WO2002083141A1 - Traitement de la fibromyalgie et du syndrome de la fatigue chronique - Google Patents

Traitement de la fibromyalgie et du syndrome de la fatigue chronique Download PDF

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Publication number
WO2002083141A1
WO2002083141A1 PCT/US2001/016522 US0116522W WO02083141A1 WO 2002083141 A1 WO2002083141 A1 WO 2002083141A1 US 0116522 W US0116522 W US 0116522W WO 02083141 A1 WO02083141 A1 WO 02083141A1
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Prior art keywords
quinoline
trans
pharmaceutically acceptable
octahydropyrazolo
octahydropyrimido
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PCT/US2001/016522
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English (en)
Inventor
David W. Robertson
Robert B. Mccall
Robert C. Marshall
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Pharmacia & Upjohn Company
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Priority claimed from PCT/US2001/010806 external-priority patent/WO2001087308A1/fr
Application filed by Pharmacia & Upjohn Company filed Critical Pharmacia & Upjohn Company
Publication of WO2002083141A1 publication Critical patent/WO2002083141A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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-( ⁇ )-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 fatigue syndrome.
  • Chronic fatigue syndrome also referred to as chronic fatigue immune disorders, chronic fatigue immune disorders syndrome, yuppie flu, fatigue - chronic, and chronic fatigue and immune dysfunction syndrome
  • CFS chronic fatigue syndrome
  • 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 are usually done to exclude other possible causes of the symptoms.
  • Fibromyalgia syndrome also referred to as fibromyalgia, fibromyositis, fibrositis, or myofasical pain syndrome
  • FMS Fibromyalgia syndrome
  • CFS and FMS are commonly used to treat CFS and FMS.
  • examples of the more common medications include hypnotics, immune suppressants, various other prescribed 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.
  • opioid antagonists sodium retention agents/beta blockers
  • calcium channel blockers/histamine blockers include anti-depressants, allergy medications, and acute anxiety medications.
  • side effects ranging from mild side effects, e.g., drowsiness, dizziness, and nausea to serious side effects, e.g., addiction and liver damage.
  • 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.
  • U.S. Patent No. 3,717,639 discloses apomorphine and methods of preparation of the same.
  • 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 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 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, 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 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, 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 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 formulations for oral or parenteral administration for treating Parkinson's syndrome, sexual dysfunction, depression, hypertension, and elevated prolactin levels.
  • 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 formulations for oral or parenteral administration for treating Parkinson's syndrome, sexual dysfunction, depression, hypertension, and elevated prolactin levels.
  • 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.
  • the invention is directed to the use of certain known compounds to treat, or 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,
  • the present invention provides for the use of several classes of compounds, and their pharmaceutically acceptable salts to treat, or prepare medicaments for treating, symptoms of fibromyalgia (FMS) or chronic fatigue syndrome (CFS).
  • FMS fibromyalgia
  • CFS chronic fatigue syndrome
  • “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 of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • “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 apomo ⁇ hine and a pharmaceutically acceptable salt thereof.
  • Apomorphine, or (R)-5,6,6a,7-Tetrahydw-6- methyl-4H-dibenzo[de,g]quinoline-10,lI-diol or 6a ⁇ -ap ⁇ hine ⁇ 10,l l-diol, can be structurally represented by formula (I)
  • a pharmaceutical composition comprising apomo ⁇ hine or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier can be administered.
  • Apomo ⁇ hine hydrochloride is preferred; however, other pharmacologically acceptable moieties thereof can be utilized as well.
  • other acceptable acid addition salts are the hydrobromide, the hydroiodide, the bisulfate, the phosphate, the acid phosphate, the lactate, the citrate, the tartarate, the salicylate, the succinate, the maleate, the gluconate, and the like.
  • Apomo ⁇ hine 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 apomo ⁇ hine comprises 0.25 to 10 milligrams (mg) of the active and as inactive ingredients, macrocrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hydroxypropylmethylcellulose, titanium dioxide, lactose, triacetin, and FD&C Blue #2 aluminum lake.
  • Apomo ⁇ hine 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 apomo ⁇ hine be administered parenterally by subcutaneous injection, intravenous injection or infusion, or by transdermal delivery.
  • the effective dosage of apomo ⁇ hine 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 apomo ⁇ hine should be easily determined by the attending physician or clinician.
  • Another suitable compound in the present invention is bromocriptine, or a pharmaceutically acceptable salt thereof.
  • Bromocriptine or (5' )-2-Bromo-12 '-hydroxy-2 ' (I-methylethyl)-5'-(2-methylpropyl)ergotaman-3 ',6',18-trione; 2-bromoergocryptine; or 2- bromo- ⁇ -ergokryptin, can be structurally represented by formula (II) below.
  • 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 Co ⁇ .) in tablet and capsule form containing 2.5 and 5 mg of bromocriptine, respectively.
  • PARLODEL® bromocriptine mesylate
  • 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 in the present invention is 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.
  • Another suitable compound in the present invention is pergolide, or a pharmaceutically acceptable salt thereof.
  • Pergolide or (8 ⁇ )-8-[(Methylthio)methylJ-6- propylergoline; D-6- ⁇ -propyl-8 ⁇ -methylmercaptomethylergoline; or LY-141B, can be structurally represented by formula (HI) below.
  • 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 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.
  • 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 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.
  • Ropinirole or 4-[2-(Dipropylamino)ethyl]-I,3- dihydro-2H-indol-2-one; 4-[2-(di-/z-propylamino)ethyl]-2(3H)-indolone; or 4-(2-di-n- propylaminoethyl)-2-(3 ⁇ )-indolone, can be structurally represented by formula (IV) below.
  • 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 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 inco ⁇ orated herein by 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 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 more preferred that ropinirole be administered orally.
  • 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 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.
  • R is H, CN, Cl - C3 alkyl, allyl or benzyl and
  • RI is H, COOH, COO(Cl -C3) alkyl or CH2 X wherein X is CN, Cl, I, Br, OH,
  • 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(an 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 2H)-pyrazolo[3,4-g]quinoline and dihydrochloride salts thereof; 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
  • a particularly preferred compound of formulae (Va) and (Vb) can have the formula (Vc)
  • R is Cl -C3 alkyl or allyl
  • RI is CH2 X wherein X is CN, CONH2, SCH3, SO2 CH3 and OCH3.
  • Another particularly preferred compound of formulae (Va) and (Vb) is a trans-(+) stereoisomer existing as a tautomeric pair of the formula (Ve)
  • R is methyl, ethyl, n-propyl, or allyl.
  • An especially preferred compound of formulae (Va) and (Vb) is quinpirole, or pharmaceutically acceptable salts thereof.
  • Compounds of formulae (la) and (lb) 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 inco ⁇ orated herein by reference.
  • 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 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.
  • Still other suitable compounds in the present invention are trans-( ⁇ )-racemates of the formula (VI)
  • NHR3, NR4 R5 and R2 is H, CH3, Cl or Br wherein R3 is methyl, ethyl or n-propyl, Cl - C3 alkyl-CO, phenyl-CO or substituted phenyl-CO wherein said substituents are 1 or 2 members of the group: Cl, 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.
  • 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 Jquinoline— 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.
  • 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 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 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.
  • 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 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 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 with a suspending agent, preservative, flavoring or coloring agent.
  • a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water 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.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a formulation in the form of a capsule can be prepared using routine encapsulation procedures.
  • 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 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 can be formulated as solutions or 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 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 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.
  • 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; 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 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 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.
  • 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 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 more drug.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne l'utilisation d'apomorphine, de bromocriptine, de pergolide, de ropinirole, d'octahydropyrazolo[3,4-g]quinolines et de trans-(±)-substitué 5,5a,6,7,8,9-,9a,10-octahydropyrimido[4,5-g]quinolines, et leurs sels pharmaceutiquement acceptables en vue de traiter, de fabriquer un médicament permettant de soigner les symptomes du syndrome de fibromyalgie et le syndrome de la fatigue chronique.
PCT/US2001/016522 2001-04-17 2001-07-11 Traitement de la fibromyalgie et du syndrome de la fatigue chronique WO2002083141A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
USPCT/US01/10806 2001-04-17
PCT/US2001/010806 WO2001087308A1 (fr) 2000-04-21 2001-04-17 Traitement de la cellulomyalgie et du syndrome de fatigue chronique

Publications (1)

Publication Number Publication Date
WO2002083141A1 true WO2002083141A1 (fr) 2002-10-24

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PCT/US2001/016522 WO2002083141A1 (fr) 2001-04-17 2001-07-11 Traitement de la fibromyalgie et du syndrome de la fatigue chronique

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11510921B2 (en) 2017-10-18 2022-11-29 Veroscience Llc Bromocriptine formulations
US11560375B2 (en) * 2016-04-20 2023-01-24 Veroscience Llc Composition and method for treating metabolic disorders

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5073555A (en) * 1988-04-04 1991-12-17 George D. McAdory Medicaments intended for combined use in the improvement of lymphocyte function to lower cholesterol levels
WO1996001561A1 (fr) * 1994-07-07 1996-01-25 The General Hospital Corporation Doing Business As Massachusetts General Hospital Procede de modulation de la fonction immunitaire
WO2000015205A2 (fr) * 1998-09-11 2000-03-23 Eisai Co., Ltd. Utilisation d'inhibiteurs acetylcholinesterases pour la preparation de compositions pharmaceutiques destinees au traitement de syndromes de douleur fonctionnelle et/ou organique
WO2001001973A2 (fr) * 1999-07-01 2001-01-11 Pharmacia & Upjohn Company Inhibiteurs de recaptage de noradrenaline hautement selectifs et leurs methodes d'utilisation
DE19938823A1 (de) * 1999-08-19 2001-02-22 Boehringer Ingelheim Pharma Medikamentöse Behandlung des Restless Leg Syndroms

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5073555A (en) * 1988-04-04 1991-12-17 George D. McAdory Medicaments intended for combined use in the improvement of lymphocyte function to lower cholesterol levels
WO1996001561A1 (fr) * 1994-07-07 1996-01-25 The General Hospital Corporation Doing Business As Massachusetts General Hospital Procede de modulation de la fonction immunitaire
WO2000015205A2 (fr) * 1998-09-11 2000-03-23 Eisai Co., Ltd. Utilisation d'inhibiteurs acetylcholinesterases pour la preparation de compositions pharmaceutiques destinees au traitement de syndromes de douleur fonctionnelle et/ou organique
WO2001001973A2 (fr) * 1999-07-01 2001-01-11 Pharmacia & Upjohn Company Inhibiteurs de recaptage de noradrenaline hautement selectifs et leurs methodes d'utilisation
DE19938823A1 (de) * 1999-08-19 2001-02-22 Boehringer Ingelheim Pharma Medikamentöse Behandlung des Restless Leg Syndroms

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11560375B2 (en) * 2016-04-20 2023-01-24 Veroscience Llc Composition and method for treating metabolic disorders
US11878974B2 (en) 2016-04-20 2024-01-23 Veroscience Llc Composition and method for treating metabolic disorders
US11510921B2 (en) 2017-10-18 2022-11-29 Veroscience Llc Bromocriptine formulations
US11883399B2 (en) 2017-10-18 2024-01-30 Veroscience Llc Bromocriptine formulations

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