[go: up one dir, main page]

US20030191149A1 - Compounds for treating fibromyalgia and chronic fatigue syndrome - Google Patents

Compounds for treating fibromyalgia and chronic fatigue syndrome Download PDF

Info

Publication number
US20030191149A1
US20030191149A1 US10/383,467 US38346703A US2003191149A1 US 20030191149 A1 US20030191149 A1 US 20030191149A1 US 38346703 A US38346703 A US 38346703A US 2003191149 A1 US2003191149 A1 US 2003191149A1
Authority
US
United States
Prior art keywords
formula
compound
cycloalkyl
alkyl
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/383,467
Inventor
Robert McCall
Robert Marshall
David Robertson
Thomas Ashley
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to US10/383,467 priority Critical patent/US20030191149A1/en
Publication of US20030191149A1 publication Critical patent/US20030191149A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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 use of neuromuscular agents, and the pharmacologically acceptable salts thereof, for the treatment of nervous system disorders, and more particularly to the use of compounds of U.S. Pat. Nos. 5,273,975, 5,436,240, 5,594,024, 5,462,947, and 4,526,892 for the treatment of symptoms of fibromyalgia syndrome and chronic fatigue syndrome.
  • Chronic fatigue syndrome also referred to as chronic fatigue immune disorders syndrome, yuppie flu; fatigue—chronic, and chronic fatigue and immune dysfunction syndrome
  • CFS chronic fatigue syndrome
  • yuppie flu a clinically defined condition characterized by profound tiredness or fatigue.
  • 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 Many medications 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. 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 ranging from mild side effects, e.g., drowsiness, dizziness, and nausea to serious side effects, e.g., addiction and liver damage
  • a method of treating symptoms of fibromyalgia syndrome or chronic fatigue syndrome which comprises administering to a patient in need of treatment a therapeutically effective amount of a heterocyclic amine-type compound of formula (A),
  • R 1 , R 2 , and R 3 are independently hydrogen, C 1-6 alkyl, C 3-5 alkenyl, C 3-5 alkynyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl- or phenyl- substituted C 1-6 alkyl, or R 1 and R 2 are joined to form a C 3-7 cyclic amine which can contain additional heteroatoms and/or unsaturation;
  • X is hydrogen, C 1-6 alkyl halogen, hydroxy, alkoxy, cyano, carboxamide, carboxyl, or carboalkoxyl;
  • A is CH, CH 2 , CH-halogen, CHCH 3 , C ⁇ O, C ⁇ S, C—SCH 3 , C ⁇ NH, C—NH 2 , C—NHCH 3 , C—NHCOOCH 3 , C—NHCN, SO 2 , or N;
  • B is CH 2 , CH, CH-halogen, C ⁇ O, N, NH or N—CH 3 , or O;
  • n is 0 or 1;
  • D is CH, CH 2 , CH-halogen, C ⁇ O, O, N, NH, or N—CH 3 .
  • Preferred compounds of formula (A) include (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one (uninverted CAS name) and (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione, and their pharmaceutically acceptable salts.
  • Also disclosed is a method of treating symptoms of fibromyalgia syndrome or chronic fatigue syndrome which comprises administering to a patient in need of treatment a therapeutically effective amount of a substituted phenylazacycloalkane-type compound of formula (B),
  • n 0-3;
  • R 1 and R 2 are independently H (provided only one is H at the same time), —OH (provided R 4 is other than hydrogen), CN, CH 2 CN, 2- or 4-CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH ⁇ CF 2 , (CH 2 ) 2 CF 3 , ethenyl, 2-propenyl, OSO 2 CH 3 , OSO 2 CF 3 , SSO 2 CF 3 , COR 4 , COOR 4 , CON(R 4 ) 2 , SO x CH 3 (where, x is 0-2), SO x CF 3 , O(CH 2 ) x CF 3 , SO 2 N(R 4 ) 2 , CH ⁇ NOR 4 , COCOOR 4 , COCOON(R 4 ) 2 , C 1-8 alkyls, C 3-8 cycloalkyls, CH 2 OR 4 , CH 2 (R 4 ) 2 , NR 4 SO 2 CF 3 , NO 2
  • R 3 is hydrogen, CF 3 , CH 2 CF 3 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkyl-methyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, —(CH 2 ) m —R 5 (where m is 1-8), CH 2 SCH 3 or a C 4 -C 8 alkyl bonded to said nitrogen and one of its adjacent carbon atoms inclusive to form a cyclic structure;
  • R 4 is independently hydrogen, CF 3 , CH 2 CF 3 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkyl-methyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluoro-butyl, —(CH 2 ) m —R 5 where m is 1-8;
  • R 5 is phenyl, phenyl (substituted with a CN, CF 3 , CH 2 CF 3 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkyl-methyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl), 2-thiophenyl, 3-thiophenyl, —NR 6 CONR 6 R 7 , or —CONR 6 R 7 ;
  • R 6 and R 7 are independently hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkyl-methyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl; and with the proviso that when R 1 is 2-CN or 4-CN, R 2 is H, R 3 is n-Pr and n is 1 or 3 then such compound is a pure enantiomer.
  • Preferred compounds of formula (B) include (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride, (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrobromide, and (3S)-3-[3-Methylsulfonyl)phenyl]-1-propylpiperidine ( 2E)-2-butenedioate (1:1).
  • a method of treating symptoms of fibromyalgia syndrome or chronic fatigue syndrome which comprises administering to a patient in need of treatment a therapeutically effective amount of a cabergoline-type compound, or pharmaceutically acceptable salts thereof, with the preferred compound of this class being cabergoline.
  • the present invention relates to therapies for fibromyalgia (FMS) and chronic fatigue syndrome (CFS), and more particularly to the use of three broad classes of compounds having dopamine receptor activities for treating the symptoms of FMS and CFS.
  • FMS fibromyalgia
  • CFS chronic fatigue syndrome
  • One class of compounds useful for treating symptoms of CFS and FMS in the present invention are those compounds, or pharmaceutically acceptable salts thereof, disclosed generically or specifically in U.S. Pat. Nos. 5,273,975 and 5,436,240. These compounds are generically referred to as heterocyclic amine type compounds and are structurally represented by formula (A),
  • R 1 , R 2 , and R 3 are independently and are hydrogen, C 1-6 alkyl, C 3-5 alkenyl, or C 3-5 alkynyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl- or phenyl- substituted C 1-6 alkyl, or R 1 and R 2 are joined to form a C 3-7 cyclic amine which can contain additional heteroatoms and/or unsaturation;
  • X is hydrogen, C 1-6 alkyl, halogen, hydroxy, alkoxy, cyano, carboxamide, carboxyl, or carboalkoxyl;
  • A is CH, CH 2 , CH-halogen, CHCH 3 , C ⁇ O, C ⁇ S, C—SCH 3 , C ⁇ NH, C—NH 2 , C—NHCH 3 , C—NHCOOCH 3 , or C—NHCN, SO 2 , or N;
  • B is CH 2 , CH, CH-halogen, C ⁇ O, N, NH, N—CH 3 or O;
  • n is 0 or 1;
  • D is CH, CH 2 , CH-halogen, C ⁇ O, O, N, NH or N—CH 3 .
  • An especially preferred compound of formula (A) in the present invention is a compound of formula (Aa),
  • the compound name for the compound of formula (Aa) is (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one (uninverted CAS name) or (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Generated by ACD/Name software).
  • Suitable pharmaceutically acceptable salts include salts of both inorganic and organic acids; examples include without limitation salts of the following acids: hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, citric, methanesulfonic, CH 3 —(CH 2 ) n1 —COOH where n 1 is 0 thru 4, HOOC—(CH 2 )n 1 —COOH where n is as defined above, HOOC—CH ⁇ CH—COOH, and ⁇ -COOH.
  • a particularly preferred salt of (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one is the maleate. i.e. (Z)-2-butenedioate, salt, which is (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one (Z)-2-butenedioate (1:1).
  • the (Z)-2-butenedioate salt is shown as formula (Ab):
  • heterocyclic amine compounds selected heterocyclic amine compounds, the most preferred being (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione, a compound of the formula (Ac) below, also referred to herein at formula (VIII),
  • U.S. Pat. No. 5,273,975 generically discloses and claims (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione, but does not give an example or specific mention of this compound.
  • (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione (VIII) is preferably made from the corresponding non-thio analog, (5R)-(methylamino)-5,6-dihydro-4H-imidao(4,5,1-ij)quinolin-(2H)-one (VII).
  • a preferred process of making (5R)-(Methylamino)-5,6-dihydro-4H-imidao(4,5,1-ij)quinolin-(2H)-one (VII) is illustrated in PREPARATION 1 and EXAMPLEs 1-6, as well as CHART A.
  • the preferred method of transforming (5R)-(methylamino)-5,6-dihydro-4H-imidao(4,5,1-ij)quinolin-(2H)-one (VII) into (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1 -ij]quinoline-2(1H)-thione (VIII) is set forth in EXAMPLE 8.
  • (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione (IX) be present as a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include salts of both inorganic and organic acids.
  • the preferred pharmaceutically acceptable salts include salts of the following acids hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, citric, methanesulfonic CH 3 —(CH 2 ) n1 —COOH where n 1 is 0 thru 4, HOOC—(CH 2 )n 1 —COOH where n is as defined above, HOOC—CH ⁇ CH—COOH, ⁇ -COOH.
  • heterocyclic amine-type compounds e.g., consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance.
  • suitable dosages forms include without limitation plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal patch, etc, with tablet being the preferred dosage form.
  • the effective dose range for oral administration of a heterocyclic amine-type compound is from about 0.30 through about 50.0 mg/dose/patient orally. Patients with milder forms of FMS or CFS would be expected to need less drug, while patients with more severe forms of the disease may be expected to need more drug.
  • the dosages to be given to a particular patient 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. Normally the drug is given once a day or twice a day; it may be given even less often for some patients.
  • Another class of compounds useful in the present invention are those compounds, or pharmaceutically acceptable salts thereof, disclosed generically or specifically in U.S. Pat. Nos. 5,594,024 and 5, 462,947, both incorporated by reference herein. These compounds are generically referred to as substituted phenylazacycloalkane-type compounds and are structurally represented by formula (B),
  • n 0-3;
  • R 1 and R 2 are independently H (provided only one is H at the same time), —OH (provided R 4 is other than hydrogen), CN, CH 2 CN, 2- or 4-CF 3 , CH 2 CF 3 , CH 2 CHF 2 , CH ⁇ CF 2 , (CH 2 ) 2 CF 3 , ethenyl, 2-propenyl, OSO 2 CH 3 , OSO 2 CF 3 , SSO 2 CF 3 , COR 4 , COOR 4 , CON(R 4 ) 2 , SO x CH 3 (where, x is 0-2), SO x CF 3 , O(CH 2 ) x CF 3 , SO 2 N(R 4 ) 2 , CH ⁇ NOR 4 , COCOOR 4 , COCOON(R 4 ) 2 , C 1-8 alkyls, C 3-8 cycloalkyls, CH 2 OR 4 , CH 2 (R 4 ) 2 , NR 4 SO 2 CF 3 , NO 2
  • R 3 is hydrogen, CF 3 , CH 2 CF 3 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkyl-methyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, —(CH 2 ) m —R 5 (where m is 1-8), CH 2 SCH 3 or a C 4 -C 8 alkyl bonded to said nitrogen and one of its adjacent carbon atoms inclusive to form a cyclic structure;
  • R 4 is independently hydrogen, CF 3 , CH 2 CF 3 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkyl-methyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluoro-butyl, —(CH 2 ) m —R 5 where m is 1-8;
  • R 5 is phenyl, phenyl (substituted with a CN, CF 3 , CH 2 CF 3 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkyl-methyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl), 2-thiophenyl, 3-thiophenyl, —NR 6 CONR 6 R 7 , or —CONR 6 R 7 ;
  • R 6 and R 7 are independently hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 9 cycloalkyl-methyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl; and with the proviso that when R 1 is 2-CN or 4-CN, R 2 is H, R 3 is n-Pr and n is 1 or 3 then such compound is a pure enantiomer.
  • Also useful in the present invention are pharmaceutically acceptable salts of compounds of formula (B), those salts being disclosed in U.S. Pat. Nos. 5,462,947 and 5,594,024, both incorporated herein by reference.
  • Both organic and inorganic acids can be employed to form pharmaceutically acceptable salts; illustrative acids include sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, ethanedisulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic, and benzoic acids.
  • These salts are readily prepared by methods known in the art.
  • a particularly suitable compound of formula (B) in the present invention is (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride (uninverted CAS name) or OSU 6162 or (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride (Generated by ACD/Name software), and is represented by formula (Ba):
  • Another particularly suitable compound of formula (B) in the present invention is (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrobromide (uninverted CAS name) or (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrobromide (Generated by ACD/Name software), and is represented by formula (Bb):
  • Conventional pharmaceutical preparations can be used for the substituted phenylazacycloalkane-type compounds, e.g., consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance; e.g., plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdernal patch, etc.
  • Preferred dosage forms are tablets.
  • the effective dose range for oral administration of a substituted phenylazacycloalkane-type compound is from about 10 to about 1000 mg/dose/patient once or twice a day.
  • the dosage and dose frequency for a particular patient 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. While normally the drug may be given once a day or twice a day, it may be given even less often for some patients.
  • a further class of compounds useful in the present invention are those compounds, or pharmaceutically acceptable salts thereof, disclosed generically or specifically in U.S. Pat. No. 4,526,892, the full disclosure of which is incorporated herein by reference. These compounds are generically referred to as cabergoline-type compounds.
  • the preferred compound in this class is cabergoline itself, or its pharmaceutically acceptable salts.
  • the chemical name for cabergoline is 1-((6-allylergolin-8 ⁇ -yl) -carbony.)-1-(3-(dimethylamino)propyl)-3-ethylurea and the structure of carbergoline is represented by formula (C):
  • Cabergoline is the generic name for the active ingredient in DOSTINEX® or CABASER® Tablets, which are marketed by Pharmacia & Upjohn, Inc. in the United States, Europe and Latin America as a treatment for hyperprolactinemic disorders and Parkinson's disease.
  • the synthesis and use of cabergoline is disclosed and claimed in U.S. Pat. No. 4,526,892, which is incorporated herein by reference.
  • cabergoline e.g., consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance, e.g., plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, etc, with tablet being the preferred dosage form.
  • active substance e.g., plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, etc, with tablet being the preferred dosage form.
  • a package insert describing CABASER®, its pharmacokinetics, clinical studies, indications and usage, contraindication and warnings, and Parkinson's disease patients is provided by Pharmacia & Upjohn, Inc.. This package insert and its descriptions are incorporated by reference into this application.
  • the effective dose range for cabergoline is from about 0.01 to about 10.0 mg/dose/patient, preferably from about 0.25 to about 10.0 mg/dose/patient, more preferably from about 1 to about 6 mg/dose/patient, and even more preferably from about 1 to about 2 mg/dose/patient orally.
  • cabergoline is typically administered once or twice a day; however, for some patients the dose frequency may be reduced to three times a week, two times a week or even once a week.
  • the combination of dosage levels and dose frequency for a particular patient may be readily adjusted by the treating physician.
  • the dose response to cabergoline in terms of efficacy and side effects appears to be mainly linked to individual sensitivity.
  • dose optimization may be obtained, for example, by administering a low initial dose of cabergoline to the patient at a dose of 0.5 to 1 mg/patient/day and adjusting the dose upward at weekly intervals to an optimal therapeutic dosage of 2, 4, 6, 8 or 10 mg/patient/day.
  • Patients with milder forms of the disease would be expected to need less drug.
  • a dose of 0.05, 0.1 or even 0.25 mg/patient may be adequate.
  • Patients with more severe forms of the disease and those who have been treated with other dopaminergic agents may be expected to need more drug.
  • the precise dosage would be readily determined by the treating physician evaluating such factors as the progression of the state of the disease, the weight and age of the patient, whether and to what extent other drugs such as L-Dopa or levodopa were administered, and other such factors as are typically evaluated by a physician before determining the dosage of a CNS drug to a patient.
  • TLC refers to thin-layer chromatography
  • HPLC refers to high pressure liquid chromatography.
  • Saline refers to an aqueous saturated sodium chloride solution.
  • Chromatography column and flash chromatography refers to purification/separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
  • IR refers to infrared spectroscopy.
  • CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are reported in ppm ( ⁇ ) downfield from TMS.
  • NMR nuclear (proton) magnetic resonance spectroscopy
  • - ⁇ refers to phenyl (C 6 H 5 ).
  • [ ⁇ ] D 25 refers to the angle of rotation of plane polarized light (specific optical rotation) at 25° with the sodium D line (589A).
  • MS refers to mass spectrometry expressed as m/e, m/z or mass/charge unit.
  • [M+H] + refers to the positive ion of a parent plus a hydrogen atom.
  • EI refers to electron impact.
  • CI refers to chemical ionization.
  • FAB refers to fast atom bombardment.
  • compositions, formulation, stability, patient acceptance and bioavailability 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.
  • the ratios of solvents used are volume/volume (v/v).
  • the ratio of the solid to the solvent is weight/volume (wt/v).
  • the filtrate from the first crop is concentrated, branched octane is added and the mixture is cooled and stirred to obtain a second crop of the title compound.
  • the slurry is filtered, the crystal cake is washed with branched octane and dried at 20-25°.
  • the MTBE phase is concentrated under reduced pressure.
  • the concentrate is cooled to 0°, filtered and washed two times with 0° MTBE.
  • the product is dried at 50° under reduced pressure with a nitrogen purge to give the title compound, CMR (CDCl 3 , 100 MHz) 153.78, 136.44, 128.69, 127.67, 127.60, 126.73, 125.86, 122.90, 122.78, 121.28, 116.92, 116.17, 108.36,44.95 and 42.376.
  • Dilute hydrochloric acid is added to make the water-soluble salt of the title compound.
  • the byproduct (R-naproxen methylamide impurity) is insoluble in water and stays in the ethyl acetate phase. Further extractions and washes are carried out for better separation of the (naproxen acetamide) impurity with minimum loss of the desired product.
  • a sodium hydroxide solution is added to the aqueous phase and the hydrochloride salt of the title compound is converted to the free base.
  • the free base is less soluble in water and is extracted into ethyl acetate.
  • the product mixture is concentrated and solvent exchanged with ethyl acetate to remove water.
  • Crystallization is performed by adding branched chain octane and cooling the mixture. The resulting slurry is filtered, washed and dried at 50° to give the title compound, CMR (CDCl 3 ) ⁇ 153.7, 136.3, 128.7, 127.8, 127.7, 125.7, 121.3, 119.9, 118.6, 107.5, 66.2, 60.1, 45.1, 42.6 and 34.0.
  • the solution is saturated with sodium chloride and extracted with methylene chloride (2.5 L, in portions).
  • the organic phase is absorbed onto silicon dioxide (40 g) and purified via column chromatography (silicon dioxide, 225 g; methanol/methylene chloride, 3.5-5.0/96.5-95). The appropriate fractions are pooled and concentrated.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hydrogenated Pyridines (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)

Abstract

The present invention provides for methods for the treatment of fibromyalgia syndrome or chronic fatigue syndrome by the administration of heterocyclic amine-type compounds, substituted phenylazacycloalkane-type compounds, or cabergoline-type compounds, or a salt of any said compound.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims the benefit of the following U.S. provisional applications: Serial No. 60/198,959 filed Apr. 21, 2000 and Serial No. 60/200,569 filed Apr. 28, 2000, under 35 U.S.C. §119(e)(1).[0001]
    • FIELD OF THE INVENTION
  • The present invention relates to the use of neuromuscular agents, and the pharmacologically acceptable salts thereof, for the treatment of nervous system disorders, and more particularly to the use of compounds of U.S. Pat. Nos. 5,273,975, 5,436,240, 5,594,024, 5,462,947, and 4,526,892 for the treatment of symptoms of fibromyalgia syndrome and chronic fatigue syndrome. [0002]
    • BACKGROUND OF THE INVENTION
  • Chronic fatigue syndrome (CFS), also referred to as chronic fatigue immune disorders syndrome, yuppie flu; fatigue—chronic, and chronic fatigue and immune dysfunction syndrome, is a clinically defined condition 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 are usually done to exclude other possible causes of the symptoms. [0003]
  • 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 features with CFS. Similar to CFS, there are no specific diagnostic tests for FMS. [0004]
  • Many medications 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. 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 ranging from mild side effects, e.g., drowsiness, dizziness, and nausea to serious side effects, e.g., addiction and liver damage [0005]
  • Accordingly, there is clearly a need for better treatments for chronic fatigue syndrome and fibromyalgia. Now, the present invention reveals several compounds that can be formulated into useful therapeutic treatments for these conditions. [0006]
    • SUMMARY OF THE INVENTION
  • Disclosed is a method of treating symptoms of fibromyalgia syndrome or chronic fatigue syndrome which comprises administering to a patient in need of treatment a therapeutically effective amount of a heterocyclic amine-type compound of formula (A), [0007]
    Figure US20030191149A1-20031009-C00001
  • or a pharmaceutically acceptable salt thereof, wherein: [0008]
  • R[0009] 1, R2, and R3 are independently hydrogen, C1-6 alkyl, C3-5 alkenyl, C3-5 alkynyl, C3-7 cycloalkyl, C4-10 cycloalkyl- or phenyl- substituted C1-6 alkyl, or R1 and R2 are joined to form a C3-7 cyclic amine which can contain additional heteroatoms and/or unsaturation;
  • X is hydrogen, C[0010] 1-6 alkyl halogen, hydroxy, alkoxy, cyano, carboxamide, carboxyl, or carboalkoxyl;
  • A is CH, CH[0011] 2, CH-halogen, CHCH3, C═O, C═S, C—SCH3, C═NH, C—NH2, C—NHCH3, C—NHCOOCH3, C—NHCN, SO2, or N;
  • B is CH[0012] 2, CH, CH-halogen, C═O, N, NH or N—CH3, or O;
  • n is 0 or 1; and [0013]
  • D is CH, CH[0014] 2, CH-halogen, C═O, O, N, NH, or N—CH3.
  • Preferred compounds of formula (A) include (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one (uninverted CAS name) and (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione, and their pharmaceutically acceptable salts. [0015]
  • Also disclosed is a method of treating symptoms of fibromyalgia syndrome or chronic fatigue syndrome which comprises administering to a patient in need of treatment a therapeutically effective amount of a substituted phenylazacycloalkane-type compound of formula (B), [0016]
    Figure US20030191149A1-20031009-C00002
  • or pharmaceutically acceptable salts thereof, wherein: [0017]
  • n is 0-3; [0018]
  • R[0019] 1 and R2 are independently H (provided only one is H at the same time), —OH (provided R4 is other than hydrogen), CN, CH2CN, 2- or 4-CF3, CH2CF3, CH2CHF2, CH═CF2, (CH2)2CF3, ethenyl, 2-propenyl, OSO2CH3, OSO2CF3, SSO2CF3, COR4, COOR4, CON(R4)2, SOxCH3 (where, x is 0-2), SOxCF3, O(CH2)xCF3, SO2N(R4)2, CH═NOR4, COCOOR4, COCOON(R4)2, C1-8 alkyls, C3-8 cycloalkyls, CH2OR4, CH2(R4)2, NR4SO2CF3, NO2, halogen, a phenyl at positions 2, 3 or 4, thienyl, furyl, pyrrole, oxazole, thiazole, N-pyrroline, triazole, tetrazole or pyridine;
  • R[0020] 3 is hydrogen, CF3, CH2CF3, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl, C2-C8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, —(CH2)m—R5 (where m is 1-8), CH2SCH3 or a C4-C8 alkyl bonded to said nitrogen and one of its adjacent carbon atoms inclusive to form a cyclic structure;
  • R[0021] 4 is independently hydrogen, CF3, CH2CF3, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl, C2-C8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluoro-butyl, —(CH2)m—R5 where m is 1-8;
  • R[0022] 5 is phenyl, phenyl (substituted with a CN, CF3, CH2CF3, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl, C2-C8 alkynyl), 2-thiophenyl, 3-thiophenyl, —NR6CONR6R7, or —CONR6R7;
  • R[0023] 6 and R7 are independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl or C2-C8 alkynyl; and with the proviso that when R1 is 2-CN or 4-CN, R2 is H, R3 is n-Pr and n is 1 or 3 then such compound is a pure enantiomer.
  • Preferred compounds of formula (B) include (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride, (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrobromide, and (3S)-3-[3-Methylsulfonyl)phenyl]-1-propylpiperidine ( 2E)-2-butenedioate (1:1). [0024]
  • Further disclosed is a method of treating symptoms of fibromyalgia syndrome or chronic fatigue syndrome which comprises administering to a patient in need of treatment a therapeutically effective amount of a cabergoline-type compound, or pharmaceutically acceptable salts thereof, with the preferred compound of this class being cabergoline. [0025]
    • DETAILED DESCRIPTION OF THE INVENTION
  • The present invention relates to therapies for fibromyalgia (FMS) and chronic fatigue syndrome (CFS), and more particularly to the use of three broad classes of compounds having dopamine receptor activities for treating the symptoms of FMS and CFS. The useful compounds identified for the method of the present invention are described in two ways, with generic descriptions of completely enabled and disclosed groups of compounds and with detailed individually described compound structures and names. [0026]
  • One class of compounds useful for treating symptoms of CFS and FMS in the present invention are those compounds, or pharmaceutically acceptable salts thereof, disclosed generically or specifically in U.S. Pat. Nos. 5,273,975 and 5,436,240. These compounds are generically referred to as heterocyclic amine type compounds and are structurally represented by formula (A), [0027]
    Figure US20030191149A1-20031009-C00003
  • wherein: [0028]
  • R[0029] 1, R2, and R3 are independently and are hydrogen, C1-6 alkyl, C3-5 alkenyl, or C3-5 alkynyl, C3-7 cycloalkyl, C4-10 cycloalkyl- or phenyl- substituted C1-6 alkyl, or R1 and R2 are joined to form a C3-7 cyclic amine which can contain additional heteroatoms and/or unsaturation;
  • X is hydrogen, C[0030] 1-6 alkyl, halogen, hydroxy, alkoxy, cyano, carboxamide, carboxyl, or carboalkoxyl;
  • A is CH, CH[0031] 2, CH-halogen, CHCH3, C═O, C═S, C—SCH3, C═NH, C—NH2, C—NHCH3, C—NHCOOCH3, or C—NHCN, SO2, or N;
  • B is CH[0032] 2, CH, CH-halogen, C═O, N, NH, N—CH3 or O;
  • n is 0 or 1; and [0033]
  • D is CH, CH[0034] 2, CH-halogen, C═O, O, N, NH or N—CH3.
  • The methods of making the compounds and the pharmaceutically preparations are described in U.S. Pat. Nos. 5,273,975 and 5,436,240, and in International Patent Application WO 00/40226. The full disclosure of the above-cited U.S. Pat. Nos. 5,273,975 and 5,436,240 and International Patent Application WO 00/40226 is incorporated herein by reference. [0035]
  • An especially preferred compound of formula (A) in the present invention is a compound of formula (Aa), [0036]
    Figure US20030191149A1-20031009-C00004
  • or pharmaceutically acceptable salt thereof. The compound name for the compound of formula (Aa) is (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one (uninverted CAS name) or (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Generated by ACD/Name software). [0037]
  • It is preferred that (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one be present in a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts include salts of both inorganic and organic acids; examples include without limitation salts of the following acids: hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, citric, methanesulfonic, CH[0038] 3—(CH2)n1—COOH where n1 is 0 thru 4, HOOC—(CH2)n1—COOH where n is as defined above, HOOC—CH═CH—COOH, and φ-COOH. For other acceptable salts, see Int. J. Pharm., 33, 201-217 (1986). A particularly preferred salt of (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one is the maleate. i.e. (Z)-2-butenedioate, salt, which is (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one (Z)-2-butenedioate (1:1). The (Z)-2-butenedioate salt is shown as formula (Ab):
    Figure US20030191149A1-20031009-C00005
  • Another group of compounds within the generic formula of the heterocyclic amine-type compounds shown above, are selected heterocyclic amine compounds, the most preferred being (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione, a compound of the formula (Ac) below, also referred to herein at formula (VIII), [0039]
    Figure US20030191149A1-20031009-C00006
  • or pharmaceutically acceptable salts thereof. [0040]
  • U.S. Pat. No. 5,273,975 generically discloses and claims (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione, but does not give an example or specific mention of this compound. (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione (VIII) is preferably made from the corresponding non-thio analog, (5R)-(methylamino)-5,6-dihydro-4H-imidao(4,5,1-ij)quinolin-(2H)-one (VII). A preferred process of making (5R)-(Methylamino)-5,6-dihydro-4H-imidao(4,5,1-ij)quinolin-(2H)-one (VII) is illustrated in PREPARATION 1 and EXAMPLEs 1-6, as well as CHART A. The preferred method of transforming (5R)-(methylamino)-5,6-dihydro-4H-imidao(4,5,1-ij)quinolin-(2H)-one (VII) into (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1 -ij]quinoline-2(1H)-thione (VIII) is set forth in EXAMPLE 8. [0041]
  • It is preferred that (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione (IX) be present as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include salts of both inorganic and organic acids. The preferred pharmaceutically acceptable salts include salts of the following acids hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, citric, methanesulfonic CH[0042] 3—(CH2)n1—COOH where n1is 0 thru 4, HOOC—(CH2)n1—COOH where n is as defined above, HOOC—CH═CH—COOH, φ-COOH. For other acceptable salts, see Int. J. Pharm., 33, 201-217 (1986). It is more preferred that (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione be present as the maleate salt, which is (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2( 1H)-thione maleate. The maleate salt is shown below as formula (Ad) or formula (IX):
    Figure US20030191149A1-20031009-C00007
  • Conventional pharmaceutical preparations can be used for the heterocyclic amine-type compounds, e.g., consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance. Suitable dosages forms include without limitation plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal patch, etc, with tablet being the preferred dosage form. [0043]
  • The effective dose range for oral administration of a heterocyclic amine-type compound is from about 0.30 through about 50.0 mg/dose/patient orally. Patients with milder forms of FMS or CFS would be expected to need less drug, while patients with more severe forms of the disease may be expected to need more drug. The dosages to be given to a particular patient 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. Normally the drug is given once a day or twice a day; it may be given even less often for some patients. [0044]
  • Another class of compounds useful in the present invention are those compounds, or pharmaceutically acceptable salts thereof, disclosed generically or specifically in U.S. Pat. Nos. 5,594,024 and 5, 462,947, both incorporated by reference herein. These compounds are generically referred to as substituted phenylazacycloalkane-type compounds and are structurally represented by formula (B), [0045]
    Figure US20030191149A1-20031009-C00008
  • wherein: [0046]
  • n is 0-3; [0047]
  • R[0048] 1 and R2 are independently H (provided only one is H at the same time), —OH (provided R4 is other than hydrogen), CN, CH2CN, 2- or 4-CF3, CH2CF3, CH2CHF2, CH═CF2, (CH2)2CF3, ethenyl, 2-propenyl, OSO2CH3, OSO2CF3, SSO2CF3, COR4, COOR4, CON(R4)2, SOxCH3 (where, x is 0-2), SOxCF3, O(CH2)xCF3, SO2N(R4)2, CH═NOR4, COCOOR4, COCOON(R4)2, C1-8 alkyls, C3-8 cycloalkyls, CH2OR4, CH2(R4)2, NR4SO2CF3, NO2, halogen, a phenyl at positions 2, 3 or 4, thienyl, furyl, pyrrole, oxazole, thiazole, N-pyrroline, triazole, tetrazole or pyridine;
  • R[0049] 3 is hydrogen, CF3, CH2CF3, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl, C2-C8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, —(CH2)m—R5 (where m is 1-8), CH2SCH3 or a C4-C8 alkyl bonded to said nitrogen and one of its adjacent carbon atoms inclusive to form a cyclic structure;
  • R[0050] 4 is independently hydrogen, CF3, CH2CF3, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl, C2-C8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluoro-butyl, —(CH2)m—R5 where m is 1-8;
  • R[0051] 5 is phenyl, phenyl (substituted with a CN, CF3, CH2CF3, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl, C2-C8 alkynyl), 2-thiophenyl, 3-thiophenyl, —NR6CONR6R7, or —CONR6R7;
  • R[0052] 6 and R7 are independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl or C2-C8 alkynyl; and with the proviso that when R1 is 2-CN or 4-CN, R2 is H, R3 is n-Pr and n is 1 or 3 then such compound is a pure enantiomer.
  • Also useful in the present invention are pharmaceutically acceptable salts of compounds of formula (B), those salts being disclosed in U.S. Pat. Nos. 5,462,947 and 5,594,024, both incorporated herein by reference. Both organic and inorganic acids can be employed to form pharmaceutically acceptable salts; illustrative acids include sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, ethanedisulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic, and benzoic acids. These salts are readily prepared by methods known in the art. [0053]
  • A particularly suitable compound of formula (B) in the present invention is (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride (uninverted CAS name) or OSU 6162 or (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride (Generated by ACD/Name software), and is represented by formula (Ba): [0054]
    Figure US20030191149A1-20031009-C00009
  • Another particularly suitable compound of formula (B) in the present invention is (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrobromide (uninverted CAS name) or (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrobromide (Generated by ACD/Name software), and is represented by formula (Bb): [0055]
    Figure US20030191149A1-20031009-C00010
  • Yet another particularly suitable compound of formula (B) in the present invention is (3S)-3-[3-Methylsulfonyl)phenyl]-1-propylpiperidine (2E)-2-butenedioate (1:1) (uninverted CAS name) or (S)-OSU6162, and is represented by formula (Bc): [0056]
    Figure US20030191149A1-20031009-C00011
  • The methods of preparing these compounds, and formulations and medicaments of the same, are described in U.S. Pat. Nos. 5,594,024 and 5,462,947, both incorporated herein by reference. [0057]
  • Conventional pharmaceutical preparations can be used for the substituted phenylazacycloalkane-type compounds, e.g., consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance; e.g., plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdernal patch, etc. Preferred dosage forms are tablets. [0058]
  • The effective dose range for oral administration of a substituted phenylazacycloalkane-type compound is from about 10 to about 1000 mg/dose/patient once or twice a day. The dosage and dose frequency for a particular patient 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. While normally the drug may be given once a day or twice a day, it may be given even less often for some patients. [0059]
  • A further class of compounds useful in the present invention are those compounds, or pharmaceutically acceptable salts thereof, disclosed generically or specifically in U.S. Pat. No. 4,526,892, the full disclosure of which is incorporated herein by reference. These compounds are generically referred to as cabergoline-type compounds. The preferred compound in this class is cabergoline itself, or its pharmaceutically acceptable salts. The chemical name for cabergoline is 1-((6-allylergolin-8β-yl) -carbony.)-1-(3-(dimethylamino)propyl)-3-ethylurea and the structure of carbergoline is represented by formula (C): [0060]
    Figure US20030191149A1-20031009-C00012
  • Cabergoline is the generic name for the active ingredient in DOSTINEX® or CABASER® Tablets, which are marketed by Pharmacia & Upjohn, Inc. in the United States, Europe and Latin America as a treatment for hyperprolactinemic disorders and Parkinson's disease. The synthesis and use of cabergoline is disclosed and claimed in U.S. Pat. No. 4,526,892, which is incorporated herein by reference. [0061]
  • Conventional pharmaceutical preparations can be used for cabergoline, e.g., consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance, e.g., plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, etc, with tablet being the preferred dosage form. [0062]
  • A package insert describing CABASER®, its pharmacokinetics, clinical studies, indications and usage, contraindication and warnings, and Parkinson's disease patients is provided by Pharmacia & Upjohn, Inc.. This package insert and its descriptions are incorporated by reference into this application. [0063]
  • The effective dose range for cabergoline is from about 0.01 to about 10.0 mg/dose/patient, preferably from about 0.25 to about 10.0 mg/dose/patient, more preferably from about 1 to about 6 mg/dose/patient, and even more preferably from about 1 to about 2 mg/dose/patient orally. At these dose levels above, cabergoline is typically administered once or twice a day; however, for some patients the dose frequency may be reduced to three times a week, two times a week or even once a week. The combination of dosage levels and dose frequency for a particular patient may be readily adjusted by the treating physician. [0064]
  • The dose response to cabergoline in terms of efficacy and side effects appears to be mainly linked to individual sensitivity. Under some circumstances and with the appropriate patients, dose optimization may be obtained, for example, by administering a low initial dose of cabergoline to the patient at a dose of 0.5 to 1 mg/patient/day and adjusting the dose upward at weekly intervals to an optimal therapeutic dosage of 2, 4, 6, 8 or 10 mg/patient/day. Patients with milder forms of the disease would be expected to need less drug. For example, in some cases a dose of 0.05, 0.1 or even 0.25 mg/patient may be adequate. Patients with more severe forms of the disease and those who have been treated with other dopaminergic agents may be expected to need more drug. The precise dosage would be readily determined by the treating physician evaluating such factors as the progression of the state of the disease, the weight and age of the patient, whether and to what extent other drugs such as L-Dopa or levodopa were administered, and other such factors as are typically evaluated by a physician before determining the dosage of a CNS drug to a patient. [0065]
  • Definitions and Convention [0066]
  • The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims. [0067]
  • Definitions [0068]
  • All temperatures are in degrees Celsius. [0069]
  • TLC refers to thin-layer chromatography. [0070]
  • HPLC refers to high pressure liquid chromatography. [0071]
  • Saline refers to an aqueous saturated sodium chloride solution. [0072]
  • Chromatography (column and flash chromatography) refers to purification/separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s). [0073]
  • IR refers to infrared spectroscopy. CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are reported in ppm (δ) downfield from TMS. [0074]
  • NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (δ) downfield from tetramethylsilane. [0075]
  • -φ refers to phenyl (C[0076] 6H5).
  • [α][0077] D 25 refers to the angle of rotation of plane polarized light (specific optical rotation) at 25° with the sodium D line (589A).
  • MS refers to mass spectrometry expressed as m/e, m/z or mass/charge unit. [M+H][0078] +refers to the positive ion of a parent plus a hydrogen atom. EI refers to electron impact. CI refers to chemical ionization. FAB refers to fast atom bombardment.
  • Pharmaceutically acceptable 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. [0079]
  • When solvent pairs are used, the ratios of solvents used are volume/volume (v/v). [0080]
  • When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v).[0081]
    • EXAMPLES
  • Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. [0082]
  • Preparation 1 (R)-Naproxen chloride [0083]
  • R-naproxen ([0084] Can. J Chem., 72(1), 142-5 (1994), 260 g), methylene chloride (3.33 kg) and DMF (8.2 ml) are added to a reactor. Oxalyl chloride (191.8 g) is slowly added to this mixture. After addition of the oxalyl chloride, the slurry is stirred at 5 to 10° and then slowly warmed to 20-25°. The resulting mixture is concentrated to remove the methylene chloride, branched octane is added to the concentrate and the mixture is again concentrated. More branched octane is added to the concentrate and the mixture is cooled to 0° and stirred to crystallize. The crystal slurry is filtered, the crystal cake is washed with octane and dried at 20-25° to obtain the title compound.
  • The filtrate from the first crop is concentrated, branched octane is added and the mixture is cooled and stirred to obtain a second crop of the title compound. The slurry is filtered, the crystal cake is washed with branched octane and dried at 20-25°. [0085]
    • Example 1
  • 1-Benzyl-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (II) [0086]
  • A mixture of 4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (I, [0087] J. Heterocyclic Chem. ,19, 837-49 (1982), 1.0 g, 5.8 mmol) in DMF (10 ml) is cooled to 0° and treated with potassium t-butoxide in THF (1.98 M, 3.2 ml, 6.3 mmol) maintaining the reaction temperature at 0°. The resulting mixture is stirred at 0° for 10 minutes. Benzyl bromide (0.73 ml, 6.1 mmol) is then added while maintaining the reaction temperature at methyl t-butyl ether (MTBE) from water followed by several water washes. The MTBE phase is concentrated under reduced pressure. The concentrate is cooled to 0°, filtered and washed two times with 0° MTBE. The product is dried at 50° under reduced pressure with a nitrogen purge to give the title compound, CMR (CDCl3, 100 MHz) 153.78, 136.44, 128.69, 127.67, 127.60, 126.73, 125.86, 122.90, 122.78, 121.28, 116.92, 116.17, 108.36,44.95 and 42.376.
    • Example 2
  • (5R,6R)-1-Benzyl-5-bromo-6-hydroxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (III) [0088]
  • 1-Benzyl-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (II, EXAMPLE 1, 240 g), acetonitrile (1.086 kg), water (227 ml) and fluoboric acid (48.5%, 13.4 g) are mixed and cooled to 0 to 5°. Dibromantin (163.5 g) is slurried into acetonitrile and is added to the reaction mixture. The reaction is carried out for about 3 hr at 0 to 5°. After the reaction is complete, methyl t-butyl ether is added over about 45 minutes keeping the reaction temperature in the pot below 10°. The slurry is cooled to −10 to −15°, stirred for an hour and then filtered. The product is washed with precooled methyl t-butyl ether, dried with 40° nitrogen to give the title compound, CMR (CDCl[0089] 3) 156.0, 137.8, 130.5, 129.6, 129.3, 129.1, 126.6, 123.6, 122.5, 119.6, 110.4, 69.9, 49.6, 47.7, 46.9 and 43.8 6.
    • Example 3
  • (5S,6S)-1-Benzyl-5-bromo-2oxol ,2,5,6tetrahydro4Himidazo[4,5,1ij]quinolin6yl(2R)-(6-methoxy-2- naphthyl)propanoate (IVA) and (5R,6R)-1-benzyl-5-bromo-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-6-yl (2R)-(6-methoxy-2-naphthyl)propanoate (IVB) [0090]
  • (5R,6R)- 1-Benzyl-5-bromo-6-hydroxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (III, EXAMPLE 2, 143 g), methylene chloride (3,136 g), N-methyl morpholine (100.2 g) and 4-dimethylaminopyridine (497 mg) are added to the reactor and the mixture is cooled to 0 to 5°. (R)-Naproxen chloride (PREPARATION 1, 118.5 g) dissolved in methylene chloride (694 ml) is added to the reactor over about 1 hr and the mixture is stirred at 0 to 5° to complete the reaction. If necessary, additional naproxen chloride is added to complete the reaction. Potassium carbonate solution diluted with water is added to the mixture. The aqueous phase is extracted with methylene chloride and the combined methylene chloride phase is washed with water. The washed mixture is concentrated by vacuum distillation and solvent exchange with ethyl acetate is performed. The concentrate is cooled to −10° and stirred. The crystal slurry is filtered and the crystal cake is washed with precooled methyl t-butyl ether and dried at 50° to give the title compound in solid form, (5S,6S)-1-benzyl-5-bromo-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-6-yl (2R)-2-(6-methoxy-2-naphthyl)propanoate (IVA), CMR (CDCl[0091] 3) δ 173.2, 157.8, 153.4, 136.1, 134.6, 133.7, 129.2, 128.8, 127.8, 127.8, 127.6, 127.2, 125.9, 125.9, 125.6, 121.5, 121.4, 119.1, 113.2, 109.0, 105, 105.6, 69.2, 55.3, 45.4, 45.2, 42.5, 41.7 and 18.3.
  • The undesired isomer, (5R,6R)-1-benzyl-5-bromo-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-6-yl(2R)-2-(6-methoxy-2-naphthyl)propanoate (IVB) is in the filtrate and can be recovered by means well known to those skilled in the art, (5R,6R)-1-benzyl-5-hydroxy-6-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one, CMR (CDCl[0092] 3) δ 173.2, 157.9, 153.4, 136.1, 135.0, 133.8, 129.2, 128.9, 128.8, 127.8, 127.6, 127.4, 125.8, 125.8, 125.7, 121.6, 121.5, 119.3, 113.1, 109.1, 105.7,68.7, 55.3, 45.3, 45.2, 42.2, 41.3 and 18.1.
    • Example 4
  • (5R,6R)-1-Benzyl-5-hydroxy-6-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (V) [0093]
  • (5S,6S)-1-Benzyl-5-bromo-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-6-yl (2R)-2-(6-methoxy-2-naphthyl)propanoate (IVA, EXAMPLE 3, 110 g) is slurried in acetonitrile (1,297 g). After adding aqueous methylamine (40 wt %, 327 g) the reaction is carried out for about 12 hr at about 30°. After the reaction is complete, the mixture is concentrated and ethyl acetate is added. Dilute hydrochloric acid is added to make the water-soluble salt of the title compound. The byproduct (R-naproxen methylamide impurity) is insoluble in water and stays in the ethyl acetate phase. Further extractions and washes are carried out for better separation of the (naproxen acetamide) impurity with minimum loss of the desired product. Then a sodium hydroxide solution is added to the aqueous phase and the hydrochloride salt of the title compound is converted to the free base. The free base is less soluble in water and is extracted into ethyl acetate. The product mixture is concentrated and solvent exchanged with ethyl acetate to remove water. Crystallization is performed by adding branched chain octane and cooling the mixture. The resulting slurry is filtered, washed and dried at 50° to give the title compound, CMR (CDCl[0094] 3) δ 153.7, 136.3, 128.7, 127.8, 127.7, 125.7, 121.3, 119.9, 118.6, 107.5, 66.2, 60.1, 45.1, 42.6 and 34.0.
    • Example 5
  • (7aS,8aR)-4-Benzyl-8-methyl-7,7a,8,8a-tetrahydroazireno[2,3-c]imidazo[4,5,1-ij]quinolin-5(4H)-one (VI) [0095]
  • (5R,6R)-1-Benzyl-5-hydroxy-6-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (V, EXAMPLE 4, 70 g) and THF (1,389 g) is concentrated to remove any by distillation as a precaution due to reactivity of n-butyllithium towards water. The mixture is cooled to about −10° and n-butyllithium is added to make the lithium salt of the starting material with formation of n-butane byproduct in an exothermic reaction. Benzenesulfonyl chloride is added slowly to make benzenesulfonate in an exothermic reaction. The reaction mixture is warmed to 20-25° to complete the reaction. Agueous potassium carbonate solution is added to scavenge the benzenesulfonic acid and the mixture is stirred to allow crystallization. Water is added to complete crystallization, the slurry is stirred, cooled and filtered. The crystal cake is washed with water followed by branched chain octane and dried at 40 to 50° to give the title compound, CMR (CDCl[0096] 3) δ 154.1, 136.3, 128.6, 127.9, 127.6, 124.3, 120.7, 119.7, 107.4, 46.7, 44.9, 40.7, 38.1 and 37.6.
    • Example 6
  • (5R)-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (VII) [0097]
  • A mixture of (7aS,8aR)-4-benzyl-8-methyl-7,7a,8,8a-tetrahydroazireno[2,3-c]imidazo[4,5,1-ij]quinolin-5(4H)-one (VI, EXAMPLE 5, 40 g) t-amyl alcohol (42.4 g) and anhydrous ammonia (1,200 g) is treated with lithium at −33°. After the lithium addition is complete, the reaction mixture changes from a yellow slurry to a dark blue mixture. This dark blue mixture is stirred for 30-60 minutes and then quenched with the addition of water. The cooling is removed from the condenser and the ammonia is allowed to evaporate. The residue is dissolved in methanol. This mixture is then concentrated to dryness to give the title compound, which is carried on directly to the next step without isolation. [0098]
    • Example 7
  • (5R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione (VIII) [0099]
    Figure US20030191149A1-20031009-C00013
  • A mixture of (5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (VII, EXAMPLE 6, 15.0 g, 73.8 mmol) and tetraphosphorus decasulfide (36.1 g, 81.2 mmol) in pyridine (300 mL) is heated in a 125° oil bath under nitrogen. The reaction is stirred for 5 hr. The mixture is cooled to 20-25° and the pyridine is removed under reduced pressure. Sodium hydroxide (2.2 N, 200 mL) is added and a vigorous reaction ensues. Additional sodium hydroxide (1 N) is added until a solution is formed. The solution is saturated with sodium chloride and extracted with methylene chloride (2.5 L, in portions). The organic phase is absorbed onto silicon dioxide (40 g) and purified via column chromatography (silicon dioxide, 225 g; methanol/methylene chloride, 3.5-5.0/96.5-95). The appropriate fractions are pooled and concentrated. The material is recrystallized from methanol/ethyl acetate/hexanes to give the title compound, mp=210-213°; IR (drift) 2940, 2907, 2884, 1483, 1458, 1391, 1366, 1354, 1254, 1239, 1229, 895, 762, 734 and 630 cm[0100] −1; NMR (300 MHz, CDCl3) δ 7.12, 7.03, 7.00, 4.30, 3.96, 3.30-3.50, 3.15, 2.88 and 2.57; MS (EI) m/z 219 (M+), 190, 189, 187, 186, 164, 163, 155, 145; HRMS (FAB) calculated for C11H13N3S (MH+)=220.0908, found=220.0904.
    • Example 8
  • (5R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione maleate(IX) [0101]
    Figure US20030191149A1-20031009-C00014
  • A solution of maleic acid (0.317 g, 2.36 mmol) in a minimal amount of methanol (˜1 mL) is added to a mixture of (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione (VIII, EXAMPLE 7, 0.493 g, 2.25 mmol) in methylene chloride. The resulting solid is collected by filtration to give the title compound; mp=195-196°; [α][0102] 25D=−60° (c 0.93, methanol); IR (drift) 3140, 3112. 3060, 2969, 1627, 1619, 1568, 1481, 1455, 1398, 1389, 1361, 1220, 868 and 747 cm−1; NMR (300 MHz, CD3OD) δ 7.20-7.30, 7.10-7.20, 6.26, 4.49, 4.31, 4.05-4.20, 3.28 and 2.83; CMR (100 MHz, DMSO-d6+CD3OD) δ 170.4, 169.4, 136.6, 131.1, 130.9, 125.1, 122.1, 116.2, 109.6, 53.9, 43.1, 31.9 and 27.2; MS (ESI) m/z=220.1 (MH+).
    Figure US20030191149A1-20031009-C00015
    Figure US20030191149A1-20031009-C00016

Claims (30)

What is claimed is:
1. A method of treating the symptoms of fibromyalgia syndrome or chronic fatigue syndrome, comprising administering to a patient in need of treatment a therapeutically effective amount of an active agent selected from the group consisting of a heterocyclic amine-type compound, a substituted phenylazacycloalkane-type compound, and a cabergoline-type compound, and pharmaceutically acceptable salts of any said compound.
2. The method of claim 1 wherein said active agent is a heterocyclic amine-type compound of formula (A),
Figure US20030191149A1-20031009-C00017
or a pharmaceutically acceptable salt thereof, wherein:
R1, R2, and R3 are independently hydrogen, C1-6 alkyl, C3-5 alkenyl, C3-5 alkynyl, C3-7 cycloalkyl, C4-10 cycloalkyl- or phenyl- substituted C1-6 alkyl, or R1 and R2 are joined to form a C3-7 cyclic amine which can contain additional heteroatoms and/or unsaturation;
X is hydrogen, C1-6 alkyl, halogen, hydroxy, alkoxy, cyano, carboxamide, carboxyl, or carboalkoxyl;
A is CH, CH2, CH-halogen, CHCH3, C═O, C═S, C—SCH3, C═NH, C—NH2, C—NHCH3, C—NHCOOCH3, C—NHCN, SO2, or N;
B is CH2, CH, CH-halogen, C═O, N, NH or N—CH3 or O;
n is 0 or 1; and
D is CH, CH2, CH-halogen, C═O, O, N, NH, or N—CH3.
3. The method of claim 2 wherein, in said formula (A), D is N or NH, and n is 0.
4. The method of claim 2 wherein, in said formula (A), A is CH, CH2, CHCH3, C═O, C═S, C—SCH3, C═NH, C—NH2, C—NHCH3, C13 NHCOOCH 3, or C—NHCN.
5. The method of claim 2 wherein, in said formula (A), A is CH or C═O.
6. The method of claim 2 wherein said compound of formula (A) is a compound of formula (Aa):
Figure US20030191149A1-20031009-C00018
7. The method of claim 2 wherein said compound of formula (A) is (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one (uninverted CAS name) or (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Generated by ACD/Name software).
8. The method of claim 2 wherein said compound of formula (A) is a compound of formula (Ab):
Figure US20030191149A1-20031009-C00019
9. The method of claim 2 wherein said compound of formula (A) is (R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)one (Z)-2-butenedioate (1:1).
10. The method of claim 2 wherein said compound of formula (A) is a compound of formula (Ac), or formula (VIII):
Figure US20030191149A1-20031009-C00020
11. The method of claim 2 wherein said compound of formula (A) is (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione.
12. The method of claim 2 wherein said compound of formula (A) is a compound of formula (Ad), or formula (IX):
Figure US20030191149A1-20031009-C00021
13. The method of claim 2 wherein said compound of formula (A) is (5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione maleate.
14. The method of claim 1 wherein said active agent is a substituted phenylazacycloalkane-type compound of formula (B),
Figure US20030191149A1-20031009-C00022
or a pharmaceutically acceptable salt thereof, wherein:
n is 0-3;
R1 and R2 are independently H (provided only one is H at the same time), —OH (provided R4 is other than hydrogen), CN, CH2CN, 2- or 4-CF3, CH2CF3, CH2CHF2, CH═CF2, (CH2)2CF3, ethenyl, 2-propenyl, OSO2CH3, OSO2CF3, SSO2CF3, COR4, COOR4, CON(R4)2, SOxCH3 (where, x is 0-2), SOxCF3, O(CH2)xCF3, SO2N(R4)2, CH═NOR4, COCOOR4, COCOON(R4)2, C1-8 alkyls, C3-8 cycloalkyls, CH2OR4, CH2(R4)2, NR4SO2CF3, NO2, halogen, a phenyl at positions 2, 3 or 4, thienyl, furyl, pyrrole, oxazole, thiazole, N-pyrroline, triazole, tetrazole or pyridine;
R3 is hydrogen, CF3, CH2CF3, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl, C2-C8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, —(CH2)m—R5 (where m is 1-8), CH2SCH3 or a C4-C8 alkyl bonded to said nitrogen and one of its adjacent carbon atoms inclusive to form a cyclic structure;
R4 is independently hydrogen, CF3, CH2CF3, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl, C2-C8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluoro-butyl, —(CH2)m—R5 where m is 1-8;
R5 is phenyl, phenyl (substituted with a CN, CF3, CH2CF3, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl, C2-C8 alkynyl), 2-thiophenyl, 3-thiophenyl, -NR6CONR6R7,or —CONR6R7;
R6 and R7 are independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C4-C9 cycloalkyl-methyl, C2-C8 alkenyl or C2-C8 alkynyl; and with the proviso that when R1 is 2-CN or 4-CN, R2 is H, R3 is n-Pr and n is 1 or 3 then such compound is a pure enantiomer.
15. The method of claim 14 wherein, in said formula (B), said R1 is CN.
16. The method of claim 14 wherein, in said formula (B), said R2 is H and R3 is n-propyl.
17. The method of claim 14 wherein, in said formula (B), said R1 is an —OSO2CF3.
18. The method of claim 14 wherein, in said formula (B), said R2 is H and R3 is a C1-8 alkyl.
19. The method of claim 14 wherein, in said formula (B), said n is 2.
20. The method of claim 14 wherein, in said formula (B), said R1 is 3-OH, R2 is H, R3 is n-propyl and R4 is a C1-8 alkyl.
21. The method of claim 14 wherein, in said formula (B), said n is 0.
22. The method of claim 14 wherein said compound of formula (B) is a compound of formula (Ba):
Figure US20030191149A1-20031009-C00023
23. The method of claim 14 wherein said compound of formula (B) is (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride (uninverted CAS name) or OSU 6162 or (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride (Generated by ACD/Name software).
24. The method of claim 14 wherein said compound of formula (B) is a compound of formula (Bb):
Figure US20030191149A1-20031009-C00024
25. The method of claim 14 wherein said compound of formula (B) is (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrobromide (uninverted CAS name) or (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrobromide (Generated by ACD/Name software).
26. The method of claim 14 wherein said compound of formula (B) is a compound of formula (Bc):
Figure US20030191149A1-20031009-C00025
27. The method of claim 14 wherein said compound of formula (B) is (3S)-3-[3Methylsulfonyl)phenyl]-1-propylpiperidine (2E)-2-butenedioate (1:1) (uninverted CAS name) or (S)-OSU6162.
28. The method of claim 1 wherein said cabergoline-type compound is 1-((6-allylergolin-8β-yl) -carbony.)-1-(3-(dimethylamino)propyl)-3-ethylurea.
29. The method of claim 1 wherein said cabergoline-type compound is cabergoline, or a pharmaceutically acceptable salt thereof.
30. The method of claim 1 wherein said active agent is a cabergoline-type compound of formula (C),
Figure US20030191149A1-20031009-C00026
or a pharmaceutically acceptable salt thereof.
US10/383,467 2000-04-21 2003-03-07 Compounds for treating fibromyalgia and chronic fatigue syndrome Abandoned US20030191149A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US10/383,467 US20030191149A1 (en) 2000-04-21 2003-03-07 Compounds for treating fibromyalgia and chronic fatigue syndrome

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US19895900P 2000-04-21 2000-04-21
US20056900P 2000-04-28 2000-04-28
US09/836,660 US6448258B2 (en) 2000-04-21 2001-04-17 Treating fibromyalgia and chronic fatigue syndrome
US10/159,913 US6555548B2 (en) 2000-04-21 2002-05-30 Compounds for treating fibromyalgia and chronic fatigue syndrome
US10/383,467 US20030191149A1 (en) 2000-04-21 2003-03-07 Compounds for treating fibromyalgia and chronic fatigue syndrome

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/159,913 Division US6555548B2 (en) 2000-04-21 2002-05-30 Compounds for treating fibromyalgia and chronic fatigue syndrome

Publications (1)

Publication Number Publication Date
US20030191149A1 true US20030191149A1 (en) 2003-10-09

Family

ID=26894316

Family Applications (3)

Application Number Title Priority Date Filing Date
US09/836,660 Expired - Fee Related US6448258B2 (en) 2000-04-21 2001-04-17 Treating fibromyalgia and chronic fatigue syndrome
US10/159,913 Expired - Fee Related US6555548B2 (en) 2000-04-21 2002-05-30 Compounds for treating fibromyalgia and chronic fatigue syndrome
US10/383,467 Abandoned US20030191149A1 (en) 2000-04-21 2003-03-07 Compounds for treating fibromyalgia and chronic fatigue syndrome

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US09/836,660 Expired - Fee Related US6448258B2 (en) 2000-04-21 2001-04-17 Treating fibromyalgia and chronic fatigue syndrome
US10/159,913 Expired - Fee Related US6555548B2 (en) 2000-04-21 2002-05-30 Compounds for treating fibromyalgia and chronic fatigue syndrome

Country Status (16)

Country Link
US (3) US6448258B2 (en)
EP (1) EP1274430B1 (en)
JP (1) JP2004502650A (en)
KR (1) KR20040007215A (en)
CN (3) CN1450898A (en)
AR (3) AR028355A1 (en)
AT (1) ATE312608T1 (en)
AU (2) AU5311401A (en)
BR (1) BR0110210A (en)
CA (1) CA2405565A1 (en)
DE (1) DE60115872T2 (en)
DK (1) DK1274430T3 (en)
ES (1) ES2253370T3 (en)
NZ (3) NZ531172A (en)
PE (1) PE20011212A1 (en)
WO (1) WO2001081343A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10702512B2 (en) * 2015-05-13 2020-07-07 A. Carlsson Research Ab Treatment of debilitating fatigue

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE46117E1 (en) 1999-12-22 2016-08-23 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission
AU5522301A (en) * 2000-04-21 2001-11-26 Upjohn Co Treatment of fibromyalgia and chronic fatigue syndrome
AR033520A1 (en) * 2000-04-27 2003-12-26 Upjohn Co (5R) - (METHYLAMINE) -5,6-DIHIDRO-4H-IMIDAZO [4,5,1-IJ] QUINOLIN-2 (1H) -TIONA
PL363365A1 (en) * 2000-08-16 2004-11-15 Pharmacia & Upjohn Company Compounds for the treatment of addictive disorders
DE10041478A1 (en) 2000-08-24 2002-03-14 Sanol Arznei Schwarz Gmbh New pharmaceutical composition
AR031152A1 (en) 2000-10-31 2003-09-10 Upjohn Co NEW TREATMENTS FOR THE CONCERNED LEG SYNDROME
JP2006506360A (en) * 2002-10-04 2006-02-23 ファルマシア・コーポレーション Pharmaceutical composition for the treatment of Parkinson's disease
MXPA05003512A (en) * 2002-10-04 2005-06-03 Pharmacia Corp Compositions and methods for treating sexual dysfunction.
JP2009501184A (en) 2005-07-13 2009-01-15 エフ．ホフマン−ラ ロシュ アーゲー Benzimidazole derivatives as 5-HT6 and 5-HT24
TWI392670B (en) * 2006-06-22 2013-04-11 Ucb Pharma Gmbh Use of substituted 2-aminotetralines for the manufacture of a medicament for the prevention, alleviation and/or treatment of various types of pain
ES2332645B1 (en) * 2009-06-30 2010-10-18 Grifols, S.A. USE OF ALFA-1-ANTITRIPSIN FOR THE PREPARATION OF MEDICINES FOR THE TREATMENT OF CHRONIC FATIGUE SYNDROME.
WO2012039660A1 (en) * 2010-09-20 2012-03-29 A. Carlsson Research Ab Phenylpiperidine compounds for the treatment of neurological and psychiatric disorders
ES2755827T3 (en) 2013-03-15 2020-04-23 Incyte Holdings Corp Tricyclic heterocycles as BET protein inhibitors
ES2635560T3 (en) 2013-07-08 2017-10-04 Incyte Holdings Corporation Tricyclic heterocycles as NET protein inhibitors
WO2015081203A1 (en) 2013-11-26 2015-06-04 Incyte Corporation Bicyclic heterocycles as bet protein inhibitors
US9315501B2 (en) 2013-11-26 2016-04-19 Incyte Corporation Bicyclic heterocycles as BET protein inhibitors
WO2015095492A1 (en) 2013-12-19 2015-06-25 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
EP3674302B1 (en) 2014-04-23 2023-03-01 Incyte Holdings Corporation 1h-pyrrolo[2,3-c]pyridin-7(6h)-ones and pyrazolo[3,4-c]pyridin-7(6h)-ones as inhibitors of bet proteins
DE102014008742A1 (en) * 2014-06-12 2015-12-17 Daimler Ag Separator for an electrochemical storage, process for producing an electrode material and electrochemical energy storage
US9527864B2 (en) 2014-09-15 2016-12-27 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
AR106520A1 (en) 2015-10-29 2018-01-24 Incyte Corp SOLID FORM AMORFA OF A BET PROTEIN INHIBITOR
CN114366748A (en) 2016-06-20 2022-04-19 因赛特公司 Crystalline solid forms of BET inhibitors
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4526892A (en) * 1981-03-03 1985-07-02 Farmitalia Carlo Erba, S.P.A. Dimethylaminoalkyl-3-(ergoline-8'βcarbonyl)-ureas
US5273975A (en) 1989-06-09 1993-12-28 The Upjohn Company Heterocyclic amines having central nervous system activity
DE69016430T2 (en) 1989-06-09 1995-06-01 Upjohn Co HETEROCYCLIC AMINES WITH CNS EFFECTIVENESS.
ES2157204T3 (en) 1991-04-17 2001-08-16 Upjohn Co DERIVATIVES OF (S) -3-PHENYLPIPERIDINE SUBSTITUTED, ITS PREPARATION AND USE AS DOPAMINE SELF-RECEPTOR ANTAGONISTS.
WO1995004056A1 (en) 1993-07-27 1995-02-09 The Upjohn Company Heterocyclic amines having central nervous system activity
JPH1053525A (en) * 1996-06-06 1998-02-24 Bitakain Seiyaku Kk Therapeutic agent for pain
US6455564B1 (en) 1999-01-06 2002-09-24 Pharmacia & Upjohn Company Method of treating sexual disturbances
AU3490300A (en) * 1999-03-12 2000-10-04 Nitromed, Inc. Dopamine agonists in combination with nitric oxide donors, compositions and methods of use
ATE319453T1 (en) 1999-07-01 2006-03-15 Pharmacia & Upjohn Co Llc REBOXETINE FOR THE TREATMENT OF FIBROMYALGIA AND OTHER SOMATOFORM DISORDERS
DE19938823A1 (en) * 1999-08-19 2001-02-22 Boehringer Ingelheim Pharma Treatment of restless leg syndrome symptoms, using synergistic combination of alpha-2 agonist, preferably clonidine, and another neuro-psychic drug, e.g. pramipexol
WO2001015677A2 (en) * 1999-08-31 2001-03-08 Alcon Laboratories, Inc. Use of 5-ht1b/1d agonists to treat otic pain

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10702512B2 (en) * 2015-05-13 2020-07-07 A. Carlsson Research Ab Treatment of debilitating fatigue

Also Published As

Publication number Publication date
CN1554343A (en) 2004-12-15
NZ522112A (en) 2004-10-29
NZ531172A (en) 2005-07-29
ES2253370T3 (en) 2006-06-01
KR20040007215A (en) 2004-01-24
DK1274430T3 (en) 2006-02-13
CN1554341A (en) 2004-12-15
DE60115872T2 (en) 2006-07-13
EP1274430B1 (en) 2005-12-14
ATE312608T1 (en) 2005-12-15
NZ531171A (en) 2005-03-24
BR0110210A (en) 2003-01-28
AR039633A2 (en) 2005-03-02
DE60115872D1 (en) 2006-01-19
CN1450898A (en) 2003-10-22
AU2001253114B2 (en) 2005-08-25
US6555548B2 (en) 2003-04-29
AU5311401A (en) 2001-11-07
EP1274430A2 (en) 2003-01-15
WO2001081343A3 (en) 2002-02-28
WO2001081343A2 (en) 2001-11-01
PE20011212A1 (en) 2001-11-21
AR028355A1 (en) 2003-05-07
JP2004502650A (en) 2004-01-29
CA2405565A1 (en) 2001-11-01
US20020143010A1 (en) 2002-10-03
US6448258B2 (en) 2002-09-10
US20020004510A1 (en) 2002-01-10
AR039632A2 (en) 2005-03-02

Similar Documents

Publication Publication Date Title
US6448258B2 (en) Treating fibromyalgia and chronic fatigue syndrome
AU2001253114A1 (en) Compounds for treating fibromyalgia and chronic fatigue syndrome
US6716854B2 (en) Treatments for restless legs syndrome
US6809112B2 (en) Method of treating sexual disturbances
AU2021381638A1 (en) Salt of benzothiazole compound, and crystal form and use thereof
ZA200208273B (en) Compounds for treating fibromyalgia and chronic fatigue syndrome.
KR20020012314A (en) Remedies or preventives for frequent urination or urinary incontinence
US20040142937A1 (en) Use of heterocyclic amine-type compounds as neuroprotective agents
JP2004509964A (en) 7-chloro-4-hydroxy-2- (2-pyridylethyl) -1,2,5,10-tetrahydropyridazino [4,5-b] quinoline-1,10-dione and its use for treating pain use
HK1068781A (en) Compounds for treating fibromyalgia and chronic fatigue syndrome
HK1068255A (en) Compounds for treating fibromyalgia and chronic fatigue syndrome

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION