 9.16 (br s, 4H).
Mass spectrum (ESI, m/z): Calcd. for
C.sub.13H.sub.14FN.sub.3S.sub.2, 296.1 (M+H), found 296.2.
EXAMPLE 255
[1063]
4-(Indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine
[1064] a) Methyl
4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxylate: The same
procedure as in Example 254, step (a) was followed using 120 mg
(0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate
(as prepared in Example 241, step (a), 41 mg (IO mol %) of
tris-(dibenzylidineacetone)dipalladium, 42 mg (15 mol %) of
racemic-2,2-bis(diphenylphosphino)-1, 1-binaphthyl , 205 mg (0.629
mmol) of cesium carbonate and 74.8 mg (0.56 mmol) of 5-aminoindan
in 900 .mu.L of toluene, and chromatographed as before using 40%
CH.sub.2Cl.sub.2-hexane to afford 100 mg (73%) of the title
compound as a yellow resin. .sup.1H-NMR (CDCl.sub.3, 400 MHz)
.delta. 2.05-2.12 (m, 2H), 2.85-2.90 (m, 4H), 3.86 (s, 3H), 6,09
(s, 1H), 6.82 (d, 1H, J =8.0 Hz), 6.93 (s, 1H), 7.14 (d, 1H, J=8.0
Hz), 7.70 (s, 1H).
[1065] b)
4-(Indan-5-ylamino)-5-methyltlliothiopleite-2-carboxamidine: The
same procedure as in Example 253, step (b) was followed using 100
mg (0.33 mmol) of methyl
4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxy- late (as
prepared in previous step), 2 mL of trimethylaluminum (2.0 M in
toluene, 4 mmol), 216 mg of ammonium chloride (4 mmol) and 2 mL of
toluene, and purified on a 2-g silica SPE column with 5%
MeOH--CH.sub.2Cl.sub.2 to afford 65 mg (65%) of the title compound
as a yellow foam. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.99
(m, 2H), 2.48 (s, 3H), 2.78 (m, 4H), 6.77 (dd, 1H, J=8.0, 1.78 Hz),
6.86 (s, 1H), 7.08 (d, 1H, J=8.1 Hz), 7.80 (s, 1H), 7.94 (s, 1H),
9.13 (br s, 4H). Mass spectrum (ESI, m/z): Calcd. for
C.sub.15H.sub.17N.sub.3S.sub.2, 304.1 (M+H), found 304.3.
EXAMPLE 256
[1066]
4-[(9-Ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxamidi-
ne
[1067] a) Methyl
4-[(9-ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-c-
arboxylate: The same procedure as in Example 254, step (a) was
followed using 120 mg (0.449 mmol) of methyl
4-bromo-5-methylthiothiophene-2-carbo- xylate (as prepared in
Example 241, step (a), 41 mg (10 mol %) of
tris-(dibenzylidineacetone)dipalladium, 42 mg (15 mol %) of
racemic-2,2-bis(diphenylphosphino)-1,1-binaphthyl, 205 mg (0.629
mmol) of cesium carbonate and 118 mg (0.56 mmol) of
3-amino-9-ethylcarbazole in 900 pL of toluene, and chromatographed
as before using 40% CH.sub.2Cl.sub.2-hexane to afford 80 mg (47%)
of the title compound as a yellow resin. .sup.1H-NMR (CDCl.sub.3,
400 MHz) .delta. 1.46 (t, 3H, J 7.2 Hz), 2.44 (s, 3H), 3.85 (s,
3H), 4.39 (q, 2H, J=7.2 Hz), 6.25 (s, 1H), 7.24 (m, 1H), 7.28 (s,
1H), 7.40 (m, 2H), 7.49 (m, 1H), 7.61 (s, 1H), 7.83 (d, 1H, J=2.1
Hz), 8.06 (d, 1H, J=7.8Hz).
[1068] b)
4-[(9-Etlzylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxa-
midine: The same procedure as in Example 253, step (b) was followed
using 80 mg (0.21 mmol) of methyl
4-[(9-ethylcarbazol-3-yl)amino]-5-methylthiot-
hiophene-2-carboxylate (as prepared in previous step), 2 mL of
trimethylaluminum (2.0 M in toluene, 4 mmol), 216 mg of ammonium
chloride (4 mmol) and 2 mL of toluene, and purified on a 2-g silica
SPE column with 5% MeOH--CH.sub.2Cl.sub.2 to afford 56 mg (70%) of
the title compound as a yellow foam. .sup.1H-NMR (DMSO-d.sub.6, 400
MHz) .delta. 1.31 (t, 3H, J=7.0 Hz), 2.50 (s, 3H), 4.42 (q, 2H,
J=7.0 Hz), 7.14 (m, 1H), 7.27 (dd, 1H, J=8.7, 2.1 Hz), 7.43 (m,
1H), 7.56 (m, 2H), 7.82 (d, 1H, J=2.0 Hz), 7.87 (s, 1H), 7.92 (s,
1H), 8.10 (d, 1H, J=7.7 Hz), 9.11 (br s, 4H). Mass spectrum (ESI,
m/z): Calcd. for C.sub.20H.sub.20N.sub.4S- .sub.2, 381.1 (M+H),
found 381.3.
EXAMPLES 257 and 258
[1069] 5-Methylthio-4-{[(4-ph
enylphenyl)sulonyl]amino]thiophene-2-carboxa- midine
trifluoroacetate
4-[Bis[(4-phenylphenyl)sulfonyl]amino]-5-methylthi-
othiophene-2-carboxamidine trifluoroacetate
[1070] a) Methyl
5-methylthio-4-[(henylsulfonyl)amino]thiophene-2-carboxyl- ate and
methyl 4-lbisf(4-phenylphenyl)sulfonyl]amino)-5-methylthio-thiophe-
ne-2-carboxylate: To an oven-dried round bottom flask with stir bar
was added a mixture of 50 mg (0.24 mmol) of methyl
4-amino-5-methylthiothioph- ene-2-carboxylate (as prepared in
Example 202), 68 mg (0.27 mmol) of 4-biphenylsulfonyl chloride and
50 mg (0.49 mmol) of 4-dimethylaminopyridine. The flask was flushed
with dry argon and anhydrous acetonitrile (3 mL) was added. The
reaction was refluxed for 3 hours and then the solvent was removed
in vacuo. The crude of the reaction was extracted with ethyl
acetate (2.times.25 mL) and 1NHCl (50 niL), The organic layer was
collected, dried (Na.sub.2SO.sub.4), filtered and concentrated
under vacuum to yield a foam that was chromatographed on silica
with 30% ethyl ether-hexane to obtain 143 mg of a mixture of methyl
5-methylthio-4-[(phenylsulfonyl)amino]thiophene-2-carboxylate and
methyl
4-{bis[(4-phenylphenyl)-sulfonyl]amino}-5-methylthiothiophene-2-ca-
rboxylate. This mixture was used in the next reaction without
further purification. Mass spectrum (ESI, m/z): Calcd. for
C.sub.19H.sub.17NO4S.sub.3, 420.0 (M+H), found 419.7.
[1071] b)
5-Methylthio-4-([(4-phenylphenyl)sulfonyl]amino]thiophene-2-carb-
oxamidine trifluoroacetate and
4-lbis[(4-phenylphenyl)sulfonyl]-amino}-5-m-
ethylthiothiophene-2-carboxamidine trifluoroacetate:
Trimethylaluminum (2.0 M in toluene, 1.36 mL, 2.72 mmol) was added
dropwise to a suspension of ammonium chloride (155 mg, 2.89 mmol)
in anhydrous toluene (2.0 mL) under Ar at 0.degree. C. The mixture
was stirred at 25.degree. C. for 30 min and then 143 mg of a
mixture of methyl 5-methylthio-4-[(phenylsulfony-
l)amino]thiophene-2-carboxylate and methyl
4-{bis[(4-phenylphenyl)sulfonyl-
]aamino}-5-methylthiothiophene-2-carboxylate (as prepared in
previous step) in anhydrous toluene (2.0 mL) was added. The
reaction mixture was heated slowly to 100.degree. C. and stirred
for 4 h. The cooled mixture was added to a vigorously stirred
slurry of silica gel (3 g) in chloroform (15 mL). The suspension
was filtered (Celite) washing with 25% MeOH--CH.sub.2Cl.sub.2
(2.times.5 mL), 50% MeOH--CH.sub.2Cl.sub.2 (2.times.5 mL) and 75%
MeOH--CH.sub.2Cl.sub.2 (2.times.5 mL). The combined washings were
concentrated and the resulting residue was purified on a 1I -g
silica SPE column with a gradient of 10-15% MeOH--CH.sub.2Cl.sub.2
saturated with ammonia to afford 66 mg of a mixture of the title
compounds as a yellow solid. This mixture was chromatographed by
preparative reverse phase HPLC performed with a Rainin SD-1 Dynamax
system and a 2-in. C.sub.18 reverse phase Dynamax 60A column using
a gradient of 30% MeOH /0.1% TFA in water to 100% MeOH and a flow
rate of 50 mLU min. to yield 15 mg
5-methylthio-4-{[(4-phenylphenyl)sulfo-
nyl]aamino}thiophene-2-carboxamidine trifluoroacetate; mass
spectrum (ESI, m/z): Calcd. for
C.sub.18H.sub.17N.sub.3O.sub.2S.sub.3, 404.0 (M+H), found 404.1;
and 11 mg of 4-{bis[(4-phenylphenyl)sulfonyl]amino}-5-methyl-
thiothiophene-2-carboxamidine trifluoroacetate. Mass spectrum (ESI,
m/z): Calcd. for C.sub.30H.sub.25N.sub.3O.sub.4S.sub.4, 619.8
(M+H), found 620.2.
EXAMPLEs 259 to 282
[1072] The same methods as for Examples 257 and 258 were used to
synthesize the following compounds:
3 Mass spec, ESI, m/z Calcd Examp Reagent Compound Formula (M + H)
Found 259 1-Naphthalenesulfonyl
5-Methylthio-4-[(2-naphthylsulfonyl)- C16H15N3O2S3 378.0 378.1
chloride amino]thiophene-2-carboxamidine 260 1-Naphthalenesulfonyl
4-[Bis(2-naphthylsulfonyl)amino]-5- C26H21N3O4S4 568.0 568.1
chloride methylthiothiophene-2-carboxamidine 261 7-Bromonaphthalene
4-{[(6-Bromo(2- C16H14BrN3O2S3 455.9 * sulfonyl chloride
naphthyl))sulfonyl]amino}-5- methylthiothiophene-2-carboxamidine
262 7-Bromonaphthalene 4-{Bis[(6-bromo(2- C26H19Br2N3O4S4 723.9 *
sulfonyl chloride naphthyl))sulfonyl]amino}-5-
methylthiothiophene-2-carboxamidine 263 2-Naphthalenesulfonyl
5-Methylthio-4-[(naphthylsulfonyl)- C16H15N3O2S3 378.0 378.1
chloride amino]thiophene-2-carboxamidine 264 2-Naphthalenesulfonyl
4-[Bis(naphthylsulfonyl)amino]-5- C26H21N3O4S4 568.7 568.3 chloride
methylthiothiophene-2-carboxami- dine 265 o-Toluenesulfonyl
4-{[(2-Methylphenyl)sulfonyl] C13H15N3O2S3 342.4 342.1 chloride
amino}-5-methylthiothiophene- 2-carboxamidine 266 o-Toluenesulfonyl
4-{Bis[(2- C20H21N3O4S4 496.6 496.1 chloride
methylphenyl)sulfonyl]amino} -5-methylthiothiophene-2-
carboxamidine 267 m-Toluenesulfonyl 4-{[(3-Methylphenyl)sulfonyl]
C13H15N3O2S3 342.0 342.1 chloride amino}-5-methylthiothiophene-
2-carboxamidine 268 m-Toluenesulfonyl 4-{Bis[(3- C20H21N3O4S4 496.6
496.0 chloride methylphenyl)sulfonyl]amino}-5-
methylthiothiophene-2-c- arboxamidine 269 p-Toluenesulfonyl
4-{[(4-Methylphenyl)sulfonyl] C13H15N3O2S3 342.0 342.1 chloride
amino}-5-methylthiothiophene- 2-carboxamidine 270 p-Toluenesulfonyl
4-{Bis[(4- C20H21N3O4S4 496.6 496.1 chloride
methylphenyl)sulfonyl]amino}-5- methylthiothiophene-2-carboxamidine
271 .alpha.-Toluenesulfonyl 5-Methylthio-4- C13H15N3O2S3 342.0
342.1 chloride {[benzylsulfonyl]amino}- thiophene-2-carboxamidine
272 4-Methoxybenzene- 4-{[(4- C13H15N3O3S3 358.0 358.1 sulfonyl
chloride Methoxyphenyl)sulfonyl]amino}-5-
methylthiothiophene-2-carboxamidine 273 4-Methoxybenzene-
4-{Bis[(4- C20H21N3O6S4 528.0 528.0 sulfonyl chloride
methoxyphenyl)sulfonyl]amino}-5- methylthiothiophene-2-carboxami-
dine 274 4-Iodobenzenesulfonyl 4-{[(4-Iodophenyl)sulfonyl]
C12H121N3O2S3 453.9 454.0 chloride amino}-5-methylthiothiophene-
2-carboxamidine 275 3,4-Dimethoxybenzene 4-{[(3,4- C14H17N3O4S3
388.0 388.1 sulfonyl chloride Dimethoxyphenyl)sulfonyl]amino}-5-
methylthiothiophene-2-carboxa- midine 276 3,4-Dimethoxybenzene
4-{bis[(3,4- C22H25N3O8S4 588.0 588.1 sulfonyl chloride
Dimethoxyphenyl)sulfonyl]amino}-5-
methylthiothiophene-2-carboxamidine 277 2-Chlorobenzenesulfonyl
4-{[(2-Chlorophenyl)sulfonyl] C12H12ClN3O2S3 361.9 362.1 chloride
amino}-5-methylthiothiophene- 2-carboxamidine 278 3-Chlorobenzene-
4-{((3-Chlorophenyl)sulfonyl] C12H12ClN3O2S3 361.9 362.1 sulfonyl
chloride amino}-5-methylthiothiophene- 2-carboxamidine 279
3-Chlorobenzene- 4-{Bis[(3- C18H15Cl2N3O4S4 535.9 537.9 sulfonyl
chloride chlorophenyl)sulfonyl]amino}-5-
methylthiothiophene-2-carboxamidine 280 4-Chlorobenzene-
4-{[(4-Chlorophenyl)sulfonyl] C12H12ClN3O2S3 361.9 362.1 sulfonyl
chloride amino}-5-methylthiothiophene- 2-carboxamidine 281
4-Chlorobenzene- 4-{Bis[(4- C18H15Cl2N3O4S4 535.9 * sulfonyl
chloride chlorophenyl)sulfonyl] amino}-5-methylthiothiophene-
2-carboxamidine 282 Benzenesulfonyl chloride 5-Methylthio-4-
C12H13N3O2S3 328.0 328.1 [(phenylsulfonyl)amino]-
thiophene-2-carboxamidine 283 Benzenesulfonyl chloride
4-[Bis(phenylsulfonyl)amino]-5- C18H17N3O4S4 468.0 467.9
methylthiophene-2-carboxamidine 284 4-tert-Butylbenzene-
4-({[4-(Tert- C16H21N3O2S3 384.0 384.2 sulfonyl chloride
butyl)phenyl]sulfonyl}amino)-5- methylthiothiophene-2-carboxamid-
ine 285 4-tert-Butylbenzene- 4-(Bis{[4-(tert- C26H33N3O4S4 580.1
580.2 sulfonyl chloride butyl)phenyl]sulfonyl}amino)-5-
methylthiothiophene-2-carboxamidine 286 Trans-.beta.-styrene
sulfonyl 4-{[((1E)-2- C14H15N3O2S3 354.0 * chloride
Phenylvinyl)sulfonyl]amino}-5- methylthiothiophene-2-carboxamidi-
ne 287 4-benzensulfonyl- 5-Methylthio-4-({[4-(phenylsulfonyl)
C16H15N3O4S5 473.9 474.1 thiophene-2-sulfonyl
(2-thienyl)]sulfonyl}amino) chloride thiophene-2-carboxamidine
*Mass spectral data inconclusive.
EXAMPLE 288
[1073] 5-Methylthio-4-phenoxythiophene-2-carboxamidine
trifluoroacetate.
[1074] a) Methyl 5-methzylthio-4-phenoxythiophene-2-carboxylate: To
an oven-dried round bottom flask with stir bar was added a mixture
of 100 mg (0.37 mmol) of methyl
4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example
241), 20 mg of Cu (0) (Brewster, R.Q. and Groening T., Organic
Syntheses, Vol. 11, Note 1, pp 445-446) and 42 mg (0.46 mmol) of
phenol. The flask was flushed with dry argon and anhydrous
tetrahydrofuran (5 mL) was added. The reaction was refluxed for 48
hours and then the solvent was removed in vacuo. The resulting
residue was purified on a 10-g silica SPE column with a gradient of
50-100% CH.sub.2Cl.sub.2-hexane to yield 48 mg of methyl
5-methylthio-4-phenoxyth- iophene-2-carboxylate (37%). .sup.1H-NMR
(CDCl.sub.3, 400 MHz) .delta. 7.39 (s, 1H), 7.32 (m, 2H), 7.09 (m,
2H), 6.97 (d, 1H, J=8.4 Hz), 3.86 (s, 3H) and 2.49 (s, 3H).
[1075] b) 5-Methylthio-4-phenoxythiophene-2-carboxamidine
trifluoroacetate: The same procedure as in Example 257, step (b)
was followed using 48.0 mg (0.17 mmol) of methyl
5-methylthio-4-phenoxythioph- ene-2-carboxylate (as prepared in the
step before), 78 mg of ammonium chloride (1.5 mmol), 0.68 ml of
trimethylaluminum (2.0 M in toluene, 1.3 mmol) and 3 ml of
anhydrous toluene and chromatographed as before using preparative
reverse phase HPLC performed with a Rainin SD-1 Dynamax system and
a 2-in. C.sub.18 reverse phase Dynamax 60A column using a gradient
of 30% MeOH /0.1% TFA in water to 100% MeOH and a flow rate of 50
mL/ min. .sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 7.66 (s, 1H),
7.39 (t, 2H, J=7.5 Hz), 7.17 (t, 2H, J=7.4 Hz), 7.02 (d, 1H, J=7.7
Hz) and 2.58 (s, 3H). Mass spectrum (ESI, m/z): Calcd.
C.sub.12H.sub.12N.sub.2OS.- sub.2, 265.0 (M+H), found 262.2.
EXAMPLE 289
[1076] 5-Methylthio-4-(phenylsulfonyl)tfiiophene-2-carboxamidinie
trifluoroacetate.
[1077] a) 4-Bromo-S-methyltlziothiophene-2-carboxylic acid: To 1.0
g (3.7 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate
(as prepared in Example 241, step (a) dissolved in 25 ml of MeOH
was added 450 mg of NaOH dissolved in 10 ml of H.sub.2O. The
reaction was stirred for 5 hours at room temperature, and then the
solvents were removed under vacuum. The residue of the reaction was
extracted with ethyl acetate (2.times.50 mL) and 1N HCl. The
organic layer was collected, dried (Na.sub.2SO.sub.4), filtered and
concentrated under vacuum to yield 833 mg (89%) of
4-bromo-5-methylthiothiophene-2-carboxylic acid as a white
solid.
[1078] b) 5-Methylthio-4-(phenylsulfonyl)thiophene-2-carboxylic
acid: To an oven-dried round bottom flask with stir bar was added
100 mg (0.39 mmol) 4-bromo-5-methylthiothiophene-2-carboxylic acid
(as prepared in Example before). The flask was flushed with dry
argon and anhydrous tetrahydrofuran (3 mL) was added. Then the
solution was cooled at -78.degree. C. before adding 511 AL of
tert-butyl lithium (0.87 mmol, 1.7 M in tetrahydrofuran). The
mixture was stirred for a period of 45 minutes and 77 mg of
benzenesulfonyl flouride (0.39 mmol) was added and the reaction was
allowed to rise to room temperature. The reaction was stirred for
12 hours and then quenched carefully with H.sub.2O. The solvents
were removed under vacuum and the residue of the reaction was
extracted with ethyl acetate (2.times.50 ml) and 1N HCl. The
organic layer was collected, dried (Na2SO.sub.4), filtered and
concentrated under vacuum to yield 130 mg of a solid. This solid
was used in the next step without further purification.
[1079] c) Methyl
5-methylthio-4-(phenylsulfonyl)tltiophene-2-carboxylate: To a
solution of 25 mg of the mixture from the previous step dissolved
in 3 mL of MeOH wa added dropwise 397 gL of
trimethylsilyldiazomethane (0.79 mmol, 2 M solution in hexanes) and
the reaction was stirred for a period of 1 hour. The solvents were
removed under vacuum. The resulting residue was purified on a 10-g
silica SPE column with a gradient of 50-100% ethyl acetate-hexane
to yield 13.8 mg of methyl 5-methylthio-4-(phenylsulfonyl)-
thiophene-2-carboxylate. Mass spectrum (ESI, m/z): Calcd.
C.sub.13HI.sub.2O.sub.4S.sub.3, 329.0 (M+H), found 329.0.
[1080] d) 5-Methylthio-4-(phenylsutfonyl)thiophene-2-carboxamidine
trifluoroacetate: The same procedure as in Example 257, step (b)
was followed using 13.8 mg (0.044 mmol) of methyl
5-methylthio-4-(phenylsulfo- nyl)thiophene-2-carboxylate (as
prepared in the step before), 20 mg of ammonium chloride (0.376
mmol), 0.176 ml of trimethylaluminum (2.0 M in toluene, 0.353 mmol)
and 3 ml of anhydrous toluene and chromatographed as before by
preparative reverse phase HPLC performed with a Rainin SD-I Dynamax
system and a 2-in. C.sub.18 reverse phase Dynamax 60A column using
a gradient of 30% MeOH /0.1% TFA in water to 100% MeOH and a flow
rate of 50 mL/ min to yield 2.3 mg of
5-methylthio-4-(phenylsulfonyl)thio- phene-2-carboxamidine .
.sup.1H-NMR (CD.sub.3OD, 400 MHz) .delta. 8.42 (s, 1H), 8.04 (m,
2H), 7.70 (m, 2H), 7.62 (m, 1H) and 2.70 (s, 3H). Mass spectrum
(ESI, m/z): Calcd. C.sub.12H.sub.12N.sub.2O.sub.2S.sub.3, 313.0
(M+H), found 313.2.
EXAMPLE 290
Tablet Preparation
[1081] Tablets containing 25.0, 50.0, and 100.0 mg, respectively,
of the following active compounds are prepared as illustrated
below:
[1082] a.
4-(4-methylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
[1083] b.
4-[4-(4-phenylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carbo-
xamidine.
4 TABLET FOR DOSES CONTAINING FROM 25-100 MG OF THE ACTIVE COMPOUND
Amount-mg Active Compound 25.0 50.0 100.00 Microcrystalline
cellulose 37.25 100.0 200.0 Modified food corn starch 37.25 4.25
8.5 Magnesium stearate 0.50 0.75 1.5
[1084] All of the active compound, cellulose, and a portion of the
cornstarch are mixed and granulated to 10% corn starch paste. The
resulting granulation is sieved, dried and blended with the
remainder of the corn starch and the magnesium stearate. The
resulting granulation is then compressed into tablets containing
25.0, 50.0, and 100.0 mg, respectively, of active ingredient per
tablet.
EXAMPLE 291
Intravenous Solution Preparation
[1085] An intravenous dosage form of the above-indicated active
compounds is prepared as follows:
5 Active Compound 0.5-10.0 mg Sodium Citrate 5-50 mg Citric Acid
1-15 mg Sodium Chloride 1-8 mg Water for Injection (USP) q.s. to 1
ml
[1086] Utilizing the above quantities, the active compound is
dissolved at room temperature in a previously prepared solution of
sodium chloride, citric acid, and sodium citrate in Water for
Injection (USP, see page 1636 of United States
Pharmacopeia/National Formulary for 1995, published by United
States Pharmacopeial Convention, Inc., Rockville, Md. (1994).
EXAMPLE 292
In vitro Inhibition of Purified Enzymes
[1087] Reagents: All buffer salts were obtained from Sigma Chemical
Company (St. Louis, Mo.), and were of the highest purity available.
The enzyme substrates, N-benzoyl-Phe-Val-Arg-p-nitroanilide (Sigma
B7632), N-benzoyl-Ee-Glu-Gly- Arg-p-nitroanilide hydrochloride
(Sigma B229 1), N-p-tosyl-Gly-Pro-Lys- p-nitroanilide (Sigma
T6140), N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide (Sigma S7388) and
N-CBZ-Val-Gly-Arg-p-nitroanilide (Sigma C.sub.727 1) were obtained
from Sigma. N-Succinyl-Ala-Ala-Pro-Arg-p- nitroanilide (BACHEM
L-1720) and N-succinyl-Ala-Ala- Pro-Val-p-nitroanilide (BACHEM
L-1770) were obtained from BACHEM (King of Prussia, Pa.).
[1088] Human .alpha.-thrombin, human factor Xa and human plasmin
were obtained from Enzyme Research Laboratories (South Bend,
Indiana). Bovine a-chymotrypsin (Sigma C.sub.4129), bovine trypsin
(Sigma T8642) and human kidney cell urokinase (Sigma U5004) were
obtained from Sigma. Human leukocyte elastase was obtained from
Elastin Products (Pacific, MO). K.sub.i Determinations: All assays
are based on the ability of the test compound to inhibit the enzyme
catalyzed hydrolysis of a peptide p-nitroanilide substrate. In a
typical K.sub.i determination, substrate is prepared in DMSO, and
diluted into an assay buffer consisting of 50 mM HEPES, 200 mM
NaCl, pH 7.5. The final concentrations for each of the substrates
is listed below. In general, substrate concentrations are lower
than the experimentally determined value for K.sub.m. Test
compounds are prepared as a 1.0 mg/mL solution in DMSO. Dilutions
are prepared in DMSO yielding 8 final concentrations encompassing a
200 fold concentration range. Enzyme solutions are prepared at the
concentrations listed below in assay buffer.
[1089] In a typical K.sub.i determination, into each well of a 96
well plate is pipetted 280 pL of substrate solution, 10 .mu.L of
test compound solution, and the plate allowed to thermally
equilibrate at 37.degree. C. in a Molecular Devices plate reader
for>15 minutes. Reactions were initiated by the addition of a 10
PL aliquot of enzyme and the absorbance increase at 405 nm is
recorded for 15 minutes. Data corresponding to less than 10% of the
total substrate hydrolysis were used in the calculations. The ratio
of the velocity (rate of change in absorbance as a function of
time) for a sample containing no test compound is divided by the
velocity of a sample containing test compound, and is plotted as a
function of test compound concentration. The data are fit to a
linear regression, and the value of the slope of the line
calculated. The inverse of the slope is the experimentally
determined K.sub.i value.
[1090] Thrombin: Thrombin activity was assessed as the ability to
hydrolyze the substrate N-succinyl-Ala-Ala-Pro-Arg-p-nitroanilide.
Substrate solutions were prepared at a concentration of 32 VM (32
pM<<Km=180 1M) in assay buffer. Final DMSO concentration was
4.3%. Purified human .alpha.-thrombin was diluted into assay buffer
to a concentration of 15 nM. Final reagent concentrations were:
[thrombin]=0.5 nM, [substrate
N-succinyl-Ala-Ala-Pro-Arg-p-nitroanilide]=32 .mu.M.
[1091] Factor X [FXa]: FXa activity was assessed as the ability to
hydrolyze the substrate N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide
hydrochloride. Substrate solutions were prepared at a concentration
of 51 .mu.M (51<<K.sub.m=1.3 mM) in assay buffer. Final DMSO
concentration was 4.3%. Purified activated human Factor X was
diluted into assay buffer to a concentration of 300 nM. Final
reagent concentrations were: [FXa]=10 nM,
[N-benzoyl-Ele-Glu-Gly-Arg-p-nitroanili- de hydrochloride]=51
.mu.M.
[1092] Plasmin: Plasmin activity was assessed as the ability to
hydrolyze the N-p-Tosyl-Gly-Pro-Lys-p-nitroanilide. Substrate
solutions were prepared at a concentration of 37 VM (37
M<<K.sub.m=243 .mu.M) in assay buffer. Final DMSO
concentration was 4.3%. Purified human plasmin was diluted into
assay buffer to a concentration of 240 nM. Final reagent
concentrations were: [Plasmin]=8 nM,
[N-p-Tosyl-Gly-Pro-Lys-p-nitroanilid- e]=37 .mu.M.
[1093] Chymotrypsin: Chymotrypsin activity was assessed as the
ability to hydrolyze N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide.
Substrate solutions were prepared at a concentration of 14 .mu.M
(14 .mu.M<<K.sub.m=62 .mu.M) in assay buffer. Final DMSO
concentration was 4.3%. Purified bovine chymotrypsin was diluted
into assay buffer to a concentration of 81 nM. Final reagent
concentrations were: [Chymotrypsin]=2.7 nM,
[N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide]=14 .mu.M.
[1094] Trypsin: Trypsin activity was assessed as the ability to
hydrolyze N-benzoyl-Phe-Val-Arg-p-nitroanilide. Substrate solutions
were prepared at a concentration of 13 .mu.M (13
.mu.M<<K.=291 .mu.M) in assay buffer. Final DMSO
concentration was 4.3%. Purified bovine trypsin was diluted into
assay buffer to a concentration of 120 nM. Final reagent
concentrations were: [Trypsin]=4 nM,
[N-benzoyl-Phe-Val-Arg-p-nitroanilid- e]=13 .mu.M.
[1095] Elastase: Elastase activity was assessed as the ability to
hydrolyze N-succinyl-Ala-Ala-Pro-Val-p-nitroanilide. Substrate
solutions were prepared at a concentration of 19 .mu.M (19
.mu.M<<K=89 .mu.M) in assay buffer. Final DMSO concentration
was 4.3%. Purified human leukocyte elastase was diluted into assay
buffer to a concentration of 750 nM. Final reagent concentrations
were: [Elastase]=25 nM,
[N-succinyl-Ala-Ala-Pro-Val-p-nitroanilide]=19 .mu.M.
[1096] Urokinase: Urokinase activity was assessed as the ability to
hydrolyze N-CBZ-Val-Gly-Arg-p-nitroanilide. Substrate solutions
were prepared at a concentration of 100 .mu.M (100 .mu.M<K.=1.2
mM) in assay buffer. Final DMSO concentration was 4.3%. Purified
human kidney urokinase was diluted into assay buffer to a
concentration of 1.2 .mu.M. Final reagent concentrations were:
[Urokinase]=40 nM, and N-CBZ-Val-Gly-Arg-p-nitroanilide]=100
mM.
[1097] The results of exemplary assays are shown in the following
table.
Protease Inhibition Data
[1098]
6 Ki Protease micromolar Example # Trypsin 0.858 8 Trypsin 0.474 52
Factor Xa 2.73 94 Factor Xa 3.00 119 Chymo- 4.90 11 trypsin tPA
9.49 1 Plasmin 7.31 12 C1S 0.940 283
[1099] Additionally, the following compounds have K.sub.i values in
the range of 0.016 to 3.5 rnicromolar for uPA:
[1100] Ex.#28, 40, 53, 79, 84, 89, 131, 138, 139, 140, 143, 145,
172, 187, 200, 204, 206, 208, 213, 220, 222, 223, 227, 233, 235,
239, 260, 281 and 288.
[1101] The results indicate that the compounds of the present
invention are inhibitors of proteases, including urokinase.
[1102] Having now fully described this invention, it will be
understood to those of ordinary skill in the art that the same can
be performed within a wide and equivalent range of conditions,
formulations, and other parameters without affecting the scope of
the invention or any embodiment thereof. All patents and
publications cited herein are fully incorporated by reference
herein in their entirety.
* * * * *