Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1998-07-06
2001-05-01
Kumar, Shailendra (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C560S312000, C560S070000, C560S070000, C560S070000, C562S444000, C562S621000, C514S563000, C514S567000
Reexamination Certificate
active
06225351
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to N-(aroyl)glycine hydroxamic acid derivatives and related compounds that are selective inhibitors of phosphodiesterase (PDE) type IV or of the production of tumor necrosis factor (TNF) and as such are useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases as well as AIDS, sepsis, septic shock, cachexia, and other diseases involving the production of TNF. The compounds of this invention may have combined PDE type IV and TNF inhibitory activity. The present invention also relates to the use of such compounds in the treatment of the above diseases in mammals, particularly humans, and to pharmaceutical compositions useful therefor.
Since the recognition that cyclic AMP is an intracellular second messenger (E. W. Sutherland, and T. W. Rall,
Pharmacol. Ref.,
1960, 12, 265), inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized (J. A. Beavo and D. H. Reifsnyder,
TIPS,
1990, 11, 150), and their selective inhibition has led to improved drug therapy (C. D. Nicholson, R. A. Challiss and M. Shahid,
TIPS,
1991, 12, 19). More particularly, it has been recognized that inhibition of PDE type IV can lead to inhibition of inflammatory mediator release (M. W. Verghese et al.,
J. Mol. Cell Cardiol.,
1989, 12, (Suppl. II), S 61) and airway smooth muscle relaxation (T. J. Torphy in
Directions for New Anti-Asthma Drugs
, eds S. R. O'Donnell and C. G. A. Persson, 1988, 37, Birkhauser-Verlag). Thus, compounds that inhibit PDE type IV, but which have poor activity against other PDE types, inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects.
TNF is recognized to be involved in many infectious and auto-immune diseases, including cachexia (W. Friers,
FEBS Letters,
1991, 285, 199). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C. E. Spooner et al.,
Clinical Immunology and Immunopatholoty,
1992, 62, S 11).
SUMMARY OF THE INVENTION
The invention relates to compounds of formula
or a pharmaceutically acceptable salt thereof,
wherein R
1
is selected from the group consisting of methyl, ethyl, difluoromethyl and trifluoromethyl;
R
2
is (C
1
-C
6
)akyl, (C
3
-C
7
)alkoxy(C
2
-C
4
)alkyl, phenoxy(C
2
-C
6
)alkyl, (C
3
-C
7
)cycloalkyl, (C
6
-C
9
)polycycloalkyl, phenyl(C
1
-C
8
)alkyl or indanyl wherein the alkyl portion of said R
2
groups is optionally substituted with one or more fluorine atoms and the aromatic portion of said R
2
groups is optionally substituted with one or more substituents independently selected from the group consisting of (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy and halogen;
AA is (AA-1) or (AA-2) wherein:
(AA-1) is
wherein R
3
and R
4
are independently selected from the group consisting of hydrogen, trifluoromethyl, (C
1
-C
6
)alkyl, —(CH
2
)
n
CO
2
H, —(CH
2
)
n
CONH
2
, —(CH
2
)
n
phenyl, —(CH
2
)
x
OH, and —(CH
2
)
x
NH
2
, wherein x ranges from 1 to 5, n ranges from 0 to 5, R
5
is hydrogen, OH or (C
1
-C
6
)alkyl, and m ranges from 0 to 5; and,
(AA-2) is
wherein p ranges from 1 to 4; and,
Y is NHOH or OH.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties.
The term “alkoxy”, as used herein, includes O-alkyl groups wherein “alkyl” is defined above.
The term “cycloalkyl”, as used herein, Includes saturated monovalent cyclo hydrocarbon radicals including cyclobutyl, cyclopentyl and cycloheptyl.
The term “polycycloalkyl”, as used herein, includes saturated monovalent polycyclo radicals comprising ring assemblies that are fused, bicyclo or tricyclo. Such ring assemblies include bicycloheptyl, bicyclobutyl, tricyclooctanyl and perhydropentalenyl.
The term “aryl”, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (C
1
-C
6
)alkoxy, (C
6
-C
10
)aryloxy, trifluoromethoxy, difluoromethoxy and (C
1
-C
6
)alkyl.
The term “treatment” as used herein, unless otherwise indicated, includes (i) methods to cure, relieve or lessen the undesirable effects of, or the undesirable symptoms associated with, conditions and diseases that respond to the inhibition of PDE type IV or the inhibition of the production of TNF, where such conditions and diseases are actively occurring in a mammal, including a human, and (ii) methods to prevent such conditions and diseases from occurring in a mammal, and (iii) methods to slow the onset of such conditions and diseases in a mammal. The terms “treat” and “treating” as used herein are defined in accord with the above definition.
The term “therapeutically effective amount” as used herein, unless otherwise indicated, means an amount effective to inhibit PDE type IV or inhibit the production of TNF, or an amount effective in the treatment, as defined above, of a condition or disease that responds to the inhibition of PDE type IV or the inhibition of the production of TNF.
The compounds of formula I include certain compounds having chiral centers which therefore exist in different enantiomeric forms. This invention relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof.
Preferred compounds of formula I include those in which R
1
is methyl.
Other preferred compounds of formula I include those in which R
2
is cyclopentyl.
Other preferred compounds of formula I include those in which AA is the moiety (i) and R
3
is hydrogen, methyl, trifluoromethyl or —CH
2
OH.
Other preferred compounds of formula I include those in which AA is the moiety (AA-1) and R
4
is hydrogen.
Other preferred compounds of formula I include those in which AA is the moiety (AA-1) and R
6
is hydrogen.
Other preferred compounds of formula I include those in which AA is the moiety (AA-1) and m is 0.
Other preferred compounds of formula I include those in which Y is —NHOH.
Specific preferred compounds of formula I include the following:
&agr;-monofluoromethyl-&agr;-N-[(3-cyclopentyloxymethoxy-4-methoxy)benzoyl]glycine hydroxamic acid;
&agr;-difluoromethyl-&agr;-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid;
&agr;-ethyl-&agr;-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid;
&agr;-propyl-&agr;-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid;
&agr;-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]-D-cystine hydroxamic acid;
&agr;-trifluoromethyl-&agr;-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid;
&agr;-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]-D-serine hydroxamic acid;
&agr;-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]glycine hydroxamic acid; and,
&agr;-N-[(3-cyclopentyloxy-4-methoxy)benzoyl]-D-alanine hydroxamic acid.
The present invention further relates to a pharmaceutical composition for the inhibition of PDE type IV or the inhibition of the production of TNF in a mammal, including a human, comprising a therapeutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention further relates to a pharmaceutical composition for the treatment of a condition or disease selected from the group consisting of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis, AIDS, septic shock and other conditions or diseases that respond to the inhibition of PDE type IV or the inhibition of the production of TNF in a mammal, including a human, comprising a
Fuller Jr. Grover F.
Ginsburg Paul H.
Kumar Shailendra
Pfizer Inc.
Richardson Peter C.
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