JP2002539248A - Treatment of osteoarthritis - Google Patents

Abstract

(57) Abstract: A compound of the formula (I) wherein R ₁ and R ₂ are independently H or methyl or a pharmaceutically acceptable salt thereof (eg, N , N -dimethyl-1-) [1- (4-Chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride, optionally in the form of its monohydrate, is used to treat osteoarthritis and gout. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method of treating osteoarthritis or gout.

According to the present invention, a therapeutically effective amount of Formula I:

[0003]

Embedded image Wherein R ₁ and R ₂ are independently H or methyl, including enantiomers and pharmaceutically acceptable salts.
A method for treating osteoarthritis is provided to a human in need thereof with a pharmaceutically acceptable diluent or carrier.

[0004] Diseases that can be suitably treated with the compounds of formula I include osteoarthritis and gout.

[0005] A preferred compound of formula I is N , N -dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine or a salt thereof, such as the hydrochloride salt. The preferred form of the hydrochloride is its monohydrate.

[0006] N , N -dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-
Methylbutylamine, N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -N -methylamine, and 1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine and The preparation of compounds of formula I, such as their salts, and their use in treating depression is described in GB Patent Specification
8602 and U.S. Pat. No. 4,522,328. N , N −
The use of compounds of formula I, such as dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine and salts thereof, in the treatment of Parkinson's disease is described in PCT publication WO 88/06444. N , N -dimethyl-1
The use of-[1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine and its salts in treating cerebral dysfunction is described in U.S. Pat. No. 4,939,175. The use of N , N -dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride in the treatment of obesity is described in US Pat.
CT publication WO90 / 06110. A particularly preferred form of this compound is the N , N -dimethyl-1- [1 described in EP 230742.
-(4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride monohydrate (Sibutramine hydrochloride). The use of N , N -dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine and salts thereof to improve glucose tolerance in humans suffering from impaired glucose tolerance or non-insulin dependent diabetes is described by P.
CT publication WO95 / 20949.

It is understood by those skilled in the art that the compounds of formula I have a chiral center. When a compound of Formula I has a single chiral center, it can exist in two enantiomeric forms. The present invention encompasses the use of individual enantiomers and mixtures of enantiomers. Enantiomers can be separated by methods known to those skilled in the art, for example, by formation of diastereoisomeric salts or complexes, which can be separated by crystallization or the like; by crystallization, gas-liquid or liquid chromatography. Via the formation of possible diastereoisomeric derivatives; by selective reaction of one enantiomer with an enantiomer-specific reagent, eg, separation of denatured and native enantiomers after enzymatic oxidation or reduction; or in a chiral environment, For example, separation can be by gas-liquid or liquid chromatography, such as on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. It is understood that if the desired enantiomer is converted to another chiral unit by one of the separation procedures described above, an additional step is required to release the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to another by asymmetric rearrangement.

Preferred compounds of formula I are N , N -dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine, N- {1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutyl} -N -methylamine, and 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine, which are racemic, individual enantiomers and mixtures thereof, and pharmaceutically acceptable And salts thereof.

[0009] Individual enantiomers can be prepared by enantioselective synthesis from optically active precursors or by separating racemates that can be prepared as described above. The enantiomers of the secondary amines of the formula I can be prepared by the method described in GB 2098602 by preparing the corresponding racemic primary amines, separating the latter into the individual enantiomers and obtaining optically pure It can also be prepared by converting the primary amine enantiomer to the required secondary amine.

A specific example of a compound of formula I is: (+)- N- [1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl { -N -methylamine; (-)- N- } 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N -methylamine; (+)-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine; (-)-1 - [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine; (+) - N - {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} - N - N - dimethylamine; ( -) - N - {1- [ 1- (4- chlorophenyl) cyclobutyl] -3-methylbutyl} - N - N - dimethyl amine.

The hydrochloride salt is preferred in each case, but the free base and other pharmaceutically acceptable salts are also suitable.

The compound of formula I can be administered in any of the known pharmaceutical dosage forms. The amount of compound to be administered will depend on a number of factors, including the age of the patient, the severity of the condition, and the patient's past medical history, and is usually at the discretion of the administering physician, but generally,
The amount of compound to be administered may range from 0.1 to 50 per day given in one or more doses.
mg, preferably in the range of 1-30 mg.

[0013] Oral dosage forms are preferred compositions for use in the present invention, which are known pharmaceutical forms for such administration, such as tablets, capsules, granules, syrups and aqueous or oily suspensions. Excipients used in preparing these compositions are those known in the art of pharmacists. Tablets are bulking agents,
For example, calcium phosphate; disintegrants, for example, corn starch;
For example, prepared from a mixture of an active compound having magnesium stearate; a binder such as microcrystalline cellulose or polyvinylpyrrolidone, and any other components known in the art, and mixing the mixture by known methods. You may make it tablet. Tablets may be coated with known methods and excipients, if desired, including enteric coating with, for example, hydroxypropylmethylcellulose phthalate. Tablets may be treated in a manner known to those skilled in the art to provide for sustained release of a compound of the present invention. If desired, such tablets may be provided with an enteric coating, by known methods, for example using cellulose acetate phthalate. Similarly, capsules containing the active compound, with or without excipients, for example hard or soft gelatin capsules, may be prepared by known methods,
If desired, enteric coatings may be applied in known manner. The contents of the capsule can be formulated using known methods to provide sustained release of the active compound. Suitably, the tablets and capsules each contain from 1 to 50 mg of the active compound.

[0014] Other dosage forms for oral administration include, for example, aqueous suspensions containing the active ingredients in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethyl cellulose, and suitable vegetable oils. For example, an oily suspension containing the compound of the present invention in peanut oil. The active compound may be formulated into granules with or without additional excipients. The granules may be taken directly by the patient or added to a suitable liquid carrier (eg, water) before ingestion. The granules may contain a disintegrant, for example, an effervescent couple formed from an acid and a carbonate or bicarbonate to facilitate diffusion in the liquid medium.

The therapeutically active compound of formula I may be formulated in a composition wherein the active compound is to remain in the patient's mouth and be administered through the oral mucosa.

[0016] Suitable dosage forms for rectal application are the known pharmaceutical forms for such applications, for example cocoa butter or polyethylene glycol-based suppositories.

Suitable dosage forms for parenteral application are the known pharmaceutical forms for such administration, for example, sterile suspensions or solutions in suitable solvents.

[0018] Dosage forms for topical administration may contain a matrix in which the pharmacologically active compound of the invention is maintained in contact with the skin and dispersed for transdermal administration. Suitable transdermal compositions comprise a pharmaceutically active compound, which may be combined with a topical vehicle such as mineral oil, petrolatum and / or a wax, for example, paraffin wax or beeswax, to enhance potential transdermal absorption such as dimethyl sulfoxide or propylene glycol. It may be prepared by mixing with an agent. Alternatively, the active compounds may be dispersed in a pharmaceutically acceptable cream, gel or ointment base. The amount of active compound contained in the topical formulation should be such that a therapeutically effective amount of the compound is delivered during the time the topical formulation is to be present on the skin.

The therapeutically active compounds of Formula I may be formulated into a composition that is diffused into the oral or nasal cavity of a patient as an aerosol. Such aerosols may be administered from a pump pack or from a pressurized pack containing a volatile propellant.

The therapeutically active compound of Formula I used in the method of the invention may be administered by continuous infusion from an extracorporeal source, for example, by intravenous infusion, or by continuous infusion from a compound source located in the body. You may. Internal sources include, for example, implanted reservoirs containing the compound to be injected, which are sustainedly released by osmosis and implantation, including (a) highly aqueous solutions such as, for example, dodecanoate or lipophilic esters. It may be a liquid, such as an oily suspension of the compound to be injected, in the form of a less soluble derivative, or (b) an implant support for the compound to be injected, for example of synthetic resin or waxy material It may be in the form of a solid. The support may be a single body containing all the compounds, or a series of individual bodies each containing a portion of the compound to be delivered. The amount of active compound present in the body source should be such that a therapeutically effective amount of the compound is delivered over time.

In some dosage forms, it may be advantageous to use the compounds of the present invention in very small sizes, such as those obtained by fluid energy milling.

In the compositions of the present invention, the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.

The present invention further provides the use of a compound of formula I in the manufacture of a medicament for treating osteoarthritis or gout.

In another embodiment, the present invention provides a pharmaceutical composition for treating osteoarthritis or gout, further comprising a pharmaceutically acceptable diluent or carrier with a compound of formula I.

Obesity is associated with osteoarthritis and gout, and the development of medial knee pain (proximal joint painful steatosis) in obese and postmenopausal middle-aged women. Potential mechanisms underlying the relationship between obesity and osteoarthritis include physical stress related to increased burden due to obesity, metabolism related to increased degree of obesity, and diet related to the development of obesity Ingredients. The increased risk of gout associated with obesity may be associated with concomitant hyperuricemia, but may also involve central fat distribution, especially in women.

Monoamine reuptake inhibitors have been used to treat certain disorders according to the present invention. However, these compounds are known to suffer from a number of disadvantages. First, these compounds are not effective in all patients.
Second, even if these compounds are effective, they may not completely cure the disorder. Third, it is known that many undesirable side effects are associated with this type of compound. These side effects include nausea, sexual dysfunction, dizziness, somnolence, sweating, tremor, xerostomia, asthenia, insomnia, diarrhea, headache, vomiting, anxiety, lethargy, dizziness, fever, rash or Allergic reactions, joint pain, muscle pain, convulsions, hypomania and mania.

Sibutramine (Formula I, R ₁ ＣＨCH ₃ , R ₂ ＣＨCH ₃ ) has a unique pharmacological profile among monoamine reuptake inhibitors. Depending on its pharmacologically active metabolites (metabolite 1, R ₁ = H, R ₂ = CH ₃ in formula I, and metabolite 2, R ₁ = H, R ₂ = H in formula I) sibutramine Serotonin (5-HT) selective reuptake inhibitor,
For example, there is a difference from fluoxetine, a selective reuptake inhibitor of noradenaline such as desipramine, a dopamine selective reuptake inhibitor such as bupropion, and a serotonin-noradenaline reuptake inhibitor such as venlafaxine (Table 1). This unique combination of pharmacological effects results in sibutramine and other compounds of formula I having the intended effect in the treatment of osteoarthritis and gout.

The following analysis is performed in a manner similar to that described in WO 98/41528.

[0029]

[Table 1] The result is the average of three or more separate measurements.

Example 1 R ₁ ＨH, R ₂ ＣＨCH _{3 in} Formula I Example 2 R ₁ ＨH, R ₂ ＨH in Formula I of a compound of Formula I in the treatment of osteoarthritis or gout Efficacy is demonstrated by clinical trials in a relevant set of populations.

The invention has been described with reference to various specific embodiments. However, many variations and modifications may be made while remaining within the scope and spirit of the invention.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), AT, AU, BG, BR, CA, CN, CZ, DE, DK, ES, FI, GB, HR, HU, ID, IL, IN, IS, JP, KR, LT, LU, LV, MX , NO, NZ, PL, PT, RO, RU, SE, SG, SI, SK, TR, UA, ZAF term (reference) 4C206 AA01 AA02 FA08 KA01 MA01 MA04 NA14 ZA96 ZC31

Claims (20)

[Claims] 1. A therapeutically effective amount of Formula I: Wherein R ₁ and R ₂ are independently H or methyl, including enantiomers and pharmaceutically acceptable salts.
A method for treating osteoarthritis or gout, comprising administering to a human in need thereof with a pharmaceutically acceptable diluent or carrier. 2. The method of claim 1, wherein osteoarthritis is treated. 3. The compound of formula I is N , N -dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride.
Or the method of 2. 4. The compound according to claim 1, wherein the compound of formula I is in the form of the monohydrate of N , N -dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride. 3. The method according to 2. 5. The method according to claim 1, wherein the compound of the formula 1 is (+) N- [1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N -methylamine. Method. 6. The compound according to claim 1, wherein the compound of the formula 1 is (-)- N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N -methylamine. the method of. 7. The method according to claim 1, wherein the compound of formula 1 is (+)-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine. 8. The method according to claim 1, wherein the compound of formula 1 is (-)-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine. Compounds according to claim 9 of formula 1, (+) - N - { 1- [1- (4- chlorophenyl) cyclobutyl] -3-methylbutyl} - N - N - dimethyl amine, according to claim 1 or 2 The method described in. Compounds according to claim 10 of formula 1, (-) - N - { 1- [1- (4- chlorophenyl) cyclobutyl] -3-methylbutyl} - N - N - dimethyl amine, according to claim 1 or 2 The method described in. Compound of claim 11 of formula 1, (±) - N - { 1- [1- (4- chlorophenyl) cyclobutyl] -3-methylbutyl} - N - methylamine, according to claim 1 or 2 the method of. 12. The method according to claim 1, wherein the compound of formula 1 is (±) -1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine. Compound of claim 13 of formula 1, (±) - N - { 1- [1- (4- chlorophenyl) cyclobutyl] -3-methylbutyl} - N - N - dimethyl amine, according to claim 1 or 2 The method described in. 14. A compound of formula I: Wherein R ₁ and R ₂ are independently H or methyl, including enantiomers and pharmaceutically acceptable salts.
Use in the manufacture of a medicament for treating osteoarthritis or gout. 15. The use according to claim 14, wherein osteoarthritis is treated. 16. The use according to claim 14, wherein the compound of formula I is N , N -dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride. 17. The compound according to claim 14, wherein the compound of formula I is N , N -dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride monohydrate. Use of. 18. A therapeutically effective amount of Formula I: Wherein R ₁ and R ₂ are independently H or methyl, including enantiomers and pharmaceutically acceptable salts.
A pharmaceutical composition for treating osteoarthritis or gout, comprising together with a pharmaceutically acceptable diluent or carrier. 19. The pharmaceutical composition according to claim 18, wherein the compound of formula I is N , N -dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride. 20. The medicament according to claim 18, wherein the compound of formula I is N , N -dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride monohydrate. Composition.