Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-27
2003-04-08
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C546S209000, C548S146000, C548S186000, C548S245000, C548S578000
Reexamination Certificate
active
06544982
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 tethered ligand 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). 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 al. (1992)
Biochemistry
31: 11713-11722; Chao et al. (1992)
Biochemistry
31 6175-6178; Rasmussen et al. (1993)
J. Biol. Chem.
268: 14322-14328). In contrast, only 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).
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 invention includes compounds having the formula
wherein
n is 0, 1, or 2;
m is 0, 1, or 2;
R is
hydrogen,
C
1-10
alkyl,
C
1-10
alkoxy,
aryl,
halogen, or
CF
3
,
—OCH
3
,
SCH
3
,
SOCH
3
,
SO
2
CH
3
,
NO
2
,
CN, or
R, in combination with R
1
, form a 5-membered heterocyclic ring having 1 or 2 heteroatoms;
R
1
is
hydrogen,
C
1-10
alkyl,
C
1-10
alkoxy,
aryl,
halogen, or
CF
3
,
—OCH
3
,
SCH
3
,
SOCH
3
,
SO
2
CH
3
,
NO
2
,
CN, or
R
1
, in combination with R, form a 5-membered heterocyclic ring having 1 or 2 heteroatoms;
R
2
is
hydrogen,
C
1-10
alkyl,
C
1-10
alkoxy,
halogen, or
CN;
R
3
is
hydrogen,
C
1-10
alkyl,
C
3-7
alkanol,
C
2-10
alkenyl,
C
3-10
cycloalkyl,
CH
2
C
3-10
cycloalkyl,
(CH
2
)
2
R
7
,
CH
2
R
7
,
CN,
CH(CH
3
)R
7
,
R
7
,
R
3
, in combination with R
4
, forms a mono ring system selected from the group consisting of;
a) a 4-8 membered saturated, partially saturated or unsaturated ring having 1 or 2 heteroatoms, unsubstituted or substituted with
1) pyridine,
2) COOEt,
3) piperidine,
4) CONH
2
,
5) C
1-4
alkyl,
R
4
is
hydrogen,
C
1-10
alkyl,
C
3-7
alkanol,
C
2-10
alkenyl,
C
3-10
cycloalkyl,
CH
2
C
3-10
cycloalkyl,
(CH
2
)
2
R
7
,
CH
2
R
7
,
CN,
CH(CH
3
)R
7
,
R
7
,
R
4
, in combination with R
3
, forms a mono ring system selected from the group consisting of;
a) a 4-8 membered saturated, partially saturated or unsaturated ring having 1 or 2 heteroatoms, unsubstituted or substituted with
1) pyridine,
2) COOEt,
3) piperidine,
4) CONH
2
,
5) C
1-4
alkyl,
R
5
is
hydrogen,
C
1-10
alkyl,
C
1-10
alkoxy,
CN,
OCF
3
, or
—O(CH
2
)
0-2
R
8
—COOCH
2
CH
3
, NO
2
, CF
3
,
aryl, unsubstituted, monosubstituted or disubstituted with
OCH
3
,
halogen,
CN,
NO
2
,
CF
3
,
OCF
3
,
OCH
2
Ph,
OCH
2
CH
2
Ph,
COOEt,
C
1-4
alkyl, or
phenyl,
phenyloxy,
halogen, or
R
5
and R
6
form a 5 membered heterocyclic ring having 1 or 2 heteroatoms;
R
6
is
hydrogen,
C
1-10
alkyl,
C
1-10
alkoxy,
CN,
OCF
3
, or
—O(CH
2
)
0-2
R
8
—COOCH
2
CH
3
, NO
2
, CF
3
,
aryl, unsubstituted, monosubstituted or disubstituted with
OCH
3
,
halogen;
CN,
NO
2
,
CF
3
,
OCF
3
,
OCH
2
Ph,
OCH
2
CH
2
Ph,
COOEt,
C
1-4
alkyl, or
phenyl,
phenyloxy,
halogen, or
R
6
and R
5
form a 5 membered heterocyclic ring having 1 or 2 heteroatoms;
R
7
is
phenyl,
CH
2
OCH
3
,
C
3-6
cycloalkyl,
R
8
is
phenyl; and
Ar
1
and Ar
2
are independently aryl or heteroaryl; and
Q is —C(O)C
1-10
alkyl, —C
1-10
alkyl, or —CH
2
C
3-10
cycloalkyl.
In a class of compounds of the invention, R
2
is hydrogen.
In a group of this class of compounds, R is hydrogen, F, Cl, I, CH
3
, —OCF
3
, SCH
3
, SOCH
3
, SO
2
CH
3
, CN, NO
2
, or phenyl.
Specific embodiments of this group of compounds include
and pharmaceutically acceptable salts thereof.
The term “alkyl” means straight or branched alkane containing 1 to about 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 straight or branched alkene containing 2 to about 10 carbon atoms, 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 straight or branched alkyne containing 2 to about 10 carbon atoms, 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 straight or branched alkane containing 1 to about 10 carbon atoms bonded to an oxygen atom, which is attached to the indicated substituted atom, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy; isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, radicals 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 “heteroaryl means a partially or fully saturated 5 or 6-membered ring system having 1 or 2 heteroatoms selected from the group consisting of N, O, and S, for example, pyridine, furan, pyrazine, pyrimidine, thiophene, pyran, pyrrole, thiazole, isoxazole, triazine, and furazan.
Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is described first followed by the adjacent functionality toward the point of attachment. For example, a methylene substituted with ethylcarbonylamino is equivalent to
The term “cycloalkyl” means straight or branched alkane containing 3 to about 10 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexy, cycloheptyl, cyclooctyl radicals and the like.
The term “heterocyclic” or “heterocycle” means a cyclic ring system containing 3 to about 10 atoms, at least one of which is a heteroatom selected from the group conistsing of N, O and S. With “n” representing the total number of ring atoms, the maximum number of heteroatoms present in the ring is equal to the number represented by one-half of “n” when n is 4, 6, 8, or
Barrow James C.
Connolly Thomas
Freidinger Roger M.
Nantermet Philippe G.
Selnick Harold G.
Camara Valerie J.
Coleman Brenda
Merck & Co. , Inc.
Parr Richard S.
Winokur Melvin
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