Phosphate salts of 6-dimethylaminomethyl-1-(3-methoxyphenyl)-1,3-dihydroxy-cyclohexane compounds
Novel 6-dimethylaminomethyl-1-(3-methoxyphenyl)-1,3-dihydroxy-cyclohexane compounds in the form of phosphate salts, related polymorphs of these compounds, processes for their preparation, pharmaceutical formulations including these compounds and polymorphs and related methods of treating or inhibiting certain diseases or conditions.
1 . A 6-dimethylaminomethyl-1-(3-methoxyphenyl)-1,3-dihydroxy-cyclohexane compound corresponding to formula (I)
wherein
R 1 denotes OH and
R 2 denotes OH and R 3 denotes H or
R 3 denotes OH and R 2 denotes H and
R 4 denotes CH 3
in the form of a salt of phosphoric acid.
2 . The compound of claim 1 , wherein said compound is in the form of a salt of a diphosphoric acid or an orthophosphoric acid or a combination thereof.
3 . The compound of claim 1 , wherein the phosphoric acid is orthophosphoric acid.
4 . The compound of claim 1 , wherein the compound has a configuration corresponding to formula Ia
5 . The compound of claim 1 , wherein R 1 and R 2 in each case denote OH, R 3 denotes hydrogen and R 4 denotes CH 3 .
6 . The compound of claim 5 , wherein said compound is present in the form of a racemic mixture.
7 . The compound of claim 6 , wherein said compound is (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol.
8 . The compound of claim 1 , wherein said compound is (+)-(1R,3R,6R)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol or (−)-(1S,3S,6S)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol.
9 . A process for preparing the compound of claim 1 , comprising the step of reacting a compound corresponding to formula (I) with phosphoric acid in a reaction medium.
10 . The process of claim 9 , wherein said compound corresponding to formula (I) is provided in the form of a hydrochloride or a free base.
11 . The process of claim 10 , wherein said compound corresponding to formula (I) is provided in a molar ratio of compound to phosphoric acid of from 2:1 to 1:2.
12 . The process of claim 10 , comprising:
providing said compound corresponding to formula (I) in the form of a free base,
suspending said compound at 10-40° C. in alcohol,
adding dilute phosphoric acid and
stirring the mixture at 0-10° C.
13 . The process of claim 12 , wherein said alcohol is isopropanol or ethanol.
14 . The process of claim 12 , further comprising the step of seeding the mixture with a phosphate salt of the compound corresponding to formula (I) at 0-10° C.
15 . A polymorph comprising the salt of claim 1 , wherein said salt is the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, exhibiting a powder diffractogram containing one or both of the following reflections: 30.0 and 33.7 (in each case ±0.2 2θ).
16 . The polymorph of claim 15 , said polymoroph also exhibiting one or more of the following reflections: 4.6, 13.8, 15.6, 15.9, 18.0, 18.4, 19.1, 19.6, 21.6, 24.9 and 32.0 (in each case ±0.2 2θ).
17 . A polymorph comprising the salt of claim 1 , wherein said salt is the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, exhibiting a powder diffractogram as shown in FIG. 1 , measured with Cu Kα radiation.
18 . A polymorph comprising the salt of claim 1 , wherein said salt is the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, exhibiting a Raman spectrum containing one or more of the following signals: 2912, 3020 and 3060 (in each case in cm −1 ±4 cm −1 ).
19 . The polymorph of claim 18 , also exhibiting one or more of the following signals: 2843, 2922, 2966 and 3089 (in each case in cm −1 ±4 cm −1 ).
20 . A polymorph comprising the salt of claim 1 , wherein said salt is the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, exhibiting a Raman spectrum with an excitation wavelength at least at 1064 nm.
21 . The process of claim 9 wherein said compound corresponding to formula (I) is (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol and said phosphoric acid is orthophosphoric acid and said process includes the step of isolating the resulting polymorph.
22 . The process of claim 21 , wherein (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol and orthophosphoric acid are provided in a molar ratio of 2:1 to 1:2.
23 . The process of claim 21 , wherein the reaction is carried out at a temperature of 10-40° C.
24 . The process of claim 21 , wherein said reaction medium comprises an alcohol.
25 . The process of claim 24 , wherein said reaction medium further comprises water.
26 . The process of claim 24 , wherein said alcohol is isopropanol or ethanol.
27 . The process of claim 21 , wherein the (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol and orthophosphoric acid are stirred at 0-10° C.
28 . The process of claim 21 , wherein the (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol and orthophosphoric acid are seeded with the polymorph at 0-10° C.
29 . A polymorph comprising the salt of claim 1 , wherein said salt is the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol exhibiting a powder diffractogram containing one or more of the following reflections: 17.0, 17.4 and 20.2 (in each case ±0.2 2θ).
30 . The polymorph of claim 29 , said polymorph also exhibiting one or more of the following reflections: 4.3, 14.6, 15.2, 15.6, 18.0 and 31.6 (in each case ±0.2 2θ).
31 . A polymorph comprising the salt of claim 1 , wherein said salt is the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, exhibiting a powder diffractogram as shown in FIG. 2 , measured with Cu Kα radiation.
32 . A polymorph comprising the salt of claim 1 , wherein said salt is the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, exhibiting a Raman spectrum containing one or both of the following signals: 2940 and 3070 (in each case in cm −1 ±4 cm −1 ).
33 . The polymorph of claim 32 , also exhibiting one or more of the following signals: 2839, 2926, 2964 and 3084 (in each case in cm −1 ±4 cm −1 ).
34 . A polymorph comprising the salt of claim 1 , wherein said salt is the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, exhibiting a Raman spectrum with an excitation wavelength of 1064 nm.
35 . The process of claim 21 further comprising the steps of stirring the resulting polymorph in acetonitrile or in a medium comprising acetonitrile and then isolating a resulting second polymorph.
36 . The process of claim 35 wherein said step of stirring the resulting polymorph in acetonitrile or in a medium based on acetonitrile is performed at elevated temperature.
37 . The process of claim 35 , wherein the medium contains >50 vol. % acetonitrile.
38 . The process of claim 35 , wherein the medium comprises an alcohol.
39 . The process of claim 35 , wherein the medium comprises ethanol.
40 . The process of claim 35 , wherein said step of stirring the resulting polymorph in acetonitrile or in a medium based on acetonitrile to form the resulting second polymorph is performed at elevated temperature.
41 . The process of claim 35 , further comprising the step of drying the resulting second polymorph under reduced pressure at a temperature of ≦60° C.
42 . A polymorph comprising the salt of claim 1 , wherein said salt is the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, exhibiting a powder diffractogram containing one or both of the following reflections: 10.7 and 11.4 (in each case ±0.2 2θ).
43 . The polymorph of claim 42 , also exhibiting one or more of the following reflections: 16.7 and 18.8 (in each case ±0.2 2θ).
44 . A polymorph comprising the salt of claim 1 , wherein said salt is the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, exhibiting a powder diffractogram as shown in FIG. 3 , measured with Cu Kα radiation.
45 . A polymorph comprising the salt of claim 1 , wherein said salt is the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, exhibiting a powder diffractogram containing one or more measured peaks recited in Table 3, measured with Cu Kα radiation.
46 . A process for preparing a polymorph comprising the salt of claim 1 , wherein said salt is the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, exhibiting a powder diffractogram containing one or both of the following reflections: 10.7 and 11.4 (in each case ±0.2 2θ) comprising:
suspending less than 10 mg of the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol for 2 days at 50° C. in acetonitrile,
removing supernatant solution,
slowly evaporating acetonitrile, and
drying the resulting polymorph under vacuum for 1 day at room temperature.
47 . A polymorph comprising the salt of claim 1 , wherein said salt is the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, exhibiting a powder diffractogram as shown in FIG. 4 , measured with Cu Kα radiation.
48 . The process of claim 35 further comprising the step of drying the resulting second polymorph at a temperature of >50° C.
49 . The process of claim 48 , wherein said drying step is performed under reduced pressure.
50 . The process of claim 48 , comprising drying the resulting second polymorph under vacuum for a period of ≧24 hours, at a temperature of >60° C.
51 . A pharmaceutical formulation comprising at least one salt as set forth in claim 1 and one or more physiologically acceptable auxiliary substances.
52 . The pharmaceutical formulation of claim 51 , wherein the pharmaceutical formulation comprises one or more polymorphs selected from the group consisting of:
a polymorph of the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, exhibiting a powder diffractogram containing one or both of the following reflections: 30.0 and 33.7 (in each case ±0.2 2θ);
a polymorph of the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol exhibiting a powder diffractogram containing one or more of the following reflections: 17.0, 17.4 and 20.2 (in each case ±0.2 2θ);
a polymorph of the orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, exhibiting a powder diffractogram containing one or both of the following reflections: 10.7 and 11.4 (in each case ±0.2 2θ); and
A polymorph of the orthophosphate salt orthophosphate salt of (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, exhibiting a powder diffractogram as shown in FIG. 4 , measured with Cu K′ radiation in an amount pharmaceutically effective for treating or inhibiting a condition from the group consisting of pain; migraine; depression; neurodegenerative diseases, preferably chosen from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease; Huntington's disease; cognitive diseases; anxiety states; panic attacks; epilepsy; coughing; urinary incontinence; diarrhea; pruritus; schizophrenia; cerebral ischemia; muscle spasms; spasms; food intake disorders; alcohol dependency; substance dependency; drug dependency; alcohol abuse; substance abuse; drug abuse; withdrawal symptoms with alcohol, substance or drug dependency; development of tolerance to substances; and gastro-esophageal reflux syndrome; or for diuresis; for antinatriuresis; for influencing the cardiovascular system; for increasing vigilance; for increasing libido; for modulation of motor activity or for local anesthesia.
53 . A method of treating or inhibiting a condition selected from the group consisting of pain; migraine; depression; neurodegenerative diseases, preferably chosen from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive diseases; anxiety states; panic attacks; epilepsy; coughing; urinary incontinence; diarrhea; pruritus; schizophrenia; cerebral ischaemias; muscle spasms; spasms; food intake disorders; alcohol dependency; substance dependency; drug dependency; alcohol abuse; substance abuse; drug abuse; withdrawal symptoms with alcohol, substance or drug dependency; development of tolerance to substances; and gastro-esophageal reflux syndrome; or for diuresis; for antinatriuresis; for influencing the cardiovascular system; for increasing vigilance; for increasing libido; for modulation of motor activity or for local anesthesia, said method comprising administering a pharmaceutically effective amount of a salt according to claim 1.