Method of treating noninflammatory cartilage damage

Details Method of treating noninflammatory cartilage damage Method of treating noninflammatory cartilage damage

2001-09-14

2003-09-16

Padmanabhan, Sreeni (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S365000, C514S359000, C514S360000, C514S372000, C514S374000, C514S383000, C514S385000, C514S439000, C514S438000, C514S600000, C514S613000

Reexamination Certificate

active

06620829

ABSTRACT:

This invention relates to a method of preventing or treating cartilage damage by administering a gamma-aminobutyric acid (GABA)analog.
BACKGROUND OF THE INVENTION
Cartilage damage is a major problem that afflicts many people worldwide. Many people engaged in athletic activities suffer from sprains and torn cartilage resulting from the physical activity. Cartilage damage is particularly prevalent within the aging population, as it generally is associated with degenerative diseases such as osteoarthritis.
Osteoarthritis (OA) is primarily a disorder of cartilage and subchondral bone, although other tissues in and around affected joints are involved. OA is a result of a complex system of interrelated mechanical, biochemical, and molecular mechanisms. OA is itself noninflammatory, although the cartilage damage that accompanies OA can initiate an inflammatory process secondary to OA. Many mechanisms can initiate the cellular and tissue events that constitute a final common pathway for osteoarthritis, including: congenital joint abnormalities; genetic defects (primary generalized OA); infectious, metabolic, endocrine, and neuropathic diseases; virtually any disease process that alters the normal structure and function of hyaline cartilage (e.g., RA, gout, chondrocalcinosis); and acute or chronic trauma (including fracture) to the hyaline cartilage or tissue surrounding it (e.g., prolonged overuse of a joint or group of joints, as in certain occupations—foundry work, coal mining, and bus driving).
Treatment includes rehabilitation, patient education, drug therapy, and surgery when all conservative treatment has failed. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are the primary agents used to treat OA-related pain. These agents inhibit prostaglandin release by blocking cyclooxygenase-mediated conversion of cell membrane lipids from arachidonic acid. Muscle relaxants used to treat OA include diazepam, cyclobenzaprine, carisoprodol, and methocarbamol (usually in low doses). Analgesic drugs occasionally may be useful. Tricyclic antidepressants may be helpful for depressed patients. Each of these drugs only treat secondary conditions associated with cartilage damage such as inflammation, muscle tension, pain, or depression, but do not prevent or treat the primary condition, which is damage to the cartilage.
PCT International Application Publication No. WO 98/58641 describes a method of preventing and treating inflammatory diseases comprising administering to a subject suffering from such disease or suspected of developing such disease and in need of treatment an effective amount of a GABA analog. A preferred embodiment utilizes a cyclic amino acid compound of Formula I:
wherein R
1
is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the pharmaceutically acceptable salts thereof. Another preferred embodiment utilizes a GABA analog of Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
R
1
is straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl of from 3 to 6 carbon atoms;
R
2
is hydrogen or methyl; and
R
3
is hydrogen, methyl, or carboxyl.
U.S. Pat. No. 6,001,876 describes a method of treating pain, especially for treatment of chronic pain disorders, using a compound of Formula II above.
PCT International Application Publication No. WO 99/37296 describes a method of treating muscular and skeletal pain comprising administering to a subject suffering from such pain an effective amount of a GABA analog, especially a compound of Formula I or II above.
However, applicant's remarkable discovery—disclosed in the instant application—that GABA analogs having the characteristic of being inhibitors of cartilage damage, or a pharmaceutically acceptable salt thereof, are useful for preventing or treating cartilage damage is not found or suggested in WO 98/58641, U.S. Pat. No. 6,001,876, or WO 99/37296.
Because many agents used to prevent or treat diseases with a component of cartilage damage actually treat secondary aspects such as inflammation or pain, but do not prevent or treat the damage to cartilage that underlies the diseases, the need for new therapies continues. We have now discovered the surprising result that a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof, are useful to prevent or treat cartilage damage. All that is required to prevent and/or treat the cartilage damage according to the invention is to administer to a subject in need of treatment a cartilage damage preventing and/or treating amount of a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof. None of the above references teach the instant method of preventing and/or treating cartilage damage.
Several GABA analogs are known. Gabapentin, a cyclic GABA analog, is now commercially available (Neurontin®, Warner-Lambert Company) and extensively used clinically for treatment of epilepsy and neuropathic pain. Such cyclic GABA analogs are described in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No. 4,087,544. Another series of GABA analogs is described in U.S. Pat. No. 5,563,175.
SUMMARY OF THE INVENTION
This invention provides a method of preventing or treating cartilage damage in a mammal suffering therefrom, comprising administering a therapeutically effective amount of a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof.
A preferred embodiment of the invention method utilizes a GABA analog that is a cyclic amino acid compound of Formula I:
wherein R
1
is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the pharmaceutically acceptable salts thereof. An especially preferred embodiment utilizes a compound of Formula I where R
1
is hydrogen and n is 5, which compound is 1-(aminomethyl)-cyclohexane acetic acid, known generically as gabapentin. Other preferred GABA analogs, or a pharmaceutically acceptable salt thereof, are compounds of Formula I wherein the cyclic ring is substituted, for example with alkyl such as methyl or ethyl. Typical of such compounds include (1-aminomethyl-3-methylcyclohexyl) acetic acid, (1-aminomethyl-3-methylcyclopentyl) acetic acid, and (1-aminomethyl-3,4-dimethylcyclopentyl) acetic acid.
In another preferred embodiment, the invention method utilizes a GABA analog of Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
R
1
is a straight or branched unsubstituted alkyl of from 1 to 6 carbon atoms, unsubstituted phenyl, or unsubstituted cycloalkyl of from 3 to 6 carbon atoms;
R
2
is hydrogen or methyl; and
R
3
is hydrogen, methyl, or carboxyl.
Diastereomers and enantiomers of compounds of Formula II can be utilized in the invention method.
An especially preferred embodiment of the invention method employs a compound of Formula II where R
2
and R
3
are both hydrogen, and R
1
is —(CH
2
)
0-2
−
i C
4
H
9
as an (R), (S), or (R,S) isomer.
A more preferred embodiment of the invention method utilizes a compound of Formula II named 3-aminomethyl-5-methyl-hexanoic acid, or especially (S)-3-(aminomethyl)-5-methylhexanoic acid, now known generically as pregabalin. Pregabalin is also known as “CI-1008” and “S-(+)-3-IBG.”
Another preferred embodiment of the invention method utilizes a compound of Formula II named 3-(1-aminoethyl)-5-methylheptanoic acid or 3-(1-aminoethyl)-5-methylhexanoic acid.
Another preferred embodiment of the invention method utilizes a GABA analog that is a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH:
or a pharmaceutically acceptable salt thereof wherein:
n is an integer of from 0 to 2;
m is an integer of from 0 to 3;
R is sulfonamide,
amide,
phosphonic acid,
heterocycle,
sulfonic acid, or
hydroxamic acid;
A′ is a bridged ring selected from:
 wherein
 is the point of attachment;
Z
1
to Z
4
are each independently selected from hydrogen and methyl;
o is an integer of from 1 to 4; and
p is an integer of from 0

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