This invention relates to the combined use of a known compound with compounds of a known class in the treatment of neurodegenerative disorders, and to products comprising the known compound and compounds of the known class.

5 The use of dichloroacetic acid (DCA) in the treatment of brain injuiy following ischaemia has been described in US Patent 4,631,294 and by Chang et al (Journal of Cerebral Blood Flow and Metabolism, 12, 1030-1038, 1992). NMDA receptor antagonists have been indicated in the treatment of neurodegenerative disorders previously (see, for example, European Patent Application 356035 and Choi, D.W. o (1987) J Neuroscience, 7(2), 369-379).

Surprisingly, we have now found that the combined use of DCA, or a pharmaceutically acceptable salt thereof, in conjunction with an NMDA receptor antagonist, is particularly advantageous.

Thus, according to the present invention, there is provided a pharmaceutical s formulation comprising: i) DCA, or a pharmaceutically acceptable salt thereof; and ii) an NMDA receptor antagonist; in admixture with a pharmaceutically acceptable diluent or carrier.

The combination of the components (i) and (ii) according to the invention may 0 have the advantage that it provides a pharmaceutical formulation which is less toxic, more efficacious, longer acting, has a broader range of activity, is more potent, produces fewer side effects, is synergistic, is more easily absorbed or has other more useful pharmacological properties than the components of the combination when used individually. Synergistic combinations are preferred. s Pharmaceutically acceptable salts of DCA which may be mentioned include alkali and alkaline earth metal salts, for example sodium and calcium salts.

NMDA receptor antagonists of particular interest are 2-amino-N-(l,2-diphenyl- l-methylethyl)-acetamide (disclosed in European Patent Application 279937), 1,2- diphenyl-2-propylamine (mentioned in European Patent Application 356035), (S)-α- o phenyl-2-pyridineethanamine (claimed in International Patent Application WO 93/20052 and the racemate of which is mentioned in European Patent Application 356035 under the alternative name of l-phenyl-2-(2-pyridinyl)-ethylamine and from which this enantiomer may be prepared by fractional crystallization), MK-801 (10,ll-dihydro-5-

methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine, US Patent 4,399, 141), cis-4- [phosphonomethyl]-2-piperidine carboxylic acid (also known as CGS 19755, Selfotel), N- (3-ethylphenyl)-N-methyl-N'-l-naphthalenyl-guanidine (also known as CNS-1102, Cerestat), N-ethyl-l-phenyl-2-(3-pyrazine)ethanamine (disclosed in International Patent Application WO 93/09095 under the name N-ethyl-lrphenyl-2-(2-pyrazine)ethanamine) or a pharmaceutically acceptable salt of any one thereof.

NMDA receptor antagonists of most particular interest are 2-amino-N-(l,2- diphenyl-l-methylethyl)-acetamide and (5)-α-phenyl-2-pyridineethanamine, or a pharmaceutically acceptable salt thereof, especially (S)-α-phenyl-2-pyridineethanamine, or a pharmaceutically acceptable salt thereof.

Although the use of one NMDA receptor antagonist is preferred, we envisage within the scope of the invention the use of two or more NMDA antagonists in combination.

The ratio of components (i) and (ii) of the formulation will vary with the particular NMDA receptor antagonist and the specific purpose for which the formulation is intended. Nevertheless, this ratio will typically be in the range 50:1-1:2, preferably 20:1-1:1, especially 10:1-1:1 by weight of the active principle (e.g., in the case of a salt, of the pharmacologically active ion).

Special combinations of components (i) and (ii) above which may be mentioned are the dichloroacetic acid salts of NMDA receptor antagonists which are basic or are capable of forming a cation. An example of such is the dichloroacetic acid salt of (S)-a- phenyl-2-pyridineethanamine.

Thus, as a further aspect of the invention, we provide a dichloroacetic acid salt of an NMDA receptor antagonist which is basic or capable of forming a cation. NMDA receptor antagonists which are basic or capable of forming a cation of particular interest are 2-amino-N-(l,2-diphenyl-l-methylethyl)-acetamide, l,2-diphenyl-2- propylamine, (5)-α-phenyl-2-pyridineethanamine), MK-801, N-(3-ethylphenyl)-N-methyl- N'-l-naphthalenyl-guanidine and N-ethyl-l-phenyl-2-(3-pyrazine)ethanamine.

NMDA receptor antagonists which are basic or capable of forming a cation of most particular interest are 2-amino-N-(l,2-diphenyl-l-methylethyl)-acetamide and (S)-a- phenyl-2-pyridineethanamine, especially (5)-α-phenyl-2-pyridineethanamine.

We also provide a dichloroacetic acid salt of an NMDA receptor antagonist which is basic or capable of forming a cation for use as a pharmaceutical.

We also provide a pharmaceutical formulation comprising a dichloroacetic acid salt of an NMDA receptor antagonist which is basic or capable of forming a cation in s admixture with a pharmaceutically acceptable diluent or carrier.

The salt may be made by a metathetical process e.g. by reacting dichloroacetic acid with a suitable salt of the NMDA receptor antagonist. The reaction may be carried out in a solvent which is inert under reaction conditions. The solvent is preferably one in which the desired salt is soluble, e.g. water. The desired salt may be 0 isolated and purified by, for example, crystallisation or freeze drying.

The formulations and salts according to the invention are useful in the treatment of neurodegenerative disorders.

Specific neurodegenerative disorders that may be mentioned include stroke, cerebral ischaemia, cerebral palsy, the effects of hypoglycaemia, epilepsy, AIDS-related s dementia, Alzheimer's disease, Huntington's chorea, Olivo-ponto-cerebellar atrophy, perinatal asphyxia, Parkinson's disease, anoxia, neuronal damage associated with substance abuse (for example, narcotics or cocaine), retinopathies, schizophrenia, ischaemic states after cardiac arrest or surgical operations, intoxication or injuries of the spinal cord and amyotrophic lateral sclerosis. We include within the term o "neurodegenerative disorders" neuronal loss or damage following head injury, brain trauma and sub-arachnoid haemorrhage.

According to the invention there is also provided a pharmaceutical pack comprising: i) DCA, or a pharmaceutically acceptable salt thereof; and 5 ii) an NMDA receptor antagonist; as a combined preparation for simultaneous, separate or sequential administration in the treatment of a neurodegenerative disorder.

By "simultaneous use" is meant administration of the two components in a single pharmaceutical formulation. 0 By "sequential use" is meant administration of the two components in separate pharmaceutical formulations, but with a short period of time between each administration, for example up to 5 minutes.

By "separate use" is meant administration of the two components in separate pharmaceutical formulations, but with a relatively longer period of time between each administration, for example from 5 minutes to 12 hours.

We prefer the administration of the two components to be simultaneous. The components may be administered by any convenient route, for example parenterally, rectally, and orally. Pharmaceutical formulations comprising the components include solid dosage forms, for example tablets, pills, capsules, powders, granules, and suppositories for oral, parenteral or rectal administration; and liquid dosage forms, for example sterile parenteral solutions or suspensions, suitably flavoured syrups, flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil and peanut oil, and elixirs and similar pharmaceutical diluents or carriers.

Solid compositions may be prepared by mixing the components with pharmaceutical carriers, for example conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums and other diluents, for example water, to form a homogeneous preformulation composition in which the components are uniformly dispersed. The solid dosage forms may be coated or otherwise compounded to prolong the action of the composition.

According to another aspect of this invention there is also provided a method of treatment or prophylaxis of a neurodegenerative disorder, which comprises the simultaneous, separate or sequential administration of: i) DCA, or a pharmaceutically acceptable salt thereof; and ii) an NMDA receptor antagonist; to a patient suffering from or at risk of suffering from such a disorder. We also provide a method of treatment or prophylaxis of a neurodegenerative disorder, which comprises the administration of a dichloroacetic acid salt of an NMDA receptor antagonist which is basic or capable of forming a cation to a patient suffering from or at risk of suffering from such a disorder.

According to another aspect of the invention there is also provided the use of a combination of

(i) DCA, or a pharmaceutically acceptable salt thereof; and

(ii) an NMDA receptor antagonist

in the manufacture of a medicament for simultaneous, separate or sequential administration in the treatment or prophylaxis of a neurodegenerative disorder.

There is also provided the use of a dichloroacetic acid salt of an NMDA receptor antagonist which is basic or capable of forming a cation in the manufacture of s a medicament for the treatment or prophylaxis of a neurodegenerative disorder.

According to another aspect of the invention there is also provided the use of

DCA, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for combination therapy by simultaneous, separate or sequential administration with an NMDA receptor antagonist for the treatment or prophylaxis of 0 a neurodegenerative disorder.

According to another aspect of the invention there is also provided the use of an NMDA receptor antagonist in the manufacture of a medicament for combination therapy by simultaneous, separate or sequential administration with DCA, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of a s neurodegenerative disorder.

For the above-mentioned uses the dosage administered will, of course, vary with the compounds employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when compounds of components (i) and (ii) are each administered at a daily dosage of from about O.lmg to about lOOmg o per kg of body weight, perhaps given in divided doses 1 to 4 times a day or in sustained release form. For man, the total daily dose of DCA is in the range of from 50mg to 5,000mg, more preferably from lOOmg to 3,500mg and for an NMDA antagonist, from 5 mg to l,400mg, more preferably from lOmg to 500mg.

5 Example 1 fSVα-Phenyl-2-pyridineethanamine dihydrochloride

This compound was prepared as described in International Patent Application WO

93/20052.

0 Example 2

Dichloroacetic acid compound with fSVα-phenyl-2-pyridineethanamine t2:!^

To a solution of the free base of the title compound of Example 1 (2.34g, 11.8mmoles) in methanol (10ml) was added dichloroacetic acid (1.5 ml) in methanol (10ml). The

mixture was stirred overnight, and then concentrated to an oil which solidified on standing. The solid was recrystallized from ethyl acetate twice to give the title compound (3.3g). M.p. 110-112°C. [o] _D = +34.53° (c= 1.01, CH ₃ OH, 23°C).

Example 3

Solutions of DCA and an NMDA receptor antagonist for intravenous administration to a human patient were prepared as follows:

(a) DCA, 3.5g/l and (S)-α-phenyl-2-pyridineethanamine dihydrochloride, 0.14g/l made up in 1 litre of isotonic saline at pH 7.4.

(b) DCA, 1.75 g/1 and (S)-α-phenyl-2-pyridineethanamine dihydrochloride, 0.07g/l made up in 1 litre of isotonic saline at pH 7.4.

(e) DCA, 3.5g/l and 2-amino-N-(l,2-diphenyl-l-methylethyl)-acetamide, 0.42g/l made up in 1 litre of isotonic saline at pH 7.4. (e) DCA, 3.5g/l and 2-amino-N-(l,2-diphenyl-l-methylethyl)-acetamide, 0.21g/l made up in 1 litre of isotonic saline at pH 7.4.