KR20010108466A - Combinations of GABA Analogs and Tricyclic Compounds to Treat Depression - Google Patents

Abstract

The present invention relates to a method of using certain analogs of glutamic acid and gamma-aminobutyric acid with tricyclic compounds to alleviate depression.

Description

Combinations of GABA Analogs and Tricyclic Compounds to Treat Depression

The GABA analogs of the present invention are known agents useful in anticonvulsant therapies for central nervous system diseases such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, general dyskinesia and convulsions. It has been suggested that such analogs can be used as antidepressants, anti-anxiety agents and antipsychotics. See WO 92/09560 (US Patent Application No. 618,692, filed November 27, 1990) and WP 93/23383 (US Patent Application No. 886,080, filed May 20, 1992).

WO 97/33858 teaches that compounds related to gabapentin are useful for treating epilepsy, syncope seizures, dyskinesia, brain diseases, neurodegenerative diseases, depression, anxiety, panic, pain and neuropathological diseases. have. WO 97/33858 does not specify what type of pain is treated.

In addition, compounds of the invention are known for the treatment of neuropathic pain (e.g., Rosner H; Rubin L; Kestenbaum A., Gabapentin adjunctive therapy inneuropathic pain states. Clin J Pain, 1996 Mar, 12: 1 , 56-8; Segal AZ; Rordorf G., Gabapentin as a novel treatment for postherpetic neuralgia.Nurology, 1996 Apr, 46: 46.1175-6; Wetzel CH; Connelly JF., Use of gabapentin in pain management.Anne 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 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 trigeminal neuralgia: report of two cases.Nurology, 1997 May, 48: 5, 1467; Waldman SD, Tutorial 28: Evaluation and Treatment of Trigeminal Neuralgia.Pain Digest (1997) 7: 21-24; Mellic k LB; 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 the management of reflex sympathetic 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, 1997 Jan, 78: 1, 98-105 and Mackin GA., Medical and pharmacologic management of upper extremity neuropathic pain syndromes. J Hand Ther, 1997 Apr-Jun, 10: 2, 96-109).

Tricyclic antidepressants are prescription drugs for endogenous depression, a condition believed to be caused by abnormalities in amine neurotransmitter reuptake at the presynaptic junction. Tricyclic antidepressants benefit from controlled release formulations for a variety of reasons. Depressed patients are at higher risk for suicide, so they are more likely to store medication and try to overdose. In addition, tricyclic antidepressants have a prolonged induction period, which often takes several weeks for the patient to gain stability from the drug. Due to prolonged induction, patients often stop taking the drug after a short period of time, thinking that the drug does not work. Release controlled drugs solve this problem by continually releasing the drug for the time needed to provide stability.

In addition, many patients who respond to tricyclic antidepressants are more likely not to relapse if they continue to take the drug. However, the compliance of patients following long term drug therapy is very low. This problem is also eliminated by controlled release drug formulations.

Representative examples of tricyclic antidepressants are shown below.

Imipramine, 2-chloroimipramine and amitriptyline; Fenfluridol; Haloperidol; Fimozide; Clozapine; Calmidazolin; And tricyclic antidepressants such as mixtures thereof and pharmaceutically acceptable salts of those mentioned above are useful in the present invention.

Summary of the Invention

The present invention relates to a method for treating a patient suffering from depression and a composition therefor. In the method according to the invention, a composition comprising a GABA analog and a tricyclic antidepressant in a pharmaceutically acceptable vehicle is administered to a patient suffering from depression. The composition according to the invention comprises both at least one GABA analog and at least one tricyclic antidepressant in an amount effective to alleviate 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 with an effective amount of a tricyclic compound. Preferred embodiments employ cyclic amino acid compounds of formula (I) and their pharmaceutically acceptable salts.

Where

R ₁ is hydrogen or lower alkyl,

n is an integer of 4-6.

A particularly preferred embodiment uses a compound of formula (I) wherein R ₁ is hydrogen and n is 4, wherein the compound is 1- (aminomethyl) -cyclohexane acetic acid with the common name gabapentin.

In another embodiment, the present invention encompasses the treatment of depression with a compound of Formula II or a pharmaceutically acceptable salt and tricyclic compound thereof.

Where

R ₁ is straight or branched chain alkyl of 1 to 6 carbon atoms, phenyl or cycloalkyl of 3 to 6 carbon atoms,

R ₂ is hydrogen or methyl,

R ₃ is hydrogen, methyl or carboxyl.

Preferred compounds of the invention are compounds as (R), (S) or (R, S) isomers wherein R ₃ and R ₂ are hydrogen and R _{1 is-} (CH ₂ ) _0-2 -i C ₄ H ₉ . .

More preferred compounds of formula II of the present invention are (S) -3- (aminomethyl) -5-methylhexanoic acid and 3-aminomethyl-5-methyl-hexanoic acid, which are currently common names pregabalin.

The present invention relates to the use of analogs of glutamic acid and gamma-aminobutyric acid (GABA) with tricyclic compounds to treat depression.

The method of the present invention uses any GABA analog. GABA analogs are any compounds derived from or based on gamma-aminobutyric acid. The compounds can be readily obtained by commercial methods or by synthetic methods known to those skilled in the art of organic chemistry. Preferred GABA analogs to be used in the methods of the invention are cyclic amino acids of formula (I). This is described in US Pat. No. 4,024,175, which is incorporated herein by reference. Another preferred method uses the GABA analog of Formula II, which is described in US Pat. No. 5,563,175, which is incorporated herein by reference.

All that is needed to practice the method of the present invention is to administer the GABA analog together with the tricyclic compound. The amount of GABA analog in the composition will generally be from about 1 to about 300 mg per kilogram body weight of the subject patient. Typical dosages will be from about 10 to about 5000 mg per day for normal weight adult patients. Typical dosages are expected to be three to 600 mg four times, 100 mg a day. Commercially available capsules of gabapentin 100 mg, 300 mg and 400 mg may be administered. Other forms include liquid formulations and film coated tablets.

If a compound of formula (II) such as pregabalin is used, the dosage is 1/6 of gabapentin. The dosage range of pregabalin is from about 0.15 mg to about 50 mg per kg body weight of the patient. Typical dosages for pregabalin will be from about 1.6 mg to about 840 mg per day with each dosage range from about 0.15 mg to about 65 mg per dose.

The range of administration of tricyclic antidepressants can be determined by those skilled in the art. Amitriptyline is available in 10, 25, 50, 75 and 150 mg tablets. The daily dose may range from 75 to 350 mg.

An advantage of the claimed compositions is that they reduce the likelihood of overdose. Overdose of antidepressants is commonly reported at poison control centers. Accordingly, doctors and pharmacists are urged to provide short-term prescriptions for two to four weeks at a time to avoid providing tools for suicide to patients who are likely to commit suicide. Thus, since antidepressants lead to potential lethal doses as the dose is increased, the patient must increase the dose in small increments up to the effective amount.

The present invention will synergistically improve mood at a lower dose, safer and faster. Different mechanisms of action of the two drugs would be more beneficial to patients.

The compounds used in the present invention may 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 solution or an aqueous alcohol solution or other suitable solvent containing the appropriate acid and evaporating the solution to isolate the salt. Examples of pharmaceutically acceptable salts include hydrochlorides, hydrobromide salts, sulfates, as well as salts such as sodium, potassium and magnesium.

Compounds of formula (II) may contain one or several asymmetric carbon atoms. The present invention includes each diastereomer or enantiomer and mixtures thereof. Each diastereomer or enantiomer can be prepared or isolated by methods already known in the art.

Pharmaceutical compositions of a compound of the invention or a salt thereof are prepared by formulating the active compound with a pharmaceutical carrier in unit dosage form. Some examples of unit dosage forms include tablets, capsules, pills, powders, aqueous and non-aqueous oral solutions and suspensions, and containers containing one or more dosage units and which can be subdivided into individual dosages. It is a parenteral solution packaged in.

Some examples of suitable pharmaceutical carriers comprising a pharmaceutical diluent include gelatin capsules; Sugars such as lactose and sucrose; Starch 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 cacao oil; Propylene glycol, glycerin; Sorbitol; Polyethylene glycol; water; Agar; Alginic acid; Isotonic saline, and phosphate buffer solutions; In addition, there are other commercially available materials commonly used in pharmaceutical formulations. The composition of the present invention may also include other ingredients such as colorants, flavors and / or preservatives. If these materials are present they are generally used in relatively small amounts. The composition may also include other therapeutic agents as needed.

The proportion of active ingredient in the composition may vary within wide limits, but for practical purposes the ratio is preferably present at a concentration of at least 10% in solid phase compositions and at a concentration of at least 2% in major liquid compositions. The most satisfactory composition is the presence of a much higher proportion of active ingredient.

The route of administration of the subject compound or salt thereof is oral or parenteral. For example, a useful intravenous dose is 5-50 mg, and a useful oral dose is 20-800 mg. The dosage will fall within the dosage range used in the treatment of pain, or will be determined by the physician's prescription according to the needs of the patient.

Advantages of using compounds of formulas (I) and (II), particularly gabapentin and pregabalin, in the present invention are that the compounds are relatively nontoxic, easy to formulate, the compounds have tolerance, and intravenous administration of the drug It includes ease. Gabapentin rarely interacts with most drugs because it is not metabolized in the liver and is excreted in vitro unchanged. In addition, the drugs are not metabolized in the body. Subjects treated with the methods of the invention are mammals, including humans.

While the invention has been described in detail with respect to specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.

Claims (19)

(a) a therapeutically effective amount of a gamma-aminobutyric acid (GABA) analog, and (b) therapeutically effective amounts of tricyclic compounds A method of treating a depressed patient, comprising administering a pharmaceutical composition comprising a. The method of claim 1, wherein the GABA analog is a compound of Formula I and a pharmaceutically acceptable salt thereof. <Formula I> Where R ₁ is hydrogen or lower alkyl, n is an integer of 4-6. The method of claim 2, wherein the compound of formula (I) comprises gabapentin. The method of claim 2 comprising about 10 mg to about 400 mg of a compound of Formula (I). The method of claim 3, comprising about 10 mg to about 400 mg of gabapentin. The method of claim 3, comprising about 10 mg to about 400 mg of gabapentin and about 25 mg to about 350 mg of a tricyclic antidepressant. The method of claim 1, wherein the GABA analog is a compound of Formula II or a pharmaceutically acceptable salt thereof. <Formula II> Where R ₁ is straight or branched chain alkyl of 1 to 6 carbon atoms, phenyl or cycloalkyl of 3 to 6 carbon atoms, R ₂ is hydrogen or methyl, R ₃ is hydrogen, methyl or carboxyl. 8. The method of claim 7, wherein the compound of formula II comprises pregabalin. 8. The method of claim 7, comprising about 0.15 mg to about 65 mg of a compound of Formula II. The method of claim 8, comprising about 0.15 mg to about 65 mg pregabalin. (a) a therapeutically effective amount of a GABA analog, and (b) therapeutically effective amounts of tricyclic compounds Containing, composition for treating depression of a person. The composition of claim 11, wherein the GABA analog is a compound of Formula I: and a pharmaceutically acceptable salt thereof. <Formula I> Where R ₁ is hydrogen or lower alkyl, n is an integer of 4-6. The composition of claim 12, wherein the compound of formula I comprises gabapentin. The composition of claim 12 comprising from about 10 mg to about 400 mg of a compound of Formula (I). The composition of claim 13, comprising about 10 mg to about 400 mg of gabapentin. The composition of claim 11, wherein the GABA analog is a compound of Formula II: or a pharmaceutically acceptable salt thereof. <Formula II> Where R ₁ is straight or branched chain alkyl of 1 to 6 carbon atoms, phenyl or cycloalkyl of 3 to 6 carbon atoms, R ₂ is hydrogen or methyl, R ₃ is hydrogen, methyl or carboxyl. The composition of claim 16, wherein the compound of Formula II comprises pregabalin. The composition of claim 16 comprising about 0.15 mg to about 65 mg of a compound of Formula II. The composition of claim 18 comprising about 0.15 mg to about 65 mg pregabalin.