Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-17
2003-12-09
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252020, C514S252110, C514S255050, C514S275000, C514S343000, C544S229000, C544S238000, C544S295000, C544S296000, C544S327000, C544S331000, C544S332000, C544S336000, C544S357000, C546S256000, C546S278400
Reexamination Certificate
active
06660738
ABSTRACT:
BACKGROUND OF THE INVENTION
Endothelins are peptides, that exist in three isoforms ET-1, ET-2, and ET-3, each encoded by a distinct gene. They have been originally discovered in the conditioned medium of porcine endothelial cells in 1988 by Yanagisawa (Yanagisawa M; Kurihara H; Kimura S; Tomobe Y; Kobayashi M; Mitsui Y; Yazaki Y; Goto K; Masaki T: A novel potent vasoconstrictor peptide produced by vascular endothelial cells [see comments]. NATURE (Mar. 31, 1988), 332(6163),
411-5.
). The active ETs are peptides of 21 amino acids with two intramolecular disulfide bridges. They are produced from preproproteins of 203 to 212 amino acids which are processed by furin-like endopeptidases to the biologically inactive big-endothelin (big-ET). The big-ETs are specifically processed to mature ETs by a hydrolytic cleavage between amino acids 21 and 22 that are Trp
21
-Val
22
(big-ET-1, big ET-2) and Trp
21
-Ile
22
in big-ET-3 respectively. Already in 1988 a specific metalloprotease was postulated to be responsible for this specific cleavage. In 1994, ECE-1 (endothelin converting enzyme-1) was purified and cloned from bovine adrenal (Xu D, Emoto N, Giaid A, Slaughter C, Kaw S, de Witt D, Yanagisawa M: ECE-1: a membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1. Cell (1994) 78: 473-485).
ECE-1 is a membrane bound type II zinc-endopeptidase with a neutral pH optimum and a zinc binding motif HExxHx(>20)E. It belongs to subfamily M13 and has a large 681 amino acid ectodomain that comprises the active site. Other members of the M13 family are NEP24.11 (neutral endopeptidase), PEX, a phosphate regulating neutral endopeptidase, and Kell blood group protein that has recently been described as a big-ET-3 processing enzyme. Members of the M13 family of human origin are characterized by a high molecular weight (>80 kDa) a number of conserved disulfide bridges and a complex glycosylation pattern. The structure of NEP has recently been solved. (Oefner et al, J. Mol. Biol. 2000, 296, 341-349). The catalytic domain of ECE and related human M13 proteinases are significantly larger (>650 amino acids) than members of matrix metalloproteases (MMPs). Unlike the family of the MMPs which belong to the metzincins and display a typical HExxHxxGxxH pattern members of the M13 family are gluzincins comprising a HExxHx(>20)E pattern. These two families are clearly different in size of catalytic domains, structure and zinc coordinating pattern of ligands. Active sites of the two families show clear differences which has clear impact on type of inhibitors and the potential selectivity.
SUMMARY OF THE INVENTION
The present invention relates to compounds of formula (I)
wherein
R
1
is hydrogen, alkylcarbonyl or arylcarbonyl;
R
2
is alkyl, alkinyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonyl, alkylcarbonylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylsulfonyl, aryl, arylalkyl, arylalkoxyalkyl, aryl(alkoxycarbonyl)alkyl, arylaminocarbonyl, diarylalkyl, aryl(carboxyalkyl) aminocarbonyl, arylcarbonyl, arylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl or the group YR
2
is heterocyclyl;
R
3
and R
4
are independently selected from the group consisting of hydrogen, alkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylthio, cycloalkyl, cycloalkylalkyl, carbamoyl, carboxy, carboxyalkyl, cyano, amino, mono- and dialkylamino, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkenyl, alkinyl, aryl, arylalkyl, arylalkyl(alkoxycarbonyl)alkyl, arylcarbonylalkyl, arylalkenyl, aryl(alkoxycarbonyl)alkyl, arylamino, arylalkylamino, aryloxy, halogen, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, trimethylsilanylethynyl or trifluormethyl;
R
5
is hydrogen, alkyl, aryl, arylalkyloxycarbonyl, or alkylcarbonyl;
X
1
, X
2
, X
3
and X
4
are CH or N with the proviso that only up to two groups of X
1
, X
2
, X
3
and X
4
are N;
Y is —O— or —NR
5
—; and
dimeric forms, and/or pharmaceutically acceptable esters, and/or pharmaceutically acceptable salts thereof, preferably pharmaceutically acceptable esters, and/or pharmaceutically acceptable salts thereof, and most preferably pharmaceutically acceptable salts thereof.
The present invention is directed to compounds which are useful as inhibitors of metalloproteases, e.g. zinc proteases, particularly zinc hydrolases, and which are effective in the prophylaxis and treatment of disease states which are associated with vasoconstriction of increasing occurrences. Examples of such disorders are high blood pressure, coronary disorders, cardiac insufficiency, renal and myocardial ischaemia, renal insufficiency, dialysis, cerebral ischaemia, cardiac infarct, migraine, subarachnoid haemorrhage, Raynaud syndrome and pulmonary high pressure. In addition the compounds are useful as cytostatic and cerebroprotective agents for inhibition of graft rejection, for organ protection and for treatment of ophthalmological diseases.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compounds of formula (I):
wherein
R
1
is hydrogen, alkylcarbonyl or arylcarbonyl;
R
2
is alkyl, alkinyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonyl, alkylcarbonylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylsulfonyl, aryl, arylalkyl, arylalkoxyalkyl, aryl(alkoxycarbonyl)alkyl, arylaminocarbonyl, diarylalkyl, aryl(carboxyalkyl)aminocarbonyl, arylcarbonyl, arylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl or the group YR
2
is heterocyclyl;
R
3
and R
4
are independently selected from the group consisting of hydrogen, alkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylthio, cycloalkyl, cycloalkylalkyl, carbamoyl, carboxy, carboxyalkyl, cyano, amino, mono- and dialkylamino, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkenyl, alkinyl, aryl, arylalkyl, arylalkyl(alkoxycarbonyl)alkyl, arylcarbonylalkyl, arylalkenyl, aryl(alkoxycarbonyl)alkyl, arylamino, arylalkylamino, aryloxy, halogen, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, trimethylsilanylethynyl or trifluormethyl;
R
5
is hydrogen, alkyl, aryl, arylalkyloxycarbonyl, or alkylcarbonyl;
X
1
, X
2
, X
3
and X
4
are CH or N with the proviso that only up to two groups of X
1
, X
2
, x
3
and X
4
are N;
Y is —O— or —NR
5
—; and
dimeric forms, and/or pharmaceutically acceptable esters, and/or pharmaceutically acceptable salts thereof.
The term “alkyl”, alone or in combination, means a straight-chain or branched-chain alkyl group containing a maximum of 7, preferably a maximum of 4, carbon atoms, e.g., methyl, ethyl, n-propyl, 2-methylpropyl (iso-butyl), 1-methylethyl (iso-propyl), n-butyl, and 1,1-dimethylethyl (t-butyl).
The term “carboxy” refers to the group —C(O)OH.
The term “carbamoyl” refers to the group —C(O)NH
2
.
The term “carbonyl” refers to the group —C(O)—.
The term “halogen” refers to the group fluoro, bromo, chloro and iodo.
The term “sulfonyl” refers to the group —S(O
2
)—.
The term “alkenyl” refers to a hydrocarbon chain as defined for alkyl having at least one olefinic double bond (including for example, vinyl, allyl and butenyl).
The term “alkinyl” refers to a hydrocarbon chain as defined for alkyl having at least one olefinic triple bond (including for example propinyl, butin-(1)-yl, etc.).
The term “alkoxy”, alone or in combination, means an alkyl ether group in which the term ‘alkyl’ has the significance given earlier, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.butoxy, tert.butoxy and the like.
The term “alkoxycarbonyl” refers to a group of the formula —C(O)R
c
wherein R
c
is alkoxy as defined above.
The term “hydroxy” refers to the group —OH, the term “cyano” to the group —CN.
The term “hydroxyalkyl” means an alkyl group as defined above which is substituted by a hydroxy group.
The term “thioalkyl” and “cyanoalkyl” refer to an alkyl group as defined above which is substituted by a —SH group or an —CN group, respectively.
“Carboxyalkyl” means a lower-alkyl as defi
Aebi Johannes
Bur Daniel
Chucholowski Alexander
Dehmlow Henrietta
Hoffmann-La Roche Inc.
Johnston George W.
Parise John P.
Rao Deepak
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