Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-10-25
2001-12-11
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S729000, C560S122000, C560S123000, C562S504000, C562S505000, C562S507000
Reexamination Certificate
active
06329429
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method for treating inflammatory diseases by administering a gamma-aminobutyric acid (GABA) analog.
BACKGROUND OF THE INVENTION
Inflammatory diseases are characterized by a complex series of histological events, including dilatation of arterioles, capillaries, and venules, with increased permeability and blood flow; exudation of fluids, including plasma proteins; and leukocytic migration into the inflammatory focus. Many forms of inflammation are localized protective responses elicited by injury or destruction of tissues, which serves to destroy, dilute, or wall off both the injurious agent and the injured tissue. The inflammatory response itself is also responsible for pathologic tissue damage. Arthritis is a particularly devastating inflammatory disease, generally affecting older people, and is characterized by the inflammatory lesions being primarily confined to articular joints. The disease is marked by pain, heat, redness, swelling, and tissue destruction. Rheumatoid arthritis is a chronic systemic disease of the joints, marked by inflammatory changes in the synovial tissue and articular structures, and by atrophy and rarefaction of the bones. This form of inflammatory disease generally progresses to deformity and ankylosis.
Numerous anti-inflammatory treatments are known and commonly used. The most common are the nonsteroidal anti-inflammatory agents such as naproxen, diflunisal, mefenamic acid, and ketorolac tromethamine. These agents generally are used to treat short term mild inflammation and pain. More severe inflammatory disease, such as arthritis, are treated with steroidal hormones and glucocorticoids, for example prednisolone, hydrocortisone acetate, and betamethasone sodium phosphate.
Because many of the anti-inflammatory agents are only short acting, and often produce severe side effects, the need for new therapies continue. We have now discovered that compounds which are analogs of gamma aminobutyric acid (GABA) are useful to treat inflammatory diseases. All that is required to prevent or treat the inflammatory disease according to this invention is to administer to a subject in need of treatment an anti-inflammatory amount of a GABA analog.
Several GABA analogs are known. Gabapentin, a cyclic GABA analog, is now commercially available and extensively used clinically for treatment of epilepsy and neuropathic pain. Such compounds are described in U.S. Pat. No. 4,024,175. Another series of GABA analogs is described in U.S. Pat. No. 5,563,175.
SUMMARY OF THE INVENTION
This invention provides a method for 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. 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 have 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 embodiment, the anti-inflammatory method of the invention utilizes a GABA analog of Formula II
or a pharmaceutically acceptable salt thereof, wherein
R
1
is a 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.
Diastereomers and enantiomers of compounds of Formula II can be utilized in the invention.
An especially preferred method of the invention employs a compound 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 utilizes 3-aminomethyl-5-methyl-hexanoic acid, and 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 compound of Formula II is 3-(1-aminoethyl)-5-methylhepanoic acid.
DETAILED DESCRIPTION OF THE INVENTION
As noted above, the method of this invention utilizes any GABA analog. A GABA analog is any compound derived from or based upon gamma-aminobutyric acid, and causes an anti-inflammatory effect in accordance with this invention. The compounds are readily available, either commercially, or by synthetic methodology well-known to those skilled in the art of organic chemistry. The preferred GABA analogs to be utilized in the method of this invention are cyclic amino acids of Formula I. These are described in U.S. Pat. No. 4,024,175 which is incorporated herein by reference. Another preferred method utilizes the GABA analogs of Formula II, and these are described in U.S. Pat. No. 5,563,175 which is incorporated herein by reference.
All that is required to practice the anti-inflammatory method of this invention is to administer a GABA analog in an amount that is effective to prevent or treat the inflammatory condition. Such anti-inflammatory amount will generally be from about 1 to about 300 mg per kg of subject body weight. Typical doses will be from about 10 to about 5000 mg per day for an adult subject of normal weight.
Pharmaceutical compositions of a GABA analog or its salts are produced by formulating the active compound in dosage unit form with a pharmaceutical carrier. Some examples of dosage unit forms are tablets, capsules, pills, powders, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses. Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline, and phosphate buffer solutions; as well as other compatible substances normally used in pharmaceutical formulations. The compositions to be employed in the invention can also contain other components such as coloring agents, flavoring agents, and/or preservatives. These materials, if present, are usually used in relatively small amounts. The compositions can, if desired, also contain other therapeutic agents commonly employed to treat inflammation, for example, aspirin, naprosyn, and similar anti-inflammatory agents.
The percentage of the active ingredients in the foregoing compositions can be varied within wide limits, but for practical purposes it is preferably present in a concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition. The most satisfactory compositions are those in which a much higher proportion of the active ingredient is present, for example, up to about 95%.
Routes of administration of the GABA analog or its salts are oral or parenteral. For example, a useful intravenous dose is between 5 and 50 mg, and a useful oral dosage is between 20 and 800 mg. The dosage is within the dosing range used in treatment of inflammatory diseases such as arthritis, or as would be determined by the needs of the patient as described by the physician.
A unit dosage form of the GABA analog to be used in this invention may also comprise other compounds useful in the thera
High Karin Nanette Westlund
Schrier Denis
Taylor, Jr. Charles Price
Ashbrook Charles W.
Deemie Robert W.
Geist Gary
Purchase, Jr. Claude F.
Warner-Lambert & Company
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