HK1068781A - Compounds for treating fibromyalgia and chronic fatigue syndrome - Google Patents

Description

Compounds for the treatment of fibromyalgia and chronic fatigue syndrome

The invention is a divisional application of Chinese patent application with application number 01806849.9 filed on 17.4.2001 and entitled "Compound for treating fibromyalgia and chronic fatigue syndrome".

Technical Field

The invention relates to the use of heterocyclic amines for the production of medicaments for the treatment of fibromyalgia syndrome and chronic fatigue syndrome.

Background

Chronic Fatigue Syndrome (CFS), also known as chronic fatigue immune disorder syndrome, epidemic in young metropolis professionals (yuppie); fatigue-chronic, and chronic fatigue and immune dysfunction syndromes, are defined clinically as disorders characterized by deep fatigue or fatigue. In addition, patients with CFS often have a variety of non-specific symptoms including weakness, muscle aches and pains, lethargy, malaise, fever, sore throat, tender lymph nodes, memory loss and/or reduced mental concentration, insomnia and depression. The exact cause of CFS is not known at present and although multiple tests are usually performed to rule out other possible causes of the condition, no specific test has yet been made to confirm the diagnosis of CFS.

Fibromyalgia syndrome (FMS), also known as fibromyalgia, fibromyositis, fibrositis, or myofascial pain syndrome, is a rheumatic disorder characterized by widespread pain occurring in fibrous tissues, muscles, tendons, and other connective tissues, fatigue, headaches, lack of restorative sleep, and numbness. FMS and CFS therefore share many common clinical features. Similar to CFS, there is also no specific diagnostic test for FMS.

A wide variety of drugs are commonly used to treat CFS and FMS. More common drugs include hypnotics, immunosuppressants, a variety of other prescribed drugs, and a range of over-the-counter drugs. Other prescribed drugs include opioid antagonists, sodium retention/beta blockers, calcium channel blockers/histamine blockers, anti-depressants, allergy medications, and acute anxiety medications. However, there are no known drugs that permanently eliminate the symptoms of CFS or FMS. In addition, many of the drugs currently used range from mild side effects such as drowsiness, dizziness and nausea to severe side effects such as addiction and liver damage.

Therefore, a need exists for a more effective method for treating chronic fatigue syndrome and fibromyalgia. In the following, the present invention discloses several compounds that can be formulated for the treatment of these conditions.

Disclosure of Invention

Disclosed is the use of a heterocyclic amine compound, and methods of use, for the preparation of a medicament for the treatment of fibromyalgia syndrome or chronic fatigue syndrome, said compound being of formula (A),

formula (A)

Or a pharmaceutically acceptable salt thereof, wherein,

R₁、R₂and R₃Each independently is hydrogen, C_1-6Alkyl radical, C_3-5Alkenyl radical, C_3-5Alkynyl, C_3-7Cycloalkyl radical, C_4-10Cycloalkyl or C substituted by phenyl_1-6Alkyl, or R₁And R₂Together forming C which may contain further hetero atoms and/or unsaturated bonds_3-7A cyclic amine;

x is hydrogen, C_1-6An alkyl group, a halogen atom, a hydroxyl group, an alkoxy group, a cyano group, an amide group, a carboxyl group or an alkoxycarbonyl group;

a is CH, CH₂CH-halo, CHCH₃、C＝O、C＝S、C-SCH₃、C＝NH、C-NH₂、C-NHCH₃、C-NHCOOCH₃、C-NHCN、SO₂Or N;

b is CH₂CH, CH-halo, C-O, N, NH or N-CH₃Or O;

n is 0 or 1, and

d is CH, CH₂CH-halo, 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 (unconverted CAS nomenclature) and (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] -quinolin-2 (1H) -thione, and pharmaceutically acceptable salts thereof.

Also disclosed is the use of a substituted phenylazacycloalkane compound for the manufacture of a medicament for the treatment of fibromyalgia syndrome or chronic fatigue syndrome, and methods of use, said compound being of formula (B),

formula (B)

Or a pharmaceutically acceptable salt thereof, wherein,

n is 0 to 3;

R¹and R²Each independently of the other is H (provided that only one is H at a time), -OH (provided that R is⁴Not hydrogen), CN, CH₂CN, 2-or 4-CF₃、CH₂CF₃、CH₂CHF₂、CH＝CF₂、(CH₂)₂CF₃Ethylenealkenyl, 2-propylenenyl, OSO₂CH₃、OSO₂CF₃、SSO₂CF₃、COR⁴、COOR⁴、CON(R⁴)₂、SO_xCH₃(wherein x is 0-2), SO_xCF₃、O(CH₂)_xCF₃、SO₂N(R⁴)₂、CH＝NOR⁴、COCOOR⁴、COCOON(R⁴)₂、C_1-8Alkyl radical, C_3-8Cycloalkyl radical, CH₂OR⁴、CH₂(R⁴)₂、NR⁴SO₂CF₃、NO₂A halogen atom, a phenyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, N-pyrrolinyl, triazolyl, tetrazolyl or pyridyl group in the 2, 3 or 4 position;

R³is hydrogen, CF₃、CH₂CF₃、C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, - (CH)₂)_m-R⁵(wherein m is 1-8), CH₂SCH₃Or C bonded to the nitrogen atom and to one of the adjacent carbon atoms to form a cyclic structure₄-C₈Alkyl (including the carbon and nitrogen atoms);

R⁴independently of each other is hydrogen, CF₃、CH₂CF₃、C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, - (CH) wherein m is 1 to 8₂)_m-R⁵；

R⁵Is phenyl, phenyl (by CN, CF)₃、CH₂CF₃、C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl substitution), 2-phenylthio, 3-phenylthio, -NR⁶CONR⁶R⁷or-CONR⁶R⁷；

R⁶And R⁷Each independently is hydrogen, C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl or C₂-C₈An alkynyl group; and

with the proviso that when R¹Is 2-CN or 4-CN, R²Is H, R³Is n-Pr and n is 1 or 3, then the 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).

Also disclosed is the use of a cabergoline compound for the preparation of a medicament for the treatment of fibromyalgia syndrome and chronic fatigue syndrome, wherein the preferred compound is cabergoline.

Detailed description of the invention

The present invention relates to the treatment of Fibromyalgia (FMS) and Chronic Fatigue Syndrome (CFS), and in particular to the use of three broad classes of compounds having dopamine receptor activity for the treatment of FMS and CFS disorders. The effective compounds are described in two ways, a general description being given of the groups of compounds that are fully feasible and disclosed, and a detailed description being given of the structures and nomenclature of the compounds, respectively.

One class of compounds of the invention useful for the treatment of CFS and FMS are those compounds disclosed generally or specifically in US patent nos. 5273975 and US5436240, or pharmaceutically acceptable salts thereof. These compounds are generally referred to as heterocyclic amine compounds and their structures are represented by formula (a),

formula (A)

Wherein the content of the first and second substances,

R₁、R₂and R₃Each independently is hydrogen, C_1-6Alkyl radical, C_3-5Alkenyl radical, C_3-5Alkynyl, C_3-7Cycloalkyl radical, C_4-10Cycloalkyl or C substituted by phenyl_1-6Alkyl, or R₁And R₂Together form a C which may contain further hetero atoms and/or unsaturated bonds_3-7A cyclic amine;

x is hydrogen, C_1-6An alkyl group, a halogen atom, a hydroxyl group, an alkoxy group, a cyano group, an amide group, a carboxyl group or an alkoxycarbonyl group;

a is CH, CH₂CH-halo, CHCH₃、C＝O、C＝S、C-SCH₃、C＝NH、C-NH₂、C-NHCH₃、C-NHCOOCH₃、C-NHCN、SO₂Or N;

b is CH₂CH, CH-halo, C-O, N, NH or N-CH₃Or O;

n is 0 or 1, and

d is CH, CH₂CH-halo, C-O, O, N, NH or N-CH₃。

The preparation and pharmaceutical formulations of said compounds are described in US patent nos. 5273975 and 5436240 and in international patent application WO 00/40226. The disclosures of the above-mentioned US patents 5273975 and US5436240 and of the International patent application WO00/40226 are incorporated herein in their entirety by reference.

Particularly preferred compounds of formula (A) in the context of the invention are compounds of formula (Aa),

formula (Aa)

Or a pharmaceutically acceptable salt thereof. The compound designated as compound of formula (Aa) is (R) -5, 6-dihydro-5- (methylamino) -4H-imidazo [4, 5, 1-ij ] -quinolin-2 (1H) -one (unconverted CAS designation) or (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] -quinolin-2 (1H) -one (produced by ACD/naming software).

Preferred is (R) -5, 6-dihydro-5- (methylamino) -4H-imidazo [4, 5, 1-ij]-quinolin-2 (1H) -one in the form of a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts include salts of inorganic and organic acids; examples include, but are not limited to, the salts of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, citric acid, methanesulfonic acid, CH wherein n1 is 0 to 4₃-(CH₂)_n1-COOH, HOOC- (CH) wherein n1 is as described above₂)_n1-COOH, HOOC-CH ═ CH-COOH, and Φ -COOH. Other acceptable salts are described in the journal of International pharmaceuticals (int. J. pharm.), 33, 201-217 (1986). A particularly preferred (R) -5, 6-dihydro-5- (methylamino) -4H-imidazo [4, 5, 1-ij]-quinolin-2 (1H) -one is the maleate salt. I.e. (Z) -2-butenedioic acid salt, which is (R) -5, 6-dihydro-5- (methylamino) -4H-imidazo [4, 5, 1-ij]-quinolin-2 (1H) -one (Z) -2-butenedioic acid salt (1: 1). The (Z) -2-butenedioic acid salt is represented by the following formula (Ab).

Formula (Ab)

Another group of heterocyclic amine compounds of the general formula shown above are selected heterocyclic amine compounds, most preferred are (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] -quinoline-2 (1H) -thione, a compound of the formula (Ac) herein also referred to as compound of formula (VIII),

of the formula (Ac) or (VIII)

Or a pharmaceutically acceptable salt thereof.

U.S. Pat. No. 5,5273975 discloses and claims protection of (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] -quinoline-2 (1H) -thione in general, but no examples are given or specific mention of this compound is made. (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] -quinoline-2 (1H) -thione (VIII) is preferably prepared from the corresponding sulfur-free analog (5R) (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] -quinolin-2 (1H) -one (VII). The preferred method for preparing (5R) (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] -quinolin- (2H) -one (VII) is described in formulation 1 and examples 1-6 and in FIG. A. A preferred method for converting (5R) (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] -quinolin- (2H) -one (VII) to (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] -quinoline-2 (1H) -thione (VIII) is described in example 8.

Preferred is (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij]-quinoline-2 (1H) -thione (IX) in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include salts of inorganic and organic acids; preferred pharmaceutically acceptable salts include the salts of the following acids: hydrochloric acid, bromine hydrideAcids, sulphuric acid, phosphoric acid, nitric acid, citric acid, methanesulfonic acid, CH wherein n1 is 0 to 4₃-(CH₂)_n1-COOH, HOOC- (CH) wherein n1 is as described above₂)_n1-COOH, HOOC-CH ═ CH-COOH, and Φ -COOH. Other acceptable salts are described in the journal of International pharmaceuticals (int. J. pharm.), 33, 201-217 (1986). More preferred is (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij]-quinoline-2 (1H) -thione in the form of the maleate salt, which is (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij]-quinoline-2 (1H) -thione maleate. The maleate is represented by formula (Ad) or formula (IX).

Of the formula (Ad) or (IX)

Conventional pharmaceutical preparations can be used for heterocyclic amines, for example, consisting essentially of an inert carrier and an effective dose of the active substance. Suitable dosage forms include, but are not limited to, conventional or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal patches and the like. The preferred dosage form is a tablet.

An orally effective dosage of a heterocyclic amine compound ranges from about 0.30 to about 50.0 mg/dose/human. Patients with minor FMS and CFS disorders are expected to require less medication, while patients with greater disorders are expected to require more medication. In prescribing biologically active drugs for use in the management of the central nervous system, locomotor and related psychological and physiological disorders described herein, an experienced physician should readily determine the dosage for a particular patient. Typically the medicament is administered once or twice daily; for some patients, the number of times may also be less.

Another class of compounds useful in the present invention are those described in US patent nos. 5594024 and 5462947, both of which are incorporated herein by reference, or pharmaceutically acceptable salts thereof. These compounds are generally referred to as substituted benzazepine hydrocarbon compounds and have a structure represented by formula (B),

formula (B)

Wherein

n is 0 to 3;

R¹and R²Each independently of the other is H (provided that only one is H at a time), -OH (provided that R is⁴Not hydrogen), CN, CH₂CN, 2-or 4-CF₃、CH₂CF₃、CH₂CHF₂、CH＝CF₂、(CH₂)₂CF₃Ethylenealkenyl, 2-propylenenyl, OSO₂CH₃、OSO₂CF₃、SSO₂CF₃、COR⁴、COOR⁴、CON(R⁴)₂、SO_xCH₃(wherein x is 0-2), SO_xCF₃、O(CH₂)_xCF₃、SO₂N(R⁴)₂、CH＝NOR⁴、COCOOR⁴、COCOON(R⁴)₂、C_1-8Alkyl radical, C_3-8Cycloalkyl radical, CH₂OR⁴、CH₂(R⁴)₂、NR⁴SO₂CF₃、NO₂A halogen atom, a phenyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, N-pyrrolinyl, triazolyl, tetrazolyl or pyridyl group in the 2, 3 or 4 position;

R³is hydrogen, CF₃、CH₂CF₃、C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutylRadical, - (CH)₂)_m-R⁵(wherein m is 1-8), CH₂SCH₃Or C bonded to the nitrogen atom and to one of the adjacent carbon atoms to form a cyclic structure₄-C₈Alkyl (including the carbon and nitrogen atoms);

R⁴independently of each other is hydrogen, CF₃、CH₂CF₃、C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutylfluorobutyl, - (CH)₂)_m-R⁵Wherein m is 1 to 8;

R⁵is phenyl, phenyl (by CN, CF)₃、CH₂CF₃、C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl substitution), 2-phenylthio, 3-phenylthio, -NR⁶CONR⁶R⁷or-CONR⁶R⁷；

R⁶And R⁷Each independently is hydrogen, C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl or C₂-C₈An alkynyl group;

with the proviso that when R¹Is 2-CN or 4-CN, R²Is H, R³Is n-Pr and n is 1 or 3, then the compound is a pure enantiomer.

Also useful herein are pharmaceutically acceptable salts of compounds of formula (B), which salts are described in U.S. Pat. Nos. 5,54629 and 5594024, both of which are incorporated herein by reference. Both inorganic and organic acids can be used to prepare pharmaceutically acceptable salts; exemplary acids include sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, citric acid, acetic acid, lactic acid, ethanedisulfonic acid, sulfamic acid, succinic acid, cyclohexylsulfamic acid, fumaric acid, maleic acid, and benzoic acid. These salts may be prepared by methods known in the art.

A particularly suitable compound of formula (B) according to the invention is (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine hydrochloride (no CAS nomenclature converted) or OSU6162 or (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine hydrochloride (produced by ACD/nomenclature software) and represented by the following formula (Ba).

Formula (Ba)

Another particularly suitable compound of formula (B) according to the invention is (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidinehydrobromide (non-unconverted CAS nomenclature) or (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidinehydrobromide (produced by ACD/nomenclature software) and is represented by the following formula (Bb).

Formula (Bb)

Another particularly suitable compound of formula (B) according to the invention is (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine (2E) -2-butenedioic acid (1: 1) (no CAS nomenclature converted) or (S) -OSU6162 and is represented by the following formula (Bc).

Formula (Bc)

The preparation and formulation of these compounds and medicaments are described in US patents 5594024 and US5462947, both of which are incorporated herein by reference.

Conventional pharmaceutical preparations may be employed for substituted phenylazacycloalkane compounds, for example, consisting essentially of an inert pharmaceutical carrier and an effective amount of the active substance; for example, conventional or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal patches and the like. The preferred dosage form is a tablet.

Orally effective dosages of substituted phenylazacycloalkane compounds range from about 10 to about 1000 mg/dose per human, once or twice daily. In prescribing biologically active drugs for use in the control of the central nervous system, locomotion, and associated psychological and physiological conditions described herein, an experienced physician should readily determine the dosage and frequency of administration for a particular patient. Typically the medicament is administered once or twice daily; for some patients, the number of times may also be less.

Another class of compounds useful in the present invention are those compounds, or pharmaceutically acceptable salts thereof, which are described generally or specifically in US patent US4526892, the entire disclosure of which is incorporated herein by reference. These compounds are generally referred to as cabergoline compounds. The preferred compound of this class of compounds is cabergoline itself, or a pharmaceutically acceptable salt thereof. The chemical name of cabergoline is 1- ((6-allylergoline-8 β -yl) -carbonyl) -1- (3- (dimethylamino) propyl) -3-ethylurea, and the structure of cabergoline is shown by formula (C).

Formula (C)

Cabergoline is a generic term for the active ingredient in dosteix  or CABASER  tablets and is marketed by Pharmacia & Upjohn in the united states, europe and latin america for the treatment of hyperprolactinemia and parkinson's disease. Methods of synthesis and use of cabergoline are disclosed and claimed in US patent US4526892, which is incorporated herein by reference.

Conventional pharmaceutical formulations may be employed for cabergoline, e.g. consisting essentially of an inert carrier and an effective dose of the active substance; for example, plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories and the like. The preferred dosage form is a tablet.

Pharmacia & Upjohn company provides package inserts describing CABASER , its pharmacokinetics, clinical studies, indications and uses, contraindications and warnings, and Parkinson's disease patients. The package insert and its description are incorporated herein by reference.

An orally effective dose of cabergoline ranges from about 0.01 to about 10.0 mg/dose/human, preferably from about 0.25 to about 10.0 mg/dose/human, more preferably from about 1 to about 6 mg/dose/human, even more preferably from about 1 to about 2 mg/dose/human. Within the above dosage ranges, cabergoline is generally administered once or twice daily; however, for some patients, the number of administrations may be reduced to three times a week, twice a week or once a week. The dosage size and number of administrations can be readily adjusted by the treating physician for a particular patient.

The therapeutic efficacy and side effects associated with the dose of cabergoline appear to be primarily related to individual sensitivity. In some cases an optimal dose may be obtained for an appropriate patient, for example, by initially administering a low dose of cabergoline to the patient at a dose of 0.5 to 1 mg/patient/day and then titrating the dose up to 2, 4, 8 or 10 mg/patient/day over a week. Less ill patients are expected to require less drug. For example, in some cases, a dose of 0.05, 0.1, or even 0.25 mg/person may be appropriate. Patients with a more severe condition and patients who have received dopaminergic treatment are expected to require larger doses. The precise dosage can be readily determined by the treating physician, taking into account such factors as the progress of the condition, the weight and age of the patient, whether and to what extent other drugs, such as L-dopa or levodopa, are administered, and other factors that the physician typically considers before determining the dosage for administering CNS drugs to the patient.

Definitions and conventions

The following definitions and explanations are for terms used throughout this specification and claims, including those used in the specification and claims.

Definition of

All temperatures are degrees celsius.

TLC refers to thin layer chromatography.

HPLC refers to high performance liquid chromatography.

The physiological saline refers to a saturated aqueous sodium chloride solution.

Chromatography (column chromatography and flash chromatography) refers to the purification/separation of compounds in the form of (carrier, eluent). It will be understood that the appropriate fractions are collected and concentrated to give the desired compound.

IR refers to infrared spectroscopy.

CMR refers to the C-13 magnetic resonance spectrum with chemical shifts expressed in ppm (δ) low magnetic field offset by TMS.

NMR refers to nuclear (proton) magnetic resonance spectroscopy with chemical shifts expressed as ppm (δ) downfield of tetramethylsilane.

Phi is phenyl (C)₆H₅)。

[α]_D ²⁵The rotation angle (specific rotation) of plane-polarized light measured at 25 ℃ with sodium D ray (589A) is referred to.

MS refers to mass spectrometry in m/e, m/z, or mass/charge units. [ M + H ]⁺]Refers to the positive parent ion plus one hydrogen atom. EI refers to electron collisions. CI isRefers to chemical ionization. FAB refers to fast atom bombardment.

Pharmaceutically (pharmaceutically acceptable) refers to those properties and/or substances that are acceptable to a patient from a pharmaceutical/toxicological point of view and to a pharmaceutical chemist from a physical/chemical point of view relating to composition, formulation, stability, patient acceptance and bioavailability.

If a solvent couple is used, the proportion of solvent used is expressed as volume/volume (v/v). The ratio of solids to solvent is weight/volume (wt/v) if it relates to the solubility of the solid in the solvent.

Detailed Description

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following examples describe in detail how to prepare the various compounds and/or carry out the various processes of the invention and are intended to be illustrative only and not limiting in any way of what is disclosed above in any way. One skilled in the art can readily identify the reactants in the process and the appropriate differences in reaction conditions and techniques.

Preparation 1

(R) -naproxen chloride

(R) -naproxen (Can.J.chem., 72(1), 142-5(1994), 260g), methyl chloride (3.33kg) and DMF (8.2ml) were added to the reactor. Oxalyl chloride (191.8g) was slowly added to the mixture. After addition of oxalyl chloride, the slurry was stirred at 5 to 10 ℃ and then slowly heated to 20-25 ℃. The resulting mixture was concentrated to remove the chlorinated methane, and branched octane was added to the concentrate before concentrating the mixture again. More branched octane was added to the concentrate and the mixture was cooled to 0 ℃ and then crystallized by stirring. The crystal slurry was filtered, and the crystal cake was washed with octane and dried at 20-25 ℃ to obtain the title compound.

The first filtrate was concentrated, branched octane was added, the mixture was cooled and stirred to give the title compound of batch 2. The slurry was filtered and the crystalline cake was washed with branched octane and dried at 20-25 ℃.

Example 1

1-benzyl-4H-imidazo [4, 5, 1-ij ] quinolin-2 (1H) -one (II)

4H-imidazo [4, 5, 1-ij)]Quinoline-2 (1H) -one (I, J.Heterocyclic Chem., 19, 837-49 (1982)) 1.0g, 5.8mmol of a mixture with DMF (10ml) was cooled to 0 ℃ and then treated with a mixture of potassium tert-butoxide and THF (1.98M, 3.2ml, 6.3mmol) while the reaction temperature was kept at 0 ℃. The resulting mixture was stirred at 0 ℃ for 10 minutes. Benzyl bromide (0.73ml, 6.1mmol) was then added while maintaining the reaction temperature, extracted from water with methyl tert-butyl ether (MTBE), and then washed several times with water. The MTBE phase was concentrated under reduced pressure. The concentrate was cooled to 0 ℃, filtered and rinsed twice with 0 ℃ MTBE. The product was dried at 50 ℃ and reduced pressure while blowing nitrogen gas to obtain the title compound, CMR (CDCl)₃100MHz)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 42.37 δ.

Example 2

Mixing (5R, 6R) -1-benzyl-5-bromo-6-hydroxy-5, 6-dihydro-4H-imidazo [4, 5, 1-ij)]Quinolin-2 (1H) -one (III) 1-benzyl-4H-imidazo [4, 5, 1-ij]Quinolin-2 (1H) -one (II, example 1, 240g), acetonitrile (1.086kg), water (227ml) and fluoroboric acid (48.5%, 13.4g) were mixed and cooled to 0 to 5 ℃. DibromoAntin (163.5g) was homogenized with acetonitrile and added to the reaction mixture. The reaction is carried out at 0 to 5 ℃ for about 3 hours. After the reaction is completed, the temperature in the reaction kettle is lower than 10 DEG CUnder these conditions, methyl t-butyl ether was added over a period of about 45 minutes. The slurry was cooled to 10 to 15 ℃, stirred for 1 hour, and then filtered. The product was flushed with pre-cooled methyl tert-butyl ether and dried with nitrogen at 40 ℃ to give the title compound CMR (CDCl)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 delta.

Example 3

(5S, 6S) -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) propionate (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) propionate (IVB) preparation of (5R, 6R) -1-benzyl-5-bromo-6-hydroxy-5, 6 dihydro-imidazo [4, 5, 1-ij)]Quinolin-2 (1H) -one (III, example 2, 143g), dichloromethane (3.136g), N-methylmorpholine (100.2g) and 4-dimethylaminopyridine (497g) were added to the reactor and the mixture was cooled to 0 to 5 ℃. (R) naproxen chloride (formulation 1, 118.5g) dissolved in methylene chloride (694ml) was added to the reactor over a period of about 1 hour and the mixture was stirred at 0 to 5 ℃ to complete the reaction. If necessary, naproxen chloride was added to complete the reaction. Potassium carbonate diluted with water was added to the mixture. The aqueous phase was extracted with dichloromethane and the combined dichloromethane phases were washed with water. The washed mixture was concentrated by vacuum distillation and solvent exchanged with ethyl acetate. The concentrate was cooled to-10 ℃ and stirred. The crystal slurry was filtered and the resulting crystal cake was washed with precooled methyl tert-butyl ether, and then dried at 50 ℃ to give the title compound, (5S, 6S) -1-benzyl-5-bromo-2-oxo-1, 2, 5, 6-tetrahydro-4H-imidazo [4, 5, 1-ij) as a solid]Quinolin-6-yl (2R) - (6-methoxy-2-naphthyl) propionate (IVA), CMR (CDCl)₃)δ173.2，157.8，153.4，136.1，134.6，133.7，129.2，128.8，127.8，127.8，127.6，127.2，125.9，125.9，125.6，121.5，121.4，119.1，113.2，109.0，105，105.6，69.2, 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) - (6-methoxy-2-naphthyl) propionate (IVB) is present in the filtrate and can be recovered by methods 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(CDCl₃) 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-imidazo [4, 5, 1-ij]Quinolin-2 (1H) -one (V) preparation of (5S, 6S) -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) propionate (IVA, example 3, 110g) was homogenized in acetonitrile (1,297 g). After addition of aqueous methylamine (40 wt%, 327g), the reaction was carried out at 30 ℃ for about 12 hours. After the reaction was complete, the mixture was concentrated and ethyl acetate was added. Dilute hydrochloric acid was added to prepare a water-soluble salt of the standard compound. The by-product (R-naproxen formamide impurity) remained in the ethyl acetate phase as it was insoluble in water. Further extraction and washing was performed in order to better separate the (naproxen acetamide) impurities and to minimize the loss of the desired product. Sodium hydroxide solution was then added to the aqueous phase to convert the hydrochloride salt of the title compound to the free base. The free base is less soluble in water and is thus extracted into ethyl acetate. The product mixture was concentrated and the solvent was changed to ethyl acetate to remove water. Crystallization was performed by adding branched octane and cooling the mixture. Filtering, washing and drying the obtained slurry at 50 ℃ to obtain theThe title compound of (1), CMR (CDCl)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, 8 a-Tetrahydroazepino (azireno) [2, 3-c ]]Imidazo [4, 5, 1-ij)]Quinolin-5 (4H) -one (VI) to avoid the reaction of butyllithium with water, p- (5R, 6R) -1-benzyl-5-hydroxy-6 (methylamino) -5, 6 dihydro-imidazo [4, 5, 1-ij) is distilled]Quinolin-2 (1H) -one (V, example 4, 70g) and THF (1,389g) were concentrated to remove water. The mixture was cooled to about-10 ℃ and butyllithium was added to produce the lithium salt of the starting material while forming (n) butane byproduct in an exothermic reaction. Benzenesulfonyl chloride was added slowly to produce the benzenesulfonate in an exothermic reaction. The reaction mixture is heated to 20-25 ℃ to complete the reaction. An aqueous potassium carbonate solution was added to remove benzenesulfonic acid and the mixture was stirred to crystallize. Water was added to complete the crystallization, the slurry was stirred, cooled and filtered. The crystalline cake was washed with water, followed by branched octane and dried at 40 to 50 ℃ to give the title compound, CMR (CDCl)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-imidazo [4, 5, 1-ij ] quinolin-2 (1H) -one (VII)

A mixture of (7aS, 8aR) -4-benzyl-8-methyl-7, 7a, 8, 8 a-tetraazacyclopropeno [2, 3-c ] -imidazo [4, 5, 1-ij ] quinolin-5 (4H) -one (VI, example 5, 40g), n-pentanol (42.4g) and anhydrous ammonia (1,200g) is treated with lithium at-33 ℃. After the addition of lithium was complete, the reaction mixture turned from a yellow slurry to a dark blue mixture. The dark blue mixture was stirred for 30-60 minutes and then cooled by addition of water. The cooling water is removed from the condenser and the ammonia is evaporated. The residue was dissolved in methanol. The mixture was then concentrated to dryness to give the title compound, which was used directly in the next step without isolation.

Example 7

(5R) -5- (methylamino) -5, 6 dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione (VIII)

Dissolving (5R) - (methylamino) -5, 6 dihydro-imidazo [4, 5, 1-ij) in pyridine (300mL)]A mixture of quinolin-2 (1H) -one (VII, example 6, 15.0g, 73.8mmol) and tetraphosphorus decasulfide (36.1g, 81.2mmol) was heated under nitrogen in an oil bath at 125 ℃. The reaction was stirred for 5 hours. The mixture was cooled to 20-25 ℃ and pyridine was removed under reduced pressure. Sodium hydroxide (2.2N, 200ml) was added to ensure a vigorous reaction. Additional sodium hydroxide (1N) was added until a solution was formed. The solution was saturated with sodium chloride and extracted with dichloromethane (2.5L in portions). The organic phase is adsorbed on silica (40g) and purified by column chromatography (silica, 225 g; methanol/dichloromethane, 3.5-5.0/96.5-95). The appropriate fractions were combined and concentrated. The material was recrystallized from methanol/ethyl acetate/hexane to give the title compound, mp ═ 210-; IR (offset) 2940, 2907, 2884, 1483, 1458, 1391, 1366, 1354, 1254, 1239, 1229, 895, 762, 734 and 630cm^-1；NMR(300MHz，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/z219 (M)⁺) 190, 189, 187, 186, 164, 163, 155, 145; HRMS (FAB) calculation C₁₁H₁₃N₃S(MH⁺) 220.0908, found 220.0904.

Example 8

(5R) -5- (methylamino) -5, 6 dihydro-imidazo [4, 5, 1-ij ] quinolin-2 (1H) -thione ester (thionealeate) (IX)

A solution of maleic acid (0.317g, 2.36mmol) in a trace of methanol (. about.1 mL) was added to (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij)]Quinoline-2 (1H) -thione (VIII, example 7, 0.493g, 2.25mmol) in a mixture with dichloromethane. Collecting the resulting solid material by filtration to obtain the title compound; mp is 195-196 ℃; [ alpha ] to]²⁵D ═ 60 ℃ (c0.93, methanol); IR (offset) 3140, 3112, 3060, 2969, 1627, 1619, 1568, 1481, 1455, 1398, 1389, 1361, 1220, 868 and 747cm^-1；NMR(300MHz，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 (100MHz, DMSO-d)₆+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)⁺).

Flow chart A

Flow chart A-sequence

Flow chart A-sequence

Claims (13)

1. Use of heterocyclic amine compounds for the preparation of a medicament for the treatment of fibromyalgia syndrome and chronic fatigue syndrome.

2. The use according to claim 1, wherein the heterocyclic amine compound is a compound of formula (A) below or a pharmaceutically acceptable salt thereof,

formula (A)

Wherein:

R₁、R₂and R₃Each independently is hydrogen, C_1-6Alkyl radical, C_3-5Alkenyl radical, C_3-5Alkynyl, C_3-7Cycloalkyl radical, C_4-10Cycloalkyl or C substituted by phenyl_1-6Alkyl, or R₁And R₂Together forming C which may contain further hetero atoms and/or unsaturated bonds_3-7A cyclic amine;

x is hydrogen, C_1-6An alkyl group, a halogen atom, a hydroxyl group, an alkoxy group, a cyano group, an amide group, a carboxyl group or an alkoxycarbonyl group;

a is CH, CH₂CH-halo, CHCH₃、C＝O、C＝S、C-SCH₃、C＝NH、C-NH₂、C-NHCH₃、C-NHCOOCH₃、C-NHCN、SO₂Or N;

b is CH₂CH, CH-halo, C-O, N, NH or N-CH₃Or O;

n is 0 or 1, and

d is CH, CH₂CH-halo, C-O, O, N, NH or N-CH₃。

3. The use of a compound as claimed in claim 2, wherein in said formula (a), D is N or NH and N is 0.

4. The use of a compound according to claim 2, wherein in said formula (a), a is CH, CH₂、CHCH₃、C＝O、C＝S、C-SCH₃、C＝NH、C-NH₂、C-NHCH₃、C-NHCOOCH₃Or C-NHCN.

5. The use of a compound as claimed in claim 2, wherein in said formula (a), a is CH or C ═ O.

6. Use of a compound according to claim 2, wherein said compound of formula (a) is a compound of formula (Aa):

formula (Aa).

7. Use of a compound according to claim 2, wherein the compound of formula (a) is (R) -5, 6-dihydro-5- (methylamino) -4H-imidazo [4, 5, 1-ij ] -quinolin-2 (1H) -one (unconverted CAS nomenclature) or (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] -quinolin-2 (1H) -one (generated by ACD/nomenclature software).

8. Use of a compound according to claim 2, wherein the compound of formula (a) is a compound of formula (Ab):

formula (Ab).

9. The use of a compound according to claim 2, wherein the compound of formula (a) is (R) -5, 6-dihydro-5- (methylamino) -4H-imidazo [4, 5, 1-ij ] -quinolin-2 (1H) -one 9(Z) -2-butenedioate (1: 1).

10. Use of a compound according to claim 2, wherein the compound of formula (a) is a compound of formula (Ac) or formula (VIII):

formula (Ac) or (VIII).

11. Use of a compound according to 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. Use of a compound according to claim 2, wherein said compound of formula (a) is a compound of formula (Ad) or formula (IX):

formula (Ad) or (IX).

13. Use of a compound according to 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.