Use of 1-phenyl-3-dimethylaminopropane Compounds for Treating Rheumatoid Pain

Abstract

The use of 1-phenyl-3-dimethylaminopropane compounds for the treatment of rheumatoid pain, especially rheumatoid arthritic pain, very especially preferably chronic rheumatoid arthritic pain.

Claims

1. A method of treating rheumatoid pain in a subject in need thereof, said method comprising administering to said subject an effective rheumatoid pain relieving amount of a 1-phenyl-3-dimethylamino-propane compound corresponding to formula I: ##STR00003## wherein X is OH, F, CI, OC(O)CH.sub.3 or H; R.sup.1 is a saturated and unsubstituted, branched or unbranched C.sub.1-4-alkyl group; R.sup.2 and R.sup.3 are each independently selected from the group consisting of H and saturated and unsubstituted, branched or unbranched C.sub.1-4-alkyl; or R.sup.2 and R.sup.3 together form a saturated or unsaturated, unsubstituted or mono- or polysubstituted C.sub.5-6-cycloalkyl group; at least three of R.sup.9 to R.sup.13 denote H, and the remainder of R.sup.9 to R.sup.13 are each independently selected from the group consisting of H, CI, F, OH, CF.sub.2H, CF.sub.3, saturated and unsubstituted, branched or unbranched OR.sup.14 and SR.sup.14, wherein R.sup.14 denotes a saturated and unsubstituted, branched or unbranched C.sub.1-3-alkyl group; or R.sup.11 and R.sup.12 together form a 3,4-OCH═CH ring; or a physiologically compatible salt thereof.

2. A method as claimed in claim 1, wherein: X is OH, F, OC(O)CH.sub.3 or H; R.sup.1 is CH.sub.3, C.sub.2H.sub.5, C.sub.4H.sub.9 or t-butyl; R.sup.2 and R.sup.3 are each independently selected from the group consisting of H, CH.sub.3, C.sub.2H.sub.5, i-propyl and t-butyl; or R.sup.2 and R.sup.3 together form a saturated and unsubstituted C.sub.5-6-cycloalkyl group; and at least four of R.sup.9 to R.sup.13 denote H, and the remainder of R.sup.9 to R.sup.13 are each independently selected from the group consisting of H, CI, F, OH, CF.sub.2H, CF.sub.3, OCH.sub.3 and SCH.sub.3.

3. A method as claimed in claim 2, wherein: R.sup.1 is CH.sub.3 or C.sub.2H.sub.5, R.sup.2 and R.sup.3 are each independently selected from the group consisting of H and CH.sub.3; or R.sup.2 and R.sup.3 together form a cyclohexyl group;

4. A method as claimed in claim 1, wherein R.sup.3 is H.

5. A method as claimed in claim 1, wherein: R.sup.9, R.sup.11, R.sup.13 and one of R.sup.10 and R.sup.12 each denote H, and the other of R.sup.10 and R.sup.12 is selected from the group consisting of CI, F, OH, CF.sub.2H, CF.sub.3, OR.sup.14 and SR.sup.14; or R.sup.9, R.sup.13 and one of R.sup.10 and R.sup.12 each denote H; and R.sup.11 and the other of R.sup.10 and R.sup.12 are each independently selected from the group consisting of OH, OCH.sub.3, CI and F; or R.sup.9, R.sup.10,R.sup.12 and R.sup.13 each denote H, and R.sup.11 is CF.sub.3, CF.sub.2H, CI or F; or R.sup.10, R.sup.11, R.sup.12 and one of R.sup.9 and R.sup.13 each denote H, and the other of R.sup.9 and R.sup.13 is OH, OC.sub.2H.sub.5 or OC.sub.3H.sub.7.

6. A method as claimed in claim 5, wherein: R.sup.9, R.sup.11, R.sup.13 and one of R.sup.10 and R.sup.12 each denote H, and the other of R.sup.10 and R.sup.12 is selected from the group consisting of OH, CF.sub.2H, OCH.sub.3 and SCH.sub.3; or R.sup.9, R.sup.13 and one of R.sup.10 and R.sup.12 each denote H; and R.sup.11 and the other of R.sup.10 and R.sup.12 each denote CI; or R.sup.9, R.sup.10,R.sup.12 and R.sub.13 each denote H, and R.sup.11 is F.

7. A method as claimed in claim 1, wherein the compound of formula I is in the form of an isolated stereoisomer.

8. A method as claimed in claim 7, wherein R.sup.3 denotes H, and the compound of Formula I is present in the form of an isolated diastereomer having the relative configuration Ia ##STR00004##

9. A method as claimed in claim 1, wherein the compound of formula I is in the form of a mixture of stereoisomers in any mixing ratio.

10. A method as claimed in claim 9, wherein the mixture is a racemic mixture.

11. A method as claimed in claim 9, wherein R.sup.3 denotes H, and the compound of Formula I is present in the form of a mixture of diastereomers wherein the diastereomer having the relative configuration Ia ##STR00005## is present in a higher proportion than the other diastereomer.

12. A method as claimed in claim 1, wherein said pain is rheumatoid arthritic pain.

13. A method as claimed in claim 1, wherein said pain is chronic rheumatoid arthritic pain.

14. A method as claimed in claim 1, wherein the compound corresponding to Formula I is selected from the group consisting of: (2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2methyl-pentan-3-ol, (+)-(2R, 3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol, (2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, (−)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol, (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, (2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2methyl-pentan-3-ol, (2 RS,3RS)-3-(3-difluoromethylphenyl)-1-dimethylamino-2methyl-pentan-3-ol, (2RS, 3RS)-1-dimethylamino-2-methyl-3-(3-methylsulfanylphenyl)-pentan-3-ol, (3RS)-1-dimethylamino-3-(3-methoxyphenyl)-4,4-dimethylpentan-3-ol, (2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol, (1RS, 2RS)-3-(3-dimethylamino-1-hydroxy-1 ,2-dimethylpropyl)-phenol, (+)-(1R, 2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenol, (1R, 2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol, (−)-(1S, 2S)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenol, (1S, 2S)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol, (RS, RS)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, (−)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, (+)-(1S, 2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, (+)-(1R, 2R)-acetic acid-3-dimethylamino-1-ethyl-1-(3-methoxy-phenyl)-2-methyl propyl ester, (2RS, 3RS)-3-(4-chlorophenyl)-1-dimethylamino-2-methylpentan-3-ol, (+)-(2R, 3R)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol, (2RS, 3RS)-4-dimethylamino-2-(3-methoxyphenyl)-3methylbutan-2-ol, and (+)-(2R, 3R)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-2-ol, and physiologically compatible salts of any of the foregoing.

15. A method as claimed in claim 14, wherein said compound is a hydrochloride salt.

16. A method as claimed in claim 14, wherein the compound corresponding to Formula I is selected from the group consisting of: (RS, RS)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol, (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol, (−)-(1S, 2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol, (1S, 2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol, and physiologically compatible salts thereof.

17. A method as claimed in claim 14, wherein said compound is (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol, (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl) phenol, or a physiologically compatible salt thereof.

Description

EXAMPLE

[0085] The compound Tapentadol ((−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-iphenol) was tested and is hereinafter abbreviated as compound (or Comp.) 1

[0086] A preclinical model for rheumatoid pain is used according Wilson et al., Pain 2006

[0087] The experiments were carried out in male albino rats (Sprague Dawley) with 135-170 g body weight. All rats were used only once. Rheumatoid arthritis was induced by intra-articular injection of CFA in one knee joint of a rat hindpaw. For this purpose the rats were anaesthetised using 3% isoflurane in oxygen. The left knee was cleaned using a Cutasept® F solution. The left knee of each rat was injected with 150 μl of CFA; containing 2 mg/ml Mycobacterium tuberculosis. The right joints were untreated. Animals were assessed for changes in weight bearing five days post intraarticular injection.

[0088] Naïve rats distribute their body weight equally between their two hind legs. After induction of arthric inflammatory pain, the weight is redistributed such that less weight is placed on the affected leg. Weight bearing on each hind leg was determined using a rat incapacitance tester (Somedic Sales AB, Hörby, Sweden). Rats were placed in an angled plexiglas chamber of the incapacitance tester with their hind paws on separate sensors, and the percentage body weight distribution was calculated over a period of 30 s. Data were expressed as percentage of contralateral weight bearing, with 100% values resulting from equal weight distribution across both hind limbs.

[0089] The present study was designed to investigate the analgesic effects of Tapentadol in chronic knee joint arthritic pain in rats after intravenous (i.v.) administration. Oxycodone was tested as comparator.

RESULTS

[0090] Tapentadol significantly reduced the CFA-induced decrease in weight bearing in a dose dependent manner, with a maximal effect of 51.0±11.2% at the dose of 4.64 mg/kg (i.v.). The analgesic efficacy of Tapentadol was close to the comparators morphine (59.6% at the dose of 2.15 mg/kg) ibuprofen (54.7% efficacy at the dose of 147 mg/kg) and oxycodone (46,1% efficacy at the dose of 0,464 mg/kg)

[0091] Higher doses of the tested compounds Tapentadol, morphine, ibuprofen and oxycodone resulted in readout (weight bearing) confounding side effects and were not analyzed.

[0092] The following table shows the analgesic effect of Tapentadol, morphine, ibuprofen and oxycodone on CFA-induced chronic arthritic pain. Data are expressed as mean percentage of maximal possible effect ±S.E.M at the highest possible dose without readout confounding side effects. (n=10):

TABLE-US-00001 Analgesic efficacy Compound @ dose [mg/kg] Tapentadol (iv) 51.0% @ 4.64 mg/kg Morphine (iv) 59.6% @ 2.15 mg/kg Ibuprofen (ip) 54.7% @ 147 mg/kg Oxycodone (i.v.) 46.1% @ 0.464 mg/kg iv = intravenous administration ip = intraperitoneal administration

[0093] The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.

LITERATURE

[0094] Colpaert FC. Evidence that adjuvant arthritis in the rat is associated with chronic pain.

[0095] Pain. 1987; 28(2):201-22. Review

[0096] Pearson CM, Wood FD. Studies of arthritis and other lesions induced in rats by the injection of mycobacterial adjuvant. VII. Pathologic details of the arthritis and spondylitis. Am J Pathol 1963; 42:73-95

[0097] Hu SJ, Zhu J. Sympathetic facilitation of sustained discharges of polymodal nociceptors.

[0098] Pain. 1989; 38(1):85-90

[0099] Schaible HG, Schmidt RF. Time course of mechanosensitivity changes in articular afferents during a developing experimental arthritis. J Neurophysiol. 1988; 60(6):2180-2195

[0100] Wilson AW, Medhurst SJ, Dixon CI, Bontoft NC, Winyard LA, Brackenborough KT, De Alba J, Clarke CJ, Gunthorpe MJ, Hicks GA, Bountra C, McQueen DS, Chessell IP.

[0101] An animal model of chronic inflammatory pain: pharmacological and temporal differentiation from acute models.

[0102] Eur J Pain. 2006; 10(6):537-549