U.S. patent number RE39,593 [Application Number 10/462,844] was granted by the patent office on 2007-04-24 for 1-phenyl-3-dimethylaminopropane compounds with a pharmacological effects.
This patent grant is currently assigned to Gruenenthal GmbH. Invention is credited to Helmut Buschmann, Elmar Friderichs, Wolfgang Strassburger.
United States Patent |
RE39,593 |
Buschmann , et al. |
April 24, 2007 |
**Please see images for:
( Certificate of Correction ) ** |
1-phenyl-3-dimethylaminopropane compounds with a pharmacological
effects
Abstract
1-phenyl-3-dimethylaminopropane compounds corresponding to the
formula I ##STR00001## a method of preparing them, and the use of
these substances as analgesic active ingredients in pharmaceutical
compositions.
Inventors: |
Buschmann; Helmut (Esplugues de
Llobregat, ES), Strassburger; Wolfgang (Wuerselen,
DE), Friderichs; Elmar (Stolberg, DE) |
Assignee: |
Gruenenthal GmbH (Aachen,
DE)
|
Family
ID: |
6524045 |
Appl.
No.: |
10/462,844 |
Filed: |
June 17, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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Reissue of: |
08466911 |
Jun 6, 1995 |
06248737 |
Jun 19, 2001 |
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Foreign Application Priority Data
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Jul 23, 1994 [DE] |
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44 26 245 |
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Current U.S.
Class: |
514/238.2;
514/452; 514/456; 514/534; 514/653; 544/86; 549/362; 558/273;
560/250; 560/252; 560/32; 560/37; 560/66; 558/190; 549/348;
514/654; 514/546; 514/488; 514/114 |
Current CPC
Class: |
C07C
215/30 (20130101); A61P 29/00 (20180101); C07D
307/79 (20130101); C07C 215/62 (20130101); C07C
217/74 (20130101); C07C 217/72 (20130101); C07C
217/62 (20130101); C07C 323/36 (20130101); A61P
29/02 (20180101); A61P 25/04 (20180101); C07C
225/10 (20130101); C07C 215/54 (20130101); C07C
219/22 (20130101); C07C 271/58 (20130101); C07C
2601/14 (20170501) |
Current International
Class: |
A61K
31/535 (20060101) |
Field of
Search: |
;544/86 ;549/362,348
;558/190,273 ;560/32,37,66,250,252
;514/231.8,114,452,456,488,534,546,653,654 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1051281 |
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Feb 1959 |
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DE |
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2412798 |
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Sep 1974 |
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DE |
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124521 |
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Mar 1977 |
|
DE |
|
3242922 |
|
May 1984 |
|
DE |
|
176049 |
|
Apr 1986 |
|
EP |
|
WO 95/21612 |
|
Aug 1995 |
|
WO |
|
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Primary Examiner: O'Sullivan; Peter
Attorney, Agent or Firm: Crowell & Moring LLP
Claims
What is claimed is:
.[.1. An isolated 1-phenyl-3-dimethylaminopropane diastereoisomer
having a configuration corresponding to formula Ia': ##STR00041## X
represents OH, F, Cl, H or an OCOR.sup.6 group in which R.sup.6 is
a C.sub.1-3-alkyl group; R.sup.1 is a C.sub.1-4-alkyl group;
R.sup.2 represents H or a C.sub.1-4-alkyl group, and R.sup.3 is
different from R.sup.2 and represents H or a straight chain
C.sub.1-4-alkyl group, and R.sup.5 represents H, and R.sup.4
represents meta-O--Z, where Z is H, C.sub.1-3-alkyl,
PO(OC.sub.1-4alkyl).sub.2, CO(OC.sub.1-5-alkyl),
CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl) or
CO--C.sub.6H.sub.4--R.sup.7, in which R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2,
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4
represents meta-S-C.sub.1-3-alkyl, meta-Cl, meta-F,
meta-CR.sup.9R.sup.10R.sup.11, ortho-OH, ortho-O--C.sub.2-3-alkyl,
para-F or para-CR.sup.9R.sup.10R.sup.11, where R.sup.9, R.sup.10
and R.sup.11 independently represent H or F, or R.sup.5 represents
para-Cl, para-F, para-OH or para-O--C.sub.1-3-alkyl, and R.sup.4
represents meta-Cl, meta-F, meta-OH or meta-O--C.sub.1-3-alkyl, or
R.sup.4 and R.sup.5 together represent 3,4-OCH.dbd.CH-- or
3,4-OCH.dbd.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.sup.1
represents a C.sub.1-4-alkyl group; R.sup.2 represents H or
CH.sub.3; R.sup.3 is different from R.sup.2 and represents H or
CH.sub.3, and R.sup.5 represents H, and R.sup.4 represents
meta-OC.sub.1-3-alkyl, meta-OH, meta-S--C.sub.1-3-alkyl, meta-F,
meta-Cl, meta-CH.sub.3, meta-CF.sub.2H, meta-CF.sub.3 or
para-CF.sub.3, or R.sup.5 represents para-Cl or para-F, and R.sup.4
represents meta-Cl or meta-F, or R.sup.4 and R.sup.5 together
represent 3,4-OCH.dbd.CH--..].
.[.3. An isolated 1-phenyl-3-dimethylaminopropane diastereoisomer
according to claim 1, wherein X represents OH, F, Cl or an
OCOR.sup.4 group in which R.sup.6 is a C.sub.1-3-alkyl
group..].
.[.4. An isolated 1-phenyl-3-dimethylaminopropane diastereoisomer
according to claim 1, wherein R.sup.2 is C.sub.1-4-alkyl..].
.[.5. An isolated 1-phenyl-3-dimethylaminopropane diastereoisomer
according to claim 1, wherein R.sup.9, R.sup.10 and R.sup.11
represent F..].
6. An isolated 1-phenyl-3-dimethylaminopropane diastereoisomer
having a configuration corresponding to .[.the.]. formula Ia,
##STR00042## wherein X represents OH, F, Cl, H or an OCOR.sup.6
group in which R.sup.6 is a C.sub.1-3-alkyl group; R.sup.1 is a
C.sub.1-4-alkyl group; R.sup.2 represents a C.sub.1-4-alkyl group,
and R.sup.5 represents H, and R.sup.4 represents meta-O--Z, where Z
is H, C.sub.1-3-alkyl, PO(OC.sub.1-4alkyl).sub.2,
CO(OC.sub.1-5-alkyl), CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl) or
CO--C.sub.6H.sub.4--R.sup.7, in which R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2,
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4
represents meta-S--C.sub.1-3-alkyl, meta-Cl, meta-F,
meta-CR.sup.9R.sup.10R.sup.11, ortho-OH, ortho-O--C.sub.2-3-alkyl,
para-F or para-CR.sup.9R.sup.10R.sup.11, where R.sup.9, R.sup.10
and R.sup.11 independently represent H or F, or R.sup.5 represents
para-Cl, para-F, para-OH or para-O--C.sub.1-3-alkyl, and R.sup.4
represents meta-Cl, meta-F, meta-OH or meta-O--C.sub.1-3-alkyl, or
R.sup.4 and R.sup.5 together represent 3,4-OCH.dbd.CH-- or
3,4-OCH.dbd.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': ##STR00043## wherein X
represents OH, F, Cl, H or an OCOR.sup.6 group in which R.sup.6 is
a C.sub.1-3-alkyl group; R.sup.1 is a C.sub.1-4-alkyl group;
R.sup.2 represents H or a C.sub.1-4-alkyl group, and R.sup.3 is
different from R.sup.2 and represents H or a straight chain
C.sub.1-4-alkyl group, and R.sup.5 represents H, and R.sup.4
represents meta-O--Z, where Z is H, C.sub.1-3-alkyl,
PO(OC.sub.1-4alkyl).sub.2, CO(OC.sub.1-5-alkyl),
CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl) or
CO--C.sub.6H.sub.4--R.sup.7, in which R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2,
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4
represents meta-S--C.sub.2-3-alkyl, meta-Cl, meta-F,
meta-CR.sup.9R.sup.10R.sup.11, ortho-OH, ortho-O--C.sub.2-3-alkyl,
para-F or para-CR.sup.9R.sup.10R.sup.11, where R.sup.9, R.sup.10
and R.sup.11 independently represent H or F, or R.sup.5 represents
para-Cl, para-F, para-OH or para-O--C.sub.1-3-alkyl, and R.sup.4
represents meta-Cl, meta-F, meta-OH or meta-O--C.sub.1-3-alkyl, or
R.sup.4 and R.sup.5 together represent 3,4-OCH.dbd.CH-- or
3,4-OCH.dbd.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 ##STR00044## wherein X represents OH, F, Cl, H or an
OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl group;
R.sup.1 is a C.sub.1-4-alkyl group; R.sup.2 represents H or a
C.sub.1-4-alkyl group and R.sup.3 represents H or a straight chain
C.sub.1-4-alkyl group, or R.sup.2 and R.sup.3 together form a
C.sub.4-7 cycloalkyl radical, and R.sup.5 represents H, and R.sup.4
represents meta-O--Z, where Z is H, C.sub.1-3-alkyl,
PO(OC.sub.1-4alkyl).sub.2, CO(OC.sub.1-5-alkyl),
CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl) or
CO--C.sub.6H.sub.4--R.sup.7, in which R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2,
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4
represents meta-S--C.sub.1-3-alkyl, meta-Cl, meta-F,
meta-CR.sup.9R.sup.10R.sup.11, ortho-OH, ortho-O--C.sub.2-3-alkyl,
para-F or para-CR.sup.9R.sup.10R.sup.11, where R.sup.9, R.sup.10
and R.sup.11 independently represent H or F, or R.sup.5 represents
para-Cl, para-F, para-OH or para-O--C.sub.1-3-alkyl, and R.sup.4
represents meta-Cl, meta-F, meta-OH or meta-O--C.sub.1-3-alkyl, or
R.sup.4 and R.sup.5 together represent 3,4-OCH.dbd.CH-- or
3,4-OCH.dbd.CHO--, or a salt thereof with a physiologically
acceptable acid.
.Iadd.9. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer having a configuration corresponding to at least
one of formulae Ia' and Ic'; ##STR00045## wherein X represents OH,
F, Cl, H or an OCOR.sup.6 group in which R.sup.6 is a
C.sub.1-3-alkyl group, R.sup.1 is a C.sub.1-4-alkyl group, R.sup.2
represents a C.sub.n-alkyl group, wherein n=1-4, R.sup.3 is
different from R.sup.2 and represents H or a straight chain
C.sub.m-alkyl group, wherein 0<m<n, and R.sup.5 represents H,
and R.sup.4 represents meta-O--Z, where Z is H, C.sub.1-3-alkyl,
PO(OC.sub.14-alkyl).sub.2, CO(OC.sub.1-5-alkyl),
CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl) or
CO--C.sub.6H.sub.4--R.sup.7, in which R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2,
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4
represents meta-S--C.sub.1-3-alkyl, meta-Cl, meta-F,
meta-CR.sup.9R.sup.10R.sup.11, ortho-OH, ortho-O--C.sub.2-3-alkyl,
para-F or para-CR.sup.9R.sup.10R.sup.11, where R.sup.9, R.sup.10
and R.sup.11 independently represent H or F, or R.sup.5 represents
para-Cl, para-F, para-OH or para-O--C.sub.1-3-alkyl, and R.sup.4
represents meta-Cl, meta-F, meta-OH or meta-O--C.sub.1-3-alkyl, or
R.sup.4 and R.sup.5 together represent 3,4-OCH.dbd.CH-- or
3,4-OCH.dbd.CHO--, or a salt thereof with a physiologically
acceptable acid..Iaddend.
.Iadd.10. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer having a configuration corresponding to formula
Ia': ##STR00046## wherein X represents OH, F, Cl, H or an
OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl group,
R.sup.1 is a C.sub.1-4-alkyl group, R.sup.2 represents a
C.sub.1-4-alkyl group, and R.sup.3 is different from R.sup.2 and
represents H or a straight chain C.sub.1-3-alkyl group, such that X
and the dimethylamino group are disposed threo in relation to each
other, and R.sup.5 represents H, and R.sup.4 represents meta-O--Z,
where Z is H, C.sub.1-3-alkyl, PO(OC.sub.14-alkyl).sub.2,
CO(OC.sub.1-5-alkyl), CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl) or
CO--C.sub.6H.sub.4--R.sup.7, in which R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2,
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4
represents meta-S--C.sub.1-3-alkyl, meta-Cl, meta-F,
meta-CR.sup.9R.sup.10R.sup.11, ortho-OH, ortho-O--C.sub.2-3-alkyl,
para-F or para-CR.sup.9R.sup.10R.sup.11, where R.sup.9, R.sup.10
and R.sup.11 independently represent H or F, or R.sup.5 represents
para-Cl, para-F, para-OH or para-O--C.sub.1-3-alkyl, and R.sup.4
represents meta-Cl, meta-F, meta-OH or meta-O--C.sub.1-3-alkyl, or
R.sup.4 and R.sup.5 together represent 3,4-OCH.dbd.CH-- or
3,4-OCH.dbd.CHO--, or a salt thereof with a physiologically
acceptable acid..Iaddend.
.Iadd.11. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 10, wherein R.sup.5 is H, and
R.sup.4 is meta-OCH.sub.3..Iaddend.
.Iadd.12. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 10, wherein R.sup.5 is H, and
R.sup.4 is meta-OH..Iaddend.
.Iadd.13. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 10, wherein X represents OH, F,
Cl, or H; R.sup.1 is a C.sub.1-4-alkyl group; R.sup.2 represents
CH.sub.3; R.sup.3 is H; and R.sup.5 represents H, and R.sup.4
represents meta-O--C.sub.1-3-alkyl, meta-OH,
meta-S--C.sub.1-3-alkyl, meta-F, meta-Cl, meta-CH.sub.3,
meta-CF.sub.2H, meta-CF.sub.3, or para-CF.sub.3, or R.sup.5
represents para-Cl, or para-F, and R.sup.4 represents meta-Cl, or
meta-F, or R.sup.4 and R.sup.5 together represent
3,4-OCH.dbd.CH--..Iaddend.
.Iadd.14. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 10, wherein X represents OH, F,
Cl, or an OCOR.sup.6group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.15. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 10, wherein R.sup.2 is CH.sub.3,
and R.sup.3 is H..Iaddend.
.Iadd.16. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 10, wherein R.sup.9, R.sup.10
and R.sup.11 represent F..Iaddend.
.Iadd.17. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 10, wherein X represents
OH..Iaddend.
.Iadd.18. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 10, wherein X represents F, Cl,
H or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.19. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 6, wherein R.sup.5 is H and
R.sup.4 is meta-OCH.sub.3..Iaddend.
.Iadd.20. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 6, wherein R.sup.5 is H and
R.sup.4 is meta-OH..Iaddend.
.Iadd.21. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 6, wherein X represents OH, F,
Cl, or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.22. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 6, wherein R.sup.9, R.sup.10 and
R.sup.11 represent F..Iaddend.
.Iadd.23. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 6, wherein X represents
OH..Iaddend.
.Iadd.24. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 6, wherein X represents F, Cl, H
or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.25. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer having a configuration corresponding to at least
one of formulae Ia' and Ic': ##STR00047## wherein X represents OH,
F, Cl, H or an OCOR.sup.6 group in which R.sup.6 is a
C.sub.1-3-alkyl group, R.sup.1 is a C.sub.1-4-alkyl group, R.sup.2
represents a C.sub.1-4-alkyl group, and R.sup.3 is different from
R.sup.2 and represents H or a straight chain C.sub.1-3-alkyl group,
such that X and the dimethylamino group are disposed threo in
relation to each other, and R.sup.5 represents H, and R.sup.4
represents meta-O--Z, where Z is H, C.sub.1-3-alkyl,
PO(OC.sub.14-alkyl).sub.2, CO(OC.sub.1-5-alkyl),
CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl) or
CO--C.sub.6H.sub.4--R.sup.7, in which R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2,
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4
represents meta-S--C.sub.1-3-alkyl, meta-Cl, meta-F,
meta-CR.sup.9R.sup.10R.sup.11, ortho-OH, ortho-O--C.sub.2-3-alkyl,
para-F or para-CR.sup.9R.sup.10R.sup.11, where R.sup.9, R.sup.10
and R.sup.11 independently represent H or F, or R.sup.5 represents
para-Cl, para-F, para-OH or para-O--C.sub.1-3-alkyl, and R.sup.4
represents meta-Cl, meta-F, meta-OH or meta-O--C.sub.1-3-alkyl, or
R.sup.4 and R.sup.5 together represent 3,4-OCH.dbd.CH-- or
3,4-OCH.dbd.CHO--, or a salt thereof with a physiologically
acceptable acid..Iaddend.
.Iadd.26. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 25, wherein X represents OH, F,
Cl, or H; R.sup.1 is a C.sub.1-4-alkyl group; R.sup.2 represents
CH.sub.3; R.sup.3 is H; and R.sup.5 represents H, and R.sup.4
represents meta-OC.sub.1-3-alkyl, meta-OH, meta-S--C.sub.1-3-alkyl,
meta-F, meta-Cl, meta-CH.sub.3, meta-CF.sub.2H, meta-CF.sub.3, or
para-CF.sub.3, or R.sup.5 represents para-Cl, or para-F, and
R.sup.4 represents meta-Cl, or meta-F, or R.sup.4 and R.sup.5
together represent 3,4-OCH.dbd.CH--..Iaddend.
.Iadd.27. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 25, wherein R.sup.5 is H and
R.sup.4 is meta-OCH.sub.3..Iaddend.
.Iadd.28. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 25, wherein R.sup.5 is H and
R.sup.4 is meta-OH..Iaddend.
.Iadd.29. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 25, wherein X represents OH, F,
Cl or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.30. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 25, wherein R.sup.2 is CH.sub.3,
and R.sup.3 is H..Iaddend.
.Iadd.31. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 25, wherein R.sup.9, R.sup.10
and R.sup.11 represent F..Iaddend.
.Iadd.32. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 25, wherein X represents
OH..Iaddend.
.Iadd.33. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 25, wherein X represents F, Cl,
H or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.34. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer having a configuration corresponding to at least
one of formulae Ia and Ic: ##STR00048## wherein X represents OH, F,
Cl, H or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group; R.sup.1 is a C.sub.1-4-alkyl group; R.sup.2 represents a
C.sub.1-4-alkyl group, and R.sup.5 represents H, and R.sup.4
represents meta-O--Z, where Z is H, C.sub.1-3-alkyl,
PO(OC.sub.14-alkyl).sub.2, CO(OC.sub.1-5-alkyl),
CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl) or
CO--C.sub.6H.sub.4--R.sup.7, in which R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2,
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4
represents meta-S--C.sub.1-3-alkyl, meta-Cl, meta-F,
meta-CR.sup.9R.sup.10R.sup.11, ortho-OH, ortho-O--C.sub.2-3-alkyl,
para-F or para-CR.sup.9R.sup.10R.sup.11, where R.sup.9, R.sup.10
and R.sup.11 independently represent H or F, or R.sup.5 represents
para-Cl, para-F, para-OH or para-O--C.sub.1-3-alkyl, and R.sup.4
represents meta-Cl, meta-F, meta-OH or meta-O--C.sub.1-3-alkyl, or
R.sup.4 and R.sup.5 together represent 3,4-OCH.dbd.CH-- or
3,4-OCH.dbd.CHO--; or a salt thereof with a physiologically
acceptable acid..Iaddend.
.Iadd.35. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 34, wherein R.sup.5 is H and
R.sup.4 is meta-OCH.sub.3..Iaddend.
.Iadd.36. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 34, wherein R.sup.5 is H and
R.sup.4 is meta-OH..Iaddend.
.Iadd.37. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 34, wherein X represents OH, F,
Cl or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.38. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 34, wherein R.sup.9, R.sup.10
and R.sup.11 represent F..Iaddend.
.Iadd.39. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 34, wherein X represents
OH..Iaddend.
.Iadd.40. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 34, wherein X represents F, Cl,
H or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.41. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer having a configuration corresponding to formula
Ic': ##STR00049## wherein X represents OH, F, Cl, H or an
OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl group,
R.sup.1 is a C.sub.1-4-alkyl group, R.sup.2 represents a
C.sub.1-4-alkyl group, and R.sup.3 is different from R.sup.2 and
represents H or a straight chain C.sub.1-3-alkyl group, such that X
and the dimethylamino group are disposed threo in relation to each
other, and R.sup.5 represents H, and R.sup.4 represents meta-O--Z,
where Z is H, C.sub.1-3-alkyl, PO(OC.sub.14-alkyl).sub.2,
CO(OC.sub.1-5-alkyl), CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl) or
CO--C.sub.6H.sub.4--R.sup.7, in which R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2,
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4
represents meta-S--C.sub.1-3-alkyl, meta-Cl, meta-F,
meta-CR.sup.9R.sup.10R.sup.11, ortho-OH, ortho-O--C.sub.2-3-alkyl,
para-F or para-CR.sup.9R.sup.10R.sup.11, where R.sup.9, R.sup.10
and R.sup.11 independently represent H or F, or R.sup.5 represents
para-Cl, para-F, para-OH or para-O--C.sub.1-3-alkyl, and R.sup.4
represents meta-Cl, meta-F, meta-OH or meta-O--C.sub.1-3-alkyl, or
R.sup.4 and R.sup.5 together represent 3,4-OCH.dbd.CH-- or
3,4-OCH.dbd.CHO--, or a salt thereof with a physiologically
acceptable acid..Iaddend.
.Iadd.42. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 41, wherein X represents OH, F,
Cl, or H; R.sup.1 is a C.sub.1-4-alkyl group; R.sup.2 represents
CH.sub.3; R.sup.8 is H; and R.sup.5 represents H, and R.sup.4
represents meta-OC.sub.1-3-alkyl, meta-OH, meta-S--C.sub.1-3-alkyl,
meta-F, meta-Cl, meta-CH.sub.3, meta-CF.sub.2H, meta-CF.sub.3, or
para-CF.sub.3, or R.sup.5 represents para-Cl, or para-F, and
R.sup.4 represents meta-Cl, or meta-F, or R.sup.4 and R.sup.5
together represent 3,4-OCH.dbd.CH--..Iaddend.
.Iadd.43. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 41, wherein R.sup.5 is H and
R.sup.4 is meta-OCH.sub.3..Iaddend.
.Iadd.44. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 41, wherein R.sup.5 is H and
R.sup.4 is meta-OH..Iaddend.
.Iadd.45. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 41, wherein X represents OH, F,
Cl or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.46. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 41, wherein R.sup.2 is CH.sub.3,
and R.sup.3 is H..Iaddend.
.Iadd.47. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 41, wherein R.sup.9, R.sup.10
and R.sup.11 represent F..Iaddend.
.Iadd.48. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 41, wherein X represents
OH..Iaddend.
.Iadd.49. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 41, wherein X represents F, Cl,
H or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.50. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer having a configuration corresponding to formula Ic:
##STR00050## wherein X represents OH, F, Cl, H or an OCOR.sup.6
group in which R.sup.6 is a C.sub.1-3-alkyl group; R.sup.1 is a
C.sub.1-4-alkyl group; R.sup.2 represents a C.sub.1-4-alkyl group,
and R.sup.5 represents H, and R.sup.4 represents meta-O--Z, where Z
is H, C.sub.1-3-alkyl, PO(OC.sub.1-4-alkyl).sub.2,
CO(OC.sub.1-5-alkyl), CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl) or
CO--C.sub.6H.sub.4--R.sup.7, in which R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2,
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4
represents meta-S--C.sub.1-3-alkyl, meta-Cl, meta-F,
meta-CR.sup.9R.sup.10R.sup.11, ortho-OH, ortho-O--C.sub.2-3-alkyl,
para-F or para-CR.sup.9R.sup.10R.sup.11, where R.sup.9, R.sup.10
and R.sup.11 independently represent H or F, or R.sup.5 represents
para-Cl, para-F, para-OH or para-O--C.sub.1-3-alkyl, and R.sup.4
represents meta-Cl, meta-F, meta-OH or meta-O--C.sub.1-3-alkyl, or
R.sup.4 and R.sup.5 together represent 3,4-OCH.dbd.CH-- or
3,4-OCH.dbd.CHO--; or a salt thereof with a physiologically
acceptable acid..Iaddend.
.Iadd.51. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 50, wherein R.sup.5 is H and
R.sup.4 is meta-OCH.sub.3..Iaddend.
.Iadd.52. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 50, wherein R.sup.5 is H and
R.sup.4 is meta-OH..Iaddend.
.Iadd.53. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 50, wherein X represents OH, F,
Cl or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.54. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 50, wherein R.sup.9, R.sup.10
and R.sup.11 represent F..Iaddend.
.Iadd.55. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 50, wherein X represents
OH..Iaddend.
.Iadd.56. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 50, wherein X represents F, Cl,
H or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.57. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 34, wherein the compound is (2S,
3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
hydrochloride (-1)..Iaddend.
.Iadd.58. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 34, wherein the compound is
(+)-(2R,
3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
hydrochloride (+1)..Iaddend.
.Iadd.59. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 34, wherein the compound is
(+)-(2R,
3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
hydrochloride (+1)..Iaddend.
.Iadd.60. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 34, wherein the compound is
(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
hydrochloride (+21)..Iaddend.
.Iadd.61.
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
hydrochloride (-21)..Iaddend.
.Iadd.62. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 34, wherein the compound is
(+)-(1RS,2RS)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
hydrochloride (+21)..Iaddend.
.Iadd.63. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 34, wherein the compound is
(+)-(2S,3S)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine
hydrochloride (+23)..Iaddend.
.Iadd.64. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 34, wherein the compound is
(-)-(2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine
hydrochloride (-23)..Iaddend.
.Iadd.65. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 34, wherein the compound is
(+)-(2RS, 3RS)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine
hydrochloride (+23)..Iaddend.
.Iadd.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': ##STR00051## wherein X represents OH, F, Cl, H or an
OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl group;
R.sup.1 is a C.sub.1-4-alkyl group; R.sup.2 represents a
C.sub.1-4-alkyl group, and R.sup.3 is different from R.sup.2 and
represents H or a straight chain C.sub.1-3-alkyl group, such that X
and the dimethylamino group are disposed threo in relation to each
other, and R.sup.5 represents H, and R.sup.4 represents meta-O--Z,
C.sub.6H.sub.4--(C.sub.1-3-alkyl) or CO--C.sub.6H.sub.4--R.sup.7,
in which R.sup.7 is ortho-OCOC.sub.1-3-alkyl or meta- or
para-CH.sub.2N(R.sup.8).sub.2, where R.sup.8 is C.sub.1-4-alkyl or
4-morpholino, or R.sup.4 represents meta-S--C.sub.1-3-alkyl,
meta-Cl, meta-F, meta-CR.sup.9R.sup.10R.sup.11, ortho-OH,
ortho-O--C.sub.2-3-alkyl, para-F or para-CR.sup.9R.sup.10R.sup.11,
where R.sup.9, R.sup.10 and R.sup.11 independently represent H or
F, or R.sup.5 represents para-Cl, para-F, para-OH or
para-O--C.sub.1-3-alkyl, and R.sup.4 represents meta-Cl, meta-F,
meta-OH or meta-O--C.sub.1-3-alkyl, or R.sup.4 and R.sup.5 together
represent 3,4-OCH.dbd.CH-- or 3,4-OCH.dbd.CHO--; or a salt thereof
with a physiologically acceptable acid, and at least one suitable
pharmaceutical carrier or adjuvant..Iaddend.
.Iadd.67. An analgesic composition according to claim 66, wherein X
represents OH, F, Cl, or H; R.sup.1 represents a C.sub.1-4-alkyl
group; R.sup.2 represents CH.sub.3; R.sup.3 is H; and R.sup.5
represents H, and R.sup.4 represents meta-OC.sub.1-3-alkyl,
meta-OH, meta-S--C.sub.1-3-alkyl, meta-F, meta-Cl, meta-CH.sub.3,
meta-CF.sub.2H, meta-CF.sub.3, or R.sup.5 represents para-Cl, or
para-F, and R.sup.4 represents meta-Cl, or meta-F, or R.sup.4 and
R.sup.5 together represent 3,4-OCH.dbd.CH--..Iaddend.
.Iadd.68. An analgesic composition according to claim 66, wherein
R.sup.5 is H and R.sup.4 is meta-OCH.sub.3..Iaddend.
.Iadd.69. An analgesic composition according to claim 66, wherein
R.sup.5 is H and R.sup.4 is meta-OH..Iaddend.
.Iadd.70. An analgesic composition according to claim 66, wherein X
represents OH, F, Cl or an OCOR.sup.6 group in which R.sup.6 is a
C.sub.1-3-alkyl group..Iaddend.
.Iadd.71. An analgesic composition according to claim 66, wherein
R.sup.2 is CH.sub.2, and R.sup.3 is H..Iaddend.
.Iadd.72. An analgesic composition according to claim 66, wherein
R.sup.9, R.sup.10 and R.sup.11 represent F..Iaddend.
.Iadd.73. An analgesic composition according to claim 66, wherein X
represents OH..Iaddend.
.Iadd.74. An analgesic composition according to claim 66, wherein X
represents F, Cl, H or an OCOR.sup.6 group in which R.sup.6 is a
C.sub.1-3-alkyl group..Iaddend.
.Iadd.75. An analgesic composition according to claim 66, wherein
the 1-phenyl-3-dimethylaminopropane diastereoisomer has a
configuration corresponding to formula Ia'..Iaddend.
.Iadd.76. An analgesic composition according to claim 66, wherein
the 1-phenyl-3-dimethylaminopropane diastereoisomer has a
configuration corresponding to formula Ic'..Iaddend.
.Iadd.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:
##STR00052## wherein X represents OH, F, Cl, H or an OCOR.sup.6
group in which R.sup.6 is a C.sub.1-3-alkyl group; R.sup.1 is a
C.sub.1-4-alkyl group; R.sup.2 represents a C.sub.1-4-alkyl group,
and R.sup.5 represents H, and R.sup.4 represents meta-O--Z, where Z
is H, C.sub.1-3-alkyl, PO(OC.sub.1-4-alkyl).sub.2,
CO(OC.sub.1-5-alkyl), CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl) or
CO--C.sub.6H.sub.4--R.sup.7, in which R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2,
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4
represents meta-S--C.sub.1-3-alkyl, meta-Cl, meta-F,
meta-CR.sup.9R.sup.10R.sup.11, ortho-OH, ortho-O--C.sub.2-3-alkyl,
para-F or para-CR.sup.9R.sup.10R.sup.11, where R.sup.9, R.sup.10
and R.sup.11 independently represent H or F, or R.sup.5 represents
para-Cl, para-F, para-OH or para-O--C.sub.1-3-alkyl, and R.sup.4
represents meta-Cl, meta-F, meta-OH or meta-O--C.sub.1-3-alkyl, or
R.sup.4 and R.sup.5 together represent 3,4-OCH.dbd.CH-- or
3,4-OCH.dbd.CHO--; or a salt thereof with a physiologically
acceptable acid, and at least one suitable pharmaceutical carrier
or adjuvant..Iaddend.
.Iadd.78. An analgesic composition according to claim 77, wherein
R.sup.5 is H and R.sup.4 is meta-OCH.sub.3..Iaddend.
.Iadd.79. An analgesic composition according to claim 77, wherein
R.sup.5 is H and R.sup.4 is meta-OH..Iaddend.
.Iadd.80. An analgesic composition according to claim 77, wherein X
represents OH, F, Cl or an OCOR.sup.6group in which R.sup.6 is a
C.sub.1-3-alkyl group..Iaddend.
.Iadd.81. An analgesic composition according to claim 77, wherein
R.sup.9, R.sup.10 and R.sup.11 represent F..Iaddend.
.Iadd.82. An analgesic composition according to claim 77, wherein X
represents OH..Iaddend.
.Iadd.83. An analgesic composition according to claim 77, wherein X
represents F, Cl, H or an OCOR.sup.6 group in which R.sup.6 is a
C.sub.1-3-alkyl group..Iaddend.
.Iadd.84. An analgesic composition according to claim 77, wherein
the 1-phenyl-3-dimethylaminopropane diastereoisomer has a
configuration corresponding to formula Ia..Iaddend.
.Iadd.85. An analgesic composition according to claim 77, wherein
the 1-phenyl-3-dimethylaminopropane diastereoisomer has a
configuration corresponding to formula Ic..Iaddend.
.Iadd.86. A method according to claim 8, wherein X represents OH,
F, Cl, or H; R.sup.1 represents a C.sub.1-4-alkyl group; R.sup.2
represents CH.sub.8; R.sup.3 represents H, and R.sup.5 represents
H, and R.sup.4 represents meta-OC.sub.1-8-alkyl, meta-OH,
meta-S--C.sub.1-3-alkyl, meta-F, meta-Cl, meta-CH.sub.3,
meta-CF.sub.2H, meta-CF.sub.3, or para-CF.sub.3, or R.sup.5
represents para-Cl, or para-F, and R.sup.4 represents meta-Cl, or
meta-F, or R.sup.4 and R.sup.5 together represent
3,4-OCH.dbd.CH--..Iaddend.
.Iadd.87. A method according to claim 8, wherein R.sup.5 is H and
R.sup.4 is meta-OCH.sub.8..Iaddend.
.Iadd.88. An method according to claim 8, wherein R.sup.5 is H and
R.sup.4 is meta-OH..Iaddend.
.Iadd.89. A method according to claim 8, wherein X represents OH,
F, Cl or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.90. A method according to claim 8, wherein R.sup.2 is
C.sub.1-4-alkyl, and R.sup.3 is different from R.sup.2 and is H or
C.sub.1-3 alkyl..Iaddend.
.Iadd.91. A method according to claim 8, wherein R.sup.9, R.sup.10
and R.sup.11 represent F..Iaddend.
.Iadd.92. A method according to claim 8, wherein X represents
OH..Iaddend.
.Iadd.93. A method according to claim 8, wherein X represents F,
Cl, H or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.94. A method according to claim 8, wherein X represents
H..Iaddend.
.Iadd.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': ##STR00053## wherein X represents OH, F, Cl,
H or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group, R.sup.1 is a C.sub.1-4-alkyl group, R.sup.2 represents a
C.sub.1-4-alkyl group, and R.sup.3 is different from R.sup.2 and
represents H or a straight chain C.sub.1-3-alkyl group, such that X
and the dimethylamino group are disposed threo in relation to each
other, and R.sup.5 represents H, and R.sup.4 represents meta-O--Z,
where Z is H, C.sub.1-3-alkyl, PO(OC.sub.14-alkyl).sub.2,
CO(OC.sub.1-5-alkyl), CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl) or
CO--C.sub.6H.sub.4--R.sup.7, in which R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2,
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4
represents meta-S--C.sub.1-3-alkyl, meta-Cl, meta-F,
meta-CR.sup.9R.sup.10R.sup.11, ortho-OH, ortho-O--C.sub.2-3-alkyl,
para-F or para-CR.sup.9R.sup.10R.sup.11, where R.sup.9, R.sup.10
and R.sup.11 independently represent H or F, or R.sup.5 represents
para-Cl, para-F, para-OH or para-O--C.sub.1-3-alkyl, and R.sup.4
represents meta-Cl, meta-F, meta-OH or meta-O--C.sub.1-3-alkyl, or
R.sup.4 and R.sup.5 together represent 3,4-OCH.dbd.CH-- or
3,4-OCH.dbd.CHO--, or a salt thereof with a physiologically
acceptable acid..Iaddend.
.Iadd.96. A method according to claim 95, wherein X represents OH,
F, Cl, or H; R.sup.1 represents a C.sub.1-4-alkyl group; R.sup.2
represents CH.sub.3; R.sup.3 represents H, and R.sup.5 represents
H, and R.sup.4 represents meta-OC.sub.1-3-alkyl, meta-OH,
meta-S--C.sub.1-3-alkyl, meta-F, meta-Cl, meta-CH.sub.3,
meta-CF.sub.2H, meta-CF.sub.3, or para-CF.sub.3, or R.sup.5
represents para-Cl, or para-F, and R.sup.4 represents meta-Cl, or
meta-F, or R.sup.4 and R.sup.5 together represent
3,4-OCH.dbd.CH--..Iaddend.
.Iadd.97. A method according to claim 95, wherein R.sup.5 is H and
R.sup.4 is meta-OCH.sub.3..Iaddend.
.Iadd.98. An method according to claim 95, wherein R.sup.5 is H and
R.sup.4 is meta-OH..Iaddend.
.Iadd.99. A method according to claim 95, wherein X represents OH,
F, Cl or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.100. A method according to claim 95, wherein R.sup.2 is
CH.sub.3, and R.sup.3 is H..Iaddend.
.Iadd.101. A method according to claim 95, wherein R.sup.9,
R.sup.10 and R.sup.11 represent F..Iaddend.
.Iadd.102. A method according to claim 95, wherein X represents
OH..Iaddend.
.Iadd.103. A method according to claim 95, wherein X represents F,
Cl, H or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.104. A method according to claim 95, wherein the
1-phenyl-3-dimethylaminopropane diastereoisomer has a configuration
corresponding to formula Ia'..Iaddend.
.Iadd.105. A method according to claim 95, wherein the
1-phenyl-3-dimethylaminopropane diastereoisomer has a configuration
corresponding to formula Ic'..Iaddend.
.Iadd.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: ##STR00054## wherein X represents OH, F, Cl, H
or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl group;
R.sup.1 is a C.sub.1-4-alkyl group; R.sup.2 represents a
C.sub.1-4-alkyl group, and R.sup.5 represents H, and R.sup.4
represents meta-O--Z, where Z is H, C.sub.1-3-alkyl,
PO(OC.sub.1-4-alkyl).sub.2, CO(OC.sub.1-5-alkyl),
CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl) or
CO--C.sub.6H.sub.4--R.sup.7, in which R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2,
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4
represents meta-S--C.sub.1-3-alkyl, meta-Cl, meta-F,
meta-CR.sup.9R.sup.10R.sup.11, ortho-OH, ortho-O--C.sub.2-3-alkyl,
para-F or para-CR.sup.9R.sup.10R.sup.11, where R.sup.9, R.sup.10
and R.sup.11 independently represent H or F, or R.sup.5 represents
para-Cl, para-F, para-OH or para-O--C.sub.1-3-alkyl, and R.sup.4
represents meta-Cl, meta-F, meta-OH or meta-O--C.sub.1-3-alkyl, or
R.sup.4 and R.sup.5 together represent 3,4-OCH.dbd.CH-- or
3,4-OCH.dbd.CHO--; or a salt thereof with a physiologically
acceptable acid..Iaddend.
.Iadd.107. A method according to claim 106, wherein X represents
OH, F, Cl or an OCOR.sup.6 group in which R.sup.6 is a
C.sub.1-3-alkyl group..Iaddend.
.Iadd.108. A method according to claim 106, wherein R.sup.9,
R.sup.10 and R.sup.11 represent F..Iaddend.
.Iadd.109. A method according to claim 106, wherein X represents
OH..Iaddend.
.Iadd.110. A method according to claim 106, wherein X represents F,
Cl, H or an OCOR.sup.6 group in which R.sup.6 is a C.sub.1-3-alkyl
group..Iaddend.
.Iadd.111. A method according to claim 106, wherein the compound is
a 1-phenyl-3-dimethylaminopropane diastereoisomer having a
configuration corresponding to formula Ia..Iaddend.
.Iadd.112. A method according to claim 106, wherein the compound is
a 1-phenyl-3-dimethylaminopropane diastereoisomer having a
configuration corresponding to formula Ic..Iaddend.
.Iadd.113. A method according to claim 106, wherein R.sup.5 is H
and R.sup.4 is meta-OCH.sub.3..Iaddend.
.Iadd.114. A method according to claim 106, wherein R.sup.5 is H
and R.sup.4 is meta-OH..Iaddend.
.Iadd.115. A method according to claim 8, wherein the compound is
(+)-(1RS,2RS)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
hydrochloride (+21)..Iaddend.
.Iadd.116. A method according to claim 8, wherein the compound is
(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
hydrochloride (+21)..Iaddend.
.Iadd.117. A method according to claim 8, wherein the compound is
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
hydrochloride (-21)..Iaddend.
.Iadd.118. A method according to claim 8, wherein the compound is
(+)-(2RS,3RS)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine
hydrochloride (+23)..Iaddend.
.Iadd.119. A method according to claim 8, wherein the compound is
(+)-(2S,3S)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine
hydrochloride (+23)..Iaddend.
.Iadd.120. A method according to claim 8, wherein the compound is
(-)-(2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine
hydrochloride (-23)..Iaddend.
.Iadd.121. A method according to claim 8, wherein the compound is
(+)-(2RS,
3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
hydrochloride (+1)..Iaddend.
.Iadd.122. A method according to claim 8, wherein the compound is
(+)-(2R,
3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
hydrochloride (+1)..Iaddend.
.Iadd.123. A method according to claim 8, wherein the compound is
(-)-(2S,
3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
hydrochloride (-1)..Iaddend.
.Iadd.124. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 6, wherein X is H..Iaddend.
.Iadd.125. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 10, wherein X is H..Iaddend.
.Iadd.126. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 25, wherein X is H..Iaddend.
.Iadd.127. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 34, wherein X is H..Iaddend.
.Iadd.128. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 41, wherein X is H..Iaddend.
.Iadd.129. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 50, wherein X is H..Iaddend.
.Iadd.130. An analgesic composition according to claim 66, wherein
X is H..Iaddend.
.Iadd.131. An analgesic composition according to claim 75, wherein
X is H..Iaddend.
.Iadd.132. An analgesic composition according to claim 76, wherein
X is H..Iaddend.
.Iadd.133. An analgesic composition according to claim 77, wherein
X is H..Iaddend.
.Iadd.134. An analgesic composition according to claim 84, wherein
X is H..Iaddend.
.Iadd.135. An analgesic composition according to claim 85, wherein
X is H..Iaddend.
.Iadd.136. A method according to claim 86, wherein X is
H..Iaddend.
.Iadd.137. A method according to claim 95, wherein X is
H..Iaddend.
.Iadd.138. A method according to claim 106, wherein X is
H..Iaddend.
.Iadd.139. A method according to claim 113, wherein X is
H..Iaddend.
.Iadd.140. A method according to claim 114, wherein X is
H..Iaddend.
.Iadd.141. An isolated 1-phenyl-3-dimethylaminopropane diastereomer
having a configuration corresponding to formula I: ##STR00055##
wherein X represents H, R.sup.1 is a C.sub.1-4-alkyl group, R.sup.2
represents a C.sub.1-4-alkyl group, R.sup.3 is different from
R.sup.2 and represents H or a straight chain C.sub.1-3-alkyl group,
and R.sup.5 represents H, and R.sup.4 represents meta-O--Z, where Z
is H, C.sub.1-3-alkyl, PO(OC.sub.14-alkyl).sub.2,
CO(OC.sub.1-5-alkyl), CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl) or
CO--C.sub.6H.sub.4--R.sup.7, in which R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2,
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4
represents meta-S--C.sub.1-3-alkyl, meta-Cl, meta-F,
meta-CR.sup.9R.sup.10R.sup.11, ortho-OH, ortho-O--C.sub.2-3-alkyl,
para-F or para-CR.sup.9R.sup.10R.sup.11, where R.sup.9, R.sup.10
and R.sup.11 independently represent H or F, or R.sup.5 represents
para-Cl, para-F, para-OH or para-O--C.sub.1-3-alkyl, and R.sup.4
represents meta-Cl, meta-F, meta-OH or meta-O--C.sub.1-3-alkyl, or
R.sup.4 and R.sup.5 together represent 3,4-OCH.dbd.CH-- or
3,4-OCH.dbd.CHO--, and wherein carbon atoms at positions 1 and 2
are both asymmetric carbons and the diastereomer has a (1R, 2R) or
(1S, 2S) configuration, or a salt thereof with a physiologically
acceptable acid..Iaddend.
.Iadd.142. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 141, wherein R.sup.5 is H, and
R.sup.4 is meta-OCH.sub.3..Iaddend.
.Iadd.143. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 141, wherein R.sup.5 is H, and
R.sup.4 is meta-OH..Iaddend.
.Iadd.144. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 141, wherein R.sup.2 represents
CH.sub.3; R.sup.3 is H; and R.sup.5 represents H, and R.sup.4
represents meta-O--C.sub.1-3-alkyl, meta-OH, meta-S--1-3-alkyl,
meta-F, meta-Cl, meta-CH.sub.3, meta-CF.sub.2H, meta-CF.sub.3, or
para-CF.sub.3, or R.sup.5 represents para-Cl, or para-F, and
R.sup.4 represents meta-Cl, or meta-F, or R.sup.4 and R.sup.5
together represent 3,4-OCH.dbd.CH--..Iaddend.
.Iadd.145. An isolated 1-phenyl-3-dimethylaminopropane
diastereoisomer according to claim 141, wherein R.sup.2 is
CH.sub.3, and R.sup.3 is H..Iaddend.
.Iadd.146. An isolated 1-phenyl-3-dimethylaminopropane diastereomer
according to claim 141, wherein R.sup.9, R.sup.10 and R.sup.11
represent F..Iaddend.
.Iadd.147. A pharmaceutically acceptable salt of
(-)-(1R,2R)-3R-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol..Iaddend.
Description
.Iadd.CROSS REFERENCE TO RELATED APPLICATION.Iaddend.
.Iadd.This application is a reissue of U.S. Pat. No.
6,248,737..Iaddend.
BACKGROUND OF THE INVENTION
The present invention relates to 1-phenyl-3-dimethylaminopropane
compounds, to a method of preparing them, and to the use of these
substances as pharmaceutical active ingredients.
The treatment of chronic and non-chronic pain situations is of
great importance in medicine. This is reflected in the large number
of publications. Thus, for example, 1-naphthyl-3-aminopropane-1-ols
with an analgesic-narcotic effect are known from EP 176 049.
Secondary and tertiary alcohols with .gamma.-amino groups are
described in J. Pharm. Sci. 59, 1038 (1970) and in J. Prakt. Chem.
323, 793 (1981); phenyl-dimethylaminopropanols containing a
para-substituted phenyl radical are described in Chem. Abstr. 54,
20963c (1960) and in Chem. Abstr. 63, 6912e (1965). These compounds
also possess analgesic properties. In contrast, the
3-dimethylaminopropan-1-ols containing 2-phenyl radicals described
in DE 32 42 922 have an antidepressant effect. The
1-phenyl-propan-1-ols described in J. Pharm. Sci. 57, 1487 (1968)
have different pharmacological effects depending on the .gamma.-aza
ring.
Opioids have been used for many years as analgesics for the
treatment of pain, although they give rise to a series of side
effects, for example addiction and dependency, respiratory
depression, gastrointestinal inhibition and obstipation. They can
therefore only be given over an extended period of time or in
higher doses subject to special precautionary measures such as
special prescription regulations (Goodman, Gilman in "The
Pharmacological Basis of Therapeutics", Pergamon Press, New York
(1990)).
Tramadol
hydrochloride--(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyp-
henyl) cyclohexanol hydrochloride--assumes a special position
amongst centrally-acting analgesics, since this active ingredient
gives rise to a pronounced inhibition of pain without the side
effects which are known for opioids (J. Pharmacol. Exptl. Ther.4
267, 331 (1993)). Tramadol is a racemate and consists of identical
amounts of (+) and (-) enantiomer. In vivo the active ingredient
forms the metabolite O-desmethyl-tramadol, which is likewise
present as a mixture of enantiomers. Investigations have shown that
both the enantiomers of tramadol and the enantiomers of tramadol
metabolites contribute to the analgesic effect (J. Pharmacol. Exp.
Ther. 260, 275 (1992)).
SUMMARY OF THE INVENTION
The underlying object of the present invention was to provide
substances with an analgesic effect, which are suitable for the
treatment of severe pain without giving rise to the side effects
which are typical of opioids.
A further object was to provide analgesic substances which do not
exhibit the side effects, for example nausea and vomiting, which
occur during treatment with tramadol in some cases.
It has been found that these stringent requirements are fulfilled
by certain 1-phenyl-3-dimethylaminopropane compounds. These
substances are characterized by a pronounced analgesic effect which
is significantly enhanced compared with that of tramadol.
The present invention accordingly relates to
1-phenyl-3-dimethylaminopropane compounds of formula I ##STR00002##
in which X represents OH, F, Cl, H or an OCOR.sup.6 group in which
R.sup.6 is a C.sub.1-3-alkyl group; R.sup.1 is a C.sub.1-4-alkyl
group; R.sup.2 represents H or a C.sub.1-4-alkyl group and R.sup.3
represents H or a straight chain C.sub.1-4-alkyl group, or R.sup.2
and R.sup.3 together constitute a C.sub.4-7 cycloalkyl radical, and
if R.sup.5 is H, R.sup.4 represents meta-O-Z, where Z is H,
C.sub.1-4-alkyl, PO(OC.sub.1-4-alkyl).sub.2, CO(OC.sub.1-5-alkyl),
CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl) or
CO--C.sub.6H.sub.4--R.sup.7, wherein R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2,
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4.
represents meta-S-C.sub.1-3-alkyl, meta-Cl, meta-F or
meta-CR.sup.9R.sup.10R.sup.11, ortho-OH, ortho-O-C.sub.2-3-alkyl,
para-F or para-CR.sup.9R.sup.10R.sup.11, where R.sup.9, R.sup.10
and R.sup.11 represent H or F, or if R.sup.5 represents Cl, F, OH
or O--C.sub.1-3-alkyl in the para-position, R.sup.4 represents Cl,
F, OH or O--C.sub.1-3-alkyl in the meta-position, or R.sup.4 and
R.sup.5 together represent 3,4-OCH.dbd.CH-- or 3,4-OCH.dbd.CHO--,
as diastereoisomers or enantiomers in the form of free bases or
salts of physiologically acceptable acids.
1-phenyl-3-dimethylaminopropane compounds of formula I are
preferred in which X constitutes OH, F, Cl or H; R.sup.1 represents
a C.sub.1-4-alkyl group; R.sup.2 represents H or CH.sub.3, and
R.sup.3 represents H or CH.sub.3, and if R.sup.5 is H, R.sup.4
represents OC.sub.1-3-alkyl, --OH, --S--C.sub.1-3-alkyl, F, Cl,
CH.sub.3, --CF.sub.2H or --CF.sub.3 in the meta-position, or
para-CF.sub.3, or if R5 is a para-Cl or para-F, R.sup.4 represents
meta-Cl or meta-F, or R.sup.4 and R.sup.5 together represent
3,4-OCH.dbd.CH--.
1-phenyl-3-dimethylaminopropane compounds of formula I are
particularly preferred in which the R.sup.2 and R.sup.3 radicals
have different meanings, in the form of their diastereoisomers of
configuration Ia ##STR00003##
The present invention also relates to a method of preparing
1-phenyl-3-dimethylaminopropane compounds of formula I, in which
the variable X represents OH, which is characterized in that a
.beta.-dimethylaminoketone of formula II ##STR00004## is reacted
with an organometallic compound of formula III ##STR00005## in
which Z represents MgCl, MgBr, MgI or Li, to form a compound of
formula I in which X represents OH.
The reaction of a .beta.-dimethylaminoketone with a Grignard
reagent of formula III, in which Z represents MgCl, MgBr or MgI, or
with an organolithium compound of formula III, can be carried out
in an a liphatic ether, for example diethyl ether and/or
tetrahydrofuran, at temperatures between -70.degree. C. and
+60.degree. C. Organolithium compounds of formula II can be
obtained by the replacement of halogen by lithium, for example, by
reacting a compound of formula III, in which Z represents Cl, Br or
I, with a solution of n-butyllithium in n-hexane.
.beta.-dimethylaminoketones of formula II can be obtained from
ketones of general formula IV ##STR00006## by reaction with
dimethylamine hydrochloride and formaldehyde in glacial acetic acid
or in a C.sub.1-4-alkyl alcohol or by reaction with
dimethylammonium ethylene chloride in acetonitrile using acetyl
chloride as a catalyst (Synthesis 1973, 703).
Upon reaction of a .beta.-dimethylaminoketone of formula II, in
which the variables R.sup.2 and R.sup.3 have different meanings,
with an organometallic compound of formula III,
1-phenyl-3-dimethylaminopropane compounds of formula I are obtained
having the relative configuration of formula Ia ##STR00007## in
which the X and the dimethylamino group are disposed threo in
relation to each other. In contrast, if the reaction for the
preparation of 1-phenyl-1-hydroxy-3-aminopropanes were carried out
according to the method disclosed in DD 124 521, i.e. if
.beta.-aminoketones corresponding to the formula ##STR00008## were
reacted with an alkyl Grignard reagent R.sup.1MgHal, this would
result in compounds with the relative configuration Ib ##STR00009##
in which the .[.OH.]. .Iadd.X .Iaddend.group and the dimethylamino
radical are disposed erythro in relation to each other.
1-phenyl-3-dimethylaminopropane compounds of formula I, in which
R.sup.4 and/or R.sup.5 constitute the OH group, can be prepared
from the corresponding
1-(4(5)-methoxyphenyl)-3-dimethylaminopropanol compounds by
selective ether cleavage with diisobutylaluminium hydride in an
aromatic hydrocarbon, for example toluene, at a temperature between
60 and 130.degree. C. (Synthesis 1975, 617).
The present invention also relates to a method of preparing
1-phenyl-3-dimethylaminopropane compounds of formula I, in which X
represents H, which is characterized in that a compound of formula
I, in which X represents Cl, is reacted with zinc borohydride, zinc
cyanoborohydride and/or tin cyanoborohydride.
The reaction is usually conducted in a solvent, for example diethyl
ether and/or tetrahydrofuran, at a temperature between 0.degree. C.
and 30.degree. C.
Compounds of formula I, in which X is H and R.sup.4 and/or R.sup.5
constitute the OH group, can be prepared from the corresponding
methoxyphenyl compounds by heating them for several hours with
concentrated hydrobromic acid (Chem. Rev. 54, 615 (1954); J. Am.
Chem. Soc. 74, 1316 (1952)).
The present invention further relates to a method of preparing
1-phenyl-3-dimethylaminopropane compounds of formula I, where X
represents F, which is characterized in that a compound of formula
I, in which X represents OH, is reacted with dimethylaminosulfur
trifluoride in a solvent.
Suitable solvents include dichloromethane, 1,1,2-trichloroethane
and/or toluene. The reaction is usually conducted at a temperature
between -50.degree. C. and +30.degree. C. (Org. React. 35, 513
(1988)). If a compound of formula I with X.dbd.OH is used in which
R.sup.4 and/or R.sup.5 constitute OH groups, these OH groups must
be protected before reaction with the fluorine compound, for
example by reaction with benzoyl chloride.
The present invention also relates to a method of preparing
1-phenyl-3-dimethylaminopropane compounds of formula I, in which X
represents Cl, which is characterized in that a compound of formula
I, in which X represents OH, is reacted with thionyl chloride.
The reaction is usually conducted in the absence of solvent at a
temperature between 0.degree. C. and 20.degree. C. Replacement of
OH by Cl is effected while maintaining the configuration.
The present invention also relates to a method of preparing
1-phenyl-3-dimethylaminopropane compounds of formula I, in which X
represents an OCOR.sup.6 group where R.sup.6 is a C.sub.1-3-alkyl,
which is characterized in that a compound of formula I, in which X
represents OH, is reacted with an acid chloride Cl--COOR.sup.6.
The reaction is preferably conducted in a solvent, for example
dichloromethane, toluene and/or tetrahydrofuran, at a temperature
between -10.degree. C. and +30.degree. C.
1-phenyl-3-dimethylaminopropane compounds of formula I, in which
R.sup.5 is H and R.sup.4 is a meta-phosphate group, meta-carbonate
group, meta-carbamate group or meta-carboxylate group, can be
obtained by the reaction of the corresponding
1-(3-hydroxyphenyl)-3-dimethylaminopropane compounds of formula I
in the form of their alkali salts with an alkali salt of a dialkyl
chlorophosphate, with an alkyl chloroformate, with an aryl
isocyanate or with a carboxylic acid chloride. These reactions are
usually conducted in a solvent, for example toluene,
dichloromethane, diethyl ether and/or tetrahydrofuran, at
temperatures between -15.degree. C. and +110.degree. C. (Drugs of
the Future 16, 443 (1991); J. Med. Chem. 30, 2008 (1987) and 32,
2503 (1989); J. Org. Chem. 43, 4797 (1978); Tetrahedron Lett. 1977,
1571; J. Pharm. Sci. 57, 774 (1968)).
The compounds of formula I can be converted in a known manner into
their salts with physiologically acceptable acids, for example
hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic
acid, formic acid, acetic acid, oxalic acid, succinic acid,
tartaric acid, mandelic acid, fumaric acid, lactic acid, citric
acid, glutamic acid and/or aspartic acid. Salt formation is
preferably effected in a solvent, for example diethyl ether,
diisopropyl ether, alkyl acetates, acetone and/or 2-butanone.
Moreover, trimethylchlorosilane in aqueous solution is suitable for
the preparation of hydrochlorides.
1-phenyl-3-dimethylaminopropane compounds of formula I are
toxicologically harmless, so that they are suitable as
pharmaceutical active ingredients in drugs.
Accordingly, the present invention also relates to the use of a
1-phenyl-3-dimethylaminopropane compound of formula I as a
pharmaceutical active ingredient. Compounds of formula I are
preferably used for the treatment of pain.
In addition to at least one 1-phenyl-3-dimethylaminopropane
compound of formula I, the analgesics according to the invention
may contain carriers, fillers, solvents, diluents, colorants and/or
binders. The selection of auxiliary substances and of the amounts
of the same to be used depends on whether the drug is to be
administered orally, intravenously, intraperitoneally,
intradermally, intramuscularly, intranasally or locally, for
example for infections of the skin, of the mucous membranes or of
the eye. Preparations in the form of tablets, dragees, capsules,
granules, drops, liquids and syrups are suitable for oral
application. Solutions, suspensions, readily reconstitutable dry
preparations, and sprays are suitable for parenteral, topical and
inhalative applications. Compounds of formula I according to the
invention in a deposit in dissolved form or in a patch, optionally
with the addition of a skin penetration promoter, are suitable
preparations for percutaneous application. Forms of preparations
which can be administered orally or percutaneously may effect
delayed release of the compounds of formula I according to the
invention.
The amount of active ingredient to be administered to patients
varies depending on the patient's weight, on the manner of
administration, the indication and the degree of severity of the
illness. 50 to 500 mg/kg of at least one
1-phenyl-3-dimethylaminopropane compound of formula I are usually
administered.
EXAMPLES
The yields of the compounds prepared have not been optimised.
All temperatures are uncorrected.
Unless otherwise indicated, petroleum ether with a boiling point of
50-70.degree. C. was used. The term "ether" denotes diethyl
ether.
Silica gel 60 (0.040-0.063 mm) manufactured by E. Merck, Darmstadt,
was used as the stationary phase for column chromatography.
This layer chromatography investigations were conducted using
prefabricated silica gel 60 F 254 HPTLC plates manufactured by E.
Merck, Darmstadt.
Racemate separation was effected on a Chiracel OD column.
The mixture ratios of the mobile phases for all chromatographic
investigations are expressed as volume/volume.
RT denotes room temperature; m.p. denotes melting point.
Example 1
##STR00010##
(2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
Hydrochloride(1)
207.63 g (1.11 mole) 3-bromoanisole dissolved in 400 ml dry
tetrahydrofuran were added drop-wise to 26.99 g (1.11 mole)
magnesium turnings in 150 ml dry tetrahydrofuran so that the
reaction mixture boiled gently. After the addition of
3-bromoanisole was complete the mixture was heated under reflux for
one hour and thereafter was cooled to 5-10.degree. C. 128.30 g
(0.89 mole) 1-dimethylamino-2-methylpentan-3-one dissolved in 400
ml tetrahydrofuran were added at this temperature. The reaction
mixture was allowed to stand overnight and then cooled again to
5-10.degree. C. The Grignard solution was decomposed by the
addition of 300 ml of 20% ammonium chloride solution. The reaction
mixture was diluted with 400 ml ether, the organic phase was
separated off and the aqueous phase was extracted twice with 250 ml
ether. The combined organic phases were dried over sodium sulphate.
After removing the solvent by distillation, the residue (212 g) was
taken up in 3200 ml 2-butanone and added to 120.60 g (1.11 mole)
trimethylchlorosilane and 20 ml water. 121.5 g of hydrochloride (1)
(38% theoretical) with a melting point of 198-199.degree. C.
crystallised out at 4-5.degree. C.
Example 2
##STR00011## Enantiomers of (1):
(-)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
Hydrochloride(-1) and
(+)-(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
Hydrochloride(+1).
The base was released from (1) with dichloromethane/sodium
hydroxide solution. After drying the solution dichloromethane was
distilled off under vacuum. The racemate was then separated on the
chiral HPLC column. The hydrochlorides, which had a melting point
of 150-151.degree. C., were prepared from the enantiomers obtained
by reaction with trimethylchlorosilane/water in 2-butanone.
(-1):
yield: 42% theoretical
[.alpha.].sub.D.sub.RT=-31.8.degree. (c=0.99; methanol)
(+1):
yield: 41% theoretical
[.alpha.].sub.D.sub.=RT+33.0.degree. (c=0.96; methanol)
Example 3
##STR00012##
(2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2-methylpentan-3-ol
Hydrochloride (2)
39 g of crude mixture were prepared analogously to Example 1 from
15 g (105 mmol) 1-dimethylamino-2-methylpentan-3-one, 35.5 g (157
mmole) 4-bromo-1,2-dichlorobenzene and 3.8 g (157 mmole) magnesium
turnings. This mixture was introduced on to a 7.times.40 cm column
packed with silica gel and eluted with 4:1 ethyl acetate/methanol.
14.9 g of base were obtained, from which 11.2 g of hydrochloride
(2) (31% theoretical) with a melting point of 183-184.degree. C.
were obtained with trimethylchlorosilane/water in
2-butanone/diisopropyl ether.
Example 4
##STR00013##
(2RS,3RS)-3-(3-isopropoxyphenyl)-1-dimethylamino-2-methylpentan-3-ol
Hydrochloride (3)
25 g of crude mixture were prepared analogously to Example 1 from
14.3 g (100 mmol) 1-dimethylamino-2-methylpentan-3-one, 20.0 g (157
mmole) 1-bromo-3-isopropoxybenzene and 2.79 g (115 mmole) magnesium
turnings. This mixture was introduced on to a 7.times.40 cm column
packed with silica gel and eluted with 15:1 ethyl acetate/methanol.
9.0 g of base were obtained, from which 8.3 g of hydrochloride (3)
(26% theoretical) with a melting point of 133-134.degree. C. were
obtained with trimethylchlorosilane/water in 2-butanone.
Example 5
##STR00014##
(2RS,3RS)-3-(3-chlorophenyl)-1-dimethylamino-2-methylpentan-3-ol
Hydrochloride (4)
63 g of crude mixture were obtained under the conditions cited for
Example 1 from 38.0 g (270 mmole)
1-dimethylamino-2-methylpentan-3-one, 74.7 g (390 mmol) 1
-bromo-3-chlorobenzene and 9.50 g (390 mmole) magnesium turnings.
This mixture was introduced on to a 7.times.45 cm column packed
with silica gel and eluted with 7:1 diisopropyl ether/methanol.
12.8 g of base were obtained, from which 10.8 g of hydrochloride
(4) (14% theoretical) with a melting point of 160-162.degree. C.
were obtained with trimethylchlorosilane/water in
2-butanone/ether.
Example 6
##STR00015##
(2RS,3RS)-1-dimethylamino-2-methyl-3-(3-trifluoromethylphenyl)-pentan-3-o-
l Hydrochloride(5)
21.2 g of crude mixture were obtained under the conditions cited
for Example 1 from 14.3 g (100 mmole)
1-dimethylamino-2-methylpentan-3-one, 29.3 g (130 mmole)
1-bromo-3-trifluoromethylbenzene and 3.2 g (130 mmole) magnesium
turnings. This mixture was introduced on to a 6.times.40 cm column
packed with silica gel and eluted with 10:1 diisopropyl
ether/methanol. 9.1 g of base were obtained, from which 7.8 g of
hydrochloride (5) (18.5% theoretical) with a melting point of
189-190.degree. C. was obtained with trimethylchlorosilane/water in
2-butanone.
Example 7
##STR00016##
(2RS,3RS)-1-dimethylamino-2-methyl-3-(3-m-tolyl)-pentan-3-ol
Hydrochloride (6)
75 g of crude mixture were obtained as in Example 1 from 47.3 g
(330 mmole) 1-dimethylamino-2-methylpentan-3-one, 64.6 g (400
mmole) 3-bromotoluene and 9.72 g (400 mmole) of magnesium turnings.
This mixture was introduced on to a 7.times.50 cm column packed
with silica gel and eluted with 7:1 diisopropyl ether/methanol.
24.3 g of base were obtained, from which 21.5 g of hydrochloride
(6) (24% theoretical) with a melting point of 154-155.degree. C.
were obtained with trimethylchlorosilane/water in 2-butanone.
Example 8
##STR00017## (2RS,
3RS)-1-dimethylamino-3-(3-fluorophenyl)-2-methylpentan-3-ol
Hydrochloride (7)
70 g of crude mixture were obtained under the conditions cited for
Example 1 from 54.0 g (380 mmole)
1-dimethylamino-2-methylpentan-3-one, 82.5 g (470 mmole)
1-bromo-3-fluorobenzene and 9.23 g (470 mmole) magnesium turnings.
This mixture was introduced on to a 7.times.50 cm column packed
with silica gel and eluted with 1:1 ethyl acetate/methanol. 13.0 g
of base were obtained, from which 11.2 g of hydrochloride (7)
(11.5% theoretical) with a melting point of 145-146.degree. C. was
obtained with trimethylchlorosilane/water in 2-butanone.
Example 9
##STR00018##
(2RS,3RS)-3-(3-difluoromethylphenyl)-1-dimethylamino-2-methylpentan-3-ol
Hydrochloride(8)
7.0 g (34 mmole) 1-bromo-3-difluoromethylbenzene, prepared from
3-bromobenzaldehyde and diethylaminosulphur trifluoride in
dichloromethane according to Org. React. 35, 513 (1988) were
dissolved in 110 ml of dry tetrahydrofuran and cooled to
-75.degree. C. After the addition of 21.12 ml (34 mmole) of a 1.6
molar solution of n-butyllithium in hexane the mixture was stirred
for one hour at -75.degree. C. 4.8 g (34 mmole)
1-dimethylamino-2-methylpentan-3-one dissolved in 15 ml of dry
tetrahydrofuran were then added dropwise. The reaction mixture was
warmed to room temperature over 2.5 hours.
Work-up was effected by the drop-wise addition of 65 ml of 5%
hydrochloric acid with cooling in an ice bath, so that the internal
temperature did not exceed 15.degree. C. After phase separation the
organic phase was extracted with 40 ml of 5% hydrochloric acid. The
combined aqueous phases were washed twice with 50 ml ether. In
order to release the base, the mixture was added to concentrated
sodium hydroxide solution and extracted with dichloromethane. 7.8 g
of crude product were obtained in this manner and was introduced on
to a 7.times.40 cm column packed with silica gel. Elution with 1:1
ethyl acetate/methanol gave 4.89 g of base, from which 4.6 g of
hydrochloride (8) (44% theoretical) with a melting point of
194-195.degree. C. was obtained with trimethylchlorosilane/water in
2-butanone.
Example 10
##STR00019##
(2RS,3RS)-1-dimethylamino-2-methyl-3-(3-methylsulphanylphenyl)-pentan-3-o-
l Hydrochloride(9)
38 g of crude mixture were obtained under the conditions cited for
Example 1 from 17.6 g (123 mmole)
1-dimethylamino-2-methylpentan-3-one, 25.0 g (123 mmole)
1-bromo-3-methylsulphanylbenzene and 3.0 g (123 mmole) magnesium
turnings. This mixture was introduced on to a 7.times.40 cm column
packed with silica gel and eluted with 10:1 ethyl acetate/methanol.
8.35 g of base were obtained, from which 7.2 g of hydrochloride (9)
(19% theoretical) with a melting point of 159-160.degree. C. were
obtained with trimethylchlorosilane/water in 2-butanone.
Example 11
##STR00020##
(2RS,3RS)-3-benzofuran-6-yl-1-dimethylamino-2-methylpentan-3-ol
Hydrochloride(10)
3.45 g (18 mmole) 6-bromobenzofurane (prepared according to EP 355
827) and 6 ml 1,2-dibromoethane, dissolved in 60 ml dry ether, were
added drop-wise over 1.5 hours to 2.12 g (87 mmole) magnesium
turnings in 30 ml dry ether; after the addition the mixture was
heated under reflux for 30 minutes. Thereafter, 2.5 g (18 mmole)
1-dimethylamino-2-methylpentan-3-one dissolved in 7.5 ml ether was
added drop-wise over 1.5 hours whilst cooling in an ice bath to
maintain an internal temperature of 5-10.degree. C. The reaction
mixture was allowed to stand for 12 hours at room temperature, and
was then cooled again to 5-10.degree. C. and added to 35 ml of 20%
aqueous ammonium chloride solution. After phase separation, the
aqueous phase was extracted twice with 50 ml ether. The combined
organic phases were dried over sodium sulphate. After removing the
solvent by distillation the residue (3.9 g) was introduced on to a
5.times.16 cm column packed with silica gel 0.95 g of base were
obtained by elution with 7:1 diisopropyl ether/methanol, from which
0.82 g of hydrochloride (10) (15.5% theoretical) with a melting
point of 162.degree. C. were obtained with
trimethylchlorosilane/water in ethyl acetate/2-butanone.
Example 12
##STR00021##
(2RS,3RS)-1-dimethylamino-2-methyl-3-(4-trifluoromethylphenyl)-pentan-3-o-
l Hydrochloride (11)
44 g of crude mixture were obtained as in Example 1 from 20 g (140
mmole) 1-dimethylamino-2-methylpentan-3-one, 31.5 g (140 mmole)
1-bromo-4-trifluoromethylbenzene, 16.5 g (680 mmole) magnesium
turnings and 47 ml 1,2-dibromomethane. This mixture was introduced
on to a 7.times.50 cm column packed with silica gel and eluted with
5:1 ethyl acetate/methanol. 16.4 g of base were obtained, from
which 12.3 g of hydrochloride (11) (27% theoretical) with a melting
point of 170-171.degree. C. were obtained with
trimethylchlorosilane/water in 2-butanone.
Example 13
(3RS)-1-dimethylamino-3-(3-methoxyphenyl)-hexan-3-ol Hydrochloride
(12)
18.5 g of crude mixture were obtained as in Example 1 from 10 g (70
mmole) 1-dimethylamino-hexan-3-one, 18.7 g (100 mmole)
1-bromo-3-methoxybenzene and 2.3 g (100 mmole) magnesium turnings.
This mixture was introduced on to a 6.times.50 cm column packed
with silica gel and eluted with 1:1 ethyl acetate/methanol. 6.84 g
of base were obtained, from which 6.15 g of hydrochloride (12) (32%
theoretical) with a melting point of 179-180.degree. C. were
obtained with trimethylchlorosilane/water in 2-butanone.
Example 14
(3RS)-1-dimethylamino-3-(3-methoxyphenyl)-heptan-3-ol Hydrochloride
(13)
17.3 g of crude mixture were obtained as in Example 1 from 10 g (64
mmole) 1-dimethylamino-heptan-3-one, 15.9 g (157 mmole)
1-bromo-3-methoxybenzene and 2.06 g (85 mmole) magnesium turnings.
This mixture was introduced on to a 6.times.40 cm column packed
with silica gel and eluted with ethyl acetate. 5.4 g of base were
obtained, from which 4.1 g of hydrochloride (13) (21% theoretical)
with a melting point of 150.degree. C. were obtained with
trimethylchlorosilane/water in 2-butanone.
Example 15
(3RS)-1-dimethylamino-3-(3-methoxyphenyl)-4,4-dimethylpentan-3-ol
Hydrochloride(14)
37 g of crude mixture were obtained as in Example 1 from 18.6 g
(118 mmole) 1-dimethylamino-4,4-dimethylpentan-3-one, 28.4 g (152
mmole) 1-bromo-3-methoxybenzene and 3.7 g (152 mmole) magnesium
turnings. This mixture was introduced on to a 7.times.40 cm column
packed with silica gel and eluted with 5:1 ethyl acetate/methanol.
2.2 g of base were obtained, from which 1.8 g of hydrochloride (14)
(5% theoretical) with a melting point of 213.degree. C. were
obtained with trimethylchlorosilane/water in 2-butanone.
Example 16
##STR00022##
(2RS,3RS)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-3-ol
Hydrochloride(15)
21 g of crude mixture were obtained as in Example 1 from 5.3 g (41
mmole) 4-dimethylamino-3-methylbutan-3-one, 23.0 g (123 mmole)
1-bromo-3-methoxybenzene and 3.0 g (123 mmole) magnesium turnings.
This mixture was introduced on to a 4.5.times.27 cm column packed
with silica gel and eluted with 4:1 ethyl acetate/methanol. 4.0 g
of base were obtained, from which 3.6 g of hydrochloride (15) (32%)
theoretical) with a melting point of 124.degree. C. were obtained
with trimethylchlorosilane/water in 2-butanone.
Example 17
##STR00023## Enantiomers of (15):
(-)-(2S,3S)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-3-ol
Hydrochloride (-15) and
(+)-(2R,3R)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-3-ol
Hydrochloride(+15).
The base was released from hydrochloride (15), which was prepared
as in Example 16, with dichloromethane/sodium hydroxide solution.
After drying and removal of dichloromethane by distillation, the
racemate was then separated into the enantiomers on a chiral HPLC
column. The hydrochlorides were obtained from the enantiomers with
trimethylchlorosilane/water in 2-butanone.
(-15):
yield: 41% theoretical
m.p.: 117-118.degree. C.
[.alpha.].sub.D.sub.RT=-38.6.degree. (c=1.05; methanol)
(+15):
yield: 41% theoretical
m.p.: 118-119.degree. C.
[.alpha.].sub.D.sub.RT=+41.0.degree. (c=1.01; methanol)
Example 18
##STR00024##
(2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol
Hydrochloride(16).
The base was released from compound (1), which was prepared as in
Example 1, with dichloromethane/sodium hydroxide solution. After
drying the solution, dichloromethane was removed by distillation.
4.3 g (17 mmole) of base were dissolved in 25 ml dry toluene and
slowly added drop-wise to 71 ml (85 mmole) of a 1.2 molar solution
of diisobutylaluminium hydride in toluene. When the addition was
complete, the mixture was heated for 8 hours under reflux and then
cooled to room temperature. The reaction mixture was diluted with
25 ml toluene. 9.4 ml ethanol followed by 9.4 ml water were added
drop-wise whilst cooling in an ice bath. After stirring for one
hour whilst cooling in the ice bath the reaction mixture was freed
from aluminium salts by filtration, and the residue was washed
three times with 50 ml toluene in each case. Thereafter the
combined organic phases were dried and toluene was removed by
distillation. 3.95 g of hydrochloride (16) (85% theoretical) with a
melting point of 213-214.degree. C. were obtained from the base
with aqueous hydrochloric acid solution in acetone.
Example 19
##STR00025## Enantiomers of (16): (-) (.[.2S,3S).].
.Iadd.1S,2S.Iaddend.)-3-(dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)--
phenol Hydrochloride (-16) and (+) (.[.2S,3S.].
.Iadd.1R,2R.Iaddend.)-3-(dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)--
phenol Hydrochloride (+16)
The enantiomers (-16) and (+16) were prepared under the conditions
cited in Example 2.
(-16):
yield: 85% theoretical
m.p.: 208-209.degree. C.
[.alpha.].sub.D.sub.RT=-34.6.degree. (c=0.98; methanol)
(+16):
yield: 85% theoretical
m.p.: 206-207.degree. C.
[.alpha.].sub.D.sub.RT=+34.4.degree. (c=1.06; methanol)
Example 20
##STR00026##
(1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropylphenol
Hydrochloride(17)
Compound (17) was prepared under the conditions cited in Example 18
starting from methoxy compound (15) which was obtained as in
Example 16.
Yield: 85% theoretical
m.p.: 232.degree. C.
Example 21
##STR00027## Enantiomers of (17):
(-)-(1S,2S)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenol
Hydrochloride(-17) and
(+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenolhydroc-
hloride(+17)
The enantiomers (-17) and (+17) were prepared under the conditions
cited in Example 2.
(-17):
yield: 82% theoretical
m.p.: 204-205.degree. C.
[.alpha.].sub.D.sub.RT=-42.0.degree. (c=0.94; methanol)
(+17):
yield: 83% theoretical
m.p.: 204-205.degree. C.
[.alpha.].sub.D.sub.RT=+41.2.degree. (c=1.01; methanol)
Example 22
##STR00028##
(+)-(1R,2R)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl)-phenol
Hydrochloride(+18) 1st Step ##STR00029##
(+)-(1R,2R)-3-(3-benzyloxyphenyl)-1-dimethylamino-2-methylpentan-3-ol
(+19)
The base was released with dichloromethane/sodium hydroxide
solution from enantiomer (+16) obtained as in Example 19, and
dichloromethane was removed by distillation after drying the
solution. 5.3 g (22 mmole) of base were dissolved in 27 ml of dry
dimethylformamide and added in several portions to 1.2 g of 50%
sodium hydride. After the addition of 2.8 ml (24 mmole) benzoyl
chloride the mixture was heated for three hours at 70.degree. C.
The reaction mixture was then cooled to room temperature and poured
on to an ice/water mixture. It was extracted three times with 70 ml
ether in each case. After drying the combined organic phases over
sodium sulphate, the solvent was distilled off and the residue was
introduced on to a 4.5.times.30 cm column packed with silica gel.
6.8 g of base (+19) (92% theoretical) were obtained as a light
yellow, highly viscous oil by elution with diisopropyl
ether/methanol. 2nd Step ##STR00030##
(+)-(2R,3R)-[3-(3-benzyloxyphenyl)-3-fluoro-2-methylpentyl]-dimethylamine-
(+20)
6.8 g (21 mmole) of (+19), dissolved in 80 ml dichloromethane, were
added dropwise at -20.degree. C. to a solution of 3.7 g (23 mmole)
diethylaminosulphur trifluoride in 30 ml of dry dichloromethane.
After the addition was complete, the mixture was stirred for 30
minutes at this temperature and then warmed to room temperature.
After stirring for a further one hour at room temperature, the
mixture was cooled to 0-5.degree. C. and hydrolysed with 50 ml
water. After phase separation, the aqueous phase was extracted
twice with 50 ml dichloromethane. The combined organic phases were
dried and freed from solvent by distillation under vacuum. The
crude mixture obtained (8.04 g) was introduced on to a 6.times.50
cm column packed with silica gel and eluted with 1:1 ethyl
acetate/methanol. 3.04 g of base (+20) (40% theoretical) were
obtained as a light yellow, viscous oil.
3rd Step:
(+)-(1R,2R)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl)-phenol
Hydrochloride(+18)
3.0 g (91 mmole) of (+20) were dissolved in 15 ml of dry methanol
and added to 0.44 g palladium on activated carbon (10% Pd) in a
hydrogenation apparatus. 215 ml hydrogen was consumed after
stirring for three hours at room temperature. The catalyst was
removed by filtration, and the methanol was removed by
distillation. 2.22 g of base were obtained, from which 2.0 g of
hydrochloride (+18) (79% theoretical) were obtained with
trimethylchlorosilane/water in 2-butanone.
m.p.: 174-176.degree. C.
[.alpha.].sub.D.sub.RT=+29.5.degree. (c=1.08; methanol)
Example 23
##STR00031##
(-)-(1S,2S)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl)-phenol
Hydrochloride(-18)
Enantiomer (-18) was obtained in a yield of 29% theoretical from
enantiomer (-16) obtained as in Example 19, under the conditions
cited in Example 22.
m.p.: 170-172.degree. C.
[.alpha.].sub.D.sub.RT=-28.4.degree. (c=1.03; methanol)
Example 24
##STR00032## (+)-(1S,.[.2R.].
.Iadd.2S.Iaddend.)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
hydrochloride (+21) 1st Step: ##STR00033##
(+)-(2R,3R)-[3-chloro-3-(-3-methoxyphenyl)-2-methylpentyl]-dimethylamine
Hydrochloride(+22)
10 g (35 mmole) of (+1), prepared as in Example 2, were added to 10
ml thionyl chloride at room temperature. Nitrogen was subsequently
passed over the reaction mixture for two hours to remove excess
thionyl chloride. After a fresh addition of 10 ml thionyl chloride
the reaction mixture was allowed to stand for 12 hours before
excess thionyl chloride was again removed over a period of 2.5
hours by means of a stream of nitrogen. After drying, the residue
was dissolved in 10 ml of ice-cold 2-butanone and mixed with
stirring with 200 ml ether and then with 140 ml diisopropyl ether.
The supernatant solvent phase was decanted off and the remaining
oil was again taken up in 10 ml 2-butanone. After the addition of
seed crystals, 300 ml diisopropyl ether were added drop-wise with
vigorous stirring over three hours, whereupon the hydrochloride
crystallised out. 9.8 g of (22) (91% theoretical) were
obtained.
m.p.: 120.degree. C. (decomposition)
[.alpha.].sub.D.sub.RT=+24.7.degree. (c=1.01; methanol) 2nd Step:
##STR00034## (+)-(.[.2R.]. .Iadd.2S.Iaddend.,
3S)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine
Hydrocholoride (+23)
46 g of dried zinc chloride were dissolved in 580 ml of dry ether
and subsequently added drop-wise to a slurry of 31 g sodium
borohydride in 1800 ml ether. After stirring for 12 hours, 500 ml
were removed by decantation from the zinc borohydride suspension
obtained and added drop-wise to 9.8 g (32 mmole) of (+22) in 200 ml
of dry ether. The reaction mixture was stirred for 72 hours at room
temperature and then added drop-wise to 40 ml of a saturated
ammonium chloride solution with cooling in an ice bath. After phase
separation, the ether phase was washed twice with saturated brine;
after drying over sodium sulphate the solvent was distilled off
under vacuum. 7.3 g of an amine-borane complex were obtained, which
were dissolved in 100 ml of dry methanol to isolate the free base.
After the addition of 7.5 g triphenylphosphine the mixture was
heated for 18 hours under reflux. After removing the solvent by
distillation the residue was added to 100 ml of 5% hydrochloric
acid, and the hydrochloric acid phase was subsequently washed twice
with 50 ml ether. Thereafter the hydrochloric acid phase was made
alkaline with concentrated sodium hydroxide solution whilst cooling
in an ice bath, and was solvent-extracted twice with 50 ml
dichloromethane. After drying the combined organic phases over
sodium sulphate the solvent was distilled off under vacuum and the
remaining residue (5.2 g) was taken up in 2-butanone. After the
addition of trimethylchlorosilane/water, 4.3 g of hydrochloride
(+23) (50% theoretical) crystallised out.
m.p.: 163-164.degree. C.
[.alpha.].sub.D.sub.RT=+25.20 (c=0.95; methanol)
3rd Step:
(+)-(1S,.[.2R.].
.Iadd.2S.Iaddend.)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
Hydrochloride(+21)
4.3 g (15 mmole) of (+23) from step 2 were added to 100 ml of
concentrated hydrobromic acid. The mixture was then heated under
reflux for two hours. After cooling to room temperature the
reaction mixture was concentrated under the vacuum from a water
pump. The residue was treated with concentrated sodium hydrogen
carbonate solution until an alkaline reaction was obtained. After
extracting twice with 50 ml dichloromethane in each case the
combined organic phases were dried over sodium sulphate.
Dichloromethane was then distilled off under vacuum and the residue
(4 g) was taken up in 2-butanone. After the addition of
trimethylchlorosilane/water, 3.8 g of hydrochloride (+21) (98%
theoretical) crystallised out.
m.p.: 194-196.degree. C.
[.alpha.].sub.D.sub.RT=+24.5.degree. (c=1.10; methanol)
Example 25
##STR00035## (-)-(1R,.[.2S.].
.Iadd.2R.Iaddend.)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
hydrochloride(-21)
Enantiomer (-21) was obtained in 45% yield under the conditions
cited in Example 24 from (-1), which was prepared as in Example
2.
m.p.: 168-170.degree. C.
[.alpha.].sub.D.sub.RT=-27.5.degree. (c=0.97; methanol)
Example 26
##STR00036## (+)-(1R,2R)-acetic
acid-3-dimethylamino-1-ethyl-1-(3-methyoxyphenyl)-2-methylpropyl
Ester Hydrochloride(+24)
The base was released from enantiomer (+1), which was prepared as
in Example 2, with dichloromethane/sodium hydroxide solution. After
drying the solution, dichloromethane was removed by distillation.
3.0 g (39 mmole) acetyl chloride were added drop-wise, whilst
cooling in an ice bath, to 10 g (35 mmole) of the base obtained,
which had been taken up in 150 ml of dry dichloromethane. After the
addition of acetyl chloride was complete, the reaction mixture was
warmed to room temperature, and after stirring for two hours was
mixed with 100 ml of saturated sodium hydrogen carbonate solution.
The organic phase was separated from the aqueous phase and the
aqueous phase was extracted twice with 50 ml dichloromethane. The
organic phases were combined and dried over sodium sulphate. After
removing the solvent by distillation, 13.4 g crude mixture were
obtained, from which 10.7 g, of hydrochloride (+24) (93%
theoretical) was obtained with trimethylchlorosilane/water in
2-butanone/ethyl acetate.
m.p.: 153.degree. C.
[.alpha.].sub.D.sub.RT=-17.3.degree. (c=1.04; methanol)
Example 27
##STR00037##
(1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-1-(3-methoxyphenyl)-propan-1-o-
l Hydrochloride(25) 1st Step: ##STR00038##
(1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-(3-methoxyphenyl)-methanol
Hydrochloride(26)
44 g crude mixture was obtained from 25 g (150 mmole)
1-dimethylaminomethyl-cyclohexane carbaldehyde, 32.9 g (180 mmole)
1-bromo-3-methoxybenzene and 4.3 g (180 mmole) magnesium turnings,
under the conditions cited in Example 1. This mixture was
introduced on to a 7.times.40 cm column packed with silica gel and
eluted with 4:1 diisopropyl ether/methanol. 38 g of base were
obtained, from which 40 g of hydrochloride (26) (85% theoretical)
with a melting point of 235.degree. C. were obtained with
trimethylchlorosilane/water in 2-butanone. 2nd Step: ##STR00039##
(1RS)-(1-dimethylaminomethyl-cyclohexyl)-(3-methoxyphenyl)-methanone
Hydrochloride(27)
The base was released from (26) with dichloromethane/sodium
hydroxide solution and after drying the solution dichloromethane
was removed by distillation. 8.3 g (30 mmole) of base were
dissolved in 30 ml n-hexane and added drop-wise to a suspension
consisting of 95 g pyridinium chlorochromate (prepared according to
Synthesis 1980, 223) absorbed on neutral alumina. After stirring
for 72 hours at room temperature the reaction mixture was mixed
with 120 ml dichloromethane, stirred for a further 2 hours and then
filtered through 30 g alumina. The filter residue was washed three
times by decantation with 50 ml dichloromethane and ether in each
case. The organic phases were combined with the filtrate and freed
from solvent by distillation. The residue obtained was taken up in
60 ml of 2 Normal sodium hydroxide solution and extracted four
times with 20 mg ethyl acetate in each case. After drying the
combined organic phases, the solvent was removed by distillation.
4.8 g crude mixture were obtained, which was introduced on to a
6.times.30 cm column packed with silica gel and eluted, firstly
with ethyl acetate, then with 9:1 ethyl acetate/methanol and
finally with 4:1 ethyl acetate/methanol. 3.8 g of base were
obtained, from which 3.1 g of hydrochloride (27) (33% theoretical)
with a melting point of 174.degree. C. were obtained with
trichlorosilane/water in 2-butanone.
3rd Step:
(1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-1-(3-methoxyphenyl)-propan-1-o-
l Hydrochloride(25)
3.0 g crude mixture was obtained, under the conditions cited in
Example 1, from 2.8 g (10 mmole) of (27) in the form of the base,
1.4 g (13 mmole) bromoethane and 0.32 g (13 mmole) magnesium
turnings, using ether as the solvent. This mixture was introduced
on to a 3.times.20 cm column packed with silica gel and eluted with
19:1 diisopropyl ether/methanol, 2.1 g of base were obtained, from
which 1.9 g of hydrochloride (25) (55% theoretical) with a melting
point of 230.degree. C. were obtained with trichlorosilane/water in
2-butanone/ethyl acetate.
Example 28
##STR00040##
(-)-(2R,3S)-{3[3-(p-isopropyl-phenyl-carbamoyl)-oxy-phenyl]-2-methylpenty-
l-dimethylamine Hydrochloride(-28)
The base was released from enantiomer (+21), which was prepared as
in Example 24, with dichloromethane/sodium hydroxide solution, and
after drying the solution dichloromethane was removed by
distillation. 2.2 g (10 mmole) of the base obtained were dissolved
in 20 ml of dry toluene and mixed with 1.8 g (11 mmole)
4-isopropylphenyl isocyanate. After stirring for 20 hours at room
temperature the toluene was removed by distillation. The residue
was reacted with trimethylchlorosilane/water in n-propyl acetate to
form 3.2 g of hydrochloride (-28) (76% theoretical).
m.p.: 151-152.degree. C.
[.alpha.].sub.D.sub.RT=-5.2.degree. (c=1.11; methanol)
Pharmacological Investigations
Writhing Test on Mice
The analgesic effectiveness of the compounds according to the
invention was investigated in the phenylquinone-induced writhing
test, modified according to I. C. Hendershot, J. Forsaith in J.
Pharmacol. Exptl. Ther. 125, 237 (1959), on mice. Male NMRI mice
with a weight between 25 and 30 g were used for this purpose. For
each dose of substance, each 10 animals received, 30 minutes after
the oral administration of a compound according to the invention,
0.3 ml per mouse of an 0.02% aqueous phenylquinone solution
(phenylbenzoquinone manufactured by Sigma, Deisenhofen; solution
prepared with the addition of 5% ethanol and kept on a water bath
at 45.degree. C.) administered intraperitoneally. Thereafter the
animals were placed individually in observation cages. The number
of pain-induced stretching movements (writhing
reaction-straightening of the body with stretching of the rear
extremities) was counted with the aid of a push-button counter. The
Ed.sub.50 value (effective dose with 50% inhibition of writhing
reaction) was calculated with a 95% confidence limit by means of
regression analysis (evaluation program supplied by Martens
EDV-Service, Eckental) from the dose-dependent decrease in the
writhing reaction, by comparison with mice tested in parallel to
which only phenylquinone had been administered. All the compounds
according to the invention which were investigated exhibited a
pronounced analgesic effect. The results are summarized in the
following Table:
TABLE-US-00001 TABLE Writhing inhibition Compound % Inhibition
according to ED.sub.50 25 mg/kg Example the invention [mg/kg per
os] per os 1 (1) 5.8 2 (-1) 22.3 2 (+1) 1.1 3 (2) 13.2 4 (3) -81.3
5 (4) 15.5 6 (5) 8.3 7 (6) 11.8 8 (7) 27.3 9 (8) 12.9 10 (9) 12.8
11 (10) 12.9 13 (12) 19.9 15 (14) 10.5 16 (15) 3.8 17 (+15) -95.2
18 (16) -100.0 19 (-16) 16.1 19 (+16) 1.0 20 (17) -87.0 21 (-17)
-58.3 21 (+17) -97.2 22 (+18) 15.7 24 (+21) 1.9
The foregoing description and examples have been set forth merely
to illustrate the invention and are not intended to be limiting.
Since modifications of the disclosed embodiments incorporating the
spirit and substance of the invention may occur to persons skilled
in the art, the invention should be construed to include all
variations within the scope of the appended claims and equivalents
thereof.
* * * * *