Colloid systems and wetting agents; subcombinations thereof; pro – Continuous liquid or supercritical phase: colloid systems;... – Aqueous continuous liquid phase and discontinuous phase...
Reexamination Certificate
2001-05-29
2002-07-16
Seaman, D. Margaret (Department: 1625)
Colloid systems and wetting agents; subcombinations thereof; pro
Continuous liquid or supercritical phase: colloid systems;...
Aqueous continuous liquid phase and discontinuous phase...
C514S252100, C514S245000, C514S307000, C544S180000, C544S238000, C544S242000, C544S336000, C546S143000
Reexamination Certificate
active
06420438
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, haematology, 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 amino substituted fused bicyclic compounds are particularly effective as inhibitors of serine proteases, especially proteases with negatively charged Pi specificity pockets, and most especially the serine proteases thrombin, trypsin, urokinase and Factor Xa. It is envisaged that compounds of the type described below will be readily bioavailable, particularly orally bioavailable.
Thus viewed from one aspect the invention provides serine protease inhibitor compounds of formula I
(where R
1
is hydrogen, halo, cyano, nitro or hydroxyl, amino, alkoxy, alkyl, aminoalkyl, hydroxyalkyl, thiol, alkylthio, aminosulphonyl, alkoxyalkyl, alkoxycarbonyl, acyloxymethoxycarbonyl or alkylamino optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl, cycloalkyl, amino, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl, alkylsulphonamido, alkylaminosulphonyl, haloalkoxy and haloalkyl;
R
2
is hydrogen, halo, methyl, amino, hydroxy or oxo; and
R is X—X—Y(R
7
)—L—Lp(D)
n
(wherein each X independently is a C, N, O or S atom or a CO, CR
1
, C(R)
2
or NR
1
group, at least one X being C, CO, CR or a C(R)
2
group;
Y (the &agr;-atom) is a nitrogen atom or a CR
1
group or Y and L taken together form a cyclic group;
R
7
is a lipophilic group, e.g. alkyl, alkenyl, mono- or bi-cycloalkyl, aryl, heteroaryl, mono- or bicycloalkylalkyl, mono- or bicycloalkylalkenyl, aralkyl, heteroaryl-alkyl, arylalkenyl, heteroarylalkenyl all optionally substituted by a group R
1
;
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;
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, thia, aza or R
1
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, 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 atoms; and fused multicyclic groups preferably contain 8 to 16 ring atoms.
In the compounds of the invention the fused ring system is preferably a 1-aminoisoquinoline system.
Particularly as a substituent on the isoquinoline ring, R
1
is preferably hydrogen, hydroxy, amino or alkyl. R
2
is preferably hydrogen. Two or more non-hydrogen R
1
(or R
2
) groups may be present on the carbocyclic (or heterocyclic) rings; however a single non-hydrogen R
1
(or R
2
) group is preferred. R
1
is preferably on the 6-position of the fused ring system.
R is depicted in formula (I) as being present on the 7-position of the fused ring system although it is also envisaged that the lipophilic group could be present on the 6-position. However, preferably the lipophilic group will be present on the 7-position of the ring.
In the compounds of the invention, where the alpha atom (Y) is carbon it preferably has the conformation that would result from construction from a D-&agr;-aminoacid NH
2
—CR
1
(R
7
)—COOH. Likewise the fourth substituent R
1
at an alpha carbon is preferably a methyl or hydroxymethyl group or most preferably hydrogen.
The linker group X—X from the fused bicyclic group to the alpha atom is preferably selected from —CH═CH—, —CONH—, —CONR
1
—, —NH—CO—, —NH—CH
2
—,—CH
2
—NH—, —CH
2
O—, —OCH
2
—, —COO—, —OC═O— and —CH
2
CHR
1
— (e.g. —CH
2
CH
2
—). Preferably, the X moiety nearest to the alpha atom is an NH or O atom, most preferably a NH group. The X moiety alpha to the fused ring system is preferably a carbon based group such as CH
2
or CO, preferably CO. 1-amino-7-carbonylisoquinoline compounds optionally saturated between the 3 and 4 positions are novel and themselves form a further aspect of the invention. 1-amino-7-substituted isoquinoline compounds optionally saturated between the 3 and 4 positions also form an aspect of the invention.
R
1
preferably represents an unsubstituted or R
1
substituted aryl or cyclohexyl group, preferably phenyl or naphthyl.
The linker group from the alpha atom to the lipophilic group is preferably CO, CH
2
NH, CONR
1
(CH
2
)
m
, (CH
2
)
m
N(R
1
)CO(CH
2
)
m
, (CH
2
)
m+2
, (CH
2
)
m
CO(CH
2
)
m
, (CH
2
)
m
OC═O, (CH
2
)
m
O or CH═CH(CH
2
)
m
(where each m is independently 0 or 1). The linker may be optionally branched, for example, to incorporate a polar functionality. In one embodiment Y and L taken together form a cyclic group and the alpha atom is therefore a carbon atom. The cyclic group can be unsubstituted or substituted and can have a ring size of from 3 to 8 atoms. Preferably, the cyclic group is a cyclic amide, most preferably wherein the amide nitrogen of the cyclic amide group is bound to the lipophilic group.
The lipophilic group preferably comprises a cycloalkyl, azacycloalkyl, diazacycloalkyl, phenyl, naphthyl, adamantyl, decalinyl, tetrahydrodecalinyl, bicycloalkyl, mono- or diazabicycloalkyl, mono- or bicyclo heteroaromatic or a linear or branched alky
Camp Nicholas Paul
Crew Andrew Philip Austin
Jones Stuart Donald
Liebeschuetz John Walter
Morgan Phillip John
Hay Martin A
Seaman D. Margaret
Tularik Limited
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