Xanthine phosphodiesterase V inhibitors

Details Xanthine phosphodiesterase V inhibitors Xanthine phosphodiesterase V inhibitors

2001-08-28

2004-11-23

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S257000, C514S263100, C514S263340, C514S213010, C544S262000, C544S245000, C544S264000, C544S267000

Reexamination Certificate

active

06821978

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to polycyclic nucleotide xanthine phosphodiesterase V inhibitors.
2. Description of Related Art
Phosphodiesterase (“PDE”) V inhibitor compounds are described by Kenneth J. Murray in
Phosphodiesterase V
A
Inhibitors, DN & P
6(3), pp. 150-156 (April, 1993), which is hereby incorporated herein by reference in its entirety, to have potential therapeutic value for a number of physiological disorders. One compound disclosed in the Murray article is MIMAX, a polycyclic xanthine PDE V inhibitor substituted at its 8-position with a —NHCH
3
group.
U.S. Pat. No. 5,409,934, which is hereby incorporated herein by reference in its entirety, discloses a series of xanthine PDE V inhibitors that are substituted at the 8-position with, among other possibilities, one of the following groups: —NO
2
, —NR
s
R
t
or —NR
6
SO
2
R
5
, where R
s
and R
t
, independently of one another, are each a hydrogen atom or an alkyl group, or R
s
and R
t
, together with the nitrogen atom to which they are both attached, form a phthalimido group, R
5
is an alkyl or aryl group, and R
6
is a hydrogen atom or —SO
2
R
7
, where R
7
is an alkyl or aryl group.
U.S. Pat. No. 5,470,579, which is hereby incorporated herein by reference in its entirety, discloses a xanthine PDE V inhibitor having a substituted or unsubstituted —NH
2
group at the 8-position, for example, —NHR, where R is a C
1
-C
6
alkyl group.
WO 93/23401, which is hereby incorporated herein by reference in its entirety, discloses xanthine PDE V inhibitors that are substituted at the 8-position with —NH(CH
2
)
2
CH(CH
2
OR
4
)
2
.
WO 92/05176, which is hereby incorporated herein by reference in its entirety, discloses 8-acylaminoxanthine PDE V inhibitors that are substituted at the 8-position with —NHCOC
6
H
5
COOH.
WO 92/05175, which is hereby incorporated herein by reference in its entirety, discloses 8-aminoxanthine PDE V inhibitors that are substituted at the 8-position with —NH
2
or —NHR, where R is an alkyl, arylalkyl or unsaturated heterocyclic (e.g., heteroaryl) group.
Specific PDE V inhibitors have been found useful for specific indications. For example, the use of PDE V inhibitors for treating impotence has met with commercial success with the introduction of sildenafil citrate, better known as Viagra® (Pfizer, N.Y., N.Y.). The chemistry and use of Viagra®, including its mechanism of action in treating erectile dysfunction, are taught in EP 0 702 555 B1, which is hereby incorporated herein by reference in its entirety. Additional PDE V inhibitors useful for treating erectile dysfunction are disclosed in WO 99/24433, which is hereby incorporated herein by reference in its entirety.
Erectile dysfunction is a treatable and highly recognized health concern, affecting more than 30 million men in the United States, including one in four over age 65. Erectile dysfunction occurs when a man consistently is unable to sustain an erection sufficient for conducting sexual intercourse. In the past, psychological reasons were the most common explanation for erectile dysfunction or it was considered a natural part of aging. However, researchers today acknowledge that more than 70 percent of instances of erectile dysfunction are due to physical or medical problems. There are several factors that may contribute to erectile dysfunction, including:
Poor blood circulation—atherosclerosis or hardening of the arteries, high blood pressure and high cholesterol.
Neurological disorders—multiple sclerosis, Alzheimer's disease and Parkinson's disease.
Hormone imbalances—diabetes, thyroid disorders and low testosterone levels.
Trauma—spinal cord injury, prostate surgery or other trauma to the pelvic area.
Prescription and over-the-counter medications—blood pressure medications, antidepressants and certain drug combinations.
Lifestyle habits—smoking, alcohol abuse and using illegal drugs.
U.S. Pat. No. 5,939,419 and U.S. Pat. No. 5,393,755, both of which are hereby incorporated herein by reference in their entirety, disclose polycyclic guanine PDE V derivatives that are useful for the treatment of cardiovascular and pulmonary disorders.
As has been shown by the representative art cited above, certain xanthine/guanine PDE V inhibitors have been found to be useful for treating cardiovascular and pulmonary disorders, while some others have been found useful for treating impotence. It has been further shown that certain xanthine PDE V inhibitors can be substituted at the 8-position by a variety of groups, including nitro and unsubstituted or substituted amino groups. The substituted amino groups include saturated heterocycles, where the nitrogen atom and its substituents together form an unsaturated heterocyclic group (e.g., —NR
x
R
y
can form a heterocycle).
It is an object of this invention to provide a polycyclic xanthine PDE V inhibitor that possesses beneficial therapeutic properties.
It is a further object of the invention to provide a polycyclic xanthine PDE V inhibitor that has especially useful pharmacological properties.
It is yet another object of the invention to provide a polycyclic xanthine PDE V inhibitor that has good metabolic stability.
It is still another object of the invention to provide a polycyclic xanthine PDE V inhibitor that is effective for treating a variety of physiological symptoms and diseases in which PDE V plays a role.
It is also an object of the invention to provide a polycyclic xanthine PDE V inhibitor that is especially effective for treating erectile dysfunction with minimal side effects.
These and other objects of the invention will become apparent as the description progresses.
Definitions and Usage of Terms
The following definitions and terms are used herein or are otherwise known to a skilled artisan. Except where stated otherwise, the following definitions apply throughout the specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “hydroxyalkyl,” “haloalkyl,” “alkoxy,” etc.
The term “chemically-compatible,” as used herein, means that a substituent or variable in a structure, process or the like is selected to be capable of resulting in a stable compound.
The term “substituted” or the phrase “with . . . one or more substituents,” as used herein, means the replacement of one or more atoms or radicals, usually hydrogen atoms, in a given structure with a chemically-compatible atom(s) or radical(s) selected from a specified group. In the situations where more than one atom or radical may be replaced with substituents selected from the same specified group, the substituents may be, unless otherwise specified, either the same or different at every position. Radicals of specified groups, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, heterocycloalkyl, aryl and heteroaryl groups, independently of or together with one another, may be substituents for any substituted group, unless otherwise known, stated or shown to be to the contrary.
Representative substituents for alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl and heterocycloalkyl groups include, but are not limited to, the following moieties: alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl, heterocycloalkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl, mono-, di- and trihaloalkyl, mono-, di- and trihaloalkoxy, amino, alkylamino, dialkylamino, alkoxy, hydroxy, halo (e.g., —Cl and —Br), nitro, oximino, —COOR
50
, —COR
50
, —SO
0-2
R
50
, —SO
2
NR
50
R
51
, NR
52
SO
2
R
50
, ═C(R
50
R
51
), ═N—OR
50
, ═N—CN, ═C(halo)
2
, ═S, ═O, —CON(R
50
R
|
), —OCOR
50
, —OCON(R
50
R
51
), —N(R
52
)CO(R
50
), —N(R
52
)COOR
50
and —N(R
52
)CON(R
50
R
51
), where:
R
50
, R
51
and R
52
may be indepe

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