1-phenyl-3-dimethylaminopropane compounds with a...

Details 1-phenyl-3-dimethylaminopropane compounds with a... 1-phenyl-3-dimethylaminopropane compounds with a...

2001-04-20

2002-02-05

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen in the nitrogen containing substituent

C549S398000, C558S190000, C558S273000, C560S032000, C560S037000, C560S066000, C560S250000, C560S252000, C564S355000, C564S356000, C564S374000, C564S440000, C564S442000, C564S443000

Reexamination Certificate

active

06344558

ABSTRACT:

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 &ggr;-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, 20936c (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 &ggr;-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-methoxyphenyl)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
in which
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 constitute a C
4-7
cycloalkyl radical, and
if R
5
is H, R
4
represents meta-O—Z, where Z is H, C
1-4
-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
, wherein 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 or meta-CR
9
R
10
R
11
, ortho-OH, ortho-O—C
2-3
-
3
-alkyl, para-F or para-CR
9
R
10
R
11
, where R
9
, R
10
and R
11
represent H or F, or
if R
5
represents Cl, F, OH or O—C
1-3
-alkyl in the para-position, R
4
represents Cl, F, OH or O—C
1-3
-alkyl in the meta-position, or
R
4
and R
5
together represent 3,4-OCH═CH
2
— or 3,4-OCH═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
1
represents a C
1-4
-alkyl group; R
2
represents H or CH
3
, and R
3
represents H or CH
3
, and if R
5
is H, R
4
represents OC
1-3
-alkyl, —OH, —S—C
1-3
-alkyl, F, Cl, CH
3
, —CF
2
H or —CF
3
in the meta-position, or para-CF
3
, or if R5 is a para-Cl or para-F, R
4
represents meta-Cl or meta-F, or R
4
and R
5
together represent 3,4-OCH═CH2—.
1-phenyl-3-dimethylaminopropane compounds of formula I are particularly preferred in which the R
2
and R
3
radicals have different meanings, in the form of their diastereoisomers of configuration Ia
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 &bgr;-dimethylaminoketone of formula II
is reacted with an organometallic compound of formula III
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 &bgr;-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 aliphatic ether, for example diethyl ether and/or tetrahydrofuran, at temperatures between −70° C. and +60° 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. &bgr;-dimethylaminoketones of formula II can be obtained from ketones of general formula IV
by reaction with dimethylamine hydrochloride and formaldehyde in glacial acetic acid or in a C
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 &bgr;-dimethylaminoketone of formula II, in which the variables R
2
and R
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
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 &bgr;-aminoketones corresponding to the formula V
were reacted with an alkyl Grignard reagent R
1
MgHal, this would result in compounds with the relative configuration Ib
in which the OH group and the dimethylamino radical are disposed erythro in relation to each other.
1-phenyl-3-dimethylaminopropane compounds of formula I, in which R
4
and/or R
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° 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° C. and 30° C.
Compounds of formula I, in which X is H and Rand/or R
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

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