Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-30
2002-06-11
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S327000, C514S330000, C514S369000, C514S375000, C514S376000, C514S422000, C546S192000, C546S226000, C548S188000, C548S200000, C548S215000, C548S230000, C548S517000, C548S538000
Reexamination Certificate
active
06403612
ABSTRACT:
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
or a pharmaceutically acceptable salt thereof, wherein
m is 0, 1 or 2;
n is 1, 2 or 3;
R and R
1
are independently selected from the group consisting of
hydrogen,
C
1-10
alkyl,
C
1-10
alkoxy,
aryl, unsubstituted, monosubstituted, independently disubstituted or independently trisubstituted with
C
1-10
alkyl,
halogen,
CN,
NO
2
,
amino C
1-10
alkyl,
CF
3
,
COOR
3
, wherein R
3
is hydrogen or C
1-10
alkyl, or
C(O)R
3
R
4
, wherein R
3
and R
4
are independently hydrogen or C
1-10
alkyl, or
S(O)
p
R
3
, wherein R
3
is hydrogen or C
1-10
alkyl, and wherein p is 0, 1, or 2;
halogen,
CF
3
,
—OCH
3
,
—SCH
3
,
SOCH
3
,
SO
2
CH
3
, or
CN;
X is
CH
2
,
S,
SO,
SO
2
,
CHOR
2
, wherein R
2
is hydrogen or C
1-10
alkyl; and
Ar is
aryl, unsubstituted, monosubstituted, independently disubstituted or independently trisubstituted with
C
1-10
alkyl,
halogen,
CN,
NO
2
,
amino C
1-10
alkyl,
CF
3
,
COOR
5
, wherein R
5
is hydrogen or C
1-10
alkyl,
C(O)R
5
R
6
, wherein R
5
and R
6
are independently hydrogen or C
1-10
alkyl, or
S(O)
p
R
5
, wherein R
5
is hydrogen or C
1-10
alkyl, and wherein p is 0, 1, or 2, or
heteroaryl, unsubstituted, monosubstituted, independently disubstituted or independently trisubstituted with
C
1-10
alkyl,
halogen,
CN,
NO
2
,
amino C
1-10
alkyl,
CF
3
,
COOR
7
, wherein R
7
is hydrogen or C
1-10
alkyl,
C(O)R
7
R
8
, wherein R
7
and R4 are independently hydrogen or C
1-10
alkyl, or
S(O)
p
R
7
, wherein R
7
is hydrogen or C
1-10
alkyl, and wherein p is 0, 1,or2.
In a class of compounds of the invention and pharmaceutically acceptable salts thereof,
m is 1;
n is 1 or 2;
R is
hydrogen, or
C
1-10
alkyl;
R
1
is C(CH
3
)
3
;
X is
CH
2
,
S,
SO,
CHOH,
CHOCH
3
; and
Ar is
aryl, unsubstituted, monosubstituted with halogen, or disubstituted same or different, with halogen.
In a group of this class of compounds and pharmaceutically acceptable salts thereof,
R is
hydrogen,
CH
3
, or
CH
2
CH
3
; and
Ar is
Specific embodiments of this group of compounds and pharmaceutically acceptable salts thereof include
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 aromatic, 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, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of heterocyclic rings include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, isoxazolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole, &bgr;-carbolinyl, phenanthridinyl, .acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The term “heteroaryl” means an aromtaic heterocyclic group, preferably 5 or 6-membered monocyclic ring systems or 8-10 membered fused bicyclic groups, having heteroatoms selected from the group consisting of N, O, and S, for example, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, or isoquinolinyl.
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
Compounds of the present invention may be chiral; included within the scope of the present invention are racemic mixtures and separated enantiomers of the general formula. Furthermore, all diastereomers, including E, Z isomers, of the general formula are included in the
Barrow James C.
Nantermet Philippe G.
Selnick Harold G.
Camara Valerie J.
Covington Raymond
Merck & Co. , Inc.
Parr Richard S.
Rotman Alan L.
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