U.S. patent application number 09/747254 was filed with the patent office on 2001-05-10 for phenanthroline derivatives.
This patent application is currently assigned to Zeneca Limited. Invention is credited to Edwards, Philip Neil, Hales, Neil James, Large, Michael Stewart.
Application Number | 20010001101 09/747254 |
Document ID | / |
Family ID | 27391133 |
Filed Date | 2001-05-10 |
United States Patent
Application |
20010001101 |
Kind Code |
A1 |
Edwards, Philip Neil ; et
al. |
May 10, 2001 |
Phenanthroline derivatives
Abstract
The present invention provides a phenanthroline derivative of
formula (I) 1 wherein, for example, R.sup.1 is hydrogen, carboxy,
cyano, nitro, (1-4C)alkyl, (1-6C)alkoxycarbonyl, (1-4C)alkylamino,
(2-4C)alkanoyl, (1-4C)alkoxy-(2-4C)alkoxy-(2-4C)alkoxycarbonyl or
N-[amino-(2-8C)alkyl]ca- rbamoyl; R.sup.2 is, for example,
hydrogen, carboxy, (1-6C)alkoxycarbonyl, carbamoyl,
N-(1-8C)alkylcarbamoyl, N,N-di-(1-8C)alkylcarbamoyl,
N-(1-4C)alkylcyclohexylcarbamoyl,
1,2,3,4-tetrahydro-isoquinolin-2-ylcarb- onyl or N,N-[di-(l
-4C)alkyl]thiocarbamoyl; R.sup.3 and R.sup.4, which may be the same
or different, are, for example, hydrogen or halo; and R.sup.5 is,
for example, hydrogen, di-(1-4C)alkylamino or halo; or a
pharmaceutically-acceptable salt thereof. The invention further
provides pharmaceutical compositions comprising phenanthroline
derivatives, processes for making the same and their use in
producing an anti-fibroproliferative effect.
Inventors: |
Edwards, Philip Neil;
(Cheshire, GB) ; Large, Michael Stewart;
(Staffordshire, GB) ; Hales, Neil James;
(Cheshire, GB) |
Correspondence
Address: |
Intellectual Property Group
Pillsbury Madison & Sutro LLP
Fifth Floor
50 Fremont Street
San Francisco
CA
94105
US
|
Assignee: |
Zeneca Limited
|
Family ID: |
27391133 |
Appl. No.: |
09/747254 |
Filed: |
December 20, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09747254 |
Dec 20, 2000 |
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09304677 |
May 4, 1999 |
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6200974 |
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09304677 |
May 4, 1999 |
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09179542 |
Oct 26, 1998 |
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09179542 |
Oct 26, 1998 |
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08957450 |
Oct 24, 1997 |
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5916898 |
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Current U.S.
Class: |
514/292 ;
546/88 |
Current CPC
Class: |
A61K 31/4745 20130101;
C07D 471/04 20130101 |
Class at
Publication: |
514/292 ;
546/88 |
International
Class: |
A61K 031/4375; C07D
471/02 |
Claims
We claim:
1. A compound of formula (I): 3wherein R.sup.1 is hydrogen, carboxy
or a metabolically labile ester derivative thereof, cyano, halo,
nitro, amino, (1-4C)alkyl, (1-4C)alkylamino, di-(1-4C)alkylamino,
(1-6C)alkoxycarbonyl, (2-4C)alkanoyl, hydroxy-(1-4C)alkyl,
carbamoyl, N-(1-4C)alkylcarbamoyl, (1-4C)alkylthio,
(1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl; phenylthio,
phenylsulfinyl or phenylsulfonyl said phenyl being optionally
substituted with 1 to 4 substituents selected from halo,
(1-4C)alkyoxy, (1-4C)alkyl, cyano, hydroxy and trifluoromethyl;
fluoro-(1-4C)alkylthio, fluoro-(1-4C)alkylsulfinyl,
fluoro-(1-4C)alkylsulfonyl, (1-4C)alkoxy-(2-4C)alkoxycarbonyl,
N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)al- koxycarbonyl,
(1-4C)alkylamino-(2-4C)alkoxycarbonyl,
di-(1-4C)alkylamino-(2-4C)alkoxycarbonyl,
(1-4C)alkoxy-(2-4C)alkoxy-(2-4C- )alkoxycarbonyl,
(2-4C)alkanoyloxy-(1-4C)alkyl, morpholino-(2-4C)alkoxycar- bonyl or
N-[amino-(2-8C)alkyl]carbamoyl; R.sup.2 is hydrogen, hydroxy,
amino, cyano, halo, (1-4C)alkyl, carboxy or a metabolically labile
ester derivative thereof, (1-4C)alkylamino, di-(1-4C)alkylamino,
(1-6C)alkoxycarbonyl, (2-4C)alkanoyl, (1-4C)alkoxy,
carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl,
N-(1-8C)alkylcarbamoyl, N,N-di-(1-8C)alkylcarbamoyl,
N-[amino-(2-8C)alkyl)carbamoyl,
N-[(1-4C)alkylamino-(1-8C)alkyl]carbamoyl,
N-[di-(1-4C)alkylamino-(1-8C)a- lkyl)carbamoyl,
N-cyclohexylcarbamoyl, N-[cyclopentyl]carbamoyl,
N-(1-4C)alkylcyclohexylcarbamoyl or
N-(1-4C)alkylcyclopentylcarbamoyl; N-phenylcarbamoyl,
N-(1-4C)alkyl-N-phenylcarbamoyl, N,N-diphenylcarbamoyl,
N-[phenyl-(1-4C)alkyl]carbamoyl,
N-(1-4C)alkyl-N-[phenyl-(1-4C)alkyl]carbamoyl, or
N,N-di-[phenyl-(1-4C)al- kyl]carbamoyl said phenyl or phenyl groups
being optionally substituted with 1 to 4 substituents selected from
halo, (1-4C)alkyoxy, (1-4C)alkyl, cyano, hydroxy and
trifluoromethyl; N-[(2-4C)alkanoyl]carbamoyl,
N-[(1-4C)alkoxycarbonyl]carbamoyl, N-[fluoro-(2-6C)alkyl]carbamoyl,
N-[fluoro-(2-6C)alkyl]-N-(1-4C)alkylcarbamoyl or
N,N-[di-fluoro-(2-6C)alk- yl]carbamoyl; pyrrolidin-1-ylcarbonyl,
piperidinocarbonyl, piperazin-1-ylcarbonyl or morpholinocarbonyl
wherein the heterocyclic group is optionally substituted with 1 to
4 substituents selected from (1-4C)alkyl and benzyl;
1,2,3,4-tetrahydro-isoquinolin-2-ylcarbonyl,
N,N-[di-(1-4C)alkyl]thiocarbamoyl, N-(2-4C)alkanoylamino or
N-[(1-4)alkoxycarbonyl]amino; R.sup.3 and R.sup.4, which may be the
same or different, are hydrogen, (1-4C)alkyl, (2-4C)alkoxy, halo,
nitro, hydroxy, fluoro-(1-4C)alkyl or pyridinyl; or R.sup.4 is
methoxy; or R.sup.3 is methoxy; and R.sup.5 is hydrogen, hydroxy,
amino, (1-4C)alkylamino, di-(1-4C)alkylamino, halo,
(1-4C)alkoxy-(2-4C)alkoxy or fluoro-(1-6C)alkoxy; pyrrolidin-1-yl,
piperidino, piperazin-1-yl or morpholino wherein the heterocyclic
group is optionally substituted with 1 to 4 substituents selected
from (1-4C)alkyl and benzyl; or a pharmaceutically-acceptable salt
thereof; provided that: R.sup.1, R.sup.2, R.sup.3 , R.sup.4 and
R.sup.5 are not together H; where R.sup.1 is carboxy and R.sup.3
and R.sup.4 are hydroxy; R.sup.2 and R.sup.5 are not together H;
where R.sup.1 is carboxy, R.sup.2 is H or OH, R.sup.3 is H and
R.sup.5 is H; R.sup.4is not H, OH alkoxy, alkyl or halo; where
R.sup.1 is carboxy, R.sup.2 is H or OH, R.sup.4 is H and R.sup.5 is
H; R.sup.3 is not H, OH alkoxy, alkyl or halo; where R.sup.1 is
ethoxycarbonyl; R.sup.2, R.sub.3, R.sup.4 and R.sup.5 are not
together H; where R.sup.1 is ethoxycarbonyl and R.sup.4 is F;
R.sup.2, R.sup.3 and R.sup.5 are not together H where R.sup.1 is
carboxy and R.sup.3 is H or alkyl; R.sup.2, R.sup.4 and R.sup.5 are
not together H; where R.sup.3 is OH; R.sup.1 , R.sup.2, R.sup.4 and
R.sup.5 are not together H; where R.sup.5 is OH, R.sup.3 is H or
alkyl, and R.sup.4 is H; R.sup.1 and R.sup.2 are not together
ethoxycarbonyl, carboxy, methoxycarbonyl or H; and where R.sup.5 is
--N(CH.sub.3).sub.2; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are not
together H.
2. A compound of claim 1:
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4--
dihydro-1,10-phenanthroline;
3-nitro-8-(4-benzylpiperazin-1-ylcarbonyl)-4--
oxo-3,4-dihydro-1,10-phenanthroline;
3-trifluoromethylsulphonyl-4-oxo-3,4-- dihydro-1,10-phenanthroline;
3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-di-
hydro-1,10-phenanthroline; or
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro- -1,10-phenanthroline;
or a pharmaceutically-acceptable salt thereof, or a metabolically
labile ester derivative of those compounds bearing a carboxy
group.
3. A pharmaceutical composition comprising one or more compounds of
formula (I): 4wherein R.sup.1 is hydrogen, carboxy or a
metabolically labile ester derivative thereof, cyano, halo, nitro,
amino, (1-4C)alkyl, (1-4C)alkylamino, di-(1-4C)alkylamino,
(1-6C)alkoxycarbonyl, (2-4C)alkanoyl, hydroxy-(1-4C)alkyl,
carbamoyl, N-(1-4C)alkylcarbamoyl, (1-4C)alkylthio,
(1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl; phenylthio,
phenylsulfinyl or phenylsulfonyl said phenyl being optionally
substituted with 1 to 4 substituents selected from halo,
(1-4C)alkyoxy, (1-4C)alkyl, cyano, hydroxy and trifluoromethyl;
fluoro-(1-4C)alkylthio, fluoro-(1-4C)alkylsulfinyl,
fluoro-(1-4C)alkylsulfonyl, (1-4C)alkoxy-(2-4C)alkoxycarbonyl,
N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)al- koxycarbonyl,
(1-4C)alkylamino-(2-4C)alkoxycarbonyl,
di-(1-4C)alkylamino-(2-4C)alkoxycarbonyl,
(1-4C)alkoxy-(2-4C)alkoxy-(2-4C- )alkoxycarbonyl,
(2-4C)alkanoyloxy-(1-4C)alkyl, morpholino-(2-4C)alkoxycar- bonyl or
N-[amino-(2-8C)alkyl]carbamoyl; R.sup.2 is hydrogen, hydroxy,
amino, cyano, halo, (1-4C)alkyl, carboxy or a metabolically labile
ester derivative thereof, (1-4C)alkylamino, di-(1-4C)alkylamino,
(1-6C)alkoxycarbonyl, (2-4C)alkanoyl, (1-4C)alkoxy,
carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl,
N-(1-8C)alkylcarbamoyl, N,N-di-(1-8C)alkylcarbamoyl,
N-[amino-(2-8C)alkyl)carbamoyl,
N-[(1-4C)alkylamino-(1-8C)alkyl]carbamoyl,
N-[di-(1-4C)alkylamino-(1-8C)a- lkyl)carbamoyl,
N-cyclohexylcarbamoyl, N-[cyclopentyl]carbamoyl,
N-(1-4C)alkylcyclohexylcarbamoyl or
N-(1-4C)alkylcyclopentylcarbamoyl; N-phenylcarbamoyl,
N-(1-4C)alkyl-N-phenylcarbamoyl, N,N-diphenylcarbamoyl,
N-[phenyl-(1-4C)alkyl]carbamoyl,
N-(1-4C)alkyl-N-[phenyl-(1-4C)alkyl]carbamoyl or
N,N-di-[phenyl-(1-4C)alk- yl]carbamoyl said phenyl or phenyl groups
being optionally substituted with 1 to 4 substituents selected from
halo, (1-4C) alkyoxy, (1-4C)alkyl, cyano, hydroxy and
trifluoromethyl; N-[(2-4C)alkanoyl]carbamoyl,
N-[(1-4C)alkoxycarbonyl]carbamoyl, N-[fluoro-(2-6C)alkyl]carbamoyl,
N-[fluoro-(2-6C)alkyl]-N-(1-4C)alkylcarbamoyl or
N,N-[di-fluoro-(2-6C)alk- yl]carbamoyl; pyrrolidin-1-ylcarbonyl,
piperidinocarbonyl, piperazin-1-ylcarbonyl or morpholinocarbonyl
wherein the heterocyclic group is optionally substituted with 1 to
4 substituents selected from (1-4C)alkyl and benzyl;
1,2,3,4-tetrahydro-isoquinolin-2-ylcarbonyl,
N,N-[di-(1-4C)alkyl]thiocarbamoyl, N-(2-4C)alkanoylamino or
N-[(1-4)alkoxycarbonyl]amino; R.sup.3 and R.sup.4, which may be the
same or different, are hydrogen, (1-4C)alkyl, (2-4C)alkoxy, halo,
nitro, hydroxy, fluoro-(1-4C)alkyl or pyridinyl; or R.sup.4 is
methoxy; or R.sup.3 is methoxy; and R.sup.5 is hydrogen, hydroxy,
amino, (1-4C)alkylamino, di-(1-4C)alkylamino, halo,
(1-4C)alkoxy-(2-4C)alkoxy or fluoro-(1-6C)alkoxy; pyrrolidin-1-yl,
piperidino, piperazin-1-yl or morpholino wherein the heterocyclic
group is optionally substituted with 1 to 4 substituents selected
from (1-4C)alkyl and benzyl; or a pharmaceutically-acceptable salt
thereof; and a pharmaceutically-acceptab- le diluent or
carrier.
4. The composition of claim 3, comprising a compound selected from:
3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-methyl-N-{2-
,4-difluorobenzyl}carbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-benzyl-N--
methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro
1,10-phenanthroline;
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihy- dro
1,10-phenanthroline;
3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenan- throline;
3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phe-
nanthroline;
3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanth-
roline;
3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthro-
line;
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline;
or 3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
or a pharmaceutically acceptable salt, or a metabolically labile
ester derivative thereof.
5. A method for producing an anti-fibroproliferative effect in a
host in need of such treatment, comprising administering an
effective amount of a composition of claim 3.
6. The method of claim 5 wherein said composition comprises:
3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-methyl-N-{2-
,4-difluorobenzyl}carbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-benzyl-N--
methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthrol-
ine;
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanth-
roline; 3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanthroli-
ne; 3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanth-
roline;
3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthro-
line;
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline;
or 3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
or a pharmaceutically acceptable salt, or a metabolically labile
ester derivative thereof.
7. A method of treating the symptoms of a fibroproliferative
disease or disorder in a host in need of such treatment comprising
administering an effective amount of a composition of claim 3.
8. The method of claim 7 wherein said composition comprises:
3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-methyl-N-{2-
,4-difluorobenzyl}carbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-benzyl-N--
methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthrol-
ine;
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanth-
roline; 3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanthroli-
ne; 3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanth-
roline;
3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthro-
line;
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline;
or 3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
or a pharmaceutically acceptable salt, or a metabolically labile
ester derivative thereof.
9. The method of claim 7 wherein the disease is rheumatoid
arthritis, chronic arthritis or osteoarthritis.
10. The method of claim 7 wherein the disease is hepatic
cirrhosis.
11. The method of claim 7 wherein the disease is pulmonary
fibrosis, renal fibrosis, cardiac fibrosis, arteriosclerosis or
tumor associated fibrosis.
12. A method of treating scar tissue formation following injury or
surgery in a host in need of such treatment comprising
administering an effective amount of a composition of claim 3.
13. The method of claim 12 wherein said composition comprises:
3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-methyl-N-{2-
,4-difluorobenzyl}carbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-benzyl-N--
methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthrol-
ine;
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanth-
roline; 3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanthroli-
ne; 3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanth-
roline; 3-(2-{morpholino
}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthr- oline;
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline;
or 3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
or a pharmaceutically acceptable salt, or a metabolically labile
ester derivative thereof.
14. The use of one or more phenanthroline derivatives of formula
(I): 5wherein R.sup.1 is hydrogen, carboxy or a metabolically
labile ester derivative thereof, cyano, halo, nitro, amino,
(1-4C)alkyl, (1-4C)alkylamino, di-(1-4C)alkylamino,
(1-6C)alkoxycarbonyl, (2-4C)alkanoyl, hydroxy-(1-4C)alkyl,
carbamoyl, N-(1-4C)alkylcarbamoyl, (1-4C)alkylthio,
(1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl; phenylthio,
phenylsulfinyl or phenylsulfonyl said phenyl being optionally
substituted with 1 to 4 substituents selected from halo,
(1-4C)alkyoxy, (1-4C)alkyl, cyano, hydroxy and trifluoromethyl;
fluoro-(1-4C)alkylthio, fluoro-(1-4C)alkylsulfinyl,
fluoro-(1-4C)alkylsulfonyl, (1-4C)alkoxy-(2-4C)alkoxycarbonyl,
N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)al- koxycarbonyl,
(1-4C)alkylamino-(2-4C)alkoxycarbonyl,
di-(1-4C)alkylamino-(2-4C)alkoxycarbonyl,
(1-4C)alkoxy-(2-4C)alkoxy-(2-4C- )alkoxycarbonyl,
(2-4C)alkanoyloxy-(1-4C)alkyl, morpholino-(2-4C)alkoxycar- bonyl or
N-[amino-(2-8C)alkyl]carbamoyl; R.sup.2 is hydrogen, hydroxy,
amino, cyano, halo, (1-4C)alkyl, carboxy or a metabolically labile
ester derivative thereof, (1-4C)alkylamino, di-(1-4C)alkylamino,
(1-6C)alkoxycarbonyl, (2-4C)alkanoyl, (1-4C)alkoxy,
carboxy-(1-4C)alkoxy, (1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl,
N-(1-8C)alkylcarbamoyl, N,N-di-(1-8C)alkylcarbamoyl,
N-[amino-(2-8C)alkyl)carbamoyl,
N-[(1-4C)alkylamino-(1-8C)alkyl]carbamoyl,
N-[di-(1-4C)alkylamino-(1-8C)a- lkyl)carbamoyl,
N-cyclohexylcarbamoyl, N-[cyclopentyl]carbamoyl,
N-(1-4C)alkylcyclohexylcarbamoyl or
N-(1-4C)alkylcyclopentylcarbamoyl; N-phenylcarbamoyl,
N-(1-4C)alkyl-N-phenylcarbamoyl, N,N-diphenylcarbamoyl,
N-[phenyl-(1-4C)alkyl]carbamoyl,
N-(1-4C)alkyl-N-[phenyl-(1-4C)alkyl]carbamoyl or
N,N-di-[phenyl-(1-4C)alk- yl]carbamoyl said phenyl or phenyl groups
being optionally substituted with 1 to 4 substituents selected from
halo, (1-4C)alkyoxy, (1-4C)alkyl, cyano, hydroxy and
trifluoromethyl; N-[(2-4C)alkanoyl]carbamoyl,
N-[(1-4C)alkoxycarbonyl]carbamoyl, N-[fluoro-(2-6C)alkyl]carbamoyl,
N-[fluoro-(2-6C)alkyl]-N-(1-4C)alkylcarbamoyl or
N,N-[di-fluoro-(2-6C)alk- yl]carbamoyl; pyrrolidin-1-ylcarbonyl,
piperidinocarbonyl, piperazin-1-ylcarbonyl or morpholinocarbonyl
wherein the heterocyclic group is optionally substituted with 1 to
4 substituents selected from (1-4C)alkyl and benzyl;
1,2,3,4-tetrahydro-isoquinolin-2-ylcarbonyl,
N,N-[di-(1-4C)alkyl]thiocarbamoyl, N-(2-4C)alkanoylamino or
N-[(1-4)alkoxycarbonyl]amino; R.sup.3 and R.sup.4, which may be the
same or different, are hydrogen, (1-4C)alkyl, (2-4C)alkoxy, halo,
nitro, hydroxy, fluoro-(1-4C)alkyl or pyridinyl; or R.sup.4 is
methoxy; or R.sup.3 is methoxy; and R.sup.5 is hydrogen, hydroxy,
amino, (1-4C)alkylamino, di-(1-4C)alkylamino, halo,
(1-4C)alkoxy-(2-4C)alkoxy or fluoro-(1-6C)alkoxy; pyrrolidin-1-yl,
piperidino, piperazin-1-yl or morpholino wherein the heterocyclic
group is optionally substituted with 1 to 4 substituents selected
from (1-4C)alkyl and benzyl in the manufacture of a medicament for
use in the production of an anti-fibroproliferative effect.
15. The use of
3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-methyl-N-{2-
,4-difluorobenzyl}carbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-8-(N-benzyl-N--
methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthrol-
ine;
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanth-
roline; 3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanthroli-
ne; 3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanth-
roline;
3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthro-
line;
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline;
or 3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
or a pharmaceutically acceptable salt, or a metabolically labile
ester derivative thereof, according to claim 14.
16. The use of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline
according to claim 14.
17. A pharmaceutical composition comprising
3-carboxy-4-oxo-3,4-dihydro-1,- 10-phenanthroline, or a
pharmaceutically-acceptable salt, or a metabolically labile ester
derivative thereof; and a pharmaceutically-acceptable diluent or
carrier.
18. A pharmaceutical composition comprising
3-carboxy-4-oxo-3,4-dihydro-1,- 10-phenanthroline and a
pharmaceutically-acceptable diluent or carrier.
19. A pharmaceutical composition comprising a
pharmaceutically-acceptable salt of
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline and a
pharmaceutically-acceptable diluent or carrier.
20. A pharmaceutical composition comprising a metabolically labile
ester derivative of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline
and a pharmaceutically-acceptable diluent or carrier.
21. A method for producing an anti-fibroproliferative effect in a
host in need of such treatment, comprising administering an
effective amount of
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline, or a
pharmaceutically-acceptable salt, or a metabolically labile ester
derivative thereof; or an effective amount of a composition
comprising 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline, or a
pharmaceutically-acceptable salt, or a metabolically labile ester
derivative thereof; and a pharmaceutically-acceptable diluent or
carrier.
22. A method for producing an anti-fibroproliferative effect in a
host in need of such treatment, comprising administering an
effective amount of
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline.
23. A method for producing an anti-fibroproliferative effect in a
host in need of such treatment, comprising administering an
effective amount of a pharmaceutically-acceptable salt of
3-carboxy-4-oxo-3,4-dihydro-1,10-phen- anthroline.
24. A method for producing an anti-fibroproliferative effect in a
host in need of such treatment, comprising administering an
effective amount of a metabolically labile ester derivative of
3-carboxy-4-oxo-3,4-dihydro-1,10- -phenanthroline.
Description
1. This application is a continuation-in-part of U.S. Ser. No.
09/179,542 filed Oct. 26, 1998, which is a continuation-in-part of
U.S. Ser. No. 08/957,450 filed on Oct. 24, 1997.
FIELD OF THE INVENTION
2. The present invention relates to phenanthroline derivatives
which inhibit the enzyme prolyl 4-hydroxylase, processes for
preparing these compounds and pharmaceutical compositions thereof.
The present invention also relates to the therapeutical use of such
compounds. More specifically, the present invention relates to the
use of the phenanthroline derivatives in disorders that are related
to the proliferation of fibrotic disorders and/or wherein the
regeneration of normal cells, in contrast to fibrotic cells, are
indicated.
BACKGROUND OF THE INVENTION
3. There are many disorders known wherein the proliferation of
fibrotic tissue is a characteristic feature. Examples of such
disorders include, for example, rheumatoid arthritis, chronic
arthritis, osteoarthritis, hepatic fibrosis, hepatic cirrhosis,
pulmonary fibrosis, renal fibrosis, cardiac fibrosis,
arteriosclerosis tumour-associated fibrosis and the formation of
scar tissue following injury or surgery. Additional examples
include disorders related to the over proliferation of connective
tissue in such areas systems as the central nervous system. Thus, a
therapeutic agent which possesses anti-fibrotic properties may be
of value in the treatment of one or more of these disorders.
4. It is known that the enzyme prolyl 4-hydroxylase is involved in
the hydroxylation of proline residues in collagenous protein, and
that 4-hydroxyproline residues are essential for the formation of
the characteristic triple helical form of collagen which is
secreted into fibrotic tissue. Consequently, a compound which
inhibits the activity of prolyl 4-hydroxylase may be of potential
value in the treatment of fibroproliferative disease, which is
characterized by excessive collagen production.
5. Various chemical compounds have been reported to inhibit prolyl
4-hydroxylase; for example, 2,2'-dipyridyl (W. Muller et al., FEBS
Letters, 90:218 (1978)), pyridine-2,4-dicarboxylic acid (K. Majamaa
et al., Eur. J. Biochem., 138:239 (1984)), pyridine-2,4-dicarboxlic
acid derivatives and pyridine-2,5-dicarboxylic acid deivatives
(European Patent Application Nos. 278452, 278453, 278454 and
281943) and heterocyclic carbonylglycines (T. J. Franklin et al.,
Biochem. Soc. Trans., 19:812-815 (1991)). However, to the extent
that these compounds have not been tested in in vivo systems,
whether these compounds may be useful in modulating collagen
production or permitting the regeneration of cells whose growth or
propagation are otherwise inhibited by the presence of collagen
overproduction has not been previously determined.
6. Despite previous efforts, a need exists for safe and effective
means for the treatment of fibroproliferative diseases and
disorders.
SUMMARY OF THE INVENTION
7. The present invention provides certain phenanthroline
derivatives useful for inhibiting prolyl 4-hydroxylase.
8. Specifically, the present invention provides phenanthroline
derivatives of formula (I) 2
9. wherein
10. R.sup.1 is hydrogen, carboxy or an ester derivative thereof,
cyano, halo, nitro, amino, (1-4C)alkyl, (1-4C)alkylamino,
di-(1-4C)alkylamino, (1-6C)alkoxycarbonyl, (2-4C)alkanoyl,
hydroxy-(1-4C)alkyl, carbamoyl, N-(1-4C)alkylcarbamoyl,
(1-4C)alkylthio, (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl,
phenylthio, phenylsulfinyl, phenylsulfonyl, fluoro-(1-4C)alkylthio,
fluoro-(1-4C)alkylsulfinyl, fluoro-(1-4C)alkylsulfonyl,
(1-4C)alkoxy-(2-4C)alkoxycarbonyl,
N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxycarbonyl,
(1-4C)alkylamino-(2-4C)alkoxycarbonyl,
di-(1-4C)alkylamino-(2-4C)alkoxyca- rbonyl,
(1-4C)alkoxy-(2-4C)alkoxy-(2-4C)alkoxycarbonyl,
(2-4C)alkanoyloxy-(1-4C)alkyl or
N-[amino-(2-8C)alkyl]carbamoyl;
11. R.sup.2 is hydrogen, hydroxy, amino, cyano, halo, (1-4C)alkyl,
carboxy or an ester derivative thereof, (1-4C)alkylamino,
di-(1-4C)alkylamino, (1-6C)alkoxycarbonyl, (2-4C)alkanoyl,
(1-4C)alkoxy, carboxy-(1-4C)alkoxy,
(1-4C)alkoxycarbonyl-(1-4C)alkoxy, carbamoyl,
N-(1-8C)alkylcarbamoyl, N,N-di-(1-8C)alkylcarbamoyl,
N-[amino-(2-8C)alkyl)carbamoyl,
N-[(1-4C)alkylamino-(1-8C)alkyl]carbamoyl,
N-[di-(1-4C)alkylamino-(1-8C)a- lkyl]carbamoyl,
N-cyclohexylcarbamoyl, N-[cyclopentyl]carbamoyl, N-phenylcarbamoyl,
N-(1-4C)alkylcyclohexylcarbamoyl,
N-(1-4C)alkylcyclopentylcarbamoyl, N-(1-4C)alkyl-N-phenylcarbamoyl,
N,N-diphenylcarbamoyl, N-[phenyl-(1-4C)alkyl]carbamoyl,
N-(1-4C)alkyl-N-[phenyl-(1-4C)alkyl)carbamoyl,
N,N-di-[phenyl-(1-4C)alkyl- )carbamoyl,
N-[(2-4C)alkanoyl]carbamoyl, N-[(1-4C)alkoxycarbonyl]carbamoyl- ,
N-[fluoro-(2-6C)alkylcarbamoyl,
N-[fluoro-(2-6C)alkyl]-N-(1-4C)alkylcarb- amoyl,
N,N-[di-fluoro-(2-6C)alkyl]carbamoyl, pyrrolidin-1-ylcarbonyl,
piperidinocarbonyl, piperazin-1-ylcarbonyl, morpholinocarbonyl,
1,2,3,4-tetrahydro-isoquinolin-2-ylcarbonyl,
N,N-[di-(1-4C)alkyl]thiocarb- amoyl, N-(2-4C)alkanoylamino or
N-[(1-4)alkoxycarbonyl]amino;
12. R.sup.3 and R.sup.4, which may be the same or different, are
hydrogen, (1-4C)alkyl, (2-4C)alkoxy, halo, nitro, hydroxy,
fluoro-(1-4C)alkyl or pyridinyl;
13. or R.sup.4 is methoxy; and
14. R.sup.5 is hydrogen, hydroxy, amino, (1-4C)alkylamino,
di-(1-4C)alkylamino, halo, (1-4C)alkoxy-(2-4C)alkoxy,
fluoro-(1-6C)alkoxy, pyrrolidin-1-yl, piperidino, piperazin-1-yl or
morpholino;
15. or a pharmaceutically-acceptable salt thereof.
16. As a further feature R.sup.1 may additionally include
morpholino-(2-4C)alkoxycarbonyl and R.sup.3 may additionally
include methoxy.
17. It will be understood that the phenyl groups in the
afore-mentioned substituents are optionally substituted with one to
four substituents selected from halo, (1-4C)alkoxy, (1-4C)alkyl,
cyano, hydroxy and trifluoromethyl. It will also be understood that
the heterocyclic groups pyrrolidin-1-yl, piperidino, piperazin-1-yl
and morpholino in the afore-mentioned substituents are optionally
substituted in any vacant position with one to four substituents
selected from (1-4C)alkyl and benzyl.
18. As used herein, the "ester derivatives" preferably includes
metabolically labile ester derivatives.
19. As used herein, the term "alkyl" includes both straight and
branched chain groups. However, reference to individual groups such
as propyl are specific for the straight chain version only. The
term "(1-4C)alkyl" includes, for example, methyl, ethyl, propyl,
iso-propyl, butyl, iso-butyl, sec-butyl and tert-butyl.
20. As used herein, the term "halo" includes, for example, fluoro,
chloro, bromo and iodo.
21. The term (1-4C)alkylamino includes methylamino, ethylamino and
propyl amino.
22. The term di-[(1-4C)alkyl]amino includes dimethylamino,
N-ethyl-N-methyl amino, diethylamino, N-methyl-N-propylamino and
dipropyl amino.
23. The term (2-4C)alkanoyl includes acetyl, propionyl and
butyryl.
24. The term (1-6C)alkoxycarbonyl includes methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and
pentoxycarbonyl.
25. The term N-[amino-(2-8C)alkyl]carbamoyl includes
N-(3-aminopropyl)carbamoyl, N-(6-aminohexyl)carbamoyl and
N-(8-aminooctyl)carbamoyl.
26. The term (1-4C)alkoxy includes methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
27. The term hydroxy-(1-4C)alkyl includes hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl.
28. The term (1-4C)alkylthio includes methylthio, ethylthio and
propylthio.
29. The term (1-4C)alkylsulfinyl includes methylsulfinyl,
ethylsulfinyl and propylsulfinyl.
30. The term (1-4C)alkylsulfonyl includes methylsulfonyl,
ethylsulfonyl and propylsulfonyl.
31. The term fluoro-(1-4C)alkylthio includes trifluoromethylthio,
2,2,2-trifluoroethylthio and 3,3,3-trifluoropropylthio.
32. The term fluoro-(1-4C)alkylsulfinyl includes
trifluoromethylsulfinyl, 2,2,2-trifluoroethylsulfinyl and
3,3,3-trifluoropropylsulfinyl.
33. The term fluoro-(1-4C)alkylsulfonyl includes
trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl and
3,3,3-trifluoropropylsulfonyl.
34. The term (1-4C)alkoxy-(2-4C)alkoxycarbonyl includes
2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl and
3-methoxypropoxycarbonyl.
35. The term N-(1-4C)alkylcarbamoyl includes N-methylcarbamoyl,
N-ethylcarbamoyl and N-butylcarbamoyl.
36. The term N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxycarbonyl
includes N,N-dimethylcarbamoylmethoxycarbonyl,
N,N-diethylcarbamoylmethoxycarbonyl- ,
2-(N,N-dimethylcarbamoyl)-ethoxycarbonyl,
2-(N,N-diethylcarbamoyl)-ethox- ycarbonyl and
3-(N,N-dimethylcarbamoyl)-propoxycarbonyl.
37. The term (1-4C)alkylamino-(2-4C)alkoxycarbonyl includes
2-(methylamino) ethoxycarbonyl, 2-(ethylamino)ethoxycarbonyl and
3-(methylamino)propylcarbonyl.
38. The term di-(1-4C)alkylamino-(2-4C)alkoxycarbonyl includes 2-
(dimethylamino)ethoxycarbonyl, 2-(diethylamino)ethoxycarbonyl,
2-(N-ethyl N- methylamino)ethoxycarbonyl and
3-(dimethylamino)propoxycarbonyl.
39. The term (1-4C)alkoxy-(2-4C)alkoxy-(2-4C)alkoxycarbonyl
includes 2-(2- methoxyethoxy)ethoxycarbonyl,
2-(2-ethoxyethoxy)ethoxycarbonyl and 3-(2-
methoxyethoxy)propoxycarbonyl.
40. The term (2-4)alkanoyloxy-(1-4C)alkyl includes acetoxymethyl,
propionyloxymethyl, butyryloxymethyl, 2-acetoxyethyl and
3-acetoxypropyl.
41. The term (2-4C)alkoxy includes ethoxy, propoxy, iso-propoxy,
butoxy, iso-butoxy, sec-butoxy and tert-butoxy.
42. The term carboxy-(1-4C)alkoxy includes carboxymethoxy,
2-carboxyethoxy and 3-carboxypropoxy.
43. The term (1-4C)alkoxycarbonyl-(1-4C)alkoxy includes
methoxycarbonylmethoxy, 2-(methoxycarbonyl)ethoxy and
2-(ethoxycarbonyl)ethoxy
44. The term N-(1-8C)alkylcarbamoyl includes N-methylcarbamoyl,
N-ethylcarbamoyl, N-butylcarbamoyl, N-hexylcarbamoyl and
N-octylcarbamoyl.
45. The term N,N-di-(1-8C)alkylcarbamoyl includes
N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
N,N-di-sec-butylcarbamoyl, N,N-dibutylcarbamoyl,
N-methyl-N-butylcarbamoyl, N-methyl-N-hexylcarbamoyl,
N-methyl-N-ethyl carbamoyl, N-ethyl-N-butylcarbamoyl,
N-ethyl-N-pentylcarbamoyl, N-ethyl-N-propylcarbamoyl and
N-ethyl-N-isopropylcarbamoyl.
46. The term N-(1-4C)alkylamino-(1-8C)alkyl]carbamoyl includes
N-[methylaminomethyl]carbamoyl, N-[ethylaminomethyl]carbamoyl,
N-[2-methylaminoethyl]carbamoyl, N-[3-methylaminopropyl]carbamoyl,
N-[6-methylaminohexyl]carbamoyl and
N-[8-methylaminooctyl]carbamoyl.
47. The term N-[di-(1-4C)alkylamino(1-8C)alkyl]carbamoyl includes
N-[dimethylaminomethyl]carbamoyl, N-[diethylaminomethyl]carbamoyl,
N-[N-methyl-N-ethylaminomethyl]carbamoyl,
N-[2-dimethylaminoethyl]carbamo- yl,
N-[6-dimethylaminohexyl]carbamoyl and
N-[8-dimethylaminooctyl]carbamoy- l.
48. The term N-(1-4C)alkyl-N-cyclohexylcarbamoyl includes
N-methyl-N-cyclohexylcarbamoyl, N-ethyl-N-cyclohexylcarbamoyl and
N-propyl-N-cyclohexylcarbamoyl.
49. The term N-(1-4C)alkyl-N-cyclopentylcarbamoyl includes
N-methyl-N-cyclopentylcarbamoyl, N-ethyl-N-cyclopentylcarbamoyl and
N-propyl-N-cyclopentylcarbamoyl.
50. The term N-(1-4C)alkyl-N-phenylcarbamoyl incudes N-methyl
-N-phenylcarbamoyl, N-ethyl-N-phenylcarbamoyl and
N-propyl-N-phenylcarbam- oyl.
51. The term N-[phenyl-(1-4C)alkyl]carbamoyl includes
N-benzylcarbamoyl, N-(2-phenylethyl)carbamoyl and
N-(3-phenylpropyl)carbamoyl.
52. The term N-(1-4C)alkyl-N-[phenyl-(1-4C)alkyl]carbamoyl includes
N-methyl-N-benzylcarbamoyl, N-ethyl-N-benzylcarbamoyl,
N-isopropyl-N-benzylcarbamoyl, N-methyl-N-(2-phenylethyl)carbamoyl,
N-ethyl-N-(2-phenylethyl)carbamoyl and
N-methyl-N-(3-phenylpropyl)carbamo- yl.
53. The term N,N-di-[phenyl-(1-4)alkyl]carbamoyl includes
N,N-dibenzylcarbamoyl, N,N-di-(2-phenylethyl)carbamoyl and
N,N-di-(3-phenylpropyl)carbamoyl.
54. The term N-[(2-4C)alkanoyl]carbamoyl includes
N-acetylcarbamoyl, N-propionylcarbamoyl and N-butyrylcarbamoyl.
55. The term N-(1-4C)alkoxycarbonyl]carbamoyl includes
N-methoxycarbonylcarbamoyl, N-ethoxycarbonylcarbamoyl and
N-propoxycarbonylcarbamoyl.
56. The term N-[fluoro-(2-6C)alkyl]carbamoyl includes
N-[2,2,2-trifluoroethyl]carbamoyl,
N-[2,2,3,3,4,4,4-heptafluorobutyl]carb- amoyl and
N-[4,4,5,5,5-pentafluoropentyl]carbamoyl.
57. The term N-[fluoro-(2-6C)alkyl]-N-(1-4C)alkylcarbamoyl includes
N-[2,2,2-trifluoroethyl]-N-ethylcarbamoyl,
N-[2,2,3,3,4,4,4-heptafluorobu- tyl]-N-methylcarbamoyl and
N-[4,4,5,5,5-pentafluoropentyl]-N-methylcarbamo- yl.
58. The term N,N-[di-fluoro-(2-6C)alkyl]carbamoyl includes
N,N-di-[2,2,3,3,4,4,4-heptafluorobutyl]carbamoyl and
N,N-di-[4,4,5,5,5-pentafluoropentyl]carbamoyl.
59. The term N,N-[di-(1-4C)alkyl]thiocarbamoyl includes
N,N-dimethylthiocarbamoyl, N,N-diethylthiocarbamoyl and
N-methyl-N-ethylthiocarbamoyl.
60. The term N-(2-4C)alkanoylamino includes
N-acetylamino-N-propionylamino and N-butyrylamino.
61. The term N-[(1-4C)alkoxycarbonyl]amino includes
N-methoxycarbonylamino, N-ethoxycarbonylamino,
N-propoxycarbonylamino and N-tert-butoxycarbonylamino.
62. The term fluoro-(1-4C)alkyl includes trifluoromethyl,
2,2,2-trifluoroethyl and 2,2,3,3,4,4,4-heptafluorobutyl.
63. The term pyridinyl includes pyridin-3-yl and pyridin-4-yl.
64. The term (1-4C)alkoxy-(2-4C)alkoxy includes 2-methoxyethoxy,
2-ethoxyethoxy and 3-methoxypropoxy.
65. The term fluoro-(1-6C)alkoxy includes 2,2,2-trifluoroethoxy,
4,4,5,5,5-pentafluoropentoxy and
2,2,3,3,4,4,4-heptafluorobutoxy.
66. The term morpholino-(2-4C)alkoxycarbonyl includes
morpholinoethoxycarbonyl.
67. Particular novel compounds of the invention include, for
example, phenanthroline derivatives of the formula (I), or
pharmaceutically-accept- able salts thereof, or a metabolically
labile ester derivative of substituents R.sup.1 and R.sup.2 when
either, or both, is a carboxy group, as defined in paragraphs (a)
to (m) hereinafter and wherein, unless otherwise stated, each of
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have any of the
meanings defined hereinbefore or in this section concerning
particular compounds of the invention:
68. (a) R.sup.1 is hydrogen, carboxy, cyano, nitro, amino,
(1-4C)alkyl, (1-4C)alkylamino, di-(1-4C)alkylamino,
(1-6C)alkoxycarbonyl, (1-4C)alkylthio, (1-4C)alkylsulfinyl,
(1-4C)alkylsulfonyl, phenylthio, phenylsulfinyl, phenylsulfonyl,
fluoro-(1-4C)alkylsulfinyl, fluoro-(1-4C)alkylsulfonyl,
(1-4C)alkoxy-(2-4C)alkoxycarbonyl,
N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxycarbonyl,
(1-4C)alkylamino-(2-4C)alkoxycarbonyl,
di-(1-4C)alkylamino-(2-4C)alkoxyca- rbonyl,
(1-4C)alkoxy-(2-4C)alkoxy-(2-4C)alkoxycarbonyl,
(2-4C)alkanoyloxy-(1-4C)alkyl or
N-[amino-(2-8C)alkyl]carbamoyl;
69. (b) R.sup.1 is hydrogen, carboxy, cyano, halo, nitro, amino,
(1-6C)alkoxycarbonyl, (2-4C)alkanoyl, hydroxy-(1-4C)alkyl,
(1-4C)alkylsulfonyl, phenylsulfonyl,
N-[amino-(2-8C)alkyl]carbamoyl, fluoro-(1-4C)alkylsulfonyl,
(1-4C)alkoxy-(2-4C)alkoxycarbonyl,
N,N-di-[(1-4C)alkyl]carbamoyl-(1-4C)alkoxycarbonyl,
(1-4C)alkoxy-(2-4C)alkoxy-(2-4C)alkoxycarbonyl or
(2-4C)alkanoyloxy-(1-4C- )alkyl;
70. (c) R.sup.1 is carboxy, cyano, nitro, (1-6C)alkoxycarbonyl,
(2-4C)alkanoyl, fluoro-(1-4C)alkylsulfonyl or
(1-4C)alkoxy-(2-4C)alkoxy-(- 2-4C)alkoxycarbonyl;
71. (d) R.sup.2 is hydrogen, hydroxy, amino, cyano, carboxy,
(1-6C)alkoxycarbonyl, (2-4C)alkanoyl, (1-4C)alkoxy,
carboxy-(1-4C)alkoxy, carbamoyl, N-[amino-(2-8C)alkyl]-carbamoyl,
N,N-di-(1-8C)alkylcarbamoyl, N-(1-4C)alkyl-N-cyclohexylcarbamoyl,
N-phenylcarbamoyl, N-(1-4C)alkyl-N-phenylcarbamoyl,
N-[phenyl-(1-4C)alkyl]carbamoyl,
N-(1-4C)alkyl-N-[phenyl-(1-4C)alkyl]carbamoyl,
N,N-di-[phenyl-(1-4C)alkyl- ]carbamoyl,
N-[(2-4C)alkanoyl]carbamoyl, N-[fluoro-(2-6C)alkyl]carbamoyl,
N-[fluoro-(2-6C)alkyl)-N-(1-4C)alkylcarbamoyl,
pyrrolidin-1-ylcarbonyl, piperidinocarbonyl,
piperazin-1-ylcarbonyl, 1,2,3,4-tetrahydroisoquinolin-
-2-ylcarbonyl, N-(2-4C)alkanoylamino,
N-[di-(1-4C)alkoxycarbonyl]amino or
N,N-[di-(1-4C)alkyl]thiocarbamoyl;
72. (e) R.sup.2 is hydrogen, carboxy, (1-6C)alkoxycarbonyl,
carbamoyl, N,N-di-(1-8C)alkylcarbamoyl, N-phenylcarbamoyl,
N-(1-4C)alkyl-N-[phenyl-(- 1-4C)alkyl]carbamoyl,
N-[fluoro-(2-6C)alkyl)carbamoyl,
1,2,3,4-tetrahydro-isoquinolin-2-ylcarbonyl, piperazin-1-ylcarbonyl
or N,N- [di-(1-4C)alkyl]thiocarbamoyl;
73. (f) R.sup.2 is hydrogen, hydroxy, carboxy,
carboxy-(1-4C)alkoxy, carbamoyl, N-(1-8C)alkylcarbamoyl,
N,N-di-(1-8C)alkylcarbamoyl, N-[amino-(2-8C)alkyl)carbamoyl,
N-[(1-4C)alkylamino-(1-8C)alkyl)carbamoyl- , N-[di-
(1-4C)alkylamino-(1-8C)alkyl)carbamoyl, N-[(2-4C)alkanoyl]carbamo-
yl, piperazin-1-ylcarbonyl, morpholinocarbonyl,
N-(2-4C)alkanoylamino or N-[(1-4C)alkoxycarbonyl]amino;
74. (g) R.sup.3 and R.sup.4, which may be the same or different,
are hydrogen, (1-4C)alkyl, halo, pyridinyl, fluoro-(1-4C)alkyl,
nitro or hydroxy;
75. (h) R.sup.3 and R.sup.4, which may be the same or different,
are hydrogen, (1-4C)alkyl, halo or pyridinyl;
76. (i) R.sup.3 and R.sup.4, which may be the same or different,
are hydrogen, halo or nitro;
77. (j) R.sup.3 is hydroxy;
78. (k) R.sup.5 is hydrogen, hydroxy, pyrrolidin-1-yl,
di-(1-4C)alkylamino, (1-4C)alkylamino, halo,
(1-4C)alkoxy-(2-4C)alkoxy or fluoro-(1-6C)alkoxy;
79. (l) R.sup.5 is hydrogen, di-(1-4C)alkylamino or halo; and
80. (m) R.sup.5 is hydrogen, hydroxy or piperazin-1-yl;
81. The phenyl groups in the afore-mentioned substituents in
paragraphs (a), (b), (d) and (e) above are optionally substituted
with one or two substituents selected from (1-4C)alkoxy, halo,
hydroxy and trifluoromethyl; and the pyrrolidin-1-yl, piperidino
and piperazin-1-yl groups in the aforementioned substituents in
paragraphs (d), (e), (f) and (k) above are optionally substituted
with one or two substituents selected from (1-4C)alkyl and
benzyl.
82. It will be understood that the following compounds are excluded
from the scope of compounds of formula (I):
3-carboxy-5,6-dihydroxy-4-oxo-3,4-- dihydro-1,10-phenanthroline;
3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phena- nthroline; 3,
8-diethoxycarbonyl-7-hydroxy-4-oxo-3,4-dihydro-1,10-phenanth-
roline;
3,8-dicarboxy-7-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
3,8-diethoxycarbonyl-7-hydroxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthro-
line;
3,8-dicarboxy-7-hydroxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroli-
ne;
5-butyl-3,8-dimethoxycarbonyl-7-hydroxy-4-oxo-3,4-dihydro-1,10-phenant-
hroline;
3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline;
7-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
7-hydroxy-4-oxo-3,4-dihy- dro-1,10-phenanthroline hydrochloride;
4-oxo-3,4-dihydro-1,10-phenanthroli- ne;
7-dimethylamino-4-oxo-3,4-dihydro-1,10-phenanthroline;
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline (Compound 12); and
5-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline. Preferably, the
following additional compounds are excluded from the scope of
compounds of formula (I):
3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline (Compound
2); 3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline
(Compound 7);
3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline (Compound
9); and 3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline
(Compound 15).
83. Thus, compounds per se preferably not within the scope of the
claimed invention include compounds of formula (I) where
84. R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are not together
H;
85. where R.sup.1 is carboxy and R.sup.3 and R.sup.4 are hydroxy;
R.sup.2 and R.sup.5 are not together H;
86. where R.sup.1 is carboxy, R.sup.2 is H or OH, R.sup.3 is H and
R.sup.5 is H; R.sup.4 is not H, OH alkoxy, alkyl or halo;
87. where R.sup.1 is carboxy, R.sup.2 is H or OH, R.sup.4 is H and
R.sup.5 is H; R.sup.3 is not H, OH alkoxy, alkyl or halo;
88. where R.sup.1 is ethoxycarbonyl; R.sup.2, R.sup.3, R.sup.4 and
R.sup.5 are not together H;
89. where R.sup.1 is ethoxycarbonyl and R.sup.4 is F; R.sup.2,
R.sup.3 and R.sup.5 are not together H
90. where R.sup.1 is carboxy and R.sup.3 is H or alkyl; R.sup.2,
R.sup.4 and R.sup.5 are not together H;
91. where R.sup.3 is OH; R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are
not together H;
92. where R.sup.5 is OH, R.sup.3 is H or alkyl, and R.sup.4 is H;
R.sup.1 and R.sup.2 are not together ethoxycarbonyl, carboxy,
methoxycarbonyl or H; and
93. where R.sup.5 is --N(CH.sub.3).sub.2; R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are not together H.
94. A preferred compound of the invention comprises a
phenanthroline derivative of the formula (I), or a
pharmaceutically-acceptable salt thereof, or a metabolically labile
ester derivative of substituents R.sup.1 and R.sup.2 when either,
or both, is a carboxy group, wherein
95. R.sup.1 is hydrogen, carboxy, cyano, nitro, amino, bromo,
methoxycarbonyl, ethoxycarbonyl, acetyl,
2,2,2-trifluoroethylsulfonyl, 2-[2-methoxyethoxy]ethoxycarbonyl,
1-hydroxyethyl, carbamoyl, methylsulfonyl, phenylsulfonyl,
N-(6-aminohexyl)carbamoyl, 2-methoxyethoxycarbonyl,
N,N-diethylcarbamoylmethoxycarbonyl or propionyloxymethyl;
96. R.sup.2 is hydrogen, hydroxy, amino, cyano, carboxy,
methoxycarbonyl, ethoxycarbonyl, acetyl, carbamoyl, methoxy,
carboxymethoxy, N-(6-aminohexyl)carbamoyl,
N-ethyl-N-butylcarbamoyl, N,Ndiethylcarbamoyl, N-N
di-sec-butylcarbamoyl, N-methyl-N-butylcarbamoyl,
N-methyl-N-hexylcarbamoyl, N-ethyl-N-propylcarbamoyl,
N-ethyl-N-isopropylcarbamoyl, N-ethyl-N-pentylcarbamoyl,
N-ethyl-N-cyclohexylcarbamoyl, N-phenylcarbamoyl,
N-methyl-N-phenylcarbam- oyl, N-(2-phenylethyl)carbamoyl,
N-methyl-N-benzylcarbamoyl, N-methyl-N-(2-phenylethyl)carbamoyl,
N-isopropyl-N-benzylcarbamoyl, N-ethyl-N-benzylcarbamoyl,
N,N-dibenzylcarbamoyl, N-[2,2,3,3,4,4,4-heptaf-
luorobutyl]carbamoyl,
N-[2,2,3,3,4,4,4-heptafluorobutyl]-N-methylcarbamoyl- ,
N-[4,4,5,5,5-pentafluoropentyl]-N-methylcarbamoyl,
1,2,3,4-tetrahydro-isoquinolin-2-ylcarbonyl,
pyrrolidin-1-ylcarbonyl, piperidinocarbonyl,
piperazin-1-ylcarbonyl, N,N-diethylthiocarbamoyl, N-acetylamino or
N-tert-butoxycarbonylamino;
97. R.sup.3 and R.sup.4, which may be the same or different, are
hydrogen, fluoro, chloro, bromo, nitro, hydroxy, pyridin-4-yl,
trifluoromethyl or methyl; and
98. R.sup.5 is hydrogen, dimethylamino, diethylamino, chloro,
bromo, hydroxy, pyrrolidin-1-yl, methylamino, 2-methoxyethoxy,
2,2,2-trifluoroethoxy or 4,4,5,5,5-pentafluoropentoxy;
99. wherein any phenyl group contained in the afore-mentioned
R.sup.1 and R.sup.2 substituents are optionally substituted with
one or two substituents selected from ethoxy, fluoro and
trifluoromethyl; and
100. any pyrrolidin-1-yl, piperidino or piperazin-1-yl group
contained in the afore-mentioned R.sup.2 substituents are
optionally substituted with one methyl or benzyl substituent in any
vacant position.
101. A further preferred compound of the invention comprises a
phenanthroline derivative of the formula (I), or a
pharmaceutically-acceptable salt thereof, or a metabolically labile
ester derivative of substituents R.sup.1 and R.sup.2 when either,
or both, is a carboxy group, wherein
102. R.sup.1 is hydrogen, carboxy, cyano, nitro, methyl, ethyl,
methoxycarbonyl, ethoxycarbonyl, methylamino, ethylamino,
dimethylamino, 2,2,2-trifluoroethylsulfonyl,
2,2,2-trifluoroethylsulfinyl, phenylsulfinyl, phenylsulfonyl,
phenylthio, methylthio, methylsulfinyl, methylsulfonyl,
2-[2-methoxyethoxy]ethoxycarbonyl, N-(6-aminohexyl)carbamoyl,
2-methoxyethoxycarbonyl, 2-(methylamino)ethoxycarbonyl,
2-(dimethylamino)ethoxycarbonyl,
N,N-diethylcarbamoylmethoxycarbonyl or propionyloxymethyl;
103. R.sup.2 is hydrogen, hydroxy, carboxy, carbamoyl,
carboxymethoxy, N-(6-aminohexyl) carbamoyl, N-ethylcarbamoyl,
N-ethyl-N-butylcarbamoyl, N-butylcarbamoyl, N,N-diethylcarbamoyl,
N,N-di-sec-butylcarbamoyl, N-methyl-N-butylcarbamoyl,
N-methyl-N-hexylcarbamoyl, N-ethyl-N-propylcarbamoyl,
N-ethyl-N-isopropylcarbamoyl, N-ethyl-N-pentylcarbamoyl,
piperazin-1-ylcarbonyl, N-[methylaminomethyl]carbamoyl,
N-[dimethylaminomethyl]carbamoyl, N-acetylcarbamoyl,
morpholinocarbonyl, N-acetylamino or
N-tert-butoxycarbonylamino;
104. R.sup.3 and R.sup.4, which may be the same or different, are
hydrogen, fluoro, chloro, bromo, methyl or pyridin-4-yl; or R.sup.3
is hydroxy; and
105. R.sup.5 is hydrogen, hydroxy or piperazin-1-yl;
106. wherein any phenyl group contained in the afore-mentioned
R.sup.1 and R.sup.2 substituents are optionally substituted with
one or two substituents selected from ethoxy, fluoro and
trifluoromethyl; and
107. any piperazin-1-yl group contained in the afore-mentioned
R.sup.2 substituents is optionally substituted with one methyl or
benzyl substituent in any vacant position.
108. A further preferred compound of the invention comprises a
phenanthroline derivative of the formula (I), or a
pharmaceutically-acceptable salt thereof, or a metabolically labile
ester derivative of substituents R.sup.1 and R.sup.2 when either,
or both, is a carboxy group, wherein
109. R.sup.1 is carboxy, cyano, nitro, ethoxycarbonyl, acetyl,
2,2,2-trifluoroethylsulfonyl or
2-[2-methoxyethoxy]ethoxycarbonyl;
110. R.sup.2 is hydrogen, carboxy, ethoxycarbonyl, carbamoyl,
N-ethyl-N-butylcarbamoyl, N-(4-ethoxyphenyl)carbamoyl,
N-methyl-N-benzylcarbamoyl, N-methyl-N-4-fluorobenzylcarbamoyl,
N-[2,2,3,3,4,4,4-heptafluorobutyl]carbamoyl,
1,2,3,4-tetrahydroisoquinoli- n-2-ylcarbonyl,
4-benzylpiperazin-1-ylcarbonyl or N,N-diethylthiocarbamoyl- ;
111. R.sup.3 and R.sup.4, which may be the same or different, are
hydrogen, fluoro or nitro; and
112. R.sup.5 is hydrogen, dimethylamino or chloro.
113. Further preferred compounds of the invention include, for
example, the following phenanthroline derivatives of the formula
(I):
114. 3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline (Compound
1);
115.
3-carboxy-8-(N-methyl-N-{2,4-difluorobenzyl}carbamoyl)-4-oxo-3,4-dihy-
dro-1,10-phenanthroline (Compound 3);
116.
3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenant-
hroline (Compound 4);
117.
3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1-
,10-phenanthroline (Compound 5);
118.
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanth-
roline (Compound 6);
119. 3,8-dicarboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
120. 8-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
121. 3-nitro-4-oxo-3,4-dihydro-1,10-phenanthroline;
122. 3-cyano-5-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
123. 5-chloro-3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;
124.
5-chloro-3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
125.
3-acetyl-8-carboxy-7-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
126.
3,8-diacetyl-7-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
127.
3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phena-
nthroline;
128.
3-carboxy-8-(4-methylpiperidinocarbonyl)-4-oxo-3,4-dihydro-1,10-phena-
nthroline;
129.
3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-fluoro-4-oxo-3,4-dihydro-1-
,10-phenanthroline;
130. 8-acetyl-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
131.
3-carboxy-8-(N-methyl-N-{2-phenylethyl}carbamoyl)-4-oxo-3,4-dihydro-1-
,10-phenanthroline;
132.
3-carboxy-8-(N-benzyl-N-isopropylcarbamoyl)-4-oxo-3,4-dihydro-1,10-ph-
enanthroline;
133.
3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-7-hydroxy-4-oxo-3,4-dihydro--
1,10-phenanthroline;
134.
3-carboxy-8-(N-methyl-N-{4-fluorobenzyl}carbamoyl)-4-oxo-3,4-dihydro--
1,10-phenanthroline;
135.
3-carboxy-8-(N,N-diethylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanthrol-
ine;
136.
8-(N-benzyl-N-methylcarbamoyl)-5-fluoro-3-nitro-4-oxo-3,4-dihydro-1,1-
0-phenanthroline;
137. 8-(N-benzyl-N-methylcarbamoyl)-3
,6-dinitro-5-methyl-4-oxo-3,4-dihydr- o-1,10-phenanthroline;
138.
8-ethoxycarbonyl-3-nitro-4-oxo-3,4-dihydro-1,10-phenanthroline;
139.
8-(N-butyl-N-ethylcarbamoyl)-3-nitro-4-oxo-3,4-dihydro-1,10-phenanthr-
oline;
140. 3-carboxy-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline;
141.
8-(N,N-di-sec-butylcarbamoyl)-3-nitro-4-oxo-3,4-dihydro-1,10-phenanth-
roline;
142.
8-(N-butyl-N-ethylcarbamoyl)-3-cyano-4-oxo-3,4-dihydro-1,10-phenanthr-
oline;
143. 3-carboxy-8-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
144.
8-(N-cyclohexyl-N-ethylcarbamoyl)-3-nitro-4-oxo-3,4-dihydro-1,10-phen-
anthroline;
145.
3-carboxy-8-(N-hexyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenan-
throline;
146.
8-(N-hexyl-N-methylcarbamoyl)-3-nitro-4-oxo-3,4-dihydro-1,10-phenanth-
roline;
147. 6-fluoro-3-nitro-4-oxo-3,4-dihydro-1,10-phenanthroline;
148.
3-carboxy-8-(N-butyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenan-
throline;
149.
3-carboxy-8-(N-ethyl-N-isopropylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phe-
nanthroline;
150.
8-(N-acetylamino)-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
151.
3-carboxy-8-(N-{4,4,5,5,5-pentafluoropentyl}-N-methylcarbamoyl)-4-oxo-
-3,4-dihydro-1,10-phenanthroline;
152.
3-carboxy-8-(N-methyl-N-ethylcarbamoyl)-7-dimethylamino-4-oxo-3,4-dih-
ydro-1,10-phenanthroline;
153.
3-carboxy-8-(N-tert-butoxycarbonylamino)-4-oxo-3,4-dihydro-1,10-phena-
nthroline;
154.
3-carboxy-6-chloro-8-(N-butyl-N-ethylcarbamoyl)-4-oxo-3,4-dihydro-1,1-
0-phenathroline;
155.
8-amino-7-bromo-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
156. 3-carboxy-8-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;
157.
3-carboxy-8-carboxymethoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
158.
8-(4-benzylpiperazin-1-ylcarbonyl)-3-nitro-4-oxo-3,4-dihydro-1,10-phe-
nanthroline; or a pharmaceutically-acceptable salt thereof, or a
metabolically labile ester derivative of those compounds bearing a
carboxy group or groups.
159. Particularly preferred compounds of the invention include, for
example, the following phenanthroline derivatives of the formula
(I):
160.
3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanth-
roline (Compound 8);
161.
3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phen-
anthroline (Compound 10);
162.
3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline
(Compound 11);
163.
8-(N-butyl-N-ethylcarbamoyl)-3-carboxy-4-oxo-3,4-dihydro-1,10-phenant-
hroline;
164. 3,6-dinitro-4-oxo-3,4-dihydro-1 ,10-phenanthroline;
165. 8-carboxy-3-nitro-4-oxo-3,4-dihydro-1,10-phenanthroline;
166.
8-(4-benzylpiperazin-1-ylcarbonyl)-3-nitro-4-oxo-3,4-dihydro-1,10-phe-
nanthroline;
167.
3-(2,2,2-trifluoroethylsulfonyl)-4-oxo-3,4-dihydro-1,10-phenanthrolin-
e;
168.
8-[N-(4-fluorobenzyl)-N-methylcarbamoyl]-3-nitro-4-oxo-3,4-dihydro-1,-
10-phenanthroline;
169.
3-carboxy-8-N,N-diethylthiocarbamoyl-4-oxo-3,4-dihydro-1,10-phenanthr-
oline;
170.
8-(N-benzyl-N-methylcarbamoyl)-3-cyano-5-fluoro-4-oxo-3,4-dihydro-1,1-
0-phenanthroline;
171.
3-acetyl-7-chloro-8-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthrol-
ine;
172.
3-carboxy-5-fluoro-8-(N-2,2,3,3,4,4,4-heptafluorobutylcarbamoyl)-4-ox-
o-3,4-dihydro-1,10-phenanthroline;
173.
3-carboxy-8-(N-4-ethoxyphenylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenan-
throline;
174.
3-carboxy-8-carbamoyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
175.
3-carboxy-4-oxo-8-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyl)-3,4-di-
hydro-1,10-phenanthroline;
176.
3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthrolin-
e (Compound 13);
177.
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline
(Compound 14); or
178.
8-(N-benzyl-N-methylcarbamoyl)-7-dimethylamino-3-ethoxycarbonyl-4-oxo
3,4-dihydro-1,10-phenanthroline;
179. or a pharmaceutically-acceptable salt thereof, or a
metabolically labile ester derivative of those compounds bearing a
carboxy group.
BRIEF DESCRIPTION OF THE DRAWINGS
180. FIG. 1 illustrates the histological results in the
isoproterenol-induced myocardial fibrosis model.
181. FIG. 2 illustrates the results of Compound 12, compared to
control, in the rat restenosis model.
182. FIG. 3 illustrates inhibition of prolyl hydroxylase by
Compound 12 in restenosis.
183. FIG. 4 illustrates oral treatment of Compound 12 in the brain
injured model.
184. FIG. 5 illustrates wound area after treatment of Compound 3 in
the dermal punch model.
185. FIG. 6 illustrates the tensile strength on dermal incisional
wound on day 7 after oral treatment of Compound 3 and Compound
12.
186. FIG. 7 illustrates the tensile strength of incisional wound
after local injections of Compound 12.
187. FIG. 8 illustrates certain embodiments of the invention.
188. FIG. 9 illustrates certain embodiments of the invention.
DETAILED DESCRIPTION OF THE INVENTION
189. A compound of the invention comprising a phenanthroline
derivative of the formula (I) as defined hereinbefore, or a
pharmaceutically-acceptable salt thereof, or a metabolically labile
ester derivative of substituents R.sup.1 and R.sup.2 when either,
or both, is a carboxy group, may be prepared by any process known
to be applicable to the preparation of structurally-related
compounds. Such procedures are provided as a further feature of the
invention and are illustrated by the examples presented herein in
which, unless otherwise stated, R.sup.1, R.sup.2, R.sup.3, R.sup.4
and R.sup.5 have any of the meanings defined hereinbefore, provided
that, when there is an amino, hydroxy or carboxy group in R.sup.1 ,
R.sup.2, R.sup.3, R.sup.4 and R.sup.5, any such group may
optionally be protected by a conventional protecting group which
may be removed when so desired by conventional means. A nitrogen
heteroatom may also be optionally protected by a conventional
protecting group which may be removed when so desired by
conventional means.
190. A suitable protecting group for an amino group is, for
example, an acyl group, for example, an alkanoyl group such as
acetyl, an alkoxycarbonyl group, for example, a methoxycarbonyl,
ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl
group, for example, benzyloxycarbonyl, or an aroyl group, for
example, benzoyl. The deprotection conditions for the above
protecting groups necessarily vary with the choice of protecting
group. Thus, for example, an acyl group such as an alkanoyl or
alkoxycarbonyl group or an aroyl group may be removed, for example,
by hydrolysis with a suitable base such as an alkali metal
hydroxide, for example, lithium or sodium hydroxide. Alternatively
an acyl group such as a tert-butoxycarbonyl group may be removed,
for example, by treatment with a suitable acid such as
hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid
and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group
may be removed, for example, by hydrogenation over a catalyst such
as palladium-on-carbon, or by treatment with a Lewis acid for
example boron tris (trifluoroacetate).
191. A suitable alternative protecting group for a primary amino
group is, for example, a phthaloyl group which may be removed by
treatment with an alkylamine, for example,
dimethylaminopropylamine, or with hydrazine.
192. A suitable protecting group for a nitrogen heteroatom is, for
example, a pivaloyloxymethyl group which may be removed by
hydrolysis with a base, for example, sodium hydroxide or ammonia,
in a suitable inert solvent or diluent, for example, methanol or
ethanol.
193. A suitable protecting group for a hydroxy group is, for
example, an acyl group, for example, an alkanoyl group such as
acetyl, an aroyl group, for example, benzoyl, or an arylmethyl
group, for example, benzyl. The deprotection conditions for the
above protecting groups will necessarily vary with the choice of
protecting group. Thus, for example, an acyl group such as an
alkanoyl or an aroyl group may be removed, for example, by
hydrolysis with a suitable base such as an alkali metal hydroxide,
for example, lithium or sodium hydroxide. Alternatively an
arylmethyl group such as a benzyl group may be removed, for
example, by hydrogenation over a catalyst such as
palladium-on-carbon.
194. A suitable protecting group for a carboxy group is, for
example, an esterifying group, for example, a methyl or an ethyl
group which may be removed, for example, by hydrolysis with a base
such as sodium hydroxide, or, for example, a tert-butyl group which
may be removed, for example, by treatment with an acid, for
example, an organic acid such as trifluoroacetic acid, or, for
example a benzyl group which may be removed, for example, by
hydrogenation over a catalyst such as palladium-on-carbon.
195. Methods for reactions (a)-(f) are described below:
196. (a) The reaction of an 8-aminoquinoline derivative with a
(1-4C)alkoxymethylene compound of the formula (II)
R.sup.1--CO--C(R.sup.2)=CH--(1-4C)alkoxy (II)
197. followed by cyclization of the reaction product; wherein
R.sup.1 is a (1-4C)alkoxy or a (1-4C)alkyl group; and R.sup.2 is a
(1-4C)alkoxycarbonyl, (1-4C)alkylsulfonyl,
fluoro-(1-4C)alkylsulfonyl or a sulfonylphenyl group; or R.sup.1
and R.sup.2 are linked, and together with the carbonyl carbon atom
to which R.sup.1 is attached, and the carbon atom to which R.sup.2
is attached, define a 1,3-dioxan-4,6-dione ring (with the carbonyl
carbon to which R.sup.1 is attached in the 4-position), and which
ring is disubstituted in the 2-position by two (1-4C)alkyl
groups:
198. The reaction is preferably carried out in the presence of a
suitable solvent such as ethanol. The reaction may also be carried
out using neat reagents. The reaction is preferably carried out a
temperature in the range 10.degree. C. to 100.degree. C.,
conveniently in the range 75.degree. C. to 80.degree. C. The
cyclization is preferably carried out in the presence of an ether
solvent such as, for example, diphenyl ether. The cyclization is
preferably carried out at a temperature in the range 180.degree. C.
to 270.degree. C., conveniently at, or near, the reflux temperature
of the solvent.
199. The preparation of starting 8-aminoquinoline derivatives is
described within the accompanying non-limiting Examples which are
provided for the purpose of illustration only. Other necessary
8-aminoquinoline derivatives are obtainable by analogous procedures
to those described or by modifications thereto which are within the
ordinary skill of an organic chemist. Suitable 8-aminoquinoline
derivatives are substituted at the 3-position by any of the R.sup.2
substituents defined hereinbefore, at the 4-position by any of the
R.sup.5 substituents defined hereinbefore, at the 5-position by any
of the R.sup.4 substituents defined hereinbefore and at the
6-position by any of the R.sup.3 substituents defined
hereinbefore.
200. The preparation of certain starting materials of the formula
(II) is described within the accompanying Examples. Other necessary
starting materials of the formula (II) are obtainable by analogous
procedures to those described or by modifications thereto which are
within the ordinary skill of an organic chemist. Other necessary
starting materials of the formula (II) are obtainable by standard
reactions of organic chemistry which are within the ordinary skill
of an organic chemist.
201. (b) For the production of those compounds of the formula (I)
in which each, or both of, the substituents R.sup.1 and R.sup.2 are
carboxy groups, the hydrolysis of a compound of the formula (I) in
which each, or both of, the substituents R.sup.1 and R.sup.2 are
(1-6C)alkoxycarbonyl groups:
202. The hydrolysis is preferably carried out in the presence of a
suitable acid or base. The reaction is also preferably carried out
in aqueous solution, and at a temperature in the range 10.degree.
C. to 110.degree. C., conveniently in the range 80.degree. C. to
100.degree. C. A suitable acid is, for example, a mineral acid such
as, for example, hydrochloric acid. A suitable base is, for
example, an alkali or alkaline earth metal carbonate or hydroxide,
for example, sodium carbonate, potassium carbonate, sodium
hydroxide or potassium hydroxide.
203. The preparation of starting materials of formula (I) in which
each, or both of, the substituents R.sup.1 and R.sup.2 are
(1-4C)alkoxycarbonyl groups is described within the accompanying
non-limiting Examples which are provided for the purpose of
illustration only. Other necessary starting materials are
obtainable by analogous procedures to those described or by
modifications thereto which are within the ordinary skill of an
organic chemist.
204. (c) For the production of those compounds of the formula (I)
which bear a nitro substituent, the nitration of a compound of the
formula (I) using a suitable nitrating agent:
205. A suitable nitrating agent is, for example, concentrated
nitric acid in acetic anhydride, concentrated nitric acid in
glacial acetic acid or a nitrate salt such as, for example,
ammonium nitrate in trifluoroacetic acid.
206. The reaction is preferably carried out at a temperature in the
range 10.degree. C. to 100.degree. C.
207. (d) The reaction of a compound of the formula (I) which bears
a carboxy substituent, or a reactive derivative thereof, with
ammonia, a primary amine or a secondary amine:
208. The reaction is preferably carried out in an inert solvent or
diluent such as, for example, dichloromethane, acetonitrile or
dimethylsulfoxide, and at a temperature in the range 0.degree. C.
to 100.degree. C. The reaction is also preferably carried out in
the presence of a suitable organic amine base such as, for example,
triethylamine.
209. A suitable reactive derivative of a carboxy substituent borne
by a compound of the formula (I) is, for example, an acyl halide,
for example, an acyl chloride formed by the reaction of the carboxy
substituent and an acid chloride, for example, thionyl chloride or
oxalyl chloride; a mixed anhydride, for example, an anhydride
formed by the reaction of the carboxy substituent and a
chloroformate such as isobutyl chloroformate; an active ester, for
example, an ester formed by the reaction of the carboxy substituent
and a phenol such as pentafluorophenol, an ester such as
pentafluorophenyl trifluoroacetate or an alcohol such as
N-hydroxybenzotriazole; an acyl azide, for example, an azide formed
by the reaction of the carboxy substituent and an azide such as
diphenylphosphoryl azide; an acyl cyanide, for example, a cyanide
formed by the reaction of the carboxy substituent and a cyanide
such as diethylphosphoryl cyanide; or the product of the reaction
of the carboxy substituent and a carbodiimide such as
dicyclohexylcarbodiimide.
210. (e) For the production of those compounds of the formula (I)
in which R.sup.1 is a (1-4C)alkoxy-(2-4C)alkoxycarbonyl or a
(1-4C)alkoxy-(2-4C)alkoxy-(2-4C)alkoxycarbonyl group, the reaction
of a compound of the formula (I) bearing an imidazol-1-ylcarbonyl
group in the 3-position with a (1-4C)alkoxy-(2-4C)alkanol or a
(1-4C)alkoxy-(2-4C)alko- xy-(2-4C)alkanol:
211. The reaction is preferably carried out in an inert solvent or
diluent such as, for example, N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidin-2-one or
dimethylsulfoxide, and at a temperature in the range 0.degree. C.
to 150.degree. C., conveniently at or near ambient temperature. The
reaction is also preferably carried out in the presence of a
suitable base such as, for example, an alkali or alkaline earth
metal carbonate, alkoxide, hydroxide or hydride, for example,
sodium carbonate, potassium carbonate, sodium ethoxide, potassium
butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or
potassium hydride, or an organometallic base such as an
alkyl-lithium, for example, n-butyl-lithium, or a
dialkylamino-lithium, for example, lithium di-isopropylamide, or,
for example, an organic amine base such as, for example, pyridine,
2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,
morpholine or diazabicyclo-[5.4.0]undec-7-ene.
212. The preparation of starting materials of the formula (I)
bearing an imidazol-1-ylcarbonyl group in the 3-position is
described within the accompanying Examples. Other necessary
starting materials of the formula (I) bearing an
imidazol-1-ylcarbonyl group in the 3-position are obtainable by
analogous procedures to those described or by modifications thereto
which are within the ordinary skill of an organic chemist.
213. A suitable value for a (1-4C)alkoxy-(2-4C)alkanol is, for
example, 2 -methoxyethanol, 2-ethoxyethanol and 3-methoxypropanol.
A suitable value for a (1-4C)alkoxy-(2-4C)alkoxy-(2-4C)alkanol is,
for example, 2-(2-methoxyethoxy)ethanol, 2-(2-ethoxyethoxy)ethanol
and 3-(2-methoxyethoxy)propanol.
214. (f) For the production of those compounds of the formula (I)
in which each, or both of, the substituents R.sup.1 and R.sup.2 are
cyano groups, the dehydration of a compound of the formula (I) in
which each, or both of, the substituents R.sup.1 and R.sup.2 are
carbamoyl groups using a suitable dehydrating agent:
215. The dehydration is preferably carried out at a temperature in
the range 0.degree. C. to 100.degree. C., conveniently at or near
ambient temperature.
216. A suitable dehydrating agent is, for example, a mixture of
trifluoroacetic anhydride and pyridine, phosphorous pentachloride
or phosphorous oxychloride.
217. The preparation of a compound of the formula (I) in which
each, or both of, the substituents R.sup.1 and R.sup.2 are
carbamoyl groups is described, for example, in the section (d)
hereinbefore and in the accompanying Examples. Other necessary
starting materials of the formula (I) in which each, or both of,
the substituents R.sup.1 and R.sup.2 are carbamoyl groups are
obtainable by analogous procedures to those described or by
modification thereto which are within the ordinary skill of an
organic chemist.
218. It will be observed that certain phenanthrolinone derivatives
of the present invention possess at least one asymmetric carbon
atom (for example, when the substituent R.sup.1 is, for example, a
1-hydroxyethyl group) and can therefore exist in racemic and
optically active forms. It is to be understood that the present
invention encompasses a racemic form of any such phenanthroline
derivative of the invention, any optically-active form thereof or a
mixture thereof which possesses prolyl 4-hydroxylase inhibitory
activity. It is a matter of common general knowledge how such
optically-active forms may be obtained by stereospecific synthesis
or by the separation of mixtures of isomeric compounds.
219. It is also to be understood that a phenanthroline derivative
of the formula (I) may exhibit the phenomenon of tautomerism. In
particular, it will be appreciated that the
4-oxo-3,4-dihydro-1,10-phenanthroline group may be in the form, for
example, of a 4-hydroxy-1,10-phenanthroline group, or in the form,
for example, of a 4-oxo-1,4-dihydro-1,10-phenanthr- oline group. It
is to be understood that the invention encompasses any tautomeric
form which possesses prolyl 4-hydroxylase inhibitory activity and
is not to be limited merely to any one tautomeric form.
220. It is also to be understood that certain phenanthroline
derivatives of the formula (I) can exist in solvated as well as
unsolvated forms such as, for example, hydrated forms. It is to be
understood that the invention encompasses all such solvated forms
which possess prolyl 4-hydroxylase inhibitory activity.
221. A suitable pharmaceutically-acceptable salt of a
phenanthroline derivative of the invention which is sufficiently
basic is an acid-addition salt with, for example, an inorganic or
organic acid, for example, hydrochloric, hydrobromic, sulphuric,
phosphoric, trifluoroacetic, citric or maleic acid. In addition a
suitable pharmaceutically-acceptable salt of a phenanthroline
derivative of the invention which is sufficiently acidic is an
alkali metal salt, for example, a calcium or magnesium salt, an
ammonium or tetra-(2-hydroxyethyl) ammonium salt or a salt with
organic amines and quaternary bases which afford a
physiologically-acceptable cation, for example, a salt with
methylamine, dimethylamine, trimethylamine, ethylenediamine,
piperidine, morpholine, pyrrolidine, piperazine, lysine, arginine,
guanidine, ethanolamine, triethanolamine, N-methylglucamine,
tetramethylammonium, hydroxide or benzyltrimethylammonium
hydroxide.
222. A suitable metabolically labile ester derivative of
substituents R.sup.1 and R.sup.2 when either, or both, is a carboxy
group are esters formed with alcohols such as indanol; adamantol;
(1-6C)alkanoyloxy-(l-4C)- alkanols such as, for example,
pivaloyloxymethyl; glycolamides;
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl alcohol,
(1-4C)alkoxycarbonyl-(1-4- C)alkanols such as, for example,
2-(methoxycarbonyl)ethyl alcohol and oxa-(1-8C)alkandiols such as,
for example, 3-oxapentan-1,5-diol and 3,6-dioxaoctan-1,8-diol.
223. When a pharmaceutically-acceptable salt of a compound of the
formula (I) is required, it may be obtained, for example, by
reaction of said compound with a suitable acid or base using a
conventional procedure. When an optically active form of a compound
of the formula (I) is required, it may be obtained by carrying out
one of the aforesaid processes using an optically active starting
material, or by resolution of a racemic form of said compound using
a conventional procedure.
224. When a metabolically labile ester derivative of substituents
R.sup.1 and R.sup.2 when either, or both, is a carboxy group is
required, it may be obtained, for example, by esterifying said
carboxy group or groups using a conventional technique.
225. As stated above, the compounds of the present invention are of
potential use in treating fibroproliferative disease, and
accordingly the present invention also concerns the use of a
compound of the formula (I), including those derivatives
hereinbefore excluded from the scope of formula (I), or a
pharmaceutically-acceptable salt thereof, or a metabolically labile
ester derivative of substituents R.sup.1 and R.sup.2 when either,
or both, is a carboxy group, in the manufacture of a medicament for
use in ameliorating fibroproliferative disease. The pharmacological
activity may be demonstrated using one or more standard test
procedures known in the art or as described in the examples.
226. A phenanthroline derivative of the present invention may
itself be active or it may be a pro-drug which is converted in vivo
to an active compound.
227. The present invention further provides a pharmaceutical
composition comprising one or more phenanthroline derivatives of
the formula (I) defined hereinbefore, and in addition those
compounds named as excluded hereinbefore, which possess useful
pharmacological activity; or a pharmaceutically-acceptable salt or
metabolically labile ester thereof. The pharmaceutical composition
which may be administered to a warm-blooded animal, including a
human, comprises one or more phenanthroline derivatives in
association with a pharmaceutically-accepta- ble diluent or
carrier.
228. A preferred pharmaceutical composition comprises the
phenanthroline derivative selected from
229. 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline (Compound
12);
230. 3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
231.
3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthrolin-
e (Compound 13);
232.
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline
(Compound 14);
233. 3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline
(Compound 15);
234. 3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
and
235.
3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline, or
a pharmaceutically-acceptable salt thereof, or a metabolically
labile ester derivative of the 3-carboxy substituent when present,
in association with a pharmaceutically-acceptable diluent or
carrier.
236. A further preferred pharmaceutical composition comprises the
phenanthroline derivative,
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthrolin- e, or a
pharmaceutically-acceptable salt thereof or a metabolically labile
ester derivative of the 3-carboxy substituent, in association with
a pharmaceutically-acceptable diluent or carrier.
237. The pharmaceutical composition may also comprise a
phenanthroline derivative of the formula (I) as defined
hereinbefore in the section relating to pharmaceutical
compositions, or a pharmaceutically-acceptable salt thereof, or a
metabolically labile ester derivative of substituents R.sup.1 and
R.sup.2 when either, or both, is a carboxy group, a cyclodextrin
and optionally a pharmaceutically- acceptable diluent or
carrier.
238. A suitable cyclodextrin is, for example, .alpha.-cyclodextrin,
.beta.-cyclodextrin or .alpha.-cyclodextrin. An alternative
suitable cyclodextrin is, for example, a cyclodextrin derivative
such as 2-hydroxypropyl-.beta.-cyclodextrin, an alkylated
cyclodextrin or a branched cyclodextrin. Preferably, the
cyclodextrin is .beta.-cyclodextrin.
239. The composition may be in a form suitable for oral use, for
example, a tablet, capsule, aqueous or oily solution, suspension or
emulsion; for topical use, for example, a cream, ointment, gel or
aqueous or oily solution or suspension; for nasal use, for example,
a snuff, nasal spray or nasal drops; for vaginal or rectal use, for
example, a suppository; for administration by inhalation, for
example, as a finely divided powder such as a dry powder, a
microcrystalline form or a liquid aerosol; for sub-lingual or
buccal use, for example, a tablet or capsule; or for parenteral use
(including intravenous, subcutaneous, intramuscular, intravascular
or infusion), for example, a sterile aqueous or oily solution,
emulsion or suspension.
240. Alternatively, the composition may be a continuous release
composition as either a solid or liquid depot formulation, as
microparticles or as microparticulate suspensions. In general the
above compositions may be prepared in a conventional manner using
conventional excipients. It is to be understood that the
pharmaceutical composition may comprise a prodrug of a
phenanthroline derivative of the formula (I) as defined
hereinbefore in the section relating to pharmaceutical
compositions. Such prodrugs include, but are not limited to,
metabolically labile ester derivatives of R.sup.1 and R.sup.2 when
either, or both, is a carboxy group; other substituents, for
example, hydroxy groups, may provide suitable positions for the
formation of prodrugs. The preparation of suitable prodrugs is
within the ordinary skill of a worker in the pharmaceutical
sciences.
241. As stated above, the present invention concerns the use of a
compound of the present invention, or a pharmaceutically-acceptable
salt thereof, or a metabolically labile ester derivative of
substituents R.sup.1 and R.sup.2 when either, or both, is a carboxy
group, in combatting fibroproliferative disease. Other agents are
currently known to possess activity against one or more
fibroproliferative diseases. Thus, for example, cyclooxygenase
inhibitory non-steroidal anti-inflammatory agents (NSAIA), such as
indomethacin, acetylsalicyclic acid, ibuprofen, sulindac, tolmetin
and piroxicam, are used in the treatment of rheumatoid arthritis.
Also certain anti-inflammatory steroidal agents such as
corticosteroidal agents, for example, beclomethasone dipropionate,
betamethasone valerate, prednisolone or triamcinolone are used in
the treatment of rheumatoid arthritis. Co-administration of a
prolyl 4-hydroxylase inhibitor of the present invention with a
NSAIA or a steroid derivative as defined hereinbefore can result in
a reduction of the dose of the latter agents which is needed to
produce a therapeutic effect. According to a further feature of the
present invention there is provided a pharmaceutical composition
which comprises a phenanthroline derivative of the formula (I) as
defined hereinbefore in the section relating to pharmaceutical
compositions, or a pharmaceutically-acceptable salt thereof, or a
metabolically labile ester derivative of substituents R.sup.1 and
R.sup.2 when either, or both, is a carboxy group, as defined
hereinbefore, in conjunction or admixture with a cyclooxygenase
inhibitory non-steroidal anti-inflammatory agent or an
anti-inflammatory steroidal agent, and a
pharmaceutically-acceptable diluent or carrier.
242. In addition certain agents are beneficial in the treatment of
liver fibrosis, for example, certain alkaloids such as colchicine
and .beta.-adrenergic receptor blocking agents such as propranolol,
atenolol, labetolol and metoprolol may be beneficial.
Co-administration of a 4-prolyl hydroxylase inhibitor of the
present invention with colchicine or a .beta.-adrenergic receptor
blocking agent can result in an improved therapeutic effect.
According to a further feature of the present invention there is
provided a pharmaceutical composition which comprises a
phenanthroline derivative of the formula (I) as defined
hereinbefore in the section relating to pharmaceutical
compositions, or a pharmaceutically-acceptable salt thereof, or a
metabolically labile ester derivative of substituents R.sup.1 and
R.sup.2 when either, or both, is a carboxy group, as defined
hereinbefore, in conjunction or admixture with colchicine or a
.beta.-adrenergic receptor blocking agent, and a
pharmaceutically-acceptable diluent or carrier.
243. The phenanthroline derivative will normally be administered to
a warm-blooded animal at a unit dose within the range 5-5000 mg per
square meter body area of the animal, i.e. approximately 1-100
mg/kg, and this normally provides a therapeutically-effective dose.
Where orally administered, the dose will preferably be 100-3500
mg/dose and more preferably 250-1250 mg/dose, administered 2-3
times daily. The daily dose will preferably be 3-150 mg/kg/day and
more preferably 7-55 mg/kg/day. A unit dose form such as a tablet
or capsule will usually contain, for example, 1-1000 mg of active
ingredient whereas a capsule will usually contain 1-500 mg of
active ingredient. However, the daily dose will necessarily be
varied depending upon the host treated, the particular route of
administration, and the severity of the illness being treated.
Accordingly the optimum dosage may be determined by the
practitioner who is treating any particular patient.
244. According to a further feature of the invention there is
provided a phenanthroline derivative of the formula (I) as defined
hereinbefore in the section relating to pharmaceutical
compositions, or a pharmaceutically-acceptable salt thereof, or a
metabolically labile ester derivative of substituents R.sup.1 and
R.sup.2 when either, or both, is a carboxy group, for use in a
method of therapeutic treatment of the human or animal body.
245. According to a further preferred feature of the invention
there is provided the phenanthroline derivative selected from
246. 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
247. 3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
248. 3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthrolline;
249.
3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthrolin-
e (Compound 13);
250.
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline
(Compound 14);
251. 3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline
(Compound 15); and
252.
3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline, or
a pharmaceutically-acceptable salt thereof, or a metabolically
labile ester derivative of the 3-carboxy substituent when present,
for use in a method of therapeutic treatment of the human or animal
body.
253. According to a further preferred feature of the invention
there is provided the phenanthroline derivative
3-carboxy-4-oxo-3,4-dihydro-1,10-p- henanthroline, or a
pharmaceutically-acceptable salt thereof, or a metabolically labile
ester derivative of the 3-carboxy substituent, for use in a method
of therapeutic treatment of the human or animal body.
254. According to a further feature of the present invention there
is provided a method for producing an anti-fibroproliferative
effect in a warm-blooded animal, such as man, in need of such
treatment which comprises administering to said animal an effective
amount of a phenanthroline derivative of the formula (I) as defined
hereinbefore in the section relating to pharmaceutical
compositions, or a pharmaceutically-acceptable salt thereof, or a
metabolically labile ester derivative of substituents R.sup.1 and
R.sup.2 when either, or both, is a carboxy group.
255. According to a further preferred feature of the invention
there is provided a method for producing an anti-fibroproliferative
effect in a warm-blooded animal, such as man, in need of such
treatment which comprises administering to said animal an effective
amount of the phenanthroline derivative selected from
256. 3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
257. 3-carboxy-5-methoxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
258. 3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
259.
3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline;
260. 3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;
261.
3-carboxy-8-(N-methyl-N-{2,4-difluorobenzyl}carbamoyl)-4-oxo-3,4-dihy-
dro-1,10-phenanthroline;
262. 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
263.
3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1-
,10-phenanthroline;
264. 5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
265.
3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenant-
hroline;
266.
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanth-
roline;
267. 3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
268.
3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanth-
roline;
269. 3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;
270.
3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phen-
anthroline;
271.
3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthrolin-
e;
272.
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline;
and
273.
3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline; or
a pharmaceutically-acceptable salt thereof, or a metabolically
labile ester derivative of the 3-carboxy substituent when
present.
274. According to a further preferred feature of the invention
there is provided a method for producing an anti-fibroproliferative
effect in a warm-blooded animal, such as man, in need of such
treatment which comprises administering to said animal an effective
amount of the phenanthroline derivative
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline or a
pharmaceutically-acceptable salt thereof, or metabolically labile
ester derivative of the 3-carboxy substituent.
275. The invention also provides the use of a phenanthroline
derivative of the formula (I) as defined hereinbefore in the
section relating to pharmaceutical compositions, or a
pharmaceutically-acceptable salt thereof, or a metabolically labile
ester derivative of substituents R.sup.1 and R.sup.2 when either,
or both, is a carboxy group, in the manufacture of a novel
medicament for use in the production of an anti-fibroproliferative
effect in a warm blooded animal, such as man.
276. According to a further preferred feature of the invention
there is provided a method for regenerating cells by producing an
anti-fibroproliferative effect in a host, such a man, in need of
such treatment which comprises administering to said host an
effective amount of one or more phenanthroline derivatives of the
formula (I) as defined hereinbefore in the section relating to
pharmaceutical compositions. Preferably a phenanthroline derivative
and a pharmaceutically-acceptable salt thereof, or a metabolically
labile ester derivative of substituents R.sup.1 and R.sup.2 when
either, or both, is a carboxy group, is selected from:
277. 3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline (Compound
1);
278.
3-carboxy-8-(N-methyl-N-{2,4-difluorobenzyl}carbamoyl)-4-oxo-3,4-dihy-
dro-1,10-phenanthroline (Compound 3);
279. 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline (Compound
12);
280.
3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1-
,10-phenanthroline (Compound 5);
281. 5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline
(Compound 2);
282.
3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenant-
hroline (Compound 4);
283.
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanth-
roline (Compound 6);
284. 3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline
(Compound 7);
285.
3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanth-
roline (Compound 8);
286. 3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline
(Compound 9);
287.
3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phen-
anthroline (Compound 10);
288.
3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline
(Compound 11);
289.
3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthrolin-
e (Compound 13);
290.
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline
(Compound 14); and
291. 3-carboxyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline
(Compound 15).
292. Preferrably, the phenanthroline derivative is
3-carboxy-4-oxo-3,4-dih- ydro-1,10-phenanthroline and compositions
thereof.
293. According to a further preferred feature of the invention
there is provided the use of a phenanthroline derivative of formula
(I) as defined hereinbefore in the section relating to
pharmaceutical compositions, preferably selected from:
294. 3-cyano-4-oxo-3,4-dihydro-1,10-phenanthroline;
295.
3-carboxy-8-(N-methyl-N-{2,4-difluorobenzyl}carbamoyl)-4-oxo-3,4-dihy-
dro-1,10-phenanthroline;
296. 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
297.
3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-methyl-4-oxo-3,4-dihydro-1-
,10-phenanthroline;
298. 5-chloro-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
299.
3-cyano-8-(N-benzyl-N-methylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenant-
hroline;
300.
3-nitro-8-(N-ethyl-N-propylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phenanth-
roline;
301. 3-carboxy-8-hydroxy-4-oxo-3,4-dihydro-1,10-phenanthroline;
302.
3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanth-
roline;
303. 3-carboxy-6-chloro-4-oxo-3,4-dihydro-1,10-phenanthroline;
304.
3-nitro-8-(4-benzylpiperazine-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phen-
anthroline;
305.
3-trifluoromethylsulfonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
306. 3-carboxy-5-methyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
307.
3-(2-{morpholino}ethoxycarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthrolin-
e;
308.
3-ethoxycarbonyl-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline;
309. 3-carboxy-4-oxo-5-methoxy-3,4-dihydro-1,10-phenanthroline;
310. 3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline;
and
311.
3-ethoxycarbonyl-6-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline, or
a pharmaceutically-acceptable salt thereof, or a metabolically
labile ester derivative of the 3-carboxy substituent when present,
in the manufacture of a novel medicament for use in the production
of an anti-fibroproliferative effect (for example for treating the
formation of scar tissue following injury or surgery) in a warm
blooded animal, such as man.
312. According to a further preferred feature of the invention
there is provided the use of the phenanthroline derivative
3-carboxy-4-oxo-3,4-dih- ydro-1,10-phenanthroline, or a
pharmaceutically-acceptable salt thereof, or a metabolically labile
ester derivative of the 3-carboxy substituent, in the manufacture
of a novel medicament for use in the production of an
anti-fibroproliferative (for example for treating the formation of
scar tissue following injury or surgery) effect in a warm blooded
animal, such as man.
313. The invention is illustrated but not limited by the following
Examples in which unless otherwise stated.
EXAMPLES
314. (i) evaporations were carried out by rotary evaporation in
vacuo and work-up procedures were carried out after removal of
residual solids by filtration;
315. (ii) operations were carried out at ambient temperature, that
is in the range 18-20.degree. C. and under an atmosphere of an
inert gas such as argon;
316. (iii) column chromatography (by the flash procedure) and
medium pressure liquid chromatography (MPLC) were performed on
Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18
reversed-phase silica (Art. 9303) obtained from E. Merck,
Darmstadt, Germany;
317. (iv) yields are given for illustration only and are not
necessarily the maximum attainable;
318. (v) the end-products of the formula (I) generally have
satisfactory microanalysis and their structures were confirmed by
NMR and mass spectral techniques [proton magnetic resonance spectra
were determined using a Jeol FX 90Q or a Bruker AM200 spectrometer
operating at a field strength of 200 MHz; chemical shifts are
reported in parts per million downfield from tetramethysilane as an
internal standard (.delta. scale) and peak multiplicities are shown
thus: s, singlet, d, doublet; dd, doublet of doublets; t, triplet,
m, multiplet; fast-atom bombardment (FAB) mass spectral data were
obtained using a VG Analytical MS9 spectrometer and xenon gas and,
where appropriate, either positive ion data or negative ion data
were collected];
319. (vi) intermediates were not generally fully characterised and
purity was assessed by thin layer chromatographic, infra-red (IR)
or NMR analysis;
320. (vii) melting points were determined using a Mettler SP62
automatic melting point apparatus, a Koffler hot plate apparatus or
an oil-bath apparatus; and
321. (viii) the following abbreviations have been used:
322. THF tetrahydrofuran;
323. DMF N,N-dimethylformamide;
324. DMSO dimethylsulfoxide; and
325. TFA trifluoroacetic acid.
Example I
326.
3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanth-
roline (Compound 8)
327. 1,1'-Carbonyldiimidazole (30.4 g ) was added to a stirred
mixture of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline (18 g)
and DMF (400 ml). The mixture was stirred at 100.degree. C. for 2.5
hours, and then cooled to ambient temperature. The resulting solid
was filtered to give
3-(imidazol-1-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline in
92% yield.
328. Sodium hydride (3.15 g, 60%) was added in portions to a
mixture of 2-(2-methoxyethoxy)ethanol (15 ml) and DMF (200 ml). The
mixture was stirred for approximately 30 minutes until
effervescence ceased.
3-(imidazol-l-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline
(21.05 g) was added and the mixture stirred for 18 hours. The
mixture was acidified to pH 5-6 with acetic acid, and evaporated to
dryness under reduced pressure. Water (50 ml) was added and the
mixture extracted with dichloromethane. The organic layer was
washed with brine, dried (MgSO.sub.4) and evaporated to dryness
under reduced pressure. The residue was purified by flash
chromatography on silica using dichloromethane, followed by a
24:1:0.1 mixture of dichloromethane methanol:triethylamine as
eluant. The product so obtained was triturated with ethyl acetate
to give 3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,-
4-dihydro-1,10-phenanthroline in 68% overall yield, mp
164-165.degree. C.
329. NMR Spectrum (D6-DMSO+D4-HOAc): 3.22(s,3H); 3.45(m,2H);
3.58(m,2H); 3.7(t,3H); 4.3 (t,2H); 7.75(dd,2H); 7.8(d,2H);
8.2(d,2H); 8.48(dd,2H); 8.55(s,1H); 9.05(dd,1H).
330. The 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline (Compound
12) used as starting material was obtained as follows:
331. A mixture of 8-aminoquinoline (14.4 g) and diethyl
ethoxymethylenemalonate (26 g) in ethanol (100 ml) was heated at
reflux for 18 hours. The mixture was cooled, filtered and the solid
washed with ethanol. The solid so obtained was added to refluxing
diphenyl ether (1000 ml), and the resulting mixture stirred at
reflux for 45 minutes. The mixture was cooled to approximately
60.degree. C. and diluted with hexane (500 ml). The mixture was
cooled to ambient temperature, filtered and the solid washed with
hexane to give 3-ethoxycarbonyl-4-oxo-3,4-dihyd-
ro-1,10-phenanthroline in 84% yield, mp 242-244.degree. C.
332. A mixture of
3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline (20 g) and
5M hydrochloric acid (100 ml) was stirred at reflux for 2 hours.
The mixture was cooled and filtered. The solid so obtained was
recrystallised from DMF to give the required starting material in
95% yield.
333. NMR Spectrum (D6-DMSO): 7.88(m,1H); 8.0(d,1H); 8.25(d,1H);
8.6(m,1H) 8.72 (m, 1H); 9.12 (m, 1H).
Example II
334. A mixture of
8-(N-butyl-N-ethylcarbamoyl)-3-ethoxycarbonyl-4-oxo-3,4--
dihydro-1,10-phenanthroline (12 g) and 2M hydrochloric acid (300
ml) was stirred at reflux for 2 hours. The mixture was cooled to
ambient temperature, filtered and the solid washed with water. The
solid so obtained was recrystallised from acetonitrile to give
8-(N-butyl-N-ethylcarbamoyl)-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthrol-
ine in 76% yield, mp 236-237.degree. C.
335. NMR Spectrum (D6-DMSO-at 100.degree. C.): 0.86(t,3H);
1.18(t,3H); 1.30(q,2H) 1.63(m,2H); 8.08(d,1H); 8.35(d,1H);
8.60(d,1H); 8.82(s,1H); 9.08 (d, 1H).
336. The
8-(N-butyl-N-ethylcarbamoyl)-3-ethoxycarbonyl-4-oxo-3,4-dihydro-1-
,10-phenanthroline used as starting material was obtained as
follows:
337. A mixture of 2-nitroaniline (41.4 g) and diethyl
ethoxymethylenemalonate (66 ml) was heated on a steam bath for 24
hours. The hot reaction mixture was treated with ethanol (300 ml),
cooled and filtered to give diethyl
(2-nitroanilino)methylenemalonate in 88% yield, mp 104-105.degree.
C.
338. Diethyl (2-nitroanilino)methylenemalonate (43 g) was added to
refluxing diphenyl ether (600 ml). The mixture was stirred at
reflux for 1.5 hours, then cooled to ambient temperature. Diethyl
ether (600 ml) was added and the mixture filtered. The solid so
obtained was washed with diethyl ether to give
3-ethoxycarbonyl-8-nitro-4-oxo-3,4-dihydroquinoline in 85% yield,
mp 241-243.degree. C.
339. A mixture of
3-ethoxycarbonyl-8-nitro-4-oxo-3,4-dihydro-quinoline (12 g) and 2M
sodium hydroxide solution (100 ml) was stirred at reflux for 1
hour. The mixture was cooled to ambient temperature and acidified
to pH 5 with glacial acetic acid. The mixture was filtered and the
solid so obtained washed with water to give
3-carboxy-8-nitro-4-oxo-3,4-dihydroqui- noline in 93% yield, mp
263-265.degree. C.
340. DMF (0.2 ml) was added to a mixture of
3-carboxy-8-nitro-4-oxo-3,4-di- hydroquinoline (30 g) and thionyl
chloride (150 ml) and the mixture stirred at reflux for
approximately 2 hours until a clear solution was obtained. The
solution was evaporated to dryness under reduced pressure, the
residue dissolved in toluene and the solution again evaporated to
dryness under reduced pressure. N-ethylbutylamine (19.1 ml, 14.14
g) followed by triethylamine (30 ml) were added dropwise to a
stirred, ice-cold solution of the residue so obtained in
acetonitrile. The mixture was stirred at ambient temperature for 1
hour and then evaporated to dryness under reduced pressure. The
residue was partitioned between water and ethyl acetate. The
orgainc layer was dried (MgSO.sub.4) and evaporated to dryness
under reduced pressure. The residue was purified by flash
chromatography on silica using a 1:19 mixture of ethyl
acetate:chloroform as eluant. There was thus obtained
3-(N-butyl-N-ethylcarbamoyl)-4-chloro-8-nitro-quinoline in 93%
yield.
341. Ammonium formate (26.5 g) was added in portions to a stirred
mixture of 3-(N-butyl-N-ethylcarbamoyl)-4-chloro-8-nitro-quinoline
(40 g), 10% palladium on carbon (20 g) and ethanol (500 ml) at
reflux. The mixture was stirred at relux for 1 hour, the hot
mixture was filtered through a pad of celite and the filtrates
evaporated to dryness. The residue was partitioned between water
and chloroform and the organic layer dried, and evaporated to
dryness under reduced pressure. There was thus obtained
3-{-butyl-N-ethylcarbamoyl)-8-amino-quinoline in 99% yield.
342. A mixture of 3-(N-butyl-N-ethylcarbamoyl)-8-amino-quinoline
(25 g) and diethyl ethoxymethylenemalonate (23.8 g) in ethanol was
heated at reflux for 18 hours. The mixture was evaporated to
dryness under reduced pressure and the residue purified by flash
chromatography on silica using chloroform, followed by 1:19 mixture
of methanol:chloroform as eluant. The solvent was evaporated and
the residue obtained on standing was added to refluxing diphenyl
ether (500 ml) . The mixture was stirred at reflux for 1.5 hours,
then cooled to ambient temperature and added to a stirred 1:1
mixture of hexane:ether (500 ml) . The mixture was stirred for 18
hours, filtered and the solid so obtained washed with diethyl ether
to give the required starting material in 55% yield, mp
128-129.degree. C.
Example III
343. A solution of concentrated nitric acid (1 ml) in acetic
anhydride (10 ml) was added dropwise to a stirred mixture of
4-oxo-3,4-dihydro-1,10-phe- nanthroline (0.98 g) in acetic
anhydride (10 ml) The mixture was stirred at ambient temperature
for 3 hours, diluted with ethyl acetate (50 ml) and filtered. The
solid so obtained was recrystallised from a mixture of DMF and
ethyl acetate to give 3,6-dinitro-4-oxo-3,4-dihydro-1,10-phenanth-
roline in 50% yield.
344. NMR Spectrum (D6-DMSO): 8.08(dd,1H); 8.92(s,1H); 8.95(s,1H);
9.06(dd, 1H); 9.23 (dd, 1H).
Example IV
345. A mixture of
8-ethoxycarbonyl-3-nitro-4-oxo-3,4-dihydro-1,10-phenanth- roline
(0.55 g) and 2M sodium hydroxide solution (5 ml) was stirred at
reflux for 2 hours. The hot suspension was neutralised with glacial
acetic acid, cooled and diluted with water. The mixture was
filtered and washed with water to give
8-carboxy-3-nitro-4-oxo-3,4-dihydro-1,10-phenan- throline in 98%
yield.
346. NMR Spectrum (D6-DMSO): 8.1(d,1H); 8.35(d,1H); 8.98(s,1H);
9.06(d,1H); 9.5(d,1H).
347. The
8-ethoxycarbonyl-3-nitro-4-oxo-3,4-dihydro-1,10-phenanthroline used
as starting material was obtained as follows:
348. A mixture of
3-ethoxycarbonyl-8-nitro-4-oxo-3,4-dihydro-quinoline (10.2 g) and
phosphorous oxychloride (10 ml) was stirred at reflux for 2 hours.
The warm reaction mixture was added cautiously to a vigorously
stirred mixture of ice, concentrated aqueous ammonia and
chloroform. The organic layer was separated, washed with water,
dried and evaporated to dryness. The residue was purified by flash
chromatography on silica using chloroform as eluant to give
4-chloro-3-ethoxycarbonyl-8-nitro-quinoline in 75% yield, mp
253-254.degree. C.
349. Ammonium formate was added to a vigorously stirred mixture of
4-chloro-3-ethoxycarbonyl-8-nitro-quinoline (5.6 g), ethanol (1000
ml) and 10% palladium on carbon catalyst (2 g). The mixture was
stirred at ambient temperature for 1 hour, filtered through a pad
of celite and the pad washed with dichloromethane. The combined
filtrate and washings were evaporated to dryness. The residue so
obtained was purified by flash chromatography on silica using
chloroform as eluant to give 3-ethoxycarbonyl-8-amino-quinoline in
58% yield, mp 94-96.degree. C.
350. A mixture of 3-ethoxycarbonyl-8-amino-quinoline (9.9 g), 2,
2-dimethyl-5-methoxymethylene-1,3-dioxan-4,6-dione (Monatsh. Chem.,
98:564-78 (1967))(10.3 g) and ethanol (80 ml) was stirred at reflux
for 2 hours. The mixture was cooled and filtered. The solid so
obtained was washed with ethanol to give
8-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yliden-
eamino)-3-ethoxycarbonylquinoline in 80% yield, mp 228-231.degree.
C.
351. The solid was added in portions over 5 minutes to stirred
diphenyl ether at 260.degree. C. and stirring was continued for 30
minutes. The mixture was cooled to ambient temperature and diluted
with hexane (200 ml). The mixture was filtered to give
8-ethoxycarbonyl-4-oxo-3,4-dihydro-- 1,10-phenanthroline as a solid
in 73% yield, mp 250-252.degree. C.
352. A mixture of
8-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline (0.8 g),
ammonium nitrate (0.26 g) and trifluoroacetic acid (10 ml) was
stirred at reflux for 6 hours. Further portions (0.26 g) of
ammonium nitrate were added after 2 hours and 4 hours at reflux.
The mixture was cooled to ambient temperature and stirred whilst
water (50 ml) was added. The mixture was filtered and the solid so
obtained was stirred with a 1:1 mixture of ethanol:chloroform. The
mixture was filtered to give the required starting material as a
solid in 60% yield.
Example V
353. A mixture of
8-carboxy-3-nitro-4-oxo-3,4-dihydro-1,10-phenanthroline (228 mg),
thionyl chloride (5 ml) and DMF (0.1 ml) was stirred at reflux for
3 hours. The mixture was cooled to ambient temperature and
evaporated to dryness. The residue was dissolved in dichloromethane
(10 ml) and the solution stirred whilst a solution of
N-benzylpiperazine (158 mg) and triethylamine (1 ml) in
dichloromethane was added over 5 minutes. The mixture was stirred
for 1 hour, washed with water, dried and evaporated to dryness. A
solution of the residue in DMSO (3 ml) and water (0.5 ml) was
heated at 90.degree. C. for 18 hours. After cooling to ambient
temperature, the solution was treated with water (20 ml) and ethyl
acetate (5 ml) and the mixture filtered. The residue was
recrystallised from a mixture of methanol and chloroform to give
8-(4-benzylpiperazin-1--
ylcarbonyl)-3-nitro-4-oxo-3,4-dihydro-1,10-phenanthroline as a
solid in 42% yield, mp 213-216.degree. C.
354. NMR Spectrum (D6-DMSO): 2.54(m,4H); 3.55-3.7(m,6H);
7.2-7.4(m,5H) 8.0(d,1H); 8.35(d,1H); 8.58(d,1H); 8.97(s,1H);
9.08(d,1H).
Example VI
355.
8-[2-Methoxycarbonyl-2-(2,2,2-trifluoroethylsulfonyl)-ethenylamino]qu-
inoline (4 g) was added to diphenyl ether (100 ml) with stirring at
260.degree. C., and stirring was continued for 2 hours. The mixture
was allowed to cool to ambient temperature and hexane (100 ml) was
added. The mixture was filtered, and the residue purified by flash
chromatography on silica using increasingly polar mixtures of
methanol and chloroform as eluant. The product so obtained was
recrystallised from acetic acid to give
3-(2,2,2-trifluoroethyl-sulfonyl)-4-oxo-3,4-dihydro-1,10-phenanthrol-
ine, mp 272-274.degree. C.
356. NMR Spectrum (D6-DMSO): 4.87(q,2H); 8.0(dd,1H); 8.03(d,1H);
8.25(d, 1H); 8.52(d, 1H); 8.64(m, 1H); 9.15(dd, 1H).
357. The
8-[2-methoxycarbonyl-2-(2,2,2-trifluoroethylsulfonyl)ethenylamino-
]quinoline used as starting material was obtained as follows:
358. 3-Chloroperbenzoic acid (22.2 g, 60%) was added in portions to
a stirred solution of methyl-2-(2,2,2-trifluoroethylthio)acetate
(J. Med. Pharm. Chem., 5:491 (1962))(6 g) in dichloromethane (120
ml). The mixture was stirred at ambient temperature for 24 hours
and then filtered. The filtrate was washed successively with
aqueous sodium hydrogen sulphite, aqueous sodium carbonate and
brine, dried and evaporated to dryness. There was thus obtained
methyl 2-(2,2,2-trifluoroethylsulfonyl)acetate in 84% yield as a
solid, mp 59-60.degree. C.
359. A mixture of 8-aminoquinoline (1.87 g), triethyl orthoformate
(2.4 ml) and methyl 2-(2,2,2-trifluoroethylsulfonyl)acetate (2.86
g) was stirred at reflux for 30 minutes. The mixture was cooled to
ambient temperature and diethyl ether (20 ml) added. The mixture
was filtered to give the required starting material in 86% yield,
mp 221-223.degree. C.
Example VII
360. A mixture of
8-[N-(4-fluorobenzyl)-N-methylcarbamoyl]-4-oxo-3,4-dihyd-
ro-1,10-phenanthroline (0.3 g), glacial acetic acid (5 ml) and
concentrated nitric acid (0.15 ml) was heated at 90.degree. C. for
18 hours. The mixture was cooled to ambient temperature and water
(20 ml) and ethyl acetate (10 ml) were added. The mixture was
filtered, and the solid so obtained recrystallised from a mixture
of DMF and ethyl acetate. There was thus obtained
8-[N-(4-fluorobenzyl)-N-methylcarbamoyl]-3-nitro--
4-oxo-3,4-dihydro-1,10-phenanthroline in 27% yield, mp
294-296.degree. C.
361. NMR Spectrum (D6-DMSO): 3.12(s,3H); 4.7(s,2H); 7.15(m,2H);
7.4(m,2H) 7.98 (d, 1H); 8.36 (d, 1H); 8.62 (d, 1H); 8.98 (s, 1H);
9.12 (d, 1H).
362. The
8-[N-(4-fluorobenzyl)-N-methylcarbamoyl]-4-oxo-3,4-dihydro-1,10-p-
henanthroline used as starting material was obtained as
follows:
363. Using a procedure analogous to that described in Example 2, in
the section relating to the prepartion of starting materials,
3-carboxy-8-nitro-4-oxo-3,4-dihydroquinoline was reacted with
N-(4-fluorobenzyl)-N-methylamine to give
3-[N-(4-fluorobenzyl)-N-methylca-
rbamoyl]-4-chloro-8-nitroquinoline in 89% yield, mp 135-137.degree.
C.
364. Using a procedure analogous to that described in Example 2, in
the section relating to the prepartion of starting materials,
3-[N-(4-fluorobenzyl)-N-methylcarbamoyl]-4-chloro-8-nitroquinoline
was hydrogenated to give
3-[N-(4-fluorobenzyl)-N-methylcarbamoyl]-8-aminoquin- oline in 99%
yield.
365. Using a procedure analogous to that described in Example 2, in
the section relating to the preparation of starting materials,
3-[N-(4-fluorobenzyl)-N-methylcarbamoyl]-8-aminoquinoline was
reacted with diethyl ethoxymethylenemalonate to give
3-ethoxycarbonyl-8-[N-(4-flu-
orobenzyl)-N-methylcarbamoyl]-4-oxo-3,4-dihydro-1,10-phenanthroline
in 64% yield, mp 206-207.degree. C.
366. Using a procedure analogous to that described in Example 2, in
the section relating to the prepartion of starting materials,
3-ethoxycarbonyl-8- [N-
(4-fluorobenzyl)-N-methylcarbamoyl]-4-oxo-3,4-dih-
ydro-1,10-phenanthroline was hydrolysed. The product so obtained
was recrystallised from acetic acid to give
3-carboxy-8-[N-(4-fluoro-benzyl)--
N-methylcarbamoyl]-4-oxo-3,4-dihydro-1,10-phenanthroline, mp
245-246.degree. C.
367. A solution of
3-carboxy-8-[N-(4-fluorobenzyl)-N-methylcarbamoyl]-4-ox-
o-3,4-dihydro-l,10-phenanthroline (0.5 g) in diphenyl ether (3 ml)
was stirred at reflux for 6 hours. The mixture was cooled and
filtered. The solid so obtained was washed with hexane and purified
by flash chromatography on silica using increasingly polar mixtures
of methanol and ethyl acetate as eluant. There was thus obtained
the required starting material.
Example VIII
368. Using a procedure analogous to that described in Example
2,3-ethoxycarbonyl-8-N,N-diethylthiocarbamoyl-4-oxo-3,4-dihydro-1,10-phen-
anthroline was hydrolysed. The product so obtained was
recrystallised from a mixture of methanol and chloroform to give
3-carboxy-8-N,N-diethylthioc-
arbamoyl-4-oxo-3,4-dihydro-1,10-phenanthroline.
369. NMR Spectrum (D6-DMSO at 100.degree. C.): [mixture of
rotamers] 1.1-1.5(m,6H); 3.4-4.3(m,4H); 8.04(d,1H); 8.35(d,1H);
8.42(d,1H); 8.82(s,1H); 9.0(d,1H).
370. The
3-ethoxycarbonyl-8-N,N-diethylthiocarbamoyl-4-oxo-3,4-dihydro-1,1-
0-phenanthroline used as starting material was obtained as
follows:
371. Using a procedure analogous to that described in Example 2, in
the section relating to the preparation of starting materials,
3-carboxy-8-nitro-4-oxo-3,4-dihydroquinoline was reacted in turn
with thionyl chloride and diethylamine, and was hydrogenated to
give 8-amino-3-N,N-diethylcarbamoylquinoline in 71% yield.
372. A mixture of 8-amino-3-N,N-diethylcarbamoylquinoline (1.22 g),
toluene (10 ml) and Lawesson's Reagent (1.22 g) was stirred at
reflux for 2 hours. The mixture was evaporated to dryness and the
residue purified by flash chromatography on silica using
increasingly polar mixtures of methanol and chloroform. There was
thus obtained 8-amino-3-N,N-diethylthi- ocarbamoylquinoline in 100%
yield.
373. Using a procedure analogous to that described in Example 2, in
the section relating to the preparation of starting materials,
8-amino-3-N,N-diethylthiocarbamoylquinoline was reacted with
diethyl ethoxymethylenemalonate, and then refluxed with diphenyl
ether to give the required starting material in 47% yield.
Example IX
374. Trifluoroacetic anhydride (0.5 ml) was added dropwise to a
stirred, ice-cooled mixture of
8-(N-benzyl-N-methylcarbamoyl)-3-carbamoyl-4-chloro-
-5-fluoro-1,10-phenanthroline (0.3 g) in pyridine (3 ml). The
mixture was stirred at ambient temperature for 1 hour. The mixture
was acidified with 3M hydrochloric acid and stirred at ambient
temperature for 18 hours. The mixture was filtered and the solid so
obtained recrystallised from a mixture of methanol and ethyl
acetate to give 8-(N-benzyl-N-methylcarbamo-
yl)-3-cyano-5-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline in 24%
yield, mp 267-269.degree. C.
375. NMR Spectrum (D6-DMSO at 100.degree. C.): 3.05(s,3H);
4.7(s,2H); 7.3-7.5(m,5H) 7.65(d,1H); 8.5(s,1H); 8.55(d,1H);
9.05(d,1H).
376. The
8-(N-benzyl-N-methylcarbamoyl)-3-carbamoyl-4-chloro-5-fluoro-1,10-
-phenanthroline used as starting material was obtained as
follows:
377. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
4-fluoro-2-nitroaniline and diethyl ethoxymethylenemalonate were
reacted, and then refluxed in diphenyl ether to give
3-ethoxycarbonyl-6-fluoro-8-n- itro-4-oxo-3,4-dihydroquinoline in
45% yield, mp 278-280.degree. C.
378. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
3-ethoxycarbonyl-6-fluoro-8-nitro-4-oxo-3,4-dihydroquinoline was
hydrolysed to give
3-carboxy-6-fluoro-8-nitro-4-oxo-3,4-dihydroquinoline in 84% yield,
mp 254-256.degree. C.
379. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
3-carboxy-6-fluoro-8-nitro-4-oxo-3,4-dihydroquinoline was reacted
with thionyl chloride and then N-benzylmethylamine to give
3-[N-benzyl-N-methylcarbamoyl]-4-chloro-6-fluoro-8-nitroquinoline
in 63% yield.
380. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
3-[N-benzyl-N-methylcarbamoyl]-4-chloro-6-fluoro-8-nitroquinoline
was hydrogenated to give
8-amino-3[N-benzyl-N-methylcarbamoyl]-6-fluoro-quino- line in 63%
yield.
381. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
8-amino-3-[N-benzyl-N-methylcarbamoyl]-6-fluoroquinoline was
reacted with diethyl ethoxymethylenemalonate, and then refluxed in
diphenyl ether. The product so obtained was recrystallised from a
mixture of ethyl acetate and hexane to give
3-ethoxycarbonyl-8-(N-benzyl-N-methylcarbamoyl)-5-fluo-
ro-4-oxo-3,4-dihydro-l,10-phenanthroline in 70% yield, mp
201-203.degree. C.
382. Using an analogous procedure to that described in Example
2,3-ethoxycarbonyl-8-(N-benzyl-N-methylcarbamoyl)-5-fluoro-4-oxo-3,4-dihy-
dro-1,10-phenanthroline was hydrolysed. The product so obtained was
recrystallised from acetic acid to give
3-carboxy-8-(N-benzyl-N-methylcar-
bamoyl)-5-fluoro-4-oxo-3,4-dihydro-1,10-phenanthroline in 81%
yield, mp 168-171.degree. C.
383. A mixture of
3-carboxy-8-(N-benzyl-N-methylcarbamoyl)-5-fluoro-4-oxo--
3,4-dihydro-l,10-phenanthroline (0.7 g) and thionyl chloride was
stirred at reflux for 30 minutes, and then evaporated to dryness. A
solution of concentrated ammonia (2 ml) and triethylamine (5 ml) in
acetonitrile (25 ml) were added to the residue, and the mixture
stirred at ambient temperature for one hour. The mixture was
evaporated to dryness, and the residue stirred with water (10 ml)
and ethyl acetate (10 ml). The mixture was filtered and the product
so obtained recrystallised from a mixture of methanol and ethyl
acetate. There was thus obtained the required starting material in
69% yield, mp 180-183.degree. C.
Example X
384. A mixture of 8-amino-4-chloro-3-ethoxycarbonylquinoline (0.3
g) and ethyl 2-ethoxymethyleneacetoacetate (Annalen, 1897, 297, 16,
0.25 g) was heated at 90.degree. C. for 2.5 hours. The mixture was
cooled to ambient temperature and the resulting solid added to
diphenyl ether at reflux. The mixture was refluxed for 45 minutes,
and cooled to 60.degree. C. The mixture was diluted with carbon
tetrachloride (50 ml) and cooled to ambient temperature with
stirring. The mixture was filtered and the solid so obtained
purified by flash chromatography on silica using increasingly polar
mixtures of methanol and chloroform. The product so obtained was
recrystallised from methanol to give
3-acetyl-7-chloro-8-ethoxycarbonyl-4-
-oxo-3,4-dihydro-1,10-phenanthroline in 29% yield, mp
288-290.degree. C.
385. NMR Spectrum (D6-DMSO): 1.4(t,3H ); 2.66(s,3H); 4.5(q,2H );
8.2(d,1H); 8.45(d,1H);
386. 8.5(d,1H); 9.27(s,1H).
387. The 8-amino-4-chloro-3-ethoxycarbonylquinoline used as
starting material was obtained as follows:
388. A mixture of 4-chloro-3-ethoxycarbonyl-8-nitroquinoline (1.4
g), ethanol (10 ml), triethylamine (0.7 ml) and 10% palladium on
carbon catalyst (0.2 g) was stirred under an atmosphere of hydrogen
for 2.5 hours. The mixture was filtered and the filtrate was
evaporated to dryness. The residue was purified by MPLC on silica
using chloroform as eluant to give the required starting material
in 24% yield, mp 110-1 12.degree. C.
Example XI
389. Using an analogous procedure to that described in Example 2,
3-ethoxycarbonyl-5-fluoro-8-(N-2,2,3,3,4,4,4-heptafluorobutyl-carbamoyl)--
4-oxo-3,4-dihydro-1,10-phenanthroline was hydrolysed to give
3-carboxy-5-fluoro-8-(N-2,2,3,3,4,4,4-heptafluorobutylcarbamoyl)-4-oxo-3,-
4-dihydro-1,10-phenanthroline in 46% yield.
390. NMR Spectrum (D6-DMSO): 4.2-4.45(2H,m); 7.9(1H,d); 8.76(1H,s)
9.0(1H,d); 9.42(1H,d);
391. 9.65(1H,t).
392. The
3-ethoxycarbonyl-5-fluoro-8-(N-2,2,3,3,4,4,4-heptafluorobutylcarb-
amoyl)-4-oxo-3,4-dihydro-1,10-phenanthroline used as starting
material was obtained as follows:
393. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
3-carboxy-6-fluoro-8-nitro-4-oxo-3,4-dihydroquinoline was reacted
with thionyl chloride and then 2,2,3,3,4,4,4-heptafluorobutylamine
to give
3-[N-2,2,3,3,4,4,4-heptafluorobutylcarbamoyl]-4-chloro-6-fluoro-8-nitroqu-
inoline in 33% yield, mp 159-160.degree. C.
394. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
3-[N-2,2,3,3,4,4,4-heptafluorobutylcarbamoyl]-4-chloro-6-fluoro-8-nitroqu-
inoline was hydrogenated to give
8-amino-6-fluoro-3-[N-2,2,3,3,4,4,4-hepta-
fluorobutylcarbamoyl]quinoline in 73% yield, mp 202-204.degree.
C.
395. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
8-amino-6-fluoro-3-[N-2,2,3,3,4,4,4-heptafluorobutylcarbamoyl]quinoline
was reacted with diethyl ethoxymethylenemalonate, and then refluxed
in diphenyl ether. There was thus obtained the required starting
material in 87% yield, mp 288-290.degree. C.
Example XII
396. Using an analogous procedure to that described in Example 2,
3-ethoxycarbonyl-8-(N-4-ethoxyphenylcarbamoyl)-4-oxo-3,4-dihydro-1,10-phe-
nanthroline was hydrolysed. The product so obtained was
recrystallised from DMF to give
3-carboxy-8-(N-4-ethoxyphenylcarbamoyl)-4-oxo-3,4-dihydr-
o-1,10-phenanthroline in 41% yield.
397. NMR Spectrum (D6-DMSO+TFA): 1.27(3H,t); 4.0(2H,m); 6.85(2H,m);
7.65(2H,m); 7.98(1H,d); 8.28(1H,d); 8.75(1H,s); 9.0(1H,d);
9.45(1H,d).
398. The
3-ethoxycarbonyl-8-(N-4-ethoxyphenylcarbamoyl)-4-oxo-3,4-dihydro--
1,10-phenanthroline used as starting material was obtained as
follows:
399. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
3-carboxy-8-nitro-4-oxo-3,4-dihydroquinoline was reacted with
thionyl chloride and then 4-ethoxyaniline to give
3-[N-4-ethoxyphenylcarbamoyl]-4- -chloro-8-nitroquinoline in 43%
yield, mp 232-233.degree. C.
400. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
3-[N-4-ethoxyphenylcarbamoyl]-4-chloro-8-nitroquinoline was
hydrogenated to give 8-amino-3-[N-4-ethoxyphenylcarbamoyl]quinoline
in 74% yield, mp 187-189.degree. C.
401. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
8-amino-3-[N-4-ethoxyphenylcarbamoyl]quinoline was reacted with
diethyl ethoxymethylenemalonate, and then refluxed in diphenyl
ether. There was thus obtained the required starting material in
70% yield.
Example XIII
402. Using an analogous procedure to that described in Example 2,
3-ethoxycarbonyl-8-carbamoyl-4-oxo-3,4-dihydro-1,10-phenanthroline
was hydrolysed. The product so obtained was recrystallised from DMF
to give 3-carboxy-8-carbamoyl-4-oxo-3,4-dihydro-1,10-phenanthroline
in 96% yield.
403. NMR Spectrum (D6-DMSO): 7.9(broad s,1H); 8.1(d,1H);
8.22(d,1H); 8.5(broad s,1H); 8.75 (S, 1H); 9.05(d,1H);
9.5(d,1H).
404. The
3-ethoxycarbonyl-8-carbamoyl-4-oxo-3,4-dihydro-1,10-phenanthrolin-
e used as starting material was obtained as follows:
405. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
3-carboxy-8-nitro-4-oxo-3,4-dihydroquinoline was reacted with
thionyl chloride and then concentrated aqueous ammonia. The product
so obtained was recrystallised from ethanol to give
3-carbamoyl-4-chloro-8-nitroquino- line in 79% yield, mp
277-279.degree. C.
406. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
3-carbamoyl-4-chloro-8-nitroquinoline was hydrogenated to give
8-amino-3-carbamoylquinoline in 54% yield, mp 164-165.degree.
C.
407. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
8-amino-3-carbamoylquinoline was reacted with diethyl
ethoxymethylenemalonate, and then refluxed in diphenyl ether. There
was thus obtained the required starting material in 64% yield.
Example XIV
408. Using an analogous procedure to that described in Example 2,
3-ethoxycarbonyl-4-oxo-8-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyl)-3,4-
-dihydro-1,10-phenanthroline was hydrolysed. The product so
obtained was recrystallised from a mixture of methanol and
chloroform to give
3-carboxy-4-oxo-8-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyl)-3,4-dihydr-
o-1,10-phenanthroline in 72% yield, mp 171-182.degree. C.
409. NMR Spectrum (D6-DMSO at 100.degree. C.) 2.96(t,2H);
3.82(t,2H); 4.8(s,2H) 7.7(m,4H); 8.1(d,1H); 8.4(d,1H): 8.72(d,1H);
8.85(s,1H); 9.18(d,1H).
410. The
3-ethoxycarbonyl-4-oxo-8-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbo-
nyl)-3,4-dihydro-1,10-phenanthroline used as starting material was
obtained as follows:
411. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
3-carboxy-8-nitro-4-oxo-3,4-dihydroquinoline was reacted with
thionyl chloride and then 1,2,3,4-tetrahydroisoquinoline to give
3-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyl)-4-chloro-8-nitro-quinoline
in 71% yield.
412. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
3-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyl)-4-chloro-8-nitro-quinoline
was hydrogenated to give
8-amino-3-(1,2,3,4-tetrahydroisoquinolin-2-ylcar- bonyl)quinoline
in 100% yield.
413. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
8-amino-3-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyl)quinoline was
reacted with diethyl ethoxymethylenemalonate, and then refluxed in
diphenyl ether. There was thus obtained the required starting
material in 50% yield, mp 238-240.degree. C.
Example XV
414. A mixture of
8-amino-3-(N-benzyl-N-methylcarbamoyl)-4-dimethylaminoqu- inoline
(1.28 g), diethyl ethoxymethylenemalonate (1 g) and ethanol (5 ml)
was heated at reflux for 2 hours. The mixture was evaporated to
dryness and a solution of the residue in diphenyl ether (70 ml) was
stirred at reflux for 1 hour. The mixture was cooled to ambient
temperature and stirred whilst a 1:2 mixture (200 ml) of diethyl
ether:hexane was added. The mixture was filtered and the solid so
obtained recrystallised from ethyl acetate. There was thus obtained
8-(N-benzyl-N-methylcarbamoyl)-7-d-
imethylamino-3-ethoxy-carbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline
in 80% yield, mp 169-170.degree. C.
415. NMR Spectrum (D6-DMSO): 1.3(m,3H); 2.85-3.35(m,9H);
4.25(m,2H); 4.35-5.3(m,2H); 7.2-7.5(m,5H); 8.0(d,1H); 8.15(m,1H);
8.5(m,1H); 8.62(s,1H).
416. The
8-amino-3-(N-benzyl-N-methylcarbamoyl)-4-dimethylamino-quinoline
used as starting material was obtained as follows:
417. Using an analogous procedure to that described in Example 2,
in the section relating to the preparation of starting materials,
3-carboxy-8-nitro-4-oxo-3,4-dihydroquinoline was reacted with
thionyl chloride and then N-benzylmethylamine. The product so
obtained was recrystallised from ethanol to give
3-(N-benzyl-N-methylcarbamoyl)-4-chlo- ro-8-nitroquinoline in 82%
yield, mp 120-121.degree. C.
418. A mixture of
3-(N-benzyl-N-methylcarbamoyl)-4-chloro-8-nitroquinoline (1.42 g),
ethanol (20 ml) and a 33% solution of dimethylamine in ethanol (5
ml) was heated at 90.degree. C. for 6 minutes. The mixture was
evaporated to dryness and the residue was partitioned between water
and ethyl acetate. The organic layer was dried and evaporated to
dryness. The residue was dissolved in ethanol and 10% palladium on
carbon catalyst (0.3 g) and ammonium formate (1 g) were added to
the solution. The mixture was stirred at reflux for 2 hours, and
the mixture filtered. The filtrate was evaporated to dryness and
the residue was partitioned between water and ethyl acetate. The
organic layer was dried and evaporated to dryness to give the
required starting material in 96% yield, which was used without
further purification.
Example XVI
Biological Data
419. To assess the enzymatic activity of compounds of the present
invention, the following assays ((a)-(d)) were used:
420. (a) An in vitro enzyme assay system, which assesses the
inhibitory properties of a test compound in a cell free system
using a highly purified preparation of prolyl 4-hydroxylase. The
enzyme preparation was obtained using the method described by N.
Kedersha and R. Berg (Collagen Related Research, 1:345 (1981)) and
the activity of a test compound was measured using the method
described by C. J. Cunliffe, T. J. Franklin and R. Gaskell
(Biochem. J., 240:617 (1986)).
421. (b) An in vitro assay system involving incubating embryonic
chick tendon cells in the presence of a test compound and measuring
the inhibition of hydroxylation at the 4-position of prolyl
residues within the available collagen. The embryonic chick tendon
cells were prepared from the leg tendons of 17-day chick embryos
using the method of P. Dehm and D. Prockop (Biochem. Biophys Acta,
240:358 (1971)). The cells were incubated in the presence of
[.sup.14C]- and [.sup.3H]-labelled L-proline and the extent of
hydroxylation at the 4-trans-position of the prolyl residues within
the collagen was determined using the procedure described by T. J.
Franklin and M. Hitchen (Biochem. J, 261:127-130 (1989)).
422. (c) An in vitro assay involving incubating cultures of 3T6
cells with a test compound and [.sup.14C]- and [.sup.3H]-labelled
L-proline, and measuring the inhibition of hydroxylation at the
4-trans-position of prolyl residues within the available collagen
using the procedure described by T. J. Franklin and M. Hitchen
(Biochem. J., 261:127-130 (1989)).
423. (d) An in vivo assay involving the measurement of the
inhibition by a test compound of hydroxylation at the
4-trans-position of prolyl residues within collagen within the
uteri of immature (20-21 day) female rats. The test compounds were
administered either orally or intraperitoneally to the rats in
which uterine collagen synthesis had been stimulated by the
subcutaneous administration of a solution of oestradiol benzoate
(0.5 .mu.g on each of two successive days) in arachis 14 oil. The
rats were dosed with 5 .mu.Curies of [.sup.14C]-L-proline and the
uteri were taken 2 hours after the dosing of the radiolabelled
proline and sonicated. Collagen was extracted by treatment of the
tissue with water at 120.degree. C. for 1 hour in an autoclave and
hydrolysed by treatment with 6N hydrochloric acid for 18 hours at
reflux temperature. The proline and 4-hydroxyproline residues were
separated by column chromatography on a reversed-phase Spherisorb
S5ODS1 column using as eluent a 89.9:10:0.1 v/v mixture of
water:isopropanol:trifluoroacetic acid to which 0.3% w/v of sodium
dodecylsulphate had been added. The ratio of radioactivity found in
each of the proline and 4-hydroxyproline fractions was determined
by liquid scintillation counting to allow the measurement of the
inhibition of hydroxylation by a test compound.
424. The compound described in Example 2 has an IC.sub.50 of 0.4
.mu.M in test (a), an IC.sub.50 of 1.2 .mu.M in test (b), an
IC.sub.50 of 5.4 .mu.M in test (c) and an inhibition of 46% at 50
mg/kg orally (compound dosed 2 hours before proline administration)
in test (d).
425. (e) An in vivo wound chamber model involving the measurement
of histological changes in granulation tissue. The test compounds
were tested in rats according to the procedures generally described
in Schilling et al., Surgery 46(4):702-710 (1959), Hunt et al., Am.
J. Surgery 114:302-307 (1967), and Grotendorst et al., J. Clin
Inves. 76:2323-2329 (1985). More specifically, stainless wire mesh
cylinders were implanted subcutaneously under the back skin of rats
(two chambers per animal). The compounds of the present invention
were then dissolved in DMSO and injected into each chamber on a
daily basis at various concentrations from either day 0-14 or day
7-14. On day 14, the chambers were collected and the granulation
tissues contained within the chambers were collected for
biochemical (collagen content) or histological evaluation.
426. (f) Various in vivo animal models to determine the
applicability of utilizing the compounds of the present invention
to treat fibrotic disorders specific to certain cell types or
organs. For example, a cardiac fibrosis model in rats, as generally
described in Kondo et al., Cardiovascu. Res. 21:248-254 (1987), and
Benjamin et al., Circulation Res. 65(3):657-670 (1989), may be used
to measure the effectiveness of the compounds of the present
invention to inhibit cardiac fibrosis, as well as provide evidence
of the regeneration of cardiac cells upon inhibition of fibrotic
cell proliferation. Similarly, the left carotid artery injury
model, as described generally in Clowes et al., Lab Invest.
49:327-33 (1983), Muller et al., Am. Col. Cardio. 19(2):418 (1992),
and Jackson, Trends Cardiovasc. Med. 4:122-130 (1994), may be used
to determine the effectiveness of the compounds of the instant
invention in vascular remodeling. Other models, such as in vivo
brain injury models (see e.g., Berry et al., Acto Neurochrurgica,
Suppl., 32:31-53 (1993), Logan et al., Brain Research 587:216-255
(1992)), in vivo kidney fibrosis models (see e.g., DiDonato et al.,
Nephron 76(2):192-200 (1997), in vivo post-surgical abdominal
adhesions model (see e.g., Cohen et al., J. Trauma 30(12):S149-154
(1990), Stein & Keiser, J. Surg. Res. 11:277 (1971),, Diegelman
et al., J. Surg. Res. 19:239-43 (1975)) may be used to determine
the effectiveness of the compounds of the instant invention to
treat fibrotic disorders related to the brain, kidney, abdomen and
dermis, as well as provide information related to the treatment of
other major organs.
Example XVII
427. The following illustrate representative pharmaceutical dosage
forms containing the compound of the formula (I) as defined
hereinbefore in the section relating to pharmaceutical composition,
or a pharmaceutically-acceptable salt thereof, or a metabolically
labile ester derivative of substituents R.sup.1 and R.sup.2 when
either, or both, is a carboxy group (hereafter compound X), for
therapeutic or prophylactic use in humans:
1 (a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 182.75
Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25
Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50
Lactose Ph. Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0
Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c)
Tablet III mg/tablet Compound X 1.0 Lactose Ph. Eur 93.25
Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75
Magnesium stearate 1.0 (d) Capsule mg/capsule Compound X 10 Lactose
Ph. Eur 488.5 Magnesium stearate 1.5 (e) Injection I (50 mg/ml)
Compound X 5.0% w/v 1 M Sodium hydroxide solution 15.0% v/v 0.1 M
Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400
4.5% w/v Water for injection to 100% (f) Injection II (10 mg/ml)
Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v 0.1 M Sodium
hydroxide solution 15.0% v/v Water for injection to 100% (g)
Injection III (1 mg/ml,buffered to pH 6) Compound X 0.1% w/v Sodium
phosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol
400 3.5% w/v Water for injection to 100% (h) Aerosol I mg/ml
Compound X 10.0 Sorbitan trioleate 13.5 Trichlorofluoromethane
910.0 Dichlorodifluoromethane 490.0 (i) Aerosol II mg/ml Compound X
0.2 Sorbitan trioleate 0.27 Trichlorofluoromethane 70.0
Dichlorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 (j)
Aerosol III mg/ml Compound X 2.5 Sorbitan trioleate 3.38
Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0
Dichlorotetrafluoroethane 191.6 (k) Aerosol IV mg/ml Compound X 2.5
Soya lecithin 2.7 Trichlorofluoromethane 67.5
Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6 (l)
Ointment /ml Compound X 40 mg Ethanol 300 .mu.l Water 300 .mu.l
1-Dodecylazacycloheptan-2-one 50 .mu.l Propylene glycol to 1 ml
428. The above formulations may be obtained by conventional
procedures well known in the pharmaceutical art. The tablets
(a)-(c) may be enteric coated by conventional means, for example,
to provide a coating of cellulose acetate phthalate. The aerosol
formulations (h)-(k) may be used in conjunction with standard,
metered dose aerosol dispensers, and the suspending agents sorbitan
trioleate and soya lecithin may be replaced by an alternative
suspending agent such as sorbitan monooleate, sorbitan
sesquioleate, polysorbate 80, polyglycerol oleate or oleic
acid.
Example XVIII
429. Following the in vivo wound chamber model described above,
fourteen of the claimed compounds tested to determine the
effectiveness of the claimed compounds in inhibiting collagen
deposition in the wound chamber. The results of these tests are set
forth at Table 1:
2TABLE 1 Mean Collagen content (% of Control) On Day 14 (after day
7-14 treatment) Compound 10 .mu.g dosage 50 .mu.g dosage 1 109.50
112.29 2 91.73 82.69 3 108.45 79.76 4 81.14 66.03 5 99.10 80.91 6
58.77 51.06 7 81.88 74.54 8 113.94 92.52 9 80.26 79.87 10 94.81
76.54 11 90.83 80.83 12 -- 80.68 13 95.55 84.26 14 72.19 70.29
430. With respect to Compound 12, apoptotic cell numbers were also
counted and data provided that treatment dose-dependently increased
positive staining of apoptotic cells. With respect to this
compound, it was also shown that, at higher doses, the compound
prevented rebound of collagen accumulation after discontinuing
administration of the compound.
431. Compounds 1 through 14 were prepared as described herein, or
using analogous processess to those described within this
specification and the Examples, or processes known to the skilled
organic chemist.
Example XIX
432. The effectiveness of one of the compounds of the present
invention to inhibit cardiac fibrosis and permit the regeneration
of cardiac cells was tested in the cardiac fibrosis model generally
described above. More specifically, Compound 12 was tested in a rat
isoproterenol-induced myocardial fibrosis model (wherein
isoproterenol was injected into rats at 1 mg/kg subcutaneously, for
four consecutive days) to determine the effectiveness of the
compound in inhibiting collagen deposition and improving
ventricular function of the heart. The compound was administered
after suspension in 1% CMC at 50 mg/kg by oral gavage twice daily
from day 4 to day 11 and histological data was evaluated on day 11
by general histology (H&E and trichrome) and
immunohistochemical staining for proliferating cell nuclear antigen
(PCNA). Cardiac function (left ventricular function) was measured
by inserting a catheter into the left ventricle for measurement of
relaxation and contraction pressure on week 6.
433. The histological results of this test are set forth in FIG. 1.
As set forth in FIG. 1, blocking collagen deposition appears to
block cardiac fibrosis. As further evidenced by FIG. 1, blocking
collagen deposition also appears to permit the regeneration of
healthy cardiac cells.
434. The effect of the compound on the left ventricular function,
as measured at week 6, is set forth in TABLE 2.
3 TABLE 2 Relaxation pressure Contraction pressure (Min-P, mm Hg)
(dP/dt, mm Hg) Normal -0.5 .+-. 0.6 4702.9 .+-. 19.6 Fibrotic 11.4
.+-. 0.31 1765 .+-. 54.9 Compound 12 2.7 .+-. 0.8 5770 .+-.
95.1
435. As set forth in Table 2, oral treatment with the
prolyl-4-hydroxylase inhibitors of the claimed invention
significantly reduced scar formation in a cardiac model and
encouraged the regeneration/hypertrophy of normal myocytes.
Blocking scarring also prevented the deterioration of cardiac
function.
Example XX
436. The effectiveness of Compound 12 in vascular remodeling, as
determined in a rat restenosis model, was determined by using a
left carotid artery injury rat model, as generally described above.
More specifically, a total of 20 male SD rats (weighing between
250-300 g) were used. Under general anesthesia, the rat right
common carotid artery and region of bifurcation were exposed
through a midline incision. A 2F Fogarty balloon catheter (Baxter)
was introduced through the external carotid artery and advanced
into the thoracic aorta. The balloon was inflated with 0.3 ml or
air to distend the common carotid artery. After three repetitions
of this procedure, the endothelium was removed completely and some
injury to smooth muscle layers throughout the common carotid artery
resulted. After removal of the catheter, the external carotid
artery was ligated and the wound closed. Compound 12 was then
suspended in 1% CMC at 50 mg/kg and given to the rats by oral
gavage twice daily from day 0-14. On day 14 after surgery, both the
common carotid artery (left as control) were harvested and fixed in
formalin. The results of this experiment are set forth in FIGS. 2
and 3. As evidenced by these figures, oral administration of
Compound 12 appears to significantly reduce the development of
neointimal formation in balloon injured carotid arteries,
indicating that the compound will be a useful agent for vascular
remodeling.
Example XXI
437. The effectiveness of the compounds of the instant invention to
inhibit the formation of scar tissue in the brain following injury
was tested using the brain injury model described above.
Specifically, experiments were conducted using rat models wherein a
lesion was made with an iridectomy knife to a depth of 3.5 mm along
a 4.5 mm line parallel with the sagittal suture, 3 mm lateral to
the mid-line and spanning the frontal-parietal suture. The animals
were orally administered Compound 12 (as formulated above at
Example 19) by oral gavage twice daily from day 0 to 14. All
animals were sacrificed at day 14 after lesion.
438. From immunohistochemical staining, the perfusion fixed brains
were post-fixed overnight at 4 degrees C. in 4% PFA in 0.1 borate
buffer containing 10% sucrose. The brains were then rapidly frozen
on powdered dry ice in Tissue Tek OCT compound and stored at -80
degrees C. Frozen sections (10 um) were mounted on poly-L-lysine
coated slides, air dried and stored at -80 degrees C. for staining
of type I collagen and GFAP. The results of such staining are set
forth in FIG. 4. As set forth in FIG. 4, oral treatment with
Compound 12 reduced collagen deposition in the scar and decreased
the activation of actrocytes. The compound also appears to reduce
physical barriers produced by the scarring and suggests improvement
of functional recovery.
Example XXII
439. The effectiveness of the compounds of the instant invention to
treat kidney fibrosis was determined using a kidney fibrosis rat
model, as generally described above. More specifically, male SD
rats weighing approximately 200-225 g each were injected
intravenously with Adriamycin (Pharmacia, MI) on day 1 and again on
day 15. The Adriamycin was dissolved in 0.5 ml sterile physiologic
saline and infused slowly into the tail vein to ensure complete
delivery and to avoid perivascular tissue destruction of the
drug.
440. Three treatment groups were established following Adriamycin
injections. The rats were randomly assigned to receive a twice
daily gavage of Compound 12 or control (1% CMC). Five animals from
each group were sacrificed on week 6, 8 or 12.
441. Histology examination provided that treatment with the
compound, versus control, prevented the development of kidney
fibrosis after Adriamycin injection and blocked the development of
renal hypertension. Cardiac function was improved on week 12 and
long term toxicity, as measured by mean body weight and bone
density on week 12, was not material.
Example XXIII
442. The effectiveness of the compounds in dermal wound healing was
tested using two wound healing models--rat punch model and rat
incisional model--as described above. The results of these
experiments, as conducted with Compound 12 and Compound 14, are set
forth in FIGS. 5, 6 and 7. As set forth in these figures,
administration of the compounds resulted in reduced tensil strength
and increased healing time, as compared to control.
* * * * *