US2004242617A1PendingUtilityA1
Combination of selected opioids with muscarine antagonists for treating urinary incontinence
Est. expirySep 18, 2021(expired)· nominal 20-yr term from priority
Inventors:Thomas Christoph
A61P 7/12A61P 43/00A61K 45/06A61P 13/02A61K 31/216A61K 31/137A61K 2300/00A61P 13/10A61P 13/00A61K 31/485
52
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Claims
Abstract
Active compound combinations of compounds of group A, particularly opioids, and compounds of group B, particularly anti-muscarine agents and other substances suitable for treatment of an increased urge to urinate or urinary incontinence. Related pharmaceutical formulations and methods of treatment of an increased urge to urinate or urinary incontinence are also provided.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating or inhibiting urinary incontinence or increased urge to urinate in a mammal, said method comprising administering to said mammal an effective amount of an active compound combination comprising at least one compound selected from group (i) and at least one compound selected from group (ii),
wherein group (i) consists of:
Group a) consisting of:
tramadol, O-demethyltramadol and O-demethyl-N-mono-demethyl-tramadol,
Group b) consisting of:
codeine
dextropropxyphene
dihydrocodeine
diphenoxylate
ethylmorphine
meptazinol
nalbuphine
pethidine (meperidine)
tilidine
tramadol
viminol
butorphanol
dextromoramide
dezocine
diacetylmorphine (heroin)
hydrocodone
hydromorphone
ketobemidone
levomethadone
levomethadyl acetate (1-α-acetylmethadol (LAAM))
levorphanol
morphine
nalorphine
oxycodone
pentazocine
piritramide
alfentanil
buprenorphine
etorphine
fentanyl
remifentanil, and
sufentanil
Group c) consisting of:
1-phenyl-3-dimethylamino-propane compounds corresponding to formula I
wherein
X is chosen from OH, F, Cl, H or OC(O)R 7 , where R 7 is chosen from C 1-3 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R 1 is chosen from C 1-4 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R 2 and R 3 in each case independently of one another are chosen from H or C 1-4 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, or
R 2 and R 3 together form a saturated C 4-7 -cycloalkyl radical, unsubstituted or mono- or polysubstituted,
R 9 to R 13 in each case independently of one another are chosen from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 14 , OCF 3 , SR 14 , NR 17 R 18 , SOCH 3 , SOCF 3 ; SO 2 CH 3 , SO 2 CF 3 CN, COOR 14 , NO 2 , CONR 17 R 18 ; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;
phenyl, unsubstituted or mono- or polysubstituted;
where R 14 is chosen from C 1-6 -alkyl; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted; PO(O—C 1-4 -alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl), CO(C 1-5 -alkyl), CO—CHR 17 —NHR 18 , CO—C 6 H 4 —R 15 , where R 15 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 16 ) 2 where R 16 is C 1-4 -alkyl or 4-morpholino, wherein in the radicals R 14 , R 15 and R 16 the alkyl groups are branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;
where R 17 and R 18 in each case independently of one another are chosen from H; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted, or
R 9 and R 10 or R 10 and R 11 together form an OCH 2 O, OCH 2 CH 2 O, OCH═CH, CH═CHO, CH═C(CH3)O, OC(CH3)═CH, (CH 2 ) 4 or OCH═CHO ring,
Group d) consisting of:
substituted 6-dimethylaminomethyl-1-phenylcyclohexane compounds corresponding to formula II
wherein
X is chosen from OH, F, Cl, H or OC(O)R 7 , where R 7 is chosen from C 1-3 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R 1 is chosen from C 1-4 -alkyl, benzyl, CF 3 , OH, OCH 2 —C 6 H 5 , O—C 1-4 -alkyl, Cl or F and
R 9 to R 13 in each case independently of one another are chosen from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 14 , OCF 3 , SR 14 , NR 17 R 18 , SOCH 3 , SOCF 3 ; SO 2 CH 3 , SO 2 CF 3 , CN, COOR 14 , NO 2 , CONR 17 R 18 ; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, unsubstituted or mono- or polysubstituted;
where R 14 is chosen from C 1-6 -alkyl; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted; PO(O—C 1-4 -alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl), CO(C 1-5 -alkyl), CO—CHR 17 —NHR 18 , CO—C 6 H 4 —R 15 , where R 15 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 16 ) 2 where R 16 is C 1-4 -alkyl or 4-morpholino, wherein in the radicals R 14 , R 15 and R 16 the alkyl groups are branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;
where R 17 and R 18 in each case independently of one another are chosen from H; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted, or
R 9 and R 10 or R 10 and R 11 together form an OCH 2 O, OCH 2 CH 2 O, OCH═CH, CH═CHO, CH═C(CH3)O, OC(CH3)═CH, (CH 2 ) 4 or OCH═CHO ring,
and
Group e) consisting of:
6-dimethylaminomethyl-1-phenyl-cyclohexane compounds corresponding to formula III
wherein
X is chosen from OH, F, Cl, H or OC(O)R 7 , where R 7 is chosen from C 1-3 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, and R 9 to R 13 in each case independently of one another are chosen from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 14 , OCF 3 , SR 14 , NR 17 R 18 , SOCH 3 , SOCF 3 ; SO 2 CH 3 , SO 2 CF 3 , CN, COOR 14 , NO 2 , CONR 17 R 18 ; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, unsubstituted or mono- or polysubstituted;
where R 14 is chosen from C 1-6 -alkyl; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted; PO(O—C 1-4 -alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl), CO(C 1-5 -alkyl), CO—CHR 17 —NHR 18 , CO—C 6 H 4 —R 15 , where R 15 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 16 ) 2 where R 16 is C 1-4 -alkyl or 4-morpholino, wherein in the radicals R 14 , R 15 and R 16 the alkyl groups are branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;
where R 17 and R 18 in each case independently of one another are chosen from H; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted, or
R 9 and R 10 or R 10 and R 11 together form an OCH 2 O, OCH 2 CH 2 O, OCH═CH, CH═CHO, CH═C(CH3)O, OC(CH3)═CH, (CH 2 ) 4 or OCH═CHO ring,
with the proviso that if R 9 , R 11 and R 13 correspond to H and one of R 10 or R 12 corresponds to H and the other corresponds to OCH 3 , X may not be OH,
wherein group (ii) consists of:
an anti-muscarine agent selected from the group consisting of: atropine, oxybutinin, propiverine, propantheline, emepronium, trospium, tolterodine, darifenacin and α,α-diphenylacetic acid 4-(N-methylpiperidyl) ester, as well as duloxetine, imipramine and desmopressin,
or a salt of any of the foregoing with a physiologically tolerated acid.
2 . The method of claim 1 , wherein one or more of said at least one compound selected from group (i) and at least one compound selected from group (ii) is present in the form of a free base.
3 . The method of claim 1 , wherein one or more of said at least one compound selected from group (i) and at least one compound selected from group (ii) is present in the form of a pure enantiomer or pure diastereoisomer.
4 . The method of claim 1 , wherein one or more of said at least one compound selected from group (i) and at least one compound selected from group (ii) is present in the form of a mixture of stereoisomers.
5 . The method of claim 1 , wherein one or more of said at least one compound selected from group (i) and at least one compound selected from group (ii) is present in the form of a racemic mixture.
6 . The method of claim 1 , wherein one or more of said at least one compound selected from group (i) and at least one compound selected from group (ii) is present in the form of a solvate.
7 . The method of claim 1 , wherein one or more of said at least one compound selected from group (i) and at least one compound selected from group (ii) is present in the form of a hydrate.
8 . The method of claim 1 , wherein said at least one compound selected from group (i) is selected from the group consisting of:
tramadol, (+)-O-demethyltramadol and (+)-O-demethyl-N-mono-demethyl-tramadol.
9 . The method of claim 1 , wherein said at least one compound selected from group (i) is (+)-tramadol.
10 . The method of claim 1 , wherein said at least one compound selected from group (i) is selected from the group consisting of:
codeine dextropropxyphene dihydrocodeine diphenoxylate ethylmorphine meptazinol nalbuphine pethidine (meperidine) tilidine viminol butorphanol dezocine nalorphine pentazocine, and buprenorphine.
11 . The method of claim 1 , wherein said at least one compound selected from group (i) is selected from the group consisting of:
codeine dextropropxyphene dihydrocodeine meptazinol nalbuphine tilidine, and buprenorphine.
12 . The method of claim 1 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula I wherein:
X is chosen from
OH, F, Cl, OC(O)CH 3 or H, or
R 1 is chosen from
C 1-4 -alkyl, saturated and unsubstituted, branched or unbranched; or
R 2 and R 3 independently of one another are chosen from
H, C 1-4 -alkyl, saturated and unsubstituted, branched or unbranched; or
R 2 and R 3 together form a C 5-6 -cycloalkyl radical, saturated or unsaturated, unsubstituted or mono- or polysubstituted, or R 9 to R 13 , where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from
H, Cl, F, OH, CF 2 H, CF 3 or C 1-4 -alkyl, saturated and unsubstituted, branched or unbranched; OR 14 or SR 14 , where R 14 is chosen from C 1-3 -alkyl, saturated and unsubstituted, branched or unbranched; or
R 12 and R 11 form a 3,4-OCH═CH ring or
if R 9 , R 11 and R 13 correspond to H, one of R 10 or R 12 also corresponds to H while the other is chosen from:
Cl, F, OH, CF 2 H, CF 3 , OR 14 or SR 14 , or
if R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, one of R 10 or R 12 also corresponds to H while the other corresponds to OH, OCH 3 , Cl or F, or
if R 9 , R 10 , R 12 and R 13 correspond to H, R 11 is chosen from CF 3 , CF 2 H, Cl or F, or
if R 10 , R 11 and R 12 correspond to H, one of R 9 or R 13 also corresponds to H while the other is chosen from OH, OC 2 H 5 or OC 3 H 7 .
13 . The method of claim 1 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula I wherein:
X is chosen from OH, F, OC(O)CH 3 or H.
14 . The method of claim 1 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula I wherein:
R 1 is chosen from CH 3 , C 2 H 5 , C 4 H 9 or t-butyl.
15 . The method of claim 1 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula I wherein:
R 2 and R 3 independently of one another are chosen from H, CH 3 , C 2 H 5 , i-propyl or t-butyl.
16 . The method of claim 1 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula I wherein:
R 2 and R 3 together form a C 5-6 -cycloalkyl radical which is saturated and unsubstituted.
17 . The method of claim 1 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula I wherein:
R 2 and R 3 together form cyclohexyl.
18 . The method of claim 1 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula I wherein:
R 9 to R 13 , where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 or SCH 3 .
19 . The method of claim 12 , wherein compounds corresponding to formula I where R 3 ═H are in the form of diastereomers corresponding to formula Ia
and are provided in mixtures with a higher content of this diastereomer compared with the other diastereomer or
are provided as a pure diastereomer or
compounds corresponding to formula I are provided in the form of the (+)-enantiomer.
20 . The method of claim 12 , wherein compounds corresponding to formula I, are provided in mixtures with a higher content of the (+)-enantiomer compared with the (−)-enantiomer of a racemic compound or are provided as the pure (+)-enantiomer.
21 . The method of claim 12 , wherein said at least one compound selected from group (i) is selected from the group consisting of:
(2RS,3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol (2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol, (+)-(2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol, (2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2-methyl-pentan-3-ol, (2RS,3RS)-3-(3-difluoromethyl-phenyl)-1-dimethylamino-2-methyl-pentan-3-ol, (2RS,3RS)-1-dimethylamino-2-methyl-3-(3-methylsulfanyl-phenyl)-pentan-3-ol, (3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-4,4-dimethyl-pentan-3-ol, (2RS,3RS)-3-(3-dimethylamino-1-ethyl1-hydroxy-2-methyl-propyl)-phenol, (1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1 ,2-dimethyl-propyl)-phenol, ,(+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol, (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol, (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (+)-(1R,2R)-acetic acid 3-dimethylamino-1-ethyl1-(3-methoxy-phenyl)-2-methyl-propyl ester, (1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-1-(3-methoxy-phenyl)-propan-1-ol, (2RS,3RS)-3-(4-chlorophenyl)-1-dimethylamino-2-methyl-pentan-3-ol, (+)-(2R,3R)-3-(3-dimethylamino-1-ethyl1-hydroxy-2-methyl-propyl)-phenol, (2RS,3RS)-4-dimethylamino-2-(3-methoxy-phenyl)-3-methyl-butan-2-ol and (+)-(2R,3R)-4-dimethylamino-2-(3-methoxy-phenyl)-3-methyl-butan-2-ol, or a hydrochloride salt of any of the foregoing.
22 . The method of claim 1 , wherein one or more of said at least one compound selected from group (i) is selected from the compounds corresponding to formula II wherein:
X is chosen from
OH, F, Cl, OC(O)CH 3 or H, or
R 1 is chosen from
C 1-4 -alkyl, CF 3 , OH, O—C 1-4 -alkyl, Cl or F, or
R 9 to R 13 , where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from
H, Cl, F, OH, CF 2 H, CF 3 or C 1-4 -alkyl, saturated and unsubstituted, branched or unbranched; OR 14 or SR 14 , where R 14 is chosen from C 1-3 -alkyl, saturated and unsubstituted, branched or unbranched; or
R 12 and R 11 form a 3,4-OCH═CH ring or
if R 9 , R 11 and R 13 correspond to H, one of R 10 or R 12 also corresponds to H while the other is chosen from:
Cl, F, OH, CF 2 H, CF 3 , OR 14 or SR 14 , or
if R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, one of R 10 or R 12 also corresponds to H while the other corresponds to OH, OCH 3 , Cl or F, or
if R 9 , R 10 , R 12 and R 13 correspond to H, R 11 is chosen from CF 3 , CF 2 H, Cl or F, or
if R 10 , R 11 and R 12 correspond to H, one of R 9 or R 13 also corresponds to H while the other is chosen from OH, OC 2 H 5 or OC 3 H 7 .
23 . The method of claim 1 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula II wherein:
X is chosen from OH, F or H.
24 . The method of claim 1 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula II wherein:
R 1 is chosen from OH, CF 3 or CH 3 .
25 . The method of claim 1 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula II wherein:
R 9 to R 13 , where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 or SCH 3 , or if R 9 , R 11 and R 13 correspond to H, one of R 10 or R 12 also corresponds to H while the other is chosen from: OH, CF 2 H, OR 14 or SCH 3 .
26 . The method of claim 22 wherein the compounds corresponding to formula II are in the form of diastereomers corresponding to formula 1 a
and are provided in mixtures with a higher content of this diastereomer compared with the other diastereomer or
are provided as a pure diastereomer, or
compounds corresponding to formula II are provided in the form of the (+)-enantiomer.
27 . The method of claim 22 , wherein compounds corresponding to formula II are provided in mixtures with a higher content of the (+)-enantiomer compared with the (−)-enantiomer of a racemic compound or are provided in the form of the pure (+)-enantiomer.
28 . The method of claim 22 , wherein said at least one compound selected from group (i) is selected from the group consisting of:
(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol, (+)-(1R,3R,6R)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol, (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-hydroxy-phenyl)-cyclohexane-1,3-diol, (1RS,3SR,6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol, (+)-(1R,2R,5S)-3-(2-dimethylaminomethyl-1-hydroxy-5-methyl-cyclohexyl)-phenol, and (1RS,2RS,5RS)-3-(2-dimethylaminomethyl-1-hydroxy-5-trifluoromethyl-cyclohexyl)-phenol, or a hydrochloride salt of any of the foregoing.
29 . The method of claim 1 , wherein one or more of said at least one compound selected from group (i) is selected from the compounds corresponding to formula III wherein:
X is chosen from
OH, F, Cl, OC(O)CH 3 or H, or
R 9 to R 13 , where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from
H, Cl, F, OH, CF 2 H, CF 3 or C 1-4 -alkyl, saturated and unsubstituted, branched or unbranched; OR 14 or SR 14 , where R 14 is chosen from C 1-3 -alkyl, saturated and unsubstituted, branched or unbranched; or
R 12 and R 11 form a 3,4-OCH═CH ring or
if R 9 , R 11 and R 13 correspond to H, one of R 10 or R 12 also corresponds to H while the other is chosen from:
Cl, F, OH, SH, CF 2 H, CF 3 , OR 14 or SR 14 , or
if R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, one of R 10 or R 12 also corresponds to H while the other corresponds to OH, OCH 3 , Cl or F, or
if R 9 , R 10 , R 12 and R 13 correspond to H, R 11 is chosen from CF 3 , CF 2 H, Cl or F, or
if R 10 , R 11 and R 12 correspond to H, one of R 9 or R 13 also corresponds to H while the other is chosen from OH, OC 2 H 5 or OC 3 H 7 .
30 . The method of claim 1 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula III wherein:
X is chosen from OH, F or H.
31 . The method of claim 1 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula III wherein:
R 9 to R 13 , where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 or SCH 3 , or if R 9 , R 11 and R 13 correspond to H, one of R 10 or R 12 also corresponds to H while the other is chosen from: OH, CF 2 H, OR 14 or SCH 3 .
32 . The method of claim 29 wherein the compounds corresponding to formula III are in the form of diastereomers corresponding to formula IIIa
and are provided in mixtures with a higher content of this diastereomer compared with the other diastereomer or
are provided as a pure diastereomer, or
compounds corresponding to formula III are provided in the form of the (+)-enantiomer.
33 . The method of claim 29 , wherein compounds corresponding to formula III, are provided in mixtures with a higher content of the (+)-enantiomer compared with the (−)-enantiomer of a racemic compound or are provided in the form of the pure (+)-enantiomer.
34 . The method of claim 29 , wherein said at least one compound selected from group (i) is selected from the group consisting of:
(+)-(1R,2R)-3-(2-dimethylaminomethyl-1-fluoro-cyclohexyl)-phenol, (+)-(1S,2S)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol or (1S,2S)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol or (−)-(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol, (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol, (−)-(1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine, and (1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine, or a hydrochloride salt of any of the foregoing.
35 . The method of claim 1 , wherein said at least one compound selected from group (ii) is selected from the group consisting of:
darifenacin, duloxetine, oxybutinin and tolterodine.
36 . The method of claim 1 , wherein said at least one compound selected from group (ii) is selected from the group consisting of:
oxybutinin and tolterodine.
37 . A composition of matter comprising as an admixture at least one compound selected from group (i) and at least one compound selected from group (ii),
wherein group (i) consists of:
Group a) consisting of:
tramadol, O-demethyltramadol or O-demethyl-N-mono-demethyl-tramadol,
Group b) consisting of:
codeine
dextropropxyphene
dihydrocodeine
diphenoxylate
ethylmorphine
meptazinol
nalbuphine
pethidine (meperidine)
tilidine
tramadol
viminol
butorphanol
dextromoramide
dezocine
diacetylmorphine (heroin)
hydrocodone
hydromorphone
ketobemidone
levomethadone
levomethadyl-acetate (1-α-acetylmethadol (LAAM))
levorphanol
morphine
nalorphine
oxycodone
pentazocine
piritramide
alfentanil
buprenorphine
etorphine
fentanyl
remifentanil
sufentanil
Group c) consisting of::
1-phenyl-3-dimethylamino-propane compounds corresponding to formula I
wherein
X is chosen from OH, F, Cl, H or OC(O)R 7 , where R 7 is chosen from C 1-3 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, R 1 is chosen from C 1-4 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
R 2 and R 3 in each case independently of one another are chosen from H or C 1-4 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, or
R 2 and R 3 together form a saturated C 4-7 -cycloalkyl radical, unsubstituted or mono- or polysubstituted, R 9 to R 13 in each case independently of one another are chosen from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 14 , OCF 3 , SR 14 , NR 17 R 18 , SOCH 3 , SOCF 3 ; SO 2 CH 3 , SO 2 CF 3 , CN, COOR 14 , NO 2 , CONR 17 R 18 ; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, unsubstituted or mono- or polysubstituted;
where R 14 is chosen from C 1-6 -alkyl; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted; PO(O—C 1-4 -alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl), CO(C 1-5 -alkyl), CO—CHR 17 —NHR 18 , CO—C 6 H 4 —R 15 , where R 15 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 16 ) 2 where R 16 is C 1-4 -alkyl or 4-morpholino, wherein in the radicals R 14 , R 15 and R 16 the alkyl groups are branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;
where R 17 and R 18 in each case independently of one another are chosen from H; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted, or
R 9 and R 10 or R 10 and R 11 together form an OCH 2 O, OCH 2 CH 2 O, OCH═CH, CH═CHO, CH═C(CH3)O, OC(CH3)═CH, (CH 2 ) 4 or OCH═CHO ring,
Group d) consisting of:
substituted 6-dimethylaminomethyl-1-phenylcyclohexane compounds corresponding to formula II
wherein
X is chosen from OH, F, Cl, H or OC(O)R 7 , where R 7 is chosen from C 1-3 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, R 1 is chosen from C 1-4 -alkyl, benzyl, CF 3 , OH, OCH 2 —C 6 H 5 , O—C 1-4 -alkyl, Cl or F and
R 9 to R 13 in each case independently of one another are chosen from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 14 , OCF 3 , SR 14 , NR 17 R 18 , SOCH 3 , SOCF 3 ; SO 2 CH 3 , SO 2 CF 3 , CN, COOR 14 , NO 2 , CONR 17 R 18 ; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, unsubstituted or mono- or polysubstituted;
where R 14 is chosen from C 1-6 -alkyl; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted; PO(O—C 1-4 -alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl), CO(C 1-5 -alkyl), CO—CHR 17 —NHR 18 , CO—C 6 H 4 —R 15 , where R 15 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 16 ) 2 where R 16 is C 1-4 -alkyl or 4-morpholino, wherein in the radicals R 14 , R 15 and R 16 the alkyl groups are branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;
where R 17 and R 18 in each case independently of one another are chosen from H; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted, or
R 9 and R 10 or R 10 and R 11 together form an OCH 2 O, OCH 2 CH 2 O, OCH═CH, CH═CHO, CH═C(CH3)O, OC(CH3)═CH, (CH 2 ) 4 or OCH═CHO ring,
Group e) consisting of:
6-dimethylaminomethyl-1-phenyl-cyclohexane compounds corresponding to formula III
wherein
X is chosen from OH, F, Cl, H or OC(O)R 7 , where R 7 is chosen from C 1-3 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, and R 9 to R 13 in each case independently of one another are chosen from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 14 , OCF 3 , SR 14 , NR 17 R 18 , SOCH 3 , SOCF 3 ; SO 2 CH 3 , SO 2 CF 3 , CN, COOR 14 , NO 2 , CONR 17 R 18 ; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, unsubstituted or mono- or polysubstituted;
where R 14 is chosen from C 1-6 -alkyl; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted; PO(O—C 1-4 -alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl), CO(C 15 -alkyl), CO—CHR 17 —NHR 18 , CO—C 6 H 4 —R 15 , where R 15 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 16 ) 2 where R 16 is C 1-4 -alkyl or 4-morpholino, wherein in the radicals R 14 , R 15 and R 16 the alkyl groups are branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;
where R 17 and R 18 in each case independently of one another are chosen from H; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted, or
R 9 and R 10 or R 10 and R 11 together form an OCH 2 O, OCH 2 CH 2 O, OCH═CH, CH═CHO, CH═C(CH3)O, OC(CH3)═CH, (CH 2 ) 4 or OCH═CHO ring,
with the proviso that if R 9 , R 11 and R 13 correspond to H and one of R 10 or R 12 corresponds to H and the other corresponds to OCH 3 , X may not be OH, and
wherein group (ii) consists of:
an anti-muscarine agent selected from the group consisting of: atropine, oxybutinin, propiverine, propantheline, emepronium, trospium, tolterodine, darifenacin and α,α-diphenylacetic acid 4-(N-methylpiperidyl) ester, as well as duloxetine, imipramine and desmopressin,
or a salt of any of the foregoing with a physiologically tolerated acid.
38 . The composition of matter of claim 36 , wherein one or more of said at least one compound selected from group (i) and at least one compound selected from group (ii) is present in the form of a pure enantiomer or pure diastereoisomer.
39 . The composition of matter of claim 36 , wherein one or more of said at least one compound selected from group (i) and at least one compound selected from group (ii) is present in the form of a mixture of stereoisomers.
40 . The composition of matter of claim 36 , wherein one or more of said at least one compound selected from group (i) and at least one compound selected from group (ii) is present in the form of a racemic mixture.
41 . The composition of matter of claim 36 , wherein one or more of said at least one compound selected from group (i) and at least one compound selected from group (ii) is present in the form of a solvate.
42 . The composition of matter of claim 36 , wherein one or more of said at least one compound selected from group (i) and at least one compound selected from group (ii) is present in the form of a hydrate.
43 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is selected from the group consisting of:
tramadol, (+)-O-demethyltramadol and (+)-O-demethyl-N-mono-demethyl-tramadol.
44 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is (+)-tramadol.
45 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is selected from the group consisting of:
codeine dextropropxyphene dihydrocodeine diphenoxylate ethylmorphine meptazinol nalbuphine pethidine (meperidine) tilidine viminol butorphanol dezocine nalorphine pentazocine, and buprenorphine.
46 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is selected from the group consisting of:
codeine dextropropxyphene dihydrocodeine meptazinol nalbuphine tilidine, and buprenorphine.
47 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula I wherein:
X is chosen from
OH, F, Cl, OC(O)CH 3 or H, or
R 1 is chosen from
C 1-4 -alkyl, saturated and unsubstituted, branched or unbranched; or
R 2 and R 3 independently of one another are chosen from
H, C 1-4 -alkyl, saturated and unsubstituted, branched or unbranched; or
R 2 and R 3 together form a C 5-6 -cycloalkyl radical, saturated or unsaturated, unsubstituted or mono- or polysubstituted, or R 9 to R 13 , where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from
H, Cl, F, OH, CF 2 H, CF 3 or C 1-4 -alkyl, saturated and unsubstituted, branched or unbranched; OR 14 or SR 14 , where R 14 is chosen from C 1-3 -alkyl, saturated and unsubstituted, branched or unbranched; or
R 12 and R 11 form a 3,4-OCH═CH ring or
if R 9 , R 11 and R 13 correspond to H, one of R 10 or R 12 also corresponds to H while the other is chosen from:
Cl, F, OH, CF 2 H, CF 3 , OR 14 or SR 14 , or
if R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, one of R 10 or R 12 also corresponds to H while the other corresponds to OH, OCH 3 , Cl or F, or
if R 9 , R 10 , R 12 and R 13 correspond to H, R 11 is chosen from CF 3 , CF 2 H, Cl or F, or
if R 10 , R 11 and R 12 correspond to H, one of R 9 or R 13 also corresponds to H while the other is chosen from OH, OC 2 H 5 or OC 3 H 7 .
48 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula I wherein:
X is chosen from OH, F, OC(O)CH 3 or H.
49 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula I wherein:
R 1 is chosen from CH 3 , C 2 H 5 , C 4 H 9 or t-butyl.
50 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula I wherein:
R 2 and R 3 independently of one another are chosen from H, CH 3 , C 2 H 5 , i-propyl or t-butyl.
51 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula I wherein:
R 2 and R 3 together form a C 5-6 -cycloalkyl radical which is saturated and unsubstituted.
52 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula I wherein:
R 2 and R 3 together form cyclohexyl.
53 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula I wherein:
R 9 to R 13 , where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 or SCH 3 .
54 . The composition of matter of claim 47 , wherein compounds corresponding to formula I where R 3 ═OH are in the form of diastereomers corresponding to formula Ia
and are provided in mixtures with a higher content of this diastereomer compared with the other diastereomer or
are provided as a pure diastereomer or
compounds corresponding to formula I are provided in the form of the (+)-enantiomer.
55 . The composition of matter of claim 47 , wherein compounds corresponding to formula I, are provided in mixtures with a higher content of the (+)-enantiomer compared with the (−)-enantiomer of a racemic compound or are provided as the pure (+)-enantiomer.
56 . The composition of matter of claim 47 , wherein said at least one compound selected from group (i) is selected from the group consisting of:
(2RS,3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol (2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol, (+)-(2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol, (2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2-methyl-pentan-3-ol, (2RS,3RS)-3-(3-difluoromethyl-phenyl)-1-dimethylamino-2-methyl-pentan-3-ol, (2RS,3RS)-1-dimethylamino-2-methyl-3-(3-methylsulfanyl-phenyl)-pentan-3-ol, (3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-4,4-dimethyl-pentan-3-ol, (2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl)-phenol, (1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1 ,2-dimethyl-propyl)-phenol, (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1 ,2-dimethyl-propyl)-phenol, (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol, (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (+)-(1R,2R)-acetic acid 3-dimethylamino-1-ethyl1-(3-methoxy-phenyl)-2-methyl-propyl ester, (1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-1-(3-methoxy-phenyl)-propan-1-ol, (2RS,3RS)-3-(4-chlorophenyl)-1-dimethylamino-2-methyl-pentan-3-ol, (+)-(2R,3R)-3-(3-dimethylamino-1-ethyl1-hydroxy-2-methyl-propyl)-phenol, (2RS,3RS)-4-dimethylamino-2-(3-methoxy-phenyl)-3-methyl-butan-2-ol and (+)-(2R,3R)-4-dimethylamino-2-(3-methoxy-phenyl)-3-methyl-butan-2-ol, or a hydrochloride salt of any of the foregoing.
57 . The composition of matter of claim 36 , wherein one or more of said at least one compound selected from group (i) is selected from the compounds corresponding to formula II wherein:
X is chosen from
OH, F, Cl, OC(O)CH 3 or H, or
R 1 is chosen from
C 1-4 -alkyl, CF 3 , OH, O—C 1-4 -alkyl, Cl or F, or
R 9 to R 13 , where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from
H, Cl, F, OH, CF 2 H, CF 3 or C 1-4 -alkyl, saturated and unsubstituted, branched or unbranched; OR 14 or SR 14 , where R 14 is chosen from C 1-3 -alkyl, saturated and unsubstituted, branched or unbranched; or
R 12 and R 11 form a 3,4-OCH═CH ring or
if R 9 , R 11 and R 13 correspond to H, one of R 10 or R 12 also corresponds to H while the other is chosen from:
Cl, F, OH, CF 2 H, CF 3 , OR 14 or SR 14 , or
if R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, one of R 10 or R 12 also corresponds to H while the other corresponds to OH, OCH 3 , Cl or F, or
if R 9 , R 10 , R 12 and R 13 correspond to H, R 11 is chosen from CF 3 , CF 2 H, Cl or F, or
if R 10 , R 11 and R 12 correspond to H, one of R 9 or R 13 also corresponds to H while the other is chosen from OH, OC 2 H 5 or OC 3 H 7 .
58 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula II wherein:
X is chosen from OH, F or H.
59 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula II wherein:
R 1 is chosen from OH, CF 3 or CH 3 .
60 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula II wherein:
R 9 to R 13 , where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 or SCH 3 , or if R 9 , R 11 and R 13 correspond to H, one of R 10 or R 12 also corresponds to H while the other is chosen from: OH, CF 2 H, OR 14 or SCH 3 .
61 . The composition of matter of claim 57 wherein the compounds corresponding to formula II are in the form of diastereomers corresponding to formula IIa
and are provided in mixtures with a higher content of this diastereomer compared with the other diastereomer or
are provided as a pure diastereomer, or
compounds corresponding to formula II are provided in the form of the (+)-enantiomer.
62 . The composition of matter of claim 57 , wherein compounds corresponding to formula II are provided in mixtures with a higher content of the (+)-enantiomer compared with the (−)-enantiomer of a racemic compound or are provided in the form of the pure (+)-enantiomer.
63 . The composition of matter of claim 57 , wherein said at least one compound selected from group (i) is selected from the group consisting of:
(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol, (+)-(1R,3R,6R)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol, (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-hydroxy-phenyl)-cyclohexane-1,3-diol, (1RS,3SR,6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol, (+)-(1R,2R,5S)-3-(2-dimethylaminomethyl-1-hydroxy-5-methyl-cyclohexyl)-phenol, and (1RS,2RS,5RS)-3-(2-dimethylaminomethyl-1-hydroxy-5-trifluoromethyl-cyclohexyl)-phenol, or a hydrochloride salt of any of the foregoing.
64 . The composition of matter of claim 36 , wherein one or more of said at least one compound selected from group (i) is selected from the compounds corresponding to formula III wherein:
X is chosen from
OH, F, Cl, OC(O)CH 3 or H, or
R 9 to R 13 , where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from
H, Cl, F, OH, CF 2 H, CF 3 or C 1-4 -alkyl, saturated and unsubstituted, branched or unbranched; OR 14 or SR 14 , where R 14 is chosen from C 1-3 -alkyl, saturated and unsubstituted, branched or unbranched; or
R 12 and R 11 form a 3,4-OCH═CH ring or
if R 9 , R 11 and R 13 correspond to H, one of R 10 or R 12 also corresponds to H while the other is chosen from:
Cl, F, OH, SH, CF 2 H, CF 3 , OR 14 or SR 14 , or
if R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, one of R 10 or R 12 also corresponds to H while the other corresponds to OH, OCH 3 , Cl or F, or
if R 9 , R 10 , R 12 and R 13 correspond to H, R 11 is chosen from CF 3 , CF 2 H, Cl or F, or
if R 10 , R 11 and R 12 correspond to H, one of R 9 or R 13 also corresponds to H while the other is chosen from OH, OC 2 H 5 or OC 3 H 7 .
65 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula III wherein:
X is chosen from OH, F or H.
66 . The composition of matter of claim 36 , wherein said at least one compound selected from group (i) is selected from the group of compounds corresponding to formula III wherein:
R 9 to R 13 , where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 or SCH 3 , or if R 9 , R 11 and R 13 correspond to H, one of R 10 or R 12 also corresponds to H while the other is chosen from: OH, CF 2 H, OR 14 or SCH 3 .
67 . The composition of matter of claim 64 , wherein the compounds corresponding to formula III are in the form of diastereomers corresponding to formula IIIa
and are provided in mixtures with a higher content of this diastereomer compared with the other diastereomer or
are provided as a pure diastereomer, or
compounds corresponding to formula III are provided in the form of the (+)-enantiomer.
68 . The composition of matter of claim 64 , wherein compounds corresponding to formula III, are provided in mixtures with a higher content of the (+)-enantiomer compared with the (−)-enantiomer of a racemic compound or are provided in the form of the pure (+)-enantiomer.
69 . The composition of matter of claim 64 , wherein said at least one compound selected from group (i) is selected from the group consisting of:
(+)-(1R,2R)-3-(2-dimethylaminomethyl-1-fluoro-cyclohexyl)-phenol, (+)-(1S,2S)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol or (1S,2S)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol or (−)-(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol, (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol, (−)-(1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine, and (1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine, or a hydrochloride salt of any of the foregoing.
70 . The composition of matter of claim 36 , wherein said at least one compound selected from group (ii) is selected from the group consisting of:
darifenacin, duloxetine, oxybutinin and tolterodine.
71 . The composition of matter of claim 36 , wherein said at least one compound selected from group (ii) is selected from the group consisting of:
oxybutinin and tolterodine.
72 . A pharmaceutical formulation comprising as an active compound combination a composition of matter according to claim 36 and suitable additives or auxiliary substances.Join the waitlist — get patent alerts
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