WO1992009560A1 - Gaba and l-glutamic acid analogs for antiseizure treatment - Google Patents
Gaba and l-glutamic acid analogs for antiseizure treatment Download PDFInfo
- Publication number
- WO1992009560A1 WO1992009560A1 PCT/US1991/008701 US9108701W WO9209560A1 WO 1992009560 A1 WO1992009560 A1 WO 1992009560A1 US 9108701 W US9108701 W US 9108701W WO 9209560 A1 WO9209560 A1 WO 9209560A1
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- Prior art keywords
- compound
- set forth
- hydrogen
- administering
- gaba
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/28—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to novel compounds that are analogs of glutamic acid and gamma-aminobutyric acid (GABA). More specifically, the analogs are useful as antiseizure therapy for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia and spasticity. It is also possible that the present invention could be used as an anti-depressant, anxiolytic and
- GABA Gamma-aminobutyric acid
- L-glutamic acid are two major neurotransmitters
- GABA is the major inhibitory
- neurotransmitter and L-glutamic acid is an excitatory transmitter (1,2).
- An imbalance in the concentration of these neurotransmitters can lead to convulsive states. Accordingly, it is clinically relevant to be able to control convulsive states by controlling the metabolism of this neurotransmitter.
- the tern seizure as used herein means excessive unsynchronized neuronal activity that disrupts normal neuronal function. In several seizure disorders there is concomitant with reduced brain GABA levels a
- GAD L-glutamic acid decarboxylase
- GABA As an inhibitory neurotransmitter, and its effect on convulsive states and other motor dysfunctions, a variety of approaches have been taken to increase the brain GABA concentration. For example, the most obvious approach was to administer GABA. When GABA is injected into the brain of a convulsing animal, the convulsions cease (10). However, if GABA is administered systemically, there is no anticonvulsant effect because GABA, under normal circumstances, cannot cross the blood brain barrier (11). In view of this limitation, there are three alternative approaches that can be taken to raise GABA levels.
- GABA lipophilic by making GABA lipophilic by conversion to hydrophobic GABA amides (13,14), imines (13), or GABA esters (15,16) so that GABA can cross the blood brain barrier.
- GABA esters Once inside the brain, these compounds require amidases and esterases to hydrolyze off the carrier group and release GABA.
- a third approach is to increase brain GABA levels by designing an activator of GAD.
- GAD GABA-dependent neuropeptide
- the anticonvulsant agent, milacemide was reported to increase the activity of GAD by 11% and as a result increase GABA concentration in the substantia nigra by up to 38% (17).
- the anticonvulsant drug sodium valproate (18) was also reported to activate GAD and increase GABA levels.
- Applicant has synthesized a series of GABA and L-glutamate analogs having the ability to activate GAD in vitro and having a dose dependent protective effect of seizure in vivo.
- One compound in particular was found to be an unexpectedly potent suppressor of seizures while the entire series of drugs do not promote the unwanted side effects of ataxia. Accordingly, the present invention provides a novel series of compounds and their method of use in suppressing seizures.
- R 1 is a straight or branched alkyl of from 1 to 6 carbons, phenyl or cycloalkyl having from 3 to 6 carbon atoms
- R 2 is hydrogen or methyl
- R 3 is hydrogen, methyl or carboxyl; or its diastereomers, or enantiomers and pharmaceutically acceptable salts thereof.
- the present invention further provides a method of treating seizure disorders by administering an anticonvulsant effective amount of the
- the present invention provides a method for increasing brain neuronal GABA and
- the alkyl moieties as represented by R 1 in Formula I can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isopentyl and neopentyl as well as other alkyl groups.
- the cycloalkyl groups represented by R 1 are exemplified by cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- the analogs are further shown herein to prevent seizure while not causing the side effect of ataxia, such a side effect being found in several anti-seizure pharmaceuticals. More specifically, the present invention provides compounds of the formula I
- R 1 is a straight or branched alkyl of from 1 to 6 carbons, phenyl or a cyloalkyl having 3 to 6 carbon atoms
- R 2 is hydrogen or methyl
- R 3 is hydrogen, methyl, or carboxyl; or its diastereomers; or enantiomers, and both pharmaceutically acceptable salts thereof.
- the most preferred compounds of the present invention are of the formula above wherein R 3 is hydrogen, R 2 is hydrogen and R 1 isobutyl. That is, the preferred compound is 4-amino-3-(2-methylpropyl) butanoic acid. It has been found that this compound is unexpectedly more potent than the other analogs synthesized in accordance herewith and tested in vivo.
- this preferred compound is the least effective one of the analogs tested in activating GAD in vitro. Accordingly, it was very unexpected that this preferred compound had such a high potentency when tested in vivo.
- the compounds made in accordance with the present invention may form pharmaceutically
- the acid addition salts of the basic compounds are prepared either by
- salts examples include hydrochlorides, hydrobromides, hydrosulfates, etc. as well as sodium, potassium and magnesium etc. salts.
- the compounds made in accordance with the present invention can contain one or several
- the invention includes the individual diastereomers or enantiomers, and the mixtures thereof.
- the individual diastereomers or enantiomers may be prepared or isolated by methods already well known in the art.
- the method for the formation of the 3-alkyl-4-aminobutanoic acids starting from 2-alkenoic esters is prepared from commercially available aldehydes and monoethyl malonate by the Knoevenagel reaction (19), with the exception of ethyl 4,4-dimethyl-2-pentenoate.
- This compound was prepared from 2,2-dimethylpropanal and ethyl lithioacetate, followed by dehydration of the beta-hydroxyester with phosphoryl chloride and pyridine.
- the compounds made by the aforementioned synthetic method can be used as pharmaceutical compositions as an anti-depressant, anxiolytic, antipsychotic, antiseizure, anti-dyskinesic, or anti-symptomatic for Huntington's or Parkinson's diseases when an effective amount of a compound of the aforementioned formula together with a
- the present invention provides a pharmaceutical composition for the suppression of seizures resulting from epilepsy, the treatment of cerebral ischemia, Parkinson's disease, Huntington's disease and
- the pharmaceutical can be used in a method for treating such disorders in mammals, including human, suffering therefrom by administering to such mammals an effective amount of the compound as described above in unit dosage form.
- compositions can be made in inert, pharmaceutically acceptable carriers which are either solid or liquid.
- solid form
- preparation include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
- the quantity of active compound in a unit dose of preparation may be varied or adjusted from one milligram to about 300 milligrams per kilogram daily, based on an average 70 kilogram patient. A daily dose range of about 1 milligram to about 50 milligrams per kilogram is preferred. The dosages, however, may be varied depending upon the requirement with a patient, the severity of the condition being treated, and the compound being employed.
- L-glutamic acid 0.5, 0.25, 0.166, 0.125, 0.10 mM
- [ 14 C]L-glutamate (10 ⁇ C i /mmol) in 50 mM potassium phosphate buffer, pH 7.2 were shaken at 37°C in separate vials with purified L-glutamic acid decarboxylase (18.75 ⁇ g; spec, act 10.85 jumol/min rag) in a total volume of 2.00 ml.
- the enzyme reactions were quenched by the addition of 200 ⁇ l of 6 M sulfuric acid to the contents of each of the vials.
- the vials were shaken for an additional 60 minutes at 37°C.
- the center wells were removed and placed in scintillation vials with 10 ml of scintillation fluid for radioactivity determination.
- the same assays were repeated except in the presence of various concentrations of the activators (2.5, 1.0, 0.5, 0.25, 0.1, 0.05 mM).
- Vmax values were determined from plots of 1/cpm versus 1/[glutamate] at various concentrations of activators. The data were expressed as the ratio of the V max in the presence of the activators to the
- Threshold maximum electroshock is an animal model test for generalized seizures that is similar to that of Piredda, S.G. et al (21). The methods for this test are described as follows.
- mice Male CF-1 mice (22-30 grams) were allowed free access to food and water prior to testing. For screening, groups of five mice were given a compound intravenously at doses of 30, 100, and 300 mg/kg and tested at 0.5, 2.0 and 4.0 hours after dosing. Drugs were either dissolved in 0.9% saline or suspended in 0.2% methylcellulose. Animals were shocked with corneal electrodes (see below) and observed for tonic hindlimb extensor seizures. Absence of hindlimb extension was taken as an anticovulsant effect.
- the electroshock apparatus delivered a 60 Hz sine wave with a current amplitude of 14 mA
- electroshock tests where conducted varying the time of testing from one hour to eight hours, the dose being 10 milligram per kilogram in mice, injected intravenously. Table 3 shows the results of these tests indicating a maximum protection after two hours of testing.
- inventions are of value as pharmacological agents, particularly for the treatement of seizures in mammals, including humans.
- High-intensity corneal electroshock consisted of 50 mA, base-to-peak sinusoidal current for 0.2 sec. All other data was from low-intensity electroshock, 17 mA base-to-peak sinusoidal current for 0.2 sec.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US61869290A | 1990-11-27 | 1990-11-27 | |
US618,692 | 1990-11-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992009560A1 true WO1992009560A1 (en) | 1992-06-11 |
Family
ID=24478754
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1991/008701 WO1992009560A1 (en) | 1990-11-27 | 1991-11-20 | Gaba and l-glutamic acid analogs for antiseizure treatment |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU9137091A (es) |
MX (1) | MX9102241A (es) |
WO (1) | WO1992009560A1 (es) |
Cited By (51)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993023383A1 (en) * | 1992-05-20 | 1993-11-25 | Northwestern University | Gaba and l-glutamic acid analogs for antiseizure treatment |
WO1998003167A1 (en) | 1996-07-24 | 1998-01-29 | Warner-Lambert Company | Isobutylgaba and its derivatives for the treatment of pain |
WO1999031074A2 (en) * | 1997-12-16 | 1999-06-24 | Warner-Lambert Company | ((cyclo)alkyl substituted)-.gamma.-aminobutyric acid derivatives (=gaba analogues), their preparation and their use in the treatment of neurological disorders |
WO2000061135A1 (en) * | 1999-04-08 | 2000-10-19 | Warner-Lambert Company | Method for the treatment of incontinence |
WO2000061234A1 (en) * | 1999-04-09 | 2000-10-19 | Warner-Lambert Company | Combinations of gaba analogs and tricyclic compounds to treat depression |
US6153650A (en) * | 1996-10-23 | 2000-11-28 | Warner-Lambert Company | Substituted gamma aminobutyric acids as pharmaceutical agents |
WO2000076958A2 (en) * | 1999-06-10 | 2000-12-21 | Warner-Lambert Company | Mono- and disubstituted 3-propyl gamma-aminobutyric acids |
US6197819B1 (en) | 1990-11-27 | 2001-03-06 | Northwestern University | Gamma amino butyric acid analogs and optical isomers |
US6242488B1 (en) | 1997-08-20 | 2001-06-05 | University Of Oklahoma | Method for preventing and treating pain |
EP1192944A1 (en) * | 2000-09-22 | 2002-04-03 | Warner-Lambert Company | Use of pregabalin for treating asthma |
US6627771B1 (en) | 1998-11-25 | 2003-09-30 | Pfizer Inc | Gamma amino butyric and acid analogs |
US6642398B2 (en) | 1999-06-10 | 2003-11-04 | Warner-Lambert Company | Mono-and disubstituted 3-propyl gamma-aminobutyric acids |
WO2003104184A1 (en) | 2002-06-11 | 2003-12-18 | Xenoport, Inc. | Methods for synthesis of acyloxyalkyl derivatives of gaba analogs |
US6833140B2 (en) | 2001-06-11 | 2004-12-21 | Xenoport, Inc. | Orally administered dosage forms of GABA analog prodrugs having reduced toxicity |
WO2005025563A1 (en) * | 2003-09-12 | 2005-03-24 | Warner-Lambert Company Llc | Combination comprising an alpha-2-delta ligand and an ssri and/or snri for treatment of depression and anxiety disorders |
US6900192B2 (en) | 2000-10-06 | 2005-05-31 | Xenoport, Inc. | Bile-acid conjugates for providing sustained systemic concentrations of drugs |
US6927036B2 (en) | 2002-02-19 | 2005-08-09 | Xero Port, Inc. | Methods for synthesis of prodrugs from 1-acyl-alkyl derivatives and compositions thereof |
US6992109B1 (en) | 1999-04-08 | 2006-01-31 | Segal Catherine A | Method for the treatment of incontinence |
US6992076B2 (en) | 2000-10-06 | 2006-01-31 | Xenoport, Inc. | Bile-acid derived compounds for providing sustained systemic concentrations of drugs after oral administration |
US7026351B2 (en) | 2002-03-20 | 2006-04-11 | Xenoport, Inc. | Cyclic 1-(acyloxy)-alkyl prodrugs of GABA analogs, compositions and uses thereof |
US7060727B2 (en) | 2002-12-11 | 2006-06-13 | Xenoport, Inc. | Prodrugs of fused GABA analogs, pharmaceutical compositions and uses thereof |
US7183259B2 (en) | 2002-05-17 | 2007-02-27 | Xenoport | Amino acid conjugates providing for sustained systemic concentrations of GABA analogues |
US7186855B2 (en) | 2001-06-11 | 2007-03-06 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
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US7420002B2 (en) | 2001-06-11 | 2008-09-02 | Xenoport | Amino acid conjugates providing for sustained systemic concentrations of GABA analogues |
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US7700652B2 (en) | 2003-09-11 | 2010-04-20 | Xenoport, Inc. | Treating urinary incontinence using prodrugs of GABA analogs |
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US7868043B2 (en) | 2008-01-25 | 2011-01-11 | Xenoport, Inc. | Mesophasic forms of (3S)-aminomethyl-5-methyl-hexanoic acid prodrugs and methods of use |
US7872046B2 (en) | 2008-01-25 | 2011-01-18 | Xenoport, Inc. | Crystalline form of a (3S)-aminomethyl-5-methyl-hexanoic acid prodrug and methods of use |
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US8026279B2 (en) | 2003-10-14 | 2011-09-27 | Xenoport, Inc. | Crystalline form of γ-aminobutyric acid analog |
US8048917B2 (en) | 2005-04-06 | 2011-11-01 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
US8062870B2 (en) | 2008-01-25 | 2011-11-22 | Xenoport, Inc. | Enantiomerically resolving acyloxyalkyl thiocarbonates used in synthesizing acyloxyalkyl carbamate prodrugs |
US8114909B2 (en) | 2003-09-17 | 2012-02-14 | Xenoport, Inc. | Treating or preventing restless legs syndrome using prodrugs of GABA analogs |
WO2013060814A3 (en) * | 2011-10-26 | 2013-06-20 | Givaudan Sa | Glutamic acid derivatives |
WO2013121061A1 (es) | 2012-02-15 | 2013-08-22 | Laboratec, S.L. | Composición farmacéutica para el tratamiento de incontinencia urinaria y enuresis |
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US8795725B2 (en) | 2004-11-04 | 2014-08-05 | Xenoport, Inc. | GABA analog prodrug sustained release oral dosage forms |
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US9757358B2 (en) | 2010-02-04 | 2017-09-12 | Laboratorios Del Dr. Esteve, S.A. | Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof |
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US9844516B2 (en) | 2010-02-04 | 2017-12-19 | Laboratorios De Dr. Esteve | Sigma ligands for use in the prevention and/or treatment of post-operative pain |
US9914705B2 (en) | 2008-04-25 | 2018-03-13 | Laboratorios Del Dr. Esteve, S.A. | 1-aryl-3-aminoalkoxy pyrazoles as sigma ligands enhancing analgesic effect of opioids and attenuating the dependency thereof |
US9931346B2 (en) | 2013-12-17 | 2018-04-03 | Laboratorios Del Dr. Esteve S.A. | Serotonin-norepinephrine reuptake inhibitors (SNRIs) and Sigma receptor ligands combinations |
DE202018105573U1 (de) | 2018-09-27 | 2018-10-19 | Laboratec | Pharmazeutische Zusammensetzung zur Behandlung der Harninkontinenz und Enuresis |
EP4227293A2 (en) | 2018-05-14 | 2023-08-16 | Xgene Pharmaceutical Inc | Crystalline forms of 1-(acyloxy)-alkyl carbamate drug conjugates of naproxen and pregabalin |
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- 1991-11-20 AU AU91370/91A patent/AU9137091A/en not_active Abandoned
- 1991-11-27 MX MX9102241A patent/MX9102241A/es unknown
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Cited By (90)
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---|---|---|---|---|
US6197819B1 (en) | 1990-11-27 | 2001-03-06 | Northwestern University | Gamma amino butyric acid analogs and optical isomers |
WO1993023383A1 (en) * | 1992-05-20 | 1993-11-25 | Northwestern University | Gaba and l-glutamic acid analogs for antiseizure treatment |
WO1998003167A1 (en) | 1996-07-24 | 1998-01-29 | Warner-Lambert Company | Isobutylgaba and its derivatives for the treatment of pain |
USRE41920E1 (en) | 1996-07-24 | 2010-11-09 | Warner-Lambert Company Llc | Isobutylgaba and its derivatives for the treatment of pain |
US6001876A (en) * | 1996-07-24 | 1999-12-14 | Warner-Lambert Company | Isobutylgaba and its derivatives for the treatment of pain |
US6153650A (en) * | 1996-10-23 | 2000-11-28 | Warner-Lambert Company | Substituted gamma aminobutyric acids as pharmaceutical agents |
US6426368B2 (en) | 1997-08-20 | 2002-07-30 | Warner-Lambert Company | Method for preventing and treating alcoholism |
US6242488B1 (en) | 1997-08-20 | 2001-06-05 | University Of Oklahoma | Method for preventing and treating pain |
EP1400526A3 (en) * | 1997-12-16 | 2004-03-31 | Warner-Lambert Company LLC | ((cyclo)alkyl substituted)- gamma -aminobutyric acid derivatives (=Gaba analogues), their preparation and their use in the treatment of neurological disorders |
WO1999031074A3 (en) * | 1997-12-16 | 1999-11-04 | Warner Lambert Co | ((cyclo)alkyl substituted)-.gamma.-aminobutyric acid derivatives (=gaba analogues), their preparation and their use in the treatment of neurological disorders |
WO1999031074A2 (en) * | 1997-12-16 | 1999-06-24 | Warner-Lambert Company | ((cyclo)alkyl substituted)-.gamma.-aminobutyric acid derivatives (=gaba analogues), their preparation and their use in the treatment of neurological disorders |
EP1400526A2 (en) * | 1997-12-16 | 2004-03-24 | Warner-Lambert Company LLC | ((cyclo)alkyl substituted)- gamma -aminobutyric acid derivatives (=Gaba analogues), their preparation and their use in the treatment of neurological disorders |
US6627771B1 (en) | 1998-11-25 | 2003-09-30 | Pfizer Inc | Gamma amino butyric and acid analogs |
EP1977745A1 (en) * | 1999-04-08 | 2008-10-08 | Warner-Lambert Company LLC | Method for the treatment of incontinence |
US6992109B1 (en) | 1999-04-08 | 2006-01-31 | Segal Catherine A | Method for the treatment of incontinence |
WO2000061135A1 (en) * | 1999-04-08 | 2000-10-19 | Warner-Lambert Company | Method for the treatment of incontinence |
WO2000061234A1 (en) * | 1999-04-09 | 2000-10-19 | Warner-Lambert Company | Combinations of gaba analogs and tricyclic compounds to treat depression |
US6642398B2 (en) | 1999-06-10 | 2003-11-04 | Warner-Lambert Company | Mono-and disubstituted 3-propyl gamma-aminobutyric acids |
CZ301608B6 (cs) * | 1999-06-10 | 2010-04-28 | Warner-Lambert Company | Derivát 3-propyl gamma-aminomáselné kyseliny a farmaceutický prostredek s jeho obsahem |
WO2000076958A3 (en) * | 1999-06-10 | 2001-04-12 | Warner Lambert Co | Mono- and disubstituted 3-propyl gamma-aminobutyric acids |
AP1397A (en) * | 1999-06-10 | 2005-04-19 | Warner Lambert Co | Mono-and disubstituted 3-propyl gamma-aminobutyric acids. |
CZ300834B6 (cs) * | 1999-06-10 | 2009-08-19 | Warner-Lambert Company Llc | Mono- a disubstituované kyseliny 3-propyl-gamma-aminomáselné |
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