Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-11-19
2004-05-25
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S357000, C514S538000, C514S563000, C514S617000, C544S353000, C544S365000, C546S194000, C546S280700, C546S281100, C560S035000, C560S251000, C562S440000, C564S157000, C564S161000, C564S246000
Reexamination Certificate
active
06740682
ABSTRACT:
This invention relates to compounds which are inhibitors of serine proteases and to pharmaceutical compositions thereof and their use in the treatment of the human or animal body.
The serine proteases are a group of proteolytic enzymes which have a common catalytic mechanism characterized by a particularly reactive Ser residue. Examples of serine proteases include trypsin, tryptase, chymotrypsin, elastase, thrombin, plasmin, kallikrein, Complement C1, acrosomal protease, lysosomal protease, cocoonase, &agr;-lytic protease, protease A, protease B, serine carboxypeptidase II, subtilisin, urokinase, Factor VIIa, Factor IXa, and Factor Xa. The serine proteases have been investigated extensively over a period of several decades and the therapeutic value of inhibitors of serine proteases is well understood.
Serine protease inhibitors play a central role in the regulation of a wide variety of physiological process including coagulation, fibrinolysis, fertilization, development, malignancy, neuromuscular patterning and inflammation. It is well known that these compounds inhibit a variety of circulating proteases as well as proteases that are activated or released in tissue. It is also becoming clear that serine protease inhibitors inhibit critical cellular processes, such as adhesion, migration, free radical production and apoptosis. In addition, animal experiments indicate that intravenously administered serine protease inhibitors, variants or cells expressing serine protease inhibitors, provide a protective effect against tissue damage.
Serine protease inhibitors have also been predicted to have potential beneficial uses in the treatment of disease in a wide variety of clinical areas such as oncology, neurology, hematology, pulmonary medicine, immunology, inflammation and infectious disease.
In particular serine protease inhibitors may be beneficial in the treatment of thrombotic diseases, asthma, emphysema, cirrhosis, arthritis, carcinoma, melanoma, restenois, atheroma, trauma, shock and reperfusion injury.
Thus for example an inhibitor of Factor Xa has value as a therapeutic agent as an anticoagulant, e.g. in the treatment and prevention of thrombotic disorders. The use of a Factor Xa inhibitor as an anticoagulant is desirable in view of the selectivity of its effect. Many clinically approved anticoagulants have been associated with adverse events owing to the non-specific nature of their effects on the coagulation cascade.
Also, there are well-known associations of al protease inhibitor deficiency with emphysema and cirrhosis and C1 esterase inhibitor deficiency with angioedema.
We have now found that certain novel amidine compounds are particularly effective as inhibitors of serine proteases, especially proteases with negatively charged P1 specificity pockets, and most especially the serine proteases thrombin, trypsin, urokinase and Factor Xa.
Thus viewed from one aspect we provide serine protease inhibitor compounds having an m-benzamidine group and a lipophilic group coupled to a cyclic group-attached carbon or nitrogen atom (hereinafter the alpha atom), the coupling of the m-benzamidine group to the alpha atom being by a linker group providing a two backbone atom linking chain, the backbone atoms being selected from C, N, O and S and at least one being C, optionally wherein one or both of the backbone atoms form part of a cyclic group and the coupling of the lipophilic group to the alpha atom being by a linker group capable of separating the alpha atom from the lipophilic group by a range of 2.3 to 6.5 Å in length.
In the compounds of the invention, the lipophilic group is itself optionally substituted by a hydrogen bond donor group. Where this is the case, the lipophilic group and its linker preferably are conformable to separate by from 7.5 to 15.0 Å the alpha atom and the hydrogen bond donor atom of the donor group.
Where distances from the alpha atom to the lipophilic group or to the hydrogen bond donor atom are mentioned, these relate to the distances between the centre of the alpha atom and the centre of the first atom of the lipophilic group or the centre of the hydrogen bond donor atom.
Such distances can be calculated from crystallographic data for any given compound from the bond lengths and bond angles for individual bonds along the length of the molecule between the alpha atom and the first atom of the lipophilic group or the hydrogen bond donor atom. Similarly such distances may be calculated with reasonable accuracy from the bond lengths and bond angles known to be typical of such individual bonds.
The linker between the alpha atom and the lipophilic group may itself be a lipophilic moiety, e.g. an alkylene chain. The nature of the linker may vary considerably—the primary requirement is that it be conformable to place part or all of the lipophilic group at a desired distance away from the alpha atom. The lipophilic group thus desirably is able to occupy at least part of a space 2.3 to 15.0 Å from the alpha atom. The length of the linker generally corresponds to 1 to 5 backbone atoms and may be a chain, branched chain or cyclic linker (e.g. a cyclic amide or an aromatic heterocycle). In one embodiment the alpha atom forms part of a cyclic group which also forms the linker to the lipophilic group.
Thus viewed from an alternative aspect the invention provides serine protease inhibitor compounds of formula I:
(where R
1
and R
2
each independently is hydrogen or hydroxyl, alkoxy, alkyl, aminoalkyl, hydroxyalkyl alkoxyalkyl, alkoxycarbonyl, acyloxymethoxycarbonyl or alkylamino optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl;
each R
3
independently is R
1
, R
2
, amino, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl, alkylsulphonamido, alkylaminosulphonyl, aminosulphonyl, haloalkoxy and haloalkyl;
each X independently is a C, N, O or S atom or a CO, CR
1
, C(R
1
)
2
or NR
1
group, at least one X being C, CO, CR
1
or C(R
1
)
2
, with the proviso that if the benzamidine group is unsubstituted (i.e. no non-hydrogen R
3
group is present) and the X—X group is —CH
2
C(R
1
)
2
— then R
1
is hydrogen or is attached to the alkylene carbon atom by a heteroatom;
L is an organic linker group containing 1 to 5 backbone atoms selected from C, N, O and S, or a branched alkyl or cyclic group;
Y (the &agr;-atom) is a nitrogen atom or a CR
1
group or Y and L taken together form a cyclic group;
Cy is a saturated or unsaturated, mono or poly cyclic, homo or heterocyclic group, preferably containing 5 to 10 ring atoms and optionally substituted by groups R
3
or phenyl optionally substituted by R
3
;
Lp is a lipophilic organic group, e.g. an alkyl, heterocyclic, alkenyl, alkaryl, cycloalkyl, polycycloalkyl, cycloalkenyl, aryl, aralkyl or haloalkyl group or a combination of two or more such groups optionally substituted by one or more of oxa, oxo, aza, thio, halo, amino, hydroxy or R
3
groups, preferably a group containing up to 25 carbon atoms;
D is a hydrogen bond donor group; and n is 0, 1 or 2);
or a physiologically tolerable salt thereof, e.g. a halide, phosphate or sulphate salt or a salt with ammonium or an organic amine such as ethylamine or meglumine.
In the compounds of the invention, where the alpha atom is carbon it preferably has the conformation that would result from construction from a D-&agr;-aminoacid NH
2
—CR
1
(Cy)—COOH and a m-carboxyl benzamidine. Likewise the fourth substituent R
1
at an alpha carbon is preferably a methyl or hydroxymethyl group or hydrogen.
In compounds of formula (I) it is envisaged that the unsubstituted or substituted amidino group could be repalced by a substituted or unsubstituted aminomethyl group although an amidino derivative is preferred.
In the compounds of the invention, unless otherwise indicated, aryl groups preferably contain 5 to 10 ring atoms optionally including 1, 2 or 3 heteroatoms selected from O, N and S; alkyl, alkenyl or alkynyl groups or alkylene moieties preferably contain up to 6 carbons; cyclic groups preferably have ring sizes of 3 to 8 ato
Chang Ceila
Hay Martin A.
Tularik Limited
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