Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-01-30
2003-02-04
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S303000, C514S350000, C514S423000, C514S438000, C514S552000, C546S118000, C546S318000, C546S323000, C548S537000, C549S077000, C558S417000, C560S027000, C564S049000, C564S051000
Reexamination Certificate
active
06515023
ABSTRACT:
BACKGROUND OF THE INVENTION
Thrombin is able to elicit many cellular responses (e.g. thrombotic, inflammatory, proliferative and atherosclerotic) that are mediated by proteolytic activation of a specific cell surface receptor known as the thrombin receptor (Vu et al. (1991)
Cell
64: 1057-1068; Rasmussen et al. (1991)
FEBS Lett
288: 123-128; Zhong et al. (1992)
J. Biol. Chem.
267: 16975-16979; Bahou et al. (1993)
J. Clin. Invest.
91: 1405-1413; McNamara et al. (1993)
J. Clin. Invest.
91: 94-98; Glembotski (1993)
J. Biol. Chem.
268: 20646-20652; and Park et al. (1994)
Cardiovasc. Res.
28: 1263-1268. The thrombin receptor has seven transmembrane-spanning domains and belongs to a family of G-protein coupled receptors (Vu et al. (1991)
Cell
64: 1057-1068 and Schwartz (1994)
Current Opin. Biotechnol.
5: 434-444). The thrombin receptor is a specific tethered ligand receptor or protease activated receptor. Activation of the receptor occurs by thrombin cleavage of an extracellular N-terminal domain. The new N-terminus through intramolecular interaction activates the receptor (Vu et al. (1991)
Cell
64: 1057-1068; Coughlin (1993)
Thromb. Haemostas.
70: 184-187; Van Obberghen-Schilling and Pouyssegur (1993)
Thromb. Haemostas.
70: 163-167; Brass et al. (1994)
Ann. NY Acad. Sci.
714: 1-12). Synthetic thrombin receptor activating peptides comprising the 6-14 amino acids of the tethered ligand were found to activate platelets equally with thrombin itself and are considered to be full agonists (Vu et al. (1991)
Cell
64: 1057-1068; Vassallo et al. (1992)
J. Biol. Chem.
267: 6081-6085; Coller et al. (1992)
Biochemistry
31: 11713-11722; Chao et al. (1992)
Biochemistry
31 6175-6178; Rasmussen et al. (1993)
J. Biol. Chem.
268: 14322-14328). The first five amino acids (SFLLR) are required for activation of the platelet thrombin receptor (Scarborough et al. (1992)
J. Biol. Chem.
267: 13146-13149;Hui et al. (1992)
Biochem. Biophys. Res. Commun.
184: 790-796). Structure activity studies, NMR experiments and molecular modeling have determined the specific requirements for each amino acid in SFLLR (Matsoukas et al. (1997)
J. Prot. Chem.
16: 113-131; Natarajan et al. (1995)
Int. J. Pept. Protein Res.
45: 145-151).
Antagonists of the thrombin receptor are medicinally useful agents for blocking the unwanted effects of thrombin on cells.
SUMMARY OF THE INVENTION
Compounds of the invention are useful for inhibiting the aggregation of blood platelets. The above-mentioned compounds, which are thrombin receptor antagonists, can be used in a method of acting upon a thrombin receptor which comprises administering a therapeutically effective but non-toxic amount of such compound to a mammal, preferably a human. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, dispersed therein, an effective but non-toxic amount of active drug is another feature of this invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention includes compounds having the structure
and pharmaceutically acceptable salts thereof, wherein
R
1
is hydrogen or C
1-10
alkyl;
R
2
is
C
1-10
alkyl,
C
3-8
cycloalkyl,
CH(CH
3
)CH
2
OCH
3
,
CH(CH
3
)CH
2
F,
CH(CH
3
)CH
2
SCH
3
,
A is hydrogen or
A
1
, A
2
, A
3
, and A
4
are independently selected from
hydrogen,
halogen,
nitro,
CN,
R
10
,
OR
10
,
NR
10
R
11
;
m is 0, 1, 2, 3, 4, or 5;
B is
hydrogen,
R
12
,
C
3-8
cycloalkyl,
CH(CH
3
)CH
2
OCH
3
,
CH(CH
3
)CH
2
F,
CH(CH
3
)CH
2
SCH
3
;
R
6
is
R
13
,
Ar
2
,
NH(Ar
2
),
C
3-8
cycloalkyl,
CH
2
Ph,
C(CH
3
)
2
NC(O)OC(CH
3
)
3
,
C(NH
2
)(CH
3
)
2
, or
OC(CH
3
)
3
,
X is
OH,
OR
4
,
OC(O)R
4
,
OC(O)Ar
1
,
NR
4
Ar
1
,
SR
4
,
S(O)R
4
,
SO
2
R
4
;
R
4
, R
9
, R
10
, R
11
, R
12
, and R
13
are independently selected from hydrogen or C
1-10
alkyl; and
Ar, Ar
1
and Ar
2
are independently selected from the group consisting of
i) aryl, unsubstituted, monosubstituted, independently disubstituted or independently trisubstituted with
C
1-10
alkyl,
CH
2
NHC(O)NH
2
,
halogen,
CN,
amino C
1-10
alkyl,
CF
3
, or
S(O)
n
R
3
, wherein R
3
is hydrogen or C
1-10
alkyl, or
ii) heteroaryl, unsubstituted, monosubstituted, independently disubstituted or independently trisubstituted with
C
1-10
alkyl,
halogen,
CN,
amino C
1-10
alkyl,
CF
3
, or
S(O)
n
R
3
, wherein R
3
is hydrogen or C
1-10
alkyl.
In a class of compounds of the invention, and pharmaceutically acceptable salts thereof,
R
4
is CH
3
, C(CH
3
)
3
, or CH
2
CH
3
;
R
10
is CH
3
;
R
13
is CH(CH
3
)
2
, CH
2
CH
3
, or CH
3
;
Ar
2
is
phenyl, unsubstituted, monosubstituted or independently disubstituted with F, S(O)
2
NH
2
, Cl, CH
2
NHC(O)NH
2
, or CH
3
,
unsubstituted, monosubstituted or independently disubstituted with F,
In a group of the class of compounds, and pharmaceutically acceptable salts thereof,
Ar is
X is
OH,
OCH
3
,
OC(O)C(CH
3
)
3
,
OC(O)C
3
,
OCH
2
CH
3
;
R
2
is
CH(CH
3
)
2
,
C(CH
3
)
3
,
CH
2
CH
3
,
CH
2
CH
2
CH
3
,
CH(CH
3
)
2
CH
2
CH
3
,
CH(CH
3
)CH
2
CH
3
,
CH(CH
2
CH
3
)
2
,
CH(CH
3
)CH
2
OCH
3
,
CH(CH
3
)CH
2
CH
2
CH
3
,
CH(CH
3
)CH
2
F, or
CH(CH
3
)CH
2
SCH
3
;
A
1
is
hydrogen,
Cl,
F,
CH
3
, or
CN;
A
2
is
hydrogen,
F, or
OCH
3
;
A
3
and A
4
are hydrogen;
m is 0, 1, or 2;
B is hydrogen;
R
6
is
CH
3
,
C(CH
3
)
3
,
CH
2
Ph,
Ph,
C(CH
3
)
2
NC(O)OC(CH
3
)
3
,
C(NH
2
)(CH
3
)
2
,
Examples of the group of compounds include
and pharmaceutically acceptable salts thereof.
The term “alkyl” means branched or straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (for example, “C
1-10
” denotes alkyl having 1 to 10 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexy, octyl radicals and the like.
The term “alkenyl” means hydrocarbon chains of either a straight of branched configuration and one or more unsaturated carbon—carbon bonds which may occur at an stable point along the chain, e.g., propylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl radicals and the like.
The term, “alkynyl” means hydrocarbon chains of either a straight or branched configuration and one or more triple carbon—carbon bonds which may occur in any stable point along the chain, e.g., ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.
The term “alkoxy” means an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, radicals and the like.
The terms “alkylene”, “alkenylene”, “phenylene”, and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure. Such “alkylene”, “alkenylene”, “phenylene”, and the like, may alternatively and equivalently be denoted herein as “-(alkyl)-”, “-(alkenyl)-” and “-(phenyl)-”, and the like.
The term “halogen” includes fluorine, chlorine, iodine and bromine.
The term “oxy” means an oxygen (O) atom.
The term “thio” means a sulfur (S) atom.
The term “aryl” means a partially saturated or fully saturated 6-14 membered ring system such as for example, phenyl, naphthyl or anthracyl. The term “Ph”, which appears in certain chemical formulas in the specification and claims, represents phenyl.
The term “cycloalkyl” means saturated ring groups, including mono-, bi-, or poly-cyclic ring systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexy, cycloheptyl, cyclooctyl, adamantyl, and the like.
The term “heterocyclic” or “heterocycle” means a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or fully unsaturated, which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized,
Barrow James C.
Breslin Michael J.
Connolly Thomas M.
Glass Kristen L.
Hutchinson John H.
Camara Valerie J.
Merck & Co. , Inc.
O'Sullivan Peter
Parr Richard S.
Winokur Melvin
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