Alpha-aminoamide derivatives useful as analgesic agents

Details Alpha-aminoamide derivatives useful as analgesic agents Alpha-aminoamide derivatives useful as analgesic agents

2000-08-29

2001-10-23

Higel, Floyd D. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S619000, C514S620000, C558S414000, C564S163000, C564S164000, C564S171000

Reexamination Certificate

active

06306903

ABSTRACT:

The present invention relates to novel and known alpha-aminoamide compounds, to a process for their preparation, to pharmaceutical composition containing them and to their use as therapeutic agents.
In particular, the compounds of the present invention are endowed with analgesic properties and are particularly useful for the treatment and alleviation of chronic and neuropathic pain.
Chronic and neuropathic pain are associated with prolonged tissue damage or injuries to the peripheral or central nervous system and result from a number of complex changes in nociceptive pathways.
Clinical manifestations of chronic pain include a sensation of burning or electric shock, feelings of bodily distortion, allodynia and hyperpathia.
Despite the large number of available analgesics, their use is limited by severe side effects and modest activity in some pain conditions. Therefore there is still a clear need to develop new compounds.
International applications WO 90/14334, WO 94/22808, WO 97/05111 and WO 97/05102 disclose substituted benzylaminopropionamide compounds active on the central nervous system and useful as anti-epileptic, anti-Parkinson, neuroprotective, antidepressant, antispastic and hypnotic agents.
The present invention is based on the finding that compounds known from the above-cited international applications and new ones, closely related thereto, have analgesic properties in mammals, including humans.
Accordingly, one object of the present invention is to provide the use of a compound of formula (I)
wherein:
A is a —(CH
2
)
m
—, —(CH
2
)
n
—X— or —(CH
2
)
v
—O— group wherein m is an integer of 1 to 4, n is zero or an integer of 1 to 4, X is —S— or —NH—, and v is zero or an integer of 1 to 5;
s is 1 or 2;
R is a furyl, thienyl, or pyridyl ring or a phenyl ring optionally substituted by one or two substitutents independently chosen from halogen, cyano, C
1
-C
4
alkyl, C
1
-C
4
alkoxy and trifluoromethyl;
R
1
is hydrogen or C
1
-C
4
alkyl;
one of R
2
and R
3
is hydrogen and the other is hydrogen or C
1
-C
4
alkyl optionally substituted by hydroxy or phenyl; or R
2
and R
3
taken together with the carbon atom to which they are linked form a C
3
-C
6
cycloalkyl ring; or R
2
and R
3
are both methyl;
R
4
is hydrogen or C
1
-C
4
alkyl;
or a pharmaceutically acceptable salt thereof;
and wherein
when A is a —(CH
2
)
5
—O— group then s is 1, R is a phenyl group optionally substituted by one or two substitutents selected independently from halogen, trifluoromethyl and C
1
-C
4
alkoxy, R
1
is hydrogen and one of R
2
and R
3
is hydrogen and the other is hydrogen or C
1
-C
4
alkyl optionally substituted hydroxy;
and wherein
when R
2
and R
3
are both methyl then R is other than furyl, thienyl or pyridyl ring, in the manufacture of a medicament for use as analgesic, in particular for the treatment and alleviation of chronic and neuropathic pain.
A —(CH
2
)
m
—, —(CH
2
)
n
— or —(CH
2
)
v
— chain may be a branched or straight chain. Alkyl and alkoxy groups may be branched or straight groups. Representative examples of C
1
-C
4
alkyl groups include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl.
Representative examples of C
1
-C
4
alkoxy groups include methoxy and ethoxy.
A C
3
-C
6
cycloalkyl group is for instance cyclopropyl, cyclopentyl or cyclohexyl, in particular cyclopentyl or cyclohexyl.
A halogen atom is fluorine, bromine, chlorine or iodine, in particular, chlorine or fluorine.
Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts with inorganic, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric acids or organic, e.g. acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic acids.
The compounds of formula (I) have asymmetric carbon atoms and therefore they can exist either as racemic mixtures or as individual optical isomers (enantiomers).
Accordingly, the present invention also include within its scope all the possible isomers and their mixtures and both the metabolites and the pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I).
Preferred compounds of formula (I) are those wherein
A is a group chosen from —CH
2
—, —CH
2
—CH
2
—, —CH
2
—S—, —CH
2
—CH
2
—S— and —(CH
2
)
v
—O— in which v is an integer of 1 to 5;
s is 1 or 2;
R is a phenyl ring optionally substituted by one or two substitutents independently chosen from halogen and cyano or a thienyl ring;
R
1
is hydrogen or C
1
-C
4
alkyl;
one of R
2
and R
3
is hydrogen and the other is C
1
-C
4
alkyl optionally substituted by hydroxy or phenyl; or R
2
and R
3
are both methyl;
R
4
is hydrogen or C
1
-C
4
alkyl; and the pharmaceutically acceptable salts thereof.
Examples of specific compounds of formula (I) are:
2-[4-(3-fluorobenzyloxy)benzylamino]-2-methyl-propanamide;
2-[4-(3-fluorobenzyloxy)benzylamino]propanamide;
2-([4-benzyloxybenzylamino)propanamide;
2-[4-(2-fluorobenzyloxy)benzylamino]propanamide;
2-[4-(4-fluorobenzyloxy)benzylamino]propanamide;
2-[4-(2-chlorobenzyloxy)benzylamino]propanamide;
2-(4-(3-chlorobenzyloxy)benzylamino]propanamide;
2-[4-(3-fluorobenzyloxy)benzylamino]-3-hydroxy-N-methylpropanamide;
2-[4-(2-fluorobenzyloxy)benzylamino]-3-hydroxy-N-methylpropanamide;
2-[4-(2-chlorobenzyloxy)benzylamino]-3-hydroxy-N-methylpropanamide;
2-[4-(3-cyanobenzyloxy)benzylamino]-3-hydroxy-N-methylpropanamide;
2-[4-(3-chlorobenzyloxy)phenylethylamino]-propanamide;
2-(4-benzyloxybenzylamino)-3-hydroxy-N-methyl-propanamide;
2-(4-(2-thenyloxy)benzylamino)-propanamide;
2-[4-(3- fluorobenzyloxy)benzylamino]-N-methylpropanamide;
2-[4-(3-fluorobenzyloxy)benzylamino]-3-hydroxy-propanamide;
2-[4-(2-(3-fluorophenyl)ethyloxy)benzylamino]-propanamide;
2-[4-(2-(3-fluorophenyl)ethyl)benzylamino]-propanamide;
2-[N-4-benzyloxybenzyl-N-methyl-amino]-propanamide;
2-[2-(4-(3-chlorobenzyloxy)phenylethyl)amino]-propanamide;
2-[4-benzylthiobenzylamino]-propanamide;
2-[4-(3-phenylpropyloxy)benzylamino]-propanamide;
2-[4-(4-phenylbutyloxy)benzylamino]-propanamide;
2-[4-(5-phenylpentyloxy)benzylamino]-propanamide;
2-[4-benzyloxybenzylamino]-3-phenyl-N-methylpropanamide;
2-[4-benzyloxybenzylamino]-3-methyl-N-methylbutanamide, if the case either as a single isomer or as a mixture thereof, and the pharmaceutically acceptable salts thereof.
An aspect of this invention relates to a pharmaceutically composition having analgesic activity, in particular against chronic and neuropathic pain, comprising a compound of formula (I), as herein defined, as an active agent and a pharmaceutically acceptable salt thereof.
A further aspect of this invention relates to a method of treating a mammal, including humans, in need of an analgesic agent, said method comprising administering thereto an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Neuropathic and chronic pain conditions in a mammal can thus be alleviated and treated. Examples of pain conditions that can be treated by a compound of formula (I) include:
peripheral neuropathies, such as trigeminal neuralgia, postherapeutic neuralgia, diabetic neuropathy, glossopharyngeal neuralgia, radiculopathy, and neuropathy secondary to metastatic infiltration, adiposis dolorosa and burn pain; and
central pain conditions following stroke, thalamic lesions and multiple sclerosis. “Treatment” as used herein covers any treatment of a condition in a mammal, particularly a human, and includes:
(i) preventing the disease from occurring in a subject which may be predisposed to the disease, but has not yet been diagnosed as having it;
(ii) inhibiting the condition, i.e., arresting its development; or
(iii) relieving the condition, i.e., causing regression of the disease.
Another object of the present inventi

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