U.S. patent application number 15/818269 was filed with the patent office on 2018-03-15 for novel aza-oxo-indoles for the treatment and prophylaxis of respiratory syncytial virus infection.
This patent application is currently assigned to Hoffmann-La Roche Inc.. The applicant listed for this patent is Hoffmann-La Roche Inc.. Invention is credited to LISHA WANG, HONGYING YUN, WEIXING ZHANG, XIUFANG ZHENG.
Application Number | 20180072725 15/818269 |
Document ID | / |
Family ID | 51302721 |
Filed Date | 2018-03-15 |
United States Patent
Application |
20180072725 |
Kind Code |
A1 |
WANG; LISHA ; et
al. |
March 15, 2018 |
NOVEL AZA-OXO-INDOLES FOR THE TREATMENT AND PROPHYLAXIS OF
RESPIRATORY SYNCYTIAL VIRUS INFECTION
Abstract
The invention provides novel compounds having the general
formula: ##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, W and X are as described herein, compositions including
the compounds and methods of using the compounds.
Inventors: |
WANG; LISHA; (BASEL, CH)
; YUN; HONGYING; (SHANGHAI, CN) ; ZHANG;
WEIXING; (SHANGHAI, CN) ; ZHENG; XIUFANG;
(SHANGHAI, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hoffmann-La Roche Inc. |
Little Falls |
NJ |
US |
|
|
Assignee: |
Hoffmann-La Roche Inc.
Little Falls
NJ
|
Family ID: |
51302721 |
Appl. No.: |
15/818269 |
Filed: |
November 20, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15041950 |
Feb 11, 2016 |
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15818269 |
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PCT/EP2014/067197 |
Aug 12, 2014 |
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15041950 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 401/06 20130101;
A61P 31/12 20180101; C07D 471/04 20130101; C07D 403/06 20130101;
A61P 31/14 20180101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 401/06 20060101 C07D401/06; C07D 403/06 20060101
C07D403/06 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 15, 2013 |
CN |
PCT/CN2013/081563 |
Claims
1.-14. (canceled)
15. A method for the treatment of respiratory syncytial virus
infection, the method comprising administering an effective amount
of a compound having formula (I): ##STR00063## wherein: W is
nitrogen or --CR.sup.9, wherein R.sup.9 is halogen; X is nitrogen
or --CR.sup.10, provided that when X is --CR.sup.10, R.sup.1 is
hydrogen, R.sup.2 is halogen, R.sup.3 is hydrogen, wherein R.sup.10
is C.sub.1-6alkylsulfonylphenyl; when X is nitrogen, R.sup.1 is
halogen, R.sup.2 is hydrogen, R.sup.3 is ##STR00064## R.sup.4 and
R.sup.5, with the carbon atom to which they are attached, form
cycloalkyl; R.sup.6 is hydrogen or C.sub.1-6alkyl; R.sup.7 is
hydrogen, aminocarbonyl, C.sub.1-6alkoxycarbonyl-C.sub.yH.sub.2y--,
C.sub.1-6alkylcarbonyl, C.sub.1-6alkylsulfonyl, carboxy or cyano,
wherein y is 0-6; R.sup.8 is C.sub.1-6alkylsulfonyl,
C.sub.1-6alkoxy, cyano or hydroxy; or pharmaceutically acceptable
salts thereof.
16. (canceled)
17. The method of claim 15, wherein W is nitrogen or --CF; X is
nitrogen or --CR.sup.10, provided that when X is --CR.sup.10,
R.sup.1 is hydrogen, R.sup.2 is chloro, R.sup.3 is hydrogen,
wherein R.sup.10 is methylsulfonylphenyl; when X is nitrogen,
R.sup.1 is chloro, R.sup.2 is hydrogen, R.sup.3 is ##STR00065##
R.sup.4 and R.sup.5, with the carbon atom to which they are
attached, form cyclopropyl; R.sup.6 is hydrogen or methyl; R.sup.7
is hydrogen, aminocarbonyl, ethoxycarbonyl, methoxycarbonyl,
ethoxycarbonylmethyl, methylcarbonyl, methyl sulfonyl, carboxy or
cyano; R.sup.8 is methoxy, methylsulfonyl, ethylsulfonyl, cyano or
hydroxy; or pharmaceutically acceptable salts thereof.
18. The method of claim 15, wherein: R.sup.1 is halogen; R.sup.2 is
hydrogen; R.sup.3 is ##STR00066## R.sup.4 and R.sup.5, with the
carbon atom to which they are attached, form cycloalkyl; R.sup.6 is
hydrogen or C.sub.1-6alkyl; R.sup.7 is hydrogen, aminocarbonyl,
C.sub.1-6alkoxycarbonyl-C.sub.yH.sub.2y--, C.sub.1-6alkylcarbonyl,
C.sub.1-6alkylsulfonyl, carboxy or cyano, wherein y is 0-6; R.sup.8
is C.sub.1-6alkylsulfonyl, C.sub.1-6alkoxy, cyano or hydroxy; W is
nitrogen; X is nitrogen.
19. The method of claim 15, wherein: R.sup.1 is chloro; R.sup.2 is
hydrogen; R.sup.3 is ##STR00067## R.sup.4 and R.sup.5, with the
carbon atom to which they are attached, form cyclopropyl; R.sup.6
is hydrogen or methyl; R.sup.7 is hydrogen, aminocarbonyl,
ethoxycarbonyl, methoxycarbonyl, ethoxycarbonylmethyl,
methylcarbonyl, methyl sulfonyl, carboxy or cyano; R.sup.8 is
methoxy, methylsulfonyl, ethyl sulfonyl, cyano or hydroxy; W is
nitrogen; X is nitrogen.
20. The method of claim 15, wherein: R.sup.1 is hydrogen; R.sup.2
is halogen; R.sup.3 is hydrogen; R.sup.4 and R.sup.5, with the
carbon atom to which they are attached, form cycloalkyl; W is
nitrogen; X is --CR.sup.10, wherein R.sup.10 is
C.sub.1-6alkylsulfonylphenyl.
21. The method of claim 15, wherein: R.sup.1 is halogen; R.sup.2 is
hydrogen; R.sup.3 is carboxyphenyl; R.sup.4 and R.sup.5, with the
carbon atom to which they are attached, form cycloalkyl; W is
--CR.sup.9, wherein R.sup.9 is halogen; X is nitrogen.
22. The method of claim 15, wherein the compound is selected from
the group consisting of:
5-{5-Chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2-
'H)-yl)methyl]-1H-benzimidazol-1-yl}pyridine-2-carbonitrile;
1'-({5-Chloro-1-[2-(methylsulfonyl)pyridin-4-yl]-1H-benzimidazol-2-yl}met-
hyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one;
1'-({5-Chloro-1-[4-(ethyl
sulfonyl)pyridin-2-yl]-1H-benzimidazol-2-yl}methyl)spiro[cyclopropane-1,3-
'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one; Ethyl
(4-{5-chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(-
2'H)-yl)methyl]-1H-benzimidazol-1-yl}phenyl)acetate;
1'-[(5-Chloro-1-phenyl-1H-benzimidazol-2-yl)methyl]spiro[cyclopropane-1,3-
'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one; Ethyl
4-{5-chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2-
'H)-yl)methyl]-1H-benzimidazol-1-yl}benzoate;
1'-({5-Chloro-1-[6-(methylsulfonyl)pyridin-3-yl]-1H-benzimidazol-2-yl}met-
hyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one;
1'-({5-chloro-1-[3-(methylsulfonyl)phenyl]-1H-benzimidazol-2-yl}methyl)sp-
iro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one;
1'-({5-chloro-1-[4-(methylsulfonyl)phenyl]-1H-benzimidazol-2-yl}methyl)sp-
iro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one; Methyl
3-{5-chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2-
'H)-yl)methyl]-1H-benzimidazol-1-yl}benzoate;
3-{5-Chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2-
'H)-yl)methyl]-1H-benzimidazol-1-yl }benzonitrile;
1'-{[1-(3-Acetylphenyl)-5-chloro-1H-benzimidazol-2-yl]methyl}spiro[cyclop-
ropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one;
1'-{[5-Chloro-1-(6-methoxypyridin-3-yl)-1H-benzimidazol-2-yl]methyl}spiro-
[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one;
1'-({5-Chloro-1-[5-(methylsulfonyl)pyridin-3-yl]-1H-benzimidazol-2-yl}met-
hyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one;
1'-({5-Chloro-1-[6-(methylsulfonyl)pyridin-2-yl]-1H-benzimidazol-2-yl}met-
hyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one;
1'-({5-Chloro-1-[3-methyl-5-(methylsulfonyl)phenyl]-1H-benzimidazol-2-yl}-
methyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one;
4-{5-Chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2-
'H)-yl)methyl]-1H-benzimidazol-1-yl}benzoic acid;
3-{5-Chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2-
'H)-yl)methyl]-1H-benzimidazol-1-yl}benzoic acid;
4-{5-Chloro-2-[(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indol]-1'(2'H)-yl-
)methyl]-1H-benzimidazol-1-yl}benzoic acid;
4-{5-Chloro-2-[(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indol]-1'(2'H)-yl-
)methyl]-1H-benzimidazol-1-yl}benzoic acid;
1'-{[5-Chloro-1-(6-hydroxypyridin-3-yl)-1H-benzimidazol-2-yl]methyl}spiro-
[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one;
1'-({6-Chloro-3-[4-(methyl
sulfonyl)phenyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-
-c]pyridin]-2'(1'H)-one; and
1'-({6-Chloro-3-[3-(methylsulfonyl)phenyl]-1H-indol-2-yl}methyl)spiro[cyc-
lopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one, or a
pharmaceutically acceptable salt thereof.
23. The method of claim 15, wherein the compound is formulated as a
pharmaceutical composition comprising a compound and at least one
therapeutically inert carrier.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of International
Application No. PCT/EP2014/067197 having an international filing
date of Aug. 12, 2014, the entire content of which is hereby
incorporated herein by reference, and which claims the benefits of
PCT/CN2013/081563 having a filing date of Aug. 15, 2013.
[0002] The present invention relates to organic compounds useful
for therapy and/or prophylaxis in a mammal, and in particular to
respiratory syncytial virus (RSV) inhibitors useful for treating
RSV infection.
FIELD OF THE INVENTION
[0003] Respiratory Syncytial Virus (RSV) belongs to the family of
Paramyxoviridae, subfamily of Pneumovirinae. The human RSV is a
major cause of acute upper and lower respiratory tract infection in
infants and children. Almost all children are infected by RSV at
least once by age of three. Natural human immunity against RSV is
incomplete. In normal adults and elder children, RSV infection is
mainly associated with upper respiratory track symptoms. Severe
case of RSV infection often leads to bronchiolitis and pneumonia,
which requires hospitalization. High-risk factors for lower
respiratory tract infections include premature birth, congenital
heart disease, chronic pulmonary disease, and immunocompromised
conditions. A severe infection at young age may lead to recurrent
wheezing and asthma. For the elderly, RSV-related mortality rate
becomes higher with advancing age.
[0004] RSV Fusion (F) protein is a surface glycoprotein on the
viral envelope which, together with the G surface glycoprotein,
mediates viral entry into host cell. The F protein initiates viral
penetration by fusing viral and host cellular membranes and
subsequently promotes viral spread after infection by melding
infected cells to adjacent uninfected cells, resulting in
characteristic syncytial formation. By inhibiting viral entry and
spread, it is expected that treatment with chemicals described here
will decrease the duration and severity of respiratory symptoms and
subsequent risk of prolonged hospitalization and complications. It
is also expected to limit the ability of individuals to transmit
RSV within households, nursing homes and the hospital setting to
other hosts potentially at high risk of complications.
[0005] There is no RSV vaccine available for human use, despite of
many attempts in subunit vaccine and live-attenuated vaccine
approaches. Virazole.RTM., the aerosol form of ribavirin, is the
only approved antiviral drug for treatment of RSV infection.
However, it is rarely used clinically, due to limited efficacy and
potential side effects. Two marketed prophylaxis antibodies were
developed by MedImmune (CA, USA).
[0006] RSV-IGIV (brand name RespiGam) is polyclonal-concentrated
RSV neutralizing antibody administered through monthly infusion of
750 mg/kg in hospital (Wandstrat T L, Ann Pharmacother. 1997
January; 31(1):83-8). Subsequently, the usage of RSV-IGIV was
largely replaced by palivizumab (brand name Synagis.RTM.), a
humanized monoclonal antibody against RSV fusion (F) protein
approved for prophylaxis in high-risk infants in 1998. When
administered intramuscularly at 15 mg/kg once a month for the
duration of RSV season, palivizumab demonstrated 45-55% reduction
of hospitalization rate caused by RSV infection in selected infants
(Pediatrics. 1998 September; 102(3):531-7; Feltes T F et al, J
Pediatr. 2003 October; 143(4):532-40). Unfortunately, palivizumab
is not effective in the treatment of established RSV infection. A
newer version monoclonal antibody, motavizumab, was designed as
potential replacement of palivizumab but failed to show additional
benefit over palivizumab in recent Phase III clinical trials
(Feltes T F et al, Pediatr Res. 2011 August; 70(2):186-91).
[0007] A number of small molecule RSV inhibitors have been
discovered. Among them, only a few reached Phase I or II clinical
trials. Arrow Therapeutics (now a group in AstraZeneca, UK)
completed a five-year Phase II trial of nucleocapsid (N) protein
inhibitor, RSV-604, in stem cell transplantation patients by
February 2010 (www.clinicaltrials.gov), but has not released the
final results. Most of other small molecules were put on hold for
various reasons.
[0008] RNAi therapeutics against RSV has also been thoroughly
studied. ALN-RSV01 (Alnylam Pharmaceuticals, MA, USA) is a siRNA
targeting on RSV gene. A nasal spray administered for two days
before and for three days after RSV inoculation decreased infection
rate among adult volunteers (DeVincenzo J. et al, Proc Natl Acad
Sci USA. 2010 May 11; 107(19):8800-5). In another Phase II trial
using naturally infected lung transplantation patients, results
were not sufficient for conclusion of antiviral efficacy, though
certain health benefits have been observed (Zamora M R et al, Am J
Respir Crit Care Med. 2011 Feb 15; 183(4):531-8). Additional Phase
IIb clinical trials in similar patient population for ALN-RSV01 are
on-going (www.clinicaltrials.gov).
[0009] Nevertheless, safe and effective treatment for RSV disease
is needed urgently.
SUMMARY OF THE INVENTION
[0010] Objects of the present invention are novel compounds of
formula I, their manufacture, medicaments based on a compound in
accordance with the invention and their production as well as the
use of compounds of formula I for the treatment or prophylaxis of
RSV infection.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0011] As used herein, the term "C.sub.1-6alkyl" alone or in
combination signifies a saturated, linear- or branched chain alkyl
group containing 1 to 6, particularly 1 to 4 carbon atoms, for
example methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl,
tert-butyl and the like. Particular "C.sub.1-6alkyl" groups are
methyl, ethyl, isopropyl and tert-butyl.
[0012] The term "--C.sub.yH.sub.2y--" alone or in combination
signifies a chemical link or a saturated, linear or branched chain
alkyl group containing from 1 to 6 carbon atoms, particularly, the
term signifies a chemical link or a saturated, linear or branched
chain alkyl group containing from 1 to 4 carbon atoms.
[0013] The term "cycloalkyl", alone or in combination, refers to a
saturated carbon ring containing from 3 to 7 carbon atoms,
particularly from 3 to 6 carbon atoms, for example, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
Particular "cycloalkyl" groups are cyclopropyl, cyclopentyl and
cyclohexyl.
[0014] The term "C.sub.1-6alkoxy" alone or in combination signifies
a group C.sub.1-6alkyl-O--, wherein the "C.sub.1-6alkyl" is as
defined above; for example methoxy, ethoxy, propoxy, iso-propoxy,
n-butoxy, iso-butoxy, 2-butoxy, tert-butoxy and the like.
Particular "C.sub.1-6alkoxy" groups are methoxy and ethoxy and more
particularly methoxy.
[0015] The term "cyano" alone or in combination refers to the group
--CN.
[0016] The term "amino", alone or in combination, refers to primary
(--NH.sub.2), secondary (--NH--) or tertiary amino
##STR00002##
[0017] The term "halogen" means fluorine, chlorine, bromine or
iodine. Halogen is particularly fluorine, chlorine or bromine.
[0018] The term "hydroxy" alone or in combination refers to the
group --OH.
[0019] The term "carbonyl" alone or in combination refers to the
group --C(O)--.
[0020] The term "carboxy" alone or in combination refers to the
group --COOH.
[0021] The term "sulfonyl" alone or in combination refers to the
group --S(O).sub.2--.
[0022] The compounds according to the present invention may exist
in the form of their pharmaceutically acceptable salts. The term
"pharmaceutically acceptable salt" refers to conventional
acid-addition salts or base-addition salts that retain the
biological effectiveness and properties of the compounds of formula
I and are formed from suitable non-toxic organic or inorganic acids
or organic or inorganic bases. Acid-addition salts include for
example those derived from inorganic acids such as hydrochloric
acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic
acid, phosphoric acid and nitric acid, and those derived from
organic acids such as p-toluenesulfonic acid, salicylic acid,
methanesulfonic acid, oxalic acid, succinic acid, citric acid,
malic acid, lactic acid, fumaric acid, and the like. Base-addition
salts include those derived from ammonium, potassium, sodium and,
quaternary ammonium hydroxides, such as for example, tetramethyl
ammonium hydroxide. The chemical modification of a pharmaceutical
compound into a salt is a technique well known to pharmaceutical
chemists in order to obtain improved physical and chemical
stability, hygroscopicity, flowability and solubility of compounds.
It is for example described in Bastin R. J., et al., Organic
Process Research & Development 2000, 4, 427-435; or in Ansel,
H., et al., In: Pharmaceutical Dosage Forms and Drug Delivery
Systems, 6th ed. (1995), pp. 196 and 1456-1457. Particular are the
sodium salts of the compounds of formula I.
[0023] Compounds of the general formula I which contain one or
several chiral centers can either be present as racemates,
diastereomeric mixtures, or optically active single isomers. The
racemates can be separated according to known methods into the
enantiomers. Particularly, diastereomeric salts which can be
separated by crystallization are formed from the racemic mixtures
by reaction with an optically active acid such as e.g. D- or
L-tartaric acid, mandelic acid, malic acid, lactic acid or
camphorsulfonic acid.
Inhibitors Of RSV Fusion Protein
[0024] The present invention provides (i) novel compounds having
the general formula I:
##STR00003##
wherein
[0025] W is nitrogen or --CR.sup.9, wherein R.sup.9 is halogen;
[0026] X is nitrogen or --CR.sup.10, provided that
[0027] when X is --CR.sup.10, R.sup.1 is hydrogen, R.sup.2 is
halogen, R.sup.3 is hydrogen, wherein R.sup.10 is
C.sub.1-6alkylsulfonylphenyl;
[0028] when X is nitrogen, R.sup.1 is halogen, R.sup.2 is hydrogen,
R.sup.3 is
##STR00004##
[0029] R.sup.4 and R.sup.5, with the carbon atom to which they are
attached, form cycloalkyl;
[0030] R.sup.6 is hydrogen or C.sub.1-6alkyl;
[0031] R.sup.7 is hydrogen, aminocarbonyl,
C.sub.1-6alkoxycarbonyl-C.sub.yH.sub.2y--, C.sub.1-6alkylcarbonyl,
C.sub.1-6alkylsulfonyl, carboxy or cyano, wherein y is 0-6;
[0032] R.sup.8 is C.sub.1-6alkylsulfonyl, C.sub.1-6alkoxy, cyano or
hydroxy; or pharmaceutically acceptable salts thereof.
[0033] Further embodiment of present invention is (ii) a compound
of formula I, wherein
[0034] W is nitrogen or --CF;
[0035] X is nitrogen or --CR.sup.10, provided that
[0036] when X is --CR.sup.10, R.sup.1 is hydrogen, R.sup.2 is
chloro, R.sup.3 is hydrogen, wherein R.sup.10 is
methylsulfonylphenyl;
[0037] when X is nitrogen, R.sup.1 is chloro, R.sup.2 is hydrogen,
R.sup.3 is
##STR00005##
[0038] R.sup.4 and R.sup.5, with the carbon atom to which they are
attached, form cyclopropyl;
[0039] R.sup.6 is hydrogen or methyl;
[0040] R.sup.7 is hydrogen, aminocarbonyl, ethoxycarbonyl,
methoxycarbonyl, ethoxycarbonylmethyl, methylcarbonyl, methyl
sulfonyl, carboxy or cyano;
[0041] R.sup.8 is methoxy, methylsulfonyl, ethylsulfonyl, cyano or
hydroxy; [0042] or pharmaceutically acceptable salts thereof.
[0043] Another embodiment of present invention is (iii) a compound
of formula I or a pharmaceutically acceptable salt thereof,
wherein
[0044] R.sup.1 is halogen;
[0045] R.sup.2 is hydrogen;
[0046] R.sup.3 is
##STR00006##
[0047] R.sup.4 and R.sup.5, with the carbon atom to which they are
attached, form cycloalkyl;
[0048] R.sup.6 is hydrogen or C.sub.1-6alkyl;
[0049] R.sup.7 is hydrogen, aminocarbonyl,
C.sub.1-6alkoxycarbonyl-C.sub.yH.sub.2y--, C.sub.1-6alkylcarbonyl,
C.sub.1-6alkylsulfonyl, carboxy or cyano, wherein y is 0-6;
[0050] R.sup.8 is C.sub.1-6alkylsulfonyl, C.sub.1-6alkoxy, cyano or
hydroxy;
[0051] W is nitrogen;
[0052] X is nitrogen.
[0053] Further embodiment of present invention is (iv) a compound
of formula I or a pharmaceutically acceptable salt thereof,
wherein
[0054] R.sup.1 is chloro;
[0055] R.sup.2 is hydrogen;
[0056] R.sup.3 is
##STR00007##
[0057] R.sup.4 and R.sup.5, with the carbon atom to which they are
attached, form cyclopropyl;
[0058] R.sup.6 is hydrogen or methyl;
[0059] R.sup.7 is hydrogen, aminocarbonyl, ethoxycarbonyl,
methoxycarbonyl, ethoxycarbonylmethyl, methylcarbonyl, methyl
sulfonyl, carboxy or cyano;
[0060] R.sup.8 is methoxy, methylsulfonyl, ethylsulfonyl, cyano or
hydroxy;
[0061] W is nitrogen;
[0062] X is nitrogen.
[0063] Another embodiment of present invention is (v) a compound of
formula I or a pharmaceutically acceptable salt thereof,
wherein
[0064] R.sup.1 is hydrogen;
[0065] R.sup.2 is halogen;
[0066] R.sup.3 is hydrogen;
[0067] R.sup.4 and R.sup.5, with the carbon atom to which they are
attached, form cycloalkyl;
[0068] W is nitrogen;
[0069] X is --CR.sup.10, wherein R.sup.10 is
C.sub.1-6alkylsulfonylphenyl.
[0070] Another embodiment of present invention is (vi) a compound
of formula I or a pharmaceutically acceptable salt thereof,
wherein
[0071] R.sup.1 is halogen;
[0072] R.sup.2 is hydrogen;
[0073] R.sup.3 is carboxyphenyl;
[0074] R.sup.4 and R.sup.5, with the carbon atom to which they are
attached, form cycloalkyl;
[0075] W is --CR.sup.9, wherein R.sup.9 is halogen;
[0076] X is nitrogen.
[0077] Particular compounds of formula I, including their activity
data, NMR data and MS data are summarized in the following Table 1
and 2.
TABLE-US-00001 TABLE 1 Structure, name and activity data of
particular compounds CPE Long Example EC.sub.50 No. Structure Name
(.mu.M) 1 ##STR00008## 5-{5-Chloro-2-[(2'-
oxospiro[cyclopropane-1,3'-pyrrolo
[2,3-c]pyridin]-1'(2'H)-yl)methyl]-
1H-benzimidazol-1-yl}pyridine-2- carbonitrile 0.0007 2-1
##STR00009## 1'-({5-Chloro-1-[2- (methylsulfonyl)pyridin-4-yl]-
1H-benzimidazol-2-yl}methyl) spiro[cyclopropane-1,3'-pyrrolo
[2,3-c]pyridin]-2'(1'H)-one 0.065 2-2 ##STR00010##
1'-({5-Chloro-1-[4- (ethylsulfonyl)pyridin-2-yl]-
1H-benzimidazol-2-yl}methyl) spiro[cyclopropane-1,3'-pyrrolo
[2,3-c]pyridin]-2'(1'H)-one 0.021 3 ##STR00011## Ethyl
(4-{5-chloro-2-[(2'- oxospiro[cyclopropane-1,3'-pyrrolo
[2,3-c]pyridin]-1'(2'H)-yl)methyl]- 1H-benzimidazol-1-yl}phenyl)
acetate 0.014 4-1 ##STR00012## 1'-[(5-Chloro-1-phenyl-1H-
benzimidazol-2-yl)methyl] spiro[cyclopropane-1,3'-pyrrolo
[2,3-c]pyridin]-2'(1'H)-one 0.017 4-2 ##STR00013## Ethyl
4-{5-chloro-2-[(2'- oxospiro[cyclopropane-1,3'-pyrrolo
[2,3-c]pyridin]-1'(2'H)-yl)methyl]- 1H-benzimidazol-1-yl}benzoate
0.006 4-3 ##STR00014## 1'-({5-Chloro-1-[6-
(methylsulfonyl)pyridin-3-yl]- 1H-benzimidazol-2-yl}methyl)
spiro[cyclopropane-1,3'-pyrrolo [2,3-c]pyridin]-2'(1'H)-one 0.004
4-4 ##STR00015## 1'-({5-chloro-1-[3- (methylsulfonyl)phenyl]-1H-
benzimidazol-2-yl}methyl) spiro[cyclopropane-1,3'-pyrrolo
[2,3-c]pyridin]-2'(1'H)-one 0.008 4-5 ##STR00016##
1'-({5-chloro-1-[4- (methylsulfonyl)phenyl]-1H-
benzimidazol-2-yl}methyl) spiro[cyclopropane-1,3'-pyrrolo
[2,3-c]pyridin]-2'(1'H)-one 0.005 4-6 ##STR00017## Methyl
3-{5-chloro-2-[(2'- oxospiro[cyclopropane-1,3'-pyrrolo
[2,3-c]pyridin]-1'(2'H)-yl)methyl]- 1H-benzimidazol-1-yl}benzoate
0.016 4-7 ##STR00018## 3-{5-Chloro-2-[(2'-
oxospiro[cyclopropane-1,3'-pyrrolo
[2,3-c]pyridin]-1'(2'H)-yl)methyl]-
1H-benzimidazol-1-yl}benzonitrile 0.007 4-8 ##STR00019##
1'-{[1-(3-Acetylphenyl)-5-chloro- 1H-benzimidazol-2-yl]methyl}
spiro[cyclopropane-1,3'-pyrrolo [2,3-c]pyridin]-2'(1'H)-one 0.019
4-9 ##STR00020## 1'-{[5-Chloro-1-(6-methoxypyridin-
3-yl)-1H-benzimidazol-2-yl] methyl}spiro[cyclopropane-
1,3'-pyrrolo[2,3-c]pyridin]- 2'(1'H)-one 0.011 5-1 ##STR00021##
1'-({5-Chloro-1-[5-(methylsulfonyl)
pyridin-3-yl]-1H-benzimidazol-2- yl}methyl)spiro[cyclopropane-
1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)- one 0.005 5-2 ##STR00022##
1'-({5-Chloro-1-[6-(methylsulfonyl)
pyridin-2-yl]-1H-benzimidazol-2- yl}methyl)spiro[cyclopropane-
1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)- one 0.005 5-3 ##STR00023##
1'-({5-Chloro-1-[3-methyl-5- (methylsulfonyl)pyridin]-1H-
benzimidazol-2-yl}methyl) spiro[cyclopropane-1,3'-pyrrolo
[2,3-c]pyridin]-2'(1'H)-one 0.019 6-1 ##STR00024##
4-{5-Chloro-2-[(2'- oxospiro[cyclopropane-1,3'-pyrrolo
[2,3-c]pyridin]-1'(2'H)-yl)methyl]- 1H-benzimidazol-1-yl}benzoic
acid 0.006 6-2 ##STR00025## 3-{5-Chloro-2-[(2'-
oxospiro[cyclopropane-1,3'-pyrrolo
[2,3-c]pyridin]-1'(2'H)-yl)methyl]- 1H-benzimidazol-1-yl}benzoic
acid 0.512 6-3 ##STR00026## 4-{5-Chloro-2-[(6'-fluoro-2'-
oxospiro[cyclopropane-1,3'- indol]-1'(2'H)-yl)methyl]-
1H-benzimidazol-1-yl}benzoic acid 0.05 7 ##STR00027##
4-{5-Chloro-2-[(6'-fluoro-2'- oxospiro[cyclopropane-1,3'-
indol]-1'(2'H)-yl)methyl]- 1H-benzimidazol-1-yl}benzoic acid 0.013
8 ##STR00028## 1'-{[5-Chloro-1-(6-hydroxypyridin-
3-yl)-1H-benzimidazol-2- yl]methyl}spiro[cyclopropane-
1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)- one 0.018 9-1 ##STR00029##
1'-({6-Chloro-3-[4- (methylsulfonyl)phenyl]-1H-
indol-2-yl}methyl)spiro [cyclopropane-1,3'-pyrrolo
[2,3-c]pyridin]-2'(1'H)-one 0.025 9-2 ##STR00030##
1'-({6-Chloro-3-[3- (methylsulfonyl)phenyl]-1H-
indol-2-yl}methyl)spiro [cyclopropane-1,3'-pyrrolo
[2,3-c]pyridin]-2'(1'H)-one 0.029
TABLE-US-00002 TABLE 2 NMR and MS data of particular compounds
Example No. .sup.1H NMR data MW data 1 .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.42 (s, 1 H), 8.41 (s, 1 H), 8.28 MS obsd.
(s, 1 H), 7.89-7.81 (m, 3 H), 7.29-7.26 (m, 2 H), 6.93-6.91 (d, J =
(ESI.sup.+) 8.8 Hz, 1 H), 6.77-6.76 (m, 1 H), 5.31 (s, 2 H),
1.65-1.62 (m, 2 H), [(M + H).sup.+] 1.59-1.56 (m, 2 H) 427 2-1
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 8.93 (d, J = 5.05 Hz,
1 H), 8.21 MS obsd. (d, J = 4.80 Hz, 1 H), 8.19-8.14 (m, 1 H), 8.12
(s, 1 H), 7.81-7.75 (ESI.sup.+) (m, 2 H), 7.35 (dd, J = 8.72, 1.64
Hz, 1 H), 7.26 (d, J = 8.84 Hz, 1 [(M + H).sup.+] H), 7.05 (d, J =
4.80 Hz, 1 H), 5.45 (s, 2 H), 3.35 (br. s., 3 H), 1.77-1.69 480 (m,
2 H), 1.63-1.56 (m, 2 H) 2-2 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. ppm 8.97 (d, J = 5.05 Hz, 1 H), MS obsd. 8.27-8.18 (m, 2
H), 8.17 (s, 1 H), 8.05 (dd, J = 5.05, 1.26 Hz, 1 H), 7.74
(ESI.sup.+) (d, J = 1.52 Hz, 1 H), 7.46 (d, J = 8.84 Hz, 1 H), 7.39
(dd, J = 8.72, [(M + H).sup.+] 1.89 Hz, 1 H), 7.11 (d, J = 4.55 Hz,
1 H), 5.56 (s, 2 H), 3.46 (q, J = 494 7.30 Hz, 2 H), 1.84-1.77 (m,
2 H), 1.75-1.68 (m, 2 H), 1.37 (t, J = 7.33 Hz, 3 H) 3 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 8.22 (s, 1 H), 8.14 (s, 1 H),
MS obsd. 8.80 (d, J = 2.0 Hz, 1 H), 7.48 (s, 4 H), 7.27 (dd, J =
4.4, 13.2 Hz, 1 (ESI.sup.+) H), 7.14 (s, 1 H), 7.12 (m, 2 H), 5.26
(d, J = 4.0 Hz, 2 H), 4.14 (q, J = [(M + H).sup.+] 7.2 Hz, 2 H),
3.80 (s, 2 H), 1.74 (m, 2 H), 1.54 (m, 2 H), 1.24 (t, J = 487 7.2
Hz, 3 H) 4-1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 8.21 (d,
J = 5.05 Hz, 1 H), 8.03 MS obsd. (s, 1 H), 7.69 (d, J = 1.52 Hz, 1
H), 7.61-7.49 (m, 3 H), 7.42-7.32 (ESI.sup.+) (m, 2 H), 7.26 (dd, J
= 8.59, 1.77 Hz, 1 H), 7.11-7.01 (m, 2 H), 5.34 [(M + H).sup.+] (s,
2 H), 1.77-1.70 (m, 2 H), 1.68-1.58 (m, 2 H) 401 4-2 .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. ppm 8.22 (d, J = 5.05 Hz, 1 H), 8.17
MS obsd. (d, J = 8.59 Hz, 2 H), 8.04 (s, 1 H), 7.75 (d, J = 1.77
Hz, 1 H), 7.50 (ESI.sup.+) (d, J = 8.59 Hz, 2 H), 7.32 (dd, J =
8.72, 1.89 Hz, 1 H), 7.16 (d, J = [(M + H).sup.+] 8.84 Hz, 1 H),
7.07 (d, J = 4.80 Hz, 1 H), 5.41 (s, 2 H), 4.46 (q, J = 473 7.24
Hz, 2 H), 1.75-1.69 (m, 2 H), 1.63-1.58 (m, 2 H), 1.45 (t, J = 7.07
Hz, 3 H) 4-3 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 8.83 (s,
1 H), 8.28-8.21 (m, 3 MS obsd. H), 8.20 (s, 1 H), 7.78 (d, J = 1.52
Hz, 1 H), 7.34 (dd, J = 8.59, 1.77 (ESI.sup.+) Hz, 1 H), 7.21 (d, J
= 8.84 Hz, 1 H), 7.08 (d, J = 4.80 Hz, 1 H), 5.42 [(M + H).sup.+]
(s, 2 H), 1.81-1.72 (m, 2 H), 1.70-1.61 (m, 2 H) 480 4-4 .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. ppm 8.24-8.21 (m, 1 H), 8.18-8.13
MS obsd. (m, 1 H), 8.10-8.07 (m, 1 H), 8.04-7.99 (m, 1 H),
7.84-7.81 (m, 1 (ESI.sup.+) H), 7.80-7.77 (m, 1 H), 7.67-7.62 (m, 1
H), 7.35-7.30 (m, 1 H), [(M + H).sup.+] 7.16-7.11 (m, 1 H),
7.08-7.04 (m, 1 H), 5.46-5.38 (m, 2 H), 3.26 479 (s, 3 H),
1.76-1.69 (m, 2 H), 1.63-1.52 (m, 2 H) 4-5 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 8.26-8.20 (m, 1 H), 8.16-8.10 MS obsd. (m,
2 H), 8.10-8.05 (m, 1 H), 7.78-7.75 (m, 1 H), 7.70-7.64 (m, 2
(ESI.sup.+) H), 7.36-7.30 (m, 1 H), 7.21-7.15 (m, 1 H), 7.09-7.04
(m, 1 H), [(M + H).sup.+] 5.43 (s, 2 H), 3.23 (s, 3 H), 1.79-1.71
(m, 2 H), 1.68-1.61 (m, 2 H) 479 4-6 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 8.61-8.44 (m, 2 H), 8.32-8.1 MS obsd. (m, 1
H), 8.15-8.05 (m, 1 H), 7.89-7.61 (m, 4 H), 7.39-7.31 (m, 1
(ESI.sup.+) H), 7.24-7.10 (m, 1 H), 5.43-5.34 (m, 2 H), 3.97 (s, 3
H), 2.18-2.06 [(M + H).sup.+] (m, 2 H), 2.02-1.92 (m, 2 H) 459 4-7
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 8.27-8.21 (m, 1 H),
8.15-8.12 MS obsd. (m, 1 H), 7.96-7.91 (m, 1 H), 7.89-7.85 (m, 3
H), 7.78-7.69 (m, 1 (ESI.sup.+) H), 7.35-7.30 (m, 1 H), 7.15-7.07
(m, 2 H), 5.42-5.33 (m, 2 H), [(M + H).sup.+] 1.81-1.62 (m, 4 H)
426 4-8 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 8.21 (d, J =
5.05 Hz, 1 H), 8.14 MS obsd. (d, J = 7.83 Hz, 1 H), 8.04 (s, 1 H),
7.96 (t, J = 1.64 Hz, 1 H), 7.76 (ESI.sup.+) (d, J = 1.52 Hz, 1 H),
7.71-7.63 (m, 1 H), 7.58-7.52 (m, 1 H), 7.31 [(M + H).sup.+] (dd, J
= 8.72, 1.89 Hz, 1 H), 7.11 (d, J = 8.84 Hz, 1 H), 7.04 (d, J = 443
4.80 Hz, 1 H), 5.41 (s, 2 H), 2.62 (s, 3 H), 1.72-1.52 (m, 4 H) 4-9
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 8.28-8.20 (m, 1 H),
8.19-8.10 MS obsd. (m, 2 H), 7.80-7.70 (m, 1 H), 7.69-7.59 (m, 1
H), 7.37-7.25 (m, 1 (ESI.sup.+) H), 7.17-7.06 (m, 2 H), 6.99-6.86
(m, 1 H), 5.36 (s, 2 H), 4.01 (s, 3 [(M + H).sup.+] H), 1.84-1.61
(m, 4 H) 432 5-1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 9.28
(d, J = 2.02 Hz, 1 H), 8.87 MS obsd. (d, J = 2.27 Hz, 1 H), 8.54
(t, J = 2.15 Hz, 1 H), 8.30-8.20 (m, 2 H), (ESI.sup.+) 7.81 (d, J =
1.77 Hz, 1 H), 7.35 (dd, J = 8.72, 1.89 Hz, 1 H), 7.20 (d, [(M +
H).sup.+] J = 8.59 Hz, 1 H), 7.08 (d, J = 4.80 Hz, 1 H), 5.41 (s, 2
H), 3.36 (s, 3 480 H), 1.80-1.70 (m, 2 H), 1.65-1.56 (m, 2 H) 5-2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 8.45 (t, J = 1.00 Hz,
1 H), MS obsd. 8.30-8.22 (m, 2 H), 8.19 (s, 1 H), 8.03 (d, J = 7.83
Hz, 1 H), 7.73 (d, J = (ESI.sup.+) 1.77 Hz, 1 H), 7.54 (d, J = 8.59
Hz, 1 H), 7.39 (dd, J = 8.72, 1.89 Hz, [(M + H).sup.+] 1 H), 7.12
(d, J = 4.80 Hz, 1 H), 5.60 (s, 2 H), 3.36 (s, 3 H), 1.85-1.78 480
(m, 2 H), 1.78-1.70 (m, 2 H) 5-3 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. ppm 8.22 (d, J = 4.80 Hz, 1 H), 8.03 MS obsd. (s, 1 H),
7.95 (s, 1 H), 7.78 (d, J = 1.77 Hz, 1 H), 7.73 (s, 1 H), 7.43
(ESI.sup.+) (s, 1 H), 7.32 (dd, J = 8.72, 1.89 Hz, 1 H), 7.13 (d, J
= 8.59 Hz, 1 H), [(M + H).sup.+] 7.06 (d, J = 5.05 Hz, 1 H), 5.43
(s, 2 H), 3.22 (s, 3 H), 2.48 (s, 3 H), 493 1.75-1.68 (m, 2 H),
1.60-1.53 (m, 2 H) 6-1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
ppm 8.22 (d, J = 4.80 Hz, 1 H), 8.16 MS obsd. (d, J = 8.59 Hz, 2
H), 8.03 (s, 1 H), 7.75 (d, J = 1.77 Hz, 1 H), 7.46 (ESI.sup.+) (d,
J = 8.34 Hz, 2 H), 7.32 (dd, J = 8.72, 1.89 Hz, 1 H), 7.16 (d, J =
[(M + H).sup.+] 8.59 Hz, 1 H), 7.07 (d, J = 4.80 Hz, 1 H), 5.41 (s,
2 H), 1.75-1.69 445 (m, 2 H), 1.65-1.58 (m, 2 H) 6-2 .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. ppm 8.25-8.19 (m, 1 H), 8.16-8.09 MS
obsd. (m, 1 H), 8.09-8.04 (m, 1 H), 7.82-7.77 (m, 1 H), 7.75-7.68
(m, 1 (ESI.sup.+) H), 7.63-7.53 (m, 1 H), 7.53-7.45 (m, 1 H),
7.34-7.25 (m, 1 H), [(M + H).sup.+] 7.19-7.12 (m, 1 H), 7.10-7.02
(m, 1 H), 5.40-5.34 (m, 2 H), 1.77-1.62 445 (m, 2 H), 1.37-1.26 (m,
2 H) 6-3 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 8.12 (d, J =
8.59 Hz, 2 H), MS obsd. 7.78-7.70 (m, 1 H), 7.36 (d, J = 8.59 Hz, 2
H), 7.29 (s, 1 H), 7.13 (d, J = (ESI.sup.+) 0.51 Hz, 1 H),
6.92-6.85 (m, 1 H), 6.78-6.69 (m, 1 H), 6.67-6.57 [(M + H).sup.+]
(m, 1 H), 5.33 (s, 2 H), 1.50 (s, 2 H), 1.45 (s, 2 H) 462 7 .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. ppm 8.22 (d, J = 5.05 Hz, 1 H),
8.05 MS obsd. (s, 1 H), 8.02 (d, J = 1.77 Hz, 2 H), 7.75 (d, J =
1.77 Hz, 1 H), 7.46 (ESI.sup.+) (d, J = 8.34 Hz, 2 H), 7.31 (dd, J
= 8.59, 1.77 Hz, 1 H), 7.14 (d, J = [(M + H).sup.+] 8.59 Hz, 1 H),
7.06 (d, J = 4.80 Hz, 1 H), 5.41 (s, 2 H), 1.76-1.69 444 (m, 2 H),
1.58-1.66 (m, 2 H) 8 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm
8.30-8.22 (m, 1 H), 8.20-8.11 MS obsd. (m, 1 H), 7.85-7.67 (m, 3
H), 7.38-7.27 (m, 2 H), 7.27-7.18 (m, 1 (ESI.sup.+) H), 7.16-7.09
(m, 1 H), 6.63-6.48 (m, 2 H), 1.88-1.70 (m, 4 H) [(M + H).sup.+]
418 9-1 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 8.15-8.10 (m,
1 H), 7.99-7.93 MS obsd. (m, 2 H), 7.63-7.58 (m, 2 H), 7.54-7.49
(m, 1 H), 7.49-7.45 (m, 1 (ESI.sup.+) H), 7.45-7.42 (m, 1 H),
7.11-7.06 (m, 1 H), 7.01-6.96 (m, 1 H), [(M + H).sup.+] 5.40 (s, 2
H), 3.19 (s, 3 H), 1.80-1.70 (m, 4 H) 478 9-2 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 8.16-8.08 (m, 2 H), 7.98-7.84 MS obsd. (m,
2 H), 7.75-7.64 (m, 1 H), 7.57-7.50 (m, 1 H), 7.50-7.36 (m, 2
(ESI.sup.+) H), 7.16-7.04 (m, 1 H), 7.04-6.96 (m, 1 H), 5.44-5.31
(m, 2 H), [(M + H).sup.+] 3.18 (s, 3 H), 1.79-1.67 (m, 4 H) 478
[0078] More particular compounds of formula I include the
following:
[0079]
5-{5-Chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin-
]-1'(2'H)-yl)methyl]-1H-benzimidazol-1-yl}pyridine-2-carbonitrile;
[0080] Ethyl
4-{5-chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2-
'H)-yl)methyl]-1H-benzimidazol-1-yl}benzoate;
[0081]
1'-({5-Chloro-1-[6-(methylsulfonyl)pyridin-3-yl]-1H-benzimidazol-2--
yl}methyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one;
[0082]
1'-({5-chloro-1-[3-(methylsulfonyl)phenyl]-1H-benzimidazol-2-yl}met-
hyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one;
[0083]
1'-({5-chloro-1-[4-(methylsulfonyl)phenyl]-1H-benzimidazol-2-yl}met-
hyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one;
[0084]
3-{5-Chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin-
]-1'(2'H)-yl)methyl]-1H-benzimidazol-1-yl}benzonitrile;
[0085]
1'-({[5-Chloro-1-(6-methoxypyridin-3-yl)-1H-benzimidazol-2-yl]methy-
l}spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one;
[0086]
1'-({5-Chloro-1-[5-(methylsufonyl)pyridin-3-yl]-1H-benzimidazol-2-y-
l}methyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one;
[0087]
1'-({5-Chloro-1-[6-(methylsufonyl)pyridin-2-yl]-1H-benzimidazol-2-y-
l}methyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one;
[0088]
4-{5-Chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin-
]-1'(2'H)-yl)methyl]-1H-benzimidazol-1-yl}benzoic acid;
[0089]
4-{5-Chloro-2-[(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indol]-1'(2-
'H)-yl)methyl]-1H-benzimidazol-1-yl}benzoic acid; and
[0090]
1'-{[5-Chloro-1-(6-hydroxypyridin-3-yl)-1H-benzimidazol-2-yl]methyl-
}spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one.
Synthesis
[0091] The compounds of the present invention can be prepared by
any conventional means. Suitable processes for synthesizing these
compounds as well as their starting materials are provided in the
schemes below and in the examples. All substituents, in particular,
R.sup.1 to R.sup.10, W and X are as defined above unless otherwise
indicated. Furthermore, and unless explicitly otherwise stated, all
reactions, reaction conditions, abbreviations and symbols have the
meanings well known to a person of ordinary skill in organic
chemistry.
[0092] General synthetic route for Compound Ia (Scheme 1)
##STR00031##
[0093] Compound Ia can be prepared according to Scheme 1.
[0094] o-Nitro-N-substituted aniline IV can be generated by
reaction of fluorobenzene IIa with amine IIIa. The reaction can be
carried out in the presence of a suitable base such as potassium
2-methylpropan-2-olate, sodium 2-methylpropan-2-olate, potassium
carbonate or ethyl-diisopropyl-amine in a suitable organic solvent
such as N,N-dimethylformamide at a temperature between 20.degree.
C. and 120.degree. C. for several hours.
[0095] o-Nitro-N-substituted aniline IV can also be generated by
reaction of aniline IIB with IIIb. The reaction can be carried out
in the presence of a suitable base such as potassium carbonate in a
suitable organic solvent such as N,N-dimethylformamide at a
temperature between 100.degree. C. and 160.degree. C. under
microwave irradiation for 30 minutes to several hours. The reaction
can also be carried out with tris(dibenzylideneacetone)dipalladium,
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and cesium
carbonate in1,4-dioxane at a temperature between 100.degree. C. and
150.degree. C. for several hours.
[0096] Diamine V can be prepared by reduction of nitro group of
o-nitro-N-substituted aniline IVa. The reaction can be carried out
in the presence of Raney nickel with hydrazine hydrate in an
organic solvent such as methanol or ethanol at a temperature
between room temperature and 80.degree. C. for 10 minutes to
several hours. The reaction can also be carried out in the presence
of Raney nickel under hydrogen atmosphere at room temperature
overnight.
[0097] 2-(Chloromethyl)benzimidazole VI can be prepared by reaction
of diamine V with bromoacetic acid. The reaction can be carried out
in an aqueous solution of hydrochloric acid at a concentration
between 4 N and 12 N at a temperature between 100.degree. C. and
150.degree. C. for several hours to several days.
2-(Chloromethyl)benzimidazole VI can also be prepared by reaction
of diamine V with 2-chloro-1,1,1-trimethoxyethane or
2-chloro-1,1,1-triethoxyethane. The reaction can be carried out by
heating diamine V with 2-chloro-1,1,1-trimethoxyethane or
2-chloro-1,1,1-triethoxyethane in the presence or absence of
4-methylbenzenesulfonic acid with or without ethanol at a
temperature between 50.degree. C. and 80.degree. C. for several
hours. Alternatively, the reaction can be carried out by heating
diamine V with 2-chloro-1,1,1-trimethoxyethane or
2-chloro-1,1,1-triethoxyethane with or without ethanol at a
temperature between 100.degree. C. and 120.degree. C. for one to
several hours under microwave irradiation.
[0098] Compound Ia can be prepared by reaction of
2-(chloromethyl)benzimidazole VI with amide VII. The reaction can
be carried out in the presence of a suitable base such as cesium
carbonate, sodium hydride or potassium tert-butoxide in an organic
solvent such as acetonitrile or N,N-dimethylformamide at a
temperature between 0.degree. C. and 100.degree. C. for one to
several hours.
[0099] General synthetic route for Compound Ib (Scheme 2)
##STR00032## ##STR00033##
[0100] Compound Ib can be prepared according to Scheme 2.
[0101] N-protected indole IX can be prepared by reaction of indole
VIII with benzenesulfonyl chloride. The reaction can be carried out
in the presence of sodium hydride in N,N-dimethylformamide at a
temperature between 0.degree. C. and room temperature for one to
several hours.
[0102] Hydroxy X can be prepared by reduction of ethyl ester IX.
The reaction can be carried out by treating alkyl ester IX with
lithium aluminum hydride in tetrahydrofuran at a temperature
between 0.degree. C. and room temperature for several hours.
[0103] 3-Iodo-indole XI can be prepared by treating
2-hydroxymethyl-indole X with 1-iodopyrrolidine-2,5-dione. The
reaction can be carried out in a suitable solvent such as
acetonitrile at 0.degree. C. for one to several hours.
[0104] 3-Phenyl indole XII can be prepared by reaction of iodo XI
with phenylboromic acid. The reaction can be carried out in the
presence of a suitable palladium catalyst such as
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride and a
suitable base such as potassium carbonate in N,N-dimethylacetamide
at a temperature between 50.degree. C. and 100.degree. C. for
several hours.
[0105] Methanesulfonate XIII can be prepared by reaction of hydroxy
XII with methanesulfonyl chloride. The reaction can be carried out
by treating hydroxy XII with methanesulfonyl chloride with a
suitable organic base such as triethylamine or
diisopropylethylamine in dichloromethane at a temperature between
0.degree. C. and room temperature for one to several hours.
[0106] Intermediate XIV can be prepared by reaction of
methanesulfonate XIII with amide VII. The reaction can be carried
out in the presence of a base such as cesium carbonate, sodium
hydride or sodium tert-butoxide in an organic solvent such as
acetonitrile or N,N-dimethylformamide at a temperature between
0.degree. C. and room temperature for one to several hours.
[0107] Compound Ib can be prepared by cleavage of benzenesulfonyl
group of XIV. The reaction can be carried out by treating XIV with
tetra-n-butylammonium fluoride in a suitable solvent such as
dichloromethane or tetrahydrofuran at room temperature for 30
minutes to several hours.
[0108] This invention also relates to a process for the preparation
of a compound of formula I comprising the reaction of [0109] (a) a
compound of formula (A)
##STR00034##
[0109] with
##STR00035##
in the presence of a base; [0110] (b) a compound of formula (B)
##STR00036##
[0110] with tetra-n-butylammonium fluoride; [0111] wherein R.sup.1
to R.sup.5, R.sup.10, W and X are defined above unless otherwise
indicated.
[0112] In step (a), the base can be for example cesium carbonate,
sodium hydride or potassium tert-butoxide.
[0113] A compound of formula I when manufactured according to the
above process is also an object of the invention.
Pharmaceutical Compositions and Administration
[0114] The invention also relates to a compound of formula I for
use as therapeutically active substance.
[0115] Another embodiment provides pharmaceutical compositions or
medicaments containing the compounds of the invention and a
therapeutically inert carrier, diluent or excipient, as well as
methods of using the compounds of the invention to prepare such
compositions and medicaments. In one example, compounds of formula
(I) may be formulated by mixing at ambient temperature at the
appropriate pH, and at the desired degree of purity, with
physiologically acceptable carriers, i.e., carriers that are
non-toxic to recipients at the dosages and concentrations employed
into a galenical administration form. The pH of the formulation
depends mainly on the particular use and the concentration of
compound, but preferably ranges anywhere from about 3 to about 8.
In one example, a compound of formula (I) is formulated in an
acetate buffer, at pH 5. In another embodiment, the compounds of
formula (I) are sterile. The compound may be stored, for example,
as a solid or amorphous composition, as a lyophilized formulation
or as an aqueous solution.
[0116] Compositions are formulated, dosed, and administered in a
fashion consistent with good medical practice. Factors for
consideration in this context include the particular disorder being
treated, the particular mammal being treated, the clinical
condition of the individual patient, the cause of the disorder, the
site of delivery of the agent, the method of administration, the
scheduling of administration, and other factors known to medical
practitioners. The "effective amount" of the compound to be
administered will be governed by such considerations, and is the
minimum amount necessary to inhibit RSV fusion protein. For
example, such amount may be below the amount that is toxic to
normal cells, or the mammal as a whole.
[0117] In one example, the pharmaceutically effective amount of the
compound of the invention administered parenterally per dose will
be in the range of about 0.1 to about 50 mg/kg, alternatively about
0.1 to about 20 mg/kg of patient body weight per day, with the
typical initial range of compound used being about 0.3 to about 15
mg/kg/day. In another embodiment, oral unit dosage forms, such as
tablets and capsules, preferably contain from about 25 to about 100
mg of the compound of the invention.
[0118] The compounds of the invention may be administered by any
suitable means, including oral, topical (including buccal and
sublingual), rectal, vaginal, transdermal, parenteral,
subcutaneous, intraperitoneal, intrapulmonary, intradermal,
intrathecal and epidural and intranasal, and, if desired for local
treatment, intralesional administration. Parenteral infusions
include intramuscular, intravenous, intraarterial, intraperitoneal,
or subcutaneous administration.
[0119] The compounds of the present invention may be administered
in any convenient administrative form, e.g., tablets, powders,
capsules, solutions, dispersions, suspensions, syrups, sprays,
suppositories, gels, emulsions, patches, etc. Such compositions may
contain components conventional in pharmaceutical preparations,
e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents,
and further active agents.
[0120] A typical formulation is prepared by mixing a compound of
the present invention and a carrier or excipient. Suitable carriers
and excipients are well known to those skilled in the art and are
described in detail in, e.g., Ansel, Howard C., et al., Ansel's
Pharmaceutical Dosage Forms and Drug Delivery Systems.
Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro,
Alfonso R., et al. Remington: The Science and Practice of Pharmacy.
Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,
Raymond C. Handbook of Pharmaceutical Excipients. Chicago,
Pharmaceutical Press, 2005. The formulations may also include one
or more buffers, stabilizing agents, surfactants, wetting agents,
lubricating agents, emulsifiers, suspending agents, preservatives,
antioxidants, opaquing agents, glidants, processing aids,
colorants, sweeteners, perfuming agents, flavoring agents, diluents
and other known additives to provide an elegant presentation of the
drug (i.e., a compound of the present invention or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
[0121] An example of a suitable oral dosage form is a tablet
containing about 25 mg to about 500 mg of the compound of the
invention compounded with about 90 to about 30 mg anhydrous
lactose, about 5 to about 40 mg sodium croscarmellose, about 5 to
about 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 to about 10
mg magnesium stearate. The powdered ingredients are first mixed
together and then mixed with a solution of the PVP. The resulting
composition can be dried, granulated, mixed with the magnesium
stearate and compressed to tablet form using conventional
equipment. An example of an aerosol formulation can be prepared by
dissolving the compound, for example 5 mg to 400 mg), of the
invention in a suitable buffer solution, e.g. a phosphate buffer,
adding a tonicifier, e.g. a salt such sodium chloride, if desired.
The solution may be filtered, e.g., using a 0.2 micron filter, to
remove impurities and contaminants.
[0122] An embodiment, therefore, includes a pharmaceutical
composition comprising a compound of Formula I, or a stereoisomer
or pharmaceutically acceptable salt thereof. In a further
embodiment includes a pharmaceutical composition comprising a
compound of Formula I, or a stereoisomer or pharmaceutically
acceptable salt thereof, together with a pharmaceutically
acceptable carrier or excipient.
Indications and Methods of Treatment
[0123] The compounds of the invention can be utilized to inhibit
RSV fusion protein, therefore prevent the virus cell syncytial
function. Accordingly, the compounds of the invention are useful
for the treatment or prophylaxis of RSV infection.
[0124] The invention relates to the use of a compound of formula I
for the treatment or prophylaxis of respiratory syncytial virus
infection.
[0125] The use of a compound of formula I for the preparation of
medicaments useful in the treatment or prophylaxis diseases that
are related to RSV infection is an object of the invention.
[0126] The invention relates in particular to the use of a compound
of formula I for the preparation of a medicament for the treatment
or prophylaxis of RSV infection.
[0127] Another embodiment includes a method of treating or
preventing RSV infection in a mammal in need of such treatment,
wherein the method comprises administering to said mammal a
therapeutically effective amount of a compound of Formula I, a
stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt
thereof.
Combination Therapy
[0128] The compounds of the invention can be used in combination
with other antiviral ingredients for the treatment or prophylaxis
of RSV infection.
EXAMPLES
[0129] The invention will be more fully understood by reference to
the following examples. They should not, however, be construed as
limiting the scope of the invention.
[0130] Abbreviations used herein are as follows:
[0131] .mu.L: microliter .mu.m: micrometer .mu.M: micromoles per
liter
[0132] AUC: area under the curve
[0133] CD.sub.3OD: deuterated methanol
[0134] CDCl.sub.3: deuterated chloroform
[0135] DMSO-d.sub.6: deuterated dimethylsulfoxide
[0136] EC.sub.50: the concentration of a compound where 50% of its
maximal protection effect against viral induced CPE is observed
[0137] g: gram
[0138] HPLC: high performance liquid chromatography
[0139] Hz: Hertz
[0140] ICR: imprinting control region
[0141] J: coupling constants
[0142] LC/MS: Liquid chromatography/mass spectrometry
[0143] LongStrain: an A subtype RSV strain obtained from ATCC with
catalog number VR-26
[0144] mg: milligram
[0145] MHz: megahertz
[0146] mL: milliliter
[0147] mm: millimeter
[0148] mmol: millimole
[0149] MS (ESI): mass spectroscopy (electron spray ionization)
[0150] NMR: nuclear magnetic resonance
[0151] obsd.: observed
[0152] Ph: phenyl
[0153] PK: Pharmacokinetics
[0154] SDPK: single dose pharmacokinetics
[0155] Prep HPLC: preparative high performance liquid
chromatography
[0156] TEA: triethylamine
[0157] TLC: thin layer chromatography
[0158] .delta.: chemical shift
[0159] ppm: parts per million
General Experimental Conditions
[0160] Intermediates and final compounds were purified by flash
chromatography using one of the following instruments: i) Biotage
SP1 system and the Quad 12/25 Cartridge module. ii) ISCO
combi-flash chromatography instrument. Silica gel Brand and pore
size: i) KP-SIL 60 .ANG., particle size: 40-60 .mu.M; ii) CAS
registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron
silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore:
200-300 or 300-400.
[0161] Intermediates and final compounds were purified by
preparative HPLC on reversed phase column using X Bridge.TM. Perp
C.sub.18 (5 .mu.m, OBD.TM. 30.times.100 mm) column or SunFire.TM.
Perp C.sub.18 (5 .mu.m, OBD.TM. 30.times.100 mm) column.
[0162] LC/MS spectra were obtained using a MicroMass Plateform LC
(Waters.TM. alliance 2795-ZQ2000). Standard LC/MS conditions were
as follows (running time 6 minutes):
[0163] Acidic condition: A: 0.1% formic acid in H.sub.2O; B: 0.1%
formic acid in acetonitrile;
[0164] Basic condition: A: 0.01% NH.sub.3.H.sub.2O in H.sub.2O; B:
acetonitrile;
[0165] Neutral condition: A: H.sub.2O; B: acetonitrile.
[0166] Mass spectra (MS): generally only ions which indicate the
parent mass are reported, and unless otherwise stated the mass ion
quoted is the positive mass ion (M+H).sup.+.
[0167] The microwave assisted reactions were carried out in a
Biotage Initiator Sixty.
[0168] NMR Spectra were obtained using Bruker Avance 400 MHz.
[0169] All reactions involving air-sensitive reagents were
performed under an argon atmosphere. Reagents were used as received
from commercial suppliers without further purification unless
otherwise noted.
[0170] The following examples were prepared by the general methods
outlined in the schemes above. They are intended to illustrate the
meaning of the present invention but should by no means represent a
limitation within the meaning of the present invention.
PREPARATIVE EXAMPLES
Example 1
5-{5-Chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2'-
H)-yl)methyl]-1H-benzimidazol-1-yl}pyridine-2-carbonitrile
[0171] Step 1: Preparation of 5-nitropyridine-2-carbonitrile
##STR00037##
[0172] A mixture of 2-bromo-5-nitropyridine (12.0 g, 59.1 mmol, CAS
No.: 4487-59-6) and copper (I) cyanide (7.94 g, 88.7 mmol) in
N,N-dimethylformamide (50 mL) was heated under reflux for 16 hours.
After being cooled down to room temperature, the reaction mixture
was poured into water and then extracted with ethyl acetate (100
mL.times.3). The combined organic layer was washed with brine, and
then dried over sodium sulfate and filtered. The filtrate was
concentrated in vacuo to afford 8.0 g of
5-nitropyridine-2-carbonitrile (yield was 90.8%).
[0173] Step 2: Preparation of 5-aminopyridine-2-carbonitrile
##STR00038##
[0174] To a solution of 5-nitropyridine-2-carbonitrile (7.0 g, 46.9
mmol) in methanol (150 mL) was added 10% palladium on carbon (2.0
g) and carbamic acid (7.0 g, 115 mmol). After being heated under
reflux for 16 hours, the resulting mixture was filtered and the
filtrate was concentrated in vacuo. The residue was dissolved in
water (150 mL) and the resulting mixture was extracted with ethyl
acetate (150 mL.times.3). The organic layer was dried over sodium
sulfate and concentrated in vacuo to afford 5.1 g of
5-aminopyridine-2-carbonitrile (yield was 91.3%).
[0175] Step 3: Preparation of
5-[(4-chloro-2-nitrophenyl)amino]pyridine-2-carbonitrile
##STR00039##
[0176] A mixture of 4-chloro-1-fluoro-2-nitrobenzene (880 mg, 5.03
mmol, CAS No.: 345-18-6), 5-aminopyridine-2-carbonitrile (1.19 g,
10.0 mmol, CAS No.: 55338-73-3) and potassium
2-methylpropan-2-olate (1.12 g, 10.0 mmol) in N,N-dimethylformamide
(20 mL) was stirred at room temperature overnight. The reaction
mixture was poured into ice-water. The precipitate was collected by
filtration to afford 0.7 g of
5-[(4-chloro-2-nitrophenyl)amino]pyridine-2-carbonitrile (yield was
50.7%).
[0177] Step 4: Preparation of
5-[(2-amino-4-chlorophenyl)amino]pyridine-2-carbonitrile
##STR00040##
[0178] To a solution of
5-[(4-chloro-2-nitrophenyl)amino]pyridine-2-carbonitrile (600 mg,
2.18 mmol) in methanol (10 mL) was added Raney nickel (200 mg)
under nitrogen protection. The resulting mixture was stirred under
hydrogen atmosphere at room temperature overnight. The resulting
mixture was filtered through a pad of silica gel. The filtrate was
concentrated in vacuo. The residue was purified by preparative TLC
(50% ethyl acetate in petroleum ether) to afford 190 mg of
5-[(2-amino-4-chlorophenyl)amino]pyridine-2-carbonitrile (yield was
35.6%).
[0179] Step 5: Preparation of
5-[5-chloro-2-(chloromethyl)-1H-benzimidazol-1-yl]pyridine-2-carbonitrile
##STR00041##
[0180] A mixture of
5-[(2-amino-4-chlorophenyl)amino]pyridine-2-carbonitrile (190 mg,
0.78 mmol) and 2-chloro-1,1,1-trimethoxyethane (602 mg, 3.89 mmol,
CAS No.: 74974-54-2) in ethanol (10 mL) was heated under reflux for
2 hours. The resulting reaction mixture was concentrated in vacuo
and the residue was purified by preparative TLC (50% ethyl acetate
in petroleum ether) to afford 200 mg of
5-[5-chloro-2-(chloromethyl)-1H-benzimidazol-1-yl]pyridine-2-carbonitrile
(yield was 84.6%).
[0181] Step 6: Preparation of dimethyl
2-(3-nitro-4-pyridyl)propanedioate
##STR00042##
[0182] To a cooled suspension of sodium hydride (22.5 g, 0.56 mol)
in dry toluene (1500 mL) was added dimethyl malonate (92 g, 0.7
mol) dropwise while stirring at a temperature between 0.degree. C.
and 10.degree. C. under N.sub.2. After the addition, the mixture
was stirred for 30 minutes. Then to the resulting mixture was added
a solution of 4-chloro-3-nitro-pyridine (75.0 g, 0.47 mmol, CAS No:
13091-23-1) in dry toluene (1000 mL) dropwise at room temperature
and then the resulting mixture was heated under reflux overnight.
After the completion of the reaction, the reaction mixture was
cooled to room temperature and then poured into ice-water and then
extracted with EtOAc (500 mL.times.3). The combined organic layer
was dried over sodium sulphate and then concentrated in vacuo. The
residue was purified by flash chromatography to afford 55 g of
dimethyl 2-(3-nitro-4-pyridyl)propanedioate (yield was 38.6%).
[0183] Step 7: Preparation of methyl
2-(3-nitro-4-pyridyl)acetate
##STR00043##
[0184] A mixture of dimethyl 2-(3-nitro-4-pyridyl)propanedioate
(5.1 g, 20 mmol), lithium chloride (1.59 g, 37.6 mmol), water (0.36
g, 20 mmol) and dimethyl sulfoxide (100 mL) was heated at
100.degree. C. for 8 hours. The reaction mixture was cooled, and
then diluted with ethyl acetate (150 mL) and then washed
successively with water (100 mL) and brine (100 mL). The combined
aqueous layers were extracted with ethyl acetate (100 mL.times.2).
The organic layer was combined, and then dried over sodium
sulphate, then filtered and concentrated in vacuo. The residue was
purified by flash chromatography to give 2.4 g of methyl
2-(3-nitro-4-pyridyl)acetate (yield was 61.2%).
[0185] Step 8: Preparation of methyl
2-(3-nitro-4-pyridyl)prop-2-enoate
##STR00044##
[0186] A mixture of methyl 2-(3-nitro-4-pyridyl)acetate (37 g,
0.189 mol), benzyl(triethyl)ammonium chloride (86 g, 1.233 mol) and
potassium carbonate (53 g, 0.378 mol) in dry toluene (1500 mL) was
degassed and then paraformaldehyde (37 g, 1.233 mol) was added in
portions to the mixture. The reaction mixture was heated with
stirring at 80.degree. C. for 1 hour. The resulting mixture was
cooled to room temperature and then the solvent was removed. The
residue was dissolved in ice-water (1000 mL), and then extracted
with ethyl acetate (500 mL.times.2). The combined organic layer was
washed with brine (500 mL), and then dried over sodium sulphate and
then concentrated in vacuo. The residue was purified by flash
column to afford 21.6 g of methyl
2-(3-nitro-4-pyridyl)prop-2-enoate as a brown solid (yield was
55%).
[0187] Step 9: Preparation of methyl
1-(3-nitro-4-pyridyl)cyclopropanecarboxylate
##STR00045##
[0188] To a degassed solution of trimethyl sulfoxonium chloride
(11.6 g, 0.072 mol, CAS No.: 47987-92-8) in dry tetrandrofuran (200
mL) was added potassium tert-butoxide (5.9 g, 0.072 mol) at
0.degree. C. The resulting mixture was stirred at room temperature
for 1 hour. Then to the resulting mixture was added dropwise a
solution of methyl 2-(3-nitro-4-pyridyl)prop-2-enoate (10 g, 0.048
mol) in dry tetrandrofuran (200 mL). The reaction mixture was
stirred at room temperature for 5 hours, and then poured into
ice-water, then extracted with ethyl acetate (500 mL.times.2). The
combined organic layer was washed with brine (500 mL), and then
dried over sodium sulphate and then concentrated in vacuo. The
residue was purified by flash column to afford 3.5 g of methyl
1-(3-nitro-4-pyridyl)cyclopropanecarboxylate as a brown solid
(yield was 33%).
[0189] Step 10: Preparation of methyl
1-(3-amino-4-pyridyl)cyclopropanecarboxylate
##STR00046##
[0190] A solution of methyl
1-(3-nitro-4-pyridyl)cyclopropanecarboxylate (3.5 g, 15.7 mmol) in
200 mL of ethanol was stirred under hydrogen (50 psi) at room
temperature for 6 hours in the presence of 10% palladium on carbon
(350 mg). The resulting mixture was filtered and the filtrate was
concentrated in vacuo to afford 2.9 g of methyl
1-(3-amino-4-pyridyl)cyclopropanecarboxylate (yield was 96%), which
was used for the next step reaction without further
purification.
[0191] Step 11: Preparation of
Spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
##STR00047##
[0192] To a solution of methyl
1-(3-amino-4-pyridyl)cyclopropanecarboxylate (2.9 g, 15 mmol) in
100 mL of water was added tetrafluoroboric acid (6.6 mL, 50 wt % in
water). The mixture was heated under reflux for 30 minutes and then
cooled to room temperature. The mixture was then adjusted to pH 8
by addition of sodium bicarbonate. The reaction mixture was
extracted with ethyl acetate (100 mL.times.5). The combined organic
layer was dried over sodium sulphate and then concentrated in vacuo
to afford 0.6 g of
spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one (yield
was 25%).
[0193] Step 12: Preparation of
5-{5-chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2-
'H)-yl)methyl]-1H-benzimidazol-1-yl}pyridine-2-carbonitrile
[0194] A mixture of
5-[5-chloro-2-(chloromethyl)-1H-benzimidazol-1-yl]pyridine-2-carbonitrile
(150 mg, 0.495 mmol),
spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one (87.0
mg, 0.544 mmol) and cesium carbonate (194 mg, 0.594 mmol) in
acetonitrile (5 mL) was stirred at room temperature overnight. The
resulting mixture was filtered and the filtrate was purified by
preparative HPLC to afford 65 mg of the title product.
Example 2-1
1'-({5-Chloro-1-[2-(methylsufonyl)pyridin-4-yl]-1H-benzimidazol-2-yl}methy-
l)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0195] Step 1: Preparation of 2,4-bis(methylsulfonyl)pyridine
##STR00048##
[0196] A mixture of 2,4-dichloropyridine (1.68 g, 11.0 mmol, CAS
No.: 26452-80-2), sodium methanesulfinate (3.96 g, 33.0 mmol, 85%
purity, CAS No.: 20277-69-4) and tetrabutylammonium chloride (917
mg, 3.3 mmol) in N,N-dimethylformamide (10 mL) was heated at
150.degree. C. under microwave irradiation for 1 hour. The
resulting mixture was then stirred with water (20 mL). The
precipitate was collected by filtration to afford 1.59 g of
2,4-bis(methylsulfonyl)pyridine as a light pale solid (yield was
61.5%).
[0197] Step 2: Preparation of
N-(4-chloro-2-nitrophenyl)-2-(methylsulfonyl)pyridin-4-amine
##STR00049##
[0198] A mixture of 2,4-bis(methylsulfonyl)pyridine (1.41 g, 6.0
mmol), 4-chloro-2-nitroaniline (1.03 g, 6.0 mmol, CAS No.: 89-63-4)
and potassium carbonate (828 mg, 6.0 mmol) in N,N-dimethylformamide
(10 mL) was heated at 160.degree. C. for 30 minutes under microwave
irradiation. The resulting mixture was diluted with ethyl acetate
(30 mL) and then washed with brine (20 mL). The organic layer was
dried over sodium sulfate and then concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (eluting
with 0-8% methanol in dichloromethane) to afford 864 mg of
N-(4-chloro-2-nitrophenyl)-2-(methylsulfonyl)pyridin-4-amine as an
orange solid (yield was 44.0%) and 294 mg of
N-(4-chloro-2-nitrophenyl)-4-(methylsulfonyl)pyridin-2-amine (yield
was 15.0%).
[0199] Step 3: Preparation of
4-chloro-N.sup.1-[2-(methylsulfonyl)pyridin-4-yl]benzene-1,2-diamine
##STR00050##
[0200] A mixture of N-(4-chloro-2-nitrophenyl)-2-(methyl
sulfonyl)pyridin-4-amine (839 mg, 2.57 mmol), Raney nickel (1.0 g
of suspension in water) and hydrazine hydrate (1.5 mL, 85% aqueous
solution) in ethanol (30 mL) was stirred at room temperature
overnight. The resulting mixture was filtered and the filtrate was
concentrated in vacuo. The residue was dissolved in dichloromethane
(20 mL) and the solution was washed with brine (15 mL). The organic
layer was dried over sodium sulfate and then concentrated in vacuo
to afford 660 mg of
4-chloro-N.sup.1-[2-(methylsulfonyl)pyridin-4-yl]benzene-1,2-diamine
(yield was 86.5%).
[0201] Step 4: Preparation of
5-chloro-2-(chloromethyl)-1-[2-(methylsulfonyl)pyridin-4-yl]-1H-benzimida-
zole
##STR00051##
[0202] A mixture of
4-chloro-N.sup.1-[2-(methylsulfonyl)pyridin-4-yl]benzene-1,2-diamine
(296 mg, 1.0 mmol) and 2-chloro-1,1,1-triethoxyethane (852 mg, 4.34
mmol) was heated at 120.degree. C. for 2 hours under microwave
irradiation. The resulting mixture was concentrated in vacuo and
the residue was stirred with petroleum ether (40 mL). The
precipitate was collected by filtration to afford 300 mg of
5-chloro-2-(chloromethyl)-1-[2-(methylsulfonyl)pyridin-4-yl]-1H-benzimida-
zole as a brown solid (yield was 84.3%).
[0203] Step 5: Preparation of
1'-({5-chloro-1-[2-(methylsulfonyl)pyridin-4-yl]-1H-benzimidazol-2-yl}met-
hyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0204] A mixture
5-chloro-2-(chloromethyl)-1-[2-(methylsulfonyl)pyridin-4-yl]-1H-benzimida-
zole (150 mg, 0.42 mmol),
spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one (74 mg,
0.46 mmol) and cesium carbonate in acetonitrile (5 mL) was heated
at 80.degree. C. for 1 hour. The resulting mixture was concentrated
in vacuo after filtration. The residue was purified by preparative
HPLC to afford 120 mg of the title product as a light brown
solid.
Example 2-2
1'-({5-Chloro-1-[4-(ethylsulfonyl)pyridin-2-yl]-1H-benzimidazol-2-yl}methy-
l)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0205] The title compound was prepared in analogy to Example 2-1 by
using sodium ethanesulfinate (CAS No.:20035-59-4) instead of sodium
methanesulfinate.
Example 3
Ethyl(4-{5-chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-
-1'(2'H)-yl)methyl]-1H-benzimidazol-1-yl}phenyl)acetate
[0206] Step 1: Preparation of ethyl
{4-[(4-chloro-2-nitrophenyl)amino]phenyl}acetate
##STR00052##
[0207] A mixture of ethyl (4-aminophenyl) acetate (205 mg, 1.14
mmol, CAS No.: 5438-70-0), 4-chloro-1-fluoro-2-nitrobenzene (200
mg, 1.14 mmol) and ethyl-diisopropyl-amine (0.80 mL, 4.57 mmol) in
N,N-dimethylformamide (5 mL) was heated at 100.degree. C. for 12
hours. The resulting mixture was diluted with water (20 mL) and
then extracted with ethyl acetate (25 mL.times.3). The combined
organic layer was washed with brine (30 mLx 2), and then dried over
sodium sulfate and then concentrated in vacuo. The crude ethyl
{4-[(4-chloro-2-nitrophenyl)amino]phenyl}acetate was used directly
for the next step without further purification.
[0208] Step 2: Preparation of ethyl
{4-[5-chloro-2-(chloromethyl)-1H-benzimidazol-1-yl]phenyl}acetate
##STR00053##
[0209] Ethyl
{4-[5-chloro-2-(chloromethyl)-1H-benzimidazol-1-yl]phenyl}acetate
was prepared in analogy to
5-chloro-2-(chloromethyl)-1-[2-(methylsulfonyl)pyridin-4-yl]-1H-benzimida-
zole in Example 2-1 by using ethyl
{4-[(4-chloro-2-nitrophenyl)amino]phenyl}acetate instead of
N-(4-chloro-2-nitrophenyl)-2-(methylsulfonyl)pyridin-4-amine.
[0210] Step 3: Preparation of ethyl
(4-{5-chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(-
2'H)-yl)methyl]-1H-benzimidazol-1-yl}phenyl)acetate
[0211] To a solution of
spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one (88 mg,
0.55 mmol) in N,N-dimethylformamide (5 mL) was added sodium
2-methylpropan-2-olate (55 mg, 0.57 mmol). The mixture was stirred
at room temperature for 30 minutes, then the reaction mixture was
added to the solution of ethyl
{4-[5-chloro-2-(chloromethyl)-1H-benzimidazol-1-yl]phenyl} acetate
(200 mg, 0.55 mmol) in N,N-dimethylformamide (5 mL) dropwise. The
mixture was stirred for 30 minutes and then neutralized to pH 7 by
addition of 10% hydrochloric acid. The resulting mixture was
purified by preparative HPLC to afford the title product.
Example 4-1
1'-[(5-Chloro-1-phenyl-1H-benzimidazol-2-yl)methyl]spiro[cyclopropane-1,3'-
-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0212] Step 1: Preparation of 4-chloro-2-nitro-N-phenylaniline
##STR00054##
[0213] A sealed vial containing a mixture of
4-chloro-2-nitroaniline (1.72 g, 10.0 mmol), iodobenzene (2.04 g,
10.0 mmol, CAS No.: 591-50-4),
tris(dibenzylideneacetone)dipalladium (183 mg, 0.20 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (231 mg, 0.40
mmol), cesium carbonate (6.52 g, 20.0 mmol) and 1,4-dioxane (10 mL)
was heated at 120.degree. C. overnight after purged and backfilled
with argon. The resulting mixture was concentrated in vacuo and the
residue was purified by flash column (eluting with 0-50% of ethyl
acetate in petroleum) to afford 1.89 g of
4-chloro-2-nitro-N-phenylaniline as brown viscous oil (yield was
75.6%).
[0214] Step 2: Preparation of
1'-[(5-chloro-1-phenyl-1H-benzimidazol-2-yl)methyl]spiro[cyclopropane-1,3-
'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0215] The title compound was prepared in analogy to Example 2-1 by
using 4-chloro-2-nitro-N-phenylaniline instead of
N-(4-chloro-2-nitrophenyl)-2-(methylsulfonyl)pyridin-4-amine.
Example 4-2
Ethyl
4-{5-chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-
-1'(2'H)-yl)methyl]-1H-benzimidazol-1-yl}benzoate
[0216] The title compound was prepared in analogy to Example 4-1 by
using ethyl 4-bromobenzoate (CAS No.: 5798-75-4) instead of
iodobenzene.
Example 4-3
1'-({5-Chloro-1-[6-(methylsulfonyl)pyridin-3-yl]-1H-benzimidazol-2-yl}meth-
yl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0217] Step 1: Preparation of
5-bromo-2-(methylsulfonyl)pyridine
##STR00055##
[0218] A mixture of 2-chloro-5-bromo-pyridine (9.80 g, 50.0 mmol,
CAS No.: 53939-30-3) and sodium methanethiolate (5.25 g, 75.0 mmol,
CAS No.: 5188-07-8) in N,N-dimethylformamide (25 mL) was stirred at
room temperature for 3 hours. The reaction mixture was diluted with
water (50 mL) and then extracted with ethyl acetate (60
mL.times.3). The combined organic layer was washed with brine (100
mL.times.2), and then dried over sodium sulfate and then
concentrated in vacuo to afford a mixture of
5-bromo-2-(methylsulfanyl)pyridine and
2,5-bis(methylsulfanyl)pyridine, which was used directly for the
next step.
[0219] To a cooled solution of the above mixture in dichloromethane
(80 mL) was added 3-chlorobenzenecarboperoxoic acid (30.2 g, 175
mmol) in portions. The resulting mixture was stirred at room
temperature for 2 days. The reaction mixture was then washed with
1N sodium hydroxide (50 mL.times.2) after filtration. The organic
layer was dried over sodium sulfate and then concentrated in vacuo
to afford 9.26 g of the crude 5-bromo-2-(methylsulfonyl)pyridine
(yield was 78.4%), which was used for the next step directly
without any purification.
[0220] Step 2: Preparation of
1'-({5-chloro-1-[6-(methylsulfonyl)pyridin-3-yl]-1H-benzimidazol-2-yl}met-
hyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0221] The title compound was prepared in analogy to Example 4-1 by
using 5-bromo-2-(methylsulfonyl) pyridine instead of
iodobenzene.
Example 4-4
1'-({5-chloro-1-[3-(methylsulfonyl)phenyl]-1H-benzimidazol-2-yl}methyl)spi-
ro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0222] The title compound was prepared in analogy to Example 4-1 by
using 1-bromo-3-(methylsulfonyl)benzene (CAS No.: 34896-80-5)
instead of iodobenzene.
Example 4-5
1'-({5-Chloro-1-[4-(methylsulfonyl)phenyl]-1H-benzimidazol-2-yl}methyl)spi-
ro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0223] The title compound was prepared in analogy to Example 4-1 by
using 1-bromo-4-(methylsulfonyl)benzene (CAS No.: 3466-32-8)
instead of iodobenzene.
Example 4-6
Methyl
3-{5-chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin-
]-1'(2'H)-yl)methyl]-1H-benzimidazol-1-yl}benzoate
[0224] The title compound was prepared in analogy to Example 4-1 by
using methyl 3-bromobenzoate (CAS No.: 618-89-3) instead of
iodobenzene.
Example 4-7
3-{5-Chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2'-
H)-yl)methyl]-1H-benzimidazol-1-yl}benzonitrile
[0225] The title compound was prepared in analogy to Example 4-1 by
using 4-chloro-1-fluoro-2-nitrobenzene and 3-bromobenzonitrile (CAS
No.: 6952-59-6) instead of 4-chloro-2-nitroaniline and
iodobenzene.
Example 4-8
1'-{[1-(3-Acetylphenyl)-5-chloro-1H-benzimidazol-2-yl]methyl}spiro[cyclopr-
opane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0226] The title compound was prepared in analogy to Example 4-1 by
using 4-chloro-1-fluoro-2-nitrobenzene and
1-(3-bromophenyl)ethanone (CAS No.: 2142-63-4) instead of
4-chloro-2-nitroaniline and iodobenzene.
Example 4-9
1'-{[5-Chloro-1-(6-methoxypyridin-3-yl)-1H-benzimidazol-2-yl]methyl}spiro[-
cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0227] The title compound was prepared in analogy to Example 4-1 by
using 4-chloro-1-fluoro-2-nitrobenzene and
5-bromo-2-methoxypyridine (CAS No.: 13472-85-0) instead of
4-chloro-2-nitroaniline and iodobenzene.
Example 5-1
1'-({5-Chloro-1-[5-(methylsulfonyl)pyridin-3-yl]-1H-benzimidazol-2-yl}meth-
yl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0228] Step 1: Preparation of
5-bromo-N-(4-chloro-2-nitrophenyl)pyridin-3-amine
##STR00056##
[0229] 5-Bromo-N-(4-chloro-2-nitrophenyl)pyridin-3-amine was
prepared in analogy to 4-chloro-2-nitro-N-phenylaniline in Example
4-1 by using 3-bromo-5-iodopyridine (CAS No.: 233770-01-9) instead
of iodobenzene.
[0230] Step 2: Preparation of
N-(4-chloro-2-nitrophenyl)-5-(methylsulfonyl)pyridin-3-amine
##STR00057##
[0231] A mixture of
5-bromo-N-(4-chloro-2-nitrophenyl)pyridin-3-amine (326 mg, 1.0
mmol), sodium methanesulfinate (240 mg, 2.0 mmol, 85% purity, CAS
No.: 20277-69-4), copper(I) iodide (38.1 mg, 0.10 mmol),
L-pyrrolidine-2-carboxylic acid (23.2 mg, 0.20 mmol) and sodium
hydroxide (8.0 mg, 0.20 mmol) in dimethyl sulfoxide (4.0 mL) and
water (0.8 mL) was heated at 150.degree. C. for 1 hour under
microwave irradiation. The resulting mixture was diluted with water
(10 mL) and then extracted with ethyl acetate (20 mL.times.2). The
combined organic layer was washed with brine (20 mL), and then
dried over sodium sulfate and then concentrated in vacuo. The
residue was purified by flash column (eluting with 0-30% ethyl
acetate in petroleum) to afford 156 mg of
N-(4-chloro-2-nitrophenyl)-5-(methylsulfonyl)pyridin-3-amine as a
brown solid (yield was 47.9%).
[0232] Step 3: Preparation of
1'-({5-chloro-1-[5-(methylsulfonyl)pyridin-3-yl]-1H-benzimidazol-2-yl}met-
hyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0233] The title compound was prepared in analogy to Example 3-1 by
using N-(4-chloro-2-nitrophenyl)-5-(methylsulfonyl)pyridin-3-amine
instead of ethyl
{4-[(4-chloro-2-nitrophenyl)amino]phenyl}acetate.
Example 5-2
1'-({5-Chloro-1-[6-(methylsulfonyl)pyridin-2-yl]-1H-benzimidazol-2-yl}meth-
yl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0234] The title compound was prepared in analogy to Example 5-1 by
using 2,6-dibromopyridine (CAS No.: 626-05-1) instead of
3-bromo-5-iodopyridine.
Example 5-3
1'-({5-Chloro-1-[3-methyl-5-(methylsulfonyl)phenyl]-1H-benzimidazol-2-yl}m-
ethyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0235] The title compound was prepared in analogy to Example 5-1 by
using 1,3-dibromo-5-methylbenzene (CAS No.: 615-59-8) instead of
3-bromo-5-iodopyridine.
Example 6-1
4-{5-Chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2'-
H)-yl)methyl]-1H-benzimidazol-1-yl}benzoic acid
[0236] A solution of ethyl
4-{5-chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2-
'H)-yl)methyl]-1H-benzimidazol-1-yl}benzoate (200 mg, 0.42 mmol,
Example 4-2) in tetrahydrofuran (4 mL) was stirred with 1M aqueous
solution of lithium hydroxide (4 mL) at room temperature for 2
hours. The resulting mixture was concentrated in vacuo to remove
the organic solvent, and then acidified with 1N hydrochloric acid
to pH<7. The precipitate was collected by filtration and then
dried in vacuo to afford 178 mg of the title product.
Example 6-2
3-{5-Chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2'-
H)-yl)methyl]-1H-benzimidazol-1-yl}benzoic acid
[0237] The title compound was prepared in analogy to Example 6-1 by
using methyl
3-{5-chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridi-
n]-1'(2'H)-yl)methyl]-1H-benzimidazol-1-yl}benzoate (Example 4-6)
instead of ethyl
4-{5-chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyri-
din]-1'(2'H)-yl)methyl]-1H-benzimidazol-1-yl}benzoate.
Example 6-3
4-{5-Chloro-2-[(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indol]-1'(2'H)-yl)-
methyl]-1H-benzimidazol-1-yl}benzoic acid
[0238] Step 1: Preparation of ethyl
4-{5-chloro-2-[(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indol]-1'(2'H)-yl-
)methyl]-1H-benzimidazol-1-yl}benzoate
##STR00058##
[0239] Ethyl
4-{5-chloro-2-[(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indol]-1'(2'H)-yl-
)methyl]-1H-benzimidazol-1-yl}benzoate was prepared in analogy to
Example 4-1 by using ethyl 4-aminobenzoate instead of
iodobenzene.
[0240] Step 2: Preparation of
4-{5-chloro-2-[(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indol]-1'(2'H)-yl-
)methyl]-1H-benzimidazol-1-yl}benzoic acid
[0241] The title compound was prepared in analogy to Example 6-1 by
using ethyl
4-{5-chloro-2-[(6'-fluoro-2'-oxospiro[cyclopropane-1,3'-indol]-1'(2-
'H)-yl)methyl]-1H-benzimidazol-1-yl}benzoate instead of ethyl
4-{5-chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2-
'H)-yl)methyl]-1H-benzimidazol-1-yl}benzoate.
Example 7
4-{5-Chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2'-
H)-yl)methyl]-1H-benzimidazol-1-yl}benzamide
[0242] A mixture of ethyl
4-{5-chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2-
'H)-yl)methyl]-1H-benzimidazol-1-yl}benzoate (95 mg, 0.20 mmol,
Example 4-2) and 7 N ammonia solution in methanol was heated at
90.degree. C. for 4 hours under microwave irradiation. The
resulting mixture was concentrated in vacuo. The residue was
purified by preparative HPLC to afford 4.0 mg of the title
product.
Example 8
1'-{[5-Chloro-1-(6-hydroxypyridin-3-yl)-1H-benzimidazol-2-yl]methyl}spiro[-
cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0243] A mixture of
1'-{[5-chloro-1-(6-methoxypyridin-3-yl)-1H-benzimidazol-2-yl]methyl}spiro-
[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one (Example 4-9)
and boron tribromide (CAS No.: 5967-37-3) in dichloromethane was
heated under reflux for 2 hours. The resulting mixture was
concentrated in vacuo and the residue was purified by preparative
HPLC to afford the title product.
Example 9-1
1'-({6-Chloro-3-[4-(methylsulfonyl)phenyl]-1H-indol-2-yl}methyl)spiro[cycl-
opropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0244] Step 1: Preparation of methyl
5-chloro-1-(phenylsulfonyl)-1H-indole-2-carboxylate
##STR00059##
[0245] To a suspension of methyl 5-chloro-1H-indole-2-carboxylate
(7.56 g, 36.0 mmol, CAS No.: 10517-21-2) and sodium hydride (1.70
g, 43.0 mmol, 60% purity in mineral oil) in N,N-dimethylformamide
(100 mL) was added benzenesulfonyl chloride (6.1 mL, 47.0 mmol, CAS
No.: 98-09-9) dropwise in an ice-water bath. After being stirred at
room temperature for 2 hours, the mixture was then poured into
ice-water (100 mL). The resulting precipitate was collected by
filtration, which was washed with petroleum ether (50 mL), and then
dried in vacuo to afford 11.6 g of methyl
5-chloro-1-(phenylsulfonyl)-1H-indole-2-carboxylate as a pale white
solid (yield was 92%).
[0246] Step 2: Preparation of
[5-chloro-1-(phenylsulfonyl)-1H-indol-2-yl]methanol
##STR00060##
[0247] To a suspension of lithium aluminium hydride (1.9 g, 50
mmol) in tetrahydrofuran (150 mL) at 0.degree. C. was added methyl
5-chloro-1-(phenyl sulfonyl)-1H-indole-2-carb oxylate (11.6 g, 33
mmol) in portions. After being stirred at room temperature for 3
hours, the resulting mixture was quenched with methanol, then
filtered through a celite pad. The filtrate was concentrated in
vacuo to afford 9.7 g of
[5-chloro-1-(phenylsulfonyl)-1H-indol-2-yl]methanol as brown oil
(yield was 91%).
[0248] Step 3: Preparation of
[6-chloro-3-iodo-1-(phenylsulfonyl)-1H-indol-2-yl]methanol
##STR00061##
[0249] To a cooled solution of
[5-chloro-1-(phenylsulfonyl)-1H-indol-2-yl]methanol (642 mg, 2.00
mmol) in acetonitrile (25 mL) was added 1-iodopyrrolidine-2,5-dione
(450 mg, 2.0 mmol, CAS No.: 516-12-1) slowly at 0.degree. C. The
resulting mixture was stirred at 0.degree. C. for 1 hour and then
concentrated in vacuo. The residue was purified by flash column to
afford
[6-chloro-3-iodo-1-(phenylsulfonyl)-1H-indol-2-yl]methanol.
[0250] Step 4: Preparation of
{6-chloro-3-[4-(methylsulfonyl)phenyl]-1-(phenylsulfonyl)-1H-indol-2-yl}m-
ethanol
##STR00062##
[0251] A mixture of
[6-chloro-3-iodo-1-(phenylsulfonyl)-1H-indol-2-yl]methanol (447 mg,
1.0 mmol), 4-methanesulfonylphenylboronic acid (200 mg, 1.0 mmol,
CAS No.: 149104-88-1),
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (41.0
mg, 0.05 mmol) and potassium carbonate (276 mg, 2.0 mmol) in
N,N-dimethylacetamide (4 mL) was heated at 80.degree. C. under
nitrogen atmosphere for 2 hours. The resulting mixture was diluted
with water (50 mL) and then extracted with ethyl acetate (100 mL).
The organic layer was dried over sodium sulfate and then
concentrated in vacuo. The residue was purified by flash column
(eluting with 2% methanol in dichloromethane) to afford 381 mg of
{6-chloro-3-[4-(methylsulfonyl)phenyl]-1-(phenylsulfonyl)-1H-indol-2-yl}m-
ethanol (yield was 80.0%).
[0252] Step 5: Preparation of
1'-({6-chloro-3-[4-(methylsulfonyl)phenyl]-1H-indol-2-yl}methyl)spiro[cyc-
lopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0253] To a cooled solution of
{6-chloro-3-[4-(methylsulfonyl)phenyl]-1-(phenylsulfonyl)-1H-indol-2-yl}m-
ethanol (380 mg, 0.80 mmol) in dichloromethane (5 mL) was added
methanesulfonyl chloride (100 mg, 0.88 mmol) and triethylamine (162
mg, 1.60 mmol) at 0.degree. C. After being stirred at for 1 hour,
the resulting mixture was diluted with dichloromethane (3 mL), and
then washed with water and brine. The organic layer was dried over
sodium sulfate and then concentrated in vacuo. The residue was
dissolved in N,N-dimethylformamide (5 mL), sodium
2-methylpropan-2-olate (77 mg, 0.80 mmol) was added to the solution
and then followed by the addition of
spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one) (128
mg, 0.80 mmol). After being stirred at room temperature overnight,
the resulting mixture was extracted with ethyl acetate (100 mL).
The organic layer was washed with water and brine, and then dried
over sodium sulfate and then concentrated in vacuo. The residue was
dissolved in dichloromethane (6 mL) and treated with
tetra-n-butylammonium fluoride (2 mL, 1M in tetrahydrofuran). After
being stirred at room temperature for 30 minutes, the mixture was
concentrated in vacuo and the residue was purified by preparative
HPLC to afford the title product.
Example 9-2
1'-({6-Chloro-3-[3-(methylsulfonyl)phenyl]-1H-indol-2-yl}methyl)spiro[cycl-
opropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one
[0254] The title compound was prepared in analogy to Example 8-1 by
using 3-methanesulfonylphenylboronic acid (CAS No.: 373384-18-0)
instead of 4-methanesulfonylphenylboronic acid.
BIOLOGICAL EXAMPLES
Example 40
Viral Cytopathic Effect (CPE) Assay
[0255] To measure anti-RSV activity of compounds, 96-well plates
are seeded with 6.times.10.sup.3 cells per well in Dulbecco's
modified Eagle's medium (DMEM) containing 10% fetal bovine serum
(FBS). Cells are infected the next day with sufficient RSV Long
strain (ATCC) to produce an approximately 80-90% cytopathic effect
after 6 days, in the presence of serial half-log diluted compound
in a total volume of 200 .mu.L per well. The viability of cells is
assessed after 6 days using Cell Counting kit-8 (Dojindo Molecular
Technologies). The absorbance at 450 nm and referenced at 630 nm is
measured to determine 50% effective concentration (EC.sub.50).
[0256] The compounds of the present invention were tested for their
anti-RSV activity, and the activation as described herein. The
Examples were tested in the above assay and found to have EC.sub.50
of about 0.0001 .mu.M to about 10 .mu.M. Particular compound of
formula (I) were found to have EC.sub.50 of about 0.0001 .mu.M to
about 1 .mu.M. Further particular compound of formula (I) were
found to have EC.sub.50 of about 0.0001 .mu.M to about 0.1
.mu.M.
[0257] Results of CPE assays are given in Table 1.
Example A
[0258] A compound of formula I can be used in a manner known per se
as the active ingredient for the production of tablets of the
following composition:
TABLE-US-00003 Per tablet Active ingredient 200 mg Microcrystalline
cellulose 155 mg Corn starch 25 mg Talc 25 mg
Hydroxypropylmethylcellulose 20 mg 425 mg
Example B
[0259] A compound of formula I can be used in a manner known per se
as the active ingredient for the production of capsules of the
following composition:
TABLE-US-00004 Per capsule Active ingredient 100.0 mg Corn starch
20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0
mg
* * * * *