MXPA02010410A - Treatment of fibromyalgia and chronic fatigue syndrome. - Google Patents

Abstract

The present invention relates to the treatment of neuromuscular disorders and, more specifically, to the use of apomorphine, bromocriptine, pergolide, ropinirole, octahydropyrazolo[3, 4 g]quinolines, and trans (plusmn;) substituted 5,5a,6,7,8,9 ,9a, 10 octahydropyrimido[4,5g]quinolines, and their pharmaceutically acceptable salts to treat, or to prepare a medicament for treating, symptoms of fibromyalgia syndrome and chronic fatigue syndrome.

Description

TREATMENT OF SYNDROMES OF FIBROMYALGIA AND CHRONIC FATIGUE FIELD OF THE INVENTION The present invention relates to the treatment of neuromuscular disorders and, more specifically, to the use of apomorphine, bromocript ina, pergolide, ropinirole, octahydropira zolo [3, 4-g] quinolines, and trans- (±) -substituted-5, 5a, 6, 7, 8, 9-, 9a, 10-octahydropyrimido [4,5-g] quinolines, and their pharmaceutically acceptable salts to treat, or to prepare a medicament for treating the symptoms of the fibromyalgia and chronic fatigue syndrome.

BACKGROUND OF THE INVENTION Chronic fatigue syndrome (CFS), also referred to as chronic fatigue immune disorders, chronic fatigue immune disorders syndrome, yuppi e fl u, chronic fatigue, and dysfunctional chronic and immune fatigue syndrome, is a condition . defined clinically characterized by fatigue or deep fatigue. Acemas, patients with CFS er. general report various non-specific symptoms, among which include weakness, muscle aches, sleep excessive, discomfort, fever, sore throat, sore lymph nodes, memory and / or mental concentration affected, insomnia, and depression. The exact cause of CFS is unknown and, to date, there are no specific tests to confirm the diagnosis of CFS, although a variety of tests are usually performed to exclude other possible causes of the symptoms. Fibromyalgia syndrome (FMS), also referred to as fibromyalgia, fibromyosi tis, fibrosizis, or myofascial pain syndrome, is a rheumatic condition characterized generally by generalized pain in fibrous tissues, muscles, tendons, and other connective tissues, fatigue, headaches, lack of restorative sleep, and numbness. In this way, the FMS shares many clinical characteristics with the CFS. Like cor. the CFS, there are no specific diagnostic tests for the FMS. Due to the similarity in clinical characteristics between CFS and FMS, CFS and FMS are often treated similarly. In general, many medications are used to treat CFS and FMS. Examples of the .- > Most common types include hypnotics, immunosuppressants, several other prescribed medications, and a series of medications without a prescription. Examples of other prescription drugs include opioid antagonists, sodium retention agents / beta blockers, calcium channel blockers / histamine blockers, antidepressants, allergy medications, and medications for severe anxiety. However, there are no known medications that permanently resolve the symptoms of either CFS or FMS. In addition, many of the currently used medications produce side effects that vary from mild side effects, for example, drowsiness, dizziness, and nausea to severe side effects, eg, addiction and liver damage. Therefore, there is clearly a need for better treatments for chronic fatigue syndrome and fibromyalgia. Now, the present invention discloses various compounds that can be used to treat, or to prepare a medicament for the treatment of these conditions. These compounds include apomorphine, bromocript ina, pergolide, ropinirole, oct ahydropy ra zolo [3, 4-g] quinolines, and trans- (±) -substituted -5.5a, 6,7,8,9-, 9a, 1 O-octahydropyrimido [4,5-g] quinolines, and their pharmaceutically acceptable salts. U.S. Patent No. 3,717,639 discloses apomorphine and the preparation methods thereof. U.S. Patent No. 5,756,483 discloses intranasal preparations for apomorphine and the use thereof as a therapy for Parkinson's disease. U.S. Patent No. 5,939,094 discloses transdermal preparations comprising apomorphine. U.S. Patent No. 6,200,983 discloses oral preparations for apomorphine and the use of apomorphine as a therapy for human sexual dysfunction. The patent of the United States No. 3,752,814 exposes Bromocript ina and the process to prepare it. U.S. Patent No. 3,752,888 discloses the information on the preparations, dosage levels and administration to inhibit lactation, as well as the synthesis process, for the bromocript ina. U.S. Patent No. 5,679,685 discloses information on preparations, dosing levels and administration of bromocript go. a to inhibit lactation.

U.S. Patent No. 4,166,182 discloses the preparation of pergolide and its oral or parenteral administration as a prolactin inhibitor and in the treatment of Parkinson's Disease. German patent application DE 4240798 discloses a pharmaceutical composition containing ergot derivatives, including pergolide, for oral, sublingual, parenteral, percutaneous or nasal administration. U.S. Patent No. 6,001,390 discloses a pharmaceutical composition containing ergot derivatives, including pergolide, for transdermal administration. United States Patents Nos. 4,452,808 and 5,336,781 disclose ropinirole and methods for preparing ropinirole and its pharmaceutically acceptable salts. U.S. Patent Nos. 4,452,808 and 4,912,126 disclose methods for preparing pharmaceutical compositions for oral, rectal, or parenteral administration of ropinirole as a treatment for cardiovascular disorders or depression. European Patent Application No. 299602A discloses the application of ropinirole to a treatment for Parkinson's disease, as well as comp; s ic ions Pharmaceuticals for oral, rectal, parenteral, or transdermal administration of ropinirole. U.S. Patent No. 5,807,570 discloses transdermal preparations and the administration of ropinirole. U.S. Patent No. 4,198,415 discloses zolo [3, 4-g] quinolines octahydropyra and the method for preparing the compounds and pharmaceutical compositions thereof for oral or parenteral administration for the treatment of parkinsonism and for inhibiting prolactin secretion . U.S. Patent No. 4,528,290 discloses preparations for oral and parenteral administration of octahydropyrazolo [3,4-g] quinolines. U.S. Patent No. 4,501,890 discloses t rans - (±) - its titidates - 5, 5a, 6, 7, 8, 9-, 9a, 10-oct ahydropyrimido [4,5-g] quinol inas and the method for preparing the same, as well as the preparations for oral or parenteral administration to treat Parkinson's syndrome, dysfunction. sexual, depression, hypertension, and elevated levels of prolactin. United States Patent No. 4,521,421 discloses information on the preparation method and formulations of trans- (±) -substituted -5.5a, 6,7,8,9-, 9a, 10-octahydro-pyrimido [4,5-g] quinolines for oral and parenteral administration to treat sexual dysfunction.

BRIEF DESCRIPTION OF THE INVENTION The invention is directed to the use of certain known compounds to treat, or to prepare the medicaments for treating the symptoms of fibromyalgia syndrome and chronic fatigue syndrome, two debilitating conditions for which there is no effective known treatment. The compounds described herein are apomorphine, bromocript ina, pergolide, ropinirole, octahydropira zolo [3,4-g] quinolines, and trans- (i) -substituted-5, 5a, 6, 7, 8, 9-, 9a, 10-octahydropyrimido [4,5-g] quinolines, and their pharmaceutically acceptable salts. The preparation of medications, dosages and administration routes will be provided to the extent necessary to identify and treat patients who need them.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides the use of various classes of compounds, and their pharmaceutically acceptable salts to treat, or prepare medicaments for treating the symptoms of fibromyalgia (FMS) or chronic fatigue syndrome (CFS). "Pharmaceutically acceptable", in the sense in which it is used herein, throughout the document refers to those properties and / or substances that are acceptable to the patient from a pharmacological / toxicological point of view and to the pharmaceutical chemist who prepares them from a physical / chemical point of view regarding the composition, formulation, stability, patient acceptance and bioavailability. By "treating" or "treating" it must be understood to make it less hard to bear, reduce or diminish, or lighten or arouse patients from the symptoms of FMS or CFS. A suitable compound in the present invention is apomorphine and a pharmaceutically acceptable salt thereof. The apomorphine, or (R) - 5, 6, 6a, 7-Tetrar.idro-6-methyl-4H-diberazo [de, g] quinolin- 1 C 1 -diol or 6aß-apor f ma- 10, 11- c 10I, can be represented structurally by the form (I) (D and it exists in a free base form or as an acid addition salt. The method of synthesis and the preparation of the pharmaceutical formulations for apomorphine are known in the art, as well as their use as a therapy for Parkinson's disease or human sexual dysfunction. See, for example, U.S. Patent Nos. 3,717,639, 5,756,483, 5,939,094, and 6,200,983, all incorporated herein by reference. For the purposes of the present invention, a pharmaceutical composition comprising apomorphine or a pharmaceutically acceptable salt thereof can be administered in an acceptable pharmaceutical carrier. The apomorphine hydrochloride is preferred; however, other pharmacologically acceptable entities can also be used. In addition to the hydrochloride salt, other acceptable acid addition salts are the hydrobromide, the hydroiodide, the bisulfate, phosphate, acid phosphate, lactate, citrate, tartarate, salicylate, succinate, maleate, gluconate, and the like. The apomorphine can be prepared in any conventional dosage form such as for example, a capsule, tablet, chewable tablet, powder, transdermal patch, suspension or solution. A typical formulation for apomorphine comprises from 0.25 to 10 milligrams (mg) of the active agent and as inactive ingredients, microcrystalline cellulose, calcium dibasic phosphate anhydrous, croscarmellose sodium, ragnesium stearate, hiaroxypropylmethylcellulose, titanium dioxide, lactose, triacetin, and aluminum lacquer FD &C 31ue # 2. The apomorphine in the appropriate pharmaceutical dosage form, known for a given route of administration, can be administered orally, sublingually, buccally, intranasally, transdermally, or parenterally. It is preferred that the aphidrin be administered parenterally by subcutaneous injection, intra-enous injection or infusion, or by transdermal delivery. The effective dosage of apomorphine in general is between about 0.2: and 6 mg / os / person, once or twice a day. the dose The exact dose to be administered and the dosage frequency of apomorphine will be easily determined by the attending physician or clinician. Another suitable compound in the present invention is bromocript ina, or a pharmaceutically acceptable salt thereof. Bromocript ina, or (5 'a) -2-Bromo-12' -hydroxy-2 '- (1-methylethyl) -5' - (2-methylpropyl) ergotaman-3 ', 6', 18-trione; 2-bromoergocript ina; or 2-bromo-a-ergocript ina, can be represented structurally by the following formula (II). (p) The method of synthesis and the preparation of the pharmaceutical formulations for bromocript ina are known in the art, as well as their use and administration to inhibit lactation. See, for example, U.S. Patent Nos. 3,752,814, 3,752,888, and 5,679,685, all incorporated herein by reference. Bromocriptine can be obtained by brominating ergocryptine in an inert solvent, with a mild brominating agent, for example, N-bromophthalimide, and purifying the resulting bromocriptine in a manner known per se. Bromocriptine can be prepared in any conventional dosage form such as, for example, a capsule, tablet, chewable tablet, powder, suspension or solution. Solid oral preparations for a long time have been commercially available as bromocriptine mesylate (PARLODEL® sold by Novartis Pharmaceuticals Corp.) in the form of a tablet and capsule containing 2.5 and 5 mg of bromocriptine, respectively. These preparations were approved in the United States for use in the treatment of certain dysfunctions associated with hyperprolact inemia and acromegaly, in the prevention of physiological lactation, and in the treatment of Parkinson's disease and the prevention of tolerance to therapy with Levodopa for Parkinson's disease.

Bromocriptine in the proper pharmaceutical dosage form known for a given administration route can be administered orally, sublingually, buccally, transdermally, or parenterally. It is preferred that bromocriptine be administered orally. The effective therapeutic amount of bromocriptine in the present invention is generally between about 2.5 and 15 mg / day / person. In general, administration of bromocriptine should be initiated at a low daily dosage of approximately 1.25 mg per day, and on an individual basis, the dosage is slowly and gradually increased until an optimal therapeutic response is reached. The exact dose to be administered and the frequency of dosing for bromocriptine will be easily determined by the attending physician or clinician. Another suitable compound in the present invention is pergolide, or a pharmaceutically acceptable salt thereof. Pergolide, u (8, ß) -8- [(Methyl thio) rszyl] -6-propylergoline; D-6-n-propyl-8β-methylmercaptcr.etilergoline; or LY-141B, it can be represented by the following formula (III). (ffl) The method of synthesis and the preparation of the pharmaceutical formulations for pergolide, as well as their use or administration as a therapy for Parkinson's disease or as a prolactin inhibitor are known in the art. See, for example, U.S. Patent Nos. 4,166,182 and 6,001,390, and German Patent Application DE 4240798, all incorporated herein by reference. Pergolide can be prepared in any conventional dosage form such as, for example, a capsule, tablet, chewable tablet, powder, suspension or solution. The preparations of solid oral pergolide for a long time he :. were commercially available as tergolide mesylate (PERMAX® by Athena Neurocs iences) in tablet form containing 0.05.0.25, and 1 mg pergolide, respectively. These preparations were carried out in the United States to be used in the treatment of Parkinson's disease. Pergolide in the proper pharmaceutical dosage form known for a given administration route can be administered orally, sublingually, buccally, transdermally, nasally, or parenterally. It is preferred that the perglycide be administered orally and parenterally, and it is more preferred that the pergolide be administered orally. The effective therapeutic amount of cergolide in the present invention is generally between about 0.75 and 5 mg / day / person. In general, pergolide administration should be started with a daily dosage of 0.05 mg during the first two days. The dosage should then be increased gradually by 0.1-0.25 mg / day every third day until an optimal therapeutic dosage is reached. The pergolide usuairent is administered er. divided doses 3 times a day. The exact dose to be administered and the frequency of dosing for pergolide will be easily determined: r the doctor or clinician; -e is attending.

Another suitable compound in the present invention is ropinirole or a pharmaceutically acceptable salt thereof. Ropinirole, or 4- [2- (Dipropi lami not) ethyl] -1, 3-dihydro-2H-indol-2-one; 4- [2- (di-n-propylamino) ethyl] -2 (3JÍ) -indolone; or 4- (2-di-n-propylaminoethyl) -2- (3H) -indolone, can be represented structurally by the following formula (IV).

(IV) Suitable salts will be apparent to those skilled in the art and include, for example, acid addition salts, preferably the hydrochloride. Ropinirole and its pharmaceutically acceptable salts can be prepared by the methods described in U.S. Patent No. 4,452,808. Information on the preparations and administration of ropinirole as a treatment for cardiovascular disease or Parkinson's disease is described in United States patents.

United Nos. 4, 912126 and 5,807,570, and EP-299,602 -A, all incorporated herein by reference. Ropinirole can be prepared in any conventional dosage form such as, for example, a capsule, tablet, chewable tablet, powder, transdermal patch, suspension or solution. Oral solid preparations of ropinirole have been commercially available as ropinirole hydrochloride (REQUIP by SmithKine Beecham) in the form of a tablet containing 0.25, lmg, 2mg, 4mg, and 5mg of ropinirole, respectively. These preparations were approved in the United States for use in the treatment of Parkinson's disease. The ropinirole in the known pharmaceutical dosage form for a given administration route can be administered orally, sublingually, transdermally, rectally, or parenterally. It is preferred that ropinirole be administered orally and parenterally, and most preferably that ropinirole be administered orally. The effective therapeutic amount of ropinirole in the present invention is generally between about 0.25 and 25 mg / day / person. It is typically administered 3 times a day. The dosage usually starts at a slow dosage at approximately 0.25 mg three times a day, and is gradually increased until a maximum therapeutic effect is achieved, balanced against the main side effects of nausea, dizziness, drowsiness and dyskinesia. The exact dose to be administered and the frequency of dosing will be easily determined by the attending physician or clinician. Other compounds suitable in the present invention are those generically or specifically disclosed in U.S. Patent Nos. 4,198,415 and 4,528,290. These compounds are generically referred to as trans- (±) -octahydro pyrazolo [3,4-g] quinolines and may exist as tautomers of the formula (Va) (Goes) and the formula b: (Vb) or their pharmaceutically acceptable salts, wherein: R is H, CN, C? -C3 alkyl, allyl or benzyl and Ri is H, COOH, COO (C? -C3) alkyl or CH2 X wherein X is CN, Cl, I, Br, OH, OCH3, SCH3, S02 CH3, 0S02 - (Cx-C3) -alkyl, 0-S02 -tolyl, OS02-phenyl or CONH2. Examples of compounds of the formula (Va or Vb) include, without limitation, the following compounds: trans- (±) -5-n-propyl-4, 4a, 5, 6, 7, 8, 8a, 9-octahydro-1H (and 2H) -pira zol or [3, 4 g] quinoline and the dihydrochloride salts thereof; trans- (±) -5-n-propyl-7-methylmercaptomethyl-4,4a, 5,6,7,8,8a, 9-octahydro-lH (and 2H) -pyrazolo [3,4-g] quinoline and dichlorhydrate salts thereof; trans- (±) -5- (C? -C3) alkyl (or allyl) -7- (C? -3C) alkoxycarbonyl-4, 4a, 5, 6, 7, 8, 8a, 9-octahydro-lH ( and 2H) -pyrazolo [3,4-g] quinoline; trans- (±) -5-n-propyl-7-ethoxycarbonyl-4,4a, 5,6,7,8,8a, 9-octahydro-lH (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] quinol ina. A particularly preferred compound of the formulas (Va1 and (Vb) may have the formula (/ c) (Vc) and the formula (Vd] (You) or a pharmaceutically acceptable salt thereof, wherein: R is C1-C3 alkyl or allyl, and Rx is CH2 X wherein X is CN, CONH2, SCH3, S02 CH3 and OCH3. Another particularly preferred compound of the formulas (Va) and (Vb) is a trans- (+) stereoisomer which exists as a tautomeric pair of the formula (Ve) (Go) and the formula (Vf) H (Vf) wherein R is methyl, ethyl, n-propyl, or allyl. An especially preferred compound of formulas (Va) and (Vb) is quinpirole, or pharmaceutically acceptable salts thereof. Quinpirole, or IH-Pirazolo [3, 4-g] quinol ina, 4,4a, 5,6,7,8,8a, 9-octahydro-5-propyl-, (4aR, 8aR) - (9CI) or ÍH-Pirazolo [3, 4-g] quinoline, 4, 4 a, 5, 6, 7, 8, 8 a, 9-octahydro-5-propyl-, (4aR-trans) -; (-) -Quinpirole; LY 156258, can be represented structurally by the following formula (Vg).

(Vg) The compounds of the formulas (Va) and (Vb) can be prepared by any of the suitable methods. Methods for preparing these compounds are also described in U.S. Patent Nos. 4,198,415 and 4,528,290, both incorporated herein by reference. The compounds of formulas (la) and (Ib) can be prepared in any conventional dosage form such as, for example, a capsule, tablet, chewable tablet, powder, transdermal patch, suspension or solution. Pharmaceutical formulations for these compounds are also described in U.S. Patent Nos. 4,198,415 and 4,528,290, both incorporated herein by reference. A compound of the formulas (Va) and (Vb) in the known pharmaceutical dosage form known for a given administration route can be administered orally, sublingually, transdermally, or parenterally. It is preferred that the compound be administered orally and parenterally. The effective therapeutic amount of a compound of formulas (Va) and (Vb) in the present invention is generally between about 0.01 and 15 mg / kg / cos per oral administration and between approximately 0.0025 and 2.5 mg / kg / dose per parenteral administration. The oral dosage is typically administered 3-4 times a day, providing a daily dosage variation of approximately 0.3 and 60 mg / kg per day. The exact dose to be administered and the frequency of dosing will be easily determined by the attending physician or clinician. Still other compounds suitable in the present invention with the trans- (±) -racemates of the formula (VI) (SAW) or stereoisomers thereof of the formula (VI, (Via) or the pharmaceutically acceptable salts thereof, wherein: R is C? -C3 alkyl or allyl, Ri is NH2, NHR3, NR4R5 and R2 is H, CH3, Cl or Br where R3 is methyl, ethyl or n-propyl , C1-C3 alkyl-CO, phenyl-CO or substituted phenyl-CO wherein the substituents are 1 or 2 members of the group: Cl, F, Br, CH3, C2 H5, CH3 0, C2 H5 0 and CF3; R4 and R5 are individually methyl, ethyl or n-propyl and the pharmaceutically acceptable acid addition salts thereof. The compounds represented by the formula (VI) are generically or specifically set forth in U.S. Patent Nos. 4,521,421 and 4,501,890, and are generically referred to as trans- (±) -substituted-5,5a, 6,7,8,9-, 9a, 10 -oct ahydropyr imido [4, 5-g] quinolines. These compounds can exist as two racemates, simply referred to as the t rans- (±) racemate and the cis- (1) racemate. The two racemates in question are the trans- (±) -racemato-t rans- (±) -2-amino-6-alkylc or allyl-4-permissibly-substituted -5, 5a, 6, 7, 8, 9, 9a, 10-octahydropyrimido [4,5-g] quinoline and the corresponding cis- (±) -racemate. T rans- (-) -enantiomer (Via) is one of the two stereoisomers represented by (VI) and is preferred for the present invention. Specifically preferred compounds include, for example, trans- (±) -2-amino-6-n-propi 1 -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 dihydrochloride -6-n-propyl-5, 5a, 6, 7, 8, 9, 9a, 10-octahydropyrimido [4,5-g] quinoline. An especially preferred compound of the formula (VI) is quineloran or the pharmaceutically acceptable salts thereof. The quineloran, or pyrido [2, 3-g] quina zolin-2-amine, 5, 5a, 6, 7, 8, 9, 9a, 10-octahydro-6-propyl-, (5aR, 9 R) - (9CI) or pyrido [2, 3-g] quinazolin-2 -amine, 5, 5a, 6, 7, 8, 9, a, 10-octahydro-6-propyl-, (5aR-trans) -, can be structurally represented by the following formula (VIb).

(VIb) The compounds of the formula (VI) and the pharmaceutically acceptable salts thereof can be prepared according to the procedures set forth in the patents of the United States of America.

Nos. 4,501,890 and 4,521,421. Information on pharmaceutical formulations for these compounds, as well as their uses and administration to treat Parkinson's syndrome, sexual dysfunction, depression, hypertension, or elevated prolactin levels, are described in the patents of the United States. United Nos. 4,501,890 and 4,521,421, both incorporated herein by reference. The compounds of the formula (VI) and their pharmaceutically acceptable salts can be prepared in any conventional dosage form such as for example, a capsule, tablet, chewable tablet, powder, transdermal patch, suspension or solution. The route of administration for these compounds in the pharmaceutical dosage form, known, suitable, for a given route of administration includes the oral, sublingual, transdermal, and parenteral route, with the oral route being the preferred route. The effective therapeutic amount of the compounds of the formula (VI), in the present invention, is generally between about 0.1 and 100 mcg / kg / dose by oral administration and between about 0.25 and 25 mcg / kg / dose by parenteral administration . Oral dosage is typically administered 3-4 times a day. the dose The exact dose to be administered and the frequency of dosing will be easily determined by the attending physician or clinician. Preparations for the compounds in the present invention can conveniently be presented in unit dosage form and can be prepared by conventional pharmaceutical techniques known in the art. These techniques include the step of producing in association the active ingredient and the pharmaceutical carriers or excipients. In general, the formulations are prepared by uniformly and intimately producing in association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. The compounds and their pharmaceutically acceptable salts that are active when administered orally can be prepared as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier or carriers, for example, ethanol, clickerine, aqueous nc solvent, for example polyethylene glycol, oils, or water with a suspending, preservative, flavoring or coloring agent. A formulation in the form of a tablet can be prepared using any suitable pharmaceutical carriers routinely used to produce solid preparations. Examples of these carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A formulation in the form of a capsule can be prepared using routine encapsulation procedures. For example, granules containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carriers, for example aqueous gums, celluloses, silicates and oils and the dispersion or suspension is then filled into a soft gelatin capsule.The compounds and their pharmaceutically acceptable salts which are Active ingredients when administered parenterally (ie, by injection or infusion) can be prepared as solutions or suspensions A formulation for parenteral administration can contain anti-o-ions, shock absorbers, bacterial tat, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The preparations can be presented in unit dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored under freeze-drying (lyophilized) conditions that require only the addition of the sterile liquid carrier, e.g., water for injections, inmeciat amenté before use. Solutions and suspensions for extemporaneous injection can be prepared from sterile powders, granules, and tablets of the kind described above. A typical suppository preparation comprises a compound described above or a pharmaceutically acceptable salt thereof which is activated when administered in this manner, with a binder and / or lubricant such as, for example, polymeric glycols, gelatins or cocoa butter or other low melted vegetable or synthetic waxes or fats. The preparations suitable for topical administration in the mouth include castillas which comprise the ingredients in a flavored base, usually sucrose and acacia or tragacanth; the tablets comprising the active ingredient in an inert base such as, for example, gelatin and glycerin, or sucrose and acacia; and buccal washes comprising the ingredient to be administered in a suitable liquid carrier. Preparations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the active ingredient to be administered in an acceptable pharmaceutical carrier. Systems for topical delivery include a transdermal patch and a transdermal gel containing the ingredient to be administered. Suitable preparations for nasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of 20 to 500 microns, which is administered in the form in which it is administered by inspiration, that is, by rapid inhalation through a nostril from a container of dust held closed towards the nose. The preparations suitable for nasal administration, wherein the carrier is a liquid, such as, for example, a nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient. The exact dosage for a given compound described above to treat the symptoms of the FMS or CFS of the present invention will depend on factors such as, for example, the route of administration, the dosage form, the particular condition to be treated, the severity of the condition that will be treated, age, weight, the general physical condition of the particular patient, another medication that the individual may be taking, and will be easily determined by the experienced physician experienced in the prescription of biologically active drugs designed to modulate the central nervous system, the movement and related psychological and physiological disorders of the type described here. Patients with milder forms of FMS and CFS could be expected to need less drug, patients with more severe forms of the disease would be expected to need more drug. It will be apparent to one of ordinary skill in the art that many changes and modifications can be made to the invention without departing from the spirit or scope of the invention.

Claims (34)

1. CLAIMS 1. A method for treating the symptoms of fibromyalgia syndrome and chronic fatigue syndrome, which comprises administering to a patient suffering from fibromyalgia syndrome or chronic fatigue syndrome an effective amount of a compound selected from the group consisting of apomorphine, bromocriptine, pergolide, ropinirole, one of the oct ahydropira zolo [3, -g] quinolines, and one of the trans- (±) -substituted-5, 5a, 6, 7, 8, 9, 9a, 10- octahydropi rimido [4,5-g] quinolines, or a pharmaceutically acceptable salt of any of those compounds.
2. 2. The method according to J to claim 1, wherein the compound is apomorphine or a pharmaceutically acceptable salt thereof.
3. 3. The method according to claim 2, wherein the effective amount of apomorphine or a pharmaceutically acceptable salt thereof is between about 0.25 and 12 mg / day.
4. 4. The method according to claim 1, wherein the compound is bromocriptine or a pharmaceutically acceptable salt thereof.
5. 5. The method according to claim 4, wherein the effective amount of bromocriptine or a pharmaceutically acceptable salt thereof is between about 2.5 and 15 mg / day.
6. 6. The method according to claim 1, wherein the compound is pergolide or a pharmaceutically acceptable salt thereof.
7. 7. The method according to claim 6, wherein the effective amount of pergolide is between about 0.75 and 5 mg / day.
8. 8. The method according to claim 1, wherein the compound is ropinirole or a pharmaceutically acceptable salt thereof.
9. 9. The method according to claim 8, wherein the effective amount of ropinirole or pharmaceutically acceptable salt thereof is between about 0.25 and 25 mg / day.
10. 10. The method according to claim 1, wherein the oct ahydropy zolo [3,4-g] quinoline is a trans (±) is tereoisomer that exists as a tautomeric pair of the formula and the formula wherein: R is H, CN, C 1 -C 3 alkyl, allyl or benzyl and Ri is H, COOH, COO (C 1 -C 3) alkyl or CH 2 X, wherein X is CN, Cl, I, Br, OH, OCH 3 , SCH3, S02CH3, OS02- (C1-C3) -alkyl, 0-S02- 1 olyl, OS02-phenyl or C0NH2, or a pharmaceutically acceptable salt thereof.
11. 11. The method according to claim 10, wherein R is C: -C3 alkyl or allyl and Rj. is H or H2 X, where X is CX, CONH2, SCH3, 0CH3 or S02 CH3.
12. 12. The method according to claim 10, wherein R is H, CN or benzyl and Ri is H.
13. 13. The method according to claim 10, wherein R is C? ~ C3 alkyl or allyl and Ri is COO (C? -C3) alkyl, or CH2 X, wherein X is Br, I, Cl, OH, OS02- (C1 -C3) alkyl, OS02-tolyl or OS02phenyl.
14. 14. The method according to claim 10, wherein the oct ahydropyrazolo [3,4-g] quinol ina is trans (±) -5-n-propyl-4, 4a, 5, 6, 7, 8, 8a, 9-octahydro -lH (and 2H) -pira zolo [3, 4-g] quinoline or the dichlorhydrate salts thereof.
15. 15. The method according to J to claim 10, wherein - the oct ahydropyrazolo [3,4-g] quinol ina is trans (±) -5-n-propyl-7-methyl-mercaptoimethyl-4, a, 5, 6.7 , 8, 3a, 9-octahydro-1H (and 2H) pyrazolo [3,4-g] quinoline with the dichlorhydrate salts thereof.
16. 16. The method according to claim 10, wherein the oct ahydropira zolo [3,4-g] quinol ina is trans (±) -5- (C: -C3) alkyl (or allyl) -7- (C1-3) alkoxycarbonyl-4,4 =, 5,6,7,8,8a, 9-octahydro-1H (and 2H) -pira zolo [3, i-z} quinol ina.
17. 17. The method according to claim 10, wherein the octahydropira zolo [3, 4-g] quinol ina is trans (±) -5-n-propyl-7-ethoxycarbonyl-4, 4a, 5, 6, 7, 8, 8a , 9-octahydro-lH (and 2H) -pyrazolo [3, 4g] quinoline.
18. 18. The method according to claim 10, wherein the octahydropyrazolo [3,4-g] quinoline is trans (±) -5-methyl-7-ethoxycarbonyl-4, 4a, 5, 6, 7, 8, 8a, 9-octahydro -lH (and 2H) -pyrazolo [3, 4g] quinoline.
19. 19. The method according to claim 10, wherein the octahydropyrazolo [3,4-g] quinoline is a trans (±) is e-isomer that exists as a tautomeric pair of the formula and the formula wherein R is C? -C3 alkyl or allyl, and Ri is CH2X, wherein X is CN, CONH2, SCH3, S02 CH3 and OCH3.
20. 20. The method according to claim 10, wherein the octahydropyrazolo [3,4-g] quinoline is a trans (+) stereoisomer that exists as a tautomeric pair of the formula and the formula wherein R is methyl, ethyl, n-propyl or allyl.
21. 21. The method according to claim 20, wherein R is n-propyl.
22. 22. The method according to claim 20, wherein the octahydropyrazolo [3,4-g] quinolone is 4aS, 8aS-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydrate. lH (and 2H) -pyrazolo [3,4-g] quinoline or a pharmaceutically acceptable salt thereof.
23. 23. The method according to claim 10, wherein the octahydropyrazolo [3,4-g] quinoline is quinpirole or a pharmaceutically acceptable salt thereof.
24. 24. The method according to claim 10, wherein the effective amount of octahicropirazolo [3,4-g] quinoline by eral administration is between about 0.3 and 60 mg / kg / day.
25. 25. The method according to claim 1, wherein the trans- (±) -substituted-5, 5a, 6, 7, 8, 9-, 9a, 10-octahydropyrimido [4, 5-g] quinol'in is a trans- (±) racemate of the formula or a stereoisomer thereof of the formula or a pharmaceutically acceptable salt thereof, wherein: R is C1-C3 alkyl or allyl, Rx is NH2, NHR3, NR4R5 and R2 is H, CH3, Cl or Br, wherein R3 is methyl, ethyl or n-propyl , C? -C3 alkyl-CO or substituted phenyl-CO, wherein the substituents are 1 or 2 members of the group: Cl, F, Br, CH3, C2H5, CH30, C2H50 and CF3, R4 and R5 are individually methyl, ethyl or n-propyl.
26. 26. The method according to claim 25, wherein the t rans- (±) -substituted-5, 5a, 6, 7, 8, 9-, 9a, 10-octahydropyrimido [4, 5-g] quinoline is trans- (± ) -2-amino-6-n-propyl-5, 5a, 6, 7, 8, 9, 9a, 10-octahydropyrimido [4, 5-g] quinoline.
27. 27. The method according to claim 25, wherein the t rans- (±) -substituted-5, 5a, 6, 7, 8, 9-, 9a, 10-octahydropyrimido [4,5-g] quinoline is trans - (- ) -2-amino-6-n-propyl-5, 5a, 6, 7, 8, 9, 9a, 10-octahydropyrimido [4, 5-g] quinoline.
28. 28. The method according to claim 25, wherein the t rans - (±) - its t-5u, 5a, 6, 7, 8, 9-, 9a, 10-octahydropyrid [4,5-g] quinoline is dihydrochloride of trans- (-) -2-amino-6-n-propyl-5, 5a, 6, 7, 8, 9, 9a, 10-octahydropyrimido [4, 5-g] quinoline.
29. 29. The method according to claim 25, wherein the t rans- (±) -substituted-5, 5a, 6, 7, 8, 9-, 9a, 10-octahydropyrimido [4, 5-g] quinoline is quineloran or a pharmaceutically acceptable salt thereof.
30. 30. The method according to claim 25, wherein the effective amount of the trans- (±) -sus ti tuida-5, 5a, 6, 7, 8, 9-, 9a, 10-octahydropyrimido [4,5-g] quinoline for oral administration it is between approximately 0.3 and 400 mcg / kg / day.
31. 31. The method according to claim 25, wherein the effective amount of the trans- (±) -substituted-5, 5a, 6, 7, 8, 9-, 9a, 10-octahydropyrimido [4,5-g] quinoline for administration parenteral is between approximately 0.75 and 100 mcg / kg / day.
32. 32. The use of a compound for preparing a medicament for treating the symptoms of fibromyalgia syndrome and chronic fatigue syndrome, wherein the compound is selected from the group consisting of apomorphine, bromocriptine, pergolide, ropinirole, one of the octahydrcpyrazolo [3, -g] quinolines, and one of the trans- (±) -sustained -5,5a, 6,7,8,9-, 9a, 10- Octahydropyrimido [4,5-g] quinolines, or a pharmaceutically acceptable salt of any of the compound.
33. 33. the use of the compound according to claim 32, wherein the amount of apomorphine or its pharmaceutically acceptable salts is between about 0.25 and 12 mg / patient / day, the amount of bromocriptine or its pharmaceutically acceptable salts is between about 2.5 and 15 mg / patient / day, the amount of pergolide and its pharmaceutically acceptable salts are between approximately 0.75 and 5 mg / patient / day, the amount of ropinirole or its pharmaceutically acceptable salts is between about 0.25 and 25 mg / patient / day, the amount of octahydropyrazolo [3,4-g] quinoline or its pharmaceutically acceptable salts is between about 0.3 and 60 mg / patient / day, and the amount of the trans- (±) -substituted-5, 5a, 6, 7, 8, 9-, 9a, 10-octahydropyrimido [4,5-g] quinoline or its pharmaceutically acceptable salts is between about 0.3 and 400 mcg / kg / day.
34. 34. The use of the compounds set forth herein to treat the symptoms of fibromyalgia syndrome and chronic fatigue syndrome. 4 2 SUM OF THE INVENTION The use of apomorphine, bromocriptine, pergolide, ropinirole, octahydropyrazolo [3, -g] quinolines, and trans- (±) -su t -tuuides-5, 5a, 6 is disclosed herein. 7, 8, 9-, 9a, 10-octahydro-pyrimido [4, 5g] quinolines, and their pharmaceutically acceptable salts to treat, or to prepare a medicament for treating the symptoms of fibromyalgia syndrome and chronic fatigue syndrome.