Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1997-01-27
2001-10-30
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C514S651000
Reexamination Certificate
active
06310252
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to pharmaceutically useful compounds, in particular [(3-alkoxy-phenoxy)-ethyl]-dialkylamine derivatives, their use as medicaments, in particular anaesthetics (e.g. local anaesthetics), pharmaceutical compositions containing them and synthetic routes to their production.
PRIOR ART
Certain [(4methoxy-phenoxy)-alkyl]-diethylamine derivatives are known as herbicides from European Patent Application 0 103 252. Their use as pharmaceuticals is not suggested.
Certain [(3- and [(4-alkoxy-phenoxy)-alkyl]-alkyl-propargyl and -cyclopropylamine derivatives are known to be useful in the treatment of psychiatric disorders from U.S. Pat. No. 3,221,054; and [(2,6-dimethoxy-phenoxy)-ethyl]-dimethylamine is known as an antidepressant from U.S. Pat. No 3,205,136. The compounds' use as anaesthetics is not suggested.
[(4-Alkoxy-phenoxy)-ethyl]-morpholine and -piperidine derivatives are known as local anaesthetics from French Patent No. 1 173 136. Moreover, certain 3-substituted phenoxyethylamine derivatives including (3-alkoxy-phenoxy)-ethyl]-diethylamine derivatives are known as local anaesthetics from U.S. Pat. No 3,105,854 and French Special Medicament Patent No. 302 M.
However, there remains a need for more effective anaesthetic compounds. Moreover there is a need particular need for effective local anaesthetics which may be administered topically to e.g. the skin.
We have found that certain compounds not specifically disclosed by, but included within, the scope of the specification of U.S. Pat. No 3,105,854 exhibit surprisingly good anaesthetic properties and are particularly useful as topical anaesthetics.
DISCLOSURE OF THE INVENTION
According to the invention there is provided a compound of formula I,
wherein
R
1
represents C
3-5
alkyl; and
R
2
and R
3
independently represent C
1-3
alkyl;
provided that when R
2
and R
3
both represent ethyl, then R
1
does not represent n-butyl i-butyl or n-pentyl;
or a pharmaceutically acceptable salt thereof (hereinafter referred to as “the compounds of the invention”).
Pharmaceutically acceptable salts include nontoxic organic or inorganic acid addition salts, e.g. hydrochloride, hydrobromide, sulphate, hydrosulphate, nitrate, lactate, acetate, citrate, benzoate, succinate, tartrate, trifluoroacetate salts and the like. Preferred acid addition salts include hydrochloride salts.
The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. All diastereoisomer may be separated using conventional techniques, e.g. chromatography or factional crystallisation. The various optical isomers ray be isolated by separation of a racemic or other mixture of the compounds using conventional e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica). All stereoisormers are included within the scope of the invention.
Alkyl groups which R
1
, R
2
and R
3
may represent may be linear or branched. Typical alkyl groups which may be mentioned include methyl, ethyl, n-propyl, i-propyl, n-butyl i-butyl n-pentyl and i-pentyl and preferred alkyl groups are those wherein R
2
and R
3
do not both represent ethyl.
Preferred compounds of the invention are those wherein R
1
represents n-propyl n-butyl or n-pentyl, R
2
represents methyl, ethyl or i-propyl, and R
3
represents i-propyl.
More preferred compounds of the invention are those wherein R
1
represents n-propyl or n-butyl, R
2
represents methyl, ethyl or i-propyl, and R
3
represents i-propyl.
Even more preferred compounds of the invention are those wherein R
1
represents n-propyl or n-butyl, R
2
represents methyl or ethyl, and R
3
represents i-propyl.
Especially preferred compounds of the invention are those wherein R
1
represents n-propyl R
2
represents methyl or ethyl, and R
3
represents i-propyl.
Most preferred compounds of the invention are those wherein R
1
represents n-propyl, R
2
represents methyl, and R
3
represents i-propyl.
Preparation
According to the invention there is also provided a process for the preparation of compounds of formula I which comprises:
(a) reaction of a compound of formula II,
wherein R
1
is as hereinbefore defined, with a compound of formula III,
HN(R
2
)R
3
III
wherein R
2
and R
3
are as hereinbefore defined, for example at elevated temperature (e.g. reflux) in the presence of a suitable organic solvent (e.g. toluene): or
(b) reaction of a compound of formula IV,
wherein R
1
is as hereinbefore defined, with a compound of formula V,
R
2
(R
3
)NCH
2
CH
2
Hal V
wherein Hal represents Cl, Br or I and R
2
and R
3
are as hereinbefore defined, or an acid addition salt thereof, for example at elevated temperature (e.g. reflux) in the presence of a suitable base (e.g. sodium ethoxide) and an appropriate organic solvent (e.g. ethanol).
Compounds of formula II may be prepared analogously to the methods described in U.S. Pat. No 3,105,854 for example by reaction of a compound of formula IV, as hereinbefore defined with a compound of formula VI,
HalCH
2
CH
2
Hal VI
wherein Hal is as hereinbefore defined. Compounds of formula II may be prepared in this way, for example at or around room temperature in the presence of a two phase solvent system and an appropriate ion pair extracting agent. Suitable organic solvents for the two phase system include excess alkyl dihalides of formula VI and suitable ion pair extracting agents include tetrabutylammonium hydroxide.
Compounds of formula IV are commercially available or may be prepared conveniently using known techniques. For example compounds of formula IV may be prepared by the reaction of resorcinol with a compound of formula VII,
R
1
Hal VII
wherein Hal and R
1
are as hereinbefore defined, for example at elevated temperature (e.g. reflux) in the presence of a suitable base (e.g. sodium ethoxide) and an appropriate organic solvent (e.g. ethanol).
Compounds of formula III, V, VI and VII are either commercially available or are available using known techniques.
The compounds of the invention may be isolated from their reaction mitures using conventional techniques.
Medical and Pharmaceutical Use
The compounds of the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceutcals.
According to a further aspect of the invention there is thus provided a compound of formula I as hereinbefore defined, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.
In particular, the compounds of the invention possess anaesthetic properties for example as demonstrated in the test described below. They are therefore useful as anaesthetics, in particular local anaesthetics and especially topically applied local anaesthetics.
The compounds of the invention are thus indicated for the treatment of pain, including localised pain.
Pharmaceutical Formulations
The compounds of the invention will normally be administered parenterally, especially topically in the form of pharmaceutical formulations comprising the active ingredient in a pharmaceutically acceptable dosage form.
We prefer administration to be topically to the skin.
Modes of topical administration of the compounds of the invention to the skin which may be mentioned include emulsions, cream, lotions, ointments and skin patches. Compositions comprising the compounds of the invention for topical administration may include other ingredients commonly used in the parenteral administration of pharmaceutically-active compounds.
According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of form
Astrazeneca AB
Barts Samuel
Pillsbury & Winthrop LLP
Sanzo Michael A.
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