U.S. patent application number 12/688298 was filed with the patent office on 2010-05-13 for novel anti-inflammatory and analgesic heterocyclic amidines that inhibit nitrogen oxide (no) production.
Invention is credited to Roberto Artusi, Antonio Giordani, Francesco MAKOVEC, Stefano Mandelli, Lucio Claudio Rovati, Ilario Verpiliq, Simona Zanzola.
Application Number | 20100120802 12/688298 |
Document ID | / |
Family ID | 34746743 |
Filed Date | 2010-05-13 |
United States Patent
Application |
20100120802 |
Kind Code |
A1 |
MAKOVEC; Francesco ; et
al. |
May 13, 2010 |
Novel Anti-Inflammatory and Analgesic Heterocyclic Amidines that
Inhibit Nitrogen Oxide (NO) Production
Abstract
Heterocyclic amidines with anti-inflammatory and analgesic
activity that inhibit nitrogen oxide production, of formula (I):
##STR00001## in which: G.sub.1 and G.sub.2 are hydrogen, halogen,
hydroxyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkyl, and an
amidino substituent of formula Q, provided that, for each compound
of formula (I), only one of the two substituents G.sub.1 or G.sub.2
is an amidino substituent of formula Q: ##STR00002## and in which
the substituents W, Y and X are combined to form 9- or 10-membered
bicyclic heteroaromatic derivatives containing up to 2 hetero atoms
in the same ring; and Z is an aryl or heteroaryl group, a linear or
branched C.sub.1-C.sub.6 alkyl or alkenyl chain, a C.sub.1-C.sub.4
alkyl-aryl group or a C.sub.1-C.sub.4 alkyl-heteroaryl group.
Inventors: |
MAKOVEC; Francesco; (Lesmo
(Milano), IT) ; Giordani; Antonio; (Pavia, IT)
; Artusi; Roberto; (Rho (Milano), IT) ; Mandelli;
Stefano; (Cambiago (Milano), IT) ; Verpiliq;
Ilario; (Pregnana Milanese (Milano), IT) ; Zanzola;
Simona; (Milano, IT) ; Rovati; Lucio Claudio;
(Monza (Milano), IT) |
Correspondence
Address: |
SUGHRUE MION, PLLC
2100 PENNSYLVANIA AVENUE, N.W., SUITE 800
WASHINGTON
DC
20037
US
|
Family ID: |
34746743 |
Appl. No.: |
12/688298 |
Filed: |
January 15, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11068347 |
Mar 1, 2005 |
7674809 |
|
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12688298 |
|
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Current U.S.
Class: |
514/266.1 ;
514/311; 514/367; 514/375; 514/394; 514/415; 546/171; 546/270.1;
548/178; 548/224; 548/310.7; 548/503 |
Current CPC
Class: |
C07D 405/04 20130101;
A61P 43/00 20180101; C07D 209/08 20130101; A61P 37/06 20180101;
C07D 403/04 20130101; C07D 235/08 20130101; C07D 277/66 20130101;
C07D 409/04 20130101; C07D 215/06 20130101; A61P 19/02 20180101;
A61P 1/04 20180101; A61P 29/02 20180101; C07D 333/54 20130101; C07D
417/04 20130101; C07D 307/79 20130101; C07D 277/64 20130101; C07D
217/04 20130101; A61P 1/00 20180101; C07D 239/74 20130101; A61P
29/00 20180101; A61P 37/00 20180101; C07D 235/18 20130101; C07D
263/57 20130101; A61P 25/04 20180101; A61P 19/10 20180101 |
Class at
Publication: |
514/266.1 ;
548/178; 548/503; 546/171; 546/270.1; 548/310.7; 548/224; 514/367;
514/415; 514/311; 514/394; 514/375 |
International
Class: |
A61K 31/428 20060101
A61K031/428; C07D 277/62 20060101 C07D277/62; C07D 209/18 20060101
C07D209/18; C07D 215/38 20060101 C07D215/38; C07D 417/04 20060101
C07D417/04; C07D 235/18 20060101 C07D235/18; C07D 263/57 20060101
C07D263/57; A61K 31/404 20060101 A61K031/404; A61K 31/47 20060101
A61K031/47; A61K 31/4184 20060101 A61K031/4184; A61K 31/517
20060101 A61K031/517; A61K 31/423 20060101 A61K031/423; A61P 29/00
20060101 A61P029/00; A61P 37/00 20060101 A61P037/00; A61P 19/10
20060101 A61P019/10; A61P 19/02 20060101 A61P019/02; A61P 25/04
20060101 A61P025/04; A61P 1/00 20060101 A61P001/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 1, 2004 |
IT |
T02004A000125 |
Claims
1. A compound represented by the general formula (I) indicated
below and in which: ##STR00099## G.sub.1 and G.sub.2 are
independently selected from hydrogen and the amidine substituent of
formula Q, provided that, for each compound of formula (I), only
one of the two substituents G.sub.1 or G.sub.2 is the amidine
substituent of formula Q; the amidine substituent of formula Q is
represented by the structure given below, in which R is methyl:
Amidine substituent of formula Q: ##STR00100## W is independently:
a bond, an unsubstituted carbon atom, or a carbon atom substituted
with a methyl, an unsubstituted nitrogen atom (.dbd.N--); Y is an
unsubstituted carbon atom, a carbon atom substituted with a methyl,
or an unsubstituted nitrogen atom (.dbd.N--); X is a substituted or
unsubstituted carbon atom (.dbd.CR.sub.1-- or .dbd.CH--), a
unsubstituted nitrogen atom substituted with a hydrogen or a
methyl, a sulfur atom (--S--) or an oxygen atom (--O--), provided
that the substituents W, Y and X give rise, suitably in
combination, to 9- or 10-membered bicyclic heteroaromatic
derivatives containing up to 2 hetero atoms in the same ring;
R.sub.3 and R.sub.4 are both hydrogen; Z is an aryl or heteroaryl
group, a linear or branched C.sub.3-C.sub.6 alkyl or alkenyl chain,
a C.sub.1-C.sub.4 alkyl-aryl group or alkenylaryl group, or a
C.sub.1-C.sub.4 alkyl-heteroaryl group in which the aryl group is a
phenyl which is unsubstituted or substituted with one or more
substituents independently selected from halogen, trifluoromethyl,
hydroxyl, nitro, cyano, carboxyl, carboxamido, carbonyl, thio,
methylthio, methanesulfonyl, methanesulfinyl, sulfonamido,
trifluoromethoxy, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkyl,
and the heteroaryl group is a 5- or 6-atom heterocyclic aromatic
ring containing one or more hetero atoms, which is unsubstituted or
substituted with one or more substituents independently selected
from halogen, trifluoromethyl, hydroxyl, nitro, cyano, carboxyl,
carbonyl, thio, methylthio, methanesulfonyl, methanesulfinyl,
trifluoromethoxy, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6 alkyl;
the C.sub.1-C.sub.4 alkyl-aryl group is a linear or branched,
saturated or unsaturated C.sub.1-C.sub.4 hydrocarbon chain
substituted with an aryl group. When the C.sub.1-C.sub.4 chain is
unsaturated, it is intended to contain only one substituted or
unsubstituted double bond; substituents for the aryl group are
independently selected from the groups defined above as
substituents for the aryl group; the C.sub.1-C.sub.4
alkyl-heteroaryl group is a linear or branched, saturated or
unsaturated C.sub.1-C.sub.4 hydrocarbon chain substituted with a
substituted or unsubstituted heteroaryl group; when the
C.sub.1-C.sub.4 chain is unsaturated, it is intended to contain
only one substituted or unsubstituted double bond; the term
"heteroaryl" means any of the heterocyclic nuclei defined above;
the compounds of formula (I) being either in free base form or as
pharmaceutically acceptable salts.
2-3. (canceled)
4. The compound according to claim 1, wherein X is a nitrogen atom
substituted with hydrogen or with methyl.
5. The compound according to claim 1, wherein X, is an oxygen
atom.
6. The compound according to claim 1, wherein Y is an unsubstituted
carbon atom (.dbd.CH--) or a carbon atom substituted with methyl
instead of a nitrogen atom (--N.dbd.) X, is a nitrogen atom
substituted with hydrogen or with methyl.
7. The compound according to claim 6 wherein X, is an oxygen
atom.
8. The compound according to claim 6, wherein X, is a sulfur
atom.
9. The compound according to claim 1, wherein W is an unsubstituted
carbon atom (.dbd.CH--) or a carbon atom substituted with methyl,
and X, is an unsubstituted nitrogen atom (.dbd.N--).
10. The compound according to claim 9, wherein Y is an
unsubstituted carbon atom (.dbd.C--) or a carbon atom substituted
with a methyl.
11. The compound according to claim 9, wherein X is an
unsubstituted carbon atom (.dbd.CH--) or a carbon atom substituted
with methyl.
12. The compound according to claim 9, wherein W is an
unsubstituted nitrogen atom (.dbd.N--), and is an unsubstituted
carbon atom (.dbd.CH--) or a carbon atom substituted with
methyl.
13. The compound according to claim 9, wherein W, is an
unsubstituted nitrogen atom (.dbd.N--), and is an unsubstituted
carbon atom (.dbd.CH--).
14. The compound according to claim 1, in the form of
pharmaceutically acceptable salts, chosen from hydrochloride,
hydrobromide, sulfate, hydrogen sulfate, methanesulfonate, maleate,
citrate, fumarate and succinate.
15. A method of treating pathological conditions associated with
inflammatory or autoimmune phenomena, comprising administering the
compound according to claim 1, or of a pharmaceutically acceptable
salt thereof.
16. A method of treating conditions comprising administering the
compound according to claim 1, or of a pharmaceutically acceptable
salt thereof, to inhibit the production of nitric oxide (NO) and of
interleukin-6 (IL-6).
17. A pharmaceutical preparation comprising, as active substance,
at least compound according to claim 1, or a pharmaceutically
acceptable salt thereof, and optionally a pharmaceutically
acceptable vehicle.
18. A method for the therapeutic treatment of pathological
conditions associated with inflammatory and autoimmune phenomena
comprising administering the pharmaceutical preparation according
to claim 17.
19. A method for controlling and preventing degenerative articular
diseases such as rheumatoid arthritis and osteoarthritis comprising
administering the pharmaceutical preparation according to claim
17.
20. A method for the analgesic treatment of pain of articular or
neuropathic origin comprising administering the pharmaceutical
preparation according to claim 17.
21. A method for the therapeutic treatment of inflammatory diseases
of the gastrointestinal tract, for instance ulcerative colitis and
Crohn's disease comprising administering the pharmaceutical
preparation according to claim 17.
22. Pharmaceutical The pharmaceutical preparation according to
claim 17, comprising pharmaceutically acceptable inactive
ingredients chosen from the group consisting of vehicles, binders,
flavourings, sweeteners, disintegrants, preserving agents,
humectants and mixtures thereof, or ingredients to facilitate
rectal, transdermal or transmucosal absorption or that allow
controlled release of the active substance over time, and also
ingredients suitable for parenteral use, for instance intravenous,
intramuscular, subcutaneous, intradermal and intra-articular
administration, in which cases the salified compounds as described
in claims 1 and 14 are preferably used.
23. A process for preparing a compound of general formula (I) in
which W, Y, X, G.sub.1, G.sub.2, R.sub.3 and R.sub.4 have the
meaning given in claim 1, which comprises the operations of
reacting a compound of formula (II) ##STR00101## in which W, Y, X,
Z, R.sub.3 and R.sub.4 are defined as for the compounds of formula
(I), while G'.sub.1 and G'.sub.2 are independently selected from:
hydrogen, halogen, hydroxyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkyl, and the amine group (--NH.sub.2), provided
that, for each compound of formula (II), only one of the two
substituents G'.sub.1 or G'.sub.2 is an amine group (--NH.sub.2),
with a compound of formula (III) ##STR00102## in which R is as
defined above in claim 1 for the amidino substituent of formula Q
and L is a leaving group, such as an alkoxy group (ethoxy or
methoxy), an alkylthio group (RS--; thiomethyl or
thiomethylnaphthyl) or an arylthio group (Ar--S; thiophenyl), in a
suitable solvent such as alcohol, acetonitrile,
N,N-dimethylformamide (DMF) or tetrahydrofuran (THF), at
temperatures of between 0.degree. C. and 50.degree. C.; optionally,
the conversion of a compound of formula (II) into a compound of
formula (I) possibly being completed by the removal of any
protecting groups present; the compounds of formula (I) are finally
recovered from the reaction mass, purified via conventional methods
and isolated in unmodified form or in the form of pharmaceutically
acceptable salts.
Description
[0001] This is a divisional of application Ser. No. 11/068,347
filed Mar. 1, 2005. The entire disclosure of the prior application,
application Ser. No. 11/068,347, and priority application
T02004A000125 are considered part of the disclosure of the
accompanying divisional application and is hereby incorporated by
reference.
DESCRIPTION
[0002] The subject of the present invention are novel
heteroaromatic amidine derivatives with anti-inflammatory and
analgesic activity, pharmaceutically acceptable salts thereof,
methods for preparing the said derivatives and formulations
thereof, and also their therapeutic use.
[0003] In particular, the present invention relates to the
compounds of Formula (I) and to the corresponding pharmaceutically
acceptable salts, which show marked anti-inflammatory and analgesic
activity, both by inhibiting the production of nitrogen oxide (NO)
and by inhibiting the production of prostaglandins, such as
PGE.sub.2, and of cytokines such as interleukin-6 (IL-6), and are
therefore useful therapeutic agents in the treatment of pathologies
associated with excessive production of NO due to expression of
inducible NOS and of inflammatory prostaglandins produced by COX-2
and cytokines such as IL-6.
[0004] Among the typical pathologies associated with anomalous
production of NO, prostaglandins and cytokines are: rheumatoid
arthritis, osteoarthritis, synovitis, neuropathies, ulcerative
colitis and Crohn's disease, and inflammatory or atherosclerotic
pathologies of the cardiovascular system.
[0005] Nitrogen oxide (NO) is a chemical mediator that is widely
involved in various physiological phenomena. At the start of the
1980s it was discovered that the factor with vasodilatory activity
released by the endothelium (endothelium-derived relaxing factor,
EDRF), which causes acetylcholine-mediated vasodilation, is not
other than NO released by the cells of the vascular endothelium.
This discovery was concomitant with the identification of the
metabolic pathway mediated by the enzyme NO synthetase (NOS),
which, starting with L-arginine, leads to L-citrulline and NO
(Moncada S., Higgs A., N. Engl. J. Med., 1993, 329 (27),
2002-12).
[0006] Three isoforms of the enzyme NOS have been identified. The
isoforms hitherto characterized are two constitutive isoforms,
known as the type I or neuronal isoform (nNOS) and the type III or
endothelial isoform (eNOS), and an inducible isoform, known as the
type II or iNOS isoform.
[0007] iNOS is induced after activation, in particular cells, in
response to an endotoxin- or cytokine-induced inflammatory
stimulus; the control of iNOS is thus regulated at the level of
synthesis of the protein, which, once expressed, produces high
concentrations of NO for relatively long times.
[0008] Macrophages, endothelial cells, endothelial smooth muscle,
chondrocytes, osteoblasts and the pulmonary epithelium are
particularly effective as regards the expression of iNOS following
an inflammatory stimulus.
[0009] A noteworthy difference between the constitutive enzymes and
the inducible enzyme is thus a delayed but more sustained and
longer-lasting production of NO mediated by the inducible enzyme,
together at the site where this mediator is released. This
determines the differences that give rise to the NO-mediated
physiological or pathophysiological effects.
[0010] Thus, whereas NO released from the constitutive enzymes acts
as a mediator within a signal translation system, for instance the
activation of guanylate cyclase by the NO released from the
endothelial cells, which, by raising the levels of cGMP, controls
the vascular tonus and muscle relaxation. On the other hand, NO
released from the inducible isoform acts as a cytotoxic molecule,
involved in body defence mechanisms (Dugas B. et al.; Res. Immunol.
1995, 146 (9) 664-70).
[0011] Thus, whereas, on the one hand, when appropriately
regulated, iNOS is an enzyme of fundamental importance for the
immune system, imbalances in the synthesis of iNOS-mediated NO may
lead to a whole range of pathologies involved in inflammatory
processes or involving the immune system as indicated
previously.
[0012] It has been demonstrated that iNOS is induced in every
species by inflammatory processes and that suppression of its
activity is effective in reducing inflammatory symptomatologies (A.
J. Hobbs et al., Annual Review of Pharmacology and Toxicology,
1999, 39, 191-220).
[0013] It is believed, on the one hand, that NO is involved,
together with other mediators, in physiological processes of
plasticity and reconstitution of bone tissue, whereas, on the other
hand, the involvement of iNOS-derived NO in the inflammatory
process and in the degeneration of the tissues characterized in
rheumatoid arthritis (RA) and osteoarthritis (OA) has been shown
(van't Hof R J, Ralston S H.; Nitric oxide and bone, Immunology,
2001 July; 103(3): 255-261).
[0014] In point of fact, iNOS has been found in the synovia and
cartilage of patients suffering from rheumatoid arthritis (RA) and
osteoarthritis (OA), and it has been demonstrated that both the
synovial cells and the chondrocytes, in vitro, are capable of
expressing iNOS by stimulation with cytokines. In addition, it has
been shown that NO is a powerful stimulator of chondrocyte and
synovial cell apoptosis, which would explain the tissue
degeneration observed in RA (Armour K J, et al., Arthritis Rheum.
2001 December; 44(12):2790-6).
[0015] The high concentration of NO in patients with ulcerative
colitis also suggests in this case an involvement of iNOS in this
pathology.
[0016] With the identification of NO as the critical mediator of a
congruous number of physiopathological processes, pharmacological
control of its production is clearly of therapeutic potential. The
first agents appearing in the literature capable of interfering
with the production of NOS-mediated NO were enzyme inhibitors which
were analogues of the substrate (L-arginine), among the following:
L-NMMA (N.sup.G-methyl-L-arginine), L-NNA
(N.sup.G-nitro-L-arginine), L-NAME (N.sup.G-nitro-L-arginine methyl
ester), L-NAA (N.sup.G-amino-L-arginine) and L-NIO
(N.sup..delta.-iminoethyl-L-ornithine).
[0017] On account of their weak selectivity between the various
isoforms, the clinical use of these inhibitors requires great care,
since inhibition of the constitutive forms may have serious
consequences, such as hypertension and more severe possible effects
such as thrombosis and tissue damage. Thus, even though the
therapeutic use of sparingly selective inhibitors is possible, the
use of agents capable of selectively controlling the production of
NO from iNOS is of greater therapeutic potential.
[0018] In the last decade, a large number of studies have appeared
in the literature, documenting intense research in this direction
(Exp. Opin. Ther. Patents, 1999, 9, 549-556; Exp. Opin. Ther.
Patents, 2000, 10, 1143-1146); among these, NOS inhibitors of
non-amino acid structure have been reported, which are for the
majority based on bioisosteres of the guanidine group present in
the structure of arginine, for instance S-alkylisothiourea,
guanidine and amidine.
[0019] All these publications and studies reveal the therapeutic
need for pharmacological agents based on modulation of the activity
of iNOS characterized by a better pharmacological profile.
[0020] Prostaglandins (PGE) are inflammation mediators generated by
the enzyme cyclooxygenase (COX). The inducible isoform (COX-2) is
overproduced ("upregulated") in the inflamed tissues and this leads
to an increased synthesis of PGE.
[0021] Interactions exist between NOS and COX systems, and the role
of NO in inflammation may therefore depend not only on its direct
effect but also on its modulatory effect on PGE bio-synthesis.
[0022] Interleukin-6 (IL-6) is a cytokine whose overexpression is
associated with the physiopathology of various human diseases, for
instance Crohn's disease [see Ho et al., J. Gastroenterol. Suppl.
14, 56-61 (2002)] or rheumatoid arthritis [see Nakahara H. et al.;
Arthritis Rheum. 48 (6), 1471-4 (2003)].
[0023] Since the enzymes iNOS and COX-2, just like the cytokine
IL-6, the effect of which has been discussed above, are expressed
in conjunction with inflammatory processes, demonstrating large
effects in the establishment and development of the discussed
pathologies, it would clearly be advantageous to be able to use a
medicinal product capable of exhibiting inhibitory action on the
iNOS-mediated production of NO and the formation of COX-2-mediated
inflammatory prostaglandins, not to mention the expression of a
cytokine, for instance IL-6.
[0024] The compounds of the present invention represented by
Formula (I) are therefore effective in treating pathologies in
which there is an appreciable effect of excessive production of NO
from iNOS and similarly conventional NSAIDs in pathologies in which
reduction of the inflammatory prostaglandins (e.g.: PGE.sub.2) is
pharmacologically useful, for instance in the treatment of
arthritis, including but not limited to osteoarthritis, rheumatoid
arthritis, neuropathic arthritis and systemic lupus
erythematosus.
[0025] The compounds of the invention may also be particularly
useful, by means of their inhibitory activity on the production of
IL-6, for the treatment of gastrointestinal pathologies, for
instance intestinal inflammations, Crohn's disease and ulcerative
colitis. Finally, the compounds of the present invention may find
use in the treatment of acute or chronic pain of articular or
neuropathic origin, in conditions in which treatment with
non-steroidal anti-inflammatory drugs (NSAIDs) or opiate analgesics
is indicated.
[0026] The compounds of Formula (I) are represented by the
following general formula:
##STR00003##
[0027] in which: [0028] G.sub.1 and G.sub.2 are independently
selected from hydrogen, halogen, hydroxyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkyl, and the amidine substituent of formula Q,
provided that, for each compound of formula (I), only one of the
two substituents G.sub.1 or G.sub.2 is the amidine substituent of
formula Q.
[0029] The amidine substituent of formula Q is represented by the
structure given below, in which R is C.sub.1-C.sub.4 alkyl or
cycloalkyl.
[0030] Amidine substituent of formula Q:
##STR00004##
[0031] In the compounds of Formula I: [0032] W is independently: a
bond, a substituted or unsubstituted carbon atom (.dbd.CR.sub.1--or
.dbd.CH--), an unsubstituted nitrogen atom (.dbd.N--); [0033] Y is
a substituted or unsubstituted carbon atom (.dbd.CR.sub.1-- or
.dbd.CH--), or an unsubstituted nitrogen atom (.dbd.N--); [0034] X
is a substituted or unsubstituted carbon atom (.dbd.CR.sub.1-- or
.dbd.CH--), a substituted or unsubstituted nitrogen atom
(--NR.sub.2-- or .dbd.N--), a sulfur atom (--S--) or an oxygen atom
(--O--);
[0035] provided that: the substituents W, Y and X give rise,
suitably in combination, to 9- or 10-membered bicyclic
heteroaromatic derivatives containing up to 2 hetero atoms in the
same ring, such as indole, benzofuran, benzothiophene,
benzimidazole, benzoxazole, benzothiazole, quinoline, quinoxaline,
quinazoline, isoquinoline or cinnoline derivatives.
[0036] The substituents R.sub.1 and R.sub.2 are independently
selected from hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkenyl and C.sub.1-C.sub.4 alkoxy.
[0037] The substituents R.sub.3 and R.sub.4 are independently
selected from hydrogen, halogen, hydroxyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 alkenyl.
[0038] Z is an aryl or heteroaryl group, or a linear or branched
C.sub.1-C.sub.6 alkyl or alkenyl chain, or a C.sub.1-C.sub.4
alkyl-aryl group or a C.sub.1-C.sub.4 alkyl-heteroaryl group in
which the aryl group is a phenyl which is unsubstituted or
substituted with one or more substituents independently selected
from halogen, trifluoromethyl, hydroxyl, nitro, cyano, carboxyl,
carboxamido, carbonyl, thio, methylthio, methanesulfonyl,
methanesulfinyl, sulfonamido, trifluoromethoxy, C.sub.1-C.sub.6
alkoxy and C.sub.1-C.sub.6 alkyl, and the heteroaryl group is a 5-
or 6-atom heteroaromatic ring containing one or more hetero atoms,
which is unsubstituted or substituted with one or more substituents
independently selected from halogen, trifluoromethyl, hydroxyl,
nitro, cyano, carboxyl, carbonyl, thio, methylthio,
methanesulfonyl, methanesulfinyl, trifluoromethoxy, C.sub.1-C.sub.6
alkoxy and C.sub.1-C.sub.6 alkyl.
[0039] The C.sub.1-C.sub.4 alkyl-aryl group is a linear or
branched, saturated or unsaturated C.sub.1-C.sub.4 hydrocarbon
chain substituted with an aryl group. When the C.sub.1-C.sub.4
chain is unsaturated, it is intended to contain only one
substituted or unsubstituted double bond. Substituents for the aryl
group are independently selected from the groups defined above as
substituents for the aryl group.
[0040] The C.sub.1-C.sub.4 alkyl-heteroaryl group is a linear or
branched, saturated or unsaturated C.sub.1-C.sub.4 hydrocarbon
chain substituted with a substituted or unsubstituted heteroaryl
group. When the C.sub.1-C.sub.4 chain is unsaturated, it is
intended to contain only one substituted or unsubstituted double
bond.
[0041] The term "heteroaryl" means any of the heterocyclic nuclei
defined above.
[0042] The compounds of formula (I) may thus be used either in free
base form or as pharmaceutically acceptable salts. The present
invention thus includes all the pharmaceutically acceptable salts
of the compounds of formula (I). Pharmacologically acceptable salts
of the compounds of formula (I) include, but are not limited to:
hydrochloride, hydrobromide, sulfate, hydrogen sulfate,
methanesulfonate, maleate, citrate, fumarate and succinate.
[0043] Pharmaceutical formulations of the compounds of the
invention may be prepared using conventional techniques. The
formulations include those suitable for oral, parenteral (including
subcutaneous, intramuscular, intravenous, intra-articular and
transdermal), topical or rectal use or other forms suitable for
obtaining the desired therapeutic effect, for example
delayed-action solid formulations for oral use allowing a slow
release of the active principle over time.
[0044] Substances commonly used in the pharmaceutical field, such
as excipients, binders, disintegrants and substances capable of
stimulating transdermal or mucosal absorption, may be used together
with the active principle in the pharmaceutical formulations.
[0045] Table 1 below, which is non-limiting, illustrates a number
of compounds of formula (I) that are the subject of the present
invention.
TABLE-US-00001 TABLE 1 Examples of compounds of formula (I) Com-
pound Structure G.sub.1 G.sub.2 W Y X Z 1 ##STR00005## Acetamidine
H Bond S N Ph 3 ##STR00006## Acetamidine H Bond S N 4-Cl-Ph 4
##STR00007## Acetamidine H Bond S N n-Pentyl 5 ##STR00008##
Acetamidine H Bond CH NH Ph 6 ##STR00009## Acetamidine H Bond CH
NMe Ph 8 ##STR00010## Acetamidine H CH CH N Ph 9 ##STR00011## H
Acetamidine Bond S N Ph 10 ##STR00012## H Acetamidine Bond S N Ph
11 ##STR00013## H Acetamidine Bond S N Benzyl 12 ##STR00014## H
Acetamidine Bond S N Styryl 13 ##STR00015## H Acetamidine Bond S N
2-MeO-5- SO.sub.2NH.sub.2-Ph 14 ##STR00016## H Acetamidine Bond S N
2-pyridyl 15 ##STR00017## H Acetamidine Bond S N 4-MeO-Ph 16
##STR00018## H Acetamidine Bond S N 2.4-(MeO).sub.2- Ph 17
##STR00019## H Acetamidine Bond S N 3-MeO-Ph 18 ##STR00020## H
Acetamidine Bond S N 2-Me-Ph 19 ##STR00021## Acetamidine H Bond N
NH 4-F-Ph 20 ##STR00022## Acetamidine H Bond N NH 4-Cl-Ph 21
##STR00023## Acetamidine H Bond N NH Ph 22 ##STR00024## Acetamidine
H Bond N NH n-pentyl 23 ##STR00025## Acetamidine H Bond N NH
2-pyrrol 25 ##STR00026## Acetamidine H Bond N NH 4-CO.sub.2Me-Ph 26
##STR00027## Acetamidine H Bond N NH 4-CO.sub.2H-Ph 27 ##STR00028##
Acetamidine H CH N N Ph 28 ##STR00029## Acetamidine H Bond CH O Ph
29 ##STR00030## H Acetamidine Bond O NH Ph 30 ##STR00031## H
Acetamidine Bond O NH 4-ClPh 31 ##STR00032## H Acetamidine Bond O
NH 3-CF.sub.3Ph 32 ##STR00033## H Acetamidine Bond O NH
4-CF.sub.3Ph 33 ##STR00034## H Acetamidine Bond O NH 2-FPh 34
##STR00035## H Acetamidine Bond O NH 3,4-ClPh 35 ##STR00036## H
Acetamidine Bond N NH 3,4-ClPh 36 ##STR00037## H Acetamidine Bond N
NH 3-CF.sub.3Ph 37 ##STR00038## H Acetamidine Bond N NH 2-OMePh 38
##STR00039## H Acetamidine Bond N NH 2-FPh 39 ##STR00040## H
Acetamidine Bond N NH 2-MePh 40 ##STR00041## Acetamidine H Bond S N
2-pyrrol 41 ##STR00042## ##STR00043## H Bond S N 2-Ph 42
##STR00044## Acetamidine H Bond O NH Ph 43 ##STR00045## H
Acetamidine Bond NR N 2-MeO-Ph 44 ##STR00046## H Acetamidine Bond N
NR 2-MeO-Ph
[0046] According to a further aspect of the present invention, the
process required for preparing the compounds of formula (I) is
described.
[0047] The compounds of the invention are prepared from a compound
of formula (II) by reaction with a compound of formula (III).
##STR00047##
[0048] in which W, Y, X, Z, R.sub.3 and R.sub.4 are defined as for
the compounds of formula (I), while G'.sub.1 and G'.sub.2 are
independently selected from: hydrogen, halogen, hydroxyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkyl, and the amine group
(--NH.sub.2), provided that, for each compound of formula (II),
only one of the substituents G'.sub.1 or G'.sub.2 is an amine group
(--NH.sub.2).
##STR00048##
[0049] in which R is as defined for the amidino substituent of
formula Q and L is a leaving group. The leaving group L is an
alkoxy group (ethoxy or methoxy), or an alkylthio group (RS--;
thiomethyl or thiomethylnaphthyl) or an arylthio group (Ar--S;
thiophenyl).
[0050] Optionally, the following steps can complete the conversion
of a compound of formula (II) into a compound of formula (I):
[0051] removal of any protecting group present [0052] conversion of
the product into the corresponding salt or solvate.
[0053] The reaction of a compound of formula (II) with a compound
of formula (III) may be performed in a suitable solvent such as:
alcohol, acetonitrile, N,N-dimethylformamide (DMF) or
tetrahydrofuran (THF), at temperatures of between 0.degree. C. and
50.degree. C., as described in the case of alkoxy-imidates (Cereda
et al., J. Med. Chem., 1990, 33, 2108-2113) or in the case of
thioimidates (Collins et al., J. Med. Chem., 1998, 41, 2858-2871;
Miosokowski et al., Synthesis, 1999, 6, 927-929; J. Eustache et al.
Tetrahedron Letters, 1995, 36, 2045-2046, or Shearer et al.,
Tetrahedron Letters, 1997, 38, 179-182).
[0054] The compounds of formula (III) are commercially available or
may be prepared as described in the given references.
[0055] The compounds of formula (II) are obtained from compounds of
formula (IV):
##STR00049##
[0056] in which W, Y, X, Z, R.sub.3 and R.sub.4 are as defined
above for the compounds of formula (I), N.sub.1 and N.sub.2 are
independently selected from: hydrogen, halogen, hydroxyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkyl, nitro group
(NO.sub.2), or protected amine group (e.g. carbamate or amide), or
a suitable precursor of an amine group, for instance a carboxyl
(COOH) or a derivative thereof (acyl chloride, ester or primary
amide), provided that, for each compound of formula (IV), only one
of the substituents N.sub.1 or N.sub.2 is a nitro group or a
protected amine group, or a suitable precursor thereof as defined
above. Suitable protecting groups for the amine group include:
t-butoxycarbonyl (BOC), benzyloxycarbonyl (Z), trifluoroacetyl,
acetyl and benzoyl.
[0057] When N.sub.1 or N.sub.2 is a nitro group, the compounds of
formula (II) are obtained by reducing a compound of formula (IV).
The reduction may be performed either using hydrogen and a catalyst
(Pd/C or PtO.sub.2), according to the usual methods of organic
chemistry (P. Rylander, Catalytic Hydrogenation in Organic
Synthesis, Academic Press, 1979), or using chemical reducing
agents, for instance stannous chloride (F. D. Bellamy et al.,
Tetrahedron Letters, 1984, 25 (8), 839-842.), iron (C. A. Merlic,
JOC, 1995, 33-65), nickel boride (Atsuko Nose, Chem. Pharm. Bull.,
1989, 37, 816-818), Raney nickel/propanol (Kuo E., Synthetic
Communication, 1985, 15, 599-6023) or sodium borohydride and Pd/C
(Petrini M., Synthesis, 1987, 713-714).
[0058] When N.sub.1 or N.sub.2 is a protected amine group, the
compounds of formula (II) may be obtained from a compound of
formula (IV) by removal of the protecting group, according to
methods known in organic chemistry (T. W. Green and P. Wuts,
Protective Groups in Organic Synthesis, 1991, J. Wiley &
Sons).
[0059] When N.sub.1 or N.sub.2 is a carboxyl group (COOH), the
conversion of a compound of formula (IV) into a compound of formula
(II) may be performed via Schmidt or Curtius degradation (H. Wolff,
Organic Reactions, 1946.3, 307; J. Saunders, Chem. Rev. 1948, 43,
203).
[0060] The compounds of formula (IV) are commercially available or
may be prepared from compounds of formula (V):
##STR00050##
[0061] in which:
[0062] a) W, Y, X, Z, R.sub.3 and R.sub.4 are as defined for the
compounds of formula (I) and P.sub.1 and P.sub.2 are independently
selected from hydrogen, halogen, hydroxyl, C.sub.1-C.sub.4 alkoxy
and C.sub.1-C.sub.4 alkyl, provided that, for each compound of
formula (V), at least one of the substituents P.sub.1 or P.sub.2 is
a hydrogen atom. In this case, the compounds of formula (IV) may be
obtained by aromatic nitration of a compound of formula (V) and,
where applicable, by separation of the desired product from the
corresponding regioisomers.
[0063] b) W, Y, X, R.sub.3 and R.sub.4 are defined as for the
compounds of formula (I), Z is a halogen or hydrogen, and P.sub.1
and P.sub.2 are independently selected from groups as defined in a)
and also nitro, amine and protected amine, provided that, for each
compound of formula (V), only one of the substituents P.sub.1 or
P.sub.2 is a nitro group, an amine group or a protected amine
group. In this case, a compound of formula (V) may be converted
into a compound of formula (IV) in which Z is aryl or heteroaryl
via formation of an aromatic-aromatic bond according to standard
methods of organic chemistry (from J. Hassan, Chem. Rev., 2002,
102, 1359-469); when, in the compounds of formula (IV), Z is an
aryl or heteroaryl group, the compounds of formula (V) are
converted into compounds of formula (IV), using the coupling of an
aryl-zinc with a suitable halide or the Stille reaction of the
appropriate stannane with the corresponding halide.
[0064] When, in the compounds of formula (V), Z is halogen, and, in
the compounds of formula (IV), Z is an aryl or heteroaryl group,
the corresponding conversion may be performed by using the coupling
of zinc derivatives with aromatic or heteroaromatic halides (Scheme
1).
[0065] According to this method, the compounds of formula (V), in
which Z is H or halogen, are reacted with n-butyllithium or
t-butyllithium, the resulting organolithium derivative (Va) is
reacted with zinc chloride to give the corresponding organozinc
reagents (Vb), which are reacted with the aryl or heteroaryl
halide, via homogeneous catalysis (palladium), to form the
compounds of formula (IV).
##STR00051##
[0066] The reaction conditions are equivalent to those reported (M.
Amat et al., J. Org. Chem., 1997, 62, 3158 and S. Hargreaves et
al., Tetrahedron Letters, 2000, 41, 1653). Alternatively, the
intermediates (Vb, Scheme 1) may be obtained directly from the
compounds of formula (V) by oxidative addition of zinc metal
(Knochel et al., Tetrahedron Lett., 1990, 31, 4413; Yamanaka et
al., Tetrahedron, 1993. 49, 9713).
[0067] Alternatively, the compounds of formula (IV) are obtained
from compounds of formula (V) in which Z is halogen (Scheme 1) by
reaction with an aryl or heteroaryl zinc derivative, using methods
identical to those mentioned previously.
[0068] Alternatively (Scheme 2), when, in the compounds of formula
(V), Z is hydrogen or halogen, and, in the compounds of formula
(IV), Z is an aryl or heteroaryl group, the conversion of (V) into
(IV) may be performed via cross-coupling catalysed by Pd stannanes
with aryl or heteroaryl halides, according to the Stille method.
The compounds of formula (V) in which Z is halogen are converted
into the corresponding arylstannanes (Vb) according to known
methods (Pereyere M., Tin in Organic Synthesis, Butterworths,
1987), i.e. by reacting a compound of formula (V) in which Z is
halogen with hexamethylditin, using
tetrakis(triphenylphosphine)palladium (0) as catalyst, in refluxing
THF (J. La Voie, J. Org. Chem., 2000, 65, 2802-2805) or by reaction
with hexabutylditin using the same catalyst, in toluene as solvent
(K. Masanori et al., Bull. Chem. Soc. Jpn, 1983, 56, 3855-3856).
This method is particularly effective when, in the compounds of
formula (V), P.sub.1 or P.sub.2 is a nitro group or in which other
substituents do not support the presence of bases and/or
nucleophiles such as alkyllithiums.
[0069] Alternatively (Scheme 2), the compounds of formula (IV) may
be obtained from compounds of formula (V) in which Z is halogen or
hydrogen by reaction with an organolithium (n-butyllithium or
t-butyllithium). In this case, the compounds of formula (V) give
the corresponding derivatives (Va), which are reacted with
trimethyltin chloride or tri-n-butyltin chloride to give the
corresponding stannanes (Vb). These intermediates are reacted with
suitable aromatic or heteroaromatic halides, under palladium
catalysis, to give the compounds of formula (IV). The conversion of
compounds of formula (V) into compounds of formula (Vb) may be
performed using known procedures (P. Jutzi, J. Organometallic
Chem., 1983, 246, 163-168). The coupling of the stannanes (Vb) with
aromatic or heteroaromatic halides is performed according to
standard procedures (P. Gros, Synthesis, 1999, 5, 754-756).
[0070] Alternatively, the compounds of formula (IV) are obtained
from compounds of formula (V) in which Z is halogen (Scheme 2), via
palladium-catalysed coupling with an aryl or heteroaryl stannane,
using the methods described above, the preferred route depending on
the compatibility of the substituents present.
##STR00052##
[0071] Alternatively (Scheme 3), the compounds of formula (IV) in
which Z is aryl and heteroaryl may be obtained from compounds of
formula (V), in which Z is hydrogen or halogen, via Suzuki coupling
of boronic derivatives with the corresponding halides. This
palladium-catalysed reaction for formation of the aryl-aryl bond
using arylboronic or heteroarylboronic derivatives is a known
process (J. Hassan, 2002, Chem Rev., 102, 1359-1469).
[0072] In this case, compounds of formula (V), in which Z is
hydrogen or halogen, are converted into the boronates (Vb) by
reaction with an alkyllithium or lithium diisopropylamide to form
the intermediates (Va), which are converted into the boronates (Vb)
by reaction with trimethyl or triisopropyl borate according to
standard procedures (A. Alvarez, J. Org. Chem., 1992, 57,
1653-1656, .smallcircle. J. G. Grieb, Synthetic Commun., 1995, 25,
214-2153).
[0073] The palladium-catalysed coupling of the intermediates (Vb),
boronic acids or esters, with suitable aryl halides gives the
compounds of formula (IV), according to known procedures (B. Maes
et al., Tetrahedron, 2000, 56, 1777-1781).
[0074] Alternatively, the compounds of formula (IV) are obtained
from the compounds of formula (V) in which Z is halogen (Scheme 3)
via Suzuki coupling with an aryl or heteroaryl boronic derivative,
using the same methods as mentioned above.
##STR00053##
[0075] Alternatively (Scheme 4), the compounds of formula (IV) in
which W, Y, X, R.sub.3 and R.sub.4 are defined as for the compounds
of formula (I), Z is a linear or branched C.sub.1-C.sub.6 chain, a
C.sub.1-C.sub.4 alkylaryl group or a C.sub.1-C.sub.4
alkylheteroaryl group, P.sub.1 and P.sub.2 are as defined in point
(b), and are obtained from the esters of formula (V) via Heck
synthesis. In this case, the compounds of formula (V) in which Z is
a suitable halogen are converted into compounds of formula (IV) in
which Z is a linear or branched C.sub.1-C.sub.6 alkenyl chain, a
C.sub.1-C.sub.4 alkenylaryl group or a C.sub.1-C.sub.4
alkenylheteroaryl group via palladium-catalysed arylation of a
terminal olefin (Heck reaction). The resulting olefins may
constitute per se compounds of formula (IV) or may be converted
(reduction reaction of the olefin to a saturated hydrocarbon) into
compounds of formula (IV) in which Z is a linear or branched
C.sub.1-C.sub.6 alkyl chain, a C.sub.1-C.sub.4 alkylaryl group or a
C.sub.1-C.sub.4 alkylheteroaryl group. The Heck reaction is
performed according to known procedures (R. F. Heck, Org. React.,
1982, 27, 345-390). In the case where the compound of formula (IV)
thus obtained, in which Z is a linear or branched, unsaturated
C.sub.1-C.sub.6 chain, needs to be converted into a compound of
formula (IV) in which Z is a saturated C.sub.1-C.sub.6 chain, via
catalytic hydrogenation, common techniques are used (P. Rylander,
Catalytic Hydrogenation in Organic Synthesis, Academic Press,
1979).
##STR00054##
[0076] c) Alternatively (Scheme 5), the compounds of formula (IV),
in which: W, Y, X, Z, R.sub.3 and R.sub.4 are as defined for the
compounds of formula (I), P.sub.1 and P.sub.2 are as defined in
point (b), are prepared by reaction of a compound of formula (VI)
with a compound of formula (VII). In the case where, for the
compounds of formula (VI), P.sub.1 and P.sub.2 are as defined
above, W is a bond or a substituted or unsubstituted carbon atom,
as defined previously. Y is a thiol group (SH), a hydroxyl group
(OH), an unsubstituted nitrogen atom, (--NH.sub.2) or a
triphenylphosphonium group P.sup.+(Ph).sub.3, X is a substituted or
unsubstituted nitrogen atom (--NH.sub.2 or --NHR.sub.2), a thiol
group (--SH) or a hydroxyl group (--OH).
##STR00055##
[0077] For the compounds of formula (VII), Z is as defined for the
compounds of formula (I), J is an oxygen atom (O) or a nitrogen
atom (N) and T is hydroxyl, hydrogen, halogen, amine or
C.sub.1-C.sub.4 alkoxy.
[0078] Non-limiting examples of the synthetic route (c) are given
in Scheme 6 below:
##STR00056## ##STR00057##
[0079] The compounds of formula (VI), like the compounds of formula
(VII), are commercially available or may be prepared from
commercially available compounds according to known procedures. In
the case of Scheme 6a, the 2-substituted benzothiazoles are
obtained from the acids of formula (VII) and from the appropriate
aminothiophenols of formula (VI) by reaction with polyphosphoric
acid (PPA) (D. Boger, J. Org. Chem., 1978, 43, 2296-2297; or D. W.
Hein et al., J. Am. Chem. Soc., 1957, 427-429). Esters, imidates or
amides of formula (VII) may be used as alternatives to the acids
reported in Schemes 6a and 6c. Alternatively, the 2-substituted
benzothiazoles are obtained from the aldehydes of formula (VII)
(Scheme 6b) by reaction with suitable aminothiophenols, catalysed
by pyridinium p-toluenesulfonate (PTS) or iron (III) chloride
(Chem. Pharm. Bull., 1998, 46, 623-630).
[0080] In the case of Scheme 6c, the 2-substituted benzoxazoles are
obtained from the respective acids of formula (VII) or derivatives
(acyl chlorides, esters, ortho esters, imidates or amides) and from
the appropriate aminophenols of formula (VI) by reaction with PPA
(J. P. Heeschen in Journal Org. Chem., 1997, 62, 3552-3561).
[0081] The benzoxazoles, Scheme 6c, are also obtained by reaction
of aminophenols with the acyl chlorides of formula (VII) in
toluene, and the corresponding amides thus formed are cyclized into
benzoxazoles, thermally or via acid catalysis (p-toluenesulfonic
acid) (R. P. Perry et al., Journal Org. Chem., 1992, 57,
2883-2887), or by POCl.sub.3-mediated cyclization.
[0082] In the case of Scheme 6d, the 2-substituted benzimidazoles
are obtained by PPA-mediated reaction of the respective acids of
formula (VII) and the phenylenediamines of formula (VI) (C. M.
Orlando et al., J. Org. Chem., 1970, 35, 3147-3148). Alternatively,
the 2-substituted benzimidazoles are obtained from the aldehydes of
formula (VII) by condensation of the corresponding bisulfite adduct
with phenylenediamines (M. A. Weidner et al., Bioorganic &
Medicinal Chem. Lett., 2001, 1545-1548).
[0083] Finally, the 2-substituted benzimidazoles, Scheme 6d, are
obtained by reaction of the phenylenediamines of formula (VI) with
the acyl chlorides corresponding to the acids of formula (VII), and
the amides are then cyclized into the corresponding benzimidazoles
as described above for the benzoxazoles. In the case of Scheme 6e,
the appropriate 2-substituted quinazolines are obtained by
acylation of the amines (VI) with the benzoic acids (VII), followed
by POCl.sub.3-mediated cyclization (A. Downes, in J. Chem Soc.,
1950, 3053-3055), and the synthesis is completed by oxidation with
DDQ or chloranil; the procedure described by J. Van den Eynde,
Synthesis, 1993, 867-869 may be used as an alternative.
[0084] In the case of Scheme 6f, the benzofuran derivatives of
formula (IV) are prepared by reaction of the corresponding
phosphoranes, obtained from the phosphonium salts of formula (VI)
and from the acyl chlorides of formula (VII). In the case of Scheme
6g, the benzothiophene derivatives of formula (IV) are prepared by
reaction of the corresponding phosphoranes obtained from
phosphonium salts of formula (VI) and from the acyl chlorides of
formula (VII)(A. Arnoldi, M. Carughi., Synthesis, 1988,
155-157).
[0085] d) Alternatively (Scheme 7), the compounds of formula (IV)
in which: W, Y, X, Z, R.sub.3 and R.sub.4 are as defined for the
compounds of formula (I), and P.sub.1 and P.sub.2 are as defined in
point (b), are prepared by cyclization reaction of a compound of
formula (XIII). The compounds of formula (XIII) are prepared by
reaction of a compound of formula (XII) with the compounds of
formula (XI). In the case where, for the compounds of formula (XI),
P.sub.1 and P.sub.2, R.sub.3 and R.sub.4 are as defined above, X is
a hydrogen atom, a nitrogen atom, a carboxylate group (COOH) or a
derivative thereof, or an aldehyde group (CHO); T is a halogen or a
sulfur atom. In the compounds of formula (XIII), W is a sulfur
atom, a substituted carbon atom (--CR.sub.1.dbd.) or an
unsubstituted carbon atom (--CH.dbd.) belonging to an olefinic or
acetylenic system; Y is a substituted or unsubstituted carbon atom
and Z is defined as for the compounds of formula (I).
##STR00058##
[0086] Representative examples of conversion of compounds of
formula (XI) into compounds of formula (IV) are given in Scheme
8.
##STR00059##
[0087] In Scheme 8a), the 2-iodobenzoic derivative, a compound of
formula (XI), is converted into the acetylenic derivative of
formula (XIII), via a Heck reaction (R. C. Larock et al., Journal
Org. Chem., 2003, 68, 5936). The compound of formula (XIII) is then
cyclized into the isocoumarin, which, by reaction with methanolic
ammonia, is converted into the corresponding isoquinolinone; the
isoquinolinone is converted into the compound of formula (IV) via
known methods, for example by conversion to 1-chloroisoquinoline,
followed by reductive dehalogenation.
[0088] As reported in Scheme 8b), the 2-bromoaniline of formula
(XI) is reacted, under Heck conditions, with styrene or with a
substituted styrene to give the compounds of formula (XIII) in
which W and Y are both carbon atoms forming part of an olefinic
bond. The cyclization of the compound of formula (XIII) into the
compound of formula (IV) is performed via catalysis with Pd (J.
LaVoie, Bio-organic & Medicinal Chem., 1996, 4, 621-630).
[0089] The following non-limiting examples describe the details of
the synthesis of the amidine derivatives of formula (I):
[0090] Examples of Preparation of Compounds of Formula (I)
According to Synthetic Route (a):
EXAMPLE 1
Compound 1
N-(2-phenylbenzothiazol-6-yl)acetamidine
[0091] Triethylamine (36.7 ml, 0.263 mol) is added to methyl
acetamidate hydrochloride (28.85 g, 0.263 mol) in acetonitrile (600
ml). The mixture is stirred at room temperature for 15 minutes and
2-phenyl-6-aminobenzothiazole (29.8 g, 0.131 mol) is added. The
resulting mixture is stirred for 72 hours at room temperature, the
solid is filtered off, suspended in ethyl acetate and basified with
1M NaOH (pH=10), and the phases are separated. The organic phase is
washed with water, dried and evaporated. The solid is
recrystallized from isopropyl ether. Yield: 14.5 g (42%); Elem.
anal. C.sub.15H.sub.13N.sub.3S; theory: C:67.39 H:4.90 N:15.72;
found C:66.78 H:5.03 N:15.60; IR (KBr): 3260, 3020, 1645, 1590
cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.05 (m, 2H); 7.9 (d, 1H);
7.35-7.55 (m, 3H); 6.95 (m, 1H); 5.9-6.2 (broad s, 2H); 1.8 (m,
3H).
1a) 2-phenyl-6-aminobenzothiazole
[0092] 2-Phenyl-6-nitrobenzothiazole (73.5 g, 0.286 mol) is added
to tin dichloride (200.74 g, 0.89 mol) in 37% HCl (300 ml). The
mixture is heated at 100.degree. C. for 40 minutes. The resulting
mixture is cooled and aqueous ammonia (pH=10) is added dropwise.
The product is extracted with chloroform and the extracts are
concentrated. The solid is recrystallized from isopropyl
ether/hexane (2/1). Yield: 29.9 g (46%); Rf (9/1
chloroform/methanol): 0.68; m.p.: 199.8-201.1.degree. C.; IR (KBr):
3450, 3305, 3190, 1619 cm.sup.-1.
1b) 2-phenyl-6-nitrobenzothiazole
[0093] 2-Phenylbenzothiazole (Aldrich, 63.89 g, 0.302 mol) is
nitrated with 100% nitric acid (190 ml, 4.53 mol) at 5.degree. C.
The mixture is stirred at 5.degree. C. for 70 minutes, quenched in
ice-water and basified with 32% NaOH (pH=10). The product is
filtered off and the solid obtained is suspended in water and
filtered off. The product is recrystallized from isopropyl ether.
Yield: 73.6 g (95%); Rf (8/2 petroleum ether/ethyl acetate): 0.76;
m.p.: 178.9-181.3.degree. ; .sup.1H-NMR (d.sub.6-DMSO): 9.16 (d,
1H); 8.35 (dd, 1H); 8.23 (d, 1H); 8.15 (dd, 1H) 7.58; (m, 4H).
EXAMPLE 2
Maleate of Compound 1-Compound 2
N-(2-phenylbenzothiazol-6-yl)acetamidine maleate
[0094] A 1M solution of maleic acid in acetone (10 ml) is added
dropwise to N-(2-phenylbenzothiazol-6-yl)acetamidine (1 g, 0.00374
mol) (Example 1), in acetone (30 ml). The product is precipitated
and filtered off. Yield: 1.09 g (77%); Elem. anal.
C.sub.15H.sub.13N.sub.3S.C.sub.4H.sub.4O.sub.4; theory C:59.51
H:4.47 N:10.96; found C:59.30 H:4.36 N:10.62; IR (KBr): 3060, 1700,
1480, 1360 cm.sup.-1.
EXAMPLE 3
Compound 3
N-[2-(4-chlorophenyl)benzothiazol-6-yl]acetamidine
[0095] Prepared in a manner similar to that of Example 1. Yield:
40%; Elem. anal. C.sub.19H.sub.17N.sub.3O.sub.4S; M.W.: 383.419;
theory C:59.70 H:4.00 N:13.92; found C:59.29 H:3.70 N:13.63; IR
(KBr): 3450, 3290, 3115, 1640 cm.sup.-1; .sup.1H-NMR
(d.sub.6-DMSO): 8.2 (d, 2H); 7.9 (m, 1H); 7.6 (d, 2H); 7.4 (m, 1H);
6.9 (m, 1H); 6.3 (broad s, 2H); 1.9 (m, 3H).
3a) 2-(4-chlorophenyl)-6-aminobenzothiazole
[0096] Prepared in a manner similar to that of Example 1a. Yield:
77%; Rf (8/2 hexane/ethyl acetate): 0.16; m.p.: 165.9-168.degree.
C.; Elem. anal. C.sub.13H.sub.9ClN.sub.2S; theory C:59.88 H:3.48
N:10.74; found C:59.22 H:3.34 N:10.84; IR (KBr): 3460, 3355, 3195,
1620 cm.sup.-1.
3b) 2-(4-chlorophenyl)-6-nitrobenzothiazole
[0097] Prepared in a manner similar to that of Example 1b from
2-(4-chlorophenyl)benzothiazole, which is prepared in a manner
similar to that of Example 4c. Yield: 84%; Rf (3/7
chloroform/toluene): 0.50; m.p.: 227.2-232.degree. C.; IR (KBr):
1515, 1340 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO): 9.16 (d, 1H);
8.35 (dd, 1H); 8.23 (d, 1H); 8.15 (dd, 1H); 7.58 (m, 4H).
EXAMPLE 4
Compound 4
N-(2-pentylbenzothiazol-6-yl)acetamidine
[0098] Triethylamine (16.6 ml, 0.119 mol) is added to methyl
acetamidate hydrochloride (5.58 g, 0.051 mol) in acetonitrile (100
ml). The mixture is stirred at room temperature for 15 minutes, and
2-pentyl-6-aminobenzothiazole(hydrochloride) (8.9 g, 0.034 mol) is
added. The resulting mixture is stirred at room temperature for 48
hours, filtered and evaporated. The residue is taken up in ethyl
acetate and the product is extracted with 0.1M HCl. The aqueous
phases are combined, basified with NaOH (pH=10) and extracted with
ethyl acetate. The extracts are washed with water. The resulting
organic phase is dried, filtered and evaporated. The solid is
recrystallized from isopropyl ether. Yield: 5.0 g (56%); Elem.
anal. C.sub.14H.sub.19N.sub.3S; M.W.: 261.39; theory C:64.33 H:7.32
N:16.07; found C:64.42 H:7.48 N:16.13; IR (KBr): 3318, 3085, 1655,
1615, 1586 cm.sup.-1.sub.; .sup.1H-NMR (d.sub.6-DMSO) 7.7 (d, 1H);
7.3 (m, 1H); 6.8 (m, 1H); 6.1 (m 2H); 3 (t, 2H); 2-0.7 (m,
12H).
4a) 2-pentyl-6-aminobenzothiazole hydrochloride
[0099] 10% Pd/C (0.88 g) is added to 2-pentyl-6-nitrobenzothiazole
(10.3 g, 0.041 mol) in methanol (250 ml). The mixture is
hydrogenated, the catalyst is filtered off and the filtrate is
evaporated. The residue is taken up in methanol, isopropyl
ether/HCl is added and the hydrochloride is precipitated. Yield:
9.29 g (89%); Rf (95/5 methylene chloride/methanol): 0.75; IR
(KBr): 3465, 3395, 2955, 1505, 1455, 1155, 810 cm.sup.-1.
4b) 2-pentyl-6-nitrobenzothiazole
[0100] 2-Pentylbenzothiazole hydrochloride (20.5 g, 0.084 mol) is
added, at 0.degree. C., to trifluoromethanesulfonic acid (44.6 ml
0.504 mol) and 100% nitric acid (10.6 ml, 0.215 mol) in methylene
chloride (270 ml), and the mixture is stirred at 0.degree. C. for
1.5 hours and at room temperature for one hour. Water (150 ml) is
added dropwise and the phases are separated. The organic phase is
washed with 0.5M NaHCO.sub.3 and with water. The resulting solution
is dried, filtered and concentrated. The solid obtained is
recrystallized from petroleum ether. Yield: 10.6 g (50%); Rf (8/2
petroleum ether/ethyl acetate): 0.71; .sup.1H-NMR (d.sub.6-DMSO)
9.05 (d, 1H); 8.25 (dd, 1H); 8.15 (d, 1H); 3.13 (t, 2H); 1.28-1.36
(m, 4H); 0.85 (t, 3H).
4c) 2-pentylbenzothiazole hydrochloride
[0101] PPA (140 g) is added to hexanoic acid (25.06 ml, 0.2 mol)
and 2-mercaptoaniline (21.84 ml, 0.2 mol). The mixture is heated at
120.degree. C. for 30 minutes. The resulting mixture is cooled and
water (200 ml) is added dropwise, followed by addition of 32% NaOH
(pH=10). The resulting mixture is extracted with ethyl acetate and
washed with water. The resulting solution is dried and evaporated,
the residue is taken up in methanol, isopropyl ether/HCl is added
and the hydrochloride is precipitated. Yield: 43.8 g (90%); Rf (8/2
petroleum ether/ethyl acetate): 0.78; m.p.: 106.6-109.0.degree. C.;
IR (KBr): 30.75, 2925, 2210, 1884, 1440, 775 cm.sup.-1.
EXAMPLE 5
Compound 5
N-(2-phenyl-1H-indol-5-yl)acetamidine
[0102] Prepared in a manner similar to that of Example 1. Yield:
(63%); Elem. anal. C.sub.16H.sub.15N.sub.3 M.W.: 249.31; theory
C:77.08 H:6.06 N:16.85; found C:76.97 H:6.29 N:16.85; IR (KBr):
3434, 3024, 1634, 1597 cm.sup.-1.sub.; .sup.1H-NMR (d.sub.6-DMSO)
7.8-6.3 (m, 9H); 1.8 (s, 3H).
5a) 2-phenyl-5-amino-1H-indole
[0103] Prepared in a manner similar to that of Example 4a. Yield:
(83%); Rf (2/1 hexane/ethyl acetate): 0.30; m.p.:
220.2-220.5.degree. C. Elem. anal. C.sub.14H.sub.12N.sub.2; theory
C:80.74 H:5.81 N:13.45; found C:80.55 H:5.76 N:13.35; IR (KBr):
3416, 3036, 1622, 1585 cm.sup.-1.
5b) 2-phenyl-5-nitro-1H-indole
[0104] This intermediate is prepared by nitration of 2-phenylindole
(6 g, 31 mmol) with NaNO.sub.3 (2.8 g, 33 mmol) in 97%
H.sub.2SO.sub.4 (200 mL) at 5.degree. C. Yield: 6.9 g (93%); m.p.:
198.7-200.degree. C. (lit. 201-203.degree. C.; Wayland, E. N. et
al. J.O.C. 1966, 65).
EXAMPLE 6
Compound 6
N-(1-methyl-2-phenyl-1H-indol-5-yl)acetamidine
[0105] Prepared in a manner similar to that of Example 1. Yield:
68%; Elem. anal. C.sub.17H.sub.17N.sub.3; theory C:77.54 H:6.51
N:15.96; found C:76.77 H:6.83 N:15.65; IR (KBr): 3441, 3013, 1634,
1597 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 7.90-7.20 (m, 6H); 6.90
(d, J=1.5 Hz, 1H); 6.60 (dd, J=8.6 Hz, 1.5 Hz, 1H); 6.40 (s, 1H);
5.90 (bs, 2H, exch. D.sub.2O); 3.75 (s, 3H); 1.8 (s, 3H).
6a) 5-amino-2-phenyl-1-methylindole
[0106] Prepared in a manner similar to that of Example 4a. Yield:
86%; Rf (2/1 hexane/ethyl acetate): 0.30; m.p.: 107.5-110.5.degree.
C. IR (KBr): 3388, 3020, 1622, 1472 cm.sup.-1.
6b) 2-phenyl-1-methyl-5-nitroindole
[0107] Sodium hydride (1.1 g, 29.0 mmol) is added to
2-phenyl-5-nitro-1H-indole (Example 5b, 6.5 g, 26.0 mmol) in 100 mL
of DMF. The mixture is stirred at room temperature for 1 hour. MeI
(1.62 mL, 26.0 mmol) is added dropwise and the mixture is stirred
at room temperature for 1 hour. The resulting mixture is poured
into H.sub.2O/ice and the product is filtered off and washed with
H.sub.2O. The solid is recrystallized from hexane and filtered off.
Yield: 6.5 g (99.7%); Rf (2/1 hexane/ethyl acetate): 0.60; IR
(KBr): 3434, 2923, 1515, 1462 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO)
8.50 (d, J=1.5 Hz, 1H); 7.90 (dd, J=8.6 Hz, 1.5 Hz, 1H); 7.80-7.30
(m, 6H); 6.75 (s, 1H); 3.75 (s, 3H).
[0108] Examples of Preparation of Compounds of Formula (I)
According to the Synthetic Route (b):
EXAMPLE 7
Compound 5
[0109] As an alternative to the method described in Example 5, this
product may be prepared as reported below:
N-(2-phenyl-1H-indol-5-yl)acetamidine
[0110] Prepared in a manner similar to that of Example 5. Yield:
60%; Elem. anal. C.sub.16H.sub.15N.sub.3; theory C:77.08 H:6.06
N:16.85; found C:77.17 H:5.89 N:16.68; IR (KBr): 3434, 3024, 1634,
1597 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 7.8-6.3 (m, 9H); 1.8 (s,
3H).
7a) 2-phenyl-5-amino-1H-indole
[0111] Bromobenzene (0.157 ml, 0.0014 mol) and
dichloro-bis(triphenylphosphine)palladium (II) (51.3 mg, 0.073
mmol) are added to 2-boronic acid
1-N-BOC-5-(N',N'-bisBOC)aminoindole (0.69 g, 0.0014 mol) in THF (10
ml). The mixture is refluxed for 24 hours, 4N HCl (4 ml) are added
and the resulting mixture is heated at 80.degree. C. for 10 hours.
The resulting mixture is basified with 4M NaOH (pH=10) and
extracted with ethyl acetate. The organic phases are combined,
washed with water, dried, filtered and concentrated. The solid
obtained is recrystallized from isopropyl ether. Rf (2/1
hexane/ethyl acetate): 0.30; m.p.: 220.2-220.5.degree. C. Elem.
anal. C.sub.14H.sub.12N.sub.2 theory C:80.74 H:5.81 N:13.45; found
C:80.55 H:5.76 N:13.35; .sup.1H-NMR (d.sub.6-DMSO) 11.0 (s, 1H,
exch. D.sub.2O); 7.8 (dd, J=8.6 Hz, 1.5 Hz, 1H); 7.6-7.20 (m, 4H);
7.05 (d, J=8.6 Hz, 1H); 6.8-6.3 (m, 3H); 4.5 (bs, 2H, exch.
D.sub.2O).
7b) 2-Boronic acid 1-N-BOC-5-(N',N'-bisBOC)aminoindole
[0112] Triisopropyl borate (0.8 ml, 0.0035 mol) is added to
1-N-BOC-5-(N',N'-bis-BOC)aminoindole (1 g, 0.0023 mol) in THF (3
ml). The mixture is cooled to -5.degree. C. and 2M lithium
diisopropylamide (1.38 ml, 0.0028 mol) is added. The mixture is
stirred at room temperature for 3 hours and 1M HCl is added (pH=3).
The resulting mixture is extracted with ethyl acetate and the
organic phase is washed with water. The resulting solution is dried
and concentrated. The solid is recrystallized from isopropyl ether.
Yield: 0.56 g (51%); .sup.1H-NMR (d.sub.6-DMSO) 8.1 (s, 2H); 8.0
(d, 1H) 7.3 (d, 1H); 7.0 (dd, 1H); 6.6 (s, 1H); 1.6 (s, 9H); 1.3
(s, 18H).
7c) 1-N-BOC-5-(N',N'-bisBOC)aminoindole
[0113] DMAP (1.66 g, 0.013 mol) and di-tert-butyl dicarbonate (32.6
g, 0.149 mol) are added to 5-aminoindole (9 g, 0.068 mol) in THF
(300 ml). The mixture is stirred at room temperature for 48 hours,
and further DMAP (0.83 g, 0.007 mol) and di-tert-butyl dicarbonate
(14.8 g, 0.068 mol) are added. The resulting mixture is stirred at
room temperature for a further 6 days. This mixture is evaporated,
and the solid is recrystallized from dilute citric acid and
filtered off. The solid is recrystallized from isopropyl ether and
filtered off. Yield: 2.04 g; m.p.: 189.6-192.7.degree. C. IR (KBr):
3450, 3140, 1740, 1470, 1160, 1120, 780 cm.sup.-1; .sup.1H-NMR
(d.sub.6-DMSO) 8 (d, 1H); 7.7 (d, 1H); 7.4 (d, 1H); 7.1 (dd, 1H);
6.7 (d, 1H); 1.6 (s, 9H); 1.3 (s, 18H).
EXAMPLE 8
Compound 8
N-(2-phenylquinol-6-yl)acetamidine
[0114] Prepared in a manner similar to that of Example 1. Yield:
48%; Elem. anal. C.sub.17H.sub.15N.sub.3; theory C:78.13 H:5.79
N:16.08; found C:77.27 H:5.91 N:15.70; IR (KBr): 3345, 3055, 1640,
1600, 1480 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.2-8.05 (m, 4H);
7.85 (d, 1H); 7.55-7.7 (m, 2H); 7.4-7.5 (m, 1H); 7.35-7.3 (dd, 1H);
7.25 (bs, 1H); 4.5 (bs, 2H); 2.1 (bs, 3H).
8a) 2-phenyl-6-aminoquinoline
[0115] Pd/C (10%; 0.60 g) is added to 2-phenyl-6-nitroquinoline (7
g, 0.028 mol) in THF (300 ml) and methanol (300 ml). The mixture is
hydrogenated at room temperature and at 1 atm. The catalyst is
filtered off, the filtrate is evaporated and the product is
recrystallized from isopropyl ether. Yield: 5.7 g (92%); Rf (9/1
chloroform/methanol): 0.56; IR (KBr): 3455, 3320, 3205, 1625, 1495
cm.sup.-1.
8b) 2-phenyl-6-nitroquinoline
[0116] 2-Chloro-6-nitroquinoline (10.5 g, 50.4 mmol) (Byoung S. L.
et al. Heterocycles. 1998, 48.12, 65), phenylboronic acid (7.4 g,
60.4 mmol), palladium dichloride bis(triphenylphosphine) (0.70 g,
1.01 mmol) and barium hydroxide (38.1 g, 0.121 mol) in 200 mL of
anhydrous THF are stirred at 65.degree. C. for 20 hours. The
mixture is diluted with water, extracted with CH.sub.2Cl.sub.2 and
evaporated, and the residue is chromatographed on silica gel (1/1
hexane/ethyl acetate). Yield: 7.8 g (62%); IR (KBr): 3475, 3357,
1592, 1479 cm.sup.-1.
[0117] Examples of Preparation of Compounds of Formula (I)
According to the Synthetic Route (c):
EXAMPLE 9
Compound 9
N-(2-phenylbenzothiazol-5-yl)acetamidine
[0118] Triethylamine (6.9 ml, 0.050 mol) is added to methyl
acetamidate hydrochloride (5.44 g, 0.050 mol) in acetonitrile (120
ml). The mixture is stirred for 15 minutes at room temperature and
2-phenyl-5-aminobenzothiazole (1.8 g, 8.56 mmol) is added. The
resulting mixture is stirred at room temperature for 72 hours. The
mixture is evaporated, the residue is taken up in ethyl acetate and
washed with sodium hydroxide, and the product is extracted with
0.1M HCl. The acidic aqueous phases are combined, basified with
NaOH (pH=10) and extracted with ethyl acetate. The extracts are
washed with water, dried and concentrated. The product is
recrystallized from isopropyl ether. Yield: 2.0 g (23%); Elem.
anal. C.sub.15H.sub.13N.sub.3S; theory C:67.39 H:4.90 N:15.72;
found C:67.38 H:5.17 N:15.61; IR (KBr): 3378, 3053, 1650, 1593
cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.01 (m, 2H); 7.88 (d, 1H);
7.53 (m, 3H); 7.39 (s, 1H); 6.90 (d, 1H); 1.91 (s, 3H).
9a) 2-phenyl-5-aminobenzothiazole
[0119] Prepared in a manner similar to that of Example 1a. Yield:
85%; Rf (8/2 petroleum ether/ethyl acetate): 0.30; IR (KBr): 3439,
3316, 3199, 1621 cm.sup.-1.
9b) 2-phenyl-5-nitrobenzothiazole
[0120] PPA (210 g) is added to benzoic acid (12.96 g, 0.104 mol)
and sodium 2-amino-4-nitrothiophenoxide (19.98 g, 0.104 mol) (V. L.
Guarda, Heterocyclic Comm., 2000, 1.6, 49-54). The mixture is
heated at 115-120.degree. C. for 10 minutes, cooled, and water (200
ml) is added dropwise, followed by addition of 32 percent NaOH
(pH=5). The product is filtered off and suspended in NaHCO.sub.3
ss, filtered off, washed with water and recrystallized from
isopropyl ether. Yield: 17.0 g (64%); IR (KBr): 1515, 1341
cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.77 (d, 1H); 8.39 (d, 1H);
8.25 (dd, 1H); 8.11 (dd, 1H); 7.61 (m, 4H).
EXAMPLE 10
Compound 10
N-[2-(2-methoxyphenyl)benzothiazol-5-yl]acetamidine
[0121] Prepared in a manner similar to that of Example 9. Yield:
67%; Elem. anal. C.sub.16H.sub.15N.sub.3OS; theory C:64.62 H:5.08
N:14.13; found C:64.71 H:5.04 N:14.29; IR (KBr): 3439, 3067, 1641,
1586, cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.31 (d, 1H); 7.93 (d,
1H); 7.29 (m, 4H); 6.71 (m, 1H); 6.05 (m, 2H); 3.95 (s, 3H).
10a) 2-(2-methoxyphenyl)-5-aminobenzothiazole
[0122] Prepared in a manner similar to that of Example 1a. Yield:
51%; Rf (85/25/1/2 chloroform/methanol/aqueous ammonia/water):
0.84; Elem. anal. C.sub.14H.sub.12N.sub.2OS; theory C:65.60 H:4.72
N:10.93; found C:65.44 H:4.61 N:10.97; IR (KBr): 3418, 3302, 3197,
1606, 1428 cm.sup.-1.
10b) 2-(2-methoxyphenyl)-5-nitrobenzothiazole
[0123] Prepared in a manner similar to that of Example 9b. Yield:
59%; Rf (8/2 petroleum ether/ethyl acetate): 0.54;
C.sub.14H.sub.10N.sub.2O.sub.3S; M.W.: 286.30.
EXAMPLE 11
Compound 11
N-[2-benzylbenzothiazol-5-yl]acetamidine
[0124] Prepared in a manner similar to that of Example 9. Yield:
43%; Elem. anal. C.sub.16H.sub.15N.sub.3S; theory C:68.30 H:5.37
N:14.93; found C:67.90 H:5.75 N:14.59; IR (KBr): 3320, 3085, 1625,
1105 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 7.8 (m, 1H); 7.3 (m,
6H); 6.8 (m, 1H); 6.0 (m, 2H); 1.9 (m, 3H).
11a) 2-benzyl-5-aminobenzothiazole
[0125] Prepared in Example 1a. Yield: 68%; Rf (95:5:0.5
chloroform/methanol/aqueous ammonia): 0.46; IR (KBr): 3410, 3305,
3205, 1595, 1463, 1425 cm.sup.-1.
11b) 2-benzyl-5-nitrobenzothiazole
[0126] Prepared in a manner similar to that of Example 9b. Yield:
69%; Rf (8:2 petroleum ether/ethyl acetate): 0.58; IR (KBr): 1525,
1335, 695 cm.sup.-1.
EXAMPLE 12
Compound 12
N-[2-styrylbenzothiazol-5-yl]acetamidine
[0127] Prepared in a manner similar to that of Example 9. Yield:
32%; Elem. anal. C.sub.17H.sub.15N.sub.3S; theory C:69.60 H:5.15
N:14.32; found C:69.89 H:5.28 N:14.11; IR (KBr): 3320, 3080, 1625
cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.0-7.1 (m, 9H); 6.9 (m, 1H);
6.1 (m, 2H); 1.9 (m, 3H).
12a) 2-styryl-5-nitrobenzothiazole
[0128] Prepared in a manner similar to that of Example 1a. Yield:
69%; Rf (8/2 petroleum ether/ethyl acetate): 0.54; IR (KBr): 1515,
1335, 740 cm.sup.-1.
12b) 2-styryl-5-aminobenzothiazole
[0129] Prepared in a manner similar to that of Example 9b. Yield:
68%; Rf (95/5/0.5 chloroform/methanol/aqueous ammonia): 0.50; IR
(KBr): 3440, 3330, 1605, 1320 cm.sup.-1.
EXAMPLE 13
Compound 13
N-[2-(5-aminosulfonyl-2-methoxyphenyl)benzothiazol-5-yl]acetamidine
hydrochloride
[0130] TEA (1.5 ml, 0.008 mol) is added to methyl acetamidate
hydrochloride (0.83 g, 0.008 mol) in acetonitrile (20 ml). The
mixture is stirred at room temperature for 15 minutes, and
2-(5-aminosulfonyl-2-methoxyphenyl)-5-aminobenzothiazole (1.0 g,
0.003 mol) is added. The mixture is stirred at 35.degree. C. for 96
hours and filtered. The solid is recrystallized from 9/1
THF/methanol. Yield: 0.22 g (18%); Elem. anal.
C.sub.16H.sub.17N.sub.4O.sub.3S.sub.2Cl; IR (KBr): 3034, 1678, 1143
cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.81 (d, 1H); 8.20 (d, 1H);
7.91 (m, 2H); 7.45 (m, 6H); 4.11 (s, 3H); 2.40 (m, 3H).
13a) 2-(5-aminosulfonyl-2-methoxyphenyl)-5-aminobenzothiazole
[0131] Chlorosulfonic acid (16 ml, 0.24 mol) and
2-(2-methoxyphenyl)-5-nitrobenzothiazole (13.5 g, 0.047 mol) are
stirred together at 0.degree. C. for 15 minutes, the mixture is
allowed to warm to room temperature and stirring is continued for
one hour. The mixture is poured into ice-water and the product is
filtered off and washed with water. The product is added
portionwise to a mixture of 32% aqueous ammonia (80 ml) and water
(150 ml) at 0.degree. C. This mixture is stirred for 2 hours at
0.degree. C., and is allowed to warm to room temperature, acidified
with HCl and filtered. The product is added to a solution of tin
dichloride (31.8 g, 0.151 mol) in conc. HCl (43 ml) at 0.degree. C.
This mixture is heated at 95.degree. C. for 60 minutes. It is
cooled and brought to pH=7.5 with NaOH. The resulting mixture is
extracted with chloroform. The extracts are concentrated and the
product obtained is recrystallized from isopropyl ether/methanol.
Yield: 1.3 g; .sup.1H-NMR (d.sub.6-DMSO) 8.81 (d, 1H); 7.87 (dd,
1H); 7.64 (d, 1H); 7.35 (m, 4H); 6.65 (dd, 2H); 4.09 (s, 3H).
EXAMPLE 14
Compound 14
N-[2-(2-pyridyl)benzothiazol-5-yl]acetamidine
[0132] Prepared from 2-(2-pyridyl)-5-aminobenzothiazole in a manner
similar to that of Example 1. Yield: 2.2 g (59%); Elem. anal.
C.sub.14H.sub.12N.sub.4S; theory C:62.66 H:4.51 N:20.88; found
C:61.92 H:4.55 N:20.65; IR (KBr): 3390, 3050, 1650, 1590 cm.sup.-1;
.sup.1H-NMR (d.sub.6-DMSO) 8.7 (d, 1H); 8.3-7.2 (m, 5H); 6.90 (m,
1H); 6.1 (m, 2H); 1.91 (m, 3H).
14a) 2-(2-pyridyl)-5-aminobenzothiazole
[0133] PPA (500 g) is added to picolinic acid (24.6 g, 0.2 mol) and
sodium 2-amino-4-nitrothiophenoxide (47 g, 0.2 mol). The mixture is
heated at 120-130.degree. C. for 6 hours. The resulting mixture is
cooled and NaOH is added dropwise (pH=10). The product is filtered
off and washed with water. The 2-(2-pyridyl)-5-nitrobenzothiazole
is recrystallized from 9/1 isopropyl ether/methanol and is added to
a solution of tin dichloride (61.6 g, 0.273 mol) in conc. HCl (50
ml) at 0.degree. C. This mixture is heated at 95.degree. C. for 120
minutes. It is cooled and NaOH is added dropwise (pH=10). The
resulting mixture is extracted with chloroform and the combined
organic phases are extracted with 0.5M HCl. The acidic aqueous
phases are combined, basified with NaOH (pH=10) and extracted with
ethyl acetate. The extracts are washed with water and evaporated.
The solid obtained is recrystallized from isopropyl ether. Yield:
3.6 g; Rf (9/1 chloroform/methanol): 0.45; IR (KBr): 3400, 3325,
3215, 1590, 1430, 1320, 780 cm.sup.-1.
EXAMPLE 15
Compound 15
N-[2-(4-methoxyphenyl)benzothiazol-5-yl]acetamidine
[0134] Prepared in a manner similar to that of Example 9. Yield:
59%; Elem. anal. C.sub.16H.sub.15N.sub.3OS; theory C:64.62 H:5.08
N:14.13; found C:64.46 H:5.10 N:13.99; IR (KBr): 3435, 3330, 3200,
1640, 1245 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.0 (m, 3H); 7.1
(m, 4H); 6.1 (m, 2H); 3.8 (s, 3H); 1.9 (m, 3H).
15a) 2-(4-methoxyphenyl)-5-aminobenzothiazole
[0135] Iron powder (45.9 g, 0.822 mol), water (70 ml) and 37%
hydrochloric acid (1.6 ml, 0.019 mol) are added to
2-(4-methoxyphenyl)-5-nitrobenzothiazole (10.95 g, 0.038 mol) in
ethanol (300 ml). The mixture is heated at 80.degree. C. for one
hour. The resulting mixture is filtered and evaporated, and the
residue is taken up in ethyl acetate and basified with NaOH
(pH=11). The organic phase is filtered and washed with water. The
resulting solution is evaporated and the product obtained is
recrystallized from isopropyl ether. Yield: (61%); Rf (9/1
chloroform/methanol): 0.60; Elem. anal. C.sub.14H.sub.12N.sub.2OS;
theory C:65.60 H:4.72 N:10.93; found C:65.44 H:4.87 N:10.37; IR
(KBr): 3440, 3320, 1600, 1465, 1245, 1170 cm.sup.-1.
15b) 2-(4-methoxyphenyl)-5-nitrobenzothiazole
[0136] Prepared in a manner similar to that of Example 9b. Yield:
45%; Rf (8/2 petroleum ether/ethyl acetate): 0.45; IR (KBr): 1600,
1515, 1485, 1255 cm.sup.-1.
EXAMPLE 16
Compound 16
N-[2-(2,4-dimethoxyphenyl)benzothiazol-5-yl]acetamidine
[0137] Prepared in a manner similar to that of Example 9. Yield:
40%; Elem. anal. C.sub.17H.sub.17N.sub.3O.sub.2S; theory C:62.36
H:5.23 N:12.83; found C:62.19 H:5.13 N:12.71; IR (KBr): 3420, 3310,
1645, 1440, 1280 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.2 (m, 1H);
7.8 (m, 1H); 6.9 (m, 4H); 6.1 (m, 2H); 4.0 (s, 3H); 3.9 (s, 3H);
1.9 (m, 3H).
16a) 2-(2,4-dimethoxyphenyl)-5-aminobenzothiazole
[0138] Prepared in a manner similar to that of Example 15a. Yield:
44%; Rf (9/1 chloroform/methanol): 0.67; Elem. anal.
C.sub.15H.sub.15N.sub.2O.sub.2S; theory C:62.70 H:5.26 N:9.75;
found C:62.87 H:4.79 N:9.16; IR (KBr): 3440, 3285, 3190, 1605,
1500, 1285, 1025 cm.sup.-1.
16b) 2-(2,4-dimethoxyphenyl)-5-nitrobenzothiazole
[0139] Prepared in a manner similar to that described in Example
9b. Yield: 54%; Rf (6/4 toluene/ethyl acetate): 0.77; IR (KBr):
3435, 2935, 1605, 1510, 1285, 816 cm.sup.-1.
EXAMPLE 17
Compound 17
N-[2-(3-methoxyphenyl)benzothiazol-5-yl]acetamidine
[0140] Prepared in a manner similar to that of Example 9. Yield:
19%; Elem. anal. C.sub.16H.sub.15N.sub.3OS; theory C:64.62 H:5.08
N:14.13; found C:64.49 H:5.62 N:12.80; IR (KBr): 3310, 3065, 1594,
1435, 1270 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 7.9 (m, 1H); 7.3
(m, 6H); 6.1 (m, 2H); 3.8 (s, 3H); 1.9 (m, 3H).
17a) 2-(3-methoxyphenyl)-5-aminobenzothiazole
[0141] Prepared in a manner similar to that of Example 15a. Yield:
70%; Rf (9/1 chloroform/methanol): 0.70; IR (KBr): 3430, 3315,
3205, 1600, 1270, 820 cm.sup.-1.
17b) 2-(3-methoxy-phenyl)-5-nitrobenzothiazole
[0142] Prepared in a manner similar to that described in Example
9b. Yield: 22%; Rf (8/2 petroleum ether/ethyl acetate): 0.57; IR
(KBr): 1673, 1515, 1340, 740 cm.sup.-1.
EXAMPLE 18
Compound 18
N-[2-(2-methylphenyl)benzothiazol-5-yl]acetamidine
[0143] Prepared in a manner similar to that of Example 9. Yield:
33%; Elem. anal. C.sub.16H.sub.15N.sub.3S; theory C:68.30 H:5.37
N:14.93; found C:68.10 H:5.32 N:1.74; IR (KBr): 3310, 3065, 1594,
1435, 1270 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 7.9 (m, 2H); 7.5
(m, 4H); 6.9 (m, 1H); 2.6 (s, 3H); 1.9 (m, 3H).
18a) 2-(2-methylphenyl)-5-aminobenzothiazole hydrochloride
[0144] Prepared in a manner similar to that of Example 15a. Yield:
65%; Rf (9/1 chloroform/methanol): 0.72; IR (KBr): 2860, 2610,
1530, 1450, 755 cm.sup.-1.
18b) 2-(2-methylphenyl)-5-nitrobenzothiazole
[0145] Prepared in a manner similar to that of Example 9b. Yield:
48%; Rf (8/2 petroleum ether/ethyl acetate): 0.67; IR (KBr): 1678,
1515, 1340 cm.sup.-1.
EXAMPLE 19
Compound 19
N-[2-(4-fluorophenyl)benzimidazol-5-yl]acetamidine
dihydrochloride
[0146] Prepared in a manner similar to that of Example 9. Yield:
36%; Elem. anal. C.sub.15H.sub.15C.sub.12FN.sub.4; theory C:52.80
H:4.43 N:16.42; found C:52.43 H:4.71 N:16.01; IR (KBr): 3042, 1677,
1616, 1441, 1233 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 11.40 (s,
1H); 9.45 (s, 1H); 8.36 (m, 3H); 7.29 (m, 6H); 2.25 (m, 3H).
19a) 2-(4-fluorophenyl)-5-aminobenzimidazole dihydrochloride
[0147] Prepared in a manner similar to that of Example 4a. Yield:
74%; Rf (95/5/0.5 chloroform/methanol/aqueous ammonia): 0.33; IR
(KBr): 2810, 1612, 1505, cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO)
10.42 (m, 5H); 8.38 (m, 2H); 7.62 (m, 7H).
19b) 2-(4-fluorophenyl)-5-nitrobenzimidazole
[0148] Prepared from 4-nitrophenylenediamine and 4-fluorobenzoic
acid, in a manner similar to that of Example 9b. Yield: 76%; Rf
(7/3 toluene/ethyl acetate): 0.54; IR (KBr): 3312, 1601, 1498, 1333
cm.sup.-1.
EXAMPLE 20
Compound 20
N-[2-(4-chlorophenyl)benzimidazol-5-yl]acetamidine
[0149] Prepared in a manner similar to that of Example 1. Yield:
54%; C.sub.15H.sub.13ClN.sub.4; IR (KBr) 3425, 3300, 3145, 1637,
1475 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8-8.2 (m, 3H); 7.3-7.7
(m, 4H); 6.9-6.5 (m, 2H); 1.8 (s, 3H).
20a) 2-(4-chlorophenyl)-5-aminobenzimidazole hydrochloride
[0150] Prepared in a manner similar to that of Example 4a. Yield:
94%; Rf (95/5/0.5 chloroform/methanol/aqueous ammonia): 0.22; IR
(KBr): 3330, 1635, 1470, 1090, 825 cm.sup.-1.
20b) 2-(4-chlorophenyl)-5-nitrobenzimidazole
[0151] Prepared from 4-chlorobenzoic acid (17.83 g, 0.114 mol) and
2-amino-5-nitroaniline (18 g, 0.114 mol), in a manner similar to
that of Example 9b. Yield: 87%; Rf (6/4 toluene/ethyl acetate):
0.61; m.p.: 302.5-305.degree. C.
EXAMPLE 21
Compound 21
N-(2-phenyl-3H-benzimidazol-5-yl)acetamidine hydrochloride
[0152] Prepared in a manner similar to that of Example 1. Yield:
39%; Elem. anal. C.sub.15H.sub.15ClN.sub.4; theory C:62.83 H:5.27
N:19.54; found C:61.59 H:6.09 N:19.02; IR (KBr): 3347, 3190, 1638,
1590, 1460 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.1-8.4 (m, 2H);
7.3-7.8 (m, 4H); 6.9 (d, J=1.5 Hz, 1H); 6.6 (dd, J=8.6 Hz, 1.5 Hz,
1H); 1.8 (s, 3H).
21a) 2-phenyl-5-aminobenzimidazole
[0153] Prepared in a manner similar to that of Example 4a. Yield:
4.2 g (74%); Rf (9/1 chloroform/methanol): 0.20; Elem. anal.
C.sub.13H.sub.11N.sub.3; theory C:74.62 H:5.29 N:20.08; found
C:73.95 H:5.26 N:19.92.
21b) 2-phenyl-5-nitrobenzimidazole
[0154] Prepared from 4-nitrophenylenediamine and benzoic acid in a
manner similar to that of Example 9b. Yield: 70%; Rf (9/1
chloroform/methanol): 0.45; IR (KBr): 3290, 1500, 1330, 1290
cm.sup.-1.
EXAMPLE 22
Compound 22
N-(2-pentyl-3H-benzimidazol-5-yl)acetamidine dihydrochloride
[0155] Prepared in a manner similar to that of Example 1. Yield:
61%; Elem. anal. C.sub.14H.sub.22Cl.sub.2N.sub.4; theory C:53.01
H:6.99 N:17.66 found C:53.20 H:7.00 N:17.63; IR (KBr): 3300, 2866,
1671, 1609 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 11.7 (bs, 1H); 9.8
(bs, 1H); 8.6 (bs, 1H); 7.8 (d, J=8.6 Hz, 1H); 7.7 (d, J=1.5 Hz,
1H); 7.4 (dd, J=8.6 Hz, 1.5 Hz, 1H); 3.14 (t, 2H); 2.41 (s, 3H);
1.90 (m, 2H); 1.57-1.05 (m, 4H); 0.87 (t, 3H).
22a) 2-pentyl-5-amino-3H-benzimidazole
[0156] Prepared in a manner similar to that of Example 4a. Yield:
98%.
22b) 2-pentyl-5-nitro-3H-benzimidazole
[0157] Prepared from 4-nitrophenylenediamine in a manner similar to
that of Example 4c. Yield: 78%; Rf (9/1 chloroform/methanol): 0.70;
.sup.1H-NMR (CDCl.sub.3) 10.2 (bs, 1H); 8.4 (d, J=1.5 Hz, 1H); 8.1
(dd, J=8.6 Hz, 1.53 Hz, 1H); 7.5 (d, J=8.6 Hz, 1H); 3.0 (t, 2H);
1.90 (m, 2H); 1.6-1.1 (m, 4H); 0.87 (t, 3H).
EXAMPLE 23
Compound 23
N-[2-(pyrrol-2-yl)-3H-benzimidazol-5-yl]acetamidine
dihydrochloride
[0158] 1N NaOH (pH=10) is added to
N-[2-(pyrrol-2-yl)-3H-benzimidazol-5-yl]acetamidine hydrobromide
(Example 24) (2.2 g, 0.007 mol) in water (30 ml). The precipitate
is filtered off and recrystallized from isopropyl ether. The solid
is taken up in methanol and the dihydrochloride is precipitated
from isopropyl ether/HCl. Yield: 1.7 g (79%); Elem. anal.
C.sub.13H.sub.15Cl.sub.2N.sub.5; theory C:50.01 H:4.84 N:22.43;
found C:50.05 H:4.79 N:22.17; IR (KBr): 3044, 1674, 1620
cm.sup.-1.
EXAMPLE 24
Compound 24
N-[2-(pyrrol-2-yl)-3H-benzimidazol-5-yl]acetamidine
hydrobromide
[0159] 2-Naphthylmethyl thioacetamidate hydrobromide (3.3 g, 0.011
mol) is added, at room temperature and with stirring, to
2-(pyrrol-2-yl)-5-amino-1H-benzimidazole (2.2 g, 0.011 mol) in
ethanol (30 ml). The mixture is stirred for 18 hours at room
temperature and filtered, and the solid is recrystallized from
isopropyl ether. Yield: 3.0 g (85%); C.sub.13H.sub.13N.sub.5.HBr;
m.p.: 197-199.degree. C.; IR (KBr): 3053, 1675, 1629, 1601, 1508
cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 11.6 (s, 1H); 11.1 (s, 1H);
9.3 (s, 1H); 8.4 (s, 1H); 7.5 (d, 1H); 7.4 (d, 1H); 7.0 (m, 2H);
6.2 (m, 2H); 2.4 (s, 3H).
24a) 2-(pyrrol-2-yl)-5-amino-1H-benzimidazole
[0160] Prepared in a manner similar to that of Example 4a. Yield:
38%; Rf (85/25/2/1 chloroform/methanol/water/aqueous ammonia):
0.67; IR (KBr): 3367, 1630 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO)
11.5 (m, 1H); 7.2 (d, 1H); 6.6-6.9 (m, 3H); 6.5 (dd, 2H); 6.1 (m,
1H).
24b) 2-(pyrrol-2-yl)-5-nitro-1H-benzimidazole
[0161] Pyrrolyl-2-carboxaldehyde (10.6 g, 0.104 mol) is added to
2-amino-4-nitroaniline (14 g, 0.090 mol) in DMF (400 ml), and the
mixture is heated at 110.degree. C. for 60 hours, cooled and
concentrated. The solid is recrystallized from water and then from
isopropyl ether. Yield: 15.5 g (71%); IR (KBr): 3100, 1596, 1506,
1327 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.2 (m, 1H); 8.0 (m,
1H); 7.5-7.7 (m, 1H); 6.9 (m, 3H); 6.2 (m, 2H).
EXAMPLE 25
Compound 25
Methyl 4-(5-acetimidoylamino-1H-benzimidazol-2-yl)benzoate
hydrochloride
[0162] Prepared in a manner similar to that of Example 1. Yield:
27%; IR (KBr): 3447, 3050, 1717, 1610, 1277 cm.sup.-1; .sup.1H-NMR
(d.sub.6-DMSO) 11.61 (s, 1H); 9.54 (s, 1H); 8.53 (d, 2H); 8.12 (d,
2H); 7.78 (m, 3H); 7.25 (dd, 2H); 6.64 (m, 3H); 3.81 (s, 3H); 2.34
(s, 3H).
25a) Methyl 4-(5-amino-1H-benzimidazol-2-yl)benzoate
[0163] Prepared in a manner similar to that of Example 4a. Yield:
57%; Rf (9/1 chloroform/methanol): 0.33; Elem. anal.
C.sub.15H.sub.13N.sub.3O.sub.2; theory C:67.40 H:4.90 N:15.72;
found C:66.24 H:4.89 N:14.54; IR (KBr): 3311, 1689, 1611, 1282,
1111 cm.sup.-1.
25b) Methyl 4-(5-nitro-1H-benzimidazol-2-yl)benzo-ate
[0164] Sodium bisulfite (7.0 g, 0.036 mol) in water (70 ml) is
added to 4-carboxybenzaldehyde (11.0 g, 0.071 mol) in ethanol (70
ml). The mixture is stirred at room temperature for 15 minutes, the
solid is filtered off, the filtrate is coevaporated with toluene
and a solution of 2-amino-5-nitroaniline (11.1 g, 0.071 mol) in DMF
(250 ml) is added. This mixture is refluxed for 3 hours and
concentrated, and the product is recrystallized from dilute HCl,
filtered off and washed with water. The solid is suspended in
methanol (300 ml) and HCl gas is bubbled through at 5-15.degree. C.
for 3 hours. The mixture is allowed to warm to room temperature and
is then refluxed for 3 hours. The solution is concentrated to 1/3
of its volume and cooled to +5.degree. C., and the precipitate is
filtered off and recrystallized from NaHCO.sub.3 and finally from
3/1 isopropyl ether/hexane. Yield: 15 g (71%); IR (KBr): 3570,
3472, 3112, 1707, 1301 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO)
7.7-8.5 (m, 7H); 5.9 (m, 1H); 3.88 (s, 3H).
EXAMPLE 26
Compound 26
4-(5-acetimidoylamino-1H-benzimidazol-2-yl)benzoic acid
[0165] Prepared in a manner similar to that of Example 1. Yield:
67%; Elem. anal. C.sub.16H.sub.14N.sub.4O.sub.2; theory C:65.30
H:4.79 N:19.04; found C:63.31 H:5.37 N:17.19; IR (KBr): 3220, 1590,
1544, 1378 cm.sup.-1.
26a) 4-(5-amino-1H-benzimidazol-2-yl)benzoic acid
[0166] Prepared in a manner similar to that of Example 4a. Yield:
83%; Rf (4/4/2 chloroform/methanol/aqueous ammonia): 0.70; IR
(KBr): 3117, 1604, 1540, 1397 cm.sup.-1.
26b) 4-(5-nitro-1H-benzimidazol-2-yl)benzoic acid
[0167] 2M NaOH (75 ml) is added, at 0.degree. C., to methyl
4-(5-nitro-1H-benzimidazol-2-yl)benzoate (15 g, 0.050 mol) (Example
26) in methanol (250 ml). The mixture is stirred at room
temperature for 20 hours and evaporated, and the residue is taken
up in water and acidified with HCl (pH=6). The resulting mixture is
stirred for 16 hours at 0.degree. C., and the product is filtered
off, washed with water and recrystallized from 9/1
methanol/isopropyl ether. Yield: 10 g (70%); IR (KBr): 3357, 1675,
1602, 1537, 1377, 1320 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO)
7.5-8.6 (m, 7H).
EXAMPLE 27
Compound 27
N-(2-phenylquinazolin-6-yl)acetamidine dihydrochloride
[0168] Isopropyl ether/HCl is added to
2-phenyl-6-(N-acetamidino)quinazoline (0.9 mg, 0.0034 mol) in
methanol (5 ml) at 0.degree. C. The product is filtered off and
recrystallized from isopropyl ether/isopropyl alcohol. Yield: 0.8 g
(20%); Elem. anal. C.sub.16H.sub.16Cl.sub.2N.sub.4; theory C:57.32
H:4.81 N:16.71; found C:56.38 H:6.05 N:15.29; IR (KBr): 3453, 3095,
1658, 1600, 1553, 1343 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 11.81
(s, 1H); 9.74 (s, 2H); 8.83 (m, 1H); 8.48 (m, 2H); 8.12 (m, 2H);
7.83 (d, 1H); 7.34 (m, 4H); 2.34 (s, 3H).
27b) N-(2-phenylquinazolin-6-yl)acetamidine
[0169] Prepared in a manner similar to that of Example 9. Yield:
20%; m.p.: 162-164.degree. C. Elem. anal. C.sub.15H.sub.13N.sub.3S;
theory C:73.26 H:5.38 N:21.36; found C:72.65 H:5.46 N:21.09; IR
(KBr): 3453, 3095, 1658, 1600, 1553, 1343 cm.sup.-1; .sup.1H-NMR
(d.sub.6-DMSO) 9.41 (s, 1H); 8.48 (m, 2H); 7.83 (d, 1H); 7.34 (m,
6H); 6.30 (m, 1H); 1.85 (s, 3H).
27c) 2-phenyl-6-aminoquinazoline
[0170] Prepared in a manner similar to that of Example 4a. Yield:
74%; Elem. anal. C.sub.14H.sub.11N.sub.3; theory C:76.00 H:5.01
N:18.99; found C:75.85 H:5.12 N:18.58; IR (KBr): 3455, 3315, 1622,
1494, 1385, 1242 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 9.21 (s,
1H); 8.45 (m, 1H); 7.50 (m, 5H); 6.85 (d, 1H); 5.88 (s, 2H).
27d) 2-phenyl-6-nitroquinazoline
[0171] 2-Phenyl-6-nitro-3,4-dihydroquinazoline (27 g, 0.106 mol)
and chloranil (32.4 g, 0.13 mol) in toluene (450 ml) are refluxed
for 60 minutes. The mixture is cooled to room temperature, and the
precipitate is filtered off and washed with toluene (350 ml). The
filtrate is suspended in 0.5N NaOH (400 ml) and the aqueous phase
is extracted with dichloromethane (100 ml). The combined organic
phases are washed with water and concentrated. The solid is
recrystallized from hexane. Yield: 8.8 g (34%); Rf (8/2 petroleum
ether/ethyl acetate): 0.71; .sup.1H-NMR (d.sub.6-DMSO) 9.91 (s,
1H); 9.18 (d, 1H); 8.61 (m, 3H); 8.24 (d, 1H); 7.55 (m, 3H).
27e) 2-phenyl-6-nitro-3,4-dihydroquinazoline
[0172] N-Benzoyl-2-amino-5-nitrobenzylamine (33 g, 0.12 mol) and
phosphoryl chloride (150 ml) are refluxed for 3 hours. The mixture
is concentrated and water is added, followed by addition of aqueous
ammonia (pH>10). The product is filtered off and recrystallized
from water, and then from 2/1 isopropyl ether/hexane. Yield: 27.6 g
(89%); IR (KBr): 3387, 3198, 1599, 1512, 1341 cm.sup.-1;
.sup.1H-NMR (d.sub.6-DMSO) 7.95 (m, 4H); 7.30 (m, 4H); 7.01 (m,
1H); 4.71 (s, 2H).
27f) N-benzoyl-2-amino-5-nitrobenzylamine
[0173] Triethylamine (116 ml, 0.835 mol) and DMAP (2.0 g, 0.016
mol) are added to 2-amino-5-nitrobenzonitrile (68 g, 0.33 mol) in
dichloromethane (1 litre). The mixture is cooled to +5.degree. C.,
and benzoyl chloride (38.8 ml, 0.33 mol) in dichloromethane (50 ml)
is added. The resulting mixture is stirred for 2 hours and then
concentrated. The residue is taken up in 10/1 water/ethanol (550
ml) and the product is filtered off and recrystallized from
isopropyl ether. Yield: 88.5 g (97%); IR (KBr): 3375, 3213, 1638,
1547, 1319 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.15 (m, 1H); 7.85
(m, 4H); 7.51 (m, 4H); 6.68 (m, 3H); 4.30 (m, 2H).
27g) 2-amino-5-nitrobenzylamine hydrochloride
[0174] Borane in THF (400 ml, 0.40 mol) is added dropwise to
2-amino-5-nitrobenzonitrile (60 g, 0.35 mol) in THF (600 ml) at
0.degree. C. The mixture is allowed to warm to room temperature and
is stirred for 16 hours. The resulting mixture is cooled to
0.degree. C. and 200 ml of absolute ethanol/HCl are added. The THF
is removed and the product is filtered off and recrystallized from
isopropyl ether. Yield: 68.8 g (96%); Rf (1:1 methanol/chloroform):
0.15; IR (KBr): 3416, 2980, 1669, 1601, 1474, 1285 cm.sup.-1.
EXAMPLE 28
Compound 28
N-(2-phenylbenzofuran-5-yl)acetamidine
[0175] 2-naphthylmethyl thioacetamidate hydrobromide (13.03 g,
0.044 mol) is added to 2-phenyl-5-aminobenzofuran (9.31 g, 0.044
mol) in ethanol (200 ml). The mixture is stirred at room
temperature for 18 hours and is then evaporated, NaOH (pH=10) is
added and the resulting mixture is extracted with ethyl acetate.
The organic phase is extracted with 0.5M HCl. The acidic aqueous
phases are combined, basified with NaOH (pH=10) and extracted with
ethyl acetate. The extracts are washed with water. The resulting
solution is evaporated and the solid obtained is recrystallized
from isopropyl ether. Yield: 7.45 g (68%); Elem. anal.
C.sub.16H.sub.14N.sub.2O; theory C:76.78 H:5.64 N:11.19; found
C:76.18 H:5.56 N:11.02; IR (KBr): 3445, 3045, 1640, 1605, 1450, 755
cm.sup.-1; .sup.1H-NMR (d.sub.6--DMSO) 7.6-8.0 (m, 2H); 7.1-7.6 (m,
6H); 6.9-6.6 (m, 1H); 5.9 (m, 2H); 1.9 (m, 3H).
28a) 2-phenyl-5-aminobenzofuran
[0176] Triethylamine (63.4 ml, 0.455 mol) is added to
2-hydroxy-5-nitrobenzylphsophonium bromide (50 g, 0.101 mol) in
refluxing toluene (600 ml), followed by addition of benzoyl
chloride (16.2 ml, 0.140 mol) in toluene (50 ml). The mixture is
refluxed for 3 hours, cooled and stirred at room temperature for 2
hours. The resulting mixture is concentrated and the product is
recrystallized from 2/1 isopropyl ether/hexane, and the
2-phenyl-5-nitrobenzofuran is filtered off. This product is
hydrogenated in THF (300 ml) and methanol (150 ml), with Pd/C (10%;
3.2 g). The catalyst is filtered off and the filtrate is
concentrated. The residue is taken up in isopropanol/MeOH/HCl, and
the hydrochloride is precipitated. It is suspended in 1M NaOH and
extracted with ethyl acetate. The extracts are washed with water
and concentrated. The solid is recrystallized from isopropyl ether.
Yield: 9.8 g (32%); Elem. anal. C.sub.14H.sub.11NO; theory C:80.36
H:5.30 N:6.70; found C:79.78 H:5.16 N:6.87; IR (KBr): 3400, 3325,
1595, 1465 cm.sup.-1.
EXAMPLE 29
Compound 29
N-(2-phenylbenzoxazol-5-yl)acetamidine
[0177] Prepared in a manner similar to that of Example 9. Yield:
29%; Elem. anal. C.sub.15H.sub.13N.sub.3O; theory C:71.70 H:5.21
N:16.72; found C:71.48 H:4.64 N:16.71; IR (KBr): 3360, 3140, 1655,
1180, 700 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8-8.2 (m, 2H);
7.4-7.8 (m, 5H); 6.9 (dd, 1H); 5.9-6.3 (broad s, 2H); 1.8 (m,
3H).
29a) 2-phenyl-5-aminobenzoxazole
[0178] Prepared in a manner similar to that of Example 4b. Yield:
83%; Rf (9/1 chloroform/methanol): 0.52; m.p.: 155.3-156.7.degree.
C. Elem. anal. C.sub.13H.sub.10N.sub.2O; theory C:74.27 H:4.79
N:13.32; found C:73.48 H:4.85 N:13.12; IR (KBr): 3435, 3320, 1545,
1480, 1180, 695 cm.sup.-1.
29b) 2-phenyl-5-nitrobenzoxazole
[0179] Prepared from 2-amino-4-nitrophenol and benzoic acid, in a
manner similar to that of Example 9b. Yield: 85%; Rf (9/1
chloroform/methanol): 0.92; Elem. anal.
C.sub.13H.sub.8N.sub.2O.sub.3; theory C:65.00 H:3.35 N:11.66; found
C:64.54 H:3.35 N:11.85; IR (KBr): 1615, 1530, 1345 cm.sup.-1.
EXAMPLE 30
Compound 30
N-[2-(4-chlorophenyl)benzoxazol-5-yl]acetamidine
[0180] Prepared in a manner similar to that of Example 28. Yield:
29%; Rf (5/2/2 butanol/acetic acid/water): 0.58; Elem. anal.
C.sub.15H.sub.12ClN.sub.3O; theory C:62.77 H:4.25 N:14.77; found
C:63.05 H:4.23 N:14.70; m.p.: 183.6-185.1.degree. C. IR (KBr):
3455, 3295, 3145, 1645, 1400, 835 cm.sup.-1; .sup.1H-NMR
(d.sub.6-DMSO) 8.1 (m, 2H); 7.6 (m, 3H); 7.1 (m, 1H); 6.9 (m, 1H);
1.9 (broad s, 3H).
30a) 2-(4-chlorophenyl)-5-aminobenzoxazole
[0181] Prepared in a manner similar to that of Example 1a. Yield:
44%; IR (KBr): 3430, 3340, 1625, 1595, 1475, 830 cm.sup.-1.
30b) 2-(4-chlorophenyl)-5-nitrobenzoxazole
[0182] Prepared in a manner similar to that of Example 9b. Yield:
28%; Rf (7/3 toluene/chloroform): 0.58; IR (KBr): 3095, 1605, 1525,
1335, 820 cm.sup.-1.
EXAMPLE 31
Compound 31
N-[2-(3-trifluromethylphenyl)benzoxazol-5-yl]acetamidine
[0183] Prepared in a manner similar to that of Example 28. Yield:
56%; Elem. anal. C.sub.16H.sub.12F.sub.3N.sub.3O; theory C:60.19
H:3.79 N:13.16; found C:60.44 H:4.22 N:13.05; m.p.:
157.9-159.2.degree. C. IR (KBr): 3330, 3105, 1660, 1615, 1280, 1175
cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.4 (m, 2H); 7.8 (m, 3H); 7.1
(m, 2H); 6.1 (m, 2H); 1.9 (m, 3H).
31a) 2-(3-trifluromethylphenyl)-5-aminobenzoxazole
[0184] Prepared in a manner similar to that of Example 4a. Yield:
80%; Rf (9/1 chloroform/methanol): 0.59; IR (KBr): 3435, 3335,
1620, 1340, 1120 cm.sup.-1.
31b) 2-(3-trifluromethylphenyl)-5-nitrobenzoxazole
[0185] 3-Trifluoromethylbenzoyl chloride (9.03 g, 0.043 mol) and
2-hydroxy-5-nitroaniline (6.58 g, 0.041 mol) in toluene (200 ml)
are refluxed for 48 hours. POCl.sub.3 (20 ml) is added, the mixture
is refluxed for a further 2 hours and concentrated, and the solid
is recrystallized from NaOH (pH=10). The product is filtered off
and recrystallized from water and finally from isopropyl ether.
Yield: 10.3 g (78%); Rf (8/2 petroleum ether/ethyl acetate): 0.58;
IR (KBr): 3085, 1620, 1531, 1425, 1340 cm.sup.-1.
EXAMPLE 32
Compound 32
N-[2-(4-trifluromethylphenyl)benzoxazol-5-yl]acetamidine
[0186] Prepared in a manner similar to that of Example 28. Yield:
56%; C.sub.16H.sub.12F.sub.3N.sub.3O; IR (KBr): 3455, 3100, 1645,
1610, 1465, 1325, 1115 cm.sup.-1.
32a) 2-(4-trifluromethylphenyl)-5-aminobenzoxazole
[0187] Prepared in a manner similar to that of Example 4a. Yield:
71%; Rf (9/1 chloroform/methanol): 0.50; IR (KBr): 3440, 3355,
1620, 1330, 1105 cm.sup.-1.
32b) 2-(4-trifluromethylphenyl)-5-nitrobenzoxazole
[0188] Prepared in a manner similar to that of Example 31b. Yield:
57%; Rf (8/2 hexane/ethyl acetate): 0.66; IR (KBr): 3105, 1610,
1530, 1345, 1115 cm.sup.-1.
EXAMPLE 33
Compound 33
N-[2-(2-fluorophenyl)benzoxazol-5-yl]acetamidine
[0189] Prepared in a manner similar to that of Example 28. Yield:
65%; C.sub.15H.sub.12FN.sub.3O; IR (KBr): 3340, 3110, 1655, 1605,
1460, 1395 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.4 (m, 2H); 7.8
(m, 3H); 7.1 (m, 2H); 6.1 (m, 2H); 1.9 (m, 3H).
33a) 2-(2-fluorophenyl)-5-aminobenzoxazole
[0190] Prepared in a manner similar to that of Example 4a. Yield:
76%; Rf (9/1 chloroform/methanol): 0.61; IR (KBr): 3430, 3325,
1585, 1480, 1445 cm.sup.-1.
33b) 2-(2-fluorophenyl)-5-nitrobenzoxazole
[0191] Prepared in a manner similar to that of Example 31b. Yield:
33%; Rf (8/2 hexane/ethyl acetate): 0.48; IR (KBr): 3095, 1615,
1525, 1485, 1340 cm.sup.-1.
EXAMPLE 34
Compound 34
N-[2-(3,4-dichlorophenyl)benzoxazol-5-yl]acetamidine
[0192] Prepared in a manner similar to that of Example 28. Yield:
75%; Elem. anal. C.sub.15H.sub.11Cl.sub.2N.sub.3O; theory C:56.27
H:3.46; N:13.12; found C:56.01 H:3.58 N:13.22; IR (KBr): 3449,
3084, 1644, 1460 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.3 (d, 2H);
8.1 (dd, 1H); 7.5-7.9 (m, 4H); 7.1 (m, 1H); 6.9 (m, 1H); 1.9 (m,
3H).
34a) 2-(3,4-dichlorophenyl)-5-aminobenzoxazole
[0193] Prepared in a manner similar to that of Example 1a. Yield:
55%; Rf (7/3 toluene/ethyl acetate): 0.37; Elem. anal.
C.sub.13H.sub.8Cl.sub.2N.sub.2O; theory C:55.94 H:2.89 N:10.04;
found C:55.55 H:3.08 N:9.82; IR (KBr): 3400, 3324, 3211, 1626, 1457
cm.sup.-1.
34b) 2-(3,4-dichlorophenyl)-5-nitrobenzoxazole
[0194] 3,4-Dichlorobenzoyl chloride (4.6 g, 0.022 mol) is added to
2-amino-4-nitrophenol (3.4 g, 0.022 mol) in toluene (250 ml) and
the mixture is refluxed for 24 hours. para-Toluenesulfonic acid
(1.0 g) is added, the mixture is refluxed for 24 hours and cooled,
and the product is filtered off. It is recrystallized from
isopropyl ether. Yield: 6.8 g; IR (KBr): 3100, 1531, 1350
cm.sup.-1.
EXAMPLE 35
Compound 35
N-[2-(3,4-dichlorophenyl)benzimidazol-5-yl]acetamidine
[0195] Prepared in a manner similar to that of Example 28. Yield:
37%; Elem. anal. C.sub.15H.sub.12Cl.sub.2N.sub.4; theory C:56.44
H:3.79 N:17.55; found C:55.84 H:4.58 N:16.59; IR (KBr): 3375, 3300,
3170, 1630, 1450, 1395 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.3
(d, 1H); 8.1 (dd, 1H); 7.7 (m, 1H); 7.4 (m, 1H); 6.9 (m, 1H); 6.7
(dd, 1H); 1.9 (broad s, 3H).
35a) 2-(3,4-dichlorophenyl)-5-aminobenzimidazole
[0196] Prepared in a manner similar to that of Example 1a. Yield:
44%; Rf (95/5/0.5 chloroform/methanol/aqueous ammonia): 0.16; IR
(KBr): 1630, 1425, 1130 cm.sup.-1.
35b) 2-(3,4-dichlorophenyl)-5-nitrobenzimidazole
[0197] Prepared from 4-nitro-2-aminophenol and 3,4-dichlorobenzoic
acid, in a manner similar to that of Example 9b. Yield: 28%; Rf
(7/3 toluene/ethyl acetate): 0.53; IR (KBr): 3290, 1495, 1440, 1335
cm.sup.-1.
EXAMPLE 36
Compound 36
N-[2-(3-trifluoromethylphenyl)benzimidazole-5-yl]acetamidine
hydrobromide
[0198] Prepared in a manner similar to that of Example 24. Yield:
51%; Elem. anal. C.sub.16H.sub.14BrF.sub.3N.sub.4; theory C:48.14
H:3.53; N:14.03; found C:48.04 H:3.85 N:13.82; IR (KBr): 3040,
1680, 1620, 1410, 1320 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.5
(m, 2H); 7.7 (m, 4H); 7.1 (m, 1H); 2.4 (broad s, 3H).
36a) 2-(3-trifluoromethylphenyl)-5-aminobenzimidazole
[0199] Prepared in a manner similar to that of Example 4a. Yield:
80%; Rf (9/1 chloroform/methanol): 0.25.
36b) 2-(3-trifluoromethylphenyl)-5-nitrobenzimidazole
[0200] Prepared in a manner similar to that of Example 31b. Yield:
41%; Rf (8/2 toluene/ethyl acetate): 0.47; IR (KBr): 3105, 1515,
1325, 1170, 1120 cm.sup.-1.
EXAMPLE 37
Compound 37
2-[(2-methoxyphenyl)benzimidazol-5-yl]acetamidine
[0201] Prepared in a manner similar to that of Example 1. Yield:
18%; Elem. anal. C.sub.16H.sub.16N.sub.4O; theory C:68.55 H:5.75
N:19.99; found C:67.79 H:5.65 N:19.60; IR (KBr): 3440, 3135, 1640,
1460, 1245 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.2 (m, 1H); 7.2
(m, 5H); 6.6 (m, 1H); 3.9 (m, 3H); 1.8 (s, 3H).
37a) 2-(2-methoxyphenyl)-5-aminobenzimidazole dihydrochloride
[0202] Prepared in a manner similar to that of Example 4a. Yield:
93%; Rf (9/1 chloroform/methanol): 0.45; IR (KBr): 2835, 2610,
1635, 1495, 1455 cm.sup.-1.
37b) 2-(2-methoxyphenyl)-5-nitrobenzimidazole
[0203] Prepared from 4-nitrophenylenediamine and 2-methoxybenzoic
acid, in a manner similar to that of Example 9b. Yield: 76%; Rf
(6/4 toluene/ethyl acetate): 0.43; IR (KBr): 3005, 1515, 1335, 750
cm.sup.-1.
EXAMPLE 38
Compound 38
N-[2-(2-fluorophenyl)benzimidazol-5-yl]acetamidine hydrobromide
[0204] Prepared in a manner similar to that of Example 24. Yield:
82%; Elem. Anal. C.sub.15H.sub.14FN.sub.4.HBr; theory C:51.59
H:4.04 N:16.04; found C:50.79 H:4.30 N:15.45; IR (KBr): 3237, 2885,
1684, 1611 cm.sup.-1.
38a) 2-(2-fluorophenyl)-5-aminobenzimidazole
[0205] Prepared in a manner similar to that of Example 4a. Yield:
100%; Rf (9/1 chloroform/methanol): 0.25.
38b) 2-(2-fluorophenyl)-5-nitrobenzimidazole
[0206] Prepared from 4-nitrophenylenediamine and 2-fluorobenzoic
acid, in a manner similar to that of Example 31b. Yield: 15%; Rf
(7/3 toluene/ethyl acetate): 0.55; IR (KBr): 2996, 1625, 1520,
1479, 1340 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.5-8.0 (m, 3H);
7.2-7.9 (m, 4H).
EXAMPLE 39
Compound 39
N-[2-(2-methylphenyl)benzimidazol-5-yl]acetamidine
[0207] Prepared in a manner similar to that of Example 28. Yield:
38%; Elem. anal. C.sub.16H.sub.16N.sub.4; theory C:72.70 H:6.10;
N:21.20; found C:71.00 H:6.45 N:20.35; IR (KBr): 3454, 3055, 1643,
1393 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 7.7 (m, 1H); 7.5 (m,
7H); 6.9 (m, 1H); 6.7 (dd, 1H); 2.6 (s, 3H); 1.9 (s, 3H).
39a) 2-(2-methylphenyl)-5-aminobenzimidazole
[0208] Prepared in a manner similar to that of Example 4a. Yield:
100%; Rf (9/1 chloroform/methanol): 0.31; IR (KBr): 2966, 1630,
1447 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8.6 (m, 1H); 7.2 (m,
6H); 6.4-6.7 (m, 3H).
39b) 2-(2-methylphenyl)-5-nitrobenzimidazole
[0209] 2-Methylbenzoyl chloride (4.1 g, 0.027 mol) is added to
2-amino-4-nitroaniline (4 g, 0.025 mol) in toluene (100 ml), and
the mixture is refluxed for 24 hours. para-Toluenesulfonic acid
(1.0 g) is added, the mixture is refluxed for 36 hours and
concentrated, and the residue is taken up in ethyl acetate. The
solution is washed with NaHCO.sub.3 and then with water. The
resulting solution is dried and concentrated, and the solid
obtained is recrystallized from isopropyl ether. Yield: 3.1 g
(48%); Rf (7/3 toluene/ethyl acetate): 0.58; .sup.1H-NMR
(d.sub.6-DMSO): 8.5 (d, 1H); 8.1 (dd, 1H); 7.7 (m, 2H); 7.4 (m,
3H); 2.6 (s, 3H).
EXAMPLE 40
Compound 40
N-[2-(pyrrol-2-yl)benzothiazol-5-yl]acetamidine
[0210] Prepared in a manner similar to that of Example 1. Yield:
28%; Elem. anal. C.sub.13H.sub.12N.sub.4S; theory C:60.91 H:4.72
N:21.85; found C:61.20 H:5.41 N:20.07; IR (KBr): 3455, 3165, 1655,
1570, 1485 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 11.5 (broad s,
1H); 7.8 (m, 1H); 7.2-6.6 (m, 4H); 6.3-5.8 (m, 3H), 1.8 (m,
3H).
40a) 2-(2-pyrrolyl)-5-aminobenzothiazole
[0211] Prepared in a manner similar to that of Example 4a. Yield:
30%; Rf (9/1 chloroform/methanol): 0.44; IR (KBr): 3455, 3360,
3125, 1570, 1460 cm.sup.-1.
40b) 2-(2-pyrrolyl)-5-nitrobenzothiazole
[0212] Prepared from sodium 2-amino-4-nitrothiophenoxide (15 g,
0.078 mol) and pyrrol-2-ylcarboxaldehyde (5.23 g, 0.055 mol) in a
manner similar to that of Example 24b. Yield: 3.9 g (29%); Rf (8/2
petroleum ether/ethyl acetate): 0.54; IR (KBr): 1595, 1510, 1480,
1335 cm.sup.-1.
EXAMPLE 41
Compound 41
N-[2-phenylbenzothiazol-5-yl]cyclopropylcarboxamidine
[0213] Prepared from 2-phenyl-5-aminobenzothiazole (example 9a) and
methyl cyclopropylcarboximidate (Patai, The Chemistry of Functional
Groups; The Chemistry of Cyano group; pp. 264-266, Zvi Rappoport,
Wiley & Sons, 1970) in a manner similar to that described in
Example 9. Yield: 57%; Elem. anal. C.sub.17H.sub.15N.sub.3O; theory
C:73.63 H:5.45 N:15.15; found C:72.06 H:5.29 N:14.69; IR (KBr):
3401, 1646, 1604, 1469 cm.sup.-1.
EXAMPLE 42
Compound 42
N-(2-phenylbenzoxazol-6-yl)acetamidine
[0214] Prepared in a manner similar to that of Example 9. Yield:
41%; Elem. anal. C.sub.15H.sub.13N.sub.3O; theory C:71.70 H:5.21
N:16.72; found C:71.06 H:4.91 N:16.62; IR (KBr): 3360, 3105, 1655,
1606 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 8-8.2 (m, 2H); 7.4-7.8
(m, 5H); 6.9 (dd, 1H); 5.9-6.3 (broad s, 2H); 1.8 (broad s,
3H).
42a) 2-phenyl-6-aminobenzoxazole
[0215] Prepared in a manner similar to that of Example 4a. Yield:
74%; Rf (9/1 chloroform/methanol): 0.64; m.p.: 212-214.degree. C.
IR (KBr): 3400, 3305, 3205, 1630 cm.sup.-1
42b) 2-phenyl-6-nitrobenzoxazole
[0216] PPA (160 g) is added to benzoic acid (14.26 g, 0.117 mol)
and 2-amino-5-nitrophenol (20 g, 0.117 mol). The mixture is heated
at 115-120.degree. C. for 30 minutes and cooled, and water (200 ml)
is added dropwise, followed by addition of 32% NaOH (pH=10). The
product is filtered off, washed with water and filtered off. It is
recrystallized from isopropyl ether. Yield: g (90%); Elem. anal.
C.sub.13H.sub.8N.sub.2O.sub.3; theory C:65.00 H:3.35 N:11.66; found
C:64.56 H:3.22 N:11.43; IR (KBr): 1551, 1515, 1340 cm.sup.-1.
EXAMPLE 43
Compound 43
N-[1-methyl-2-(2-methoxyphenyl)benzimidazol-5-yl]acetamidine
dihydrochloride
[0217] Prepared in a manner similar to that of Example 28. Yield:
78%; Elem. anal. C.sub.17H.sub.20Cl.sub.2N.sub.4O; theory C:55.59
H:5.49 N:15.25; found C:54.36 H:6.05 N:14.86; IR (KBr): 3450, 3020,
1605, 1490, 1260 cm.sup.-1; .sup.1H-NMR (d.sub.6-DMSO) 12.04 (broad
s, 1H); 9.78 (broad s, 1H); 8.65 (broad s, 1H); 8.12 (d, 1H); 7.85
(s, 1H); 7.77 (dt, 1H); 7.71 (dd, 1H); 7.52 (dd, 1H); 7.39 (d, 1H);
7.27 (t, 1H); 3.90 (s, 3H); 3.86 (s, 3H); 2.43 (s, 3H).
43a) 1-methyl-2-(2-methoxyphenyl)-5-aminobenzimidazole and
1-methyl-2-(2-methoxyphenyl)-6-aminobenzimidazole
[0218] Prepared in a manner similar to that of Example 4a. The
amines of the two isomers are separated by flash chromatography on
a column of silica gel (ethyl acetate).
1-methyl-2-(2-methoxyphenyl)-6-aminobenzimidazole
[0219] Yield: 2.21 g; Rf (95/5/0.5 chloroform/methanol/aqueous
ammonia): 0.33; Elem. anal. C.sub.15H.sub.15N.sub.3O; theory
C:71.12 H:5.97 N:16.59; found C:69.71 H:6.10 N:15.29; IR (KBr):
3230, 3200, 2935, 1625, 1460, 1245 cm.sup.-1; .sup.1H-NMR
(d.sub.6-DMSO) 7.3 (m, 5H); 6.6 (m, 2H); 3.8 (s, 3H), 3.4 (s,
3H).
1-methyl-2-(2-methoxyphenyl)-5-aminobenzimidazole
[0220] Yield: 4.0 g; Rf (95/5/0.5 chloroform/methanol/aqueous
ammonia): 0.25; Elem. anal. C.sub.15H.sub.15N.sub.3O; theory
C:71.12 H:5.97 N:16.59; found C:69.69 H:6.53 N:15.03; IR (KBr):
3230, 3200, 2935, 1625, 1460, 1245 cm.sup.-1; .sup.1H-NMR
(d.sub.6-DMSO) 7.5 (m, 2H); 7.1 (m, 3H); 6.7 (m, 2H); 3.8 (s, 3H);
3.4 (s, 3H).
43b) 1-methyl-2-(2-methoxyphenyl)-5-nitrobenzimidazole and
1-methyl-2-(2-methoxyphenyl)-6-nitrobenzimidazole
[0221] Sodium hydride (22 g, 0.055 mol) and methyl iodide (3.15 ml,
0.050 mol) are added to 2-(2-methoxyphenyl)-5-nitrobenzimidazole
(Example 37b, 12.38 g, 0.046 mol) in DMF (120 ml) at 0-5.degree. C.
The mixture is stirred at room temperature for 5 days. Water (300
ml) is added and the solid is filtered off and recrystallized from
water, and then from 9/1 isopropyl ether/acetonitrile, to give a
mixture of the two isomers in a ratio of about 65:35 respectively.
Yield: 9.3 g (72%); Rf (9/1 toluene-methanol): 0.41 (isomer-6) and
0.36 (isomer 5); Elem. anal. C.sub.15H.sub.13N.sub.3O.sub.3; theory
C:63.59 H:4.62 N:14.83; found C:63.34 H:4.50 N:14.70.
EXAMPLE 44
Compound 44
N-[1-methyl-2-(2-methoxyphenyl)benzimidazol-6-yl]acetamidine
[0222] Prepared in a manner similar to that of Example 28 from
1-methyl-2-(2-methoxyphenyl)-6-aminobenzimidazole, Example 43a.
[0223] Yield: 87%; Elem. anal. C.sub.17H.sub.18N.sub.4O; theory
C:69.37 H:6.16 N:19.03; found C:67.95 H:6.02 N:18.38; IR (KBr):
3450, 3350, 1650, 1605, 1470, 1255 cm.sup.-1; .sup.1H-NMR
(d.sub.6-DMSO) 7.54 (dt, 1H); 7.49 (d, 1H); 7.45 (dd, 1H); 7.22 (d,
1H); 7.11 (t, 1H); 6.92 (broad s, 1H); 6.65 (d, 1H); 3.82 (s, 3H);
3.51 (s, 3H); 1.90 (s, 3H).
[0224] A number of physicochemical characteristics of compounds
1-44 are collated and given in Table 2.
TABLE-US-00002 TABLE 2 Physicochemical characteristics of
representative compounds of formula (1) Melting Empirical Molecular
point Rf Compound formula weight (C..degree.) (TLC) 1
C.sub.15H.sub.13N.sub.3S 267.35 161.0-162.1 0.54.sup.(a) 2
C.sub.15H.sub.13N.sub.3S.cndot.C.sub.4H.sub.4O.sub.4 383.41
202.5-203.2 0.54.sup.(a) 3 C.sub.15H.sub.12ClN.sub.3S 301.79
212.2-213.5 0.49.sup.(a) 4 C.sub.14H.sub.19N.sub.3S 261.39
112.6-114.7 0.53.sup.(a) 5 C.sub.16H.sub.15N.sub.3 249.31
217.7-220.0 0.30.sup.(a) 6 C.sub.17H.sub.17N.sub.3 263.34
184.6-185.8 0.40.sup.(a) 7 C.sub.16H.sub.15N.sub.3 249.31
218.0-220.0 0.30.sup.(a) 8 C.sub.17H.sub.15N.sub.3 261.33
143.0-144.4 0.52.sup.(a) 9 C.sub.15H.sub.13N.sub.3S 267.35
177.0-178.0 0.48.sup.(a) 10 C.sub.16H.sub.15N.sub.3OS 297.37
163.0-165.0 0.45.sup.(a) 11 C.sub.16H.sub.15N.sub.3S 281.38
117.9-120.0 0.47.sup.(a) 12 C.sub.17H.sub.15N.sub.3S 293.38
90.8-91.8 0.55.sup.(a) 13
C.sub.16H.sub.16N.sub.4O.sub.3S.sub.2.cndot.HCl 412.91 244.0-248.0
0.40.sup.(a) 14 C.sub.14H.sub.12N.sub.4S 268.34 187.2-188.9
0.29.sup.(a) 15 C.sub.16H.sub.15N.sub.3OS 297.37 203.0-204.7
0.47.sup.(a) 16 C.sub.17H.sub.17N.sub.3O.sub.2S 327.40 156.4-158.3
0.50.sup.(a) 17 C.sub.16H.sub.15N.sub.3OS 297.37 141.6-145.6
0.54.sup.(a) 18 C.sub.16H.sub.15N.sub.3S 281.38 188.4-189.8
0.50.sup.(a) 19 C.sub.15H.sub.13FN.sub.4.cndot.2 HCl 341.22
283.7-286.3 0.55.sup.(b) 20 C.sub.15H.sub.13ClN.sub.4 284.75
153.6-156.0 0.61.sup.(a) 21 C.sub.15H.sub.14N.sub.4.cndot.HCl
286.76 164.0-166.0 0.50.sup.(a) 22
C.sub.14H.sub.20ClN.sub.4.cndot.2HCl 317.22 276.9-278.3
0.50.sup.(a) 23 C.sub.13H.sub.13N.sub.5.cndot.2HCl 312.20
318.0-322.0 0.54.sup.(b) 24 C.sub.13H.sub.13N.sub.5.cndot.HBr
320.19 197.0-199.0 0.54.sup.(b) 25
C.sub.17H.sub.16N.sub.4O.sub.2.cndot.2HCl 381.26 284.0-288.0
0.20.sup.(a) 26 C.sub.16H.sub.14N.sub.4 O.sub.2 294.31 271.5-274.3
0.59.sup.(d) 27 C.sub.16H.sub.14N.sub.4.cndot.2HCl 335.24
162.0-168.0 0.35.sup.(a) 28 C.sub.16H.sub.14N.sub.2O 250.30
204.8-205.9 0.24.sup.(a) 29 C.sub.15H.sub.13N.sub.3 O 251.28 .sup.
171.2-173.4.degree. 0.35.sup.(a) 30 C.sub.15H.sub.12ClN.sub.3O
285.73 183.6-185.1 0.58.sup.(b) 31 C.sub.16H.sub.12F.sub.3N.sub.3O
319.29 157.9-159.2 0.64.sup.(a) 32 C.sub.16H.sub.12F.sub.3N.sub.3O
319.29 179.2-181.0 0.59.sup.(b) 33 C.sub.15H.sub.12FN.sub.3O 269.27
157.9-159.2 0.64.sup.(c) 34 C.sub.15H.sub.12Cl.sub.2N.sub.3O 320.17
182.0-184.0 0.73.sup.(c) 35 C.sub.15H.sub.12Cl.sub.2N.sub.4 319.19
207.4-209.0 0.38.sup.(c) 36
C.sub.16H.sub.14F.sub.3N.sub.4.cndot.HBr 399.20 284.3-285.4
0.62.sup.(b) 37 C.sub.16H.sub.16N.sub.4 O 280.33 190.5-192.8
0.13.sup.(a) 38 C.sub.15H.sub.14FN.sub.4.cndot.HBr 349.21
266.8-269.0 0.58.sup.(b) 39 C.sub.16H.sub.16N.sub.4 264.33
154.0-158.0 0.40.sup.(c) 40 C.sub.13H.sub.12N.sub.4S 256.33
166.7-169.1 0.31.sup.(a) 41 C.sub.17H.sub.15N.sub.3O 277.32
137.4-138.9 0.63.sup.(b) 42 C.sub.15H.sub.13N.sub.3 O 251.28
176.3-177.8 0.44.sup.(a) 43 C.sub.17H.sub.18N.sub.4O.cndot.2HCl
367.27 253.1-254.7 0.27.sup.(a) 44 C.sub.17H.sub.18N.sub.4O 294.35
205.6-207.1 0.48.sup.(b) .sup.(a)Eluent: 85/25/1/2
CHCl.sub.3/MeOH/NH.sub.3/H.sub.2O; .sup.(b)Eluent: 5/2/2
n-butanol/AcOH/H.sub.2O; .sup.(c)Eluent: 73/25/2
CHCl.sub.3/MeOH/NH.sub.3; .sup.(d)Eluent: 4/4/2
CHCl.sub.3/MeOH/NH.sub.3.
[0225] Other representative examples of compounds of Formula (I)
are listed below:
[0226] N-[2-(3-methylphenyl)benzothiazol-5-yl]acetamidine;
[0227] N-[2-(4-methylphenyl)benzothiazol-5-yl]acetamidine;
[0228] N-[2-(2-fluorophenyl)benzothiazol-5-yl]acetamidine;
[0229] N-[2-(3-fluorophenyl)benzothiazol-5-yl]acetamidine;
[0230] N-[2-(4-fluorophenyl)benzothiazol-5-yl]acetamidine;
[0231] N-[2-(2-chlorophenyl)benzothiazol-5-yl]acetamidine;
[0232] N-[2-(3-chlorophenyl)benzothiazol-5-yl]acetamidine;
[0233] N-[2-(4-chlorophenyl)benzothiazol-5-yl]acetamidine;
[0234] N-[2-(3,4-dichlorophenyl)benzothiazol-5-yl]acetamidine;
[0235]
N-[2-(4-trifluoromethylphenyl)benzothiazol-5-yl]acetamidine;
[0236]
N-[2-(1-Methyl-1H-pyrrol-2-yl)benzothiazol-5-yl]acetamidine;
[0237] N-(2-Furan-2-ylbenzothiazol-5-yl)acetamidine;
[0238] N-(2-Furan-3-ylbenzothiazol-5-yl)acetamidine;
[0239] N-(2-phenylethylbenzothiazol-5-yl)acetamidine;
[0240] N-(2-Pentylbenzothiazol-5-yl)acetamidine;
[0241] N-[2-(4-fluorophenyl)benzothiazol-6-yl]acetamidine;
[0242] N-[2-(3-fluorophenyl)benzoxazol-5-yl]acetamidine;
[0243] N-[2-(4-fluorophenyl)benzoxazol-5-yl]acetamidine;
[0244] N-[2-(2,4-difluorophenyl)benzoxazol-5-yl]acetamidine;
[0245] N-[2-(3,4-difluorophenyl)benzoxazol-5-yl]acetamidine;
[0246] N-[2-(2-chlorophenyl)benzoxazol-5-yl]acetamidine;
[0247] N-[2-(3-chlorophenyl)benzoxazol-5-yl]acetamidine;
[0248] N-[2-(2-methoxyphenyl)benzoxazol-5-yl]acetamidine;
[0249] N-[2-(3-methoxyphenyl)benzoxazol-5-yl]acetamidine;
[0250] N-[2-(4-methoxyphenyl)benzoxazol-5-yl]acetamidine;
[0251] N-[2-(2,4-dimethoxyphenyl)benzoxazol-5-yl]acetamidine;
[0252] N-[2-(2-methylphenyl)benzoxazol-5-yl]acetamidine;
[0253] N-[2-(3-methylphenyl)benzoxazol-5-yl]acetamidine;
[0254] N-[2-(4-methylphenyl)benzoxazol-5-yl]acetamidine;
[0255] N-(2-benzylbenzoxazol-5-yl)acetamidine;
[0256] N-(2-styrylbenzoxazol-5-yl)acetamidine;
[0257] N-(2-phenylethylbenzoxazol-5-yl)acetamidine;
[0258] N-[2-(2-fluorophenyl)benzoxazol-6-yl]acetamidine;
[0259] N-[2-(3-fluorophenyl)benzoxazol-6-yl]acetamidine;
[0260] N-[2-(4-fluorophenyl)benzoxazol-6-yl]acetamidine;
[0261] N-[2-(2-chlorophenyl)benzoxazol-6-yl]acetamidine;
[0262] N-[2-(3-chlorophenyl)benzoxazol-6-yl]acetamidine;
[0263] N-[2-(4-chlorophenyl)benzoxazol-6-yl]acetamidine;
[0264] N-[2-(3,4-dichlorophenyl)benzoxazol-6-yl]acetamidine;
[0265]
N-[2-(3-trifluoromethylphenyl)benzoxazol-6-yl]acetamidine;
[0266]
N-[2-(4-trifluoromethylphenyl)benzoxazol-6-yl]acetamidine;
[0267] N-[2-(2-methoxyphenyl)benzoxazol-6-yl]acetamidine;
[0268] N-[2-(3-methoxyphenyl)benzoxazol-6-yl]acetamidine;
[0269] N-[2-(4-methoxyphenyl)benzoxazol-6-yl]acetamidine;
[0270] N-[2-(2,4-dimethoxyphenyl)benzoxazol-6-yl]acetamidine;
[0271] N-[2-(2-methylphenyl)benzoxazol-6-yl]acetamidine;
[0272] N-[2-(3-methylphenyl)benzoxazol-6-yl]acetamidine;
[0273] N-[2-(4-methylphenyl)benzoxazol-6-yl]acetamidine;
[0274] N-[2-(3-fluorophenyl)-3H-benzimidazol-5-yl]acetamidine;
[0275] N-[2-(2-chlorophenyl)-3H-benzimidazol-5-yl]acetamidine;
[0276] N-[2-(3-chlorophenyl)-3H-benzimidazol-5-yl]acetamidine;
[0277]
N-[2-(4-trifluoromethylphenyl)-3H-benzimidazol-5-yl]acetamidine;
[0278] N-[2-(3-methoxyphenyl)-3H-benzimidazol-5-yl]acetamidine;
[0279] N-[2-(4-methoxyphenyl)-3H-benzimidazol-5-yl]acetamidine;
[0280]
N-[2-(3,4-dimethoxyphenyl)-3H-benzimidazol-5-yl]acetamidine;
[0281] 4-(5-acetimidoylamino-1H-benzimidazol-2-yl)benzamide;
[0282] N-[2-(pyrrol-3-yl)-3H-benzimidazol-5-yl]acetamidine;
[0283] N-[2-(furan-2-yl)-3H-benzimidazol-5-yl]acetamidine;
[0284] N-[2-(furan-3-yl)-3H-benzimidazol-5-yl]acetamidine;
[0285] N-[2-(thien-2-yl)-3H-benzimidazol-5-yl]acetamidine;
[0286] N-[2-(thien-3-yl)-3H-benzimidazol-5-yl]acetamidine;
[0287] N-[2-(2-methoxyphenyl)quinol-6-yl]acetamidine;
[0288] N-[2-(3-methoxyphenyl)quinol-6-yl]acetamidine;
[0289] N-[2-(4-methoxyphenyl)quinol-6-yl]acetamidine;
[0290] N-[2-(2-fluorophenyl)quinol-6-yl]acetamidine;
[0291] N-[2-(3-fluorophenyl)quinol-6-yl]acetamidine;
[0292] N-[2-(4-fluorophenyl)quinol-6-yl]acetamidine;
[0293] N-[2-(2-chlorophenyl)quinol-6-yl]acetamidine;
[0294] N-[2-(3-chlorophenyl)quinol-6-yl]acetamidine;
[0295] N-[2-(4-chlorophenyl)quinol-6-yl]acetamidine;
[0296] N-[2-(3,4-dichlorophenyl)quinol-6-yl]acetamidine;
[0297] N-[2-benzylquinol-6-yl]acetamidine;
[0298] N-[2-phenylethylquinol-6-yl]acetamidine;
[0299] N-(2-phenylquinol-7-yl)acetamidine;
[0300] N-[2-(2-methoxyphenyl)quinol-7-yl]acetamidine;
[0301] N-[2-(3-methoxyphenyl)quinol-7-yl]acetamidine;
[0302] N-[2-(4-methoxyphenyl)quinol-7-yl]acetamidine;
[0303] N-[2-(2-fluorophenyl)quinol-7-yl]acetamidine;
[0304] N-[2-(3-fluorophenyl)quinol-7-yl]acetamidine;
[0305] N-[2-(4-fluorophenyl)quinol-7-yl]acetamidine;
[0306] N-[2-(2-chlorophenyl)quinol-7-yl]acetamidine;
[0307] N-[2-(3-chlorophenyl)quinol-7-yl]acetamidine;
[0308] N-[2-(4-chlorophenyl)quinol-7-yl]acetamidine;
[0309] N-[2-(3,4-dichlorophenyl)quinol-7-yl]acetamidine;
[0310] N-(3-phenylisoquinol-6-yl)acetamidine;
[0311] N-[3-(4-fluorophenyl)isoquinol-6-yl]acetamidine;
[0312] N-[3-(4-chlorophenyl)isoquinol-6-yl]acetamidine;
[0313]
N-[3-(4-trifluoromethylphenyl)isoquinol-6-yl]acetamidine;
[0314] N-[3-(3,4-dichlorophenyl)isoquinol-6-yl]acetamidine;
[0315] N-[2-(2-methoxyphenyl)quinazolin-6-yl]acetamidine;
[0316] N-[2-(3-methoxyphenyl)quinazolin-6-yl]acetamidine;
[0317] N-[2-(4-methoxyphenyl)quinazolin-6-yl]acetamidine;
[0318] N-[2-(2-fluorophenyl)quinazolin-6-yl]acetamidine;
[0319] N-[2-(3-fluorophenyl)quinazolin-6-yl]acetamidine;
[0320] N-[2-(4-fluorophenyl)quinazolin-6-yl]acetamidine;
[0321] N-[2-(2-chlorophenyl)quinazolin-6-yl]acetamidine;
[0322] N-[2-(3-chlorophenyl)quinazolin-6-yl]acetamidine;
[0323] N-[2-(4-chlorophenyl)quinazolin-6-yl]acetamidine;
[0324]
N-[2-(4-trifluoromethylphenyl)quinazolin-6-yl]acetamidine;
[0325] N-[2-(3,4-dichlorophenyl)quinazolin-6-yl]acetamidine;
[0326] N-(2-benzylquinazolin-6-yl)acetamidine;
[0327] N-(2-styrylquinazolin-6-yl)acetamidine;
[0328] N-(2-phenylethylquinazolin-6-yl)acetamidine;
[0329] N-(2-phenylquinazolin-7-yl)acetamidine;
[0330] N-(2-phenyl-1H-indol-5-yl)acetamidine;
[0331] N-[2-(2-methoxyphenyl)-1H-indol-5-yl]acetamidine;
[0332] N-[2-(3-methoxyphenyl)-1H-indol-5-yl]acetamidine;
[0333] N-[2-(4-methoxyphenyl)-1H-indol-5-yl]acetamidine;
[0334] N-[2-(2-methylphenyl)-1H-indol-5-yl]acetamidine;
[0335] N-[2-(2-fluorophenyl)-1H-indol-5-yl]acetamidine;
[0336] N-[2-(3-fluorophenyl)-1H-indol-5-yl]acetamidine;
[0337] N-[2-(4-fluorophenyl)-1H-indol-5-yl]acetamidine;
[0338] N-[2-(2-chlorophenyl)-1H-indol-5-yl]acetamidine;
[0339] N-[2-(3-chlorophenyl)-1H-indol-5-yl]acetamidine;
[0340] N-[2-(4-chlorophenyl)-1H-indol-5-yl]acetamidine;
[0341] N-[2-(3-trifluoromethyl)-1H-indol-5-yl]acetamidine;
[0342]
N-[2-(4-trifluoromethylphenyl)-1H-indol-5-yl]acetamidine;
[0343] N-[2-(3,4-dichlorophenyl)-1H-indol-5-yl]acetamidine;
[0344] N-(1-methyl-3-phenyl-1H-indol-5-yl)acetamidine;
[0345]
N-(1-methyl-3-(4-chlorophenyl)-1H-indol-5-yl]acetamidine;
[0346] N-[2-(2-methoxyphenyl)benzofuran-5-yl]acetamidine;
[0347] N-[2-(3-methoxyphenyl)benzofuran-5-yl]acetamidine;
[0348] N-[2-(4-methoxyphenyl)benzofuran-5-yl]acetamidine;
[0349] N-[2-(2-methylphenyl)benzofuran-5-yl]acetamidine;
[0350] N-[2-(2-fluorophenyl)benzofuran-5-yl]acetamidine;
[0351] N-[2-(3-fluorophenyl)benzofuran-5-yl]acetamidine;
[0352] N-[2-(4-fluorophenyl)benzofuran-5-yl]acetamidine;
[0353] N-[2-(2-chlorophenyl)benzofuran-5-yl]acetamidine;
[0354] N-[2-(3-chlorophenyl)benzofuran-5-yl]acetamidine;
[0355] N-[2-(4-chlorophenyl)benzofuran-5-yl]acetamidine;
[0356] N-[2-(3-trifluoromethyl)benzofuran-5-yl]acetamidine;
[0357]
N-[2-(4-trifluoromethylphenyl)benzofuran-5-yl]acetamidine;
[0358] N-[2-(3,4-dichlorophenyl)benzofuran-5-yl]acetamidine;
[0359] N-(2-benzylbenzofuran-5-yl)acetamidine;
[0360] N-(2-styrylbenzofuran-5-yl)acetamidine;
[0361] N-(2-phenylethylbenzofuran-5-yl)acetamidine;
[0362] N-(2-phenylbenzothiophen-5-yl)acetamidine;
[0363] N-[2-(2-methoxyphenyl)benzothiophen-5-yl]acetamidine;
[0364] N-[2-(3-methoxyphenyl)benzothiophen-5-yl]acetamidine;
[0365] N-[2-(4-methoxyphenyl)benzothiophen-5-yl]acetamidine;
[0366] N-[2-(2-fluorophenyl)benzothiophen-5-yl]acetamidine;
[0367] N-[2-(3-fluorophenyl)benzothiophen-5-yl]acetamidine;
[0368] N-[2-(4-fluorophenyl)benzothiophen-5-yl]acetamidine;
[0369] N-[2-(2-chlorophenyl)benzothiophen-5-yl]acetamidine;
[0370] N-[2-(3-chlorophenyl)benzothiophen-5-yl]acetamidine;
[0371] N-[2-(4-chlorophenyl)benzothiophen-5-yl]acetamidine;
[0372]
N-[2-(4-trifluoromethylphenyl)benzothiophen-5-yl]acetamidine;
[0373] N-[2-(3,4-dichlorophenyl)benzothiophen-5-yl]acetamidine;
[0374] N-(2-benzylbenzothiophen-5-yl)acetamidine;
[0375] N-(2-styrylbenzothiophen-5-yl)acetamidine;
[0376] N-(2-phenylethylbenzothiophen-5-yl)acetamidine;
[0377] N-(2-phenylquinoxalin-6-yl)acetamidine;
[0378] N-[2-(4-fluorophenyl)quinoxalin-6-yl)acetamidine;
[0379] N-[2-(4-chlorophenyl)quinoxalin-6-yl)acetamidine;
[0380] N-[2-(3,4-dichlorophenyl)quinoxalin-6-yl]acetamidine;
[0381] N-(2-benzylquinoxalin-6-yl)acetamidine;
[0382] N-(2-styrylquinoxalin-6-yl)acetamidine;
[0383] N-(2-phenylethylquinoxalin-6-yl)acetamidine;
[0384] N-(2-phenylcinnolin-6-yl)acetamidine;
[0385] N-[2-(4-fluorophenyl)cinnolin-6-yl)acetamidine;
[0386] N-[2-(4-chlorophenyl)cinnolin-6-yl)acetamidine;
[0387] N-[2-(3,4-dichlorophenyl)cinnolin-6-yl]acetamidine;
[0388] N-(2-benzylcinnolin-6-yl)acetamidine;
[0389] N-(2-styrylcinnolin-6-yl)acetamidine;
[0390] N-(2-phenylethylcinnolin-6-yl)acetamidine;
PHARMACOLOGICAL ACTIVITY
[0391] a) The inhibitory activity on the formation of NO measured
as NO.sub.2 .sup.- (nitrite) and PGE.sub.2 was studied in vitro on
culture media of rabbit articular chondrocytes stimulated with the
cytokine IL-1.beta. (1 ng/ml) for 48 hours. For the preparation of
the chondrocytes, the method described by Berenbaum et al. [FEBS
Letters 340, 51-55 (1994)] was followed. Briefly, fragments of
cartilage removed aseptically from the articular heads of rabbit
shoulder, hip and knee were finely ground and digested at
37.degree. C. in hyaluronidase, trypsin and collagenase solutions,
giving, after filtration through sterile gauze and centrifugation
at 600.times.g and suitable dilution with 10% DMEM-FCS 10%, a
concentration per well of about 1.times.10.sup.5 cells. The cells
were maintained under these conditions until confluent (about 15
days), the medium being replaced every 3 days. At this point, the
test products dissolved in the medium were added to each sample
and, after 20 minutes, 350 .mu.l of IL-1.beta. were added, to give
a final concentration of 1 ng/ml. The stimulation lasted 48 hours
at 37.degree. C. (incubation in air/7% CO.sub.2). A nitrite assay
was subsequently performed on the cell supernatant, as described by
Green et al. [Anal. Biochem. 126, 131-138 (1982)], and of PGE.sub.2
by RIA assay. The results obtained are shown in Table 3, in which
is given, for a number of the compounds that are the subject of the
invention and that are already illustrated in Table 1, the
IC.sub.50, i.e. the concentration (micromolar) of antagonist
capable of inhibiting the formation of nitrites and PGE.sub.2 by
50% relative to the control group, i.e. relative to the cells
stimulated with IL-1.beta. but without addition of antagonists.
TABLE-US-00003 TABLE 3 in vitro Activity on rabbit articular
chondrocytes stimulated with IL-1.beta. Inhibition % IC.sub.50
(.times. 10.sup.-6 M) Compound Structure NO PGE.sub.2 1
##STR00060## 6.5 2.4 3 ##STR00061## IN (tox 30) 1.9 4 ##STR00062##
6.9 6.6 5 ##STR00063## 3.4 1.2 6 ##STR00064## IN (tox 30) IN (tox
30) 8 ##STR00065## 47.9 2.3 9 ##STR00066## 18.0 4.2 10 ##STR00067##
IN (tox 100) 5.9 11 ##STR00068## 15.0 7.4 12 ##STR00069## 88.9 1.3
13 ##STR00070## IN 16.2 14 ##STR00071## IN 42.5 15 ##STR00072## IN
(tox 30) 7.4 16 ##STR00073## IN (tox 30) IN 17 ##STR00074## IN (tox
30) 1.3 18 ##STR00075## 6.2 1.2 19 ##STR00076## 78 0.7 20
##STR00077## 22.8 0.4 21 ##STR00078## 84.5 0.8 22 ##STR00079## 123
31.5 23 ##STR00080## 250 2.0 25 ##STR00081## 174 IN 26 ##STR00082##
IN IN 27 ##STR00083## 67.5 9.0 28 ##STR00084## 7.8 0.5 29
##STR00085## 28.6 3.2 30 ##STR00086## IN (tox 30) 0.3 31
##STR00087## 11.2 2.9 32 ##STR00088## 8.1 0.6 33 ##STR00089## 47.0
13.8 34 ##STR00090## 4.3 0.4 35 ##STR00091## IN 0.4 36 ##STR00092##
IN IN 37 ##STR00093## 32.1 2.8 38 ##STR00094## IN IN 39
##STR00095## 199 9.9 40 ##STR00096## IN 8.4 41 ##STR00097## IN 4.0
42 ##STR00098## 42.9 5.1 L-NAME -- 71.0 IN CELECOXIB -- IN 0.02
Note: IN = <25% inhibitory activity at 30 .times. 10.sup.-6 M
Tox = cellular toxicity
[0392] From the data given in Table 3, it may be deduced that some
of the test compounds that are subjects of the invention show a
powerful inhibitory effect, at the micromolar level, on the
production of NO.
[0393] The most active compounds are the benzothiazole derivatives,
compounds 1, 4 and 18, the indole derivative 5, the benzofuran
derivative 28 and the benzoxazole derivative 34, all having an
activity of between 3 and 8 micromolar.
[0394] Generally, a substitution with halogen on the phenyl group
increases the activity: see for example compound 34 (3,4-dichloro
derivative relative to the unsubstituted analogous compound,
compound 29), thus there is often a corresponding increase in the
cytotoxicity that precludes the objective evaluation of the
activity of these compounds. It should also be noted that the
NO-synthase inhibitor reference compound, L-NAME, shows activity
that is about 10-fold less powerful than that of the best compounds
that are the subject of the invention on this experimental model
(IC.sub.50 71 micromolar).
[0395] Some of the compounds that are the subject of the invention
also inhibit the IL-1.beta.-induced production of prostaglandins
(PGE.sub.2) at sub-micromolar concentrations. Thus, the
benzimidazole compounds 19, 20, 21 and 35, the benzoxazole
compounds 30 and 34 and the benzofuran compound 28 inhibit the
formation of PGE.sub.2 at concentrations (IC.sub.50) of between 0.3
and 0.8 micromolar.
[0396] The inhibitory activity on the production of PGE.sub.2 by
many of the compounds that are the subject of the invention is
probably at least partly due to their capacity to inhibit the
production of NO.
[0397] In point of fact, it has been described that NO potentiates
the cytokine-induced production of PGE.sub.2 in a variety of cell
systems [see for example Watkins et al.; Br. J. Pharmacol. 121
(1997), 1482-1488].
[0398] This effect appears to be due to the amplification of the
expression of COX-2 (Tetsuka et al.; J. Clin. Invest. 97 (1996),
2051-2056). For the compounds that are the subject of the invention
that show little activity as NO-production inhibitors while
inhibiting the production of PGE.sub.2 at the submicromolar level,
for instance the benzimidazole derivatives 19, 20, 21 and 35 or the
benzothiazole derivatives 12, the inhibitory activity on PGE.sub.2
production is probably associated with a direct action on the
inducible cyclooxygenase enzyme.
[0399] The selective antagonist of the inducible cyclooxygenase
(COX-2), Celecoxib, chosen as comparative compound, was found to be
about ten times more powerful in inhibiting the production of
PGE.sub.2 than the most active compounds that are the subject of
the invention, whereas it was entirely inactive as regards
inhibiting the production of NO.
[0400] Some of the compounds that are the subject of the invention
also demonstrated inhibition of the expression (mRNA) of IL-6 in
isolated human chondrosarcoma cells (SW 1353) stimulated with
IL-1.beta.. In practice, the RNA extracted from the cells was
back-transcribed to c-DNA by means of a thermocycler
(BioRad--"iCycler") and subsequently amplified via the Real Time
PCR technique using a probe and a primer specific for IL-6, from
the company Applied Biosystem, and the thermocycler 7000 Sequence
Detection System (Applied Biosystem).
[0401] Using this technique, for example, compounds 5, 8, 9, 18,
27, 28 and 29 were found to inhibit the expression of IL-6 in SW
1353 cells stimulated for 6 hours with IL-1.beta. with an IC.sub.50
of between 1.5 and 6 micromolar. The capacity of IL-6 to inhibit
the expression of messenger RNA may be considered as large, since
the increase in the expression of this cytokine is associated with
the physiopathology of various human diseases, for instance Crohn's
disease, as described previously.
[0402] Some of the compounds that are the subject of the invention,
which showed the strongest activity in the in vitro tests described
hereinabove, were evaluated "in vivo" in rats on experimental
models of inflammation and hyperalgesia induced by Zymosan. This is
a phlogogenic agent, consisting of a protein-glycoside complex,
extracted from the cell walls of raw yeast, which is capable of
inducing rapid degranulation of neutrophils, an increase in the
production of TNF-.alpha., interleukin-1 (IL-1), IL-6 and
stimulation of NO generation by monocytes and macrophages
(ZymosaN:Merck Index XIII ed. No. 10250, p. 1818).
[0403] The experiments consisted of sub-plantar intradermal
injection into the animal of 4 mg of Zymosan suspended in 100 .mu.l
of sterile physiological solution, while the test compounds were
administered orally 30 minutes before injection of the phlogogenic
agent.
[0404] Measurement of the inflammation of the injected paw and of
the consequent hyperalgesic effects was performed 2, 4 and 6 hours
after the administration of Zymosan. The oedema was evaluated as
the increase in volume of the injected paw within the period 0-6
hours, relative to the initial value of the volume of the paw, i.e.
before the injection of Zymosan (basal value).
[0405] The measurements of the variation of the volume of the paw
were recorded using a hydroplethysmometer (Mod. 7150, Basile,
Italy), which consists of two plastic cuvettes containing a
surfactant liquid, the larger one being used for immersion of the
paw, connected to the smaller one which contains a transducer
capable of recording small displacements of volume of the liquid
used for the measurement. The paw is immersed in the cuvettes up to
the tibiotarsal joint. The volume of liquid displaced by the paw
indicates the magnitude of the inflammation.
[0406] For each test compound, at least three doses were used
(generally 10, 20 and 40 mg/kg) with at least five animals per
group x dose, so as to be able to calculate an ED.sub.30, i.e. the
dose in mg/kg capable of reducing by 30% the Zymosan-induced volume
increase, relative to the group of control animals, i.e. animals
injected only with the phlogogenic agent and treated orally with
distilled water.
[0407] The hyperalgesia induced by the intradermal administration
of Zymosan was evaluated on these animals and at the same times
described previously for the evaluation of the oedema, using the
Randall-Selitto method [Arch. Int. Pharmacodyn. 111, 409
(1957)].
[0408] In practice, an analgesimeter was used (Basile, Italy),
which consists in applying to the inflamed paw a weight in the form
of a rounded-tipped cone, on which the applied force is gradually
increased. When the animal makes a noise following the pain
stimulus, the operator blocks the punch and records the force,
expressed in grams, which was applied to the paw (the cut-off value
is 500 grams). The difference in the mechanical pain threshold
between the basal value (generally about 230-250 grams) and that
recorded at the indicated times after injection of the phlogogenic
agent, generally 130-140 g for the control animals 6 hours after
injection of the phlogogenic agent, is defined as mechanical
hyperalgesia. In this case also, an ED.sub.30 was calculated, i.e.
the dose in mg/kg capable of increasing the pain threshold by 30%
(mechanical hyperalgesia) in the animals treated with the test
compounds relative to the group of control animals.
[0409] The results thus obtained are given in Table 4, which
presents the ED.sub.30 values for the anti-inflammatory and
anti-hyperalgesic activity for a number of compounds that are the
subject of the invention, compared with those obtained with
Celecoxib and L-NAME.
TABLE-US-00004 TABLE 4 Anti-inflammatory and analgesic activity
(measured in the range 0-6 hours) in rat paw injected with Zymosan.
(ED.sub.30 mg/kg os) Analgesic Anti- activity inflammatory
(mechanical Mean activity anti- (Oedema + Compounds (oedema)
hyperalgesia) Analgesia) 1 12.6 6.7 9.7 5 39.4 19.3 29.4 8 19.8
11.8 15.8 9 33.9 31.3 32.6 27 24.6 13.0 18.8 28 20.8 24.4 22.6
Celecoxib 79.4 69.2 74.3 L-NAME IN IN IN Note: the compound L-NAME
was entirely inactive up to the maximum dose administered (50
mg/kg).
[0410] As may be deduced from the data given above in Table 4, many
of the compounds that are the subject of the invention, for
instance the benzothiazole derivatives, compounds 1 and 9, the
indole derivative, compound 5, the quinoline derivative, compound
8, the quinazoline derivative, compound 27, and the benzofuran
derivative, compound 28, show powerful anti-inflammatory and
anti-hyperalgesic action even when administered orally, indicating
that they therefore have good bioavailability. On average, using
the compounds illustrated, and considering overall both the
anti-oedema-generating activity and the analgesic activity, an
activity about 2 to 7 times higher than that of the selective COX-2
antagonist Celecoxib is obtained.
[0411] The NO-synthase antagonist L-NAME was inactive up to the
maximum dose tested (50 mg/kg) since, besides having an intrinsic
activity that is generally lower than that of the compounds that
are the subject of the invention, it may probably also be poorly
absorbed via the oral route.
[0412] In conclusion, by means of the combined action of inhibition
of the production of NO and, indirectly, that of the prostaglandin
PGE.sub.2, along with the action of inhibiting the expression of
pro-inflammatory cytokines such as IL-6, many of the compounds that
are the subject of the invention show in vivo an anti-inflammatory
and analgesic effect that is greater than both that of Celecoxib,
i.e. a powerful and selective antagonist of inducible
cyclooxygenase (COX-2), and than that of L-NAME, an NO-synthase
antagonist.
* * * * *