U.S. patent application number 10/139674 was filed with the patent office on 2002-12-12 for thienylazolylalkoxyethanamines, their preparation and their application as medicaments.
This patent application is currently assigned to LABORATORIOS DEL DR. ESTEVE, S.A.. Invention is credited to Andaluz-Mataro, Blas, Frigola-Constansa, Jordi, Merce-Vidal, Ramon.
Application Number | 20020188017 10/139674 |
Document ID | / |
Family ID | 8303465 |
Filed Date | 2002-12-12 |
United States Patent
Application |
20020188017 |
Kind Code |
A1 |
Merce-Vidal, Ramon ; et
al. |
December 12, 2002 |
Thienylazolylalkoxyethanamines, their preparation and their
application as medicaments
Abstract
The thienylazolylalkoxyethanamines (I) where R1 is a hydrogen
atom, a halogen atom or a lower alkyl radical; R2, R3 and R4
represent, independently, a hydrogen atom or a lower alkyl radical;
and Az represents a five-member nitrogenated hetercyclic aromatic
group, N-methyl-substituted, that contains from one to three
nitrogen atoms. They have analgesic activity in mammals, including
humans. The compounds (I) can be obtained, for example, by reaction
of a derivative of hydroxy-thienylazol (IV) with a derivative of a
suitable N-(ethyl)amine. The compounds (IV) are useful
intermediates in the synthesis of the compounds (I). The compounds
(I) have an application in human and/or veterinary medicine.
Inventors: |
Merce-Vidal, Ramon;
(Barcelona, ES) ; Andaluz-Mataro, Blas;
(Barcelona, ES) ; Frigola-Constansa, Jordi;
(Barcelona, ES) |
Correspondence
Address: |
Ladas & Parry
26 West 61st Street
New York
NY
10023
US
|
Assignee: |
LABORATORIOS DEL DR. ESTEVE,
S.A.
|
Family ID: |
8303465 |
Appl. No.: |
10/139674 |
Filed: |
May 6, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10139674 |
May 6, 2002 |
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09673186 |
Oct 12, 2000 |
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6410582 |
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09673186 |
Oct 12, 2000 |
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PCT/ES99/00098 |
Apr 15, 1999 |
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Current U.S.
Class: |
514/406 ;
548/364.1 |
Current CPC
Class: |
C07D 409/04 20130101;
A61P 25/04 20180101; A61P 29/00 20180101; C07D 409/06 20130101;
A61P 43/00 20180101; A61K 31/4155 20130101 |
Class at
Publication: |
514/406 ;
548/364.1 |
International
Class: |
C07D 49/02 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 15, 1998 |
ES |
P 9800793 |
Claims
1. A derivative of thienylazolylalkoxyethanamine of general formula
(I) 59in which R1 is a hydrogen or halogen atom, or an alkyl
radical of 1 to 4 carbon atoms; R2, R3 and R4 represent,
independently, an atom of hydrogen or an alkyl radical of 1 to 4
carbon atoms; and Az represents a nitrogenated heterocyclic
aromatic five-member ring, N-methyl substituted, that contains from
one to three atoms of nitrogen, of general formula (III) 60in which
Z1, Z2 and Z3, independently, represent an atom of nitrogen or CH,
and its physiologically acceptable salts:
2. A compound according to claim 1, in which the halogen atom
represents a fluorine, chlorine, or bromine atom.
3. A compound according to claim 1, selected from the following
group: [1]
5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol-
; [2] Citrate of
5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-m-
ethyl-1H-pyrazol; [3]
5-{.alpha.-[2-(dimethylamino)ethoxy]-3-thienylmethyl-
}-1-methyl-1H-pyrazol; [4]
2-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylm-
ethyl}-1-methyl-1H-imidazol; [5]
5-{.alpha.-[2-(dimethylamino)ethoxy]-3-me-
thyl-2-thienylmethyl-}-1-methyl-1H-pyrazol; [6]
5-{.alpha.-[2-(dimethylami- no)ethoxy]-5-methyl-2-thienylmethyl
}-1-methyl-1H-pyrazol; [7]
5-{.alpha.-[2-(dimethylamino)ethoxy]-5-bromo-2-thienylmethyl}-1-methyl-1H-
-pyrazol; [8]
5-{.alpha.-[2-(dimethylamino)ethoxy]-4-bromo-2-thienylmethyl-
}-1-methyl-1H-pyrazol; [9]
5-{1-[2-(dimethylamino)ethoxy]-1-(2-thienyl)eth-
yl}-1-methyl-1H-pyrazol; [10]
(+)-5-{.alpha.-[2-(dimethylamino)ethoxy]-2-t-
hienylmethyl}-1-methyl-1H-pyrazol; [11]
(-)-5-{.alpha.-[2-(dimethylamino)e-
thoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol; [12] Citrate of
(+)-5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylmethyl)}-1-methyl-1H-py-
razol; [13] Citrate of
(-)-5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylm-
ethyl}-1-methyl-1H-pyrazol; [14] D-toluoyltartrate of
(+)-5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyr-
azol; and [15] D-toluoyltartrate of
(-)-5-{.alpha.-[2-(dimethylamino)ethox-
y]-2-thienylmethyl}-1-methyl-1H-pyrazol.
4. Procedure for obtaining a derivative of
thienylazolylalkoxyethanamine of general formula (I), according to
claim 1, which comprises making a compound of general formula (IV)
61in which R1, R2 and Az have the meaning indicated in claim 1;
with a compound of general formula (V) 62in which R3 and R4 have
the meaning indicated in claim 1, and X represents a halogen atom
or a leaving group.
5. Procedure for obtaining a derivative of
thienylazolylalkoxyethanamine of general formula (I), according to
claim 1, which comprises making a compound of general formula (VI)
react 63in which R1 and R2 have the meaning indicated in claim 1,
and Y represents a halogen atom. a leaving group or a hydroxyl
group; with a compound of general formula (VII) 64in which R3 and
R4 have the meaning indicated in claim 1.
6. Procedure for obtaining a derivative of
thienylazolylalkoxyethanamine of general formula (I), according to
claim 1, enantiomerically pure, that comprises effecting the
resolution of the racemic mixtures of general formula (I), by
forming a salt with an enantiomerically pure acid.
7. Procedure for obtaining a physiologically acceptable salt of a
derivative of thienylazolylalkoxyethanamine of general formula (I),
according to claim 1, that comprises making react a compound of
general formula (I) with an inorganic acid or with an organic acid
in the presence of a solvent.
8. A pharmaceutical composition characterised because it contains,
at least, one derivative of thienylazolylalkoxyethanamine of
general formula (I), or one of its physiologically acceptable
salts, according to any of the claims 1 to 3, and a
pharmaceutically acceptable excipient.
9. Use of a thienylazolylalkoxyethanamine of general formula (I),
or one of its physiologically acceptable salts, according to any of
the claims 1 to 3, in the elaboration of a medicament with
analgesic activity in mammals, including man.
10. A compound of general formula (IV), as an intermediate for the
preparation of a compound of general formula (I), according to
claim 1 65in which R1 and R2 have the meanings mentioned in claim 1
and Az represents N-methylpyrazol.
11. A compound according to claim 10, selected from the following
group: [16]
5-(.alpha.-hydroxy-2-thienylmethyl)-1-methyl-1H-pyrazol; [17]
5-(.alpha.-hydroxy-3-methyl-2-thienylmethyl)-1-methyl-1H-pyrazol;
[18]
5-(.alpha.-hydroxy-5-methyl-2-thienylmethyl)-1-methyl-1H-pyrazol;
[19]
5-(.alpha.-hydroxy-5-bromo-2-thienylmethyl)-1-methyl-1H-pyrazol;
[20]
5-(.alpha.-hydroxy-4-bromo-2-thienylmethyl)-1-methyl-1H-pyrazol;
and [21] 5-[1-hydroxy-1-(2-thienyl)ethyl]-1-methyl-1H-pyrazol.
12. Procedure for obtaining a compound of general formula (IV),
according to claim 10, in which R2 represents a hydrogen atom, that
comprises effecting the reduction of a compound of general formula
(VIII) 66in which R1 has the meaning indicated in claim 1, and Az
represents N-methylpyrazol.
13. Procedure according to claim 12, in which said reduction is
effected by the use of a reducing agent selected from the group
formed by metallic hydrides or with hydrogen in the presence of a
catalyst.
14. Procedure for obtaining a compound of general formula (IV),
according to claim 10, that comprises adding to a carbonyl compound
of general formula (IX) 67in which R1 and R2 have the meaning
indicated in claim 1; an or2anometallic reagent of general
formulaAz-Min which Az represents N-methylpyrazol, and M represents
a lithium atom or the MgX function of the Grignard reagents, where
X represents a halogen.
15. Procedure for obtaining a compound of general formula (IV),
according to claim 10, that comprises adding to carbonyl compound
of general formula (X) 68in which R2 has the meaning indicated in
claim 1 and Az represents N-methylpyrazol, an organometallic
reagent of general formula (XI) 69in which R1 has the meaning
indicated in claim 1, and M represents a lithium atom or the MgX
function of the Grignard reagents, where X represents a halogen.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to new
thienylazolylalkoxyethanamines of general formula (I), as well as
their physiologically acceptable salts, to the procedures for their
preparation, to their application as medicaments in human and/or
veterinary therapy and to the pharmaceutical compositions that
contain them. 1
[0002] The new compounds object of the present invention can be
used in the pharmaceutical industry as intermediates and for the
preparation of medicaments.
[0003] The invention also relates to new derivatives of
thienylazolylcarbinols, of general formula (IV), useful as starting
materials or intermediates in the synthesis of the compounds of
general formula (I).
BACKGROUND OF THE INVENTION
[0004] In our patent application EP 289380 we have described
different derivatives of phenylpyrazolylcarbinols, of general
formula (II) 2
[0005] in which R1 represents a hydrogen atom or an alkyl group; R2
represents an aminoalkyl radical and Het represents an azol.
[0006] We have now discovered that substituting a benzene ring for
a thiopheno ring gives rise to new compounds of general formula (I)
that show some interesting biological properties. These properties
make the new compounds particularly useful for use in human and/or
veterinary therapy. The compounds object of this patent are useful
as agents with analgesic activity.
DETAILED DESCRIPTION OF THE INVENTION
[0007] The present invention provides new compounds with potent
analgesic activity.
[0008] The compounds object of the present invention correspond to
the general formula (I) 3
[0009] in which
[0010] R1 represents a hydrogen atom, a halogen atom or a lower
alkyl radical; R2, R3 and R4 represent a hydrogen atom or a lower
alkyl radical; and Az represents an nitrogenated heterocyclic
aromatic five-member ring, N-methyl substituted, that contains from
one to three atoms of nitrogen, of general formula (III) 4
[0011] in which Z1, Z2 and Z3, independently, represent an atom of
nitrogen or CH. with the condition that. at least, one of Z1, Z2 or
Z3 is CH.
[0012] The term "lower alkyl" represents a linear or branched
carbon chain that includes from 1 to 4 atoms of carbon, such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and
terc-butyl for example.
[0013] The new compounds of general formula (I) have at least one
asymmetric carbon and so can be prepared enantiomerically pure or
as racemates. The racemates of the compounds (I) can be resolved
into their optical isomers by conventional methods, such as for
example separation by chiral chromatography or fractionated
crystallisation of their diastereoisomeric salts, which can be
prepared by reaction of the compounds (I) with enantiomerically
pure acids. Similarly, they can also be obtained by
enantioselective synthesis using chiral precursors, preferably
enantiomerically pure thienylazolylcarbinols.
[0014] The present invention relates equally to the physiologically
acceptable salts of the compounds of general formula (I), in
particular the addition salts of mineral acids such as
hydrochloric, hydrobromic, phosphoric, sulphuric, nitric acids and
organic acids such as citric, malic, fumaric, tartaric or its
derivatives, p-toluensulphonic, methanesulphonic, canphosulfonic,
etc., acids.
[0015] In an embodiment. the invention provides a compound of
formula (I) wherein R1 is a halogen atom wherein said halogen atom
represents a fluorine, chlorine, or bromine atom.
[0016] In a particular embodiment, the invention provides a
compound of formula (I) selected from the following group:
[0017] [1]
5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl--
1H-pyrazol;
[0018] [2] Citrate of
5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylmethyl-
}-1-methyl-1H-pyrazol;
[0019] [3]
5-{.alpha.-[2-(dimethylamino)ethoxy]-3-thienylmethyl}-1-methyl--
1H-pyrazol;
[0020] [4]
2-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl--
1H-imidazol;
[0021] [5]
5-{.alpha.-[2-(dimethylamino)ethoxy]-3-methyl-2-thienylmethyl}--
1-methyl-1H-pyrazol;
[0022] [6]
5-{.alpha.-[2-(dimethylamino)ethoxy]-5-methyl-2-thienylmethyl}--
1-methyl-1H-pyrazol;
[0023] [7]
5-{.alpha.-[2-(dimethylamino)ethoxy]-5-bromo-2-thienylmethyl}-1-
-methyl-1H-pyrazol;
[0024] [8]
5-{.alpha.-[2-(dimethylamino)ethoxy]-4-bromo-2-thienylmethyl}-1-
-methyl-1H-pyrazol;
[0025] [9] 5-{1-[2-(dimethylamino)ethoxy]-1-(2-thienyl)ethyl
}-1-methyl-1H-pyrazol;
[0026] [10]
(+)-5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-me-
thyl-1H-pyrazol;
[0027] [11]
(-)-5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-me-
thyl-1H-pyrazol;
[0028] [12] Citrate of
(+)-5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylm-
ethyl)}-1-methyl-1H-pyrazol;
[0029] [13] Citrate of
(-)-5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylm- ethyl
}-1-methyl-1H-pyrazol;
[0030] [14] D-toluoyltartrate of
(+)-5-{.alpha.-[2-(dimethylamino)ethoxy]--
2-thienylmethyl}-1-methyl-1H-pyrazol; and
[0031] [15] D-toluoyltartrate of
(-)-5-{.alpha.-[2-(dimethylamino)ethoxy]--
2-thienylmethyl}-1-methyl-1-1H-pyrazol.
[0032] The new derivatives of general formula (I), in which R1, R2,
R3, R4 and Az have the aforementioned meaning, can be prepared
according to the methods that are now described:
Method A
[0033] By reaction of a compound of general formula IV 5
[0034] with a compound of general formula V 6
[0035] in which R1 to R4 and Az have the aforementioned meaning and
X represents a halogen atom, preferably chlorine, or a leaving
group such as tosiloxy or mesiloxy.
[0036] The reaction of the compound of general formula IV with a
compound of general formula V in the form a base or salt, is
carried out in the presence of an appropriate solvent such as a
hydrocarbon such as benzene or toluene for example or in
halogenated solvents such as chloromethane or tetrachloromethane or
in ethers such as tetrahydrofurane or in aprotic dipolar solvents
such as dimethylsulphoxide or dimethylformamide.
[0037] The reaction is preferably carried out in the presence of an
appropriate base such as the mineral bases such as sodium hydroxide
or potassium hydroxide or the carbonates or bicarbonates of sodium
or potassium for example.
[0038] The reaction is preferably carried out in the presence of a
phase transfer catalyst such as tetrabutylamonium bromide,
triethylbenzylamonium chloride or crown ethers, in a temperature
range lying between room temperature and the solvent reflux
temperature.
Method B
[0039] By reaction of a compound of general formula VI 7
[0040] with a compound of general formula VII 8
[0041] in which R1 to R4 and Az have the aforementioned meaning and
Y represents a halogen atom, preferably chlorine, a leaving group
such as tosiloxy or mesiloxy or a hydroxyl radical.
[0042] The reaction of the compound of general formula VI with a
compound of general formula VII in the form a base or salt, is
carried out in the presence of an appropriate solvent such as a
hydrocarbon such as benzene or toluene for example or in
halogenated solvents such as chloromethane or tetrachloromethane or
in ethers such as tetrahydrofurane or in aprotic dipolar solvents
such as dimethylsulphoxide or dimethylformamide.
[0043] The reaction is preferably carried out in the presence of an
appropriate base such as the mineral bases such as sodium hydroxide
or potassium hydroxide or the carbonates or bicarbonates of sodium
or potassium for example.
[0044] The reaction can be carried out in the presence of a phase
transfer catalyst such as tetrabutylamonium bromide,
triethylbenzylamonium chloride or the crown ethers, in a
temperature range lying between room temperature and the solvent
reflux temperature.
[0045] When Y represents a hydroxyl radical the reaction is
preferably carried out in the presence of a strong acid such as
sulphuric acid, in or not in the presence of an appropriate solvent
such as benzene and in a temperature range lying between room
temperature and the reflux temperature of the solvent.
Method C
[0046] By reduction of a compound of general formula VIII 9
[0047] in which R1 and Az have the aforementioned meaning,
[0048] whereupon an intermediate compound is obtained of general
formula IV in which R1 and Az have the aforementioned meaning and
R2 represents a hydrogen atom.
[0049] The reduction is carried out with hydrides such as aluminium
hydride and lithium hydride in an appropriate solvent such as for
example an ether such as tetrahydrofurane, dimethylether or
dioxane, or else with boron hydride and sodium in an alcohol such
as methanol or ethanol, or else with hydrogen in an appropriate
solvent such as an alcohol, hydrocarbon or ether with an
appropriate catalyst such as Raney nickel, platinum oxide or
palladium. In the case of hydrogenation the pressure of hydrogen
preferably lies between 1.01 and 20.2 bars (1 and 20 atmospheres),
the temperatures vary between 20 and 100.degree. C. and the
reaction time between 1 and 24 hours.
Method D
[0050] By addition of organometallic compounds to carbonyl
compounds, for example, by the reaction of a carbonyl compound of
general formula IX 10
[0051] with organometallic reagents of general formula Az-M (Method
D-1) or else (Method D-2), by reaction of a carbonyl compound of
general formula X 11
[0052] with organometallic reagents of general formula XI 12
[0053] in which R1, R2 and Az have the aforementioned meaning and M
represents an atom of lithium or the MgX function of the Grignard
reagents, where X represents a halogen, preferably a bromine atom,
whereupon an intermediate compound is obtained of general formula
IV in which R1, R2 and Az have the aforementioned meaning.
Method E
[0054] The salts of the compounds of general formula (i) are
prepared by the reaction of a compound of general formula (I) with
an inorganic acid such as hydrochloric acid, hydrobromic acid,
phosphoric acid, sulphuric acid, nitric acid or with organic acids
such as citric, malic, fumaric, tartaric or its derivatives,
p-toluensulphonic, methansulphonic, etc., acid, in an appropriate
solvent such as methanol, ethanol, ethyl ether, ethyl acetate,
acetonitrile or acetone, obtaining the corresponding salts with the
usual techniques of precipitation or crystallisation.
Method F
[0055] The preparation of the compounds of general formula (I) in
enantiomerically pure form in accord with the present invention is
based on the optical resolution of a racemic amine by the
employment of an optically active acid in which at least one of the
enantiomers is capable of forming a diastereoisomeric salt between
an enantiomer of the compound of general formula (I) and an
enantiomer of a chiral acid, such as tartaric acid and its
dibenzoyltartaric, ditoluyltartaric, and other derivatives, malic
acid, mandelic acid and their derivatives, canphorsulphonic acid
and its derivatives, among others. The chiral acid employed can be
used either on its own or forming part of a mixtures with other
inorganic and organic acids, either chiral or non-chiral, such as
hydrochloric acid, p-toluensulphonic, methansulphonic acid, in
molar ratios that range from 0.5% to 50%. Preferably, the chiral
acid is selected from (-)-ditoluoyl-L-tartaric acid and
(+)-ditoluoyl-D-tartaric acid, either on their own or else mixed,
individually, with p-toluensulphonic acid.
[0056] The procedure is carried out in an appropriate solvent such
as water, acetone, acetonitrile, methanol, ethanol, isopropanol,
ter-butanol, dichloromethane, chloroform, carbon tetrachloride,
dimethylformamide, dimethylsulphoxide, ethyl acetate,
tetrahydrofurane, 1,4-dioxane, ethylenglycol, 1,2-dimethoxyethane,
and in general any solvent susceptible to being used in a chemical
process. The procedure can be carried out in a temperature range
lying between -20.degree. C. and the reflux temperature of the
reaction mixture. The diastereoisomeric salt, once formed, can be
separated by conventional methods such as fractionated
crystallisation, chromatography and other methods. This resolution
procedure can be used to resolve racemic mixtures of a compound of
general formula (I) (that is to say, those mixtures in which the
two enantiomers are found in a 1:1 ratio) or to resolve non-racemic
mixtures of a compound of general formula (I) (mixtures in which
one of the enantiomers is the major component), obtained by any
physical or chemical method.
[0057] The invention provides pharmaceutical compositions that
comprise, as well as an acceptable pharmaceutical excipient, at
least one compound of general formula (I) or one of their
physiologically acceptable salts. The invention also relates to the
use of a compound of general formula (I) and its physiologically
acceptable salts in the manufacture of a medicament with analgesic
activity.
[0058] The invention also relates to new derivatives of
thienylazolylcarbinols, of general formula (IV) 13
[0059] in which
[0060] R1 is a hydrogen or halogen atom, or an alkyl radical of 1
to 4 carbon atoms;
[0061] R2 is an atom of hydrogen or an alkyl radical of 1 to 4
carbon atoms; and
[0062] Az is N-methylpyrazol.
[0063] Compounds of formula (IV) are useful as starting materials
or intermediates in the synthesis of the compounds of general
formula (I).
[0064] In a particular embodiment, the invention provides a
compound of formula (IV) selected from the following group:
[0065] [16]
5-(.alpha.-hydroxy-2-thienylmethyl)-1-methyl-1H-pyrazol;
[0066] [17]
5-(.alpha.-hydroxy-3-methyl-2-thienylmethyl)-1-methyl-1H-pyraz-
ol;
[0067] [18]
5-(.alpha.-hydroxy-5-methyl-2-thienylmethyl)-1-methyl-1H-pyraz-
ol;
[0068] [19]
5-(.alpha.-hydroxy-5-bromo-2-thienylmethyl)-1-methyl-1H-pyrazo-
l;
[0069] [20]
5-(.alpha.-hydroxy-4-bromo-2-thienylmethyl)-1-methyl-1H-pyrazo- l;
and
[0070] [21]
5-[1-hydroxy-1-(2-thienyl)ethyl]-1-methyl-1H-pyrazol.
[0071] In the following examples the preparation of new compounds
according to the invention is indicated. Also described are some
ways of use typical for the different fields of application, as
well as galenic formulas applicable to the compounds object of the
invention.
[0072] The examples that are now indicated, are for illustrative
purposes, and should in no way limit the extent of the
invention.
Method A
EXAMPLE 1
Preparation of
5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-met-
hyl-1H-pyrazol
[0073] A mixture of 18 g of
5-(.alpha.-hydroxy-2-thienylmethyl)-1-methyl-1- H-pyrazol, 26.7 g
of N-(2-chloroethyl)dimethylamine chlorohydrate, 150 ml of NaOH
50%, 300 ml of toluene and 1 g of tetrabutylamonium bromide were
shaken under reflux for 24 hours. After cooling, the organic phase
was separated, washed with water, and dried over sodium sulphate
and evaporated to dryness. 21.4 g (87%) of
5-{.alpha.-[2-(dimethylamino)ethox-
y]-2-thienylmethyl}-1-methyl-1H-pyrazol were obtained in the form
of an oil.
[0074] The compounds identified by the examples 3 to 9 are obtained
by the same method of preparation described for example 1 and the
data for the identification of the products are presented in Table
1.
Method B
EXAMPLE 1
Preparation of
5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-met-
hyl-1H-pyrazol
[0075] A mixture of 8.7 9 of
5-(.alpha.-hydroxy-2-thienylmethyl)-1-methyl-- 1H-pyrazol, 6.23 g
of 2-(dimethylamino)ethanol and 0.5 ml of sulphuric acid
concentrated in 80 ml of toluene were shaken under reflux connected
to a Dean-Stark for 8 hours. After cooling, the organic phase is
separated, washed with sodium bicarbonate and water, and dried over
sodium sulphate and evaporated to dryness. 4.7 g (40%) of
5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol
were obtained.
[0076] The compounds identified by examples 3 to 9 are obtained by
the same preparation method as that described in example 1 and the
data for the identification of the products are presented in table
1.
Method C
EXAMPLE 16
Preparation of
5-(.alpha.-hydroxy-2-thienylmethyl)-1-methyl-1H-pyrazol
[0077] 3.2 9 of boron hydride and sodium are added to a solution of
3.2 g of 5-(.alpha.-oxo-2-thienylmethyl)-1-methyl-1H-pyrazol in 100
ml of methanol. The mixture is shaken for 1 hour and water added.
Next, the solution is extracted with chloroform, washed with water
and dried over sodium sulphate and evaporated to dryness. 2.9 9
(90%) of an oil is obtained which is
5-(.alpha.-hydroxy-2-thienylmethyl)-1-methyl-1H-pyrazol- .
[0078] The compounds identified by the examples 17 to 20 are
obtained by the same preparation method described for example 16
and the data for the identification of the products are shown in
Table 3.
Method D
EXAMPLE 16
Preparation of
5-(.alpha.-hydroxy-2-thienylmethyl)-1-methyl-1H-pyrazol
[0079] 100 ml of a solution of 1.6 M butilite In hexane are added
dropwise to a solution, cooled to -5.degree. C. and maintained
under a nitrogen atmosphere, of 11.6 g of N-methylpyrazol in 100 ml
of tetrahydrofurane anhydride. To the resulting suspension, a
solution of 15.9 g of 2-thiophenocarboxaldehyde in tetrahydrofurane
anhydride is added dropwise at a temperature of -78.degree. C. The
reaction is shaken for 4 hours, and the temperature allowed to rise
to -20.degree. C. before hydrolysing with 100 ml of water. The
tetrahydrofurane is evaporated off and the aqueous phase extracted
with chloroform. The organic phase is washed with water, and dried
over sodium sulphate and evaporated to dryness. The resulting crude
product is suspended in petrol ether and decanted. 23.5 g (85%) of
an oil are obtained, this oil being 5-(.alpha.-hydroxy-2-thienyl-
methyl)-1-methyl-1H-pyrazol.
[0080] The compounds identified by the examples 17 to 21 are
obtained by the same preparation method described for example 16
and the data for the identification of the products are shown in
Table 3.
Method E
EXAMPLE 2
Preparation of the citrate of
5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thien-
ylmethyl}-1-methyl-1H-pyrazol.
[0081] A solution of 16.2 g of monohydrate citric acid in 40 ml of
ethanol are added to a solution of 20.5 g of
5{.alpha.-[2-(dimethylamino)ethoxy]--
2-thienylmethyl}-1-methyl-1H-pyrazol in 50 ml of ethanol. 31 g
(88%) of citrate of
5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-
-1H-pyrazol precipitate out as a white solid with a melting point
of 115-116.degree. C. The data for the identification of the
product are presented in Table 1.
[0082] The compounds identified by the examples 12 and 13 are
obtained by the same preparation method described for example 2 and
the data for the identification of the products are presented in
Table 2.
Method F
EXAMPLE 11
Preparation of
(-)-5-{.alpha.-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-
-methyl-1H-pyrazol
[0083] 12.09 g of (-)-di-O,O'-p-toluoyl-L-tartaric acid are added
to a solution of 16.6 g of
(.+-.)-5-{.alpha.-2[2-(dimethylamino)ethoxy]-2-thie-
nylmethyl}-1-methyl-1H-pyrazol in 63 ml of isopropanol. The
solution is heated and 5.95 g of p-toluensulphonic acid monohydrate
are added. Next, the solution is allowed to cool and 158 ml of
ethyl ether added to it. 9.4 g of L-ditoluoyltartrate precipitate
out as a white solid whose diastereoisomeric ratio determined by
.sup.1H-NMR, capillary electrophoresis and HPLC in an AGP
(.alpha.-glycoprotein) chiral column is (94:6). 9.2 g of this solid
are treated with 0.16 g (0.06 equivalents) of p-toluensulphonic
acid monohydrate and re-crystallisation carried out in 44 ml of
isopropanol. 6.8 g of L-ditoluoyltartrate (95.4:4.6) are obtained.
The following re-crystallisation in 30 ml of isopropanol with 91.3
mg (0.046 equivalents) of p-toluensulphonic acid monohydrate leads
to 5.55 g of salt (97.7:2.3). A final re-crystallisation in
isopropanol with 38.1 mg (0.023 equivalents) of p-toluensulphonic
acid monohydrate yields 4.34 g of L-ditoluoyltartrate of
(-)-5-{-{.alpha.-[2-(dimethylamin-
o)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol (example 15) as a
white solid with a m.p. of 130-131.degree. C.; an enantiomeric
purity of 98.5% (97% ee) as determined by HPLC on an AGP
(.alpha.-glycoprotein) chiral column; [.alpha.].sub.D=-85.4 (c=2.0
MeOH). By alkanisation of the L-ditoluoyltartrate salt of
(-)-5{-{.alpha.-[2-(dimethylamino)ethoxy]-2-t-
hienylmethyl}-1-methyl-1H-pyrazol, the product
(-)-5-{-{.alpha.-[2-(dimeth-
ylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazol is obtained in
quantitative fashion [.alpha.].sub.D=-31.8 (c=2.0 MeOH).
[0084] The compounds identified by the examples 10 and 14 are
obtained by the same preparation method described for examples 11
and 15 and the data for the identification of the products are
presented in Table 2.
1TABLE 1 14 Base or m.p. Ex. Az Tfn R2 R3 R4 salt (.degree. C.)
.sup.1H-NMR (MHz) (solvent) .delta. IR cm.sup.-1 1 15 16 H H
CH.sub.3 Base Oil (300 MHz) (CDCl.sub.3) 2.24(s, 6H), 2.54(t, J=6
Hz, 2H), 3.58(m, 2H), 3.79(s, 3H), 5.76(s, 1H), 6.17(d, J=1.8 Hz,
1H), 6.83(m, 1H), 6.93(m, 1H), 7.28(m, 1H), 7.38(d, J=1.8 Hz, 1H)
(film) 2944, 2863, 2821, 2771, 1457, 1100, 1092, 1066, 1056, 1042,
705, 651 2 17 18 H H CH.sub.3 Citrate 115-116 (300 MHz)
(DMSO-d.sub.6) 2.51(AB system, J=15 Hz, 2H), 2.71(AB system, J=15
Hz, 2H), 2.66(s, 6H), 3.18(m, 2H), 3.70-3.80(br, 5H, (.delta.=3.74,
s)), 6.07(s, 1H), 6.16(s, 1H), 7.01(m, 1H), 7.10(m, 1H), 7.34(s,
1H), 7.57(m, 1H) (KBr) 3300-2300 (broad), 1732, 1589, 1475, 1398, #
1380, 1356, 1220, 1203, 1183 3 19 20 H H CH.sub.3 Base oil (300
MHz) (CDCl.sub.3) 2.24(s, 6H), 2.54(t, J=6 Hz, 2H), 3.56(m, 2H),
3.77(s, 3H), 5.59(s, 1H), 6.08(d, J=1.8 Hz, 1H), 6.99(dd, J=5 Hz,
J'=1.2 Hz, 1H), 7.19(m, 1H), 7.30(dd, J=5 Hz, J'=3 Hz, 1H), 7.37(d,
J=1.8 Hz, 1H). (film) 2942, 2819, 2769, 1456, 1103, 783, 753 4 21
22 H H CH.sub.3 Base oil (300 MHz) (CDCl.sub.3) 2.24(s, 6H),
2.56(m, 2H), 3.54(m, 1H), 3.56(s, 3H), 3.67(m, 1H), 5.90(s, 1H),
6.77(m, 1H), 6.85(d, J=1.2 Hz, 1H), 6.93(m, 1H), 6.98(d, J=1.2 Hz),
7.27(m, 1H) (film) 2943, 2864, 2820, 2770, 1496, 1456, 1278, 1103,
1056, 772, 702 5 23 24 H H CH.sub.3 base oil (300 MHz) (CDCl.sub.3)
2.14(s, 3H), 2.23(s, 6H), 2.54(t, J=6 Hz, 2H), 3.59(m, 2H), 3.84(s,
3H), 5.74(s, 1H), 6.04(s, 1H), 6.80(d, J=5.0 Hz, 1H), 7.18(d, J=.50
Hz, 1H), 7.33(s, 1H) (film) 2944, 2865, 2821, 2772, 1455, 1100,
1092, 1067, 1055, 1042, 782, 715 6 25 26 H H CH.sub.3 base oil (300
MHz) (CDCl.sub.3) 2.24(s, 6H), 2.43(s, 3H), 2.53(t, J=6 Hz, 2H),
3.56(m, 2H), 3.80(s, 3H), 5.65(s, 1H), 6.17(d, J=1.5 Hz, 1H),
6.62(d, J=2.4 Hz, 1H), 7.37(d, J=1.5 Hz, 1H) (film) 2944, 2863,
2820, 2772, 1456, 1286, 1101, 1092, 1067, 1055, 1042, 798, 783,
762, 652 7 27 28 H H CH.sub.3 base oil (300 MHz) (CDCl.sub.3)
2.25(s, 6H), 2.55(t, J=6 Hz, 2H), 3.57(m, 2H), 3.80(s, 3H), 5.68(s,
1H), 6.20(d, J=2.1 Hz, 1H), 6.56(d, J=4 Hz 1H), 6.90(d, J=4 Hz,
1H), 7.40(d, J=2.1 Hz, 1H) (film) 2943, 2864, 2821, 2772, 1441,
1101, 1093, 1066, 1055, 1042, 968, 793, 761, 651. 8 29 30 H H
CH.sub.3 base Oil (300 MHz) (CDCl.sub.3) 2.23(s, 6H), 2.53(t, J=5.7
Hz, 2H), 3.57(m, 2H), 3.78(s, 3H), 5.72(s, 1H), 6.18(d, J=2.1 Hz,
1H), 6.74(d, J=1.5 Hz, 1H), 7.19(d, J=1.5 Hz, 1H), 7.39(d, J=2.1
Hz, 1H) (film) 2994, 2864, 2821, 2772, 1456, 1344, 1101, 1093,
1056, 1042, 780 9 31 32 CH.sub.3 H CH.sub.3 base oil (300 MHz)
(CDCl.sub.3) 1.91(s, 3H), 2.26(s, 6H), 2.52(m, 2H), 3.17(m, 1H),
3.59(m, 1H), 3.63(s, 3H), 6.31(d, J=1.5 Hz, 1H), 6.58(m, 1H),
6.88(m, 1H), 7.21(m, 1H), 7.41(d, J=1.5 Hz, 1H) (film) 2940, 2819,
2770, 1456, 1369, 1235, 1108, 1041, 930, 699.
[0085]
2TABLE 2 33 Optical Enantiomerical Melting point Example Az Tfn R2
Base or salt isomer purity % Specific rotation (.degree. C.) 10 34
35 H Base (+) 99 +31.8 (c = 2.0 CH.sub.2Cl.sub.2) Oil 11 36 37 H
Base (+) 98.5 -31.8 (c = 2.0 CH.sub.2Cl.sub.2) Oil 12 38 39 H
Citrate (+) 99 +2.8 (c = 2.0 CH.sub.2Cl.sub.2) 121-122 13 40 41 H
Citrate (-) 98.5 -2.3 (c = 2.0 CH.sub.2Cl.sub.2) 121-122 14 42 43 H
(D)-ditoluoyl tartrate (+) 99 +87.5 (c = 2.0 CH.sub.2Cl.sub.2)
130-131 15 44 45 H (L)-ditoluoyl tartrate (-) 98.5 +85.4 (c = 2.0
CH.sub.2Cl.sub.2) 130-131
[0086]
3TABLE 3 46 Base or Melting point Ex. Az Thiopheno R2 salt
(.degree. C.) .sup.1H-NMR (MHz) (Solvent) .delta. IR, cm.sup.-1 16
47 48 H Base Oil (300 MHz) (CDCl.sub.3) 3.67(s, 3H), 5.00(d, J=4.5
Hz, 1H), 6.06(d, J=4.5 Hz, 1H), 6.16(s, 1H), 6.84(m, 1H), 6.94(m,
1H), 7.23(s, 1H), 7.27(d, J=5.1 Hz, 1H) (film) 3210 (broad), 1433,
1400, 1284, 1201, 1055, 1037, 1003, 781, 760, 706 17 49 50 H Base
109-111 (300 MHz) (CDCl.sub.3) 2.19(s, 3H), 2.63(d, J=4.5 Hz, 1H),
3.82(s, 3H), 6.13(d, J=4.5 Hz, 1H), 6.16(d, J=1.5 Hz, 1H), 6.83(d,
J=5.1 Hz, 1H), 7.20(d, J=5.1 Hz, 1H), 7.37(d, J=1.5 Hz, 1H) (KBr)
3199 (broad), 1400, 1282, 1200, 1060, 998, 940, 796, 776, 732 18 51
52 H Base 131-132 (300 MHz) (CDCl.sub.3) 2.46(s, 3H), 2.79(d, J=4.6
Hz, 1H), 3.80(s, 3H), 6.04(d, J=4.6 Hz, 1H), 6.25(d, J=1.8 Hz, 1H),
6.62(d, J=3.3 Hz, 1H), 6.70(d, J=3.3 Hz, 1H), 7.39(d, J=1.8 Hz, 1H)
(KBr) 3163 (broad), 3100, 1282, 1206, 1025, 1010, 801, 788 19 53 54
H Base 107-109 (300 MHz) (CDCl.sub.3) 3.76(s, 3H), 3.86(br, 1H),
6.02(s, 1H), 6.20(d, J=1.8 Hz), 6.61(d, J=4.0 Hz, 1H), 6.91(d,
J=4.0 Hz, 1H), 7.32(d, J=1.8 Hz, 1H) (KBr) 3170 (broad), 3104,
1440, 1395, 1205, 1181, 1025, 1011, 966, 800, 791 20 55 56 H Base
95-6 (300 MHz) (CDCl.sub.3) 3.60(br, 1H), 3.78(s, 3H), 6.08(s, 1H),
6.20(d, J=1.8 Hz, 1H), 6.80(s, 1H), 7.21(s, 1H), 7.35(d, J=1.8 Hz,
1H) (KBr) 3112 (broad), 1397, 1343, 1205, 1182, 1132, 1052, 823,
795, 768 21 57 58 H Base 130-131 (300 MHz) (CDCl.sub.3) 2.00(s,
3H), 3.27(br, 1H), 3.68(s, 3H), 6.26(d, J=2.0 Hz, 1H), 6.68 8m,
1H), 6.91(m, 1H), 7.23(m, 1H), 7.32(d, J=2.0 Hz, 1H) (KBr) 3264
(broad), 1384, 1221, 1159, 1114, 802, 779, 707
Analgesic Activity: Inhibition of Contortions Induced by
Phenylbenzoquinone in Mice
[0087] The method described by Siegmund (E. Siegmund, et al, Proc.
Exp. Biol Med., 1957, 95, 729) has been used. Male Swiss mice are
used, weighing between 17 and 22 grams and in groups of at least
four animals.
[0088] The contortions are induced by injecting i.p.
phenyl-p-benzoquinone (25 ml/Kg of a solution of 0.02%
ethanol/water--5% v/v--with Evans blue at a mixing ratio of 0.1%
p/v). The contortions are counted for 15 minutes after the moment
of the injection. The products to be tested are suspended in Arabic
gum (5% p/v) and distilled water and administered orally, at a
dosage of 160 mg/Kg, 60 minutes before the phenylbenzoquinone
injection. The inhibition of contortions produced by each product
is determined, taking the contortions of a group of animals given a
control as a reference. These animals only receive the vehicle
orally, 60 minutes before administration of phenylbenzoquinone.
[0089] The results obtained with some of the products are indicated
by way of example in table
4TABLE 4 Analgesic activity: Inhibition of contortions induced by
phenylbenzoquinone in mice Dosage of product: 160 mg/Kg, oral
administration Product % Inhibition of contortions Example 1 71
Example 2 65 Example 5 45 Example 9 37 Example 12 52 Example 13 87
Acetylsalicylic acid 51 N-acetyl-p-aminophenol 34
[0090] Taking into account the good pharmacodynamic properties, the
derivatives of thienylazolylalkoxyethanamine according to the
invention can be used in a satisfactory fashion in human and animal
therapy, in particular in the treatment of pain of moderate to
strong intensity, such as sciatic, lumbago, dorsalgias, sprains,
fractures, dislocations, post-operation pain, toothache, etc.
[0091] In human therapy, the administration dosage of the compounds
of the present invention varies as a function of the seriousness of
the affliction to be treated. Normally this dosage will lie between
100 and 400 mg/day. The compounds of the invention are administered
in the form of capsules, as tablets, or injectable solutions or
suspensions, for example.
[0092] Next, by way of example, two particular galenic forms of the
compounds object of the present invention will be presented.
Pharmaceutical Formulations
[0093] Example of an injectable formula (i.m, i.v.):
5 Example 2 20 mg Sodium chloride sufficient quantity HCl 0.1 N or
NaOH 0.1 N sufficient quantity Water for injection, to 1 ml Example
of a formula for a tablet Example 2 30 mg Corn starch 46 mg
Colloidal silicon dioxide 1.15 mg Magnesium stearate 1.15 mg
Povidone K-90 4.60 mg Pre-gellatinised starch 4.60 mg
Micro-crystalline cellulose 23 mg Lactose, to 230 mg
* * * * *