N-terminal D(-)-penicillamine peptides as aldehyde...

Details N-terminal D(-)-penicillamine peptides as aldehyde... N-terminal D(-)-penicillamine peptides as aldehyde...

2000-12-22

2004-02-03

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S329000, C530S330000, C530S331000, C514S018700, C562S558000

Reexamination Certificate

active

06686336

ABSTRACT:

BACKGROUND
The metabolism of low molecular weight primary alcohols, such as methanol and ethanol, produces aldehydes which are toxic to mammals. When ethanol is metabolized, for example, acetaldehyde (AcH) is produced. Similar to many other aldehydes that are present in the environment or produced by metabolism of an alcohol, acetaldehyde is a toxic compound that may play an etiologic role in the initiation of alcoholic liver disease (ALD), as well as in ethanol-associated digestive cancers in Asian populations with low activity aldehyde dehydrogenase 2 (ALDH-2). Chronic alcoholics have higher blood AcH levels compared to non-alcoholics after consuming alcoholic beverages and are, therefore, more susceptible to its toxic effects. It is now well-established that this ethanol-derived AcH binds covalently to cellular proteins and such AcH modified proteins can elicit an immune response manifested by formation of antibodies to these AcH-bound epitopes. In rodents treated with ethanol, AcH binds to hemoglobin and other plasma proteins, to tubulin, and to a specific cystolic liver protein, as well as to liver collagen. AcH-protein conjugates of hemoglobin have also been detected in humans after consumption of alcohol.
Based on the premise that AcH may play an etiologic role in alcohol-related diseases, the development of AcH sequestration agents has been pioneered. Structure-activity studies suggest that the ideal AcH sequestering agent should have an acidic functional group to impart water solubility, and 1,2- or 1,3-disubstitution with functional groups such as sulfhydryl, amino, or hydroxyl. Of the trifunctional compounds tested that met these requirements, only &bgr;-mercapto-&agr;-amino acids with one or two substituents at the &bgr;-position were effective in sequestering AcH in vivo. Thus, as depicted in
FIG. 1
, D(−)-penicillamine (1) and &bgr;,&bgr;-tetramethylene-DL-cysteine (2) were found to be the best &bgr;-mercapto-&agr;-amino acid sequestration agents for AcH in vivo (see Nagasawa et al.,
J. Med. Chem,
1987, 1373-1378).
Although 1 is used clinically to treat Wilson's disease and hereditary cystinuria and to treat rheumatoid arthritis refractory to conventional therapy, its potential for renal and hematological toxicity limits its usefulness as a sequestration agent for AcH. Accordingly, there continues to be a need for aldehyde sequestering agents. Such agents may preferably have improved properties (e.g., reduced toxicity compared to existing agents). There is also a need for pharmacological tools for the further study of the physiological processes associated with alcohol-related diseases and ambient exposure to toxic alcohols and aldehydes.
SUMMARY OF THE INVENTION
These and other needs are met by the present invention which provides aldehyde sequestering agents. Accordingly there is provided a compound of the invention which is a compound of formula I:
wherein
R
1
is an amino acid or peptide; and
R
2
and R
3
are each independently, hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, or (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl; or R
2
and R
3
together with the carbon to which they are attached form a 3, 4, 5, or 6-membered carbocyclic or heterocyclic ring, optionally substituted on carbon with (C
1
-C
6
)alkyl, (C
1
-C
6
)haloalkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, or (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkoxy;
or a salt thereof,
provided R
2
and R
3
are not both hydrogen.
The invention also provides synthetic intermediates useful for preparing a compound of formula I. Accordingly, the invention also provides a compound of formula II:
wherein
R
1
is an amino acid or peptide;
R
2
and R
3
are each independently, hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, or (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl; or R
2
and R
3
together with the carbon to which they are attached form a 3, 4, 5, or 6-membered carbocyclic or heterocyclic ring, optionally substituted on carbon with (C
1
-C
6
)alkyl, (C
1
-C
6
)haloalkyl, (C
3
-C
6
)cycloalkyl, (C
3-
C
6
)cycloalkyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, or (C
3-
C
6
)cycloalkyl(C
1
-C
6
)alkoxy, provided R
2
and R
3
are not each hydrogen;
R
4
and R
5
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, or (C
3-
C
6
)cycloalkyl(C
1
-C
6
)alkyl; or R
4
and R
5
together with the carbon to which they are attached form a 3, 4, 5, or 6-membered carbocyclic or heterocyclic ring, optionally substituted on carbon with (C
1
-C
6
)alkyl, (C
1
-C
6
)haloalkyl, (C
3
-C
6
)cycloalkyl, (C
3-
C
6
)cycloalkyl(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, or (C
3-
C
6
)cycloalkyl(C
1
-C
6
)alkoxy; and
R
6
is R
a
—C═O—), wherein R
a
hydrogen, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)(cycloalkyl)alkyl, or aryl;
provided R
4
and R
5
are not both hydrogen.
The invention also provides a composition comprising a compound of formula I, or a salt thereof, in combination with a diluent or carrier.
The invention also provides a therapeutic method for treating toxic exposure to an aldehyde in a mammal, comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula I, or a salt thereof.
The invention also provides a method for controlling body odor associated with the secretion of an aldehyde by a mammal, comprising administering to a mammal in need thereof an effective amount of a compound of formula I, or a salt thereof.
The invention provides a therapeutic method for preventing or treating an alcohol-related disease in a mammal, comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula I, or a salt thereof.
The invention also provides a compound of formula I, or a salt thereof, for use in medical therapy (preferably for use in sequestering toxic aldehydes in vivo in mammals) as well as the use of a compound of formula I, or a salt thereof, for the manufacture of a medicament useful for the treatment of an alcohol related disease in a mammal (e.g. a human).
The invention also provides a method for sequestering aldehydes from an emission stream of a source of air pollution comprising contacting the emission stream with a compound of formula I or a salt thereof.


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patent: 5106834 (1992-04-01), Bovy et al.
patent: 5112741 (1992-05-01), Palmer et al.
patent: 5202354 (1993-04-01), Matsuoka et al.
patent: 5525481 (1996-06-01), Kaufman et al.
patent: 93/10747 (1993-06-01), None
patent: 99/03879 (1999-01-01), None
“L- and D-Pencillamine Hydrochlorides”,In: Biochemical Preparations, Biochemical Preparations, Inc., pp. 111-118, (1953).
Alexander, C.S., et al., “Lowering of Blood Acetaldehyde Levels—A Possible Approach to Prevention of Alcoholic Cardiomyopathy”,Recent Advances in Studies on Cardiac Structure and Metabolism, vol. 12, Cardiac Adaptation, pp. 345-350, (1978).
Aschwanden, C., “The smell of age”,Modern Drug Discovery, p. 58, (Sep.).
Cohen, J.F., et al., “N-Terminal Dipeptides of D(-)-Penicillamine as Sequestering Agents for Acetaldehyde”,Journal of Medicinal Chemistry, pp. 5 p., (1999).
Goldstein, J.L., et al., “Nonfarnesylated Tetrapeptide Inhibitors of Protein Farnesyltransferase”,The Journal of Biological Chemistry, 266, 15575-15578, (1991).
Magnier, M., “It Stinks: The Smell of Aging”,Los Angeles Times, p. 60-62, (Jul. 14, 1999).
Nagasawa, H.T., et al., “2,5,5-Trimethylthiazolidine-4-carboxylic Acid, a D(-)-Penicillamine-Directed Pseudometabolite of Ethanol. Detoxication Mechanism for Acetaldehyde”,Journal of Medicinal Chemistry, pp. 1274-1279, (Dec. 1978).
Nagasawa, H.T., et al., “Beta-Substituted Cysteines as Sequestering Agents for Ethanol-Derived Acetaldehyde”,J. Med. Chem., 30, 1373-1378, (1987).
Nagasawa, H.T., et al., “Chapter 3: Alcoholism: Aldehyde Dehydrogenase Inhibitors as Alcohol Deterrent Agents”,In: Biomedical Chemistry: Applying Chemical Principles to the Understanding and Treatment of Disease, P.F. Torrence, Ed., Wiley-Interscience, pp. 73-97, (2000).
Nagasawa, H.T., et al., “Lowering of Blood A

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