NZ514401A - Combinations of GABA analogs and tricyclic compounds to treat depression - Google Patents
Combinations of GABA analogs and tricyclic compounds to treat depressionInfo
- Publication number
- NZ514401A NZ514401A NZ514401A NZ51440100A NZ514401A NZ 514401 A NZ514401 A NZ 514401A NZ 514401 A NZ514401 A NZ 514401A NZ 51440100 A NZ51440100 A NZ 51440100A NZ 514401 A NZ514401 A NZ 514401A
- Authority
- NZ
- New Zealand
- Prior art keywords
- formula
- compound
- gabapentin
- use according
- hydrogen
- Prior art date
Links
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Classifications
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- A—HUMAN NECESSITIES
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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Landscapes
- Health & Medical Sciences (AREA)
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Abstract
A combination of a GABA analog of formula (I) or (II) or a salt thereof and a tricyclic compound (such as amitriptyline) is used to treat depression. In formula (I): R1 is H or alkyl and n is 4 to 6 and in formula (II): R1 is alkyl, phenyl or cycloalkyl; R2 is H or methyl and R3 is H, methyl or carboxyl.
Description
<div class="application article clearfix" id="description">
<p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number 514401 <br><br>
5144 01 <br><br>
WO 00/61234 PCT/US00/03983 <br><br>
COMBINATIONS OF GABA ANALOGS AND TRICYCLIC COMPOUNDS TO TOEAT DEPRESSION <br><br>
BACKGROUND OF THE INVENTION <br><br>
1. Field Of The Invention . <br><br>
The present invention relates to the use of analogs of glutamic acid and gamma-aminobutyric acid (GABA) in combination with tricyclic compounds for the treatment of depression. <br><br>
2. Description of Related Art <br><br>
The GABA analogs of the present 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 (United States Serial Number 618,692 filed November 27, 1990) and WP 93/23383 (United States Serial Number 886,080 filed May 20,1992). <br><br>
WO 97/33858 teaches that compounds related to gabapentin are useful or treating epilespy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, and neuropathological disorders. WO 97/33858 does not specify what forms of pain are treated. <br><br>
WO 00/61234 <br><br>
PCT/US00/03983 <br><br>
Additionally, the compounds of the invention are known for treatment of neuropathic pain. For example, see Rosner H; Rubin L; Kestenbaum A., Gabapentin adjunctive therapy in neuropathic pain states. Clin J Pain, 1996 Mar, 5 12:1, 56-8; Segal AZ; Rordorf G., Gabapentin as a novel treatment for postherpetic neuralgia. Neurology, 1996 Apr, 46:4,1175-6; Wetzel CH; Connelly JF., Use of gabapentin in pain management Ann Pharmacother, 1997 Sep, 31:9, 1082-3; Zapp JJ., Postpoliomyelitis pain treated with gabapentin [letter]. Am Fam Physician, 1996 Jun, 53:8, 2442, 2445; Cheville A, et al., Neuropathic pain in 10 radiation myelopathy:a case report Program book, American Pain Society (14th Annual Scientific Meeting). Abstract #95823, p. A-l 15; Sist T; Filadora V; Miner M; Lema M., Gabapentin for idiopathic trigeminal neuralgia: report of two cases. Neurology, 1997 May, 48:5, 1467; Waldman SD, Tutorial 28: Evaluation and Treatment of Trigeminal Neuralgia. Pain Digest (1997) 7:21-24; MellickLB; 15 Mellick GA., Successful treatment of reflex sympathetic dystrophy with gabapentin [letter]. Am J Emerg Med, 1995 Jan, 13:1,96; Mellick GA; Seng MI., The use of gabapentin in the treatment of reflex sympathetic dystrophy and a phobic disorder. Am J Pain Manage 1995; 5:7-9; Mellick GA; Mellicy LB; Mellick LB., Gabapentin in die management of reflex sympathetic dystrophy 20 [letter]. J Pain Symptom Manage, 1995 May, 10:4, 265-6; Mellick GA; Mellick LB., Reflex sympathetic dystrophy treated with gabapentin. Arch Phys Med Rehabil, 1997 Jan, 78:1, 98-105 and Mackin GA., Medical and phannacologic management of upper extremity neuropathic pain syndromes. J Hand Ther, 1997 <br><br>
WO 00/61234 <br><br>
PCT/US00/03983 <br><br>
Tricyclic antidepressants are prescribed for endogenous depression, a condition thought to be caused by a defect in the uptake of amine 5 neurotransmitters at the presynaptic junctions. The tricyclic antidepressants benefit from a controlled delivery formulation for a number of reasons. Depressed patients are at a higher risk for suicide, and thus more likely to hoard the drug and then attempt to take an overdose. Furthermore, tricyclic antidepressants have a long induction period, sometimes taking several weeks before patients obtain 10 relief from the drug. As a result of the long induction period, patients often stop using the medication after a short period of time because they think it is not working. A controlled delivery form of the drug solves these problems by providing continuous release of the drug for the time period necessary to provide relief. <br><br>
15 <br><br>
Additionally, many patients who respond to tricyclic antidepressants are much more likely to avoid a relapse if they are maintained on the drug. However, patient compliance to long-term drug regimens is generally very poor. This problem is also eliminated with controlled release drug formulations. <br><br>
20 <br><br>
WO 00/61234 PCT/US00/03983 <br><br>
Representative examples of tricyclic antidepressants are shown below. <br><br>
R - GHCCHsfcNCCHsh tmhriptylme <br><br>
10 <br><br>
15 <br><br>
R . (CH2)3N(CH3)2 hmpramine <br><br>
R = (CH2)3NHCH3 desipramine <br><br>
R = CH2CH(CH3)CH2N(CH3)2 trimipramine <br><br>
20 <br><br>
R = (CH2)}NHCH3 pro uipty line <br><br>
WO 00/61234 <br><br>
PCT/US00/03983 <br><br>
-5- <br><br>
Tricyclic antidepressant drugs such as imipramine. 2 —chloroimipramine and amiciptyline; penfluridol; haloperidol; pimozide; clozapine; caimidazolin: and, mixtures and phannaceutically acceptable salts of any of the foregoing are useful in the present invention <br><br>
The invention relates to methods and compositions for treating patients suffering from depression. According to the invention, compositions comprising a gaba analog and a tricyclic antidepressant in a pharmaceutically-acceptable vehicle are administered to a patient suffering from depression. Compositions according to the invention comprise synergistically effective amounts of at least least one gaba analog and at least one tricyclic antidepressant both in amounts effective to alleviate symptoms of depression! <br><br>
This invention provides the use of synergistically effective amounts of a GABA analog of Formula I <br><br>
SUMMARY OF THE INVENTION <br><br>
I^N— CH2—r CH2 CO2RJ <br><br>
(ch2)n <br><br>
I <br><br>
WO 00/61234 PCT/US00/03983 <br><br>
-6- <br><br>
wherein Ri is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the <br><br>
- pharmaceutically acceptable salts thereof, and a tricyclic compound, in the manufacture of a medicament for treating depression. An especially preferred embodiment utilizes a compound of Formula I where Ri is hydrogen and n is 4, <br><br>
which compound is l-(aminomethyl)-cyclohexane acetic acid, known generically as gabapentin. <br><br>
In another embodiment, the invention includes the use of synergistically effective amounts of a GABA analog of Formula II. <br><br>
Formula II <br><br>
*3*2 <br><br>
, i i <br><br>
H2NCHCCH2C00H n <br><br>
I <br><br>
*1 <br><br>
or a pharmaceutically acceptable salt thereof wherein <br><br>
Ri is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl of from 3 to 6 carbon atoms; <br><br>
*2 is hydrogen or methyl; and <br><br>
R3 is hydrogen, methyl, or carboxyl; and tricyclic compounds, <br><br>
and a tricyclic compound, <br><br>
in the manufacture of a medicament for treating depression <br><br>
Preferred compounds of the invention are those wherein R3 and Rj are hydrogen, and Rj is -(CH2)o_2-i C4H9 as an (R), (S), or (R^5) isomer. <br><br>
INTELLECTUAL PROPERTY " OFFICE OF M.Z <br><br>
15 AUG 2003 received <br><br>
WO 00/61234 PCT/US00/03983 <br><br>
-7- <br><br>
The more preferred compounds of Formula II invention are (S>3- <br><br>
(aminomethyl)-5-methyIhexanoic acid and 3-aminomethyI-5-metfayI-hexanoic acid, now known genexicaliy as pregabalin. <br><br>
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS <br><br>
The invention utilizes a GABA analog. A GABA analog is any compound derived from or based upon gamma-aminobutyric acid. 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 Fonnula I. Tliese are desciibed in U.S. Patent 4,024,175, which is incorporated herein by reference. Another preferred method utilizes the GABA analogs of Formulae, and these axe described in U.S. Patent 5,563,175, which is incorporated herein by reference. <br><br>
All that is required to practice the invention is to administer a GABA analog in combination with tricyclic compounds. Hie amount of GABA analog in the composition 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 far an aduh subject of normal weight It is expected that common doses that might be administered could be from 100 mg three times a day up to 600 mg four times a day. Commercially available capsules of 100 mg, 300 mg, and 400 mg of gabapentin can be administered. Alternate fonns include liquids and film-coated <br><br>
INTELLECTUAL PROPERTY OFFICE OF NI.Z <br><br>
1 5 AUG 2003 received <br><br>
WO 00/61234 <br><br>
PCT/US00/03983 <br><br>
-8- <br><br>
tablets. <br><br>
If a compound of Formula II, such as pregabalin is used, the dosage level is one sixth that of gabapentin. The dosage range for pregabalin is from about 5 0.1S mg to about SO mg per kg per day of subject body weight Typical dosages for pregabalin will be from about 1.6 mg to about 840 mg per day with individual dosages ranging from abut 0.15 mg to about 65 mg per dose. <br><br>
The dosage range for the tricyclic antidepressant can be determined by one 10 skilled in the ait Amitriptyline is available in 10, 23. 50, 75 and 150 mg tablets. Daily dosages can range from between 75 to 350 mg. <br><br>
A benefit of the claimed compositions is to lessen the chance of overdose. Overdoses of antidepressants are common reports to poison control centers. As a 15 result, physicians and pharmacists are encouraged to provide small prescriptions (2 to 4 weeks) at a time to avoid providing a potential suicide victim with the tools to do it Antidepressant are therefore potential lethal as the dose is increased and patients have to be titrated up to an effective dose. <br><br>
20 This invention would allow for a synergistic improvement in mood with lower doses (therefore) safer and potentially fester. The different mechanism of action of the two drugs would offer greater benefit to patients. <br><br>
The compounds of the present invention may form pharmaceutically 25 acceptable salts with both organic and inorganic acids or bases. For example, the <br><br>
WO 00/61234 PCT/US00/03983 <br><br>
-9- <br><br>
acid addition salts of the basic compounds are prepared either by dissolving the free base in aqueous or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution. Examples of phaxmaceutically acceptable salts are hydrochlorides, hydrobromides, 5 hydrosulfates, etc. as well as sodium, potassium, and magnesium, etc. salts, <br><br>
The compounds of the Formula II can contain one or several asymmetric carbon atoms. The invention includes the individual diastereomers or enantiomers, and the mixtures thereof. The individual diastereomers or enantiomers may be 10 prepared or isolated by methods already well-known in the art <br><br>
Formulating the active compound in dosage unit form with a pharmaceutical carrier produces pharmaceutical compositions of the compound of the present invention or its salts. Some examples of dosage unit forms are tablets, IS 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. <br><br>
20 Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as lactose and sucrose; starches such as com starch and potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose <br><br>
10 <br><br>
WO 00/61234 PCT/US00/03983 <br><br>
-10- <br><br>
acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil; olive oil, com 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 of 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. <br><br>
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 15 much higher proportion of the active ingredient is present <br><br>
Routes of administration of the subject compound 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 20 range used in treatment of pain or as would be with the needs of the patient as described by the physician. <br><br>
The advantages of using the compounds of Fonnula I and n, especially <br><br></p>
</div>
Claims (19)
1. The use of synergistically effective amounts of:<br><br> (a) a GABA analog of Formula I:<br><br> , H2N— O^TrC-r-O^GO^i<br><br> (. J I<br><br> (^A<br><br> wherein Ri is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the pharmaceutically acceptable salts thereof; and (b) a tricyclic compound;<br><br> in the manufacture of a medicament for treating depression.<br><br> 10<br><br> 15<br><br>
2. The use according to claim 1, wherein Formula I comprises gabapentin.<br><br>
3. The use according to claim 1, wherein the medicament comprises from about 10 mg to about 400 mg of the compound of Formula I.<br><br>
4. The use according to claim 2, wherein the medicament comprises from about 10 mg to about 400 mg of gabapentin.<br><br> 20<br><br> INTELLECTUAL PROPERTY<br><br> OFRCE OF M.Z<br><br> 15 AUG 2003 received<br><br> WO 00/61234<br><br> PCT/OS00/03983<br><br> -13-<br><br>
5. The use according to claim 2, wherein the medicament comprises firom about 10 mg to about 400 mg of gabapentin and from about 25 mg to about 350 mg of tricyclic antidepressant.<br><br>
6. The use of synergistically effective amounts of (a) a GABA analog of Formula (II):<br><br> or a pharmaceutically acceptable salt thereof wherein<br><br> R| is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl of from 3 to 6 carbon atoms;<br><br> is hydrogen or methyl; and R3 is hydrogen, methyl, or carboxyl; and (b) a tricyclic compound;<br><br> in the manufacture of a medicament for treating depression.<br><br>
7. The use according to claim 6, wherein Formula II comprises pregabalin.<br><br>
8. The use according to claim 6, wherein the medicament comprises from about. 15 mg to about 65 mg of the compound of Formula II.<br><br>
9. The use according to claim 7, wherein the medicament comprises from about .15 mg to about 65 mg of pregabalin.<br><br>
10. A composition for treating depression in a human comprising<br><br> *3*2<br><br> h2nchcch2cooh n<br><br> r.<br><br> 1<br><br> synergistically effective amounts of:<br><br> (a) a GABA analog of Fonnula I:<br><br> 15 AUG 2003<br><br> received<br><br> WO 00/61234<br><br> PCT/US00/03983<br><br> -14-<br><br> H2N— CH27-CTCH2CO2R1<br><br> C J I<br><br> (ch2)n wherein Rj is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the pharmaceutically acceptable salts thereof; and (b) a tricyclic compound.<br><br>
11. The composition according to claim 10, wherein Formula I comprises gabapentin.<br><br>
12. The composition according to claim 10, comprising from about 10 mg to about 400 mg of the compound of Formula I.<br><br>
13. The composition according to claim 11, comprising from about 10 mg to about 400 mg of gabapentin.<br><br>
14. A composition for treating depression in a human comprising synergistically effective amounts of:<br><br> (a) a GABA analog of Fonnula II:<br><br> *3*2<br><br> I I<br><br> h2nchcch2cooh n<br><br> I !<br><br> Ri or a pharmaceutically acceptable salt thereof wherein<br><br> Rj is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl of from 3 to 6 carbon atoms;<br><br> R2 is hydrogen or methyl; and<br><br> R3 is hydrogen, methyl, or carboxyl; and (b) a tricyclic compound.<br><br> INTELLECTUAL PROPERTY OFFICE OF N.Z<br><br> 15 AUG 2003 received<br><br> WO 00/61234 PCT/US00/03983<br><br> -15-<br><br>
15. The composition according to claim 14, wherein Formula II comprises pregabalin.<br><br>
16. The composition according to claim 14, comprising from about .15 mg to about 65 mg of the compound of Formula II.<br><br>
17. The composition according to claim 16, comprising from about . 15 mg to about 65 mg of pregabalin.<br><br>
18. The use according to claim 1 or claim 6 where the compound is specifically set forth herein.<br><br>
19. A composition according to claim 10 or claim 14 where the compound is specifically set forth herein.<br><br> </p> </div>
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US12857199P | 1999-04-09 | 1999-04-09 | |
PCT/US2000/003983 WO2000061234A1 (en) | 1999-04-09 | 2000-02-16 | Combinations of gaba analogs and tricyclic compounds to treat depression |
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NZ514401A true NZ514401A (en) | 2003-10-31 |
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EP (1) | EP1180058A1 (en) |
JP (1) | JP2002541224A (en) |
KR (1) | KR20010108466A (en) |
AU (1) | AU3492900A (en) |
CA (1) | CA2367494A1 (en) |
HU (1) | HUP0200733A3 (en) |
IL (1) | IL145736A0 (en) |
NZ (1) | NZ514401A (en) |
TR (1) | TR200102850T2 (en) |
WO (1) | WO2000061234A1 (en) |
ZA (1) | ZA200108259B (en) |
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USRE41920E1 (en) | 1996-07-24 | 2010-11-09 | Warner-Lambert Company Llc | Isobutylgaba and its derivatives for the treatment of pain |
JP2005518411A (en) * | 2002-01-16 | 2005-06-23 | エンド ファーマシューティカルズ インコーポレーテッド | Pharmaceutical compositions and methods for treating disorders of the central nervous system |
MXPA06002789A (en) * | 2003-09-12 | 2006-06-14 | Pfizer | Combinations comprising alpha-2-delta ligands and serotonin / noradrenaline re-uptake inhibitors. |
EP1675582A1 (en) * | 2003-09-12 | 2006-07-05 | Warner-Lambert Company LLC | Combination comprising an alpha-2-delta ligand and an ssri and/or snri for treatment of depression and anxiety disorders |
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DE2410821A1 (en) * | 1974-03-07 | 1975-09-18 | Hoechst Ag | PHARMACEUTICAL COMBINATION PREPARATIONS WITH PSYCHOTROPIC EFFECT AND METHOD FOR THEIR PRODUCTION |
FR2453643A2 (en) * | 1977-06-24 | 1980-11-07 | Synthelabo | PHARMACEUTICAL COMPOSITIONS ACTIVE ON THE CENTRAL NERVOUS SYSTEM |
US5025035A (en) * | 1990-10-12 | 1991-06-18 | Warner-Lambert Company | Method of treating depression |
WO1992009560A1 (en) * | 1990-11-27 | 1992-06-11 | Northwestern University | Gaba and l-glutamic acid analogs for antiseizure treatment |
EP0726073A3 (en) * | 1995-02-10 | 1998-07-08 | Eduardo Samuel Bleiweiss | Pharmaceutical compositions containing at least one of haloperidol, imipramine or trifluoroperazine |
-
2000
- 2000-02-16 JP JP2000610562A patent/JP2002541224A/en active Pending
- 2000-02-16 HU HU0200733A patent/HUP0200733A3/en unknown
- 2000-02-16 CA CA002367494A patent/CA2367494A1/en not_active Abandoned
- 2000-02-16 KR KR1020017012788A patent/KR20010108466A/en not_active Application Discontinuation
- 2000-02-16 NZ NZ514401A patent/NZ514401A/en unknown
- 2000-02-16 WO PCT/US2000/003983 patent/WO2000061234A1/en not_active Application Discontinuation
- 2000-02-16 IL IL14573600A patent/IL145736A0/en unknown
- 2000-02-16 AU AU34929/00A patent/AU3492900A/en not_active Abandoned
- 2000-02-16 EP EP00913490A patent/EP1180058A1/en not_active Withdrawn
- 2000-02-16 TR TR2001/02850T patent/TR200102850T2/en unknown
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HUP0200733A2 (en) | 2002-07-29 |
WO2000061234A1 (en) | 2000-10-19 |
KR20010108466A (en) | 2001-12-07 |
AU3492900A (en) | 2000-11-14 |
HUP0200733A3 (en) | 2003-04-28 |
JP2002541224A (en) | 2002-12-03 |
IL145736A0 (en) | 2002-07-25 |
ZA200108259B (en) | 2003-03-26 |
EP1180058A1 (en) | 2002-02-20 |
CA2367494A1 (en) | 2000-10-19 |
TR200102850T2 (en) | 2002-03-21 |
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