USRE39593EExpiredUtilityPatentIndex 97
1-phenyl-3-dimethylaminopropane compounds with a pharmacological effects
Est. expiryJul 23, 2014(expired)· nominal 20-yr term from priority
A61P 25/04C07C 323/36C07C 225/10C07C 217/62C07C 215/62C07C 271/58C07C 219/22C07D 307/79C07C 217/72C07C 2601/14C07C 215/30C07C 215/54C07C 217/74A61P 29/02A61P 29/00
97
PatentIndex Score
59
Cited by
71
References
147
Claims
Abstract
1-phenyl-3-dimethylaminopropane compounds corresponding to the formula I a method of preparing them, and the use of these substances as analgesic active ingredients in pharmaceutical compositions.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. An isolated 1-phenyl-3-dimethylaminopropane diastereoisomer having a configuration corresponding to formula Ia′:
X represents OH, F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 -alkyl group;
R 1 is a C 1-4 -alkyl group;
R 2 represents H or a C 1-4 -alkyl group, and
R 3 is different from R 2 and represents H or a straight chain C 1-4 -alkyl group, and
R 5 represents H, and R 4 represents meta-O—Z,
where Z is H, C 1-3 -alkyl, PO(OC 1-4 alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl) or CO—C 6 H 4 —R 7 , in which R 7 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 8 ) 2 , where R 8 is C 1-4 -alkyl or 4-morpholino,
or R 4 represents meta-S-C 1-3 -alkyl, meta-Cl, meta-F, meta-CR 9 R 10 R 11 , ortho-OH, ortho-O—C 2-3 -alkyl, para-F or para-CR 9 R 10 R 11 , where R 9 , R 10 and R 11 independently represent H or F, or
R 5 represents para-Cl, para-F, para-OH or para-O—C 1-3 -alkyl, and R 4 represents meta-Cl, meta-F, meta-OH or meta-O—C 1-3 -alkyl, or
R 4 and R 5 together represent 3,4-OCH═CH— or 3,4-OCH═CHO—; or a salt thereof with a physiologically acceptable acid.
2. An isolated 1-phenyl-3-dimethylaminopropane diastereoisomer according to claim 1 , wherein
X represents OH, F, Cl or H; R 1 represents a C 1-4 -alkyl group; R 2 represents H or CH 3 ; R 3 is different from R 2 and represents H or CH 3 , and R 5 represents H, and R 4 represents meta-OC 1-3 -alkyl, meta-OH, meta-S—C 1-3 -alkyl, meta-F, meta-Cl, meta-CH 3 , meta-CF 2 H, meta-CF 3 or para-CF 3 , or R 5 represents para-Cl or para-F, and R 4 represents meta-Cl or meta-F, or R 4 and R 5 together represent 3,4-OCH═CH—.
3. An isolated 1-phenyl-3-dimethylaminopropane diastereoisomer according to claim 1 , wherein X represents OH, F, Cl or an OCOR 4 group in which R 6 is a C 1-3 -alkyl group.
4. An isolated 1-phenyl-3-dimethylaminopropane diastereoisomer according to claim 1 , wherein R 2 is C 1-4 -alkyl.
5. An isolated 1-phenyl-3-dimethylaminopropane diastereoisomer according to claim 1 , wherein R 9 , R 10 and R 11 represent F.
6. An isolated 1-phenyl-3-dimethylaminopropane diastereoisomer having a configuration corresponding to the formula Ia,
wherein
X represents OH, F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 -alkyl group;
R 1 is a C 1-4 -alkyl group;
R 2 represents a C 1-4 -alkyl group, and
R 5 represents H, and R 4 represents meta-O—Z,
where Z is H, C 1-3 -alkyl, PO(OC 1-4 alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl) or CO—C 6 H 4 —R 7 , in which R 7 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 8 ) 2 , where R 8 is C 1-4 -alkyl or 4-morpholino, or R 4 represents meta-S—C 1-3 -alkyl, meta-Cl, meta-F, meta-CR 9 R 10 R 11 , ortho-OH, ortho-O—C 2-3 -alkyl, para-F or para-CR 9 R 10 R 11 , where R 9 , R 10 and R 11 independently represent H or F, or
R 5 represents para-Cl, para-F, para-OH or para-O—C 1-3 -alkyl, and R 4 represents meta-Cl, meta-F, meta-OH or meta-O—C 1-3 -alkyl, or
R 4 and R 5 together represent 3,4-OCH═CH— or 3,4-OCH═CHO—;
or a salt thereof with a physiologically acceptable acid.
7. An analgesic composition comprising at least one 1-phenyl-3-dimethylaminopropane diastereoisomer having a configuration corresponding to formula Ia′:
wherein
X represents OH, F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 -alkyl group;
R 1 is a C 1-4 -alkyl group;
R 2 represents H or a C 1-4 -alkyl group, and
R 3 is different from R 2 and represents H or a straight chain C 1-4 -alkyl group, and
R 5 represents H, and R 4 represents meta-O—Z,
where Z is H, C 1-3 -alkyl, PO(OC 1-4 alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl) or CO—C 6 H 4 —R 7 , in which R 7 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 8 ) 2 , where R 8 is C 1-4 -alkyl or 4-morpholino,
or R 4 represents meta-S—C 2-3 -alkyl, meta-Cl, meta-F, meta-CR 9 R 10 R 11 , ortho-OH, ortho-O—C 2-3 -alkyl, para-F or para-CR 9 R 10 R 11 , where R 9 , R 10 and R 11 independently represent H or F, or
R 5 represents para-Cl, para-F, para-OH or para-O—C 1-3 -alkyl, and R 4 represents meta-Cl, meta-F, meta-OH or meta-O—C 1-3 -alkyl, or
R 4 and R 5 together represent 3,4-OCH═CH— or 3,4-OCH═CHO—; or a salt thereof with a physiologically acceptable acid, and at least one conventional pharmaceutical carrier or adjuvant.
8. A method of treating a mammal suffering from pain, said method comprising administering to said mammal an effective analgesic amount of a 1-phenyl-3-dimethylaminopropane compound corresponding to formula I
wherein
X represents OH, F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 -alkyl group;
R 1 is a C 1-4 -alkyl group;
R 2 represents H or a C 1-4 -alkyl group and R 3 represents H or a straight chain C 1-4 -alkyl group, or R 2 and R 3 together form a C 4-7 cycloalkyl radical, and
R 5 represents H, and R 4 represents meta-O—Z,
where Z is H, C 1-3 -alkyl, PO(OC 1-4 alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl) or CO—C 6 H 4 —R 7 , in which R 7 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 8 ) 2 , where R 8 is C 1-4 -alkyl or 4-morpholino,
or R 4 represents meta-S—C 1-3 -alkyl, meta-Cl, meta-F, meta-CR 9 R 10 R 11 , ortho-OH, ortho-O—C 2-3- alkyl, para-F or para-CR 9 R 10 R 11 , where R 9 , R 10 and R 11 independently represent H or F, or
R 5 represents para-Cl, para-F, para-OH or para-O—C 1-3 -alkyl, and R 4 represents meta-Cl, meta-F, meta-OH or meta-O—C 1-3 -alkyl, or
R 4 and R 5 together represent 3,4-OCH═CH— or 3,4-OCH═CHO—, or a salt thereof with a physiologically acceptable acid.
9. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer having a configuration corresponding to at least one of formulae Ia′ and Ic′;
wherein
X represents OH, F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group,
R 1 is a C 1-4 - alkyl group,
R 2 represents a C n - alkyl group, wherein n= 1 - 4 ,
R 3 is different from R 2 and represents H or a straight chain C m - alkyl group, wherein 0 <m<n, and
R
5
represents H, and R
4
represents meta-O—Z,
where Z is H, C 1-3 - alkyl, PO ( OC 14 - alkyl ) 2 , CO ( OC 1-5 - alkyl ) , CONH—C 6 H 4 —( C 1-3 - alkyl ) or CO—C 6 H 4 —R 7 , in which R 7 is ortho - OCOC 1-3 - alkyl or meta - or para - CH 2 N ( R 8 ) 2 , where R 8 is C 1-4 - alkyl or 4 - morpholino,
or R 4 represents meta - S—C 1-3 - alkyl, meta - Cl, meta - F, meta - CR 9 R 10 R 11 , ortho - OH, ortho - O—C 2-3 - alkyl, para - F or para - CR 9 R 10 R 11 , where R 9 , R 10 and R 11 independently represent H or F, or
R 5 represents para - Cl, para - F, para - OH or para - O—C 1-3 - alkyl, and R 4 represents meta - Cl, meta - F, meta - OH or meta - O—C 1-3 - alkyl, or
R 4 and R 5 together represent 3 , 4 - OCH═CH— or 3 , 4 - OCH═CHO—,
or a salt thereof with a physiologically acceptable acid.
10. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer having a configuration corresponding to formula Ia′:
wherein
X represents OH, F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group,
R 1 is a C 1-4 - alkyl group,
R 2 represents a C 1-4 - alkyl group, and
R 3 is different from R 2 and represents H or a straight chain C 1-3 - alkyl group, such that X and the dimethylamino group are disposed threo in relation to each other, and
R
5
represents H, and R
4
represents meta-O—Z,
where Z is H, C 1-3 - alkyl, PO ( OC 14 - alkyl ) 2 , CO ( OC 1-5 - alkyl ) , CONH—C 6 H 4 —( C 1-3 - alkyl ) or CO—C 6 H 4 —R 7 , in which R 7 is ortho - OCOC 1-3 - alkyl or meta - or para - CH 2 N ( R 8 ) 2 , where R 8 is C 1-4 - alkyl or 4 - morpholino,
or R 4 represents meta - S—C 1-3 - alkyl, meta - Cl, meta - F, meta - CR 9 R 10 R 11 , ortho - OH, ortho - O—C 2-3 - alkyl, para - F or para - CR 9 R 10 R 11 , where R 9 , R 10 and R 11 independently represent H or F, or
R 5 represents para - Cl, para - F, para - OH or para - O—C 1-3 - alkyl, and R 4 represents meta - Cl, meta - F, meta - OH or meta - O—C 1-3 - alkyl, or
R 4 and R 5 together represent 3 , 4 - OCH═CH— or 3 , 4 - OCH═CHO—,
or a salt thereof with a physiologically acceptable acid.
11. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 10 , wherein R 5 is H, and R 4 is meta - OCH 3 .
12. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 10 , wherein R 5 is H, and R 4 is meta - OH.
13. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 10 , wherein X represents OH, F, Cl, or H; R 1 is a C 1-4 - alkyl group; R 2 represents CH 3 ; R 3 is H; and R 5 represents H, and R 4 represents meta - O—C 1-3 - alkyl, meta - OH, meta - S—C 1-3 - alkyl, meta - F, meta - Cl, meta - CH 3 , meta - CF 2 H, meta - CF 3 , or para - CF 3 , or R 5 represents para - Cl, or para - F, and R 4 represents meta - Cl, or meta - F, or R 4 and R 5 together represent 3 , 4 - OCH═CH—.
14. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 10 , wherein X represents OH, F, Cl, or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
15. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 10 , wherein R 2 is CH 3 , and R 3 is H.
16. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 10 , wherein R 9 , R 10 and R 11 represent F.
17. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 10 , wherein X represents OH.
18. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 10 , wherein X represents F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
19. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 6 , wherein R 5 is H and R 4 is meta - OCH 3 .
20. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 6 , wherein R 5 is H and R 4 is meta - OH.
21. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 6 , wherein X represents OH, F, Cl, or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
22. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 6 , wherein R 9 , R 10 and R 11 represent F.
23. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 6 , wherein X represents OH.
24. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 6 , wherein X represents F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
25. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer having a configuration corresponding to at least one of formulae Ia′ and Ic′:
wherein
X represents OH, F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group,
R 1 is a C 1-4 - alkyl group,
R 2 represents a C 1-4 - alkyl group, and
R 3 is different from R 2 and represents H or a straight chain C 1-3 - alkyl group, such that X and the dimethylamino group are disposed threo in relation to each other, and
R
5
represents H, and R
4
represents meta-O—Z,
where Z is H, C 1-3 - alkyl, PO ( OC 14 - alkyl ) 2 , CO ( OC 1-5 - alkyl ) , CONH—C 6 H 4 —( C 1-3 - alkyl ) or CO—C 6 H 4 —R 7 , in which R 7 is ortho - OCOC 1-3 - alkyl or meta - or para - CH 2 N ( R 8 ) 2 , where R 8 is C 1-4 - alkyl or 4 - morpholino,
or R 4 represents meta - S—C 1-3 - alkyl, meta - Cl, meta - F, meta - CR 9 R 10 R 11 , ortho - OH, ortho - O—C 2-3 - alkyl, para - F or para - CR 9 R 10 R 11 , where R 9 , R 10 and R 11 independently represent H or F, or
R 5 represents para - Cl, para - F, para - OH or para - O—C 1-3 - alkyl, and R 4 represents meta - Cl, meta - F, meta - OH or meta - O—C 1-3 - alkyl, or
R 4 and R 5 together represent 3 , 4 - OCH═CH— or 3 , 4 - OCH═CHO—,
or a salt thereof with a physiologically acceptable acid.
26. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 25 , wherein X represents OH, F, Cl, or H; R 1 is a C 1-4 - alkyl group; R 2 represents CH 3 ; R 3 is H; and R 5 represents H, and R 4 represents meta - OC 1-3 - alkyl, meta - OH, meta - S—C 1-3 - alkyl, meta - F, meta - Cl, meta - CH 3 , meta - CF 2 H, meta - CF 3 , or para - CF 3 , or R 5 represents para - Cl, or para - F, and R 4 represents meta - Cl, or meta - F, or R 4 and R 5 together represent 3 , 4 - OCH═CH—.
27. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 25 , wherein R 5 is H and R 4 is meta - OCH 3 .
28. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 25 , wherein R 5 is H and R 4 is meta - OH.
29. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 25 , wherein X represents OH, F, Cl or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
30. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 25 , wherein R 2 is CH 3 , and R 3 is H.
31. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 25 , wherein R 9 , R 10 and R 11 represent F.
32. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 25 , wherein X represents OH.
33. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 25 , wherein X represents F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
34. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer having a configuration corresponding to at least one of formulae Ia and Ic:
wherein
X represents OH, F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group;
R 1 is a C 1-4 - alkyl group;
R 2 represents a C 1-4 - alkyl group, and
R
5
represents H, and R
4
represents meta-O—Z,
where Z is H, C 1-3 - alkyl, PO ( OC 14 - alkyl ) 2 , CO ( OC 1-5 - alkyl ) , CONH—C 6 H 4 —( C 1-3 - alkyl ) or CO—C 6 H 4 —R 7 , in which R 7 is ortho - OCOC 1-3 - alkyl or meta - or para - CH 2 N ( R 8 ) 2 , where R 8 is C 1-4 - alkyl or 4 - morpholino,
or R 4 represents meta - S—C 1-3 - alkyl, meta - Cl, meta - F, meta - CR 9 R 10 R 11 , ortho - OH, ortho - O—C 2-3 - alkyl, para - F or para - CR 9 R 10 R 11 , where R 9 , R 10 and R 11 independently represent H or F, or
R 5 represents para - Cl, para - F, para - OH or para - O—C 1-3 - alkyl, and R 4 represents meta - Cl, meta - F, meta - OH or meta - O—C 1-3 - alkyl, or
R 4 and R 5 together represent 3 , 4 - OCH═CH— or 3 , 4 - OCH═CHO—;
or a salt thereof with a physiologically acceptable acid.
35. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 34 , wherein R 5 is H and R 4 is meta - OCH 3 .
36. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 34 , wherein R 5 is H and R 4 is meta - OH.
37. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 34 , wherein X represents OH, F, Cl or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
38. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 34 , wherein R 9 , R 10 and R 11 represent F.
39. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 34 , wherein X represents OH.
40. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 34 , wherein X represents F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
41. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer having a configuration corresponding to formula Ic′:
wherein
X represents OH, F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group,
R 1 is a C 1-4 - alkyl group,
R 2 represents a C 1-4 - alkyl group, and
R 3 is different from R 2 and represents H or a straight chain C 1-3 - alkyl group, such that X and the dimethylamino group are disposed threo in relation to each other, and
R
5
represents H, and R
4
represents meta-O—Z,
where Z is H, C 1-3 - alkyl, PO ( OC 14 - alkyl ) 2 , CO ( OC 1-5 - alkyl ) , CONH—C 6 H 4 —( C 1-3 - alkyl ) or CO—C 6 H 4 —R 7 , in which R 7 is ortho - OCOC 1-3 - alkyl or meta - or para - CH 2 N ( R 8 ) 2 , where R 8 is C 1-4 - alkyl or 4 - morpholino, or R 4 represents meta - S—C 1-3 - alkyl, meta - Cl, meta - F, meta - CR 9 R 10 R 11 , ortho - OH, ortho - O—C 2-3 - alkyl, para - F or para - CR 9 R 10 R 11 , where R 9 , R 10 and R 11 independently represent H or F, or
R 5 represents para - Cl, para - F, para - OH or para - O—C 1-3 - alkyl, and R 4 represents meta - Cl, meta - F, meta - OH or meta - O—C 1-3 - alkyl, or
R 4 and R 5 together represent 3 , 4 - OCH═CH— or 3 , 4 - OCH═CHO—,
or a salt thereof with a physiologically acceptable acid.
42. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 41 , wherein X represents OH, F, Cl, or H; R 1 is a C 1-4 - alkyl group; R 2 represents CH 3 ; R 8 is H; and R 5 represents H, and R 4 represents meta - OC 1-3 - alkyl, meta - OH, meta - S—C 1-3 - alkyl, meta - F, meta - Cl, meta - CH 3 , meta - CF 2 H, meta - CF 3 , or para - CF 3 , or R 5 represents para - Cl, or para - F, and R 4 represents meta - Cl, or meta - F, or R 4 and R 5 together represent 3 , 4 - OCH═CH—.
43. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 41 , wherein R 5 is H and R 4 is meta - OCH 3 .
44. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 41 , wherein R 5 is H and R 4 is meta - OH.
45. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 41 , wherein X represents OH, F, Cl or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
46. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 41 , wherein R 2 is CH 3 , and R 3 is H.
47. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 41 , wherein R 9 , R 10 and R 11 represent F.
48. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 41 , wherein X represents OH.
49. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 41 , wherein X represents F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
50. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer having a configuration corresponding to formula Ic:
wherein
X represents OH, F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group;
R 1 is a C 1-4 - alkyl group;
R 2 represents a C 1-4 - alkyl group, and
R
5
represents H, and R
4
represents meta-O—Z,
where Z is H, C 1-3 - alkyl, PO ( OC 1-4 - alkyl ) 2 , CO ( OC 1-5 - alkyl ) , CONH—C 6 H 4 —( C 1-3 - alkyl ) or CO—C 6 H 4 —R 7 , in which R 7 is ortho - OCOC 1-3 - alkyl or meta - or para - CH 2 N ( R 8 ) 2 , where R 8 is C 1-4 - alkyl or 4 - morpholino,
or R 4 represents meta - S—C 1-3 - alkyl, meta - Cl, meta - F, meta - CR 9 R 10 R 11 , ortho - OH, ortho - O—C 2-3 - alkyl, para - F or para - CR 9 R 10 R 11 , where R 9 , R 10 and R 11 independently represent H or F, or
R 5 represents para - Cl, para - F, para - OH or para - O—C 1-3 - alkyl, and R 4 represents meta - Cl, meta - F, meta - OH or meta - O—C 1-3 - alkyl, or
R 4 and R 5 together represent 3 , 4 - OCH═CH— or 3 , 4 - OCH═CHO—;
or a salt thereof with a physiologically acceptable acid.
51. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 50 , wherein R 5 is H and R 4 is meta - OCH 3 .
52. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 50 , wherein R 5 is H and R 4 is meta - OH.
53. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 50 , wherein X represents OH, F, Cl or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
54. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 50 , wherein R 9 , R 10 and R 11 represent F.
55. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 50 , wherein X represents OH.
56. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 50 , wherein X represents F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
57. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 34 , wherein the compound is ( 2 S, 3 S )- 1 - dimethylamino - 3 -( 3 - methoxyphenyl )- 2 - methylpentan - 3 - ol hydrochloride (− 1 ).
58. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 34 , wherein the compound is (+)-( 2 R, 3 R )- 1 - dimethylamino - 3 -( 3 - methoxyphenyl )- 2 - methylpentan - 3 - ol hydrochloride (+ 1 ).
59. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 34 , wherein the compound is (+)-( 2 R, 3 R )- 1 - dimethylamino - 3 -( 3 - methoxyphenyl )- 2 - methylpentan - 3 - ol hydrochloride (+ 1 ).
60. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 34 , wherein the compound is (+)-( 1 S, 2 S )- 3 -( 3 - dimethylamino - 1 - ethyl - 2 - methylpropyl )- phenol hydrochloride (+ 21 ).
61. (−)-( 1 R, 2 R )- 3 -( 3 - dimethylamino - 1 - ethyl - 2 - methylpropyl )- phenol hydrochloride (− 21 ).
62. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 34 , wherein the compound is (+)-( 1 RS, 2 RS )- 3 -( 3 - dimethylamino - 1 - ethyl - 2 - methylpropyl )- phenol hydrochloride (+ 21 ).
63. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 34 , wherein the compound is (+)-( 2 S, 3 S )-[ 3 -( 3 - methoxyphenyl )- 2 - methylpentyl ]- dimethylamine hydrochloride (+ 23 ).
64. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 34 , wherein the compound is (−)-( 2 R, 3 R )-[ 3 -( 3 - methoxyphenyl )- 2 -methylpentyl]- dimethylamine hydrochloride (− 23 ).
65. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 34 , wherein the compound is (+)-( 2 RS, 3 RS )- [ 3 -( 3 - methoxyphenyl )- 2 - methylpentyl ]- dimethylamine hydrochloride (+23).
66. An analgesic composition comprising at least one 1 - phenyl - 3 - dimethylaminopropane diastereoisomer having a configuration corresponding to at least one of formulae Ia′ and Ic′:
wherein
X represents OH, F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group;
R 1 is a C 1-4 - alkyl group;
R 2 represents a C 1-4 - alkyl group, and
R 3 is different from R 2 and represents H or a straight chain C 1-3 - alkyl group, such that X and the dimethylamino group are disposed threo in relation to each other, and
R 5 represents H, and R 4 represents meta-O—Z, C 6 H 4 —( C 1-3 - alkyl ) or CO—C 6 H 4 —R 7 , in which R 7 is ortho - OCOC 1-3 - alkyl or meta - or para - CH 2 N ( R 8 ) 2 , where R 8 is C 1-4 - alkyl or 4 - morpholino,
or R 4 represents meta - S—C 1-3 - alkyl, meta - Cl, meta - F, meta - CR 9 R 10 R 11 , ortho - OH, ortho - O—C 2-3 - alkyl, para - F or para - CR 9 R 10 R 11 , where R 9 , R 10 and R 11 independently represent H or F, or
R 5 represents para - Cl, para - F, para - OH or para - O—C 1-3 - alkyl, and R 4 represents meta - Cl, meta - F, meta - OH or meta - O—C 1-3 - alkyl, or
R 4 and R 5 together represent 3 , 4 - OCH═CH— or 3 , 4 - OCH═CHO—;
or a salt thereof with a physiologically acceptable acid, and at least one suitable pharmaceutical carrier or adjuvant.
67. An analgesic composition according to claim 66 , wherein
X represents OH, F, Cl, or H; R 1 represents a C 1-4 - alkyl group; R 2 represents CH 3 ; R 3 is H; and R 5 represents H, and R 4 represents meta - OC 1-3 - alkyl, meta - OH, meta - S—C 1-3 - alkyl, meta - F, meta - Cl, meta - CH 3 , meta - CF 2 H, meta - CF 3 , or R 5 represents para - Cl, or para - F, and R 4 represents meta - Cl, or meta - F, or R 4 and R 5 together represent 3 , 4 - OCH═CH—.
68. An analgesic composition according to claim 66 , wherein R 5 is H and R 4 is meta - OCH 3 .
69. An analgesic composition according to claim 66 , wherein R 5 is H and R 4 is meta - OH.
70. An analgesic composition according to claim 66 , wherein X represents OH, F, Cl or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
71. An analgesic composition according to claim 66 , wherein R 2 is CH 2 , and R 3 is H.
72. An analgesic composition according to claim 66 , wherein R 9 , R 10 and R 11 represent F.
73. An analgesic composition according to claim 66 , wherein X represents OH.
74. An analgesic composition according to claim 66 , wherein X represents F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
75. An analgesic composition according to claim 66 , wherein the 1 - phenyl - 3 - dimethylaminopropane diastereoisomer has a configuration corresponding to formula Ia′.
76. An analgesic composition according to claim 66 , wherein the 1 - phenyl - 3 - dimethylaminopropane diastereoisomer has a configuration corresponding to formula Ic′.
77. An analgesic composition comprising at least one 1 - phenyl - 3 - dimethylaminopropane diastereoisomer having a configuration corresponding to at least one of formulae Ia and Ic:
wherein
X represents OH, F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group;
R 1 is a C 1-4 - alkyl group;
R 2 represents a C 1-4 - alkyl group, and
R
5
represents H, and R
4
represents meta-O—Z,
where Z is H, C 1-3 - alkyl, PO ( OC 1-4 - alkyl ) 2 , CO (OC 1-5 - alkyl ) , CONH—C 6 H 4 —( C 1-3 - alkyl ) or CO—C 6 H 4 —R 7 , in which R 7 is ortho - OCOC 1-3 - alkyl or meta - or para - CH 2 N ( R 8 ) 2 , where R 8 is C 1-4 - alkyl or 4 - morpholino,
or R 4 represents meta - S—C 1-3 - alkyl, meta - Cl, meta - F, meta - CR 9 R 10 R 11 , ortho - OH, ortho - O—C 2-3 - alkyl, para - F or para - CR 9 R 10 R 11 , where R 9 , R 10 and R 11 independently represent H or F, or
R 5 represents para - Cl, para - F, para - OH or para - O—C 1-3 - alkyl, and R 4 represents meta - Cl, meta - F, meta - OH or meta - O—C 1-3 - alkyl, or
R 4 and R 5 together represent 3 , 4 - OCH═CH— or 3 , 4 - OCH═CHO—;
or a salt thereof with a physiologically acceptable acid, and at least one suitable pharmaceutical carrier or adjuvant.
78. An analgesic composition according to claim 77 , wherein R 5 is H and R 4 is meta - OCH 3 .
79. An analgesic composition according to claim 77 , wherein R 5 is H and R 4 is meta - OH.
80. An analgesic composition according to claim 77 , wherein X represents OH, F, Cl or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
81. An analgesic composition according to claim 77 , wherein R 9 , R 10 and R 11 represent F.
82. An analgesic composition according to claim 77 , wherein X represents OH.
83. An analgesic composition according to claim 77 , wherein X represents F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
84. An analgesic composition according to claim 77 , wherein the 1 - phenyl - 3 - dimethylaminopropane diastereoisomer has a configuration corresponding to formula Ia.
85. An analgesic composition according to claim 77 , wherein the 1 - phenyl - 3 - dimethylaminopropane diastereoisomer has a configuration corresponding to formula Ic.
86. A method according to claim 8 , wherein
X represents OH, F, Cl, or H; R 1 represents a C 1-4 - alkyl group; R 2 represents CH 8 ; R 3 represents H, and R 5 represents H, and R 4 represents meta - OC 1-8 - alkyl, meta - OH, meta - S—C 1-3 - alkyl, meta - F, meta - Cl, meta - CH 3 , meta - CF 2 H, meta - CF 3 , or para - CF 3 , or R 5 represents para - Cl, or para - F, and R 4 represents meta - Cl, or meta - F, or R 4 and R 5 together represent 3 , 4 - OCH═CH—.
87. A method according to claim 8 , wherein R 5 is H and R 4 is meta - OCH 8 .
88. An method according to claim 8 , wherein R 5 is H and R 4 is meta - OH.
89. A method according to claim 8 , wherein X represents OH, F, Cl or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
90. A method according to claim 8 , wherein R 2 is C 1-4 - alkyl, and R 3 is different from R 2 and is H or C 1-3 alkyl.
91. A method according to claim 8 , wherein R 9 , R 10 and R 11 represent F.
92. A method according to claim 8 , wherein X represents OH.
93. A method according to claim 8 , wherein X represents F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
94. A method according to claim 8 , wherein X represents H.
95. A method according to claim 8 , wherein the compound of formula I has a configuration corresponding to at least one of formulae Ia′ and Ic′:
wherein
X represents OH, F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group,
R 1 is a C 1-4 - alkyl group,
R 2 represents a C 1-4 - alkyl group, and
R 3 is different from R 2 and represents H or a straight chain C 1-3 - alkyl group, such that X and the dimethylamino group are disposed threo in relation to each other,
and R
5
represents H, and R
4
represents meta-O—Z,
where Z is H, C 1-3 - alkyl, PO ( OC 14 - alkyl ) 2 , CO ( OC 1-5 - alkyl ) , CONH—C 6 H 4 —( C 1-3 - alkyl ) or CO—C 6 H 4 —R 7 , in which R 7 is ortho - OCOC 1-3 - alkyl or meta - or para - CH 2 N ( R 8 ) 2 , where R 8 is C 1-4 - alkyl or 4 - morpholino,
or R 4 represents meta - S—C 1-3 - alkyl, meta - Cl, meta - F, meta - CR 9 R 10 R 11 , ortho - OH, ortho - O—C 2-3 - alkyl, para - F or para - CR 9 R 10 R 11 , where R 9 , R 10 and R 11 independently represent H or F, or
R 5 represents para - Cl, para - F, para - OH or para - O—C 1-3 - alkyl, and R 4 represents meta - Cl, meta - F, meta - OH or meta - O—C 1-3 - alkyl, or
R 4 and R 5 together represent 3 , 4 - OCH═CH— or 3 , 4 - OCH═CHO—,
or a salt thereof with a physiologically acceptable acid.
96. A method according to claim 95 , wherein
X represents OH, F, Cl, or H; R 1 represents a C 1-4 - alkyl group; R 2 represents CH 3 ; R 3 represents H, and R 5 represents H, and R 4 represents meta - OC 1-3 - alkyl, meta - OH, meta - S—C 1-3 - alkyl, meta - F, meta - Cl, meta - CH 3 , meta - CF 2 H, meta - CF 3 , or para - CF 3 , or R 5 represents para - Cl, or para - F, and R 4 represents meta - Cl, or meta - F, or R 4 and R 5 together represent 3 , 4 - OCH═CH—.
97. A method according to claim 95 , wherein R 5 is H and R 4 is meta - OCH 3 .
98. An method according to claim 95 , wherein R 5 is H and R 4 is meta - OH.
99. A method according to claim 95 , wherein X represents OH, F, Cl or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
100. A method according to claim 95 , wherein R 2 is CH 3 , and R 3 is H.
101. A method according to claim 95 , wherein R 9 , R 10 and R 11 represent F.
102. A method according to claim 95 , wherein X represents OH.
103. A method according to claim 95 , wherein X represents F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
104. A method according to claim 95 , wherein the 1 - phenyl - 3 - dimethylaminopropane diastereoisomer has a configuration corresponding to formula Ia′.
105. A method according to claim 95 , wherein the 1 - phenyl - 3 - dimethylaminopropane diastereoisomer has a configuration corresponding to formula Ic′.
106. A method according to claim 8 , wherein the compound of formula I has a configuration corresponding to at least one of formulae Ia and Ic:
wherein
X represents OH, F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group;
R 1 is a C 1-4 - alkyl group;
R 2 represents a C 1-4 - alkyl group, and
R
5
represents H, and R
4
represents meta-O—Z,
where Z is H, C 1-3 - alkyl, PO ( OC 1-4 - alkyl ) 2 , CO ( OC 1-5 - alkyl ) , CONH—C 6 H 4 —( C 1-3 - alkyl ) or CO—C 6 H 4 —R 7 , in which R 7 is ortho - OCOC 1-3 - alkyl or meta - or para - CH 2 N ( R 8 ) 2 , where R 8 is C 1-4 - alkyl or 4 - morpholino, or
R 4 represents meta - S—C 1-3 - alkyl, meta - Cl, meta - F, meta - CR 9 R 10 R 11 , ortho - OH, ortho - O—C 2-3 - alkyl, para - F or para - CR 9 R 10 R 11 , where R 9 , R 10 and R 11 independently represent H or F, or
R 5 represents para - Cl, para - F, para - OH or para - O—C 1-3 - alkyl, and R 4 represents meta - Cl, meta - F, meta - OH or meta - O—C 1-3 - alkyl, or
R 4 and R 5 together represent 3 , 4 - OCH═CH— or 3 , 4 - OCH═CHO—;
or a salt thereof with a physiologically acceptable acid.
107. A method according to claim 106 , wherein X represents OH, F, Cl or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
108. A method according to claim 106 , wherein R 9 , R 10 and R 11 represent F.
109. A method according to claim 106 , wherein X represents OH.
110. A method according to claim 106 , wherein X represents F, Cl, H or an OCOR 6 group in which R 6 is a C 1-3 - alkyl group.
111. A method according to claim 106 , wherein the compound is a 1 - phenyl - 3 - dimethylaminopropane diastereoisomer having a configuration corresponding to formula Ia.
112. A method according to claim 106 , wherein the compound is a 1 - phenyl - 3 - dimethylaminopropane diastereoisomer having a configuration corresponding to formula Ic.
113. A method according to claim 106 , wherein R 5 is H and R 4 is meta - OCH 3 .
114. A method according to claim 106 , wherein R 5 is H and R 4 is meta - OH.
115. A method according to claim 8 , wherein the compound is (+)-( 1 RS, 2 RS )- 3 -( 3 - dimethylamino - 1 - ethyl - 2 - methylpropyl )- phenol hydrochloride (+ 21 ).
116. A method according to claim 8 , wherein the compound is (+)-( 1 S, 2 S )- 3 -( 3 - dimethylamino - 1 - ethyl - 2 - methylpropyl )- phenol hydrochloride (+ 21 ).
117. A method according to claim 8 , wherein the compound is (−)-( 1 R, 2 R )- 3 -( 3 - dimethylamino - 1 - ethyl - 2 - methylpropyl )- phenol hydrochloride (− 21 ).
118. A method according to claim 8 , wherein the compound is (+)-( 2 RS, 3 RS )-[ 3 -( 3 - methoxyphenyl )- 2 - methylpentyl ]- dimethylamine hydrochloride ( + 23 ).
119. A method according to claim 8 , wherein the compound is (+)-( 2 S, 3 S )-[ 3 -( 3 - methoxyphenyl )- 2 - methylpentyl] - dimethylamine hydrochloride (+ 23 ).
120. A method according to claim 8 , wherein the compound is (−)-( 2 R, 3 R )-[ 3 -( 3 - methoxyphenyl )- 2 - methylpentyl] - dimethylamine hydrochloride (− 23 ).
121. A method according to claim 8 , wherein the compound is (+)-( 2 RS, 3 RS )- 1 - dimethylamino - 3 -( 3 - methoxyphenyl )- 2 - methylpentan -3- ol hydrochloride (+ 1 ).
122. A method according to claim 8 , wherein the compound is (+)-( 2 R, 3 R )- 1 - dimethylamino - 3 -( 3 - methoxyphenyl )- 2 - methylpentan -3- ol hydrochloride (+ 1 ).
123. A method according to claim 8 , wherein the compound is (−)-( 2 S, 3 S )- 1 - dimethylamino - 3 -( 3 - methoxyphenyl )- 2 - methylpentan -3- ol hydrochloride (− 1 ).
124. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 6 , wherein X is H.
125. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 10 , wherein X is H.
126. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 25 , wherein X is H.
127. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 34 , wherein X is H.
128. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 41 , wherein X is H.
129. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 50 , wherein X is H.
130. An analgesic composition according to claim 66 , wherein X is H.
131. An analgesic composition according to claim 75 , wherein X is H.
132. An analgesic composition according to claim 76 , wherein X is H.
133. An analgesic composition according to claim 77 , wherein X is H.
134. An analgesic composition according to claim 84 , wherein X is H.
135. An analgesic composition according to claim 85 , wherein X is H.
136. A method according to claim 86 , wherein X is H.
137. A method according to claim 95 , wherein X is H.
138. A method according to claim 106 , wherein X is H.
139. A method according to claim 113 , wherein X is H.
140. A method according to claim 114 , wherein X is H.
141. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereomer having a configuration corresponding to formula I:
wherein
X represents H,
R 1 is a C 1-4 - alkyl group,
R 2 represents a C 1-4 - alkyl group,
R 3 is different from R 2 and represents H or a straight chain C 1-3 - alkyl group,
and
R
5
represents H, and R
4
represents meta-O—Z,
where Z is H, C 1-3 - alkyl, PO ( OC 14 - alkyl ) 2 , CO ( OC 1-5 - alkyl ) , CONH—C 6 H 4 —( C 1-3 - alkyl ) or CO—C 6 H 4 —R 7 , in which R 7 is ortho - OCOC 1-3 - alkyl or meta - or para - CH 2 N ( R 8 ) 2 , where R 8 is C 1-4 - alkyl or 4 - morpholino,
or R 4 represents meta - S—C 1-3 - alkyl, meta - Cl, meta - F, meta - CR 9 R 10 R 11 , ortho - OH, ortho - O—C 2-3 - alkyl, para - F or para - CR 9 R 10 R 11 , where R 9 , R 10 and R 11 independently represent H or F, or
R 5 represents para - Cl, para - F, para - OH or para - O—C 1-3 - alkyl, and R 4 represents meta - Cl, meta - F, meta - OH or meta - O—C 1-3 - alkyl, or
R 4 and R 5 together represent 3 , 4 - OCH═CH— or 3 , 4 - OCH═CHO—, and
wherein carbon atoms at positions 1 and 2 are both asymmetric carbons and the diastereomer has a ( 1 R, 2 R ) or ( 1 S, 2 S ) configuration,
or a salt thereof with a physiologically acceptable acid.
142. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 141 , wherein R 5 is H, and R 4 is meta - OCH 3 .
143. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 141 , wherein R 5 is H, and R 4 is meta - OH.
144. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 141 , wherein R 2 represents CH 3 ; R 3 is H; and R 5 represents H, and R 4 represents meta - O—C 1-3 - alkyl, meta - OH, meta - S— 1 - 3 - alkyl, meta - F, meta - Cl, meta - CH 3 , meta - CF 2 H, meta - CF 3 , or para - CF 3 , or R 5 represents para - Cl, or para - F, and R 4 represents meta - Cl, or meta - F, or R 4 and R 5 together represent 3 , 4 - OCH═CH—.
145. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereoisomer according to claim 141 , wherein R 2 is CH 3 , and R 3 is H.
146. An isolated 1 - phenyl - 3 - dimethylaminopropane diastereomer according to claim 141 , wherein R 9 , R 10 and R 11 represent F.
147. A pharmaceutically acceptable salt of (−)-( 1 R, 2 R )- 3 R -( 3 - dimethylamino - 1 - ethyl - 2 - methylpropyl )- phenol.Cited by (0)
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