Compounds derived from an amine nucleus and pharmaceutical...

Details Compounds derived from an amine nucleus and pharmaceutical... Compounds derived from an amine nucleus and pharmaceutical...

2001-11-29

2003-07-22

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S378000, C548S215000, C548S233000, C548S240000, C548S245000

Reexamination Certificate

active

06596747

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to compounds that have multiple beneficial pharmacological effects, and more particularly, to aryl amine-based compounds that inhibit activity of Factor VIIa and/or IMPDH enzyme. The compounds of the present invention and pharmaceutical compositions containing them advantageously may be used as therapeutic agents for treating disorders associated with the activity of Factor VIIa and/or IMPDH.
BACKGROUND OF THE INVENTION
Inosine monophosphate dehydrogenase (IMPDH) has been shown to be a key enzyme in the regulation of cell proliferation and differentiation. IMPDH is involved in the de novo synthesis of guanosine nucleotides, which are required for cells to divide and replicate. Because B and T lymphocytes depend on the de novo pathway, inhibitors of IMPDH have been shown to possess immunosuppressive activities, as well as antineoplastic, antiviral, and antiparasitic activities. IMPDH inhibitors have been proven advantageous in mammals—e.g. the prodrug of MPA (CellCept®) and other IMPDH inhibitors are useful drugs for treating transplant rejection and autoimmune disorders, including HIV. Various other IMPDH inhibitors are in clinical studies, including Vertex compound (VX-497), and/or have been approved for use in humans. See, e.g., Compilation,
Current Medicinal Chemistry,
Vol. 6, No. 7 (July 1999), Contents: Inhibition of Inosine Monophosphate Dehydrogenase (IMPDH), at 519 (“Over 300 literature citations now address the characterization, mechanism, and biological functions of IMPDH, its role as a target for both antileukemic and immunosuppressive therapy, and its inhibition by chemotherapeutic agents.”)
Coagulation factors circulating in the blood, including Factors VII, IX, X, and XI, participate in a series of reactions to produce thrombin and trigger blood coagulation. When the coagulation system is triggered (e.g., when trauma occurs), the coagulation factors are transformed into activated factors (e.g., Factors VIIa, IXa, Xa, XIa, etc.). The activated factors undergo an ordered series of reactions that ultimately lead to the conversion of Factor X to Factor Xa, which then catalyzes the conversion of prothrombin to thrombin. Thrombin is an enzyme that occupies a central position in the coagulation process. Disturbances in the natural balance between pro- and anti-coagulant forces may result in bleeding and/or thrombotic diseases. Consequently, an elevated plasma level of coagulation factors, particularly Factor VIIa, is a risk factor for fatal myocardial infarction and associated with coronary artery disease and other abnormalities of the coagulation system, e.g., thrombosis, ischemic vascular disease, intravascular clotting, stroke, embolisms, and so forth. Inhibitors of Factor VIIa may prove useful in treating these and other diseases.
As may be appreciated, those in the field of pharmaceutical research continue to seek to develop new compounds and compositions having increased effectiveness and bioavailability and/or having fewer side effects. There is particularly an interest in developing agents that can selectively and directly inhibit key enzymes and proteins having significant biolological effects such as IMPDH and Factor VIIa. The compounds of this invention are useful as inhibitors of IMPDH and/or Factor VIIa, and thus may have multiple beneficial pharmacological properties.
SUMMARY OF THE INVENTION
The present invention provides compounds of the following formulae (I), their enantiomers, diastereomers, tautomers and pharmaceutically acceptable salts, prodrugs and solvates thereof:
wherein:
D is a monocyclic or bicyclic ring system optionally containing up to 4 heteroatoms selected from N, O, and S, and wherein a CH
2
adjacent to any of said N, O or S heteroatoms is optionally substituted with oxo (═O), and wherein D is optionally substituted by one to four (CR
9
R
10
)
n
E groups;
A is R
3
or R
4
, provided that if A is R
3
, then D is a monocyclic or bicyclic heterocyclic ring system wherein a CH
2
adjacent to any of N, O or S heteroatoms in said ring is optionally substituted with oxo (═O), and wherein D is optionally substituted by one to four (CR
9
R
10
)
n
E groups;
R
3
is a 5- or 6-membered saturated or unsaturated heterocyclic ring system containing up to 4 heteroatoms selected from N, O, and S, said heterocyclic ring system being optionally substituted with 0-3 R
5
, wherein when R
5
is hydroxy, the heterocycle may undergo tautomerization to an oxo species, or exist as an equilibrium mixture of both tautomers;
R
4
is selected from H, halogen, NO
2
, CF
3
, C
0
-C
4
alkylCN, C
1
-C
4
alkoxy-, C
0
-C
4
alkylhydroxy, C
1
-C
4
alkyl-, C
1
-C
4
alkylcarbonyl-, C
0
-C
4
alkylOCOR
6
, C
0
-C
4
alkylOC(═O)OR
6
, C
0
-C
4
alkylOC(═O)NR
6
R
7
, C
0
-C
4
alkylNR
6
R
7
, C
0
-C
4
alkylNR
7
C(═O)OR
6
, C
0
-C
4
alkylNR
6
SO
2
NR
6
R
7
, C
0
-C
4
alkylNR
7
SO
2
R
6
, C
0
-C
4
alkylSR
6
, C
0
-C
4
alkylS(O)R
6
, C
0
-C
4
alkylSO
2
R
6
, SO
3
R
7
, C
0
-C
4
alkylSO
2
NR
6
R
7
, C
0
-C
4
alkyl SO
2
NR
7
CO(CR
9
R
10
)
q
R
6
, C
0
-C
4
alkylCO
2
R
6
, C
0
-C
4
alkylCONR
6
R
7
, and C
0
-C
4
CONR
7
SO
2
(CR
9
R
10
)
q
R
6
;
R
5
is selected from H, halogen, NO
2
, C
1
-C
4
alkyl, C
3
-C
10
cycloalkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, haloalkyl, haloalkoxy, OH, oxo, C
1
-C
4
alkoxy, C
1
-C
4
alkylcarbonyl, CN, NR
6
R
7
, SR
7
, S(O)R
7
, SO
2
R
7
, SO
3
R
7
, SO
2
NR
6
, CO
2
R
6
, and CONR
6
R
7
;
R is H or C
1
-C
4
alkyl;
R
1
and R
2
are each independently selected from H, halogen, NO
2
, C
1
-C
4
alkyl, C
3
-C
10
cycloalkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, haloalkyl, haloalkoxy, OR
6
, O(CR
9
R
10
)
r
CO
2
R
6
, O(CR
9
R
10
)
m
NR
6
R
7
, O(CR
9
R
10
)
p
CN, O(CR
9
R
10
)
r
C(═O)NR
6
R
7
, C
1
-C
4
alkylcarbonyl-, CN, NR
6
R
7
, NR
7
(CR
9
R
10
)
r
CO
2
R
6
, NR
7
OR
6
, NR
7
(CR
9
R
10
)
m
OR
6
, NR
7
CH[(CR
9
R
10
)
p
OR
6
]
2
, NR
7
C[(CR
9
R
10
)
p
OR
6
]
3
, NR
7
C(═O)R
6
, NR
7
(CR
9
R
10
)
m
OR
6
, NR
7
(CR
9
R
10
)
m
NR
6
R
7
, NR
7
(CR
9
R
10
)
m
SO
2
(CR
9
R
10
)
q
R
6
, SR
7
, S(O)R
7
, SO
2
R
7
, SO
2
NR
6
, SO
3
R
7
, CO
2
R
6
, and CONR
6
R
7
; or, alternatively, R
1
and R
2
, when on adjacent carbon atoms, may be taken together to be methylenedioxy or ethylenedioxy;
R
6
, R
7
and R
8
are each independently selected from H, C
1
-C
6
alkyl, C
3
-C
10
cycloalkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
1
-C
6
alkylcarbonyl, C
3
-C
7
cycloalkyl(C
0
-C
5
alkyl)carbonyl, C
1
-C
6
alkoxycarbonyl, aryl(C
0
-C
5
alkyl)carbonyl, aryl(C
1
-C
5
alkoxy)carbonyl, heterocyclic(C
0
-C
5
alkyl)carbonyl, heterocyclic(C
1
-C
5
alkoxy)carbonyl, C
1
-C
6
alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C
0
-C
4
alkylaryl, C
0
-C
4
alkylheterocyclic, wherein said cycloalkyl, aryl or heterocyclic groups are substituted with 0-2 substituents independently selected from the group consisting of C
1
-C
4
alkyl, hydroxy, C
1
-C
4
alkoxy, F, Cl, Br, haloalkyl, NO
2
and CN;
or, alternatively, R
6
and R
7
, or R
6
and R
8
, or R
7
and R
8
, when both substituents are on the same nitrogen atom [as in (—NR
6
R
7
) or (—NR
7
R
8
)], can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclo[3,2,2]nonan-3-yl, and 1-tetrazolyl, said heterocycle being optionally substituted with 0-3 groups selected from oxo, C
0
-C
4
alkylOH, C
0
-C
4
alkylOC
1
-C
4
alkyl, C
0
-C
4
alkylCONH
2
, C
0
-C
4
alkylCO
2
C
0
-C
4
alkyl, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, C
3
-C
7
cycloalkyl, —C
0
-C
6
alkylcarbonyl, C
3
-C
7
cycloalkylcarbonyl, C
1
-C
6
alkoxycarbonyl, C
3
-C
7
cycloalkoxycarbonyl, —NHCOalkyl, aryl, heteroaryl, arylalkoxycarbonyl, heteroarylalkoxycarbonyl, C
1
-C
6
alkylsulfonyl, arylsulfonyl and heteroarylsulfonyl;
B is a monocyclic or bicyclic ring system optionally containing up to 4 heteroatoms selected from N, O, and S, and wh

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