Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-09-08
2003-12-16
Spector, Lorraine (Department: 1647)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007100, C435S007210, C435S006120, C536S023500
Reexamination Certificate
active
06664069
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the use of GABA
B
receptor agonists for the inhibition of transient lower esophageal sphincter relaxations; for the treatment of gastro-esophageal reflux disease; and/or for the treatment of regurgitation in infants.
BACKGROUND ART
Reflux
In some humans, the lower esophageal sphincter (LES) is prone to relaxing more frequently than in other humans. As a consequence, fluid from the stomach can pass into the esophagus since the mechanical barrier is temporarily lost at such times, an event hereinafter referred to as “reflux”.
Gastro-esophageal reflux disease (GERD) is the most prevalent upper gastrointestinal tract disease. Current therapy has aimed at reducing gastric acid secretion, or by reducing esophageal acid exposure by enhancing esophageal clearance, lower esophageal sphincter tone and gastric emptying. The major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter. However, recent research (e.g. Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, 517-535) has shown that most reflux episodes occur during transient lower esophageal sphincter relaxations (TLESR), i.e. relaxations not triggered by swallows. It has also been shown that gastric acid secretion usually is normal in patients with GERD.
Consequently, there is a need for compounds which reduce the incidence of TLESR and thereby prevent reflux. Ideally, the compound should have an effect duration of approximately 12 h, since most reflux occurs during daytime and postprandially.
A pharmaceutical composition comprising a local anaesthetic, adapted to inhibit relaxation of the lower esophageal sphincter, is disclosed in WO 87/04077 and in U.S. Pat. No. 5,036,057.
GABA
B
Receptor Agonists
GABA (4-aminobutanoic acid) is an endogenous neurotransmitter in the central and peripheral nervous systems. Receptors for GABA have traditionally been divided into GABA
A
and GABA
B
receptor subtypes. GABA
B
receptors (for a review see Kerr, D. I. B. and Ong, J. (1995) Pharmac. Ther. vol. 67, pp. 187-246) belong to the superfamily of G-protein coupled receptors. GABA
B
receptor agonists are described as being of use in the treatment of CNS disorders, such as muscle relaxation in spinal spasticity, cardiovascular disorders, asthma, gut motility disorders such as irritable bowel syndrome and as prokinetic and anti-tussive agents. GABA
B
receptor agonists have also been disclosed as useful in the treatment of emesis (WO 96/11680).
The GABA
B
receptor agonist baclofen (4-amino-3-(4-chlorophenyl)butanoic acid) (Swiss patent No. CH 449,046) has been the most studied of the GABA analogs.
Other GABA
B
receptor agonists or partial agonists are disclosed in: EP 0356128; EP 0181833; EP 0399949; EP 0463969; and FR 2,722,192. For a review on the chemistry of GABA
B
modulators, see Froestl, W. and Mickel, S. J. in: The GABA Receptors, pp.271-296 (Eds. S. J. Enna and N. G. Bowery, Humana Press Inc., Totowa, N.J., U.S.A. 1997)
It is known in the art that drug screening can be improved by using cells which are transfected with a cloned receptor gene. Such transfected cells may offer several advantages over traditional screening, the most important being presumably selectivity. Another advantage of transfected cells is that they allow to assessment of the activity of drugs on cloned human receptors. The fact that the GABA
B
receptor has recently been cloned (Kaupmann et al., Nature 386(6622), 239-246, Mar. 20, 1997) thus offers the opportunity to to develop more specific drugs acting on the GABA
B
receptor. The said article discloses two subtypes of the receptor from rat, designated GABA
B
R1a and GABA
B
R1b, but it was made very clear that several other subtypes could be isolated.
DISCLOSURE OF THE INVENTION
It has been found surprisingly that GABA
B
receptor agonists can be used for the inhibition of transient lower esophageal sphincter relaxations, and thus for the treatment of gastro-esophageal reflux disease.
Consequently, the present invention provides the use of a GABA
B
receptor agonist for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations (TLESR), or more specifically, for the treatment of gastroesophageal reflux disease. For the purpose of this invention, the term “agonist” should be understood as including both full agonists as well as partial agonists, wherby a “partial agonist” should be understood as a compound capable of partially, but not fully, activating the GABA
B
receptor.
The inhibition of TLESR also implies that the compounds can be used for the treatment of regurgitation in infants. Effective managment of regurgitation in infants would be an important way of managing lung disease due to aspiration of regurgitated gastric contents, and for managing failure to thrive due to excessive loss of ingested nutrient.
In a preferred form of the invention, the GABA
B
receptor agonist is a substituted aminopropyl acid derivative where the acidic head is a carboxylic group, a phosphinic group, a phosphonous group or a sulfinic group.
Examples of compounds having agonistic or partially agonistic affinity to GABA
B
receptors and which thus can be used according to the invention are:
4-aminobutanoic acid (GABA),
4-amino-3-(4-chlorophenyl)butanoic acid(baclofen),
4-amino-3-phenylbutanoic acid,
4-amino-3-hydroxybutanoic acid,
4-amino-3-(4-chlorophenyl)-3-hydroxyphenylbutanoic acid,
4-amino-3-(thien-2-yl)butanoic acid,
4-amino-3-(5-chlorothien-2-yl)butanoic acid,
4-amino-3-(5-bromothien-2-yl)butanoic acid,
4-amino-3-(5-methylthien-2-yl)butanoic acid,
4-amino-3-(2-imidazolyl)butanoic acid,
4-guanidino-3-(4-chlorophenyl)butanoic acid,
3-amino-2-(4-chlorophenyl)-1-nitropropane,
(3-aminopropyl)phosphonous acid,
(4-aminobut-2-yl)phosphonous acid,
(3-amino-2-methylpropyl)phosphonous acid,
(3-aminobutyl)phosphonous acid,
(3-amino-2-(4-chlorophenyl)propyl)phosphonous acid,
(3-amino-2-(4-chlorophenyl)-2-hydroxypropyl)phosphonous acid,
(3-amino-2-(4-fluorophenyl)propyl)phosphonous acid,
(3-amino-2-phenylpropyl)phosphonous acid,
(3-amino-2-hydroxypropyl)phosphonous acid,
(E)-(3-aminopropen-1-yl)phosphonous acid,
(3-amino-2-cyclohexylpropyl)phosphonous acid,
(3-amino-2-benzylpropyl)phosphonous acid,
[3-amino-2-(4-methylphenyl)propyl]phosphonous acid,
[3-amino-2-(4-trifluoromethylphenyl)propyl]phosphonous acid,
[3-amino-2-(4-methoxyphenyl)propyl]phosphonous acid,
[3-amino-2-(4-chlorophenyl)-2-hydroxypropyl]phosphonous acid,
(3-amino propyl)methylphosphinic acid,
(3-amino-2-hydroxypropyl)methylphosphinic acid,
(3-aminopropyl)(difluoromethyl)phosphinic acid,
(4-aminobut-2-yl)methylphosphinic acid,
(3-amino-1-hydroxypropyl)methylphosphinic acid,
(3-amino-2-hydroxypropyl)(difluoromethyl)phosphinic acid,
(E)-(3-aminopropen-1-yl)methylphosphinic acid,
(3-amino-2-oxo-propyl)methyl phosphinic acid,
(3-aminopropyl)hydroxymethylphosphinic acid,
(5-aminopent-3-yl)methylphosphinic acid,
(4-amino-1,1,1-trifluorobut-2-yl)methylphosphinic acid,
(3-amino-2-(4-chlorophenyl)propyl)sulfinic acid,
3-aminopropylsulfinic acid.
Preferably, the compound having agonistic or partially agonistic affinity to a GABA
B
receptor is any one of the following compounds:
4-amino-3-(4-chlorophenyl)butanoic acid (baclofen),
(3-aminopropyl)methylphosphinic acid,
(3-amino-2-hydroxypropyl)methylphosphinic acid,
4-aminobutanoic acid (GABA),
(3-amino-2-(4-chlorophenyl)propyl)sulfinic acid,
(3-aminopropyl)(difluoromethyl)phosphinic acid,
(3-amino-2-oxo-propyl)methyl phosphinic acid,
4-amino-3-(5-chlorothien-2-yl)butanoic acid,
(3-aminopropyl)phosphonous acid.
The use of pharmaceutically acceptable salts of GABA
B
ligands for the disclosed purposes is also included in the invention. Most known GABA
B
ligands such as for example baclofen, (3-aminopropyl)methylphosphinic acid and (3-amino-2-(S)-hydroxypropyl)methylphosphinic acid are of amphoteric nature and may be present in the form of internal salts. They also can form acid addition salts and salts with bases. Such salts are particularly pharma
Andrews Paul L. R.
Lehmann Anders
Seharaseyon Jegatheesan
Spector Lorraine
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