U.S. patent application number 09/850826 was filed with the patent office on 2001-12-06 for urokinase inhibitors.
Invention is credited to McClellan, William J., Nienaber, Vicki L., Rockway, Todd W., Steele, Andrew W., Stewart, Kent D., Weitzberg, Moshe, Wendt, Michael D..
Application Number | 20010049374 09/850826 |
Document ID | / |
Family ID | 26733710 |
Filed Date | 2001-12-06 |
United States Patent
Application |
20010049374 |
Kind Code |
A1 |
Steele, Andrew W. ; et
al. |
December 6, 2001 |
Urokinase inhibitors
Abstract
Compounds having the formula 1 are inhibitors of urokinase and
are useful in the treatment of diseases in which urokinase plays a
role. Also disclosed are urokinase-inhibiting compositions and a
method of inhibiting urokinase in a mammal.
Inventors: |
Steele, Andrew W.; (Novi,
MI) ; McClellan, William J.; (Waukegan, IL) ;
Rockway, Todd W.; (Grayslake, IL) ; Stewart, Kent
D.; (Gurnee, IL) ; Weitzberg, Moshe; (Highland
Park, IL) ; Wendt, Michael D.; (Vernon Hills, IL)
; Nienaber, Vicki L.; (Gurnee, IL) |
Correspondence
Address: |
Steven F. Weinstock
Abbott Laboratories
Department 377/ AP6D-2
100 Abbott Park Road
Abbott Park
IL
60064-6050
US
|
Family ID: |
26733710 |
Appl. No.: |
09/850826 |
Filed: |
May 8, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09850826 |
May 8, 2001 |
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09129989 |
Aug 6, 1998 |
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6258822 |
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60054982 |
Aug 6, 1997 |
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Current U.S.
Class: |
514/275 ;
514/311; 514/461; 514/620; 546/169; 564/157 |
Current CPC
Class: |
C07B 2200/07 20130101;
C07C 311/13 20130101; C07D 277/30 20130101; C07D 231/12 20130101;
C07B 2200/09 20130101; C07D 239/42 20130101; C07C 323/62 20130101;
C07D 213/74 20130101; C07D 295/155 20130101; C07C 271/64 20130101;
C07D 307/64 20130101; C07C 275/40 20130101; C07C 2602/08 20170501;
C07C 275/42 20130101; C07C 257/18 20130101; C07C 2601/08 20170501;
C07D 307/54 20130101; C07C 275/64 20130101; C07C 271/22 20130101;
C07D 217/02 20130101; C07D 307/18 20130101; C07C 311/16 20130101;
C07C 271/30 20130101; C07C 2601/10 20170501; C07C 2601/14 20170501;
C07D 333/24 20130101; C07C 271/28 20130101; C07C 259/18 20130101;
C07D 241/18 20130101; C07D 295/088 20130101; C07C 2601/02 20170501;
C07D 307/79 20130101; C07C 323/60 20130101; C07C 2601/04
20170501 |
Class at
Publication: |
514/275 ;
514/311; 514/461; 514/620; 546/169; 564/157 |
International
Class: |
A61K 031/47; A61K
031/165; C07D 215/38; C07C 237/48 |
Claims
What is claimed is:
1. A compound having the formula 19Z is selected from the group
consisting of (1) nitrogen; (2) methine; and (3) methine
substituted with --NR.sub.1R.sub.2; A is selected from the group
consisting of (1) hydrogen and (2) --L.sub.AR.sub.A; B is selected
from the group consisting of (1) hydrogen and (2) --L.sub.BR.sub.B
and C is selected from the group consisting of (1) hydrogen and (2)
--L.sub.CR.sub.C, with the proviso that at least one of A, B or C
is other than hydrogen; and with the proviso that when A is other
than hydrogen, at least one of B or C is other than hydrogen,
wherein for A, B, and C, L.sub.A, L.sub.B and L.sub.C are
independently selected from the group consisting of (1) a covalent
bond, (2) --(CH.sub.2).sub.m--, (3) --NR.sub.1--, (4)
--NR.sub.2C(X)NR.sub.3--, (5) --C(X)--, (6) --NR.sub.1C(X)--(7)
--C(X)NR.sub.2--, (8) --CH.dbd.CH--, (9) --C.ident.C--, (10)
--O--(11) --S(O).sub.t--, (12)
--C.ident.C(CH.sub.2).sub.nNR.sub.2C(X)--, (13)
--C(X)NR.sub.2(CH.sub.2).sub.nC.ident.C--, (14)
--(CH.sub.2).sub.nNSO.sub- .2--, (15)
--NR.sub.2SO.sub.2(CH.sub.2).sub.nC.ident.C--, (16)
--C.ident.C(CH.sub.2).sub.nNR.sub.2SO.sub.2NR.sub.3--, (17)
--NR.sub.2SO.sub.2NR.sub.3(CH.sub.2).sub.nC.ident.C--, (18)
--SO.sub.2NR.sub.2--, (19) --NR.sub.2SO.sub.2--, (20)
--NR.sub.2SO.sub.2NR.sub.3--, (21) --N.dbd.N--, (22)
--C(X)N(OR.sub.2)--, (23) --N(OR.sub.2)C(X)--, (24)
--HC.dbd.CH(CH.sub.2).sub.nNR.sub.2C(X)--, (25)
--(CH.sub.2).sub.nNR.sub.2C(X)CH.dbd.CH--, (26)
--CH.dbd.CH(CH.sub.2).sub.nNSO.sub.2--, (27)
--NR.sub.2SO.sub.2(CH.sub.2)- .sub.nCH.dbd.CH--, (28)
--(CH.sub.2).sub.nNR.sub.2SO.sub.2NR.sub.3--, (29)
--NR.sub.2SO.sub.2NR.sub.3(CH.sub.2).sub.nCH.dbd.CH--, (30)
--NR.sub.2C(O)O--, (31) --OC(O)NR.sub.2--, (32) --CH.dbd.NO--, (33)
--ON.dbd.CH-- and (34) 20wherein W is selected from the group
consisting of (a) --O--, (b) --S--, (c) --NR.sub.1-- and (d)
--(CH.sub.2).sub.m--, wherein each functional group is depicted
with its right-hand end being the end which is attached to the
naphthyl or quinolyl ring and its left-hand end being the end which
is attached to R.sub.A, R.sub.B or R.sub.C; R.sub.A, R.sub.B and
R.sub.C are independently selected from the group consisting of (1)
aryl; (2) arylalkoxy, wherein the alkylene group is of one to six
carbon atoms; (3) alkyl of one to ten carbon atoms; (4) alkenyl of
two to ten carbon atoms; (5) alkoxycarbonyl of one to six carbon
atoms; (6) alkynyl of two to ten carbon atoms; (7) halogen; (8)
--NR.sub.1R.sub.2; (9) heterocycle; (10) cycloalkenyl of four to
twelve carbon atoms; (11) cycloalkyl of three to twelve carbon
atoms; (12) --NR.sub.1C(O)NR.sub.2R.sub.3; and (13)
--NR.sub.1C(O)R.sub.50, wherein R.sub.50 is alkyl of one to six
carbon atoms; wherein, at each occurence, R.sub.1 is selected from
the group consisting of (1) hydrogen; (2) an N-protecting group;
(3) alkyl of one to six carbon atoms; (4) alkenyl of two to six
carbon atoms; (5) alkynyl of two to six carbon atoms; (6) aryl; (7)
arylalkyl, wherein the alkylene group is of one to six carbon
atoms; (8) cycloalkyl of three to eight carbon atoms and (9)
cycloalkylalkyl, wherein the cycloalkyl group is of three to eight
carbon atoms, and the alkylene group is of one to ten carbon atoms;
and wherein, at each occurence, R.sub.2 and R.sub.3 are
independently selected from the group consisting of (1) hydrogen;
(2) alkyl of one to six carbon atoms; (3) alkenyl of two to six
carbon atoms; (4) alkynyl of two to six carbon atoms; (5) aryl; (6)
arylalkyl, wherein the alkylene group is of one to six carbon atoms
(7) cycloalkyl of three to eight carbon atoms and (8)
cycloalkylalkyl, wherein the cycloalkyl group is of three to eight
carbon atoms, and the alkylene group is of one to ten carbon atoms;
and wherein, at each occurence, X is selected from the group
consisting of (1) O and (2) S; and wherein, at each occurence, m is
one to five, n is zero to four and t is zero to two; and wherein,
at each occurence, the alkyl, alkenyl, alkynyl, aryl, heterocycle,
cycloalkyl, and cycloalkenyl groups are optionally substituted.
2. A compound according to claim 1 wherein A and C are hydrogen and
B is --L.sub.BR.sub.B.
3. A compound according to claim 2 selected from the group
consisting of 7-(2-hydroxyethoxy)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt; methyl
5-[7-[(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoate;
mono(trifluoroacetate) salt;
5-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]- pentanoic acid,
mono(trifluoroacetate) salt; methyl
4-[[[7-amino(hydroxyimino)methyl]-2-naphthalenyl]
oxy]methyl]benzoate; methyl
2-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]acetate,
mono(trifluoroacetate) salt;
7-[2-(4-morpholinyl)ethoxy]-2-naphthalenecar- boximidamide,
bis(trifluoroacetate) salt; 2-[[6-(aminoiminomethyl)-2-napht-
halenyl]oxy]acetic acid, mono(trifluoroacetate) salt; and methyl
4-[6-(aminoiminomethyl)-2-naphthalenyl]oxy]methyl]benzoate,
mono(trifluoroacetate) salt.
4. A compound according to claim 1 wherein A and B are hydrogen;
and C is --L.sub.CR.sub.C.
5. A compound according to claim 4 selected from the group
consisting of
8-(carbonylbenzyloxy)amino-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)-1-naphthalenyl)aceta- mide
mono(trifluoroacetate) salt; methyl
[7-(aminoiminomethyl)-1-naphthale- nyl)carbamate
mono(trifluoroacetate) salt; methyl 3-[[7-(aminoiminomethyl)-
-1-naphthalenyl]amino]-3-oxopropionate mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)-1-naphthalenyl]-2-(phenylmethoxy)acetamide
mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)-1-naphthalenyl]-1,3--
benzodioxole-5-carboxamide mono(trifluoroacetate) salt,
N-[7-(aminoiminomethyl)-1-naphthalenyl]benzenemethanesulfonamide
mono(trifluoroacetate) salt, methyl
[7-(aminoiminomethyl)-1-naphthalenyl]- methylcarbamate,
mono(trifluoroacetate) salt; propyl
[7-(aminoiminomethyl)-1-naphthalenyl]carbamate,
mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)-1-naphthalenyl]-N'-methylurea,
mono(trifluoroacetate) salt; ethyl
[7-(aminoiminomethyl)-1-naphthalenyl)c- arbamate,
mono(trifluoroacetate) salt; N-[7-(aminoiminomethyl)-1-naphthale-
nyl)propanamide, mono (trifluoroacetate) salt;
N-[7-(aminoiminomethyl)-1-n- aphthalenyl)-2-methoxyacetamide,
mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)-1-naphthalenyl]urea, mono(trifluoroacetate)
salt; N-[7-(aminoiminomethyl)-1-naphthalenyl]-2-hydroxyacetamide,
mono(trifluoroacetate) salt;
8-(2-pyrimidinylamino)-2-naphthalenecarboxim- idamide,
bis(trifluoroacetate) salt; 8-amino-2-naphthalenecarboximidamide,
bis(trifluoroacetate) salt;
8-(2-pyridinylamino)-2-naphthalenecarboximida- mide,
bis(trifluoroacetate) salt; and
N-hydroxy-8-(2-pyrimidinylamino)-2-n- aphthalenecarboximidamide,
mono(trifluoroacetate) salt.
6. A compound according to claim 1 wherein A is --L.sub.AR.sub.A, B
is --L.sub.BR.sub.B, and C is hydrogen.
7. A compound according to claim 6 which is 6,
7-dimethoxy-2-naphthaleneca- rboximidamide mono(trifluoroacetate)
salt.
8. A compound according to claim 1 wherein A is --L.sub.AR.sub.A; B
is hydrogen; and C is --L.sub.CR.sub.C.
9. A compound according to claim 8 selected from the group
consisting of methyl
6-(aminoiminomethyl)-4-[(methoxycarbonyl)amino]-2-naphthalenecarbo-
xylate mono(trifluoroacetate) salt;
6-methoxy-8-benzyloxy-2-naphthalenecar- boximidamide
mono(trifluoroacetate) salt; 2-[(7-aminoiminomethyl-3-methoxy- -I
-naphthalenyl)oxy]acetamide mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-4-(3-furanyl)-N-
[4-(trifluoromethyl)phenyl]-2-napht- halenecarboxamide,
mono(trifluoroacetate) salt; 6-(aminoiminomethyl)-4-(3--
furanyl)-N-(4-pyridinyl)-2-naphthalenecarboxamide, dihydrochloride;
6-(aminoiminomethyl)-4-(3-furanyl)-N-(1H,
pyrazol-3-yl)-2-naphthalenecarb- oxamide, dihydrochloride;
6-(aminoiminomethyl)-4-(3-furanyl)-N-(3-pyridiny-
l)-2-naphthalenecarboxamide, dihydrochloride; methyl
[7-(aminoiminomethyl)-3-[[[4-(aminomethyl)phenyl]amino]carbonyl]-1-naphat-
halenyl]carbamate, bis(trifluoroacetate) salt;
6-(aminoiminomethyl)-4-(3-f-
uranyl)-N-(2-pyridinyl)-2-naphthalenecarboxamide, dihydrochloride;
6-(aminoiminomethyl)-4-(3-furanyl)-N-phenyl-2-naphthalenecarboxamide,
monohydrochloride;
6-(aminoiminomethyl)-4-[1-(methylsulfonyl)-1H-pyrazol--
4-yl]-N-phenyl-2-naphthalenecarboxamide, monohydrochloride;
6-(aminoiminomethyl)-4-[5-(methylthio)-3-furanyl)]-N-phenyl-2-naphthalene-
carboxamide, monohydrochloride;
6-(aminoiminomethyl)-N-[4-(aminomethyl)phe-
nyl]-4-(2-pyrimidinylamino)-2-naphthalenecarboxamide,
tris(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-phenyl-4-(2-pyrimidin-
ylamino)-2naphthalenecarboxamide, mono(trifluoroacetate) salt;
N-[(4-(aminomethyl)phenyl]-6-[amino(hydroxyimino)methyl]-4-(2-pyrimidinyl-
amino)-2-naphthalenecarboxamide, bis(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-[4-(hydroxymethyl)phenyl]-4-(2-pyrimidinylamino)-2-
-naphthalenecarboxamide, mono(trifluoroacetate) salt; methyl
[3-[[[4-(aminomethyl)phenyl]amino]carbonyl]-7-[4-amino(hydroxyimino)methy-
l]-1-naphthalenyl]carbamate, bis(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-phenyl-4-(tetrahydro-3-furanyl)-2-naphthalenecarbo-
xamide,monohydrochloride;
6-[amino(hydroxyimino)methyl]-N-phenyl-4-(2-pyri-
midinylamino)-2-naphthalenecarboxamide;
6-(aminoiminomethyl)-4-[5-(ethylth-
io)-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,monohydrochloride;
6-(aminoiminomethyl)-4-[5-(propylthio)-3-furanyl]-N-phenyl-2-naphthalenec-
arboxamide,monohydrochloride;
6-(aminoiminomethyl)-N-phenyl-4-(2-pyrrolidi-
nyl)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-4-[5-(propylsulfonyl)-3-furanyl]-N-phenyl-2-naphthal-
enecarboxamide, monohydrochloride;
6-(aminoiminomethyl)-4-[5-[methylthio)m-
ethyl]-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,
monohydrochloride;
6-(aminoiminomethyl)-4-[5-(methoxymethyl)-3-furanyl]-N-phenyl-2-naphthale-
necarboxamide, monohydrochloride; naphthalenecarboxamide,
mono(trifluoroacetate) salt; and
6-(aminoiminomethyl)-4-[5-(ethythio)tetr-
ahydro-3-furanyl]-N-phenyl-2-naphthalenecarboxamide,
monohydrochloride.
10. A compound according to claim 1 wherein A is --L.sub.AR.sub.A,
B is --L.sub.BR.sub.B, and C is --L.sub.CR.sub.C.
11. A compound according to claim 10 which is 6, 7,
8-trimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate)
salt.
12. A compound according to claim 1 wherein A is hydrogen; B is
--L.sub.BR.sub.B; and C is L.sub.CR.sub.C.
13. A compound according to claim 12 selected from the group
consisting of 7, 8-Dimethoxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
2-[(7-aminoiminomethyl)-2-methoxy-1-naphthalenyl)oxy]acetamide
mono(trifluoroacetate) salt;
7-benzyloxy-8-iodo-2-naphthalenecarboximidam- ide
mono(trifluoroacetate) salt; methyl
[(7-aminoiminomethyl-2-methoxy-1-n- aphthalenyl)oxy]acetate
mono(trifluoroacetate) salt;
2-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-yl-acetic acid
mono(trifluoroacetate) salt;
1-[(7-aminoiminomethyl-2-methoxy-1-naphthale-
nyl)oxy]-3-hydroxypropane mono(trifluoroacetate) salt;
1-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-bromopropane
mono(hydrochloride) salt;
3-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl- )oxy]propene
mono(trifluoroacetate) salt; 1-[(7-aminoiminomethyl-2-methoxy-
-1-naphthalenyl)oxy]-3-phenylpropane mono(hydrochloride) salt;
1-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-[1-(3,4-dimethoxy)-
phenyl]propane mono(hydrochloride) salt;
7-methoxy-8-(2-furanyl)-2-naphtha- lenecarboximidamide
mono(trifluoroacetate) salt; (E)- {7-methoxy-8-[2-(phenyl)ethenyl]
} -2-naphthaleneimidamide mono(trifluoroacetate) salt 7-(2
hydroxyethoxy)-8-iodo-2-naphthalenecarbo- ximidamide
mono(trifluoroacetate, salt, 7-propoxy-8-iodo-2-naphthalenecarb-
oximidamide mono(trifluoroacetate) salt;
7-methoxy-8-(1H-pyrazol-4-yl)-2-n- aphthalenecarboximidamide
bis(trifluoroacetate) salt;
7-methoxy-8-iodo-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
7-methoxy-8-(3-furanyl)-2-naphthalenecarboximidamide
mono(methanesulfonate) salt;
7-methoxy-8-(2-benzofuranyl)naphthalene-2-ca- rboximidamide
mono(methanesulfonate) salt; (E)-8-[2-(1
,3-benzodioxol-5-yl)ethenyl]-2-naphthalenecarboximidamide
mono(methanesulfonate) salt;
(.+-.)-7-methoxy-8-(tetrahydro-3-furanyl)-2--
naphthalenecarboximidamide mono(methanesulfonate) salt;
7-methoxy-8-[2-pyrimidinyl(oxy)]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
7-methoxy-8-[2-thiazoyl(oxy)]naphthalene-2-c- arboximidamide
mono(trifluoroacetate) salt; 7-methoxy-8-(4-nitrophenoxy)-2-
-naphthalenecarboximidamide mono(trifluoroacetate) salt;
7-methoxy-8-pentafluorophenoxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
7-methoxy-8-[N-2-pyrimidinyl(amino)]-2-napht- halenecarboximidamide
mono(trifluoroacetate) salt; 4-[7-(aminoiminomethyl)-
-2-methoxy-1-naphthalenyl]dihydro-2(3 H)-fiuranone
mono(trifluoroacetate) salt;
7-methoxy-8-(1-acetyl-1H-pyrazolyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
7-methoxy-8-[1-(methylsulfonyl)-1H-4-pyrazol-
yl]-2-naphthalenecarboximidamide mono(trifluoroacetate) salt;
6-[2-(4-aminophenyl)ethoxy]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt; methyl
[3-methoxy-6-(aminoiminomethyl)-4-nap- hthalenyl]carbamate
mono(trifluoroacetate) salt; 7-methoxy-8-[2-pyrimidiny-
l(amino)]-2-naphthalenecarboximidamide bis(trifluoroacetate) salt;
methyl [7-(aminoiminomethyl)-2-methoxy-1-naphthalenyl)carbamate,
mono(trifluoroacetate) salt;
7-methoxy-8-(2-pyrimidinylamino)-2-naphthale- necarboximidamide,
bis(trifluoroacetate) salt; 7-methoxy-8-[(phenylmethyl)-
amino]-2-naphthalenecarboximidamide, mono(trifluoroacetate) salt,
7-methoxy-8-(phenylamino)-2-naphthalenecarboximidamide,
mono(trifluoroacetate) salt;
7-methoxy-8-[(4-methoxyphenyl)amino]-2-napht-
halenecarboximidamide, mono(trifluoroacetate) salt;
(E)-3-[7-(aminoiminomethyl)-2-methoxy-1-naphthalenyl)-2-propenamide,
mono(trifluoroacetate) salt;
7-methoxy-8-(3-oxo-1-cyclopenten-1-yl)-2-nap-
hthalenecarboximidamide, mono(trifluoroacetate) salt; methyl
4-[[[7-(aminoiminomethyl)-1-(2-pyrimidinylamino)-2-naphthalenyl]oxy]methy-
l]benzoate, mono(trifluoroacetate) salt;
4-[[[7-(aminoiminomethyl)-1-(2-py-
rimidinylamino)-2-naphthalenyl]oxy]methyl] benzoic acid,
mono(trifluoroacetate) salt;
7-methoxy-8-(pyrazinyloxy)-2-naphthalenecarb- oximidamide,
dimethanesulfonate salt; 7-methoxy-8-(phenylthio)-2-naphthale-
necarboximidamide, methanesulfonate; and
7-methoxy-8-(pyrazinylamino)-2-na- phthalenecarboximidamide,
bis(trifluoroacetate) salt.
14. A compound selected from the group consisting of 7,
8-dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate)
salt; 6, 7, 8-trimethoxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt; 6,
7-dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate)
salt; 2-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]acetamide
mono(trifluoroacetate) salt;
7-benzyloxy-8-iodo-2-naphthalenecarboximidam- ide
mono(trifluoroacetate) salt; methyl
[(7-aminoiminomethyl-2-methoxy-1-n- aphthalenyl)oxy]acetate
mono(trifluoroacetate) salt;
2-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-yl-acetic acid
mono(trifluoroacetate) salt;
1-[(7-aminoiminomethyl-2-methoxy-1-naphthale-
nyl)oxy]-3-hydroxypropane mono(trifluoroacetate) salt; phenylmethyl
[7-(aminoiminomethyl)-1-naphthalenyl)carbamate
mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)-1-naphthialenyl)acetamide
mono(trifluoroacetate) salt; methyl
[7-(aminoiminomethyl)-1-naphthalenlyl- )carbamate
mono(trifluoroacetate) salt; methyl 3-[[7-(aminoiminomethyl)-1--
naphthalenyljamino]-3-oxopropanoate mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)-1-naphthalenyl1-2-(phenylmethoxy)acetamide
mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)-1-naphthalenyl]-1,3--
benzodioxide-3-carboxamide mono(trifluoroacetate) salt;
N-[7-(aminoiminomethyl)-1-naphthalenyl]benzenemethanesulfonamide
mono(trifluoroacetate) salt;
1-[(7-aminoiminomethyl-2-methoxy-1-naphthale-
nyl)oxy]-3-bromopropane mono(hydrochloride) salt;
3-[(7-aminoiminomethyl-2- -methoxy-1-naphthalenyl)oxy]propene
mono(trifluoroacetate) salt;
1-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-phenylpropane
mono(hydrochloride) salt;
1-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl- )oxy]-3-
[1-(3,4-dimethoxy)phenyl]-propane mono(hydrochloride) salt;
7-methoxy-8-(2-furanyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt; methyl
6-(aminoiminomethyl)-4-[(methoxycarbo-
nyl)amino]-2-naphthalenecarboxylate mono(trifluoroacetate) salt;
(E)-6-[2-(phenyl)ethenyl]-2-naphthaleneimidamide
mono(trifluoroacetate) salt;
7-(2-hydroxyethoxy)-8-iodo-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
7-(2-hydroxyethoxy)-2-naphthalenecarboximida- mide
mono(trifluoroacetate) salt;
6-methoxy-8-benzyloxy-2-naphthalenecarbo- ximidamide
mono(trifluoroacetate) salt; 2-[(7-aminoiminomethyl-3-methoxy-1-
-naphthalenyl)oxy]acetamide mono(trifluoroacetate) salt;
7-propoxy-8-iodo-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt; 7-methoxy-8-(l
H-pyrazol-4-yl)-2-naphthalenecarboximidamide mono(trifluoroacetate)
salt; 7-methoxy-8-iodo-2-naphthalenecarboximidamid- e
mono(trifluoroacetate) salt;
7-methoxy-8-(3-furanyl)-2-naphthalenecarbox- imidamide
mono(methanesulfonate) salt; 7-methoxy-8-(2-benzofuranyl)naphtha-
lene-2-carboximidamide mono(methanesulfonate) salt;
(E)-8-[2-(1,3-benzodioxol-5-yl)ethenyl]-2-naphthalenecarboximidamide
mono(methanesulfonate) salt;
(.+-.)-7-methoxy-8-(tetrahydro-3-furanyl)-2--
naphthalenecarboximidamide mono(methanesulfonate) salt;
7-methoxy-8-[2-pyrimidinyl(oxy)]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
7-methoxy-8-[2-thiazoyl(oxy)]naphthalene-2-c- arboximidamide
mono(trifluoroacetate) salt; 7-methoxy-8-(4-nitrophenoxy)-2-
-naphthalenecarboximidamide mono(trifluoroacetate) salt;
7-methoxy-8-pentafluorophenoxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
7-methoxy-8-[N-2-pyrimidinyl(amino)]-2-napht- halenecarboximidamide
mono(trifluoroacetate) salt; N-(6-aminoiminomethyl-2-
-naphthalenyl)-N'-benzylurea mono(trifluoroacetate) salt;
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-methylurea
mono(trifluoroacetate) salt;
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-iso- propylurea
mono(trifluoroacetate) salt; N-(6-aminoiminomethyl-2-naphthalen-
yl)-N'-phenyl-N'-methylurea mono(trifluoroacetate) salt;
6-aminonaphthalene-2-carboximidamide mono(trifluoroacetate) salt;
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-cyclohexylurea
mono(trifluoroacetate) salt;
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-ben- zyloxyurea
mono(trifluoroacetate) salt; 1, 1-dimethylethyl
[4-[[(6-cyano-2-naphthalenyl)amino]carbonyl]phenyl]carbamate
mono(trifluoroacetate) salt
N-[6-(aminoiminomethyl)-2-naphthalenyl]-4-(am- inomethyl)benzamide
mono(trifluoroacetate) salt; 4-[7-(aminoiminomethyl)-2-
-methoxy-1-naphthalenyl]dihydro-2(3H)-furanone
mono(trifluoroacetate) salt;
7-methoxy-8-(1-acetyl-1H-pyrazolyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt; 7-methoxy-8-
[1-(methylsulfonyl)-1H-4-pyrazo- lyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt; methyl
[3-methoxy-6-(aminoiminomethyl)-4-naphthalenyl]carbamate
mono(trifluoroacetate) salt;
7-methoxy-8-[2-pyrimidinyl(amino)]-2-naphtha- lenecarboximidamide;
and bis(trifluoroacetate) salt.
15. A method for inhibiting urokinase in a mammal in need of such
treatment, comprising adminstering to the mammal a therapeutically
effective amount of a compound of claim 1.
16. A composition for inhibiting urokinase comprising both a
pharmaceutical carrier and a therapeutically effective amount of a
compound of claim 1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 08/901,040, filed Jul. 25, 1997, pending.
BACKGROUND OF THE INVENTION
[0002] The present invention provides naphthamidine compounds which
inhibit the urokinase enzyme, pharmaceutical compositions
containing these compounds and medical methods of treatment using
these compounds.
TECHNICAL FIELD
[0003] 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. Plasminogen activation
(cleavage of this bond by the urokinase enzyme) results in
formation of plasmin, a potent general protease.
[0004] Many cell types use urokinase as a key initiator of
plasmin-mediated proteolytic degradation or modification of
extracellular support structures such as extracellular matrix (ECM)
and basement membrane (BM). Cells exist, move and interact with
each other in tissues and organs within the physical framework
provided by ECM and BM. Movement of cells within ECM or across BM
requires local proteolytic degradation or modification of the
structures and allows cells to invade adjacent areas previously
unavailable prior to the degradation or modification.
[0005] Cellular invasiveness intiated by urokinase is central to a
variety of normal and disease-state physiological processes (Blasi,
F., Vassalli, J. D., and Dano, K. J. Cell Biol. 104:801-804, 1987;
Dano, K., Anderson, P. A., Grondahl-Hansen, J., Kristensen, P.,
Nielsen, L. S., and Skriver, L. 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 remodelling during wound repair
and organ differentiation, fibrosis, tumor invasion, metastatic
spread of tumor cells from primary to secondary sites and tissue
destruction in arthritis. Amiloride, for example, a known urokinase
inhibitor of only moderate potency, has been reported to inhibit
tumor metastasis in vivo (Kellen, J. A., Mirakian, A. Kolin, A.
Anticancer Res. 8:1373-1376, 1988) and angiogenesis/capillary
network formation in vitro (Alliegro, M. C. and Glaser, B. M. J.
Cell Biol. 115[3 Pt 2]: 402a, 1991).
[0006] Inhibitors of urokinase, therefore, have mechanism-based
anti-angiogenic, anti-arthritic, anti-inflammatory,
anti-retinopathic (for angiogenesis-dependent retinopathies),
contraceptive and tumoristatic uses.
SUMMARY OF THE INVENTION
[0007] In its principle embodiment, the present invention provides
a compound or a pharmaceutically acceptable salt, ester or prodrug
thereof, of formula (I) 2
[0008] Z is selected from the group consisting of
[0009] (1) nitrogen;
[0010] (2) methine; and
[0011] (3) methine substituted with --NR.sub.1R.sub.2;
[0012] A is selected from the group consisting of
[0013] (1) hydrogen and
[0014] (2) --L.sub.AR.sub.A;
[0015] B is selected from the group consisting of
[0016] (1) hydrogen and
[0017] (2) --L.sub.BR.sub.B and
[0018] C is selected from the group consisting of
[0019] (1) hydrogen and
[0020] (2) --L.sub.CR.sub.C,
[0021] with the proviso that at least one of A, B or C is other
than hydrogen; and
[0022] with the proviso that when A is other than hydrogen, at
least one of B or C is other than hydrogen,
[0023] wherein for A, B, and C, L.sub.A, L.sub.B and L.sub.C are
independently selected from the group consisting of
[0024] (1) a covalent bond,
[0025] (2) --CH.sub.2).sub.m--,
[0026] (3) --NR.sub.1--,
[0027] (4) --NR.sub.2C(X)NR.sub.3--,
[0028] (5) --C(X)--,
[0029] (6) --NR.sub.2C(X)--,
[0030] (7) --C(X)NR.sub.2--,
[0031] (8) --CH.dbd.CH--,
[0032] (9) --C.ident.C--,
[0033] (10) --O--,
[0034] (11) --S(O).sub.t--,
[0035] (12) --C.dbd.--C(CH.sub.2).sub.nNR.sub.2C(X)--,
[0036] (13) --C(X)NR.sub.2(CH.sub.2).sub.nC.ident.--C--,
[0037] (14) --(CH.sub.2).sub.nNSO.sub.2--,
[0038] (15) --NR.sub.2SO.sub.2(CH.sub.2).sub.nC.ident.C--,
[0039] (16)
--C.ident.--C(CH.sub.2).sub.nNR.sub.2SO.sub.2NR.sub.3--,
[0040] (17)
--NR.sub.2SO.sub.2NR.sub.3(CH.sub.2).sub.nC.ident.C--,
[0041] (18) --SO.sub.2NR.sub.2--,
[0042] (19) --NR.sub.2SO.sub.2--,
[0043] (20) --NR.sub.2SO.sub.2NR.sub.3--,
[0044] (21) --N.dbd.N--,
[0045] (22) --C(X)N(OR.sub.2)--,
[0046] (23) --N(OR.sub.2)C(X)--,
[0047] (24) --HC.dbd.CH(CH.sub.2).sub.nNR.sub.2C(X)--,
[0048] (25) --(CH.sub.2).sub.nNR.sub.2C(X)CH.dbd.CH--,
[0049] (26) --CH.dbd.CH(CH.sub.2).sub.nNSO.sub.2--,
[0050] (27) --NR.sub.2SO.sub.2(CH.sub.2).sub.nCH.dbd.CH--,
[0051] (28) --(CH.sub.2).sub.nNR.sub.2SO.sub.2NR.sub.3--,
[0052] (29)
--NR.sub.2SO.sub.2NR.sub.3(CH.sub.2).sub.nCH.dbd.CH--,
[0053] (30) --NR.sub.2C(O)O--,
[0054] (31) --OC(O)NR.sub.2--,
[0055] (32) --CH--NO--,
[0056] (33) --ON.dbd.CH-- and
[0057] (34) 3
[0058] wherein W is selected from the group consisting of
[0059] (a) --O--,
[0060] (b) --S--,
[0061] (c) --NR.sub.1-- and
[0062] (d) --(CH.sub.2).sub.m--,
[0063] wherein each functional group is depicted with its
right-hand end being the end which is attached to the naphthyl or
quinolyl ring and its left-hand end being the end which is attached
to R.sub.A, R.sub.B or R.sub.C;
[0064] R.sub.A, R.sub.B and R.sub.C are independently selected from
the group consisting of
[0065] (1) aryl;
[0066] (2) arylalkoxy, wherein the alkylene group is of one to six
carbon atoms;
[0067] (3) alkyl of one to ten carbon atoms;
[0068] (4) alkenyl of two to ten carbon atoms;
[0069] (5) alkoxycarbonyl of one to six carbon atoms;
[0070] (6) alkynyl of two to ten carbon atoms;
[0071] (7) halogen;
[0072] (8) --NR.sub.1R.sub.2;
[0073] (9) heterocycle;
[0074] (10) cycloalkenyl of four to twelve carbon atoms;
[0075] (11) cycloalkyl of three to twelve carbon atoms;
[0076] (12) --NR.sub.1C(O)NR.sub.2R.sub.3; and
[0077] (13) --NR.sub.1 C(O)R.sub.50, wherein R.sub.50 is alkyl of
one to six carbon atoms;
[0078] wherein, at each occurence, R.sub.1 is selected from the
group consisting of
[0079] (1) hydrogen;
[0080] (2) an N-protecting group;
[0081] (3) alkyl of one to six carbon atoms;
[0082] (4) alkenyl of two to six carbon atoms;
[0083] (5) alkynyl of two to six carbon atoms;
[0084] (6) aryl;
[0085] (7) arylalkyl, wherein the alkylene group is of one to six
carbon atoms;
[0086] (8) cycloalkyl of three to eight carbon atoms and
[0087] (9) cycloalkylalkyl, wherein the cycloalkyl group is of
three to eight carbon atoms, and the alkylene group is of one to
ten carbon atoms; and
[0088] wherein, at each occurence, R.sub.2 and R.sub.3 are
independently selected from the group consisting of
[0089] (1) hydrogen;
[0090] (2) alkyl of one to six carbon atoms;
[0091] (3) alkenyl of two to six carbon atoms;
[0092] (4) alkynyl of two to six carbon atoms;
[0093] (5) aryl;
[0094] (6) arylalkyl, wherein the alkylene group is of one to six
carbon atoms
[0095] (7) cycloalkyl of three to eight carbon atoms and
[0096] (8) cycloalkylalkyl, wherein the cycloalkyl group is of
three to eight carbon atoms, and the alkylene group is of one to
ten carbon atoms; and
[0097] wherein, at each occurence, X is selected from the group
consisting of
[0098] (1) 0 and
[0099] (2) S; and
[0100] wherein, at each occurence,
[0101] m is one to five,
[0102] n is zero to four and
[0103] t is zero to two; and
[0104] wherein, at each occurence, the alkyl, alkenyl, alkynyl,
aryl, heterocycle, cycloalkyl, and cycloalkenyl groups are
optionally substituted.
[0105] The present invention also relates to a method of inhibiting
urokinase in a mammal, particularly humans, by administering a
therapeutically effective amount of a composition comprising a
compound of formula (I).
[0106] The present invention also relates to pharmaceutical
compositions which comprise a therapeutically effective amount of a
compound of formula (I) in combination with a pharmaceutically
acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
[0107] As used throughout this specification and the appended
claims, the following terms have the meanings specified:
[0108] The term "alkyl," as used herein, represents a monovalent
group derived from a straight or branched chain saturated
hydrocarbon by the removal of a single hydrogen atom and is
exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and
tert-butyl, neopentyl and the like and may be optionally
substituted with one, two, three or four substituents independently
selected from the group consisting of (1) alkoxy of one to six
carbon atoms; (2) alkylsulfinyl of one to six carbon atoms; (3)
alkylsulfonyl of one to six carbon atoms; (4) amino; (5) aryl; (6)
arylalkoxy, wherein the alkylene group is of one to six carbon
atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10) cycloalkyl
of three to eight carbon atoms; (11) halo; (12) heterocycle; (13)
(heterocycle)oxy; (14) (heterocycle)oyl; (15) hydroxy; (16)
N-protected amino; (17) nitro; (18) oxo; (19) spiroalkyl of three
to eight carbon atoms; (20) thioalkoxy of one to six carbon atoms;
(21) --CO.sub.2R.sub.2; (22) --C(O)NR.sub.2R.sub.3; (23)
--SO.sub.2R.sub.4, wherein R.sub.4 is selected from the group
consisting of (a) alkyl, (b) aryl and (c) arylalkyl, wherein the
alkylene group is of one to six carbon atoms; (24)
--SO.sub.2NR.sub.5R.sub.6, wherein R.sub.5 and R.sub.6 are
independently selected from the group consisting of (a) hydrogen,
(b) alkyl, (c) aryl and (d) arylalkyl, wherein the alkylene group
is of one to six carbon atoms; (25) --NR.sub.7R.sub.8, wherein
R.sub.7 and R.sub.8 are independently selected from the group
consisting of (a) hydrogen; (b) an N-protecting group; (c) alkyl of
one to six carbon atoms; (d) alkenyl of two to six carbon atoms;
(e) alkynyl of two to six carbon atoms; (f) aryl; (g) arylalkyl,
wherein the alkylene group is of one to six carbon atoms; (h)
cycloalkyl of three to eight carbon atoms and (i) cycloalkylalkyl,
wherein the cycloalkyl group is of three to eight carbon atoms, and
the alkylene group is of one to ten carbon atoms, with the proviso
that no two groups are bound to the nitrogen atom through a
carbonyl group or a sulfonyl group.
[0109] The term "alkanoyl," as used herein, represents an alkyl
group, as defined herein, attached to the parent molecular group
through a carbonyl group, as defined herein, and is exemplified by
formyl, acetyl, propionyl, butanoyl and the like.
[0110] The term "alkenyl," as used herein, represents monovalent
straight or branched chain groups containing a carbon-carbon double
bond derived from an alkene by the removal of one hydrogen atom and
is exemplified by ethenyl, 1-propenyl, 2-propenyl,
2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like and may be
optionally substituted with one, two, three or four substituents
independently selected from the group consisting of (1) alkoxy of
one to six carbon atoms; (2) alkylsulfinyl of one to six carbon
atoms; (3) alkylsulfonyl of one to six carbon atoms; (4) amino; (5)
aryl; (6) arylalkoxy, wherein the alkylene group is of one to six
carbon atoms; (7) aryloyl; (8) azido; (9) carboxaldehyde; (10)
cycloalkyl of three to eight carbon atoms; (11) halo; (12)
heterocycle; (13) (heterocycle)oxy; (14) (heterocycle)oyl; (15)
hydroxy; (16) N-protected amino; (17) nitro; (18) oxo; (19)
spiroalkyl of three to eight carbon atoms; (20) thioalkoxy of one
to six carbon atoms; (21) --CO.sub.2R.sub.2; (22)
--C(O)NR.sub.2R.sub.3; (23) --SO.sub.2R.sub.4, wherein R.sub.4 is
selected from the group consisting of (a) alkyl, (b) aryl and (c)
arylalkyl, wherein the alkylene group is of one to six carbon
atoms; (24) --SO.sub.2NR.sub.5R.sub.6, wherein R.sub.5 and R.sub.6
are independently selected from the group consisting of (a)
hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the
alkylene group is of one to six carbon atoms; (25)
--NR.sub.7R.sub.8, wherein R.sub.7 and R.sub.8 are independently
selected from the group consisting of (a) hydrogen; (b) an
N-protecting group; (c) alkyl of one to six carbon atoms; (d)
alkenyl of two to six carbon atoms; (e) alkynyl of two to six
carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkylene group
is of one to six carbon atoms; (h) cycloalkyl of three to eight
carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group
is of three to eight carbon atoms, and the alkylene group is of one
to ten carbon atoms, with the proviso that no two groups are bound
to the nitrogen atom through a carbonyl group or a sulfonyl
group.
[0111] The term "alkoxy," as used herein, represents an alkyl group
attached to the parent molecular group through an oxygen atom.
[0112] The term "alkoxyalkyl" as used herein, represents an alkyl
group to which is attached an alkoxy group.
[0113] The term "alkoxycarbonyl," as used herein, represents an
ester group; i.e. an alkoxy group, attached to the parent molecular
group through a carbonyl group and is exemplified by
methoxycarbonyl, ethoxycarbonyl and the like.
[0114] The term "alkylene," as used herein, represents a saturated
divalent hydrocarbon group derived from a straight or branched
chain saturated hydrocarbon by the removal of two hydrogen atoms,
and is exemplified by methylene, ethylene, isopropylene and the
like.
[0115] The term "alkylsulfinyl," as used herein, represents an
alkyl group attached to the parent molecular group through an
--S(O)-- group.
[0116] The term "alkylsulfinylalkyl," as used herein, represents an
alkyl group, as defined herein, substituted by a sulfinyl
group.
[0117] The term "alkylsulfonyl," as used herein, represents an
alkyl group attached to the parent molecular group through an
--SO.sub.2-- group.
[0118] The term "alkylsulfonylalkyl," as used herein, represents an
alkyl group, as defined herein, substituted by a sulfonyl
group.
[0119] The term "alkynyl," as used herein, represents monovalent
straight or branched chain groups of two to six carbon atoms
containing a carbon-carbon triple bond derived from an alkyne by
the removal of one hydrogen atom and is exemplified by ethynyl,
1-propynyl, and the like and may be optionally substituted with
one, two, three or four substituents independently selected from
the group consisting of (1) alkoxy of one to six carbon atoms; (2)
alkylsulfinyl of one to six carbon atoms; (3) alkylsulfonyl of one
to six carbon atoms; (4) amino; (5) aryl; (6) arylalkoxy, wherein
the alkylene group is of one to six carbon atoms; (7) aryloyl; (8)
azido; (9) carboxaldehyde; (10) cycloalkyl of three to eight carbon
atoms; (11) halo; (12) heterocycle; (13) (heterocycle)oxy; (14)
(heterocycle)oyl; (15) hydroxy; (16) N-protected amino; (17) nitro;
(18) oxo; (19) spiroalkyl of three to eight carbon atoms; (20)
thioalkoxy of one to six carbon atoms; (21) --C0.sub.2R.sub.2; (22)
--C(O)NR.sub.2R.sub.3; (23) --SO.sub.2R.sub.4, wherein R.sub.4 is
selected from the group consisting of (a) alkyl, (b) aryl and (c)
arylalkyl, wherein the alkylene group is of one to six carbon
atoms; (24) --SO.sub.2NR.sub.5R.sub.6, wherein R.sub.5 and R.sub.6
are independently selected from the group consisting of (a)
hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the
alkylene group is of one to six carbon atoms; (25)
--NR.sub.7R.sub.8, wherein R.sub.7 and R.sub.8 are independently
selected from the group consisting of (a) hydrogen; (b) an
N-protecting group; (c) alkyl of one to six carbon atoms; (d)
alkenyl of two to six carbon atoms; (e) alkynyl of two to six
carbon atoms; (f) aryl; (g) arylalkyl, wherein the alkylene group
is of one to six carbon atoms; (h) cycloalkyl of three to eight
carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group
is of three to eight carbon atoms, and the alkylene group is of one
to ten carbon atoms, with the proviso that no two groups are bound
to the nitrogen atom through a carbonyl group or a sulfonyl
group.
[0120] The term "amino," as used herein, represents an --NH.sub.2
group.
[0121] The term "aminoalkyl," as used herein, represents an alkyl
group, as defined herein, substituted by an amino group.
[0122] The term "aryl," as used herein, represents a mono- or
bicyclic carbocyclic ring system having one or two aromatic rings
and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl,
1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the
like and may be optionally substituted with one, two, three, four
or five substituents independently selected from the group
consisting of (1) alkanoyl of one to six carbon atoms; (2) alkyl of
one to six carbon atoms; (3) alkoxy of one to six carbon atoms; (4)
alkoxyalkyl, wherein the alkyl and alkylene goups are independently
of one to six carbon atoms; (5) alkylsulfinyl of one to six carbon
atoms; (6) alkylsulfinylalkyl, wherein the alkyl and alkylene
groups are independently of one to six carbon atoms; (7)
alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl,
wherein the alkyl and alkylene groups are independently of one to
six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group
is of one to six carbon atoms; (11) amino; (12) aminoalkyl of one
to six carbon atoms; (13) aryl; (14) arylalkyl, wherein the
alkylene group is of one to six carbon atoms; (15) aryloyl; (16)
azido; (17) azidoalkyl of one to six carbon atoms; (18)
carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkylene
group is of one to six carbon atoms; (20) cycloalkyl of three to
eight carbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl
group is of three to eight carbon atoms and the alkylene group is
of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six
carbon atoms; (24) heterocycle; (25) (heterocycle)oxy; (26)
(heterocycle)oyl; (27) hydroxy; (28) hydroxyalkyl of one to six
carbon atoms; (29) nitro; (30) nitroalkyl of one to six carbon
atoms; (31) N-protected amino; (32) N-protected aminoalkyl, wherein
the alkylene group is of one to six carbon atoms; (33) oxo; (34)
thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl,
wherein the alkyl and alkylene groups are independently of one to
six carbon atoms; (36) --(CH.sub.2).sub.qCO.sub.2R.sub.2, wherein q
is zero to four; (37) --(CH.sub.2).sub.qC(O)NR.sub.2R.sub.3; (38)
(CH.sub.2).sub.qSO.sub.2R.sub.4, wherein R.sub.4 is selected from
the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl,
wherein the alkylene group is of one to six carbon atoms; (39)
(CH.sub.2).sub.qSO.sub.2NR.sub.5R.sub.6, wherein R.sub.5 and
R.sub.6 are independently selected from the group consisting of(a)
hydrogen, (b) alkyl, (c) aryl and(d) arylalkyl, wherein the
alkylene group is of one to six carbon atoms; (40)
--(CH.sub.2).sub.qNR.sub.7R.sub.8, wherein R.sub.7 and R.sub.8 are
independently selected from the group consisting of (a) hydrogen,
(b) an N-protecting group, (c) alkyl of one to six carbon atoms,
(d) alkenyl of two to six carbon atoms, (e) alkynyl of two to six
carbon atoms, (f) aryl, (g) arylalkyl, wherein the alkylene group
is of one to six carbon atoms, (h) cycloalkyl of three to eight
carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group
is of three to eight carbon atoms, and the alkylene group is of one
to ten carbon atoms, with the proviso that no two groups are bound
to the nitrogen atom through a carbonyl group or a sulfonyl group;
(41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44) aryloxy;
(45) cycloalkoxy; (46) cycloalkylalkoxy; and (47) arylalkoxy.
[0123] The term "arylalkyl," as used herein, represents an aryl
group attached to the parent molecular group through an alkyl
group.
[0124] The term "arylalkoxy," as used herein, represents an
arylalkyl group attached to the parent molecular group through an
oxygen atom.
[0125] The term "aryloxy," as used herein, represents an aryl group
which is attached to the parent molecular group through an oxygen
atom.
[0126] The term "aryloyl," as used herein, represents an aryl group
which is attached to the parent molecular group through a carbonyl
group.
[0127] The term "azido," as used herein, represents an --N.sub.3
group.
[0128] The term "azidoalkyl," as used herein, represents an alkyl
group, as defined herein, substituted by an azido group.
[0129] The term "carbonyl," as used herein, represents a C.dbd.O
group.
[0130] The term "carboxaldehyde," as used herein, represents a
--CHO group.
[0131] The term "(carboxaldehyde)alkyl," as used herein, represents
an alkyl group, as defined herein, substituted by a carboxaldehyde
group.
[0132] The term "carboxy," as used herein, represents a --CO.sub.2H
group.
[0133] The term "carboxyalkyl," as used herein, represents an alkyl
group, as defined herein, substituted by a carboxy group.
[0134] The term "cycloalkyl," as used herein represents a
monovalent saturated cyclic hydrocarbon group and is exemplified by
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
bicyclo[2.2. 1 ]heptyl and the like. The cycloalkyl groups of this
invention can be optionally substituted with (1) alkanoyl of one to
six carbon atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy
of one to six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and
alkylene goups are independently of one to six carbon atoms; (5)
alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl,
wherein the alkyl and alkylene groups are independently of one to
six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8)
alkylsulfonylalkyl, wherein the alkyl and alkylene groups are
independently of one to six carbon atoms; (9) aryl; (10) arylalkyl,
wherein the alkyl group is of one to six carbon atoms; (11) amino;
(12) aminoalkyl of one to six carbon atoms; (13) aryl; (14)
arylalkyl, wherein the alkylene group is of one to six carbon
atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six
carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl,
wherein the alkylene group is of one to six carbon atoms; (20)
cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl,
wherein the cycloalkyl group is of three to eight carbon atoms and
the alkylene group is of one to ten carbon atoms; (22) halo; (23)
haloalkyl of one to six carbon atoms; (24) heterocycle; (25)
(heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy; (28)
hydroxyalkyl of one to six carbon atoms; (29) nitro; (30)
nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32)
N-protected aminoalkyl, wherein the alkylene group is of one to six
carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms;
(35) thioalkoxyalkyl, wherein the alkyl and alkylene groups are
independently of one to six carbon atoms; (36)
--(CH.sub.2).sub.qCO.sub.2R.sub.2, wherein q is zero to four; (37)
--(CH.sub.2).sub.qC(O)NR.sub.2R.sub.3; (38)
--(CH.sub.2).sub.qSO.sub.2R.sub.4, wherein R.sub.4 is selected from
the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl,
wherein the alkylene group is of one to six carbon atoms; (39)
--(CH.sub.2).sub.qSO.sub.2NR.sub.5R.sub.6, wherein R.sub.5 and
R.sub.6 are independently selected from the group consisting of(a)
hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl, wherein the
alkylene group is of one to six carbon atoms; (40)
--(CH.sub.2).sub.qNR.sub.7R.sub.8, wherein R.sub.7 and R.sub.8 are
independently selected from the group consisting of (a) hydrogen,
(b) an N-protecting group, (c) alkyl of one to six carbon atoms,
(d) alkenyl of two to six carbon atoms, (e) alkynyl of two to six
carbon atoms, (f) aryl, (g) arylalkyl, wherein the alkylene group
is of one to six carbon atoms, (h) cycloalkyl of three to eight
carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group
is of three to eight carbon atoms, and the alkylene group is of one
to ten carbon atoms, with the proviso that no two groups are bound
to the nitrogen atom through a carbonyl group or a sulfonyl group;
(41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44) aryloxy;
(45) cycloalkoxy; (46) cycloalkylalkoxy; and (47) arylalkoxy.
[0135] The term "cycloalkenyl," as used herein represents a
monovalent cyclic hydrocarbon having at least one carbon-carbon
double bond. The cycloalkenyl groups of this invention can be
optionally substituted with (1) alkanoyl of one to six carbon
atoms; (2) alkyl of one to six carbon atoms; (3) alkoxy of one to
six carbon atoms; (4) alkoxyalkyl, wherein the alkyl and alkylene
goups are independently of one to six carbon atoms; (5)
alkylsulfinyl of one to six carbon atoms; (6) alkylsulfinylalkyl,
wherein the alkyl and alkylene groups are independently of one to
six carbon atoms; (7) alkylsulfonyl of one to six carbon atoms; (8)
alkylsulfonylalkyl, wherein the alkyl and alkylene groups are
independently of one to six carbon atoms; (9) aryl; (10) arylalkyl,
wherein the alkyl group is of one to six carbon atoms; (11) amino;
(12) aminoalkyl of one to six carbon atoms; (13) aryl; (14)
arylalkyl, wherein the alkylene group is of one to six carbon
atoms; (15) aryloyl; (16) azido; (17) azidoalkyl of one to six
carbon atoms; (18) carboxaldehyde; (19) (carboxaldehyde)alkyl,
wherein the alkylene group is of one to six carbon atoms; (20)
cycloalkyl of three to eight carbon atoms; (21) cycloalkylalkyl,
wherein the cycloalkyl group is of three to eight carbon atoms and
the alkylene group is of one to ten carbon atoms; (22) halo; (23)
haloalkyl of one to six carbon atoms; (24) heterocycle; (25)
(heterocycle)oxy; (26) (heterocycle)oyl; (27) hydroxy; (28)
hydroxyalkyl of one to six carbon atoms; (29) nitro; (30)
nitroalkyl of one to six carbon atoms; (31) N-protected amino; (32)
N-protected aminoalkyl, wherein the alkylene group is of one to six
carbon atoms; (33) oxo; (34) thioalkoxy of one to six carbon atoms;
(35) thioalkoxyalkyl, wherein the alkyl and alkylene groups are
independently of one to six carbon atoms; (36)
--(CH.sub.2).sub.qCO.sub.2R.sub.2, wherein q is zero to four; (37)
--(CH.sub.2).sub.qC(O)NR.sub.2R.sub.3; (38)
--(CH.sub.2).sub.qSO.sub.2R.sub.4, wherein R.sub.4 is selected from
the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl,
wherein the alkylene group is of one to six carbon atoms; (39)
--(CH.sub.2).sub.qSO.sub.2NR.sub.5R.sub.6, wherein R.sub.5 and
R.sub.6 are independently selected from the group consisting of(a)
hydrogen, (b) alkyl, (c) aryl and(d) arylalkyl, wherein the
alkylene group is of one to six carbon atoms; (40)
--(CH.sub.2).sub.qNR.sub.7R.sub.8, wherein R.sub.7 and R.sub.8 are
independently selected from the group consisting of (a) hydrogen,
(b) an N-protecting group, (c) alkyl of one to six carbon atoms,
(d) alkenyl of two to six carbon atoms, (e) alkynyl of two to six
carbon atoms, (f) aryl, (g) arylalkyl, wherein the alkylene group
is of one to six carbon atoms, (h) cycloalkyl of three to eight
carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group
is of three to eight carbon atoms, and the alkylene group is of one
to ten carbon atoms, with the proviso that no two groups are bound
to the nitrogen atom through a carbonyl group or a sulfonyl group;
(41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44) aryloxy;
(45) cycloalkoxy; (46) cycloalkylalkoxy; and (47) arylalkoxy.
[0136] The term "cycloalkoxy," as used herein represents a
cycloalkyl group, as defined herein, attached to the parent
molecular group through an oxygen atom.
[0137] The term "cycloalkylalkoxy," as used herein, represents an
alkoxy group, as defined herein, to which is attached a cycloalkyl
group.
[0138] The term "cycloalkylalkyl," as used herein, represents a
cycloalkyl group, as defined herein, attached to the parent
molecular group through an alkyl group.
[0139] The term "haloalkyl," as used herein, represents an alkyl
group, as defined herein, substituted by one, two, or three halogen
atoms and is exemplified by chloromethyl, bromoethyl,
trifluoromethyl and the like.
[0140] The term "halogen," as used herein, represents F, Cl, Br and
I.
[0141] The term "heterocycle," as used herein, represents a 5-, 6-
or 7-membered ring containing one, two or three heteroatoms
independently selected from the group consisting of nitrogen,
oxygen and sulfur. The 5-membered ring has zero to two double bonds
and the 6- and 7-membered rings have zero to three double bonds.
The term "heterocycle" also includes bicyclic, tricyclic and
tetracyclic groups in which any of the above heterocyclic rings is
fused to one or two rings independently selected from the group
consisting of an aryl ring, a cyclohexane ring, a cyclohexene ring,
a cyclopentane ring, a cyclopentene ring and another monocyclic
heterocyclic ring such as indolyl, quinolyl, isoquinolyl,
tetrahydroquinolyl, benzofuryl, benzothienyl and the like.
Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl,
pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl,
imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl,
piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,
isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl,
thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl,
quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl,
benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl,
isoindazoyl, triazolyl, tetrazolyl, oxadiazolyl, uricyl,
thiadiazolyl, pyrimidyl, tetrahydrofuranyl, dihydrofuranyl,
tetrahydrothienyl, dihydrothienyl, dihydroindolyl,
tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl,
dithiazolyl, benzofuranyl, benzothienyl and the like. Heterocyclic
groups also include compounds of the formula 4
[0142] wherein F is selected from the group consisting of
--CH.sub.2--, --CH.sub.2O-- and --O--, and G is selected from the
group consisting of --C(O)-- and --(C(R')(R")).sub.v--, wherein R'
and R" are independently selected from the group consisting of
hydrogen or alkyl of one to four carbon atoms, and v is one to
three and includes groups such as 1,3-benzodioxolyl,
1,4-benzodioxanyl and the like. Any of the heterocycle groups
mentioned herein may be optionally substituted with one, two,
three, four or five substituents independently selected from the
group consisting of (1) alkanoyl of one to six carbon atoms; (2)
alkyl of one to six carbon atoms; (3) alkoxy of one to six carbon
atoms; (4) alkoxyalkyl, wherein the alkyl and alkylene goups are
independently of one to six carbon atoms; (5) alkylsulfinyl of one
to six carbon atoms; (6) alkylsulfinylalkyl, wherein the alkyl and
alkylene groups are independently of one to six carbon atoms; (7)
alkylsulfonyl of one to six carbon atoms; (8) alkylsulfonylalkyl,
wherein the alkyl and alkylene groups are independently of one to
six carbon atoms; (9) aryl; (10) arylalkyl, wherein the alkyl group
is of one to six carbon atoms; (11) amino; (12) aminoalkyl of one
to six carbon atoms; (13) aryl; (14) arylalkyl, wherein the
alkylene group is of one to six carbon atoms; (15) aryloyl; (16)
azido; (17) azidoalkyl of one to six carbon atoms; (18)
carboxaldehyde; (19) (carboxaldehyde)alkyl, wherein the alkylene
group is of one to six carbon atoms; (20) cycloalkyl of three to
eight carbon atoms; (21) cycloalkylalkyl, wherein the cycloalkyl
group is of three to eight carbon atoms and the alkylene group is
of one to ten carbon atoms; (22) halo; (23) haloalkyl of one to six
carbon atoms; (24) heterocycle; (25) (heterocycle)oxy; (26)
(heterocycle)oyl; (27) hydroxy; (28) hydroxyalkyl of one to six
carbon atoms; (29) nitro; (30) nitroalkyl of one to six carbon
atoms; (31) N-protected amino; (32) N-protected aminoalkyl, wherein
the alkylene group is of one to six carbon atoms; (33) oxo; (34)
thioalkoxy of one to six carbon atoms; (35) thioalkoxyalkyl,
wherein the alkyl and alkylene groups are independently of one to
six carbon atoms; (36) --(CH.sub.2).sub.qCO.sub.2R.sub.2, wherein q
is zero to four; (37) --(CH.sub.2).sub.qC(O)NR.sub.2R.sub.3; (38)
--(CH.sub.2).sub.qSO.sub.2R.sub.4, wherein R.sub.4 is selected from
the group consisting of (a) alkyl, (b) aryl and (c) arylalkyl,
wherein the alkylene group is of one to six carbon atoms;(39)
--(CH.sub.2).sub.qSO.sub.2NR.sub.5R.sub.6, wherein R.sub.5 and
R.sub.6 are independently selected from the group consisting of(a)
hydrogen, (b) alkyl, (c) aryl and(d) arylalkyl, wherein the
alkylene group is of one to six carbon atoms; (40)
--(CH.sub.2).sub.qNR.sub.7R.sub.8, wherein R.sub.7 and R.sub.8 are
independently selected from the group consisting of (a) hydrogen,
(b) an N-protecting group, (c) alkyl of one to six carbon atoms,
(d) alkenyl of two to six carbon atoms, (e) alkynyl of two to six
carbon atoms, (f) aryl, (g) arylalkyl, wherein the alkylene group
is of one to six carbon atoms, (h) cycloalkyl of three to eight
carbon atoms and (i) cycloalkylalkyl, wherein the cycloalkyl group
is of three to eight carbon atoms, and the alkylene group is of one
to ten carbon atoms, with the proviso that no two groups are bound
to the nitrogen atom through a carbonyl group or a sulfonyl group;
(41) oxo; (42) perfluoroalkyl; (43) perfluoroalkoxy; (44) aryloxy;
(45) cycloalkoxy; (46) cycloalkylalkoxy; and (47) arylalkoxy.
[0143] The term "(heterocycle)oxy," as used herein, represents a
heterocycle group, as defined herein, attached to the parent
molecular group through oxygen.
[0144] The term "(heterocycle)oyl," as used herein, represents a
heterocycle group, as defined herein, attached to the parent
molecular group through a carbonyl group.
[0145] The term "hydroxy" as used herein, represents an --OH
group.
[0146] The term "hydroxyalkyl," as used herein, represents an alkyl
group, as defined herein, substituted by one to three hydroxy
groups, with the proviso that no more than one hydroxy group may be
attached to a single carbon atom of the alkyl group and is
exemplified by hydroxymethyl, dihydroxypropyl and the like.
[0147] The term "methine" as used herein, represents a =C(H)--
group.
[0148] The term "N-protected amino," as used herein, refers to an
amino group, as defined herein, to which is attached an
N-protecting or nitrogen-protecting group, as defined herein.
[0149] The term "N-protected aminoalkyl," as used herein, refers to
an alkyl group, as defined herein, which is substituted by an
N-protecting or nitrogen-protecting group, as defined herein.
[0150] The term "nitro," as used herein, represents an --NO.sub.2
group.
[0151] The term "nitroalkyl," as used herein, represents an alkyl
group substituted by an --NO.sub.2 group.
[0152] The terms "N-protecting group" or "nitrogen protecting
group" as used herein, represent those groups intended to protect
an amino group against undersirable reactions during synthetic
procedures. Commonly used N-protecting groups are disclosed in
Greene, "Protective Groups In Organic Synthesis," (John Wiley &
Sons, New York (1981)), which is incorporated herein by reference.
N-protecting groups comprise acyl groups such as formyl, acetyl,
propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl,
trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl,
.alpha.-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,
4-nitrobenzoyl and chiral auxiliaries such as protected or
unprotected D, L or D, L-amino acids such as alanine, leucine,
phenylalanine and the like; sulfonyl groups such as
benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming
groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,
2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
2-nitro-4,5-dimethoxybenzyloxycarbonyl,
3,4,5-trimethoxybenzyloxycarbonyl- ,
1-(p-biphenylyl)-1-methylethoxycarbonyl,
.alpha.,.alpha.-dimethyl-3,5-di- methoxybenzyloxycarbonyl,
benzhydryloxycarbonyl, t-butyloxycarbonyl,
diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl,
methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl,
phenoxycarbonyl, 4-nitrophenoxy carbonyl,
fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,
adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and
the like; arylalkyl groups such as benzyl, triphenylmethyl,
benzyloxymethyl and the like and silyl groups such as
trimethylsilyl and the like. Preferred N-protecting groups are
formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl,
phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and
benzyloxycarbonyl (Cbz).
[0153] The term "oxo," as used herein, represents=0.
[0154] The term "perfluoroalkyl," as used herein, represents an
alkyl group, as defined herein, wherein each hydrogen radical bound
to the alkyl group has been replaced by a fluoride radical.
Perfluoroalkyl groups are exemplified by trifluoromethyl,
pentafluoroethyl, and the like.
[0155] The term "perfluoroalkoxy," as used herein, refers to a
perfluoroalkyl group, as defined herein, attached to the parent
molecular group through an oxygen atom.
[0156] The term "pharmaceutically acceptable salt," as use herein,
represents those salts which are, within the scope of sound medical
judgement, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts are well
known in the art. For example, S. M. Berge, et al. describe
pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 1977, 66:1-19. The salts can be prepared in situ during
the final isolation and purification of the compounds of the
invention or separately by reacting the free base group with a
suitable organic acid. Representative acid addition salts include
acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate,
benzoate, bisulfate, borate, butyrate, camphorate,
camphersulfonate, citrate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,
glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,
hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,
malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
propionate, stearate, succinate, sulfate, tartrate, thiocyanate,
toluenesulfonate, undecanoate, valerate salts and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium and the like, as well as
nontoxic ammonium, quaternary ammonium, and amine cations,
including, but not limited to ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine and the like. The term "pharmaceutically
acceptable ester," as used herein, represents esters which
hydrolyze in vivo and include those that break down readily in the
human body to leave the parent compound or a salt thereof. Suitable
ester groups include, for example, those derived from
pharmaceutically acceptable aliphatic carboxylic acids,
particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic
acids, in which each alkyl or alkenyl group preferably has not more
than 6 carbon atoms. Examples of particular esters includes
formates, acetates, propionates, butyates, acrylates and
ethylsuccinates.
[0157] The term "pharmaceutically acceptable prodrugs" as used
herein, represents those prodrugs of the compounds of the present
invention which are, within the scope of sound medical judgement,
suitable for use in contact with with the tissues of humans and
lower animals with undue toxicity, irritation, allergic response,
and the like, commensurate with a reasonable benefit/risk ratio,
and effective for their intended use, as well as the zwitterionic
forms, where possible, of the compounds of the invention.
[0158] The term "prodrug," as used herein, represents compounds
which are rapidly transformed in vivo to the parent compound of the
above formula, for example, by hydrolysis in blood. A thorough
discussion is provided in T. Higuchi and V. Stella, Pro-drugs as
Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series,
Edward B. Roche, ed., Bioreversible Carriers in Drug Design,
American Pharmaceutical Association and Pergamon Press, 1987, and
Judkins, et al.Synthetic Communications, 26(23), 4351-4367 (1996),
each of which is incorporated herein by reference.
[0159] The term "spiroalkyl," as used herein, represents an
alkylene diradical, both ends of which are bonded to the same
carbon atom of the parent group to form a spirocyclic group.
[0160] The term "sulfonyl," as used herein, represents an
--SO.sub.2-group.
[0161] The term "thioalkoxy," as used herein, represents represents
an alkyl group attached to the parent molecular group through a
sulfur atom.
[0162] The term "thioalkoxyalkyl," as used herein, represents an
alkyl group substituted by a thioalkoxy group.
[0163] Asymmetric or chiral centers may exist in the compounds of
the present invention. The present invention contemplates the
various stereoisomers and mixtures thereof. Individual
stereoisomers of compounds of the present invention are prepared
synthetically from commercially available starting materials which
contain asymmetric or chiral centers or by preparation of mixtures
of enantiomeric compounds followed by resolution well-known to
those of ordinary skill in the art. These methods of resolution are
exemplified by (1) attachment of a racemic mixture of enantiomers,
designated (.+-.), to a chiral auxiliary, separation of the
resulting diastereomers by recrystallization or chromatography and
liberation of the optically pure product from the auxiliary or (2)
direct separation of the mixture of optical enantiomers on chiral
chromatographic columns. Enantiomers are designated herein by the
symbols "R" or "S," depending on the configuration of subsitiuents
around the chiral carbon atom.
[0164] Geometric isomers may also exist in the compounds of the
present invention. The present invention contemplates the various
geometric isomers and mixtures thereof resulting from the
arrangement of substituents around a carbon-carbon double bond and
designates such isomers as of the Z or E configuration, wherein the
term "Z" represents substituents on the same side of the
carbon-carbon double bond and the term "E" represents substituents
on opposite sides of the carbon-carbon double bond.
PREFERRED EMBODIMENTS
[0165] Preferred compounds of the present invention have formula
(I), wherein
[0166] A and C are hydrogen and
[0167] B is --L.sub.BR.sub.B, wherein
[0168] --LB-- is --O--, and
[0169] R.sub.B is alkyl of two to six carbon atoms, and
[0170] wherein the alkyl group is substituted.
[0171] More preferred embodiments of the present invention have
formula (I), wherein
[0172] A is --L.sub.AR.sub.A and
[0173] B and C are hydrogen,
[0174] wherein --L.sub.A-- is selected from the group consisting
of
[0175] (1) a covalent bond,
[0176] (2) --(CH.sub.2).sub.m--,
[0177] (3) --NR.sub.2C(X)--,
[0178] (4) --C(X)NR.sub.2--,
[0179] (5) --NR.sub.2C(X)NR.sub.3--,
[0180] (6) --C.ident.C--,
[0181] (7) --CH.dbd.CH--,
[0182] (8) --C(X)NR.sub.2(CH.sub.2).sub.nC.ident.C--
[0183] (9) --C(X)--,
[0184] (10) --O--,
[0185] (11) --OC(O)NR.sub.2-- and
[0186] (12) 5
[0187] and wherein
[0188] R.sub.A is selected from the group consisting of
[0189] (1) amino;
[0190] (2) aryl;
[0191] (3) alkyl of one to ten carbon atoms;
[0192] (4) arylalkyl, wherein the alkylene group is of one to ten
carbon atoms;
[0193] (5) cycloalkyl of three to eight carbon atoms;
[0194] (6) arylalkoxy, wherein the alkylene group is of one to ten
carbon atoms and
[0195] (7) heterocycle, wherein the heterocycle is selected from
the group consisting of
[0196] (1) furanyl,
[0197] (2) thienyl and
[0198] (3) imidazolyl; and
[0199] wherein, at each occurence, R.sub.2 is selected from the
group consisting of
[0200] (1) hydrogen and
[0201] (2) alkyl of one to six carbon atoms; and
[0202] wherein, at each occurence,
[0203] m is two,
[0204] n is one,
[0205] R.sub.1 and R.sub.3 are hydrogen,
[0206] W and X are O,
[0207] aryl is phenyl,
[0208] the alkyl group and the aryl group are optionally
substituted and
[0209] the alkenyl group is substituted.
[0210] Still more preferred compounds of the present invention have
formula (I), wherein
[0211] A and B are hydrogen;
[0212] C is --L.sub.CR.sub.C;
[0213] --L.sub.C-- is selected from the group consisting of
[0214] (1) a covalent bond,
[0215] (2) --OC(O)NR.sub.2--,
[0216] (3) --SO.sub.2NR.sub.2--,
[0217] (4) --C(X)NR.sub.2--,
[0218] (5) --NR.sub.1-- and
[0219] (6) --O--;
[0220] R.sub.C is selected from the group consisting of
[0221] (1) alkyl of one to six carbon atoms;
[0222] (2) aryl;
[0223] (3) arylalkyl, wherein the alkylene group is of one to six
carbon atoms and
[0224] (4) hererocycle, wherein the heterocycle is selected from
the group consisting of
[0225] (1) furanyl;
[0226] (2) pyrimidinyl; and
[0227] (3) 6
[0228] wherein F is --O--, G is --(C(R')(R")).sub.v--, R' and R"
are hydrogen and v is one;
[0229] X is O; and
[0230] wherein, at each occurence,
[0231] R.sub.1 and R.sub.2 are H,
[0232] aryl is phenyl and
[0233] the alkyl is optionally substituted.
[0234] Still more preferred compounds of the present invention have
formula (I) wherein
[0235] A is --L.sub.AR.sub.A,
[0236] B is --L.sub.BR.sub.B,
[0237] C is hydrogen,
[0238] --L.sub.A-- and --L.sub.B-- are --O--, and
[0239] R.sub.A and R.sub.B are alkyl of one to six carbon
atoms.
[0240] Still more preferred compounds of the present invention have
formula (I) wherein
[0241] A is --L.sub.AR.sub.A,
[0242] B is --L.sub.BR.sub.B,
[0243] C is --L.sub.CR.sub.C,
[0244] --L.sub.A--, --L.sub.B--, and --L.sub.C-- are --O-- and
[0245] R.sub.A, R.sub.B, and R.sub.C are alkyl of one to six carbon
atoms.
[0246] Still more preferred compounds of the present invention have
formula (I) wherein
[0247] A is hydrogen;
[0248] B is --L.sub.BR.sub.B;
[0249] C is --L.sub.CR.sub.C;
[0250] --L.sub.B-- is --O--;
[0251] --L.sub.C-- is selected from the group consisting of
[0252] (1) a covalent bond,
[0253] (2) --O--,
[0254]
[0255] (3) --CH.dbd.CH--,
[0256] (4) --NR-- and
[0257] (5) --NR.sub.2C(O)O--;
[0258] R.sub.B is selected from the group consisting of
[0259] (1) alkyl and
[0260] (2) arylalkyl, wherein the alkylene group is of one to six
carbon atoms;
[0261] R.sub.C is selected from the group consisting of
[0262] (1) alkyl of one to six carbon atoms;
[0263] (2) alkenyl of one to six carbon atoms;
[0264] (3) halogen;
[0265] (4) aryl and
[0266] (5) heterocycle, wherein
[0267] the heterocycle is selected from the group consisting of
[0268] (1) benzofuranyl;
[0269] (2) tetrahydrofuranyl;
[0270] (3) pyrimidinyl;
[0271] (4) pyrazolyl;
[0272] (5) furanyl;
[0273] (6) pyrimidinyl;
[0274] (7) thiazolyl and
[0275] (8) 7
[0276] wherein F is --O--, G is --(C(R')(R")).sub.v--, R' and R"
are hydrogen and v is one; and
[0277] wherein, at each occurence,
[0278] aryl is phenyl and
[0279] alkyl, aryl and heterocycle are optionally substituted.
[0280] Preferred compounds falling within the scope of formula (1)
include:
[0281] 7, 8-dimethoxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0282] 6, 7, 8-trimethoxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0283] 6, 7-dimethoxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0284]
2-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]acetamide
mono(trifluoroacetate) salt;
[0285] 7-benzyloxy-8-iodo-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0286] methyl
[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]acetate
mono(trifluoroacetate) salt;
[0287]
2-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-yl-acetic acid
mono(trifluoroacetate) salt;
[0288]
N-[4-(aminomethyl)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxami-
de bis(trifluoroacetate) salt;
[0289]
N-[4-(amino)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamide
bis(trifluoroacetate) salt;
[0290]
1-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-hydroxypropa-
ne mono(trifluoroacetate) salt;
[0291] phenylmethyl [7-(aminoiminomethyl)-1-naphthalenyl)carbamate
mono(trifluoroacetate) salt;
[0292] N-[7-(aminoiminomethyl)-1-naphthalenyl)acetamide
mono(trifluoroacetate) salt;
[0293] methyl [7-(aminoiminomethyl)-1-naphthalenyl)carbamate
mono(trifluoroacetate) salt;
[0294] methyl
3-[[7-(aminoiminomethyl)-1-naphthalenyl]amino]-3-oxopropanoa- te
mono(trifluoroacetate) salt;
[0295]
N-[7-(aminoiminomethyl)-1-naphthalenyl]-2-(phenylmethoxy)acetamide
mono(trifluoroacetate) salt;
[0296] N-[7-(aminoiminomethyl)-1-naphthalenyl]
-1,3-benzodioxole-5-carboxa- mide mono(trifluoroacetate) salt;
[0297]
N-[7-(aminoiminomethyl)-1-naphthalenyl]benzenemethanesulfonamide
mono(trifluoroacetate) salt;
[0298]
1-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-bromopropane
mono(hydrochloride) salt;
[0299] 3-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]propene
mono(trifluoroacetate) salt;
[0300]
1-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-phenylpropan-
e mono(hydrochloride) salt;
[0301]
1[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-[1-(3,4-dimet-
hoxy)phenyl] -propane mono (hydrochloride) salt;
[0302] 7-methoxy-8-(2-furanyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0303] methyl
6-(aminoiminomethyl)-4-[(methoxycarbonyl)amino]-2-naphthalen-
ecarboxylate mono(trifluoroacetate) salt;
[0304] (E)-(7-methoxy-8-[2-(Phenyl)ethenyl])-2-naphthaleneimidamide
mono(trifluoroacetate) salt
6-(4-phenylbutynyl)-2-naphthalenecarboximidam- ide
mono(trifluoroacetate) salt;
[0305] 7-(2-hydroxyethoxy)-8-iodo-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0306] 7-(2-hydroxyethoxy)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0307] 6-(4-methyl-1-pentynyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0308] 6-(5-phenylpentynyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0309] 6-(3-phenyl-1-propynyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0310] 6-(phenylethynyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0311]
3-amino-N-[3-[6-(aminoiminomethyl)-2-naphthalenyl]-2-propynyl]benza-
mide mono(trifluoroacetate) salt;
[0312]
4-amino-N-[3-(6-aminoiminomethyl-2-naphthalenyl)-2-propynyl]benzami-
de mono(trifluoroacetate) salt;
[0313]
(S)-2-amino-N-[1-[(6-aminoiminomethyl-2-naphthalenyl)carbonyl]cyclo-
hexyl]propionamide bis(trifluoroacetate) salt;
[0314] 6-methoxy-8-benzyloxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0315]
2-[(7-aminoiminomethyl-3-methoxy-1-naphthalenyl)oxy]acetamide
mono(trifluoroacetate) salt;
[0316] N-(6-aminoiminomethyl-2-naphthalenyl)-N'-phenylurea
mono(trifluoroacetate) salt;
[0317] (E)-6-[2-(phenyl)ethenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0318] 6-[2-(phenyl)ethyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0319] 7-propoxy-8-iodo-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0320] (.+-.) 6-(3-phenyloxiranyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0321] (E)-6-[2-(2-thienyl)ethenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0322] 6-(3-oxobutyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0323] 6-(3-methoxyphenyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0324]
N-[3-(methyl)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamide
mono(trifluoroacetate) salt;
[0325] 6-(2-formylphenoxy)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0326] 6-(2-formylphenyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0327] 6-[2-hydroxymethyl)phenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0328] 6-(3-oxo-l-butenyl)-2-naphthalenecarboximidamide mono
(trifluoroacetate) salt;
[0329] 7-methoxy-8-(1H-pyrazol-4-yl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0330] 7-methoxy-1-iodo-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0331] N-phenyl-6-aminoiminomethyl-2-naphthalenecarboxamide
mono(methanesulfonate) salt;
[0332]
4-[(6-aminoiminomethyl-2-naphthalenyl)oxy]-N-methylbenzeneacetamide
mono(trifluoroacetate) salt;
[0333] 6-[[2-(methylthio)phenyl]-2-naphthalenecarboximidamide
mono(methanesulfonate) salt;
[0334]
6-[2-(2-thiomethoxoxyethyl)phenyl]naphthalene-2-carboximidamide
mono(methanesulfonate) salt;
[0335] 7-methoxy-8-(3-furanyl)-2-naphthalenecarboximidamide mono(
methanesulfonate) salt;
[0336] 7-methoxy-8-(2-benzofuranyl)naphthalene-2-carboximidamide
mono(methanesulfonate) salt;
[0337]
(E)-8-[2-(1,3-benzodioxol-5-yl)ethenyl]-2-naphthalenecarboximidamid-
e mono(methanesulfonate) salt;
[0338]
(.+-.)-7-methoxy-8-(tetrahydro-3-furanyl)-2-naphthalenecarboximidam-
ide mono(methanesulfonate) salt;
[0339]
6-[[4-(2-aminoethyl)phenyl]ethynyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0340]
7-methoxy-8-[2-pyrimidinyl(oxy)]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0341] 7-methoxy-8-[2-thiazoyl(oxy)]naphthalene-2-carboximidamide
mono(trifluoroacetate) salt;
[0342] 7-methoxy-8-(4-nitrophenoxy)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0343] 7-methoxy-8-pentafluorophenoxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0344]
7-methoxy-8-[N-2-pyrimidinyl(amino)]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0345] N-(6-aminoiminomethyl-2-naphthalenyl)-N'-benzylurea
mono(trifluoroacetate) salt;
[0346] N-(6-aminoiminomethyl-2-naphthalenyl)-N'-methylurea
mono(trifluoroacetate) salt;
[0347] N-(6-aminoiminomethyl-2-naphthalenyl)-N'-isopropylurea
mono(trifluoroacetate) salt;
[0348]
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-phenyl-N'-methylurea
mono(trifluoroacetate) salt;
[0349] 6-aminonaphthalene-2-carboximidamide mono(trifluoroacetate)
salt;
[0350] N-(6-aminoiminomethyl-2-naphthalenyl)-N'-cyclohexylurea
mono(trifluoroacetate) salt;
[0351] N-(6-aminoiminomethyl-2-naphthalenyl)-N'-benzyloxyurea
mono(trifluoroacetate) salt;
[0352] 1,1-dimethylethyl
[4-[[(6-cyano-2-naphthalenyl)amino]carbonyl]pheny- l]carbamate
mono(trifluoroacetate) salt
[0353]
N-[6-(aminoiminomethyl)-2-naphthalenyl]-4-(aminomethyl)benzamide
mono(trifluoroacetate) salt;
[0354] ethyl [6-(aminoiminomethyl)-2-naphthalenyl]carbamate
mono(trifluoroacetate) salt;
[0355] 1,1-dimethylethyl
[4-[[[6-aminoiminomethyl)-2-naphthalenyl)amino]ca-
rbonyl]amino]phenyl] carbamate mono(trifluoroacetate) salt;
[0356] (E)-6-[2-(phenylthio)ethenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0357] (E)-6-[2-(2-furanyl)ethenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0358] (E)-6-
[2-(1H-imidazol-1-yl)ethenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0359]
(E)-4-[2-(6-aminoiminomethyl-2-naphthalenyl)ethenyl]benzenesulfonam-
ide mono(trifluoroacetate) salt;
[0360] (E)-4-[2-(6-aminoiminomethyl-2-naphthalenyl)ethenyl]benzoic
acid mono(trifluoroacetate) salt;
[0361]
4-[7-(aminoiminomethyl)-2-methoxy-1-naphthalenyl]dihydro-2(3H)-fura-
none mono(trifluoroacetate) salt;
[0362]
7-methoxy-8-(1-acetyl-1H-pyrazolyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt;
[0363]
7-methoxy-8-[1-(methylsulfonyl)-1H-4-pyrazolyl]-2-naphthalenecarbox-
imidamide mono(trifluoroacetate) salt;
[0364]
(E)-4-[2-(6-aminoininomethyl-2-naphthalenyl)ethenyl]benzamide
mono(trifluoroacetate) salt;
[0365] 6-[2-(4-aminophenyl)ethoxy]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt; methyl
[3-methoxy-6-(aminoiminomethyl)-4-nap- hthalenyl]carbamate
mono(trifluoroacetate) salt;
[0366]
7-methoxy-8-[2-pyrimidinyl(amino)]-2-naphthalenecarboximidamide
bis(trifluoroacetate) salt; fhthalenecarboxamide,
mono(trifluoroacetate) salt;
[0367] 6-(4-aminophenyl)-2-naphthalenecarboximidamide,
bis(trifluoroacetate) salt;
[0368] methyl
2-[4-[[[6-(aminoiminomethyl)-2-naphthalenyl]carbonyl]amino]--
phenoxy]acetate,mono(trifluoroacetate) salt;
[0369]
(E)-6-[2-[(3-hydroxymethyl)phenyl]ethenyl]-2-naphthalenecarboximida-
mide, mono(trifluoroacetate) salt;
[0370] 6-(2-phenyl-1-cyclopropyl)-2-naphthalenecarboximidamide,
mono(trifluoroacetate) salt;
[0371]
(E)-6-[2-[4-(aminomethyl)phenyl]ethenyl]-2-naphthalenecarboximidami-
de, bis(trifluoroacetate) salt;
[0372]
(E)-6-[2-[4-(1,2-dihdyroxyethyl)phenyl]ethenyl]-2-naphthalenecarbox-
imidamide, mono(trifluoroacetate) salt;
[0373]
(E)-6-[2-[4-(1R-amino-2-hydroxyethyl)phenyl]ethenyl]-2-naphthalenec-
arboximidamide, bis(trifluoroacetate) salt;
[0374]
7-methoxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,
bis(trifluoroacetate) salt;
[0375]
(E)-6-[2-[[4-(dimethylamino)methyl]phenyl]ethenyl]-2-naphthalenecar-
boximidamide, bis(trifluoroacetate) salt;
[0376]
(E)-6-[2-[4-(hydroxymethyl)phenyl]ethenyl]-2-naphthalenecarboximida-
mide, mono(trifluoroacetate) salt;
[0377]
4-[[6-(aminoiminomethyl)-2-naphthalenyl]ethynyl]-L-phenylalanine,
mono(trifluoroacetate) salt;
[0378] 6-(3-formylphenyl)-2-naphthalenecarboximidamide,
mono(trifluoroacetate) salt;
[0379]
(E)-6-[2-(1,2,3,4-tetrahydro-6-isoquinolinyl)ethenyl]-2-naphthalene-
carboximidamide, bis(trifluoroacetate) salt;
[0380]
(E)-6-[2-[3-(2-hydroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximid-
amide, mono(trifluoroacetate) salt;
[0381]
6-(aminoiminomethyl)-N-(2,3-dihydro-1H-inden-5-yl)-2-naphthalenecar-
boxamide, mono(trifluoroacetate) salt;
[0382] 6-[(4-aminophenyl)ethynyl]-2-naphthalenecarboximidamide,
bis(trifluoroacetate) salt;
[0383] 1,1-dimethylethyl
[2-[3-[[6-(aminoiminomethyl)-2-naphathalenyl]ethy-
nyl]-6-methoxyphenyl]ethyl]carbamate, mono(trifluoroacetate)
salt;
[0384] 1,1-dimethylethyl
[[4-[[6-(aminoiminomethyl)-2-naphathalenyl]ethyny-
l]-phenyl]methyl]carbamate, mono(trifluoroacetate) salt;
[0385]
6-[[4-(aminomethyl)phenyl]ethynyl]-2-naphthalenecarboximidamide,
bis(trifluoroacetate) salt;
[0386]
6-[[3-(2-aminoethyl)-4-methoxyphenyl]ethynyl]-2-naphthalenecarboxim-
idamide, bis(trifluoroacetate) salt;
[0387]
6-[[4-(hydroxymethyl)phenyl]ethynyl]-2-naphthalenecarboximidamide,
mono(trifluoroacetate) salt;
[0388]
6-[(1,2,3,4-tetrahydro-6-isoquinolinyl)ethynyl]-2-naphthalenecarbox-
imidamide, bis(trifluoroacetate) salt;
[0389]
6-(aminoiminomethyl)-N-(4-methylphenyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate) salt;
[0390] 1,1-dimethylethyl
[[4-[[[6-(aminoiminomethyl)-2-naphathalenyl]amino-
]-carbonyl]phenyl]methyl]carbamate, mono(trifluoroacetate)
salt;
[0391] N-[6-(aminoiminomethyl)-2-naphthalenyl)benzamide,
mono(trifluoroacetate) salt;
[0392] 1,1-dimethylethyl
[[4-[[[6-(aminoiminomethyl)-2-naphathalenyl]amino-
]carbonyl]-cyclohexyll]methyl]carbamate, mono(trifluoroacetate)
salt;
[0393]
N-[6-(aminoiminomethyl)-2-naphthalenyl]-N'-(4-aminophenyl)urea,
bis(trifluoroacetate) salt;
[0394]
N-[6-(aminoiminomethyl)-2-naphthalenyl]-4-4-(aminomethyl)cyclohexan-
ecarboxamide, bis(trifluoroacetate) salt;
[0395]
N-[6-(aminoiminomethyl)-2-naphthalenyl]-N'-[(4-aminomethyl)phenyl]u-
rea, bis(trifluoroacetate) salt;
[0396]
6-(aminoiminomethyl)-N-(4-ethylphenyl)-2-naphthalenecarboxamide,
acetate salt;
[0397]
6-(aminoiminomethyl)-N-(2-naphthalenyl)-2-naphthalenecarboxaminde,
mono(trifluoroacetate) salt;
[0398] 6-(5-phenyl-2-oxazolyl)-2-naphthalenecarboximidamide,
mono(trifluoroacetate) salt;
[0399] 6-(5-phenyl-2-thiazolyl)-2-naphthalenecarboximidamide,
mono(trifluoroacetate) salt;
[0400]
6-(aminoiminomethyl)-N-(1,2,3,4-tetrahydro-6-quinolinyl)-2-naphthal-
enecarboxamide, bis(trifluoroacetate) salt;
[0401]
6-[amino(hydroxyimino)methyl]-N-phenyl-2-naphthalenecarboxamide;
[0402]
6-[4-[(hydroxymethyl)phenyl]methoxy]-2-naphthalenecarboximidamide,
methanesulfonate salt;
[0403] 6-(2-pyridinylethynyl)-2-naphthalenecarboximidamide,
mono(trifluoroacetate) salt;
[0404]
N-[4-(aminocarbonyl)phenyl]-6-(aminoiminomethyl)-2-naphthalenecarbo-
xamide, mono(trifluoroacetate) salt;
[0405]
6-(aminoiminomethyl)-N-(2-thiazolyl)-2-naphthalenecarboxamide,
monohydrochloride
[0406]
6-(aminoiminomethyl)-N-(6-methoxy-3-pyridinyl)-2-naphthalenecarboxa-
mide, monohydrochloride
[0407]
6-(aminoiminomethyl)-N-(1,3-benzodioxol-5-yl)-2-naphthalenecarboxam-
ide, mono(trifluoroacetate) salt;
[0408]
6-(aminoiminomethyl)-N-(1,2,3,4-tetrahydro-2,4-dioxo5-pyrimidinyl)--
2-naphthalenecarboxamide, monohydrochloride
[0409] 6-(aminoiminomethyl)-N-(3
,5-difluorophenyl)-2-naphthalenecarboxami- de,
mono(trifluoroacetate) salt;
6-(aminoiminomethyl)-N-(1H-pyrazol-3-yl)--
2-naphthalenecarboxamide,
[0410] mono(trifluoroacetate) salt;
[0411]
6-(aminoiminomethyl)-N-(5-methyl-3-isoxazolyll)-2-naphthalenecarbox-
amide, mono(trifluoroacetate) salt;
[0412] 6-(aminoiminomethyl)-N-(pyrazinyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate) salt;
[0413]
6-(aminoiminomethyl)-N-(6-methyl-2-pyridinyl)-2-naphthalenecarboxam-
ide, mono(trifluoroacetate) salt;
[0414]
6-(aminoiminomethyl)-N-(3,4,5-trimethoxyphenyl)-2-naphthalenecarbox-
amide, monohydrochloride
[0415]
6-(aminoiminomethyl)-N-(3-methyl-2-pyridinyl)-2-naphthalenecarboxam-
ide, bis(trifluoroacetate) salt;
[0416]
6-(aminoiminomethyl)-N-(5-bromo-2-thiazolyll)-2-naphthalenecarboxam-
ide, mono(trifluoroacetate) salt;
[0417]
6-(aminoiminomethyl)-N-(5-methyl-2-pyridinyl)-2-naphthalenecarboxam-
ide, mono(trifluoroacetate) salt;
[0418]
6-(aminoiminomethyl)-N-(4-methyl-2-thiazolyl)-2-naphthalenecarboxam-
ide, mono(trifluoroacetate) salt;
[0419]
6-(aminoiminomethyl)-N-(6-quinolinyl)-2-naphthalenecarboxamide,
bis(trifluoroacetate) salt;
[0420]
6-(aminoiminomethyl)-N-(1H-indazol-6-yl)-2-naphthalenecarboxamide,
bis(trifluoroacetate) salt;
[0421]
6-(aminoiminomethyl)-N-(1H-indazol-5-yl)-2-naphthalenecarboxamide,
bis(trifluoroacetate) salt;
[0422]
6-(aminoiminomethyl)-N-(1H-indol-5-yl)-2-naphthalenecarboxamide,
mono(trifluoroacetate) salt;
[0423]
6-(aminoiminomethyl)-N-(5-pyrimidinyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate) salt;
[0424]
6-(aminoiminomethyl)-N-(3-pyridazinyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate) salt;
[0425]
6-(aminoiminomethyl)-N-(5-bromo-2-pyridinyl)-2-naphthalenecarboxami-
de, mono(trifluoroacetate) salt;
[0426]
6-(aminoiminomethyl)-N-[3-(1-methylethoxy)phenyl]-2-naphthalenecarb-
oxamide, mono(trifluoroacetate) salt;
[0427]
6-(aminoiminomethyl)-N-(1H-imidazolyl)-2-naphthalenecarboxamide,
bis(trifluoroacetate) salt;
[0428]
6-[2-[4-(hydroxymethyl)phenyl]-1-cyclopropyl]-2-naphthalenecarboxim-
idamide, mono(trifluoroacetate) salt;
[0429]
N-(ethoxycarbonyl)-6-(2-phenyl-1-cyclopropyl)-2-naphthalenecarboxim-
idamide
[0430]
6-(aminoiminomethyl)-N-(2-methyl-6-quinolinyl)-2-naphthalenecarboxa-
mide, bis(trifluoroacetate) salt;
[0431]
6-(aminoiminomethyl)-N-(3-propoxyphenyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate) salt;
[0432] 6-(aminoiminomethyl)-N-[3-(1-ethylpropoxy)phenyl]
-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
[0433]
6-(aminoiminomethyl)-N-[3-(cyclopentyloxy)phenyl]-2-naphthalenecarb-
oxamide, mono(trifluoroacetate) salt;
[0434]
6-(aminoiminomethyl)-N-(3-phenoxyphenyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate) salt;
[0435]
6-(aminoiminomethyl)-N-[3-(phenylmethoxy)phenyl]-2-naphthalenecarbo-
xamide, mono(trifluoroacetate) salt;
[0436]
6-(aminoiminomethyl)-N-(3-ethoxyphenyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate) salt;
[0437]
6-(aminoiminomethyl)-N-(4-nitrophenyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate) salt;
[0438]
6-(aminoiminomethyl)-N-[3-(cyclobutylmethoxy)phenyl]-2-naphthalenec-
arboxamide,mono(trifluoroacetate) salt;
[0439]
6-[amino(ethoxycarbonyl)imino]-N-[3-(1-methylethoxy)phenyl]-2-napht-
halenecarboxamide;
[0440] 6-(aminoiminomethyl)-4-[5-(ethylsulfonyl)-3-furanyl]
-N-phenyl-2-naphthalenecarboxamide, monohydrochloride;
[0441] methyl
[7-(aminoiminomethyl)-2-methoxy-1-naphthalenyl)carbamate,
mono(trifluoroacetate) salt;
[0442]
7-methoxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,
bis(trifluoroacetate) salt;
[0443]
7-methoxy-8-[(phenylmethyl)amino]-2-naphthalenecarboximidamide,
mono(trifluoroacetate) salt;
[0444] 7-methoxy-8-(phenylamino)-2-naphthalenecarboximidamide,
mono(trifluoroacetate) salt;
[0445]
7-methoxy-8-[(4-methoxyphenyl)amino]-2-naphthalenecarboximidamide,
mono(trifluoroacetate) salt;
[0446]
(E)-3-[7-(aminoiminomethyl)-2-methoxy-1-naphthalenyl)-2-propenamide-
, mono(trifluoroacetate) salt;
[0447]
7-methoxy-8-(3-oxo-1-cyclopenten-1-yl)-2-naphthalenecarboximidamide-
, mono(trifluoroacetate) salt;
[0448] methyl
4-[[[7-(aminoiminomethyl)-1-(2-pyrimidinylamino)-2-naphthale-
nyl]oxy]methyl]benzoate, mono(trifluoroacetate) salt;
[0449]
4-[[[7-(aminoiminomethyl)-1-(2-pyrimidinylamino)-2-naphthalenyl]oxy-
]methyl] benzoic acid, mono(trifluoroacetate) salt;
[0450] 7-methoxy-8-(pyrazinyloxy)-2-naphthalenecarboximidamide,
dimethanesulfonate salt;
[0451] 7-methoxy-8-(phenylthio)-2-naphthalenecarboximidamide,
methanesulfonate;
[0452] 7-methoxy-8-(pyrazinylamino)-2-naphthalenecarboximidamide,
bis(trifluoroacetate) salt;
[0453] methyl
5-[7-[(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoate,
mono(trifluoroacetate) salt;
[0454] 5-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoic acid,
mono(trifluoroacetate) salt;
[0455] methyl
4-[[[7-amino(hydroxyimino)methyl]-2-naphthalenyl]oxy]methyl]-
benzoate;
[0456] methyl 2-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]acetate,
mono(trifluoroacetate) salt;
[0457] 7-[2-(4-morpholinyl)ethoxy]-2-naphthalenecarboximidamide,
bis(trifluoroacetate) salt;
[0458] 2-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]acetic acid,
mono(trifluoroacetate) salt;
[0459] methyl
4-[6-(aminoiminomethyl)-2-naphthalenyl]oxy]methyl]benzoate,
mono(trifluoroacetate) salt;
[0460] methyl [7-(aminoiminomethyl)-1-naphthalenyl]methylcarbamate,
mono(trifluoroacetate) salt;
[0461] propyl [7-(aminoiminomethyl)-1-naphthalenyl]carbamate,
mono(trifluoroacetate) salt;
[0462] N-[7-(aminoiminomethyl)-1-naphthalenyl]-N'-methylurea,
mono(trifluoroacetate) salt;
[0463] ethyl [7-(aminoiminomethyl)-1-naphthalenyl)carbamate,
mono(trifluoroacetate) salt;
[0464] N-[7-(aminoiminomethyl)-1-naphthalenyl)propanamide,
mono(trifluoroacetate) salt;
[0465] N-[7-(aminoiminomethyl)-1-naphthalenyl)-2-methoxyacetamide,
mono(trifluoroacetate) salt;
[0466] N-[7-(aminoiminomethyl)-1-naphthalenyl]urea,
mono(trifluoroacetate) salt;
[0467] N-[7-(aminoiminomethyl)-1-naphthalenyl]-2-hydroxyacetamide,
mono(trifluoroacetate) salt;
[0468] 8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,
bis(trifluoroacetate) salt;
[0469] 8-amino-2-naphthalenecarboximidamide, bis(trifluoroacetate)
salt;
[0470] 8-(2-pyridinylamino)-2-naphthalenecarboximidamide,
bis(trifluoroacetate) salt;
[0471]
N-hydroxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,
mono(trifluoroacetate) salt;
[0472]
6-(aminoiminomethyl)-4-(3-furanyl)-N-[4-(trifluoromethyl)phenyl]-2--
naphthalenecarboxamide, mono(trifluoroacetate) salt;
[0473]
6-(aminoiminomethyl)-4-(3-furanyl)-N-(4-pyridinyl)-2-naphthalenecar-
boxamide, dihydrochloride;
[0474]
6-(aminoiminomethyl)-4-(3-furanyl)-N-(1H-pyrazol-3-yl)-2-naphthalen-
ecarboxamide, dihydrochloride;
[0475]
6-(aminoiminomethyl)-4-(3-furanyl)-N-(3-pyridinyl)-2-naphthalenecar-
boxamide, dihydrochloride;
[0476] methyl
[7-(aminoiminomethyl)-3-[[[4-(aminomethyl)phenyl]amino]carbo-
nyl]-1-naphathalenyl]carbamate, bis(trifluoroacetate) salt;
[0477]
6-(aminoiminomethyl)-4-(3-furanyl)-N-(2-pyridinyl)-2-naphthalenecar-
boxamide, dihydrochloride;
[0478]
6-(aminoiminomethyl)-4-(3-furanyl)-N-phenyl-2-naphthalenecarboxamid-
e, monohydrochloride
[0479]
6-(aminoiminomethyl)-4-[1-(methylsulfonyl)-1H-pyrazol-4-yl]-N-pheny-
l-2-naphthalenecarboxamide, monohydrochloride;
[0480]
6-(aminoiminomethyl)-4-[5-(methylthio)-3-furanyl)]-N-phenyl-2-napht-
halenecarboxamide, monohydrochloride;
[0481]
6-(aminoiminomethyl)-N-[4-(aminomethyl)phenyl]-4-(2-pyrimidinylamin-
o)-2-naphthalenecarboxamide, tris(trifluoroacetate) salt;
[0482]
6-(aminoiminomethyl)-N-phenyl-4-(2-pyrimidinylamino)-2naphthaleneca-
rboxamide, mono(trifluoroacetate) salt;
[0483]
N-[(4-(aminomethyl)phenyl]-6-[amino(hydroxyimino)methyl]-4-(2-pyrim-
idinylamino)-2-naphthalenecarboxamide, bis(trifluoroacetate)
salt;
[0484]
6-(aminoiminomethyl)-N-[4-(hydroxymethyl)phenyl3-4-(2-pyrimidinylam-
ino)-2-naphthalenecarboxamide, mono(trifluoroacetate) salt;
[0485] methyl
[3-[[[4-(aminomethyl)phenyl]amino]carbonyl]-7-[4-amino(hydro-
xyimino)methyl]-1-naphthalenyl]carbamate, bis(trifluoroacetate)
salt;
[0486]
6-(aminoiminomethyl)-N-phenyl-4-(tetrahydro-3-furanyl)-2-naphthalen-
ecarboxamide,monohydrochloride;
[0487]
6-[amino(hydroxyimino)methyl]-N-phenyl4-(2-pyrimidinylamino)-2-naph-
thalenecarboxamide
[0488]
6-(aminoiminomethyl)-4-[5-(ethylthio)-3-furanyl]-N-phenyl-2-naphtha-
lenecarboxamide,monohydrochloride;
[0489] 6-(aminoiminomethyl)-4-
[5-(propylthio)-3-furanyl]-N-phenyl-2-napht-
halenecarboxamide,monohydrochloride;
[0490]
6-(aminoiminomethyl)-N-phenyl-4-(2-pyrrolidinyl)-2-naphthalenecarbo-
xamide, mono(trifluoroacetate) salt;
[0491]
6-(aminoiminomethyl)-4-[5-(propylsulfonyl)-3-furanyl]-N-phenyl-2-na-
phthalenecarboxamide, monohydrochloride;
[0492]
6-(aminoiminomethyl)-4-[5-[methylthio)methyl]-3-furanyl]-N-phenyl-2-
-naphthalenecarboxamide, monohydrochloride;
[0493]
6-(aminoiminomethyl)-4-[5-(methoxymethyl)-3-furanyl]-N-phenyl-2-nap-
hthalenecarboxamide, monohydrochloride;
[0494]
6-(aminoiminomethyl)-4-[5-(methylsulfonyl)-3-furanyl]-N-phenyl-2-na-
phthalenecarboxamide, mono(trifluoroacetate) salt; and
[0495]
6-(aminoiminomethyl)-4-[5-(ethythio)tetrahydro-3-furanyl]-N-phenyl--
2-naphthalenecarboxamide, monohydrochloride.
DETERMINATION OF UROKINASE INHIBITION
[0496] The efficacy of the compounds of this invention as urokinase
inhibitors was determined by measuring the inhibition of the
urokinase enzyme Abbokinase (Abbott Laboratories, Abbott Park,
Ill.) on substrate S-2444, of formula pyroGlu-Arg-pNA-HCl
(DiaPharma Group, Inc. Distributor of Chromogenix) at 200
.mu.M.
[0497] The assay was performed in a 96 well polystyrene, flat
bottom plate in a 50 mM Tris/0.15 M NaCl+0.5 % Pluronic F-68 (Sigma
P-5556), pH 7.4 (with HCl) buffer. The compounds of this invention,
10 mM in DMSO, were diluted with DMSO to eight half log
concentrations, for example: 1200 .mu.M, 400 .mu.M, 120 .mu.M, 40
.mu.M, 12 .mu.M, 4 .mu.M, 1 .mu.M and 0.4 .mu.M. Four
concentrations were chosen, then 5 .mu.l of each were diluted to a
total assay volume of 200 .mu.l. The final compound concentrations
in the assay, according to the above example, were 30 .mu.M, 10
.mu.M, 3 .mu.M, 1 .mu.M, 0.3 .mu.M, 0.1 .mu.M, 0.03 .mu.M and 0.01
.mu.M, respectively. The substrate S-2444 was used at 200 .mu.M in
the assay. Several vials were reconstituted as directed on the
vial, aliquoted and stored frozen. The enzyme was further diluted
in assay buffer and 10 .mu.l was used in the assay. Enzyme
concentration in the assay was 2-3 nM. The assay was performed as
follows: 175 .mu.L of buffer was pipetted into the polystyrene
plate, 5 .mu.L solution of a compound of this invention in DMSO was
added, the mixture was vortexed, 10 .mu.L of enzyme in buffer was
added, the mixture was vortexed, 10 .mu.L of substrate in water was
added, the mixture was vortexed, and the plate was placed in a
Spectromax.RTM. (Molecular Devices Corporation, Sunnyvale, Calif.)
plate reader to follow the course of the reaction for 15 min at 405
nm. The Spectromax.RTM. calculated the reaction rates which were
used to calculate percent inhibition of the compounds of this
invention versus the reaction rate of the enzyme in the absence of
any inhibitor. The Ki's of the inhibitors were calculated from the
percent inhibition and previously established Km. The compounds of
this invention inhibit urokinase as shown by the data for
representative examples in Table 1.
1TABLE 1 Inhibitory Potency of Representative Compounds Against
Urokinase Example IC.sub.50 (.mu.M) 1 6.6 2 9.8 3 36 4 0.5 5 2.5 6
2.3 7 3.5 8 0.1 9 1.1 10 3.2 14 0.33 15 2.5 16 0.03 17 4.26 18 0.42
19 2.21 20 0.803 21 1.7 22 1.7 23 4.0 24 4.9 25 2.1 26 0.04 27 0.93
28 2.1 29 2.5 30 3.6 31 2.93 32 4.6 33 2.4 34 3.5 35 3.97 36 1.75
37 2.34 38 6.35 39 12.2 40 0.31 41 2.38 42 2.08 43 2.2 44 0.35 45
2.94 46 2.4 47 4.8 48 1.3 49 3.3 50 6.13 51 4.7 52 4.7 53 2.96 54
2.7 55 0.9 56 2.9 57 3.4 58 2.53 59 0.41 60 0.72 61 0.73 62 0.64 63
0.37 64 0.56 65 0.54 66 3.13 67 2.78 68 1.74 69 1.38 70 2.57 71
2.39 72 4.30 73 3.3 74 1.61 75 2.09 76 0.96 77 0.23 78 3.57 79 0.96
80 1.93 81 3.21 82 3.08 83 2.24 84 10.0 85 1.38 86 3.6 87 0.63 88
2.73 89 6.5 90 0.07 91 0.05 92 0.04 93 2.36 95 1.73 96 0.86 97 1.31
98 0.24 99 3.02 100 3.16 101 0.8 102 0.34 103 0.57 104 1.2 105 0.84
106 0.76 107 2.34 108 0.996 109 2.85 110 111 4.17 112 0.45 113
0.403 114 0.344 115 0.063 116 0.045 117 0.278 118 0.121 119 4.41
120 0.93 121 0.89 122 0.33 123 1.24 124 0.12 125 0.23 126 0.87 127
0.085 129 4.84 131 4.18 132 0.96 133 0.044 134 0.064 135 1.91 136
1.67 137 0.82 138 0.46 139 2.64 140 0.46 141 0.00117 142 0.54 143
0.36 144 1.26 145 2.59 146 0.372 147 0.213 148 0.81 149 3.8 150
0.16 152 0.083 153 0.877 154 0.035 155 2.33 156 0.18 157 3.12 158
0.09 159 2.23 160 2.62 161 1.59 162 1.33 163 0.03 164 0.45 165
0.00068 166 0.002 167 0.052 168 0.003 170 0.695 171 >30 174 0.17
176 5.011 177 14.9 179 1.61 180 0.097 181 8.92 182 >30 184 0.375
185 3.19 186 2.98 187 0.613 188 0.22 189 1.3 190 0.565 191 0.887
192 1.6 193 0.85 194 0.56 195 1.3 196 0.62 197 2.03 198 0.504 199
2.3 200 0.037 201 0.077 202 0.792 203 0.624 204 0.331 205 0.337 206
5.73 207 4.12 208 0.96 209 0.82 210 0.78 211 0.072 212 5.09 213
4.58 214 2.559 215 1.1 216 >30 217 0.67 218 0.086 219 0.103 220
0.03 221 0.52 222 0.346 223 0.07 224 1.773 225 0.104 226 >30 227
0.015 228 0.025 229 0.117 230 0.103 231 0.015 232 0.123
Pharmaceutical Compositions
[0498] The present invention also provides pharmaceutical
compositions which comprise compounds of the present invention
formulated together with one or more non-toxic pharmaceutically
acceptable carriers. The pharmaceutical compositions may be
specially formulated for oral administration in solid or liquid
form, for parenteral injection or for rectal administration.
[0499] The pharmaceutical compositions of this invention can be
administered to humans and other animals orally, rectally,
parenterally, intracisterually, intravaginally, intraperitoneally
or topically (such as powders, ointments or drops), bucally or as
an oral or nasal spray. The term "parenteral" administration, as
used herein, refers to modes of administration which include
intravenous, intramuscular, intraperitoneal, intrasternal,
subcutaneous and intraarticular injection and infusion.
[0500] Pharmaceutical compositions of this invention for parenteral
injection comprise pharmaceutically acceptable sterile aqueous or
nonaqueous solutions, dispersions, suspensions or emulsions as well
as sterile powders for reconstitution into sterile injectable
solutions or dispersions just prior to use. Examples of suitable
aqueous and nonaqueous carriers, diluents, solvents or vehicles
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol and the like), and suitable mixtures
thereof, vegetable oils (such as olive oil) and injectable organic
esters such as ethyl oleate. Proper fluidity can be maintained, for
example, by the use of coating materials such as lecithin, by the
maintenance of the required particle size in the case of
dispersions and by the use of surfactants.
[0501] These compositions may also contain adjuvants such as
preservative, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid and the
like. It may also be desirable to include isotonic agents such as
sugars, sodium chloride and the like. Prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents (such as aluminum monostearate and gelatin)
which delay absorption.
[0502] In some cases, in order to prolong the effect of the drug,
it is desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This may be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug then depends upon its rate of dissolution which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally administered drug form is
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0503] Injectable depot forms are made by forming microencapsule
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by
filtration through a bacterial-retaining filter or by incorporating
sterilizing agents in the form of sterile solid compositions which
can be dissolved or dispersed in sterile water or other sterile
injectable media just prior to use.
[0504] Solid dosage forms for oral administration include capsules,
tablets, pills, powders and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol and silicic acid;
b) binders such as carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidone, sucrose and acacia; c) humectants such as
glycerol; d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates and sodium carbonate; e) solution retarding agents such
as paraffin; f) absorption accelerators such as quaternary ammonium
compounds; g) wetting agents such as cetyl alcohol and glycerol
monostearate; h) absorbents such as kaolin and bentonite clay and
i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also comprise buffering agents. Solid compositions of a
similar type may also be employed as fillers in soft and
hard-filled gelatin capsules using such excipients as lactose or
milk sugar as well as high molecular weight polyethylene glycols
and the like.
[0505] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and may also be of a composition such that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally or in delayed
fashion. Examples of embedding compositions which can be used
include polymeric substances and waxes.
[0506] The active compounds may also be in micro-encapsulated form,
if appropriate, with one or more of the above-mentioned
excipients.
[0507] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid
dosage forms may contain inert diluents commonly used in the art
such as water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan and mixtures thereof.
[0508] Besides inert diluents, the oral compositions may also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring and perfuming agents.
Suspensions, in addition to the active compounds, may contain
suspending agents such as ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol and sorbitan esters, microcrystalline
cellulose, aluminum metahydroxide, bentonite, agar-agar, and
tragacanth and mixtures thereof. Compositions for rectal or vaginal
administration are preferably suppositories which can be prepared
by mixing the compounds of this invention with suitable
non-irritating excipients or carriers such as cocoa butter,
polyethylene glycol or a suppository wax which are solid at room
temperature but liquid at body temperature and therefore melt in
the rectum or vaginal cavity and release the active compound.
[0509] Compounds of the present invention can also be administered
in the form of liposomes. As is known in the art, liposomes are
generally derived from phospholipids or other lipid substances.
Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals which are dispersed in an aqueous medium. Any non-toxic,
physiologically acceptable and metabolizable lipid capable of
forming liposomes can be used. The present compositions in liposome
form can contain, in addition to a compound of the present
invention, stabilizers, preservatives, excipients and the like. The
preferred lipids are the phospholipids and the phosphatidyl
cholines (lecithins), both natural and synthetic. Methods to form
liposomes are known in the art, for example, Prescott, Ed., Methods
in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976),
p. 33 et seq.
[0510] Dosage forms for topical administration of a compound of
this invention include powders, sprays, ointments and inhalants.
The active compound is mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants which may be required. Opthalmic
formulations, eye ointments, powders and solutions are also
contemplated as being within the scope of this invention.
[0511] Actual dosage levels of active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active compound(s) that is effective to
achieve the desired therapeutic response for a particular patient,
compositions, and mode of administration. The selected dosage level
will depend upon the activity of the particular compound, the route
of administration, the severity of the condition being treated and
the condition and prior medical history of the patient being
treated. However, it is within the skill of the art to start doses
of the compound at levels lower than required for to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved. Generally dosage levels of
about 1 to about 50, more preferably of about 5 to about 20 mg, of
active compound per kilogram of body weight per day when
administered orally to a mammalian patient. If desired, the
effective daily dose may be divided into multiple doses for
purposes of administration, e.g. two to four separate doses per
day.
Preparation of Compounds of this Invention
[0512] The compounds of this invention may be prepared by a variety
of synthetic routes. Representative procedures are outlined in the
following Schemes 1-6.
Abbreviations
[0513] Abbreviations which have been used in the descriptions of
the schemes and the examples that follow are: THF for
tetrahydrofuran; DMF for N,N-dimethylformamide; OEt.sub.2 for
diethyl ether; EDC for
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; NMM
for N-methylmorpholine; LDA for lithium diisopropylamide; TFA for
trifluoroacetic acid; DMSO for dimethylsulfoxide; DMAP for
4-(N,N-dimethylamino)pyridine; HATU for
O-(azabenzotriazole-1-yl)-N,N,N',-
N'-tetramethyluroniumhexafluorophosphate; Boc for
tert-butylcarbonyloxy; DDQ for
2,3-dichloro-5,6-dicyano-1,4-benzoquinone; Bn for benzyl; DPPA for
diphenylphosphoryl azide; DCC for dicyclohexylcarbodiimide; EDC for
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; SEM
for 2-(trimethylsilyl)ethoxymethyl; dppf for
1,1'-bis(diphenylphosphino)ferro- cene; and dba for
dibenzylideneacetone. Starting materials, reagents and solvents
were purchased from Aldrich Chemical Company (Milwaukee, Wis.).
[0514] As shown in Scheme 1, naphthalenecarbonitriles 4, 5 and 6
were prepared by treating 3-cyanopropionaldehyde diethyl acetal 2
with a strong base such as lithium diisopropylamide then treating
the resulting anion with the appropriately substituted benzaldehyde
1 followed by cyclization and aromatization of the corresponding
cyanohydrins 3 with a Lewis acid such as sulfuric acid. 8
[0515] A, B and C are hydrogen and --L.sub.AR.sub.A,
--L.sub.BR.sub.B, --L.sub.CR.sub.C
[0516] --L.sub.A--, --L.sub.B-- and --L.sub.C-- are --O--
[0517] R.sub.A, R.sub.B and R.sub.C are alkyl 9
[0518] 4: A is hydrogen; B and C are OCH.sub.3
[0519] 5: A, B and C are OCH.sub.3
[0520] 6: A and B are OCH.sub.3, and C is hydrogen
[0521] As shown in Scheme 2, selective demethylation of 4 with a
Lewis acid such as AlCl.sub.3 or BBr.sub.3, preferably AlC.sub.3,
provided 7. 7 was treated with a base such as potassium carbonate,
sodium hydride or cesium fluoride followed by R.sub.C--X, wherein X
is a leaving group, to provide 8 (--L.sub.C-- is --O--).
Alternatively, treatment of 7 with trifluoromethanesulfonic
anhydride or 1,1,1-trifluoro-N-phenyl-N-[(triflu-
oromethyl)sulfonyl]methanesulfonamide provided 9 which may be
treated with R.sub.C--B(OH).sub.2, 10
[0522] wherein R.sub.C is unsubstituted or substituted aryl or
heterocycle, in the presence of a palladium catalyst, preferably
Pd(II)Cl.sub.2(dba) or Pd(Ph.sub.3P).sub.4, and base, preferably
cesium fluoride or potassium carbonate, to provide 10.
Alternatively, 9 may be treated with R.sub.C--NR.sub.1R.sub.2,
wherein R.sub.C is unsubstituted or substituted aryl or
heterocycle, and at least one of R.sub.1 or R.sub.2 is hydrogen, in
the presence of a strong base, such as potassium t-butoxide, and a
catalyst, such as Pd(II)Cl.sub.2(dba), to provide 11. 11
[0523] R.sub.C is unsubstituted or substituted aryl
[0524] or heterocycle
[0525] 10: --L.sub.C-- is a covalent bond
[0526] 11:--L.sub.C-- is --NR.sub.1--
[0527] As shown in Scheme 3, selective O-triflation of 12 followed
by protection of the amino group of the resulting 13 with
acid-labile carbobenzlyoxy provided 14. Conversion of 14 to 15 was
achieved with KCN in the presence of a palladium catalyst,
preferably tris(dibenzylideneacetone)dipalladium(0)-chloroform
adduct, and deprotection of 15 to provide 16 was accomplished with
acid, preferably 30% HBr in acetic acid. Treatment of 15 with
acylating agents R.sub.CC(O)Cl and base, preferably triethylamine,
diisopropylethylamine or potassium carbonate provided intermediate
17. 12
[0528] --L.sub.C-- is --C(O)NR.sub.1-- or --OC(O)NR.sub.1-- and
[0529] R.sub.C is unsubstituted or substituted alkyl,
[0530] alkeneyl, hererocycle or aryl
[0531] As shown in Scheme 4, selective demethylation of the
8-methoxy group of 18 with a Lewis acid such as AlCl.sub.3 or
BBr.sub.3, preferably AlC1.sub.3, was followed by reprotection of
phenol 19 by alkylation with Bn-X, wherein X is Cl, Br or I, in the
presence of a base such as potassium carbonate, sodium hydride or
cesium fluoride. 20 was prepared by deprotonation of this
intermediate with a strong, non-nucleophilic base such as lithium,
sodium or potassium diisopropylamide or alkoxide followed by
treatment with an alkyl formate, preferably ethyl formate to
provide enol 20. Treatment of 20 with hydroxylamine provided
isoxazole 21 which may be opened with lithium, sodium or potassium
alkoxide, preferably sodium methoxide, to provide 22. Carbonyl
reduction with concomitant alkene formation with achieved with
sodium borohydride to provide 23, and aromatization with DDQ and
catalytic debenzylation with hydrogen and a palladium catalyst,
preferably palladium on carbon, provided 24. 24 was alkylated by
treatment with a base such as potassium carbonate, sodium hydride
or cesium fluoride followed by treatment R.sub.C--X. 13
[0532] A is --L.sub.AR.sub.A, and C is --L.sub.CR.sub.C, wherein C
is --L.sub.CR.sub.C, wherein L.sub.C is --O-- and
[0533] --L.sub.A-- and --L.sub.C-- are --O-- and R.sub.A is alkyl
R.sub.C is arylalkyl 14
[0534] A is --L.sub.AR.sub.A, wherein
[0535] --L.sub.A-- is --O-- and R.sub.A is alkyl
[0536] As shown in Scheme 5, monohydrolysis of 25 with one
equivalent of base such as lithium, sodium or potassium hydroxide
provided the acid-ester 26. Treatment of 26 with thionyl chloride
or oxalyl chloride/DMF followed by treatment with ammonia provided
amide 27. Treatment of 27 with a dehydrating agent such as thionyl
chloride or phosphorus oxychloride provided nitrile 28.
[0537] Regioselective nitration of 28 with nitric acid/potassium
nitrate followed by reduction of the nitro group with a palladium
catalyst, preferably palladium on carbon, provided intermediate 31,
which was treated with R.sub.CC(O)Cl or R.sub.COC(O)Cl and base,
preferably diisopropylethylamine or potassium carbonate, to provide
37.
[0538] Hydrolysis of 28 with one equivalent of lithium, sodium or
potassium hydroxide to form carboxylic acid 29 followed by
treatment with DPPA or thionyl chloride then sodium azide and
hydrolysis of the intermediate isocyanate 32 with acid, preferably
sulfuric acid, provided amine 33. Alternatively, treatment of 32
with a primary or secondary amine provided urea 34
(--L.sub.A--=--N.sub.R.sub.1C(X)R.sub.2--, wherein X is O).
[0539] 29 may be coupled to primary or secondary amines, and 33 may
be coupled to carboxylic acids to form amides 35 and 36,
respectively. In either case, the amines and carboxylic acids are
coupled using a dehydrating agent such as DCC, EDC or HATU. 15
[0540] --L.sub.C-- is --C(X)NR.sub.1-- or --OC(O)NR.sub.1-- and
[0541] R.sub.C is unsubstituted or substituted alkyl,
[0542] alkeneyl, hererocycle or aryl;
[0543] X is O 16
[0544] --L.sub.A-- is --C(X)NR.sub.1--
[0545] wherein X is O
[0546] As shown in Scheme 6, intermediates wherein --L.sub.A-- is
--C.ident.C-- or --C.dbd.C-- were prepared by treatment of of 38
with a triflating agent, preferably trifluoromethanesulfonyl
anhydride, to form 39, followed by coupling of the appropriate
substituted alkenes or unsubstituted or substituted alkynes using a
palladium catalyst, preferably palladium (II) acetate, to form 40.
17
[0547] As shown in Scheme 7, conversion of the nitrile
intermediates to the carboximidamide urokinase inhibitors 41 was
achieved by three methods: (1) treatment of the intermediate
carbonitriles with a non-nucleophilic base such as lithium, sodium
or potassium bis(trimethylsilylamide), preferably lithium
bis(trimethylsilylamide) followed by hydrolysis with acid,
preferably HCl; (2) treatment of the nitrile with acid, preferably
HCl, followed by treatment with ammonium acetate; and (3) treatment
of the nitrile with H.sub.2S followed by treatment with ammonia gas
in methanol. Of the three methods, the H.sub.2S/NH.sub.3/methanol
method is preferred. The compounds of the invention were
precipitated as hydrochloride or methane sulfonate salts or were
purified by reversed phase medium pressure chromatography to form
mono- or bis-trifluoroacetate salts. 18
Synthetic Methods
[0548] The foregoing may be better understood by reference to the
following examples which illustrate the methods by which the
compounds of the invention may be prepared and are not intended to
limit the scope of the invention as defined in the appended
claims.
EXAMPLE 1
7, 8-Dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate)
salt
EXAMPLE 1A
7, 8-Dimethoxy-2-naphthalenecarbonitrile
[0549] A solution of freshly prepared LDA in THF at -78 .degree. C.
was treated dropwise with 3-cyanopropionaldehyde diethyl acetal
(3.0 g) in THF (5 mL), stirred for 1 h, treated with
2,3-dimethoxybenzaldehyde (3.2 g) in THF (5 mL), warmed to room
temperature over 90 min, treated with water (40 mL), concentrated
and extracted with chloroform. The organic layer was washed with
brine, dried (MgSO.sub.4) and concentrated to provide 1.5 g of a
yellow oil.
[0550] MS (DCI/NH.sub.3) m/e 341 (M+H.sub.2O).sup.+.
[0551] A solution of the oil in methanol (5 mL) was added dropwise
to 20% aqueous sulfuric acid (100 mL) at 90.degree. C. The solution
was heated for 90 min, cooled to room temperature and extracted
with chloroform. The combined organic extracts are washed with
brine, dried (MgSO.sub.4) and concentrated to provide 1.0 g of a
brown solid which was purified by flash chromatography on silica
gel with 3:1 hexane/ethyl acetate to provide 800 mg of the title
compound.
[0552] MS (DCI/NH.sub.3) m/e 231 (M+H.sub.2O).sup.+.
EXAMPLE 1B
7, 8-Dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate)
salt
[0553] A solution of Example 1 (200 mg) in THF (5 mL) at 0.degree.
C. was treated with lithium bis(trimethylsilylamide) (1.0 M in
hexane, 1.1 mL), stirred for 18 h at room temperature, treated with
10% HCl (10 mL), stirred for 24 h at room temperature, concentrated
and purified by medium pressure liquid chromatography on a 30
cm.times.2 cm C-18 column (40 micron, J .T Baker) with UV detection
at 250 nM with solvent mixtures in a gradient ranging from 90%A
(0.1% aq TFA)/10%B (methanol) to 10%A/90%B over 160 min at a flow
rate of 5 mL/min (fractions were collected every 2 min for 100 min
and analyzed by TLC (10:1:1 acetonitrile/water/acetic acid) for
product) to provide 100 mg of the title compound.
[0554] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.41 (s, 3H),
4.62 (s, 3H), 7.41 (d, 1H), 7.43 (dd, 1H), 7.60 (d, 1H), 7.80 (d,
1H), 8.49 (d, 1H), 9.31 (bs, 2H), 9.48 (bs, 2H);
[0555] MS (DCI/NH.sub.3) m/e 231 (M+H).sup.+.
[0556] Anal. calcd for C.sub.13H.sub.14N.sub.2O.sub.2TFA: C, 52.33;
H, 4.39; N, 8.14. Found: C, 51.91; H, 4.35; N, 8.05.
EXAMPLE 2
6, 7, 8-trimethoxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 2A
6, 7, 8-trimethoxy-2-naphthalenecarbonitrile
[0557] The title compound was prepared as described in Example 1A
but substituting 2, 3, 4-trimethoxybenzaldehyde for 2,
3-trimethoxybenzaldehyde.
[0558] MS (DCI/NH.sub.3) m/e 261 (M+H.sub.2O).sup.+.
EXAMPLE 2B
6, 7, 8-trimethoxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0559] The title compound was prepared and purified as described in
Example 1 B to provide 100 mg of the title compound.
[0560] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 3.91 (s, 3H),
3.98 (s, 3H), 4.06 (s, 3H), 7.36 (s, 1H), 7.75 (dd, 1H) 7.99 (d,
1H), 8.49 (d, 1H), 9.18 (bs, 2H), 9.38 (bs, 2H);
[0561] MS (DCI/NH.sub.3) m/e 261 (M+H).sup.+.
[0562] Anal. calcd for C.sub.14H.sub.16N.sub.2O.sub.3TFA: C, 51.34;
H, 4.58; N, 7.48. Found: C, 50.91; H, 4.25; N, 7.35.
EXAMPLE 3
6, 7-dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate)
salt
EXAMPLE 3A
6, 7-dimethoxy-2-naphthalenecarbonitrile
[0563] The title compound was prepared as described in Example 1A
but substituting 3,4-dimethoxybenzaldehyde for 2,
3-dimethoxy-benzaldehyde to provide 1.3 g of the title
compound.
[0564] MS (DCI/NH.sub.3) m/e 231 (M+H.sub.2O).sup.+.
EXAMPLE 3B
6, 7-dimethoxy-2-naphthalenecarboximidamide mono(trifluoroacetate)
salt
[0565] The title compound was prepared and purified as described in
Example 1B to provide 100 mg of the title compound.
[0566] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 3.92 (s, 3H),
3.94 (s, 3H), 7.41 (s, 1H), 7.44 (s, 1H), 7.69 (dd, 1H), 7.93 (d,
1H), 8.49 (d, 1H), 9.18 (bs, 2H), 9.38 (bs, 2H);
[0567] MS (DCI/NH.sub.3) m/e 231 (M+H).sup.+.
[0568] Anal. calcd for C.sub.13H.sub.14N.sub.2O.sub.2TFA: C, 52.33;
H, 4.39; N 8.14. Found: C, 52.15; H, 4.20; N 8.10.
EXAMPLE 4
2-F(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxylacetamide
mono(trifluoroacetate) salt
EXAMPLE 4A
7-Methoxy-8-hydroxynaphthalene-2-carbonitrile
[0569] A solution of Example 1A (1 g) in methylene chloride (100
mL) at 0.degree. C. was treated with AlCl.sub.3, stirred for 4 h at
0.degree. C. and at room temperature for 18 h, poured into water
(200 mL) containing 6N HCl (20 mL), stirred for 1 h and diluted
with methylene chloride (100 mL). The layers were separated, and
the organic layer was washed with brine and dried (MgSO.sub.4) to
provide 810 mg of the title compound as an off-white solid.
[0570] MS (DCI/NH.sub.3) m/e 217 (M+H.sub.2O).sup.+.
EXAMPLE 4B
1,1-Dimethylethyl
2-[(7-Cyano-2-methoxy-1-naphthalenyl)oxy]acetate
[0571] A slurry Example 4A (100 mg), K.sub.2CO.sub.3 (70 mg),
t-butyl bromoacetate (120 mg) and tetrabutylammonium iodide (25 mg)
in DMF (3 mL) was stirred for 18 h at room temperature, diluted
with water (20 mL) and extracted with ethyl acetate. The organic
extract was washed with saturated NaHCO.sub.3 and brine, dried
(Na.sub.2SO.sub.4) and concentrated to provide 200 mg of the title
compound as a clear oil.
[0572] MS (DCI/NH.sub.3) m/e 331 (M+H.sub.2O).sup.+.
EXAMPLE 4C
2-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxylacetamide
mono(trifluoroacetate) salt
[0573] Example 4B (100 mg) in methanol (5 mL) at 0.degree. C. was
treated with HCl(g), stirred for 18 h at room temperature and
concentrated to provide an off-white solid. The solid was treated
with 2N NH.sub.3 in methanol (10 mL), heated at 50.degree. C. for
3.5 h, cooled and concentrated to a yellow solid which was purified
as described in Example 1B to provide 10 mg of the title compound.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.93 (s, 3H), 4.79 (s,
2H), 7.55 (d, 2H), 7.65 (dd, 1H), 7.72 (d, 1H), 7.85 (d, 1H), 8.09
(d, 1H), 8.7 (d, 1H), 9.03 (bs, 2H), 9.45 (bs, 2H);
[0574] MS (DCI/NH.sub.3) m/e 274 (M+H).sup.+.
[0575] Anal. calcd for C.sub.14H.sub.15N.sub.3O.sub.3TFA: C, 49.62;
H, 4.16; N, 10.85. Found: C, 49.33; H, 4.03; N, 10.50.
EXAMPLE 5
7-Benzyloxy-8-iodo-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 5A
7-Benzyloxy-8-iodo-2-naphthalenecarbonitrile
[0576] The title compound was prepared as described in Example 43A
but substituting benzyl bromide for propyl iodide.
[0577] MS (DCI/NH.sub.3) m/e 403 (M+NH.sub.4).sup.+.
EXAMPLE 5B
7-Benzyloxy-8-iodo-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0578] The title compound was prepared from Example 5A according to
the procedure of Example 1B.
[0579] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.30 (br, 4H),
8.44 (s, 1H), 8.12 (d, 1H), 7.71 (d, 2H), 7.67 (dd, 1H), 7.57 (d,
2H), 7.45-7.34 (m, 3H), 5.45 (s, 2H);
[0580] MS (DCI/NH.sub.3) m/e 403 (M+H).sup.+.
[0581] Anal. calcd for C.sub.18H.sub.15N.sub.2OI.TFA: C, 46.53; H,
3.12; N, 5.43. Found: C; 46.55; H, 3.10; N, 5.19.
EXAMPLE 6
Methyl [(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]acetate
mono(trifluoroacetate) salt
EXAMPLE 6A
Methyl [(7-cyano-2-methoxy-1-naphthalenyl)oxy]acetate
[0582] A solution of Example 4A (600 mg), Cs.sub.2CO.sub.3 (500
mg), t-butyl bromoacetate (120 mg) and tetrabutylammonium iodide
(25 mg) in DMF (15 mL) was stirred for 18 h at room temperature,
diluted with water (20 mL) and extracted with ethyl acetate. The
organic extract was washed with saturated NaHCO.sub.3 and brine,
dried (Na.sub.2SO.sub.4) and concentrated to provide 800 mg of the
title compound as a clear oil.
[0583] MS (DCI/NH.sub.3) m/e 331 (M+H.sub.2O).sup.+.
EXAMPLE 6B
Methyl l(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]acetate
mono(trifluoroacetate) salt
[0584] Example 6A (100 mg) in methanol (30 mL) at 0.degree. C. was
treated with HCl(g), stirred for 18 h at room temperature and
concentrated to provide an off-white solid. The solid was treated
with ammonium acetate (100 mg) in methanol (10 mL), heated at
40.degree. C. for 15 h, cooled and concentrated to a yellow solid
which was purified as described in Example 1B to provide 10 mg of
the title compound.
[0585] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.65 (s, 3H),
3.93 (s, 3H), 4.79 (s, 2H), 7.65 (dd, 1H), 7.72 (d, 1H), 7.85 (d,
1H), 8.09 (d, 1H), 8.7 (d, 1H), 9.03 (bs, 2H), 9.45 (bs, 2H);
[0586] MS (DCI/NH.sub.3) m/e 289 (M+H).sup.+.
[0587] Anal. calcd for C.sub.15H.sub.16N.sub.2O.sub.4TFA: C, 50.75;
H, 4.26; N, 6.96. Found: C, 50.42; H, 4.03; N, 6.77.
EXAMPLE 7
[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]acetic acid
mono(trifluoroacetate) salt
[0588] A solution of Example 6B (100 mg) and LiOH.H.sub.2O (150 mg)
in 1:1 THF/H.sub.2O (10 mL) at 5.degree. C. was stirred 45 min and
concentrated to provide an off-white solid. The solid was dissolved
in 1N HCl (20 mL), stirred 48 h at room temperature and filtered.
The resulting white solid was purified as described in Example 1B
to provide 20 mg of the title compound.
[0589] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.93 (s, 3H),
4.79 (s, 2H), 7.65 (dd, 1H), 7.72 (d, 1H), 7.85 (d, 1H), 8.09 (d,
1H), 8.7 (d, 1H), 9.23 (bs, 2H), 9.45 (bs, 2H); MS (DCI/NH.sub.3)
m/e 275 (M+H).sup.+.
[0590] Anal. calcd for C.sub.14H.sub.14N.sub.2O.sub.4.TFA: C,
49.49; H, 3.89; N, 7.21. Found: C, 47.53; H, 3.71; N, 6.83.
EXAMPLE 8
N-[4-(Aminomethyl)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamide
bis(trifluoroacetate) salt
EXAMPLE 8A
2, 6-Naphthalenedicarboxylic acid, monomethyl ester
[0591] A suspension of dimethyl 2, 6-naphthalenedicarboxylic acid
(39.6 g, 162 mmole) in dioxane (1.20 L) was heated at 70-80.degree.
C. until all solid dissolved, slowly treated with 1 equivalent of
KOH in methanol, stirred for additional 30 minutes at 70.degree.
C., cooled to room temperature, filtered and washed with dioxane
and diethyl ether, dissolved in water, treated with IN HCl until
the aqueous layer was acidic to pH paper, filtered, washed with
water and dried under vacuum to provide 33 g of a white powder.
[0592] MS (DCI/NH.sub.3) m/e 231 (M+H).sup.+.
EXAMPLE 8B
6-(Chlorocarbonyl)-2-naphthalenecarboxylic acid, methyl ester
[0593] A suspension of Example 8A (15 g, 65 mmole) in toluene (190
mL) was treated with thionyl chloride (20 mL, 276 mmole) then DMAP
(15 mg), heated at reflux for 1 h and heated at 85.degree. C. for
an additional 35 min. The condenser was replaced with a distilling
head and 60 mL of solvent was removed. The thick precipitate which
formed while cooling to room temperature was triturated with hexane
and filtered to provide 14.8 g of white solid.
[0594] MS (DCI/NH.sub.3) m/e 249 (M+H).sup.+.
EXAMPLE 8C
6-(Aminocarbonyl)-2-naphthalenecarboxylic acid, methyl ester
[0595] A solution of Example 8B (15 g, 60.3 mmole) in methylene
chloride (400 mL) at room temperature was treated with dry ammonia
gas to precipitate the product. The mixture was stirred for an
additional 15 min and filtered. The solid was washed with water and
dried under vacuum to yield 13.3 g of a white powder.
[0596] MS (DCI/NH.sub.3) m/e 230 (M+H).sup.+.
EXAMPLE 8D
6-Cyano-2-naphthalenecarboxylic acid, methyl ester
[0597] A suspension of Example 8C (31 g, 135 mmole) in trimethyl
phosphate (450 mL) was treated with triphosgene (27 g, 136 mmole),
stirred for 20 min at room temperature and heated in an oil bath at
80.degree. C. for 1 h. The product precipated from the solution
while cooling to room temperature. The thick slurry was treated
with water and filtered, and the white solid was thoroughly washed
with water and dried under vacuum to provide 26.3 g of the title
compound.
[0598] MS (DCI/NH.sub.3) m/e 212 (M+H).sup.+.
EXAMPLE 8E
6-Cyano-2-naphthalenecarboxylic acid
[0599] Example 8D (1.9 g, 9 mmole) in 1:1 THF/H.sub.2O (40 mL) was
treated with LiOH.H.sub.2O (1.9 g, 45 mmole), stirred 90 min at
room temperature and concentrated to a thick slurry. The slurry was
dissolved in water (20 mL), acidified to pH 2 with solid citric
acid and extracted with ethyl acetate. The combined organic
extracts were washed with brine, dried (Na.sub.2SO.sub.4) and
concentrated to provide 1.6 g of the title compound as a white
solid.
[0600] MS (DCI/NH.sub.3) m/e 197 (M+H).sup.+.
EXAMPLE 8F
tert-Butoxycarbonylamino -4-aminomethylaniline
[0601] 4-Aminomethylaniline (2 g) in 2:1 THF/H.sub.2O (30 mL) was
treated with Boc anhydride (3.93 g), stirred at room temperature
for 18 h, diluted with water and concentrated to white slurry. The
slurry was dissolved in ethyl acetate, washed with water and brine,
dried (Na.sub.2SO.sub.4) and concentrated to provide 2.4 g of a
yellow solid.
[0602] MS (DCI/NH.sub.3) m/e 223 (M+H).sup.+.
EXAMPLE 8G
N-[4-(aminomethyl)phenyl]-6-cyano-2-naphthalenecarboxamide
[0603] A solution of Example 8E (200 mg) and hunig's base (180
.mu.L) in DMF (5 mL) at 5.degree. C. was treated with HATU (193
mg), stirred for 1 h at 5.degree. C., treated with Example 8F (120
mg) and diisopropylethylamine (100 .mu.L) in DMF (5 mL), stirred
for 8 h at room temperature, diluted with ethyl acetate (100 mL),
washed sequentially with 1N H.sub.3PO.sub.4, saturated sodium
bicarbonate and brine, dried (Na.sub.2SO.sub.4) and concentrated to
provide a yellow oil which was purified on silica gel with 1%
methanol/methylene chloride to provide 200 mg of the title
compound.
[0604] MS (DCI/NH.sub.3) m/e 419 (M+H.sub.2O).sup.+.
EXAMPLE 8H
N-[4-(aminomethyl)phenyl]-6-aminoininomethyl-2-naphthalenecarboxamide
bis(trifluoroacetate) salt
[0605] The title compound was prepared from Example 8G (200 mg) by
the procedure and purification from Example 5B to provide 37 mg of
the title compound.
[0606] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.08 (m, 2H),
7.45 (d, 2H), 7.88 (d, 2H), 7.95 (dd, 1H), 8.18 (dd,1H), 8.20 (bs,
3H), 8.23 (d,1H), 8.35 (d,1H), 8.58 (s,1H), 8.70 (s, 1H), 9.39 (s,
2H), 9.55 (s, 2H), 10.68 (s, 1H);
[0607] MS (DCI/NH.sub.3) m/e 319 (M+H).sup.+.
[0608] Anal. calcd for C.sub.19H.sub.17N.sub.4O.TFA: C, 50.56; H,
3.69; N, 10.25; Found: C, 50.18; H, 3.59; N, 10.11.
EXAMPLE 9
N-[4-(amino)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamide
bis(trifluoroacetate) salt EXAMPLE 9A
N-[4-(amino)phenyl-6-cyano-2-naphthalenecarboxamide
[0609] The title compound was prepared according to the procedure
described for Example 8G but substituting 1,4-diaminobenzene for
Example 8F. MS (DCI/NH.sub.3) m/e 288 (M+H).sup.+.
EXAMPLE 9B
N-[4-(amino)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamide
bis(trifluoroacetate) salt
[0610] The title compound was prepared with Example 9A (100 mg)
following the procedure and purification from Example 6B.
[0611] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.15 (d, 2H),
7.75 (d, 2H), 7.95 (dd, 1H), 8.18 (dd, 1H), 8.23 (d, 1H), 8.35 (d,
1H), 8.58 (s, 1H), 8.70 (s, 1H), 9.25 (s, 2H), 9.48 (s, 2H), 10.58
(s, 1H);
[0612] MS (DCI/NH.sub.3) m/e 305 (M+H).sup.+.
[0613] Anal. calcd for C.sub.18H.sub.16N.sub.4O.2TFA: C, 49.63; H,
3.41; N, 10.52; Found: C, 46.57; H, 3.62; N, 10.66.
EXAMPLE 10
1-
[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-hydroxypropane
mono(trifluoroacetate) salt
EXAMPLE 10A
1-[(7-Cyano-2-methoxy-1-naphthalenyl)oxy]-3-[(2-tetrahydro-2H-pyranyl
oxy)propane mono(trifluoroacetate) salt
[0614] A suspension of Example 4A (200 mg) and Cs.sub.2CO.sub.3
(0.32 g) in DMF (15 mL) was treated with
2-(3-bromopropyl)-tetrahydro-2H-pyran (0.25 g), stirred at room
temperature for 18 h then diluted with water (100 mL) and ethyl
acetate (50 mL). The organic layer was separated, washed with 10%
citric acid, water and brine, dried (MgSO.sub.4) and concentrated
to provide 320 mg of an oil.
[0615] MS (DCI/NH.sub.3) m/e 323 (M+H).sup.+.
EXAMPLE 10B
1-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-hydroxypropane
mono(trifluoroacetate) salt
[0616] Example 10A (0.3 g) was processed and purified according to
the procedure of Example 1B to provide 110 mg of an off-white
solid.
[0617] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.97 (q, 2H),
3.67 (t, 2H), 4.20 (t, 2H), 7.61-7.70 (m, 3H), 7.84 (d,1H), 8.08
(d, 1H), 8.50 (d, 1H);
[0618] MS (DCI/NH.sub.3) m/e 275 (M+H).sup.+.
[0619] Anal. calcd for
C.sub.13H.sub.13N.sub.3O.sub.2.TFA.0.75H.sub.20: C, 50.81; H, 5.14;
N, 6.97. Found: C, 51.23; H, 5.28; N, 6.97.
EXAMPLE 11
8-amino-2-naphthalenecarbonitrile hydrobromide
EXAMPLE 11A
2-Trifluoromethanesulfonyloxy-8-aminonaphthelene
[0620] A solution of 8-amino-2-naphthol (10 g) and triethylamine
(12 mL) in dioxane (200 mL) was treated with
N-phenyltrifluoromethane sulfonimide (25 g) in dioxane (80 mL),
stirred for 4 h and concentrated. The resulting dark brown solid
was triturated with hexane and filtered to provide 12 g of the
title compound as a brown solid.
[0621] MS (DCI/NH.sub.3) m/e 292 (M+H).sup.+.
EXAMPLE 11B
2-Trifluoromethanesulfonyloxy-8-carbonylbenzyloxyaminonaphthelene
[0622] A solution of Example 11A (2 g) in 10% aq Na.sub.2CO.sub.3
(20 mL) and dioxane (250 mL) was treated with benzylchloroformate
(2 mL) in dioxane (20 mL), stirred at room temperature for 5 h then
extracted with ethyl acetate. The organic layer was dried
(MgSO.sub.4) and concentrated, and the crude product was
chromatographed on silica gel with 7:1 hexane/ethyl acetate to
provide 2.5 g (86%) of the title compound.
[0623] MS (DCI/NH.sub.3) m/e 443 (M+NH.sub.4).sup.+.
EXAMPLE 11C
8-(N-carbonylbenzyloxy)-2-naphthalenecarbonitrile
[0624] Tris(dibenzylideneacetone)dipalladium(O)-chloroform adduct
(120 mg), 1,1'-bis(diphenylphosphino)-ferrocene (260 mg), potassium
cyanide (766 mg), Example 11B (2.5 g) and N-methyl-2-pyrrolidione
(5 mL) were combined sequentially, stirred at room temperature
until a yellow reaction complex formed then warmed to 80.degree. C.
for 40 min. The dark brown reaction mixture was cooled to room
temperature and chromatographed on silica gel with 9:1 hexane/ethyl
acetate to provide 1.5 g of the title compound as a colorless
solid.
[0625] MS (DCI/NH.sub.3) m/e 292 (M+NH.sub.4).sup.+
EXAMPLE 11D
8-Amino-2-naphthalenecarbonitrile hydrobromide
[0626] Example 11C (1.4 g) was treated with a solution of 30% HBr
in acetic acid (5 mL) and stirred at room temperature for 6 h. The
reaction mixture was treated with diethyl ether and filtered to
provide 1.1 g of the title compound as a yellow solid.
[0627] MS (DCI/NH.sub.3) m/e 86 (M+NH.sub.4).sup.+
EXAMPLE 12
General Acylation Procedure
[0628] A suspension of Example 10D (1 equivalent), triethylamine (1
equivalent) and DMAP (0.25 equivalents) in methylene chloride
(0.3M) was treated dropwise with the appropriate acid chloride (1.1
equivalents) in methylene chloride (0.3 M), stirred at room
temperature for 30 min and treated with water (50 mL). The organic
layer was dried (MgSO.sub.4), concentrated and used in following
reactions without further purification.
EXAMPLE 13
General Amidine Synthesis Procedure
[0629] A solution of crude acylation products from Example 12 (ca.
100 mg) at room temperature in 10:1 pyridine:triethylamine (10 mL)
was treated with hydrogen sulfide for 5 min, stirred at room
temperature for 18 h, diluted with water (50 mL) and extracted with
ethyl acetate. The ethyl acetate was dried (MgSO.sub.4) and
concentrated. The residue was dissolved in acetone (30 mL), treated
with methyl iodide (2 mL), refluxed for 1 hour, evaporated to
dryness, redissolved in methanol (25 mL), treated with ammonium
acetate (100 mg), stirred for 18 h at room temperature,
concentrated and purified as described in Example 1B to provide
Examples 14-20 as white solids.
EXAMPLE 14
8-(carbonylbenzyloxy)amino-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0630] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 5.14 (s, 2H),
7.36-7.50 (m, 5H), 7.67-7.90 (m, 4H), 8.14 (d, 1H), 8.67 (s, 1H),
9.08 (s, 2H), 9.37 (s, 2H), 9.78 (s, 1H);
[0631] MS (DCI/NH.sub.3) m/e 320 (M+H).sup.+.
[0632] Anal. calcd for
C.sub.19H.sub.15N.sub.3O.sub.2.1.5TFA-0.5H.sub.20: C, 52.91; H,
3.94; N, 8.41. Found: C, 52.86; H, 4.07; N, 8.18.
EXAMPLE 15
N-[7-(aminoiminomethyl)-1-naphthalenyl)acetamide
mono(trifluoroacetate) salt
[0633] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 4.19 (s, 3H),
7.66-7.88 (m, 3H), 8.12-8.16 (m, 2H), 8.69 (s, 1H), 8.98 (d, 1H),
9.16 (s, 2H), 9.47 (s, 2H), 10.14 (s, 1H);
[0634] MS (DCI/NH.sub.3) m/e 228 (M+H).sup.+.
[0635] Anal. calcd for
C.sub.14H.sub.12N.sub.3O.1.2TFA.0.25H.sub.2O: C, 50.18; H, 4.02; N,
11.40. Found: C, 50.62; H, 4.47; N, 10.90.
EXAMPLE 16
Methyl [7-(aminoiminomethyl)-1-naphthalenyl)carbamate
mono(trifluoroacetate) salt
[0636] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 3.88 (s, 3H),
7.67-7.85 (m, 4H), 8.14 (d, 1H), 8.6 (s, 1H), 8.28 (s, 3H), 9.67
(s, 1H);
[0637] MS (DCI/NH.sub.3) m/e 244 (M+H).sup.+.
[0638] Anal. calcd for C.sub.13H.sub.13N.sub.3O.sub.2.TFA: C,50.43;
H, 3.95; N, 11.76. Found: C, 50.12; H, 4.05; N, 11.61.
EXAMPLE 17
Methyl
3-[[7-(aminoiminomethyl)-1-naphthalenyl]amino]-3-oxopropionate
mono(trifluoroacetate) salt
[0639] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 3.69 (s, 2H),
3.71 (s, 3H), 7.69 (m, 4H), 8.18 (d, 1H), 8.58 (s, 1H), 9.11 (s,
2H), 9.48 (s, 2H);
[0640] MS (DCI/NH.sub.3) m/e 286 (M+H).sup.+.
[0641] Anal. calcd for
C.sub.15H.sub.14N.sub.3O.sub.3.1.1TFA-H.sub.2O: C, 48.18; H, 4.26;
N, 9.80. Found: C, 48.30; H, 4.09; N, 9.58.
EXAMPLE 18
N-[7-(aminoiminomethyl)-1-naphthalenyl]-2-(phenylmethoxy)acetamide
mono(trifluoroacetate salt
[0642] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 4.29 (s, 2H),
4.73 (s, 2H), 7.33-7.48 (m, 5H), 7.69 (m, 4H), 8.17 (d, 1H), 8.47
(s, 1H), 9.21 (br, 4H), 10.0 (s, 1H);
[0643] MS (DCI/NH.sub.3) m/e 334 (M+H).sup.+.
[0644] Anal. calcd for
C.sub.20H.sub.18N.sub.3O.sub.2.1TFA-H.sub.2O: C, 56.77; H, 4.76; N,
9.03. Found: C, 56.84; H, 4.49; N, 8.93.
EXAMPLE 19
N-[7-(aminoiminomethyl)-1-naphthalenyl]-1,3-benzodioxole-5-carboxamide
mono(trifluoroacetate) salt
[0645] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 6.19 (1H, 2H),
7.12 (d, 1H), 7.65-7.79 (m, 5H), 7.97 (d, 1H), 8.20 (s, 1H), 8.53
(s, 1H), 9.2 (br s, 3H), 10.35 (s, 2H);
[0646] MS (DCI/NH.sub.3) m/e 334 (M+H).sup.+.
[0647] Anal. calcd for C.sub.18H.sub.14N.sub.3O.sub.2.TFA: C,
55.82; H, 3.68; N, 9.30. Found: C, 55.69; H, 33.61; N, 9.23.
EXAMPLE 20
N-[7-(aminoiminomethyl)-1-naphthalenyl]benzenemethanesulfonamide
mono(trifluoroacetate) salt
[0648] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 4.60 (s, 2H),
7.32-7.33 (m, 5H), 7.67-7.70 (m, 2H), 7.82 (d,1H), 7.92 (d,1H),
8.17 (s, 1H), 8.70 (s, 1H), 9.14 (s, 2H), 9.35 (s, 2H), 9.19 (s,
1H);
[0649] MS (DCI/NH.sub.3) m/e 340 (M+H).sup.+.
[0650] Anal. calcd for
C.sub.18H.sub.17N.sub.3O.sub.2S.TFA.H.sub.2O: C, 50.95; H, 4.28; N,
8.91; Found: C, 50.76; H, 3.70; N, 8.65.
EXAMPLE 21
1-[(7-aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-bromopropane
mono (hydrochloride) salt
EXAMPLE 21A
1-[(7-Cyano-2-methoxy-1-naphthalenyl)oxy]-3-bromopropane
mono(hydrochloride) salt
[0651] The title compound was prepared from Example 4A,
1,3-dibromopropane and the procedure of Example 10A.
[0652] MS (DCI/NH.sub.3) m/e 337 (M+NH.sub.4).sup.+.
EXAMPLE 21B
1-f(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-bromopropane
mono(hydrochloride) salt
[0653] The title compound was prepared from Example 21A and the
procedure of Example 1B. After HCl hydrolysis, the solution was
cooled to 0.degree. C., and the white solid which precipitated was
filtered and dried to provide the title compound.
[0654] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.35 (m, 2H),
3.86 (t, 2H), 4.00 (s, 3H), 4.25 (t, 2H), 7.65 (dd, 1H), 7.70 (d,
1H), 7.90 (d, 1H), 8.10 (d, I1H), 8.55 (s, 1H), 9.15 (br s, 2H),
9.42 (br s, 2H);
[0655] MS (DCI/NH.sub.3) m/e 337 (M+H).sup.+.
[0656] Anal. calcd for
C.sub.15H.sub.17BrN.sub.2O.sub.2.HCl.0.75H.sub.20: C, 46.53; H,
5.08; N, 7.23. Found: C, 46.65; H, 5.11; N, 7.16.
EXAMPLE 22
3-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]propene
mono(trifluoroacetate) salt
EXAMPLE 22A
3- [(7-Cyano-2-methoxy-1-naphthalenyl)oxy]propene
[0657] The title compound was obtained as a biproduct from the
procedure of Example 21 A.
[0658] MS (DCI/NH.sub.3) m/e 257 (M+NH.sub.4).sup.+.
EXAMPLE 22B
3-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]propene
mono(trifluoroacetate) salt
[0659] The title compound was prepared from Example 22A and the
procedure and purification in Example 1B.
[0660] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.00 (s, 3H),
4.70 (d, 2H), 5.22 (d, 1H), 5.42 (d, 1H), 6.18 (m, 1H), 7.62 (dd,
1H), 7.85 (d, 1H), 8.10 (d, 1H), 8.50 (s, 1H), 9.12 (br s, 2H),
9.45 (br s, 2H);
[0661] MS (DCI/NH.sub.3) m/e 257 (M+H).sup.+.
[0662] Anal. calcd for
C.sub.15H.sub.16N.sub.2O.sub.2.TFA.0.25H.sub.20: C, 54.47; H, 4.71;
N, 7.47. Found: C, 54.61; H, 4.38; N, 7.40.
EXAMPLE 23
1-[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-phenylpropane
mono(hydrochloride) salt
EXAMPLE 23A
1-[(7-Cyano-2-methoxy-1-naphthalenyl)oxy]-3-phenylpropane
[0663] The title compound was prepared from Example 4A,
1-bromo-3-phenylpropane, and the procedure of Example 10A.
[0664] MS (DCI/NH.sub.3) m/e 335 (M+NH.sub.4).sup.+.
EXAMPLE 23B
1-
[(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-phenylpropane
mono(hydrochloride) salt
[0665] The title compound was prepared from Example 23A and the
procedure of Example 21B.
[0666] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.21 (m, 2H), 2.94
(t, 2H), 4.00 (s, 3H), 4.22 (t, 2H), 7.18 (m, 1H), 7.28 (m, 4H),
7.62 (m, 2H), 7.79 (d, 1H), 8.02 (d, 1H), 8.62 (s, 1H);
[0667] MS (DCI/NH.sub.3) m/e 335 (M+H).sup.+.
[0668] HRMS (FAB) calcd m/e for C.sub.21H.sub.23N.sub.2O.sub.2.HCl:
335.1760 (M+H).sup.+. Found m/e 335.1762.
EXAMPLE 24
1-F(7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-1-(3
,4-dimethoxy)phenyl]propane mono(hydrochloride) salt
EXAMPLE 24A
1-Bromo-3-(3,4-dimethoxyphenyl)propane
[0669] The title compound was prepared from
3-(3,4-dimethoxyphenyl)-1-prop- anol as described in Journal of the
American Chemical Society, 95, 8749 (1973), which is incorporated
herein by reference, to provide the title compound.
[0670] MS (DCI/NH.sub.3) m/e 276 (M+NH.sub.4).sup.+.
EXAMPLE 24B
1-I(7-Cyano-2-methoxy-1-naphthalenyl)oxy]-3-
[1-(3,4-dimethoxy)phenyl]prop- ane
[0671] The title compound was prepared from Examples 4A and 24A and
the procedure of Example 10A.
[0672] MS (DCI/NH.sub.3) m/e 395 (M+NH.sub.4).sup.+.
EXAMPLE 24C
1-1 (7-Aminoiminomethyl-2-methoxy-1-naphthalenyl)oxy]-3-l 1-(3
4-dimethoxy phenyl propane mono(hydrochloride) salt
[0673] The title compound was prepared from Example 24B and the
procedure of Example 21 B.
[0674] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.11 (m, 2H),
2.80 (t, 2H), 3.74 (s, 6H), 3.98 (s, 3H), 4.15 (t, 2H), 6.75-6.92
(m, 3H), 7.65 (dd, 1H), 7.70 (d, 1H), 7.86 (d, 1H), 8.10 (d, 1H),
8.55 (s, 1H), 9.15 (br s, 2H), 9.53 (br s, 2H),
[0675] MS (DCI/NH.sub.3) m/e 395 (M+H).sup.+.
[0676] Anal. calcd for
C.sub.23H.sub.26N.sub.2O.sub.4.HCl.0.5H.sub.2O: C, 62.79; H, 6.42;
N, 6.37. Found: C, 63.08; H, 6.38; N, 6.17.
EXAMPLE 25
7-Methoxy-8-(2-furanyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 25A
7-Methoxy-8-trifluoromethanesulfonyloxy-2-naphthalenecarbonitrile
[0677] A solution of Example 4A (310 mg) in methylene chloride (5
mL) at 0.degree. C. was treated with
1,1,1-trifluoro-N-phenyl-N-[(trifluoromethy-
l)sulfonyl]methanesulfonamide (614 mg) and triethylamine (240 mL),
stirred for 18 h at room temperature, diluted with methylene
chloride (100 mL), washed with water and 20% aq NaOH, dried
(MgSO.sub.4) and concentrated to provide 560 mg of the title
compound as a white solid.
[0678] MS (DCI) m/e 349 (M+H.sub.2O).sup.+.
EXAMPLE 25B
Furan-2-boronic acid
[0679] A solution of furan (5.3 mL, 73 mmole) in diethyl ether (67
mL) at -20.degree. C. was treated with n-butyllithium (2.5 M in
hexanes, 26 mL, 65 mmole), stirred for 2 hours at -20.degree. C.
and transferred by cannula to a -20.degree. C. solution of
triisopropyl borate (33 mL, 147 mmole) in diethyl ether (17 mL).
The thick mixture was warmed to room temperature, treated with 3N
HCl (200 mL) and extracted with diethyl ether. The extracts were
washed with IN KOH, and the KOH layer was cooled to 0.degree. C.
and acidified with 6N HCl. The acidic solution was extracted with
diethyl ether, and the acidic ether extracts were washed with
brine, dried (MgSO.sub.4) and concentrated to provide the title
compound.
[0680] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 6.45 (dd, 1H),
7.05 (t, 1H), 7.80 (dd, 1H), 8.19 (s, 2H).
EXAMPLE 25C
7-Methoxy-8-(2-furanyl)-2-naphthalenecarbonitrile
[0681] Example 25A (1.10 mmol) was combined with Pd(OAc).sub.2
(0.11 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (0.22 mmol) in
DMF (5 mL), stirred for 10 min, treated with Example 25B (1.32
mmol) and Cs.sub.2CO.sub.3 (3.3 mmol), heated at 85.degree. C. for
6 h, cooled to room temperature and chromatographed on silica gel
with 10% ethyl acetate/hexane to provide the title compound.
[0682] MS (DCI/NH.sub.3) m/e 250 (M+H).sup.+.
EXAMPLE 25D
8-(2-Furanyl)-7-methoxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0683] The title compound was prepared from Example 25C and the
procedure and purification in Example 1B.
[0684] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.97 (s, 3H),
6.73 (m, 1H), 6.80 (m, 1H), 7.64 (dd, 1H), 7.78 (d, 1H), 7.91 (m,
1H), 8.16 (d, 1H), 8.20 (d, 1H), 8.30 (s, 1H), 9.08 (br s, 2H),
9.40 (br s, 2H);
[0685] MS (DCI/NH.sub.3) m/e 267 (M+H).sup.+.
[0686] Anal. calcd for C.sub.16H.sub.14N.sub.2O.sub.2.TFA: C,
56.85; H, 3.98; N, 7.37. Found: C, 56.68; H, 3.67; N, 7.35.
EXAMPLE 26
methyl
6-(aminoiminomethyl)-4-[(methoncarbonyl)amino]-2-naphthalenecarboxy-
late mono(trifluoroacetate) salt
EXAMPLE 26A
2-Cyano-1-nitro-6-carboxynaphthalene methyl ester
[0687] A solution of 2-cyano-6-methylnaphthoate (5.2 g) in
concentrated sufuric acid (75 mL) at 0.degree. C. was treated with
potassium nitrate (1.03 eq) in one portion, stirred for 10 min,
poured onto ice (500 g) and extracted with ethyl acetate. The ethyl
acetate layer was washed with water, 1N NaOH and brine, dried
(MgSO.sub.4), treated with silica gel and filtered. Concentration
of the ethyl acetate to ca. 200 mL precipitated the product. The
mixture was heated until all solid dissolved, treated with MeOH (20
mL) and ether (20 mL) and stirred overnight. The resulting solid
was filtered and washed with methanol to provide 2.31 g of the
title compound as a cream-colored solid. The mother liqueuor was
evaporated, treated with methylene chloride (250 mL) then solid
silica gel, filtered and concentrated. Crystalization from ethyl
acetate/methanol provided an additional 1.6 g of product for a
total yield: 3.91 g (62%).
[0688] MS (DCI/NH.sub.3) m/e 257 (M+H).sup.+.
EXAMPLE 26B
2-Cyano-1-amino-6-carboxynaphthalene methyl ester
[0689] A solution of Example 26A (1 g, 3.9mmole) and 10% Pd on
carbon (112 mg) in ethyl acetate (80 mL) was stirred under 1 atm of
hydrogen for 9 h, purged with nitrogen for 1 h, filtered and
evaporated to provide 810 mg (92%) of the title compound as a
yellow solid.
[0690] MS (DCI/NH.sub.3) m/e 227 (M+NH.sub.4).sup.+.
EXAMPLE 26C
6-Cyano-4-[(methoxycarbonyl)amino]-2-naphthalenecarboxylic acid,
methyl ester
[0691] A solution of Example 26B (2.50 mmol) in methylene chloride
(40 mL) was treated sequentially with diisopropylethylamine (2 mL)
and methylchloroformate (195 .mu.L, 2.52 mmole), stirred for 2 h,
treated with methanol (10 mL), stirred for an additional 10
minutes, diluted with methylene chloride (60 mL), washed with water
and brine, dried (MgSO4) and evaporated. The residue was purified
on silica gel using 10% ethyl acetate/hexane to provide 280 mg
(59%) of light yellow solid.
[0692] MS (DCI/NH.sub.3) m/e 285 (M+H).sup.+.
EXAMPLE 26D
Methyl
6-(aminoininomethyl)-4-[(methoxycarbonyl)amino]-2-naphthalenecarbox-
ylate mono(trifluoroacetate) salt
[0693] The title compound was prepared using Example 26C (125 mg,
0.44 mmol) and the procedure in Example 40D to provide 35mg of a
white solid.
[0694] .sup.1H NMR (DMSO-d.sub.6) .delta. 3.78 (s, 3H), 3.95 (s,
3H), 7.89 (dd, 1H), 8.37-8.40 (m, 3H), 8.53 (s, 1H), 8.740 (s, 1H)
9.18 (br s, 2H), 9.45 (br s, 2H), 9.90 (s, 1H), 8.42 (s, 1H), 8.63
(d, 1H), 9.18 (br s, 4H), 10.58 (s, 1H);
[0695] MS (DCI/NH.sub.3) m/e 302 (M+H).sup.+.
[0696] Anal. calcd for
C.sub.15H.sub.15N.sub.3O.sub.4.TFA.1.5H.sub.2O: C, 46.16; H, 4.33;
N, 9.50. Found: C, 45.96; 46.16; H, 4.06; N, 9.12.
EXAMPLE 27
(E)-{7-Methoxy-8-12-(Phenyl)ethenyl]}-2-naphthaleneimidamide
mono(trifluoroacetate) salt
EXAMPLE 27A
(E)-{7-Methoxy-8-[2-(Phenyl)ethenyl]}-2-naphthalenecarbonitrile
[0697] Example 25A and styrene boronic ester, prepared according to
the procedure of Journal of the American Chemical Society, 97 5249
(1975), which is incorporated herein by reference, was processed
according to the procedure described in Example 26B to provide the
title compound.
[0698] MS (DCI/NH.sub.3) m/e 303 (M+NH.sub.4).sup.+.
EXAMPLE 27B
(E)-{7-Methoxy-8-[2-(Phenyl)ethenyl]}-2-naphthaleneimidamide
mono(trifluoroacetate) salt
[0699] The title compound was prepared from Example 27A and the
procedure of Example 1B.
[0700] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.98 (s, 3H),
7.28 (t, 2H), 7.39 (t, 2H), 7.64 (m, 5H), 8.00 (d, 1H), 8.10 (d,
1H), 8.62 (s, 1H), 9.22 (br s, 2H), 9.42 (br s, 2H);
[0701] MS (DCI/NH.sub.3) m/e 303 (M+H).sup.+.
[0702] Anal. calcd for C.sub.20H.sub.18N.sub.2O.TFA: C, 63.46; H,
4.60; N, 6.73. Found: C, 63.10; H, 4.73; N, 6.43.
EXAMPLE 28
6-(4-Phenylbutynyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 28A
6-Hydroxy-2-naphthalenecarbonitrile
[0703] A solution of 6-bromo-2-naphthol (25.0 g, 112 mmol) and
copper(I) cyanide (11 g, 123 mmol) in DMF (30 mL) was heated at
135.degree. C. for 18 h, cooled, diluted with ethyl acetate (50
mL), triturated with 10% aq sodium hydroxide and filtered through
Celite.RTM.. The filtrate was acidified to pH 2 and extracted with
ethyl acetate. The combined extracts were concentrated, dissolved
in ethanol (150 mL) and triturated with water to precipitate 14.01
g of the title compound.
[0704] MS (DCI/NH.sub.3) nm/e 170 (M+H).sup.+.
EXAMPLE 28B
6-(Trifluoromethanesulfonyloxy)-2-naphthalenecarbonitrile
[0705] A solution of Example 28A (14.01 g, 82.8 mmol) and
triethylamine (9.2 g, 91.1 mmol) in methylene chloride (40 mL) at
0.degree. C. was treated dropwise with trifluoromethylsulfonic
anhydride (28 g, 99.4 mmol), warmed to 25.degree. C. for 48 h,
concentrated, redissolved in ethanol (50 mL) and triturated with
water to precipitate 8.4 g of the title compound.
[0706] MS (DCI/NH.sub.3) m/e 319 (M+NH.sub.4).sup.+.
EXAMPLE 28C
6-(4-Phenylbutynyl)-2-naphthalenecarbonitrile
[0707] The title compound was prepared from Example 28B,
4-phenyl-1-butyne and the procedure of Example 57B.
[0708] MS (DCI/NH.sub.3) m/e 299 (M+NH.sub.4).sup.+.
EXAMPLE 28D
6-(4-Phenylbutynyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0709] The title compound was prepared from Example 28C and the
procedure of Example 1B.
[0710] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.80 (t, 2H),
2.95 (t, 2H), 7.22 (m, 1H), 7.36 (m, 4H), 7.58 (d, 1H), 7.82 (d,
1H), 8.05 (d, 1H), 8.10 (d, 2H), 8.45 (s, 1H), 9.10 (br s, 2H),
9.42 (br s, 2H);
[0711] MS (DCI/NH.sub.3) m/e 299 (M+H).sup.+.
[0712] Anal. calcd for C.sub.21H.sub.18N.sub.2.TFA.0.75H.sub.2O: C,
64.86; H, 4.85; N, 6.58. Found: C, 64.78; H, 4.64; N, 6.03.
EXAMPLE 29
7-(2-Hydroxyethoxy)-8-iodo-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 29A
3-[[(11-Dimethylethyl)dimethylsilyl]oxy]-1-propanol,
4-nitrobenzenesulfonate
[0713] A solution of 3-t-butlydimethylsiloxy-1-propanol, prepared
by the method of McDougal, et al. JOC, 1986, 51, 3388, which is
incorporated herein by reference, (7.6 g, 40 mmol) and
diisopropylethylamine (10.4 mL, 60 mmol) in methylene chloride (200
mL) at 0.degree. C. was treated with p-nitrophenylsulfonyl chloride
(9.7 g, 44 mmol), stirred for 3 h, poured into saturated
NaHCO.sub.3 and extracted with diethyl ether. The extracts were
washed with brine, dried (Na.sub.2SO.sub.4), and concentrated. The
residue was chromatographed on silica gel with 5% ethyl
acetate/hexanes to provide 6.00 g of the title compound.
[0714] MS (DCI/NH.sub.3) m/e 395 (M+NH.sub.4).sup.+.
EXAMPLE 29B
7-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethoxy]-8-iodo-2-naphthaleneca-
rbonitrile
[0715] The title compound was prepared in a manner analogous to
that of Example 43A but substituting Example 29A for propyl
iodide.
[0716] MS (DCI/NH.sub.3) m/e 468 (M+H).sup.+.
EXAMPLE 29C
7-(2-Hydroxyethoxy)-8-iodo-2-naphthalenecarbonitrile
[0717] The title compound was prepared in a manner analogous to
that of Example 53F but substituting Example 29B for Example
53E.
[0718] MS (DCI/NH.sub.3) m/e 357 (M+H).sup.+.
EXAMPLE 29D
7-(2-Hydroxyethoxy)-8-iodo-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0719] The title compound was prepared from Example 29B according
to the procedure of Example 1B.
[0720] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.96 (m, 2H),
3.69 (t, 2H), 4.33 (t, 2H), 4.58 (br, 1H), 7.63 (d, 1H), 7.66 (dd,
1H), 8.12 (dd, 2H), 8.42 (s, 1H), 9.20 (s, 2H), 9.53 (s, 2H);
[0721] MS (DCI/NH.sub.3) m/e 245 (M+H).sup.+;
[0722] Anal. calcd for
C.sub.13H.sub.12N.sub.2O.sub.21.TFA.0.21H.sub.2O: C, 53.07; H,
4.85; N, 7.74.
[0723] Found: C, 53.07; H, 4.75; N, 7.65.
EXAMPLE 30
7-(2-Hydroxyethoxy)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 30A
7-(2-Hydroxyethoxy)-2-naphthalenecarbonitrile
[0724] Example 29B (120 mg, 0.26 mmol), palladium(II)Cl.sub.2dppf
(46 mg, 0.03 mmol) and diisopropylamine (263 mg, 2.6 mmol) were
heated in a sealed tube for 2 h at 100.degree. C., cooled to room
temperature, diluted with ethyl acetate, washed with water, dried
(Na.sub.2SO.sub.4), and concentrated. The residue was purified on
silica gel with 15% ethyl acetate/hexanes to provide 85 mg of the
title compound.
[0725] MS (DCI/NH.sub.3) m/e 342 (M+H).sup.+.
EXAMPLE 30B
7-(2-Hydroxyethoxy)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0726] The title compound was prepared from Example 29B according
to the procedure of Example 1B.
[0727] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.96 (m, 2H),
3.69 (t, 2H), 4.33 (t, 2H), 4.58 (br, 1H), 7.63 (d, 1H), 7.66 (dd,
1H), 8.12 (dd, 2H), 8.42 (s, 1H), 9.20 (s, 2H), 9.53 (s, 2H);
[0728] MS (DCI/NH.sub.3) m/e 228 (M+H).sup.+;
[0729] Anal. calcd for C.sub.14H.sub.15N.sub.2O.sub.2.TFA: C,
53.78; H, 4.51; N, 7.84.
[0730] Found: C, 53.60; H, 4.30; N, 7.81.
EXAMPLE 31
6-(4-Methyl-1-pentynyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 31A
6-(4-Methyl-1-pentynyl)-2-naphthalenecarbonitrile
[0731] The title compound was obtained from Example 28B,
4-methyl-1-pentyne and the procedure of Example 57B.
[0732] MS (DCI/NH.sub.3) m/e 251 (M+NH.sub.4).sup.+.
EXAMPLE 31 B
6-(4-Methyl-1-pentynyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0733] The title compound was prepared from Example 31A and the
procedure of Example 1B.
[0734] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.05 (d, 6H),
1.90 (m, 1H), 2.20 (d, 2H), 7.62 (dd, 1H), 7.82 (dd, 1H), 8.09 (d,
1H), 8.12 (d, 1H), 8.18 (s, 1H), 8.48 (s, 1H), 9.12 (br s, 2H),
9.42 (br s, 2H);
[0735] MS (DCI/NH.sub.3) m/e 251 (M+H).sup.+.
[0736] Anal. calcd for C.sub.17H.sub.18N.sub.2.TFA: C, 62.63; H,
5.26; N, 7.69. Found: C, 64.85; H, 5.32; N, 7.46.
EXAMPLE 32
6-(5-Phenylpentynyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 32A
6-(5-Phenylpentynyl)-2-naphthalenecarbonitrile
[0737] The title compound was obtained from Example 28B,
5-phenyl-1-pentyne and the procedure of Example 57B.
[0738] MS (DCI/NH.sub.3) m/e 313 (M+NH.sub.4).sup.+.
EXAMPLE 32B
6-(5-Phenylpentynyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0739] The title compound was prepared from Example 32A and the
procedure of Example 1B.
[0740] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.90 (m, 2H),
2.80 (t, 2H), 3.39 (t, 2H), 7.19-7.37 (m, 5H), 7.62 (dd, 1H), 7.82
(dd, 1H), 8.08 (d, 1H), 8.15 (d, 1H), 8.18 (s, 1H), 8.48 (s, 1H),
9.15-9.45 (br d, 4H);
[0741] MS (DCI/NH.sub.3) m/e 313 (M+H).sup.+.
[0742] Anal. calcd for C.sub.22H.sub.20N.sub.2.TFA: C, 67.60; H,
4.96; N, 6.57. Found: C, 67.32; H, 5.21; N, 6.27.
EXAMPLE 33
6-(3-Phenyl-1-propynyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 33A
6-(3-Phenyl-1-propynyl)-2-naphthalenecarbonitrile
[0743] The title compound was obtained from Example 28B,
3-phenyl-1-propyne and the procedure of Example 57B.
[0744] MS (DCI/NH.sub.3) m/e 285 (M+NH.sub.4).sup.+.
EXAMPLE 33B
6-(3-Phenyl-1-propynyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0745] The title compound was prepared from Example 33A and the
procedure of Example 5B.
[0746] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.00 (s, 2H),
7.28-7.50 (m, 5H), 7.70 (dd, 1H), 7.85 (dd, 1H), 8.09 (d, 1H), 8.15
(d, 1H), 8.21 (s, 1H), 8.49 (s, 1H), 9.21 (br s, 2H), 9.45 (br s,
2H);
[0747] MS (DCI/NH.sub.3) m/e 285 (M+H).sup.+.
[0748] Anal. calcd for C.sub.20H.sub.16N.sub.2.TFA.0.25H.sub.2O: C,
65.59; H, 4.38; N, 6.95. Found: C, 65.43; H, 3.95; N, 6.70.
EXAMPLE 34
6-(Phenylethynyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 34A
6-(Phenylethynyl)-2-naphthalenecarbonitrile
[0749] The title compound was obtained from Example 28B,
phenylacetylene and the procedure of Example 57B. MS (DCI/NH.sub.3)
m/e 271 (M+NH.sub.4).sup.+.
EXAMPLE 34B
6-(Phenylethynyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0750] The title compound was prepared from Example 34A and the
procedure of Example 1B.
[0751] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.49 (t, 3H),
7.62 (m, 2H), 7.80 (dd, 1H), 7.86 (dd, 1H), 8.15 (d, 1H), 8.19 (d,
1H), 8.38 (s, 1H), 8.52 (s, 1H), 9.38 (br s, 4H);
[0752] MS (DCI/NH.sub.3) m/e 271 (M+H).sup.+.
[0753] Anal. calcd for C.sub.19H.sub.14N.sub.2.TFA: C, 65.62; H,
3.93; N, 7.29. Found: C, 65.64; H, 4.11; N, 7.21.
EXAMPLE 35
3-Amino-N-[3-[6-(aminoiminomethyl)-2-naphthalenyl1-2-propynyl]benzamide
mono(trifluoroacetate) salt
EXAMPLE 35A
6-(3-Amino-1-propynyl)-2-naphthalenecarbonitrile
[0754] The title compound was obtained from Example 28B, propargyl
amine and the procedure of Example 41A.
[0755] MS (DCI/NH.sub.3) m/e 207 (M+NH.sub.4).sup.+.
EXAMPLE 35B
3-Amino-N-[3-(6-cyano-2-naphthalenyl)-2-propynyl]benzamide
[0756] A solution of Example 35A (100 mg, 0.49 mmole),
3-aminobenzoic acid (73 mg, 0.53 mmole), EDC (141 mg, 0.74 mmole)
and DMAP (89mg, 0.74 mmole), in THF (5.5 mL) was stirred at room
temperature for 2.5 h and concentrated. The residue was dissolved
in methylene chloride, washed with 1N HCl, water, saturated
NaHCO.sub.3, and brine, dried (MgSO.sub.4), concentrated and
purified by flash chromatography on silica gel with 2%
ethanol/methylene chloride to provide the title compound.
[0757] MS (DCI/NH.sub.3) m/e 326 (M+H).sup.+.
EXAMPLE 35C
3-Amino-N-[3-[6-(aminoiminomethyl)-2-naphthalenyyl]-2-propynyl]
benzamide mono(trifluoroacetate) salt
[0758] The title compound was prepared from Example 35B and the
procedure of Example 1B.
[0759] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.32 (d, 2H), 5.69
(br s, 2H), 6.58 (d, 2H), 7.62 (m, 3H), 7.82 (d, 1H), 8.08 (d, 1H),
8.14 (d, 1H), 8.20 (s, 1H), 8.43 (s, 1H), 8.60 (t, 1H), 9.19 (br s,
2H), 9.42 (br s, 2H);
[0760] MS (DCI/NH.sub.3) m/e 343 (M+H).sup.+.
[0761] Anal. calcd for C.sub.21H.sub.18N.sub.4O.TFA.0.25H.sub.20:
C, 59.93; H, 4.26; N, 12.16. Found: C, 59.86; H, 3.97; N,
11.93.
EXAMPLE 36
4-Amino-N-[3-(6-aminoiminomethyl-2-naphthalenyl)-2-propynyl]benzamide
mono(trifluoroacetate) salt
EXAMPLE 36A
4-Amino-N-[3-(6-cyano-2-naphthalenyl)-2-propynyl]benzamide
[0762] Example 35A and 4-aminobenzoic acid were subjected to the
conditions described in Example 35B to afford the title
compound.
[0763] MS (DCI/NH.sub.3) m/e 326 (M+H).sup.+.
EXAMPLE 36B
4-Amino-N-[3-(6-aminoiminomethyl-2-naphthalenyl)-2-propynyl]benzamide
mono(trifluoroacetate) salt
[0764] The title compound was prepared from Example 36A and the
procedure of Example 5B.
[0765] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.38 (d, 2H),
6.89 (m, 1H), 7.20 (m, 2H), 7.22 (s, 1H), 7.63 (dd, 1H), 7.82 (dd,
1H), 8.09 (d, 1H), 8.12 (d, 1H), 8.20 (s, 1H), 8.46 (s, 1H), 8.95
(t, 1H), 9.19 (br s, 2H), 9.42 (br s, 2H);
[0766] MS (DCI/NH.sub.3) m/e 343 (M+H).sup.+.
[0767] Anal. calcd for C.sub.21H.sub.16N.sub.4O.2.5TFA: C, 49.27;
H, 3.19; N, 8.54. Found: C, 49.27; H, 3.33; N, 8.89.
EXAMPLE 37
(S)-2-Amino-N-[1-[(6-aminoiminomethyl-2-naphthalenyl)carbonyl]cyclohexyl]p-
ropionamide bis(trifluoroacetate) salt
EXAMPLE 37A
6-[(1-Aminocyclohexyl)ethynyl]-2-naphthalenecarbonitrile
[0768] The title compound was obtained from Example 28B,
1-ethynylcyclohexylamine and the procedure of Example 41A.
[0769] MS (DCI/NH.sub.3) m/e 275 (M+NH.sub.4).sup.+.
EXAMPLE 37B
(S)-2-Amino-N-[1-[(6-cyano-2-naphthalenyl)carbonyl]cyclohexyl]propionamide
[0770] Example 37A and N-(t-butoxycarbonyl)-L-alanine were
subjected to the conditions described in Example 35B to provide the
title compound.
[0771] MS (DCI/NH.sub.3) m/e 446 (M+H).sup.+.
EXAMPLE 37C
(S)-2-Amino-N-F
1-[(6-aminoiminomethyl-2-naphthalenyl)carbonyl]cyclohexyl]-
propionamide bis(trifluoroacetate) salt
[0772] The title compound was a rearrangement product of Example
37B resulting from the procedure of Example 5B.
[0773] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.24 (d, 3H),
1.40-1.62 (m, 8H), 2.15-2.26 (s, 1H), 2.29-2.38 (s, 1H), 3.51 (d,
1H), 3.78 (d, 1H), 3.82 (s, 1H), 7.90 (dd, 2H), 8.09 (dd, 1H), 8.18
(d, 1H), 8.37 (d, 1H), 8.55 (s, 1H), 8.78 (s, 1H), 9.31 (s, 2H),
9.50 (s, 2H);
[0774] MS (DCI/NH.sub.3) m/e 381 (M+H).sup.+.
[0775] Anal. calcd for
C.sub.23H.sub.28N.sub.4O.sub.2.2TFA.2H.sub.2O: C, 49.39; H, 5.22;
N, 8.53. Found: C, 49.15; H, 4.79; N, 8.70.
EXAMPLE 38
6-methoxy-8-benzyloxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 38A
8-Hydroxy-6-methoxy-3 4-dihydro-2H-naphthalen-1-one
[0776] A solution of 6, 8-dimethoxy-3,
4-dihydro-2H-naphthalen-1-one (15 g, 72.8 mmole), prepared
according to the procedure of J. Chem. Soc., London 2782 (1955),
which is incorporated herein by reference, in methylene chloride
(150 mL) at 0.degree. C. was treated portionwise with AlCl.sub.3
(14.3 g, 107 mmole), stirred for 20 h at room temperature, poured
onto ice with stirring and extracted with methylene chloride when
the ice melted. The extracts were washed with water and brine,
dried (MgSO.sub.4) and concentrated to provide 13.8 g of the title
compound.
[0777] MS (DCI/NH.sub.3) m/e 193 (M+H).sup.+.
EXAMPLE 38B
8-Benzyloxy-6-methoxy-3,4-dihydro-2H-naphthalen-1-one
[0778] A mixture of Example 38A (2.5 g, 13 mmole), benzyl bromide
(2.1 mL, 17.8 mmole), K.sub.2CO.sub.3 powder (14.3 g, 100 mmole),
and 2-butanone (88 mL) was stirred at reflux for 4 h, treated with
additional benzyl bromide (1.0 mL, 8.5 mmole), stirred at reflux
for an additional 3 h, cooled to room temperature, filtered and
concentrated. The residue was dissolved in methylene chloride,
washed with IN HCl, water and brine, dried (MgSO.sub.4) and
concentrated. The crude product was purified on silica gel with 30%
ethyl acetate/hexanes to provide the title compound.
[0779] MS (DCI/NH.sub.3) m/e 283 (M+H).sup.+.
EXAMPLE 38C
3,4-Dihydro-2-(hydroxymethylene)-6-methoxy-8-(phenylmethoxy)-1(2H)-naphtha-
lenone
[0780] Sodium metal (1.29 g, 55.9 mmole) was added portionwise to a
mixture of ethanol (4.2 mL) and benzene (15 mL). The mixture was
stirred at reflux for 1.5 h, cooled to 0.degree. C. and treated
dropwise with ethyl formate (5.6 mL, 70 mmole) then dropwise with
of a solution of Example 38B (6.7g, 23.8 mmole) in benzene (20 mL),
stirred at room temperature for 2 h, cooled to 0.degree. C.,
treated sequentially with ice/water and 6N HCl (75 mL) and
extracted with ethyl acetate. The extracts were washed with brine,
dried (MgSO.sub.4) and concentrated to provide the title
compound.
[0781] MS (DCI/NH.sub.3) m/e 311 (M+H).sup.+.
EXAMPLE 38D
4,5-Dihydro-7-methoxy-9-(phenylmethoxy)naphth[2,1-d]isoxazole
[2,1-d]isoxazole
[0782] A suspension of Example 38C (7.5 g, 24.3 mmole),
hydroxylamine hydrochloride (4.0 g, 57.6 mmole) and acetic acid (63
mL) was stirred at 110.degree. C. for 7 min, cooled to room
temperature, diluted with water and extracted with methylene
chloride. The extracts were washed with water and brine, dried
(MgSO.sub.4), and concentrated. The crude product was purified by
flash chromatography on silica gel with 30% ethyl acetate/hexanes
to provide the title compound.
[0783] MS (DCI/NH.sub.3) m/e 308 (M+H).sup.+.
EXAMPLE 38E
8-Benzyloxy-2-cyano-6-methoxy-3,4-dihydronaphthalen-1-one
[0784] Sodium methoxide, prepared from sodium metal (0.17 g, 7.35
mmol) in methanol (3.9 mL), was treated dropwise with a solution of
Example 38D (1.5 g, 4.9 mmole) in benzene (50 mL), stirred at room
temperature for 4.5 h, treated sequentially with water and IN HCl
and extracted with ethyl acetate. The extracts were washed with
brine, dried (MgSO.sub.4) and concentrated to provide the title
compound.
[0785] MS (DCI/NH.sub.3) m/e 308 (M+H).sup.+.
EXAMPLE 38F
2-Cyano-6-methoxy-8-Benzyloxy-3,4-dihydronaphthalene
[0786] A suspension of Example 38E (2.6 g, 8.6 mmole) in absolute
ethanol (25 mL) at room temperature was treated portionwise with
NaBH.sub.4 (1.6 g), stirred for 20 min at room temperature and for
20 min at reflux, cooled to room temperature, treated with water
(20 mL) and concentrated. The residue was dissolved in methylene
chloride, washed with water and brine, dried (MgSO.sub.4), filtered
and concentrated to provide 2.6 g of an orange foam. The foam was
stirred at reflux for 20 min with p-toluenesulfonic acid
monohydrate (0.52 g, 2.7 mmole) in benzene (52 mL), cooled to room
temperature, diluted with ethyl acetate, washed with water and
brine, dried (MgSO4) and concentrated to provide the title
compound.
[0787] MS (DCI/NH.sub.3) m/e 309 (M+NH.sub.4).sup.+.
EXAMPLE 38G
2-Cyano-6-methoxy-8-benzyloxynaphthalene
[0788] A solution of Example 38F (0.4 g, 1.4 mmole),
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.79 g, 3.5 mmole) in
benzene (40 mL) was stirred at reflux for 4 hours, treated with
additional 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.4 g, 1.8
mmole), stirred at reflux for an additional 5 h, cooled to room
temperature, diluted with ethyl acetate, washed with saturated
NaHCO.sub.3 and brine, dried (MgSO.sub.4) and concentrated to
provide the title compound.
[0789] MS (DCI/NH.sub.3) m/e 290 (M+H).sup.+.
EXAMPLE 38H
8-Benzyloxy-6-methoxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0790] The title compound was prepared from Example 38G and the
procedure of Example 1B.
[0791] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.38 (d, 2H),
6.89 (m, 1H), 7.20 (m, 2H), 7.22 (s, 1H), 7.63 (dd, 1H), 7.82 (dd,
1H), 8.09 (d, 1H), 8.12 (d, 1H), 8.20 (s, 1H), 8.46 (s, 1H), 8.95
(t, 1H), 9.19 (br s, 2H), 9.42 (br s, 2H);
[0792] MS (DCI/NH.sub.3) m/e 307 (M+H).sup.+.
[0793] Anal. calcd for C.sub.19H.sub.18N.sub.2O.sub.2.TFA: C,
60.00; H, 4.56; N, 6.66. Found: C, 59.93; H, 4.46; N, 6.51.
EXAMPLE 39
2-[(7-Aminoiminomethyl-3-methoxy-1-naphthalenyl)oxy]acetamide
mono(trifluoroacetate) salt
EXAMPLE 39A
6-Methoxy-8-hydroxy-2-naphthalenecarbonitrile
[0794] A mixture of Example 38G (1.62 g, 5.6 mmole) and 10% dry
Pd/C (0.50 g) in methanol (150 mL) was hydrogenated in a Parr
shaker at room temperature under 4 atm for 30 h. The mixture was
filtered and concentrated to provide the title compound.
[0795] MS (DCI/NH.sub.3) m/e 217 (M+NH.sub.4).sup.+.
EXAMPLE 39B
2-[(7-Cyano-3-methoxy-1-naphthalenyl)oxy]acetamide
[0796] Example 39A and 2-bromoacetamide were subjected to the
conditions described in Example 5A to provide the title
compound.
[0797] MS (DCI/NH.sub.3) m/e 274 (M+NH.sub.4).sup.+.
EXAMPLE 39C
2-[(7-Aminoiminomethyl-3-methoxy-1-naphthalenyl)oxy]acetamide
mono(trifluoroacetate) salt
[0798] The title compound was prepared from Example 39B and the
procedure of Example 1B.
[0799] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.93 (s, 3H),
4.70 (s, 2H), 6.70 (d, 1H), 7.09 (d, 1H), 7.65 (s, 2H), 7.82 (dd,
1H), 7.99 (d, 1H), 8.70 (s, 1H), 9.05 (s, 2H), 9.38 (s, 2H);
[0800] MS (DCI/NH.sub.3) m/e 274 (M+H).sup.+.
[0801] Anal. calcd for C.sub.14H.sub.15N.sub.3O.sub.3.TFA: C,
49.62; H, 4.16; N, 10.85. Found: C, 49.68; H, 4.24; N, 10.61.
EXAMPLE 40
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-phenylurea
mono(trifluoroacetate) salt
EXAMPLE 40A
6-Cyano-2-naphthalenecarbonyl chloride
[0802] A suspension Example 8E (4.4 g, 22.3 mmol) in toluene (100
mL) was treated with thionyl chloride (6.0 mL) and DMAP (5 mg),
heated at 55.degree. C. for 1h, treated with additional thionyl
chloride (3 mL), warmed to 95.degree. C. for 1h, cooled to room
temperature, stirred in hexane (75 mL) for 2.5 h and filtered to
provide 3.62 of the title compound as a white powder. The filtrate
was concentrated and triturated with ether to provide an additional
1.02 g of the title compound.
[0803] MS (DCI/NH.sub.3) m/e 215 (M+H).sup.+.
EXAMPLE 40B
2-Cyano-6-naphthoyl azide
[0804] A solution of Example 40A (1.65 g, 7.65 mmole) in acetone
(600 mL) at room temperature was treated with a solution of sodium
azide (3 g, 46 mmole) in water (10 mL), stirred for 1.5 h and
diluted with water (60 mL). The resulting solid was filtered,
washed with water and dried to provide 4.24 g of the title compound
as a white powder.
[0805] MS (DCI/NH.sub.3) m/e 240 (M+NH.sub.4).sup.+.
EXAMPLE 40C
N-(6-cyano-2-naphthalenyl)-N'-phenylurea
[0806] A solution of Example 40B (221.2 mg, 1 mmole) in toluene (18
mL) was heated at 85.degree. C for 1 h then at 95.degree. C. for
1.5 h, cooled to room temperature, treated with aniline (240 [L,
2.63 mmole), stirred for 25 min and treated with ether (10 mL). The
resulting solid was collected, washed with ether and dried under
vacuum to yield 230 mg of white powder.
[0807] MS (DCI/NH.sub.3) m/e 305 (M+NH.sub.4).sup.+.
EXAMPLE 40D
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-phenylurea
mono(trifluoroacetate) salt
[0808] A solution of Example 40C (148 mg, 0.5 mmole) in 10:1
pyridine:triethylamine (10 mL) was treated with H.sub.2S for 5 min,
stirred at room temperature for 18 h and concentrated. The
resulting solid was dissolved in acetone (15 mL), treated with
iodomethane (0.8 mL, 12.8 mmole), stirred for 2 h, diluted with
ether (10 mL), filtered, washed with ether and dried under vacuum.
The resulting solid was dissolved in methanol, treated with 2N
NH.sub.3 in methanol (2 mL), warmed to 50.degree. C. for 4 h and
concentrated. The product was purified according to the procedure
described in Example 1B to provide 62 mg of the title compound.
[0809] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.00 (t, 1H),
7.31 (dd, 2H), 7.52 (d, 1H), 7.65 (dd, 1H), 7.76 (dd, 1H, 8.02 (d,
2H), 8.30 (s, 1H), 8.39 (s, 1H), 9.05 (br s, 2H), 9.11 (s, 1H),
9.33 (br s, 2H), 9.42 (s, 1H);
[0810] MS (DCI/NH.sub.3) m/e 305 (M+H).sup.+;
[0811] Anal. calcd for C.sub.18H.sub.16N.sub.4O.TFA: C, 57.42; H,
4.10; N, 13.39. Found: C, 57.50; H, 4.05; N, 13.08.
EXAMPLE 41
(E)-6-[2-(Phenyl)ethenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 41A
(E)-6-12-(Phenyl)ethenyl]-2-naphthalenecarbonitrile
[0812] A solution of Example 28B (350 mg, 1.16 mmol), styrene (157
mg, 1.51 mmol), palladium (II) acetate (26 mg, 0.12 mmol),
triphenylphosphine (61 mg, 0.23 mmol), triethylamine (2 mL) and
acetonitrile (1 mL) in a sealed tube with minimal head volume was
heated at 100.degree. C. for 19 h, diluted with ethyl acetate (20
mL), washed with water, dried (MgSO4) and concentrated with silica
gel (4 g). The mixture was chromatographed on silica gel with 10%
ethyl acetate/hexane to provide 160 mg of the title compound.
[0813] MS (DCI/NH.sub.3) m/e 273 (M+NH.sub.4).sup.+.
EXAMPLE 41B
(E)-6-[2-(Phenyl)ethenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0814] The title compound was prepared from Example 41A from the
procedure of Example 1B. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 7.33 (t, 1H), 7.4 (t, 2H), 7.5 (d, 2H), 7.69 (d, 1H), 7.70
(d, .sup.1H), 7.81 (dd, 1H), 8.03 (dd, 1H), 8.10 (d, 1H), 8.13 (d,
1H), 8.17 (s, 1H), 8.44 (s, 1H), 8.97 (s, 2H), 9.41 (s, 2H);
[0815] MS (DCI/NH.sub.3) m/e 273 (M+H).sup.+;
[0816] Anal. calcd for C.sub.19H.sub.16N.sub.2.TFA: C, 65.28; H,
4.43; N, 7.25. Found: C; 64.95; H, 4.60; N, 6.42.
EXAMPLE 42
6-[2-(Phenyl)ethyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 42A
6-[2-(Phenyl)ethyl]-2-naphthalenecarbonitrile
[0817] A mixture of Example 57B (80 mg, 0.31 mmol) and palladium on
carbon (20% water, 50 mg) in methanol (5 mL) was stirred under 1
atm of hydrogen for 0.5 h, filtered and concentrated to provide 72
mg of the title compound.
[0818] MS (DCI/NH.sub.3) m/e 275 (M+NH.sub.4).sup.+.
EXAMPLE 42B
6-[2-(Phenyl)ethyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0819] The title compound was prepared from Example 42A and the
procedure of Example 1B.
[0820] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.03 (m, 2H),
7.23 (m, 5H), 7.60 (dd, 1H), 7.76 (dd, 1H), 7.85 (s, 1H), 8.03 (t,
2H), 8.42 (s, 1H), 8.99 (s, 2H), 9.39 (s, 2H);
[0821] MS (DCI/NH.sub.3) m/e 275 (M+H).sup.+.
[0822] Anal. calcd for C.sub.19H.sub.16N.sub.2O.1.33TFA: C, 61.29;
H, 4.59; N, 6.61. Found: C; 61.56; H, 4.62; N, 5.21.
EXAMPLE 43
7-Propoxy-8-iodo-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 43A
7-propoxy-8-iodo-2-naphthalenecarbonitrile
[0823] Example 53A (65 mg, 0.25 mmol) in DMF (2 mL) was treated
with propyl iodide (40 mL), stirred at 65.degree. C. for 1 h,
diluted with water and extracted with diethyl ether. The organic
extracts were dried (MgSO.sub.4) and concentrated, and the residue
was purified on silica gel with 10% ethyl acetate/hexanes to
provide 160 mg of the title compound.
[0824] MS (DCI/NH.sub.3) m/e 355 (M+H).sup.+.
EXAMPLE 43B
7-Propoxy-8-iodo-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0825] The title compound was prepared from the product in Example
43A according to the procedure of Example 1B.
[0826] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.09 (t, 3H),
1.82 (m, 2H), 4.23 (t, 2H), 7.62 (d, 1H), 7.65 (dd, .sup.1H), 8.12
(dd, 2H), 9.15 (s, 2H), 9.42 (s, 1H), 9.53 (s, 2H);
[0827] MS (DCI/NH.sub.3) m/e 355 (M+H).sup.+.
[0828] Anal. calcd. for
C.sub.14H.sub.15N.sub.2OI.TFA.0.26C.sub.7H.sub.8: C, 43.49; H,
3.70; N, 5.69. Found: C; 43.50; H, 3.59; N, 5.75.
EXAMPLE 44
(.+-.)6-(3-Phenyloxiranyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 44A
(.+-.)-6-(3-Phenyloxiranyl)-2-naphthalenecarbonitrile
[0829] A solution of Example 41A (69 mg, 0.27 mmol) and
m-chloroperbenzoic acid (70 mg, 0.41 mmol) in methylene chloride (3
mL) was stirred at 25.degree. C. for 3 days, concentrated, loaded
on a silica gel column (pretreated with 0.1 % triethylamine in
ethyl acetate) and eluted with 10% ethyl acetate/hexane) to provide
72 mg of the title compound.
[0830] MS (DCI/NH.sub.3) m/e 289 (M+NH.sub.4).sup.+.
EXAMPLE 44B
(.+-.)-6-(3-Phenyloxiranyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0831] The title compound was prepared with Example 44A from the
procedure of Example 1B.
[0832] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.24 (d, 1H),
4.35 (d, 1H), 7.43 (m, 5H), 7.67 (dd, 1H), 7.83 (dd, 1H), 8.12 (s,
1H), 8.13 (d, 1H), 8.16 (d, 1H), 8.50 (s, 1H), 9.03 (s, 2 H), 9.44
(s, 2H);
[0833] MS (DCI/NH.sub.3) m/e 289 (M+H).sup.+.
[0834] Anal. calcd for C.sub.19H.sub.16N.sub.2O.1.3 TFA: C, 64.52;
H, 4.55; N, 6.51. Found: C; 64.35; H, 4.60; N, 5.87.
EXAMPLE 45
(E)-6-[2-(2-Thienyl)ethenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 45A
2-Vinylthiophene
[0835] A suspension of methyltriphenylphosphonium bromide (19.13 g,
53.5 mmol) in THF (100 mL) was treated dropwise with 2M
butyllithium in THF (17.8 mL) then dropwise with 2-carboxythiophene
(5 g, 44.6 mmol), stirred for 30 min then distilled at
74-78.degree. C. to provide the title compound.
[0836] MS (DCI/NH.sub.3) m/e 111 (M+H).sup.+.
EXAMPLE 45B
(E)-6-[2-(2-Thienyl)ethenyl]-2-naphthalenecarbonitrile
[0837] The title compound was prepared from the product of Example
45A and the procedure of Example 41A.
[0838] MS (DCI/NH.sub.3) m/e 279 (M+NH.sub.3).sup.+.
EXAMPLE 45C
(E)-6-[2-(2-Thienyl)ethenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0839] The title compound was prepared from Example 45B and the
procedure of Example 1B.
[0840] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 7.12 (dd, 2H),
7.15 (d, 1H), 7.32 (d, 1H), 7.6 (d, 1H), 7.74 (d, 1H), 7.80 (dd,
1H), 7.9-8.1 (m, 3H), 8.14 (s, 1H), 8.43 (s, 1H), 9.03 (s, 2H),
9.42 (s, 2H);
[0841] MS (DCI/NH.sub.3) m/e 279 (M+H).sup.+;
[0842] Anal. calcd. for C.sub.17H.sub.14N.sub.2O.sub.2S.TFA: C,
53.77; H, 3.56; N, 6.60. Found: C; 54.88; H, 3.66; N, 6.45.
EXAMPLE 46
6-(3-Oxobutyl)-2-naphthalenecarboximidamide mono(trifluoroacetate)
salt
EXAMPLE 46A
6-(3-Oxobutyl)-2-naphthalenecarbonitrile
[0843] The title compound was prepared from Example 28B,
1-buten-3-ol and the procedure of Example 41A.
[0844] MS (DCI/NH.sub.3) m/e 241 (M+NH.sub.4).sup.+.
EXAMPLE 46B
6-(3-Oxobutyl)-2-naphthalenecarboximidamide mono(trifluoroacetate)
salt
[0845] The title compound was prepared from Example 46A and the
procedure of Example 1B.
[0846] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.13 (s, 1H),
2.94 (m, 4H), 7.57 (dd, 1H) 7.78 (dd, 1H), 7.85 (s, 1H), 8.01 (d,
1H), 8.05 (d, 1H), 8.43 (s, 1H), 8.48 (m, 2H), 9.06 (s, 2H), 9.40
(s, 2H);
[0847] MS (DCI/NH3) m/e 241 (M+H).sup.+;
[0848] Anal. calcd. for C.sub.15H.sub.16N.sub.2O.1.3TFA: C, 54.31;
H. 4.48; N, 7.19. Found: C; 54.33; H, 4.35; N, 7.27.
6-(3-Methoxyphenyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 47A
6-(3-Methoxyphenyl)-2-naphthalenecarbonitrile
[0849] A solution of Example 28B (300 mg, 1 mmol), palladium (II)
acetate (22 mg, 0.1 mmol) and 1-1'-bis(diphenyphosphino)ferrocene
(111 mg, 0.2 mmol) was stirred in DMF (3 mL) for 15 min, treated
with Cs.sub.2CO.sub.3 (813 mg, 2.5 mmol) and 3-methoxyphenylboronic
acid (228 mg, 1.5 mmol), stirred for 20 min at 80.degree. C.,
cooled, treated with pH 7 buffer (10 mL) and extracted with diethyl
ether. The ether extracts were dried (MgSO4), concentrated and
purified on silica gel with 10% ethyl acetate/hexane to provide 140
mg of the title compound as a white solid.
[0850] MS (DCI/NH.sub.3) m/e 277 (M+NH.sub.4).sup.+.
EXAMPLE 47B
6-(3-Methoxyphenyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0851] The title compound was prepared from Example 47A and the
procedure of Example 1B.
[0852] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.88 (s, 3H),
7.03 (m, 1H), 7.44 (m, 3H), 7.84 (dd, 1H), 8.05 (dd, 1H), 8.19 (d,
1H), 8.21 (d, 1H), 41 (s, 1H), 8.51 (s, 1H), 9.11 (s, 2H), 9.45 (s,
2H);
[0853] MS (DCI/NH.sub.3) m/e 277 (M+H).sup.+;
[0854] Anal. calcd for C.sub.18H.sub.16N.sub.2O.TFA.0.2H.sub.2O: C,
61.03; H, 4.45; N, 7.12. Found: C; 61.03; H, 4.11; N, 6.86.
EXAMPLE 48
N-[3-(methyl)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamide
mono(trifluoroacetate) salt
EXAMPLE 48A
N-[3-(methyl)phenyl]-6-cyano-2-naphthalenecarboxamide
[0855] The title compound was prepared from 3-methyl
phenylisocyanate, Example 55C and the procedure from Example
55C.
[0856] MS (DCI/NH.sub.3) m/e 287 (M+H).sup.+.
EXAMPLE 48B
N-[3-(methyl)phenyl]-6-aminoiminomethyl-2-naphthalenecarboxamide
mono(trifluoroacetate) salt
[0857] The title compound was prepared from Example 48A and the
procedure of Example 1B.
[0858] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.34 (s, 3H),
6.96 (d, 1H), 7.27 (t, 1H), 7.62 (d, 1H), 7.66 (s, 1H), 7.91 (dd,
1H), 8.15 (dd, 1H), 8.29 (d, 1H), 8.31 (d, 1H), 8.54 (s, 1H), 8.68
(s, 1H), 9.15 (s, 2H), 9.49 (s, 2H), 10.46 (s, 1H);
[0859] MS (DCI/NH.sub.3) m/e 304 (M+H).sup.+;
[0860] Anal. calcd for
C.sub.19H.sub.17N.sub.3O.TFA.0.12C.sub.7H.sub.8: C, 61.23; H, 4.46;
N, 9.81. Found: C; 61.12; H, 4.42; N, 9.43.
EXAMPLE 49
6-(2-Formylphenoxy)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 49A
6-(2-Formylphenoxy)-2-naphthalenecarbonitrile
[0861] A solution of 2-hydroxybenzaldehyde (72 mg, 0.59 mmol),
6-bromo-1-cyanonaphthalene (150 mg, 0.65 mmol), and
Cs.sub.2CO.sub.3 (248 mg, 0.76 mmol) in DMF (10 mL) was heated at
90.degree. C. for 2 days, treated with water and extracted with
ethyl acetate. The combined organic extracts were dried
(MgSO.sub.4) and concentrated, and the crude product was purified
by column chromatography with 10% ethyl acetate/hexane to provide
40 mg of the title compound.
[0862] MS (DCI/NH.sub.3) m/e 291 (M+NH.sub.4).sup.+.
EXAMPLE 49B
6-(2-Formylphenoxy)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0863] The title compound was prepared with Example 49A and the
procedure of Example 1B.
[0864] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 7.19 (d, 1H),
7.44 (t, 1H), 7.56 (s, 1H), 7.60 (d, 1H), 7.79 (m, 2H), 7.94 (dd,
1H), 8.01 (d, 1H), 8.2 (d, 1H), 8.51 (s, 1H), 9.03 (s, 2H), 9.41
(s, 2H), 10.35 (s, 1H);
[0865] MS (DCI/NH.sub.3) m/e 291 (M+H).sup.+.
[0866] Anal. calcd. for
C.sub.18H.sub.14N.sub.2O.sub.2.TFA.1.7H.sub.2O: C, 55.16; H, 4.27;
N, 6.43. Found: C; 55.17; H, 3.92; N, 5.94.
EXAMPLE 50
6-(2-Formylphenyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 50A
6-(2-Formylphenyl)-2-naphthalenecarbonitrile
[0867] The title compound was prepared from Example 28B,
2-formylphenylboronic acid and the procedure of Example 47A.
[0868] MS (DCI/NH.sub.3) m/e 275 (M+NH.sub.4).sup.+.
EXAMPLE 50B
6-(2-Formylphenyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0869] The title compound was prepared from Example 50A and the
procedure of Example 1B.
[0870] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.71-7.64 (m,
2H), 7.79 (d, 1H), 7.81 (s, 1H), 7.88 (dd, 1H),7.9 (d, 1H), 8.16
(d, 1H), 8.23 (t, 2H), 8.56 (s, 1H), 9.05 (s, 2H), 9.48 (s, 2H),
9.92 (s, 1H);
[0871] MS (DCI/NH.sub.3) m/e 275 (M+H).sup.+;
[0872] Anal. calcd for C.sub.18H.sub.14N.sub.2O.TFA: C, 61.86; H,
3.89; N, 7.21. Found: C; 61.98; H, 3.59; N, 6.88.
EXAMPLE 51
6-[2-(Hydroxymethyl)phenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 51A
6- [2-(Hydroxymethyl)]-2-naphthalenecarbonitrile
[0873] Example 50A (98 mg, 0.38 mmol) and sodium borohydride (15
mg, 0.80 mmol) were dissolved in methanol (10 mL) and stirred for
0.5 h. The solution was concentrated, and the residue was purified
on silica gel with 30% ethyl acetate/hexane to provide 90 mg of the
title compound.
[0874] MS (DCI/NH.sub.3) m/e 277 (M+NH.sub.4).sup.+.
EXAMPLE 51B
6-[2-(Hydroxymethyl)phenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0875] The title compound was prepared from Example 51A and the
procedure of Example 1B.
[0876] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.46 (s, 2H),
9.06 (s, 2H), 8.54 (s, 1H), 8.16 (t, 2H), 8.07 (s, 1H), 7.85 (dd,
1H), 7.74 (dd, 1H), 7.63 (d, 1H), 7.49-7.34 (m, 3H), 4.46 (s,
2H);
[0877] MS (DCI/NH.sub.3) m/e 277 (M+H).sup.+;
[0878] Anal. calcd. for C.sub.18H.sub.16N.sub.2O.1.44TFA: C, 56.93;
H, 3.99; N, 6.36. Found: C; 56.94; H, 3.88; N, 6.46.
EXAMPLE 52
6-(3-Oxo-1-butenyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 52A
[0879] 6-(3-Oxo-1-butenyl)-2-naphthalenecarbonitrile
[0880] The title compound was prepared from methyl acrylate,
Example 28B and the procedure of Example 41A. MS (DCI/NH.sub.3) m/e
222 (M+H).sup.+.
EXAMPLE 52B
6-(3-Oxo-1-butenyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0881] The title compound was prepared from Example 52A and the
procedure of Example 1B.
[0882] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.46 (s, 2H),
9.13 (s, 2H), 8.48 (s, 1H), 8.38 (s, 1H), 8.18 (d, 1H), 8.15 (d,
1H), 8.01 (dd, 1H), 7.85 (dd, 1H), 7.82 (d, 1H), 7.03 (d, 1H), 2.40
(s, 1H); MS (DCI/NH.sub.3) m/e 239 (M+H).sup.+.
[0883] Anal. calcd for C.sub.15H.sub.14N.sub.2O.1.58TFA: C, 52.13;
H, 3.75; N, 6.69. Found: C; 52.09; H, 3.63; N, 6.64.
EXAMPLE 53
7-Methoxy-8-(1H-pyrazol-4-yl)-2-naphthalenecarboximidamide
bis(trifluoroacetate) salt
EXAMPLE 53A
7-hydroxy-8-iodo-2-naphthalenecarbonitrile
[0884] A mixture of 7-cyano-2-naphthol (22.3 g, 131.8 mmol), sodium
carbonate (29.3 g, 277 mmol) and 12 (31.8 g, 125.2 mmol) in water
(500 mL) and THF (80 mL) at 0.degree. C. was stirred at room
temperature for 3 h, acidified with 1 M HCl and extracted with
ethyl acetate. The extracts were washed with saturated
Na.sub.2S.sub.2O.sub.3 and brine, dried (Na.sub.2SO.sub.4) and
concentrated. The product was recrystallized from ethyl acetate to
yield 33 g of the title compound.
[0885] MS (DCI/NH.sub.3) m/e 313 (M+NH.sub.4).sup.+.
EXAMPLE 53B
7-Methoxy-8-iodo-2-naphthalenecarbonitrile
[0886] Example 53A (36.7 g, 124.2 mmol) in methanol (500 mL) and
ethyl acetate (300 mL) was treated over 3 h with 2M
trimethylsilyldiazomethane in hexane (260 mL), stirred for 24 h,
concentrated and recrystallized from ethyl acetate to provide 36.4
g of the title compound.
[0887] MS (DCI/NH.sub.3) m/e 327 (M+NH.sub.4).sup.+.
EXAMPLE 53C
4-Iodo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazole
[0888] A slurry of NaH (1.94 g, 48.5 mmol) in THF (40 mL) at
0.degree. C. was treated with a solution of 4-iodopyrazole (8.97 g,
46.2 mmol) in THF (20 mL), stirred for 1 h, treated with SEM
chloride (9.00 mL, 50.8 mmol), stirred at room temperature for 1 h,
poured into water and extracted with ethyl acetate. The extracts
were washed with brine, dried (MgSO.sub.4) and concentrated. The
residue was chromatographed on silica gel with 10% ethyl
acetate/hexanes to provide 14.4 g of the title compound.
[0889] MS (DCI/NH.sub.3) m/e 325 (M+H).sup.+.
EXAMPLE 53D
[1-[[2-(Trimethylsilyl)ethoxy]methyl]-1H-pyrazol4-yl]boronic
acid
[0890] Example 53C (12.97 g, 40 mmol) in THF (250 mL) at
-78.degree. C. was treated with 2.5 M butyllithium in hexanes (17.6
mL, 44 mmol), stirred at -78.degree. C. for 10 min, treated with
trimethyl borate (11.36 mL, 100 mmol), warmed to room temperature,
treated with 3M HCl (400 mL) and extracted with ethyl acetate. The
extracts were concentrated, and the residue was dissolved in 1 M
NaOH (500 mL), extracted with diethyl ether, acidified with
concentrated HCl and extracted with ethyl acetate. The extracts
were washed with brine, dried (Na.sub.2SO.sub.4), and concentrated.
The residue was chromatographed on silica gel with ethyl acetate to
provide 2.20 g of the title compound.
[0891] MS (DCI/NH.sub.3) m/e 199 (M-B(OH).sub.2).sup.+.
EXAMPLE 53E
7-Methoxy-8-[1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazol-4-yl]-2-naphtha-
lenecarbonitrile
[0892] Examples 53B (1.55 g, 5 mmol) and 53D (1.45 g, 6 mmol) were
subjected to the procedure described in Example 47A to provide 1.64
g of the title compound.
[0893] MS (DCI/NH.sub.3) m/e 380 (M+H).sup.+.
EXAMPLE 53F
7-Methoxy-8-(1H-pyrazol-4-yl)-2-naphthalenecarbonitrile
[0894] A solution of Example 53E (1.84 g, 4.85 mmol) in THF (10 mL)
was treated with 1 M tetrabutylammonium fluoride in THF (24 mL),
refluxed for 6 h and concentrated. The residue was chromatographed
on silica gel with 1:1 ethyl acetate/hexanes to provide 0.88 g of
the title compound.
[0895] MS (DCI/NH.sub.3) m/e 267 (M+NH.sub.4).sup.+.
EXAMPLE 53G
7-Methoxy-8-(1H-pyrazol-4-yl)-2-naphthalenecarboximidamide
bis(trifluoroacetate) salt
[0896] The title compound was prepared from Example 53F and the
procedure of Example 1B.
[0897] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.89 (s, 3H),
7.60 (dd, 1H), 7.71 (d, 1H), 7.92 (s, 2H), 8.05 (d, .sup.1H), 8.12
(d, 1H), 8.29 (s, 1H), 9.33 (s, 2H), 9.34 (s, 2H);
[0898] MS (DCI/NH.sub.3) mi/e 267 (M+H).sup.+;
[0899] Anal. calcd. for C.sub.15H.sub.14N.sub.4O.2.8TFA: C, 42.30;
H, 2.90; N, 9.59. Found: C; 42.54; H, 3.11; N, 9.03.
EXAMPLE 54
7-Methoxy-8-iodo-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0900] The title compound was prepared from Example 53B and the
procedure of Example 1B.
[0901] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.01 (s, 3H),
7.65 (m, 2H), 8.12 (d, 1H), 8.15 (d, 1H), 8.42 (s, 1H), 9.14 (s,
2H), 9.52 (s, 2H);
[0902] MS (DCI/NH.sub.3) m/e 327 (M+H).sup.+.
[0903] Anal. calcd for C.sub.12H.sub.12N.sub.2OI.1.2TFA: C, 37.28;
H, 2.87; N,.6.04. Found: C; 37.35; H, 2.47; N, 5.93.
EXAMPLE 55
N-phenyl-6-aminoiminomethyl-2-naphthalenecarboxamide
mono(methanesulfonate) salt
Example 55A
2-Trifluoromethanesulfonyloxy-6-bromonaphthalene
[0904] A solution of 6-bromo-2-naphthol (4.96 g, 22.25 mmol),
N-phenyltrifluoromethanesulfonate (7.95 g, 22.25 mmol), and
diisopropylethylamine (7.75 mL, 44.5 mmol) in methylene chloride
(25 mL) were stirred for 3 h at room temperature, poured into water
and extracted with diethyl ether. The extracts were washed with
brine, dried (MgSO4), and concentrated. The residue was
chromatographed on silica gel with 3% ethyl acetate/hexane to
provide 7.89 g of the title compound.
[0905] MS (DCI/NH.sub.3) m/e 354 and 356 (M+H).sup.+.
EXAMPLE 55B
6-Bromo-2-naphthalenecarbonitrile
[0906] Example 55A (7.89 g, 22.2 mmol) was combined with
Zn(CN).sub.2 (1.33 g, 11.33 mmol) and Pd(PPh.sub.3).sub.4 (256 mg,
0.22 mmol) in DMF (50 mL), heated at 90.degree. C. for 3 h, cooled
to room temperature, treated with saturated NaHCO.sub.3 and
extracted with diethyl ether. The extracts were washed with brine,
dried over (MgSO.sub.4), and condensed. The residue was
chromatographed on silica gel with 5% ethyl acetate/hexanes to
provide 2.67 g of the title compound.
[0907] MS (DCI/NH.sub.3) m/e 231 and 233 (M+H).sup.+.
EXAMPLE 55C
N-phenyl-6-cyano-2-naphthalenecarboxamide
[0908] A solution of Example 55B (224 mg, 0.965 mmol) in THF (3 mL)
and hexanes (1 mL) at -100.degree. C. was treated with 2.5 M
butyllithium in hexanes (0.386 mL, 0.965 mmol), stirred at
-100.degree. C. for 5 min, treated with phenyl isocyanate (0.115
mL, 1.06 mmol), warmed to room temperature, treated with pH 7
buffer (0.5 mL) and concentrated. The residue was chromatographed
on silica gel with 20% ethyl acetate/hexanes as eluent, to provide
54 mg of the title compound:
[0909] MS (DCI/NH.sub.3) m/e 273 (M+H).sup.+.
EXAMPLE 55D
N-phenyl-6-aminoiminomethyl-2-naphthalenecarboxamide
mono(methanesulfonate) salt
[0910] A solution of Example 55C (52 mg, 0.191 mmol) in THF (2 mL)
was treated with 1M lithium bis(trimethylsilyl)amide in THF (0.6
mL), stirred for 18 h, treated with 2M HCl (4 mL), stirred for
another 24 h, made basic with saturated Na.sub.2CO.sub.3 and
extracted with ethyl acetate. The extracts were washed with brine,
dried (Na.sub.2SO.sub.4) and concentrated. The crude product was
dissoved into a minimal amount of methanol (ca.1 mL), treated with
methanesulfonic acid (1 drop), diluted with diethyl ether (400 mL)
and filtered to provide 15 mg of the title compound. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.32 (s, 3H), 7.15 (dd, 1H), 7.40
(dd, 2H), 7.83 (d, 2H), 7.90 (dd, 1H), 8.17 (dd, 1H), 8.25 (d, 1H),
8.34 (d, 1H), 8.57 (s, 1H), 8.70 (s, 1H), 9.09 (br s, 2H), 9.51 (br
s, 2H);
[0911] MS (DCI/NH.sub.3) m/e 290 (M+H).sup.+.
[0912] Anal. calcd for C.sub.18H.sub.16N.sub.3O.1.1
CH.sub.3SO.sub.3H: C, 57.96; H, 4.95; N, 10.61. Found: C, 58.03; H,
4.48; N, 10.36.
EXAMPLE 56
4-[(6-Aminoiminomethyl-2-naphthalenyl)oxy]-N-methylbenzeneacetamide
mono(trifluoroacetate) salt
EXAMPLE 56A
N-methyl-3-hydroxyphenylacetamide
[0913] A solution of 3-hydroxyphenylacetic acid (1.00 g, 6.57 mmol)
and oxalyl chloride (0.63 mL, 7.22 mmol) in methylene chloride (20
mL) was treated dropwise with pyridine (0.6 mL, 7.37 mmol), stirred
for 90 min, poured into 40% aqueous methylamine (30 mL), stirred
for 15 min, concentrated, dissolved into 1 M HCl and extracted with
ethyl acetate. The extracts were washed with brine, dried
(MgSO.sub.4) and concentrated. The residue was chromatographed on
silica gel with ethyl acetate to provide 260 mg of the title
compound.
[0914] MS (DCI/NH.sub.3) m/e 166 (M+H).sup.+.
EXAMPLE 56B
4-[(6-Cyano-2-naphthalenyl)oxy]-N-methylbenzeneacetamide
[0915] A mixture of Example 56A (245 mg, 1.48 mmol), Example 55B
(344 mg, 1.48 mmol) and Cs.sub.2CO.sub.3 (530 mg, 1.63 mmol) in DMF
(3 mL) was stirred for 72 h at 120.degree. C., cooled and
chromatographed on silica gel with 1:1 ethyl acetate/hexanes to
provide 54 mg of the title compound.
[0916] MS (DCI/NH.sub.3) m/e 317 (M+H).sup.+.
EXAMPLE 56C
4-1(6-Aminoiminomethyl-2-naphthalenyl)oxy]-N-methylbenzeneacetamide
mono(trifluoroacetate) salt
[0917] The title compound was prepared from Example 56B and the
procedure of Example 55D.
[0918] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.33 (s, 3H),
2.58 (d, 3H), 3.42 (s, 2H), 7.05 (m, 2H),7.12 (d, 1H), 7.40 (dd,
1H), 7.45 (m, 2H), 7.79 (dd, 1H), 7.98 (q, 1H), 8.02 (d, 1H), 8.15
(d, 1H), 8.49 (s, 1H), 8.99 (br s, 2H), 9.39 (br s, 2H);
[0919] MS (DCI/NH.sub.3) m/e 334 (M+H).sup.+.
[0920] Anal. calcd for
C.sub.19H.sub.17N.sub.3O.sub.21.5CH.sub.3SO.sub.3H: C, 54.08; H,
5.28; N, 8.80. Found: C, 53.80; H, 5.37; N, 8.52.
EXAMPLE 57
6-[2-(Methylthio)phenyl]-2-nahthalenecarboximidamide
mono(methanesulfonate) salt
EXAMPLE 57A
2-Cyanonaphthalene-6-boronic acid
[0921] A solution of Example 55B (6.37 g, 27.45 mmol) in THF (220
mL) and hexanes (50 mL) at -100.degree. C. was treated with 2.5 M
butyllithium in hexanes (11.0 mL, 27.5 mmol), stirred at
-100.degree. C. for 10 min, treated with trimethyl borate (7.8 mL,
68.6 mmol), warmed to room temperature, treated with 3M HCl (400
mL) and extracted with ethyl acetate. The extracts were
concentrated and the residue was dissolved into 1M NaOH (500 mL),
extracted with diethyl ether, acidified with 12M HCl and extracted
with ethyl acetate. The extracts were washed with brine, dried
(Na2SO4), and concentrated. The residue was dissolved into minimal
methanol and ethyl acetate and triturated with hexanes to yield
2.74 g of the title compound.
[0922] MS (DCI/NH.sub.3) m/e 215 (M+NH.sub.4).sup.+.
EXAMPLE 57B
6-[2-(Methylthio)phenyl]-2-naphthalenecarbonitrile
[0923] A solution of 2-bromothioanisole (0.147 mL, 1.10 mmol),
Pd(OAc).sub.2 (24 mg, 0.11 mmol) and
1,1'-bis(diphenylphosphinoferrocene) (120 mg, 0.22 mmol) in DMF (5
mL) was stirred for 10 min, treated with Example 57A (260 mg, 1.32
mmol) and Cs.sub.2CO.sub.3 (1.07 g, 3.3 mmol), heated at 85.degree.
C. for 6 h, cooled to room temperature and chromatographed on
silica gel with 10% ethyl acetate/hexanes to provide 155 mg of the
title compound.
[0924] MS (DCI/NH.sub.3) m/e 231 (M+NH.sub.4).sup.+.
EXAMPLE 57C
6-[2-(Methylthio)phenyl]-2-naphthalenecarboximidamide
mono(methanesulfonate) salt
[0925] The title compound was prepared from Example 57B and the
procedure of Example 55D.
[0926] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8 2.32 (s, 3H), 2.40 (s,
3H), 7.34 (m, 2H), 7.45 (m, 2H), 7.82 (dd, 2H), 7.95 (dd, 1H), 8.06
(s, 1H), 8.15 (d, 1H), 8.20 (d, 1H), 8.55 (s, 1H), 9.03 (br s, 2H),
9.56 (br s, 2H);
[0927] MS (DCI/NH.sub.3) m/e 293 (M+H).sup.+.
[0928] Anal. calcd for C.sub.18H.sub.17N.sub.2S.CH.sub.3SO.sub.3H:
C, 58.18; H, 5.18; N, 7.12. Found: C, 57.97; H, 5.31; N, 6.97.
EXAMPLE 58
6-[2-(2-Thiomethoxoxyethyl)phenyl]naphthalene-2-carboximidamide
mono(methanesulfonate) salt
EXAMPLE 58A
2-(2-Bromoethyl)bromobenzene
[0929] A solution of 2-bromophenethyl alcohol (5.05 g, 25.1 mmol)
and pyridine (3.65 mL, 45.2 mmol) in acetonitrile (60 mL) was
treated with Ph.sub.3PBr.sub.2 (13.8 g, 32.65 mmol), stirred at
0.degree. C. for 2 h, diluted with hexanes and filtered through a
plug of silica gel with 25% diethyl ether/hexanes to provide 6.0 g
of the title compound.
[0930] MS (DCI/NH.sub.3) m/e 263 (M+H).sup.+.
EXAMPLE 58B
2-(2-Thiomethoxyethyl)bromobenzene
[0931] A solution of Example 58A (990 mg, 3.75 mmol) and sodium
thiomethoxide (290 mg, 4.12 mmol) in DMF (5 mL) was heated at
90.degree. C. for 5 h, cooled and chromatographed on silica gel
with 1% ethyl acetate/hexanes to provide 646 mg of the title
compound.
[0932] MS (DCI/NH.sub.3) m/e 231, 233 (M+H).sup.+.
EXAMPLE 58C
6- [2-(2-Thiomethoxyethyl)phenyl]-2-naphthalenecarbonitrile
[0933] The title compound was prepared from Example 58B (300 mg,
1.30 mmol), Example 57A (260 mg, 1.32 mmol) and the procedure
described in Example 57B.
[0934] MS (DCI/NH.sub.3) m/e 321 (M+NH.sub.4).sup.+.
EXAMPLE 58D
6-[2-(2-Thiomethoxoxyethyl)phenyl]naphthalene-2-carboximidamide
mono(methanesulfonate) salt
[0935] The title compound was prepared from Example 58C and the
procedure from Example 55D.
[0936] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.78 (s, 3H),
2.31 (s, 3H), 2.55 (m, 2H), 2.85 (m, 2H), 7.30-7.48 (m, 4H), 7.66
(dd, 1H), 7.85 (dd, 1H), 8.04 (s, 1H), 8.18 (d, 1H), 8.20 (d, 1H),
8.55 (s, 1H), 9.01 (br s, 2H), 9.43 (br s, 2H);
[0937] MS (DCI/NH.sub.3) m/e 321 (M+H).sup.+.
[0938] Anal. calcd for
C.sub.20H.sub.20N.sub.2S.sub.2.1.35CH.sub.3SO.sub.3- H: C, 56.96;
H, 5.69; N, 6.22. Found: C, 57.08; H, 5.49; N, 6.14.
EXAMPLE 59
7-Methox -8-(3-furanyl)-2-naphthalenecarboximidamide
mono(methanesulfonate) salt
EXAMPLE 59A
7-Methoxy-8-(3-furanyl)-2-naphthalenecarbonitrile
[0939] The title compound was prepared from Example 53B,
furan-3-boronic acid (873 mg, 7.80 mmol) and the procedure of
Example 57B.
[0940] MS (DCI/NH.sub.3) m/e 267 (M+NH.sub.4).sup.+.
EXAMPLE 59B
7-Methoxy-8-(3-furanyl)-2-naphthalenecarboximidamide
mono(methanesulfonate) salt
[0941] The title compound was prepared from Example 58C and the
procedure from Example 55D.
[0942] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.34 (s, 3H),
3.91 (s, 3H), 6.76 (s, 2H), 7.62 (dd, 1H), 7.74 (d, 1H), 7.87 (dd,
1H), 7.96 (s, 1H), 8.12 (d, 1H), 8.15 (d, 1H), 8.25 (s, 1H), 8.96
(br s, 2H), 9.35 (br s, 2H);
[0943] MS (DCI/NH.sub.3) m/e 267 (M+H).sup.+.
[0944] Anal. calcd for
C.sub.16H.sub.14N.sub.2.O.sub.2CH.sub.3SO.sub.3H: C, 55.77; H,
5.00; N, 7.63. Found: C, 55.73; H, 4.61; N, 7.48.
EXAMPLE 60
7-Methoxy-8-(2-benzofuranyl)naphthalene-2-carboximidamide
mono(methanesulfonate) salt
EXAMPLE 60A
7-Methoxy-8-(2-benzofuranyl)-2-naphthalenecarbonitrile
[0945] The title compound was prepared from Example 53B (166 mg,
0.50 mmol), benzofuran-2-boronic acid (113 mg, 0.70 mmol) and the
procedure of Example 57B.
[0946] MS (DCI/NH.sub.3) m/e 317 (M+NH.sub.4).sup.+.
EXAMPLE 60B
7-Methoxy-8-(2-benzofuranyl)naphthalene-2-carboximidamide
mono(methanesulfonate) salt
[0947] The title compound was prepared from Example 60A (72 mg,
0.240 mmol) and the procedure from Example 55D.
[0948] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.30 (s, 3H),
3.98 (s, 3H), 7.24 (s, 1H), 7.36 (m, 2H), 7.67 (m, 2H), 7.75 (m,
1H), 7.84 (d, 1H), 8.21 (d, 1H), 8.30 (d, 1H), 8.32 (s, 1H), 8.88
(br s, 2H), 9.39 (br s, 2H);
[0949] MS (DCI/NH.sub.3) m/e 317 (M+H).sup.+.
[0950] Anal. calcd for
C.sub.20H.sub.16N.sub.2O.sub.2.1.3CH.sub.3SO.sub.3H- : C, 57.98; H,
4.84; N, 6.35. Found: C, 57.79; H, 4.78; N, 6.22.
EXAMPLE 61
(E)-8-[2-(1,3-Benzodioxol-5-yl)ethenyl]-2-naphthalenecarboximidamide
mono(methanesulfonate) salt
EXAMPLE 61A
(E)-8-[2-(1,3-Benzodioxol-5-yl)ethenyl]-2-naphthalenecarbonitrile
[0951] Example 53B (75 mg, 0.243 mmol), PdCl.sub.2(dppf) (20 mg,
0.024 mmol), 3,4-methylenedioxystyrene (43 mg, 0.291 mmol) and
diisopropylethylamine (0.170 mL, 0.97 mmol) in
N-methylpyrrolidinone (2 mL) were stirred at 90.degree. C. for 18
h, cooled to room temperature and chromatographed on silica gel
with 20% ethyl acetate/hexanes to provide 46 mg of the title
compound.
[0952] MS (DCI/NH.sub.3) m/e 347 (M+NH4).sup.+.
EXAMPLE 61B
(E)-8-[2-(1,3-Benzodioxol-5-yl)ethenyl]-2-naphthalenecarboximidamide
mono(methanesulfonate) salt
[0953] The title compound was prepared from Example 61A (43 mg,
0.131 mmol) and the procedure from Example 55D.
[0954] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8 2.32 (s, 3H), 4.01 (s,
3H), 6.07 (s, 2H), 6.96 (d, 2H), 7.10 (d, 2H), 7.32 (d, 2H), 7.45
(s, 1H), 7.56 (d, 1H), 7.66 (d, 2H), 7.72 (d, 1H), 8.06 (s, 1H),
8.03 (d, 1H), 8.12 (d, 1H), 8.66 (s, 1H), 8.96 (br s, 2H), 9.44 (br
s, 2H);
[0955] MS (DCI/NH.sub.3) m/e 347 (M+H).sup.+.
[0956] Anal. calcd for
C.sub.21H.sub.18N.sub.2O.sub.3.1.1CH.sub.3SO.sub.3H- : C, 58.72; H,
4.99; N, 6.20. Found: C, 58.77; H, 5.07; N, 5.99.
EXAMPLE 62
(.+-.)-7-Methoxy-8-(tetrahydro-3-furanyl)-2-naphthalenecarboximidamide
mono(methanesulfonate) salt
EXAMPLE 62A
(.+-.)-7-methoxy-8-[3-hydroxy-1-(hydroxymethyl)-1-propenyl]-2-naphthalenec-
arbonitrile
[0957] A solution of Example 53B (3.09 g, 10 mmol), PdCl.sub.2 (120
mg, 1 mmol), cis-2-butene-1,4-diol (1.23 mL, 15 mmol) and
NaHCO.sub.3 (1.01 g, 12 mmol) in N-methylpyrrolidinone (10 mL) was
stirred at 130.degree. C. for 1 h, cooled to room temperature and
chromatographed on silica gel with 30% ethyl acetate/hexanes to
provide 2.19 g of the title compound as a mixture of
diastereomers.
[0958] MS (DCI/NH.sub.3) m/e 269 (M+H).sup.+.
EXAMPLE 62B
(.+-.)7-Methoxy-8-(tetrahydro-3-furanyl)-2-naphthalenecarbonitrile
[0959] Example 62A (140 mg, 0.52 mmol) in methylene chloride (3 mL)
at 0.degree. C. was treated with triethylsilane (0.166 mL, 1.04
mmol) and BF.sub.3OEt.sub.2 (0.096 mL, 0.78 mmol), stirred at room
temperature for 4 h, concentrated and chromatographed on silica gel
with 25% ethyl acetate/hexanes to provide 100 mg of the title
compound.
[0960] MS (DCI/NH.sub.3) m/e 271 (M+NH.sub.4).sup.+.
EXAMPLE 62C
(.+-.)7-Methoxy-8-(tetrahydro-3-furanyl)-2-naphthalenecarboximidamide
mono(methanesulfonate) salt
[0961] The title compound was prepared from Example 62B (96 mg,
0.379 mmol) and the procedure from Example 55D.
[0962] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.20 (m, 1H),
2.33 (m, 1H), 2.39 (s, 3H), 3.99 (s, 3H), 3.90-4.03 (m, 3H), 4.11
(m, 1H), 4.42 (m, 1H), 7.64 (d, 1H), 7.68 (d, 1H), 8.01 (d, 1H),
8.10 (d, 1H), 8.70 (s, 1H), 9.01 (br s, 2H), 9.41 (br s, 2H),
[0963] MS (DCI/NH.sub.3) m/e 271 (M+H).sup.+.
[0964] Anal. calcd for
C.sub.16H.sub.18N.sub.2O.sub.2.1.2CH.sub.3SO.sub.3H- : C, 53.57; H,
5.96; N, 7.26. Found: C, 53.67; H, 5.78; N, 6.72.
EXAMPLE 63
6-[[4-(2-Aminoethyl)phenyl]ethynyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 63A
6-(Trimethylsilylethynyl)-2-naphthalenecarbonitrile
[0965] Example 28B and trimethylsilylacetylene were submitted to
the conditions described in Example 42C to provide the title
compound.
[0966] MS (DCI/NH.sub.3) m/e 267 (M+NH.sub.4).sup.+.
EXAMPLE 63B
6-Ethynyl-2-naphthalenecarbonitrile
[0967] A mixture of Example 63A (0.4 g, 1.6 mmole) and
K.sub.2CO.sub.3 (0.4 g, 3.2 mmole) in methanol (16 mL) was stirred
at room temperature for 18 h, concentrated, treated with water and
extracted with methylene chloride. The organic layer was washed
with 0.5 NHCl and brine, dried (MgSO.sub.4) and evaporated to
provide the title compound.
[0968] MS (DCI/NH.sub.3) m/e 195 (M+NH.sub.4).sup.+.
EXAMPLE 63C
4-Bromo-(N-tert-butoxycarbonyl)phenethylamine
[0969] 4-Bromophenethylamine and di-t-butyldicarbonate were
subjected to the conditions described in Synthesis, 48, 1986 to
provide the title compound.
[0970] MS (DCI/NH.sub.3) m/e 319 (M+NH.sub.4).sup.+.
EXAMPLE 63D
6-[[4-(2-N-tert-butoxycarbonylaminoethyl)phenylethynyll
-2-naphthalenecarbonitrile
[0971] The title compound was obtained with Examples 63B and C from
the procedure described in Example 57B to provide the title
compound.
[0972] MS (DCI/NH.sub.3) m/e 414 (M+NH.sub.4).sup.+.
EXAMPLE 63E
6-[[4-(2-Aminoethyl)phenyl]ethynyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0973] The title compound was prepared with Example 63D and the
procedure of Example 5B.
[0974] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.90 (t, 2H),
3.09 (m, 2H) 7.36 (d, 2H), 7.60 (d, 2H), 7.76 (d, 2H), 7.76 (dd,
1H), 7.85 (s, 2H), 7.87 (dd, 1H), 8.13 (d, 1H), 8.18 (d, 1H), 8.31
(s, 1H), 8.50 (s, 1H), 9.18 (s, 2H), 9.45 (s, 2H);
[0975] MS (DCI/NH.sub.3) m/e 314 (M+H).sup.+.
[0976] Anal. calcd for C.sub.21H.sub.19N.sub.3.2TFA.H.sub.2O: C,
53.67; H, 4.14; N, 7.15. Found: C, 53.37; H, 3.93; N, 7.17.
EXAMPLE 64
7-Methoxy-8-[2-pyrimidinyl(oxy)]-2-naphthalenecarboximidamide
mono(trifluoroacetate)
EXAMPLE 64A
7-Methoxy-8-[2-pyrimidinyl(oxy)]-2-naphthalenecarbonitrile
[0977] Example 4A (125 mg, 0.627 mmol) and 2-chloropyrimidine (143
mg, 1.25 mmol) were subjected to the procedure described in Example
6A to provide 101 mg of the title compound.
[0978] MS (DCI/NH.sub.3) m/e 278 (M+H).sup.+.
EXAMPLE 64B
7-Methoxy-8-[2-pyrimidinyl(oxy)]-2-naphthalenecarboximidamide
mono(trifluoroacetate)
[0979] The title compound was prepared with Example 64A and the
procedure of Example 1B.
[0980] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.51 (s, 3H),
3.83 (s, 3H), 7.18 (t, 1H), 7.70 (dd, 1H), 7.80 (d, 1H), 8.05 (d,
1H), 8.19 (d, 1H), 8.34 (s, 1H), 8.62 (d, 2H), 9.07 (br s, 2H),
9.45 (br s, 2H);
[0981] MS (DCI/NH.sub.3) m/e 295 (M+H).sup.+.
[0982] Anal. calcd for C.sub.20H.sub.16N.sub.4O.sub.4.1.33TFA: C,
40.48, H, 2.60; N, 8.35. Found: C, 40.25; H, 2.94; N, 8.92.
EXAMPLE 65
7-Methoxy-8-[2-thiazoyl(oxy)]naphthalene-2-carboximidamide
mono(trifluoroacetate) salt
EXAMPLE 65A
7-Methoxy-8-[2-thiazoyl(oxy)1-2-naphthalenecarbonitrile
[0983] A mixture of Example 4A (250 mg, 1.25 mmol), 2-bromothiazole
(225 mL, 2.50 mmol) and CsF (209 mg, 1.38 mmol) in DMSO (4 mL) was
stirred at 120.degree. C. for 4 days, cooled and chromatographed on
silica gel with 30% ethyl acetate/hexanes to provide 162 mg of the
title compound.
[0984] MS (DCI/NH.sub.3) m/e 283 (M+H).sup.+.
EXAMPLE 65B
7-Methoxy-8-[2-thiazoyl(oxy)]naphthalene-2-carboximidamide
mono(trifluoroacetate) salt
[0985] The title compound was prepared with Example 65A and the
procedure of Example 1B. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 3.98 (s, 3H) 7.25 (m, 2H), 7.73 (dd, 1H), 7.86 (d, 1H),
8.12 (d, 1H), 8.22 (d, 1H), 8.35 9.09 (bs, 2H), (s, 1H), 9.48 (bs,
2H).
[0986] MS (DCI/NH.sub.3) m/e 300 (M+H).sup.+.
[0987] Anal. calcd for C.sub.15H.sub.13N.sub.3O.sub.2S.TFA: C,
49.40; H, 3.41; N, 10.70. Found: C, 49.10; H, 3.40; N, 10.69.
EXAMPLE 66
7-Methoxy-8-(4-nitrophenoxy)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 66A
7-Methoxy-8-(4-nitrophenoxy)-2-naphthalenecarbonitrile
[0988] The title compound was prepared from Example 4A (125 mg,
0.627 mmol), 1,4-dinitrobenzene (143 mg, 1.25 mmol) and the
procedure described in Example 65A to provide 227 mg of the title
compound.
[0989] MS (DCI/NH.sub.3) m/e 338 (M+NH.sub.4).sup.+.
EXAMPLE 66B
7-Methoxy-8-(4-nitrophenoxy)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0990] The title compound was prepared with Example 66A and the
procedure of Example 55D.
[0991] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.43 (br s, 2H),
8.94 (br s, 2H), 8.25 (m, 4H), 8.15 (d, 1H), 7.88 (d, 1H), 7.72
(dd, 1H), 7.05 (d, 2H), 3.91 (s, 3H), 2.30 (s, 3H);
[0992] MS (DCI/IH.sub.3) m/e 338 (M+H).sup.+.
[0993] Anal. calcd for
C.sub.18H.sub.15N.sub.3O.sub.4.1.75CH.sub.3SO.sub.3- H: C, 46.93;
H, 4.39; N, 8.31. Found: C, 47.17; H, 4.32; N, 8.12.
EXAMPLE 67
7-Methoxy-8-pentafluorophenoxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 67A
7-Methoxy-8-pentafluorophenoxy-2-naphthalenecarbonitrile
[0994] Example 4A (100 mg, 0.50 mmol) and hexafluorobenzene (115
mL, 1.00 mmol) were subjected to the procedure described in Example
65A to provide 150 mg of the title compound.
[0995] MS (DCI/NH.sub.3) m/e 383 (M+NH.sub.4).sup.+.
EXAMPLE 67B
7-Methoxy-8-pentafluorophenoxy-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[0996] The title compound was prepared with Example 67A and the
procedure of Example 55D.
[0997] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.31 (s, 3H),
3.82 (s, 3H), 7.87 (dd, 1H), 7.88 (d, 1H), 8.02 (d, 1H), 8.20 (d,
1H), 8.65 (s, 1H), 9.04 (br s, 2H), 9.47 (br s, 2H);
[0998] MS (DCI/NH.sub.3) m/e 383 (M+H).sup.+.
[0999] Anal. calcd for
C.sub.18H.sub.11N.sub.2F.sub.5O.sub.2.1.2CH.sub.3SO- .sub.3H: C,
46.67; H, 3.19; N, 5.68. Found: C, 46.55; H, 3.00; N, 5.58.
EXAMPLE 68
7-Methoxy-8-[N-2-phenylamino)]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 68A
7-Methoxy-8-[N-2-phenyl(amino)]-2-naphthalenecarbonitrile
[1000] A solution of Example 25A (309 mg, 1.00 mmol), aniline
(0.109 mL, 1.2 mmol), NaOtBu (115 mg, 1.2 mmol),
Pd.sub.2(dba).sub.3 (10 mg, 0.01 mmol) and dppf (17 mg, 0.03 mmol)
in toluene (5 mL) was stirred for 3 h at 100.degree. C., cooled and
chromatographed on silica gel with 10% ethyl acetate/hexanes to
provide 175 mg of the title compound.
[1001] MS (DCI/NH.sub.3) m/e 275 (M+H).sup.+.
EXAMPLE 68B
7-Methoxy-8-(N-2-phenylamino)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[1002] The title compound was prepared with Example 68A and the
procedure of Example 55D.
[1003] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.95 (s, 3H),
5.92 (bs, 1H), 6.61 (d, 2H), 6.94 (t, 1H), 7.16 (dd, 2H), 7.45 (dd,
1H), 7.48 (d, 1H), 7.76 (d, 1H), 7.88 (d, 1H), 8.13 (d, 1H), 9.08
(bs, 2H), 9.31 (bs, 2H).
[1004] MS (DCI/NH.sub.3) m/e 292 (M+H).sup.+.
[1005] Anal. Calcd for C.sub.18H.sub.17N.sub.3O.TFA: C, 59.26; H,
4.48; N, 10.37. Found: C, 59.20; H, 4.32; N, 10.15.
EXAMPLE 69
N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-benzylurea
mono(trifluoroacetate) salt
EXAMPLE 69A
N-(6-Cyano-2-naphthalenyl)-N'-benzylurea
[1006] The title compound was prepared with Example 40A,
benzylamine and the procedure from Example 40B.
[1007] MS (DCI/NH.sub.3) m/e 302 (M+H).sup.+.
EXAMPLE 69B
N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-benzylurea
mono(trifluoroacetate) salt
[1008] The title compound was prepared with Example 69A and the
procedure from Example 40D.
[1009] 1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.35 (d, 2H), 6.91
(t, 1H), 7.35-7.24 (m, 5H), 7.59 (dd, 11H), 7.72 (dd, 1H), 7.95 (d,
1H), 7.96 (d, 1H), 8.22 (d, 1H), 8.35 (d, 1H), 8.92 (br s, 2H),
9.13 (s, 1H), 9.32 (br s, 2H).
[1010] MS (DCI/NH.sub.3) m/e 319 (M+H).sup.+.
[1011] Anal. calcd for C.sub.`9H.sub.`8N.sub.4O.TFA: C, 50.57; H,
4.24; N, 15.72. Found: C, 50.34; H, 4.15; N, 15.54.
EXAMPLE 70
N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-methylurea
mono(trifluoroacetate) salt
EXAMPLE 70A
N-(6-Cyano-2-naphthalenyl)-N'-methylurea
[1012] The title compound was prepared with Example 40A (221.2 mg,
1.00 mmole) and methylamine (2.3 mL, 2.34 mmol) in THF (10 mL)
according to the procedure from Example 40B.
[1013] MS (DCI/NH.sub.3) m/e 226 (M+H).sup.+.
EXAMPLE 70B
N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-methylurea
mono(trifluoroacetate) salt
[1014] The title compound was prepared with Example 70A and the
procedure of Example 40D.
[1015] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.69 (d, 3H),
6.32 (q, 1H), 7.60 (dd, 1H), 7.73 (dd, 1H), 7.93 (d, 1H), 7.95 (d,
1H, 8.19 (d, 1H), 8.49 (d, 1H), 9.09 (s, 1H), 9.15 (br. s, 4H);
[1016] MS (DCI/NH.sub.3) m/e 243 (M+H).sup.+.
[1017] Anal. calcd for C.sub.13H.sub.14N.sub.4O.TFA: C, 50.57; H,
4.24; N, 15.72. Found: C, 50.34; H, 4.15; N, 15.54.
EXAMPLE 71
N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-isopropylurea
mono(trifluoroacetate) salt
EXAMPLE 71A
N-(6-Cyano-2-naphthalenyl)-N'-isopropylurea
[1018] The title compound was prepared with Example 40A,
isopropylamine and the procedure from Example 40B.
[1019] MS (DCI/NH.sub.3) m/e 254 (M+H).sup.+.
EXAMPLE 71B
N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-isopropylurea
mono(trifluoroacetate) salt
[1020] The title compound was prepared with Example 71A and the
procedure of Example 5B. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 1.13 (d, 6H), 3.76-3.84 (m, 1H), 6.28 (d, 1H), 7.55 (dd,
1H), 7.72 (dd, 1H), 7.94 (d, 1H), 7.95 (d, 1H), 8.19 (d, 1H), 8.34
(d, 1H), 8.85 (s, 1H), 9.3 (br s, 2H), 9.0(brs,2H);
[1021] MS (DCI/NH.sub.3) m/e 271 (M+H).sup.+.
[1022] Anal. calcd for C.sub.15H.sub.18N.sub.4O.TFA: C, 53.12; H,
4.98; N, 14.58. Found: C, 15.13; H, 4.84; N, 14.50.
EXAMPLE 72
N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-phenyl-N'-methylurea
mono(trifluoroacetate) salt Example 72A
N-(6-Cyano-2-naphthalenyl)-N'-phenyl-N'-methylurea
[1023] The title compound was prepared with Example 40A,
N-methyl-N-phenylamine and the procedure from Example 40B.
[1024] MS (DCI/NH.sub.3) m/e 302 (M+H).sup.+.
EXAMPLE 72B
N-(6-Aminoiminomethyl-2-naphthalenyl)-N'-phenyl-N'-methylurea
mono(trifluoroacetate) salt
[1025] The title compound was prepared with Example 72A and the
procedure of Example 40D.
[1026] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.33 (s, 311H),
7.25-7.47 (m, 5H), 7.71-7.77 (m, 2H), 7.95 (two overlaping
doublets, 2H), 8.16 (d, 1H), 8.35 (d, 1H), 8.64 (s, 1H), 8.96 (br
s, 2H), 9.34 (br s, 2H);
[1027] MS (DCI/NH.sub.3) mi/e 319 (M+H).sup.+.
[1028] Anal. calcd for C.sub.20H.sub.17N.sub.4O.TFA: C, 58.33; H,
4.43; N, 11.96. Found: C, 58.38; H, 4.69; N, 11.82.
EXAMPLE 73
6-Aminonaphthalene-2-carboximidamide mono(trifluoroacetate)
salt
EXAMPLE 73A
6-Phenylcarbaynoyl-2-naphthalenecarbonitrile
[1029] The title compound was prepared from Example 40A, phenol and
the procedure from Example 40B.
[1030] MS (DCI/NH.sub.3) m/e 289 (M+H).sup.+.
EXAMPLE 73B
6-Amninonaphthalene-2-carboximidamide mono(trifluoroacetate)
salt
[1031] The title compound was prepared from Example 73A and the
procedure of Example 40D.
[1032] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 6.01 (br s, 2H),
6.86 (d, 1H), 7.06 (dd, 1H), 7.58-7.67 (m, 2H), 7.74 (d, I1H), 8.21
(d, 1H), 8.74 (br s, 2H), 9.16 (br s, 2H);
[1033] MS (DCI/NH) m/e 196 (M+H).sup.+.
[1034] Anal. calcd for C.sub.12H.sub.10N.sub.3.TFA: C, 52.18; H,
4.04; N, 14.04. Found: C, 51.92; H, 3.87; N, 13.80.
EXAMPLE 74
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-cyclohexylurea
mono(trifluoroacetate) salt
EXAMPLE 74A
N-(6-Cyano-2-naphthalenyl)-N'-cyclohexylurea
[1035] The title compound was prepared with Example 40A,
cyclohexylamine and the procedure from Example 40B.
[1036] MS (DCI/NH.sub.3) m/e 294 (M+H).sup.+.
EXAMPLE 74B
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-cyclohexylurea
mono(trifluoroacetate) salt
[1037] The title compound was prepared with Example 74A and the
procedure of Example 40D.
[1038] .sup.1H NMR (300 MHz, DMSO-d6) .delta. 1.14-1.39 (m, 5H),
1.54-1.58 (m, 1H), 1.65-1.72 (m, 2H), 1.81-1.86 (m, 2H), 3.46-3.52
(m, 1H), 6.36 (d, 1H), 7.55 (dd, 1H), 7.72 (dd, 1H), 7.93 (d, 1H),
7.95 (d, 1H), 8.18 (d, 1H), 8.35 (d, 1H), 8.87 (s, 1H), 9.00 (br s,
2H), 9.28 (br s, 2H);
[1039] MS (DCI/NH.sub.3) m/e 311 (M+H).sup.+.
[1040] Anal. calcd for C.sub.19H.sub.21N.sub.4O.TFA: C, 56.60; H,
5.46; N, 13.20. Found: C, 56.61; H, 5.72; N, 13.03.
EXAMPLE 75
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-benzyloxyurea
mono(trifluoroacetate) salt
EXAMPLE 75A
N-(6-cyano-2-naphthalenyl)-N'-benzylurea
[1041] The title compound was prepared with Example 40A,
0-benzylhydroxylamine and the procedure from Example 40B.
[1042] MS (DCI/NH.sub.3) m/e 318 (M+H).sup.+.
EXAMPLE 75B
N-(6-aminoiminomethyl-2-naphthalenyl)-N'-benzyloxyurea
mono(trifluoroacetate) salt
[1043] The title compound was prepared with Example 75A and the
procedure of Example 40D.
[1044] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.87 (s, 2H),
7.25-7.42 (m, 3H), 7.48-7.51 (m, 2H), 7.75 (dd, 1H), 7.75 (dd, 1H),
7.97 (d, 2H), 8.30 (d, I1H), 8.38 (d, I1H), 8.97 (br s, 2H), 9.21
(s, I1H), 9.3 5 (br s, 2H), 9.77 (s, 1H);
[1045] MS (DCI/NH.sub.3) m/e 335 (M+H).sup.+.
[1046] Anal. calcd for C.sub.19H.sub.18N.sub.4O.sub.2.TFA: C,
56.25; H, 4.27; N, 12.49. Found: C, 56.26; H, 4.39; N, 12.30.
EXAMPLE 76
1,1-Dimethylethyl [4-
[[(6-aminoiminomethyl-2-naphthalenyl)amino]carbonyl]-
phenyl]carbamate mono(trifluoroacetate) salt
EXAMPLE 76A
6-Amino-2-naphthalenecarbonitrile
[1047] Sulfuric acid (45mL) was treated with Example 40B (6.5 g),
stirred for 30 min, warmed to room temperature for 20 min, poured
onto ice, diluted with water to approximately 500 mL, cooled to
0.degree. C. and treated with 50% aq sodium hydroxide such that the
temperature did not exceed 3 5.degree. C. The light solid which
precipitated was filtered, washed with water to pH 7, dried under
vacuum and purified on silica gel with 20% ethyl acetate/ hexanes
to provide 3.3 g of the title compound. MS (DCI/NH.sub.3) m/e 169
(M+H).sup.+.
EXAMPLE 76B
1,1-Dimethylethyl
[4-[F(6-cyano-2-naphthalenyl)amino]carbonyl]phenyl]carba- mate
mono(trifluoroacetate) salt
[1048] The title compound was prepared from Example 76A,
4-N-Boc-aminomethylbenzoic acid, the procedure from Example 35B
with methylene chloride in place of THF.
[1049] MS (DCI/NH.sub.3) m/e 417 (M+H).sup.+.
EXAMPLE 76C
1,1-Dimethylethyl [-2-naphthalenyl)amino]carbonyl]phenyl]carbamate
mono(trifluoroacetate) salt
[1050] The title compound was prepared with Example 76B and the
procedure of Example 40D.
[1051] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.30 (s, 9H),
4.22 (d, 2H), 7.42 (d, 2H), 7.49 (t, 1H), 7.79 (dd, 1H), 7.95-8.00
(m, 3H), 8.09 (d, 2H), 8.42 (s, 1H), 8.63 (d, 1H), 9.18 (br s, 4H),
10.58 (s, 1H);
[1052] MS m/e 434 (M+H).sup.+.
[1053] Anal. calcd for C.sub.24H.sub.27N.sub.5O.sub.3.TFA: C,
59.56; H, 5.00; N, 10.29. Found: C, 58.55; H, 4.85; N, 10.41.
EXAMPLE 77
N-[6-(Aminoiminomethyl)-2-naphthalenyl]-4-(aminomethyl)benzamide
mono(trifluoroacetate) salt
EXAMPLE 77A
N-[6-(Aminoiminomethyl)-2-naphthalenyl]-4-(aminomethyl)benzamide
mono(trifluoroacetate) salt
[1054] A solution of Example 76B (35 mg, 0.07 mmole) in 1:1
TFA/methylene chloride was stirred at room temperature for 1 h then
concentrated. The residue was dissolved in water (12 mL), filtered
through a 0.45.mu. filter and concentrated. The solid was suspended
in diethyl ether and filtered to yield 27 mg of the title compound
as a white solid.
[1055] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.17 (q, 2H),
7.65 (d, 2H), 7.80 (dd, 1H), 7.99 (dd, 1H), 8.06-8.12 (m, 4H), 8.30
(br s, 2H), 8.44 (d, 1H), 8.64 (d, 1H), 9.13 (br s, 2H), 9.40 (br
s, 2H), 10.70 (s, 1H);
[1056] MS (DCI/NH.sub.3) m/e 319 (M+H).sup.+.
[1057] Anal. calcd for
C.sub.19H.sub.18N.sub.4O.2.25TFA.0.5H.sub.2O: C, 48.34; H, 3.67; N,
9.59. Found: C, 48.45; H, 3.74; N, 9.45.
EXAMPLE 78
Ethyl [6-(aminoiminomethyl)-2-naphthalenyl]carbamate
mono(trifluoroacetate) salt
EXAMPLE 78A
Ethyl (6-cyano-2-naphthalenyl)carbamate mono(trifluoroacetate)
salt
[1058] The title compound was prepared with Example 40A, ethanol
and the procedure from Example 40B.
[1059] MS (DCI/NH.sub.3) m/e 241 (M+H).sup.+.
EXAMPLE 78B
Ethyl 16-(aminoiminomethyl)-2-naphthalenyl]carbamate
mono(trifluoroacetate) salt
[1060] The title compound was prepared with Example 78A and the
procedure of Example 40D.
[1061] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.29 (t, 3H),
4.19 (q, 2H), 7.69 (dd, 1H), 7.76 (dd, 1H), 8.1 (d, 2H), 8.23 (d,
1H), 8.38 (d, 1H), 9.03 (br s, 2H), 9.33 (br s, 2H), 10.11 (s,
1H);
[1062] MS (DCI/NH.sub.3) m/e 258 (M+H).sup.+.
[1063] Anal. calcd for C.sub.14H.sub.15N.sub.3O.sub.2.TFA: C,
51.76; H, 4.34; N, 11.32. Found: C, 51.32; H, 4.15; N, 10.93.
EXAMPLE 79
1,1-dimethylethyl
[4-[[[6-aminoiminomethyl)-2-naphthalenyl)amino]carbonyl]-
amino]phenyl carbamate mono(trifluoroacetate) salt
EXAMPLE 79A
1,1-Dimethyl
[4-[[[(6-cyano-2-naphthalenyl)amino]carbonyl]amino]phenyl]car-
bamate
[1064] The title compound was prepared with Example 40B,
4-(N-tert-butoxycarbonylamino)-aminobenzene and the procedure from
Example 40C.
[1065] MS (DCI/NH.sub.3) m/e 403 (M+H).sup.+.
EXAMPLE 79B
1,1-dimethylethyl
[4[[[6-aminoiminomethyl)-2-naphthalenyl)amino]carbonyl]a-
mino]phenyl carbamate mono(trifluoroacetate) salt
[1066] The title compound was prepared with Example 79A and the
procedure of Example 40D.
[1067] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.22 (s, 9H),
7.38 (s, 4H), 7.62 (dd, 1H), 7.75 (dd, 1H), 8.00 (d, 2H), 8.27 (d,
1H), 8.38 (d, 1H), 8.77 (s, 1H), 8.90 (br s, 2H), 9.16 (s, 1H),
9.20 (s, 1H), 9.33 (br s, 2H);
[1068] MS (DCI/NH.sub.3) m/e 420 (M+H).sup.+.
[1069] Anal. calcd for C.sub.23H.sub.25N.sub.5O.sub.3.2.TFA: C,
56.28; H, 4.91; N, 13.13. Found: C, 56.18; H, 5.07; N, 12.44.
EXAMPLE 80
(E)-6-[2-(Phenylthio)ethenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 80A
(E)-6-[2-(Phenylthio)ethenyl]-2-naphthalenecarbonitrile
[1070] The title compound was prepared from Example 55B,
phenylvinyl sulfide and the procedure of Example 57B.
[1071] MS (DCI/NH.sub.3) m/e 305 (M+NH.sub.4).sup.+.
EXAMPLE 80B
(E)-6-[2-(Phenylthio)ethenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[1072] The title compound was prepared from Example 80A and the
procedure of Example 1B.
[1073] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8 6.91 (d, 1H),
7.52-7.33 (m, 5H), 7.50 (d, 1H), 7.75-7.83 (m, 1H), 7.98-8.89 (m,
1H), 8.08-8.80 (m, 3H), 8.44 (m, 1H), 9.03 (s, 2H), 9.40 (s,
2H);
[1074] MS (DCI/NH.sub.3) m/e 305 (M+H).sup.+.
[1075] Anal. calcd for C.sub.19H.sub.16N.sub.2S.1.1TFA: C, 59.55;
H, 4.03; N, 6.57. Found: C, 59.53; H, 4.12; N, 6.60.
EXAMPLE 81
(E)-6-[2-(2-Furanyl)ethenyl1-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 81A
2-Vinylfuran
[1076] A solution of methyl(triphenylphosphonium)bromide (26.78 g,
75 mmol) in toluene (80 mL) was treated with butyllithium in
hexanes (27.5 mL, 68.75 mmol) then furfural (6 g, 62.5 mmol),
stirred for 0.5 h and distilled at 69-72.degree. C. to provide the
title compound as a clear, colorless liquid with some toluene
contaminant.
[1077] MS (DCI/NH.sub.3) m/e 83 (M+H).sup.+.
EXAMPLE 81B
(E)-6- F2-(2-Furanyl)ethenyl]-2-naphthalenecarbonitrile
[1078] The title compound was prepared from Examples 55B and 81A
and the procedure of Example 57B.
[1079] MS (DCI/NH.sub.3) m/e 263 (M+NH.sub.4).sup.+.
EXAMPLE 81C
(E)-6-[2-(2-Furanyl)ethenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[1080] The title compound was prepared from Example 81B and the
procedure of Example 1B.
[1081] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 6.61 (dd, 1H),
6.66 (d, 1H), 7.19 (d, 1H), 7.38 (d, 1H), 7.77 (d, 1H), 7.80 (dd,
1H), 8.14-7.97 (m, 3H), 8.44 (s, 1H), 9.05 (s, 2H), 9.42 (s,
2H);
[1082] MS (DCI/NH.sub.3) m/e 263 (M+H).sup.+.
[1083] Anal. calcd for C.sub.17H.sub.13N.sub.2O.1.2TFA: C, 58.49;
H, 3.85; N, 7.04. Found: C, 58.45; H, 3.78; N, 7.36.
EXAMPLE 82
(E)-6-[2-(1H-Imidazol-1-yl)ethenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 82A
(E)-6- [2-( 1H-Imidazol-1-yl)ethenyl]-2-naphthalenecarbonitrile
[1084] The title compound was prepared from Example 55B,
1-vinylimidazole and the procedure of Example 42C.
[1085] MS (DCI/NH.sub.3) m/e 263 (M+NH.sub.4).sup.+.
EXAMPLE 82B
(E)-6-[2-(1H-Imidazol-1-yl)ethenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[1086] The title compound was prepared from Example 82B and the
procedure of Example 40D.
[1087] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.44 (s, 2H),
9.14 (s, 2H), 8.15 (d, 1H), 8.17-8.05 (m, 4H), 7.93 (d, 1H), 7.84
(dd, 1H), 7.59 (s, 1H), 7.49 (d, 1H);
[1088] MS (DCI/NH.sub.3) m/e 263 (M+H).sup.+.
[1089] Anal. calcd for C.sub.16H.sub.13N.sub.4.2.7TFA: C, 45.28; H,
2.97; N, 9.91. Found: C, 45.33; H, 3.52; N, 9.79.
EXAMPLE 83
(E)-4-[2-(6-Aminoiminomethyl-2-naphthalenyl)ethenyl]benzenesulfonamide
mono(trifluoroacetate) salt
EXAMPLE 83A
4-vinylsulfonamide
[1090] A solution of thionyl chloride (7.5 mL) and
4-t-butylcatachol (45 mg, 0.3 mmol) in DMF (9 mL) at 0.degree. C.
was treated with 4-vinylbenzene sulfonic acid sodium salt (3 g,
14.6 mmol), stirred for 6 h, stored at -10.degree. C. for 3 days,
poured into ice water and extracted with benzene. The organic layer
was washed with water, dried (Na.sub.2SO.sub.4), filtered and
concentrated to provide 4-vilylsulfonyl chloride as a clear,
colorless oil. A portion of the chloride (1 g, 4.95 mmol) was
dissolved in THF (10 mL), cooled to 0.degree. C., treated dropwise
with concentrated ammonium hydroxide until gas evolution ceased and
extracted with ethyl acetate. The combined extracts were dried
(Na.sub.2SO.sub.4), and concentrated to provide 707 mg of the title
compound as a pale yellow solid.
[1091] MS (DCI/NH.sub.3) m/e 201(M+NH.sub.4).sup.+.
EXAMPLE 83B
(E)-4-F2-(6-Cyano-2-naphthalenyl)ethenyl]benzenesulfonamide
[1092] The title compound was prepared from Example 55B, Example
83A and the procedure of Example 57B.
[1093] MS (DCI/NH.sub.3) m/e 352 (M+NH.sub.4).sup.+.
EXAMPLE 83C
(E)-4-[2-(6-Aminoiminomethyl-2-naphthalenyl)ethenyl]benzenesulfonamide
mono(trifluoroacetate) salt
[1094] The title compound was prepared from Example 83B and the
procedure of Example 40D.
[1095] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8 9.43 (s, 2H), 9.05 (s,
2H), 8.46 (s, 1H), 8.21 (s, 1H), 8.16-7.95 (m, 3H), 7.86 (s, 2H),
7.84-7.67 (m, 2H), 7.62 (d, 11H), 7.4-7.36 (m, 2H);
[1096] MS (DCI/NH.sub.3) m/e 352 (M+H).sup.+.
[1097] Anal. calcd for
C.sub.19H.sub.17N.sub.3O.sub.2S.1.5C.sub.2F.sub.3O.- sub.2H: C,
50.84; H. 3.59; N, 8.11. Found: C, 50.83; H, 3.89; N, 7.88.
EXAMPLE 84
(E)-4-[2-(6-Aminoiminomethyl-2-naphthalenyl)ethenyl]benzoic acid
mono(trifluoroacetate) salt
EXAMPLE 84A
(E)-4-[2-(6-Cyano-2-naphthalenyl)ethenyl]benzoic acid
[1098] The title compound was prepared from Example 55B,
4-vinylbenzoic acid and the procedure of Example 57B.
[1099] MS (DCI/NH.sub.3) m/e 300 (M+H).sup.+.
EXAMPLE 84B
(E)-4-[2-(6-Aminoiminomethyl-2-naphthalenyl)ethenyl]benzoic acid
mono(trifluoroacetate) salt
[1100] The title compound was prepared with Example 84A and the
procedure of Example 40D.
[1101] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8 7.62-7.58 (m, 2H),
7.90 (d, 2H), 7.98 (d, 1H), 8.12-8.04 (m, 3H), 8.20 (s, 1H), 8.56
(s, 1H), 9.07 (bs, 2H), 9.35 (bs, 2H).
[1102] MS (DCI/NH.sub.3) m/e 317 (M+H).sup.+.
[1103] Anal. calcd for C.sub.20H.sub.16N.sub.2O.sub.2.TFA: C,
61.40; H, 3.98; N, 6.51. Found: C, 61.10; H, 3.63; N, 6.45.
EXAMPLE 85
4-[7-(Aminoiminomethyl)-2-methoxy-1-naphthalenyl]dihydro-2(3H)-furanone
mono(trifluoroacetate) salt
EXAMPLE 85A
4-(7-Cyano-2-methoxy-1-naphthalenyl)dihydro-2(3H)-furanone
[1104] Example 62A (269 mg, 1.00 mmol) and pyridinium
chlorochromate (360 mg, 1.67 mmol) in methylene chloride (15 mL)
were stirred at room temperature for 24 h, filtered through
Celite.RTM. and concentrated. The residue was chromatographed on
silica gel with 20% ethyl acetate/ hexanes to provide 170 mg of the
title compound.
[1105] MS (DCI/NH.sub.3) m/e 285 (M+NH.sub.4).sup.+.
EXAMPLE 85B
4-[7-(Aminoiminomethyl)-2-methoxy-1-naphthalenyl]dihydro-2(3H)-furanone
mono(trifluoroacetate) salt
[1106] The title compound was prepared from Example 85A and the
procedure of Example 40D.
[1107] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.96-2.75 (m,
2H), 3.96 (s, 3H), 4.33 (m, 1H), 4.66 (t, 1H), 8.85 (m, 1H), 7.68
(dd, 1H), 7.73 (d, 1H), 8.08 (d, 1H), 8.12 (d, 1H), 8.67 (s, 1H),
9.14 (s, 2H), 9.43 (s, 2H);
[1108] MS (DCI/NH.sub.3) m/e 285 (M+H).sup.+.
[1109] Anal. calcd for C.sub.16H.sub.16N.sub.2O.sub.3.1.1TFA: C,
53.72; H, 4.24; N, 6.91. Found: C, 53.75; H, 4.26; N, 6.94.
EXAMPLE 86
7-Methoxy-8-(1-acetyl-1H-pyrazolyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 86A
7-Methoxy-8-(1-acetyl-1H-pyrazolyl)-2-naphthalenecarbonitrile
[1110] A solution of Example 53F (90 mg, 0.361 mmol) in THF (2 mL)
was treated with a 0.5 M solution of potassium
bis(trimethylsilyl)amide in toluene (0.866 mL, 0.433 mmol), stirred
for 5 min, treated with acetyl chloride (38 mL, 0.542 mmol),
stirred for 10 min and concentrated. The crude product was
chromatographed on silica gel with 25% ethyl acetate/hexanes to
yield 67 mg of the title compound.
[1111] MS MS (DCI/NH.sub.3) m/e 309 (M+NH.sub.4).sup.+.
EXAMPLE 86B
7-Methoxy-8-(1-acetyl-1H-pyrazolyl)-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[1112] The title compound was prepared with Example 86A and the
procedure of Example 40D.
[1113] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.89 (s, 3H),
7.59 (d, 1H), 7.92 (s, 2H), 8.06 (d, 1H), 8.12 (d, 1H), 8.28 (s,
1H), 8.94 (s, 2H), 9.34 (s, 2H);
[1114] MS (DCI/NH.sub.3) m/e 309 (M+H).sup.+.
[1115] Anal. calcd for C.sub.17H.sub.16N.sub.4O.sub.2.1.9TFA: C,
47.59; H, 3.44; N, 10.67. Found: C, 54.03; H, 4.06; N, 13.26.
EXAMPLE 87
7-Methoxy-8-[1-(methylsulfonyl)-1H-4-pyrazolyl]-2-naphthalenecarboximidami-
de mono(trifluoroacetate) salt
EXAMPLE 87A
7-Methoxy-8-[1-(methylsulfonyl)-1H-4-pyrazolyl]-2-naphthalenecarbonitrile
[1116] The title compound was prepared from Example 53F (190 mg,
0.762 mmol), methanesulfonyl chloride (0.088 mL, 1.14 mmol) and the
procedure of Example 86A to provide 122 mg of the title
compound.
[1117] MS (DCI/NH.sub.3) m/e 345 (M+NH.sub.4).sup.+.
EXAMPLE 87B
7-Methoxy-8-[]1-(methylsulfonyl)-1H-4-pyrazolyl]-2-naphthalenecarboximidam-
ide mono(trifluoroacetate) salt
[1118] The title compound was prepared from Example 87A and the
procedure of Example 40D.
[1119] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.75 (s, 3H),
3.98 (s, 3H) 7.64 (dd, 1H), 7.78 (d, 1H), 8.15 (s, 1H), 8.18 (s,
1H), 8.21 (s, 1H), 8.24 (s, 1H), 8.62 (s, 1H), 8.97 (s, 2H), 9.40
(s, 2H);
[1120] MS (DCI/NH.sub.3) m/e 345 (M+H).sup.+.
[1121] Anal. calcd for C.sub.16H.sub.16N.sub.4O.sub.3S.1.4TFA: C,
44.75; H, 3.47; N, 11.09. Found: C, 44.59; H, 3.86; N, 11.38.
EXAMPLE 88
(E)-4-[2-(6-Aminoininomethyl-2-naphthalenyl)ethenyl]benzamide
mono(trifluoroacetate) salt
EXAMPLE 88A
Example 85A (E)-4-[2-(6-Cyano-2-naphthalenyl)ethenyl]benzamide
[1122] Example 85A (160 mg, 0.54 mmol) in thionyl chloride (4 ml)
was refluxed for 0.5 h, cooled to 0.degree. C., treated with
concentrated aqueous ammonia until gas evolution ceased, diluted
with ethyl acetate, heated to dissolve residual solids, washed with
water, dried (MgSO4) and concentrated to provide 100 mg of the
title compound as an orange solid.
[1123] MS (DCI/NH.sub.3) m/e 316 (M+NH.sub.4).sup.+.
EXAMPLE 88B
(E)-4-[2-(6-Aminoininomethyl-2-naphthalenyl)ethenyl]benzamide
mono(trifluoroacetate) salt
[1124] The title compound was prepared with Example 88A and the
procedure of Example 1B.
[1125] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.34 (br, 1H),
7.51 (d, 1H), 7.56 (d, 2H), 7.73 (d, 2H), 7.82 (m, 2H), 7.90 (d,
2H), 7.96 (br, 1H), 8.09 (q, 3H), 8.17 (s, 1H), 8.43 (s, 1H), 9.01
(s, 2H), 9.40 (s, 2H);
[1126] MS (DCI/NH.sub.3) m/e 316 (M+H).sup.+.
[1127] Anal. calcd for C.sub.20H.sub.17N.sub.3O.1.1TFA: C, 60.09;
H, 4.11; N, 9.44. Found: C, 60.22; H, 4.13; N, 8.79.
EXAMPLE 89
6-[2-(4-Aminophenyl)ethoxy]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
EXAMPLE 89A
6-[2-(4-Aminophenyl)ethoxy]-2-naphthalenecarbonitrile
[1128] A solution of Example 4A, (300 mg), Cs.sub.2CO.sub.3 (1.2 g
), 4-aminophenethylbromide (470 mg) and tetrabutylammonium iodide
(10 mg) in DMF (5 ml) was stirred for 18 h at room temperature,
diluted with water and extracted with ethyl acetate. The organic
extract was washed with saturated aq NaHCO.sub.3 and brine, dried
(Na.sub.2SO.sub.4) and concentrated to provide 200 mg of the title
compound as a dark brown oil.
[1129] MS (DCI/NH.sub.3) m/e 306 (M+NH.sub.4).sup.+.
EXAMPLE 89B
6-[2-(4-Aminophenyl)ethoxy]-2-naphthalenecarboximidamide
mono(trifluoroacetate) salt
[1130] The title compound was prepared with Example 89A according
to the procedure of Example 5B.
[1131] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.15 (t, 2H),
3.6 (bs, 3H), 4.35 (t, 2H), 6.93 (d, 2H), 7.24 (d, 2H) 7.38 (dd,
1H), 7.55 (d, 1H), 7.78 (dd, 1H), 7.98 (dd, 1H), 8.21 (d, 1H), 8.4
(d, 1H), 9.21 (bs, 2H), 9.39 (bs, 2H);
[1132] MS m/e 306 (M+H).sup.+.
[1133] Anal. calcd for C.sub.19H.sub.19N.sub.3O.2TFA: C, 51.79; H,
3.97; N, 7.88; Found: C, 50.99; H, 4.68; N, 7.59.
EXAMPLE 90
Methyl [3-methoxy-6-(aminoiminomethyl)-4-naphthalenyl]carbamate
mono(trifluoroacetate) salt
EXAMPLE 90A
7-Methoxy-2-trifluoromethanesulfonyloxy naphthalene
[1134] A solution of 7-methoxy-2-naphthol (3.24 g, 18 mmole) in DMF
(20 mL) and methylene chloride (20 mL) was treated with N-phenyl
trifluoromethanesulfonimide (6.6 g, 18 mmole) and triethylamine
(5.2 mL, 37 mmole), stirred 20 h at room temperature, diluted with
CH.sub.2Cl.sub.2 (100 mL) , washed sequentially with distilled
water, 20 % KOH and brine, dried (MgSO.sub.4) and concentrated to
provide the title compound as a clear oil.
[1135] MS (DCI/NH.sub.3): m/e 272 (M+NH.sub.4).sup.+.
EXAMPLE 90B
7-Methoxy-2-naphthalenecarbonitrile
[1136] Example 90A (12 mmole), zinc cyanide (12 mmole),
Pd(OAc).sub.2 (0.3 mmole) and triphenylphosphine (1.2 mmole) in DMF
(40 mL) was heated for 6 h at 85.degree. C., diluted with ethyl
acetate (200 mL), washed with saturated NaHCO.sub.3, brine, dried
(MgSO.sub.4) and concentrated to a dark oily residue. Purification
of the residue on silica gel with 1:1 hexane: methylene chloride
then CH.sub.2Cl.sub.2 provided 1.8 g of the title compound as a
white solid.
[1137] MS (DCI/NH.sub.3) m/e 201 (M+NH.sub.4).sup.+.
EXAMPLE 90C
7-Methoxy-8-nitro-2-naphthalenecarbonitrile
[1138] Example 90B (3 g, 16.4 mmole) in acetic anhydride (30 mL) at
0.degree. C. was treated with fuming HNO.sub.3 (1.2 mL), and the
resulting thick slurry was diluted with water (20 mL), stirred 20
min then filtered and dried in vacuo to provide 3.69 g of the title
compound as a yellow solid.
[1139] MS (DCI/NH.sub.3) m/e 246 (M+NH.sub.4).sup.+.
EXAMPLE 90D
7-Methoxy-8-amino-2-naphthonitrile
[1140] Example 90 C (3.69 g, 16.1 mmole) and 10% Pd/C (0.4 g) in
ethyl acetate (100 mL) was stirred under a hydrogen atmosphere for
2 h at room temperature, filtered and concentrated to provide 3 g
of the title compound as a yellow solid.
[1141] MS (DCI/NH.sub.3) m/e 217 (M+NH.sub.4).sup.+.
EXAMPLE 90E
Methyl [3-methoxy-6-cyano-4-naphthalenyl]carbamate
[1142] Example 90D (81 mg, 0.41 mmol) in dioxane (7 mL) and 10%
NaOH (15 mL) was treated with methyl chloroformate (112 mg. 0.98
mmol), stirred for 2 h, diluted with ethyl acetate, washed with
water, dried (MgSO.sub.4) and concentrated to provide 105 mg of the
title compound. MS (DCI/NH.sub.3) m/e 274 (M+NH.sub.3).sup.+.
EXAMPLE 90F
Methyl [3-methoxy-6-(aminoiminomethyl)-4-naphthalenyl]carbamate
mono(trifluoroacetate) salt
[1143] The title compound was prepared from Example 90E according
to the procedure of Example 40D. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6) .delta. 9.48 (s, 2H), .delta. 99 (s, 2H), 8.93 (br,
1H), 8.34 (s, 1H), 8.12 (d, 1H), 8.04 (d, 1H), 7.72 (d, 1H), 7.65
(dd, 1H), 3.95 (s, 3H);
[1144] MS (DCI/NH.sub.3) m/e 274 (M+H).sup.+;
[1145] Anal. calcd for C.sub.14H.sub.15N.sub.3O.sub.3.1.8TFA: C,
44.07; H, 3.53; N, 8.74. Found: C, 44.14; H. 3.20; N, 8.53.
EXAMPLE 91
7-Methoxy-8-[2-pyrimidinyl(amino)]-2-naphthalenecarboximidamide
bis(trifluoroacetate) salt
EXAMPLE 91A
7-Methoxy-8-[2-pyrimidinyl(amino)]-2-naphthalenecarbonitrile
[1146] A solution of Example 90D (230 mg, 1.2 mmole),
2-chloropyrimidine (280 mg, 2 mmole), sodium-tert-butoxide (120 mg,
1.2 mmole), Pd(dba).sub.3-CHCl.sub.3 and dppf in toluene (5 mL) was
heated in a sealed tube for 18 h at 100.degree. C., diluted with
ethyl acetate (100 mL), washed with brine, dried (MgSO.sub.4) and
concentrated to provide 100 mg of a brown oil.
[1147] MS (DCI/NH.sub.3) m/e 294 (M+NH.sub.4).sup.+.
EXAMPLE 91B
7-Methoxy-8-[2-pyrimidinyl(amino)1-2-naphthalenecarboximidamide
bis(trifluoroacetate) salt
[1148] The title compound was prepared in a manner analogous to
that of Example 40D. .sup.1H-NMR (300 MHz, DMSO-d6) .delta. 9.43
(s, 2H), 9.11 (s, 2H), 8.46 (s, 1H), 8.16 (br, 3H), 8.15 (d, 1H),
8.04 (d, 1H), 7.82 (dd, 1H), 7.75 (d, 1H), 7.54 (s, 1H) 7.50 (d,
1H), 4.08 (d, 2H);
[1149] MS (DCI/NH.sub.3) m/e 294 (M+H).sup.+.
[1150] Anal. calcd for C.sub.16H.sub.15N.sub.5O.3.8TFA: C, 39.01;
H, 2.61; N,9.64; Found: C, 39.01; H, 3.06; N, 9.63.
EXAMPLE 92
6-(aminoiminomethyl)-N-[4-(hydroxymethyl)phenyl]-2-naphthalenecarboxamide,
mono (trifluoroacetate)(salt)
EXAMPLE 92A
4-amino-benzyloxy-tert-butyldimethylsilyl ether
[1151] A solution of 4-aminobenzyl alcohol (1 g, 8.1 mmol) in DMF
(20 mL) was treated with imidazole (0.54 g, 8.1 mmol) and
tert-butyl dimethylsilyl chloride (1.22 g, 8.12 mmol), stirred
overnight at room temperature, diluted with ethyl acetate (100 mL),
washed with 1 N H.sub.3PO.sub.4, saturated NaHCO.sub.3 and 10%
NaCl, dried (Na.sub.2SO.sub.4) and concentrated to an oil which was
purified on silica gel with 3: 1 hexanes: ethyl acetate to provide
0.5 g of a clear oil.
[1152] MS m/z 238 (M+H).sup.+.
EXAMPLE 92B
[1153] Example 92A (0.3, 1.1 mmol) and 6-carboxy-2-naphthonitrile,
Example 8E (0.2 g, 1 mmol) were processed as described in Example
95C to provide 100 mg of the desired compound.
[1154] MS m/z 434 (M+NH.sub.4).sup.+.
EXAMPLE 92C
[1155] A solution of Example 92B in 1 M tetrabutyl ammonium
fluoride THF solution (2 mL) was stirred for 1 hour at room
temperature, quenched with 10% NH.sub.4Cl solution (50 mL) and
diluted with ethyl acetate (100 mL). The layers were separated, and
the organic layer was washed with 10% NaCl, dried (MgSO.sub.4) and
concentrated to provide a light brown oil which was triturated with
methylene chloride and filtered to provide 0.1 g of the desired
compound as a white solid.
[1156] MS m/z 320 (M+NH.sub.4).sup.+.
EXAMPLE 92D
6-(aminoiminomethyl-N-[4-(hydroxymethyl)phenyl
l-2-naphthalenecarboxamide mono(trifluoroacetate)(salt)
[1157] Example 92C (0.1 g, 0.33 mmol) was processed and purified
according to the procedure in Example 95D to provide 15 mg of the
desired compound.
[1158] MS m/z 320 (M+H).sup.+;
[1159] .sup.1H NMR 300 MHz, (DMSO-d.sub.6): .delta. 10.45 (s, 1H),
9.45 (bs, 4H), 8.75 (s, 1H), 8.59 (s, 1H), 8.32 (d, 1H), 8.22 (d,
1H), 8.18 (dd, 1H), 7.92 (dd, 1H), 7.85 (d, 2H), 7.45 (d, 2H), 4.20
(s, 2H);
[1160] Anal. calc'd for C.sub.19H.sub.17N.sub.3O.sub.2.TFA: C,
58.20; H, 4.19; N, 9.70. Found: C, 57.80; H, 3.91; N, 9.35.
EXAMPLE 93
6-(4-aminophenyl)-2-naphthalenecarboximidamide,
bis(trifluoroacetate) salt
EXAMPLE 93A
[1161] 6-cyano-2-naphthalene boronic acid (0.3 g, 1.64 mmol),
4-iodoaniline (0.36 g, 1.64 mmol), Palladium[1, 1'-Bis
(diphenylphosphino)-ferrocene] dichloride (0.13 g, 0.164 mmol) and
CsF (0.75 g, 4.92 mmol) are mixed together in DMF (8 mL) heated 20
hours. at 80.degree. C. The mixture is diluted with ethyl acetate
(100 mL) washed with 1 N H.sub.3PO.sub.4, saturated NaHCO.sub.3,
10% NaCl, dried over anhydrous sodium sulfate. The drying agent
filtered, solvent removed under vacuum leaving a brown solid. The
solid is purified on silica gel eluting with 3: 1 hexanes: ethyl
acetate. The fractions corresponding to the desired compound are
concentrated under vacuum leaving a yellow solid. 0.2 g, 75%.
[1162] MS (M+NH.sub.4.sup.+): 262.
EXAMPLE 93B
6-(4-aminophenyl)-2-naphthalenecarboximidamide,
bis(trifluoroacetate) salt
[1163] The desired compound is obtained from the material prepared
in Example 93A (0.1 g, 0.41 mmol) using the procedure described in
Example 94D Yield: 35 mg, 53%
[1164] MS (M+H).sup.+262;
[1165] .sup.1H NMR 300 MHz, (DMSO-d.sub.6): .delta. 9.45 (bs, 2H),
9.35 (bs, 2H), 8.45 (d, 1H), 8.22 (s, 1H), 8.15 (d, 1H), 8.10 (d,
1H), 7.99 (dd, 1H), 7.79 (dd, 1H), 7.65 (d, 2H), 6.95 (d, 2H), 4.80
(bs, 3H);
[1166] Anal. calc'd: C.sub.21H.sub.17N.sub.3O.sub.6F.sub.6: C,
51.54, H, 3.50, N, 8.59, Found: C, 51.95, H, 3.84.
EXAMPLE 95
methyl
2-[4-[[[6-(aminoiminomethyl)-2-naphthalenyl]carbonyl]amino]phenoxy]-
acetate, mono(trifluoroacetate) salt
EXAMPLE 95A
[1167] 4-Acetamidophenol (5 g, 33 mmol) is dissolved in THF (100
mL) treated with Cesium carbonate (10.25 g, 33 mmol) and Methyl
bromoacetate (3.4 mL, 36 mmol) and stirred 24 hours at room
temperature. The reaction mixture is diluted with water (100 mL)
and concentrated under vacuum. The residue is dissolved in ethyl
acetate (100 mL) washed with 1 N H.sub.3PO.sub.4 (20 mL), saturated
NaHCO.sub.3 (20 mL), 10% NaCl (20 mL) and dried over anhydrous
Na.sub.2SO.sub.4. The drying agent is filtered and the solvent
removed under vacuum leaving the desired compound as a white solid,
6.8 g, (92%).
[1168] MS (M+NH.sub.4.sup.+): 241.
EXAMPLE 95B
[1169] The material obtained in Example 95A is treated with 2 N HCl
(75 mL) and refluxed for 3 hours. The clear mixture is cooled to
room temperature then concentrated under vacuum to an off white
solid as the desired compound. 6 g, 92%.
[1170] MS (M+NH.sub.4.sup.+): 198.
EXAMPLE 95C
[1171] 6-carboxy-2-naphthonitrile (0.1 g, .51 mmol) is dissolved in
DMF (5 mL) cooled in an ice bath to 5.degree. C. To the homogeneous
mixture is added Diisopropylethylamine (0.18 mL, 1.05 mmol) and
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU). The resultant slurry is stirred at
5.degree. C. 45 minutes. To this slurry is added the material
obtained in Example 95B (0.12 g, 0.56 mmol) and the mixture is
stirred at room temperature overnight. The next day, the reaction
mixture is diluted with ethyl acetate (100 mL) washed with 1 N
H.sub.3PO.sub.4 (20 mL), saturated NaHCO.sub.3 (20 mL), 10% NaCl,
dried over anhydrous Na.sub.2SO.sub.4 filtered and solvent removed
under vacuum yielding the desired compound as a brown solid. 0.28
g, 65%.
[1172] MS (M+NH.sub.4)+:378.
EXAMPLE 95D
methyl
2-[4-[[6-(aminoiminomethyl)-2-naphthalenyl]carbonyl]amino]phenoxy]a-
cetate, mono(trifluoroacetate) salt
[1173] The material obtained in Example 95C (0.28 g, 0.78 mmol) is
dissolved in methanol saturated with HCl (g) (30 mL) stirred 18
hours at room temperature. The solvent removed under vacuum and the
resultant yellow solid is treated with 2 M NH.sub.3/methanol (20
mL). This solution is refluxed 6 hours, cooled, solvent removed
under vacuum and the resulting brown solid is purified by reverse
phase HPLC. The desired compound is obtained from lyophilization.
19.3 mg, 20%.
[1174] MS (M+H).sup.+: 378
[1175] .sup.1HNMR 300 MHz, (DMSO-d.sub.6): .delta. 10.45 (s, 1H),
9.45 (bs, 4H), 8.65 (d, 1H), 8.59 (s, 1H), 8.15 (d, 1H), 8.10 (d,
1H), 8.08 (d, 1H), 7.92 (d, 1H), 7.75 (d, 2H), 6.98 (d, 2H), 4.80
(s, 2H), 3.75 (s, 3H),
[1176] Anal. calc'd: C.sub.23H.sub.21N.sub.3O.sub.6F.sub.3: C,
56.10, H, 4.3, N, 8.53, Found: C, 55.80, H, 3.93, N, 8.33.
EXAMPLE 96
(E)-6-[2-[(3-hydroxymethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide
mono(trifluoroacetate)(salt)
EXAMPLE 96A
[1177] The above was prepared from 3-iodobenzyl alcohol using the
procedure in Example 41A.
[1178] MS (DCI/NH.sub.3) m/z (M+NH.sub.3).sup.+303.
EXAMPLE 96B
(E)-6-[2-[(3-hydroxymethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
[1179] The above was prepared from Example 96A using method from
Example 40D.
[1180] MS (DCI/NH.sub.3) m/z (M+H).sup.+303;
[1181] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.18 (br, 4H),
8.45 (s, 1H), 8.17 (s, 1H), 8.13-8.04 (m, 3H), 7.81 (dd, 1H), 7.64
(s, 1H), 7.57 (d, 2H), 7.51 (d, 1H) 7.39 (t, 1H), 7.28 (d, 1H),
5.27 (t, 1H), 4.55 (d, 2H);
[1182] Anal. calc'd for C.sub.22H.sub.19N.sub.2O.sub.3F.sub.33/10
TFA: C, 60.64; H, 4.35; N, 6.28. Found: C, 60.53; H, 4.87; N,
6.57.
EXAMPLE 97
6-(2-phenyl-1-cyclopropyl)-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
EXAMPLE 97A
[1183] Copper (I) chloride (43 mg, 0.4 mmol), powdered zinc (26 mg,
0.4 mmol) were suspended in 1 mL dioxane for 18 hours. The product
from Example 41B (60 mg, 0.2 mmol) was added and stirred and heated
at 95.degree. C. for 20 hours. The reaction mixture was
concentrated on silica gel and purified by silica gel
chromatography to give the desired compound.
[1184] MS (DCI/NH.sub.3) m/z (M+NH.sub.3).sup.+287.
EXAMPLE 97B
6-(2-phenyl- -cyclopropyl)-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
[1185] The above was prepared from Example 1 using method from
Example 1B.
[1186] MS (DCI/NH.sub.3) m/z (M+H).sup.+287;
[1187] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.41 (s, 2H),
9.16 (s, 2H), 8.46 (s, 1H), 7.83 (d, 2H), 7.62 (s, 1H), 7.58 (dd,
1H), 7.34 (dd, 1H), 7.35-7.29 (m, 3H), 7.25-7.17 (m, 2H) 2.38-2.28
(m, 2H), 1.61 (t, 2H);
[1188] Anal. calc'd for C.sub.22H.sub.19N.sub.2O.sub.2F.sub.31/10
TFA: C, 65.00; H, 4.70; N, 6.84. Found: C, 65.22; H, 5.23; N,
5.10.
EXAMPLE 98
(E)-6-[2-[
4-(aminomethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,
bis(trifluoroacetate)(salt)
EXAMPLE 98A
[1189] The desired compound was prepared using ethene under 500 atm
pressure in a manner; Analagous to that of Example 41A.
[1190] MS (DCI/NH.sub.3) m/z (M+NH.sub.3).sup.+197.
EXAMPLE 98B
[1191] 4-(Aminomethyl)-iodobenzene hydrochloride (1 g, 3.7 mmol)
and Boc anhydride (1.22 g, 5.6 mmol) were mixed with 10% NaOH (15
mL), ethyl acetate (20 mL) and stirred 2 hours. The organic layer
was washed with 5% sodium bicarbonate (2x, 10 mL), dried (magnesium
sulfate), and concentrated to give 1.22 g of desired compound.
[1192] MS (DCI/NH.sub.3) m/z (M+NH.sub.3).sup.+351.
EXAMPLE 98C
[1193] The desired compound was prepared using the product from
Example s 98A and 98B in a manner analagous to that of Example
41A.
[1194] MS (DCI/NH.sub.3) m/z (M+NH.sub.3).sup.+402.
EXAMPLE 98D
(E)-6-[2-[4-(aminomethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,
bis(trifluoroacetate)(salt)
[1195] The above product was prepared in a manner analogous to that
of Example 40D with the addition of trifluoroacetic acid in
methylene chloride to remove the Boc group.
[1196] MS (DCI/NH.sub.3) m/z (M+H).sup.+302;
[1197] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.43 (s, 2H),
9.11 (s, 2H), 8.46 (s, 1H), 8.16 (br, 3H), 8.15 (d, 1H), 8.04 (d,
1H), 7.82 (dd, 1H), 7.75 (d, 1H), 7.54 (s, 1H) 7.50 (d, 1H), 4.08
(d, 2H);
[1198] Anal. calc'd for C.sub.24H.sub.21N.sub.3O.sub.4F.sub.62/5
TFA: C, 50.46; H, 3.63; N, 6.99. Found: C; 50.37; H, 3.86; N,
7.05.
EXAMPLE 99
methyl [7-(aminoiminomethyl)-2-methoxy-I-naphthalenyl)carbamate,
mono(trifluoroacetate)(salt)
[1199] The desired compound was prepared using material prepared as
described in Example 90D and utilizing the procedures described in
Example 91A and Example 40D.
[1200] MS (DCI/NH.sub.3) m/z (M+H).sup.+306;
[1201] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.33 (s, 2H),
8.98 (s, 2H), 8.63 (s, 1H), 7.99 (d, 1H), 7.60 (dd, 1H), 7.58 (s,
1H), 7.54 (d, 1H), 7.35-7.20 (m, 5H), 4.52 (s, 2H);
[1202] Anal. calc'd for C.sub.21H.sub.20N.sub.3O.sub.3F.sub.313/5
TFA: C, 44.03; H, 3.19; N, 5.89. Found: C; 43.97; H, 3.55; N,
6.10.
EXAMPLE 100
7-methoxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,
bis(trifluoroacetate)(salt)
[1203] The desired compound was prepared using material prepared as
described in Example 90D and utilizing the procedures described in
Example 91A and Example 40D.
[1204] MS (DCI/NH.sub.3) m/z (M+H).sup.+322;
[1205] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.35 (s, 2H),
8.90 (s, 2H), 8.34 (s, 1H), 8.11 (d, 1H), 7.90 (d, 1H), 7.72 (d,
1H), 7.60 (dd, 1H), 7.47 (s, 2H), 6.70 (d, 2H) 6.49 (d, 2H), 3.88
(s, 3H), 3.64 (s, 3H);
[1206] Anal. calc'd for C.sub.21H.sub.20N.sub.3O.sub.4F.sub.31/10
TFA: C, 56.90; H, 4.53; N, 9.38. Found: C; 56.88; H, 4.41; N,
9.43.
EXAMPLE 101
7-methoxy-8-[(phenylmethyl)amino]-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
EXAMPLE 101A
4-Bromostyrene (4.8 g, 26.2 mmol) was dissolved in 100 mL THF and
cooled to -78.degree. C.
[1207] Butyl lithium (2.5 M in hexanes, 28.8 mmol) was added
dropwise and stirred 5 minutes. Iodine in THF was added dropwise
until an orange/red color persisted. Concentrated aqueous ammonium
chloride (20 mL) was added and the reaction was warmed to room
temperature, diluted with ether, washed with 10%
Na.sub.2S.sub.2O.sub.5 solution (1x, 50 mL), and brine (1x, 50 mL),
dried (magnesium sulfate), and concentrated to give the desired
compound.
[1208] MS (DCI/NH.sub.3) m/z 122.
EXAMPLE 101B
[1209] The product from 104A (2.35 g, 10.2 mmol), 1.6 mL 60%,
N-methylmorphiline-N-oxide/water solution, 3.75 mL acetone, 0.1 mL
water were stirred 1 hour. 20 mL Osmium tetroxide/tert-butanol
solution (0.02 mmol/mL) was added and stirred at 0.degree. C. for
20 hours. The reaction was concentrated on silica gel and purified
by silica gel chromatography to give the desired compound.
[1210] MS (DCI/NH.sub.3) m/z (M+NH.sub.3).sup.+282.
EXAMPLE 110C
[1211] The desired compound from Example 104B is coupled using
Method 41A.
[1212] MS (DCI/NH.sub.3) m/z (M+NH.sub.3).sup.+333.
EXAMPLE 10D
7-methoxy-8-[(phenylmethyl)amino]-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
[1213] The above was prepared from Example 104C using method
described in Example 40D.
[1214] MS (DCI/NH.sub.3) m/z (M+H).sup.+333;
[1215] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.42 (s, 2H),
9.12 (s, 2H), 8.45 (s, 1H), 8.15-8.05 (m, 4H), 7.81 (dd, 1H), 7.63
(d, 2H), 7.48 (d, 2H), 7.39 (d, 2H), 4.56 (t, 1H), 3.45 (d,
2H);
[1216] Anal. calc'd for C.sub.23H.sub.21N.sub.2O.sub.4F.sub.32/5
TFA: C, 58.19; H, 4.39; N, 5.71. Found: C, 58.17; H, 4.41; N,
5.87.
EXAMPLE 102
7-methoxy-8-(phenylamino)-2-naphthalenecarboximidamide
mono(trifluoroacetate)(salt)
EXAMPLE 102A
[1217] Tert-butylcarbamate (3.62 g, 15.7 mmol) was dissolved in 63
mL propanol. 118 mL NaOH/water solution (0.4 N), tert-butyl
hypochlorite (5.5 mL, 47.8 mmol), and (DHQD).sub.2PHAL (612 mg,
0.61 mmol) in 50 mL propanol were added and stirred 10 minutes. The
product from Example 2 (3.62 g, 15.7 mmol), and K.sub.2OsO.sub.4-2
water (211 mg, 0.63 mmol) were added and stirred 24 hours. The
reaction was concentrated and recrystallized from ethanol/hexanes
to give the desired compound.
[1218] MS (DCI/NH.sub.3) m/z (M+NH.sub.3).sup.+381.
EXAMPLE 102B
[1219] The above was prepared from Example 102 using the method
described in Example 41A.
[1220] MS (DCI/NH.sub.3) m/z (M+H).sup.+415.
EXAMPLE 102C
7-methoxy-8-(phenylamino)-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
[1221] The above was prepared from Example 102B using the method
described in Example 94D.
[1222] MS (DCI/NH.sub.3) ml/z (M+H).sup.+264;
[1223] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.42 (s, 2H),
9.07 (s, 2H), 8.45 (s, 1H), 8.33 (br, 3H), 8.16-8.03 (m, 4H) 7.75
(d, 2H), 7.56 (s, 2H), 7.49 (d, 2H), 5.49 (br 1 h), 4.28 (br 1H),
3.62 (m, 2H);
[1224] Anal. calc'd for C.sub.25H.sub.23N.sub.3O.sub.5F.sub.6.5
TFA: C, 37.30; H, 2.51; N, 3.74. Found: C; 37.06; H13.12; N,
4.42.
EXAMPLE 103
7-methoxy-8-[(4-methoxyphenyl)amino]-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
EXAMPLE 103A
[1225] 4-Bromobenzaldehyde (600 mg, 3.24 mmol), 16.2 mL
dimethylamine in THF (32.4 mmol), and sodium triacetoxyborohydride
(1.24 g, 5.8 mmol) were suspended in dichloroethane (10 mL). The
reaction mixture was concentrated, diluted with water acidified to
pH=2 and extracted with ether (3.times., 20 mL). The aqueous
solution was basified with NaOH/water to pH=12 and extracted with
methylene chloride (3.times., 30 mL, acidified with HCl/methanol
and concentrated to give the desired compound.
[1226] MS (DCI/NH.sub.3) m/z (M).sup.+214.
EXAMPLE 103B
[1227] The above was prepared from Example 107A using method from
Example 41A.
[1228] MS (DCI/NH.sub.3) m/z (M+H).sup.+313.
EXAMPLE 103C
7-methoxy-8-[(4-methoxyphenyl)amino]-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
[1229] The above was prepared from Example 103 using method from
Example 40D.
[1230] MS (DCI/NH.sub.3) m/z (M+H).sup.+294;
[1231] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.43 (s, 2H),
9.11 (s, 2H), 8.46 (s, 1H), 8.18-8.06 (m, 4H), 7.84 (d, 4H), 7.60
(s, 2H), 7.56 (s, 1H), 4.53 (s, 2H), 3.05 (s, 6H);
[1232] Anal. calc'd for C.sub.26H.sub.25N.sub.3O.sub.4F.sub.67/5
TFA: C, 48.46; H, 3.73; N, 5.91. Found: C, 48.36; H, 4.25; N,
6.19.
EXAMPLE 104
(E)-6-[2-[4-(1,2-dihydroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidami-
de, mono(trifluoroacetate)(salt)
EXAMPLE 104A
[1233] The above was prepared from 4-bromobenzyl alcohol and the
compound prepared in Example 98A using the method from Example
41A.
[1234] MS (DCI/NH.sub.3) m/z (M+NH.sub.3).sup.+303.
EXAMPLE 104B
(E)-6-[2-[4-(1,2-dihdyroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidami-
de, mono(trifluoroacetate)(salt)
[1235] The above was prepared from Example 104A using method from
Example 40D.
[1236] MS (DCI/NH.sub.3) m/z (M+H).sup.+303;
[1237] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.00 (br, 4H),
8.44 (s, 1H), 8.15-8.01 (m, 4H), 7.81 (dd, 1H), 7.64 (d, 2H), 7.48
(d, 1H), 7.36 (d, 2H), 5.21 (br, 1H) 4.53 (s, 2H);
[1238] Anal. calc'd for C.sub.22H.sub.19N.sub.2O.sub.3F.sub.34/5
TFA: C, 55.84; H, 3.93; N, 5.52. Found: C, 55.60; H, 3.93; N,
6.41.
EXAMPLE 105
(E)-6-[2-[4-(1R-amino-2-hydroxyethyl)phenyy]ethenyl]-2-naphthalenecarboxim-
idamide, bis(trifluoroacetate)(salt)
EXAMPLE 105A
[1239] Using the procedure described for Example 121 A, and
substituting N-BOC-p-iodophenylalanine (BACHEM Bioscience Inc.) for
4-iodoaniline, the desired compound was obtained.
[1240] MS (DCI/NH.sub.3) m/z 458 (M+NH.sub.4).sup.+;
[1241] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.35 (s, 9H), 2.90
(t, 1H), 3.09 (dd, 1H), 4.15 (m, 1H), 7.20 (d, 1H), 7.36 (d, 2H),
7.56 (d, 2H), 7.78 (d, 1H), 7.85 (d, 1H), 8.12 (d, 1H), 8.17 (d,
1H), 8.32 (s, 1H), 8.62 (s, 11H).
EXAMPLE 105B
[1242] Using the product obtained in Example 105A and the procedure
described in Example 40D the desired compound was obtained.
[1243] MS (ESI) m/z 458 (M+H).sup.+;
[1244] .sup.1H NMR (300 MHz, DMSO) .delta. 1.35 (s, 9H), 2.90 (dd,
1H), 3.10 (dd, 1H), 4.13 (m, 1H), 7.10 (d, 1H), 7.36 (d, 2H), 7.55
(d, 2H), 7.78 (dd, 1H), 7.85 (dd, 1H), 8.13 (d, 1H), 8.19 (d, 1H),
8.30 (s, 1H), 8.50 (s, 11H), 9.22 (s, 2H), 9.42 (s, 2H).
EXAMPLE 105C
(E)-6-[2-[4-(1R-amino-2-hydroxyethyl)phenyl]ethenyl]-2-naphthalenecarboxim-
idamide, bis(trifluoroacetate)(salt)
[1245] Using the product obtained in Example 105B and the procedure
described for Example 124D, the desired compound was obtained.
[1246] MS (ESI) m/z 358 (M+H).sup.+;
[1247] .sup.1H NMR (300 MHz, DMSO) .delta. 3.02 (m, 1H), 3.19 (dd,
1H), 3.63 (t, 1H), 7.39 (d, 2H), 7.58 (d, 2H), 7.76 (d, 1H), 7.88
(d, 1H), 8.15 (d, 1H), 8.19 (d, 1H), 8.30 (s, 1H), 8.51 (s, 1H),
9.41 (s, 2H), 9.80 (s, 2H);
[1248] Anal. calc'd for
C.sub.24H.sub.20F.sub.3N.sub.3O.sub.4H.sub.2O: C, 58.90; H, 4.53;
N, 8.59. Found: C, 58.75; H, 4.22; N, 8.28.
EXAMPLE 106
7-methoxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,
bis(trifluoroacetate)(salt)
EXAMPLE 106A
[1249] Sodium borohydride (0.22 g, 5.8 mmol) was added to a
suspension of (4-bromobenzoyl)methanol (2.5 g, 11.6 mmol, Maybridge
Chem. Co.) and 25 mL abs. ethanol. The reaction mixture was stirred
at reflux for 1 hour. After cooling to room temperature, the
ethanol was evaporated under vacuum, and water was added to the
residue. The mixture was extracted with CH.sub.2Cl.sub.2. The
extracts were washed with saturated aqueous sodium chloride, dried
over MgSO.sub.4, filtered, and evaporated under vacuum to afford
the desired compound.
[1250] MS (DCI/NH.sub.3) m/z 234/236 (M+NH.sub.4).sup.+;
[1251] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.10 (t, 1H), 2.62
(d, 1H), 3.63 (m, 1H), 3.78 (m, 1H), 4.81 (m, 1H), 7.25 (d, 2H),
7.50 (d, 2H).
EXAMPLE 106B
[1252] Using the product obtained in Example 106A and the procedure
described in Example A-226218-A, the desired compound was
obtained.
[1253] MS (DCI/NH.sub.3) m/z 331 (M+NH.sub.4).sup.+;
[1254] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.45 (t, 1H), 4.59
(q, 1H), 4.76 (t, 1H), 5.36 (d, 1H), 7.42 (d, 2H), 7.59 (d, 2H),
7.78 (dd, 1H), 7.85 (dd, 1H), 8.10 (d, 1H), 8.15 (d, 1H), 8.30 (s,
1H), 8.61 (s, 1H).
EXAMPLE 106C
7-methoxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,
bis(trifluoroacetate)(salt)
[1255] Using the product obtained in Example 106B, and the
procedure described in Example 40D, the desired compound was
obtained.
[1256] MS (ESI) m/z 331 (M+H).sup.+;
[1257] .sup.1H NMR (300 MHz, DMSO) .delta. 3.45 (t, 1H), 4.59 (q,
1H), 4.78 (t, 1H), 5.38 (d, 1H), 7.42 (d, 2H), 7.59 (d, 2H), 7.78
(dd, 1H), 7.84 (dd, 1H), 8.12 (d, 1H), 8.18 (d, 1H), 8.31 (s, 1H),
8.50 (s, 1H), 9.20 (s, 2H), 9.43 (s, 2H);
[1258] Anal. calc'd for
C.sub.23H.sub.19F.sub.3N.sub.2O.sub.4H.sub.2O: C, 59.74; H, 4.58;
N, 6.06. Found: C, 59.95; H, 4.17; N, 6.13.
EXAMPLE 107
(E)-6-[2-[[4-(dimethylamino)methyl]phenyl]ethenyl]-2-naphthalenecarboximid-
amide, bis(trifluoroacetate)(salt)
EXAMPLE 107A
[1259] Using the procedure described for Example 121A, and
substituting 3-benzyloxybromobenzene (Chem. Ber.124 (1), 163, 1991)
for 4-iodoaniline, the desired compound was obtained.
[1260] MS (DCI/NH.sub.3) m/z 377 (M+NH.sub.4).sup.+; .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 5.11 (s, 2H), 7.02 (d, 1H), 7.20 (m,
2H), 7.29 (d, 1H), 7.31 (d, 1H), 7.42 (m, 3H), 7.60-7.75 (m, 3H),
7.89 (t, 2H), 8.08 (s, 1H), 8.21 (s, 1H).
EXAMPLE 107B
(E)-6-[2-[[4-(dimethylamino)methyl]phenyl]ethenyl1-2-naphthalenecarboximid-
amide, bis(trifluoroacetate)(salt)
[1261] Using the product obtained in Example 108B, and the
procedure described in Example 40D, the desired compound was
obtained.
[1262] MS (ESI) m/z 377 (M+H).sup.+;
[1263] .sup.1H NMR (300 MHz, DMSO) .delta. 5.18 (S, 2H), 7.12 (dd,
1H), 7.22 (d, 1H), 7.28 (m, 1H), 7.40 (t, 3H), 7.45 (t, 3H), 7.79
(dd, 1H), 7.85 (dd, 1H), 8.16 (d, 1H), 8.20 (d, 1H), 8.35 (s, 1H),
8.50 (s, 1H), 9.30 (s, 1H);
[1264] Anal. calc'd for C.sub.28H.sub.21F.sub.3N.sub.2O.sub.3.0.25
H.sub.20: C, 67.94; H, 4.38; N, 5.66. Found: C, 67.80; H, 4.48; N,
5.43.
EXAMPLE 108
(E)-6-[2-[4-(hydroxymethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
[1265] Using the product obtained in Example 108A and the procedure
described in Example 94D the desired compound was obtained.
[1266] MS (ESI) m/z 287 (M+H).sup.+;
[1267] .sup.1H NMR (300 MHz, DMSO) .delta. 6.89 (m, 1H), 6.98 (t,
1H), 7.03 (d, 1H), 7.29 (t, 1H), 7.78 (dd, 1H), 7.88 (dd, 1H), 8.13
(d, 1H), 8.17 (d, 1H), 8.32 (s, 1H), 8.50 (s, 1H), 9.40 (s,
5H);
[1268] Anal. calc'd for C.sub.21H.sub.15F.sub.3N.sub.2O.sub.3.0.5
H.sub.20: C, 61.62; H, 3.94; N, 6.84. Found: C, 61.29; H, 3.81; N,
6.59.
EXAMPLE 109
4-[[6-(aminoiminomethyl)-2-naphthalenyl]ethynyl]-L-phenylalanine,
mono (trifluoroacetate)(salt)
EXAMPLE 109A
[1269] To a solution of the product from Example 8D (2.13 g, 10.08
mmol) and LiBH.sub.4 (121 mg, 5.55 mmol) in THF (5 mL) was added
toluene (2 mL), and the THF was boiled off using a short-path
distillation apparatus over several hours. The reaction was then
heated at 70.degree. C. for 2 hours, cooled, quenched with 1 M HCl,
and extracted with 2x ethyl acetate. The extracts were washed with
water and brine, dried over Na.sub.2SO.sub.4, and condensed. The
crude product was chromatographed on SiO.sub.2 using 50% ethyl
acetate/hexanes as eluent, to yield 1.12 g (61%) of the desired
compound.
[1270] MS (DCI (NH.sub.3)) m/z 201 (M+NH.sub.4).sup.+;
[1271] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.22 (s, 1H), 7.90
(m, 3H), 7.61 (m, 2H), 4.92 (d, 2H), 1.84 (t, 1H).
EXAMPLE 109B
[1272] To a solution of the product from Example 109A (2.12 g,
11.57 mmol) and LiBr (1.11 g, 12.73 mmol) in DMF (100 mL) was added
PBr.sub.3 (1.21 mL, 12.73 mmol) at 0.degree. C., and the reaction
was warmed to room temperature, and stirred for 1 hours. The
reaction was then quenched with pH 7 buffer, and extracted with
3.times.diethyl ether/hexanes. The extracts were washed with
2.times.water and 2.times.brine, dried over Na.sub.2SO.sub.4, and
condensed, to yield 2.72 g (96%) of the desired compound.
[1273] MS (DCI (NH.sub.3)) m/z 185 (M+NH.sub.4-Br).sup.+;
[1274] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.22 (s, 1H), 7.92
(s, 1H), 7.90 (s, 2H), 7.62 (dd, 2H), 4.64 (s, 2H).
EXAMPLE 109C
[1275] To a solution of NaH (60% in mineral oil, 44 mg, 1.1 mmol)
in DMF (5 mL) was added 4-ethylphenol (122 mg, 1.0 mmol), and the
reaction was stirred at room temperature for 20 minutes. The
product from Example 109B (270 mg, 1.1 mmol) was then added, and
the reaction was stirred for 10 minutes. The crude reaction mixture
was chromatographed on SiO.sub.2 using hexanes as eluent, to yield
220 mg (77%) of the desired compound.
[1276] MS (DCI (NH.sub.3)) m/z 305 (M+NH.sub.4).sup.+;
[1277] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.22 (s, 1H), 7.95
(s, 1H), 7.93 (s, 1H), 7.91 (s, 1H), 7.66 (dd, 1H), 7.61 (dd, 1H),
7.15 (d, 2H), 6.94 (d, 2H), 5.22 (d, 2H), 2.60 (q, 2H), 1.21 (t,
3H).
EXAMPLE 109D
4-[[6-(aminoiminomethyl)-2-naphthalenyl]ethynyl]-L-phenylalanine,
mono(trifluoroacetate)(salt)
[1278] The desired compound was prepared from Example 109C and the
procedure of Example 55D.
[1279] MS (DCI/NH.sub.3) m/z 305 (M+H).sup.+;
[1280] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.15 (t, 3H),
2.14 (s, 3H), 2.56 (q, 2H), 5.30 (s, 2H), 6.98 (d, 2H), 7.14 (d,
2H), 7.74 (dd, 1H), 7.82 (dd, 1H), 8.15 (m, 3H), 8.48 (s, 1H), 9.01
(br s, 2H), 9.62 (br s, 2H);
[1281] Anal. calc'd for C.sub.20H.sub.20N.sub.2O.1.4
CH.sub.4SO.sub.3: C, 58.56; H, 5.88; N, 6.38. Found: C, 58.55; H,
5.56; N, 6.39.
EXAMPLE 111
6-(3-formylphenyl)-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(sa- lt)
EXAMPLE 111A
[1282] The product from Example 28B (334 mg, 1.11 mmol), palladium
acetate (25 mg, 0.11 mmol), dppf (123 mg, 0.22 mmol) were dissolved
in degassed DMF (5 mL) and stirred at room temperature for 1/2
hour. Cesium carbonate (902 mg, 2.8 mmol) and 2-formylphenylboronic
acid (251 mg, 1.27 mmol) were added and stirred under nitrogen at
80.degree. C. for 1 hour, poured into pH 7 buffer, extrated with
diethyl ether (3.times., 20 mL), and dried. The desired compound
was purified by chromotography eluting with 10% ethyl acetate/
hexanes.
[1283] MS (DCI/NH.sub.3) m/z (M+NH.sub.3).sup.+275.
EXAMPLE 111B
6-(3-formylphenyl)-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(sa- lt)
[1284] The above product was prepared in a manner analogous to that
of Example 1B.
[1285] MS (DCI/NH.sub.3) m/z (M+H).sup.+274;
[1286] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 10.16 (s, 1H),
9.47 (s, 2H), 9.10 (s, 2H), 8.54 (s, 1H), 8.52 (s, 1H), 8.41 (s,
1H), 8.28-8.23 (m, 3H), 8.12 (dd, 1H), 8.00 (dd, 1H), 7.87 (dd,
1H), 7.80 (t, 1H);
[1287] Anal. calc'd for C.sub.20H.sub.15N.sub.2O.sub.3F.sub.32/5
TFA: C, 59.28; H, 3.70; N, 6.34. Found: C; 59.36; H, 3.89; N,
7.21.
EXAMPLE 112
(E)-6-[2-(1,2,3,4-tetrahydro-6-isoquinolinyl)ethenyl]-2-naphthalenecarboxi-
midamide, bis(trifluoroacetate)(salt)
EXAMPLE 112A
[1288] The above was prepared from Example 127 using method
described in Example 41A.
[1289] MS (DCI/NH.sub.3) m/z (M+H).sup.+411.
EXAMPLE 112B
(E)-6-[2-(1,2,3,4-tetrahydro-6-isoquinolinyl)ethenyl]-2-naphthalenecarboxi-
midamide, bis(trifluoroacetate)(salt)
[1290] The desired compound was prepared by the method described in
Example 40D.
[1291] MS (DCI/NH.sub.3) m/z (M+H).sup.+328;
[1292] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.36 (s, 2H),
9.25 (s, 2H), 9.10 (d, 2H), 8.41 (s, 1H), 7.99 (t, 2H), 7.89 (d,
1H), 7.78 (d, 1H), 7.71 (dd, 1H), 7.56 (m, 4H), 7.43 (s, 1H), 3.11
(br, 2H) 2.16 (br 2H), 1.78 (br, 2H);
[1293] Anal. calc'd for C.sub.26H.sub.23N.sub.3O.sub.4F.sub.63/5
TFA: C, 52.31; H, 3.81; N, 6.72. Found: C, 52.13; H, 4.42; N,
7.23.
EXAMPLE 113
(E)-6-[2-[3-(2-hydroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
EXAMPLE 113A
[1294] The above was prepared from 2-bromo-3 (hydroxyethyl)alcohol
and the compound prepared in Example 98A using method described in
Example 41A.
[1295] MS (DCI/NH.sub.3) m/z (M+NH.sub.3).sup.+317.
EXAMPLE 113B
(E)-6-[2-[3-(2-hydroxyethyl)phenyl]ethenyl]-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
[1296] The above was prepared from Example 113A using method
described in Example 40D.
[1297] MS (DCI/NH.sub.3) m/z (M+H).sup.+317;
[1298] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 8.9 (br, 4H),
8.46 (s, 1H), 8.17 (s, 1H), 8.13-8.03 (m, 3H), 7.82 (dd, 1H), 7.54
(s, 2H), 7.49 (s, 2H), 7.33 (t, 1H) 7.18 (d, 1H), 4.71 (t, 1H),
3.66 (m, 2H), 2.78 (t, 2H);
[1299] Anal. calc'd for C.sub.23H.sub.21N.sub.2O.sub.3F.sub.33/10
TFA: C, 61.41; H, 4.66; N, 6.09. Found: C, 64.18; H, 4.92; N,
6.51.
EXAMPLE 114
6-(aminoiminomethyl)-4-(3-furanyl)-N-[4-(trifluoromethyl)phenyl]-2-naphtha-
lenecarboxamide, mono(trifluoroacetate)(salt)
EXAMPLE 114A
[1300] The product from Example 152B (100 mg, 0.36 mmol),
4-(trifluoromethyl)aniline (86 mg, 0.53 mmol), and DMAP (5 mg, 0.04
mmol) were dissolved in THF (5 mL) and stirred for 24 hours. The
reaction mixture was concentrated on silica gel and purified by
chromotography (Biotage Flash 40) using ethyl acetate/hexanes.
[1301] MS (ESI) m/z (M+H).sup.+406.
EXAMPLE 114B
6-(aminoiminomethyl)-4-(3-furanyl)-N-[4-(trifluoromethyl)phenyl]-2-naphtha-
lenecarboxamide, mono(trifluoroacetate)(salt)
[1302] The above was prepared from Example 114A using method
described in Example 1B.
[1303] MS (CI) m/z (M+H).sup.+424;
[1304] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 10.91 (s, 1H),
9.51 (s, 2H), 9.11 (s, 2H), 8.69 (s, 1H), 8.62 (s, 1H), 8.43-8.35
(m, 2H), 8.18 (d, 1H), 8.06 (d, 2H), 7.98 (t, 1H), 7.92 (dd, 1H),
7.78 (dd, 2H) 7.14 (m, 1H);
[1305] Anal. calc'd for C.sub.25H.sub.17N.sub.3O.sub.4F.sub.61/10
TFA: C, 55.37; H, 3.15; N, 7.70. Found: C, 55.44; H, 3.15; N, 7.3
1.
EXAMPLE 115
6-(aminoiminomethyl)-4-(3-furanyl)-N-(4-pyridinyl)-2-naphthalenecarboxamid-
e dihydrochloride
EXAMPLE 115A
[1306] The above product was prepared in the manner of Example
114A.
[1307] MS (ESI) m/z (M+H).sup.+340.
EXAMPLE 115B
6-(aminoiminomethyl)-4-(3-furanyl)-N-(4-pyridinyl)-2-naphthalenecarboxamid-
e, dihydrochloride
[1308] The above was prepared from Example 115A using method
described in Example 1 B.
[1309] MS (AP/CI) m/z (M+H).sup.+357;
[1310] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 12.43 (s, 1H),
9.69 (s, 2H), 9.40 (s, 2H), 8.94 (s, 1H), 8.81 (d, 2H), 8.65 (s,
1H), 8.58-8.56 (m, 2H), 8.49 (s, 1H), 8.42 (d, 1H), 8.30 (m, 1H)
7.97-7.95 (m, 2H), 7.27 (s, 1H);
[1311] Anal. calc'd for C.sub.21H.sub.18N.sub.4O.sub.2Cl.sub.237/10
HCl: C, 44.65 H, 3.88 N, 9.92. Found: C, 44.72; H, 3.70; N,
9.51.
EXAMPLE 116
6-(aminoiminomethyl)-4-(3-furanyl)-N-(1H-pyrazol-3-yl)-2-naphthalenecarbox-
amide, dihydrochloride
EXAMPLE 116A
[1312] The above product was prepared in the manner of Example
114A.
[1313] MS (ESI) m/z (M+H).sup.+329.
EXAMPLE 116B
6-(aminoiminomethyl)-4-(3-furanyl)-N-(1H-pyrazol-3-yl)-2-naphthalenecarbox-
amide, dihydrochloride
[1314] The above was prepared from Example 116A using method
described in Example 1B.
[1315] MS (CI) m/z (M-H).sup.+344;
[1316] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 11.16 (s, 1H),
9.52 (s, 2H), 9.10 (s, 2H), 8.69 (s, 1H), 8.61 (s, 1H), 8.35 (m,
2H), 8.24 (s, 1H), 7.96-7.88 (m, 3H), 7.69 (m, 1H), 7.15 (s, 1H)
6.69 (m, 1H);
[1317] Anal. calc'd for C.sub.19H.sub.17N.sub.5O.sub.2Cl.sub.29/10
HCl: C, 50.63; H, 4.00; N, 15.54. Found: C, 51.05; H, 4.62; N,
14.26.
EXAMPLE 117
6-(aminoiminomethyl)-4-(3-furanyl)-N-(3-pyridinyl)-2-naphthalenecarboxamid-
e, dihydrochloride
EXAMPLE 117A
[1318] The above product was prepared in the manner of Example
114A.
[1319] MS (ESI) m/z (M+H).sup.+340.
EXAMPLE 117B
6-(aminoiminomethyl)-4-(3-furanyl)-N-(3-pyridinyl)-2-naphthalenecarboxamid-
e, dihydrochloride
[1320] The above was prepared from Example 117B using method
described in Example 1 B.
[1321] MS (CI) m/z (M+H).sup.+357;
[1322] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 10.90 (s, 1H),
9.59 (s, 2H), 9.26 (s, 2H), 9.03 (s, 2H), 8.74 (s, 1H), 8.63 (s,
1H), 8.42-8.26 (m, 3H), 8.22 (s, 1H), 7.97-7.91 (m, 2H), 7.47-7.43
(m, 2H), 7.17 (s, 1H);
[1323] Anal. calc'd for C.sub.21H.sub.18N.sub.4O.sub.2Cl.sub.255/10
HCl: C, 40.00 H, 3.76 N, 8.89. Found: C, 40.09; H, 3.78; N,
8.44.
EXAMPLE 118
6-(aminoiminomethyl)-N-(2,
3-dihydro-1H-inden-5-yl)-2-naphthalenecarboxami- de,
mono(trifluoroacetate)(salt)
EXAMPLE 118A
[1324] To a solution of the compound prepared in Example 8E (303
mg, 1.4 mmol) in THF (30 mL) and propylene oxide (15 mL) was added
two drops of Et.sub.3N followed by the 5-aminoindene (300 mg, 2.2
mmol). The reaction was stirred at room temperature overnight. The
solvent was evaporated and the product was purified via
crystallization from ether to yield 226 mg (56%) of the product as
white solid. Mass spectrum (CI+), 313 (M+1).sup.+.
EXAMPLE 118B
6-(aminoiminomethyl)-N-(2,3-dihydro-1H-inden-5-yl)-2-naphthalenecarboxamid-
e, mono(trifluoroacetate)(salt)
[1325] The compound prepared in Example 118A (205 mg, 0.66 mmol) in
THF (20 mL) at room temperature, was added butyl lithium (1 mL, 1
mmol) followed by chlorotrimethyl silane (180L, 1.5 mmol). After 10
minutes the mixture was charged with additional butyl lithium (3
mL, 3 mmol). The reaction was stirred at room temperature,
overnight. The reaction mixture was added a solution of 4 N HCl in
dioxane stirred for an hour then added water and evaporated. The
product was purified by MPLC RP C.sub.18 with methanol-water and
0.1 % TFA as eluent chromatography. The yield of the product as TFA
salt with 0.25% water as white solid 51 mg (17%).
[1326] MS (ESI+) 330 (M+1).sup.+;
[1327] .sup.1H NMR (DMSO-d6) 10.45 (s, 1H), 9.51 (s, 2H), 9.21 (s,
2H), 8.66 (s, 1H), 8.55 (s, 1H), 8.32 (d, J=8.5 Hz, 1H), 8.20 (Abq,
J=9.0 Hz, 2H), 7.90 (dd, J.sub.1=9.0 Hz, J.sub.2=1.5 Hz, 1H), 7.73
(s, 1H), 7.53 (dd, J.sub.1=8.0 Hz, J.sub.2=1.5 Hz, 1H), 7.22 (d,
J=8.1 Hz, 1H), 2.91-2.82 (m, 4H), 2.04 (quintet, J=7.3 Hz, 2H);
[1328] Anal. calc'd for C.sub.21H.sub.19N.sub.3O.TFA.0.25 H.sub.2O
C: 61.67; H, 4.61; N, 9.38. Found: C: 61.63; H, 4.43; N, 9.25.
EXAMPLE 119
methyl 5-[7-[(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoate,
mono(trifluoroacetate) (salt)
EXAMPLE119A
7-hydroxy-2-cyanonaphthalene
[1329] 7-methoxy-2-cyanonaphthalene (2.79 g, 5.23 mmol) and
tetrabutylammonium iodide (17 mg, 0.157 mmol) were combined in a
mixture of benzene (35 mL) and cyclohexanes (17.5 mL). The
resulting solution was added to a rapidly stirring, cooled
(ice/water) suspension of aluminum triiodide (6.21 g, 15.23 mmol)
in a mixture of benzene (35 mL) and cyclohexanes (17.5 mL) under an
inert atmosphere. After the addition, the resulting suspension was
heated at reflux for 2.5 hours. The heating was removed and after
cooling to near room temperature, the reaction mixture was cooled
in an ice bath and quenched by the addition of water (100 mL). The
resulting mixture was further diluted with 2 M aqueous sodium
thiosulfate solution (50 mL) and extracted with ethyl acetate
(3.times.80 mL). The combined organic layers were dried and
evaporated. The resulting solid was dissolved in a minimum of hot
ethyl acetate, diluted hot with hexanes to the cloud point and
placed in a refrigerator for 2 hours. The desired compound was
collected by filtration, (1.99 g, 77%).
[1330] MS (DCI (NH3)) m/z 187 (M+NH.sub.4).sup.+.
EXAMPLE 119B
[1331] The resulting product from Example 119A was treated with
methyl 5-bromovalerate in an analogous manner as described in
Example 119A.
[1332] MS (DCI (NH3)) m/z 301 (M+NH.sub.4).sup.+.
EXAMPLE 119C
methyl 5-[7-[(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoate,
mono(trifluoroacetate) (salt)
[1333] The resulting product from Example 119B (380 mg, 1.3412
mmol) was treated in an analogous manner as described in Example
94D to yield the desired compound (369 mg, 73%).
[1334] MS (DCI (NH3)) m/z 301 (M+H).sup.+;
[1335] .sup.1H NMR (300 MHz, DMSO-d6) .delta. 1.785 (m, 4H), 2.425
(t, 2H), 3.600 (s, 3H), 4.150 (t, 2H), 7.380 (dd, 1H), 7.460 (d,
1H), 7.640 (dd, 1H), 7.980 (d, 1H), 8.070 (d, 1H), 8.322 (d, 111),
9.230 (v br s, 3H);
[1336] Anal. calc'd for
C.sub.17H.sub.20N.sub.2O.sub.3.C.sub.2HO.sub.2F.su- b.3: C, 55.07;
H, 5.11; N, 6.76. Found: C, 54.96; H, 5.22; N, 6.66.
EXAMPLE 120
(E)-3-[7-(aminoiminomethyl)-2-methoxy-1-naphthalenyl)-2-propenamide,
mono(trifluoroacetate)(salt)
EXAMPLE 120A
[1337] The product obtained from Example 53B and acrylamide were
subjected to the conditions described in Example 41A to provide the
desired compound.
[1338] MS (DCI/NH.sub.3) m/z 253 (M+H).sup.+.
EXAMPLE 120B
(E)-3-[7-(aminoiminomethyl)-2-methoxy-1-naphthalenyl)-2-propenamide,
mono(trifluoroacetate)(salt)
[1339] The product obtained from Example 120A was subjected to the
conditions described in Example 94D to provide the desired
compound.
[1340] MS (DCI/NH.sub.3) m/z 270 (M+H).sup.+;
[1341] .sup.1H NMR (300 MHz, DMSO) .delta. 4.02 (s, 3H), 6.90 (d,
1H), 7.22 (s, 1H), 7.62-7.70 (m, 2H), 7.74 (d, 1H), 8.02 (d, 1H),
8.11 (d, 1H), 8.15 (d, 1H), 8.58 (s, 1H), 9.18 (s, 2H), 9.50 (s,
2H);
[1342] Anal. calc'd for
C.sub.17H.sub.16F.sub.3N.sub.3O.sub.4.H.sub.2O: C, 50.88; H, 4.52;
N, 10.47. Found: C, 50.89; H, 4.32; N, 10.43.
EXAMPLE 121
6-[(4-aminophenyl)ethynyl1-2-naphthalenecarboximidamide,
bis(trifluoroacetate)(salt)
EXAMPLE 121A
[1343] A mixture of the product obtained in Example 63B (130 mg,
0.73 mmol), 4-iodoaniline (173 mg, 0.79 mmol), dichlorobis
(triphenylphosphine)palladium (II) (25 mg, 0.0325 mmol), copper (I)
iodide (2.7 mg, 0.0186 mmol), DMF (0.65 mL), and triethylamine
(1.95 mL) was degassed with N.sub.2 and was stirred at
75.degree.-80.degree. for 1.5 hour. The mixture was cooled to room
temperature, diluted with CH.sub.2Cl.sub.2, washed with water,
dried (MgSO.sub.4), filtered, and evaporated under vacuum to afford
an oil which was purified by flash chromatography, eluting with 3:
1 hexanes: ethyl acetate to afford the desired compound.
[1344] MS (DCI/NH.sub.3) m/z 269 (M+H).sup.+.
EXAMPLE 121B
6-[(4-aminophenyl)ethynyl]-2-naphthalenecarboximidamide,
bis(trifluoroacetate)(salt)
[1345] Using the product obtained in Example 121 A and the
procedure described in Example 40D, the desired compound was
obtained.
[1346] MS (DCI/NH.sub.3) m/z 286 (M+H).sup.+;
[1347] .sup.1H NMR (300 MHz, DMSO) .delta. 6.80 (d, 2H), 7.29 (d,
2H), 7.70 (dd, 1H), 7.85 (dd, 1H), 8.09 (d, 1H), 8.14 (d, I1H),
8.20 (s, 1H), 8.45 (s, I1H), 9.09 (s, 2H), 9.42 (s, 2H);
[1348] Anal. calc'd for C.sub.23H.sub.17F.sub.6N.sub.3O.sub.4.0.25
H.sub.2O: C, 53.34; H, 3.41; N, 8.1 1. Found: C, 53.45; H, 3.70;
N,7.76.
EXAMPLE 122
1,1-dimethylethyl
[2-[3-[6-(aminoiminomethyl)-2-naphathalenyl]ethynyl]-6-m-
ethoxyphenyl]ethyl]carbamate, mono(trifluoroacetate)(salt)
EXAMPLE 122A
[1349] Using 5-bromo-2-methoxyphenethylamine hydrobromide
(Transworld), and the procedure described in Example 63C, the
desired compound was obtained.
[1350] MS (DCI/NH.sub.3) m/z 330 (M+H).sup.+.
EXAMPLE 122B
[1351] Using the procedure described for Example 121 A, and
substituting the product obtained in Example 122A for
4-iodoaniline, the desired compound was obtained.
[1352] MS (ESI) m/z 427 (M+H).sup.+.
EXAMPLE 122C
1,1-dimethylethyl
[2-[3-[6-(aminoiminomethyl)-2-naphathalenyl]ethynyl]-6-m-
ethoxyphenyl]ethyl]carbamate, mono(trifluoroacetate)(salt)
[1353] Using the product obtained in Example A-226638-B and the
procedure described in Example 40-D, the desired compound was
obtained.
[1354] MS (DCI/NH.sub.3) m/z 444 (M+H).sup.+;
[1355] .sup.1H NMR (300 MHz, DMSO) .delta. 1.38 (s, 9H), 2.70 (t,
2H), 3.15 (q, 2H), 3.85 (s, 3H), 6.89 (t, 1H), 7.04 (d, 1H), 7.37
(d, 1H), 7.49 (dd, 1H), 7.75 (dd, 1H), 7.85 (dd, 1H), 8.11 (d, 1H),
8.16 (d, 1H), 8.30 (s, 1H), 8.48 (s, 1H), 9.07 (s, 2H), 9.42 (s,
2H)
[1356] Anal. calc'd for C.sub.29H.sub.30F.sub.3N.sub.3O.sub.5.0.25
H.sub.2O: C, 61.97; H, 5.47; N, 7.48. Found: C, 61.81; H, 5.14; N,
7.21.
EXAMPLE 123
1,1-dimethylethyl
[[4-[[6-(aminoiminomethyl)-2-naphathalenyl]ethynyl]pheny-
l]methyl]carbamate, mono(trifluoroacetate)(salt)
EXAMPLE 123A
[1357] Using 4-bromobenzylamine, and the procedure described in
Example 63C, the desired compound was obtained.
[1358] MS (DCI/NH.sub.3) m/z 303 (M+NH.sub.4).sup.+.
EXAMPLE 123B
[1359] Using the procedure described for Example 121A, and
substituting the product obtained in Example 123 for 4-iodoaniline,
the desired compound was obtained.
[1360] MS (DCI/NH.sub.3) m/z 400 (M+NH.sub.4).sup.+.
EXAMPLE 123C
[1361] 1,1-dimethylethyl
[[4-[6-(aminoiminomethyl)-2-naphathalenyl]ethynyl-
]phenyl]methyl]carbamate, mono(trifluoroacetate)(salt)
[1362] Using the product obtained in Example 123B and the procedure
described in Example 40D, the desired compound was obtained.
[1363] MS (DCI/NH.sub.3) m/z 400 (M+H).sup.+;
[1364] .sup.1H NMR (300 MHz, DMSO) .delta. 1.40 (s, 9H), 4.18 (d,
2H), 7.34 (d, 2H), 7.45 (t, 1H), 7.58 (d, 2H), 7.78 (dd, 1H), 7.86
(dd, 1H), 8.15 (d, 1H), 8.19 (d, 1H), 8.31 (s, 1H), 8.50 (s, 1H),
9.10-9.42 (s, 4H);
[1365] Anal. calc'd for C.sub.27H.sub.26F.sub.3N.sub.3O.sub.4: C,
63.15; H, 5.10; N, 8.18. Found: C, 62.95; H, 4.97; N, 8.09.
EXAMPLE 124
6-[[4-(aminomethyl)phenyl]ethynyl]-2-naphthalenecarboximidamide,
bis(trifluoroacetate)(salt)
[1366] Trifluoroacetic acid (0.73 mL) was added dropwise to a
suspension of the product obtained in Example 123C (80 mg, 0.2
mmol) and 1.5 mL CH.sub.2Cl.sub.2. The reaction mixture was stirred
for 0.25 hour at room temperature, then was evaporated to dryness
under vacuum. Toluene was added and evaporated under vacuum several
times to afford a tan solid which was purified by reverse phase
chromatography, eluting with methanol/0.1 % aqueous TFA to afford
the desired compound.
[1367] MS (APCI) m/z 300 (M+H).sup.+;
[1368] .sup.1H NMR (300 MHz, DMSO) .delta. 4.10 (s, 2H), 7.55 (d,
2H), 7.70 (d, 2H), 7.79 (dd, 1H), 7.89 (dd, 1H), 8.16 (d, 1H), 8.19
(d, 1H), 8.20 (s, 2H), 8.36 (s, 1H), 8.53 (S, 1H), 9.20 (s, 2H),
9.44 (s, 2H);
[1369]
[1370] Anal. calc'd for C.sub.24H.sub.19F.sub.6N.sub.3O.sub.4: C,
54.66; H, 3.63; N, 7.97. Found: C, 54.42; H, 3.57; N, 7.76.
EXAMPLE 125
6-[[3-(2-aminoethyl)-4-methoxyphenyl]ethynyl]-2-naphthalenecarboximidamide-
, bis(trifluoroacetate)(salt)
[1371] Using the product obtained in Example 122C and the procedure
described for Example 124, the desired compound was obtained.
[1372] MS (ESI) m/z 344 (M+H).sup.+;
[1373] .sup.1H NMR (300 MHz, DMSO) .delta. 2.90 (t, 2H), 3.06 (t,
2H), 3.88 (s, 3H), 7.11 (d, 1H), 7.44 (d, 1H), 7.57 (dd, 1H), 7.75
(dd, 1H), 7.82 (s, 2H), 7.88 (dd, 1H), 8.12 (d, 1H), 8.17 (d, 1H),
8.28 (s, 1H), 8.50 (s, 1H), 9.20 (s, 2H), 9.45 (s, 2H);
[1374] Anal. calc'd for C.sub.26H.sub.23F.sub.6N.sub.3O.sub.5.0.5
H.sub.2O: C, 53.80; H, 4.17; N, 7.24. Found: C, 53.89; H, 4.3 1; N,
6.83.
EXAMPLE 126
6-[[4-(hydroxymethyl)phenyl]ethynyl]-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
EXAMPLE 126A
[1375] Using the procedure described for Example 121 A, and
substituting 4-bromobenzyl alcohol for 4-iodoaniline, the desired
compound was obtained.
[1376] MS (DCI/NH.sub.3) m/z 301 (M+NH.sub.4).sup.+.
EXAMPLE 126B
6-[[4-(hydroxymethyl)phenyl]ethynyl]-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
[1377] Using the product obtained in Example 126A and the procedure
described in Example 94B the desired compound was obtained.
[1378] MS (ESI) m/z 301 (M+H).sup.+;
[1379] .sup.1H NMR (300 MHz, DMSO) .delta. 4.58 (d, 2H), 5.32 (t,
1H), 7.41 (d, 2H), 7.59 (d, 1H), 7.79 (dd, 1H), 7.86 (dd, 1H), 8.12
(d, 1H), 8.18 (d, 1H), 8.32 (s, 1H), 8.50 (s, 1H), 9.14 (s, 2H),
9.46 (s, 2H);
[1380] Anal. calc'd for C.sub.22H.sub.17F.sub.3N.sub.2O.sub.3. 0.5
H.sub.2O: C, 62.41; H, 4.29; N, 6.62. Found: C, 62.56; H, 4.13; N,
6.65.
EXAMPLE 127
6-[(1,2,3,4-tetrahydro-6-isoquinolinyl)ethynyl]-2-naphthalenecarboximidami-
de, bis(trifluoroacetate)(salt)
EXAMPLE 127A
[1381] A solution of boron tribromide (1.2 mL, 12.5 mmol) and 12.5
mL CH.sub.2Cl.sub.2 was added dropwise to a -78.degree. solution of
6-methoxytetrahydroisoquinoline (1.0 g, 5.0 mole, Ore. Synth., 67,
60, 1988) and 38 mL CH.sub.2Cl.sub.2. The reaction mixture was
stirred for 1 hour at -78.degree., 1 hour at 0.degree., and 0.25
hour at room temperature. The reaction mixture was cooled to
-78.degree., and 20 mL methanol was added dropwise. The solution
was stirred for 1 hour at room temperature. Solvent was evaporated
under vacuum and the residue was dried under vacuum to afford the
desired compound.
[1382] MS (DCI) m/z 150 (M+H).sup.+.
EXAMPLE 127B
[1383] The product obtained in Example 127A (1.15 g, 5.0 mmol) was
subjected to the conditions described in Example 63C. A 2.1 g
portion of this material was stirred at reflux for 1.5 hour with 60
mL methanol and 9 mL 10% aqueous NaOH. After cooling to room
temperature, methanol was evaporated under vacuum. Water was added
and the solution was acidified with 6 N HCl. The mixture was
extracted with CH.sub.2Cl.sub.2. The organic layer was washed with
water, saturated aqueous sodium chloride, dried (MgSO.sub.4),
filtered, and solvent evaporated under vacuum to afford the desired
compound.
[1384] MS (DCI/NH.sub.3) m/z 267 (M+NH.sub.4).sup.+.
EXAMPLE 127C
[1385] Using the product from Example 127B and the procedure
described in Example 28B, the desired compound was obtained.
[1386] MS (DCI/NH.sub.3) m/z 399 (M+NH.sub.4).sup.+.
EXAMPLE 127D
[1387] Using the procedure described for Example 121 A, and
substituting the product obtained in Example 127C for
4-iodoaniline, the desired compound was obtained.
[1388] MS (DCI/NH.sub.3) m/z 426 (M+NH.sub.4).sup.+.
EXAMPLE 127E
[1389] Using the product obtained in Example 127D and the procedure
described in Example 40D, the desired compound was obtained.
[1390] MS (ESI) m/z 426 (M+H).sup.+;
[1391] .sup.1H NMR (300 MHz, DMSO) .delta. 1.45 (s, 9H), 2.82 (t,
2H), 3.59 (t, 2H), 4.58 (s, 2H), 7.29 (d, 1H), 7.42 (d, 2H), 7.76
(dd, 1H), 7.83 (dd, 1H), 8.15 (d, 1H), 8.19 (d, 1H), 8.35 (s, 1H),
8.51 (s, (1H), 9.20 (s, 2H), 9.45 (s, 2H).
EXAMPLE 127F
6-[(1,2,3,4-tetrahydro-6-isoquinolinyl)ethynyl]-2-naphthalenecarboximidami-
de, bis(trifluoroacetate)(salt)
[1392] Using the product obtained in Example 127E and the procedure
described in Example 124D, the desired compound was obtained.
[1393] MS (ESI) m/z 326 (M+H).sup.+;
[1394] .sup.1H NMR (300 MHz, DMSO) .delta. 3.03 (t, 2H), 3.42 (t,
2H), 4.35 (s, 2H), 7.35 (d, 1H), 7.46 (d, 2H), 7.78 (dd, 1H), 7.89
(dd, 1H), 8.15 (d, 1H), 8.19 (d, 1H), 8.35 (s, 1H), 8.52 (s, 1H),
9.17 (s, 2H), 9.31 (s, 2H), 9.48 (s, 2H);
[1395] Anal. calc'd for C.sub.26H.sub.21F.sub.6N.sub.3O.sub.4: C,
56.42; H, 3.82; N, 7.59. Found: C, 56.31; H, 3.81;N, 7.42.
EXAMPLE 129
5-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoic acid,
mono(trifluoroacetate)(salt)
EXAMPLE 129A
[1396] The resulting product from Example 119A (250 mg, 1.477 mmol)
was treated with methyl 5-bromovalerate in an analogous manner as
described in Example 11 9B to yield the desired compound (394 mg,
94%).
[1397] .sup.MS(DCI (NH3)) m/z 301 (M+NH.sub.4).sup.+.
EXAMPLE 129B
5-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]pentanoic acid,
mono(trifluoroacetate)(salt)
[1398] The resulting product from Example 129A (262 mg, 0.8723
mmol) was treated in an analogous manner as described in Example
94D to yield the ester amidine product. The product (140 mg, 0.542
mmol) was dissolved in methanol (11 mL). To this was added a
solution of lithium hydroxide (68.2 mg, 1.626 mmol) in water (3 mL)
and the resulting mixture was stirred at room temperature under an
inert atmosphere for 18 hours. The reaction was evaporated and the
residue purified by reverse phase chromatography to yield the
desired compound (184 mg, 74%).
[1399] MS (DCI (NH3)) m/z 287 (M+H).sup.+;
[1400] .sup.1H NMR (300 MHz, DMSO-d6) .delta. 1.711 (m, 2H), 1.817
(m, 2H), 2.320 (t, 2H), 4.144 (t, 2H), 7.377 (dd, 1H), 7.472 (d,
1H), 7.632 (dd, 1H), 7.980 (d, 1H), 8.081 (d, 1H), 8.329 (s 1H),
9.100 (br s, 2H), 9.390 (br s, 2H), 12.100 (br s, 1H);
[1401] Anal. calc'd for
C.sub.16H.sub.18N.sub.2O.sub.3(C.sub.2HO.sub.2F.su- b.3)
1.15.H.sub.2O 0.65: C, 51.22; H, 4.80; N, 6.53. Found: C, 51.30; H,
5.07; N, 6.12.
EXAMPLE 131
7-methoxy-8-(3-oxo-1-cyclopenten-1-yl)-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
EXAMPLE 131A
[1402] The material prepared as described in Example 25A (0.5 g,
1.5 mmol) and the 3-tributylstannyl-2-cyclopentenone prepared as
described by Labourde et al. Tet Letters 31, (13), 1837-1840 (1990)
are coupled via Pd catalyst as described by the method of Stille et
al. JACS 109, 5478-5486 (1987) yielding after flash chromatography
with 3: 1 hexanes/ethyl acetate a white solid. 300 mg, 72%.
[1403] MS (DCI/NH.sub.3): 281 (M+NH.sub.4).
EXAMPLE 131B
7-methoxy-8-(3-oxo-1-cyclopenten-1-yl)-2-naphthalenecarboximidamide,
mono (trifluoroacetate) (salt)
[1404] The material prepared above (130 mg, 0.4 mmol) is prepared
according to the H.sub.2S/pyridine method described in Example 40D.
The desired compound was obtained as an off-white solid after
reverse phase chromatography. 52 mg, 45%.
[1405] MS (DCI/NH3): M+H+281
[1406] .sup.1H NMR (DMSO-d6): 9.45 (bs, 2H); 9.12 (bs, 2H),
8.25-8.32 (m, 2H), 8.20 (dd, 1H), 7.86 (d, 1H), 7.75 (dd, 1H), 6.42
(m, 1H), 4.05 (s, 3H), 3.15 (m, 2H), 2.75 (m, 2H)
[1407] Anal. calc'd for C.sub.19H.sub.17N.sub.2O.sub.4F.sub.3.1.75
TFA: C, 57.87; H, 4.35; N, 7.10. Found: C, 51.37; H, 4.21; N,
7.14.
EXAMPLE 132
6-(aminoiminomethyl)-N-(4-methylphenyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
EXAMPLE 132A
[1408] p-Toluidine (0.11 g, 1 mmol), and the cyano ester prepared
in Example 8E (0.2 g, 1 mmol) are coupled according to the
procedure described in Example 8G, providing an off-white solid as
the desired compound (0.16 g, 56%).
[1409] MS (ESI +): 287 (M+); 285 (M-).
EXAMPLE 132B
6-(aminoiminometyl)-N-(4-methylphenyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
[1410] The desired compound is prepared according to the procedure
described in Example 6B and purified as described in Example 1B,
yielding a white solid (35 mg, 35%).
[1411] MS (ESI+): 304 (M+)
[1412] 1HNMR (DMSO-d6): 10.55 (s, 1H); 9.45 (bs, 2H); 9.15 (bs,
2H); 8.65 (s, 1H); 8.58 (s, 1H); 8.32 (d, 1H), 8.20 (d, 1H), 8.19
(dd, 1H); 7.96 (dd, 1H), 7.75 (d, 2H), 7.12 (d, 2H), 2.35 (s,
3H);
[1413] Anal. calc'd for C.sub.21H18N.sub.3O.sub.3F.sub.3: C, 60.43;
H, 4.35; N, 10.07 Found: C, 59.94; H, 4.06; N, 9.80.
EXAMPLE 133
methyl
4-[[7-(aminoiminomethyl)-1-(2-pyrimidinylamino)-2-naphthalenyl]oxy]-
methyl1 benzoate, mono(trifluoroacetate)(salt)
EXAMPLE 133A
[1414] The material described in Example 91A is treated with
A1I.sub.3 according to the procedure described in Example 119A and
alkylated with 4-CarbomethoxyBenzylbromide according to the
procedure described in Example 109B, yielding the desired compound
as a white solid, 100 mg, 83%.
[1415] MS (ESI +, -): 411 (M+) ; 409 (M-).
EXAMPLE 133B
methyl
4-[[[7-(aminoiminomethyl)-1-(2-pyrimidinylamino)-2-naphthalenyl]oxy-
]methyl]benzoate, mono(trifluoroacetate)(salt)
[1416] The desired compound is prepared according to the procedure
described in Example 40D and purified according to the procedure
described in Example 119B, yielding a light yellow solid, (49 mg,
50%).
[1417] MS (ESI +, -): 428 (M+); 426 (M-)
[1418] .sup.1H NMR (DMSO-d6): 9.45 (bs, 2H); 9.15 (s, 1H); 8.97
(bs, 2H); 8.45 (dd, 1H); 8.38 (d, 1H); 8.15 (d, 1H), 8.09 (d, 1H),
7.95 (d, 2H); 7.76 (d, 1H), 7.68 (dd, 1H), 7.35 (d, 2H), 6.85 (d,
2H), 5.39 (s, 2H); 3.85 (s, 3H);
[1419] Anal. calc'd for C.sub.26H.sub.22N.sub.5O.sub.5F.sub.3: C,
57.67; H, 4.10; N, 12.93 Found: C, 55.34; H, 3.88; N, 12.05.
EXAMPLE 134
4-[[[7-(aminoiminomethyl)-1-(2-pyrimidinylamino)-2-naphthalenyl]oxy]methyl-
]benzoic acid, mono(trifluoroacetate)(salt)
[1420] The material prepared in Example 134 (40 mg) is dissolved in
1: 1 THF/water. To the clear solution is added LiOH.water (9 mg),
the resulting clear solution is stirred 18 hours at room
temperature. The reaction mixture is concentrated to a yellow
solid. The solid is dissolved in distilled water, acidified to pH 2
with 3 N HCl and stirred 2 hours at room temperature. The desired
compound is isolated by filtration, dried under vacuum as a yellow
solid. Yield: 39 mg (46%)
[1421] MS (APCI): M+H.sup.+: 414
[1422] .sup.1H NMR (DMSO-d6): 9.45 (bs, 2H); 9.15 (s, 1H); 8.97
(bs, 2H); 8.45 (dd, 1H); 8.38 (d, 1H); 8.15 (d, 1H), 8.09 (d, 1H),
7.95 (d, 2H); 7.76 (d, 1H), 7.68 (dd, 1H), 7.35 (d, 2H), 6.85 (d,
2H), 5.39 (s, 2H);
[1423] Anal. calc'd for C.sub.25H.sub.20N.sub.5O.sub.5F.sub.3Cl.3
H.sub.2O: C, 48.67; H, 4.25; N, 11.35 Found: C, 49.64; H, 4.44; N,
11.69.
EXAMPLE 135
1,1-dimethylethyl
[[4-[[[6-(aminoiminomethyl)-2-naphathalenyl]amino]carbon-
yl]phenyl]methyl]carbamate mono(trifluoroacetate)(salt)
EXAMPLE 135A
[1424] The material prepared in Example 8B was added to cold
(0.degree. C) sulfuric acid (45 mL). Within 1 minutes at 0.degree.
C. bubling started to form. Allowed to bubble at 0.degree. C. for
30 minutes than slowly warmed to room temperature. Left at room
temperature for 20 minutes, then poured into ice and diluted with
water (to approx. 500 mL). The suspension was placed in an ice bath
and carefully added a solution of 50% aqueuos sodium hydroxide so
that the temperature would not exceed 3 5.degree. C. The light
yellow solid was filtered than washed with water till the wash
became neutral to pH paper (7.0). The product was dried under
vacuum. The product was purified on silica gel column using 20%
ethyl acetate 80% hexanes as eluent to yield 3.3 g (67%) of light
yellow solid.
[1425] MS m/z 169 (M+1).sup.+.
EXAMPLE 135B
[1426] A solution of Example 135A (135 mg, 0.8 mmol),
4-N-Boc-aminomethylbenzoic acid (404 mg, 1.6 mmol) and EDCI (307
mg, 1.6 mmol) in methylene chloride (25 mL), at room temperature,
was added DMAP (3 mg) and stirred overnight. The reaction mixture
was diluted with methylene chloride (60 mL) then washed 2% aqueous
hydrochloric acid (2.times.30 mL), water (20 mL), 0.5 M aqeuos
sodium hydroxide (2.times.50 mL) and brine. The organic phase was
dried over magnesium sulfate and evaporated. The product was
purified via on silica column usinga gradient of 25% to 60% ethyl
acetate in hexanes as eluent. Yield 175 mg (54%) of white
powder.
EXAMPLE 135C
1,1-dimethylethyl [[4-
[[6-(aminoiminomethyl)-2-naphathalenyl]amino]carbon-
yl]-phenyl]methyl]carbamate, mono(trifluoroacetate)(salt)
[1427] The reaction was carried out in the same manner as described
in Example 40D. Yield 110 mg (64%).
[1428] MS m/z 408 (M+1).sup.+, 425 (M+18).sup.+
[1429] .sup.1H NMR: 3.30 (s, 9H), 4.22 (d, 2H, J=7.1 Hz), 7.42 (d,
2H, J=8.5 Hz), 7.49 (t, 1H, J=7.1 Hz), 7.79 (dd, 1H, J1=8.2 Hz,
J2=2.0 Hz), 7.95-8.00 (m, 3H), 8.09 (d, 2H, J=8.4 Hz), 8.42 (s,
1H), 8.63 (d, 1H, J=2.0 Hz), 9.18 (br s, 4H), 10.58 (s, 1H);
[1430] Anal. calc'd for C.sub.26H.sub.27F.sub.3N.sub.4O.sub.5: C,
58.55; H, 4.85; N, 10.41. Found: C, 58.64; H, 5.11; N, 10.52.
EXAMPLE 136
N-[6-(aminoiminomethyl)-2-naphthalenyl)benzamide,
mono(trifluoroacetate)(s- alt)
[1431] The desired compound is prepared as described in Example
135;
[1432] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.67 (s, 1H), 9.25
(br.s, 4H), 8.65 (d, J=1.5 Hz, 1H), 8.43 (d, J=1.4 Hz, 1H), 8.10
(d, J=9.2 Hz, 2H), 8.03-7.97 (m, 3H), 7.81-7.78 (m, 1H), 7.65-7.55
(m, 3H).
[1433] MS (ESI/NH.sub.3) m/z 290 (M+H).sup.+;
[1434] Anal. calc'd for C.sub.18H.sub.15N.sub.3O.CF.sub.3COOH: C,
59.55; H, 4.00; F, 14.13; N, 10.42. Found: C, 50.47; H, 3.88; F,
14.42; N, 10.39.
EXAMPLE 137
1,1-dimethylethyl
[[4-[[[6-(aminoiminomethyl)-2-naphathalenyl]amino]carbon-
yl]cyclohexyll]methyl]carbamate, mono(trifluoroacetate)(salt)
EXAMPLE 137A
[1435] To a solution of the 6-Amino-2-naphthalenecarbonitrile
prepared in Example 73 (100 mg, 0.6 mmol) in methylene chloride (35
mL) at room temperature, was added
1-carboxy-4-(Boc-aminomethyl)cyclohexanes (280 mg, 1.1 mmol)
followed by 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide
hydrochloride (EDAC, 225 mg, 1.2 mmol). After 5 minutes to the
reaction mixture was added DMAP (20 mg, catalytic). The reaction
was stirred at room temperature for 72 hours. The reaction mixture
was diluted 7: 3 ethyl acetate: hexanes then filtered through
silica gel and washed with the same solvent mixture.
[1436] The organic solvent was washed by aq. Acid (2% Hcl,
2.times.50 mL), water and aq. Base (10% NaOH, 50 mL). The solvent
was dried over magnesium sulfate filtered and evaporated.
Crystalization from ether/ hexanes afforded the product as white
solid. Yield 166 mg (68%).
[1437] MS (DCI/NH.sub.3) m/z 408 (M+H).sup.+.
EXAMPLE 137B
1,1-dimethylethyl
[[4-[[[6-(aminoiminomethyl)-2-naphathalenyl]amino]carbon-
yl]-cyclohexyl]methyl]carbamate, mono(trifluoroacetate)(salt)
[1438] A solution of the substrate (Example 137A) in Pyr: Et.sub.3N
(10: 1, 20 mL) was bubbled H.sub.2S for 5 minutes. Stirred at room
temperature overnight. The reaction mixture was added ethyl acetate
(100 mL) followed by 1% aq. KHSO4 (60 mL) and separated; washed
organic layer with water (2.times.50 mL), sodium bicarb. And brine,
dried over magnesium sulfate & evaporated. To a suspension of
the resulting solid in acetone (25 mL) and added MeI (1.0 mL).
Stirred at 50.degree. C. for 2 hours, all dissolved. Evaporated
solvent to a complete dryness and added methanol (30 mL) and
ammonium acetate (150 mg). The mixture was stirred at room
temperature overnight. Purification by Reverse Phase C.sub.18 MPLC.
After evaporation added toluene & evaporated (2.times.40 mL).
The resulting oil was treated with methanol and ether and the
product precipitated as white solid (72 mg, 43%).
[1439] MS (ESI/NH.sub.3) m/z 425 (M+H).sup.+;
[1440] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 10.24 (s, 1H), 9.05
(br.s, 4H), 8.49 (s, 1H), 8.38 (d, J=1.7 Hz, 1H), 8.03-8.00 (m,
2H), 7.77-7.74 (m, 2H), 6.93-6.91 (m, 1H), 2.83-2.79 (m, 2H),
2.40-2.30 (ml), 1.92-1.75 (m, 4H), 1.50-1.45 (m, 1H), 1.39 (s, 9H),
0.96-0.91 (m, 4H);
[1441] Anal. calc'd for
C.sub.24H.sub.32N.sub.4O.sub.3.CF.sub.3COOH: C, 57.98; H, 6.18; N,
10.40. Found: C, 57.63; H, 6.24; N,10.21.
EXAMPLE 138
N-[6-(aminoiminomethyl)-2-naphthalenyl]-N'-(4-aminophenyl)urea,
bis(trifluoroacetate)(salt)
EXAMPLE 138A
[1442] To a solution of the compound prepared in Example 40B (194.2
mg, 1 mmol) in dioxane (10 mL) at room temperature, was added
4-phenylenediamine mono Boc (416, 5 mg, 2 mmol). The product
started to precipitate within minutes. After an hour the reaction
mixture was added ether (5 mL) and the white solid product was
filtered and washed with ether to yield 350 mg (87%).
[1443] MS (DCI/NH.sub.3) m/z 403 (M+H).sup.+.
EXAMPLE 138B
[1444] A solution of the corresponding nitrile prepared in Example
138A (105 mg, 0.36 mmol) in Pyr: Et.sub.3N (10: 1, 20 mL) was
bubbled H.sub.2S for 5 minutes and stirred at room temperature
overnight. The reaction mixture was diluted with ethyl acetate (100
mL) washed with aqueous 0.25 N HCl (25 mL) followed by water (2x50
mL), saturated solution of sodium bicarbonate, and brine, dried
over magnesium sulfate & evaporated. To a solution of the
resulting solid in acetone (25 mL) was added MeI (1.0 mL)and
stirred at 50.degree. C. for 30 minutes--very strong precipitate
was observed. Added ether and filtered the yellow precipitated. The
yellow solid was added methanol (10 mL) and ammonium acetate (150
mg) and stirred at room temperature overnight. Purified as
described in Example 1B. Yield of the white solid 69 mg.
[1445] MS (DCI/NH.sub.3) m/z 420 (M+H).sup.+.
EXAMPLE 138C
N-[6-(aminoiminomethyl)-2-naphthalenyl]-N'-(4-aminophenyl)urea,
bis(trifluoroacetate)(salt)
[1446] The Boc protected substrate (Example 138B) was dissolved in
methylene chloride: TFA 1: 1 (25 mL) and stirred at room
temperature for 1 hour. Evaporated solvent under vacuum added
toluene & evaporated again. Added water & little
acetonitrile, filtered & lyophilized. 36 mg of white solid.
[1447] MS (ESI/NH.sub.3) m/z 320 (M+H).sup.+;
[1448] 1H NMR (300 MHz, DMSO-d.sub.6) 9.26 (br.s, 2H), 9.21 (br.s,
1H), 8.85 (br.s, 2H), 8.31 (d, J=1.7 Hz, 1H), 8.18 (d, J=1.7 Hz,
1H), 7.95-7.91 (m, 2H), 7.68 (dd, J1=6.6 Hz, J2=2.0 Hz, 1H), 7.57
(dd, J1=9.2 Hz, J2=1.4 Hz, 1H), 7.34 (d, J=8.8 Hz, 2H), 6.91 (d,
J=8.4 Hz, 2H);
[1449] Anal. calc'd for
C.sub.18H.sub.17N.sub.5O.2CF.sub.3COOHH.H.sub.2O: C, 46.73; H,
3.74; N, 12.39. Found: C, C, 47.03; H, 3.55; N, 12.36.
EXAMPLE 139
N-[6-(aminoiminomethyl)-2-naphthalenyl]-4-4-(aminomethyl)cyclohexanescarbo-
xamide, bis(trifluoroacetate)(salt)
[1450] A solution of the substrate prepared in Example 137 as TFA
salt (45 mg) in methylene chloride: TFA 1: 1 (20 mL) was stirred at
room temperature for 1 hour. The solvent was evaporated under
vacuum, added toluene & evaporated (20 mL.times.2). Dissolved
in water, filtered-0.45.mu. frit and lyophilized. 35 mg, white
solid as bis TFA salt.
[1451] MS (ESI/NH.sub.3) m/z 325 (M+H).sup.+;
[1452] .sup.1HNMR (300 MHz, DMSO-d.sub.6) 10.31 (s, 1H), 9.31
(br.s, 2H), 9.10 (br.s, 2H), 8.49 (s, 1H), 8.39 (s, 1H), 8.04-8.00
(m, 2H), 7.78-7.71 (m, 2H), 2.71 (d, J=7.0 Hz, 2H), 2.44-2.36 (m,
1H)1.96-1.85 (m, 4H), 1.61-1.42 (m, 3H), 1.09-1.02 (m, 2H);
[1453] Anal. calc'd for C.sub.19H.sub.24N.sub.4O.2CF.sub.3COOH: C,
50.00; H, 4.74; N, 10.14. Found: C, 49.95; H, 4.70; N, 09.96.
EXAMPLE 140
N-[6-(aminoiminomethyl)-2-naphthalenyl]-N'-[(4-aminomethyl)phenyl]urea
bis(trifluoroacetate)(salt)
EXAMPLE 140A
[1454] To a solution of the isocyanate prepared in Example 40B (140
mg, 0.72 mmol) in dioxane (8.0 mL) at room temperature, was added
4-N-Boc-aminomethylbenzoic acid (320 mg, 1.44 mmol) and stirred for
1 hour. The product was precipitating during the reaction. The
mixture diluted with ether (15 mL), filtered and washed with ether
to yield 215 mg (72%) of white solid.
[1455] MS (DCI/NH.sub.3) m/z 417 (M+H).sup.+.
EXAMPLE 140B
[1456] A solution of the nitrile (Example 140A) (198 mg, 0.47 mmol)
in 10: 1 pyridine: triethylamine (10 mL) was treated with H.sub.2S
for 5 min, stirred at room temperature for 18 h and concentrated.
The resulting solid was dissolved in acetone (15 mL), treated with
iodomethane (0.8 mL, 12.8 mmol), stirred for 2 hours, diluted with
ether (10 mL), filtered, washed with ether and dried under vacuum.
The resulting solid was dissolved in methanol (4 mL) and was added
NH.sub.4OAc (200 mg, 2.6 mmol) at room temperature overnight. The
product was purified according to the procedure described in
Example 1B to provide 112 mg (54%) of the corresponding
amidine.
[1457] MS (DCI/NH.sub.3) m/z 434 (M+H).sup.+.
EXAMPLE 140C
N-[6-(aminoiminomethyl)-2-naphthalenyl]-N'-F(4-aminomethyl)phenyl]urea,
bis(trifluoroacetate)(salt)
[1458] A solution of the substrate (Example 140B) in methylene
chloride: TFA 1: 1 (20 mL) was stirred at room temperature for 1
hour. The solvent was evaporated under vacuum, added toluene &
evaporated (20 mL.times.2). Dissolved in water, filtered--0.45.mu.
frit and lyophilized. 38.1 mg, white solid.
[1459] MS (ESI/NH.sub.3) m/z 334 (M+H).sup.+;
[1460] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.68 (s, 1H), 9.45 (s,
1H), 9.35 (br.s, 2H), 9.08 (br. s, 2H), 8.40 (d, J=1.7 Hz, 1H),
8.31 (d, J=1.8 Hz, 1H), 8.10 (br.s, 3H), 8.04-7.99 (m, 2H), 7.76
(dd, J1=8.8 Hz, J2=1.8 Hz, 1H), 7.67 (dd, J1=8.8 Hz, J2=1.7 Hz,
1H), 7.58 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 3.98 (br. s,
2H);
[1461] Anal. calc'd for
C.sub.19H.sub.19N.sub.5O.sub.1.2.CF.sub.3COOHH.H.s- ub.2O: C,
47.67; H, 4.00; F, 19.67; N, 12.09. Found: C, 47.33; H, 3.70; F,
19.59; N, 11.71.
EXAMPLE 141
methyl
[7-(aminoiminomethyl)-3-[[[4-(aminomethyl)phenyl]amino]carbonyl]-1--
naphathalenyl]carbamate bis(trifluoroacetate)(salt)
EXAMPLE 141A
[1462] To a solution of the ester, prepared as described in Example
26, (747 mg, 2.63 mmol) in dioxane (10 mL) was added acetone (1 mL)
and an excess of sodium hydroxide (1 N in water, 10 mL). After 1
hour the mixture was added water (40 mL) and ethyl acetate (85 mL)
then was acidified with 10% aq. HCl. The ethyl acetate layer was
separated washed with water (2.times.20 mL) then brine, dried over
magnesium sulfate filtered and evaporated. The product was isolated
as a light yellow solid.
[1463] MS m/z 271 (M+1).sup.+.
EXAMPLE 141B
[1464] To a suspension of naphthoic acid derivative, prepared in
Example 141A (270 mg, 1.1 mmol) in methylene chloride (8.0 mL) was
added diisopropylethylamine (DIEA, 485 .mu.L, 2.8 mmol) followed by
O-(azabenzotriazole-1-yl)-N, N, N',
N'-tetramethyluroniumhexafluorophosph- ate (HATU, 527 mg, 1.39
mmol). After 10 minutes added the 4-N-Boc-aminomethylaniline (370
mg, 1.7 mmol). After an hour, added ethyl acetate (120 mL) and
washed organic layer with 5% aq. citric acid (50 mL), water
(2.times.40 mL) and brine (50 mL). The rxn was dried over magnesium
sulfate filtered through small amount of silica and evaporated.
Purification on silica eluting with ethyl acetate in hexanes. The
product, after concentration, was added ethyl acetate and ether and
filtered to yield 350.0 mg (70%) of yellow solid.
[1465] MS m/z 447 (M+1)
EXAMPLE 141C
[1466] A suspension of the naph derivative (Example 141B) (300 mg,
0.67 mmol) in ethyl acetate (20 mL) was added 120 mg of the Pd
catalysit then stirred at room temperature, under hydrogen, at
atmospheric pressure and stirred for 1 hour.. The crude was carried
on to the next step without any purifications or analysis.
[1467] To a solution of the crude amine in dioxane (25 mL) and 10%
aqeuos sodium carbonate (2.5 mL) was added the methyl chloroformate
(1.0 mL, large excess). After 2 hours the rxn was quenched with
methanol then diluted with ethyl acetate (80 mL) and water (50 mL).
The ethyl acetate layer was separated, dried over magnesium sulfate
filtered and evaporated. The product was separated on silica column
using a gradient of ethyl acetate in hexanes (from 5 to 30% ethyl
acetate in hexanes). Yield 140 mg of off white solid.
[1468] MS m/z 492 (M+18).sup.+.
EXAMPLE 141D
[1469] The desired compound was prepared as described in Example
26. MS m/z 492 (M+1.sup.+.
EXAMPLE 141E
methyl
[7-(aminoiminomethyl)-3-[[[4-(aminomethyl)phenyl]amino]carbonyl]-1--
naphathalenyl]carbamate, bis(trifluoroacetate)(salt)
[1470] A solution of the substrate (Example 141 D) in a mixture of
methylene chloride: TFA 4: 1 (20 mL) was stirred at room
temperature for 15 minutes. The solvent was concentrated under
vacuum, and separated on RP C18 MPLC. Yield, 21 mg off white
solid.
[1471] MS m/z 392 (M+18).sup.+
[1472] .sup.1H NMR (DMSO): 3.783 (s, 3H), 4.03 (q, 2H, J=5.5 Hz),
7.47 (d, 2H, j=8.4 Hz), 7.85 (d, 2H, j=8.4 Hz), 7.94 (d, 1H, j=8.8
Hz), 8.15 (wide s, 2H), 8.31 (d, 1H, j=8.8 Hz), 8.33 (s, 1H), 8.47
(s, 1H), 8.74 (s, 1H), 9.29 (s, 2H), 9.47 (s, 2H), 9.90 (s, 1H),
10.68 (s, 1H).
[1473] Anal. calc'd for C.sub.25H.sub.25F.sub.6N.sub.5O.sub.8 (base
molecule +2 TFA+1H.sub.2O): C, 47.04; H, 3.70; N, 10.52. Found: C,
47.10; H, 3.95; N, 10.99.
EXAMPLE 142
6-(aminoiminomethyl)-N-(4-ethylphenyl)-2-naphthalenecarboxamide,
acetate(salt)
EXAMPLE 142A
[1474] The reaction was carried out in the same manner as described
in Example 141 B. Yield 374 mg (61%) of white powder.
[1475] MS DCI/NH3): m/z 301 (M+NH.sub.4+).
EXAMPLE 142B
6-(aminoiminomethyl)-N-(4-ethylphenyl)-2-naphthalenecarboxamide,
acetate(salt)
[1476] The reaction was carried out in the same manner as described
for the naphthyl analog prepared in Example 141D, 313 mg. The solid
that precipitated during the last step was filtered and washed in
ether to yield 71 mg (18%) of white solid, as acetate salt.
[1477] MS (ECI) m/z 301 (M+H).sup.+;
[1478] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.19 (t, J=7.4
Hz, 3H), 2.60 (q, J=7.4 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.72 (d,
J=8.5 Hz, 2H), 7.94 (dd, J1=8.8 Hz, J2=1.7 Hz, 1H), 8.08-8.23 (m,
3H), 8.47 (d, J=1.7 Hz, 1H), 8.63 (s, 1H), 10.43 (br. s, 1H);
[1479] Anal. calc'd for C.sub.20H.sub.19N.sub.3O.AcOH.0.5 H.sub.2O:
C, 68.38; H, 6.26; N, 10.87. Found: C, 68.56; H, 6.21; N,
10.67.
EXAMPLE 143
6-(aminoiminomethyl)-N-(2-naphthalenyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
EXAMPLE 143A
[1480] To a solution of the acid chloride prepared as described in
Example 8B (341 mg, 1.6 mmol) in methylene chloride (20 mL) was
added a solution of the 2-Amino naphthalene (249 mg, 1.74 mmol) in
methylene chloride (10 mL) and propylene oxide (12 mL). The rxn was
stirred at room temperature overnight. The reaction mixture was
added ether and the product was filtered, washed with ether and
hexanes and dried under vacuum. Yield 440 mg (86%).
[1481] MS (DCI/NH3) m/z 340 (M+NH.sub.4).sup.+.
EXAMPLE 143B
6-(aminoiminomethyl)-N-(2-naphthalenyl)-2-naphthalenecarboxamide
mono(trifluoroacetate)(salt)
[1482] The desired compound is prepared as described in Example 141
B. Yield of white solid 40 mg (10%).
[1483] MS (ESI) m/z 340 (M+H).sup.+;
[1484] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 7.43-7.55 (m, 2H),
7.86-7.96 (m, 5H), 8.20-8.28 (m, 2H), 8.08-8.23 (m, 3H), 8.34 (d,
J=8.8 Hz, 1H), 8.50 (d, J=1.7 Hz, 1H), 8.57 (d, J=1.3 Hz, 1H), 8.75
(s, 1H), 9.33 (br. s, 4H) 10.75 (s, 1H);
[1485] Anal. calc'd for C.sub.22H.sub.17N.sub.3O.TFA.0.25 H.sub.2O:
C, 62.95; H, 4.07; N, 9.18. Found: C, 63.09; H, 3.72; N, 8.99.
EXAMPLE 144
6-(5-phenyl-2-oxazolyl)-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
EXAMPLE 144A
[1486] To a suspension of the phenacyl amine hydrochloride
(Aldrich) (415 mg, 2.42 mmol) in a mixrure of methylene chloride
(50 mL) and propylene oxide (15 mL) at room temperature was added a
solution of the 2-nitrile-6-acidchloride (560 mg, 2.6 mmol) in
methylene chloride (30 mL) followed by DMF (3.0 mL). The reaction
was stirred at room temperature overnight. The reaction mixture was
added ether (15 mL) and the product was filtered and washed with
hexanes to yield 555 mg (73%) of white solid.
[1487] MS (DCI/NH.sub.3) m/z 315 (M+H).sup.+.
EXAMPLE 144B
[1488] A suspension of the substrate (Example 144A) (354 mg, 1.12
mmol) in phosphorous oxychloride (3.5 mL) was boiled for 1.5 hours.
The reaction mixture was poured into ice and the mixture was added
ethyl acetate (80 mL) and aqeuous solution of 10% potassium
carbonate (100 mL). The organic layer was separated, washed with
brine dried over magnesium sulfate and evaporated. Added ether and
filtered 249 mg (75%).
[1489] MS (DCI/NH.sub.3) m/z 297 (M+H).sup.+.
EXAMPLE 144C
6-(5-phenyl-2-oxazolyl)-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
[1490] To a solution of the substrate Example 144B (132 mg, 0.44
mmol) in THF (20 mL) at room temperature was added a solution of 1
N LiHMDS in hexanes (1.5 mL, 1.5 mmol) and stirred overnight.
Quenched with 4 N HCl in dioxane (1 mL). After 10 minutes added a
few drops of water and stirred for additional 30 minutes. The
solvent was evaporated under vacuum and the residue was purified on
reverse phase chromatography. Yield 58 mg of white solid 41%).
[1491] MS (ESI/NH.sub.3) m/z 314 (M+H).sup.+;
[1492] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.50 (s, 2H), 9.19 (s,
2H), 8.86 (s, 1H), 8.55 (s, 1H), 8.38-8.26 (m, 3H), 7.98 (s, 1H),
7.96-7.89 (m, 3H), 7.58-7.54 (m, 2H), 7.47-7.42 (m, 1H);
[1493] Anal. calcd for C.sub.20H.sub.15N.sub.3O.1.15CF.sub.3COOH:
C, 60.26; H, 3.66; N, 9.45; F, 14.75. Found: C, 60.11; H, 3.81; N,
9.20; F, 14.81.
EXAMPLE 145
6-(5-phenyl-2-thiazolyl)-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
EXAMPLE 145A
[1494] A suspension of the substrate, prepared in Example 144A,
(340 mg, 1.1 mmol) and Lawesson's reagent (600 mg, 1.48 mmol) was
heated to 85.degree. C. for 48hours. Solvent was evaporated to
dryness and the product was isolated via silica column using 10%
ethyl acetate in hexanes as eluent. Yield: 200.0 mg (59%) of yellow
solid.
[1495] MS (DCI/NH.sub.3) m/z 313 (M+H).sup.+.
EXAMPLE 145B
6-(5-phenyl-2-thiazolyl)-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
[1496] To a solution of the substrate, Example 145A (180 mg, 0.58
mmol) in THF (20 mL) at room
[1497] temperature was added a solution of 1 N LiHMDS in hexanes
(2.0 mL, 2.0 mmol) and stirred overnight. Quenched with 4 N HCl in
dioxane (1 mL). After 10 minutes added a few drops of water and
stirred for additional 30 minutes. The solvent was evaporated under
vacuum and the residue was purified on MPLC RPC18. Yield 36 mg
(19%) of white solid.
[1498] MS (ESI/NH.sub.3) m/z 330 (M+H).sup.+;
[1499] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.49 (s, 2H), 9.14 (s,
2H), 8.71 (s, 1H), 8.52 (s, 1H), 8.47 (s, 1H), 8.35-8.22 (m, 3H),
7.90-7.78 (m, 3H), 7.55-7.50 (m, 2H), 7.46-7.43 (m, 1H);
[1500] Anal. calc'd for
C.sub.20H.sub.`5N.sub.3S.CF.sub.3COOH.H.sub.2O: C, 57.26; H, 3.93;
N, 9.11. Found: C, 56.83; H, 3.55; N, 8.79.
EXAMPLE 146
6-(aminoiminomethyl)-4-(3-furanyl)-N-(2-pyridinyl)-2-naphthalenecarboxamid-
e, dihydrochloride
EXAMPLE 146A
[1501] The above product was prepared in the manner of Example
114A.
[1502] MS (ESI) m/z (M+H).sup.+340.
EXAMPLE 146B
6-(aminoiminomethyl)-4-(3-furanyl)-N-(2-pyrdinyl)-2-naphthalenecarboxamide-
, dihydrochloride
[1503] The above was prepared from Example 146A using method
described in 145B.
[1504] MS (CI) m/z (M+H).sup.+357;
[1505] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 11.27 (s, 1H),
9.56 (s, 2H), 9.17 (s, 2H), 8.76 (s, 1H), 8.63 (s, 1H), 8.45-8.24
(m, 5H), 7.96-7.89 (m, 3H), 7.25 (m, 2H), 7.18 (s, 1H);
[1506] Anal. calc'd for C.sub.21H.sub.18N.sub.4O.sub.2Cl.sub.219/10
HCl: C, 54.33 H, 4.75 N, 12.07. Found: C, 54.89; H, 5.28; N,
9.81.
EXAMPLE 147
6-(aminoiminomethyl)-N-(
1,2,3,4-tetrahydro-6-quinolinyl)-2-naphthalenecar- boxamide,
bis(trifluoroacetate)(salt)
EXAMPLE 147A
[1507] The reaction was carried out in exactly the same manner as
described for Example 11 8A using 6-aminoquinoline to yield the
product in 72%. Mass spectrum (CI+) 324 (M+l).sup.+.
EXAMPLE 147B
[1508] The reaction was carried out in exactly the same manner as
described for Example 11 8B to yield the product in 45% (off white
solid). Mass spectrum (ESI+) 341 (M+1).sup.+.
EXAMPLE 147C
6-(aminoiminomethyl)-N-(1,2,3,4-tetrahydro-6-quinolinyl)-2-naphthalenecarb-
oxamide, bis(trifluoroacetate)(salt)
[1509] To a suspension of the substrate, Example 147B (261 mg, 0.6
mmol) in degassed methanol (15 mL) was added platinum oxide (10 mg,
cat.). The reaction mixture was charged with hydrogen at
atmospheric pressure and stirred vigorously overnight. The next day
the solution was filtered through celite to remove the catalyst,
and the product was purified over mplc with RPC1 8 silica using
methanol (+0.1% TFA) and water (+0.1% TFA) as eluent. Yield 122 mg
of white solid and bis TFA salt.
[1510] MS (ESI+) 345 (M+1).sup.+;
[1511] .sup.1H NMR (DMSO-d6) 10.51 (s, 1H), 9.65 (s, 2H), 9.50 (s,
2H), 8.64 (s, 1H), 8.52 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.12 (Abq,
J=9.0 Hz, 2H), 7.86 (d, J=9.0 Hz, 1H), 7.61 (s, 1H), 7.56 (d, J=8.0
Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 3.28 (t, J=5.5 Hz, 2H), 2.75 (t,
J=6.3 Hz, 2H), 1.92-1.86 (m, 2H);
[1512] Anal. calc'd for C.sub.21H.sub.20N.sub.4O+2.25 TFA+0.25
H.sub.2O: C, 50.59 (50.46); H, 3.79 (3.79); N, 9.25 (9.25); F,
21.18 (20.83).
EXAMPLE 148
7-methoxy-8-(pyrazinyloxy)-2-naphthalenecarboximidamide,
dimethanesulfonate(salt)
EXAMPLE 148A
[1513] The product from Example 4A (125 mg, 0.627 mmol) was
combined with chloropyrazine (112 mL, 1.25 mmol) and
Cs.sub.2CO.sub.3 (409 mg, 1.25 mmol) in N-methylpyrrolidinone (4
mL), and the reaction was stirred at 130.degree. C. for 1 hour. The
reaction was cooled, and the crude mixture was chromatographed on
SiO.sub.2 using 40% ethyl acetate/hexanes as eluent, to yield 75 mg
(43%) of the desired compound.
[1514] MS (DCI (NH.sub.3) m/z 278 (M+H).sup.+.
EXAMPLE 148B
7-methoxy-8-(pyrazinyloxy)-2-naphthalenecarboximidamide,
dimethanesulfonate(salt)
[1515] The product from Example 148A (70 mg, 0.252 mmol) was
subjected to the procedure described in Example 1B to yield the
desired compound (106 mg, 71%). m.p. 155.degree. C.
[1516] MS (DCI (NH.sub.3) m/z 295 (M+H).sup.+;
[1517] .sup.1H NMR (300 MHz, DMSO) .delta. 9.42 (br s, 2H), 9.04
(br s, 2H), 8.72 (s, 1H), 8.38 (d, J=3 Hz, 1H), 8.36 (m, 1H), 8.21
(d, J=9 Hz, 1H), 8.09 (m, 1H), 8.06 (d, J=9 Hz, 1H), 7.82 (d, J=9
Hz, 1H), 7.73 (dd, J=9, 2 Hz, 1H), 3.83 (s, 3H), 2.38 (s, 3H);
[1518] Anal. calc'd for
C.sub.18H.sub.22N.sub.4S.sub.2O.sub.8.1.1CH.sub.4S- O.sub.3: C,
38.74; H, 4.49; N, 9.46. Found: C, 38.68; H, 4.53; N, 9.34.
EXAMPLE 149
7-methoxy-8-(phenylthio)-2-naphthalenecarboximidamide,
methanesulfonate
EXAMPLE 149A
[1519] To a solution of NaH (48 mg, 60%, 1.2 mmol) in HMPA (2 mL)
was added PhSH (0.133 mL, 1.3 mmol), and the reaction was stirred
for 5 minutes. To this was added the product from Example 53B (309
mg, 1 mmol), and the reaction was heated at 100.degree. C. for 3
hours. The crude reaction mixture was chromatographed on SiO.sub.2
using 20% ethyl acetate/hexanes as eluent. The product was taken up
in ethyl acetate (10 mL) and methanol (10 mL), and treated with a 2
M solution of TMSCHN.sub.2 (10 mL). The reaction was stirred for 60
minutes and condensed. The crude product was chromatographed on
SiO2 using 15% ethyl acetate/hexanes as eluent, to yield 115 mg
(39%) of the desired compound:
[1520] MS (DCI (NH.sub.3) m/z 309 (M+NH.sub.4).sup.+.
EXAMPLE 149B
7-methoxy-8-(phenylthio)-2-naphthalenecarboximidamide,
methanesulfonate
[1521] The desired compound was prepared from Example 149A and the
procedure of Example 55D.
MS (DCI/NH.sub.3) m/z 309 (M+H).sup.+;
[1522] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.33 (s, 3H),
3.96 (s, 3H), 6.96 (d, 2H), 7.11 (dd, 1H), 7.20 (d, 1H), 7.22 (d,
1H), 7.69 (dd, 1H), 7.82 (d, 1H), 8.22 (d, 1H), 8.33 (d, 1H), 8.81
(s, 1H), 9.01 (br s, 2H), 9.46 (br s, 2H);
[1523] Anal. calc'd for C.sub.18H.sub.16N.sub.2OS.1.15
CH.sub.4SO.sub.3: C, 54.91; H, 4:96; N, 6.69. Found: C, 54.70; H,
5.15; N, 6.58.
EXAMPLE 150
7-methoxy-8-(pyrazinylamino)-2-naphthalenecarboximidamide,
bis(trifluoroacetate)(salt)
[1524] The desired compound was prepared from the product prepared
in Example 90D using the method described in Example 91A, then
converted to the amidine as described in Example 40D.
[1525] MS (DCI/NH.sub.3) m/z (M+H).sup.+294;
[1526] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.39 (s, 2H),
9.02 (s, 2H), 8.95 (s, 1H), 8.40 (d, 1H), 8.14 (d, 1H), 8.03 (s,
2H), 7.92 (dd, 1H), 7.84 (d, 1H), 7.76 (d, 1H) 7.66 (dd 1H), 3.90
(s, 3H);
[1527] Anal. calc'd for C.sub.20H.sub.17N.sub.5O.sub.5F.sub.61/2
TFA: C, 43.79; H, 3.07; N, 12.20. Found: C; 43.81; H, 3.22; N,
12.24.
EXAMPLE 152
6-(aminoiminomethyl)-4-(3-furanyl)-N-phenyl-2-naphthalenecarboxamide,
monohydrochloride
EXAMPLE 152A
[1528] To a solution of the product from Example 8D (5.50 g, 26.04
mmol) in CH.sub.2Cl.sub.2 (125 mL) was added
dibromodimethylhydantoin (4.47 g, 15.62 mmol) and
trifluoromethanesulfonic acid (2.51 mL, 28.41 mmol), and the
reaction was stirred at 23.degree. C. in the dark for 18 hours. The
mixture was poured into aqueous NaHSO.sub.3, the solution was made
basic with Na.sub.2CO.sub.3, and extracted with 3.times.ethyl
acetate, and the extracts were washed with brine, dried over
Na.sub.2SO.sub.4, and condensed. The product was recrystallized
from ethanol/ethyl acetate, to yield 5.80 g (77%) of the desired
compound.
[1529] MS (DCI (NH.sub.3) m/z 307 (M+NH.sub.4).sup.+.
EXAMPLE 152B
[1530] To a solution of the product from Example 152A (1.40 g,
4.826 mmol) in THF (40 mL), water (10 mL), and methanol (10 mL) was
added LiOH.water (405 mg, 9.65 mmol), and the reaction was stirred
for 18 hours. The mixture was poured into 1 M HCl and extracted
with 3.times.ethyl acetate, and the extracts were washed with
brine, dried over Na.sub.2SO.sub.4, and condensed, to yield 1.23 g
(92%) of the desired compound.
[1531] MS (DCI (NH.sub.3)) m/z 295 (M+NH.sub.4).sup.+.
EXAMPLE 152C
[1532] To a solution of the product from Example 152B (440 mg, 1.60
mmol), in toluene (25 mL) was added oxalyl chloride (0.140 mL, 1.6
mmol), and the reaction was stirred at 80.degree. C. for 18 hours.
The toluene was boiled off until HCl evolution ceased, and the
reaction was then cooled. Aniline (1 mL, 11 mmol) was added, and
the reaction was stirred for 10 min, nad poured into 1 M HCl. The
solution was extracted with 3.times.ethyl acetate, and the extracts
were washed with brine, dried over Na.sub.2SO.sub.4, and condensed,
to yield 560 mg (99%) of the desired compound.
[1533] MS (DCI (NH.sub.3)) m/z 370 (M+NH.sub.4).sup.+.
EXAMPLE 152D
[1534] The desired compound was prepared from Example 152C (408 mg,
1.16 mmol), furan-3-boronic acid (182 mg, 1.62 mmol) and the
procedure of Example 57B, to yield 220 mg (56%) of the desired
compound.
[1535] MS (DCI (NH3)) m/z 356 (M+NH.sub.4).sup.+.
EXAMPLE 152E
6-(aminoiminomethyl)-4-(3-furanyl)-N-phenyl-2-naphthalenecarboxamide,
monohydrochloride
[1536] The desired compound was prepared from Example 152D and the
procedure of Example 40D.
[1537] MS (DCI/NH.sub.3) m/z 356 (M+H).sup.+;
[1538] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.15 (m, 2H),
7.41 (dd, 2H), 7.83 (d, 2H), 7.91 (d, 1H), 7.99 (dd, 1H), 8.19 (d,
1H), 8.38 (s, 1H), 8.41 (d, 1H), 8.62 (s, 1H), 8.69 (s, 1H), 9.15
(br s, 2H), 9.55 (br s, 2H);
[1539] Anal. calc'd for C.sub.22H.sub.17N.sub.3O.sub.2.2.75 HCl: C,
57.99; H, 4.37; N, 9.22. Found: C, 57.85; H, 4.84; N, 9.44.
EXAMPLE 153
6-(aminoiminomethyl)-4-[1-(methylsulfonyl)-1H-pyrazol-4-yl]-N-phenyl-2-nap-
hthalenecarboxamide, monohydrochloride
EXAMPLE 153A
[1540] The desired compound was prepared from the product from
Example 53D and the product from Example 152A by the procedure of
Example 47A.
[1541] MS (DCI/NH.sub.3) m/z 408 (M+H).sup.+.
EXAMPLE 153B
[1542] The desired compound was prepared from the product from
Example 153A, by the procedure of Example 53F.
[1543] MS (DCI/NH.sub.3) m/z 278 (M+H).sup.+.
EXAMPLE 153C
[1544] The desired compound was prepared from the product from
Example 153B, by the procedure of Example 87A (86A).
[1545] MS (DCI/NH.sub.3) m/z 373 (M+NH.sub.4).sup.+.
EXAMPLE 153D
[1546] The desired compound was prepared from the product from
Example 153C, by the procedures of Example s 152B and 152C
[1547] MS (DCI/NH.sub.3) m/z 356 (M-SO.sub.2Me+NH.sub.4).sup.+.
EXAMPLE 153E
6-(aminoiminomethyl)-4-1-(methylsulfonyl)-1H-pyrazol-4-yl]
-N-phenyl-2-naphthalenecarboxamide, monohydrochloride
[1548] The desired compound was prepared from Example 153D and the
procedure of Example 40D.
[1549] MS (DCI/NH.sub.3) NONE;
[1550] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.99 (s, 3H),
7.14 (t, 1H), 7.40 (t, 2H), 7.84 (d, 2H), 7.91 (d, 1H), 8.08 (s,
1H), 8.15 (d, 1H), 8.35 (m, 2H), 8.65 (br s, 2H), 9.33 (br s, 2H),
9.61 (br s, 2H), 10.58 (s, 1H);
[1551] Anal. calc'd for C.sub.22H.sub.19N.sub.5SO.sub.3.2.75 HCl:
C, 49.51; H, 4.11; N. 13.12. Found: C, 49.44; H, 3.83; N,
12.09.
EXAMPLE 154
6-(aminoiminomethyl-4-[5-(methylthio)-3-furanyl)]-N-phenyl-2-naphthaleneca-
rboxamide, monohydrochloride
EXAMPLE 154A
[1552] To a solution of 2-trimethylsilyl-3-bromofuran (4.17 g,
19.03 mmol) in THF (40 mL) at -78.degree. C. was added a 1.5 M
solution of LDA (12.7 mL, 19.03 mmol), and the reaction was stirred
at -78.degree. C. for 1 hour. Methyl disulfide (1.89 mL, 20.93
mmol) was then added, and the reaction was allowed to warm to room
temperature overnight. The reaction was poured into saturated
aqueous NH.sub.4Cl solution, and extracted with 3.times.diethyl
ether. The combined extracts were washed with brine, dried over
Na.sub.2SO.sub.4, and condensed. The crude material was
chromatographed on SiO.sub.2 using hexanes as eluent, to yield 3.02
g (60%) of the desired compound.
[1553] MS (DCI/NH.sub.3) m/z 265, 267 (M+H).sup.+.
EXAMPLE 154B
[1554] A solution of the product from Example 154A (2.68 g, 10.1
mmol) and a 1 M solution of TBAF (20.2 mL) in THF (20 mL) was
stirred for 30 minutes. The reaction was condensed and The desired
compound was chromatographed on SiO.sub.2 using hexanes as eluent,
to yield 1.39 g (71%) of 2-methylthio-4-bromofuran. This material
was taken on directly to the next step. To a solution of this
product (7 mmol) in THF (25 mL) at -78.degree. C. was added a 2.5 M
solution of BuLi (2.8 mL, 7 mmol), and the reaction was stirred for
5 minutes. Bu.sub.3SnCl (1.90 mL, 7 mmol) was then added, the
reaction was stirred for 30 min, and then allowed to warm to room
temperature. The reaction was poured into saturated aqueous
NH.sub.4Cl solution, and extracted with 3x diethyl ether. The
combined extracts were washed with brine, dried over
Na.sub.2SO.sub.4, and condensed. The crude material was
chromatographed on SiO2 using hexanes as eluent, to yield 1.24 g
(30%) of the desired compound.
[1555] MS (DCI/NH.sub.3) m/z 404 (M+H).sup.+.
EXAMPLE 154C
[1556] A solution of the product from Example 154B (920 mg, 2.28
mmol), the product from Example 152A (662 mg, 2.28 mmol), and
PdCl.sub.2 (PPh.sub.3).sub.2 (161 mg, 0.23 mmol) in CH.sub.3CN (15
mL) was stirred for 18 hours at 80.degree. C. The reaction was
condensed and the crude material was chromatographed on SiO.sub.2
using 20% ethyl acetate/hexanes as eluent, to yield 671 mg (91%) of
the desired compound.
[1557] MS (DCI/NH.sub.3) m/z 324 (M+H).sup.+.
EXAMPLE 154D
[1558] The desired compound was prepared from the product from
Example 154C, by the procedure of Example 152 B.
[1559] MS (DCI/NH.sub.3) m/z 310 (M+H).sup.+.
EXAMPLE 154E
[1560] The desired compound was prepared from the product from
Example 154D, by the procedure of Example 152C.
[1561] MS (DCI/NH.sub.3) m/z 402 (M+NH.sub.4).sup.+.
EXAMPLE 154F
6-(aminoiminomethyl)-4-[5-(methylthio)-3-furanyl)l-N-phenyl-2-naphthalenec-
arboxamide, monohydrochloride
[1562] The desired compound was prepared from Example 154E and the
procedure of Example 144C.
[1563] MS (DCI/NH.sub.3) m/z 402 (M+H).sup.+;
[1564] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.54 (s, 3H),
7.15 (t, 1H), 7.24 (s, 1H), 7.40 (t, 2H), 7.84 (d, 2H), 7.92 (dd,
1H), 8.19 (d, 1H), 8.39 (d, 1H), 8.44 (s, 1H), 8.61 (s, 1H), 8.69
(s, 1H), 9.35 (br s, 4H), 10.61 (s, 1H);
[1565] Anal. calc'd for C.sub.23H.sub.19N.sub.3SO.sub.2.2.25 HCl:
C, 57.14; H, 4.43; N, 8.69. Found: C, 57.13; H, 4.21; N, 8.56.
EXAMPLE 155
methyl [7-(aminoiminomethyl)-1-naphthalenyl]methyl carbamate,
mono(trifluoroacetate) (salt)
[1566] The desired compound is prepared according to the procedures
described in Example s 12 and 13. Yield: 40 mg (42%) of white
solid
[1567] MS m/z: 258 (M+H).sup.+
[1568] .sup.1H NMR (DMSO, 300 MHz): 3.28 (s, 3H), 3.82 (br, 3H),
7.66 (dd, 1H, J1=7.5 Hz, J2=1.4 Hz), 7.78 (m, 1H), 8.89 (Dd, 1H,
J1=8.8 Hz, J2=2.0 Hz), 8.05 (d, 1H, 8.1 Hz), 8.24 (d, 1H, 8.8 Hz),
8.30 (s, 1H), 9.09 (s, 2H), 9.52 (s, 2H);
[1569] Anal. calc'd for C.sub.14H.sub.15N.sub.3O.sub.2.1.25
C.sub.2F.sub.3O.sub.2H.0.25 H.sub.2O: C, 49.02; H, 4.18; N, 10.39.
Found: C, 48.81; H, 3.91; N, 10.15.
EXAMPLE 156
propyl [7-(aminoiminomethyl)-1-naphthalenyl]carbamate,
mono(trifluoroacetate)(salt)
[1570] The desired compound is prepared according to the procedures
described in Example s 12 and 13. Yield: 52 mg (46%) of white
solid
[1571] MS m/z: 272 (M+H).sup.+
[1572] .sup.1H NMR (DMSO, 300 MHz): 0.97 (t, 3H, J1=J2=7.1 Hz),
1.67 (Sextet, 2H, J=7.1 Hz), 4.19 (t, 3H, J1=J2=6.8 Hz). 7.71 (d,
1H, 8.5 Hz), 7.83 (m, 3H), 8.14 (d, 1H, J=8.5 Hz), 8.67 (s, 1H),
9.22 (Br, 3H), 9.63 (s, 1H);
[1573] Anal. calc'd for C.sub.15H.sub.17N.sub.3O.sub.2.0.25
C.sub.2F.sub.3O.sub.2H.0.75 H.sub.2O: C, 49.18; H, 4.66; N, 9.83.
Found: C, 49.27; H, 4.87; N, 10.02.
EXAMPLE 157
[1574] N-[7-(aminoiminomethyl)-1-naphthalenyl]-N'-methylurea,
mono(trifluoroacetate)(salt)
[1575] The desired compound is prepared according to the procedures
described in Example s 12 and 13. Yield: 36 mg (54%) of white
solid
[1576] MS m/z: 243 (M+H).sup.+
[1577] .sup.1H NMR (DMSO, 300 MHz): 2.80 (d, 1H), 6.45 (d, 1H),
7.70 (m, 2H), 7.82 (dd, J=8.9 Hz, J2=2.1 Hz), 8.08 (dd, 7.4 Hz,
J=1.3 Hz), 8.17 (d, 1H, J=8.5 Hz), 8.62 (s, 1H), 8.72 (s, 1H), 9.07
(s, 2H), 9.47 (s, 2H), (s, 2H);
[1578] Anal. calc'd for C.sub.13H.sub.14N.sub.4O.1.5
C.sub.2F.sub.3O.sub.2H.0.5 H.sub.2O: C, 45.50; H, 3.94; N, 13.27.
Found: C, 45.22; H, 3.86; N, 13.12.
EXAMPLE 158
ethyl [7-(aminoiminomethyl)-1-naphthalenyl)carbamate,
mono(trifluoroacetate)(salt)
[1579] The desired compound is prepared according to the procedures
described in Example s 12 and 13. Yield: 70 mg (76%) of white
solid
[1580] MS m/z: 258 (M+H).sup.+
[1581] .sup.1H NMR (DMSO, 300 MHz): 1.30 (t, 3H, J1=J2=7.4 Hz),
4.20 (q, 2H, J=7.0 Hz), 7.80 (m, 4H), 8.15 (d, 8.5 Hz), 8.68 (s,
1H), 9.13 (s, 2H), 9.38 (s, 2H), 9.66 (s, 1H);
[1582] Anal. calc'd for C.sub.14H.sub.15N.sub.3O.sub.2.1.5
C.sub.2F.sub.3O.sub.2H: C, 47.67; H, 3.88; N, 9.81. Found: C,
47.97; H, 3.85; N, 9.78.
EXAMPLE 159
N-[7-(aminoiminomethyl)-1-naphthalenyl)propanamide,
mono(trifluoroacetate)(salt)
[1583] The desired compound is prepared according to the procedures
described in examples 12 and 13.
[1584] Yield: 20 mg (23 %) of white solid
[1585] MS m/z: 242 (M+H).sup.+
[1586] .sup.1H NMR (DMSO, 300 MHz): 1.18 (t, 3H, 7.4 Hz), 3.38 (m,
2H), 7.89 (m, 3H), 7.81 (dd, 1H, J1=8.4 Hz, J2=1.9 Hz), 7.87 (d,
1H, 8.5 Hz), 8.58 (s, 1H), 9.02 (s, 2H), 9.47 (s, 2H), 9.97 (s,
1H).
[1587] Anal. calc'd for C.sub.14H.sub.15N.sub.3O.1.15
C.sub.2F.sub.3O.sub.2H. 0.25 H.sub.2O: C, 51.94; H, 4.45; N, 11.15;
Found: C, 52.02; H, 4.24; N, 10.76.
EXAMPLE 160
N-[7-(aminoiminomethyl)-1-naphthalenyl)-2-methoxyacetamide,
mono(trifluoroacetate)(salt)
[1588] The desired compound is prepared according to the procedures
described in Example s 12 and 13. Yield: 30 mg (30%) of white
solid
[1589] MS m/z: 258 (M+H).sup.+
[1590] .sup.1H NMR (DMSO, 300 MHz): 3.49 (s, 3H), 4.18 (s, 2H),
7.80 (m, 3H), 7.93 (d, 1H, 7.7 Hz), 8.47 (d, 1H, 8.5 Hz), 8.47 (s,
1H), 9.10 (s, 2H), 9.46 (s, 2H), 9.99 (s, 2H);
[1591] Anal. calc'd for
C.sub.14H.sub.15N.sub.3O.sub.2.1C.sub.2F.sub.3O.su- b.2H.1.25
H.sub.2O: C, 48.80; H, 4.73; N, 10.67. Found: C, 48.53; H, 4.34; N,
10.54;
[1592] .sup.1H NMR (DMSO, 300 MHz): 2.16 (s, 3H), 4.85 (s, 2H),
7.82 (m, 4H), 8.18 (d, 1H, J=8.18 Hz), 8.55 (s, 1H), 9.10 (s, 2H),
9.44 (s, 2H), 10.24 (s, 1H);
[1593] Anal. calc'd for
C.sub.15H.sub.15N.sub.3O.sub.3.1C.sub.2F.sub.3O.su- b.2H.1H.sub.2O:
C, 48.93; H, 4.35; N, 10.07. Found: C, 48.82; H, 4.27; N,
10.00.
EXAMPLE 161
N-[7-(aminoiminomethyl )-1-naphthalenyl]urea,
mono(trifluoroacetate)(salt)
[1594] The desired compound is prepared according to the procedures
described in Example s 12 and 13. Yield: 35 mg (54%) of yellownish
solid
[1595] MS m/z: 229 (M+H).sup.+
[1596] .sup.1H NMR (DMSO, 300 MHz): 6.22 (s, 2H), 7.65 (m, 2H),
7.77 (dd, J1=8.8 Hz, J2=1.5 Hz). 8.57 (s, 1H), 8.79 (s, 1H), 9.07
(s, 2H), 9.49 (br, 2H);
[1597] Anal. calc'd for C.sub.12H.sub.12N.sub.4O.1
C.sub.2F.sub.3O.sub.2H.- 0.75 H.sub.2O: C, 40.90; H, 3.33; N,
11.95. Found: C, 40.95; H, 3.64; N, 12.31.
EXAMPLE 162
N-[7-(aminoiminomethyl)-1-naphthalenyl]-2-hydroxyacetamide,
mono(trifluoroacetate)(salt)
[1598] The desired compound is prepared according to the procedures
described in Examples 12 and 13. Yield: 24 mg (37%) of white
solid
[1599] MS m/z: 244 (M+H).sup.+
[1600] .sup.1H NMR (DMSO, 300 MHz): 4.18 (s, 2H), 5.82 (br, 1H).
7.67 (m, 1H), 7.85 (m, 3H), 8.20 (d, 1H), 9.18 (s, 2H), 9.42 (s,
2H), 9.89 (s, 1H);
[1601] Anal. calc'd for C.sub.13H.sub.13N.sub.3O.sub.2.1
C.sub.2F.sub.3O.sub.2H.0.75 H.sub.2O: C, 48.59; H, 4.21; N, 11.33.
Found: C, 48.64; H, 3.89; N, 11.25.
EXAMPLE 163
8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,
bis(trifluoroacetate)(salt)
[1602] The desired compound is prepared according to the procedures
described in Examples 91A and 13.Yield: 28 mg (28%) of pale yellow
solid
[1603] MS m/z: 264 (M+H).sup.+
[1604] .sup.1H NMR (DMSO, 300 MHz): 6.90 (t, 1H, J1=J2=4.7 Hz),
7.69 (d, J=7.8 Hz), 7.80 (1H, J=8.1 Hz), 7.81 (1H, dd, J1 =8.4 Hz,
J2=2.1 Hz), 8.08 (1H, dd, J1=7.4 Hz, J2=0.6 Hz), 8.14 (1H, d, J=8.5
Hz), 8.49 (d, 2H), 8.75 (1H, d, J=1.7 Hz). 9.06 (s, 2H), 9.37 (s,
2H), 9.60 (s, 1H);
[1605] Anal. calc'd for C.sub.15H.sub.13N.sub.5.2.25
C.sub.2F.sub.3O.sub.2H.0.25 H.sub.2O: C, 44.67; H, 4.283.03; N,
13.36. Found: C, 44.49; H, 2.80; N, 13.40.
EXAMPLE 164
8-amino-2-naphthalenecarboximidamide,
bis(trifluoroacetate)(salt)
[1606] To a solution of crude 8-amino-2-nitrile-naphthalene
prepared as described in Example 10 at room temperature in 10:1
pyridine: triethylamine (10 mL) was bubbled hydrogen sulfide for 5
minutes and stirred at room temperature overnight. The reaction
mixture was added water (50 mL) and the product was extracted into
ethyl acetate (3.times.30 mL) . The combined organic solvent was
dried over magnesium sulfate, filtered and evaporated. The
resulting yellow substance was taken up in acetone (30 mL) then
added methyl iodide (2 mL). The reaction mixture was boiled for 1
hour, then evaporated to dryness. To the resulting yellow substance
in methanol (25 mL) was added ammonium acetate (100 mg) and stirred
at room temperature overnight. The solvent was removed under vacuum
and the product was purified via reverse phase chromatography using
0.1 % TFA/water and 0.1 % TFA/methanol as eluent.
[1607] MS m/z: 186 (M+H).sup.+
[1608] .sup.1H NMR (DMSO, 300 MHz): 5.14 (br, 3H), 6.80 (dd, 1H,
J1=7.8 Hz, J2=1 Hz), 7.17 (d, 1H, J=7.8 Hz), 7.40 (dd, 1H,
J1=J2=7.8 Hz), 7.70 (dd, 1H, J1=8.9 Hz, J2=2.1 Hz), 7.91 (d, 1H,
J=8.5 Hz), 8.65 (s, 1H), 8.95 (s, 2H), 9.23 (s, 2H);
[1609] Anal. calc'd for C.sub.11H.sub.11N.sub.3.2.5
C.sub.2F.sub.3O.sub.2H.0.75 H.sub.2O: C, 39.72; H, 3.13; N, 8.69.
Found: C, 40.01; H, 3.19; N, 8.88.
EXAMPLE 165
6-(aminoiminomethyl)-N-[4-(aminomethyl)phenyl]-4-(2-pyrimidinylamino)-2-na-
phthalenecarboxamide, tris(trifluoroacetate)(salt)
EXAMPLE 165A
[1610] A suspension of 2-nitrile-6-methyester naphthalene Example
8D (5.0 g, 23 mmol) in concentrated sulfuric acid (50 mL) at
-5.degree. C. was added a solid potassium nitrate. The colour of
reaction mixture was gradually changed into a dark brown. The
reaction mixture was stirred for 15 minutes and was poured into
ice-water. Collected the precipitate and washed with water. The
crude product was recrystallized from ethyl acetate and ethanol.
Yield 4.3 g (68%) of pale yellow powder.
EXAMPLE 165B
[1611] To a solution of
2-nitrile-6-methylester-8-nitro-naphthalene, Example 165A (3.5 g,
13.6 mmol) in a mixture of THF (100 mL) and ethyl acetate (120 mL)
was added 10% Pd-C (350 mg). The reaction mixture was placed under
hydrogen at atmospheric pressure (balloon) and stirred at room
temperature for 3 5 hour. The mixture was filtered through celite
and silica gel, washed with ethyl acetate and evaporated. The
resulting solid was washed with ether (20 mL). Yield 2.20 g (71%)
of yellow powder.
EXAMPLE 165C
[1612] A mixture containing
2-Nitrile-6-methylester-8-amino-naphthalene, Example 165B (2.8 g,
12.3 mmol), BINAP (116 mg, 0.186 mmol), Pd.sub.2 (DBA).sub.3 (64
mg, 0.061 mmol), NaO-t-Bu (1.667 g, 17.6 mmol), 2-Bromopyrimidine
(2.363 g, 14.9 mmol) and Toluene (80 mL) in an oven-dried flask
under nitrogen, was stirred at room temperature for 10 minutes. The
reaction mixture was heated to 80.degree. C. for 1 hour. At the end
of the reaction (TLC, hexanes+ethyl acetate=4: 1), brine 9200 mL)
was added. Extracted the mixture with CH.sub.2Cl.sub.2. (4x250 mL).
Evaporated the solvent. Yield 3.5 g (93%) of pale yellow
powder.
EXAMPLE 165D
[1613] To a suspension of 2-nitrile-6-methylester-8-N-
(2-pyrimidine)-naphthalene, Example 165C (5.2 g, 17.1 mmol ) in
ethanol (150 mL) was added potassium carbonate (3.54 g, 33.3 mmol)
in water (200 mL). The resulting suspension was heated at
120.degree. C. for 2 hours, at that time all the suspension turned
into a clear solution. The mixture is cooled down, then acidified
with 2 N HCl. The resulting precipitate was collected by filtration
to yield 4.5 g (90%) of pale yellow powder. No further purification
was required for the next step.
EXAMPLE 165E
[1614] To a cold (0.degree. C.) solution of
2-nitrile-8-N-(2-pyrimidine)-6- -carboxylic acid-naphthaleneExample
165D (5.0 g, 17.2 mmol) in DMF (150 mL) was added DIEA (7.6 mL,
42.6 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N-
,N',N'-tetramethyluroniumhexafluorophosphate (9.8 g, 25.7 mmol)
followed by tert-Butoxycarbonylamino-4-aminomethylaniline (5.74 g,
20 mmol). The resuting reaction mixture was stirred for about 1
hour. The reaction was quenched with water (200 mL) and the
resulting precipitate was collected by filtration to yield 3.26 g
(38%) of pale yellow powder.
EXAMPLE 165F
[1615] To a solution of the substrate, Example 165E (3.0 g, 6.07
mmol) in pyridine (150 mL) was added triethylamine (9 mL). H.sub.2S
was passed for 10 minutes and the resulting mixture was stirred at
room temperature for 48 hour. 100 mL of water was added to the
reaction mixture and the precipitate was Collected by filtration.
Yield (3.0 g (93%) of yellow solid.
EXAMPLE 165G
[1616] To a solution of the thioamide, Example 165F in acetone (200
mL) was added MeI (6 mL) and the mixture was stirred at room
temperature overnight. The mixture was evaporated to dryness to
yield 1.2 g (78%) of yellow solid.
EXAMPLE 165H
6-(aminoiminomethyl)-N-[4-(aminomethyl)phenyl]-4-(2-pyrimidinylamino)-2-na-
phthalenecarboxamide, tris(trifluoroacetate)(salt)
[1617] To a solution of the imidate ester, Example 165G, (1.5 g,
2.2 mmol) in methanol (50 mL ) was added ammonium acetate (0.5 g,
6.4 mmol) and stirred at room temperature overnight. After
evaporation of the solvent the residue was treated with ether (3x25
mL) and the ether was decanterd out. The residue was dissolved in a
mixture of 10: 1: 1 acetonitrile: water: acetic acid (50 mL). After
addition of ether (100 mL), the Boc protected product precipitated
as an acetate salt and was colleted by filtration. The solid was
added 1: 1 TFA: methylene chloride (50 mL) containing thioanisole
(0.5 mL). The reaction mixture was stirred at room temperature
overnight. The product was purified over RPC.sub.18 chromatography
using water: methanol with 0.1% TFA as eluent. Yield after
lyophilization 0.5 g (54%) of pale yellow solid.
[1618] MS m/z: 412 (M+H).sup.+
[1619] .sup.1H NMR (DMSO, 300 MHz): 4.02 (q, 2H, J=5.8), 6.94 (dd,
1H, J12=J2=4.8 Hz), 7.45 (d, 2H, J=8.5 Hz), 7.84 (d, 2H, J=8.4 Hz),
7.92 (dd, 1H, J1=8.5 Hz, J2=1.7 Hz), 8.13 (br, 3H), 8.30 (d, 1H,
J=8.9 Hz), 8.41 (s, 1H), 8.52 (d., 2H), 8.55 (s, 1H), 8.81 (s, 1H),
9.19 (s, 2H), 9.43 (s, 2H), 9.75 (s, 1H), 10.62 (s, 1H);
[1620] Anal. calc'd for C.sub.23H.sub.21N.sub.7O.2.5
C.sub.2F.sub.3O.sub.2H.1 H.sub.2O: C, 43.49; H, 3.22; N, 11.83.
Found: C, 43.54; H, 3.34; N, 11.69.
EXAMPLE 166
6-(aminoiminomethyl)-N-phenyl-4-(2-pyrimidinylamino)-2-naphthalenecarboxam-
ide, mono(trifluoroacetate) (salt)
[1621] The same procedure as described in Examples 165 substituting
aniline for 4-amino benzyl amine.
[1622] MS m/z: 383 (M+H).sup.+
[1623] .sup.1H NMR (DMSO, 300 MHz): 6.93-6.96 (m, 1H), 7.14 (dd,
1H, J1=7.3 Hz, J2=7.4 Hz), 7.40 (dd, 2H, J1=J2=7.3 Hz), 7.80 (, d,
2H, J=8.1 Hz), 7.91 (d, 1H, J=8.9 Hz), 8.30 (d, 1H, J=9.0 Hz), 8.41
(s, 1H), 8.52-8.54 (m, 3H), 8.80 (s, 1H), 9.16 (s, 2H), 9.45 (s,
2H), 9.78 (s, 1H), 10.55 (s, 1H);
[1624] Anal. calc'd for C.sub.22H.sub.18N.sub.6O.2
C.sub.2F.sub.3O.sub.2H.- 0.25 H.sub.2O: C, 50.78; H, 3.28; N,
13.31. Found: C, 50.85; H, 3.28; N, 13.31.
EXAMPLE 167
N-[(4-(aminomethyl)phenyl]-6-[amino(hydroxyimino)methyl]-4-(2-pyrimidinyla-
mino)-2-naphthalenecarboxamide, bis(trifluoroacetate)(salt)
[1625] To a suspension of compound, prepared in Example 165 E (0.20
g, 0.40 mmol ) in methanol (40 mL) and water (20 mL) was added
hydroxylamine hydro-chloride (112 mg, 1.75 mmol) and sodium
carbonate (85 mg, 0.80 mmol), the reaction mixture was stirred for
48 hours at room temperature, TLC showed no reaction. Th reaction
mixture was heated at reflux for 10 hours and removed the most of
the solvents, the precipitate was collected by filtration, gave 1.2
g of pale yellow solid. The solid was disoolved in 1: 1
TFA+CH.sub.2Cl.sub.2 (30 mL) and sitrred at room temperature for 24
hours. The solvents was removed under vaccuum and the residue was
loaded to a R18 reverse phase column. The fraction was lyophilized
and yielded a pale yellow powder (80 mg, 66%).
[1626] MS m/z: 428 (M+H).sup.+
[1627] .sup.1H NMR (DMSO, 300 MHz): 4.02 (q, 2H, J=6.1 Hz), 6.92
(dd, 1H, J1=J2=5.1 Hz), 7.46 (d, 2H, 8.4 Hz), 7.85 (d, 2H, J=8.5
Hz), 7.88 (d, 1H, 9 Hz), 8.12 (br, 3H), 8.22 (d, 1H, J=8.9 Hz),
8.40 (s, .sup.1H), 8.48 (s, 1H), 8.51 (d, 2H, J=4.8 Hz), 8.64 (s,
1H), 9.74 (s, 2H), 10.61 (s, 2H);
[1628] Anal. calc'd for C.sub.23H.sub.21N.sub.7O.sub.2.2.9
C.sub.2F.sub.3O.sub.2H.1.25 H.sub.2O: C, 44.31; H, 3.41; N, 12.56;
F, 21.17 Found: C, 44.08; H, 3.30; N, 12.50, F, 21.25.
EXAMPLE 168
6-(aminoiminomethyl)-N-[4-(hydroxymethyl)phenyl]-4-(2-pyrimidinylamino)-2--
naphthalenecarboxamide, mono(trifluoroacetate)(salt)
[1629] The desired compound is prepared as described in Example 165
using 4-amino benzyl alcohol instead of 4-amino benzylamine.
[1630] MS m/z: 413 (M+H).sup.+
[1631] .sup.1H NMR (DMSO, 300 MHz): 4.48 (s, 2H), 6.94 (dd, 1H, 2H,
J=8.8 Hz), J1=J2=4.8 Hz), 7.32 (d, 2H, J=8.8 Hz), 7.90 (dd, 1H,
J1=8.5 Hz, J2=1.7 Hz), 8.28 (d, 2H, J=8.8 Hz), 8.41 (s, 1H), 8.54
(d, 2H, J=4.8 Hz), 8.55 (dd, 1H, J=1.3 Hz), 8.80 (s, 1H), 9.08 (s,
2H), 9.43 (s, 2H), 9.73 (s, 1H), 10.48 (s, 1H);
[1632] Anal. calc'd for C.sub.23H.sub.20N.sub.6O.sub.2: C, 49.06;
H, 3.83; N, 12.81; F, 16.50. Found: C, 48.74; H, 3.86; N, 12.63, F,
16.54.
EXAMPLE 170
methyl
[3-[[[4-(aminomethyl)phenyl]amino]carbonyl]-7-[4-amino(hydroxyimino-
)methyl]-1-naphthalenyl]carbamate, bis(trifluoroacetate)(salt)
EXAMPLE 170A
[1633] To a suspension of the nitrile, Example 141D (213 mg, 0.45
mmol) and hydroxylamine hydrochloride (338 mg, 4.86 mmol) in
methanol (40 mL) water (5 mL) was added potassium carbonate (538
mg, 3.9 mmol) stirred at room temperature overnight. The solvent
was evaporated and the resulting solid was washed with ether and
hexanes to yield the product as white solid 153 mg (62%).
[1634] MS (ECI) m/z 508 (M+H).sup.+.
EXAMPLE 170B
methyl
[3-[[[4-(aminomethyl)phenyl]amino]carbonyl]-7-[4-amino(hydroxyimino-
)methyl-1-naphthalenyl]carbamate, bis(trifluoroacetate)(salt)
[1635] The Boc protected substrate, Example 170A was added 3 mL of
4 N HCl in dioxane and stirred at room temperature for 20 minutes.
The solvent was evaporated under vacuum and the product was
separated on MPLC with a column of RP C.sub.18 using methanol-water
+0.1%TFA as eluent. Yield of white solid 117 mg (79%).
[1636] MS (ECI) m/z 408 (M+H).sup.+;
[1637] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.77 (S, 3H),
4.03 (s, 2H), 4.01 (q, J=5.9 2H), 7.46 (d, J=8.5 Hz, 2H), 7.86 (d,
J=8.5 Hz, 2H), 7.90 (dd, J.sub.1=8.5, Hz, J.sub.2=1.4 Hz, 1H),
8.09-8.15 (m, 4H), 8.17 (d, J=8.4 Hz, 1H), 8.29 (s, 1H), 8.42 (s,
1H), 8.56 (s, 1H), 9.80 (s, 1H), 10.62 (s, 1H);
[1638] Anal. calc'd for C.sub.21H.sub.21N.sub.5O.sub.4.2.5 TFA.0.5
H.sub.2O: C, 44.52; H, 3.52; F, 20.3 1; N, 9.98. Found: C, 44.78;
H, 3.57; F, 19.82; N, 9.87.
EXAMPLE 171
6-[amino(hydroxyimino)methyl1-N-phenyl-2-naphthalenecarboxamide
[1639] The title compound is prepared as described by Judkins et
al., Synthetic Communications 26 (23), 4351-4367 (1996). The
compound prepared in Example 55C (0.1 g, .36 mmole) is dissolved in
a 10: 1 mixture of Toluene: methanol to which is added
hydroxylamine hydrochloride (3.6 mmole) and potassium tert-butoxide
(3.6 mmole). The resulting slurry is refluxed for 17 hr., cooled,
solvents removed under vacuum. The residue is taken up in distilled
water (30 ml) extracted with ethyl acetate (2.times.100 ml). The
combined organic extracts are washed with 10% NaCl (50 ml), dried
over anhydrous Na.sub.2SO.sub.4. The sample is filtered of drying
agent and the solvent removed under vacuum leaving a white solid
(65 mg). The material is purified by medium pressure reverse phase
chromatography as described in Example 1. The title compound is
obtained as white solid (45 mg)
[1640] MS (m/z) M+H.sup.+: 306
[1641] .sup.1H NMR (DMSO-d.sub.6): 10.51 (s, 1H), 9.32 (s, OH),
8.70 (s, 1H), 8.57 (s, 1H), 8.34 (d, 1H), 8.25 (d, 1H), 8.17 (dd,
1H), 7.90 (dd, 1H), 7.83 (d, 2H), 7.40 (dd, 2H), 7.15 (dd, 1H),
6.25 (bs, 2H).
[1642] Analysis: calc'd for C.sub.20H.sub.16N.sub.3O.sub.4F.sub.3:
C, 57.28, H, 3.85, N, 10.02; Found C, 56.89, H, 3.65, N, 9.90.
EXAMPLE 174
8-(2-pyridinylamino)-2-naphthalenecarboximidamide,
bis(trifluoroacetate) salt
EXAMPLE 174A
[1643] To a solution of the product from 11D (168 mg, 1.00 mmol) in
5 mL toluene was added 2-bromopyridine (0.105 mL, 1.1 mmol), NaOtBu
(135 mg, 1.4 mmol), Pd.sub.2dba.sub.3 (92 mg, 0.1 mmol), and P
(o-tolyl).sub.3 (122 mg, 0.4 mmol), and the reaction was stirred
for 24 hours at 100.degree. C. The reaction was cooled, and the
crude reaction mixture was chromatographed on SiO.sub.2 using 50%
ethyl acetate/hexanes as eluent to yield 80 mg (33%) of the desired
compound.
[1644] MS (DCI (NH.sub.3)) m/z 246 (M+H).sup.+.
EXAMPLE 174B
8-(2-pyridinylamino)-2-naphthalenecarboximidamide,
bis(trifluoroacetate) salt
[1645] The product from Example 174A (121 mg, 0.493 mmol) was
dissolved in THF (2 mL) and 0.543 mL of a I M solution of LiN
(TMS).sub.2 in THF was added. The reaction was stirred for 5 min,
and TMSCl (0.069 mL, 0.543 mmol) was added. After stirring for 30
min, another 1.09 mL of the 1 M solution of LiN (TMS).sub.2 was
added. The reaction was stirred for 18 hours, and 10 mL of a 2 M
aq. HCl solution was added. The reaction was stirred for another 24
hours, and was basicified with saturated aq. Na.sub.2CO.sub.3. The
mixture was extracted with 3.times.ethyl acetate, and the extracts
were washed with brine, dried over Na.sub.2SO.sub.4, and condensed.
The crude product was purified by reverse-phase HPLC to yield the
desired compound (21 mg, 7%): m.p. 137-147.degree. C.
[1646] MS (DCI (NH.sub.3) m/z 263 (M+H).sup.+;
[1647] .sup.1H NMR (300 MHz, DMSO) .delta. 9.98 (br s, 1H), 9.46
(br s, 2H), 9.27 (br s, 2H), 8.74 (s, 1H), 8.21 (d, J=9 Hz, 1H),
8.11 (d, J=6 Hz, 1H), 8.02 (d, J=9 Hz, 1H), 7.81-7.95 (m, 3H), 7.75
(dd, J=9, 9 Hz, 1H), 7.16 (m, 1H), 6.95 (m, 1H), 2.55 (s, 3H);
[1648] Anal. calc'd for
C.sub.16H.sub.14N.sub.4.3.1C.sub.2HF.sub.3O.sub.2: C, 43.30; H,
2.80; N, 9.10. Found: C, 43.14; H, 3.04; N, 9.90.
EXAMPLE 176
6-[4-[(hydroxymethyl)phenyl]methoxy]-2-naphthalenecarboximidamide,
methanesulfonate(salt)
EXAMPLE 176A
[1649] To a solution of NaH (60% in mineral oil, 1.17 g, 29.3 mmol)
in THF (50 mL) was added 4-bromobenzyl alcohol (5.22 g, 27.9 mmol)
in THF (50 mL), and the reaction was stirred at room temperature
for 20 minutes. p-Methoxybenzyl chloride (4.07 mL, 30 mmol) was
then added, and the reaction was stirred at 50.degree. C. for 2
hours. The mixture was poured into water and extracted with
3.times.diethyl ether, and the extracts were washed with brine,
dried over Na.sub.2SO.sub.4, and condensed. The crude reaction
mixture was chromatographed on SiO.sub.2 using hexanes as eluent,
to yield 7.39 g (86%) of the desired compound.
[1650] MS (DCI (NH.sub.3)) m/z 326 (M+NH.sub.4).sup.+;
[1651] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.47 (d, 2H), 7.28
(d, 2H), 7.23 (d, 2H), 6.90 (d, 2H), 4.48 (s, 3H), 4.47 (s, 2H),
3.91 (s, 3H).
EXAMPLE 176B
[1652] To a solution of the product from Example 176A (6.80 g,
22.13 mmol) in THF (100 mL) and hexanes (20 mL) at -100.degree. C.
was added a 2.5 M solution of BuLi (8.85 mL, 22.13 mmol), and the
reaction was stirred for 2 minutes. DMF (3.43 mL, 44.3 mmol) was
then added, and the reaction was warmed to room temperature. The
mixture was poured into water and extracted with 3.times.diethyl
ether, and the extracts were washed with brine, dried over
Na.sub.2SO.sub.4, and condensed. The crude reaction mixture was
taken up in methanol (100 mL) and NaBH.sub.4 (1.0 g, 26.2 mmol) was
added in portions. A few drops of water were added, and the mixture
condensed. The residue was chromatographed on SiO.sub.2 using 20%
ethyl acetate/hexanes as eluent, to yield 3.32 g (58%) of the
desired compound.
[1653] MS (DCI (NH.sub.3)) m/z 276 (M+NH.sub.4).sup.+;
[1654] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.38 (s, 4H), 7.29
(d, 2H), 6.90 (d, 2H), 4.70 (s, 2H), 4.54 (s, 2H), 4.49 (s, 2H),
3.81 (s, 3H), 1.62 (s, 1H).
EXAMPLE 176C
[1655] To a solution of the product from Example 176B (193 mg,
0.747 mmol), the product from Example 28A (139 mg, 0.822 mmol), and
Ph.sub.3P (216 mg, 0.822 mmol) in THF (10 mL) at 0.degree. C. was
added diethylazodicarboxylate (0.129 mL, 0.822 mmol), and the
reaction was stirred for 90 minutes at room temperature. The crude
reaction mixture was condensed, and the residue was chromatographed
on SiO.sub.2 using 10% ethyl acetate/hexanes as eluent, to yield
225 mg (74%) of the desired compound.
[1656] MS (DCI (NH.sub.3)) m/z 427 (M+NH.sub.4).sup.+;
[1657] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.15 (s, 1H), 7.81
(d, 1H), 7.77 (d, 1H), 7.58 (dd, 1H), 7.48 (d, 2H), 7.42 (d, 2H),
7.02-7.15 (m, 4H), 6.90 (d, 2H), 5.21 (s, 2H), 4.56 (s, 2H), 4.51
(s, 2H), 3.91 (s, 311).
EXAMPLE 176D
[1658] To a solution of the product from Example 176C (220 mg,
0.537 mmol) in CH.sub.2CI.sub.2 (40 mL) and water (7 mL) was added
DDQ (244 mg, 1.07 mmol), and the reaction was stirred for 90
minutes. The crude reaction mixture was taken up in
CH.sub.2Cl.sub.2, washed with 2.times.aqueous NaHCO.sub.3 and
brine, dried over Na.sub.2SO.sub.4, and condensed. The residue was
chromatographed on SiO.sub.2 using 50% ethyl acetate/hexanes as
eluent, to yield 89 mg (57%) of the desired compound.
[1659] MS (DCI (NH.sub.3)) m/z 307 (M+NH.sub.4).sup.+;
[1660] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.15 (s, 11H),
7.81 (d, 1H), 7.77 (d, 1H), 7.57 (dd, 1H), 7.49 (d, 2H), 7.41 (d,
2H), 7.33 (dd, 1H), 7.21 (d, 1H), 5.21 (s, 2H), 4.74 (s, 2H), 1.63
(br s, 11H);
EXAMPLE 176E
6-[4-[(hydroxymethyl)phenyl]methoxy]-2-naphthalenecarboximidamide,
methanesulfonate(salt)
[1661] The desired compound was prepared from Example 176D and the
procedure of Example 55D.
[1662] MS (DCI/NH.sub.3) m/z 307 (M+H).sup.+;
[1663] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.31 (s, 3H),
4.52 (s, 2H), 5.25 (s, 2H), 7.37 (d, 2H), 7.39 (dd, 1H), 7.47 (d,
2H), 7.59 (d, 1H), 7.79 (dd, 1H), 8.00 (d, 1H), 8.03 (d, 1H), 8.41
(s, 1H), 8.89 (br s, 2H), 9.34 (br s, 2H);
[1664] Anal. calc'd for C.sub.19H.sub.18N.sub.2O.sub.2.1.15
CH.sub.4SO.sub.3: C, 58.06; H, 5.46; N, 6.72. Found: C, 58.24; H,
5.62; N, 6.59.
EXAMPLE 177
N-hydroxy-8-(2-pyrimidinylamino)-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
[1665] The desired compound is prepared from the nitrile described
in Example 163 and utilizing the procedure described in Example
167. Yield as a white powder: 50 mg
[1666] MS m/z: 280 (M+H).sup.+
[1667] .sup.1H NMR (DMSO, 300 MHz): 6.90 (dd, 11H, J1=J2=5.2 Hz),
7.45 (m, 3H), 8.0 (d, 11H, J=8.5 Hz), 8.14 (d, 1H, J=8.4 Hz), 8.49
(d, J=5.3 Hz), 8.61 (s, 1H), 9.58 (s, 1H);
[1668] Anal. calc'd for C.sub.15H.sub.13N.sub.5O.2.0
C.sub.2F.sub.3O.sub.2H.0.5 H.sub.2O: C, 44.20; H, 3.12; N, 13.56.
Found: C, 44.24; H, 2.94; N, 13.49.
EXAMPLE 179
6-(2-pyridinylethynyl)-2-naphthalenecarboximidamide,
mono(trifluoroacetate)(salt)
EXAMPLE 179A
[1669] Using the product obtained in Example 28B, 2-ethynylpyridine
(Lancaster Chemical Corp.) and the procedure described in Example
121A, the desired compound was obtained.
[1670] MS (DCI/NH.sub.3) m/z 255 (M+H).sup.+.
EXAMPLE 179B
[1671] Using the product obtained in Example 179A and the procedure
described in Example 94D the desired compound was obtained.
[1672] MS (DCI) m/z 272 (M+H).sup.+;
[1673] .sup.1H NMR (300 MHz, DMSO) 8 7.45-7.50 (m, 1H), 7.72 (d,
1H), 7.82 (dd, 1H), 7.86-7.92 (m, 2H), 8.18 (d, 1H), 8.22 (d, 1H),
8.42 (s, 1H), 8.54 (s, 1H), 8.68 (m, 1H), 9.25 (s, 2H), 9.49 (s,
2H);
[1674] Anal. calc'd for C.sub.20H.sub.14F.sub.3N.sub.3O.sub.2.0.25
H.sub.2O: C, 61.62; H, 3.75; N, 10.78. Found: C, 61.72; H, 3.64; N,
10.66.
EXAMPLE 180
6-(aminoiminomethyl)-N-phenyl-4-(tetrahydro-3-furanyl)-2-naphthalenecarbox-
amide, monohydrochloride
EXAMPLE 180A
[1675] The desired compound was prepared from the product from
Example 152 by the procedure of Example 62A.
[1676] MS (DCI/NH.sub.3) m/z 340 (M-H.sub.2O).sup.+.
EXAMPLE 180B
[1677] The desired compound was prepared from the product from
Example 180A by the procedure of Example 62B.
[1678] MS (DCI/NH.sub.3) m/z 343 (M+H).sup.+.
EXAMPLE 180C
[1679] The desired compound was prepared from Example 180B and the
procedure of Example 55D.
[1680] MS (DCI/NH.sub.3) m/z 360 (M+H).sup.+;
[1681] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.20 (m, 1H),
2.52 (m, 1H), 3.85 (dd, 1H), 3.94 (ddd, 1H), 4.08 (ddd, 1h), 4.26
(dddd, 1H), 4.39 (dd, 1H), 7.14 (t, 1H), 7.40 (t, 2H), 7.81 (d,
2H), 7.95 (d, 1H), 8.08 (s, 1H), 8.32 (d, 1H), 8.59 (s, 1H), 8.79
(s, 1H), 9.25 (br s, 2H), 9.61 (br s, 2H);
[1682] Anal. calc'd for C.sub.22H.sub.21N.sub.3O.sub.2.2.6 HCl: C,
58.18; H, 5.24; N, 9.25. Found: C, 58.21; H, 4.91; N, 9.13.
EXAMPLE 181
6-1amino(hydroxyimino)methyl]-N-phenyl-4-(2-pyrimidinylamino)-2-naphthalen-
ecarboxamide
[1683] Prepared in a similar manner as described in Example 177
using the material prepared in Example 166.
[1684] MS m/z: 399 (M+H).sup.+
[1685] .sup.1H NMR (DMSO, 300 MHz): 6.88 (dd, 1H, 4.7 Hz), 7.11
(dd, 1H, J1=J2=7.5 Hz), 7.37 (dd, 2H, J1=J2=7.5 Hz), 7.82 (d, 2H,
J=8.8 Hz), 7.94 (dd, 1H, J1=8.5 Hz, J2=1.4 Hz), 8.04 (d, 1H, J=8.8
Hz), 8.31 (s, 1H), 8.43 (dd, 1H, J=14 Hz), 8.74 (d, 2H, J=4.7 Hz),
8.52 (s, 1H), 9.55 (s, 1H), 9.85 (s, 2H), 10.41 (s, 1H);
[1686] Anal. calc'd for C.sub.22H.sub.18N.sub.6O.sub.2.0.4
H.sub.2O: C, 65.14; H, 4.67; N, 20.72. Found: C, 65.57; H, 4.45; N,
20.18.
EXAMPLE 182
methyl
4-[[[7-amino(hydroxyimino)methyl]-2-naphthalenyl]oxy]methyl]benzoat-
e
[1687] The resulting product from Example 213A (110 mg, 0.347
mmol), hydroxylamine hydrochloride (26.5 mg, 0.381 mmol),
triethylamine (53 Vil, 0.381 mmol) and N, N-dimethylformamide (12
mL) were combined in a four inch glass pressure tube. The tube was
sealed and heated for 24 hours at 80.degree. C. The tube was cooled
to room temperature and additional hydroxylamine hydrochloride
(48.1 mg, 0.693 mmol) and triethylamine (96.6 .mu.l, 0.693 mmol) in
N, N-dimethylformamide (2 mL) was added. The tube was resealed and
heated for 24 hours at 80.degree. C. The addition, as above, was
repeated a second time, the tube was resealed and heated for 72
hours at 80.degree. C. The reaction mixture was concentrated to a
solide residue which was purified by column chromatography on
silica gel (60 g) eluted with 15% acetone in methylene chloride to
yield the target compound as a white solid (43 mg, 50% based on
recovered starting material).
[1688] MS (DCI (NH3)) m/z 351 (M+H).sup.+;
[1689] .sup.1H NMR NMR (300 MHz, DMSO-d6) .delta. 3.860 (s, 3H),
5.349 (s, 2H), 5.860 (s, 2H), 7.280 (dd, 1H), 7.381 (d, 1H), 7.660
(d, 2H), 7.688 (dd, 1H), 7.805 (d, 1H), 7.850 (d, 1H), 8.010 (d,
2H), 8.070 (s, 1H), 9.724 (s, 1H);
[1690] Anal. calc'd for C.sub.20H.sub.18N.sub.2O.sub.4.0.15
H.sub.2O: C, 68.04; H, 5.22; N, 7.93. Found: C, 68.06; H, 5.05; N,
7.87.
EXAMPLE 184
N-[4-(aminocarbonyl)phenyl-6-(aminoiminomethyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate) salt
EXAMPLE 184A
[1691] A suspension of the product obtained in Example 8A (300 mg,
1.39 mmol) and 5 mL dichloromethane was added dropwise to a
0.degree. solution of 4-aminobenzamide (207 mg, 1.52 mmol),
triethylamine (0.44 mL, 3.2 mmol), and 10 mL dichloromethane. The
reaction mixture was stirred for 0.5 hour at 0.degree. and for 18
hours at room temperature. Excess ether was added with stirring and
the resultant solid was filtered, washed with 1 N HCl, water, and
was dried under vacuum to afford the desired compound.
[1692] MS (DCI) m/z 333 (M+NH.sub.3).sup.+.
EXAMPLE 184B
N-[4-(aminocarbonyl)phenyl]-6-(aminoiminomethyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate) salt
[1693] Using the product obtained in Example 184A and the procedure
described in Example 4C the desired compound was obtained.
[1694] MS (DCI) m/z 333 (M+H).sup.+;
[1695] .sup.1H NMR (300 MHz, DMSO) .delta. 10.76 (S, 1H), 9.51 (S,
2H), 9.14 (S, 2H), 8.74 (S, 1H), 8.56 (S, 1H), 8.33 (D, 1H, J=8.8
Hz), 8.26 (D, 1H, J=8.8 HZ Hz), 8.16 (DD, 1H, J=8.46, 1.11 Hz),
7.91 (M, 6H), 7.31 (S, 1H);
[1696] Anal. calc'd for C.sub.20H.sub.17F.sub.3N.sub.4O.sub.4.1.5
H.sub.2O: C, 53.28; H, 4.26; N, 11.83. Found: C, 53.47; H, 3.86; N,
11.96.
EXAMPLE 185
methyl 2-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]acetate,
mono(trifluoroacetate)(salt)
EXAMPLE 185A
[1697] 7-methoxy-2-cyanonaphthalene, (2.79 g, 5.23 mmol) and
tetrabutylammonium iodide (17 mg, 0.157 mmol) were combined in a
mixture of benzene (35 mL) and cyclohexanes (17.5 mL). The
resulting solution was added to a rapidly stirring, cooled
(ice/water) suspension of aluminum triiodide (6.21 g, 15.23 mmol)
in a mixture of benzene (35 mL) and cyclohexanes (17.5 mL) under an
inert atmosphere. After the addition, the resulting suspension was
heated at reflux for 2.5 hours. The heating was removed and after
cooling to near room temperature, the reaction mixture was cooled
in an ice bath and quenched by the addition of water (100 mL). The
resulting mixture was further diluted with 2 M aqueous sodium
thiosulfate solution (50 mL) and extracted with ethyl acetate
(3.times.80 mL). The combined organic layers were dried and
evaporated. The resulting solid was dissolved in a minimum of hot
ethyl acetate, diluted hot with hexanes to the cloud point and
placed in a refrigerator for 2 hours. The desired compound was
collected by filtration, (1.99 g, 77%).
[1698] MS (DCI (NH.sub.3)) m/z 187 (M+NH.sub.4).sup.+.
EXAMPLE 185B
[1699] The resulting product from Example 185A (217 mg, 1.283 mmol)
was combined with cesium carbonate (460 mg, 1.411 mmol) and
tetrabuthylammonium iodide (catalytic) in DMF (7 mL). To this was
added t-butyl bromoacetate (193 .mu.L, 1.283 mmol) and the
resulting mixture was stirred 2 hours under an inert atmosphere.
The reaction mixture was diluted with water (100 mL) and extracted
with ethyl acetate (2.times.50 mL). The combined organic layers
were dried and evaporated. The residue was purified by column
chromatography to yield the desired compound as an oil (332 mg,
91%):
[1700] MS (DCI (NH.sub.3)) m/z 284 (M+H).sup.+, 301
(M+NH.sub.4).sup.+.
EXAMPLE 185C
methyl 2-[[6-(aminoiminomethyl)-2-naphthalenyl]oxy]acetate,
mono(trifluoroacetate)(salt)
[1701] The product from Example 185B (323 mg, 1.140 mmol) was
dissolved in anhydrous methanol (32 mL) under an inert atmosphere
and cooled to 0.degree. C. Anhydrous hydrogen chloride was bubbled
into the solution until it became saturated. The reaction was
stirred for 15 minutes at 0.degree. C. and saturated again with
anhydrous hydrogen chloride. After stirring for an additional 20
minutes at 0.degree. C. the solution was saturated one final time
with anhydrous hydrogen chloride and stirred 18 hours while warming
to room temperature. The reaction was evaporated to a solid and
dried under high vacuum for 2 hours. The solid was slurried in
methanol (64 mL), ammonium acetate (220 mg, 2.850 mmol) was added,
and the mixture was heated at reflux 2 hours. The reaction was
evaporated and purified by reverse phase chromatography to give the
desired compound (265 mg, 90%).
[1702] MS (DCI (NH3)) m/z 259 (M+H).sup.+;
[1703] .sup.1H NMR (300 MHz, DMSO-d6) .delta. 3.735 (s, 3H), 4.995
(s, 2H), 7.430 (dd, 1H), 7.458 (s, 1H), 7.669 (dd, 1H), 8.025 (d,
1H), 8.095 (d, 1H), 8.325 (d, 1H), 9.090 (br s, 1H), 9.410 (br s,
1H;
[1704] Anal. calc'd for C.sub.14H.sub.14N.sub.2O.sub.3
(C.sub.2HO.sub.2F.sub.3) 1.05: C, 51.16; H, 4.01; N, 7.41. Found:
C, 51.35; H, 3.98; N, 7.48.
EXAMPLE 186
6-(aminoiminomethyl)-N-(2-thiazolyl)-2-naphthalenecarboxarnide,
monohydrochloride
EXAMPLE 186A
[1705] The above product was prepared in the manner of Example 8A
using 2-aminothiazole.
[1706] MS (APCI) m/z (M+H).sup.+280.
EXAMPLE 186B
6-(aminoiminomethyl)-N-(2-thiazolyl)-2-naphthalenecarboxamide,
monohydrochloride
[1707] The above was prepared from Example 1B.
[1708] MS (APCI) m/z (M+H).sup.+297;
[1709] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 12.88 (s, 1H),
9.59 (s, 2H), 9.30 (s, 2H), 8.87 (s, 1H), 8.59 (s, 1H), 8.32-8.22
(m, 4H), 7.93 (dd, J=1.8, 8.4 Hz, 1H), 7.61 (d, J=3.3 Hz, 1H), 7.33
(d, J=3.3 Hz, 1H);
[1710] Anal. calc'd for C.sub.15H.sub.13N.sub.4OClS 2/5 HCl: C,
52.03; H, 3.89; N, 16.18. Found: C, 52.01; H, 3.88; N, 16.12.
EXAMPLE 187
6-(aminoiminomethyl)-N-(6-methoxy-3-pyridinyl)-2-naphthalenecarboxamide,
monohydrochloride
EXAMPLE 187A
[1711] The above product was prepared in the manner of Example 8A
using 5-amino-2-methoxypyridine.
[1712] MS (APCI) m/z (M+H).sup.+304.
EXAMPLE 187B
6-(aminoiminomethyl)-N-(6-methoxy-3-pyridinyl)-2-naphthalenecarboxamide,
monohydrochloride
[1713] The above was prepared as described Example 1B (144D).
[1714] MS (CI) m/z (M+H).sup.+321;
[1715] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 10.71 (s, 1H),
9/60 (s, 2H), 9.41 (s, 2H), 8.76 (s, 1H), 8.60 (s, 2H), 8.30 (d,
J=9, 1H), 8.25-8.12 (m, 4H), 7.93 (dd, J=1.8, 8.7 Hz, 1H), 6.89 (d,
J=9.0 Hz, 1H), 3.87 (s, 3H);
[1716] Anal. calc'd for C.sub.20H.sub.17N.sub.4O.sub.4F.sub.31/2
TFA: C, 51.47; H, 3.60; N, 11.45. Found: C, 51.39; H, 3.88; N,
11.65.
EXAMPLE 188
6-(aminoiminomethyl)-N-(1,3-benzodioxol-5-yl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
EXAMPLE 188A
[1717] The above product was prepared in the manner of Example 8A
using 3, 4-methylenedioxyaniline.
[1718] MS (APCI) m/z (M+H).sup.+317.
EXAMPLE 188B
[1719] The above was prepared as described Example 1B.
[1720] MS (CI) m/z (M+H).sup.+334;
[1721] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.70 (s, 1H),
8.20 (s, 2H), 9.96 (s, 1H), 7.81-87.63 (m, 3H), 7.31 (dd, J=1.8,
8.4 Hz, 1H), 7.11 (d, J=4.2 Hz, 1H), 6.91 (dd, J=4.5, 10.8 Hz), 6.4
(d, J=8.4 Hz, 1H), 5.59 (s, 2H);
[1722] Anal. calc'd for C.sub.21H.sub.16N.sub.3O.sub.3F.sub.33/5
TFA: C, 55.44; H, 3.48; N, 8.77. Found: C, 55.44; H, 3.52; N,
8.85.
EXAMPLE 189
6-(aminoiminomethyl)-N-(1, 2, 3, 4-tetrahydro-2,
4-dioxo5-pyrimidinyl)-2-n- aphthalenecarboxamnide,
monohydrochloride
EXAMPLE 189A
[1723] The above product was prepared in the manner of Example 8A
using 5-aminouracil.
[1724] MS (APCI) m/z (M-H).sup.+305.
EXAMPLE 189B
6-(aminoiminomethyl)-N-(1, 2, 3, 4-tetrahydro-2,
4-dioxo5-pyrimidinyl)-2-n- aphthalenecarboxamide,
monohydrochloride
[1725] The above was prepared as described in Example 1B.
[1726] MS (CI) m/z (M+H).sup.+324;
[1727] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 11.50 (s, 1H),
10.90 (m, 1H), 9.53 (s, 3H), 9.21 (s, 2H), 8.70 (s, 1H), 8.55 (s,
1H), 8.33 (d, J=8.4 Hz, 1H), 8.20 (d, J=8.7 Hz, 1H), 8.13-8.09 (m,
2H), 8.00 (s, 1H), 7.88 (dd, J=1.8, 8.4 Hz, 1H);
[1728] Anal. calc'd for C.sub.16H.sub.14N.sub.5O.sub.3Cl 2/5 HCl:
C, 51.49; H, 3.88; N, 18.76. Found: C, 51.87; H, 4.01; N,
17.68.
EXAMPLE 190
6-(aminoiminomethyl)-N-(3,
5-difluorophenyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
EXAMPLE 190A
[1729] The above product was prepared in the manner of Example 8A
using 3, 5-difluoroaniline.
[1730] MS (APCI) m/z (M-H).sup.+307.
EXAMPLE 190B
6-(aminoiminomethyl)-N-(3,
5-difluorophenyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
[1731] The above was prepared as described in Example 1B.
[1732] MS (CI) m/z (M+H).sup.+326;
[1733] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 10.93 (s, 1H),
9.53 (s, 2H), 9.34 (s, 2H), 8.71 (s, 1H), 8.58 (s, 1H), 8.33 (d,
J=8.4 Hz, 1H), 8.26 (d, J=8.7 Hz, 1H), 8.14 (m, 1H), 7.92 (dd,
J=0.9, 8.1 Hz, 1H), 7.61 (d, J=7.8 Hz, 2H), 7.04-6.97 (m, 1H);
[1734] Anal. calc'd for C.sub.20H.sub.14N.sub.3O.sub.2F.sub.52/5
TFA: C, 54.92; H, 3.21; N, 9.42. Found: C, 54.96; H, 3.36; N,
9.37.
EXAMPLE 191
6-(aminoiminomethyl)-N-(1H-pyrazol-3-yl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
EXAMPLE 191A
[1735] The above product was prepared in the manner of Example 8A
using 3-aminopyrazole.
[1736] MS (APCI) m/z (M+H).sup.+263.
EXAMPLE 191B
6-(aminoiminomethyl)-N-(1H-pyrazol-3-yl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
[1737] The above was prepared as described in Example 1B.
[1738] MS (CI) m/z (M+H).sup.+280;
[1739] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 11.13 (s, 1H),
9.55 (s, 2H), 9.37 (s, 2H), 8.75 (s, 1H), 8.55 (s, 1H), 8.23 (d,
J=8.4 Hz, 1H), 8.12 (s, 2H), 7.90 (d, J=8.4 Hz, 1H), 7.70 (s, 1H),
6.69 (s, 1H);
[1740] Anal. calc'd for C.sub.17H.sub.14N.sub.5O.sub.3F.sub.37/10
TFA: C, 46.53; H, 3.12; N, 14.70. Found: C, 46.47; H, 3.16; N,
14.85.
EXAMPLE 192
6-(aminoiminomethyl)-N-(5-methyl-3-isoxazolyl])-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
EXAMPLE 192A
[1741] The above product was prepared in the manner of Example 8A
using 3-amino-5-methylisoxazole.
[1742] MS (APCI) m/z (M+H).sup.+278.
EXAMPLE 192B
6-(aminoiminomethyl)-N-(5-methyl-3-isoxazolyl])-2-naphthalenecarboxamide,
mono (trifluoroacetate)(salt)
[1743] The above was prepared as described in Example 1B.
[1744] MS (CI) m/z (M+H).sup.+295;
[1745] .sup.1H-NMR (300 MHz, d.sub.6-DMSO) .delta. 11.62 (s, 1H),
9.52 (s, 2H), 9.33 (s, 2H), 8.78 (s, 1H), 8.55 (dd, 1H), 8.31-8.16
(m, 3H), 7.90 (dd, 1H), 6.81 (s, 1H), 2.44 (s, 3H)
[1746] Anal. calc'd for C18H.sub.15N.sub.4O.sub.4F.sub.3: C, 52.95;
H, 3.70; N, 13.72. Found: C, 52.73; H, 3.64; N, 13.24.
EXAMPLE 193
6-(aminoiminomethyl)-N-(pyrazinyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
EXAMPLE 193A
[1747] The above product was prepared in the manner of Example 8A
using 2-aminopyrazine.
[1748] MS (APCI) m/z (M-H).sup.+275.
EXAMPLE 193B
6-(aminoiminomethyl)-N-(pyrazinyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
[1749] The above was prepared as described in Example 1B.
[1750] MS (CI) m/z (M+H).sup.+292;
[1751] .sup.1H-NMR (300 MHz, d.sub.6-DMSO) .delta. 11.41 (s, 1H),
9.52 (s, 2H), 9.49 (s, 1H), 9.27 (s, 2H), 8.83 (s, 1H), 8.56 (s,
1H), 8.53-8.46 (m, 2H), 8.30 (d, 1H), 8.23 (s, 2H), 7.90 (dd,
1H);
[1752] Anal. calc'd for C.sub.18H.sub.14N.sub.5O.sub.3F.sub.3: C,
49.36; H, 3.16; N, 15.15 1/2 TFA. Found: C, 49.53; H, 3.22; N,
14.87.
EXAMPLE 194
6-(aminoiminomethyl)-N-(6-methyl-2-pyridinyl)-2-naphthalenecarboxamide
mono(trifluoroacetate)(salt)
EXAMPLE 194A
[1753] The above product was prepared in the manner of Example 8A
using 2-amino-6-methylpyridine.
[1754] MS (APCI) m/z (M+H).sup.+288.
EXAMPLE 194B
6-(aminoiminomethyl)-N-(6-methyl-2-pyridinyl)-2-naphthalenecarboxamide
mono(trifluoroacetate)(salt)
[1755] The above was prepared as described in Example 1B.
[1756] MS (CI) m/z (M+H).sup.+305;
[1757] .sup.1H-NMR (300 MHz, d.sub.6-DMSO) .delta. 11.02 (s, 1H),
9.53 (s, 2H), 9.37 (s, 2H), 8.80 (s, 1H), 8.55 (s, 1H), 8.29 (d,
1H), 8.20 (s, 2H), 8.07 (d, 1H), 7.89 (d, 1H), 7.78 (t, 1H), 7.08
(d, 1H), 2.48 (s, 3H);
[1758] Anal. calc'd for C.sub.20H.sub.17N.sub.4O.sub.3F.sub.3: C,
48.74; H, 3.33; N, 10.20 7/5 TFA. Found: C, 48.74; H, 3.59; N,
10.11.
EXAMPLE 195
6-(aminoiminomethyl)-N-(3, 4
5-trimethoxyphenyl)-2-naphthalenecarboxamide, monohydrochloride
EXAMPLE 195A
[1759] The above product was prepared in the manner of Example 8A
using 3, 4, 5-trimethoxyaniline.
[1760] MS (APCI) m/z (M+H).sup.+363.
EXAMPLE 195B
6-(aminoiminomethyl)-N-(3, 4,
5-trimethoxyphenyl)-2-naphthalenecarboxamide- ,
monohydrochloride
[1761] The above was prepared as described in Example 1B.
[1762] MS (CI) m/z (M+H).sup.+380,
[1763] .sup.1H-NMR (300 MHz, d.sub.6-DMSO) .delta. 10.54 (s, 1H),
9.61 (s, 2H), 9.34 (s, 2H), 8.72 (s, 1H), 8.59 (s, 1H), 8.33-8.15
(m, 3H), 7.91 (dd, 1H), 7.30 (s, 2H), 3.80 (s, 9H)
[1764] Anal. calc'd for C.sub.21H.sub.22N.sub.3O.sub.4Cl 63/10 HCl:
C, 39.09; H, 4.42; N, 6.51. Found: C, 38.94; H, 4.60; N, 7.61.
EXAMPLE 196
6-(aminoiminomethyl)-N-(3-methyl-2-pyridinyl)-2-naphthalenecarboxamide.
bis(trifluoroacetate)(salt)
EXAMPLE 196A
[1765] Using the procedure described for Example 184A and
substituting 2-amino-3-picolene for 4-aminobenzamide, the desired
compound was obtained.
[1766] MS (DCI) m/z 288 (M+H).sup.+.
EXAMPLE 196B
6-(aminoiminomethyl)-N-(3-methyl-2-pyridinyl)-2-naphthalenecarboxamide
bis(trifluoroacetate)(salt)
[1767] Using the procedure described in Example 1B and the product
obtained in Example 196A, the desired compound was obtained.
[1768] MS (DCI) m/z 305 (M+H).sup.+;
[1769] .sup.1H NMR (300 MHz, DMSO) .delta. 10.85 (s, 1H), 9.52 (s,
2H), 9.22 (s, 2H), 8.76 (s, 1H), 8.56 (s, 1H), 8.35 (dd, 1H,
J=4.41, 1.10), 8.32 (d, 1H, J=8.80), 8.22 (m, 2H), 7.90 (dd, 1H,
J=8.83, 1.84), 7.80 (dd, 1H, J=7.73, 1.11), 7.31 (dd, 1H, J=7.72,
4.78), 2.26 (s, 1H);
[1770] Anal. calc'd for C.sub.22H.sub.18F.sub.6N.sub.4O.sub.3.0.75
H.sub.2O: C, 48.40; H, 3.60; N, 10.26. Found: C, 48.81; H, 3.66; N,
10.43.
EXAMPLE 197
6-(aminoiminomethyl)-N-(5-bromo-2-thiazolyl])-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
EXAMPLE 197A
[1771] Using the procedure described for Example 184A and
substituting 2-amino-5-bromothiazole for 4-aminobenzamide, the
desired compound was obtained.
[1772] MS (DCI) m/z 358 (M+H).sup.+.
EXAMPLE 197B
6-(aminoiminomethyl)-N-(5-bromo-2-thiazolyl])-2-naphthalenecarboxamide,
mono (trifler acetate)(salt)
[1773] Using the procedure described in Example 1B and the product
obtained in Example 197A, the desired compound was obtained.
[1774] MS (ESI+) m/z 375 (M+H).sup.+;
[1775] .sup.1H NMR (300 MHz, DMSO) .delta. 10.85 (s, 1H), 9.55 (s,
2H), 9.24 (s, 2H), 8.87 (s, 1H), 8.57 (d, 1H, J=1.69), 8.31 (d, 1H,
J=8.47), 8.25 (d, 2H, J=1.01), 7.92 (dd, 1H, J=8.48, 2.04), 7.71
(s, 1H);
[1776] Anal. calc'd for
C.sub.17H.sub.12BrF.sub.3SN.sub.4O.sub.3.1.25 H.sub.2O.0.25 TFA: C,
38.90; H, 2.75; N, 10.37. Found: C, 38.97; H, 3.24; N, 10.66.
EXAMPLE 198
6-(aminoiminomethyl)-N-(5-methyl-2-pyridinyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
EXAMPLE 198A
[1777] Using the procedure described for Example 184A and
substituting 2-amino-5-picolene for 4-aminobenzamide, the desired
compound was obtained.
[1778] MS (ESI+) m/z 288 (M+H).sup.+.
EXAMPLE 198B
6-(aminoiminomethyl)-N-(5-methyl-2-pyridinyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
[1779] Using the procedure described in Example 1B and the product
obtained in Example 198A, the desired compound was obtained.
[1780] MS (DCI) m/z 305 (M+H).sup.+;
[1781] .sup.1H NMR (300 MHz, DMSO) .delta. 1.01 (s, 1H), 9.50 (s,
2H), 9.16 (s, 2H), 8.79 (s, 1H), 8.54 (s, 1H), 8.30 (d, 1H,
J=9.19), 8.27 (d, 1H, J=1.47), 8.20 (s, 2H), 8.15 (d, 1H, J=8.83),
7.89 (dd, 1H, J=8.46, 1.48), 7.72 (dd, 1H, J=8.46, 1.84), 2.31 (s,
3H);
[1782] Anal. calc'd for C.sub.20H.sub.17F.sub.3N.sub.4O.sub.3.0.25
H.sub.2O.0.2 TFA: C, 54.98; H, 4.00; N, 12.57. Found: C, 54.99; H,
3.59; N, 12.43.
EXAMPLE 199
6-(aminoiminomethyl)-N-(4-methyl-2-thiazolyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
EXAMPLE 199A
[1783] Using the procedure described for Example 184A and
substituting 2-amino-5-methyl benzothiazole for 4-aminobenzamide,
the desired compound was obtained.
[1784] MS (ESI-) m/z 293 (M+H).sup.-.
EXAMPLE 199B
6-(aminoiminomethyl)-N-(4-methyl-2-thiazolyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
[1785] Using the procedure described in Example 1 B and the product
obtained in Example 199A, the desired compound was obtained.
[1786] MS (ESI+) m/z 311 (M+H).sup.+;
[1787] .sup.1H NMR (300 MHz, DMSO) .delta. 9.51 (s, 2H), 9.25 (s,
2H), 8.86 (s, 1H), 8.55 (s, 1H), 8.30 (d, 1H, J=8.48), 8.25 (d, 1H,
J=2.03), 7.91 (dd, 1H, J=8.48, 1.70), 6.87 (s, 1H), 2.34 (s,
3H);
[1788] Anal. calc'd for C.sub.18H.sub.15F.sub.3N.sub.4SO.sub.3.0.5
TFA: C, 47.40; H, 3.25; N, 11.64. Found: C, 47.90; H, 3.36; N,
11.71.
EXAMPLE 200
6-(aminoiminomethyl)-4-[5-(ethylthio)-3-furanyl]-N-phenyl-2-naphthalenecar-
boxamide monohydrochloride
EXAMPLE 200A
[1789] The desired compound was prepared from
2-trimethylsilyl-3-bromofura- n and diethyldisulfide by the
procedure of Example 154A.
[1790] MS (DCI/NH.sub.3) m/z 279, 281 (M+H).sup.+.
EXAMPLE 200B
[1791] A solution of the product from Example 200A (8.60 g, 30.8
mmol) in THF (20 mL) and a 1 M solution of TBAF (61.6 mL) was
stirred for 24 hours. The reaction was condensed and
chromatographed on SiO.sub.2 using hexanes as eluent, to yield 3.32
g (52%) of 2-ethylthio-4-bromofuran. The desired compound was
prepared from this material by the procedure of Example 57A.
[1792] MS (DCI/NH.sub.3) m/z 127 (M-B (OH).sub.2).sup.+.
EXAMPLE 200C
[1793] The desired compound was prepared from the product from
Example 200B and the product from Example 152C by the procedure of
Example 57B.
[1794] MS (DCI/NH.sub.3) m/z 416 (M+NH.sub.4).sup.+.
EXAMPLE 200D
6-(aminoiminomethyl)-4-[5-(ethylthio)-3-furanyl]-N-phenyl-2-naphthalenecar-
boxamide monohydrochloride
[1795] The desired compound was prepared from Example 200C and the
procedure of Example 144C.
[1796] MS (DCI/NH.sub.3) m/z 416 (M+H).sup.+;
[1797] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.20 (t, 2H),
2.02 (q, 2H), 7.15 (t, 1H), 7.34 (s, 1H), 7.10 (t, 2H), 7.83 (d,
2H), 7.92 (dd, 1H), 8.20 (d, 1H), 8.40 (d, 1H), 8.47 (s, 1H), 8.60
(s, 1H), 8.69 (s, 1H), 9.21 (br s, 2H), 9.58 (br s, 2H), 10.61 (s,
1H);
[1798] Anal. calc'd for C.sub.24H.sub.21N.sub.3SO.sub.2.1.5 HCl: C,
61.31; H, 4.82; N, 8.94. Found: C, 61.39; H, 4.89; N, 9.03.
EXAMPLE 201
6-(aminoiminomethyl)-4-[5-(propylthio)-3-furanyl]-N-phenyl-2-naphthaleneca-
rboxamide, monohydrochloride
EXAMPLE 201A
[1799] The desired compound was prepared from
2-trimethylsilyl-3-bromofura- n and dipropyldisulfide by the
procedure of Example 154A.
[1800] MS (DCI/NH.sub.3) m/z 293, 295 (M+H).sup.+.
EXAMPLE 201B
[1801] The desired compound was prepared from the product from
Example 201A by the procedure of 154B.
[1802] MS (DCI/NH.sub.3) m/z 432 (M+H).sup.+.
EXAMPLE 201 C
[1803] The desired compound was prepared from the product from
Example 201 B and the product from Example 152C by the procedure of
Example 154C.
[1804] MS (DCI/NH.sub.3) m/z 430 (M+NH.sub.4).sup.+.
EXAMPLE 201D
6-(aminoiminomethyl)-4-[5-(propylthio)-3-furanyl-N-phenyl-2-naphthalenecar-
boxamide, monohydrochloride
[1805] The desired compound was prepared from Example 201 C and the
procedure of Example 144C.
[1806] MS (DCI/NH.sub.3) m/z 430 (M+H).sup.+;
[1807] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8 1.01 (t, 3H), 1.66
(qt, 2H), 2.89 (t, 2H), 7.15 (t, 1H), 7.34 (s, 1H), 7.40 (t, 2H),
7.84 (d, 2H), 7.92 (dd, 1H), 8.20 (d, 1H), 8.40 (d, 1H), 8.47 (s,
1H), 8.60 (s, 1H), 8.69 (s, 1H), 9.22 (br s, 2H), 9.58 (br s, 2H),
10.61 (s, 1H);
[1808] Anal. calc'd for C.sub.25H.sub.23N.sub.3SO.sub.2.1.25 HCl:
C, 63.20; H, 5.14; N, 8.84. Found: C, 63.24; H, 5.16; N, 8.93.
EXAMPLE 202
6-(aminoiminomethyl)-N-(6-quinolinyl)-2-naphthalenecarboxamide,
bis(trifluoroacetate)(salt)
EXAMPLE 202A
[1809] To a solution of the acid chloride, Example 8B, (331 mg, 1.5
mmol) in THF (15 mL), at room temperature, was added propylene
oxide (10 mL), DMAP (5 mg), a drop of triethylamine and finally
6-aminoquinoline (288 mg, 2.0 mmol). After 4 hours at room
temperature, added ethyl acetate (10 mL) and ether (20 mL) and
filtered the off-white solid product. Yield 357 mg (72%).
[1810] MS (DCI/NH.sub.3) m/z 324 (M+H).sup.+.
EXAMPLE 202B
6-(aminoiminomethyl)-N-(6-quinolinyl)-2-naphthalenecarboxamide
bis(trifluoroacetate)(salt)
[1811] The desired compound was prepared as described in Example
1B.
[1812] MS (ESI+) m/z 341 (M+H).sup.+, (ESI.sup.-) 339
(M-1).sup.-;
[1813] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.98 (s, 1H),
9.53 (s, 2H), 9.25 (s, 2H), 8.93-8.91 (m, 1H), 8.77 (s, 1H), 8.67
(d, J=1.8 Hz, 1H), 8.58 (s, 1H), 8.53 (d, J=8.5 Hz, 1H), 8.37-8.09
(m, 5H), 7.93 (dd, J1=8.5 Hz, J2=1.8 Hz, 1H), 7.65-7.62 (m,
1H);
[1814] Anal. calc'd for C.sub.21H.sub.16N.sub.4O.2TFA: C, 52.83; H,
3,19; N, 9.86. Found: C, 52.62; H, 2.94; N, 9.74.
EXAMPLE 203
6-(aminoiminomethyl)-N-(1H-indazol-6-yl)-2-naphthalenecarboxamide,
bis(trifluoroacetate)(salt)
EXAMPLE 203A
[1815] The desired compound was prepared as described for Example
202A but substituting 6-aminoquinoline for 6-aminoindazole to
provide 285 mg of the desired compound.
[1816] MS: ESI+: 313 (M+1); ESI-311 (M-1).
EXAMPLE 203B
6-(aminoiminomethyl)-N-(1H-indazol-6-yl)-2-naphthalenecarboxamide
bis(trifluoroacetate)(salt)
[1817] To a suspension of the ammonium chloride (140 mg, 2.6 mmol)
in Toluene (2 mL) at 0.degree. C. was slowly added a solution of 2
N trimethylaluminium in toluene (871 .mu.L, 1.74 mmol). After 5
minute the reaction mixture was allowed to warm to room temperature
for 30 minutes. To the solution of the aluminium reagent at room
temperature was added the nitrile, Example 203A from section (a)
and the reaction mixture was heated to 100.degree. C. for 48 hours.
The reaction mixture was cooled down then was poured into a
suspension of silica in chloroform and stirred for an hour. The
silica was filtered then washed with methanol. The solvent was
concentrated and purified by medium pressure liquid chromatography
on a 30 cm.times.2 cm C-18 column (40 micron, J. T. Baker) with UV
detection at 250 nM with solvent mixtures in a gradient ranging
from 90%A (0.1% aq TFA)/I10%B (methanol) to 10%A/90%B over 160
minutes at a flow rate of 5 mL/min (fractions were collected every
2 minutes for 100 min, to provide 42 mg of the desired
compound.
[1818] MS (ESI+) m/z 330 (M+H).sup.+, (ESI-) 328 (M-1).sup.-;
[1819] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.65 (s, 1H),
9.47 (m, 4H), 8.65 (s, 2H), 8.50 (s, 2H), 8.25-8.23 (m, 2H),
8.17-8.10 (m, 2H), 7.94 (s, 1H), 7.86-7.84 (dd, J1=8.8 Hz, J2=1.6
Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H);
[1820] Anal. calc'd for C.sub.19H.sub.15N.sub.5 O.2 TFA: C, 49.56;
H, 3.07; N, 12.56. Found: C, 49.68; H, 3.10; N, 12.47.
EXAMPLE 204
6-(aminoiminomethyl)-N-(1H-indazol-5-yl)-2-naphthalenecarboxamide
bis(trifluoroacetate)(salt)
EXAMPLE 204A
[1821] The desired compound was prepared as described for Example
202A but substituting 6-aminoquinoline for 5-aminoindazole to
provide 362 mg of the desired compound.
[1822] MS: ESI+: 313 (M+1); ESI-311 (M-1).
EXAMPLE 204B
6-(aminoiminomethyl)-N-(1H-indazol-5-yl)-2-naphthalenecarboxamide.
bis(trifluoroacetate)(salt)
[1823] The desired compound was prepared as described for Example
203B to provide 55 mg of the desired compound.
[1824] MS (ESI.sup.+) m/z 330 (M+H).sup.+, (ESI.sup.-) 328
(M-1).sup.-;
[1825] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.06 (s, 1H),
10.58 (s, 1H), 9.51 (s, 2H), 9.15 (s, 2H), 8.71 (d, j=1.9 Hz, 1H),
8.56 (d, j=1.9 Hz, 1H), 8.34-8.17 (m, 4H), 8.10 (s, 1H), 7.90 (dd,
J1=8.5 Hz, J2=1.7 Hz, 1H), 7.63 (dd, J1=8.9 Hz, J2=1.7 Hz, 1H),
7.56 (d, J=8.8 Hz, 1H);
[1826] Anal. calc'd for C.sub.19H.sub.15N.sub.5 O.TFA.1.75
H.sub.2O: C, 53.11; H, 4.14; N, 14.75. Found: C, 53.20; H, 3.99; N,
14.42.
EXAMPLE 205
6-(aminoiminomethyl)-N-(1H-indol-5-yl)-2-naphthalenecarboxamide
mono(trifluoroacetate)(salt)
EXAMPLE 205A
[1827] The desired compound was prepared as described for Example
202A but substituting 6-aminoquinoline for 6-aminoindene to provide
744 mg of the desired compound.
[1828] MS: (ESI).sup.+: 329 (M+1).sup.+ and (ESI)-: 327 (M-1)-.
EXAMPLE 205B
6-(aminoiminomethyl)-N-(1H-indol-5-yl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
[1829] The desired compound was prepared as described for Example
203B to provide 90 mg of the desired compound.
[1830] MS (ESI.sup.+) m/z 329 (M+H).sup.+, (ESI.sup.-) 327
(M-1).sup.-;
[1831] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.09 (s, 1H),
10.40 (s, 1H), 9.51 (s, 2H), 9.15 (s, 2H), 8.71 (s, 1H), 8.55 (s,
1H), 8.32 (d, J=8.4 Hz, 1H), 8.26-8.17 (m, 2H), 8.05 (d, J=2.6 Hz,
1H), 7.90 (dd, J1=8.4 Hz, J2=1.8 Hz, 1H), 7.46-7.35 (m, 3H),
6.45-6.43 (m, 1H);
[1832] Anal. calc'd for C.sub.20H.sub.16N.sub.4 O.TFA: C, 59.73; H,
3.87; N, 12.66. Found: C, 59.27; H, 4.17; N, 12.74.
EXAMPLE 206
7-[2-(4-morpholinyl)ethoxy-2-naphthalenecarboximidamide.
bis(trifluoroacetate)(salt)
EXAMPLE 206A
[1833] The nitrile was prepared as described in Example 119A using
2-chloroethylmorpholine.
[1834] MS (DCI (NH.sub.3)) m/z 283 (M+H).sup.+.
EXAMPLE 206B
7-[2-(4-morpholinyl)ethoxy]-2-naphthalenecarboximidamide
bis(trifluoroacetate)(salt)
[1835] The desired compound was prepared as described in Example 11
9B, as an off-white solid (50% yield).
[1836] MS (DCI (NH.sub.3)) m/z 300 (M+H).sup.+;
[1837] .sup.1H NMR (300 MHz, DMSO-d6) .delta. 3.500 (br m, 4H),
3.700 (br m, 2H), 3.990 (br m, 4H), 4.490 (brm, 2H), 7.435 (dd,
1H), 7.530 (d, 1H), 7.680 (dd, 1H), 8.035 (d, 1H), 8.100 (d, 1H),
8.345 (d 1H), 9.165 (br s, 2H), 9.420 (br s, 2H);
[1838] Anal. calc'd for C.sub.17H.sub.21N.sub.3O.sub.2
(C.sub.2HO.sub.2F.sub.3).sub.2.15: C, 46.98; H, 4.29; N, 7.72.
Found: C, 47.00; H, 4.32; N, 7.77.
EXAMPLE 207
6-(aminoiminomethyl)-N-phenyl-4-(2-pyrimidinyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
EXAMPLE 207A
[1839] The desired compound was prepared from the product from
Example 152A, by the procedure of Example 68A.
[1840] MS (DCI/NH.sub.3) m/z 281 (M4H).sup.+
EXAMPLE 207B
[1841] The desired compound was prepared from the product from
Example 207A by the procedure of Example 152B.
[1842] MS (DCI/NH.sub.3) m/z 267 (M+H).sup.+.
EXAMPLE 207C
[1843] A solution of the product from Example 207B (220 mg, 0.826
mmol), diisopropylethyl amine (0.288 mL, 1.65 mmol), and
O-(7-azabenzotriazol-1-- yl)-N, N, N', N'-tetramethyluronium
hexafluorophosphate (314 mg, 0.826 mmol) in DMF (10 mL) was stirred
for 30 minutes at 0.degree. C. Aniline (0.083 mL, 0.909 mmol) was
added, and the reaction was stirred at room temperature for 4
hours. The reaction was poured into saturated aqueous
Na.sub.2CO.sub.3 solution, and extracted with 3x ethyl acetate. The
combined extracts were washed with water and brine, dried over
Na.sub.2SO.sub.4, and condensed. The crude material was
recrystallized from ethanol/hexanes to yield 212 mg (75%) of the
desired compound.
[1844] MS (DCI/NH.sub.3) m/z 342 (M+H).sup.+.
EXAMPLE 207D
6-(aminoiminomethyl)-N-phenol-4-(2-pyrrolidinyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
[1845] The desired compound was prepared from Example 207C and the
procedure of Example 1B.
[1846] MS (DCI/NH.sub.3) m/z 359 (M+H).sup.+;
[1847] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.02 (t, 4H),
3.55 (t, 4H), 7.13 (t, 1H), 7.38 (t, 2H), 7.41 (s, 1H), 7.80 (m,
3H), 8.08 (s, 1H), 8.18 (d, 1H), 8.67 (s, 1H), 9.10 (br s, 2H),
9.43 (br s, 2H), 10.41 (br s, 1H);
[1848] Anal. calc'd for C.sub.22H.sub.22N.sub.4O.1.0
C.sub.2HF.sub.3O.sub.2: C, 61.01; H, 4.91; N, 11.86. Found: C,
60.47; H, 5.36; N, 7.39.
EXAMPLE 208
6-(aminoiminomethyl)-N-(5-pyrimidinyl)-2-naphthalenecarboxamide,
mono (trifluoroacetate)(salt)
EXAMPLE 208A
[1849] The above product was prepared in the manner of Example 8A
using 5-aminopyrimidne.
[1850] MS (APCI) m/z (M+H).sup.+275.
EXAMPLE 208B
6(aminoiminomethyl)-N-(5-pyrimidinyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
[1851] The above was prepared as described in Example 1B.
[1852] MS (CI) m/z (M+H).sup.+292;
[1853] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 10.99 (s, 1H),
9.52 (s, 2H), 9.27 (s, 2H), 9.24 (s, 2H), 8.98 (s, 1H), 8.76 (s,
1H), 8.58 (s, 1H), 8.36-8.18 (m, 3H), 7.92 (dd, J=1.5, 8.4 Hz,
1H);
[1854] Anal. calc'd for C.sub.18H.sub.14N.sub.5O.sub.3F.sub.37/10
TFA: C, 47.97; H, 3.05; N, 14.40. Found: C, 47.78; H, 3.05; N,
14.67.
EXAMPLE 209
6-(aminoiminomethyl)-N-(3-pyridazinyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
EXAMPLE 209A
[1855] 3-Amino-6-chloropyridazine (1.05 g, 8.2 mmol) was dissolved
in 10 mL methanol with 2 mL ammonia/methanol. Palladium/carbon (200
mg, 10%) was added and stirred under 1 atm hydrogen for 4 hours.
The reaction was filtered, concentrated, and used without further
purification.
[1856] MS (CI) m/z (M+H).sup.+96.
EXAMPLE 209B
[1857] The above product was prepared in the manner of Example 12
using the product from Example 209A.
[1858] MS (APCI) m/z (M+H).sup.+275.
EXAMPLE 209C
6-(aminoiminomethyl)-N-(3-pyridazinyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
[1859] The above was prepared from Example 209B as described in
Example 1B.
[1860] MS (CI) m/z (M+H).sup.+292;
[1861] .sup.1H-NMR (300 MHz, d.sub.6-DMSO) .delta. 11.72 (s, 1H),
9.51 (s, 2H), 9.22 (s, 2H), 9.06 (m, 1H), 8.86 (s, 1H), 8.56 (s,
1H), 8.45 (d, 1H), 8.31 (d, 1H), 8.23 (s, 2H), 7.90 (dd, 1H), 7.78
(dd, 1H)
[1862] Anal. calc'd for C.sub.18H.sub.14N.sub.5O.sub.3F.sub.31/2
TFA: C, 49.29; H, 3.16; N, 14.73. Found: C, 49.56; H, 3.23; N,
14.73.
EXAMPLE 210
6-(amino aminomethyl)-N-(5-bromo
-2-pyridinyl)-2-naphthalenecarboxami de.
mono(trifluoroacetate)(salt)
EXAMPLE 210A
[1863] Using the product obtained in Example 8E,
2-amino-5-oromopyruine, and the procedure described for Example 8G
the desired compound was obtained.
[1864] MS (APCI+) m/z 352 (M+H).sup.+.
EXAMPLE 210B
6-(aminoiminomethyl)-N-(5-bromo-2-pyridinyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
[1865] Using the procedure described in Example 1 B and the product
obtained in Example 210A, the desired compound was obtained.
[1866] MS (DCI) m/z 369 (M+H).sup.+;
[1867] .sup.1H NMR (300 MHz, DMSO) .delta. 11.30 (s, 1H), 9.51 (s,
2H), 9.17 (s, 2H), 8.80 (s, 1H), 8.57 (d,
[1868] .sup.1H, J=2.57), 8.55 (s, 1H), 8.31 (d, 1H, J=8.45), 8.26
(d, 1H, J=8.82), 8.19-8.24 (m, 2H, ), 8.14 (dd, 1H, J=2.57, 9.19),
7.90 (dd, 1H, J=1.83, 8.82;
[1869] Anal. calc'd for C.sub.19H.sub.14BrF.sub.3N.sub.4O.sub.3: C,
47.22; H, 2.92; N, 11.59. Found: C, 47.60; H. 3.01; N, 11.30.
EXAMPLE 211
6-(aminoiminomethyl)-N-]3-( I
-methylethoxy)phenyl]-2-naphthalenecarboxami- de
mono(trifluoroacetate)(salt)
EXAMPLE 211A
[1870] The above product was prepared in the manner of Example 12
using 3-isopropoxyaniline.
[1871] MS (APCI) m/z (M+H).sup.+331.
EXAMPLE 211B
6-(aminoiminomethyl)-N-[3-(1-methylethoxy)phenyl]-2-naphthalenecarboxamide-
, mono(trifluoroacetate)(salt)
[1872] The above was prepared from Example 211A using method
1B.
[1873] MS (CI) m/z (M+H).sup.+348;
[1874] .sup.1H-NMR (300 MHz, d.sub.6-DMSO) .delta. 10.50 (s, 1H),
9.50 (s, 2H), 9.22 (s, 2H), 8.67 (s, 1H), 8.56 (s, 1H), 8.31 (d,
1H), 8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.51 (m, 1H), 7.36 (m, 1H),
7.26 (t, 1H), 6.68 (dd, 1H), 4.59 (m, 1H), 1.30 (d, 6H)
[1875] Anal. calc'd for C.sub.23H.sub.22N.sub.3O.sub.4F.sub.31/5
TFA: C, 57.96; H, 4.61; N, 8.66. Found: C, 57.99; H, 4.90; N,
8.68.
EXAMPLE 212
2-[[6-(aminoiminomethyl)-2-naphthalenyl]oxylacetic acid,
mono(trifluoroacetate)(salt)
[1876] The product from Example 185C (140 mg, 0.542 mmol) was
dissolved in methanol (11 mL). To this was added a solution of
lithium hydroxide (68.2 mg, 1.626 mmol) in water (3 ml,) hours. The
reaction was evaporated and the residue purified by reverse phase
chromatography to yield the desired compound (102 mg, 52%).
[1877] MS (DCI (NH3)) m/z 245 (M+H).sup.+;
[1878] .sup.1H NMR (300 MHz, DMSO-d6) .delta. 4.875 (s, 2H), 7.420
(s, 1H), 7.435 (dd, 1H), 7.660 (dd, 1H), 8.015 (d, 1H), 8.100 (d,
1H), 8.340 (d, 1H), 9.125 (br s, 1H), 9.420 (br s, 1H;
[1879] Anal. calc'd for C.sub.13H.sub.12N.sub.2O.sub.3
(C.sub.2HO.sub.2F.sub.3).sub.1.30: C, 47.74; H, 3.42; N, 7.14.
Found: C, 47.93; H, 3.36; N, 7.17.
EXAMPLE 213
methyl 4-[6-(aminoiminomethyl)-2-naphthalenyl]oxylmethyl]benzoate,
mono(trifluoroacetate)(salt)
EXAMPLE 213A
[1880] The resulting product from Example 185A was treated with
methyl 4-(bromomethyl)benzoate in an analogous manner as described
in Example 11 9B.
[1881] MS (DCI (NH3)) m/z 335 (M+NH.sub.4).sup.+.
EXAMPLE 213B
methyl 4-[6-(aminoiminomethyl)-2-naphthalenyl]oxylmethyl]benzoate,
mono(trifluoroacetate)(salt)
[1882] The resulting product from Example 213A (250 mg, 0.788 mmol)
was treated in an analogous manner as described in Example 1 l9C to
yield the desired compound (130 mg, 79%).
[1883] MS (DCI (NH3)) m/z 335 (M+H).sup.+;
[1884] .sup.1H NMR (300 MHz, DMSO-d6) .delta. 3.870 (s, 3H), 5.400
(s, 2H), 7.500 (dd, 1H), 7.540 (d, 1H), 7.619 (dd, 1H), 7.620 (d,
2H), 8.025 (d, 2H), 8.026 (d, 1H), 8.090 (d, 1H), 8.410 (d, 1H),
9.260 (v br s, 3H);
[1885] Anal. calc'd for
C.sub.14H.sub.14N.sub.2O.sub.3.C.sub.2HO.sub.2F.su- b.3.H.sub.2O
0.70: C, 57.32; H, 4.46; N, 6.08. Found: C, 57.33; H, 4.70; N,
5.95.
EXAMPLE 214
6-(aminoiminomethyl)-N-(1H-imidazolyl)-2-naphthalenecarboxamide,
bis(trifluoroacetate)(salt)
EXAMPLE 214A
[1886] Using the product obtained in Example 8E, 2-aminoimidazole,
and the procedure described for Example 8G the desired compound was
obtained.
[1887] MS (ESI-) m/z 261 (M+H).sup.-.
EXAMPLE 214B
[1888] Using the product described in Example 1B and the product
obtained in Example 214A, the desired compound was obtained.
[1889] MS (ESI+) m/z 280 (M+H).sup.+;
[1890] .sup.1H NMR (300 MHz, DMSO) .delta. 9.50 (s, 2H), 9.16 (s,
2H), 8.78 (s, 1H), 8.53 (s, 1H), 8.26-8.31 (m, 2H), 8.20 (d, 1H,
J=8.46), 7.88 (dd, 1H, J=1.84, 8.83), 6.95 (s, 2H);
[1891] Anal. calc'd for C.sub.17H.sub.14F.sub.3N.sub.5O.sub.3.0.2
TFA.H.sub.2O: C, 48.14; H, 3.76; N, 16.13. Found: C, 48.54; H,
3.40; N, 16.02.
EXAMPLE 215
6-[2-[4-(hydroxymethyl)phenyl]-1-cyclopropyl]-2-naphthalenecarboximidamide-
, mono(trifluoroacetate)(salt)
EXAMPLE 215A
[1892] The material prepared as described in Example 104 (210 mg,
.52 mmol) is dissolved in THF (6 mL) and added dropwise to 10 mL
diazomethane cooled to 0.degree. C. then added Pd (OAc).sub.2 (9.8
mg). Vigorous bubbling occurs for 5 minutes. the resulting black
slurry is stirred 20 min, filtered and solvent removed under vacuum
leaving 0.1 g clear oil.
[1893] MS (DCI/NH.sub.3): m/z (M+NH.sub.4.sup.+): 316.
EXAMPLE 215B
6-12-[4-(hydroxymethyl)phenyl]-1-cyclopropyl]-2-naphthalenecarboximidamide-
, mono(trifluoroacetate)(salt)
[1894] The desired compound is prepared as described in Example 1,
purified by reverse phase chromatography to give 19.9 mg of white
solid.
[1895] MS (DCI/NH.sub.3) m/z (M+H).sup.+316;
[1896] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) 5 9.41 (s, 2H), 9.16 (s,
2H), 8.46 (s, 1H), 8.08 (d, 2H), 8.03 (d, 1H), 7.85 (s, 1H), 7.75
(dd, 1H), 7.58 (dd, 1H), 7.3-7.1 (m, 4H), 4.49 (s, 2H), 2.38-2.48
(m, 2H), 1.61-1.70 (m, 2H);
[1897] Anal. calc'd for C.sub.23H.sub.21N.sub.2O.sub.2F.sub.3 1
H.sub.2O: C, 62.10; H, 4.80; N, 6.29. Found: C, 62.00; H, 4, 75; N,
6.25.
EXAMPLE 216
N-(ethoxycarbonyl)-6-(2-phenyl-1-cyclopropyl)-2-naphthalenecarboximidamide
[1898] The sample described in Example 97 (130 mg, 0.45 mmol) is
dissolved in DMF (3 mL) cooled to 0.degree. C. and treated with
triethylamine (0.01 mL) and ethyl chloroformate (0.05 mL). The
resulting solution is stirred three days at room temperature then
diluted with 100 mL ethyl acetate washed with distilled water (20
mL), dried over anhydrous sodium sulfate, filtered and solvent
removed under vacuum leaving a clear oil. The oil is purified by
silica gel chromatography eluting with 2.1 hexanes/ethyl acetate,
lyophilized and the desired compound is isolated as a white powder
(55 mg).
[1899] MS (DCI/NH.sub.3) m/z (M+H).sup.+359;
[1900] .sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. 9.21 (s, 2H),
8.46 (s, 1H), 7.83 (d, 2H), 7.62 (s, 1H), 7.58 (dd, 1H), 7.34 (dd,
1H), 7.35-7.29 (m, 3H), 7.25-7.17 (m, 2H) 4.1 (q, 2H), 2.38-2.28
(m, 2H), 1.61 (t, 2H), 1.25 (t, 3)H);
[1901] Anal. calc'd for C.sub.23H.sub.22N.sub.2O.sub.2 C, 77.07; H.
6.19; N. 7.82. Found: C, 76.63; H. 6.05; N. 7.45.
EXAMPLE 217
6-(aminoiminomethyl)-N-(2-methyl-6-quinolinyl)-2-naphthalenecarboxamide,
bis(trifluoroacetate)(salt)
[1902] The desired compound is prepared in a similar manner as
described in Example 8E and 144C.
[1903] MS m/z: 355 (M+H).sup.+
[1904] .sup.1H NMR (DMSO, 300 MHz): 10.95 (s, 1H), 9.51 (s, 2H),
9.14 (s, 2H), 8.75 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 8.35 (dd,
1H, J1=J2=8.5 Hz), 8.28 (dd, 1H, J1=J2=8.5 Hz), 8.19 (dd, 1H,
J1=J2=8.8 Hz), 8.15 (dd, 1H, J1=J2=8.3 Hz), 8.04 (dd, 1H, J1=J2=8.8
Hz), 7.91 (dd, 1H, J1=8.4 Hz, J2=8.8 Hz), 7.60 (dd, 1H, J1=J2=8.1
Hz). 5.99 (S, 3H);
[1905] Anal. calc'd for C.sub.22H.sub.18N.sub.4O.2.25
C.sub.2F.sub.3O.sub.2H.2 H.sub.2O: C, 49.20; H, 3.78; N, 8.66; F,
19.82. Found: C, 49.02; H, 3.36; N, 8.66.
EXAMPLE 218
6-(aminoiminomethyl)-N-(3-propoxyphenyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
EXAMPLE 218A
[1906] 3-Aminophenol (1 g, 7.2 mmol), triphenylphosphine (2.25 g,
8.6 mmol), and 1-propanol (0.517 g, 8.6 mmol) were dissolved in 25
mL anhydrous THF. Diethylazodicarboxylate (1.5 g, 8.6 mmol) was
added dropwise over 1 minute. The solution was allowed to stir 15
minutes and poured slowly into hexanes while stirring. Filtration
through silica gel/celite afforded the product as a viscous yellow
oil.
[1907] MS (APCI) m/z (M+H).sup.+152.
EXAMPLE 218B
[1908] The above product was prepared in the manner of Example 12
using the product from Example 218A.
[1909] MS (APCI) m/z (M+H).sup.+331.
EXAMPLE 218C
6-(aminoiminomethyl)-N-(3-propoxyphenyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
[1910] The above was prepared from Example 218 as described in
Example 1B.
[1911] MS (CI) m/z (M+H).sup.+348;
[1912] .sup.1H-NMR (300 MHz, d.sub.6-DMSO) .delta. 10.51 (s, 1H),
9.50 (s, 2H), 9.18 (s, 2H), 8.68 (s, 1H), 8.55 (s, 1H), 8.32 (d,
1H), 8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.52-7.33 (m, 2H), 7.27 (t,
1H), 6.73 (dd, 1H), 3.94 (t, 2H), 1.75 m, 2H), 1.00 (t, 3H)
[1913] Anal. calc'd for C.sub.23H.sub.22N.sub.3O.sub.4F.sub.31/20
TFA: C, 59.49; H, 4.77; N, 9.02. Found: C, 59.43; H, 4.94; N,
9.10.
EXAMPLE 219
6-(aminoiminomethyl)-N-[3-(1-ethylpropoxy)phenyl]-2-naphthalenecarboxamide
mono (trifluoroacetate)(salt)
EXAMPLE 219A
[1914] The above product was prepared in the manner of Example 218A
using 3-pentanol.
[1915] MS (APCI) m/z (M+H).sup.+180.
EXAMPLE 219B
[1916] The above product was prepared in the manner of Example 12
using the product from Example 219A.
[1917] MS (APCI) m/z (M+H).sup.+359.
EXAMPLE 219C
6-(aminoiminomethyl)-N-[3-(1-ethylpropoxy)phenyl]-2-naphthalenecarboxamide-
, mono(trifluoroacetate)(salt)
[1918] The above was prepared from Example 219B as described in
Example 1B.
[1919] MS (CI) m/z (M+H).sup.+376;
[1920] .sup.1H-NMR (300 MHz, d.sub.6-DMSO) .delta. 10.47 (s, 1H),
9.49 (s, 2H), 9.14 (s, 2H), 8.67 (s, 1H), 8.55 (s, 1H), 8.31 (d,
1H), 8.25-8.16 (m, 2H), 7.90 (dd, 1H), 7.51 (s, 1H), 7.38 (m, 1H),
7.26 (t, 1H), 6.72 (dd, 1H), 4.18 (m, 1H), 1.65 (m, 4H), 0.93 (t,
6H)
[1921] Anal. calc'd for C.sub.25H.sub.26N.sub.3O.sub.4F.sub.3: C,
61.34; H, 5.35; N, 8.58. Found: C, 61.05; H, 5.42; N, 8.22.
EXAMPLE 220
6-(aminoiminomethyl)-N-[3-(cyclopentyloxy]phenyl]-2-naphthalenecarboxamide-
, mono(trifluoroacetate)(salt)
EXAMPLE 220A
[1922] The above product was prepared in the manner of Example 218A
using cyclopentanol.
EXAMPLE 220B
[1923] The above product was prepared in the manner of Example 12
using the product from Example 220A.
[1924] MS (APCI) m/z (M+H).sup.+357.
EXAMPLE 220C
6-(aminoiminomethyl)-N-[3-(cyclopentyloxy)phenyl]-2-naphthalenecarboxamide
mono(trifluoroacetate)(salt)
[1925] The above was prepared from Example 220B as described in
Example 1B.
[1926] MS (CI) m/z (M+H).sup.+374;
[1927] .sup.1H-NMR (300 MHz, d.sub.6-DMSO) .delta. 10.50 (s, 1H),
9.51 (s, 2H), 9.30 (s, 2H), 8.68 (s, 1H), 8.56 (s, 1H), 8.32 (d,
1H), 8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.49 (m, 1H), 7.38 (m, 1H),
7.26 (t, 1H), 6.72 (dd, 1H), 4.79 (m, 1H), 1.96-1.08 (m, 8H).
[1928] Anal. calc'd for C.sub.25H.sub.24N.sub.3O.sub.4F.sub.3 2/5
TFA: C, 60.68; H, 5.06; N, 8.49. Found: C, 60.68; H, 5.33; N,
8.65.
EXAMPLE 221
6-(aminoiminomethyl)-N-(3-phenoxyphenyl)-2-naphthalenecarboxamide
mono(trifluoroacetate)(salt)
EXAMPLE 221A
[1929] The above product was prepared in the manner of Example 218A
using 3-phenoxyanline.
[1930] MS (APCI) m/z (M+H).sup.+365.
EXAMPLE 221 B
6-(aminoiminomethyl)-N-(3-phenoxyphenyl)-2-naphthalenecarboxamide
mono(trifluoroacetate)(salt)
[1931] The above was prepared from Example 221 A as described in
Example 1B.
[1932] .sup.1H-NMR (300 MHz, d.sub.6-DMSO) .delta. 10.61 (s, 1H),
9.50 (s, 2H), 9.20 (s, 2H), 8.66 (s, 1H), 8.54 (s, 1H), 8.30 (d,
1H), 8.22 (d, 1H), 8.12 (dd, 1H), 7.90 (dd, 1H), 7.64-7.57 (m, 2H),
7.46-7.37 (m, 3H), 7.17 (m, 1H), 7.06 (m, 2H), 6.79 (dd, 1H),
[1933] MS (CI) m/z (M+H).sup.+382;
[1934] Anal. calc'd for C.sub.26H.sub.20N.sub.3O.sub.4F.sub.3: C,
63.03; H, 4.07; N, 8.48. Found: C, 62.87; H, 4.24; N, 8.08.
EXAMPLE 222
6-(aminoiminomethyl)-N-[3-(phenylmethoxy]phenyl]-2-naphthalenecarboxamide
mono(trifluoroacetate)(salt)
[1935] The above product was prepared in the manner of Example 218A
using 3-benzyloxyaniline.
[1936] MS (APCI) m/z (M+H).sup.+379.
EXAMPLE 222B
6-(aminoiminomethyl)-N-[3-(phenylmethoxy)phenyl]-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
[1937] The above was prepared from Example 222A as described in
1B.
[1938] MS (CI) m/z (M+H).sup.+396;
[1939] .sup.1H-NMR (300 MHz, d.sub.6-DMSO) .delta. 10.53 (s, 1H),
9.50 (s, 2H), 9.22 (s, 2H), 8.68 (s, 1H), 8.55 (s, 1H), 8.31 (d,
1H), 8.23 (d, 1H), 8.14 (dd, 1H), 7.90 (dd, 1H), 7.61-7.27 (m, 8H),
6.80 (dd, 1H), 5.13 (s, 2H)
[1940] Anal. calc'd for C.sub.27H.sub.22N.sub.3O.sub.4F.sub.3: C,
63.65; H, 435; N, 8.25. Found: C, 63.48; H, 4.27; N, 8.07.
EXAMPLE 223
6-(aminoiminomethyl)-N-(3-ethoxyphenyl)-2-naphthalenecarboxamide
mono (trifluoro acetate) (salt)
EXAMPLE 223A
[1941] The above product was prepared in the manner of Example 218A
using 3-ethoxyaniline.
[1942] MS (APCI) m/z (M+H).sup.+317.
EXAMPLE 223B
6-(aminoiminomethyl)-N-(3-ethoxyphenyl)-2-naphthalenecarboxamide
mono(trifluoroacetate)(salt)
[1943] The above was prepared from Example 223A as described in
Example 1B.
[1944] MS (CI) m/z (M+H).sup.+334;
[1945] .sup.1H-NMR (300 MHz, d.sub.6-DMSO) .delta. 10.52 (s, 1H),
9.50 (s, 2H), 9.24 (s, 2H), 8.68 (s, 1H), 8.55 (s, 1H), 8.32 (d,
1H), 8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.51 (m, 1H), 7.38 (m, 1H),
7.26 (t, 1H), 6.72 (dd, 1H), 4.04 (q, 2H), 1.34 (t, 3H)
[1946] Anal. calc'd for C.sub.22H.sub.20N.sub.3O.sub.4F.sub.3: C,
59.06; H, 4.51; N, 9.39. Found: C, 58.69; H, 4.54; N, 9.82.
EXAMPLE 224
6-(aminoiminomethyl)-N-(4-nitrophenyl)-2-naphthalenecarboxamide,
mono(trifluoroacetate)(salt)
EXAMPLE 224A
[1947] The above product was prepared in the manner of Example 218A
using 4-nitroaniline.
[1948] MS (APCI) m/z (M+H).sup.+318.
EXAMPLE 224B
6-(aminoiminomethyl)-N-(4-nitrophenyl)-2-naphthalenecarboxamide,
mono (trifluoro acetate)(salt)
[1949] The above was prepared from Example 224A as described in
Example 1B.
[1950] MS (CI) m/z (M+H).sup.+335;
[1951] .sup.11H-NMR (300 MHz, d.sub.6-DMSO) .delta. 11.15 (s, 1H),
9.55 (s, 2H), 9.22 (s, 2H), 8.77 (s, 1H), 8.58 (s, 1H), 8.36-8.12
(m, 7H)
[1952] Anal. calc'd for C.sub.20H.sub.15N.sub.4O.sub.5F.sub.31/10
TFA: C, 52.54; H, 3.29; N, 12.10. Found: C, 53.58; H, 3.37; N,
12.50.
EXAMPLE 225
6-(aminoiminomethyl)-N-[3-(cyclobutylmethoxy)phenyl]-2-naphthalenecarboxam-
ide mono(trifluoroacetate)(salt)
EXAMPLE 225A
[1953] The above product was prepared in the manner of Example 218A
using cyclobutylmethanol.
[1954] MS (APCI) m/z (M+H).sup.+177.
EXAMPLE 225B
[1955] The above product was prepared in the manner of Example 225A
using the product from
EXAMPLE 11
[1956] MS (APCI) m/z (M+H).sup.+357.
EXAMPLE 225C
6-(aminoiminomethyl)-N-[3-(cyclobutylmethoxy)phenyl]-2-naphthalenecarboxam-
ide, mono(trifluoroacetate)(salt)
[1957] The above was prepared from Example 225B as described in
Example 1B.
[1958] MS (CI) m/z (M+H).sup.+374;
[1959] .sup.1H-NMR (300 MHz, d.sub.6-DMSO) .delta. 10.50 (s, 1H),
9.50 (s, 2H), 9.20 (s, 2H), 8.68 (s, 1H), 8.55 (s, 1H), 8.32 (d,
1H), 8.25-8.13 (m, 2H), 7.90 (dd, 1H), 7.51 (m, 1H), 7.38 (m, 1H),
7.26 (t, 1H), 6.72 (dd, 1H), 3.95 (d, 2H), 2.11-1.81 (m, 7H);
[1960] Anal. calc'd for C.sub.25H.sub.24N.sub.3O.sub.4F.sub.37/5
TFA: C, 59.09; H, 5.22; N, 8.27. Found: C, 59.02; H, 5.20; N.
8.55.
EXAMPLE 226
6-[amino(ethoxycarbonyl)imino]-N-[3-(1-methylethoxy)phenyl]-2-naphthalenec-
arboxamide
[1961] The above was prepared from Example 211 A using method
described in Example 216.
[1962] .sup.1H-NMR (300 MHz, d.sub.6-DMSO) .delta. 10.41 (s, 1H),
9.24 (br, 2H), 8.67 (s, 1H), 8.59 (s, 1H), 8.12-7.96 (m, 4H), 7.47
(s, 1H), 7.36 (m, 1H), 7.25 (t, 1H), 6.67 (dd, 1H), 4.58 (m, 1H),
4.11 (q, 2H), 1.30 (m, 9H)
[1963] Anal. calc'd for C.sub.24H.sub.25N.sub.3O.sub.41/4 H.sub.2O:
C, 67.99; H, 6.06 N, 9.91. Found: C, 67.99; H, 6.07; N, 9.64.
EXAMPLE 227
6-(aminoiminomethyl)-4-F5-(ethylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalen-
ecarboxamide, monohydrochloride
EXAMPLE 227A
[1964] A solution of the product from Example 200C (670 mg, 1.68
mmol) and mCPBA (725 mg, 3.36 mmol) in CH.sub.2Cl.sub.2 (25 mL) was
stirred for 1 hour. The reaction was condensed and chromatographed
on SiO.sub.2 using 50% ethyl acetate/hexanes as eluent, to yield
585 mg (81%) of the desired compound.
[1965] MS (DCI/NH.sub.3) m/z 448 (M+NH.sub.4).sup.+.
EXAMPLE 227B
6-(aminoiminomethyl)-4-[5-(ethylsulfonyl)-3-furanyl]-N-phenyl-2-naphthalen-
ecarboxamide monohydrochloride
[1966] The desired compound was prepared from Example 227A and the
procedure of Example 13.
[1967] MS (DCI/NH.sub.3) m/z 448 (M+H).sup.+;
[1968] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.29 (t, 3H),
3.50 (q, 2H), 7.16 (t, 1H), 7.42 (t, 2H), 7.83 (d, 2H), 7.95 (dd,
1H), 8.05 (s, 1H), 8.28 (s, 1H), 8.43 (d, 1H), 8.57 (s, 1H), 8.74
(s, 1H), 8.79 (s, 1H), 9.19 (br s, 2H), 9.59 (br s, 2H), 10.61 (s,
1H);
[1969] Anal. calc'd for C.sub.24H.sub.22N.sub.3SO.sub.4.1.0 HCl 1.0
H.sub.2O: C, 57.43; H, 4.82; N, 8.37. Found: C, 57.21; H, 5.04; N,
8.34.
EXAMPLE 228
6-(aminoiminomethyl)-4-[5-(propylsulfonyl)-3-furanyl]-N-phenyl-2-naphthale-
necarboxamide, monohydrochloride
EXAMPLE 228A
[1970] The desired compound was prepared from the product from
Example 201C by the procedure of Example 227A.
[1971] MS (DCI/NH.sub.3) m/z 462 (M+NH.sub.4).sup.+.
EXAMPLE 228B
6-(aminoiminomethyl)-4-[5-(propylsulfonyl)-3-furanyl]-N-phenyl-2-naphthale-
necarboxamide, monohydrochloride
[1972] The desired compound was prepared from Example 228A and the
procedure of Example 13.
[1973] MS (DCI/NH.sub.3) m/z 462 (M+H).sup.+;
[1974] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.03 (t, 3H), 1.
75 (qt, 2H), 3.48 (q, 2H), 7.16 (t, 1H), 7.41 (t, 2H), 7.84 (d,
2H), 7.95 (dd, 1H), 8.05 (s, 1H), 8.28 (d, 1H), 8.42 (d, 1H), 8.58
(s, 1H), 8.77 (s, 1H), 8.82 (s, 1H), 9.28 (br s, 2H), 9.63 (br s,
2H), 10.66 (s, 1H);
[1975] Anal. calc'd for C.sub.25H.sub.24N.sub.3SO.sub.4. 1.0
HCl.1.5 H.sub.2O: C, 57.20; H, 5.18; N, 8.00. Found: C, 56.86; H,
5.08; N, 8.28.
EXAMPLE 229
6-(aminoiminomethyl)-4-[5-[methylthio)methyl]-3-furanyl]-N-phenyl-2-naphth-
alenecarboxamide, monohydrochloride
EXAMPLE 229A
[1976] To a solution of 2-trimethylsilyl-3-bromofuran (10.41 g,
47.5 mmol) in THF (100 mL) at --78.degree. C. was added a 1.5 M
solution of LDA (34.8 mL, 52.25 mmol), and the reaction was stirred
at --78.degree. C. for 1 hour. DMF (4.41 mL, 57.0 mmol) was then
added, and the reaction was allowed to warm to room temperature and
stirred for 1 hour. The reaction was poured into saturated aqueous
NH.sub.4Cl solution, and extracted with 3.times.diethyl ether. The
combined extracts were washed with brine, dried over
Na.sub.2SO.sub.4, and condensed. The crude material was taken up in
methanol (200 mL) and NaBH.sub.4 (1.15 g, 24.0 mmol) was added in
portions to the stirred solution. After 30 min, the solution was
consensed, taken up in pH7 buffer, and extracted with 3x ethyl
acetate. The combined extracts were washed with brine, dried over
Na.sub.2SO.sub.4, and condensed. The crude product was
chromatographed on SiO.sub.2 using 30% ethyl acetate/hexanes as
eluent, to yield 5.52 g (47%) of the desired compound.
[1977] MS (DCI/NH.sub.3) m/z 250 (M+H).sup.+.
EXAMPLE 229B
[1978] To a solution of the product from Example 229A (5.52 g,
22.15 mmol) and LiCl (1.03 g, 24.36 mmol) in DMF (60 mL) at
0.degree. C. was added PCI.sub.3 (2.12 mL, 24.36 mmol), and the
reaction was stirred at room temperature for 1 hour. The reaction
was poured into saturated aqueous NH.sub.4Cl solution, and
extracted with 3.times.diethyl ether/hexanes. The combined extracts
were washed with 2.times.water, 2.times.brine, dried over
Na.sub.2SO.sub.4, and condensed to yield 4.70 g (79%) of the
desired compound.
EXAMPLE 229C
[1979] A solution of the product from Example 229B (4.70 g, 17.56
mmol) and MeSNa (1.35 g, 19.3 mmol) in DMF (40 mL) was stirred at
room temperature for 3 hours. The reaction was poured into
saturated aqueous NaHCO.sub.3 solution, and extracted with
3.times.Diethyl ether. The combined extracts were washed with
brine, dried over Na.sub.2SO.sub.4, and condensed. The crude
product was chromatographed on SiO.sub.2 using 30% ethyl
acetate/hexanes as eluent, to yield 4.00 g (82%) of the desired
compound.
EXAMPLE 229D
[1980] The desired compound was prepared from the product from
Example 229C by the procedure of Example 154B.
[1981] MS (DCI/NH.sub.3) m/z 308 (Bu.sub.3Sn+NH.sub.4).sup.+.
EXAMPLE 229E
[1982] The desired compound was prepared from the product from
Example D and the product from Example 152C by the procedure of
Example 154C.
[1983] MS (DCI/NH.sub.3) m/z 416 (M+NH.sub.4).sup.+.
EXAMPLE 229F
6-(aminoiminomethyl)-4-[5-[methylthio)methyl]-3-furanyl]-N-phenyl-2-naphth-
alenecarboxamide, monohydrochloride
[1984] The desired compound was prepared from Example 229E and the
procedure of Example 144C.
[1985] MS (DCI/NIH.sub.3) m/z 416 (M+H).sup.+;
[1986] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.15 (s, 3H),
3.87 (s, 2H), 7.14 (t, 1H), 7.40 (t, 2H), 7.84 (d, 2H), 7.92 (dd,
1H), 8.19 (d, 1H), 8.32 (s, 1H), 8.39 (d, 1H), 8.64 (s, 1H), 8.69
(s, 1H), 9.31 (br s, 2H), 9.61 (br s, 2H), 10.62 (s, 1H);
[1987] Anal. calc'd for C.sub.24H.sub.21N.sub.3SO.sub.2.1.4 HCl: C,
61.79; H. 4.84; N. 9.01. Found: C, 61.83; H. 4.82; N. 9.13.
EXAMPLE 230
6-(aminoiminomethyl)-4-[5-[methoxymethyl)-3-firamu]-N-phenyl-2-naphthalene-
carboxamide, monohydrochloride
Example 230A
[1988] The desired compound was prepared from
2-trimethylsilyl-3-bromofura- n and chloromethyl methyl ether by
the procedure of Example 154A.
EXAMPLE 230B
[1989] The desired compound was prepared from the product from
Example 230A by the procedure of Example 154B.
[1990] MS (DCI/NH.sub.3) m/z 308 (Bu.sub.3Sn+NH.sub.4).sup.+.
[1991] The desired compound was prepared from the product from
Example 230B and the product from Example 152C by the procedure of
Example 154C.
[1992] MS (DCI/NH.sub.3) m/z 400 (M+NH.sub.4).sup.+.
EXAMPLE 230D
6-(aminoiminomethyl)-4-[5-(methoxymethyl)-3-furanyl]-N-phenyl-2-naphthalen-
ecarboxamide, monohydrochloride
[1993] The desired compound was prepared from Example 230C and the
procedure of Example 144C.
[1994] MS (DCI/NH.sub.3) m/z 400 (M+H).sup.+;
[1995] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.38 (s, 3H),
4.49 (s, 2H), 7.14 (t, 1H), 7.18 (t, 1H), 7.40 (t, 2H), 7.84 (d,
2H), 7.92 (dd, 1H), 8.19 (d, 1H), 8.38 (d, 1H), 8.42 (s, 1H), 8.64
(s, 1H), 8.70 (s, 1H), 9.32 (br s, 2H), 9.62 (br s, 2H), 10.68 (s,
1H);
[1996] Anal. calc'd for C.sub.24H.sub.21N.sub.3O.sub.3.2.8 HCl: C,
57.48; H, 4.78; N, 8.38. Found: C, 57.40; H, p.44; N, 8.38.
EXAMPLE 231
6-(aminoiminomethyl)-4-[5-(methylsulfonyl)-3-furanyl]-N-phenyl-2-naphthale-
necarboxamide, mono(trifluoroacetate)(salt)
EXAMPLE 231A
[1997] The desired compound was prepared from the product from
Example 152C by the procedure of Example 227A.
[1998] MS (DCl/NH.sub.3) m/z 434 (M+NH.sub.4).sup.+.
EXAMPLE 231 B
6-(aminoiminomethyl)-4-[5-(methylsulfonyl)-3-furanyl]-N-phenyl-2-naphthale-
necarboxamide, mono(trifluoroacetate)(salt)
[1999] The desired compound was prepared from Example 231A and the
procedure of Example 13.
[2000] MS (DCI/NH.sub.3) m/z 434 (M+H).sup.+;
[2001] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.44 (s, 3H),
7.16 (t, 1H), 7.40 (t, 2H), 7.82 (d, 2H), 7.91 (s, 1H), 7.95 (dd,
1H), 8.00 (s, 1H), 8.36 (s, 1H), 8.43 (d, 1H), 8.57 (s, 1H), 8.75
(s, 2H), 9.18 (br s, 2H), 9.53 (br s, 2H);
[2002] Anal. calc'd for C.sub.23H.sub.19N.sub.3SO.sub.4.1.0
C.sub.2HF.sub.3O.sub.2: C, 54.84; H, 3.68; N, 7.67. Found: C,
55.05; H. 3.74; N, 7.75.
EXAMPLE 232
6-(aminoiminomethyl)-4-[5-(ethythio)tetrahydro-3-furanyl]-N-phenyl-2-napht-
halenecarboxamide, monohydrochloride EXAMPLE 232A
[2003] The desired compound was prepared from the product from
Example 152A by the procedure of Example 62A.
[2004] MS (DCI/NH.sub.3) m/z 315 (M+NH.sub.4).sup.+.
EXAMPLE 232B
[2005] A solution of the product from Example 232A (1.62 g, 5.45
mmol), ethanethiol (2.2 mL), and conc. HCl (0.80 mL) in CHCl.sub.3
(22 mL) was stirred at room temperature for 3 hours and condensed.
The crude product was chromatographed on SiO.sub.2 using 15% ethyl
acetate/hexanes as eluent, to yield 1.20 g (65%) of the desired
compound.
[2006] MS (DCI/NH.sub.3) m/z 359 (M+NH.sub.4).sup.+.
EXAMPLE 232C
[2007] The desired compound was prepared from the product from
Example 232B by the procedure of Example 152B.
[2008] MS (DCI/NH.sub.3) m/z 345 (M+NH.sub.4).sup.+.
EXAMPLE 232D
[2009] The desired compound was prepared from the product from
Example 232C by the procedure of Example 207C.
[2010] MS (DCI/NH.sub.3) m/z 420 (M+NH.sub.4).sup.+.
EXAMPLE 232E
6-(aminoiminomethyl)-4-[5-(ethythio)tetrahydro-3-furanyl]-N-phenyl-2-napht-
halenecarboxamide, monohydrochloride
[2011] The desired compound was prepared from Example 232D and the
procedure of Example 144C.
[2012] MS (DCI/NH.sub.3) m/z 420 (M+H).sup.+;
[2013] .sup.1NMR (300 MHz, DMSO-d.sub.6) .delta. 1.18 (dt, 3H),
2.42 (m, 1H), 3.50 (dq, 2H), 3.74 (m, 1H), 3.93 (m, 1h), 4.39 (m,
1H), 4.54 (m, 1H), 5.38 (dd, 0.5H), 5.42 (dd, 0.5H), 7.14 (t, 1H),
7.40 (t, 2H), 7.82 (d, 2H), 7.95 (d, 1H), 8.06 (s, 0).5H), 8.20 (s,
0.5H), 8.32 (d, 1H), 8.60 (s, 1H), 8.71 (s, 0.5H), 8.80 (s, 0.5H),
9.32 (br s, 2H), 9.62 (br s, 2H), 10.59 (br s, 1H);
[2014] Anal. calc'd for C.sub.24H.sub.25N.sub.3O.sub.2S.1.0 HCl: C,
63.22; H, 5.75; N, 9.21. Found: C, 62.93; H, 5.58; N, 9.01.
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