JP2002541224A - Combination of GABA analogs and tricyclic compounds for the treatment of depression - Google Patents

Abstract

  (57) [Summary] The present invention relates to a method of alleviating depression using certain analogs of glutamic acid and γ-aminobutyric acid together with a tricyclic compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

【Technical field】

The present invention provides glutamate and gamma-aminobutyric acid (GAB) for the treatment of depression.
It relates to the use of an analogue of A) in combination with a tricyclic compound.

[0002]

[Background Art]

The GABA analogs of the present invention are known drugs useful for anticonvulsant therapy of disorders of the central nervous system such as epilepsy, Huntington's disease, cerebral ischemia, Parkinson's disease, tardive dyskinesia and convulsions. It has also been suggested that these compounds can be used as antidepressants, anxiolytics, and antipsychotics. WO 92/09560 (1990
US Patent Application No. 618,692 filed November 27, and WP 93/23383 (May 20, 1992)
See U.S. patent application Ser.

[0003] WO 97/33858 includes compounds related to gabapentin that include epilepsy, syncope,
It is taught to be useful in the treatment of hypokinetic, cranial nerve disorders, neurodegenerative disorders, depression, anxiety, panic, pain, and neuropathological disorders. WO 97/33858
It is not specified what type of pain is to be treated.

In addition, the compounds of the invention are known for treating neuropathic pain. For example, Rosner H, Rubin L, Kesstenbaum A, Gabapentin adjunctive therapy in
neuropathic pain states. Clin J Pain, 1966, Mar. 12: 1, 56-58; Segal AZ
, Rordorf G, Gabapentin as a novel treatment for postherpetic neuralgia.
Neurology, 1966, Apr. 46: 4, 1175-1176; Wetzel CH; Connelly JF., Use of
gabapentin in pain management.Ann Pharmacother, 1997, Sep. 31: 9, 1082
-1083; Zapp JJ., Postpoliomyelitis pain treated with gabapentin [letter]
Am Fam Physician, 1996, Jun. 53: 8, 2442, 2445; Cheville A et al., Neuropat.
hic pain in radiation myelopathy: a case report.Program book, American
Pain Society (14th Annual Scientific Meeting). Abstract # 95823, p. A-115
; Sist T; Filadora V; Miner M; Lema M., Gabapentin for idiopathic trigem
inal neuralgia: report of two cases. Neurology, 1997, May 48: 5, 1467; W
aldman SD, Tutorial 28: Evaluation and Treatment of Trigeminal Neuralgia
Pain Digest (1997) 7: 21-24; Mellick LB; Mellick GA., Successful trea
tment of reflex sympathetic dystrophy with gabapeptin [letter]. Am J Eme
rg 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., Gaba
pentin in the management of reflex symathetic dystrophy [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, 1
997 Jan, 78: 1, 98-105 and Mackin GA., Medical and pharmacologic mana
gement of upper extremity neuropathic pain syndromes.J Hand Ther, 1997
reference.

[0005] Tricyclic antidepressants are prescribed for endogenous depression, a condition thought to be caused by defective uptake of amine neurotransmitters at the presynaptic junction. Tricyclic antidepressants are advantageously used as controlled delivery formulations for a number of reasons. Depressed patients are at increased risk of suicide and tend to secretly store medication and attempt to overdose. In addition, tricyclic antidepressants have a long lag phase, and it may take several weeks for patients to achieve drug remission. Because of the long induction period, patients often discontinue medication shortly after thinking that the drug is not working. Controlled delivery drugs solve these problems by continuously releasing the drug for as long as needed to provide remission.

[0006] In addition, many patients who respond to tricyclic antidepressants tend to avoid recurrence if they are maintained on the drug. However, patient compliance with long-term medication standards is generally very poor. This problem is also eliminated with controlled release formulations.

[0007] Representative examples of tricyclic antidepressants are as follows.

Embedded image

[0008] Tricyclic antidepressants such as imipramine, 2-chloroimipramine and amitriptyline; penfluridol; haloperidol; pimozide; clozapine; carmidazoline and mixtures and pharmaceutically acceptable salts of any of the above compounds are described herein. Useful for the invention.

[0009]

Summary of the Invention

The present invention relates to methods and compositions for treating patients suffering from depression. According to the method of the present invention, a composition comprising a GABA analog and a tricyclic antidepressant in a pharmaceutically acceptable excipient is administered to a patient suffering from depression. The compositions of the invention comprise both the at least one GABA analog and the at least one tricyclic antidepressant in an amount effective to ameliorate the symptoms of depression.

The present invention provides a method of treating depression comprising administering to a patient suffering from depression an effective amount of a GABA analog and an effective amount of a tricyclic antidepressant. In a preferred embodiment, Formula I:

Embedded image Wherein R ₁ is hydrogen or lower alkyl, and n is an integer from 4 to 6) and their pharmaceutically acceptable salts. In a particularly preferred embodiment, compounds of formula I in which R ₁ is hydrogen and n is 4 are used, ie 1- (aminomethyl) -cyclohexaneacetic acid, commonly known as gabapentin.

In another embodiment, the present invention provides a compound of formula II:

Embedded image Wherein R ₁ is linear or branched alkyl having ₁ to 6 carbon atoms, phenyl or cycloalkyl having 3 to 6 carbon atoms, R ₂ is hydrogen or methyl, R ₃ is hydrogen, methyl or carboxyl) and the treatment of depression with tricyclic compounds.

Preferred compounds of the present invention are those wherein R ₃ and R ₂ as (R), (S) or (R, S) isomers are hydrogen and R ₁ is — (CH ₂ ) _0-2- iC ₄ H ₉ compound.

Further preferred compounds of the formula II according to the invention are (S) -3- (aminomethyl) -5-methyl-hexanoic acid and 3-aminomethyl-5, which are now commonly known as pregabalin. Methyl-hexanoic acid.

[0014]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The method of the present invention uses any GABA analog. GABA analogs are any compounds derived from or based on γ-aminobutyric acid. These compounds are readily available commercially or by synthetic methods well known to those skilled in the art of organic chemistry. Preferred GABA used in the method of the invention
Analogs are cyclic amino acids of Formula I. These are described in U.S. Patent No. 4,024,175, which is incorporated herein by reference. Another preferred method uses GABA analogs of Formula II, which are described in U.S. Patent No. 5,563,175, which description is incorporated herein by reference.

All that is required in the practice of the method of the present invention is to administer the GABA analog in combination with a tricyclic compound. The amount of the GABA analog in the composition will generally be from about 10 mg / kg to about 300 mg / kg of the subject's body weight. A typical dose is from about 10 mg / kg to about 5000 mg / kg of normal weight of an adult subject. Typical doses that can be administered are from 100 mg three times daily to 600 mg four times daily. Gabapentin 1
00 mg, 300 mg and 400 mg can be administered using commercially available capsules. Another form includes a liquid or film coated tablet.

When a compound of formula II is used, for example, pregabalin, the dosage level is one sixth of that of gabapentin. The dosage range of pregabalin is from about 0.15 mg / kg to about 50 mg / kg body weight of the subject. A typical dosage range for pregabalin is from about 1.6 mg to about 840 mg per day, with individual dosage ranges from about 0.15 mg to about 65 mg per administration.

The dosage range of the tricyclic antidepressant can be determined by one skilled in the art.
Amitriptyline is available in 10, 25, 50, 75 and 150 mg tablets. Daily dosages can range from 75 to 350 mg.

An advantage of the claimed composition is that it reduces the chance of overdose. Overdose of antidepressants is a general report of the Addiction Control Center. As a result,
Physicians and pharmacists will provide less prescribing (2-4 weeks) to avoid providing the potential for suicide sacrifice with tools for suicide. Antidepressants are therefore more likely to be lethal as the dose is increased, and patients must be gradually increased until an effective dose is reached.

According to the present invention, it is believed that lower doses (ie) are safer, and perhaps faster, to enable a synergistic improvement in mood. The different mechanisms of action of the two drugs will provide greater benefit to the patient.

The compounds of the present invention form pharmaceutically acceptable salts with organic and inorganic acids or bases. For example, acid addition salts of basic compounds are prepared by dissolving the free base in an aqueous or hydroalcoholic solution containing a suitable acid or other suitable solvent and evaporating the solution to isolate the salt. You. Examples of pharmaceutically acceptable salts include hydrochloride, hydrobromide, bisulfate and the like, and salts such as sodium, potassium and magnesium.

The compounds of the formula II can contain one or several asymmetric carbon atoms. The present invention includes the individual diastereomers or enantiomers and mixtures thereof. The individual diastereomers or enantiomers can be prepared or isolated by methods already known in the art.

The active compound is formulated into a unit dosage form with a pharmaceutical carrier to produce a pharmaceutical composition of a compound of the present invention or a salt thereof. Some examples of dosage unit forms include tablets, capsules,
There are pills, powders, aqueous and non-aqueous oral solutions and suspensions, parenteral solutions which can be packaged in containers which can contain one or some larger number of dosage units and can be divided into individual doses.

Some examples of suitable pharmaceutical carriers including pharmaceutical diluents include 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 theobroma oil, propylene glycol, glycerin, sorbitol, polyethylene glycol, water, agar, alginic acid, isotonic There are saline and phosphate buffer solutions and other compatible materials commonly used in pharmaceutical formulations. The compositions of the present invention also include
It may contain other ingredients such as colorants, flavors and / or preservatives. These materials, when present, are typically used in relatively small amounts. These compositions can, if desired, also contain other therapeutic agents.

While the percentage of active ingredient in the compositions described above can be varied within wide limits, for practical purposes at least 10% in solid compositions and at least 2% in primary liquid compositions. It is preferred to be present in a concentration. The most satisfactory compositions are those in which the active ingredient is present in a higher proportion.

The administration route of the compound of the present invention or a salt thereof is oral or parenteral. For example, a useful intravenous dose is 5 to 50 mg and a useful oral dose is 20 to 800 mg. Dosage will be determined by a physician within the range of those used for treating pain or as described above according to the needs of the patient.

The advantages of the use of the compounds of the formulas I and II, in particular gabapentin and pregabalin, according to the invention include the relatively non-toxic nature of the compounds, the ease of preparation, the good tolerance to the compounds and the intravenous administration of the drugs. Ease is included. Gabapentin is not metabolized in the liver, but rather is excreted unchanged from the body, so that it has little interaction with the major classes of drugs. Furthermore, these drugs are not metabolized in vivo. The subject treated by the method of the present invention is a mammal, including a human.

Although the present invention has been described in detail with reference to specific embodiments thereof, those skilled in the art will recognize that many modifications and variations may be made therein without departing from the spirit and scope of the invention. It is obvious that this is possible.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AU, BA, BB, BG, BR, CA, CN, CR, CU, CZ, DM, EE, GD, GE, HR, HU, ID, IL, IN, IS, JP, KP, KR, LC, LK, LR, LT, LV, MA , MG, MK, MN, MX, NO, NZ, PL, RO, SG, SI, SK, SL, TR, TT, UA, US, UZ, VN, YU, ZA (72) Douglas A. Inventor Sartell 07901, New Jersey, United States. Summit. Edgemont Avenue 30 F term (reference) 4C084 AA16 CA59 MA02 MA17 MA23 MA35 MA37 MA43 MA52 NA05 ZA122 4C086 AA01 AA02 BC31 MA23 MA35 MA37 MA52 NA05 ZA12 4C206 AA01 FA09 FA44 MA37 MA43 MA55 MA57 MA72 NA05 ZA12

Claims (19)

[Claims] 1. A method of treating a depressed patient, comprising administering a pharmaceutical composition comprising (a) a therapeutically effective amount of a GABA analog, and (b) a therapeutically effective amount of a tricyclic compound. 2. The GABA analog has the formula I: Wherein R ₁ is hydrogen or lower alkyl and n is an integer from 4 to 6; and the pharmaceutically acceptable salts thereof. 3. The method according to claim 2, wherein the compound of formula I comprises gabapentin. 4. The method of claim 2, comprising from about 10 mg to about 400 mg of the compound of formula I. 5. The method of claim 3, comprising about 10 mg to about 400 mg of gabapentin. 6. About 10 mg to about 400 mg of gabapentin and about 25 mg to about 3 mg.
4. The method of claim 3, comprising 50 mg of a tricyclic antidepressant. 7. The GABA analog has the formula II: Wherein R ₁ is linear or branched alkyl having ₁ to 6 carbon atoms, phenyl or cycloalkyl having 3 to 6 carbon atoms, R ₂ is hydrogen or methyl, The method according to claim 1, wherein R ₃ is hydrogen, methyl or carboxyl) or a pharmaceutically acceptable salt thereof. 8. The method of claim 7, wherein the compound of Formula II comprises pregabalin. 9. The method of claim 7, comprising from about 0.15 mg to about 65 mg of the compound of formula II. 10. The method of claim 8, comprising about 0.15 mg to about 65 mg of pregabalin. 11. A composition for treating human depression, comprising: (a) a therapeutically effective amount of a GABA analog; and (b) a therapeutically effective amount of a tricyclic compound. 12. The GABA analog has the formula I: (In the formula, R ₁ is hydrogen or lower alkyl, n represents an integer of 4-6) compounds and composition according to claim 11 their pharmaceutically acceptable salts. 13. The composition according to claim 12, wherein the compound of formula I comprises gabapentin. 14. The composition according to claim 12, comprising from about 10 mg to about 400 mg of the compound of formula I. 15. The composition of claim 13, comprising about 10 mg to about 400 mg of gabapentin. 16. The GABA analog has the formula II: Wherein R ₁ is linear or branched alkyl having ₁ to 6 carbon atoms, phenyl or cycloalkyl having 3 to 6 carbon atoms, R ₂ is hydrogen or methyl, R ₃ is hydrogen, methyl or carboxyl) or a pharmaceutically acceptable salt thereof. 17. The composition according to claim 16, wherein the compound of formula II comprises pregabalin. 18. The composition of claim 16, comprising about 0.15 mg to about 65 mg of the compound of formula II.
A composition as described. 19. The composition of claim 18, comprising from about 0.15 mg to about 65 mg of pregabalin.
A composition as described.