Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1998-07-15
1999-12-14
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
A61K 31195
Patent
active
060018763
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is the use of analogs of glutamic acid and gamma-aminobutyric acid (GABA) in pain therapy, as the compounds exhibit analgesic/antihyperalgesic action. Advantages of the use of the compounds includes the finding that repeated use does not lead to tolerance nor is there a cross-tolerance between morphine and the compounds.
The compounds of the invention are known agents useful in antiseizure therapy for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity. It has also been suggested that the compounds can be used as antidepressants, anxiolytics, and antipsychotics. See WO 92/09560 (U.S. Ser. No. 618,692 filed Nov. 27, 1990) and WP 93/23383 (U.S. Ser. No. 886,080 filed May 20, 1992).
SUMMARY OF THE INVENTION
The instant invention is a method of using a compound of Formula I below in the treatment of pain, especially for treatment of chronic pain disorders. Such disorders include, but are not limited to, inflammatory pain, postoperative pain, osteoarthritis pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic and postherpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, bum pain, and other forms of neuralgic, neuropathic, and idiopathic pain syndromes.
A compound are those of Formula I ##STR1## or a pharmaceutically acceptable salt thereof wherein R.sub.1 is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl of from 3 to 6 carbon atoms;
Diastereomers and enantiomers of compounds of Formula I are included in the invention.
Preferred compounds of the invention are those according to claim 1 wherein R.sub.3 and R.sub.2 are hydrogen, and R.sub.1 is --(CH.sub.2).sub.0-2 --i C.sub.4 H.sub.9 as an (R), (S), or (R,S) isomer.
The more preferred compounds of the invention are (S)-3-(aminomethyl)-5-methylhexanoic acid and 3-aminomethyl-5-methyl-hexanoic acid.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1. Effect of Gabapentin (1-(aminomethyl)-cyclohexaneacetic acid), CI-1008 ((S)-3-(aminomethyl)-5-methylhexanoic acid), and 3-aminomethyl-5-methyl-hexanoic acid in the Rat Paw Formalin Test
Test compounds were administered s.c. 1 hour before an intraplantar injection of 50 .mu.L formalin. The time spent licking/biting the injected paw during the early and late phases was scored. Results are shown as the mean .+-.SEM of 6 to 8 animals per group. *P<0.05 and **P<0.01 significantly different from vehicle (Veh.) treated controls (ANOVA followed by Dunnett's t-test).
FIG. 2. Effect of Gabapentin and CI-1008 on Carrageenin-Induced Mechanical Hyperalgesia
Nociceptive pressure thresholds were measured in the rat using the paw pressure test. Baseline (BL) measurements were taken before animals were administered with 100 .mu.L of 2% carrageenin by intraplantar injection. Results are shown as mean (.+-.SEM) of 8 animals per group. Gabapentin (GP), CI-1008, or morphine (MOR; 3 mg/g) was administered s.c. 3.5 hours after carrageenin. *P<0.05 and **P<0.01 significantly different from vehicle control group at the same time point (ANOVA followed by Dunnett's t-test).
FIG. 3. Effect of Gabapentin and CI-1008 on Carrageenin-Induced Thermal Hyperalgesia
Nociceptive thermal thresholds were measured in the rat using the Hargreaves apparatus. Baseline (BL) measurements were taken before animal s were administered with 100 .mu.L of 2% carrageenin by intraplantar injection. Results are shown as mean (.+-.SEM) of 8 animals per group. Gabapentin (GP) or CI-1008 was administered s.c. 2.5 hours after carrageenin. *P<0.05 and **P<0.01 significantly different from vehicle control group at the same time point (ANOVA followed by Dunnett's t-test).
FIG. 4. Effect of (a) Morphine, (b) Gabapentin, and (c) S-(+)-3-Isobutylgaba on Thermal Hyperalgesia in the Rat Postoperative Pain Model
Gabapentin or S-(+)-3 isobutylgaba was administer
REFERENCES:
patent: 5563175 (1996-10-01), Silverman et al.
Anderson Elizabeth M.
Reamer James H.
Warner-Lambert & Company
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