Alkyl amino acid derivatives useful as pharmaceutical agents

Details Alkyl amino acid derivatives useful as pharmaceutical agents Alkyl amino acid derivatives useful as pharmaceutical agents

2002-11-21

2004-03-09

Killos, Paul J. (Department: 1625)

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

Organic compounds

Carboxylic acid esters

Reexamination Certificate

active

06703522

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel alkyl amino acid derivatives useful as pharmaceutical agents, to processes for their production, to pharmaceutical compositions containing them, and to their use for the treatment of the neurological conditions set out below.
BACKGROUND TO THE INVENTION
U.S. Pat. No. 5,563,175 describes compounds of the formula (I)
in which:
R
1
represents straight or branched C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl or phenyl;
R
2
represents hydrogen or methyl; and
R
3
represents hydrogen, methyl or carboxyl.
The compounds (including their pharmaceutically acceptable salts) are analogues of &ggr;-aminobutyric acid (GABA) and were stated to activate GAD, to bind to a novel binding site, to be useful in anti-seizure therapy for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive diskinesia and spasticity, and also to exhibit antidepressant, anxiolytic and antipsychotic activity. The most preferred compounds were those where R
3
and R
2
were hydrogen and R
1
was isobutyl, the (S)-(+) enantiomer of formula (II) being the most preferred.
That compound is variously called 4-amino-3-(2-methylpropyl)butanoic acid, 3-(aminomethyl)-5-methylhexanoic acid, &bgr;-isobutyl-&ggr;-aminobutyric acid, isobutyl-GABA, isobutylgaba and pregabalin.
U.S. Pat. No. 6,001,876 discloses that the above compounds are useful in pain therapy. U.S. Pat. No. 5,840,956 discloses methods for making (±)-isobutylgaba and for obtaining from it (S)-isobutylgaba. The disclosures of all the above patents are hereby incorporated by reference.
SUMMARY OF THE INVENTION
A problem with which this invention is concerned is the production of compounds useful in the manner of pregabalin, especially in pain therapy, that when administered to humans or other animals provide an increased duration of active ingredient in the plasma.
That problem is unexpectedly solved, according to the invention, by pro-drugs of pregabalin the compounds of the formula (III)
in which:
P is hydrogen or methyl;
Q is a labile amine- or amide-forming organic group that becomes removed in the human or animal body;
R
1
is straight or branched C
2
-C
6
alkyl, C
3
-C
6
cycloalkyl or phenyl;
R
2
is hydrogen or methyl; and
R
3
is hydrogen, methyl or carboxyl;
R
4
is hydrogen or a labile ester-forming group selected from substituted and unsubstituted C
1
-C
6
alkyl, benzyl and phenyl groups that become removed in the human or animal body, and
a pharmaceutically acceptable salt of any salt-forming compound within the above class,
but excluding compounds in which R
1
is phenyl and R
2
, R
3
and R
4
are each hydrogen.
It is believed that a pro-drug of the above formula when administered to a human or other animal, especially a mammal, enters the bloodstream by passive diffusion along the whole length of the intestine, which gives a much longer duration of effectiveness. The pro-drug may not itself be biologically active, but decomposes to the corresponding active compound in plasma.
Certain of the compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are biologically equivalent to unsolvated forms and are encompassed within the scope of the invention. Certain of the compounds of the invention possess one or more chiral centers and each center may exist in the R or S configuration. The invention includes all enantiomeric and epimeric forms as well as the appropriate mixtures thereof. It also includes salts of any of the above compounds with physiologically acceptable cations or anions.
The invention also provides a method for making a compound of the formula (III) above, which comprises:
coupling a compound of the formula:
in which P and R
1
-R
4
have the meanings given above and in which said compound is in the form of a free base or an ammonium salt with a compound of the formula (VI)
or QCl, where (in each case) Q has the meaning given above;
and the invention also provides a method for making a compound of the formula (III) above, which comprises coupling a compound of the formula (V) that is a carboxylic acid, optionally employing the further step of esterifying the carboxyl group with a substituted or unsubstituted C
1
-C
6
alkanol, benzyl alcohol or phenol.
The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (III) above and a pharmaceutically acceptable carrier.
In a further aspect the invention provides the use of a compound of formula (III) in the manufacture of a medicament for the treatment of any of the following:
epilepsy;
a faintness attack;
hypokinesia;
a cranial disorder;
a neurodegenerative disorder;
depression;
anxiety;
panic;
pain;
a neuropathological disorder;
a digestive disorder.
In a further aspect, the invention provides a method for treating any of the above disorders which comprises administering a therapeutically effective amount of a compound of formula (III) to a human or animal in need of said treatment.
DESCRIPTION OF PREFERRED FEATURES
One class of pro-drugs of the invention, which is preferred on account of the relatively high activity of the parent compound, comprises isobutylgaba pro-drugs of the formula (IV)
in which P, Q and R
4
have the meanings given above, and pharmaceutically acceptable salts of any salt-forming compound within the above class.
Where R
4
is not hydrogen, it is desirable that it should be more labile than Q so that under physiological conditions the free acid forms first and unwanted reactions between the amino and carboxyl groups are avoided. Suitable values of R
4
other than hydrogen are ethyl, iso-propyl, benzyl, phenyl, methyl and t-butyl.
The group Q may be one which can be removed hydrolytically under physiological conditions, in which case it may be
in which:
R
5
is hydrogen, straight or branched chain C
1
-C
6
alkyl, phenyl or benzyl in which the benzene ring may be substituted or unsubstituted; and
Y is hydrogen, straight or branched chain C
1
-C
6
alkyl, or —CH
2
CO
2
R
6
in which R
6
represents straight or branched chain C
1
-C
6
alkyl
Alternatively, the group Q may be one which can be removed enzymatically under physiological conditions, in which case it may be selected from
in which:
R
7
is hydrogen, straight or branched chain, phenyl or benzyl in which either or each benzene ring may be substituted or unsubstituted; and
X represents a phenyl group or any of the side chains of the 20 naturally encoded &agr;-amino acids.
In a preferred group of compounds Q is
wherein R
7
is C
1
-C
6
alkyl (preferably methyl or t-butyl) or phenyl.
Compounds according to the invention include inter alia:
(S)-3-(Benzoylaminomethyl)-5-methylhexanoic acid;
(S)-Benzyl 3-(acylaminomethyl)-5-methylhexanoate;
(S)-3-[N-(acetoxymethyleneoxycarbonyl)aminomethyl]-5-methylhexanoic acid;
(S)-3-[N-((2,2-dimethylpropionyloxy)methyleneoxycarbonyl)-aminomethyl]-5-methylhexanoic acid;
(S)-3-[N-(benzoyloxymethyleneoxycarbonyl)aminomethyl]-5-methylhexanoicacid; and
pharmaceutically acceptable salts of any of the above.
Various methods may be used to prepare compounds according to the invention e.g. from starting materials disclosed in the patents referred to above.
For example, amide prodrugs of pregabalin may be prepared by reacting pregabalin with an acid chloride in an ether e.g. tetrahydrofuran at ambient temperatures. A carboxylic acid group of the resulting prodrug may be converted to an ester group by reaction with an alcohol e.g. by reaction with benzyl alcohol in the presence of 1,3-dicyclohexyldiimide (DCC) and 4-dimethylaminopyridine (DMAP) in a halogenated hydrocarbon solvent e.g. dichloromethane (DCM) at ambient temperatures. (Acyloxy)alkyl carbamate prodrugs of pregabalin may be prepared by reacting pregabalin with an acyloxyalkyl p-nitrophenyl carbonate in an ether e.g. tetrahydrofuran at ambient temperatures.
These reactions are illustra

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