WO2000059496A1 - Use of low affinity nmda antagonists for the treatment of headache - Google Patents

Abstract

The invention relates to the use of low affinity NMDA antagonist for the treatment of headache. Preferred compounds include compounds of formula (I): wherein R1 is pyridyl, phenyl or 4-fluorophenyl; R2 is phenyl or 4-fluorophenyl; R3 is hydrogen, C¿1-6? alkyl or methoxycarbonyl; R?4¿ is hydrogen or methyl; and R5 is hydrogen or COCH¿2?NH2.

Description

USE OF LOW AFFINITY NMDA ANTAGONISTS FOR THE TREATMENT OF HEADACHE

The present invention relates to the use of certain pharmaceutical compounds for the treatment of headache.

Compounds having NMDA (N-methyl-D-aspartate) antagonist activity are known in the art, for example see Watkins et al., Trends in Pharmacological Science, j_l:25, 1990.

In particular certain compounds are disclosed in EP 279 937 and EP 633 879 as having NMDA antagonist activity and as being useful for treating various CNS disorders such as epilepsy. It has now surprisingly been found that the low affinity NMDA antagonist compounds of EP 633 879 as exemplified by (S)-l-phenyl-2-(2-pyridyl)ethanamine reduce the incidence of headache in stroke patients, indicating that this compound is potentially useful for the treatment of headache.

In a first aspect the invention therefore provides the use of a low affinity NMDA antagonist for the treatment of headache. Headache includes all types of headache such as stroke-related headache, tension headache and migraine. It will be understood that NMDA antagonists of the invention can be used therapeutically or prophylactically.

Particularly suitable compounds include the compounds known as memantine, budipine, amantidine, 5-aminocarbonyl-10,l l-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, dextromethorphan and NPS 1506, and the compounds disclosed in EP 279 937 and EP 633 879. Preferred compounds include compounds of formula (I):

wherein:

R¹ is pyridyl, phenyl or 4-fluorophenyl;

R" is phenyl or 4-fluorophenyl;

R³ is hydrogen, Cι_₆ alkyl or methoxycarbonyl;

R⁴ is hydrogen or methyl; and

R⁵ is hydrogen or COCH₂NH₂, and metabolites thereof, both as free bases and pharmaceutically acceptable salts thereof.

Preferably the compound of formula (I) is l-phenyl-2-(2-pyridyl)ethanamine or a pharmaceutically acceptable salt or metabolite thereof, more preferably the (S) isomer.

A further preferred compound is 2-amino-N-(l,2-diphenyl-l-methylethyl)acetamide (Remacemide; EP 279 937) or a pharmaceutically acceptable salt or metabolite thereof.

The present invention includes compounds of formula (I) in the form of salts, in particular acid addition salts. Suitable salts include all known pharmaceutically acceptable salts including those formed with both organic and inorganic acids. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric. lactic, malic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids. Hydrochloride and malate salts are particularly preferred. The invention also provides a method of treating or preventing headache that comprises administering to a patient a low affinity NMDA antagonist or a pharmaceutically acceptable salt thereof.

In a further aspect the invention provides a low affinity NMDA antagonist, in particular a compound of formula (I), in the manufacture of a medicament for use in the prevention or treatment of headache.

Suitable daily dose ranges are from about 0.5 mg/kg to about 5 mg/kg. Unit doses may be administered conventionally once or more than once a day; for example, 2. 3, or 4 times a day; more usually 1 or 2 times a day. A typical dosing regime for (S)-l-phenyl-2-(2- pyridyl)ethanamine would be oral once or twice a day at 30, 60, 120 or 150 mg. Or alternatively, oral once or twice a day at 25, 50, 100, 150 or 200 mg.

The pharmaceutical composition comprising the compound of the invention may conveniently be tablets, pills, capsules, syrups, powders or granules for oral administration; sterile parental or subcutaneous solutions, suspensions for parental administration; or suppositories for rectal administration; all of which are well known in the art.

The following example illustrates the invention.

Example

Human stroke patients were treated with either various doses of (S)-l-phenyl-2-(2- pyridyl)ethanamine or with placebo, and the incidence of headache was recorded. The incidence of headache was significantly reduced in those patients treated with (S)- 1 -phenyl-2-(2-pyridyl)ethanamine (Table).

(S)-l-phenyl-2-(2-pyridyl)ethanamine was administered to 124 patients, and placebo to 46 patients. Table

Claims

O 00/59496CLAIMS

1. Use of a low affinity NMDA antagonist for the treatment of headache.

2. Use according to Claim 1 where the compound having low affinity NMDA antagonist activity is a compound of formula (I):

wherein:

R , 1 : is pyridyl, phenyl or 4-fluorophenyl;

R² is phenyl or 4-fluorophenyl;

R is hydrogen, Cι_₆ alkyl or methoxycarbonyl;

R is hydrogen or methyl; and

R⁵ is hydrogen or COCH₂NH₂, or a pharmaceutically acceptable salt thereof.

3. Use according to Claim 1 or Claim 2 where the compound of formula (I) is remacemide or a pharmaceutically acceptable salt or metabolite thereof.

4. Use according to Claim 1 or Claim 2 where the compound of formula (I) is (S)-l-phenyl-2-(2-pyridyl)ethanamine or a pharmaceutically acceptable salt thereof.

5. Use according to any one of Claims 1 to 4 wherein the headache is stroke-related headache.

6. A method of treating or preventing headache in a mammal which comprises administering to a person in need thereof a therapeutically effective amount of a compound having low affinity NMDA antagonist activity or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition for treating or preventing headache in a mammal which contains (S)-l-phenyl-2-(2-pyridyl)ethanamine or a pharmaceutically acceptable salt thereof.