Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-05-04
2001-03-13
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253030, C514S292000, C544S126000, C544S361000, C546S088000
Reexamination Certificate
active
06200974
ABSTRACT:
FIELD OF THE INVENTION
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
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.
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.
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.
Despite previous efforts, a need exists for safe and effective means for the treatment of fibroproliferative diseases and disorders.
SUMMARY OF THE INVENTION
The present invention provides certain phenanthroline derivatives useful for inhibiting prolyl 4-hydroxylase.
Specifically, the present invention provides phenanthroline derivatives of formula (I)
wherein
R
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)alkoxycarbonyl, (1-4C)alkoxy-(2-4C)alkoxy-(2-4C)alkoxycarbonyl, (2-4C)alkanoyloxy-(1-4C)alkyl or
N
-[amino-(2-8C)alkyl]carbamoyl;
R
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)alkyl]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)alkylcarbamoyl,
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]thiocarbamoyl, N-(2-4C)alkanoylamino or
N
-[(1-4)alkoxycarbonyl]amino;
R
3
and R
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
4
is methoxy; and
R
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;
or a pharmaceutically-acceptable salt thereof.
As a further feature R
1
may additionally include morpholino-(2-4C)alkoxycarbonyl and R
3
may additionally include methoxy.
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.
As used herein, the “ester derivatives” preferably includes metabolically labile ester derivatives.
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.
As used herein, the term “halo” includes, for example, fluoro, chloro, bromo and iodo.
The term (1-4C)alkylamino includes methylamino, ethylamino and propyl amino.
The term di-[(1-4C)alkyl]amino includes dimethylamino,
N
-ethyl-
N
-methyl amino, diethylamino,
N
-methyl-
N
-propylamino and dipropyl amino.
The term (2-4C)alkanoyl includes acetyl, propionyl and butyryl.
The term (1-6C)alkoxycarbonyl includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and pentoxycarbonyl.
The term N-[amino-(2-8C)alkyl]carbamoyl includes
N
-(3-aminopropyl)carbamoyl,
N
-(6-aminohexyl)carbamoyl and
N
-(8-aminooctyl)carbamoyl.
The term (1-4C)alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
The term hydroxy-(1-4C)alkyl includes hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl.
The term (1-4C)alkylthio includes methylthio, ethylthio and propylthio.
The term (1-4C)alkylsulfinyl includes methylsulfinyl, ethylsulfinyl and propylsulfinyl.
The term (1-4C)alkylsulfonyl includes methylsulfonyl, ethylsulfonyl and propylsulfonyl.
The term fluoro-(1-4C)alkylthio includes trifluoromethylthio, 2,2,2-trifluoroethylthio and 3,3,3-trifluoropropylthio.
The term fluoro-(1-4C)alkylsulfinyl includes trifluoromethylsulfinyl, 2,2,2-trifluoroethylsulfinyl and 3,3,3-trifluoropropylsulfinyl.
The term fluoro-(1-4C)alkylsulfonyl includes trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl and 3,3,3-trifluoropropylsulfonyl.
The term (1-4C)alkoxy-(2-4C)alkoxycarbonyl includes 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl and 3-methoxypropoxycarbonyl.
The term
N
-(1-4C)alkylcarbamoyl includ
Edwards Philip Neil
Hales Neil James
Large Michael Stewart
Bengtsson W. Patrick
Pillsbury Madison & Sutro LLP
Powers Fiona T.
Wu Nan
Zeneca Limited
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