NZ522115A

NZ522115A - Selected compounds for the treatment of fibromyalgia and chronic fatigue syndrome

Info

Publication number: NZ522115A
Application number: NZ522115A
Authority: NZ
Inventors: David W Robertson; Robert B Mccall; Robert C Marshall
Original assignee: Upjohn Co
Priority date: 2000-04-21
Filing date: 2001-04-17
Publication date: 2004-07-30
Also published as: AU2001255223B2; JP2004502651A; AU5522301A; CA2404704A1; BR0110188A; EP1280530A1; WO2001087308B1; CN1418099A; HK1054190A1; WO2001087308A1; KR20020089510A; MXPA02010410A; ZA200208272B

Abstract

Use of a compound selected from the group consisting of apomorphine, pergolide, ropinirole, octahydropyrazolo[3,4- g]quinolines, and trans-(+/-)-substituted-5,5a,6,7,8,9-,9a,10-octahydropyrimido[4,5g]quinolines, and their pharmaceutically acceptable salts for the treatment of neuromuscular disorders is disclosed, particularly for the preparation of a medicament for treating, symptoms of fibromyalgia syndrome and chronic fatigue syndrome.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 522115 00226.PCT1 intellectual property office of n.z TREATMENT OF FIBROMYALGIA AND ^ 0 MAY 200^ CHRONIC FATIGUE SYNDROME RECEIVED FIELD OF THE INVENTION 5221 15 5 The present invention relates to the manufacture of medicaments for the treatment of neuromuscular disorders and, more specifically, to the use of apomorphine, pergolide, ropinirole, octahydropyrazolo[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, symptoms of fibromyalgia syndrome and chronic 10 fatigue syndrome. BACKGROUND OF THE INVENTION Chronic fatigue syndrome (CFS), also referred to as chronic fatigue immune disorders, chronic fatigue immune disorders syndrome, yuppie flu, fatigue - chronic, and chronic fatigue and immune dysfunction syndrome, is a clinically defined condition 15 characterized by profound tiredness or fatigue. In addition, patients with CFS generally report various nonspecific symptoms, including weakness, muscle aches and pains, excessive sleep, malaise, fever, sore throat, tender lymph nodes, impaired memory and/or mental concentration, insomnia, and depression. The exact cause of CFS is unknown and, to date, there are no specific tests to confirm the diagnosis of CFS, though a variety of tests 20 are usually done to exclude other possible causes of the symptoms. Fibromyalgia syndrome (FMS), also referred to as fibromyalgia, fibromyositis, fibrositis, or myofasical pain syndrome* is a rheumatic condition generally characterized by widespread pain in fibrous tissues, muscles, tendons, and other connective tissues, fatigue, headaches, lack of restorative sleep, and numbness. Thus, FMS shares many clinical 25 features with CFS. Similar to CFS, there are no specific diagnostic tests for FMS. Because of the similarity in clinical features between CFS and FMS, CFS and FMS are often treated similarly. ;Many medications are commonly used to treat CFS and FMS. Examples of the more common medications include hypnotics, immune suppressants, various other prescribed ;* 30 medications, and an array of non-prescription medications. Examples of other prescription drugs include opioid antagonists, sodium retention agents/beta blockers, calcium channel blockers/histamine blockers, anti-depressants, allergy medications, and acute anxiety medications. However, there are no known medications that permanently resolve the -l - WO 01/87308 PCT/US01/10806 symptoms of either CFS or FMS. In addition, many of the currently used medications produce side effects ranging from mild side effects, e.g., drowsiness, dizziness, and nausea to serious side effects, e.g., addiction and liver damage. Accordingly, there is clearly a need for better treatments for chronic fatigue 5 syndrome and fibromyalgia. Now, the present invention reveals several compounds that can be used to treat, or to prepare a medicament for treating, these conditions. These compounds include apomorphine, bromocriptine, pergolide, ropinirole, octahydropyrazolo[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. 10 U.S. Patent No. 3,717,639 discloses apomorphine and methods of preparation of the same. U.S. Patent No. 5,756,483 discloses intranasal formulations for apomorphine and the use of the same as a therapy for Parkinson disease. U.S. Patent No 5,939,094 discloses transdermal formulations comprising apomorphine. U.S. Patent No. 6,200,983 discloses oral formulations for apomorphine and the use of apomorphine as a therapy for human 15 sexual dysfunction. U.S. Patent No. 3,752,814 discloses bromocriptine and the process of making the same. U.S. Patent No.3,752,888 discloses information on the formulations, dose levels and administration for inhibiting lactation, as well as process of synthesis, for bromocriptine. U.S. Patent No.5,679,685 discloses information on the formulations, dose levels and 20 administration of bromocriptine for inhibiting 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, 25 percutaneous or nasal administration. U.S. Patent No. 6,001,390 discloses a pharmaceutical composition containing ergot derivatives, including pergolide, for transdermal administration. U.S. Patent 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 30 and 4,912,126 discloses 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 use of ropinirole as a treatment for Parkinson's disease, as well as pharmaceutical compositions for oral, rectal, -2- 00226.PCT1 The effective dosage of apomorphine is generally from about 0.25 to about 6 mg/dose/person, once or twice per day. The exact dose to be administered and the dose frequency of apomorphine should be easily determined by the attending physician or clinician. pharmaceutically acceptable salt thereof. Bromocriptine, or (5'a)-2-Bromo-12'-hydroxy-2'-(l-methylethyl)-5'-(2-methylpropyl)ergotaman-3',6',18-trione; 2-bromoergocryptine; or 2-bromo-a-ergokryptin, can be structurally represented by formula (II) below. The method of synthesis and preparation of pharmaceutical formulations for bromocriptine, as well as its use and administration for inhibiting lactation, is known in the art. See, e.g., U.S. Patent Nos 3,752,814, 3,752,888, and 5,679,685, all incorporated herein by reference. Bromocriptine may be obtained by brominating ergocryptine in an inert solvent, with a mild brominating agent, e.g. N-bromophthalimide, and purifying the resulting bromocriptine in manner known per se. Bromocriptine can be prepared in any conventional dosage form such as a capsule, tablet, chewable tablet, powder, suspension or solution. Solid oral preparations have long been commercially available as bromocriptine mesylate (PARLODEL® marketed by Novartis Pharmaceuticals Corp.) in tablet and capsule form containing 2.5 and 5 mg of bromocriptine, respectively. These preparations are approved in the United States for use in the treatment of certain hyperprolactinemia-associated dysfunctions and acromegaly, in the prevention of physiological lactation, and in the treatment of Parkinson's disease and prevention of tolerance to Levodopa therapy for Parkinson's disease. Herein described is bromocriptine, or a Br od -5- INTELLECTUAL PROPERTY OFFICE OF N.Z. 00226.PCT1 ! \ Bromocriptine in the known appropriate pharmaceutical dosage form for a given route of administration may be administered orally, sublingually, buccally, transdermally, or parenterally. It is preferred that bromocriptine be administered orally. The therapeutic effective amount of bromocriptine i is 5 generally from about 2.5 to about 15 mg/day/person. Normally, administration of bromocriptine should be initiated at a low daily dosage of about 1.25 mg per day, and on an individual basis, the dosage is increased slowly and gradually until an optimal therapeutic response is achieved. The exact dose to be administered and the dose frequency for bromocriptine should be easily determined by the attending physician or clinician. 10 A suitable compound for use in the present invention is pergolide, or a pharmaceutically acceptable salt thereof. Pergolide, or (8J3 )-8-[(Methylthio)methyl]-6-propylergoline; D-6-n-propyl-8P-methylmercaptomethylergoline; or LY-141B, can be structurally represented by formula (III) below. „sch3 15 (m) The method of synthesis and preparation of pharmaceutical formulations for pergolide, as well as its use and administration as a therapy for Parkinson's disease or as a prolactin inhibitor, is known in the art. See, e.g., U.S. Patent Nos. 4,166,182 and 6,001,390, and German patent application DE 4240798, all incorporated herein by reference. 20 Pergolide can be prepared in any conventional dosage form such as a capsule, tablet, chewable tablet, powder, suspension or solution. Solid oral pergolide preparations have long been commercially available as pergolide mesylate (PERMAX® by Athena Neurocsiences) in tablet form containing 0.05,0.25, and 1 mg of pergolide, respectively. These preparations are approved in the United States for use in the treatment of Parkinson's 25 disease. Pergolide in the known appropriate pharmaceutical dosage form for a given route of administration may be administered orally, sublingually, buccally, transdermally, nasally, or parenterally. It is preferred that pergolide be administered orally and parenterally, and more preferred that pergolide be administered orally. -6- intellectual property OFFICE OF N.Z. - 6 may 2004 WO 01/87308 PCT/US01/10806 By "treat" or "treating" it is meant to make less hard to bear, reduce or decrease, or lighten or relieve patients of the symptoms of FMS or CFS. A suitable compound in the present invention is apomorphine and a pharmaceutically acceptable salt thereof. Apomorphine, or (R)-5,6,6a,7-Tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline-10,ll-diol or 6aP-aporphine-10,l 1-diol, can be structurally represented by formula (I) OH HOv 0) and exists in a free base form or as an acid addition salt. 10 The method of synthesis and preparation of pharmaceutical formulations for apomorphine, as well as its use as a therapy for Parkinson disease or human sexual dysfunction, is known in the art. See, e.g., 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 15 apomorphine or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier can be administered. Apomorphine hydrochloride is preferred; however, other pharmacologically acceptable moieties thereof can be utilized as well. In addition to the hydrochloride salt, other acceptable acid addition salts are the hydrobromide, the hydroiodide, the bisulfate, the phosphate, the acid phosphate, the lactate, the citrate, the 20 tartarate, the salicylate, the succinate, the maleate, the gluconate, and the like. Apomorphine can be prepared in any conventional dosage form such as a capsule, tablet, chewable tablet, powder, transdermal patch, suspension or solution. A typical formulation for apomorphine comprises 0.25 to 10 milligrams (mg) of the active and as inactive ingredients, microcrystalline cellulose, anhydrous dibasic calcium phosphate, 25 croscarmellose sodium, magnesium stearate, hydroxypropylmethylcellulose, titanium dioxide, lactose, txiacetin, and FD&C Blue #2 aluminum lake. Apomorphine in the known appropriate pharmaceutical dosage form for a given route of administration may be administered orally, sublingually, buccally, intranasally, transdermally, or parenterally. It is preferred that apomorphine be administered parenterally 30 by subcutaneous injection, intravenous injection or infusion, or by transdermal delivery. -4- 00226.PCT1 parenteral, or transdermal administration of ropinirole. U.S. Patent No. 5,807,570 discloses transdermal formulations and administration of ropinirole. U.S. Patent No. 4,198,415 discloses octahydropyrazolo[3,4-g]quinolines and method for preparing the compounds and pharmaceutical compositions thereof for oral or 5 parenteral administration for treating Parkinsonism and for inhibiting prolactin secretion. U.S. Patent No. 4,528,290 discloses the formulations for oral and parenteral administration for octahydropyrazolo[3,4-g]quinolines. U.S. Patent No. 4,501,890 discloses trans-(±)-substituted-5,5a,6,7,8,9-,9a,10-octahydropyrimido[4,5-g]quinolines and method for preparing the same, as well 10 formulations for oral or parenteral administration for treating Parkinson's syndrome, sexual dysfunction, depression, hypertension, and elevated prolactin levels. U.S. Patent No. 4,521,421 discloses information on method of preparation and formulations of trans-(±)-substituted-5,5a,6,7,8,9-,9a,10- octahydropyrimido[4,5-g]quinolines for oral and parenteral administration for treating sexual dysfunction. 15 SUMMARY OF THE INVENTION The invention is directed to the use of certain known compounds to prepare medicaments for treating, symptoms of fibromyalgia syndrome and chronic fatigue syndrome, two debilitating conditions for which no known effective treatments exist. The compounds described herein are apomorphine, bromocriptine, pergolide, ropinirole, 20 octahydropyrazolo[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. The preparation of medicaments, dosages and routes of administration are all provided to the extent needed to identify and treat patients in need thereof. DETAILED DESCRIPTION OF THE INVENTION 25 The present invention provides for the use of several classes of compounds, and their pharmaceutically acceptable salts to prepare medicaments for treating, symptoms of fibromyalgia (FMS) or chronic fatigue syndrome (CFS). "Pharmaceutically acceptable" as used throughout the entire document refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point 30 of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability. intellectual PROPERTY \ -3- office of n.z. 1 -g may 2004 i WO 01/87308 PCT/US01/10806 The therapeutic effective amount of pergolide in the present invention is generally from about 0.75 to about 5 mg/day/person. Normally, administration of pergolide should be initiated with a daily dosage of 0.05 mg for the first two days. The dosage should then be gradually increased by 0.1 - 0.25 mg/day every third day until an optimal therapeutic dosage 5 is achieved. Pergolide is usually administered in divided doses 3 times per day. The exact dose to be administered and the dose frequency for pergolide should be easily determined by the attending physician or clinician. Another suitable compound in the present invention is ropinirole or a pharmaceutically acceptable salt thereof. Ropinirole, or 4-[2-(Dipropylamino)ethyl]-l,3-10 dihydro-2H-indol-2-one; 4-[2-(di-n-propylamino)ethyl]-2(3if)-indolone; or 4-(2-di-n-propylaminoethyl)-2-(3H)-indolone, can be structurally represented by formula (IV) below. 15 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 formulations and administration of ropinirole as a treatment for cardiovascular disorders or Parkinson's disease is described in U.S. Patent Nos. 4,912126 and 5,807,570, and EP-299602-A, all incorporated herein by 20 reference. Ropinirole can be prepared in any conventional dosage form such as a capsule, tablet, chewable tablet, powder, transdermal patch, suspension or solution. Solid oral ropinirole preparations have been commercially available as ropinirole hydrochloride (REQUIP by SmithKline Beecham) in tablet form containing 0.25, 1 mg, 2 mg, 4 mg, and 5 25 mg of ropinirole, respectively. These preparations are approved in the United States for use in the treatment of Parkinson's disease. Ropinirole in the known appropriate pharmaceutical dosage form for a given route of administration may be administered orally, sublingually, transdermally, rectally, or parenterally. It is preferred that ropinirole be administered orally and parenterally, and 30 more preferred that ropinirole be administered orally. H (IV) Suitable salts will be apparent to those skilled in the art and include, for example -7- WO 01/87308 PCT/US01/10806 The therapeutic effective amount of ropinirole in the present invention is generally from about 0.25 to about 25 mg/day /person. It is typically given 3 times daily. The dosage is normally initiated at a low dosage at about 0.25 mg three times daily, and increased gradually to achieve a maximum therapeutic effect, balanced against the principal side 5 effects of nausea, dizziness, somnolence and dyskinesia. The exact dose to be administered and the dose frequency should be easily determined by the attending physician or clinician. Other suitable compounds 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 can exist as 10 tautomers of formula (Va) R (Va) and formula (Vb) R (Vb) 15 or their pharmaceutically acceptable salts, wherein: R is H, CN, CI - C3 alkyl, allyl or benzyl and R1 is H, COOH, COO(Cl -C3) alkyl or CH2 X wherein X is CN, CI, I, Br, OH, OCH3, SCH3, S02 CH3, 0S02 -(CI -C.sub.3)-alkyl, 0--S02 -tolyl, 0S02 -phenyl or CONH2. 20 Examples of compounds of formula (Va or Vb) include, but are not limited to, following compounds: trans-(±)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)-pyrazolo[3,4-g]quinoline and dihydrochloride salts thereof; trans-(±)-5-n-propyl-7-methylmercaptomethyl-4,4a,5,6,7,8,8a,9-octahydro-lH( and 25 2H)-pyrazolo[3,4-g]quinoline and dihydrochloride salts thereof; -8- WO 01/87308 PCT/USO1/10806 trans-(±)-5-(Cl -C3)alkyl (or allyl)-7-(Cl -C3)alkoxy carbonyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)-pyrazolo[3,4-g]quinoline; trans-(±)-5-n-propyl-7-ethoxycarbonyI-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)-pyrazolo[3,4-g]quinoline; and 5 trans-(±)-5-methyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)- pyrazolo[3,4-g]quinoline. A particularly preferred compound of formulae (Va) and (Vb) can have the formula (Vc) H / >r HN H H I R (Vc) 10 and formula (Vd) R or a pharmaceutically acceptable salt thereof, wherein: 15 R is CI -C3 alkyl or allyl, and R1 is CH2 X wherein X is CN, CONH2, SCH3, S02 CH3 and OCH3. -9- WO 01/87308 PCT/USO1/10806 Another particularly preferred compound of formulae (Va) and (Vb) is a trans-(+) stereoisomer existing as a tautomeric pair of the formula (Ve) R (Ve) and formula (Vf) H R (Vf) wherein R is methyl, ethyl, n-propyl, or allyl. An especially preferred compound of formulae (Va) and (Vb) is quinpirole, or pharmaceutically acceptable salts thereof. Quinpirole, or lH-Pyrazolo[3,4-g]quinoline, 4,4a,5,6,7,8,8a,9-octahydro-5-propyl-, (4aR,8aR)- (9CI) or 1 H-Pyrazolo[3,4-g]quinoline, 4,4a,5,6,7,8,8a,9-octahydro~5-propyl-, (4aR-trans)~; (-)-Quinpirole; LY 156258, can be structurally represented by the formula (Vg) below. m \ I h n-Pr (Vg) Compounds of formulae (Va) and (Vb) can be prepared by any suitable methods. Methods for preparing these compounds are further described in U.S. Patent Nos. 4,198,415 and 4,528,290, both incorporated herein by reference. Compounds of formulae (la) and (lb) -10- WO 01/87308 PCT/US01/10806 can be prepared in any conventional dosage form such as a capsule, tablet, chewable tablet, powder, transdermal patch, suspension or solution. Pharmaceutical formulations for these compounds are further described in U.S. Patent Nos. 4,198,415 and 4,528,290, both incorporated herein by reference. 5 A compound of formulae (Va) and (Vb) in the known appropriate pharmaceutical dosage form for a given route of administration may be administered orally, sublingually, transdermally, or parenterally. It is preferred that the compound be administered orally and parenterally. The therapeutic effective amount of a compound of formulae (Va) and (Vb) in the 10 present invention is generally from about 0.01 to about 15 mg/kg/dose by oral administration and from about 0.0025 to about 2.5 mg/kg/dose by parenteral administration. The oral dosage is typically given 3-4 times per day, giving a daily dosage range of about 0.3 to about 60 mg/kg per day. The exact dose to be administered and the dose frequency should be easily determined by the attending physician or clinician. 15 Still other suitable compounds in the present invention are trans-(±)-racemates of the formula (VI) (VD 20 or stereoisomers thereof of formula (Via) (Via) or pharmaceutically acceptable salts thereof, wherein: R is CI - C3 alkyl or allyl, R1 is NH2, NHR3, NR4 R5 and R2 is H, CH3, CI or Br wherein R3 is methyl, ethyl or n-propyl, 25 CI - C3 alkyl-CO, phenyl-CO or substituted phenyl-CO wherein said substituents are 1 or 2 - II - WO 01/87308 PCT/US01/10806 members of the group: CI, F, Br, CH3, C2 H5, CH3 O, C2 H5 O and CF3; R4 and R5 are individually methyl, ethyl or n-propyl and pharmaceutically-acceptable acid addition salts thereof. Compounds represented by formula (VI) are generically or specifically disclosed 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- octahydropyrimido[4,5-g]quinolines. These compounds can exist as two racemates, ordinarily denominated as the trans-(+) racemate and the cis-(±) racemate. The two racemates in question are the trans-(±)-racemate~trans-(+)-2-amino-6-alkyl or allyl-4-permissibly-substituted-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g ]quinoline~and the corresponding cis-(±)-racemate. The trans-(-)-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-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. An especially preferred compound of formula (VI) is quinelorane or pharmaceutically acceptable salts thereof. Quinelorane, 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)-, can be structurally represented by formula (VIb) below. The compounds of formula (VI) and pharmaceutically acceptable salts thereof can be prepared according to the procedures set forth in U.S. Patent Nos, 4,501,890 and 4,521,421. Information on the pharmaceutical formulations for these compounds, as well as their use and administration for treating Parkinson's syndrome, sexual dysfunction, depression, hypertension, and elevated prolactin levels, is described in U.S. Patent Nos, 4,501,890 and 4,521,421, both incorporated herein by reference. Pr-n H (VIb) -12- WO 01/87308 PCT/US01/10806 The compounds of formula (VI) and their pharmaceutically acceptable salts can be prepared in any conventional dosage form such as a capsule, tablet, chewable tablet, powder, transdermal patch, suspension or solution. Route of administration for these compounds in the known appropriate pharmaceutical dosage form for a given route of 5 administration includes oral, sublingual, transdermal, and parenteral route, with oral being the preferred route. The therapeutic effective amount of the compounds of formula (VI) in the present invention is generally from about 0.1 to about 100 mcg/kg/dose by oral administration and from about 0.25 to about 25 mcg/kg/dose by parenteral administration. The oral dosage is 10 typically given 3-4 times per day. The exact dose to be administered and the dose frequency should be easily determined by the attending physician or clinician. The formulations for the compounds in 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 15 the active ingredient and pharmaceutical carriers or excipients. In general, the formulations are prepared by uniformly and intimately bringing into 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 which are active when 20 given orally can be formulated 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(s), for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water 25 with a suspending agent, preservative, flavoring or coloring agent. A formulation in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A formulation in the form of a capsule can be prepared using routine encapsulation 30 procedures. For example, pellets 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 carrier(s), for example - 13- WO 01/87308 PCT/US01/10806 aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. The compounds and their pharmaceutically acceptable salts which are active when administered parenterally (i.e. by injection or infusion) can be formulated as solutions or 5 suspensions. A formulation for parenteral administration may contain anti-oxidants, buffers, bacteriostats, and solutes which render 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 formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in 10 freeze-dried (lyophilized) conditions requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described. A typical suppository formulation comprises a compound described above or a 15 pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats. Formulations suitable for topical administration in the mouth include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; 20 pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the ingredient to be administered in a suitable liquid carrier. Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the active ingredient to be administered in a 25 pharmaceutical acceptable carrier. Topical delivery systems include a transdermal patch and a transdermal gel containing the ingredient to be administered. Formulations suitable 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 manner in which snuff is administered, i.e., by rapid inhalation 30 through the nasal passage from a container of the powder held close up to the nose. Suitable formulations for nasal administration, wherein the carrier is a liquid, as for example, a nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient. - 14- </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO

01/87308 PCT/US01/10806 The exact dosage for a given compound described above for treating symptoms of FMS or CFS of the present invention will depend on factors such as route of administration, the dosage form, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other 5 medication the individual may be taking, and should be easily determined by a skilled physician with experience in prescribing biologically active drugs designed to modulate central nervous system, movement and related psychological and physiological disorders of the type described here. Patients with milder forms of FMS and CFS would be expected to need less drug, patients with more severe forms of the disease may be expected to need 10 more drug. It will be apparent to one of ordinary skill in the art that many changes and modifications can be made in the invention without departing from the spirit or scope of the invention. 15 - 15- 00226.PCT1 WHAT WE CLAIM IS: 1. A use of a compound selected from the group consisting of apomorphine, pergolide, ropinirole, one of the octahydropyrazolo[3,4-g]quinolines, and one of the trans-(±)-substituted-5,5a,6,7,8,9-,9a, 10- octahydropyrimido[4,5-g]quinolines, or a pharmaceutically acceptable salt of any said compound, in the manufacture of a medicament for treating the symptoms of fibromyalgia syndrome and chronic fatigue syndrome.
2. The use of claim 1 wherein said compound is apomorphine or a pharmaceutically acceptable salt thereof. 3. The use of claim 2 wherein the medicament is formulated to administer from about 0.25 to about 12 mg/day of apomorphine or pharmaceutically acceptable salt thereof. 4. The use of claim 1 wherein said compound is pergolide or a pharmaceutically acceptable salt thereof. 5. The use of claim 4 wherein the medicament is formulated to administer from about 0.75 to about 5 mg/day of pergolide. 6. The use of claim 1 wherein said compound is ropinirole or a pharmaceutically acceptable salt thereof. 7. The use of claim 6 wherein the medicament is formulated to administer from about 0.25 to about 25 mg/day of ropinirole or a pharmaceutically acceptable salt thereof. « -16- intellectual property I OFFICE OF N.Z. 1 - 6 MAY 2004 00226.PCT1 8. The use of claim 1 wherein said octahydropyrazolo[3,4-g]quinoline is a trans-(+)stereoisomer existing as a tautomeric pair of the formula 5 hn- i N- h and formula n: hn. Ri C h r wherein: 10 R is H, CN, CI - C3 alkyl, allyl or benzyl and Rl is H, COOH, COO(Cl -C3) alkyl or CH2 X wherein X is CN, CI, I, Br, OH, OCH3, SCH3, S02 CH3,0S02 -(CI -C3)~alkyl, 0--S02 -tolyl, 0S02 -phenyl or CONH2, or a pharmaceutically-acceptable salt thereof. 15 9. The use of claim 8 wherein R is CI-C3 alkyl or allyl and Rl is H or CH2 X wherein X is CN, CONH2, SCH3, OCH3 or S02 CH3. 10. The use of claim 8 wherein R is H, CN or benzyl and Rl is H. 20 11. The use of claim 8 wherein R is CI-C3 alkyl or allyl and Rl is COO(Cl-C3) alkyl, or CH2 X wherein X is Br, I, CI, OH, 0S02 -(CI -C3) alkyl, 0S02 -tolyl or 0S02 -phenyl. 12. The use of claim 8 wherein said octahydropyrazolo[3,4-g]quinoline is trans-25 (±)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-1 H(and 2H)-pyrazolo[3,4-g]quinoline or dihydrochloride salts thereof. -17- intellectual property office of n.z. - 6 MAY 2004 00226.PCT1 13. The use of claim 8 wherein said octahydropyrazolo[3,4-g]quinoIine is trans-(±)-5-n-propyl-7-methylmercaptomethyl-4,4a,5,6,7,8,8a,9-octahydro-1 H( and 2H)-pyrazolo[3,4-g]quinolin or dihydrochloride salts thereof. 14. The use of claim 8 wherein said octahydropyrazolo[3,4-g]quinoline is trans-(±)-5-(Cl -C3)alkyl (or allyl)-7-(Cl -C3)alkoxy carbonyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)-pyrazolo[3,4-g]quinoline. 15. The use of claim 8 wherein said octahydropyrazolo[3,4-g]quinoline is trans-(+)-5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)-pyrazolo[3,4-g]quinoline. 16. The use of claim 8 wherein said octahydropyrazolo[3,4-g]quinoline is trans-(±)-5-methyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)-pyrazolo[3,4-glquinoline. 17. The use of claim 8 wherein said octahydropyrazolo[3,4-g]quinoline is a trans-(±)stereoisomer existing as a tautomeric pair of the formula r and formula h wherein R is CI -C3 alkyl or allyl, and Rl is CH2 X wherein X is CN, CONH2, SCH3, S02 CH3 and OCH3. intellectual property office of n.z. - 6 may 2004 D en riven 20 18. The use of claim 8 wherein said octahydropyrazolo[3,4-g]quinoline is a trans= (±)tereoisomer existing as a tautomeric pair of the formula h HN and formula wherein R is methyl, ethyl, n-propyl or allyl. 19. The use of claim 18 wherein R is n-propyl. 10 20. The use of claim 18wherein said octahydropyrazo!o[3,4-g]quinoline is 4aS,8aS-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)-pyrazolo[3,4-g]quinoline or a pharmaceutically acceptable salt thereof. 21. The use of claim 8 wherein said octahydropyrazolo[3,4-g]quinoline is 15 quinpirole or a pharmaceutically acceptable salt thereof. 22. The use of claim 8 wherein the medicament is formulated for oral administration of from about 0.3 to about 60 mg/kg/day of said octahydropyrazolo[3,4-g]quinoline. 23. The use of claim 1 wherein said trans-(±)-substituted-5,5a,6,7,8,9-,9a,10-octahydropyrimido[4,5-g]quinoline is a trans-(±) racemate of the formula or stereoisomer thereof of formula 19- intellectual property office of n.z. -6 MAY 2004 or a pharmaceutically acceptable salt thereof, wherein: R is CI - C3 alkyl or allyl, Rl is NH2, NHR3, NR4 R5 and R2 is H, CH3, CI or Br wherein R3 is methyl, ethyl or n-propyl, 5 CI - C3 alkyl-CO, phenyl-CO or substituted phenyl-CO wherein said substituents are 1 or 2 members of the group: CI, F, Br, CH3, C2 H5, CH3 O, C2 H5 O and CF3; R4 and R5 are individually methyl, ethyl or n-propyl. 24. The use of claim 23 wherein said trans-(±)-substituted-5,5a,6,7,8,9-,9a,10- 10 octahydropyrimido[4,5-g]quinoline is trans-(±)-2-arnino-6-n-propyI-5,5a,6,7,8,9,9a, 10-octahydropyrimido[4,5-g Jquinoline. 25. The use of claim 23 wherein said trans-(±)-substituted-5,5a,6,7,8,9-,9a,10-octahydropyrimido[4,5-g]quinoUne is trans-(-)-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10- 15 octahydropyrimido[4,5-g]quinoline. i ■ 26. The use of claim 23 wherein saidtrans-(±)-substituted-5,5a,6,7,8,9-,9a,10-octahydropyrimido[4,5-g]quinoiine is trans-(-)-2-amino-6-n-propyl-5,5a,6,7,8,9,9a, 10-octahydropyrimido[4,5-g]quinoline dihydrochloride. 20 27. The use of claim 23 wherein said trans-(±)-substituted-5,5a,6,7,8,9-,9a,10-octahydropyrimido[4,5-g]quinoline is quinelorane or a pharmaceutically acceptable salt thereof. 25 28. The use of claim 23 wherein the medicament is formulation for oral administration of from about 0.3 to about 400 mcg/kg/day of said trans-(±)-substituted-5,5a,6,7,8,9-9a,10-octahydropyrimido[4,5-g]quinoline. -20- intellectual property office of n.z. - 6 MAY 2004 29. The use of claim 23 wherein the medicament is formulated for parenteral administration of from about 0.75 to about 100 mcg/kg/day of said trans-(±)-substituted-5,5a,6,7,8,9-9a,10-octahydropyrimido[4,5-g]quinoline. 30. A use as claimed in claim 1 substantially as herein described with reference to any example thereof. END OF CLAIMS -6 may 2wt -21- RECElVED Intellectual Property Office of New Zealand IP Summary Report Page: 1 of 1 Date: 11 May 2004 Time: 13:16:37 (iprip02 3.00.17) (86) International Application number: PCT/US01/1080 6 (87) WO Publication number: W001/87308 Elected: Y (22) NZ Filing date: 17 April 2001 (30) Priority Data: (31)00 198960 (32) 21 April 2000 (33) US Date entered National phase: 21 October 2002 (71) Applicant: PHARMACIA & UPJOHN COMPANY, 301 Henrietta Street, Kalamazoo, Michigan 49001, United States of America (72) Inventors: Robertson, David W McCall, Robert B Marshall, Robert C Contact: A J PARK, 6th Floor, Huddart Parker Building, 1 Post Office Square, Wellington, New Zealand Client Ref: 447017 DCC/JXS/akh Status: 50 Examination <^522115 Version number: 2 IP type: Patent PCT Inward Date actions completed: Filed 25 October 2002 (51) Classification: A61K31/40, A61K31/445, A61K31/47, A61K31/48, A61K31/505, A61P4
3/00 Office title: Selected compounds for the treatment of fibromyalgia and chronic fatigue^synjlrome (54) Applicant title: Treatment of fibromyalgia and chronic fatigue syndrome (57) Abstract: Patent 522115 Use of a compound selected from the group consisting of apomorphine, pergolide, ropinirole, octahydropyrazolo[3,4-g]quinolines, and trans-(+/-)-substituted-5,5a,6,7,8,9-,9a,10-octahydropyrimido[4,5g]quinolines, and their pharmaceutically acceptable salts for the treatment of neuromuscular disorders is disclosed, particularly for the preparation of a medicament for treating, symptoms of fibromyalgia syndrome and chronic fatigue syndrome. End of^eport' r V) ■ </div>