U.S. patent application number 09/424934 was filed with the patent office on 2002-07-18 for benzimidazole derivatives.
Invention is credited to ANDERSEN, MARC W., BOYD, FRANK LESLIE JR., CHAMBERLAIN, STANLEY DAWES, DALUGE, SUSAN MARY, DEATON, DAVID NORMAN, DRACH, JOHN CHARLES, FREEMAN, GEORGE ANDREW, TOWNSEND, LEROY B..
Application Number | 20020094963 09/424934 |
Document ID | / |
Family ID | 26311687 |
Filed Date | 2002-07-18 |
United States Patent
Application |
20020094963 |
Kind Code |
A1 |
DRACH, JOHN CHARLES ; et
al. |
July 18, 2002 |
BENZIMIDAZOLE DERIVATIVES
Abstract
The present invention relates to certain bezimidazole
derivatives and their use in medical therapy particularly for the
treatment or prophylaxis of virus infections such as those caused
by herpes viruses. The invention also relates to the preparation of
the benzimidazole derivatives and pharmaceutical formulations
containing them.
Inventors: |
DRACH, JOHN CHARLES; (ANN
ARBOR, MI) ; TOWNSEND, LEROY B.; (ANN ARBOR, MI)
; BOYD, FRANK LESLIE JR.; (RALEIGH, NC) ;
CHAMBERLAIN, STANLEY DAWES; (RESEARCH TRIANGLE PARK, NC)
; DALUGE, SUSAN MARY; (RESEARCH TRIANGLE PARK, NC)
; DEATON, DAVID NORMAN; (RESEARCH TRIANGLE PARK, NC)
; ANDERSEN, MARC W.; (RALEIGH, NC) ; FREEMAN,
GEORGE ANDREW; (RESEARCH TRIANGLE PARK, NC) |
Correspondence
Address: |
NIXON & VANDERHYE
1100 NORTH GLEBE ROAD
8TH FLOOR
ARLINGTON
VA
22201-4714
US
|
Family ID: |
26311687 |
Appl. No.: |
09/424934 |
Filed: |
March 17, 2000 |
PCT Filed: |
June 8, 1998 |
PCT NO: |
PCT/EP98/03380 |
Current U.S.
Class: |
514/43 |
Current CPC
Class: |
C07H 19/052 20130101;
A61P 31/12 20180101; C07D 405/04 20130101; A61P 9/00 20180101; A61P
31/22 20180101; A61P 31/20 20180101; C07D 235/24 20130101; C07D
235/30 20130101 |
Class at
Publication: |
514/43 |
International
Class: |
A61K 031/70; A01N
043/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 10, 1997 |
GB |
9711982.0 |
Jul 11, 1997 |
GB |
9714552.8 |
Claims
1. A compound of formula (I) 19wherein: R.sup.1 is halogen,
hydroxy, azido, C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.6-14arylC.sub.2-6alkenyl,
C.sub.6-14arylC.sub.2-6- alkynyl, or --NR.sup.19R.sup.20 (where
R.sup.19 and R.sup.20 may be the same or different and are
hydrogen, C.sub.1-8alkyl, cyanoC.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-7cycloalkyl,
C.sub.1-8alkylC.sub.3-7cycloalkyl, C.sub.2-6alkenyl,
C.sub.3-7cycloalkylC.sub.1-8alkyl, C.sub.2-6alkynyl,
C.sub.6-14aryl, C.sub.6-14arylC.sub.1-6alkyl,
heterocycleC.sub.1-8alkyl, C.sub.1-8alkylcarbonyl,
C.sub.6-14arylsulfonyl, or R.sup.19R.sup.20 together with the N
atom to which they are attached form a 3, 4, 5 or 6 membered
heterocyclic ring), OR.sup.21 (where R.sup.21 is hydrogen,
C.sub.1-8alkyl, C.sub.3-7cycloalkyl, or C.sub.6-14aryl), or
SR.sup.22 (where R.sup.22 is hydrogen, C.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, C.sub.3-7cycloalkyl, or C.sub.6-14aryl);
R.sup.2 is hydrogen or halogen; R.sup.3 and R.sup.4 may be the same
or different and are hydrogen, halogen, C.sub.1-8alkyl,
C.sub.6-14aryl, heterocycleC.sub.6-14aryl, C.sub.1-8alkoxy,
haloC.sub.1-8alkyl or --SR.sup.24 (where R.sup.24 is hydrogen,
C.sub.1-8alkyl, C.sub.6-14aryl, or C.sub.6-14arylC.sub.1-8alkyl- );
Z is a substituent of formula (Ia), (Ib), or (Ic) 20wherein:
R.sup.5 is hydrogen, C.sub.1-8alkyl, haloC.sub.1-8alkyl or
C.sub.1-8alkoxy; R.sup.6 is hydrogen, hydroxy, halogen,
C.sub.1-8alkyl, hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl or
C.sub.1-8alkoxy; R.sup.7 is hydrogen, hydroxy, halogen,
C.sub.1-8alkyl, hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl,
C.sub.1-8alkoxy, or R.sup.6 and R.sup.7 together form a ketone or
alkene; R.sup.8-R.sup.11 may be the same or different and are
hydrogen, hydroxy, halogen, C.sub.2-8alkyl, hydroxyC.sub.1-8alkyl,
haloC.sub.1-8alkyl, C.sub.1-8alkoxy, or any of R.sup.8 and R.sup.9
or R.sup.10 and R.sup.11 together form a ketone or alkene;
R.sup.12-R.sup.18 may be the same or different and are hydrogen,
hydroxy, C.sub.1-8alkyl or hydroxyC.sub.1-8alkyl; or a
pharmaceutically acceptable derivative thereof, provided that a
compound of formula (I) cannot be
2,5-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-xylopyranosyl)-1H-benzimidazole
or
5,6-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-arabinopyranosyl)-benzimidaz-
ole-2-thione; further provided that when Z is a substituent of
formula (Ia): a) R.sup.2, R.sup.3, and R.sup.4 cannot all be
hydrogen, and b) R.sup.1 cannot be NR.sup.19R.sup.20 where R.sup.19
and R.sup.20 together with the N atom to which they are attached
form a 5 membered heterocyclic ring containing S; further provided
that when Z is a substituent of formula (Ib): a) R.sup.1 cannot be
NR.sup.19R.sup.20 where R.sup.19 and R.sup.20 together with the N
atom to which they are attached form a 5 membered heterocyclic ring
containing S; and further provided that when Z is a substituent of
formula (Ic): a) and when R.sup.15-R.sup.18 are all hydrogen, then
R.sup.1 cannot be hydroxy, amino or SR.sup.22 where R.sup.22 is H;
and b) R.sup.1 cannot be NR.sup.19R.sup.20 where R.sup.19 and
R.sup.20 together with the N atom to which they are attached form a
5 membered heterocyclic ring containing S.
2. A compound of formula (II) 21wherein: R.sup.1 is halogen,
hydroxy, azido, C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.6-14arylC.sub.2-6alkenyl,
C.sub.6-14arylC.sub.2-6- alkynyl, or --NR.sup.19R.sup.20 (where
R.sup.19 and R.sup.20 may be the same or different and are
hydrogen, C.sub.1-8alkyl, cyanoC.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-7cycloalkyl,
C.sub.1-8alkylC.sub.3-7cycloalkyl, C.sub.2-6alkenyl,
C.sub.3-7cycloalkylC.sub.1-8alkyl, C.sub.2-6alkynyl,
C.sub.6-14aryl, C.sub.6-14arylC.sub.1-6alkyl,
heterocycleC.sub.1-8alkyl, C.sub.1-8alkylcarbonyl,
C.sub.6-14arylsulfonyl, or R.sup.19R.sup.20 together with the N
atom to which they are attached form a 3, 4, 5 or 6 membered
heterocyclic ring), OR.sup.21 (where R.sup.21 is hydrogen,
C.sub.1-8alkyl, C.sub.3-7cycloalkyl, or
10. Use of a compound according to any one of claims 1 to 7 for the
manufacture of a medicament for the treatment or prophylaxis of a
viral infection.
11. A method of treatment of a virus infection in an animal which
comprises treating said animal with a therapeutically effective
amount of a compound as defined according to any one of claims 1 to
7.
12. A method according to claim 11 wherein the virus infection is a
herpes virus infection.
13. A method according to claim 11 wherein the virus infection is a
cytomegalovirus infection.
14. A method according to claim 11 wherein the virus infection is a
Hepatitis B virus infection.
15. A compound formula (XI): 22or a pharmaceutically acceptable
derivative thereof.
16.
2-Bromo-5,6-dichloro-1-.beta.-D-ribopyranosyl-1H-benzimidazole.
17. A pharmaceutically acceptable derivative of a compound
according to claims 15 or 16.
18. A pharmaceutical formulation comprising
2-bromo-5,6-dichloro-1-.beta.-- D-ribopyranosyl-1H-benzimidazole
together with a pharmaceutically acceptable carrier therefor.
19. Use of a compound according to claims 15 or 16 for the
manufacture of a medicament for the treatment or prophylaxis of a
viral infection.
20. A method of treatment or prevention of the symptoms or effects
of a virus infection in an infected animal which comprises treating
said animal with a therapeutically effective amount of a compound
as defined according to claims 15 or 16.
21. A method according to claim 20 wherein the virus infection is a
herpes virus infection.
22. A method according to claim 20 wherein the virus infection is a
cytomegalovirus infection.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to certain benzimidazole
derivatives and their use in medical therapy particularly for the
treatment or prophylaxis of virus infections such as those caused
by herpes viruses. The invention also relates to the preparation of
the benzimidazole derivatives and pharmaceutical formulations
containing them.
BACKGROUND OF THE INVENTION
[0002] Of the DNA viruses, those of the herpes group are the source
of the most common viral illnesses in man. The group includes
herpes simplex virus types 1 and 2 (HSV), varicella zoster virus
(VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human
herpes virus type 6 (HHV-6) and human herpes virus type 7 (HHV-7)
and type 8 (HHV-8). HSV-1 and HSV-2 are some of the most common
infectious agents of man. Most of these viruses are able to persist
in the host's neural cells; once infected, individuals are at risk
of recurrent clinical manifestations of infection which can be both
physically and psychologically distressing.
[0003] HSV infection is often characterized by extensive and
debilitating lesions of the skin, mouth and/or genitals. Primary
infections may be subclinical although tend to be more severe than
infections in individuals previously exposed to the virus. Ocular
infection by HSV can lead to keratitis or cataracts thereby
endangering the host's sight. Infection in the new-born, in
immunocompromised patients or penetration of the infection into the
central nervous system can prove fatal.
[0004] VZV is a herpes virus which causes chickenpox and shingles.
Chickenpox is the primary disease produced in a host without
immunity, and in young children is usually a mild illness
characterized by a vesicular rash and fever. Shingles or zoster is
the recurrent form of the disease which occurs in adults who were
previously infected with VZV. The clinical manifestations of
shingles are characterized by neuralgia and a vesicular skin rash
that is unilateral and dermatomal in distribution. Spread of
inflammation may lead to paralysis or convulsions. Coma can occur
if the meninges become affected. VZV is of serious concern in
patients receiving immunosuppressive drugs for transplant purposes
or for treatment of malignant neoplasia and is a serious
complication of AIDS patients due to their impaired immune
system.
[0005] In common with other herpes viruses, infection with CMV
leads to a lifelong association of virus and host. Congenital HCMV
disease is characterized by jaundice, hepatosplenomegaly, petechial
rash and multiple organ dysfunction and is associated with
long-term sequelae such as hearing loss and mental deficiency.
Infection can result in retinitis leading to blindness or, in less
severe forms, failure to thrive, and susceptibility to chest and
ear infections. CMV infection in patients whose immune systems are
immature or who are immunocompromised for example as a result of
malignancy, treatment with immunosuppressive drugs following
transplantation or infection with Human Immunodeficiency Virus, may
give rise to retinitis, colitis, esophagistis, hepatitis,
meningoencephalitis, pneumonitis, gastrointestinal disorders and
neurological diseases. In addition, these CMV disease syndromes can
affect patients who are not immunocompromised.
[0006] The main disease caused by EBV is acute or cnliionic
infectious mononucleosis (glandular fever). Examples of other EBV
or EBV associated diseases include lymphoproliferative disease
which frequently occurs in persons with congenital or acquired
cellular immune deficiency, X-linked lymphoproliferative disease
which occurs namely in young boys, EBV-associated B-cell tumors,
Hodgkin's disease, nasopharyngeal carcinoma, Burkitt lymphoma,
non-Hodgkin B-cell lymphoma, thymomas and oral hairy leukoplakia.
EBV infections have also been found in association with a variety
of epithelial-cell-derived tumors of the upper and lower
respiratory tracts including the lung.
[0007] HHV-6 has been shown to be a causative agent of infantum
subitum in children and of kidney rejection and interstitial
pneumonia in kidney and bone marrow transplant patients,
respectively, and may be associated with other diseases such as
multiple sclerosis. There is also evidence of repression of stem
cell counts in bone marrow transplant patients. HHV-7 is of
undetermined disease etiology. HHV-8 has been implicated in
cancer.
[0008] Hepatitis B virus (HBV) is a viral pathogen of world-wide
major importance. The virus is etiologically associated with
primary hepatocellular carcinoma and is thought to cause 80% of the
world's liver cancer. Clinical effects of infection with HBV range
from headache, fever, malaise, nausea, vomiting, anorexia and
abdominal pains. Replication of the virus is usually controlled by
the immune response, with a course of recovery lasting weeks or
months in humans, but infection may be more severe leading to
persistent chronic liver disease outlined above.
[0009] GB 682,960, GB 690,119 and GB 696,952 disclose benzimidazole
glycosides useful as intermediates in the preparation of
therapeutic substances. Mochalin et. al. (SU 443035; Zh. Org. Khim.
12(1), 58-63 (1976)) describe the synthesis of certain
unsubstituted benzimidazole pyranosides. Gosselin et. al.
(Antiviral Chem. Chemother. 5(4), 243-56, 1994) disclose certain
5,6,Townsend et. al. (Chemical Reviews, vol. 70 no. 3, 1970)
discloses certain 1-glycosylbenzimidazoles. U.S. Pat. No. 5,585,394
discloses 1-benzenesulfonyl-1,3-dihyro-2H-benzimidazol-2-one
derivatives which have affinity for the vasopressin and oxytocin
receptors. EP 0 521 463 A2 describes certain cyclohexanol analogues
for antiviral and anti-parasitic use.
DETAILED DESCRIPTION OF THE INVENTION
[0010] It has now been discovered that certain 6-membered
ring-containing benzimidazole derivatives are useful for the
treatment or prophylaxis of viral infections. According to a first
aspect of the present invention, there is provided compounds of
formula (I) 1
[0011] wherein:
[0012] R.sup.1 is halogen, hydroxy, azido, C.sub.1-8alkyl,
C.sub.1-8alkoxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.6-14arylC.sub.2-6alkenyl, C.sub.6-14arylC.sub.2-6alkynyl, or
--NR.sup.19R.sup.20 (where R.sup.19 and R.sup.20 may be the same or
different and are hydrogen, C.sub.1-8alkyl, cyanoC.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-7cycloalkyl,
C.sub.1-8alkylC.sub.3-7cycloalkyl, C.sub.2-6alkenyl,
C.sub.3-7cycloalkylC.sub.1-8alkyl, C.sub.2-6alkynyl,
C.sub.6-14aryl, C.sub.6-14arylC.sub.1-6alkyl,
heterocycleC.sub.1-8alkyl, C.sub.1-8alkylcarbonyl,
C.sub.6-14arylsulfonyl, or R.sup.19R.sup.20 together with the N
atom to which they are attached form a 3, 4, 5 or 6 membered
heterocyclic ring), OR.sup.21 (where R.sup.21 is hydrogen,
C.sub.1-8alkyl, C.sub.3-7cycloalkyl, or C.sub.6-14aryl), or
SR.sup.22 (where R.sup.22 is hydrogen, C.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, C.sub.3-7cycloalkyl, or C.sub.6-14aryl);
[0013] R.sup.2 is hydrogen or halogen;
[0014] R.sup.3 and R.sup.4 may be the same or different and are
hydrogen, halogen, C.sub.1-8alkyl, C.sub.6-14aryl,
heterocycleC.sub.6-14aryl, C.sub.1-8alkoxy, haloC.sub.1-8alkyl or
--SR.sup.24 (where R.sup.24 is hydrogen, C.sub.1-8alkyl,
C.sub.6-14aryl, or C.sub.6-14arylC.sub.1-8alkyl- );
[0015] Z is a substituent of formula (Ia), (Ib), or (Ic) 2
[0016] wherein:
[0017] R.sup.5 is hydrogen, C.sub.1-8alkyl, haloC.sub.1-8alkyl or
C.sub.1-8alkoxy;
[0018] R.sup.6 is hydrogen, hydroxy, halogen, C.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl or C.sub.1-8alkoxy;
[0019] R.sup.7 is hydrogen, hydroxy, halogen, C.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.1-8alkoxy, or
R.sup.6 and R.sup.7 together form a ketone or alkene;
[0020] R.sup.8-R.sup.11 may be the same or different and are
hydrogen, hydroxy, halogen, C.sub.2-8alkyl, hydroxyC.sub.1-8alkyl,
haloC.sub.1-8alkyl, C.sub.1-8alkoxy, or any of R.sup.8 and R.sup.9
or R.sup.10 and R.sup.11 together form a ketone or alkene;
[0021] R.sup.12-R.sup.18 may be the same or different and are
hydrogen, hydroxy, C.sub.1-8alkyl or hydroxyC.sub.1-8alkyl;
[0022] or a pharmaceutically acceptable derivative thereof,
[0023] provided that a compound of formula (I) cannot be
2,5-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-xylopyranosyl)-1H-benzimidazole
or
5,6-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-arabinopyranosyl)-benzimidaz-
ole-2-thione;
[0024] further provided that when Z is a substituent of formula
(Ia):
[0025] a) R.sup.2, R.sup.3, and R.sup.4 cannot all be hydrogen;
and
[0026] b) R.sup.1 cannot be NR.sup.19R.sup.20 where R.sup.19 and
R.sup.20 together with the N atom to which they are attached form a
5 membered heterocyclic ring containing S;
[0027] further provided that when Z is a substituent of formula
(Ib):
[0028] a) R.sup.1 cannot be NR.sup.19R.sup.20 where R.sup.19 and
R.sup.20 together with the N atom to which they are attached form a
5 membered heterocyclic ring containing S; and
[0029] further provided that when Z is a substituent of formula
(Ic):
[0030] a) and when R.sup.15-R.sup.18 are all hydrogen, then R.sup.1
cannot be hydroxy, amino or SR.sup.22 where R.sup.22 is H; and
[0031] b) R.sup.1 cannot be N.sup.19R.sup.20 where R.sup.19 and
R.sup.20 together with the N atom to which they are attached form a
5 membered heterocyclic ring containing S.
[0032] Particularly preferred R.sup.1 groups include halogen and
--NR.sup.19R.sup.20 where R is hydrogen and R is C.sub.1-8alkyl
(particularly C.sub.1-3alkyl, with isopropyl being especially
preferred), C.sub.3-7cycloalkyl (cyclopropyl is especially
preferred), C.sub.1-8alkylC.sub.3-7cycloalkyl or
C.sub.3-7cycloalkylC.sub.1-8alkyl.
[0033] In certain particularly preferred compounds, R.sup.2 is
hydrogen.
[0034] Particularly preferred R.sup.3 and R.sup.4 groups include
hydrogen, halogen (chlorine is especially preferred), and
C.sub.1-8alkoxy, (particularly C.sub.1-3alkoxy, with methoxy being
especially preferred). In certain particularly preferred compounds,
one or both of R.sup.3 and R.sup.4 are chlorine, desirably
both.
[0035] In certain especially preferred compounds, R.sup.5 is
hydrogen.
[0036] Particularly preferred substituents at R.sup.6-18 include
hydrogen, hydroxy, C.sub.1-8alkyl (particularly C.sub.1-3alkyl,
with methyl and ethyl being especially preferred) and
hydroxyC.sub.1-8alkyl (particularly hydroxyC.sub.1-3alkyl, with
hydroxymethyl being especially preferred).
[0037] Preferred compounds of formula (I) are compounds wherein Z
is substituent of formula (Ia).
[0038] Other preferred compounds of formula (I) are compounds
wherein Z is a substituent of formula (Ib).
[0039] In a further aspect of the present invention, there is
provided compounds of formula (II) 3
[0040] wherein:
[0041] R.sup.1 is halogen, hydroxy, azido, C.sub.1-8alkyl,
C.sub.1-8alkoxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.6-14arylC.sub.2-6alkenyl, C.sub.6-14arylC.sub.2-6alkynyl, or
--NR.sup.19R.sup.20 (where R.sup.19 and R.sup.20 may be the same or
different and are hydrogen, C.sub.1-8alkyl, cyano(.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-7cycloalkyl,
C.sub.1-8alkylC.sub.3-7cycloalkyl, C.sub.2-6alkenyl,
C.sub.3-7cycloalkylC.sub.1-8alkyl, C.sub.2-6alkynyl,
C.sub.6-14aryl, C.sub.6-14arylC.sub.1-6alkyl,
heterocycleC.sub.1-8alkyl, C.sub.1-8alkylcarbonyl,
C.sub.6-14arylsulfonyl, or R.sup.19 R.sup.20 together with the N
atom to which they are attached form a 3, 4, 5 or 6 membered
heterocyclic ring), OR.sup.21 (where R.sup.21 is hydrogen,
C.sub.1-8alkyl, C.sub.3-7cycloalkyl, or C.sub.6-14aryl), or
SR.sup.22 (where R.sup.22 is hydrogen, C.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, C.sub.3-7cycloalkyl, or C.sub.6-14aryl);
[0042] R.sup.2 is hydrogen or halogen;
[0043] R.sup.3 and R.sup.4 may be the same or different and are
hydrogen, halogen, C.sub.1-8alkyl, C.sub.6-14aryl,
heterocycleC.sub.6-14aryl, C.sub.1-8alkoxy, haloC.sub.1-8alkyl or
--SR.sup.24 (where R.sup.24 is hydrogen, C.sub.1-8alkyl,
C.sub.6-14aryl, or C.sub.6-14arylC.sub.1-8alkyl- );
[0044] R.sup.5 is hydrogen, C.sub.1-8alkyl, haloC.sub.1-8alkyl,
C.sub.1-8alkoxy;
[0045] R.sup.6 is hydrogen, hydroxy, halogen, C.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.1-8alkoxy;
[0046] R.sup.7 is hydrogen, hydroxy, halogen, C.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.1-8alkoxy, or
R.sup.6 and R.sup.7 together form a ketone or alkene;
[0047] R.sup.8-R.sup.11 may be the same or different and are
hydrogen, hydroxy, halogen, C.sub.2-8alkyl, hydroxyC.sub.1-8alkyl,
haloC.sub.1-8alkyl, C.sub.1-8alkoxy, or any of R.sup.8 and R.sup.9
or R.sup.10 and R.sup.11 together form a ketone or alkene;
[0048] or a pharmaceutically acceptable derivative thereof,
[0049] provided that a compound of formula (I) cannot be
2,5-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-xylopyranosyl)-1H-benzimidazole
or
5,6-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-arabinopyranosly)-benzimidaz-
ole-2-thione;
[0050] further provided that when Z is a substituent of formula
(Ia):
[0051] a) R.sup.2, R.sup.3, and R.sup.4 cannot all be hydrogen;
and
[0052] b) R.sup.1 cannot be NR.sup.19R.sup.20 where R.sup.19 and
R.sup.20 together with the N atom to which they are attached form a
5 membered heterocyclic ring containing S.
[0053] A preferred embodiment of the present invention are
compounds of formula (III) 4
[0054] wherein:
[0055] R.sup.1 is halogen, hydroxy, azido, C.sub.1-8alkyl,
C.sub.1-8alkoxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.6-14arylC.sub.2-6alkenyl, C.sub.6-14arylC.sub.2-6alkynyl, or
--NR.sup.19R.sup.20 (where R.sup.19 and R.sup.20 may be the same or
different and are hydrogen, C.sub.1-8alkyl, cyanoC.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-7cycloalkyl,
C.sub.1-8alkylC.sub.3-7cycloalkyl, C.sub.2-6alkenyl,
C.sub.3-7cycloalkylC.sub.1-8alkyl, C.sub.2-6alkynyl,
C.sub.6-14aryl, C.sub.6-14arylC.sub.1-6alkyl,
heterocycleC.sub.1-8alkyl, C.sub.1-8alkylcarbonyl,
C.sub.6-14arylsufonyl, or R.sup.19R.sup.20 together with the N atom
to which they are attached form a 3, 4, 5 or 6 membered
heterocyclic ring), OR.sup.21 (where R.sup.21 is hydrogen,
C.sub.1-8alkyl, C.sub.3-7cycoalkyl, or C.sub.6-14aryl), or
SR.sup.22 (where R.sup.22 is hydrogen, C.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, C.sub.3-7cycloalkyl, or C.sub.6-14aryl);
[0056] R.sup.2 is hydrogen or halogen;
[0057] R.sup.3 and R.sup.4 may be the same or different and are
hydrogen, halogen, C.sub.1-8alkyl, C.sub.6-14aryl,
heterocycleC.sub.6-14aryl, C.sub.1-8alkoxy, haloC.sub.1-8alkyl or
--SR.sup.24 (where R.sup.24 is hydrogen, C.sub.1-8alkyl,
C.sub.6-14aryl, or C.sub.6-14arylC.sub.1-8alkyl- );
[0058] R.sup.5 is hydrogen, C.sub.1-8alkyl, haloC.sub.1-8alkyl,
C.sub.1-8alkoxy;
[0059] R.sup.6 is hydrogen, hydroxy, halogen, C.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.1-8alkoxy;
[0060] R.sup.7 is hydrogen, hydroxy, halogen, C.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.1-8alkoxy, or
R.sup.6 and R.sup.7 together form a ketone or alkene;
[0061] R.sup.8R.sup.11 maybe the same or different and are
hydrogen, hydroxy, halogen, C.sub.2-8alkyl, hydroxyC.sub.1-8alkyl,
haloC.sub.1-8alkyl, C.sub.1-8alkoxy, or any of R.sup.8 and R.sup.9
or R.sup.10 and R.sup.11 together form a ketone or alkene;
[0062] or a pharmaceutically acceptable derivative thereof,
[0063] provided that a compound of formula (I) cannot be
2,5-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-xylopyranosyl)-1H-benzimidazole
or
5,6-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-arabinopyranosyl)-benzimidaz-
ole-2-thione;
[0064] further provided that when Z is a substituent of formula
(Ia):
[0065] a) R.sup.2, R.sup.3, and R.sup.4 cannot all be hydrogen;
and
[0066] b) R.sup.1 cannot be NR.sup.19R.sup.20 where R.sup.19 and
R.sup.20 together with the N atom to which they are attached form a
5 membered heterocyclic ring containing S.
[0067] Compounds of formula (I) in which Z is a substituent of
formula (Ic) provide a further aspect of the invention.
[0068] Preferred compounds of formula (I), (II), and (III) are
those wherein:
[0069] R.sup.1 is halogen;
[0070] R.sup.2 is hydrogen;
[0071] R.sup.3 and R.sup.4 are halogen;
[0072] R.sup.5 and R.sup.7 are hydrogen;
[0073] R.sup.6 is hydroxy or hydrogen;
[0074] R.sup.8 and R.sup.10 are hydroxy;
[0075] R.sup.9 and R.sup.11 are hydrogen;
[0076] R.sup.12 is hydrogen, C.sub.1-8alkyl, or
hydroxyC.sub.1-8alkyl;
[0077] R.sup.13 is hydroxy;
[0078] R.sup.14-R.sup.18 may be the same or different and are
hydrogen or hydroxy;
[0079] or a pharmaceutically acceptable derivative thereof.
[0080] A preferred compound of Formula (III) is
2-bromo-5,6-dichloro-1-.be- ta.-D-ribopyranosyl-1H-benzimidazole,
represented by formula (XI): 5
[0081] The compounds of formula (I) including compounds of formula
(II) and (Ill) above and their pharmaceutically acceptable
derivatives are hereinafter referred to as the compounds according
to the invention.
[0082] The compounds according to the invention contain one or more
asymmetric carbon atoms and thus occur as racemates and racemic
mixtures, single enantiomers, diastereomeric mixtures and
individual diastereomers. All such isomeric forms of these
compounds are expressly included in the present invention. Each
stereogenic carbon may be of the R or S configuration. Although the
specific compounds exemplified in this application may be depicted
in a particular stereochemical configuration, compounds having
either the opposite stereochemistry at any given chiral center or
mixtures thereof are also envisioned.
[0083] The present invention includes within its scope each
possible alpha and beta anomer of the compounds of formula (I) and
their physiologically functional derivatives, substantially free of
the other anomer, that is to say no more than about 5% w/w of the
other anomer.
[0084] Compounds of formula (I) in the beta anomeric form are
preferred.
[0085] Preferred compounds of the present invention include:
[0086]
(3S,4R,5R,6S)-2-Bromo-5,6-dichloro-1-(tetrahydro4,5-dihydroxy-6-(hy-
droxymethyl)-2H-pyran-3-yl)-1H-benzimidazole;
[0087]
(.+-.)-Trans-2-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohexa-
nol;
[0088]
(.+-.)-(1R*,2S*,3R*)-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)--
1,2-cyclohexanediol;
[0089]
2-bromo-5,6-dichloro-1-.beta.-D-ribopyranosyl-1H-benzimidazole;
[0090]
5,6-dichloro-N-(1-methylethyl)-1-.beta.-D-ribopyranosyl-1H-benzimid-
azol-2-amine;
[0091]
2-bromo-5,6-dichloro-4-fluoro-1-.beta.-D-ribopyranosyl-1H-benzimida-
zole;
[0092]
2-bromo-5,6,-dichloro-1-(2,3,4-tri-O-acetyl-.beta.-D-ribopyranosyl)-
-1H-benzimidazole;
[0093]
2-bromo-5,6-dichloro-1-.beta.-L-ribopyranosyl-1H-benzimidazole;
[0094]
2-bromo-6-chloro-5-methyl-1-.beta.-D-ribopyranosyl-1H-benzimidazole-
; and
[0095]
2-bromo-5,6,-dichloro-1-(4-deoxy-.beta.-D-erythro-pentopyranosyl)-1-
H-benzimidazole;
[0096]
2-Bromo-5,6-dichloro-1-(beta-L-ribopyranosyl)-1H-benzimidazole;
[0097]
2-Bromo-5,6-dichloro-1-(beta-L-xylopyranosyl)-1H-benzimidazole;
[0098]
2-Bromo-5,6-dichloro-1-(2-deoxy-alpha-D-erythro-pentopyranosyl)-1H--
benzimidazole;
[0099] or pharmaceutically acceptable derivatives thereof.
[0100] The term "alkyl", alone or in combination with any other
term, refers to a straight-chain or branch-chain saturated
aliphatic hydrocarbon radical containing the specified number of
carbon atoms, or where no number is specified, preferably from 1-10
and more preferably from 1-6 carbon atoms. Examples of alkyl
radicals include, but are not limited to, methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isoamyl, n-hexyl and the like, with methyl and ethyl being
preferred.
[0101] The term "alkenyl," alone or in combination with any other
term, refers to a straight-chain or branched-chain mono- or
poly-unsaturated aliphatic hydrocarbon radical containing the
specified number of carbon atoms, or where no number is specified,
preferably from 2-10 carbon atoms and more preferably, from 2-6
carbon atoms. References to alkenyl groups include groups which may
be in the E- or Z-form or a mixture thereof and which when they
contain at least three carbon atoms, may be branched. Examples of
alkenyl radicals include, but are not limited to, ethenyl, E- and
Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutyenyl, E-
and Z-pentenyl, E-and Z-hexenyl, E,E-, E,Z-, Z, E- and
Z,Z-hexadienyl and the like.
[0102] The term "alkynyl" refers to hydrocarbon groups of either a
straight or branched configuration with one or more carbon-carbon
triple bonds which may occur in any stable point along the chain,
such as ethynyl, propynyl, butynyl, pentynyl, and the like.
[0103] The term "alkoxy" refers to an alkyl ether radical, wherein
the term "alkyl" is defined above. Examples of suitable alkyl ether
radicals include, but are not limited to, methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy
and the like, with methoxy being preferred.
[0104] Alkenyl and alkynyl substituents may optionally contain one
or more heteroatoms such as nitrogen, sulfur, or oxygen.
[0105] The term "aryl," alone or in combination with any other
term, refers to a carbocyclic aromatic radical (such as phenyl or
naphthyl) containing the specified number of carbon atoms,
preferably from 6-14 carbon atoms, and more preferably from 6-10
carbon atoms, optionally substituted with one or more substituents
selected from C1-6 alkoxy, (for example methoxy), nitro, halogen,
(for example chloro), amino, carboxylate and hydroxy. Examples of
aryl radicals include, but are not limited to phenyl, naphthyl,
indenyl, indanyl, azulenyl, fluorenyl, anthracenyl and the
like.
[0106] The term "heterocycle" and "heterocyclic" radical, unless
otherwise defined herein, refers to a stable 3-7 membered
monocyclic heterocyclic ring or 8-11 membered bicyclic heterocyclic
ring which is either saturated or unsaturated, and which may be
optionally benzofused if monocyclic. Each heterocycle consists of
one or more carbon atoms and from one to four heteroatoms selected
from the group consisting of nitrogen, oxygen and sulfur. As used
herein, the terms "nitrogen and sulfur heteroatoms" include any
oxidized form of nitrogen and sulfur, and the quaternized form of
any basic nitrogen. A heterocyclyl radical may be attached at any
endocyclic carbon or heteroatom which results in the creation of a
stable structure. Preferred heterocycles include 5-7 membered
monocyclic heterocycles and 8-10 membered bicyclic heterocycles.
Examples of such groups include imidazolyl, imidazolinoyl,
imidazolidinyl, quinolyl, isoqinolyl, indolyl, indazolyl,
indazolinolyl, perhydropyridazyl, pyridazyl, pyridyl, pyrrolyl,
pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl,
piperidinyl, pyranyl, pyrazolinyl, piperzinyl, pyrimidinyl,
pyridazinyl, morpholinyl, thiamorpholinyl, furyl, thienyl,
triazolyl, thiazolyl, carbolinyl, tetrazolyl, thiazolidinyl,
benzofuranoyl, thiamorpholinyl sulfone, oxazolyl, benzoxazolyl,
oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, isoxozolyl,
isothiazolyl, furazanyl, tetrahydropyranyl, tetrahydrofuranyl,
thiazolyl, thiadiazoyl, dioxolyl, dioxinyl, oxathiolyl,
benzodioxolyl, dithiolyl, thiophenyl, tetrahydrothiophenyl,
sulfolanyl, dioxanyl, dioxolanyl, tetahydrofurodihydrofuranyl,
tetrahydropyranodihydrofuranyl, dihydropyranyl,
tetradyrofurofuranyl and tetrahydropyranofuranyl.
[0107] Preferred heterocycles include imadazolyl, pyrrolyl,
pyrrolinyl, piperidinyl, piperazinyl, and morpholinyl.
[0108] The term "halogen" refers to a radical of fluorine,
chlorine, bromine or iodine.
[0109] The term "haloC.sub.1-8alkyl" means a C.sub.1-8alkyl group
in which one or more hydrogens is replaced by halo and preferably
containing one, two or three halo groups. Examples of such groups
include trifluoromethyl and fluoroisopropyl.
[0110] The term "pharmaceutically effective amount" refers to an
amount effective in treating a virus infection, for example a CMV
or HBV infection, in a patient either as monotherapy or in
combination with other agents. The term "treating" as used herein
refers to the alleviation of symptoms of a particular disorder in a
patient, or the improvement of an ascertainable measurement
associated with a particular disorder, and may include the
suppression of symptom recurrance in an asymptomatic patient such
as a patient in whom a viral infection has become latent. The term
"prophylactically effective amount" refers to an amount effective
in preventing a virus infection, for example a CMV or HBV
infection, or preventing the occurrence of symptoms of such an
infection, in a patient. As used herein, the term "patient" refers
to a mammal, including a human.
[0111] The term "pharmaceutically acceptable carrier or adjuvant"
refers to a carrier or adjuvant that may be administered to a
patient, together with a compound of this invention, and which does
not destroy the pharmacological activity thereof and is nontoxic
when administered in doses sufficient to deliver a therapeutic
amount of the antiviral agent.
[0112] As used herein, the compounds according to the invention are
defined to include pharmaceutically acceptable derivatives or
prodrugs thereof. A "pharmaceutically acceptable derivative" or
"pharmaceutically acceptable prodrug" means any pharmaceutically
acceptable salt, ester, salt of an ester, or other derivative of a
compound of this invention which, upon administration to a
recipient, is capable of providing (directly or indirectly) a
compound of this invention or an inhibitorily active metabolite or
residue thereof. Particularly favored derivatives and prodrugs are
those that increase the bioavailability of the compounds of this
invention when such compounds are administered to a mammal (e.g.,
by allowing an orally administered compound to be more readily
absorbed into the blood) or which enhance delivery of the parent
compound to a biological compartment (e.g., the brain or lymphatic
system) relative to the parent species.
[0113] The compounds according to the invention may be used in the
form of salts derived from inorganic or organic acids. Included
among such acid salts, for example, are the following: acetate,
adipate, alginate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, citrate, camphorate, camphorsulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,
pamoate, pectianate, persulfate, phenylproprionate, picrate,
pivalate, propionate, succinate, tartrate, thiocyanate, tosylate
and undecanoate.
[0114] Pharmaceutically acceptable salts of the compounds according
to the invention include those derived from pharmaceutically
acceptable inorganic and organic acids and bases. Examples of
suitable acids include hydrochloric, hydrobromic, sulfuric, nitric,
perchloric, fumaric, maleic, phosphoric, glycollic, lactic,
salicyclic, succinic, toluene-p-sulfonic, tartaric, acetic, citric,
methanesulfonic, ethanesulfonic, formic, benzoic, malonic,
naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such
as oxalic, while not in themselves pharmaceutically acceptable, may
be employed in the preparation of salts useful as intermediates in
obtaining the compounds of the invention and their pharmaceutically
acceptable acid addition salts.
[0115] Salts derived from appropriate bases include alkali metal
(e.g. sodium), alkaline earth metal (e.g., magnesium), ammonium and
N-W+4 (wherein W is C.sub.1-4 alkyl). Physiologically acceptable
salts of a hydrogen atom or an amino group include salts or organic
carboxylic acids such as acetic, lactic, tartaric, malic,
isethionic, lactobionic and succinic acids; organic sulfonic acids
such as methanesulfonic, ethanesulfonic, benzenesulfonic and
p-toluenesulfonic acids and inorganic acids such as hydrochloric,
sulfuric, phosphoric and sulfamic acids. Physiologically acceptable
salts of a compound with a hydroxy group include the anion of said
compound in combination with a suitable cation such as Na.sup.+,
NH.sub.4.sup.+, and NW.sub.4.sup.+ (wherein W is a C.sub.1-4alkyl
group).
[0116] Pharmaceutically acceptable salts include salts of organic
carboxylic acids such as ascorbic, acetic, citric, lactic,
tartaric, malic, maleic, isothionic, lactobionic, p-aminobenzoic
and succinic acids; organic sulphonic acids such as
methanesulphonic, ethanesulphonic, benzenesulphonic and
p-toluenesulphonic acids and inorganic acids such as hydrochloric,
sulphuric, phosphoric, sulphamic and pyrophosphoric acids.
[0117] For therapeutic use, salts of the compounds according to the
invention will be pharmaceutically acceptable. However, salts of
acids and bases which are non-pharmaceutically acceptable may also
find use, for example, in the preparation or purification of a
pharmaceutically acceptable compound.
[0118] Preferred salts include salts formed from hydrochloric,
sulfuric, acetic, succinic, citric and ascorbic acids.
[0119] Preferred esters of the compounds according to the invention
are independently selected from the following groups: (1)
carboxylic acid esters obtained by esterification of the hydroxy
groups, in which the non-carbonyl moiety of the carboxylic acid
portion of the ester grouping is selected from straight or branched
chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl),
alkoxyalkyl (for example, methoxymethyl), aralkyl (for example,
benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for
example, phenyl optionally substituted by, for example, halogen,
C.sub.1-4alkyl, or C.sub.1-4alkoxy or amino); (2) sulfonate esters,
such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl);
(3) amino acid esters (for example, L-valyl or L-isoleucyl); (4)
phosphonate esters and (5) mono-, di- or triphosphate esters. The
phosphate esters may be further esterified by, for example, a
C.sub.1-20 alcohol or reactive derivative thereof, or by a 2,3-di
(C.sub.6-24)acyl glycerol.
[0120] In such esters, unless otherwise specified, any alkyl moiety
present advantageously contains from 1 to 18 carbon atoms,
particularly from 1 to 6 carbon atoms, more particularly from 1 to
4 carbon atoms, Any cycloalkyl moiety present in such esters
advantageously contains from 3 to 6 carbon atoms. Any aryl moiety
present in such esters advantageously comprises a phenyl group.
[0121] Preferred carboxylic acid esters of compounds according to
the invention include the acetate, butyrate and valerate esters.
L-valyl is a particularly preferred amino acid ester.
[0122] Any reference to any of the above compounds also includes a
reference to a pharmaceutically acceptable salts thereof.
[0123] In a further aspect of the invention there are provided the
compounds according to the invention for use in medical therapy
particularly for the treatment or prophylaxis of viral infections
such as herpes viral infections. Compounds according to the
invention have been shown to be active against CMV infections,
although early results suggest that these compounds could also be
active against other herpes virus infections such as HSV-1 and-2,
HHV 6, 7, and 8, VZV, EBV as well as against HBV infections.
[0124] Other viral conditions which may be treated in accordance
with the invention have been discussed in the introduction
hereinbefore. The compounds according to the invention are
particularly suited to the treatment or prophylaxis of CMV
infections and associated conditions. Examples of CMV conditions
which may be treated in accordance with the invention have been
discussed in the introduction hereinbefore.
[0125] According to another aspect, the present invention provides
a method for the treatment or prevention of the symptoms or effects
of a viral infection in an infected animal, for example, a mammal
including a human, which comprises treating said animal with a
therapeutically effective amount of a compound according to the
invention. According to a particular embodiment of this aspect of
the invention, the viral infection is a herpes virus infection,
such as CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV- or HHV-8. A
further aspect of the invention includes a method for the treatment
or prevention of the symptoms or effects of an HBV infection.
[0126] The compounds according to the invention may also be used in
adjuvant effects, for example Kaposi's sarcoma.
[0127] The present invention further provides a method for the
treatment of a clinical condition in an animal, for example, a
mammal including a human which clinical condition includes those
which have been discussed in the introduction hereinbefore, which
comprises treating said animal with a therapeutically effective
amount of a compound according to the invention. The present
invention also includes a method for the treatment or prophylaxis
of any of the aforementioned infections or conditions.
[0128] In yet a further aspect, the present invention provides the
use of a compound according to the invention in the manufacture of
a medicament for the treatment or prophylaxis of any of the above
mentioned viral infections or conditions.
[0129] The above compounds according to the invention and their
pharmaceutically acceptable derivatives may be employed in
combination with other therapeutic agents for the treatment of the
above infections or conditions. Combination therapies according to
the present invention comprise the administration of at least one
compound of the present invention and at least one other
pharmaceutically active ingredient. The active ingredient(s) and
pharmaceutically active agents may be administered simultaneously
in either the same or different pharmaceutical formulations or
sequentially in any order. The amounts of the active ingredient(s)
and pharmaceutically active agent(s) and the relative timings of
administration will be selected in order to achieve the desired
combined therapeutic effect. Preferably the combination therapy
involves the administration of one compound according to the
invention and one of the agents mentioned herein below.
[0130] Examples of such further therapeutic agents include agents
that are effective for the treatment of viral infections or
associated conditions such as (1 alpha, 2 beta, 3
alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]gu- anine [( )BHCG,
SQ-34514], oxetanocin-G (3,4-bis-(hydroxymethyl)-2-oxetano-
syl]guanine), acyclic nucleosides (e.g. acyclovir, valaciclovir,
famciclovir, ganciclovir, penciclovir), acyclic nucleoside
phosphonates (e.g.
(S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC),
ribonucleotide reductase inhibitors such as 2-acetylpyridine
5-[(2-chloroanilino)thiocarbonyl)thiocarbonohydrazone,
3'azido-3'-deoxythymidine, other 2',3'-dideoxynucleosides such as
2',3'-dideoxycytidine, 2',3'-dideoxyadenosine,
2',3'-dideoxyinosine, 2',3'-didehydrothymidine, protease inhibitors
such as indinavir, ritonavir, nelfinavir,
[3S-[3R*(1R*,2S*)]]-[3[[(4-aminophenyl)sulfonyl](2-
-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro-3-furany-
l ester (141W94), oxathiolane nucleoside analogues such as
(-)-cis-1-(2-hydroxymethyl)-1,3-oxathiolane 5-yl)-cytosine
(lamivudine) or
cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine
(FTC), 3'-deoxy-3'-fluorothymidine,
5-chloro-2',3'-dideoxy-3'-fluorouridine,
(-)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-m-
ethanol, ribavirin, 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine
(H2G), tat inhibitors such as
7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2-(H)on- e (Ro5-3335),
7-chloro-1,3-dihydro-5-(1H-pyrrol-2yl)-3H-1,4-benzodiazepin--
2-amine (Ro24-7429), interferons such as .alpha.-interferon, renal
excretion inhibitors such as probenecid, nucleoside transport
inhibitors such as dipyridamole; pentoxifylline, N-acetylcysteine
(NAC), Procysteine, .alpha.-trichosanthin, phosphonoformic acid, as
well as immunomodulators such as interleukin II orthymosin,
granulocyte macrophage colony stimulating factors, erythropoetin,
soluble CD.sub.4 and genetically engineered derivatives thereof, or
non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as
nevirapine (BI-RG-587), loviride ((.alpha.-APA) and delavuridine
(BHAP), and phosphonoformic acid, and
1,4-dihydro-2H-3,1-benzoxazin-2-ones NNRTIs such as
(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-be-
nzoxazin-2-one (L-743,726 or DMP-266), and quinoxaline NNRTIs such
as isopropyl
(2S)-7-fluoro-3,4-dihydro-2-ethyl-3-oxo-1(2H)-quinoxalinecarbox-
ylate (HBY1293).
[0131] More preferably the combination therapy involves the
administration of one of the above mentioned agents and a compound
within one of the preferred or particularly preferred sub-groups
within formula (I) as described above. Most preferably the
combination therapy involves the joint use of one of the above
named agents together with one of the compounds of formula (I)
specifically named herein.
[0132] The present invention further includes the use of a compound
according to the invention in the manufacture of a medicament for
simultaneous or sequential administration with at least one other
therapeutic agent, such as those defined hereinbefore.
[0133] In a further aspect of the present invention there is
provided a method of treatment or prophylaxis of restenosis by
administration of a compound according to the invention.
[0134] Restenosis is the narrowing of the blood vessels which can
occur after injury to the vessel wall, for example injury caused by
balloon angioplasty or other surgical techniques, and is
characterized by excessive proliferation of smooth muscle cells in
the walls of the blood vessel treated. Restenosis following
angioplasty (RFA) occurs in patients who have been treated for
coronary artery disease by balloon angioplasty. It is thought that
in many patients suffering from RFA, viral infection, particularly
by CMV and/or HHV-6, of the patient plays a pivotal role in the
proliferation of the smooth muscle cells in the coronary vessel
treated.
[0135] Restenosis can occur following a number of surgical
techniques, for example, transplant surgery, vein grafting,
coronary by-pass grafting and, most commonly, following
angioplasty.
[0136] Angioplasty is a surgical techniques wherein atherosclerotic
stenoses in the peripheral, renal and coronary vasculature are
opened up by compressing and/or tearing the plaque on the vessel
walls, typically by means of a pressurized balloon catheter.
Unfortunately, in 25 to 50% of cases, particularly those involving
the coronary vasculature, the treated vessel restenoses within a
few months so that the operation must be repeated. Alternatives to
the balloon catheter, such as pulsed lasers and rotary cutters,
have been developed with a view to reducing or preventing
restenosis following angioplasty, but have met with limited
success. A number of drugs including anti-coagulants and
vasodilators have also been tried with disappointing or equivocal
results.
[0137] There is now a strong body of evidence, from work done both
in vitro and in vivo, indicating that restenosis is a
multifactorial process. Several cytokines and growth factors,
acting in concert, stimulate the migration and proliferation of
vascular smooth muscle cells (SMC) and production of extracellular
matrix material, which accumulate to occlude the blood vessel. In
addition growth suppressors act to inhibit the proliferation of
SMC's and production of extracellular matrix material.
[0138] The present invention further includes a process for the
preparation of compounds of formula (I) and pharmaceutically
acceptable derivatives thereof which comprises:
[0139] A) Reacting a compound of formula (I) wherein R.sup.1 is
hydrogen and R.sup.2, R.sup.3, and R.sup.4 are as hereinbefore
defined, and R.sup.5-R.sup.18 are as hereinbefore defined, with a
suitable halogenation agent such as N-bromosuccinimide (NBS); or
when R.sup.1 is a suitable leaving atom or group, for example, a
halo atom such as bromine or an organo (for example alkyl)
sulphone, or organo (for example alkyl or aralkyl) suiphonate such
as methylsulphone (MeS(O).sub.2--), methylsulphonate
(MeS(O).sub.2O--) or tosylate (4-MePhS(O).sub.2O--), with a
nucleophile such as amines, alkoxides, mercaptides; or
[0140] B) Reacting a compound of formula (IV) 6
[0141] wherein R.sup.1 is hydrogen, a halo atom,
--NR.sup.19R.sup.20 (wherein R.sup.19 and R.sup.20 are as
hereinbefore defined), and R.sup.2, R.sup.3, R.sup.4 and R.sup.5
are as hereinbefore described with a compound of formula (Va),
(Vb), or (Vc) 7
[0142] wherein R.sup.5-R.sup.18 are as is hereinbefore defined and
L is a suitable leaving group for example, a halo (for example,
fluoro, chloro or bromo), an organosulphonyloxy, an alkyl or
arylthio (for example, phenylthio) or an aryl or aliphatic ester
group such as benzoate or acetate, or a methoxy. Alternatively,
intermediates of formula (Vb) and (Vc) where L is amino may be
reacted with appropriate aromatic nitro compounds as described in
WO96/07646. Thereafter or simultaneously therewith one or more of
the following further steps may be additionally performed in any
desired or necessary order:
[0143] (i) removing any remaining protecting group(s);
[0144] (ii) converting a compound of formula (I) or a protected
form thereof into a further compound of formula (I) or protected
form thereof;
[0145] (iii) converting the compound of formula (I) or a protected
form thereof into a pharmaceutically acceptable derivative of the
compound of formula (I) or a protected form thereof;
[0146] (iv) converting a pharmaceutically acceptable derivative of
the compound of formula (I) or a protected form thereof into the
compound of formula (I) or a protected form thereof;
[0147] (v) converting a pharmaceutically acceptable derivative of
the compound of formula (I) or a protected form thereof into
another pharmaceutically acceptable derivative of the compound of
formula (I) or a protected form thereof;
[0148] (vi) where necessary, separating the enantiomers and
diastereomers of the compound of formula (I) or of a protected
derivative thereof or of a pharmaceutically acceptable derivative
of a compound of formula (I) using methods known to persons skilled
in the art.
[0149] A. Process A may conveniently be used for the preparation of
a compound of formula (I) wherein R.sup.1 is a halogen. Such
compounds may conveniently be prepared by reacting a compound of
formula (I) wherein R.sup.1 is hydrogen and R.sup.2-R.sup.18 are as
hereinbefore defined with a halogenating agent. Halogenation may be
effected in a conventional manner, for example, bromination using a
brominating agent such as N-bromosuccinimide (NBS) in an aprotic
solvent such as tetrahydrofuran (THF) or preferably 1,4-dioxane
heated to 60-150.degree. C.
[0150] Compounds of formula (I) wherein R.sup.1 is
--NR.sup.19R.sup.20 (wherein R.sup.19 and R.sup.20 are as
hereinbefore defined) may conveniently be prepared from compounds
of formula (I) wherein R.sup.1 is a halo atom, such as bromo or
chloro atom, by reaction with an appropriate amine
HNR.sup.19R.sup.20, wherein R.sup.19 and R.sup.20 are as
hereinbefore defined. Typically, the reaction is effected at an
elevated temperature, 70-80.degree. C., in an organic solvent such
as ethanol or dimethylsulfoxide. Amines of formula
HNR.sup.19R.sup.20 are commercially available or are readily
prepared by a person skilled in the art.
[0151] Compounds of formula (I) wherein R.sup.1 is --OR.sup.21
(wherein R.sup.21 is as hereinbefore defined) may conveniently be
prepared from compounds of formula (I) wherein R.sup.1 is a halo
atom, such as bromo or chloro atom, by reaction with an appropriate
alcohol of formula HOR.sup.21 (wherein R.sup.21 is as hereinbefore
defined). Typically, the reaction is effected at -20 to 100.degree.
C., preferably at 25.degree. C., in HOR.sup.21 or dimethylsulfoxide
as solvent and in the presence of a strong base such as sodium
hydride. Alcohols of formula HOR.sup.21 are available commercially
or may be readily prepared by a person skilled in the art.
[0152] Compounds of formula (I) wherein R.sup.1 is --SR.sup.22
(wherein R.sup.22 is as hereinbefore defined) may conveniently be
prepared from compounds of formula (I) wherein R.sup.1 is a halo
atom, such as bromo or chloro atom, by reaction with an appropriate
thiol of formula HSR.sup.22 (wherein R.sup.22 is as hereinbefore
defined). Typically, the reaction is effected at -20 to 100.degree.
C., preferably at 25.degree. C., in N,N-dimethylformamide or
dimethylsulfoxide as solvent and in the presence of a strong base
such as sodium or potassium hydride. Thiols of formula HSR.sup.22
are available commercially or may be readily prepared by a person
skilled in the art.
[0153] Compounds of formula (I) in which R.sup.3 or R.sup.4 is an
aryl or heterocyclic group and R.sup.5-R.sup.18 are as herebefore
may be prepared from compounds of formula (I) in which R.sup.3 or
R.sup.4 is a halo atom, such as a bromo atom, by reaction with an
aryl or heterocyclic trialkyltin (IV) reagent. These reactions are
typically effected in the presence of a palladium catalyst such as
tetrakis(triphenylphosphine)pall- adium (0), palladium (II)
acetate, or palladium (II) chloride bis(acetonitrile) also in the
presence of a solvent such as N,N-dimethylformamide and at an
elevated temperature, preferably 90.degree. C. The desired aryl or
heterocyclic trialkyltin (IV) reagent may be obtained commercially
or may be readily prepared by a person skilled in the art.
[0154] The protecting groups may be removed by conventional
chemical techniques well known to a skilled person.
[0155] Compounds of formula (I) wherein any of R.sup.6-R.sup.18 is
a hydroxy group or R.sup.6-R.sup.11 is either a hydroxy group or a
fluorine atom and R.sup.1-R.sup.5 are as hereinbefore defined may
be prepared from a corresponding compound of formula (I) wherein
any of R.sup.6-R.sup.18 is a protected hydroxy group or
R.sup.6-R.sup.11 is a protected hydroxy group or a fluorine atom.
Conventional protecting groups may be used for R.sup.6-R.sup.18.
Advantageously, ester groups such as those described above in
relation to the esters of compounds of formula (I) may be used.
These protecting groups may be removed either by conventional
chemical techniques such as sodium carbonate in water and methanol
or enzymatically, for example, using pig liver esterase.
Alternatively, R.sup.6-R.sup.18 may include silyl ethers such as
tert-butyldiphenyl-, tert-butyldimethyl-, and triisopropylsilyl
ethers which may be deprotected to give a hydroxyl group using an
appropriate fluoride source, for example HF/pyridine, Bu.sub.4NF or
Et.sub.4NF or a cyclic acetal or ketal such as benzylidene or
isopropylidene which can be removed under acidic conditions, for
example, using tosic acid and methanol.
[0156] Alternatively, the compounds of formula (I) where any of
R.sup.6-R.sup.18 is a protected hydroxy group or R.sup.6-R.sup.11
is either a protected hydroxy group or a fluorine atom and R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 are as hereinbefore defined may be
reacted with an agent or under conditions whereby the leaving group
R.sup.1 is converted to the desired R.sup.1 group simultaneously
with removal of the protecting groups. Examples of such agents
include cyclopropylamine and other primary and secondary amines
providing that these agents are sufficiently nucleophilic and are
not sterically hindered.
[0157] B. Compounds of formula (I) wherein R.sup.1 is as
hereinbefore defined may be prepared by reaction of a compound of
formula (IV) wherein R.sup.1 is as hereinbefore defined and
R.sup.2, R.sup.3, and R.sup.4 are as hereinbefore defined, with a
compound of formula (V), wherein R.sup.5-R.sup.18 are as
hereinbefore defined and protected when appropriate and L is as
hereinbefore described. The reaction of compounds of formula (IV)
with those of formula (V) may be effected using a Lewis acid such
as trimethylsilyl trifluoromethanesulfonate, stannic chloride, or
boron trifluoride, the former being preferred. The reaction is
generally effected in an aprotic solvent and at an elevated
temperature, for example, in acetonitrile at 15-30.degree. C. or
1,2-dichloroethane at 70-90.degree. C. Alternatively, the reactions
of compounds of formula (IV) with those of formula (V) may be
effected by applying procedures of pyrimidine nucleoside synthesis
as described and referenced by Tohru Ueda in Chemistry of
Nucleosides and Nucleotides, vol. 1 (Leroy B. Townsend, ed.) pp.
1-112, Plenum Press, New York, 1988 or purine nucleoside synthesis
as described and referenced by Prem C. Srivastva, Roland K. Robins
and Rich B. Meyer, Jr., ibid, pp. 113-281 or pyranose nucleoside
synthesis as described and referenced by P. Herdewiijn, A. Van
Aerschot, J. Balzarini and E. De Clerq in Nucleosides and
Nucleotides, Volume 10, 1991, pp. 119-127, and U.S. Pat. No.
5,399,580, incorporated herein by reference hereto.
[0158] The compound of formula (IV) is advantageously
trimethylsilylated at the N.sub.1-position in the above procedures
to improve solubility; for example, by treatment with
trimethylsilylchloride, hexamethyl disilazane or, most preferably,
N,O-bis(trimethylsilyl)acetamide (BSA). The silylation can be
effected in a solvent, preferably 1,2-dichtoroethane or
acetonitrile, preferably at 70-80.degree. C. After completion of
the silylation reaction, a Lewis acid may be added, followed by the
addition of the compound of formula (V).
[0159] Compounds of formula (Va) may be purchased, for example,
from Aldrich (Milwaukee, Ill.) or Pfanstiehl (Waukegan, Ill.) or
may be prepared by literature methods well known to persons skilled
in the art, for example J. Barbat et al, Carbohydrate Research, 116
(1983), pp. 312-316; M. Fuertes et al., J. Org. Chem., 40 (1975),
pp. 2372-2377; L. Lemer et al. , J. Med. Chem., 30 (1987), pp.
1521-1525.
[0160] Compounds of formula (Va) in which R.sup.5 is as
hereinbefore defined and only one of R.sup.6-R.sup.11 is an
unprotected hydroxyl and L is methoxy may undergo deoxygenation via
a phenyl thiocarbonate prepared by reaction of the previous free
hydroxyl with a chlorothionoformate such as
phenylchlorothioformate. The intermediate thionocarbonate is
removed via a reductant, such as tributyltin hydride. This reaction
is typically effected in the presence of a radical initiator,
2,2'-azobisisobutyronitr- ile, for example, and in the presence of
an aromatic solvent, toluene for example. This intermediate can
then eventually be converted to a compound of formula (Va) in which
hydroxyls are protected as esters, acetyl esters for example, by
reaction with an acid, acetic acid for example, and an acylating
agent, acetic anhydride for example. This reaction is typically
effected in the acylating agent as solvent at 0-100.degree. C.
alternatively, deoxygenation may be effected. for example, as
described by P. Collins and R. Ferrier in Monosaccharides (1995),
John Wiley & Sons, New York, p. 213, and references
therein.
[0161] Fluorinated compounds of formula (Va) may be prepared by
methods known to one skilled in the art, for example, by reaction
of an unprotected hydroxyl group of a compound of formula (Va) with
a fluorinating agent, diethylaminosulfur trifluoride for example.
This reaction is typically effected in an aprotic solvent, such as
chloroform or toluene, and at an elevated temperature,
advantageously 75.degree. C. Fluorinated and other halogenated
deoxy sugars of formula (Va) may also be prepared in analogous
fashion as described for like and different carbohydrates by P.
Collins and R. Ferrier in Monosaccharides (1995), John Wiley &
Sons, New York, pp. 248-262 and references therein.
[0162] Compounds of formula (Va) in which R.sup.5 is as
hereinbefore defined and only one of R.sup.6-R.sup.11 is an
unprotected hydroxy may be oxidized to a ketone by methods known to
persons skilled in the art, for example methods described or
referenced by R. C. Petter et al. in Tetrahedron Letters, 30
(1989), pp. 659-662, S. Czernecki et al. in Tetrahedron Letters, 26
(1985), pp. 1699-1702, or M. Hudlicky in Oxidations in Organic
Chemistry ACS Monograph 186 (1990), American Chemical Society,
Washington D.C. Such ketone compounds may be treated with
appropriate Grignard reagents or alkyl metal reagents and carbon
nucleophiles to effect alkylation to give a new compound of formula
(Va), for example, as described by P. Collins and R. Ferrier in
Monosaccharides (1995), John Wiley & Sons, New York, p. 3092
and references therein. Additionally Wittig reagents may be
employed to prepare olefins of formula (Va), for example, as
described by P. Collins and R. Ferrier, ibid, p. 263 and references
therein or as described by R. C. Petter et al. in Tetrahedron
Letters, 30 (1989), pp. 659-662. Hydroboration-oxidation of olefins
of formula (Va) using procedures described by H. Redlich et al. in
Synthesis, (1992), pp. 112-1118 or as described by Acton et al. in
the Journal of Medicinal Chemistry, 22 (1972), pp. 518-526, leads
to hydroxyl methyl derivatives of formula (Va). Additionally,
hydride reagents may be used to effect inversion of hydroxyl
stereochemistry of R.sup.6-R.sup.11 from such a described ketone by
methods known to persons skilled in the art and using commonly
accepted appropriate practices of carbonyl reduction as those
described by M. Hudlicky in Reductions in Organic Chemistry ACS
Monograph 188 (1996), American Chemical Society, Washington, D.C.,
pp. 149-190.
[0163] Compounds of formula (Vb) and (Vc) may be made by methods
known to persons skilled in the art.
[0164] Compounds of formula (IV), wherein R.sup.1 is hydrogen or a
halo atom, most preferably chloro or bromo, and R.sup.2, R.sup.3,
and R.sup.4 are as hereinbefore defined, may be prepared in
accordance with the methods described in PCT specification
WO92/07867 incorporated herein by reference. Alternatively,
compounds of formula (IV), wherein R.sup.1 is hydrogen or a halo
atom, most preferably chloro or bromo, and R.sup.2, R.sup.3, and
R.sup.4 are as hereinbefore defined, may be prepared in accordance
with the methods described by Leroy Townsend, et al. J. Med. Chem.,
Vol. 38, 1995, pg. 4098.
[0165] Alternatively, compounds of formula (IV) wherein R.sup.1 is
--NR.sup.19R.sup.20, wherein R.sup.19 and R.sup.20 are as
hereinbefore defined, may be prepared by reacting a compound of
formula (VI) 8
[0166] wherein R.sup.2, R.sup.3, and R.sup.4 are as hereinbefore
defined, with an agent capable of cyclizing the diamine into a
benzimidazole. Typically, compounds of formula (VI) may be reacted
with an isothiocyanate of formula (VII)
S.dbd.C.dbd.NR.sup.19 (VII)
[0167] wherein R.sup.19 is as hereinbefore defined. The reaction
may be carried out in the presence of an agent to promote
cyclization such as methyl iodide or a carbodiimide such as
dicyclohexyl carbodiimide or
1-cyclohexyl-3-2-morpholinoethyl)carbodiimide
metho-p-toluenesulfonate in the presence of an aprotic aromatic
solvent such as toluene and most preferably pyridine and at an
elevated temperature, preferably 75-150.degree. C.
[0168] Compounds of formula (VII) may be prepared by methods well
known to a skilled person or readily available in the chemical
literature or obtained commercially.
[0169] Compounds of formula (IV) wherein R.sup.1 is hydrogen may be
obtained commercially or alternatively may be prepared by reacting
a compound of formula (VI) wherein R.sup.2, R.sup.3, and R.sup.4
are as hereinbefore defined with formamidine or most preferably
formic acid at ambient temperature to 100.degree. C.,
advantageously 80.degree. C.
[0170] Compounds of formula (VI) may be obtained commercially or
may be prepared by methods known to persons skilled in the art or
readily available in the chemical literature.
[0171] Alternatively, compounds of formula (VI) may be conveniently
prepared from compounds of formula (VII) 9
[0172] wherein R.sup.2, R.sup.3 , and R.sup.4 are as hereinbefore
defined, in the presence of a most preferably hydrochloric acid,
and in the presence of a solvent such as ethyl alcohol and in the
temperature range of 50-78.degree. C. (B. Fox and T. L. Threlfall,
Org. Syn. Coll. Vol. 5, 1973, p. 346). Alternatively, such ortho
phenylenediamines may be prepared in the presence of a reducing
agent such as Raney nickel also in the presence of hydrogen. This
reaction is also run in the presence of a solvent, ethyl alcohol
for example, at ambient temperature (K. Dimroth, et al, Org. Syn.
Coll. Vol. 5, 1973, p.1130). Alternatively, such ortho
phenylenediamines may be prepared in the presence of a reducing
agent such as sodium hydrosulfite. Typically this reaction is
effected in the presence of a polar, protic solvent, preferably a
mixture of water and ethanol, and at an elevated temperature,
preferably reflux.
[0173] Compounds of formula (VIII) may be prepared by methods well
known to a skilled person or are readily available commercially.
Alternatively, compounds of formula (VIII), where R.sup.2 is a
halogen atom such as fluorine, chlorine or bromine atom, and
R.sup.3 and R.sup.4 are as hereinbefore defined, may be prepared
from compounds of formula (VIII) wherein R.sup.2 is hydrogen by
reaction with an appropriate halogenating agent such as
1-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate),
N-chlorosuccinimide or N-bromosuccinimide, in the presence of an
aprotic solvent such as acetonitrile or N,N-dimethylformamide and
at an elevated temperature from 50-100.degree. C.
[0174] Alternatively, compounds of formula (VII) wherein R.sup.4 is
--SR.sup.24 (wherein R.sup.24 is as hereinbefore defined) may be
prepared from compounds of formula (VII) wherein R.sup.4 is a halo
atom and R.sup.2 and R.sup.3 are as hereinbefore defined by
reaction with HSR.sup.24. This reaction is typically effected in
the presence of a strong base such as sodium or potassium hydride
and in the presence of a solvent such as dimethylsulfoxide, most
preferably N,N-dimethylformamide at ambient temperatures.
[0175] Alternatively, compounds of formula (VII) may advantageously
be prepared from compounds of formula (IX), 10
[0176] wherein R.sup.25 is hydrogen, R.sup.26 is a protecting group
such as an amide, trifluoroacetamide for example, and R.sup.2,
R.sup.3, and R.sup.4 are as hereinbefore defined, by reaction with
a nitrating agent such as nitric acid. This reaction is effected in
a solvent such as sulfuric acid at temperatures of -20 to
25.degree. C., most preferably at 0.degree. C. The protecting
group, R.sup.26, may be conveniently removed at the end of the
reaction sequence with either acid, 2 normal sulfuric acid for
example, or base, sodium carbonate in methanol and water for
example, at temperatures of 25-100.degree. C.
[0177] Compounds of formula (IX) wherein R.sup.25 is hydrogen and
R.sup.26 is a protecting group such as an amide, trifluoroacetamide
for example, and R.sup.2, R.sup.3 and R.sup.4 are as hereinbefore
defined, may be prepared from compounds of formula (IX) wherein
R.sup.25 and R.sup.26are hydrogen and R.sup.2, R.sup.3 and R.sup.4
are as hereinbefore defined by reaction with an appropriate
acylating agent such as trifluoroacetic anhydride. These reactions
are effected in the presence of an aprotic solvent such as
acetontrile, most preferably 1,4-dioxane, from -10 to 40.degree.
C., advantageously at 0.degree. C.
[0178] Alternatively, compounds of formula (VIII) in which R.sup.2,
R.sup.3 and R.sup.4 are as hereinbefore defined can be prepared
from compounds of formula (X) 11
[0179] wherein R.sup.27 is a halo atom, fluoro or chloro atom for
example, by reaction with ammonia. These reactions are typically
effected in the presence of a solvent such as ethyl alcohol or
1,4-dioxane and at elevated temperatures, advantageously
100.degree. C.
[0180] Compounds of formula (IX) in which R.sup.25 and R.sup.26 are
hydrogen and R.sup.2, R.sup.3 and R.sup.4 are as hereinbefore
defined may be prepared by methods well known to a skilled person
or readily available in the chemical literature or obtained
commercially.
[0181] Compounds of formula (X) may be obtained commercially or may
be readily prepared by a person skilled in the art.
[0182] Compounds of formula (I) wherein Z is a substituent of
formula (Ib) may be made according to Scheme I or by any method
known to persons skilled in the art. 12
[0183] Compounds of formula (I) wherein Z is a substituent of
formula (Vb) or (Vc) may be made according to U.S. Pat. Nos.
5,399,580, 5,534,535 and WO96/07646, incorporated herein by
reference hereto.
[0184] The compounds according to the invention, also referred to
herein as the active ingredient, may be administered for therapy by
any suitable route including oral, rectal, nasal, topical
(including transdermal, buccal and sublingual), vaginal and
parenteral (including subcutaneous, intramuscular, intravenous,
intradermal, and intravitreal). It will be appreciated that the
preferred route will vary with the condition and age of the
recipient, the nature of the infection and the chosen active
ingredient.
[0185] In general a suitable dose for each of the above-mentioned
conditions will be in the range of 0.01 to 250 mg per kilogram body
weight of the recipient (e.g. a human) per day, preferably in the
range of 0.1 to 100 mg per kilogram body weight per day and most
preferably in the range 0.5 to 30 mg per kilogram body weight per
day and particularly in the range 1.0 to 20 mg per kilogram body
weight per day. Unless otherwise indicated, all weights of active
ingredient are calculated as the parent compound of formula (I);
for salts or esters thereof, the weights would be increased
proportionally. The desired dose may be presented as one, two,
three, four, five, six or more sub-doses administered at
appropriate intervals throughout the day. In some cases the desired
dose may be given on alternative days These sub-doses may be
administered in unit dosage forms, for example, containing 10 to
1000 mg or 50 to 500 mg, preferably 20 to 500 mg, and most
preferably 100 to 400 mg of active ingredient per unit dosage
form.
[0186] While it is possible for the active ingredient to be
administered alone it is preferable to present it as a
pharmaceutical formulation. The formulations of the present
invention comprise at least one active ingredient, as defined other
therapeutic agents. Each carrier must be "acceptable" in the sense
of being compatible with the other ingredients of the formulation
and not injurious to the patient.
[0187] Formulations include those suitable for oral, rectal, nasal,
topical (including transdermal, buccal and sublingual), vaginal or
parenteral (including subcutaneous, intramuscular, intravenous,
intradermal, and intravitreal) administration. The formulations may
conveniently be presented in unit dosage form and may be prepared
by any methods well known in the art of pharmacy. Such methods
represent a further feature of the present invention and include
the step of bringing into association the active ingredients with
the carrier which constitutes one or more accessory ingredients. In
general, the formulations are prepared by uniformly and intimately
bringing into association the active ingredients with liquid
carriers or finely divided solid carriers or both, and then if
necessary shaping the product.
[0188] The present invention further includes a pharmaceutical
formulation as hereinbefore defined wherein a compound of formula
(I) or a pharmaceutically acceptable derivative thereof and at
least one further therapeutic agent are presented separately from
one another as a kit of parts.
[0189] Compositions suitable for transdermal administration may be
presented as discrete patches adapted to remain in intimate contact
with the epidermis of the recipient for a prolonged period of time.
Such patches suitably contain the active compound 1) in an
optionally buffered, aqueous solution or 2) dissolved and/or
dispersed in an adhesive or 3) dispersed in a polymer. A suitable
concentration of the active compound is about 1% to 25%, preferably
about 3% to 15%. As one particular possibility, the active compound
may be delivered from the patch by electrotransport or
iontophoresis as generally described in Pharmaceutical Research 3
(6), 318 (1986).
[0190] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
caplets, cachets or tablets each containing a predetermined amount
of the active ingredients; as a powder or granules; as a solution
or a suspension in an aqueous or non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The
active ingredient may also be presented as a bolus, electuary or
paste.
[0191] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active
ingredients in a free-flowing form such as a powder or granules,
optionally mixed with a binder (e.g. povidone, gelatin,
hydroxypropylmethyl cellulose), lubricant, inert diluent,
preservative, disintegrant (e.g. sodium starch glycollate,
cross-linked povidone, cross-linked sodium carboxymethyl cellulose)
surface-active or dispersing agent. Molded tablets may be made by
molding a mixture of the powdered compound moistened with an inert
liquid diluent in a suitable machine. The tablets may optionally be
coated or scored and may be formulated so as to provide slow or
controlled release of the active ingredients therein using, for
example, hydroxypropylmethyl cellulose in varying proportions to
provide the desired release profile. Tablets may optionally be
provided with an enteric coating, to provide release in parts of
the gut other than the stomach.
[0192] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredients in a
flavored base, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0193] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising, for example, cocoa
butter or a salicylate.
[0194] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0195] Pharmaceutical formulations suitable for rectal
administration wherein the carrier is a solid are most preferably
presented as unit dose suppositories. Suitable carriers include
cocoa butter and other materials commonly used in the art. The
suppositories may be conveniently formed by admixture of the active
combination with the softened or melted carrier(s) followed by
chilling and shaping in molds.
[0196] Formulations suitable for parenteral administration include
aqueous and nonaqueous isotonic sterile injection solutions which
may contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents; and liposomes
or other microparticulate systems which are designed to target the
compound to blood components or one or more organs. The
formulations may be presented in unit-dose or multi-dose sealed
containers, for example, ampoules and vials, and may be stored in a
freeze-dried (lyophilized) condition requiring only the addition of
the sterile liquid carrier, for example water for injection,
immediately prior to use. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and
tablets of the kind previously described.
[0197] Preferred unit dosage formulations are those containing a
daily dose or daily subdose of the active ingredients, as
hereinbefore recited, or an appropriate fraction thereof.
[0198] It should be understood that in addition to the ingredients
particularly mentioned above the formulations of this invention may
include other agents conventional in the art having regard to the
type of formulation in question, for example, those suitable for
oral administration may include such further agents as sweeteners,
thickeners and flavoring agents.
[0199] The following examples are intended for illustration only
and are not intended to limit the scope of the invention in any
way. "Active ingredient" denotes a compound according to the
invention or multiples thereof or a physiologically functional
derivative of any of the aforementioned compounds.
GENERAL PROCEDURES
General Procedure I: Reduction of Substituted Nitroanilines to
Substituted Phenylenediamines
[0200] The appropriate substituted nitroaniline (115-145 mmol),
ethanol and Raney nickel (7-8 g wet) (Aldrich, Milwaukee) were
combined in a stirred Parr reactor which was pressurized with
hydrogen (between 200 and 300 psig). The mixture was allowed to
stir at rt overnight, after which time the reactor was
depressurized and the mixture was filtered through Celite and the
solvents were removed in vacuo to yield a solid appropriate for
ring closure to a benzimidazole as describe in General Procedure
II.
General Procedure II: Synthesis of Substituted Benzimidazole Bases
from Substituted Phenylenediamines
[0201] To the appropriate substituted phenylenediamine dissolved in
enough aqueous 4N HCl to make a 100 mM solution was added 1.25-1.3
equivalents/phenylenediamine of aqueous 88% formic acid. The
resulting solution was refluxed between 3 and 18 h followed by
cooling to rt and neutralization to pH 7, as determined by
indicator paper, with either aqueous sodium nydioxide or ammonium
hydroxide. The resulting solid was filtered into a sintered glass
funnel, washed with copious amounts of water, air dried then vacuum
dried at 50.degree. C. for 24 h or longer. Benzimidazoles thus
prepared were suitable for coupling to peracetylated
ribopyranose.
General Procedure III: Coupling of 2-bromo-1H-benzimidazoles or
2-unsubstituted benzimidazoles with peracetylated pyranoses
[0202] The appropriate benzimidazole was magnetically stirred under
a nitrogen atmosphere in an oven dried round bottomed flask
equipped with a stir bar and reflux condenser in anhydrous
1,2-dichloroethane (Aldrich, Milwaukee) or acetonitrile (Aldrich,
Milwaukee). To the stirring suspension was added 1
equivalent/benzimidazole of N,O-bis(trimethylsilyl)acetamide and
the resulting mixture was refluxed for 1 to 3 h. The resulting
solution was allowed to cool to rt. To this solution was added 1
equivalent/benzimidazole of a peracetylated pyranose followed by
0.50 to 1.1 equivalent/benzimidazole of trimethylsilyl
trifluoromethanesulfonate (Aldrich, Milwaukee) or 1.4 to 5
equivalents stannic chloride/benzimidazole from a 1 M solution in
dichloromethane (Aldrich, Milwaukee). The new mixture was then
heated in an oil bath ca. 85.degree. C. between 0.5 to 24 h as
determined by conversion of starting material to product(s) by TLC.
Reactions were quenched by pouring the reaction into ca. 7% aqueous
sodium bicarbonate and extraction with dichloromethane or ethyl
acetate until product was not apparent in the aqueous layer. The
organic layer was dried over magnesium sulfate, filtered and
solvent removed using a rotrary evaporator. The products were
further purified by silica gel column chromatography.
General Procedure IV: Bromination of N-1 Benzimidazole Pyranosides
Unsubstituted at C-2
[0203] Typically a benzimidazole pyranoside unsubstituted at C-2
was dissolved in refluxed in a rb with an attached reflux condenser
and magnetic stirring under a nitrogen atmosphere by an oil bath at
ca. 85.degree. C. 2 equivalents/benzimidazole pyranoside of
N-bromosuccinimide (NBS, Aldrich, Milwaukee) was added every 15 min
to the refluxing solution until bromination of starting material
was complete as evidenced by TLC. The reaction was quenched by
pouring into cold 7% aqueous sodium bicarbonate and extraction with
dichloromethane until product was not apparent in the aqueous
layer. The dichloromethane layer was further washed with 4
equivalent volumes of aqueous sodium bicarbonate then 1 volume of
water. The organic layer was dried over magnesium sulfate, filtered
and solvent removed using a rotrary evaporator. The products were
further purified by silica gel column chromatography.
General Procedure V: Deprotection of N-1 2-Bromobenzimidazole
Acetylated Pyranosides by 1M Aqueous Lithium Hydroxide
[0204] The appropriate N-1 2-bromobenzimidazole acetylated
pyranoside was dissolved in enough dioxane to make a solution
between 100 and 200 mM. To the solution was added 1.3
equivalents/acetate to be deblocked of aqueous 1M LiOH. The mixture
was allowed to stir between 0.25 and 1 h followed by the addition
of enough pH 7 phosphate buffer (VWR, West Chester) to make the
resulting solution neutral as shown by pH indicator strips. The
mixture was extracted with ethyl acetate until product was not
present in the aqueous layer as indicated by TLC. The ethyl acetate
layer was washed with 1 equal volume of water, then dried over
magnesium sulfate, filtered and solvent removed using a rotary
evaporator. Products were further purified by trituration of the
solid in dichloromethane and collection of the solid by vacuum
filtration onto a sintered glass funnel.
General Procedure VI: Deprotection of N-1 2-Bromobenzimidazole
Acetylated Pyranosides by Sodium Carbonate in 4:4:1
Ethanol:Methanol:Water Mixture
[0205] Every 100 mg of the appropriate N-1 2-bromobenzimidazole
acetylated pyranoside was dissolved in 4 ml of methanol followed by
the addition of an equivalent volume of ethanol. 2.2 equivalents of
sodium carbonate/acetate to be deprotected was added dropwise to
the alcoholic solution in an aqueous solution one-fourth the volume
of methanol previously used. The suspension was allowed to stir
between 2 and 24 h. When TLC indicated that deprotection of
acetates from the pyranoside was complete, the suspension was
filtered, diluted with water and the solution made neutral with
acetic acid as demonstrated by pH indicator paper. The mixture was
partitioned between ethyl acetate and water. The aqueous layer was
repeatedly extracted with ethyl acetate until all product was in
the organic layer. The combined ethyl acetate extracts were dried
over magnesium sulfate, filtered and evaporated on a rotary
evaporator. Products were further purified by trituration of the
resulting solid in dichloromethane and collection of the new solid
by vacuum filtration onto a sintered glass funnel.
SYNTHETIC EXAMPLES
Example 1
2-Bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzim-
idazole
[0206] As described in General Procedure III,
2-bromo-5,6-dichlorobenzimid- azole (4.0 g, 15 mmol),
N,O-bis(trimethylsiyl)acetamide (Aldrich, 3.7 ml, 15 mmol), and
1,2-dichloroethane (Aldrich Sure Seal, 75 ml) were combined and
refluxed under nitrogen for 0.5 h. The solution was cooled to room
temperature and trimethylsilyl triflate (Aldrich, 3.2 ml, 16 mmol)
was added. Immediately, 4.8 g (15 mmol) solid
1,2,3,4-tetra-O-acetyl-b-D-ribo- pyranose (beta-D-ribopyranose
1,2,3,4-tetraacetate, Aldrich, Milwaukee) was added. The solution
was stirred under nitrogen at reflux for 0.5 h, then poured into 7%
aqueous sodium bicarbonate and extracted with dichloromethane. The
organic layers was dried with magnesium sulfate (anhyd.), filtered,
and evaporated. The crude residue was purified on a silica gel
column (5.times.20 cm, 230-400 mesh) with CH.sub.2Cl.sub.2 to give
2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H--
benzimidazole which was fractionated in two parts based on elution.
The faster product fraction was impure (1.9 g) and purified by a
second column to give 1.4 g (2.7 mmol); the slower product fraction
was (3.0 g, 5.7 mmol) for a total yield of 56%; m.p.
100-110.degree. C.; .sup.1H NMR (DMSO-d.sub.6) .delta.8.39 (s, 1H),
7.91 (s, 1H), 5.95-5.92 (d, 1H, J=9.6 Hz), 5.73-5.70 (d, 1H, J=9.6
Hz), 5.67 (bs, 2H), 4.13-4.09 (dd, 1H, J=6.3 Hz and J=5.8 Hz),
4.00-3.95 (overlapping dd, 1H), 2.19 (s, 3H), 1.98 (s, 3H), 1.74
(s, 3H).
[0207] Anal. Calcd. for C.sub.18H.sub.17N.sub.2O.sub.7Cl.sub.2Br:
C, 41.25; H, 3.27; N, 5.34. Found: C, 41.35; H, 3.28; N, 5.38.
Example 2
2-Bromo-5,6-dichloro-1-beta-D-ribopyranosyl-1H-benzimidazole
[0208] 3.0 g (5.7 mmol)
2-Bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-beta-D--
ribopyranosyl)-1H-benzimidazole was deprotected as outlined in
General Procedure V by being dissolved in 60 ml dioxane and the
resultant solution cooled in an ice bath between 0 and 5.degree. C.
To this solution was added all at once, 22 ml (22 mmol) of 1M aq.
LiOH. The mixture was removed from the ice bath and allowed to stir
at ambient temperature for 1 h. The mixture was diluted with 120 ml
of pH 7 phosphate buffer and extracted with ethyl acetate. The
ethyl acetate layer was dried over magnesium sulfate (anhyd.),
filtered and solvents evaporated. The residue was triturated in
dichloromethane and 1.7 g (4.3 mmol, 75% yield) of
2-bromo-5,6-dichloro-1-beta-D-ribopyranosyl-1H-benzim- idazole was
collected by vacuum filtration. The product was dried in a vacuum
oven at 50.degree. C. overnight; m.p. 175.degree. C. (decomposes);
.sup.1H NMR (DMSO-d.sub.6) .delta.7.96 (s, 1H), 7.07 (s, 1H),
5.64-5.62 (d, J=9.2 Hz), 5.19-5.17 (d, 1H, J=6.4 Hz), 5.13-5.12 (d,
1H, J=3.2 Hz), 4.86-4.84 (d, 1H, J=6.5 Hz), 4.12-4.06 (m, 1H),
3.98-3.92 (m, 2H), 3.68-3.63 (m, 2H).
[0209] Anal. Calcd. for C.sub.12H.sub.11N.sub.2O.sub.4Cl.sub.2Br:
C, 36.21; H, 2.79; N, 7.04. Found: C, 36.18; H, 2.91; N, 6.88.
Example 3
5,6-Dichloro-N-1(1-methylethyl)-1-beta-D-ribopyranosyl-1H-benzimidazole-2--
amine
[0210] 2-Bromo-5,6-dichloro-1-beta-D-ribopyranosyl-1H-benzimidazole
(0.15 g, 0.29 mmol) was dissolved in 5 ml of absolute ethanol,
treated with 5 ml of isopropylamine (Fluka, Ronkonkoma, N.Y.),
heated in a glass pressure tube (Ace, Vineland, N.J.) and stirred
with a magnetic stir bar. The tube was sealed with a screw cap and
heated in an oil bath at 85.degree. C. for 3 days. At this time,
TLC indicated complete conversion of starting material and the
solvents were removed on a rotary evaporator. The product residue
was triturated in dichloromethane to give
5,6-dichloro-N-1(1-methylethyl)-1-beta-D-ribopyranosyl-1H-benzimidazole-2-
-amine (0.070 g, 0.19 mmol, 66% yield) as a tan solid;. MS (EI+):
m/z (rel. intensity) 375.9 (1.0, M.sup.+); .sup.1H NMR
(DMSO-d.sub.6) .delta.7.37 (s, 1H), 7.33 (s, 1H), 6.47-6.45 (d, 1H,
J=7.5 Hz), 5.36-5.34 (d, 1H, J=9.1 Hz), 5.08-5.07 (d, 1H, J=3.2
Hz), 4.93-4.91 (d, 1H, J=7.7 Hz), 4.84-4.82 (d, 1H, J=6.5 Hz),
4.10-3.90 (overlapping m, 3H), 3.90-3.80 (m, 1H), 3.71-3.65
(overlapping dd, 1H), 3.62-3.59 (dd, 1H), 3.14-3.13 (d, 1H, J=5.1
Hz), 1.19-1.17 (d, 1H, J=6.5 Hz).
Example 4
2-Bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-beta-L-ribopyranosyl)-1H-benzim-
idazole
[0211] As described in General Procedure III,
2-bromo-5,6-dichlorobenzimid- azole (2.0 g, 7.6 mmol),
N,O-bis(trimethylsiyl)acetamide (Aldrich, 1.9 ml, 7.6 mmol), and
acetonitrile (Aldrich Sure Seal, 75 ml) were combined and refluxed
under nitrogen for 0.5 h. The solution was cooled to room
temperature and a 1.0 M solution of stannic chloride in
dichloromethane (Aldrich, 15.2 ml, 15 mmol) was added. Immediately,
2.4 g (7.6 mmol) solid 1,2,3,4-tetra-O-acetyl-beta-L-ribopyranose
(as prepared and described for the D-tetraacetate by H. M. Kissman,
C. Pidacks and B. R. Baker in J. Am. Chem. Soc. 1955, 77, 18-24; mp
110.degree. C.) was added. The solution was stirred under nitrogen
at reflux for overnight, then poured into 7% aqueous sodium
bicarbonate and extracted with ethyl acetate. The organic layer was
dried with magnesium sulfate (anhyd), filtered, and evaporated. The
crude residue was purified on a silica gel column (2.5.times.20 cm,
230-400 mesh) with hexanes and a step gradient from 10 to 20% ethyl
acetate to give 2-bromo-5,6-dichloro-1-(2,3,4-tri-O--
acetyl-beta-L-ribopyranosyl)-1H-benzimidazole (1.61 g, 3.1 mmol,
40%); MS (API+): m/z (rel. intensity) 524 (0.17, M.sup.+); .sup.1H
NMR (DMSO-d.sub.6) .delta.8.39 (s, 1H), 7.91 (s, 1H), 5.95-5.92 (d,
1H, J=9.6 Hz), 5.73-5.70 (d, 1H, J=9.6 Hz), 5.67 (bs, 2H),
4.13-4.09 (dd, 1H, J=6.3 Hz and J=5.8 Hz), 4.00-3.95 (overlapping
dd, 1H), 2.19 (s, 3H), 1.98 (s, 3H), 1.74 (s, 3H).
Example 5
2-Bromo-5,6-dichloro-1-beta-L-ribopyranosyl-1H-benzimidazole
[0212] An alcoholic solution of
2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-
-beta-L-ribopyranosyl)-1H-benzimidazole (0.50 g, 0.95 mmol) was
deprotected according to General Procedure VI with 0.61 g (5.8
mmol) of sodium carbonate in 5 ml of water. After stirring
overnight at ambient temperature, the mixture was filtered and
treated as described in General Procedure VI to give
2-bromo-5,6-dichtoro-1-beta-L-ribopyranosyl-1H-benzi- midazole
(0.27 g, 0.68 mmol, 72% yield); MS (API+): m/z (rel. intensity) 398
(1.0, M.sup.+); .sup.1H NMR (DMSO-d.sub.6) .delta.7.96 (s, 1H),
7.07 (s, 1H), 5.64-5.62 (d, J=9.2 Hz), 5.19-5.17 (d, 1H, J=6.4 Hz),
5.13-5.12 (d, 1H, J=3.2 Hz), 4.86-4.84 (d, 1H, J=6.5 Hz), 4.12-4.06
(m, 1H), 3.98-3.92 (m, 2H), 3.68-3.63 (m, 2H).
Example 6
5,6-Dichloro-N-1(1-methylethyl)-1-beta-L-ribopyranosyl-1H-benzimidazole-2--
amine
[0213]
2-Bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-beta-L-ribopyranosyl)-1H-
-benzimidazole (1.0 g, 1.9 mmol) was dissolved in 5 ml of ethanol
and treated with 8 ml of isopropylamine in a glass pressure tube
(Ace) with a magnetic stir for 3 days. At this time, TLC indicated
complete conversion of starting material and the solvents were
removed on a rotary evaporator. The product residue was triturated
in dichloromethane to give
5,6-dichloro-N-1(1-methylethyl)-1-beta-D-ribopyranosyl-1H-benzimidazole-2-
-amine (0.070 g, 0.19 mmol, 66% yield) as a white solid; MS (API+):
m/z (rel. intensity) 376 (1.0, M.sup.+); .sup.1H NMR (DMSO-d.sub.6)
.delta.7.37 (s, 1H), 7.33 (s, 1H), 6.476-6.45 (d, 1H, J=7.0 Hz),
5.36-5.34 (d, 1H, J=8.8 Hz), 5.08-5.07 (d, 1H, J=2.4 Hz), 4.93-4.91
(d, 1H, J=7.7 Hz), 4.84-4.82 (d, 1H, J=6.3 Hz), 4.10-3.90 (bs, 3H),
3.90-3.80 (bs, 1H), 3.71-3.65 (overlapping dd, 1H), 3.62-3.59
(overlapping dd, 1H), 1.19-1.17 (d, 1H, J=6.3 Hz).
Example 7
2-Bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-beta-D-xylopyranosyl)-1H-benzim-
idazole
[0214] 2-Bromo-5,6-dichlorobenzimidazole (0.25 g, 0.94 mmol),
N,O-bis(trimethylsiyl) acetamide (Aldrich, 1.4 ml, 5.6 mmol), and
acetonitrile (Aldrich Sure Seal, 20 ml) were combined and
magnetically stirred under a nitrogen atmosphere for 1.5 h. To the
silylated base was added 0.30 g (0.94 mmol)
1,2,3,4-tetra-O-acetyl-xylopyranose (Aldrich, Milwaukee) followed
by stannic chloride (1.4 mmol, 0.12 ml, Aldrich, Milwaukee). The
solution stirred under nitrogen overnight, and additional stannic
chloride (0.35 ml, 4.1 mmol) was added the following day. One hour
after the second addition of stannic chloride, the reaction was
poured into saturated aqueous sodium sulfate, and filtered through
a celite pad which was washed with chloroform and water. The
filtrate layers were separated. The chloroform layer was washed
with 2.times.150 ml saturated aq. sodium bicarbonate then with
1.times.150 ml of water. The organic layer was dried with magnesium
sulfate (anhyd), filtered, and evaporated. The crude residue was
purified on a silica gel column (2.5.times.20 cm, 230-400 mesh)
with hexanes and a step gradient from 0 to 25% ethyl acetate to
give the product, 2-bromo-5,6-dichloro-1-(2,3,4-t-
ri-O-acetyl-beta-D-xylopyranosyl)-1H-benzimidazole (0.13 g, 0.24
mmol, 26%); .sup.1H NMR (DMSO-d.sub.6) .delta.8.47-8.42 (bs, 1H),
7.91 (s, 1H), 6.07-6.02 (bs, 1H), 5.66-5.54 (bs, 3H), 4.18-4.13 (m,
1H), 3.95-3.89 (m, 2H), 2.02 (s, 3H), 1.99 (s, 3H), 1.77 (bs,
3H).
[0215] Anal. Calcd. for C.sub.18H.sub.17N.sub.2O.sub.7Cl.sub.2Br:
C, 41.25; H, 3.27; N, 5.34. Found: C, 41.32; H, 3.29; N, 5.31.
Example 8
2-Bromo-5,6-dichloro-1-beta-D-xylopyranosyl-1H-benzimidazole
[0216] To
2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-beta-D-xylopyranosyl)-
-1H-benzimidazole (0.083 g, 0.16 mmol) magnetically stirring in 7
ml of tetrahydrofuran was added sodium carbonate (0.13 g, 1.2 mmol)
in 1 ml of water. The mixture was allowed to stir at rt for 7 days,
then heated at reflux for 2 h. The mixture was cooled to rt,
neutralized with acetic acid (0.059 ml, 1.0 mmol) and stirred for
an additional 0.5 h at rt. The product,
2-Bromo-5,6-dichloro-1-beta-D-xylopyranosyl-1H-benzimidazole, was
purified on a silica gel column (2.5.times.10 cm, 230-400 mesh)
eluting with ethyl acetate (0.40 g, 0.10 mmol, 63%); m.p.
149.6.degree. C. (decomposes); .sup.1H NMR (DMSO-d.sub.6)
.delta.7.95 (s, 1H), 7.90-7.80 (bs, 1H), 5.48-5.46 (d, J=5.2 Hz),
5.40-5.30 (bs, 1H), 5.23-5.19 (m, 2H), 3.96-3.90 (m, 1H), 3.85-3.50
(2 overlapping bs, 2H), 3.43-3.20 (m, 2H obscured by HOD peak).
Example 9
6-Chloro-5-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazo-
le and
5-Chloro-6-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benz-
imidazole
[0217] As described in General Procedure III,
5-chloro-6methylbenzimidazol- e (1.0 g, 6 mmol),
N,O-bis(trimethylsiyl)acetamide (Aldrich, 1.3 ml, 5.2 mmol), and
1,2-dichloroethane (Aldrich Sure Seal, 30 mL) were combined and
refluxed under nitrogen for 0.5 h. The solution was cooled to room
temperature and trimethylsilyl triflate (Aldrich, 1.3 ml, 6.7 mmol)
was added. Immediately, 2.0 g (6.3 mmol) solid
1,2,3,4-tetra-O-acetyl-b-D-rib- opyranose (beta-D-ribopyranose
1,2,3,4-tetraacetate, Aldrich, Milwaukee) was added. The solution
was stirred under nitrogen at reflux overnight, then poured into 7%
aqueous sodium bicarbonate and extracted with chloroform. The
organic layer was dried with magnesium sulfate (anhyd), filtered,
and evaporated. The crude residue was purified on a silica gel
column (5.times.20 cm, 230-400 mesh) eluting with a step gradient
of 0.25 to 2.5% methanol in chloroform to give 0.07 g (0.16 mmol)
5-Chloro-6-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidaz-
ole; MS (AP+): m/z (rel. intensity) 447 (1.0, M.sup.+23 (Na))
.sup.1H NMR (DMSO-d.sub.6) .delta.8.36 (s, 1H), 7.90 (s, 1H), 7.68
(s, 1H), 5.97-5.95 (d, 1H, J=9.1 Hz), 5.72-5.69 (m, 2H), 5.41-5.40
(m, 1H), 4.02-3.92 (m, 2H), 2.42 (s, 3H), 2.20 (s, 3H), 1.98 (s,
3H), 1.69 (s, 3H) and 0.090 g (0.21 mmol)
6-Chloro-5-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1-
H-benzimidazole .sup.1H NMR (DMSO-d.sub.6) .delta.8.36 (s, 1H),
8.06 (s, 1H), 7.60 (s, 1H), 5.99-5.96 (d, 1H, J=9.6 Hz), 5.73-5.66
(m, 2H), 5.45-5.40 (m, 1H), 4.02-3.92 (m, 2H), 2.37 (s, 3H), 2.20
(s, 3H), 1.98 (s, 3H), 1.69 (s, 3H) and 0.13 g (0.31 mmol) of a
mixture of the two regioisomers (11% total yield).
Example 10
2-Bromo-5-chloro-6-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-ben-
zimidazole
[0218] The title compound was prepared according to General
Procedure IV using)
5-Chloro-6-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-ben-
zimidazole (0.12 g, 0.28 mmol), 20 ml tetrahydrofuran (Aldrich Sure
Seal, Milwaukee), and a total of 2.0 g (11 mmol) of
N-bromosuccinimide that was added over 2 h. The product from
work-up by General Procedure IV was partially purified on a silica
gel column (2.5.times.20 cm, 230-400 mesh) with dichloromethane
containing 0.5% methanol to give
2-Bromo-5-chloro-6-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-be-
nzimidazole (0.097 g) of sufficient purity for the next step;
.sup.1H NMR (DMSO-d.sub.6) .delta.7.99 (s, 1H), 7.66 (s, 1H),
5.93-5.90 (d, 1H, J=8.9 Hz), 5.69-5.62 (m, 3H), 4.02-3.92 (m, 2H),
2.41 (s, 3H), 2.20 (s, 3H), 1.99 (s, 3H), 1.73 (s, 3H)
Example 11
2-Bromo-5-chloro-6-methyl-1-beta-D-ribopyranosyl-1H-benzimidazole
[0219]
2-Bromo-5-chloro-6-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-
-1H-benzimidazole (0.097 g) was deprotected as outlined in General
Procedure V by being dissolved in 5 ml dioxane and the resultant
solution cooled in an ice bath between 0 and 5.degree. C. To this
solution was added all at once, 0.78 ml (0.78 mmol) of 1M aq. LiOH.
The mixture was removed from the ice bath and allowed to stir at
ambient temperature for 0.5 h. The mixture was diluted with 50 ml
of pH 7 phosphate buffer and extracted with ethyl acetate. The
ethyl acetate layer was dried over magnesium sulfate (anhyd.),
filtered and solvents evaporated. The residue was triturated in
dichloromethane and 0.028 g (0.074 mmol) of
2-bromo-5,6-dichloro-1-beta-D-ribopyranosyl-1H-benzimidazole was
collected by vacuum filtration. The product was dried in a vacuum
oven at 50.degree. C. overnight; m.p. 150.degree. C. (foams); MS
(AP+): m/z (rel intensity) 400 (1.0, M.sup.+23 (Na)); .sup.1H NMR
(DMSO-d.sub.6) .delta.7.67 (s, 1H), 7.65 (s, 1H), 5.62-5.60 (d,
J=8.9 Hz), 5.13 (bs, 2H), 4.88-4.87 (m, 1H), 4.13 (bs, 1H), 4.00
(bs, 2H), 3.93 (m, 1H), 2.40 (s, 3H).
Example 12
2-Bromo-6-chloro-5-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-ben-
zimidazole
[0220] The title compound was prepared according to General
Procedure IV using
6-Chloro-5-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benz-
imidazole (0.37 g, 0.87 mmol), 30 ml tetrahydrofuran (Aldrich Sure
Seal, Milwaukee), and a total of 1.2 g (7.0 mmol) of
N-bromosuccinimide that was added in ca 0.2
equivalents/benzimidazole every 15 min over 1 h. The product from
work-up by General Procedure IV was purified on a silica gel column
(2.5.times.20 cm, 230-400 mesh) with dichloromethane containing
0.5% methanol to give
2-Bromo-6-chloro-5-methyl-(2,3,4-tri-O-acetyl-beta--
D-ribopyranosyl)-1H-benzimidazole (0.33 g, 0.66 mmol, 75%); MS
(ES+): m/z (rel. intensity) 526 (1.0, M.sup.+23 (Na)); .sup.1H NMR
(DMSO-d.sub.6) .delta.8.18 (s, 1H), 7.62 (s, 1H), 5.97-5.904 (d,
1H, J=9.4 Hz), 5.78-5.60 (m, 3H), 4.20-4.10 (m, 1H), 4.05-3.97 (m,
1H) 2.41 (s, 3H) 2.25 (s, 3H), 2.04 (s, 3H) 1.78 (s, 3H)
Example 13
2-Bromo-6-chloro-5-methyl-1-beta-D-ribopyranosyl-1H-benzimidazole
[0221]
2-Bromo-6-chloro-5-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-
-1H-benzimidazole (0.097 g) was deprotected as outlined in General
Procedure V by being dissolved in 6 ml dioxane at rt. To this
solution was added all at once, 2.6 ml (2.6 mmol) of 1M aq. LiOH.
The mixture stirred at ambient temperature for 0.25 h. The mixture
was diluted with 50 ml of pH 7 phosphate buffer and extracted with
ethyl acetate. The ethyl acetate layer was dried over magnesium
sulfate (anhyd.), filtered and solvents evaporated. The residue was
triturated in dichloromethane and
2-bromo-6-chloro-5-methyl-1-beta-D-ribopyranosyl-1H-benzimidazole
was collected by vacuum filtration. The product was dried in a
vacuum oven at 50.degree. C. overnight yet still contained 0.2 mol
dichloromethane as evidenced by microanalysis and .sup.1H NMR; 0.15
g (57%); (m.p. 170-175.degree. C. (decomposes); .sup.1H NMR
(DMSO-d.sub.6) .delta.7.76 (s, 1H), 7.62 (s, 1H), 5.67-5.63 (d, 1H,
J=9.3 Hz), 5.20-5.15 (m, 2H), 4.92-4.89 (d, 1H, J=6.6 Hz), 4.15 (m,
1H), 4.05 (bs, 1H), 3.98-3.90 (m, 1H) 3.75-3.70 (m, 2H), 2.42 (s,
3H).
[0222] Anal. Calcd. for C.sub.13H.sub.14N.sub.2O.sub.4ClBr 0.20
CH.sub.2Cl.sub.2: C, 40.18; H, 3.68; N, 7.10. Found: C, 40.16; H,
3.66; N, 7.13
Example 14
6-Chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole
and
5-Chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole
[0223] As per General Procedure III. 5-chloro-1H-benzimidazole (1.0
g, 6.5 mmol), N,O-bis(trimethlsilyl)acetamide (1.6 ml, 6.6 mmol),
in 50 ml 1,2-dichloroethane (Aldrich Sure Seal, Milwaukee) were
heated at 85.degree. C. for 0.75 h under a nitrogen atmosphere then
allowed to cool to rt. Trimethylsilyl trifluoromethanesulfonate
(1.4 ml, 7.2 mmol) and 2.0 g (6.3 mmol) solid
1,2,3,4-tetra-O-acetyl-b-D-ribopyranose (beta-D-ribopyranose
1,2,3,4-tetraacelate, Aldrich, Milwaukee) was added and the mixture
was heated in an oil bath at 85.degree. C. for 24 h under a
nitrogen atmosphere. The reaction was then poured into 7% aqueous
sodium bicarbonate and extracted with dichloromethane. The organic
layer was dried with magnesium sulfate (anhyd), filtered, and
evaporated. The crude residue was purified on a silica gel column
(2.5.times.20 cm, 230-400 mesh) with CH.sub.2Cl.sub.2 and an
increasing gradient of methanol from 0.25 to 0.5% to provide the
title compounds as a mixture of regioisomers. The regioisomers were
separated by HPLC on a semi-preparative Chiralpak OD lot No.
369-712-30802 eluting with a mobile phase of 90% hexanes and 10%
ethanol at a flow rate of 8.0 ml/min and a pressure of 260 psi with
signal detection at 254 nM.
5-Chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole
eluted first (RT=18.8 min) and 0.13 g was obtained after
evaporation of the solvent. .sup.1H NMR (DMSO-d.sub.6) .delta.8.46
(s, 1H), 7.94-7.91 (d, 1H, J=8.7 Hz), 7.71-7.70 (d, 1H, J=1.9 Hz),
7.30-7.27 (dd, 1H, J=1.9 Hz, J=8.7 Hz), 6.02-6.00 (d, 1H, J=9.1
Hz), 5.70-5.67 (m, 2H), 5.48-5.34 (m, 1H) 4.04-3.93 (m, 2H), 2.20
(s, 3H), 1.98 (s, 3H), 1.69 (s, 3H).
6-Chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole
eluted from the chiral column last (RT=28.9 min) and 0.20 g was
obtained after evaporation of the solvent. .sup.1H NMR
(DMSO-d.sub.6) .delta.8.43 (s, 1H), 8.10-8.09 (d, 1H, J=2.0 Hz),
7.64-7.62 (d, 1H, J=8.8 Hz), 7.25-7.23 (dd, 1H, J=2.0 Hz, J=8.7
Hz), 6.03-6.00 (d, 1H, J=9.5 Hz), 5.76-6.60 (m, 2H), 5.50-5.40 (m,
1H), 4.04-3.93 (m, 2H), 2.20 (s, 3H), 1.98 (s, 3H), 1.69 (s,
3H).
Example 15
2-Bromo-5-chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazol-
e
[0224] The title compound was prepared according to General
Procedure IV using
5-chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole
(0.17 g, 0.41 mmol), 30 ml tetrahydrofuran (Aldrich Sure Seal,
Milwaukee), and a total of 2.6 g (7.0 mmol) of N-bromosuccinimide
that was added over 2 h. The product from work-up by General
Procedure IV was purified on a silica gel column (2.5.times.20 cm,
230-400 mesh) with dichloromethane containing 1.0% methanol to give
2-Bromo-5-chloro-(2,3,4--
tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.15 g, 0.31
mmol, 76%); MS (ES+): m/z (rel. intensity) 511 (0.25, M.sup.+23
(Na)) .sup.1H NMR (DMSO-d.sub.6) .delta.8.02-8.00 (d, 1H, J=8.7),
7.68 (d, 1H, J=2.1 Hz), 7.30-7.27 (dd, 1H, J=1.9 Hz, J=8.9 Hz),
5.96-5.93 (d, 1H, J=8.9 Hz), 5.67-5.62 (m, 2H), 5.55-5.45 (m, 1H),
4.20-3.90 (m, 2H), 2.20 (s, 3H), 1.99 (s, 3H), 1.73 (s, 3H).
Example 16
2-Bromo-5-chloro-1-beta-D-ribopyranosyl-1H-benzimidazole
[0225]
2-Bromo-5-chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzi-
midazole (0.15 g, 0.31 mmol) was deprotected as outlined in General
Procedure V by being dissolved in 5 ml dioxane at rt. To this
solution was added all at once, 1.2 ml (1.2 mmol) of 1M aq. LiOH.
The mixture stirred at ambient temperature for 0.25 h. The mixture
was diluted with 15 ml of pH 7 phosphate buffer and extracted with
ethyl acetate. The ethyl acetate layer was dried over magnesium
sulfate (anhyd.), filtered and solvents evaporated. The residue was
triturated in dichloromethane and
2-bromo-5-chloro-1-beta-D-ribopyranosyl-1H-benzimidazole was
collected by vacuum filtration. The product was dried in a vacuum
oven at 50.degree. C. (0.041 g, 0.11 mmol 37%); m.p. 120.degree. C.
(foams), 150.degree. C. (decomposes); .sup.1H NMR (DMSO-d.sub.6)
.delta.7.70-7.67 (m, 2H), 7.24-7.22 (d, 1H, J=8.7 Hz), 5.64-5.61
(d, 1H, J=9.2 Hz), 5.16 (bs, 1H), 4.07-4.05 (overlapping dd, 1H),
3.98 (bs, 1H), 3.87-3.66 (m, 1H), 3.68-3.66 (d, 2H, J=8.5 Hz).
Example 17
2-Bromo-6-chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazol-
e
[0226] The title compound was prepared according to General
Procedure IV using
6-chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole
(0.20 g, 0.41 mmol), 30 ml tetrahydrofuran (Aldrich Sure Seal,
Milwaukee), and a total of 0.30 g (0.17 mmol) of N-bromosuccinimide
that was added over 0.5 h. The product from work-up by General
Procedure IV was purified on a silica gel column (2.5.times.20 cm,
230-400 mesh) with dichloromethane containing 1.0% methanol to give
2-Bromo-6-chloro-(2,3,4--
tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.11 g, 0.22
mmol, 54%); MS (AP+): m/z (rel. intensity) 511 (0.10, M.sup.+23
(Na)) .sup.1H NMR (DMSO-d.sub.6) .delta.8.16 (s, 1H), 7.60-7.58 (d,
1H, J=8.7 Hz), 7.28-7.26 (dd, 1H, J=1.9 Hz, J=8.6 Hz), 5.95-5.92
(d, 1H, J=9.7 Hz), 5.67-5.60 (m, 3H), 4.13-4.09 (dd, 1H, J=5.3 Hz,
J=9.2 Hz), 4.00-3.90 (overlapping dd, 1H) 2.20 (s, 3H), 1.98 (s,
3H), 1.74 (s, 3H).
Example 18
2-Bromo-6-chloro-1-beta-D-ribopyranosyl-1H-benzimidazole
[0227]
2-Bromo-6-chloro-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzi-
midazole (0.11 g, 0.22 mmol) was deprotected as outlined in General
Procedure V by being dissolved in 5 ml dioxane at rt. To this
solution was added all at once, 0.86 ml (0.86 mmol) of 1M aq. LiOH.
The mixture stirred at ambient temperature for 0.25 h. The mixture
was diluted with 15 ml of pH 7 phosphate buffer and extracted with
ethyl acetate. The ethyl acetate layer was dried over magnesium
sulfate (anhyd.), filtered and solvents evaporated. The residue was
triturated in dichloromethane and
2-bromo-6-chloro-1-beta-D-ribopyranosyl-1H-benzimidazole was
collected by vacuum filtration. The product was dried in a vacuum
oven at 50.degree. C. (0.028 g, 0.077 mmol 35%); m.p. 100.degree.
C. (foams), 140.degree. C. (decomposes); .sup.1H NMR (DMSO-d.sub.6)
.delta.7.74-7.73 (d, 1H, J=1.8 Hz), 7.60-7.58 (d, 1H, J=8.7 Hz),
7.26-7.23 (dd, 1H, J=1.9 Hz, J=8.7 Hz), 5.64-5.61 (d, 1H, J=9.3
Hz), 5.13 (bs, 1H), 4.12-4.10 (d, 1H, J=9.2 Hz), 3.99 (s, 1H),
3.94-3.90 (m, 1H), 3.68 (s, 1H) 3.67-3.66 (d, 1H, J=3.9 Hz).
Example 19
5,6-Difluoro-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole
[0228] As per General Procedure III. 5,6-difluoro-1H-benzimidazole
(1.0 g, 6.5 mmol), N,O-bis(trimethisilyl)acetamide (1.6 ml, 6.5
mmol), in 50 ml 1,2-dichloroethane (Aldrich Sure Seal, Milwaukee)
were heated at 85.degree. C. for 2.5 h under a nitrogen atmosphere
then allowed to cool to rt. Trimethylsilyl
trifluoromethanesulfonate (1.4 ml, 7.2 mmol) and 2.0 g (6.3 mmol)
solid 1,2,3,4-tetra-O-acetyl-b-D-rilopyranose (beta-D-ribopyranose
1,2,3,4-tetraacetate, Aldrich, Milwaukee) was added and the mixture
was heated in an oil bath at 85.degree. C. for 24 h under a
nitrogen atmosphere. The reaction was then poured into 7% aqueous
sodium bicarbonate and extracted with dichloromethane. The organic
layer was dried with magnesium sulfate (anhyd), filtered, and
evaporated. The crude residue was purified on a silica gel column
(2.5.times.20 cm, 230-400 mesh) with CH.sub.2Cl.sub.2 and an
increasing gradient of methanol from 0.5 to 2% to provide the title
compound as a white foam (1.1 g, 2.6 mmol, 40%); MS (API+): m/z
(rel. intensity) 524 (0.10, M.sup.+1); .sup.1H NMR (DMSO-d.sub.6)
.delta.8.47 (s, 1H), 8.20-8.16 (m, 1H), 7.76-7.71 (m, 1H),
6.02-6.00 (d, 1H, J=9.5 Hz), 5.75-5.69 (m, 2H), 5.53-5.40 (m, 1H),
4.05-3.94 (m, 1H), 2.22 (s, 3H), 2.00 (s, 3H), 1.73 (s, 3H).
Example 20
2-Bromo-5,6-difluoro-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzim-
idazole
[0229] The title compound was prepared according to General
Procedure IV using
5,6-difluoro-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimi-
dazole (1.1 g, 2.6 mmol), 60 ml tetrahydrofuran (Aldrich Sure Seal,
Milwaukee), and a total of 2.8 g (16 mmol) of N-bromosuccinimide
that was added in 3 ca. equivalent portions. The product from
work-up by General Procedure IV was purified on a silica gel column
(2.5.times.20 cm, 230-400 mesh) with hexanes and an increasing
gradient from 5% to 20% ethyl acetate to give 1.0 g (2.0 mmol, 77%
yield); MS (ES+): m/z (rel. intensity) 514 (1.0, M.sup.+23 (Na));
.sup.1H NMR (DMSO-d.sub.6) .delta.8.26-8.21 (m, 1H), 7.73-7.69 (m,
1H), 5.93-5.91 (d, 1H, J=9.0 Hz), 5.69-5.62 (m, 3H), 4.11-3.90 (m,
2H), 2.20 (s, 3H), 1.98 (s, 3H), 1.73 (s, 3H).
Example 21
2-Bromo-5,6-difluoro-1-beta-D-ribopyranosyl-1H-benzimidazole
[0230]
2-Bromo-5,6-difluoro-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-
-benzimidazole (0.88 g, 1.8 mmol), 20 ml dioxane and 7 ml (7 mmol)
of 1 M aqueous LiOH was used to prepare
2-bromo-5,6-difuoro-1-beta-D-ribopyranos- yl-1H-benzimidazole (0.23
g, 0.63 mmol, 35% yield) according to General Procedure V; MS
(ES+): m/z (rel. intensity) 388 (1.0, M.sup.+23 (Na)); .sup.1H NMR
(DMSO-d.sub.6) .delta.7.83-7.79 (m, 1H), 7.73-7.68 (m, 1H),
5.62-5.60 (d, 1H, J=9.4 Hz), 4.10-4.08 (d, 1H, J=9.4 Hz), 3.97-3.95
(bs, 2H) 3.67-3.65 (d, 2H, J=8.2 Hz).
Example 22
5,6-Dichloro-4-fluoro-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzi-
midazole
[0231] As described in General Procedure III,
5,6-dichloro-4-fluorobenzimi- dazole (1.3 g, 6.3 mmol),
N,O-bis(trimethylsiyl)acetamide (Aldrich, 1.6 ml, 6.3 mmol), and
1,2-dichloroethane (Aldrich Sure Seal, 30 mL) were combined and
refluxed under nitrogen for 0.5 h. The solution was cooled to room
temperature and trimethylsilyl triflate (Aldrich, 0.67 ml, 3.5
mmol) was added. Immediately, 2.0 g (6.3 mmol) solid
1,2,3,4-tetra-O-acetyl-b-D-ribopyranose (beta-D-ribopyranose
1,2,3,4-tetraacetate, Aldrich, Milwaukee) was added. The solution
was stirred under nitrogen at reflux overnight, then poured into 7%
aqueous sodium bicarbonate and extracted with dichloromethane. The
organic layer was dried with magnesium sulfate (anhyd), filtered,
and evaporated. The crude residue was purified on a silica gel
column (5.times.20 cm, 230-400 mesh) eluting with 0.5% methanol in
chloroform followed by purification on a Biotage medium pressure
chromatography cartridge system eluting with 1:1 mixture of ethyl
acetate and hexanes to give 1.3 g (2.8 mmol, 44%) of
5,6-dichloro-4-fluoro-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benz-
imidazole; MS (ES+): m/z (rel intensity) 485 (1.0, M.sup.+23 (Na));
.sup.1H NMR (DMSO-d.sub.6) .delta.8.57 (s, 1H), 8.28 (s, 1H),
6.07-6.04 (d, 1H, J=9.6 Hz), 5.74-5.67 (m, 2H), 5.49-5.40 (m, 1H),
4.04-3.92 (m, 2H), 2.20 (s, 3H), 1.98 (s, 3H), 1.71 (s, 3H).
Example 23
2-Bromo-5,6-dichloro-4-fluoro-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)--
1H-benzimidazole
[0232] The title compound was prepared according to General
Procedure IV using
5,6-dichloro-4-fluoro-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1-
H-benzimidazole (1.3 g, 2.8 mmol), 30 ml tetrahydrofuran (Aldrich
Sure Seal, Milwaukee), and a total of 5.0 g (28 mmol) of
N-bromosuccinimide that was added in 5 ca. equivalent portions over
35 min. The product from work-up by General Procedure IV was
purified on a silica gel column (2.5.times.20 cm, 230-400 mesh)
with 0.5% methanol in dichloromethane to give 1.5 g (2.8 mmol)
2-bromo-5,6-dichloro-4-fluoro-1-(2,3,4-tri-O-acetyl-
-beta-D-ribopyranosyl)-1H-benzimidazole; MS (AP+): m/z (rel.
intensity) 564 (0.02, M.sup.+23 (Na)); .sup.1H NMR (DMSO-d.sub.6)
.delta.8.31 (s, 1H), 5.97-5.95 (d, 1H, J=9.1 Hz), 5.70-5.62 (m,
3H), 4.14-4.10 (dd, 1H), 4.02-3.97 (overlapping dd, 1H), 2.20 (s,
3H), 1.98 (s, 3H), 1.75 (s, 3H).
Example 24
2-Bromo-5,6-dichloro-4-fluoro-1-beta-D-ribopyranosyl-1H-benzimidazole
[0233]
2-Bromo-5,6-dichloro-4-fluoro-1-(2,3,4-tri-O-acetyl-beta-D-ribopyra-
nosyl)-1H-benzimidazole (1.5 g, 2.8 mmol), 25 ml dioxane and 11 ml
(11 mmol) of 1 M aqueous LiOH was used to prepare
2-bromo-5,6-dichloro-4-fluo-
ro-1-beta-D-ribopyranosyl-1H-benzimidazole (0.57 g, 1.3 mmol, 46%
yield) according to General Procedure V; m.p. 165.degree. C.
(foams); MS (ES+): m/z (rel. intensity) 438 (1.0, M.sup.+23 (Na));
.sup.1H NMR (DMSO-d.sub.6) .delta.7.94 (s, 1H), 5.72-5.69 (d, 1H,
J=9.2 Hz), 5.28-5.26 (d, 1H, J=6.2 Hz), 5.22-5.20 (d, 1H, J=3.5
Hz), 4.93-4.91 (d, 1H, J=8.6 Hz), 4.16-4.11 (m, 1H) 4.05-3.95 (bs,
2H), 3.69-3.60 (m, 2H).
[0234] Anal. Calcd. for C.sub.12H.sub.10N.sub.2O.sub.4FCl.sub.2Br:
C, 34.64; H, 2.42; N, 6.73. Found: C, 34.47; H, 2.48; N, 6.69.
Example 25
6-Chloro-5-fluoro-1-(2,3,4-triacetyl-beta-D-ribopyranosyl)-1H-benzimidazol-
e and
5-Chloro-6-fluoro-1-(2,3,4-triacetyl-beta-D-ribopyranosyl)-1H-benzim-
idazole
[0235] 6-Chloro-5-fluorobenzimidazole (Maybridge, 0.536 g, 3.1
mmoles) was slurred in 1,2-dichloroethane (Aldrich, Sure Seal, 35
ml). BSA (Aldrich, 388 .mu.L, 1.5 mmoles, 1 eq.) was added and the
mixture refluxed in a 90.degree. C. oil bath 1 hour.
2,3,4-Triacetyl-beta-D-pyranoside (Aldrich, 1.0 g, 3.1 mmoles, 1
eq.) was dried by boiling in toluene. Excess toluene was removed in
vacuo. The carbohydrate was dissolved in 1,2-dichloroethane (15 ml)
and added to the reaction by cannula. Trifluoromethyltriflate
(Aldrich, 668 .mu.L, 3.4 mmoles, 1.1 eq) was carefully added and
the reaction refluxed overnight. The reaction was cooled to room
temperature and washed with brine (3.times.) until the pH was
.about.7. The dichloroethane solution was dried with MgSO.sub.4,
filtered and solvent removed in vacuo. The products, 1:1 ratio,
were purified as a mixture by chromatography on 300 g of silica gel
eluted with ethyl acetate/hexane (2:1, v/v) followed by neat ethyl
acetate in 33% yield; 0.45 g. .sup.1H NMR (DMSO-d.sub.6)
.delta.8.48 (d, 1H, Ar--H, J=9 Hz), 8.29 (d, 1H, Ar--H, J=7 Hz),
8.15 (d, 1H, Ar--H, J=10 Hz), 7.87 (d, 1H, Ar--H, J=6 Hz), 7.69 (d,
1H, Ar--H, J=10 Hz), 6.0 (m, 2H, H-1'), 5.7 (m, 2H), 5.65 (m, 2H),
5.45 (m, 2H,), 4.0 (m, overlaps with ethyl acetate), 2.2 (s, 6H,
acetate), 1.97 (s, 6H, acetate), 1.95 (s, ethyl acetate), 1.70 (s,
6H, acetate), 1.14 (t, ethyl acetate).
Example 26
2-Bromo-6-chloro-5-fluoro-1-(2,3,4-triacetyl-beta-D-ribopyranosyl-1H-benzi-
midazole and
2-Bromo-5-chloro-6-fluoro-1-(2,3,4-triacetyl-beta-D-ribopyran-
osyl)-1H-benzimidazole
[0236]
6-Chloro-5-fluoro-1-(2,3,4triacetyl-beta-D-pyranosyl)-1H-benzimidaz-
ole and
5-Chloro-6-fluoro-1-(2,3,4-triacetyl-beta-D-pyranosyl)-1H-benzimid-
azole (0.39 g, 0.91 mmoles) were dried by boiling with toluene.
Excess toluene was removed in vacuo. THF (Aldrich, Sure Seal, 13
ml) was added and the solution heated to reflux in a 85.degree. C.
oil bath. NBS (Aldrich, 0.31 g, 1.8 mmoles, 2 eq.) was added and
reaction refluxed for 7 minutes. The reaction was cooled and poured
into cold saturated sodium bicarbonate solution. The products were
extracted with ethyl acetate. The organic solution was dried with
MgSO.sub.4, filtered and solvents removed in vacuo. The residue was
purified by chromatography on 40 g of silica gel eluted with ethyl
acetate/hexane (1:2, v/v). The product containing fractions were
combined and solvents removed. The products were obtained in an
approximately 1:1 ratio in 30% yield, 0.14 g. .sup.1H NMR (DMSOd6)
.delta.8.34 (d, 1H, Ar--H, J=7 Hz), 8.22 (d, 1H, Ar--H, J=10 Hz),
7.86 (d, 1H, Ar--H, J=7 Hz), 7.69 (d, 1H, Ar--H, J=10 Hz), 5.95 (m,
2H, H-1'), 5.7 (m, 6H), 4.1(m, 2H), 4.0 (m, overlaps with ethyl
acetate), 2.2 (s, 6H, acetate), 1.97 (s, 6H, acetate), 1.95 (s,
ethyl acetate), 1.70 (s, 6H, acetate), 1.14 (t, ethyl acetate).
Example 27
2-Bromo-6-chloro-5-fluoro-1-(beta-D-ribopyranosyl)-1H-benzimidazole
and
2-Bromo-5-chloro-6-fluoro-1-(beta-D-ribopyranosyl)-1H-benzimidazole
[0237]
2-Bromo-6-chloro-5-fluoro-1-(2,3,4-triacetyl-beta-D-pyranosyl)-1H-b-
enzimidazole and
2-Bromo-5-chloro-6-fluoro-1-(2,3,4-triacetyl-beta-D-pyran-
osyl)-1H-benzimidazole (0.14 g, 0.28 mmoles) were dissolved in
dioxane (Aldrich, 5 ml). Lithium hydroxide hydrate (Aldrich, 0.037
g, 0.88 mmoles, 3 eq.) was dissolved in water (2.0 ml) and added to
the reaction. The solution was stirred at room temperature for 1
hr. The pH of the reaction was adjusted to 7 with 1N HCl. The
products were extracted with ethyl acetate (2.times.), dried with
MgSO.sub.4, filtered and solvents removed in vacuo. The residue was
purified by chromatography on 30 g of silica gel eluted with ethyl
acetate/hexane (2:1, v/v). The product containing fractions were
combined and solvents removed in vacuo. The products were obtained
in an approximately 1:1 ratio in 50% yield, 0.14 g. MS (FAB+):
m+1/z, 381, .sup.1H NMR (DMSO-d.sub.6) .delta.7.90 (d, 1H, Ar--H,
J=7 Hz), 7.85 (d, 1H, Ar--H, J=7 Hz), 7.79 (d, 1H, Ar--H, J=10 Hz),
7.68 (d, 1H, Ar--H, J=10 Hz), 5.6 (m, 2H, H-1'), 5.2 (brs, 4H, OH),
4.8 (brs, 2H, OH), 4.1 (m, 2H), 4.0 (m, overlaps with ethyl
acetate), 3.65 (m, 4H), 1.95 (s, ethyl acetate), 1.14 (t, ethyl
acetate).
Example 28
5,6-Dichloro-1-beta-D-ribopyranosyl-1H-benzimidazole
[0238]
5,6-Dichloro-1-(2,3,4-triacetyl-beta-D-ribopyranosyl)-1H-benzimidaz-
ole was prepared starting with 5,6-dichloro-benzimidazole (Townsend
and Revankar, Chem. Rev. 1970, 70:389) by the procedure used in
example 25. The title compound was prepared from the triacetyl
product by the method of example 26. MS (APCH(-)): m-1/z 317
.sup.1H NMR (DMSO-d.sub.6) .delta.8.43 (s, 1H, H-2), 7.97 (s, 1H,
Ar--H), 7.92(s, 1H, Ar--H), 5.54 (d, 1H, H-1', J=9 Hz), 5.1(brs,
2H, OH), 4.86(brs, 1H, OH), 4.0(m, overlaps with ethyl acetate),
3.8 (m, 1H), 3.7 (m, 1H), 3.6 (m, 1H), 1.95 (s, ethyl acetate),
1.14 (t, ethyl acetate).
Example 29
4,5,6-Trifluorobenzimidazole
[0239] 2,3,4-Trifluoro-6-nitroanline (Maybridge, 30 g, 156 mmoles)
was dissolved in ethanol (200 ml). Water (10 ml) was added followed
by Raney Nickel catalyst (3 g, wet). Reduction under 50 psi H.sub.2
was continued for 4 hrs. The reaction was filtered and the solvents
removed in vacuo. The residue was dissolved in 4N HCl (1 L) and
formic acid (6.5 ml, 1.1 eq.) was added. The reaction was refluxed
overnight. After filtration, the pH was adjusted to 7 with NaOH
(5N). The crude product (24 g) was collected by filtration and
purified by chromatography on silica gel (500 g) eluted with ethyl
acetate/hexane (7:1, v/v). The product containing fractions were
combined and solvents removed in vacuo. The product was obtained in
71% yield, 19 g. MS (APCH(+)): m+1/z 173, .sup.1H NMR
(DMSO-d.sub.6) .delta.8.31 (s, 1H, H-2), 7.49 (m, 1H, H-7).
Example 30
1-(2,3,4-Triacetyl-beta-D-ribopyranosyl)-4,5,6-trifluoro-1H-benzimidazole
and
1-(2,3,4-Triacetyl-beta-D-ribopyranosyl)-5,6,7-trifluoro-1H-benzimida-
zole
[0240] The product of example 6 was converted to the title
compounds by the method used in example 25. The products were
obtained in a ratio of 1:5, 7-F/4-F isomers. Isomer ratios were
confirmed by NMR-NOESY correlation. In the case of the 4-fluoro
analog. NOE from the 7-H into the sugar protons was clearly present
whereas in the case of the 7-fluoro analog no NOE was observed. MS
(APCH(+)): m+1/z 431, .sup.1H NMR (DMSO-d.sub.6) .delta.8.56 (s,
0.2H, H-2, (7-fluoro analog)), 8.53 (s, 1H, H-2, (4-fluoro
analog)), 8.1 (m, 1H, H-7, (4-fluoro analog)), 7.65 (m, 0.2H, H-4,
(7-fluoro analog)), 6.02 (d, 1.2H, H-1', J=10 Hz), 5.7 (m, 2H),
5.55(m, 0.2H), 5.45 (m, 2H), 5.25 (m, 0.2H), 4.0 (m, overlaps with
ethyl acetate), 2.2 (s, 3.6H, acetate), 1.97 (s, 3.6H, acetate),
1.95 (s, ethyl acetate), 1.70 (s, 3.6H, acetate), 1.14 (t, ethyl
acetate).
Example 31
2-Bromo-1-(2,3,4-triacetyl-beta-D-ribopyranosyl)-4,5,6-trifluoro-1H-benzim-
idazole and
2-Bromo-1-(2,3,4-triacetyl-beta-D-ribopyranosyl)-5,6,7-trifluo-
ro-1H-benzimidazole
[0241] The products of example 30 were converted to the title
compounds by the method used in example 26. MS (EI(+)): m+1/z 508,
.sup.1H NMR (DMSO-d.sub.6) .delta.8.15 (m, 1H, H-7, (4-fluoro
analog)), 7.7 (m, 0.2H, H-4, (7-fluoro analog)), 6.51 (d, 0.2H, J=5
Hz), 5.7 (m, 0.2H), 5.6 (m 2.4H), 5.3 (d, 0.12H), 4.2 (m, 0.2H),
4.1(m, 1.15H), 4.0 (m, overlaps with ethyl acetate), 2.2 (s, 6H,
acetate), 1.97 (s, 6H, acetate), 1.95 (s, ethyl acetate), 1.70 (s,
6H, acetate), 1.14 (t, ethyl acetate).
Example 32
2-Bromo-1-(beta-D-ribopyranosyl)-4,5,6-trifluoro-1H-benzimidazole
and
2-Bromo-1-(beta-D-ribopyranosyl)-5,6,7-trifluoro-1H-benzimidazole
[0242] The products of example 31 were converted to the title
compounds by the method used in example 27. Partial purification by
chromatography resulted in a ratio of 1:7 for the 7-fluoro/4-fluoro
compounds. .sup.1H NMR (DMSO-d.sub.6) .delta.7.75 (m, 1H, H-2,
(4-fluoro analog)), 7.65 (s, 0.15H, H-2, (7-fluoro analog)), 5.63
(d, 1H, H-1', J=9 Hz), 5.25 (brs, 0.15H, OH), 5.2(m, 1.15H, OH),
5.15 (d, 1H, OH), 4.95 (d, 0.15H, OH), 4.85(d, 1H, OH), 4.1(m,
1.15H), 4.0 (m, 2.3H), 3.65 (m, 2.3H). Analysis:
(C.sub.12H.sub.10BrF.sub.3N.sub.2O.sub.4-1/10H.sub.2O-2/10
C.sub.4H.sub.8O.sub.2), Calculated: C-38.19, H-2.95, N-6.96. Found
C-38.19, H-3.10, N-6.81.
Example 33
6-Chloro-4,5-difluoro-1-(2,3,4-triacetyl-beta-D-ribopyranosyl)-1H-benzimid-
azole and
5-Chloro-6,7-difluoro-1-(2,3,4-triacetyl-beta-D-ribopyranosyl)-1-
H-benzimidazole
[0243] a) 4-Chloro-2,3-difluoro-6-nitroaniline
[0244] 2,3-Difluoro-6-nitroaniline (15.4 g, 88.7 mmol),
N-chlorosuccinimide (14.9 g, 111.4 mmol) and N,N-dimethylformamide
(250 ml) were combined and were heated to 80-90.degree. C. for
several hours, after which time the mixture was poured into ice
water. The product was extracted with ethyl acetate which was then
washed with water, saturated aqueous sodium chloride, dried over
magnesium sulfate, filtered and the solvents were removed in vacuo
to leave a yellow, viscous oil. .sup.1H NMR (DMSO-d.sub.6) .delta.:
8.03 (dd, J=7.3, 2.2 Hz, 1H, Ar--H), 7.65 (br s, 2H, NH.sub.2).
[0245] b) 6-Chloro-4,5-difluorobenzimidazole
[0246] 4-Chloro-2,3-difluoro-6-nitroanline (6 g, 28.8 mmoles) was
converted to the title compound by the method used in example 6. MS
(APCH(-)): m-1/z 187, .sup.1H NMR (DMSO-d.sub.6) .delta.8.36 (s,
1H, H-2), 7.61 (m, 1H, H-7).
[0247] c)
6-Chloro-4,5-difluoro-1-(2,3,4-triacetyl-beta-D-ribopyranosyl)-1-
H-benzimidazole and
5-Chloro-6,7-difluoro-1-(2,3,4-triacetyl-beta-D-ribopy-
ranosyl)-1H-benzimidazole
[0248] The product of example 33b was converted to the title
compounds by the method used in example 1. The products were
obtained in a ratio of 1:6, 7-F/4-F isomers. Isomer ratios were
confirmed by NMR-NOESY correlation. in the case of the 4-fluoro
analog, NOE from the 7-H into the sugar protons was clearly present
whereas in the case of the 7-fluoro analog no NOE was observed. MS
(APCH(+)): m+Na/z 469, .sup.1H NMR (DMSO-d.sub.6) .delta.8.57 (s,
1.15H, H-2), 8.2 (m, 1H, H-7, (4-fluoro analog)), 7.8 (m, 0.15H,
H-4, (7-fluoro analog)), 6.1 (m, 1.15H, H-1'), 5.7 (m, 2.3H),
5.55(m, 0.15H), 5.45 (m, 1H), 5.25 (m, 0.15H), 4.0 (m, 2.3H), 2.2
(s, 3.45H, acetate), 1.97 (s, 3.45H, acetate), 1.70 (s, 3.45H,
acetate).
Example 34
2-Bromo-6-chloro-4,5-difluoro-1-(2,3,4-triacetyl-beta-D-ribopyranosyl)-1H--
benzimidazole and
2-Bromo-5-chloro-6,7-difluoro-1-(2,3,4-triacetyl-beta-D--
ribopyranosyl)-1H-benzimidazole
[0249] The products of example 33c were converted to the title
compounds by the method used in example 2. Partial purification by
chromatography resulted in a ratio of 1:5 for the 7-fluoro/4-fluoro
compounds. MS (EI(+)): m+1/z 524, .sup.1H NMR (DMSO-d.sub.6)
.delta.8.23 (d, 1H, H-7, J=5 Hz,(4-fluoro analog)), 7.82 (d, 0.2H,
H-4, J=6 Hz, (7-fluoro analog)), 5.95 (m, 1.2H), 5.7 (m, 2.4H), 5.3
(m, 0.2H), 5.1 (m, 0.2H), 4.2 (m, 0.2H), 4.1(m, 1.2H), 4.0 (m,
overlaps with ethyl acetate), 3.9 (m, 0.2H), 3.5 (t, 0.4H), 2.2 (s,
3.4H, acetate), 1.97 (s, 3.4H, acetate), 1.95 (s, ethyl acetate),
1.70 (s, 3.4H, acetate), 1.14 (t, ethyl acetate).
Example 35
2-Bromo-6-chloro-4,5-difluoro-1-(beta-D-ribopyranosyl)-1H-benzimidazole
[0250] The product of example 34 was converted to the title
compound by the method used in example 27. The title compound was
isolated by chromatography. MS (FAB+): m+1/z 399, .sup.1H NMR
(DMSO-d.sub.6) .delta.7.8 (m, 1H, H-7), 5.64 (d, 1H, H-1', J=9 Hz),
5.20 (d, 1H, OH, J=6 Hz), 5.14 (d, 1H, OH, J=3 Hz), 4.85 (d, 1H,
OH, J=6 Hz), 4.1 (m, 1H), 4.0 (m, 2H+ethyl acetate), 3.65 (m, 2H),
1.95 (s, ethyl acetate), 1.14 (t, ethyl acetate).
Example 36
(3S,5S,6R)-2-Bromo-5,6-dichloro-1-(tetrahydro-5-hydroxy-6-(hydroxymethyl)--
2H-pyran-3-yl)-1H-benzimadazole
[0251] a)
(3S,5S,6R)-5,6-Dichloro-1-(tetrahydro-5-hydroxy-6-(hydroxymethyl-
)-2H-pyran-3-yl)-1H-benzimidazole
[0252]
2R,4-.alpha.-R,7R,8-.alpha.-S-perhydro-7-hydroxy-2-phenylpyrano(3,2-
-D)1,3)dioxin (Tetrahedron Letters, 1996, 8147 and references cited
therein) (2.50 g, 10.6 mmol), triphenylphosphine (Aldrich, 4.16 g,
15.87 mmol as 99%) and 5,6-dichlorobenzimidazole (Townsend and
Revankar, Chem. Rev. 1970, 70:389, and references cited therein)
(3.00 g, 15.87 mmol) were stirred in anhydrous tetrahydrofuran (50
ml) at 0.degree. C. (external ice bath) under nitrogen as a
solution of diethyl azodicarboxylate (Aldrich, 2.60 ml, 15.87 mmol
as 97%) in tetrahydrofuran (10 ml) was added over 30 min. The
reaction mixture was allowed to warm to room temperature, stirred
72 hours, then diluted with chloroform (300 ml) and washed with
saturated aqueous sodium bicarbonate (100 ml). The organic layer
was dried (sodium sulfate), filtered, and the solvents evaporated
under reduced pressure. The residual gum was treated with 300 ml of
80% aqueous acetic acid at 80.degree. C. for 1 h. The reaction
mixture was diluted with 100 ml of water and extracted with diethyl
ether (4.times.100 ml). The aqueous phase was concentrated and
purified by flash chromatography on silica gel 60. The title
compound was eluted with 5-25% methanol-chloroform as a white solid
(2.20 g, 65%); m.p. 197.degree. C.; 1H-NMR (DMSO-d.sub.6, 200 MHz)
.delta.: 8.56, 8.09, 7.99 (s, each 1H), 4.92 (d, J=5.5 Hz, 1H),
4.87 (bs, 1H), 4.69 (t, J=6.3 Hz, 1H), 4.25 (d, J=12 Hz, 1H), 3.91
(dd, J=12.9, 2.7 Hz, 1H), 3.71-2.53 (m, 4H), 2.28-2.25 (m, 1H),
1.97-1.89 (m, 1H).
[0253] Anal. Calcd. for C.sub.13H14N2O3Cl2: C, 49.23; H, 4.45; N,
8.83; Cl, 22.36. Found: C, 49.31; H, 4.48; N, 8.80; Cl, 22.26.
[0254] b)
(3S,5,S,6R)-2-Bromo-1-(5-acetoxy-6-acetoxymethyl)-tetrahydro-2H--
pyran-3-yl)-1H-benzimidazole
[0255] To a stirred solution of
(3S,5S,6R)-5,6-dichloro-1-(tetrahydro-5-hy-
droxy-6-(hydroxymethyl)-2H-pyran-3-yl)-1H-benzimidazole (part a of
this example, 1.00 g, 3.47 mmol) in anhydrous pyridine (10 ml) was
added acetic anhydride (1.30 ml, 13.9 mmol). After 12 hours the
reaction mixture was concentrated under reduced pressure,
coevaporating with toluene to a viscous oil. Ethanol (ca. 5 ml) was
added (with external ice cooling) and the mixture was again
coevaporated with toluene (2.times.) until acetic acid odor was
absent. The oil was redissolved in chloroform (200 ml) and washed
successively with 0.1 N HCl (50 ml), saturated aqueous sodium
bicarbonate (50 ml), and brine (50 ml). The organic layer was dried
(sodium sulfate) then suction-filtered through flash silica gel 60
(3.times.4 cm), washing with ethyl acetate. Evaporation of the
solvents under reduced pressure left an off-white semi solid
residue (1.37 g). A solution of this solid in anhydrous
tetrahydrofuran (20 ml) was refluxed under nitrogen while
N-bromosuccinimide (Aldrich, 1.22 g, 6.83 mmol) was added in one
portion. After 10 min. at reflux, the yellow solution was cooled to
room temperature, diluted with chloroform (75 ml), and washed with
saturated aqueous sodium bicarbonate (3.times.50 ml). The organic
layer was dried (sodium sulfate), filtered, and concentrated under
reduced pressure, affording 1.95 g (86%) of the title compound as a
brown gum which was used without further purification; 1H-NMR
(DMSO-d6, 200 MHz) .delta.: 8.45, 7.98 (s, each 1H), 5.00 (m, 1H),
4.81 (m, 1H), 4.45-3.81 (m, 5H), 2.30 (m, 2H), 2.31 (s, 6H).
[0256] c)
(3S,5S,6R)-2-Bromo-5,6-dichloro-1-(tetrahydro-5-hydroxy-6(hydrox-
ymethyl)-2H-pyran-3-yl)-1H-benzimadazole
[0257]
(3S,5S,6R)-5,6-Dichloro-1-(tetrahydro-5-hydroxy-6-(hydroxymethyl)-2-
H-pyran-3-yl)-1H-benzimidazole (part b of this example, 0.80 g,
1.67 mmol) was stirred in 1:1 methanol-ethanol (10 ml) with a
solution of sodium carbonate (0.200 g, 1.68 mmol) in water (5 ml)
for 5 hours at room temperature followed by 2 hours at 60.degree.
C. The pH was then adjusted to 5 with glacial acetic acid and the
solvents evaporated in vacuo. The resudual solid was stunted in
water, filtered and dried in vacuo, affording the title compound as
a white solid (0.500 g, 90%); m.p. 286-288.degree. C.; [.alpha.]20D
47.2.degree. (c 0.125, 1:1 EtOH-CHCl3); 1H-NMR (DMSO-d6, 200 MHz)
.delta.: 8.60, 7.93 (s, 1H each), 5.07 (d, J=4.4 Hz, 1H), 4.97 (m,
1H), 4.86 (t, J=4.9 Hz, 1H), 4.26 (m, 1H), 4.04 (m, 1H), 3.74-3.39
(m, 4H), 2.18 (m, 2H).
[0258] Anal. Calcd. for C13H13BrCl2N2O3: C, 39.42; H, 3.31; N,
7.07; total halogen as Cl, 17.90. Found: C, 39.51; H, 3.35; N,
6.98; total halogen as Cl, 17.88.
Example 37
(3S,5S,6R)-5,6-Dichloro-2-(cyclopropylamino)-1H-(tetrahydro-5-hydroxy-6-(h-
ydroxymethyl)2H-pyran-3-yl)-1H-benzimidazole
[0259] A solution of
(3S,5S,6R)-2-bromo-5,6-dichloro-1-(tetrahydro-5-hydro-
xy-6-(hydroxymethyl)-2H-pyran-3-yl)-1H-benzimadazole (part c of
previous example, 1.00, 2.08 mmol) and cyclopropyl amine (Aldrich,
1.50 ml, 20.0 mmol) in absolute ethanol (20 ml) was refluxed under
nitrogen for 24 h at which point TLC (silica gel plates developed
with 5% methanol-chloroform) indicated complete conversion to lower
Rf product. 1 N sodium hydroxide (2.10 ML) was added and the
reaction mixture was concentrated under reduced pressure. The
residual solids were chromatographed on silica gel 60. The title
compound eluted with 10% methanol-chloroform as a white foam, after
evaporation of solvents (0.60 g, 75%); m.p. 130.degree. C.;
[.alpha.]20D+24.8.degree. (c 0.25, EtOH); 1H-NMR (DMSO-d6, 200
MHz), .delta.: 7.77 (s, 1H), 7.44 (s, 2H,), 4.96 (d, J=5 Hz, 1H),
4.83 (t, J=5 Hz, 1H), 4.66 (m, 1H), 4.22 (m, 1H), 3.92 (m, dd,
J=13.9 Hz, 4 Hz, 1H), 3.71-3.55 (m, 3H), 3.33 (m, 1H), 2.79 (m,
1H), 2.12-1.75 (m, 2H), 0.75-0.48 (m, 4H).
[0260] Anal. Calcd. for C16H19Cl2N3O.0.5H2O: C, 50.41; H, 5.29; N,
11.02; Cl, 18.60. Found: C, 50.29; H, 5.29; N, 11.00; Cl,
18.66.
Example 38
(3R,5R,6S)-2-Bromo-5,6-dichloro-1-(tetrahydro-5-hydroxy-6-(hydroxymethyl)--
2H-pyran-3-yl)-1H-benzimadazole
[0261] The title compound was prepared as described in example 1,
starting from L-glucose-derived
2S,4-.alpha.-S,7S,8-.alpha.-R-perhydro-7-hydroxy-2-
-phenylpyrano(3,2-D)1,3)dioxin ((Tetrahedron Letters, 1996, 8147
and references cited therein): m.p. 286-287.degree. C.;
[.alpha.]20D+0.16 (c 0.62, 1:1 MeOH/CHCl3); 1H-NMR (CDCl3, 200 MHz)
data was identical to that of the enantiomer (example 36).
[0262] Anal. Calcd. for C13H13BrCl2N2O3: C, 39.42; H, 3.31; N,
7.07; total halogen as Cl, 17.90. Found: C, 39.70; H, 3.45; N,
7.02; total halogen as Cl, 17.85.
Example 39
(3R,5R,6S)-5,6-Dichloro-2-(cyclopropylamino)-1-(tetrahydro-5-hydroxy-6-(hy-
droxymethyl)2H-pyran-3-yl)-1H-benzimidazole
[0263] The title compound was prepared in the same manner as the
enantiomer (example 37), starting from L-glucose-derived
2S,4-.alpha.-S,7S,8-.alpha.-R-perhydro-7-hydroxy-2-phenylpyrano(3,2-D)1,3-
)dioxin ((Tetrahedron Letters, 1996, 8147 and references cited
therein): m.p. 98-99.degree. C.; [.alpha.]20D-23.2.degree. (c 0.28,
EtOH); 1H-NMR (CDCl3, 200 MHz) identical to that of the enantiomer
(example 37).
[0264] Anal. Calcd. for C16H19Cl2N3O3. 3.0 H2O: C, 45.08; H, 5.91;
N, 9.86; Cl, 16.63. Found: C, 45.00; H, 5.87; N, 9.79; Cl,
16.70.
Example 40
(3R,4S,5S,6R)-2-Bromo-5,6-dichloro-1-(tetrahydro-4,5-dihydroxy-6-(Hydroxym-
ethyl)-2H-pyran-3-yl)-1H-benzimidazole
[0265] a)
(3S,5S,6R)-5,6-dichloro-1-(6-(((tert-butyldimethylsilyl)oxy)meth-
yl)-tetrahydro-5-hydroxy-2H-pyran-3-yl)-1H-benzimidazole
[0266] To a stirred suspension of
(3S,5S,6R)-5,6-dichloro-1-(tetrahydro-5--
hydroxy-6-(hydroxymethyl)-2H-pyran-3-yl)-1H-benzimidazole (example
36, 1.50 g, 4.73 mmol) in 15 ML of dry DMF at 0.degree. C. was
added imidazole (0.40 g, 5.68 mmol) followed by
tert-butyldimethylsilyl chloride (0.81 g, 5.20 mmol). The reaction
was allowed to warm to room temperature, stirred overnight then
diluted with water (100 ML) and extracted with chloroform (100 ML).
The organic layer was dried over sodium sulfate, filtered and the
solvents were removed under reduced pressure. Purification by flash
chromatography on silica gel 60 eluting with 50% ethyl
acetate-hexanes afforded the title compound as a white solid (1.00
g, 50%) along with 0.40 g recovered starting material; m.p.
143-155.degree. C.; 1H-NMR (DMSO-d6, 200 MHz) .delta.:8.51, 8.09,
8.00 (s, each 1H), 4.90 (d, J=5.6 Hz, 1H), 4.89 (m, 1H), 4.26 (m,
1H), 3.91 (m, 1H), 3.86 (m, 1H), 3.55-3.42 (m, 1H), 3.32-3.24 (m,
2H), 2.29-2.19 (m, 1H). 1.97-1.83 (m, 1H), 0.91 (s, 9H), 0.97, 0.78
(s, each 3H).
[0267] Anal. Calcd. for C19H28Cl2N2O3Si. 0.40 H2O: C, 52.03; H,
6.62; N, 6.39; Cl, 16.16. Found: C, 52.20; H, 6.57; N, 6.39; Cl,
16.02.
[0268] b)
(3S,6R)-5,6-Dichloro-1-(3,6-dihydro-6-(((tert-butyldimethylsilyl- )
oxy)methyl)-2H-pyran-3-yl)-1H-benzimidazole
[0269] To a stirred solution of
(3S,5S,6R)-5,6-dichloro-1-(6-((tert-butyld-
imethylsilyl)oxy)methyl)-tetrahydro-5-hydroxy-2H-pyran-3-yl)-1H-benzimidaz-
ole (part a of this example, 1.51 g, 3.58 mmol) in 20 ML of
anhydrous methylene chloride at 0.degree. C. was added triethyl
amine (1.50 ML, 10.74 mmol) followed by dropwise addition of
methanesulfonyl chloride (0.42 ML, 5.37 mmol). The reaction was
stirred 10 minutes then poured into ice-water (50 ML) and extracted
with methylene chloride (2.times.50 ML). The combined organic
extracts were washed successively with saturated ammonium chloride
and bine (50 ML each), then dried over sodium sulfate. Filtration
and removal of solvents under reduced pressure afforded the crude
mesylate (1.83 g) as a white foam which was dissolved in toluene
(25 ML), treated with 1,8-diazobicyclo[5.4.0]undec-7-ene (1.40 ML,
8.95 mmol) and heated at reflux for 48 h. The reaction mixture was
cooled to room temperature, diluted with ethyl acetate (100 ML) and
washed with saturated aqueous ammonium chloride (50 ML) then brine
(50 ML). The organic extracts were suction-filtered through a plug
of flash silica gel, washing with additional ethyl acetate (50 ML),
and the solvents were evaporated under reduced pressure affording
1.37 g (94%) of the title compound as a tan oil; 1H-NMR (DMSO-d6,
200 MHz) .delta.:8.39, 8.14, 7.98 (s, each 1H), 6.25 (bd, J=10.5
Hz, 1H), 6.10 (bd, J=10.2 Hz, 1H), 5.15 (m, 1H), 4.28 (m, 1H), 3.84
(m, 4H), 0.91 (s, 9H), 0.11, 0.97 (s, each 3H).
[0270] c)
(3R,4S,5S,6R)-1-(6-((tert-butyldimethylsilyl)oxy)-tetrahydro-4,5-
-dihydroxy-2H-pyran-3-yl)-5,6-dichloro-1H-benzimidazole
[0271] To a stirred solution of the olefin (part b of this example,
1.30 g, 3.14 mmol) in 30 ML of acetone-water (8:1) was added
4-methylmorpholine N-oxide (0.42 g, 3.45 mmol) followed by osmium
tetroxide (0.60 ML of a 2.5% solution in tert-butanol). The
reaction was stirred 24 h then treated with an additional 0.6 ML of
osmium tetroxide solution and stirred an additional 24 h. The
reaction mixture was concentrated and chromatographed on silica gel
60. The title compound eluted with 2% methanol-chloroform as a
white glass, after evaporation of solvents (1.14 g, 81%); m.p.
128-130.degree. C.; 1H-NMR (DMSO-d6, 200 MHz) .delta.: 8.52, 8.01,
7.98 (s, each 1s), 5.49 (d, J=4 Hz, 1H), 4.68 (d, J=6.7 Hz, 1H),
4.58 (m, 1H), 4.18 (m, 2H), 3.95 (m, 1H), 3.84 (m, 2H), 3.66 (m,
1H), 3.48 (m, 1H), 0.90 (s, 9H), 0.96, 0.07 (s, each 3H).
[0272] Anal. Calcd. for C19H28Cl2N2O4Si. 1.0 H2O: C, 49.03;H, 6.50;
N, 6.02; Cl, 15.23. Found: C, 49.03;H, 6.54; N, 5.98; Cl,
15.13.
[0273] d)
(3R,4S,5S,6R)-5,6-dichloro-1-(tetrahydro-4,5-dihydroxy-6-(hydrox-
ymethyl)-2H-pyran-3-yl)-1H-benzimidazole
[0274] A solution of
(3R,4S,5S,6R)-1-(6-((tert-butyldimethylsilyl)oxy)-tet-
rahydro-4,5-dihydroxy-2H-pyran-3-yl)-5,6-dichloro-1H-benzimidazole
(part c of this example, 1.08 g, 3.00 mmol) in THF (100 ML) and 1 N
HCl (3 ML) was stirred overnight. The reaction mixture was
concentrated under reduced pressure and the crude residue purified
by flash chromatography on silica gel 60. The title compound eluted
with 10% methanol-chloroform as a white crystalline solid, after
evaporation of solvents 0.704 g, 88%); m.p. 160-162.degree. C.;
1H-NMR (DMSO-d6, 200 MHz) .delta.: 8.59, 8.00 (s, each 1H), 5.46
(d, J=4.1 Hz, 1H), 4.72 (t, J=6.6 Hz, 1H), 4.73 (d, 1H), 4.58 (m,
1H), 4.15 (m, 2H), 3.96 (m, 1H), 3.70-3.39 (m, 4H).
[0275] Anal. Calcd. for C13H14Cl2N2O4. 1.5H2O: C, 43.35;H, 4.76, N,
7.78, Cl, 19.69. Found: C, 43.63;H, 4.60, N, 7.53, Cl, 19.94.
[0276] e)
(3R,4S,5S,6R)-2-Bromo-5,6-dichloro-1-(4,5-diacetoxy-6-(acetoxyme-
thyl) tetrahydro-2H-pyran-3-yl)-1H-benzimidazole
[0277] To a stirred solution of
(3R,4S,5S,6R)-5,6-dichloro-1-(tetrahydro-4- ,5-
dihydroxy-6-(hydroxymethyl)-2H-pyran-3-yl)-1H-benzimidazole (part d
of this example, 0.600 g, 1.80 mmol) in anhydrous pyridine (50 ml)
was added acetic anhydride (2.00 ml, 21.0 mmol). After 12 hours the
reaction mixture was concentrated under reduced pressure,
coevaporating with toluene to a viscous oil. Ethanol (ca. 5 ml) was
added (with external ice cooling) and the mixture was again
coevaporated with toluene (2.times.) until acetic acid odor was
absent. The oil was redissolved in chloroform (500 ml) and washed
successively with 0.1 N HCl (100 ml), saturated aqueous sodium
bicarbonate (100 ml), and brine (50 ml). The organic layer was
dried (sodium sulfate) and suction-filtered through a plug
(3.times.4 cm) of flash silica gel 60, washing with chloroform.
Evaporation of the solvents under reduced pressure left an
off-white foam (0.867 g, 1.89 mmol) which was dissolved in
anhydrous tetrahydrofuran (Aldrich Sure Seal, 15 ml), heated to
reflux under nitrogen with stirring, and N-bromosuccinimide
(Aldrich, 0.670 g, 3.78 mmol) was developed with 10%
methanol-chloroform indicated the reaction was complete. The yellow
solution was cooled to room temperature, diluted with chloroform
(200 ML) and washed with saturated aqueous sodium bicarbonate
(3.times.50 ML). The organic layer was dried (sodium sulfate),
filtered, and concentrated under reduced pressure. The crude
residue was purified by flash chromatography on silica gel 60.
Elution with 2% methanol-chloroform afforded a yellow foam after
removal of solvents. Trituration in ethanol-water and filtration
gave the title compound as a white crystalline solid (0.98 g, 83%);
m.p. 196-199.degree. C.; 1H-NMR (DMSO-d6, 200 MHz) .delta.: 8.27,
8.00 (s, each 1H), 5.58 (dd, J=8.4, 3.1 Hz, 1H), 5.17 (t, J=2.8 Hz,
1H), 5.09 (m, 1H), 4.55-4.17 (m, 5H), 2.15, 2.04, 1.93 (s, each
3H).
[0278] Anal. Calcd. for C19H19BrCl2N2O7: C, 42.40; H, 3.56; N,
5.21; total halogen as Cl, 13.18. Found: C, 42.58; H, 3.64; N,
5.16; total halogen as Cl, 13.22.
[0279] f)
(3R,4S,5S,6R)-2-Bromo-5,6-dichloro-1-(tetrahydro4,5-dihydroxy-6--
(hydroxymethyl)-2H-pyran-3-yl)-1H-benzimidazole
[0280]
(3R,4S,5S,6R)-2-Bromo-5,6-dichloro-1-(4,5-diacetoxy-6-(acetoxymethy-
l) tetrahydro-2H-pyran-3-yl)-1H-benzimidazole (part e of this
example, 0.810 g, 1.53 mmol) was dissolved in 1:1 methanol-ethanol
(100 ML) and treated with a solution of sodium carbonate (0.163 g,
1.53 mmol) in water (10 ML). After 0.5 h at room temperature, TLC
analysis indicated a single new spot (silica gel, 10%
methanol-chloroform). The pH was then adjusted to 5 with glacial
acetic acid and the solvents evaporated in vacuo. The residual
solid was slurried in water until the solids were free-flowing,
then suction-filtered and dried overnight in vacuo affording the
title compound as a white solid (0.510 g, 81%); m.p.
207-209.degree. C.; [.alpha.]20D-162.degree. (c 0.26, EtOH); 1H-NMR
(DMSO-d6, 200 MHz) .delta.: 8.30, 8.28 (s, each 1H), 5.26 (d, J=5.5
Hz, 1H), 5.13 (d, J=4.2 Hz, 1H), 5.05 (t, J=4.7 Hz, 1H), 5.04 (m,
1H), 4.78 (m, 1H), 4.33-4.00 (m, 3H), 3.84-3.68 (m, 3H).
[0281] Anal. Calcd. for C13H13BrCl2N2O4: C, 37.89; H, 3.13; N,
6.80; halogen as Cl, 17.20. Found: C, 38.08; H, 3.2; N, 6.86; total
halogen as Cl, 17.15.
Example 41
(3R,4S,5S,6R)-5,6-Dichloro-2-(cyclopropylamino)-1-(tetrahydro4,5-dihydroxy-
-6-(hydroxymethyl)-2H-pyran-3-yl)-1H-benzimidazole
[0282] A solution of
(3R,4S,5S,6R)-2-Bromo-5,6-dichloro-1-(tetrahydro4,5-d-
ihydroxy-6-(hydroxymethyl)-2H-pyran-3-yl)-1H-benzimidazole (Example
40, part e, 0.300 g, 0.728 mmol) and cyclopropyl amine (Aldrich,
2.50 ML, 36 mmol) in absolute ethanol (10 ML) was refluxed under
nitrogen for 24 h. 1 N sodium hydroxide (0.73 ml) was added and the
reaction mixture was concentrated under reduced pressure. The
residual solids were chromatographed on silica gel 60. Title
compound was eluted with 10% methanol-chloroform as a white foam,
after evaporation of solvents (0.100 g, 34%); m.p. 244.degree. C.
(decomposition); [.alpha.]20D+6.4 (c 0.25, MeOH); 1H-NMR (DMSO-d6,
200 MHz) .delta.: 7.65, 7.41 (s, each 1H), 7.37 (bs, 1H), 5.33 (m,
1H), 4.91 (m, 2H), 4.36 (m, 1H), 4.10-3.90 (m, 3H), 3.69 (m, 3H),
2.80 (m, 1H), 2.45 (m, m, 1H), 0.72-0.51 (m, 4H).
[0283] Anal. Calcd. for C16H19Cl2N3O4 . 3.0 H2O: C, 43.10; H, 5.74;
N, 9.42; Cl, 15.90. Found: C, 43.27; H, 5.56; N, 9.37; Cl,
15.64.
Example 42
(3S,4R,5R,6S)-2-Bromo-5,6-dichloro-1-(tetrahydro-4,5-dihydroxy-6-(hydroxym-
ethyl)-2H-pyran-3-yl)-1H-benzimidazole
[0284] The title compound was prepared in the same manner as the
enantiomer described in example 40 starting from L-glucose-derived
2S,4-.alpha.-S,7S,8-.alpha.-R-perhydro-7-hydroxy-2-phenylpyrano(3,2-D)1,3-
)dioxin ((Tetrahedron Letters, 1996, 8147 and references cited
therein): m.p. 207-208.degree. C.; [.alpha.]20D+175 (c 0.25, EtCH);
1H-NMR (CDCl3, 200 Mhz) data was identical to that of the
enantiomer.
[0285] Anal. Calcd. for C13H13BrCl2N2O4: C, 37.89; H, 3.18; N,
6.80; total halogen as Cl, 17.20. Found: C, 38.17; H, 3.24; N,
6.76; total halogen as Cl, 17.13.
Example 43
(3S,4R,5R,6S)-5,6-Dichloro-2-(cyclopropylamino)-1-(tetrahydro-4,5-dihydrox-
y-6-(hydroxymethyl)-2H-pyran-3-yl)-1H-benzimidazole
[0286] The title compound was prepared in the same manner as the
enantiomer (example 41) starting from L-glucose-derived
2S,4-.alpha.-S,7S,8-.alpha.-R-perhydro-7-hydroxy-2-phenylpyrano(3,2-D)1,3-
)dioxin ((Tetrahedron Letters, 1996, 8147 and references cited
therein): m.p. 164.degree. C.; [.alpha.]20D-8.4 (c 0.25, MeOH);
1H-NMR (CDCl3, 200 Mhz) identical to that reported in example
41.
[0287] Anal. Calcd. for C16H19Cl2N3O4 . 0.60H2O: C, 48.16; H, 5.10,
N, 10.53, Cl, 17.77. Found: C, 48.18; H, 5.05, N, 10.38, Cl,
17.65.
Example 44
(3S,4R,5R,6S)-5,6-Dichloro-2-(isopropylamino)-1-(tetrahydro-4,5-dihydroxy--
6-(hydroxymethyl)-2H-pyran-3-yl)-1H-benzimidazole
[0288] A solution of
(3S,4R,5R,6S)-2-bromo-5,6-dichloro-1-(tetrahydro-4,5--
dihydroxy-6-(Hydroxymethyl)-2H-pyran-3-yl)-1H-benzimidazole
(Example 42, 0.328 g, 0.795 mmol) in isopropylamine (10 ml) was
heated to 100.degree. C. in a sealed tube overnight. 1 N sodium
hydroxide (0.80 ml) was added and the reaction mixture was
concentrated under reduced pressure. The residual solids were
chromatographed on silica gel 60. Title compound was eluted with
2-10% methanol-chloroform as a white foam, after evaporation of
solvents (0.15 g, 51%); m.p. 123.degree. C.; [.alpha.]20D-23.0 (c
0.25, MeOH); 1H-NMR (DMSO-d6, 200 Mhz) .delta.7.59, 7.39 (s, each
1H), 7.15 (bs, 1H), 5.44 (m, 1H), 4.90 (m, 2H), 4.39 (m, 1H),
4.14-3.61 (m, 7H), 1.23 (d, J=6.4 Hz, 6H).
[0289] Anal. Calcd. for C16H21Cl2N3O. 0.30 H2O. 0.20 EtOH: C,
48.82; H, 5.66; N, 10.17; Cl, 17.16. Found: C, 48.84; H, 5.69; N,
10.08; Cl, 17.07.
Example 45
(.+-.)-trans-2-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohexanol
[0290] a)
(.+-.)-trans-2-(5,6-Dichloro-1H-benzimidazol-1-yl)cyclohexanol
[0291] 5,6-Dichlorobenzimidazole (Townsend and Revankar, Chem. Rev.
1970, 70:389, and references cited therein) (5.00 g, 26.0 mmol) was
dissolved in N,N-dimethylformamide (65 ml) and sodium hydride (60%
oil dispersion, 50 mg) was added. The solution was heated to
145.degree. and cyclohexene oxide (Aldrich, 7.8 g, 26 mmol) was
added in 3 portions over 3 hours. The solution was neutralized with
1 N hydrochloric acid, and evaporated to a purple solid. The solid
was recrystallized from ethanol to give title compound as pink
crystals (12.55 g, 88%); m.p. 236-238.degree. C.
[0292] Anal. Calcd. for C13H14Cl2N2O: C, 54.75; H, 4.95; N, 9.82;
Cl, 24.86. Found: C, 54.91; H, 4.84; N, 9.80; Cl, 24.93.
[0293] b)
(.+-.)-trans-2-(5,6-Dichloro-1H-benzimidazol-1-yl)cyclohexyl
Acetate
[0294]
(.+-.)-trans-2-(5,6-Dichloro-1H-benzimidazol-1-yl)cyclohexanol
(part a of this example, 6.25 g, 21.9 mmol) was stirred in acetic
anhydride (3 ml)-pyridine (50 ml) for 18 h. Volatiles were
evaporated and the residue partitioned between chloroform and
saturated aqueous sodium bicarbonate. The chloroform solution was
filtered through Celite/charcoal and evaporated to give title
compound as an off-white solid (6.92 g, 97%), m.p. 145-147.degree.
C.
[0295] Anal. Calcd. for C15H16Cl2N2O2: C, 55.06; H, 4.93; N, 8.56;
Cl, 21.67. Found: C, 55.15; H, 4.88; N, 8.64; Cl, 21.77.
[0296] c)
(.+-.)-trans-2-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)cycloh-
exyl Acetate
[0297] (.+-.)-Trans-2-(5,6-dichloro-1H-benzimidazol-1-yl)cyclohexyl
acetate (part b of this example, 6.62 g, 20.2 mmol) in
tetrahydrofuran (120 ml) was refluxed while N-bromosuccinimide
(7.20 g, 40.5 mmol) was added in one portion. Reflux was continued
for 10 minutes. The solution was cooled and diluted with chloroform
(200 ml). The chloroform solution was extracted with aqueous sodium
bicarbonate, then water, and dried (sodium sulfate). Evaporation of
volatiles in vacuo left white crystals, after trituration from
ethyl acetate-hexanes (5.77 g, 70%), m.p. 167-169.degree. C.
[0298] Anal. Calcd. for C15H15BrCl2N2O2: C, 44.37; H, 3.72; N,
6.90; total halogen as Cl, 26.19. Found: C, 44.41; H, 3.69; N,
6.84; total halogen as Cl, 26.19.
[0299] d)
(.+-.)-Trans-2-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)cycloh-
exanol
[0300]
(.+-.)-Trans-2-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohexy-
l acetate (part c of this example, 500 mg, 1.23 mmol) was dissolved
in methanol half-saturated with ammonia (at 0.degree. C.) and the
solution stirred at room temperature for 18 hours. Volatiles were
evaporated and the residual solid recrystallized from
methanol-water to give title compound as white crystals (350 mg,
78%), m.p. 186-188.degree. C.; 1H-NMR (DMSO-d6, 200 MHz) .delta.:
8.23, 7.93 (both s, each 1, 2 aromatic CH), 4.99 (d, J=4.7 Hz, 1,
OH), 4.3-4.1 (m, 2, OCH and NCH), 2.4-1.3 (m, 8, 4CH2).
[0301] Anal. Calcd. for C13H13BrCl2N2O: C, 42.89; H, 3.60; N, 7.70;
total halogen as Cl, 29.21. Found: C, 42.99; H, 3.68; N, 7.61;
total halogen as Cl, 29.14.
[0302] e) Separation of the Enantiomers of
(.+-.)-Trans-2-(2-bromo-5,6-dic-
hloro-1H-benzimidazol-1-yl)cyclohexanol
[0303] The enantiomers of
(.+-.)-trans-2-(2-bromo-5,6-dichloro-1H-benzimid-
azol-1-yl)cyclohexanol were separated on a Rainin preparative
chiral HPLC instrument using a 2 cm Chiralpak.RTM. AD amylose
column (Chiral Technology Inc., Exton, Pa.). Using a mobile phase
of 90% hexanes-10% isopropyl alcohol and a flow rate of 6.0 ml/min,
the enantiomers were eluted with retention times of 10.40 and 13.68
min. Fractions containing each peak were pooled and solvents
evaporated. Each enantiomer was shown to be free of the other by
analytical chiral HPLC on an analytical Chiralpak.RTM. AD amylose
column (Chiral Technology Inc., Exton, Pa.). The enantiomer with a
retention time of 10.40 min was isolated, after evaporation of
solvents and drying at 0.1 mm Hg, as white powder, m.p.
206-207.degree. C.; 1H-NMR (DMSQ-d6, 200 Mhz) identical with that
of the racemate described in part d of this example.
[0304] Anal. Calcd. for C13H13BrCl2N2O. 0.225 hexanes: C, 44.95; H,
4.25; N, 7.31; total halogen as Cl, 27.74. Found: C, 45.00; H,
4.02; N, 7.26; total halogen as Cl, 27.59.
[0305] The enantiomer with a retention time of 13.79 min was
isolated, after evaporation of solvents and drying at 0.1 mm Hg, as
white powder, m.p. 201-202.degree. C.; 1H-NMR (DMSO-d6, 200 Mhz)
identical with that of the racemate described in part d of this
example.
[0306] Anal. Calcd. for C13H13BrCl2N2O. 0.285 hexanes: C, 45.46; H,
4.41; N, 7.21; total halogen as Cl, 27.37. Found: C, 45.67; H,
4.13; N, 7.17; total halogen as Cl, 27.07.
Example 46
(.+-.)-trans-2-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]cyc-
lohexanol
[0307]
(.+-.)-trans-2-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohexy-
l acetate (Example 45, part c, 1.00 g, 2.46 mmol) and
cyclopropylamine (5.0 ml) were refluxed in absolute ethanol (15 ml)
for 3 days. The solution was cooled and 1 N sodium hydroxide (2.4
ml) was added. The residual solid was crystallized from
ethanol-water to provide title compound as off-white powder (0.56
g, 67%), m.p. 149-151.degree. C.; 1H-NMR (DMSO-d6, 200 MHz)
.delta.: 7.55, 7.39 (both s, each 1, 2 aromatic CH), 6.90 (m, 1,
NH), 4.73 (d, J=5.2 Hz, 1, OH), 4.1-3.8 (m, 2, OCH and NCH),
2.8-2.65 (m, 1, CHNH), 2.2-1.9 and 1.8-1.2 (m, 8, 4 CH2), 0.75-0.45
(m, 4, 2 cyclopropyl CH2).
[0308] Anal. Calcd. for C16H19Cl2N3O: C, 55.89; H, 5.69; N, 12.22;
Cl, 20.62. Found: C, 55.90; H, 5.78; N, 12.22; Cl, 20.67.
Example 47
(.+-.)-(1R*, 2S*,
3R*)-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-c-
yclohexanediol
[0309] a) (.+-.)-(1R*, 2S*,
3R*)-3-(4,5-Dichloro-2-nitroanilino)-1,2-cyclo- hexanediyl
Diacetate
[0310] (.+-.)-(1R*, 2S*, 3R*)-3-Aminocyclohexane-1,2-diol
hydrochloride (Tetrahedron Letters 1984, 25: 3259) (6.42 g, 38.3
mmol) was refluxed in t-butyl alcohol (50 ml) with anhydrous
potassium carbonate (Aldrich, 16.2 g, 0.115 mole as 98%) and
1,2,4-trichloro-5-nitrobenzene (9.10 g, 39 mmol as 97%) for 2 days.
Volatiles were evaporated and the residue chromatographed on silica
gel. Elution with 1% methanol-chloroform gave the major product as
a yellow powder (4.77 g, 39%), after crystallization from
ethanol-water. This material was stirred in pyridine (45 ml)-acetic
anhydride (8.4 ml) for 2 days. Volatiles were evaporated and the
residue chromatographed on silica gel. Title compound was eluted
with chloroform to give, after crystallization from ethyl
acetate-hexanes, orange crystals (4.30 g, 71%), m.p.
178-180.degree. C. dec.
[0311] Anal. Calcd. for C16H18Cl2N2O6: C, 47.42; H, 4.48; N, 6.91;
Cl, 17.50. Found: C, 57.50; H, 4.47; N, 6.90; Cl, 17.41.
[0312] b) (.+-.)-(1R*, 2S*,
3R*)-3-(5,6-Dichloro-1H-benzimidazol-1-yl)-1,2- -cyclohexanediyl
Diacetate
[0313] (.+-.)-(1R*, 2S*,
3R*)-3-(4,5-Dichloro-2-nitroanilino)-1,2-cyclohex- anediyl
diacetate (part a of this example, 5.65 g, 13.9 mmol) in n-propanol
(250 ml) was shaken with Raney nickel (Aldrich, ca. 0.50 g) under
hydrogen (50 psi) for 2 h. Filtration through Celite and
evaporation of solvent left the 5,6-diaminobenzimidazole
intermediate. Triethylorthoformate (250 ml) and 4 drops of
methanesulfonic acid were added and the solution stirred at room
temperature for 2 days. Volatiles were evaporated in vacuo and the
residual material chromatographed on silica gel. Title compound
eluted with 2% methanol-ethyl acetate as off-white solid (1.87 g,
35%), m.p. 163-165.degree. C.
[0314] Anal. Calcd. for C17H18Cl2N2O4: C, 53.00; H, 4.71; N, 7.27;
Cl, 18.41. Found: C, 52.85; H, 4.72; N, 7.17; Cl, 18.35.
[0315] c) (.+-.)-(1R*, 2S*,
3R*)-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-
-yl)-1,2-cyclohexanediyl Diacetate
[0316] (.+-.)-(1R*, 2S*,
3R*)-3-(5,6-Dichtoro-1H-benzimidazol-1-yl)-1,2-cy- clohexanediyl
diacetate (part b of this example, 1.58 g, 4.10 mmol) was dissolved
in dry N,N dimethylformamide (6.4 ml) and maintained at 65.degree.
C. under nitrogen while N-bromosuccinimide (1.46 g, 8.2 mmol) was
added in 2 portions over 1 h. Volatiles were evaporated in vacuo
and the residue was chromatographed on silica gel. Title compound
was eluted with ethyl acetate as an off-white powder (0.95 g, 49%),
m.p. 71-79.degree. C.,
[0317] Anal. Calcd. for C17H17BrCl2N2O4: C, 43.99; H, 3.69; N,
6.04; total halogen as Cl, 22.92. Found: C, 44.04; H, 8.83; N,
6.01; total halogen as Cl, 22.85.
[0318] d) (.+-.)-(1R*, 2S*,
3R*)-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-
-yl)-1,2-cyclohexanediol
[0319] (.+-.)-(1R*, 2S*,
3R*)-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl-
)-1,2-cyclohexanediyl diacetate (part c of this example, 700 mg,
1.51 mmol) was dissolved in ethanol (12 ml)-methanol (12 ml)-water
(3 ml). Sodium carbonate (160 mg, 1.5 mmol) was added and the
mixture was stirred vigorously for 3 h. Volatiles were evaporated
in vacuo and the residual solids were slurried in water. The solid
was recrystallized from ethanol to give title compound as white
powder (260 mg, 45%), m.p. 197-199.degree. C. dec.; 1H-NMR
(DMSO-d6, 200 MHz) .delta.: 8.26 and 7.92 (both s, each 1, 2
aromatic CH), 4.8-4.6 (m, 3, OCH and 2OH),.4.26-4.20 (m, 1, NCH),
4.17-3.98 (m, 1, OCH), 2.24-2.19 (m, 1, 1/2 CH2), 1.84-1.74 (m, 4,
2 CH2), 1.60-1.53 (m, 4, 1, 1/2 CH2).
[0320] Anal. Calcd. for C13H13BrCl2N2O2: C, 41.08; H, 3.45; N,
7.37; total halogen as Cl, 27.98. Found: C, 41.18; H, 3.49; N,
7.31; total halogen as Cl, 27.92.
[0321] e) Separation of the Enantiomers of (.+-.)-(1R*, 2S*,
3R*)-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclohexanediol
[0322] The enantiomers of (.+-.)-(1R*, 2S*,
3R*)-3-(2-bromo-5,6-dichloro-1-
H-benzimidazol-1-yl)-1,2-cyclohexanediol were separated on a Rainin
preparative chiral HPLC instrument using a 2 cm Chiralpak.RTM. AD
amylose column (Chiral Technology Inc., Exton, Pa.). Using a mobile
phase of 90% hexanes-10% isopropyl alcohol and a flow rate of 6.0
ml/min, the enantiomers were eluted with retention times of 14.28
and 19.25 min. Fractions containing each peak were pooled and
solvents evaporated. Each enantiomer was shown to be free of the
other by analytical chiral HPLC on an analytical Chiralpak.RTM. AD
amylose column (Chiral Technology Inc., Exton, Pa.). After
evaporation of souvenirs and drying at 0.1 mm Hg, both enantiomers
were isolated as white powders, m.p. 200.degree. C. dec.; 1H-NMR
(DMSO-d6, 200 Mhz) identical with that of the racemate described in
part d of this example.
Example 48
(.+-.)-(1R*,2S*,3R*)-3-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol--
1-yl]-1,2-cyclohexanediol
[0323]
(.+-.)-(1R*,2S*,3R*)-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)--
1,2-cyclohexanediyl diacetate (464 mg, 1.00 mmol) and
cyclopropylamine were reacted as in example 46. The solution was
cooled and 1 N sodium hydroxide (one equivalent) was added.
Volatiles were evaporated in vacuo and the residual solid was
crystallized from methanol to provide title compound as off-white
powder (271 mg, 76%), m.p. >250.degree. C.; 1H-NMR (DMSO-d6, 200
MHz) .delta.: 7.62, 7.44 (both s, each 1, 2 aromatic CH), 7.00-6.95
(m, 1, NH),.4.66 (d, J=6.2 Hz, 1, OH), 4.56 (d, J=2.7 Hz, 1, OH),
4.3-3.9 (m, 3, 2 OCH and NCH), 2.8-2.65 (m, 1, NCH), 2.1-1.4 (m, 6,
3 CH2), 0.75-0.45 (m, 4, 2 CH2 of cyclopropyl).
[0324] Anal. Calcd. for C16H19Cl2N3O: C, 54.09; H, 5.39; N, 11.83;
Cl, 19.69. Found: C, 53.81; H,5.44; N, 11.60; Cl, 19.98.
Example 49
(.+-.)-(1R*,2S*,4R*)4-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohexa-
ne-1,2-diol
[0325] (a)
(.+-.)-{1-[2-(Trimethylsilyl)ethyl]oxycarbonylamino}cyclohex-3--
ene
[0326] Diphenylphosphoryl azide (8.58 ml, 39.64 mmol) was added to
triethylamine (5.52 ml, 39.64 mmol) in toluene (80 ml) and the
reaction was heated to 75.degree. C. Then,
(.+-.)-cyclohex-3-enecarboxylic acid (5.00 g, 39.64 mmol) in
toiuene (20 ml) was added dropwise and the reaction was stirred for
1 hr. Then, 2-(trimethylsilyl)ethanol (6.53 ml, 47.56 mmol) was
added and the reaction was stirred at 60.degree. C. for 17 hr. The
reaction was cooled and 1.0 N sodium hydroxide added. The mixture
was extracted with ethyl acetate, dried with magnesium sulfate,
filtered, and concentrated. The residue was purified by column
chromatography eluting with ethyl acetate:hexanes (1:9) to give the
title compound (7.46 g, 78%). Rf=0.40 (1:4 ethyl acetate:hexanes);
1H-NMR (CDCl3, 300 MHz) .delta.5.67-5.55 (m, 2H), 4.59 (br s, 1H),
4.12 (t, 2H, J=8), 3.80 (s, 1H), 2.36 (d, 1H, J=7), 2.09 (m, 2H),
1.89-1.81 (m, 2H), 1.57-1.48 (m, 1H), 0.95 (t, 2H, J=8), 0.01 (s,
9H); MS (ES) M+Na =264.
[0327] (b)
(.+-.)-(1R*,3S*,5R*)-(2-Nitro4,5-dichlorophenyl)-(2,2-dimethyl--
hexahydro-benzo-1,3-dioxol-5-yl)amine and
(.+-.)-(1S*,3R*,5R*)-(2-nitro-4,-
5-dichlorophenyl)-(2,2-dimethyl-hexahydro-benzo-1,3-dioxol-5-yl)amine
[0328] 4-Methylmorpholine N-oxide (4.85 g, 41.42 mmol) was added to
(.+-.)-{1-[2-(trimethylsilyl)ethyl]oxycarbonylamino}cyclohex-3-ene
(part a of this experiment (10.00 g, 41.42 mmol) in acetone:water
(9:1, 83 ml), then osmium tetroxide (10.5 mg, 41.4 mmol) was added
and the reaction was stirred for 15 hr and concentrated. The
residue was purified by column chromatography eluting with ethyl
acetate to give the diols as a mixture of isomers (1:1) (10.53 g,
93%). The product was taken up in acetone (192 ml) and pyridinium
para-toluenesulfonate (960.8 mg, 3.82 mmol) was added. The reaction
was heated at reflux for 19 hr, cooled, and concentrated. The
residue was purified by column chromatography eluting with ethyl
acetate:hexanes (2:3) to give the acetonides (9.20 g, 76%). The
residue was taken up in acetonitrile (146 ml) and
tetraethylammonium fluoride hydrate (5.37 g, 32.08 mmol) was added.
The mixture was heated at reflux for 19 hr, cooled, and
concentrated. The residue was taken up in dioxane (146 ml) and
potassium carbonate (8.06 g, 58.32 mmol) was added. Then,
2-fluoro-4,5-dichloronitrobenzene (6.43 g, 30.62 mmol) was added
and the reaction was heated at 70.degree. C. for 66 hr. The mixture
was cooled, brine added, extracted with ethyl acetate, dried with
magnesium sulfate, filtered, and concentrated. The residue was
purified by column chromatography eluting with ethyl
acetate:hexanes (1:4) to give the title compounds (8.54 g, 81%).
Rf=0.24 (1:4 ethyl acetate:hexanes); 1H-NMR (CDCl3, 300 MHz)
.delta.8.26 (s, 1H), 7.92 (d, 1H, J=7), 6.99 (s, 1H), 4.34 (m, 1H),
4.17 (q, 1H, J=8), 3.78 (m, 1H), 2.41 (d, 1H, J=14), 2.15-2.00 (m,
1H), 1.97-1.88 (m, 1H), 1.84-1.62 (m, 2H), 1.55 (s, 3H), 1.40-1.32
(m, 1H), 1.35 (s, 3H); MS (ES) M+Na=384. Rf=0.15 (1:4 ethyl
acetate:hexanes); 1H-NMR (CDCl3, 300 MHz) d 8.57 (d, I H, J=7),
8.27 (s, 1H), 6.89 (s, 1H), 4.29 (q, 1H, J=5), 4.16 (q, 1H, J=6),
3.66 (m, 1H), 2.10 (m, 2H), 1.91-1.67 (m, 4H), 1.57 (s, 3H), 1.36
(s, 3H); MS (ES) M+H=361.
[0329] (c)
(.+-.)-(1R*,3S*,5R*)-4,5-Dichloro-N-[2,2-dimethyl-hexahydro-ben-
zo(1,3)dioxol-5-yl]-benzene-1,2-diamine
[0330] Raney nickel (1.21 g, 100 wt %) was added to
(.+-.)-(1R*,3S*,5R*)-(2-nitro-4,5-dichlorophenyl)-(2,2-dimethyl-hexahydro-
-benzo-1,3-dioxol-5-yl)amine and
(.+-.)-(1S*,3R*,5R*)-(2-nitro-4,5-dichlor-
o-phenyl)-(2,2-dimethyl-hexahydro-benzo-1,3-dioxol-5-yl)amine (part
b of this example, 1.21 g, 3.35 mmol) in methanol (17 ml) at rt
under an argon atmosphere. The reaction was fitted with a hydrogen
balloon, repeatedly evacuated and purged with hydrogen, then
allowed to stir for 3 hr. The reaction was purged with nitrogen,
filtered through Celite.RTM., and concentrated. The residue was
purified by column chromatography eluting with ethyl
acetate:hexanes (3:2) to give the title compound (720 mg, 65%).
Rf=0.29 (3:2 ethyl acetate:hexanes); 1H-NMR (CD3OD, 300 MHz)
.delta.6.74 (s, 1H), 6.58 (s, 1H), 4.36 (q, 1H, J=5), 4.18-4.12 (m,
1H), 3.57-3.47 (m, 1H), 2.33 (d, 1H, J=15), 2.00-1.86 (m, 2H),
1.74-1.59 (m, 2H), 1.52 (s, 3H), 1.33 (s, 3H), 1.30-1.22 (m, 1H);
MS (ES) M+H=331.
[0331] (d)
(.+-.)-[1R*,3S*,5R*)-5,6-Dichloro-1-(2,2-dimethyl-hexahydro-ben-
zo[1,3]dioxol-5-yl)-1H-benzimidazole
[0332]
(.+-.)-(1R*,3S*,5R*)4,5-Dichloro-N-[2,2-dimethyl-hexahydro-benzo(1,-
3)dioxol-5-yl]-benzene-1,2-diamine (part of this experiment, 720 mg
2.17 mmol) was taken up in triethyl orthoformate (11 ml) and the
reaction was heated at 80.degree. C. for 14 hr and concentrated.
The residue was purified by column chromatography eluting with
methanol:ethyl acetate (1:99) to give the title compound (673.1 mg,
91%). Rf=0.23 (ethyl acetate); 1H-NMR (CD3OD, 300 MHz) .delta.8.37
(s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 4.71-4.63 (m, 1H), 4.49-4.45
(m, 1H), 4.30-4.24 (m,.sub.1H), 2.50-2.44 (m, 1H), 2.36-2.26 (m,
1H), 2.12-2.01 (m, 2H), 1.97-1.83 (m, 2H), 1.57 (s, 3H), 1.36 (s,
3H); MS (ES) M+H=341.
[0333] (e)
(.+-.)-(1R*,2S*,4R*)-4-(5,6-Dichloro-1H-benzimidazol-1-yl)cyclo-
hexane-1,2-diol
[0334] Pyrdinium para-toluenesulfonate (33.6 mg, 134.7 mmol) was
added to
(.+-.)-5,6-dichloro-1-(2,2-dimethyl-hexahydro-benzo[1,3]dioxol-5-yl)-1H-b-
enzimidazole (part d of this experiment, 459.6 mg, 1.35 mmol) in
methanol (7 ml) and the reaction was heated at reflux for 19 hr and
concentrated. The residue was purified by column chromatography
eluting with methanol:ethyl acetate (1:9) to give the title
compound (184.4 mg, 45%). Rf=0.19 (1:9 methanol:ethyl acetate);
1H-NMR (CD3OD, 300 MHz) .delta.8.36 (s, 1H), 7.91 (s, 1H), 7.80 (s,
1H), 4.70 (tt, 1H, J=12,4), 4.11 (d, 1H, J=3), 3.79-3.73 (m, 1H),
2.26 (dq, 1H, J=13, 3), 2.15-2.10 (m, 2H), 2.06-1.99 (m, 2H),
1.88-1.85 (m, 1H); MS (ES) M+H=301.
[0335] (f)
(.+-.)-[1R*,3S*,5R*]-2-Bromo-5,6-dichloro-1-(2,2-dimethyl-hexah-
ydro-benzo[1,3]dioxol-5-yl)-1H-benzimidazole
[0336] N-bromosuccinimide (702 mg, 3.94 mmol) was added to
(.+-.)-(1R*,2S*,4R*)-4-(5,6-dichloro-1H-benzimidazol-1-yl)cyclohexane-1,2-
-diol (part e of this example, 673.1 mg, 1.97 mmol) in
tetrahydrofuran (20 ml) at reflux and the reaction was stirred for
15 min. The mixture was poured into ice water, saturated sodium
bicarbonate added, extracted with ethyl acetate, dried with
magnesium sulfate, filtered, and concentrated. The residue was
purified by column chromatography eluting with ethyl
acetate:hexanes (2.3) to give the title compound (187.7 mg, 23%)
and recovered starting material (459.6 mg, 68%). Rf=0.35 (2:3 ethyl
acetate:hexanes); 1H-NMR (CDCl3, 300 MHz) 67 7.78 (s, 1H), 7.49 (s,
1H), 4.96-4.92 (m, 1H), 4.50-4.48 (m, 1H), 4.39-4.33 (m, 1H), 2.39
(dt, 1H, J=14, 3), 2.16-1.92 (m, 5H), 1.60 (s, 3H), 1.38 (s, 3H);
MS (ES) M+H=421.
[0337] (g)
(.+-.)-(1R*,2S*,4R*)-4-(2-Bromo-5,6-dichloro-1H-benzimidazol-1--
yl)cyclohexane-1,2-diol
[0338] Pyridinium para-toluenesulfonate (part f of this example,
11.2 mg, 44.7 mmol) was added to
(.+-.)-[1R*,3S*,5R*]-2-bromo-5,6-dichloro-1-(2,2--
dimethyl-hexahydro-benzo[1,3]dioxol-5-yl)-1H-benzimidazole (part f
of this example, 187.7 mg, 446.8 mmol) in methanol (9 ml) and the
reaction was heated at reflux for 14 hr and concentrated. The
residue was purified by column chromatography eluting with
methanol:ethyl acetate (1:99) to give the title compound (130.2 mg,
77%). Rf=0.23 (ethyl acetate); 1H-NMR (CD3OD, 300 MHz) .delta.7.98
(s, 1H), 7.73 (s, 1H), 5.03 (tt, 1H, J=13, 4), 4.12 (s, 1H), 3.86
(dt, 1H, J=11, 4), 2.54 (dt, 1H, J=13,2), 2.38 (dq, 1H, J=13, 5),
2.05-1.83 (m, 4H); MS (ES) M+H=381.
Example 50
(.+-.)-(1R*,2S*,4R*)-4-(2-isopropylamino-5,6-dichloro-1H-benzimidazol-1-yl-
)cyclohexane-1,2-diol
[0339] Isopropylamine (99.5 mg, 1.68 mmol) was added to
(.+-.)-(1R*,2S*,4R*)-4-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohe-
xane-1,2-diol (Example 49, part g, 64.0 mg, 168.4 mmol) in ethanol
(3.4 ml) and the reaction was heated at 100.degree. C. in a sealed
tube for 67 hr. The reaction was cooled, saturated sodium carbonate
added, extracted with ethyl acetate, dried with magnesium sulfate,
and concentrated. The residue was purified by column chromatography
eluting with methanol:ethyl acetate (1:19) to give the title
compound (47.9 mg, 79%). Rf=0.24 (1:19 ethyl acetate); 1H-NMR
(CD3OD, 300 MHz) .delta.7.46 (s, 1H), 7.31 (s, 1H), 4.44 (ft, 1H,
J=13, 4), 4.11 (s, 1H), 4.05 (h, 1H, J=7), 3.82 (dt, 1H, J=10, 4),
2.41 (dt, 1H, J=13, 2), 2.26 (dq, 1H, J=13, 4), 2.04-1.75 (m, 4H),
1.29 (d, 6H, J=6); MS (ES) M+H=358.
Example 51
(.+-.)-(1S*,2R*,4R*)-4-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-cyclohe-
xane-1,2-diol
[0340] (a)
(.+-.)-(1S*,2R*,4R*)-4-(5,6-Dichloro-1H-benzimidazol-1-yl)cyclo-
hexane-1,2-diol
[0341] Raney nickel (1.81 g, 25wt %) was added to
(.+-.)-(1R*,3S*,5R*)-(2--
nitro-4,5-dichlorophenyl)-(2,2-dimethyl-hexahydro-benzo-1,3-dioxol-5-yl)am-
ine and
(.+-.)-(1S*,3R*,5R*)-(2-nitro-4,5-dichlorophenyl)-(2,2-dimethyl-he-
xahydro-benzo-1,3-dioxol-5-yl)amine (Example 49, part b, 7.25 g,
20.07 mmol) in methanol (100 ml) at rt under an argon atmosphere.
The reaction was fitted with a hydrogen balloon, repeatedly
evacuated and purged with hydrogen, then allowed to stir for 15 hr.
The reaction was purged with nitrogen, filtered through
Celite.RTM., and concentrated. The residue was purified by column
chromatography eluting with methanol:ethyl acetate (1:99) to give
the benzimidazolediol (2.88 g, 49%) as well as the other isomer.
The residue was taken up in triethyl orthoformate (49 ml) and the
reaction was heated at 80.degree. C. for 17 hr and concentrated.
The residue was purified by column chromatography eluting with
methanol:ethyl acetate (1:19) to give the residue as a mixture of
ortho ester isomers (3.39 g, 96%). Part of the residue (1.04 g,
2.91 mmol) was taken up in 1.0 N hydrochloric acid:tetrahydrofuran
(1:1, 14.6 ml) and the reaction was stirred for 16 hr. Then,
saturated sodium carbonate was added, the mixture was extracted
with ethyl acetate, dried with magnesium sulfate, filtered, and
concentrated. The residue was purified by column chromatography
eluting with methanol:ethyl acetate (1:9) to give the title
compound (753.2 mg, 86%). Rf=0.19 (1.9 methanol:ethyl acetate);
1H-NMR (CD3OD, 300 MHz) .delta.8.35 (s, 1H), 7.92 (s, 1H), 7.81 (s,
1H), 4.48 (tt, 1H, J=12, 4), 3.99 (d, 1H, J=3), 3.79 (dt, 1H, J=11,
4), 2.29 (q, 1H, J=12), 2.18 (dq, 1H, J=13, 4), 2.08-1.97 (m, 2H),
1.86-1.66 (m, 2H); MS (ES) M+H=301.
[0342] (b)
(.+-.)-(1S*,2R*,4R*)-4-(2-Bromo-5,6-dichloro-1H-benzimidazol-1--
yl)cyclohexane-1,2-diol
[0343] Triethylamine (694.7 mg, 6.86 mmol) was added to
(.+-.)-(1S*,2R*,4R*)-4-(5,6-dichloro-1H-benzimidazol-1-yl)cyclohexane-1,2-
-diol (part a of this example, 689.2 mg, 2.29 mmol) in methylene
chloride (23 ml). Then, 4-dimethylaminopyridine (28.2 mg, 0.23
mmol) was added, followed by acetic anhydride (475.0 ml, 5.03 mmol)
and the reaction was stirred for 14 hr. The mixture was quenched
with sodium carbonate, extracted with methylene chloride, dried
with magnesium sulfate, filtered, and concentrated. The residue was
purified by column chromatography eluting with ethyl
acetate:hexanes (9:1) to give the acetates (834.2 mg, 95%). The
residue was taken up in tetrahydrofuran (20 ml) and
N-bromosuccinimide (706.2 mg, 3.97 mmol) was added to the mixture
at reflux. After 15 min, the mixture was poured into ice water,
saturated sodium bicarbonate added, extracted with ethyl acetate,
dried with magnesium sulfate, filtered, and concentrated. The
residue was purified by column chromatography eluting with ethyl
acetate:hexanes (1:1) to give bromide (623.2 mg, 68%). The residue
was taken up in dioxane:water (1:1, 9 ml), lithium hydroxide
monohydrate (316.6 mg, 7.54 mmol) added, and stirred for 3 hr. The
mixture was extracted with ethyl acetate, dried with magnesium
sulfate, filtered, and concentrated. The residue was purified by
column chromatography eluting with methanol:ethyl acetate (1:99) to
give the title compound (326.3 mg, 91%). Rf=0.26 (ethyl acetate);
1H-NMR (CD3OD, 300 MHz) .delta.8.01 (s, 1H), 7.75 (s, 1H), 4.68
(tt, 1H, J=13, 4), 4.00 (s, 1H), 3.80-3.73 (m, 1H), 2.67-2.43 (m,
2H), 2.05-1.98 (m, 1H), 1.91-1.86 (m, 1H), 1.73-1.62 (m, 2H); MS
(ES) M+H=381.
Example 52
(.+-.)-(1S*,2R*,4R*)-4-(2-Isopropylamino-5,6-dichloro-1H-benzimidazol-1-yl-
)cyclohexane-1,2-diol
[0344] Isopropylamine (227.8 mg, 3.85 mmol) was added to
(.+-.)-(1S*,2R*,4R*)-4-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohe-
xane-1,2-diol (Example 51, part b, 146.5 mg, 385.4 mmol) in ethanol
(3.9 ml) and the reaction was heated at 100.degree. C. in a sealed
tube for 68 hr. The reaction was cooled, saturated sodium carbonate
added, extracted with ethyl acetate, dried with magnesium sulfate,
and concentrated. The residue was purified by column chromatography
eluting with methanol:ethyl acetate (1:19) to give the title
compound (104.1 mg, 75%). Rf=0.20 (1:19 methanol:ethyl acetate);
1H-NMR (CD3OD, 300 MHz) .delta.7.53 (s, 1H), 7.36 (s, 1H), 4.31
(tt, 1H, J=13, 4), 4.06 (h, 1H, J=7), 3.97 (s, 1H), 3.75-3.68 (m,
1H), 2.50 (q, 1H, J=12), 2.39 (dq, 1H, J=13, 4), 2.02-1.96 (m, 1H),
1.78-1.49 (m, 3H), 1.29 (d, 3H, J=7), 1.28 (d, 3H, J=7); MS (ES)
M+H=358.
Example 53
2-Bromo-5,6-dichloro-1-(4-deoxy-.beta.-D-erythro-pentopyranosyl)-1H-benzim-
idazole
[0345] 2-Bromo-5,6-dichloro-benzimidazole (0.5 g, 1.9 mmoles) which
can be prepared by the method of Townsend and Drach (U.S. Pat. No.
5,248,672) was added to 1,2-dichloroethane (Aldrich, Sure Seal, 35
ml). N,O-Bis(trimethylsilyl) acetamide (0.23 ml, 0.95 mmoles, 1
eq.) was added and the reaction heated to reflux for thirty minutes
in a 95.degree. C. oil bath.
4-Deoxy-1-methoxy-2,3-diacetyl-D-erythro-pentopyranoside (0.5 g,
2.1 mmoles) which can be prepared by the method of Kinoshita, et.
al. (Carbohydrate Research, 1982, 102, 298-301) was boiled in
toluene to remove water. The excess toluene was removed in vacuo
and the residue dissolved in 1,2-dichloroethane (15 ml). The
carbohydrate solution was added to the reaction followed by
trimethylsilyl trifluoromethanesulfonat- e (0.5 ml, 2.3 mmoles, 1.2
eq.). The reaction was heated for 18 hrs. Ice water (100 ml) was
added. The organic layer was collected and washed with saturated
sodium bicarbonate followed by brine. The organic solution was
dried with MgSO.sub.4, filtered, and the solvent removed in vacuo.
The product was purified by chromatography on a 2.5.times.10 cm
column of silica gel eluted with chloroform/methanol (98:2, v/v).
The product containing fractions were combined and the solvents
removed in vacuo. A 65% yield of
2-Bromo-5,6-dichloro-1-(4-deoxy-2,3-diacetyl-.beta.-D-erythr-
o-pentopyranosyl)-1H-benzimidazole was obtained. MS (GC-Cl+): mtz,
465, M+H.sup.+. A portion of the diacetyl compound (0.11 g, 0.24
mmoles) was deblocked by treatment in EtOH/H.sub.2O (1/1, vL/v, 16
ml) with Na.sub.2CO.sub.3 (0.1 g, 0.95 mmoles, 4 eq.) at rt for 1
hr: The product was purified by chromatography on a 4.times.6.5 cm
column of silica gel eluted with ethyl acetate/hexane (1:1, v/v).
MS (GC-Cl+): m/z, 381, M+H.sup.+. .sup.1H NMR (DMSO-d6) .delta.7.98
(s, 1H, aryl), 7.92 (s, 1H, aryl), 5.67 (d, 1H, H-1', J.sub.1',2'=9
Hz), 5.18(bs, 1H, OH), 5.02 (bs, 1H, OH), 4.06 (m, 2H, H-2', 3'),
3.8 (m, 2H, H-5'), 2.1 (m, 1H, H-4'), 1.67 (m, 1H, H-4').
Example 54
1-(2,3,4-Tri-O-acetyl-.alpha.-L-lyxopyranosyl)-2,5,6-trichlorobenzimidazol-
e
[0346] A three-necked 100 ml round bottom flask with a stirrer was
charged with 2,5,6-trichlorobenzimidazole(which may be prepared in
accordance with the methods described in PCT specifications
WO92/07867, 354 mg; 1.6 mmol) and the system evacuated and
backflushed with argon. Dry acetonitrile (40 ml) was added to this
suspension followed by the addition of N,
O-bis(trimethylsilyl)acetamide (325 mg, 1.6 mmol). To the stirred
solution was added 1,2,3,4-tetra-O-acetyl-.alpha.-L-lyxopyranosid-
e (M. Fuertes, J. T. Witkowski and R. K. Robins, J. Org. Chem., 40,
(1975), pp. 2372-2377, 488mg, 1.53 mmol) followed immediately by
the addition of trimethylsilyl trifluoromethanesulfonate (466 mg,
2.1 mmol) via a gastight syringe. The reaction was continued at
room temperature for 18 hours. The solvent was evaporated in vacuo
to yield a yellow oil which was subjected to column chromatography
(silica, 40.times.200 mm, 2% methanol in dichloromethane). The
appropriate fractions were combined to yield 303 mg (42.7%) of the
title compound as a white foam. .sup.1H NMR (DMSO-d.sub.6; 200 MHz)
.delta.8.012 (s, 1H), 6.013 (d, 1H, J=9.4 Hz), 5.502 (d, 1H, J=9.53
Hz), 5.426 (s, 1H), 5.051 (d, 1H, J=3.81 Hz), 4.220 (dd, 2H,
J=13.70 Hz, J=22.45 Hz), 2.269 (s, 3H), 1.801 (s, 3H).
Example 55
1-(.alpha.-L-Lyxopyranosyl)-2,5,6-trichlorobenzimidazole
[0347] A 100 ml round bottom flask was charged with
1-(2,3,4-Tri-O-acetyl-.alpha.-L-lyxopyranosyl)-2,5,6-trichlorobenzimidazo-
le (303 mg, 0.65 mmol) and this was dissolved in 50 ml of an
equimolar mixture of ethanol and water. To the stirred solution was
added anhydrous sodium carbonate (212 mg, 2.0 mmol) and the
reaction mixture allowed to stir at room temperature for 3 hours.
The A solution was neutralized with acetic acid and the solvent
evaporated in vacuo. the resultant solid was dissolved in ethyl
acetate and this was washed successively with water, sat.
NaHCO.sub.3 solution, and sat. NaCl solution (1.times.50 ml each).
The organic layer was dried over sodium sulfate and the solvent
evaporated in vacuo to yield, upon vacuum drying, 205 mg (89.1%) of
the title compound as a white foam. mp 184-184.5.degree. C. .sup.1H
NMR (DMSO-d.sub.6, 360 MHz) .delta.7.980 (s, 1H), 7.922 (s, 1H),
5.644 (d, 1H, J=9.26 Hz), 5.489 (d, 1H, J=3.24 Hz), 5.401 (d, 1H,
J=3.76 Hz), 5.266 (d, 1H, J=6.52 Hz), 4.245 (m, 1H), 3.924 (d, 1H,
J=2.81 Hz), 3.905 (dd, 2H, J=11.64 Hz, J=72.50 Hz). Anal. Calcd.
for C, 40.76; H, 3.14; N, 7.92. Found: C, 40.78; H, 3.28; N,
7.75.
Example 56
2-Bromo-5,6-dichloro-1-(3'-deoxy-3'-C-hydroxymethyl-.beta.-D-ribopyranosyl-
)-1H-benzimidazoie
[0348] a.
2,4-Di-O-Acetyl-1,6-anhydro-3-deoxy-3-C-hydroxymethyl-.alpha.-D--
ribopyranose
[0349]
3-Deoxy-3-C-hydroxymethyl-1,2-isopropylidene-.alpha.-D-ribofuranose
(2.8 g, 13.7 mmoles), which can be prepared by the method of Acton,
Goerner, and etc., (J. Med. Chem. (1979), 22(5), 518-25) was
dissolved in dioxane (75 ml) and 0.1 N HCl (75 ml) and heated in an
80.degree. C. oil bath overnight. The pH of the reaction was very
carefully adjusted to 5 with 0.1 N NaOH. Most of the water was
removed by evaporation in vacuo. Ethanol was added and evaporated
in vacuo (3.times.) to remove residual water. Toluene was added and
evaporated (3.times.). The residue was dissolved in dry pyridine
(50 ml, anhydrous, Aldrich Chemical Co.) and acetic anhydride (10.4
ml, 110 mmoles) was added. The reaction was stirred at RT
overnight. Methanol was added and the solvents removed in vacuo.
Toluene (50 ml) was added and removed in vacuo (5.times.) to remove
residual pyridine, acetic anhydride, and acetic acid. The product
was isolated by chromatography on a 4 by 15 cm column of silica gel
eluted with hexane/ethyl acetate (7:3, v/v). MS (GC-CI+): m/z, 350,
M+NH.sub.4.sup.1. .sup.1H NMR (DMSO-d.sub.6) .delta.5.2 (s, 1H,
H1), 4.9 (m, 1H, H4), 4.75 (s, 1H, H-2), 4.1(d, 1H, H-6), 3.85 (dd,
1H, H-6), 3.75 (dd, 1H, H-5), 3.2 (t, 1H, H-5), 2.8(m, 1H, H-3),
2.05 (s, 6H, acetyls).
[0350] b.
1,2,4-triacetyl-3-deoxy-3-C-hydroxymethyl-D-ribopyranose
[0351]
2,4-Di-O-acetyl-1,6-anhydro-3-deoxy-3-C-hydroxymethyl-.alpha.-D-rib-
opyranose (0.5 g, 1.5 mmoles) was dissolved in acetic anhydride
(7.5 ml) and acetic acid (19.5 ml). Concentrated sulfuric acid (1.3
ml) was added and the reaction was stirred at RT overnight. GC-MS
indicated the formation of two major products in approximately a
1:1 ratio along with 2 minor products. Ice (50 g) was added to the
reaction. The products were extracted with ether (2.times.). The
organic solution was dried with magnesium sulfate, filtered, and
the solvent removed in vacuo. Toluene was added to the residue and
evaporated in vacuo (3.times.) to remove residual water. The
desired product; 1,2,4-triacetyl-3-deoxy-3-C-hydroxym-
ethyl-D-ribopyranose, was isolated as a mixture of anomers along
with a second product by chromatography on 4 by 15 cm column of
silica gel eluted with hexane/ ethyl acetate (7:3, v/v). The
mixture was used in the next step without further purification.
[0352] c.
2-Bromo-5,6-dichloro-1-(3'-deoxy-3'-C-hydroxymethyl-.beta.-D-rib-
opyranosyl)-1H-benzimidazole
[0353] 2-Bromo-5,6-dichloro-benzimidazole (0.36 g, 1.4 mmoles)
which can be prepared by the method of Townsend and Drach (US Pat.
No. 5,248,672) was added to 1,2-dichloroethane (Aldrich, Sure Seal,
20 ml). N,O-Bis(trimethylsilyl) acetamide (0.19 ml, 0.76 mmoles, 1
eq.) was added and the reaction heated to reflux for thirty minutes
in a 95.degree. C. oil bath.
1,2,4-Triacetyl-3-deoxy-3-C-hydroxymethyl-D-ribopyranose (0.45 g,
1.4 mmoles, 1 eq.) was boiled in toluene to remove water. The
excess toluene was removed in vacuo and the residue dissolved in
1,2-dichloroethane (15 ml). The carbohydrate solution was added to
the reaction followed by trimethylsilyl trifluoromethanesulfonate
(0.365 ml, 1.7 mmoles, 1.2 eq.). The reaction was heated for 50 min
in an 85.degree. C. oil bath. The reaction was cooled to RT and ice
water (100 ml) was added. The organic layer was collected and
washed with saturated sodium bicarbonate and brine. The organic
solution was dried with MgSO.sub.4, filtered, and the solvent
removed in vacuo. The product was purified by chromatography on a
4.times.15 cm column of silica gel eluted with chloroform/methanol
(98:2, v/v). The product containing fractions were combined and the
solvents removed in vacuo.
[0354] Isolation of the final product was accomplished by
deprotection of the acetyl groups. The acetylated product was
dissolved in 15 ml ethanol/water (1:1, v/v) Na.sub.2CO.sub.3 (1.2
g) was added and the reaction stirred at RT overnight. The reaction
was neutralized by the addition of 1 N HCl then diluted with sat.
NaCI (1 vol.). The product was extracted with ethyl acetate
(2.times.). After removal of the solvent in vacuo, the product was
isolated by chromatography on a 4 by 6 cm column of silica gel
eluted with chloroform/methanol (95:5, v/v). MS (ES+): m/z, 411,
M+H.sup.+. 1-Br, 2-Cl pattern was noted. .sup.1H NMR (DMSO-d.sub.6)
.delta.7.99 (s, 1H, aryl), 7.96 (s, 1H, aryl), 5.94 (d,1H, H-1',
J.sub.1',2'=9 Hz), 5.45(bs, 1H, OH), 5.25 (bs, 1H, OH), 4.45(bs,
1H, OH), 4.25 (m, 1H, H-2'), 4.1(m, 1H, H-4') 4.0(m, 2H, H-6') 3.8
(m, 1H, H-5'), 3.7 (m, 1H, H-5'), 2.3 (m, 1H, H-3').
Example 57
2-Bromo-5,6-dichloro-1-beta-L-xylopyranosyl-1H-benzimidazole
[0355] a. 1,2,3,4-tetra-O-acetyl-beta-L-xylopyranose
[0356] L-xylose (11.48 g, 76.5 mmol) was combined with pyridine
(Aldrich, 250 ml) and concentrated to a volume of 50 ml. The
solution was cooled in an ice bath, and acetic anhydride (Aldrich,
30 ml, 321 mmol) was added dropwise over 30 min. After 4 h, the
reaction was warmed to room temperature and stirred overnight.
Ethanol (100 ml) was added and the reaction stirred 1 h. The
reaction was concentrated to 50 ml, diluted with 200 ml ethanol and
evaporated. The residue was partitioned between ethyl acetate and
water. The ethyl acetate was washed successively with water, 7%
aqueous sodium bicarbonate and saturated aqueous sodium chloride,
then dried over anhydrous magnesium sulfate and evaporated. The
residue was chilled and the resulting solid was recrystallized from
isopropanol to yield 13.99 g (44.0 mmol, 57% yield) of
1,2,3,4-tetra-O-acetyl-beta-L-xylopyranose. .sup.1H NMR
(DMSO-d.sub.6) .delta.5.79-5.77 (d, 1H), 5.28-5.24 (t, 1H),
4.89-4.82 (m, 2H), 3.98-3.94 (dd, 1H), 3.67-3.62 (dd, 1H), 2.03 (s,
3H), 1.98 (s, 3H), 1.97 (s, 1.96 (s, 3H).
[0357] b.
2-Bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-beta-L-xylopyranosyl)-
-1H-benzimidazole
[0358] As described in General Procedure III,
2-bromo-5,6-dichlorobenzimid- azole (1.0 g, 3.8 mmol),
N,O-bis(trimethylsilyl) acetamide (Aldrich, 1.0 ml, 4.1 mmol), and
1,2-dichloroethane (Aldrich Sure Seal, 25 ml) were combined and
refluxed under nitrogen for 0.5 h. The solution was cooled
50.degree. C. and trimethylsilyl trifluoromethanesulfonate
(Aldrich, 0.8 ml, 4.1 mmol) was added. immediately, 1.4 g (4.4
mmol) solid 1,2,3,4-tetra-O-acetyl-beta-L-xylopyranose was added.
The solution was stirred under nitrogen at reflux for 0.25 h, then
poured into 7% aqueous sodium bicarbonate and extracted with
dichloromethane. The organic layers were dried with magnesium
sulfate (anhyd), filtered, and evaporated. The crude residue was
crystallized from chloroform and hexane to give 1.11 g (56% yield)
of 2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-beta-L-xylopyra-
nosyl)-1H-benzimidazole. .sup.1H NMR (CDCl.sub.3) .delta.7.80 (s,
1H), 7.76 (s, 1H), 5.68-5.64 (m, 1H), 5.55-5.51 (m, 1H), 5.32-5.25
(m, 1H), 4.48-4.43 (dd, 1H), 3.69-3.61 (t, 1H), 2.15 (s, 3H), 2.10
(s, 3H), 1.90 (s, 3H).
[0359] c.
2-Bromo-5,6-dichloro-1-beta-L-xylopyranosyl-1H-benzimidazole
[0360] An ethanolic solution of
2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-
-alpha-L-xylopyranosyl)-1H-benzimidazole (0.81 g, 1.54 mmol) was
deprotected in a modification of General Procedure VI with 0.64 g
(6.03 mmol) of sodium carbonate in 5 ml of water. After stirring
overnight at ambient temperature, the mixture was treated as
described in General Procedure VI to give crude product which was
recrystallized from 1-chlorobutane, ethyl acetate and hexane to
give 0.21 g (0.53 mmol, 34% yield) of
2-bromo-5,6-dichloro-1-beta-L-xylopyranosyl-1H-benzimidazole, mp
164-165.degree. C. .sup.1H NMR (CD.sub.3OD) .delta.8.04 (s, 1H),
7.83 (s, 1H), 5.53-5.50 (d, 1H), 4.14-4.09 (dd, 1H), 3.93 (bm, 1H),
3.83-3.75 (m, 1H), 3.55-3.46 (m, 2H).
Example 58
5,6-Dichloro-N-1(1-methylethyl)-1-beta-L-xylopyranosyl-1H-benzimidazole-2--
amine
[0361]
2-bromo-5,6-dichloro-1-(2,3,4-tri-O-acetyl-beta-L-xylopyranosyl)-1H-
-benzimidazole (0.25 g, 0.48 mmol) was dissolved in 10 ml of
absolute ethanol, treated with 5 ml of isopropylamine (Fluka,
Ronkonkoma, N.Y.), heated in a glass pressure tube (Ace, Vineland,
N.J.) and stirred with a magnetic stir bar. The tube was sealed
with a screw cap and heated in an oil bath at 85.degree. C. for 40
h. At this time, TLC indicated complete conversion of starting
material and the solvents were removed on a rotary evaporator. The
product residue was purified by filtration through a silica gel pad
eluting with 10% methanol in chloroform to give
5,6-dichloro-N-1(1-methylethyl)-1-beta-L-xylopyranosyl-1H-benzimidazole-2-
-amine (0.15 g, 0.40 mmol, 83% yield). .sup.1H NMR (CD.sub.3OD)
.delta.7.38 (s, 1H), 7.31 (s, 1H), 5.34-5.31 (d, 1H), 4.10-4.02 (m,
2H), 3.90-3.84 (t, 1H), 3.77-3.69 (m, 1H), 3.51-3.42 (m, 2H), 1.30
(d, 3H), 1.28 (d, 3H).
Example 59
2-Bromo-5,6-dichloro-1-(3,4-di-O-acetyl-2-deoxy-alpha-D-erythro-pentopyran-
osyl)-1H-benzimidazole and
2-Bromo-5,6-dichloro-1-(3,4-di-O-acetyl-2-deoxy-
-beta-D-erythro-pentopyranosyl)-1H-benzimidazole
[0362] As described in General Procedure III,
2-bromo-5,6-dichlorobenzimid- azole (0.52 g, 2.0 mmol),
N,O-bis(trimethylsilyl) acetamide (Aldrich, 0.53 ml, 2.2 mmol), and
1,2-dichloroethane (Aldrich Sure Seal, 20 ml) were combined and
refluxed under nitrogen for 0.25 h. The solution was cooled to
50.degree. C. and trimethylsilyl trifluoromethanesulfonate
(Aldrich, 0.42 ml, 2.2 mmol) was added. Immediately, 0.51 g (2.0
mmol) solid 1,3,4-tri-O-acetyl-2-deoxy-D-erythro-pentopyranose (as
prepared and described by R. Allerton and W. G. Overend in J. Chem.
Soc. 1951, 1480-1484) was added. The solution was stirred under
nitrogen at 50.degree. C. for 0.5 h, then poured into 7% aqueous
sodium bicarbonate and extracted with dichloromethane. The organic
layer was dried with magnesium sulfate (anhyd), filtered, and
evaporated. The crude residue was purified on a silica gel column
eluting with a step gradient of 0.1% to 1% methanol in
dichloromethane to give 0.47 g (1.0 mmol, 52% yield)
2-bromo-5,6-dichloro-1-(3,4-di-O-acetyl-2-deoxy-alpha-D-erythro-pentopyra-
nosyl)-1H-benzimidazole; .sup.1H NMR (CD.sub.3OD) .delta.8.11 (s,
1H), 7.80 (s, 1H), 6.11-6.07 (dd, 1H), 5.37-5.32 (m, 2H), 4.24-4.19
(dd, 1H), 4.05-4.00 (dd, 1H), 2.68-2.56 (q, 1H), 2.32 (s, 3H),
2.20-2.15 (m, 1H), 2.01 (s, 3H) ;and 0.13 g (0.28 mmol, 14% yield)
2-bromo-5,6-dichloro-1-(3-
,4-di-O-acetyl-2-deoxy-beta-D-erythro-pentopyranosyl)-1H-benzimioazoie;
.sup.1H NMR (CD.sub.3OD) .delta.8.02 (s, 1H), 7.76 (s, 1H),
6.13-6.10 (d, 1H), 5.62 (bs, 1H), 5.29-5.23 (m, 1H), 4.15-4.03 (m,
2H), 2.76-2.70 (t, 1H), 2.19 (s, 3H), 2.15-2.14 (m, 1H), 2.00 (s,
3H).
Example 60
2-Bromo-5,6-dichloro-1-(2-deoxy-alpha-D-erythro-pentopyranosyl)-1H-benzimi-
dazole
[0363] An ethanolic solution of
2-bromo-5,6-dichloro-1-(3,4-di-O-acetyl-2--
deoxy-alpha-D-erythro-pentopyranosyl)-1H-benzimidazole (0.21 g,
0.45 mmol) was deprotected in a modification of General Procedure
VI with 0.12 g (1.17 mmol) of sodium carbonate in 1 ml of water.
After stirring overnight at ambient temperature, the mixture was
treated as described in General Procedure VI. The crude product was
triturated in ethyl acetate to give 0.11 g (0.29 mmol, 65% yield)
of 2-bromo-5,6-dichloro-1-(2-deoxy--
alpha-D-erythro-pentopyranosyl)-1H-benzimidazole. .sup.1H NMR
(DMSO-d.sub.6) .delta.8.15 (s, 1H), 7.96 (s, 1H), 5.80-5.77 (d,
1H), 5.12 (bs, 1H), 4.97 (m, 1H), 3.97-3.90 (m, 2H), 3.78-3.70 (m,
2H), 2.42-2.35 (m,1H), 1.83-1.79 (m,1H).
Example 61
5,6-Dichloro-N-1(1-methylethyl)-1-(2-deoxy-alpha-D-erythro-pentopyranosyl)-
-1H-benzimidazole-2-amine
[0364]
2-bromo-5,6-dichloro-1-(3,4-di-O-acetyl-2-deoxy-alpha-D-erythro-pen-
topyranosyl)-1H-benzimidazole (0.098 g, 0.21 mmol) was dissolved in
4 ml of absolute ethanol, treated with 2 ml of isopropylamine
(Fluka, Ronkonkoma, N.Y.), heated in a glass pressure tube (Ace,
Vineland, N.J.) and stirred with a magnetic stir bar. The tube was
sealed with a screw cap and heated in an oil bath at 85.degree. C.
for 24 h. At this time, TLC indicated complete conversion of
starting material and the solvents were removed on a rotary
evaporator. The residue was triturated in dichloromethane to give
0.062 g (0.17 mmol, 82% yield)
5,6-dichloro-N-1(1-methylethyl)-1-(2-deoxy-alpha-D-erythro-pentopyranosyl-
)-1H-benzimidazole-2-amine. .sup.1H NMR (DMSO-d.sub.6) .delta.7.63
(s, 1H), 7.38 (s, 1H), 5.64-5.60 (d, 1H), 5.06 (bs, 1H), 4.93 (bs,
1H), 4.02-3.89 (m, 2H), 3.80-3.65 (m, 2H), 3.60-3.55 (d, 1H),
2.41-2.29 (q, 1H), 1.68-1.65 (d, 1H), 1.23 (s, 3H), 1.21 (s,
3H).
Example 62
2-Bromo-5,6-dichloro-1-(2-deoxy-beta-D-erythro-pentopyranosyl)-1H-benzimid-
azole
[0365] An ethanolic solution of
2-bromo-5,6-dichloro-1-(3,4-di-O-acetyl-2--
deoxy-beta-D-erythro-pentopyranosyl)-1H-benzimidazole (0.13 g, 0.28
mmol) was deprotected in a modification of General Procedure VI
with 0.077 g (0.73 mmol) of sodium carbonate in 1 ml of water.
After stirring overnight at ambient temperature, the mixture was
treated as described in General Procedure VI. The crude product was
triturated in dichloromethane and hexane to give 0.06 g (0.16 mmol,
56% yield) of
2-bromo-5,6-dichloro-1-(2-deoxy-beta-D-erythro-pentopyranosyl)-1H-benzimi-
dazole. .sup.1H NMR (DMSO-d.sub.6) .delta.8.01 (s, 1H), 7.92 (s,
1H), 5.96-5.94 (d, 1H), 5.02 (s, 1H), 4.90-4.89 (d, 1H), 4.01 (s,
1H), 3.94-3.86 (m, 1H), 3.74-3.72 (d, 2H), 2.42-2.39 (m,
1H-partially underneath residual DMSO signal), 1.90-1.87 (d,
1H).
Example 63
2-Bromo-5-chloro-6-methylthio-1-beta-D-ribopyranosyl-1H-benzimidazole
and
2-Bromo-6-chloro-5-methylthio-1-beta-D-ribopyranosyl-1H-benzimidazole
[0366] a. 4-Chloro-2-nitro-5-methylthioaniline
[0367] Sodium methanethiolate (4.06 g, 58.0 mmol, Aldrich) was
suspended in 80 ml dimethylformamide. 4,5-Dichloro-2-nitroaniline
(10.0 g, 48.3 mmol, Aldrich) was added portionwise. Additional
sodium methanethiolate (4.38 g, 62.5 mmol) was added over several h
until starting material was consumed. The reaction mixture was
poured into water (400 ml) and the resulting precipitate was
collected by filtration and dried to give 9.05 (41.4 mmol, 86%
yield) of the title compound. .sup.1H NMR (CDCl.sub.3) .delta.8.15
(s, 1H), 6.44 (s, 1H), 2.52 (s, 3H).
[0368] b. 3-Chloro-4-methylthio-1,2-phenylenediamine
[0369] A mixture of 9.05 g (41.4 mmol)
4-chloro-2-nitro-5-methylthioanilin- e and 28.82 g (165.6 mmol,
Aldrich) sodium hydrosulfite was refluxed in 200 ml of ethanol and
80 ml of water for 1 h. The reaction mixture was evaporated, the
residue was diluted with water and extracted with dichioromethane.
The dichioromethane layers were washed with saturated aqueous
sodium chloride, dried over anhydrous magnesium sulfate and
filtered. The solvent was removed under reduced pressure to give
7.58 g (40.2 mmol, 97% yield) of the title compound. .sup.1H NMR
(CDCl.sub.3) .delta.6.79 (s, 1H), 6.73 (s, 1H), 2.44 (s, 3H).
[0370] c. 5-Chloro-6-methylthiobenzimidazole
[0371] A solution of 3-chloro-4-methylthio-1,2-phenylenediamine
(5.0 g, 26.5 mmol) in 75 ml ethanol was treated with
triethylorthoformate (6.6 ml, 39.7 mmol, Aldrich) and
trifluoroacetic acid (0.51 ml, 6.6 mmol, Aldrich). After stirring
0.25 h, the reaction mixture was concentrated under reduced
pressure. The residue was crystallized from dichloromethane, ethyl
acetate and hexane to give 2.19 g of the title compound in the
first crop and 1.54 g in the second crop. The total yield was 3.73
g (18.8 mmol, 71% yield). .sup.1H NMR (DMSO-d.sub.6) .delta.8.49
(s, 1H), 7.80 (s, 1H), 7.52 (s, 1H), 2.56 (s, 3H).
[0372] d.
5-Chloro-6-methylthio-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl-
)-1H-benzimidazole and
6-Chloro-5methylthio-1-(2,3,4-tri-O-acetyl-beta-D-r-
ibopyranosyl)-1H-benzimidazole
[0373] As described in General Procedure III,
5-chloro-6-methylthiobenzimi- dazole (3.73 g, 18.8 mmol),
N,O-bis(trimethylsilyl) acetamide (Aldrich, 4.9 ml, 20.7 mmol), and
1,2-dichloroethane (Aldrich Sure Seal, 100 ml) were combined and
refluxed under nitrogen for 0.25 h. The solution was cooled to
40.degree. C. and trimethylsilyl trifluoromethanesulfonate
(Aldrich, 4.0 ml, 20.7 mmol) was added. immediately, 7.17 g (22.5
mmol) solid 1,2,3,4-tetra-O-acetyl-beta-D-ribopyranose was added.
The solution was stirred under nitrogen at reflux for 3 h, then
poured into 7% aqueous sodium bicarbonate and extracted with
dichloromethane. The organic layers were dried with magnesium
sulfate (anhyd), filtered, and evaporated. The residue was purified
by two successive silica gel columns eluting with dichioromethane
and a step gradient from 0 to 50% acetone to give 0.36 g (0.8 mmol,
4% yield) of the title compounds as a regioisomeric mix
(.about.1.7:1). .sup.1H NMR (DMSO-d.sub.6) .delta.8.46 (s, 1.6H),
8.22 (s, 1H), 7.82 (s, 0.6H), 7.72 (s, 0.6H), 7.58 (s, 1H),
6.12-6.03 (m, 1.6H), 5.79-7.76 (m, 3.2H), 4.06-4.00 (m, 3.2H), 2.63
(s, 3H), 2.27-2.26 (d, 7.8H), 1.76 (s, 6.6H).
[0374] e.
2-Bromo-5-chloro-6-methylthio-1-(2,3,4-tri-O-acetyl-beta-D-ribop-
yranosyl)-1H-benzimidazole and
2-Bromo-6-chloro-5-methylthio-1-(2,3,4-tri--
O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole
[0375] The title compound was prepared according to General
Procedure IV using
5-chloro-6-methylthio-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl
)-1H-benzimidazole and
6-chloro-5-methylthio-1-(2,3,4-tri-O-acetyl-beta-D-
-ribopyranosyl)-1H-benzimidazole as a mixture of regioisomers (0.36
g, 0.79 mmol), 30 ml tetrahydrofuran (Aldrich Sure Seal,
Milwaukee), and a total of 1.68 g (9.4 mmol) of N-bromosuccinimide
that was added over 2 h. The product from work-up by General
Procedure IV was purified on a silica gel column with
dichloromethane and a step gradient from 0-0.5% methanol. This
provided 0.18 g (0.34 mmol) of the title compounds as a mix of
regioisomers. The regioisomers were separated by SFC on a
semi-preparative Chiralcel OD lot No. S017OD00CJ-HC001 eluting with
a mobile phase of 90% carbon dioxide and 10% methanol at a flow
rate of 2.0 ml/min and a pressure of 3000 psi at a temperature of
40.degree. C. with signal detection at 254 nm.
2-Bromo-5-chloro-6-methylthio-1-(2,3,4-tri-O--
acetyl-beta-D-ribopyranosyl)-1H-benzimidazole eluted first (RT=5.78
min) and 0.047 g was obtained after evaporation of the solvent.
.sup.1H NMR (DMSO-d.sub.6) .delta.7.79 (s, 1H), 7.68 (s, 1H),
6.03-6.00 (d,1H), 5.78-5.74 (m, 2H), 5.57 (m, 1H), 4.23-4.17 (m,
1H), 4.09-4.01 (t, 1H), 2.64 (s, 3H) 2.26 (s, 3H), 2.04) (s, 3H),
1.80 (s, 3H).
2-Bromo-6-chloro-5-methylthio-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-
-1H-benzimidazole eluted from the chiral column last (RT=7.22 min)
and 0.057 g was obtained after evaporation of the solvent. 1H NMR
(DMSO-d.sub.6) .delta.8.27 (s,1H), 7.51 (s, 1H), 5.98-5.95 (d, 1H),
5.78-5.72 (m, 3H), 4.17-4.16 (m, 1H), 4.06-3.98 (t, 1H), 2.26 (s,
3H), 2.04 (s, 3H), 1.79 (s, 3H).
[0376] f.
2-Bromo-5-chloro-6-methylthio-1-beta-D-ribopyranosyl-1H-benzimid-
azole
[0377] An ethanolic solution of
2-bromo-5-chloro-6-methylthio-1-(2,3,4-tri-
-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.047 g, 0.09
mmol) was deprotected in a modification of General Procedure VI
with 0.036 g (0.34 mmol) of sodium carbonate in 0.5 ml of water.
After stirring 1 h at ambient temperature, the mixture was treated
as described in General Procedure VI. The product was dried
overnight in vacuo to give
2-bromo-5-chloro-6-methylthio-1-beta-D-ribopyranosyl-1H-benzimidazole
(0.035 g, 0.09 mmol, 98% yield). .sup.1H NMR (DMSO-d.sub.6)
.delta.7.73 (s, 1H), 7.37 (s, 1H), 5.63-5.60 (d, 1H), 5.16-5.14 (m,
2H), 4.91-4.89 (d, 1H), 4.00-3.99 (m, 2H), 3.86 (m, 1H), 3.71-3.68
(m, 2H), 2.52 (s, 3H).
[0378] g.
2-Bromo-6-chloro-5-methylthio-1-beta-D-ribopyranosyl-1H-benzimid-
azole
[0379] An ethanolic solution of
2-bromo-6-chloro-5-methylthio-1-(2,3,4-tri-
-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.057 g, 0.09
mmol) was deprotected in a modification of General Procedure VI
with 0.044 g (0.41 mmol) of sodium carbonate in 0.5 ml of water.
After stirring 1.5 h at ambient temperature, the mixture was
treated as described in General Procedure VI. The product was dried
overnight in vacuo to give
2-bromo-6-chloro-5-methylthio-1-beta-D-ribopyranosyl-1H-benzimidazole
(0.042 g, 0.08 mmol, 98% yield). .sup.1H NMR (DMSO-d.sub.6)
.delta.7.79 (s, 1H), 7.49 (s, 1H), 5.61-5.59 (d, 1H), 5.16-5.12 (m,
2H), 4.86-4.84 (d, 1H), 3.98 (m, 3H), 3.68-3.65 (m, 2H), 2.49 (s,
3H).
EXAMPLES 64-68
[0380] 13
[0381] General Chemical Procedures: Melting points were determined
on a Thomas-Hoover apparatus and are uncorrected. Silica gel,
SilicAR 40-63 microns 230-400 mesh (Mallinckrodt) was used for
column chromatography. Thin layer chromatography (TLC) was
performed on prescored SilicAR 7GF plates (Analtech, Newark, Del.).
TLC plates were developed in the following solvent systems: system
1 (35% EtOAc/Hexanes, v/v), system 2 (50% EtOAc/Hexanes, v/v),
system 3 (10% MeOH/CH.sub.2Cl.sub.2, v/v), system 4 (15%
MeOH/CH.sub.2Cl.sub.2, v/v). Compounds were visualized by
illuminating with UV light (254 nm) or/and by treatment with 10%
methanolic sulfuric acid followed by charring on a hot plate.
Evaporations were carried out under reduced pressure (water
aspirator) with the bath temperature not exceeding 50 C, unless
specified otherwise. NMR spectra were recorded on either a Bruker
300 or 500 MHz instrument. Chemical shifts are expressed in d
values (ppm) relative to the chemical shift of the residual DMSO-d5
(d 2.50 ppm) contained in the solvent DMSO-d6. All NMR assignments
reported were made by homonuclear decoupling experiments. Unless
otherwise noted, all materials were obtained from commercial
suppliers.
Example 64
1,2,3,4-Tetra-O-acetyl-D-lyxopyranose (1)
[0382] Acetic anhydride (23 mL, 240 mmol) was added to a stirred
solution of D-lyxose (4.5 g, 30 mmol) in pyridine (90 mL) at room
temperature. After 15 h, the reaction mixture was poured into ice
water (200 mL) and extracted with dichloromethane (1.times.300 mL).
The organic extract was washed with water (1.times.50 mL), dried
over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated
under reduced pressure. After several coevaporations with toluene
(3.times.10 mL), the residue was subjected to silica gel
chromatography (5.times.15 cm) using a solution of ethyl acetate
and hexane (1:1, v/v). Fraction 7 contained 1.6 g (17%) of the pure
a anomer of 1 [R.sub.f (system 1): 0.40] which crystallized upon
drying, and fractions 8-40 contained 6.8 g (71%) of a mixture of
anomers of 1 [R.sub.f (system 1): 0.40 (major) and 0.35 (minor)]
which also crystallized upon drying. Characteristics of the pure a
anomer:
[0383] mp: 96-98 C; .sup.1H NMR (DMSO-d.sub.6): d 5.89 (d, 1H, J
=3.1Hz, H-1), 5.20 (dd, 1H, J=9.1 and 3.4 Hz, H-3), 5.12 (t, 1H,
J=3.3 Hz, H-2), 5.1-5.0 (m, 1H, H-4), 3.92 (dd, 1H, J=11.6 and 4.9
Hz, H-5), 3.7-3.6 (m, 1H, H-5'). Anal. (C.sub.13H.sub.18O.sub.9)
C,H.
[0384] Characteristics of the mixture of anomers: mp: 87-89 C.
Example 65
2,5,6-Trichloro-1-(a-D-lyxopyranosyl)benzimidazole (4)
[0385] 2,5,6-Trichlorobenzimidazole (3.0 g, 13.6 mmol) was
suspended in acetonitrile (250 mL) and the mixture was stirred at
55 C. BSA (4.9 mL, 20 mmol) was added, and the reaction mixture
stirred for an additional 15 min. Compound 1 (4.8 g, 15 mmol) in
acetonitrile (20 mL) and TMSOTf (3.8 mL, 20 mmol) were added to the
clear solution, and the mixture was stirred at 55 C for an
additional 18 h. A saturated aqueous solution of NaHCO.sub.3 (10
mL) was added and the mixture was diluted with ethyl acetate (100
mL). The organic extract was washed with water (3.times.10 mL),
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure. The residue was subjected to silica gel
chromatography [5.times.15 cm, eluent: gradient of methanol (0-1%)
in dichloromethane]. The compound (4.9 g), isolated from fractions
9-48 [R.sub.f (system 1): 0.16], was dissolved in a solution of
ethanol and water (9:1, v/v, 150 mL) and sodium carbonate (6.5 g,
61 mmol) was then added. The reaction mixture was stirred for 18 h,
then acetic acid (3 mL) was added and the mixture was evaporated to
dryness. Water (20 mL) and ethyl acetate (100 mL) were added to the
residue. The organic extract was washed with water (2.times.10 mL),
dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness.
The residue was suspended in boiling dichloromethane (50 mL) and
methanol was added until complete dissolution. Compound 4
crystallized from this solution (2.47 g, 44%).
[0386] R.sub.f(system 3): 0.24; mp: 170-172 C (decomp.); .sup.1H
NMR (DMSO-d.sub.6): d 8.00 and 7.97 (2 s, 2H, H-4 and H-7), 5.64
(d, H, J=0.2 Hz, H-1), 5.50 (d, 1H, J=2.9 Hz, D.sub.2O
exchangeable), 5.41 (d, 1H, J=3.6 Hz, D.sub.2O exchangeable), 5.28
(d, 1H, J=6.4 Hz, OH-2'), 4.2 (m, 1H, H-2'), 4.02 (d, 1H, J=11.9
Hz) 3.92 (m, 1H), 3.8-3.6 (m, 2H, H-5' and H-5"); Anal.
(C.sub.12H.sub.11Cl.sub.3N.sub.2O.sub.4.1/4 H.sub.2O) C,H,N.
Example 66
2-Bromo-5,6-dichloro-1-(a-D-lyxopyranosyl)benzimidazole (5)
[0387] 2-Bromo-5,6-dichlorobenzimidazole (1.06 g, 4.0 mmol) was
suspended in acetonitrile (70 mL) and the mixture was stirred at 35
C. BSA (1.46 mL, 6.0 mmol) was added, and the reaction mixture
stirred for an additional 5 min. Compound 1 (1.52 g, 4.8 mmol) in
acetonitrile (10 mL) and TMSOTf (1.15 mL, 1.5 mmol) were added to
the clear solution, and the mixture was stirred at 35 C for an
additional 17 h. A saturated aqueous solution of NaHCO.sub.3 (5 mL)
was added and the mixture was diluted with ethyl acetate (20 mL).
The organic extract was washed with water (3.times.5 mL), dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure. The residue was chromatographed on a silica gel
column [3.times.15 cm, eluent: gradient of methanol (0-1%) in
chloroform]. The compound (1.15 g), isolated from fractions 8-21
[R.sub.f (system 1): 0.18], was dissolved in a solution of ethanol
and water (9:1, v/v, 46 mL) and sodium carbonate (1.5 9, 14 mmol)
was added. The reaction mixture was stirred 17 h, then acetic acid
(1 mL) was added and the mixture was evaporated to dryness. Water
(30 mL) was added to the residue and the resulting precipitate was
washed (2.times.10 mL) with more water, then suspended in boiling
dichloromethane. Methanol was added until complete dissolution of
the solid. 5 crystallized from this solution (220 mg, 26%), and
also from the aqueous layer (150 mg, 18%). Both batches had same
NMR. Characteristics of 5 crystallized in water. R.sub.f (system
3): 0.25; mp: 169-171 C (decomp.); .sup.1H NMR (DMSO-d.sub.6): d
7.99 and 7.95 (2 s, 2H, H-4 and H-7), 5.63 (d, 1H, J=9.1 Hz, H-1'),
5.49 (bs, 1H, D.sub.2O exchangeable), 5.41 (bs, 1H, D.sub.2O
exchangeable), 5.22 (d, 1H, J=6.2 Hz, OH-2'), 4.24 (m, 1H, H-2'),
4.0-3.8 (m, 2H, H-3'and H-4), 3.8-3.6 (m, 2H, H-5' and H-5"); Anal.
(C.sub.12H.sub.11BrCl.sub.2N.sub.2O- .sub.4.H.sub.2O) C,H,N.
Example 67
5,6-Dichloro-2-isopropylamino-1-(a-D-lyxopyranosyl)benzimidazole
(6)
[0388] Compound 4 (300 mg, 0.85 mmol) was dissolved in ethanol (6
mL). Isopropylamine (5.5 mL, 65 mmol) was added to the solution,
the flask was sealed and the reaction mixture stirred at 60 C for 2
days. The mixture was decanted and evaporated to dryness. The
residue from the evaporation was dissolved in ethyl acetate (50 mL)
and then washed with water (3.times.5 mL). The organic extract was
dried over sodium sulfate, filtered and the filtrate was evaporated
under reduced pressure. The residue was subjected to silica gel
chromatography [2.times.15 cm, eluent: gradient of methanol (5-8%)
in dichloromethane]. Fractions that contained the major spot
[R.sub.f (system 3): 0.24] were evaporated and the resulting solid
was suspended in boiling chloroform. Methanol was added until
complete dissolution of the solid. Compound 6 crystallized from
this solution (260 mg, 81%). All attempts to obtain 6 free of
chloroform failed.
[0389] R.sub.f (system 3): 0.24; mp: 214-218 C (decomp.); .sup.1H
NMR (DMSO-d.sub.6): d 7.55 and 7.36 (2 s, 2H, H4 and H-7), 6.47 (d,
1H, NH, J=6.8 Hz), 5.5-5.3 (m, 3H, H-1', OH-4' and OH-3'), 4.94 (d,
1H, J=7.9 Hz, OH-2'), 4.2 (m, 1H, H-2'), 4.1-3.9 (m, 3H, H-3', H-4'
and CH(CH3)3), 3.7 (m, 2H, H-5',5"), 1.21 (d, 6H,
CH(CH.sub.3).sub.3, J=6.4 Hz); Anal.
(C.sub.15H.sub.19Cl.sub.2N.sub.3O.sub.4.1/10 CHCl.sub.3) C,H,N.
Example 68
2-Cycloheptylamino-5,6-dichloro-1-(a-D-iyxopyranosyl)benzimidazole
(7)
[0390] Compound 4 (200 mg, 0.57 mmol) was dissolved in ethanol (4
mL). Cycloheptylamine (3.6 mL, 28 mmol) was added, the flask was
sealed and the reaction mixture stirred at 60 C for 2 days. The
mixture was decanted and evaporated to dryness at 65 C under high
vacuum. The residue was dissolved in ethyl acetate (20 mL), and
crystals of cycloheptylammonium chloride were removed by
filtration. The organic extract was dried over sodium sulfate,
filtered and the filtrate was evaporated under reduced pressure.
The residue was subjected to silica gel chromatography [2.times.15
cm, eluent: gradient of methanol (0-6%) in dichloromethane].
Fractions that contained the major spot [R.sub.f(system 3): 0.30]
were evaporated and the resulting solid was suspended in boiling
dichloromethane. Methanol was added until complete dissolution of
the solid. Compound 7 crystallized from this solution (150 mg,
61%).
[0391] R.sub.f (system 3): 0.30; mp: 160-165 C (decomp.); .sup.1H
NMR (DMSO-d.sub.6): d 7.52 and 7.36 (2 s, 2H, H-4 and H-7), 6.43
(d, 1H, NH, J=7.0 Hz), 5.5-5.3 (m, 3H, H-1', OH-4' and OH-3'), 4.95
(d, 1H, J=8.0 Hz, OH-2'), 4.2 (m, 1H, H-2'), 4.0-3.9 (m, 3H, H-3',
H4' and CH(CH.sub.2).sub.n), 3.7 (m, 2H, H-5',5"), 2.0-1.9 (bs, 2H,
cycloheptyl), 1.7-1.4 (m, 10H, cycloheptyl); Anal.
(C.sub.19H.sub.25Cl.sub.2N.sub.3O.su- b.4) C,H,N.
Example 69
Human Cytomegalovirus Assay
[0392] HCMV strain AD169 was grown on monolayers of human embryonic
lung cells (MRC5 cells) in 96 well plates. After infection of the
cells at a ratio of approximately 0.01 infectious virus particles
per cell, the compounds to be tested were added to selected wells
at six different concentrations, each in triplicate. The same
concentrations of compound were also applied to wells containing
monolayers of uninfected cells in order to assess compound
cytotoxicity. The plates were incubated for 5 days, and the minimum
cytotoxic dose was estimated from microscopic examination. The IC50
for antiviral effect was estimated from measurements of HCMV DNA in
each well by blofting and quantitative specific DNA hybridization,
similar to the method of Gadler (Antimicrob. Agents Chemother.
1983, 24, 370-374).
Example
[0393] HCMV
[0394] IC50
1 1 1.0 .mu.M 2 0.7 .mu.M 3 22 .mu.M 13 6 .mu.M 24 0.9 .mu.M
Example 70
Hepatitis B Virus Assay
[0395] The activity of compounds against Hepatitis B Virus was
assessed as described in Jansen, R. et al., Antimicrobial Agents
and Chemotherapy, Vol. 37, No. 3, pp. 441-447, 1993. Representative
IC.sub.50 values for the compounds according to the invention were
in the range of 0.001-10 .mu.M.
Example 71
Tablet Formulation
[0396] The following formulations A, B and C are prepared by wet
granulation of the ingredients with a solution of povidone,
followed by addition of magnesium stearate and compression.
2 Formulation A mg/tablet Active ingredient 250 Lactose B.P. 210
Povidone B.P. 15 Sodium Starch Glycollate 20 Magnesium Stearate 5
500
[0397]
3 Formulation B mg/tablet Active Ingredient 250 Lactose B.P. 150
Avicel PH 101 60 Povidone B.P. 15 Sodium Starch Glycollate 20
Magnesium Stearate 5 500
[0398]
4 Formulation C mg/tablet Active Ingredient 250 Lactose B.P. 200
Starch 50 Povidone 5 Magnesium Stearate 4 509
[0399] The following formulations, D and E, are prepared by direct
compression of the admixed ingredients. The lactose in formulation
E is of the direct compression type (Dairy Crest-Zeparox).
5 Formulation D mg/tablet Active Ingredient 250 Pregelatinized
Starch NF15 150 400
[0400]
6 Formutation E mg/tablet Active Ingredient 250 Lactose B.P. 150
Avicel 100 500
[0401] Formulation F (Controlled Release Formulation)
[0402] The formulation is prepared by wet granulation of the
ingredients with a solution of povidone followed by the addition of
magnesium stearate and compression.
7 mg/tablet Active Ingredient 500 Hydroxypropylmethylcellulose 112
(Metnocel K4M Premium) Lactose B.P. 53 Povidone B.P. 28 Magnesium
Stearate 7 700
[0403] Drug release takes place over a period of about 6-8 hours
and is complete after 12 hours.
Example 72
Capsule Formulations
[0404] Formulation A
[0405] A capsule formulation is prepared by admixing the
ingredients of formulation D in Example 1 above and filling into a
two-part hard gelatin capsule. Formulation B (infra) is prepared in
a similar manner.
8 Formulation B mg/capsule Active Ingredient 250 Lactose B.P. 143
Sodium Starch Glycollate 25 Magnesium Stearate 2 420
[0406]
9 Formulation C mg/capsule Active Ingredient 250 Macrogel 4000 B.P.
350 600
[0407] Capsules of formulation C are prepared by melting the
Macrogel 4000 B.P., dispersing the active ingredient in the melt
and filling the melt into a two-part hard gelatin capsule.
10 Formulation D mg/capsule Active Ingredient 250 Lecithin 100
Arachis Oil 100 450
[0408] Capsules of formulation D are prepared by dispersing the
active ingredient in the lecithin and arachis oil and filling the
dispersion into soft, elastic gelatin capsules.
11 Formulation E mg/capsule Active Ingredient 150.0 Vitamin E TPGS
400.0 Polyethylene Glycol 400 NF 200.5 Propylene Glycol USP
39.5
[0409] Four (4) kilograms (kg) of Vitamin E TPGS (obtained from
Eastman Chemical Co.) was heated at 50.degree. C. until liquefied.
To the liquified Vitamin E TPGS, 2.005 kg of polyethylene glycol
400 (PEG400) (low aldehyde, <10 ppm, obtained from Union Carbide
or Dow Chemical Co.) heated to 50.degree. C. was added and mixed
until a homogeneous solution was formed. The resultant solution was
heated to 65.degree. C. 1.5 kg of active ingredient was dissolved
in the liquefied solution of Vitamin E TPGS and PEG 400. 0.395 kg
of propylene glycol at room temperature was added and mixed until a
homogenous solution was formed. The solution was cooled to
28-35.degree. C. The solution was then de-gassed. The mixture was
preferably encapsulated at 28-35.degree. C. at a fill weight
equivalent to 150 mg of volatiles-free compound, into Size 12
oblong, white opaque soft gelatin capsules using a capsule filling
machine. The capsule shells were dried to a constant fill moisture
of 3-6% water and a shell hardness of 7-10 Newtons, and placed in a
suitable container.
[0410] Formulation F (Controlled Release Capsule)
[0411] The following controlled release capsule formulation is
prepared by extruding ingredients a, b, and c using an extruder,
followed by spheronization of the extrudate and drying. The dried
pellets are then coated with release-controlling membrane (d) and
filled into a two-piece, hard gelatin capsule.
12 mg/capsule (a) Active Ingredient 250 (b) Microcrystalline
Cellulose 125 (c) Lactose B.P. 125 (d) Ethyl Cellulose 13 513
Example 73
Injectable Formulation
[0412]
13 Formulation A mg Active Ingredient 200 Hydrochloric Acid
Solution 0.1M or 4.0 to 7.0 Sodium Hydroxide Solution 0.1M q.s. to
pH Sterile water q.s. to 10 ml
[0413] The active ingredient is dissolved in most of the water
(350-40.degree. C.) and the pH adjusted to between 4.0 and 7.0 with
the hydrochloric acid or the sodium hydroxide as appropriate. The
batch is then made up to volume with water and filtered through a
sterile micropore filter into a sterile 10 ml amber glass vial
(type 1) and sealed with sterile closures and overseals.
14 Formulation B Active Ingredient 125 mg Sterile, Pyrogen-free, pH
7 Phosphate Buffer, q.s. to 25 ml
[0414]
15 Formulation C: Intramuscular Injection Active Ingredient 200 mg
Benzyl Alcohol 0.10 g Glycofurol 75 1.45 g Water for injection q.s.
to 3.00 ml
[0415] The active ingredient is dissolved in the glycofurol. The
benzyl alcohol is then added and dissolved, and water added to 3
ml. The mixture is then filtered through a sterile micropore filter
and sealed in sterile 3 ml amber glass vials (type 1).
Example 74
Syrup
[0416]
16 Active Ingredient 250 mg Sorbitol Solution 1.50 g Glycerol 2.00
g Sodium Benzoate 0.005 g Flavor, Peach 17.42.3169 0.0125 ml
Purified Water q.s. to 5.00 ml
[0417] The active ingredient is dissolved in a mixture of the
glycerol and most of the purified water. An aqueous solution of the
sodium benzoate is then added to the solution, followed by addition
of the sorbital solution and finally the flavor. The volume is made
up with purified water and mixed well.
Example 75
Suppository
[0418]
17 mg/capsule suppository Active Ingredient 250 Hard Fat, B.P.
(Witepsol H15-Dynamit Nobel) 1770 2020
[0419] One-fifth of the Witepsol H15 is melted in a steam-jacketed
pan at 45.degree. C. maximum. The active ingredient is sifted
through a 200 .mu.m sieve and added to the molten base with mixing,
using a Silverson fitted with a cutting head, until a smooth
dispersion is achieved. Maintaining the mixture at 45.degree. C.,
the remaining Witepsol H15 is added to the suspension and stirred
to ensure a homogenous mix. The entire suspension is passed through
a 250 .mu.m stainless steel screen and, with continuous stirring,
is allowed to cool to 45.degree. C. At a temperature of 38.degree.
C. to 40.degree.0 C., 2.02 g of the mixture is filled into
suitable, 2 ml plastic molds. The suppositories are allowed to cool
to room temperature.
Example 76
Pessaries
[0420]
18 mg/pessary Active Ingredient 250 Anhydrate Dextrose 380 Potato
Starch 363 Magnesium Stearate 7 1000
[0421] The above ingredients are mixed directly. C.sub.6-14aryl),
or SR.sup.22 (where R.sup.22 is hydrogen, C.sub.1 8alkyl,
hydroxyC.sub.1-8alkyl, C.sub.3-7cycloalkyl, or C.sub.6-14aryl);
[0422] R.sup.2 is hydrogen or halogen;
[0423] R.sup.3 and R.sup.4 may be the same or different and are
hydrogen, halogen, C.sub.1-8alkyl, C.sub.6-14aryl,
heterocycleC.sub.6-14aryl, C.sub.1-8alkoxy, haloC.sub.1-8alkyl or
--SR.sup.24 (where R.sup.24 is hydrogen, C.sub.1-8alkyl,
C.sub.6-14aryl, or C.sub.6-14arylC.sub.1-8alkyl- );
[0424] R.sup.5 is hydrogen, C.sub.1-8alkyl, haloC.sub.1-8alkyl,
C.sub.1-8alkoxy;
[0425] R.sup.6 is hydrogen, hydroxy, halogen, C.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.1-8alkoxy;
[0426] R.sup.7 is hydrogen, hydroxy, halogen, C.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.1-8alkoxy, or
R.sup.6 and R.sup.7 together form a ketone or alkene;
[0427] R.sup.8-R.sup.11 may be the same or different and are
hydrogen, hydroxy, halogen, C.sub.2-8alkyl, hydroxyC.sub.1-8alkyl,
haloC.sub.1-8alkyl, C.sub.1-8alkoxy, or any of R.sup.8 and R.sup.9
or R.sup.10 and R.sup.11 together form a ketone or alkene;
[0428] or a pharmaceutically acceptable derivative thereof,
[0429] provided that a compound of formula (III) cannot be
2,5-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-xylopyranosyl)-1H-benzimidazole
or
5,6-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-arabinopyranosyl)-benzimidaz-
ole-2-thione;
[0430] further provided that:
[0431] a) R.sup.2, R.sup.3, and R.sup.4 cannot all be hydrogen;
and
[0432] b) R.sup.1 cannot be NR.sup.19R.sup.20 where R.sup.19 and
R.sup.20 together with the N atom to which they are attached form a
5 membered heterocyclic ring containing S.
[0433] 3. A compound of formula (III) 14
[0434] wherein:
[0435] R.sup.1 is halogen, hydroxy, azido, C.sub.1-8alkyl,
C.sub.1-8alkoxy, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.6-14arylC.sub.2-6alkenyl, C.sub.6-14arylC.sub.2-6alkynyl, or
--NR.sup.19R.sup.20 (where R.sup.19 and R.sup.20 may be the same or
different and are hydrogen, C.sub.1-8alkyl, cyanoC.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.3-7cycloalkyl,
C.sub.1-8alkylC.sub.3-7cycloalkyl, C.sub.2-6alkenyl,
C.sub.3-7cycloalkylC.sub.1-8alkyl, C.sub.2-6alkynyl,
C.sub.6-14aryl, C.sub.6-14arylC.sub.1-6alkyl,
heterocycleC.sub.1-8alkyl, C.sub.1-8alkylcarbonyl,
C.sub.6-14arylsulfonyl, or R.sup.19R.sup.20 together with the N
atom to which they are attached form a 3, 4, 5 or 6 membered
heterocyclic ring), OR.sup.21 (where R.sup.21 is hydrogen,
C.sub.1-8alkyl, C.sub.3-7cycloalkyl, or C.sub.6-14aryl), or
SR.sup.22 (where R.sup.22 is hydrogen, C.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, C.sub.3-7cycloalkyl, or C.sub.6-14aryl);
[0436] R.sup.2 is hydrogen or halogen;
[0437] R.sup.3 and R.sup.4 may be the same or different and are
hydrogen, halogen, C.sub.1-8alkyl, C.sub.6-14aryl,
heterocycleC.sub.6-14aryl, C.sub.1-8alkoxy, haloC.sub.1-8alkyl or
--SR.sup.24 (where R.sup.24 is hydrogen, C.sub.1-8alkyl,
C.sub.6-14aryl, or C.sub.6-14arylC.sub.1-8alkyl- );
[0438] R.sup.5 is hydrogen, C.sub.1-8alkyl, haloC.sub.1-8alkyl,
C.sub.1-8alkoxy;
[0439] R.sup.6 is hydrogen, hydroxy, halogen, C.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.1-8alkoxy;
[0440] R.sup.7 is hydrogen, hydroxy, halogen, C.sub.1-8alkyl,
hydroxyC.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.1-8alkoxy, or
R.sup.6 and R.sup.7 together form a ketone or alkene;
[0441] R.sup.8-R.sup.11 may be the same or different and are
hydrogen, hydroxy, halogen, C.sub.2-8alkyl, hydroxyC.sub.1-8alkyl,
haloC.sub.1-8alkyl, C.sub.1-8alkoxy, or any of R.sup.8 and R.sup.9
or R.sup.10 and R.sup.11 together form a ketone or alkene;
[0442] or a pharmaceutically acceptable derivative thereof,
[0443] provided that a compound of formula (II) cannot be
2,5-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-xylopyranosyl)-1H-benzimidazole
or
5,6-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-arabinopyranosyl)-benzimidaz-
ole-2-thione;
[0444] further provided that:
[0445] a) R.sup.2, R.sup.3, and R.sup.4 cannot all be hydrogen;
and
[0446] b) R.sup.1 cannot be NR.sup.19R.sup.20 where R.sup.19 and
R.sup.20 together with the N atom to which they are attached form a
5 membered heterocyclic ring containing S.
[0447] 4. A compound of Formula (I) 15
[0448] wherein Z is a substituent of Formula (Ia), (Ib), or (Ic)
16
[0449] and wherein R.sup.1 is halogen; R.sup.2 is hydrogen; R.sup.3
and R.sup.4 are halogen; R.sup.5 and R.sup.7 are hydrogen; R.sup.6
is hydroxy or hydrogen; R.sup.8 and R.sup.10 are hydroxy; R.sup.9
and R.sup.11 are hydrogen; R.sup.12 is hydrogen, C.sub.1-8alkyl, or
hyroxyC.sub.1-8alkyl; R.sup.13 is hydroxy; R.sup.14-R.sup.18 may be
the same or different and are hydrogen or hydroxy; or a
pharmaceutically acceptable derivative thereof.
[0450] 5. A compound of Formula (II) 17
[0451] wherein R.sup.1 is halogen; R.sup.2 is hydrogen; R.sup.3 and
R.sup.4 are halogen; R.sup.5 and R.sup.7 are hydrogen; R.sup.6 is
hydroxy or hydrogen; R.sup.8 and R.sup.10 are hydroxy; R.sup.9 and
R.sup.11 are hydrogen; or a pharmaceutically acceptable derivative
thereof.
[0452] 6. A compound of Formula (III) 18
[0453] wherein R.sup.1 is halogen; R.sup.2 is hydrogen; R.sup.3 and
R.sup.4 are halogen; R.sup.5 and R.sup.7 are hydrogen; R.sup.6 is
hydroxy or hydrogen; R.sup.8 and R.sup.10 are hydroxy; R.sup.9 and
R.sup.11 are hydrogen; or a pharmaceutically acceptable derivative
thereof.
[0454] 7. A compound selected from the group consisting of
[0455] (3S,4R,5R,6S
)-2-Bromo-5,6-dichloro-1-(tetrahydro-4,5-dihydroxy-6-(-
hydroxymethyl)-2H-pyran-3-yl)-1H-benzimidazole;
[0456]
(.+-.)-Trans-2-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohexa-
nol;
[0457] (.+-.)-(1R*, 2S*,
3R*)-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl-
)-1,2-cyclohexanediol;
[0458]
2-bromo-5,6-dichloro-1-.beta.-D-ribopyranosyl-1H-benzimidazole;
[0459]
5,6-dichloro-N-(1-methylethyl)-1-.beta.-D-ribopyranosyl-1H-benzimid-
azol-2-amine;
[0460]
2-bromo-5,6-dichloro-4-fluoro-1-.beta.-D-ribopyranosyl-1H-benzimida-
zole;
[0461]
2-bromo-5,6,-dichloro-1-(2,3,4-tri-O-acetyl-.beta.-D-ribopyranosyl)-
-1H-benzimidazole;
[0462]
2-bromo-5,6-dichloro-1-.beta.-L-ribopyranosyl-1H-benzimidazole;
[0463]
2-bromo-6-chloro-5-methyl-1-.beta.-D-ribopyranosyl-1H-benzimidazole-
; and
[0464]
2-bromo-5,6,-dichloro-1-(4-deoxy-.beta.-D-erythro-pentopyranosyl)-1-
H-benzimidazole;
[0465] or a pharmaceutically acceptable derivative thereof.
[0466] 8. A pharmaceutically acceptable derivative of a compound
according to any one of claims 1 to 7.
[0467] 9. A pharmaceutical composition comprising a compound as
defined in any one of claims 1 to 7 together with a
pharmaceutically acceptable carrier therefor.
* * * * *