KR20020089510A - Treatment of Fibromyalgia and Chronic Fatigue Syndrome - Google Patents

Abstract

The present invention relates to apomorphine, bromocriptine, pergolide, rofinilol for the treatment of neuromuscular diseases, more specifically for the preparation of a medicament for treating or treating the symptoms of fibromyalgia syndrome and chronic fatigue syndrome. , Octahydropyrazolo [3,4-g] quinoline and trans- (±) -substituted-5,5a, 6,7,8,9-, 9a, 10-octahydropyrimido [4,5-g] Quinoline and their pharmaceutically acceptable salts.

Description

Treatment of Fibromyalgia Syndrome and Chronic Fatigue Syndrome {Treatment of Fibromyalgia and Chronic Fatigue Syndrome}

Chronic Fatigue Immune Disease, Chronic Fatigue Immune Syndrome, Yupflu, and Fatigue-Chronic, and Chronic Fatigue Syndrome (CFS), also called Chronic Fatigue and Immunodeficiency Syndrome, are clinically defined as conditions characterized by severe fatigue or fatigue have. In addition, CFS patients generally complain of a variety of nonspecific symptoms, including weakness, muscle aches and pains, excessive sleep, malaise, fever, sore throat, sensitive lymph nodes, memory loss and / or mental concentration, insomnia and depression. . To this day, the exact cause of CFS is unknown, and many tests have been done to rule out possible causes other than CFS that usually cause the above symptoms, but there are no specific diagnostic tests to confirm that it is CFS.

Fibromyalgia syndrome (FMS), also called fibromyalgia, fibromyalitis, fibromyalitis, or myofascial pain syndrome, is commonly referred to as systemic pain, fatigue, headache, lack of recovery sleep, and feeling in fibrous tissues, muscles, tendons, and other connective tissues. It is a rheumatic condition characterized by numbness. As such, FMS has many of the same clinical features as CFS. Similar to CFS, there is no special diagnostic test for FMS. Due to the similarity of the clinical features of CFS and FMS, CFS and FMS are often treated similarly.

A number of agents are commonly used to treat CFS and FMS. Examples of very common agents include hypnotics, immunosuppressants, various other prescription drugs, and combinations of over-the-counter drugs. Examples of other prescription drugs include opiate antagonists, sodium retention agents / beta blockers, calcium channel blockers / histamine blockers, antidepressants, allergic agents, and acute anxiety agents. However, no drug is known that permanently resolves the symptoms of CFS or FMS. Moreover, many of the drugs currently in use have side effects ranging from mild side effects such as drowsiness, dizziness and nausea to serious side effects such as addiction and liver damage.

Thus, there is a clear need for improved methods of treatment of chronic fatigue syndrome and fibromyalgia. In the present invention, several compounds have been identified that can be used to treat the above conditions or to prepare a medicament for treating them. These compounds are apomorphine, bromocriptine, pergolide, ropinillol, octahydropyrazole [3,4-g] quinoline and trans- (±) -substituted-5,5a, 6,7,8,9 -, 9a, 10-octahydropyrimido [4,5-g] quinoline and pharmaceutically acceptable salts thereof.

U. S. Patent No. 3,717, 639 describes apomorphine and its preparation. US Pat. No. 5,756,483 describes an intranasal preparation of apomorphine and its use as a therapeutic agent for Parkinson's disease. U.S. Patent 5,939,094 describes transdermal formulations comprising apomorphine. US Pat. No. 6,200,983 describes oral preparations of apomorphine and the use of apomorphine as a therapeutic agent for human sexual dysfunction.

U. S. Patent No. 3,752, 814 describes bromocriptine and its preparation. US Pat. No. 3,752,888 describes information on methods of synthesizing bromocriptine, as well as formulations, dosages, and administration thereof for inhibiting lactation. US Pat. No. 5,679,685 describes information on formulation, dosage and administration of bromocriptine for inhibiting lactation.

US Pat. No. 4,166,182 describes a method for preparing pergolide and its oral or parenteral administration as a prolactin inhibitor and in the treatment of Parkinson's disease. German Patent Application No. 4,240,798 describes pharmaceutical compositions for oral, sublingual, parenteral, percutaneous or nasal administration containing ergot derivatives including pergolides. US Pat. No. 6,001,390 discloses pharmaceutical compositions for transdermal administration containing ergot derivatives including pergolides.

U.S. Patent Nos. 4,452,808 and 5,336,781 describe ropinirole and ropinirole and methods for preparing pharmaceutically acceptable salts thereof. U.S. Patent Nos. 4,452,808 and 4,912,126 describe methods of preparing pharmaceutical compositions for oral, rectal or parenteral administration of lopinirol as a therapeutic agent for cardiovascular disease or depression. European Patent Application No. 299602A describes the use of ropineniol as a therapeutic agent for Parkinson's disease as well as pharmaceutical compositions for oral, rectal, parenteral or transdermal administration of ropinirol. US Pat. No. 5,807,570 describes transdermal formulations and administration of ropinirole.

U.S. Pat. No. 4,198,415 describes octahydropyrazolo [3,4-g] quinoline and methods of making the compounds and pharmaceutical compositions for oral or parenteral administration that treat Parkinson's disease and inhibit prolactin secretion. US Pat. No. 4,528,290 describes formulations for oral and parenteral administration of octahydropyrazolo [3,4-g] quinoline.

US Pat. No. 4,501,890 discloses trans- (±) -substituted-5,5a, 6,7,8,9-, 9a, 10-octahydropyrimido [4,5-g] quinoline and methods for making it, and Parkinson Formulations for oral or parenteral administration to treat illness, sexual dysfunction, depression, high blood pressure and elevated levels of prolactin are described. US Pat. No. 4,521,421 discloses trans- (±) -substituted-5,5a, 6,7,8,9-, 9a, 10-octahydropyrimido [4, for oral and parenteral administration to treat sexual dysfunction. Information on the preparation and preparation of 5-g] quinoline is described.

Summary of the Invention

The present invention relates to the use of certain known compounds for the treatment of or the manufacture of a medicament for treating the symptoms of fibromyalgia syndrome and chronic fatigue syndrome, for which no effective method of treatment is known. The compounds described herein include apomorphine, bromocriptine, pergolide, lopinirol, octahydropyrazolo [3,4-g] quinoline and trans- (±) -substituted-5,5a, 6,7 , 8,9-, 9a, 10-octahydropyrimido [4,5-g] quinoline and pharmaceutically acceptable salts thereof. The preparation, dosage and route of administration of the medicament are all provided to the extent necessary to identify and treat the patient in need thereof.

The present invention relates to apomorphine, bromocriptine, pergolide, rofinilol for the treatment of neuromuscular diseases, more specifically for the manufacture of a medicament for treating or treating the symptoms of fibromyalgia syndrome and chronic fatigue syndrome. , Octahydropyrazolo [3,4-g] quinoline and trans- (±) -substituted-5,5a, 6,7,8,9-, 9a, 10-octahydropyrimido [4,5-g] Quinoline and their pharmaceutically acceptable salts.

The present invention provides the use of several compounds and their pharmaceutically acceptable salts for the manufacture of a medicament for treating or treating the symptoms of fibromyalgia syndrome (FMS) or chronic fatigue syndrome (CFS). As used throughout this application, “pharmaceutically acceptable” means that it is acceptable to the patient from a pharmacological / toxicological point of view regarding the composition, formulation, stability, water solubility and bioavailability of the patient, and to a pharmaceutical chemist from a physical / chemical point of view. Refers to the nature and / or substance of which it is made. By “treating” or “treating” is meant that patients with symptoms of FMS or CFS tolerate FMS or CFS relatively easily, alleviate or reduce, or alleviate or eliminate FMS or CFS.

Compounds suitable for the present invention are apomorphine and pharmaceutically acceptable salts thereof. Apomorphine or (R) -5,6,6a, 7-tetrahydro-6-methyl-4H-dibenzo [de, g] quinoline-10,11-diol or 6aβ-amorphine-10,11-diol Can be represented by the structural formula (I) and exist in free base form or as acid addition salts.

The use of apomorphine as a therapeutic agent for Parkinson's disease or human sexual dysfunction, as well as methods of synthesizing apomorphine and preparation of pharmaceutical formulations thereof are known in the art (US Pat. No. 3,717,639, incorporated herein by reference). 5,756,483, 5,939,094 and 6,200,983.

For the purposes of the present invention, pharmaceutical compositions comprising apomorphine or a pharmaceutically acceptable salt thereof may be administered in a pharmaceutically acceptable carrier. Apomorphine hydrochloride is preferred, but other pharmacologically acceptable residues thereof may also be used. In addition to hydrochloride, other acceptable acid addition salts include hydrobromide, iodide, bisulfate, phosphate, acid phosphate, lactate, citrate, tartarate, salicylate, succinate, maleate, gluconate, etc. There is this.

Apomorphine can be prepared in any conventional dosage form such as capsules, tablets, chewable tablets, powders, transdermal patches, suspensions or solutions. Typical formulations of apomorphine include 0.25 to 10 mg (mg) as active ingredient, microcrystalline cellulose, anhydrous calcium phosphate, croscarmellose sodium, magnesium stearate, hydroxypropylmethylcellulose, titanium dioxide as inactive ingredients , Lactose, triacetin and FD & C Blue # 2 aluminum rake.

Apomorphine can be administered orally, sublingually, buccally, intranasally, transdermally, or parenterally in known pharmaceutical dosage forms suitable for a given route of administration. Apomorphine is preferably administered parenterally by subcutaneous injection, intravenous injection or infusion, or by percutaneous delivery.

Effective dosages of apomorphine are generally from about 0.25 to about 6 mg / patient per unit dose and are administered once or twice per day. The exact dosage and frequency of administration of apomorphine to be administered should be determined by the attending physician or clinician.

Another suitable compound of the present invention is bromocriptine or a pharmaceutically acceptable salt thereof. Bromocriptine or (5'α) -2-bromo-12'-hydroxy-2 '-(1-methylethyl) -5'-(2-methylpropyl) ergotaman-3 ', 6' , 18-trione; 2-Bromoergocriptine or 2-bromo-α-ergocriptine may be represented by the structural formula of Formula II.

Methods of synthesizing bromocriptine and preparation of pharmaceutical formulations thereof, and their use and administration for inhibiting lactation are known in the art (US Pat. No. 3,752,814, incorporated herein by reference). 3,752,888 and 5,679,685).

Bromocriptine can be obtained by brominating ergocryptin in an active solvent with a weak bromination agent such as N-bromophthalimide and purifying the resulting bromocriptine by methods known in the art. Bromocriptine may be prepared in any conventional dosage form such as capsules, tablets, chewable tablets, powders, suspensions or solutions. Solid oral preparations include bromocriptine mesylate (PARLODEL®) in the form of tablets (containing 2.5 mg bromocriptine) and capsules (containing 5 mg bromocriptine); Novartis Pharmaceutical Commercially available from J. Corporation) has long been available. This formulation has been approved in the United States for the treatment of certain prolactin hypersecretion-associated insufficiency and acromegaly, prevention of physiological lactation and treatment of Parkinson's disease and resistance to levodopa therapy of Parkinson's disease.

Bromocriptine can be administered orally, sublingual, buccal, transdermal or parenteral in known pharmaceutical dosage forms suitable for a given route of administration. Bromocriptine is preferably administered orally.

The therapeutically effective amount of a bromocriptine of the invention is generally about 2.5 to about 15 mg / day per person. Typically, administration of bromocriptine begins with a low daily dose of about 1.25 mg daily, depending on the individual, and the dose is gradually and gradually increased until an optimal therapeutic response is achieved. The exact dosage and frequency of administration of bromocriptine to be administered should be determined by the attending physician or clinician.

Other suitable compounds of the present invention are pergolides or pharmaceutically acceptable salts thereof. Pergolide or (8β) -8-[(methylthio) methyl] -6-propylergoline; D-6- n -propyl-8β-methylmercaptomethylergoline; Alternatively, LY-141B may be represented by the structural formula of Formula III below.

Methods of synthesizing pergolides and preparation of pharmaceutical formulations thereof, and their use and administration as therapeutics or prolactin inhibitors of Parkinson's disease are known in the art (US Pat. No. 4,166,182, incorporated herein by reference). No. 6,001,390 and German Patent Application No. 4240798).

Pergolides can be prepared in any conventional dosage form such as capsules, tablets, chewable tablets, powders, suspensions or solutions. Solid oral pergolide preparations have been commercially available for long periods of pergolide mesylate (PERMAX®; manufactured by Athena Neurosciences) containing 0.05, 0.25 and 1 mg of pergolide, respectively. . This formulation is approved in the United States for the treatment of Parkinson's disease.

Pergolides can be administered orally, sublingual, buccal, transdermal, nasal or parenteral in known pharmaceutical dosage forms suitable for a given route of administration. Pergolides are preferably administered orally and parenterally, more preferably pergolides.

The therapeutically effective amount of the pergolide of the present invention is generally about 0.75 to about 5 mg / day per person. Typically, pergolides should be started at a daily dosage of 0.05 mg for the first two days. Thereafter, the dosage should be gradually increased by 0.1 to 0.25 mg per day from the third day until the optimal therapeutic dose is achieved. Pergolides are typically administered in three divided doses per day. The exact dosage and frequency of administration of pergolide to be administered should be determined by the attending physician or clinician.

Another suitable compound of the present invention is ropinillol or a pharmaceutically acceptable salt thereof. Ropinirole or 4- [2- (dipropylamino) ethyl] -1,3-dihydro-2H-indol-2-one; 4- [2- (di- n -propylamino) ethyl] -2 (3H) -indoleone; Or 4- (2-di-n-propylaminoethyl) -2- (3H) -indoleone may be represented by the structural formula IV.

Suitable salts are apparent to those skilled in the art and include, for example, acid addition salts, preferably hydrochloride salts.

Ropinirol and its pharmaceutically acceptable salts can be prepared by the methods described in US Pat. No. 4,452,808. Information on the formulation and administration of ropinillol as a therapeutic agent for cardiovascular or Parkinson's disease is described in US Pat. Nos. 4,912,126 and 5,807,570 and European Patent Publication No. 29602A, which are incorporated herein by reference.

Ropinirol can be prepared in any conventional dosage form such as capsules, tablets, chewable tablets, powders, transdermal patches, suspensions or solutions. Solid oral ropinillol preparations include ropinillol hydrochloride (REQUIP®) in the form of tablets containing 0.25, 1 mg, 2 mg, 4 mg and 5 mg of ropinillol, respectively; Production) has been commercially available. This formulation is approved in the United States for the treatment of Parkinson's disease.

Ropinirol may be administered orally, sublingually, transdermally, rectally or parenterally in known pharmaceutical dosage forms suitable for a given route of administration. Rofinirol is preferably administered orally and parenterally, and rofinirol is more preferably administered orally.

The therapeutically effective amount of rofinirol of the invention is generally from about 0.25 to about 25 mg / day per person. It is typical to administer three times a day. Dosage typically starts at a low dose of about 0.25 mg three times a day and gradually increases to achieve a balanced, controlled maximum therapeutic effect against major side effects such as nausea, dizziness, drowsiness and dyskinesia. The exact dosage and frequency of administration of ropinillol to be administered should be determined by the attending physician or clinician.

Other suitable compounds of the present invention are those which are generic or described in detail in US Pat. Nos. 4,198,415 and 4,528,290. These compounds are generally referred to as trans- (±) -octahydropyrazolo [3,4-g] quinoline and may exist as tautomers of formula Va and of formula Vb or pharmaceutically acceptable salts thereof.

Where

R is H, CN, C ₁ -C ₃ alkyl, allyl or benzyl,

R ₁ is H, COOH, COO (C ₁ -C ₃ ) alkyl or CH ₂ X,

X is CN, Cl, I, Br, OH, OCH ₃ , SCH ₃ , SO ₂ CH ₃ , OSO _2- (C ₁ -C ₃ ) -alkyl, OSO ₂ -tolyl, OSO ₂ -phenyl or CONH ₂ .

Examples of the compound of formula Va or Vb include but are not limited to the following compounds.

Trans- (±) -5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H (and 2H) -pyrazolo [3,4-g] quinoline and its di Hydrochloride salts;

Trans- (±) -5-n-propyl-7-methylmercaptomethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H (and 2H) -pyrazolo [3,4 -g] quinoline and its dihydrochloride salt;

Trans _{- (±) -5- (C 1} -C 3) alkyl (or allyl) -7- (C ₁ -C ₃₎ alkoxycarbonyl -4,4a, 5,6,7,8,8a, 9- Octahydro-1H (and 2H) -pyrazolo [3,4-g] quinoline;

Trans- (±) -5-n-propyl-7-ethoxycarbonyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H (and 2H) -pyrazolo [3,4 -g] quinoline; And

Trans- (±) -5-methyl-7-ethoxycarbonyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H (and 2H) -pyrazolo [3,4-g ] Quinoline.

Particularly preferred compounds of formula Va and Vb are the following formula Vc and the following formula Vd or pharmaceutically acceptable salts thereof.

Where

R is C ₁ -C ₃ alkyl or allyl,

R ₁ is CH ₂ X,

X is CN, CONH ₂ , SCH ₃ , SO ₂ CH ₃ and OCH ₃ .

Other particularly preferred compounds of formula Va and Vb are the trans-(+) stereoisomers which exist as tautomeric pairs of formulas Ve and Vf.

Where

R is methyl, ethyl, n-propyl or allyl.

Particularly preferred compounds of formula Va and Vb are quinpyrrole or pharmaceutically acceptable salts thereof. Quinpyrrole or 1H-pyrazolo [3,4-g] quinoline, 4,4a, 5,6,7,8,8a, 9-octahydro-5-propyl-, (4aR, 8aR)-(9CI) or 1H-pyrazolo [3,4-g] quinoline, 4,4a, 5,6,7,8,8a, 9-octahydro-5-propyl-, (4aR-trans)-; (-)-Quinpyrrole; LY 156258 can be represented by the structural formula of Formula Vg.

Compounds of formulas Va and Vb can be prepared by any suitable method. Methods of making such compounds are described in more detail in US Pat. Nos. 4,198,415 and 4,528,290, both of which are incorporated herein by reference. The compounds of formulas (la) and (lb) may be prepared in any conventional dosage form such as capsules, tablets, chewable tablets, powders, transdermal patches, suspensions or solutions. Pharmaceutical formulations of such compounds are described in more detail in US Pat. Nos. 4,198,415 and 4,528,290, both of which are incorporated herein by reference.

The compounds of formula Va and Vb may be administered orally, sublingually, transdermally or parenterally in known pharmaceutical dosage forms suitable for a given route of administration. The compound is preferably administered orally and parenterally.

A therapeutically effective amount of a compound of formulas Va and Vb of the present invention is generally administered orally at about 0.01 to about 15 mg / kg per unit dose, and parenterally at about 0.0025 to about 2.5 mg / kg per unit dose. Oral administration typically provides three to four administrations per day to provide a daily dosage range of about 0.3 to about 60 mg / kg per day. The exact dosage and frequency of administration of the compounds of formulas Va and Vb to be administered should be determined by the attending physician or clinician.

Another suitable compound of the invention is the trans- (±) -racemate of formula VI or a stereoisomer of formula VIa or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable acid addition salt thereof.

Where

R is C ₁ -C ₃ alkyl or allyl,

R ₁ is NH ₂ , NHR ₃ , NR ₄ R ₅ ,

R ₂ is H, CH ₃ , Cl or Br,

R ₃ is methyl, ethyl or n-propyl, C ₁ -C ₃ alkyl-CO, phenyl-CO or substituted phenyl-CO wherein the substituents are Cl, F, Br, CH ₃ , C ₂ H ₅ , CH ₃ O, C ₂ H ₅ O and CF _{3 It} is one or two groups selected from the group consisting of),

R ₄ and R ₅ are each methyl, ethyl or n-propyl.

Compounds represented by formula (VI) are those described generally or specifically in US Pat. Nos. 4,521,421 and 4,501,890 and are trans- (±) -substituted-5,5a, 6,7,8,9-, 9a Commonly referred to as 10-octahydropyrimido [4,5-g] quinoline. Such compounds may exist in two racemates commonly referred to as trans- (±) racemates and cis- (±) racemates. The corresponding two racemates are trans- (±) -racemate-trans- (±) -2-amino-6-alkyl or allyl-4-substituted-5,5a, 6,7,8,9 , 9a, 10-octahydropyrimido [4,5-g] quinoline- and the corresponding cis- (±) -racemate. The trans-(-)-mirror pair stereoisomer (VIa) is one of two stereoisomers represented by Formula VI and is a preferred compound in the present invention. Examples of particularly preferred compounds are trans- (±) -2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline , Trans-(-)-2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline and trans-(- ) -2-amino-6-n-propyl-5,5a, 6,7,8,9,9a, 10-octahydropyrimido [4,5-g] quinoline dihydrochloride salt.

Particularly preferred compounds of formula VI are quinellolan or a pharmaceutically acceptable salt thereof. Quinellolan or pyrido [2,3-g] quinazolin-2-amine, 5,5a, 6,7,8,9,9a, 10-octahydro-6-propyl-, (5aR, 9aR)- (9CI) or pyrido [2,3-g] quinazolin-2-amine, 5,5a, 6,7,8,9,9a, 10-octahydro-6-propyl, (5aR-trans)- It can be represented by the structural formula of the formula (VIb).

Compounds of Formula VI and pharmaceutically acceptable salts thereof may be prepared according to the procedures described in US Pat. Nos. 4,501,890 and 4,521,421. The use and administration of these compounds for the treatment of Parkinson's disease, sexual dysfunction, depression, hypertension and elevated levels of prolactin, as well as information on pharmaceutical formulations of these compounds are both US Pat. No. 4,501,890, which is incorporated herein by reference. And 4,521,421.

Compounds of Formula (VI) and pharmaceutically acceptable salts thereof may be prepared in any conventional dosage form such as capsules, tablets, chewable tablets, powders, transdermal patches, suspensions or solutions. Routes of administration of these compounds include oral, sublingual, transdermal and parenteral routes in known pharmaceutical dosage forms suitable for a given route of administration, with oral routes being preferred.

A therapeutically effective amount of a compound of Formula VI of the present invention is generally administered orally at about 0.1 to about 100 mcg / kg per unit dose, and parenterally at about 0.25 to about 25 mcg / kg per unit dose. It is typical to administer orally 3 to 4 times a day. The exact dosage and frequency of administration of the compound of formula VI to be administered should be determined by the attending physician or clinician.

Formulations of the compounds of the present invention may conveniently be presented in unit dosage form and may be prepared by conventional pharmaceutical techniques known in the art. Such techniques include the step of bringing into association the active ingredient and the pharmaceutical carrier or excipient. In general, formulations may be prepared by associating the active ingredient uniformly and tightly with the liquid carrier or the finely divided solid carrier or both and then molding the product, if necessary.

Compounds that are active upon oral administration and pharmaceutically acceptable salts thereof may be formulated in liquid form, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

Liquid formulations generally comprise the compound or a pharmaceutically acceptable salt thereof with a suspending agent, preservative, flavoring or coloring agent in a suitable liquid carrier such as ethanol, glycerin, a non-aqueous solvent such as polyethylene glycol, oil or water. Consisting of a suspension or a solution.

Formulations in tablet form may be prepared using any suitable pharmaceutical carrier (s) commonly used to prepare solid formulations. Examples of such carriers are magnesium stearate, starch, lactose, sucrose and cellulose.

Formulations in capsule form can be prepared using conventional encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into hard gelatin capsules, or alternatively the dispersion or suspension can be in any suitable pharmaceutical carrier (s) such as aqueous gum, cellulose, These dispersions or suspensions can be filled into soft gelatin capsules after preparation using silicates or oils.

For example, a compound and its pharmaceutically acceptable salts active during parenteral administration by injection or infusion can be formulated in solution or suspension. Formulations for parenteral administration may contain aqueous and non-aqueous sterile suspensions which may contain antioxidants, buffers, bacteriostatics and solutes that make the formulation isotonic with the recipient's blood, and suspending agents and thickeners. The formulations may be present in single or multiple dose containers, such as sealed ampoules and vials, and stored in a freeze-dried state, which only requires the addition of a sterile liquid carrier, such as water for injection, immediately before use. Instant injections and suspensions can be prepared from sterile powders, granules, and tablets of the kind described above.

Typical suppository formulations contain the aforementioned compounds or pharmaceutically acceptable salts thereof, which are active when administered in this manner, together with lubricants and / or binders such as polymer glycols, gelatin or cocoa butter or other low melting vegetable or synthetic waxes or fats. Include.

Formulations suitable for monthly topical administration typically include lozenges comprising the ingredient in a sucrose and a flavourant base such as acacia or tragacanth; Mouthwashes comprising the pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia and the dosage ingredient in a suitable liquid carrier.

Formulations suitable for topical administration to the skin can be provided as ointments, creams, gels and pastes comprising the active ingredient to be administered in a pharmaceutically acceptable carrier. Topical delivery systems include transdermal patches and transdermal gels containing the components to be administered.

Formulations suitable for nasal administration in which the carrier is in solid form include coarse powders having a particle size of, for example, 20 to 500 microns, which is administered in such a way as to inhale from the container of the powder adhered to the nose and pass through the nasal passage quickly. . For example, formulations suitable for nasal administration in which the carrier is liquid, such as nasal sprays or nasal drops, include aqueous or oily solutions of the active ingredient.

The precise dosage of the aforementioned compounds for treating the symptoms of FMS or CFS of the present invention may be prescribed to the route of administration, dosage form, specific disease to be treated, severity of disease to be treated, age, weight, general physical condition of a particular patient, individual It depends on factors such as other medications that can be determined and should be determined by an experienced physician who has been prescribed a physiologically active drug designed to control the above-mentioned types of central nervous system, exercise and related psychological and physiological diseases. do. Mild FMS and CFS patients are expected to require fewer drugs, while patients with the more severe disease are expected to require more drugs.

Those skilled in the art will clearly understand that various changes and modifications can be made in the present invention without departing from the spirit or scope of the present invention.

Claims (19)

Apomorphine, bromocriptine, pergolide, rofinirol, octahydropyrazolo [3,4-g] quinoline, and trans- (±) -substituted-5,5a, 6,7,8,9 A patient suffering from fibromyalgia syndrome or chronic fatigue syndrome with an effective amount of a compound selected from the group consisting of 9a, 10-octahydropyrimido [4,5-g] quinoline, or a pharmaceutically acceptable salt of any of said compounds A method of treating the symptoms of fibromyalgia syndrome and chronic fatigue syndrome, comprising administering to. The method of claim 1, wherein the compound is apomorphine or a pharmaceutically acceptable salt thereof. The method of claim 2, wherein the effective amount of apomorphine or a pharmaceutically acceptable salt thereof is about 0.25 to about 12 mg / day. The method of claim 1, wherein the compound is bromocriptine or a pharmaceutically acceptable salt thereof. The method of claim 4, wherein the effective amount of bromocriptine or a pharmaceutically acceptable salt thereof is about 2.5 to about 15 mg / day. The method of claim 1, wherein the compound is a pergolide or a pharmaceutically acceptable salt thereof. The method of claim 6, wherein the effective amount of pergolide is from about 0.75 to about 5 mg / day. The method of claim 1, wherein the compound is ropinillol or a pharmaceutically acceptable salt thereof. The method of claim 8, wherein the effective amount of ropinillol or a pharmaceutically acceptable salt thereof is about 0.25 to about 25 mg / day. The method of claim 1, wherein said octahydropyrazolo [3,4-g] quinoline is a trans- (±) stereoisomer or pharmaceutically acceptable salt thereof present as a tautomeric pair of Formula Va and Formula Vb. . <Formula Va> <Formula Vb> Where R is H, CN, C ₁ -C ₃ alkyl, allyl or benzyl, R ₁ is H, COOH, COO (C ₁ -C ₃ ) alkyl or CH ₂ X, X is CN, Cl, I, Br, OH, OCH ₃ , SCH ₃ , SO ₂ CH ₃ , OSO _2- (C ₁ -C ₃ ) -alkyl, OSO ₂ -tolyl, OSO ₂ -phenyl or CONH ₂ . The method of claim 10, wherein R is C ₁ -C ₃ alkyl or allyl, R ₁ is H or CH ₂ X, and X is CN, CONH ₂ , SCH ₃ , OCH ₃ or SO ₂ CH ₃ . The method of claim 10, wherein R is H, CN, or benzyl, and R ₁ is H. 12. The compound of claim 10, wherein R is C ₁ -C ₃ alkyl or allyl, R ₁ is COO (C ₁ -C ₃ ) alkyl or CH ₂ X, and X is Br, I, Cl, OH, OSO _2- ( C ₁ -C ₃ ) alkyl, OSO ₂ -tolyl or OSO ₂ -phenyl. The method of claim 10, wherein the octahydropyrazolo [3,4-g] quinoline is trans- (±) -5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro -1H (and 2H) -pyrazolo [3,4-g] quinoline or its dihydrochloride salt. The method of claim 10, wherein the octahydropyrazolo [3,4-g] quinoline is trans- (±) -5-n-propyl-7-methylmercaptomethyl-4,4a, 5,6,7,8 , 8a, 9-octahydro-1H (and 2H) -pyrazolo [3,4-g] quinoline or a dihydrochloride salt thereof. The method of claim 10, wherein the octahydropyrazolo [3,4-g] quinoline is trans- (±) -5- (C ₁ -C ₃ ) alkyl (or allyl) -7- (C ₁ -C ₃ ) Alkoxy carbonyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H (and 2H) -pyrazolo [3,4-g] quinoline. The method of claim 10, wherein the octahydropyrazolo [3,4-g] quinoline is trans- (±) -5-n-propyl-7-ethoxycarbonyl-4,4a, 5,6,7,8 , 8a, 9-octahydro-1H (and 2H) -pyrazolo [3,4-g] quinoline. The method of claim 10, wherein the octahydropyrazolo [3,4-g] quinoline is trans- (±) -5-methyl-7-ethoxycarbonyl-4,4a, 5,6,7,8,8a , 9-octahydro-1H (and 2H) -pyrazolo [3,4-g] quinoline. The method of claim 10, wherein said octahydropyrazolo [3,4-g] quinoline is a trans- (±) stereoisomer present as a tautomeric pair of Formula Vc and Formula Vd. <Formula Vc> <Formula Vd> Where R is C ₁ -C ₃ alkyl or allyl, R ₁ is CH ₂ X, X is CN, CONH ₂ , SCH ₃ , SO ₂ CH ₃ and OCH ₃ .