U.S. patent application number 09/838192 was filed with the patent office on 2002-01-24 for 1-phenyl-3-dimethylaminopropane compounds with a pharmacological effect.
This patent application is currently assigned to Gruenenthal GmbH. Invention is credited to Buschmann, Helmut, Friderichs, Elmar, Strassburger, Wolfgang.
Application Number | 20020010178 09/838192 |
Document ID | / |
Family ID | 6524045 |
Filed Date | 2002-01-24 |
United States Patent
Application |
20020010178 |
Kind Code |
A1 |
Buschmann, Helmut ; et
al. |
January 24, 2002 |
1-phenyl-3-dimethylaminopropane compounds with a pharmacological
effect
Abstract
1-phenyl-3-dimethylaminopropane compounds corresponding to the
formula I 1 a method of preparing them, and the use of these
substances as analgesic active ingredients in pharmaceutical
compositions.
Inventors: |
Buschmann, Helmut; (Aachen,
DE) ; Strassburger, Wolfgang; (Wuerselen, DE)
; Friderichs, Elmar; (Stolberg, DE) |
Correspondence
Address: |
CROWELL & MORING LLP
INTELLECTUAL PROPERTY GROUP
P.O. BOX 14300
WASHINGTON
DC
20044-4300
US
|
Assignee: |
Gruenenthal GmbH
|
Family ID: |
6524045 |
Appl. No.: |
09/838192 |
Filed: |
April 20, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09838192 |
Apr 20, 2001 |
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08466911 |
Jun 6, 1995 |
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6248737 |
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Current U.S.
Class: |
514/237.8 ;
514/114; 514/464; 514/534; 514/649; 544/162; 549/462; 558/190;
560/37; 564/355 |
Current CPC
Class: |
C07C 323/36 20130101;
A61P 29/02 20180101; C07D 307/79 20130101; C07C 271/58 20130101;
C07C 215/62 20130101; C07C 219/22 20130101; A61P 29/00 20180101;
A61P 25/04 20180101; C07C 217/72 20130101; C07C 215/54 20130101;
C07C 2601/14 20170501; C07C 215/30 20130101; C07C 217/74 20130101;
C07C 225/10 20130101; C07C 217/62 20130101 |
Class at
Publication: |
514/237.8 ;
514/114; 514/649; 514/464; 514/534; 544/162; 549/462; 558/190;
560/37; 564/355 |
International
Class: |
A61K 031/66; A61K
031/5375; A61K 031/343; A61K 031/24; A61K 031/137 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 23, 1994 |
DE |
P 44 26 245.0 |
Claims
What is claimed is:
1. A 1-phenyl-3-dimethylaminopropane compound corresponding to
formula I 41wherein 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.1- 1, 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-- as diastereoisomers or enantiomers; or a salt
thereof with a physiologically acceptable acid.
2. A compound 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 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. A compound according to claim 1, wherein R.sup.2 and R.sup.3
have different meanings; said compound being present in the form of
a diastereoisomer having the configuration Ia 42
4. A method of preparing a 1-phenyl-3-dimethylaminopropane compound
according to claim 1, in which X represents OH, said method
comprising reacting a .beta.-dimethylaminoketone of formula II
43with an organometallic compound of formula III 44in which Z
represents MgCl, MgBr, MgI or Li.
5. A method of preparing a 1-phenyl-3-dimethylaminopropane compound
according to claim 1, in which X represents H, said method
comprising reacting a compound of formula I in which X represents
Cl with at least one substance selected from the group consisting
of zinc borohydride, zinc cyanoborohydride and tin
cyanoborohydride.
6. A method of preparing a 1-phenyl-3-dimethylaminopropane compound
according to claim 1, in which X represents F, said method
comprising reacting a compound of formula I in which X represents
OH with dimethylaminosulfur trifluoride in a solvent.
7. A method of preparing a 1-phenyl-3-dimethylaminopropane compound
according to claim 1, in which X represents Cl, said method
comprising reacting a compound of formula I in which X represents
OH with thionyl chloride.
8. A method of preparing a 1-phenyl-3-dimethylaminopropane compound
according to claim 1, in which X represents an OCOR.sup.6 group in
which R.sup.6 is C.sub.1-3-alkyl group, said method comprising
reacting a compound of formula I in which X represents OH with an
acid chloride Cl--COOR.sup.6.
9. 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 45wherein 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.1- 1, 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.
10. An analgesic composition comprising at least one
1-phenyl-3-dimethylaminopropane compound corresponding to formula I
46wherein 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.1- 1, 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.
Description
BACKGROUND OF THE INVENTION
[0001] 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.
[0002] 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, 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 .gamma.-aza ring.
[0003] 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)).
[0004] Tramadol
hydrochloride--(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-me-
thoxyphenyl)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
[0005] 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.
[0006] 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.
[0007] 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.
[0008] The present invention accordingly relates to
1-phenyl-3-dimethylaminopropane compounds of formula I 2
[0009] in which
[0010] 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;
[0011] R.sup.1 is a C.sub.1-4-alkyl group;
[0012] 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
[0013] 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
[0014] 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
[0015] R.sup.4 and R.sup.5 together represent
3,4-OCH.dbd.CH.sub.2-- or 3,4-OCH.dbd.CHO--, as diastereoisomers or
enantiomers in the form of free bases or salts of physiologically
acceptable acids.
[0016] 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 R.sup.5 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.CH2--.
[0017] 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 3
[0018] 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 4
[0019] is reacted with an organometallic compound of formula III
5
[0020] in which Z represents MgCl, MgBr, MgI or Li, to form a
compound of formula I in which X represents OH.
[0021] 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 aliphatic 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 6
[0022] 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).
[0023] 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 7
[0024] 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 V 8
[0025] were reacted with an alkyl Grignard reagent R.sup.1MgHal,
this would result in compounds with the relative configuration Ib
9
[0026] in which the OH group and the dimethylamino radical are
disposed erythro in relation to each other.
[0027] 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).
[0028] 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.
[0029] 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.
[0030] 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)).
[0031] 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.
[0032] 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=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.
[0033] 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.
[0034] 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.
[0035] 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.
[0036] 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.
[0037] 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)).
[0038] 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.
[0039] 1-phenyl-3-dimethylaminopropane compounds of formula I are
toxicologically harmless, so that they are suitable as
pharmaceutical active ingredients in drugs.
[0040] 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.
[0041] 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.
[0042] 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
[0043] The yields of the compounds prepared have not been
optimised.
[0044] All temperatures are uncorrected.
[0045] Unless otherwise indicated, petroleum ether with a boiling
point of 50-70.degree. C. was used. The term "ether" denotes
diethyl ether.
[0046] Silica gel 60 (0.040-0.063 mm) manufactured by E. Merck,
Darmstadt, was used as the stationary phase for column
chromatography.
[0047] Thin layer chromatography investigations were conducted
using prefabricated silica gel 60 F 254 HPTLC plates manufactured
by E. Merck, Darmstadt.
[0048] Racemate separation was effected on a Chiracel OD
column.
[0049] The mixture ratios of the mobile phases for all
chromatographic investigations are expressed as volume/volume.
[0050] RT denotes room temperature; m.p. denotes melting point.
Example 1
[0051] 10
(2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
hydrochloride (1)
[0052] 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
[0053] 11
[0054] Enantiomers of (1):
(-)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
hydrochloride (-1)
[0055] and
(+)-(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
hydrochloride (+1).
[0056] 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.
[0057] (-1): yield: 42% theoretical
[0058] [.alpha.].sub.D.sub..sup.RT=-31.8.degree. (c=0.99;
methanol)
[0059] (+1): yield: 41% theoretical
[0060] [.alpha.].sub.D.sub..sup.RT=+33.0.degree. (c=0.96;
methanol)
Example 3
[0061] 12
(2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2-methylpentan-3-ol
hydrochloride (2)
[0062] 39 g of crude mixture were prepared analogously to Example 1
from 15 g (105 mmole) 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
[0063] 13
(2RS,3RS)-3-(3-isopropoxyphenyl)-1-dimethylamino-2-methylpentan-3-ol
hydrochloride (3)
[0064] 25 g of crude mixture were prepared analogously to Example 1
from 14.3 g (100 mmole) 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
[0065] 14
(2RS,3RS)-3-(3-chlorophenyl)-1-dimethylamino-2-methylpentan-3-ol
hydrochloride (4)
[0066] 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 mmole)
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
[0067] 15
(2RS,3RS)-1-dimethylamino-2-methyl-3-(3-trifluoromethylphenyl)-pentan-3-ol
hydrochloride (5)
[0068] 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-on- e, 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
[0069] 16
(2RS,3RS)-1-dimethylamino-2-methyl-3-(3-m-tolyl)-pentan-3-ol
hydrochloride (6)
[0070] 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/wate- r
in 2-butanone.
Example 8
[0071] 17
(2RS,3RS)-1-dimethylamino-3-(3-fluorophenyl)-2-methylpentan-3-ol
hydrochloride (7)
[0072] 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
[0073] 18
(2RS,3RS)-3-(3-difluoromethylphenyl)-1-dimethylamino-2-methylpentan-3-ol
hydrochloride (8)
[0074] 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 drop-wise. The reaction mixture was
warmed to room temperature over 2.5 hours.
[0075] 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
[0076] 19
(2RS,3RS)-1-dimethylamino-2-methyl-3-(3-methylsulphanylphenyl)-pentan-3-ol
hydrochloride (9)
[0077] 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
[0078] 20
(2RS,3RS)-3-benzofuran-6yl-1-dimethylamino-2-methylpentan-3-ol
hydrochloride (10)
[0079] 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-on- e 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
[0080] 21
(2RS,3RS)-1-dimethylamino-2-methyl-3-(4-trifluoromethylphenyl)-pentan-3-ol
hydrochloride (11)
[0081] 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-dibromoethane. 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)
[0082] 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)
[0083] 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)
[0084] 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
[0085] 22
(2RS,3RS)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-3-ol
hydrochloride (15)
[0086] 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
[0087] 23
[0088] Enantiomers of (15):
(-)-(2S,3S)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-3-ol
hydrochloride (-15)
[0089] and
(+)-(2R,3R)-4-dimethylamino-2-(3-methoxyphenyl)-3-methylbutan-3-ol
hydrochloride (+15).
[0090] 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.
[0091] (-15):
[0092] yield: 41% theoretical
[0093] m.p.: 117-118.degree. C.
[0094] [.alpha.].sub.D.sub..sup.RT=-38.6.degree. (c=1.05;
methanol)
[0095] (+15):
[0096] yield: 41% theoretical
[0097] m.p.: 118-119.degree. C.
[0098] [.alpha.].sub.D.sub..sup.RT=+41.0.degree. (c=1.01;
methanol)
Example 18
[0099] 24
(2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol
hydrochloride (16).
[0100] 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
[0101] 25
[0102] Enantiomers of (16):
(-)(2S,3S)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol
hydrochloride (-16)
[0103] and
(+)(2S,3S)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol
hydrochloride (+16)
[0104] The enantiomers (-16) and (+16) were prepared under the
conditions cited in Example 2.
[0105] (-16):
[0106] yield: 85% theoretical
[0107] m.p.: 208-209.degree. C.
[0108] [.alpha.].sub.D.sub..sup.RT=-34.6.degree. (c=0.98;
methanol)
[0109] (+16):
[0110] yield: 85% theoretical
[0111] m.p.: 206-207.degree. C.
[0112] [.alpha.].sub.D.sub..sup.RT=+34.4.degree. (c 1.06;
methanol)
Example 20
[0113] 26
(1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropylphenol
hydrochloride (17)
[0114] Compound (17) was prepared under the conditions cited in
Example 18 starting from methoxy compound (15) which was obtained
as in Example 16.
[0115] Yield: 85% theoretical
[0116] m.p.: 232.degree. C.
Example 21
[0117] 27
[0118] Enantiomers of (17):
(-)-(1S,2S)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenol
hydrochloride (-17)
[0119] and
(+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)-phenolhydroch-
loride (+17)
[0120] The enantiomers (-17) and (+17) were prepared under the
conditions cited in Example 2.
[0121] (-17):
[0122] yield: 82% theoretical
[0123] m.p.: 204-205.degree. C.
[0124] [.alpha.].sub.D.sub..sup.RT=-42.0.degree. (c=0.94;
methanol)
[0125] (+17):
[0126] yield: 83% theoretical
[0127] m.p.: 204-205.degree. C.
[0128] [.alpha.].sub.D.sub..sup.RT=+41.2.degree. (c=1.01;
methanol)
Example 22
[0129] 28
(+)-(1R,2R)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl)-phenol
hydrochloride (+18)
[0130] 1st Step 29
(+)-(1R,2R)-3-(3-benzyloxyphenyl)-1-dimethylamino-2-methylpentan-3-ol
(+19)
[0131] 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.
[0132] 2nd Step 30
(+)-(2R,3R)-[3-(3-benzyloxyphenyl)-3-fluoro-2-methylpentyl]-dimethylamine
(+20)
[0133] 6.8 g (21 mmole) of (+19), dissolved in 80 ml
dichloromethane, were added drop-wise 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.
[0134] 3rd Step:
(+)-(1R,2R)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl)-phenol
hydrochloride (+18)
[0135] 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.
[0136] m.p.: 174-176.degree. C.
[0137] [.alpha.].sub.D.sub..sup.RT=+29.5.degree. (c=1.08;
methanol)
Example 23
[0138] 31
(-)-(1S,2S)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl)-phenol
hydrochloride (-18)
[0139] 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.
[0140] m.p.: 170-172.degree. C.
[0141] [.alpha.].sub.D.sub..sup.RT=-28.4.degree. (c=1.03;
methanol)
Example 24
[0142] 32
(+)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
hydrochloride (+21)
[0143] 1st Step: 33
(+)-(2R,3R)-[3-chloro-3-(-3-methoxyphenyl)-2-methylpentyl]-dimethylamine
hydrochloride (+22)
[0144] 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.
[0145] m.p.: 120.degree. C. (decomposition)
[0146] [.alpha.].sub.D.sub..sup.RT=+24.7.degree. (c=1.01;
methanol)
[0147] 2nd Step: 34
(+)-(2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine
hydrochloride (+23)
[0148] 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.
[0149] m.p.: 163-164.degree. C.
[0150] [.alpha.].sub.D.sub..sup.RT=+25.2.degree. (c=0.95;
methanol)
[0151] 3rd Step:
(+)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
hydrochloride (+21)
[0152] 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/w- ater, 3.8 g of hydrochloride (+21) (98%
theoretical) crystallised out.
[0153] m.p.: 194-196.degree. C.
[0154] [.alpha.].sub.D.sub..sup.RT=+24.5.degree. (c=1.10;
methanol)
Example 25
[0155] 35
(-)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
hydrochloride (-21)
[0156] Enantiomer (-21) was obtained in 45% yield under the
conditions cited in Example 24 from (-1), which was prepared as in
Example 2.
[0157] m.p.: 168-170.degree. C.
[0158] [.alpha.].sub.D.sub..sup.RT=-27.5.degree. (c=0.97;
methanol)
Example 26
[0159] 36
(+)-(1R,2R)-acetic
acid-3-dimethylamino-1-ethyl-1-(3-methyoxyphenyl)-2-met- hylpropyl
ester hydrochloride (+24)
[0160] 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 dropwise,
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.
[0161] m.p.: 153.degree. C.
[0162] [.alpha.].sub.D.sub..sup.RT=-17.3.degree. (c=1.04;
methanol)
Example 27
[0163] 37
(1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-1-(3-methoxyphenyl)-propan-1-ol
hydrochloride (25)
[0164] 1st Step: 38
(1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-(3-methoxyphenyl)-methanol
hydrochloride (26)
[0165] 44 g crude mixture was obtained from 25 g (150 mmole)
1-dimethylaminomethylcyclohexane 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.
[0166] 2nd Step: 39
(1RS)-(1-dimethylaminomethyl-cyclohexyl)-(3-methoxyphenyl)-methanone
hydrochloride (27)
[0167] 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.
[0168] 3rd Step:
(1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-1-(3-methoxyphenyl)-propan-1-ol
hydrochloride (25)
[0169] 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
[0170] 40
(-)-(2R,3S)-{3[3-(p-isopropyl-phenyl-carbamoyl)-oxy-phenyl]-2-methylpentyl-
-dimethylamine hydrochloride (-28)
[0171] 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).
[0172] m.p.: 151-152.degree. C.
[0173] [.alpha.].sub.D.sub..sup.RT=-5.2.degree. (c=1.11;
methanol)
PHARMACOLOGICAL INVESTIGATIONS
Writhing Test on Mice
[0174] 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:
1TABLE 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
[0175] 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.
* * * * *