Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-03-01
2003-07-22
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S120000, C514S129000, C558S169000, C558S178000, C562S011000
Reexamination Certificate
active
06596711
ABSTRACT:
FIELD OF THE INVENTION
The present invention is related to novel compounds having affinity to one or more GABA
B
receptors, as well as to their pharmaceutically acceptable salts, solvates and stereoisomers. The invention is also related to processes for their preparation, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds in therapy.
BACKGROUND AND PRIOR ART
Reflux
Gastro-oesophageal reflux disease (GORD) is the most prevalent upper gastrointestinal tract disease. Current therapy has aimed at reducing gastric acid secretion, or at reducing oesophageal acid exposure by enhancing oesophageal clearance, lower oesophageal sphincter tone and gastric emptying. The major mechanism behind reflux has earlier been considered to depend on a hypotonic lower oesophageal 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 oesophageal sphincter relaxations, hereinafter referred to as TLOSR, i.e. relaxations not triggered by swallows. It has also been shown that gastric acid secretion usually is normal in patients with GORD.
Consequently, there is a need for compounds which reduce the incidence of TLOSR and thereby prevent reflux.
A pharmaceutical composition comprising a local anaesthetic, adapted to inhibit relaxation of the lower oesophageal sphicter is disclosed in WO 87/04077 and in U.S. Pat. No. 5,036,057. Recently GABA
B
-receptor agonists have been shown to inhibit TLOSR, as disclosed in WO 98/11885.
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 belong to the superfamily of G-protein coupled receptors. GABA
B
receptor agonists are being 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 (IBS) 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) and recently, as mentioned above, in the inhibition of TLOSR (WO 98/11885).
The most studied GABA
B
receptor agonist is baclofen (4-amino-3-(chlorophenyl)butanoic acid) disclosed in the Swiss patent No. CH 449,046. Baclofen has for several years been used as an antispastic agent. EP 0356128 describes the use of the specific compound (3-aminopropyl)methylphosphinic acid, as a potent GABA
B
receptor agonist, in therapy. EP 0181833 discloses substituted 3-aminopropylphosphinic acids which are found to have very high affinities towards GABA
B
receptor sites. In analogy to baclofen, the compounds can be used as for instance muscle relaxants. EP 0399949 discloses derivatives of (3-aminopropyl)methylphosphinic acid which are described as potent GABA
B
receptor agonists. These compounds are stated to be useful as muscle relaxants. EP 0463969 and FR 2722192 are both applications related to 4-aminobutanoic acid derivatives having different heterocyclic substituents at the 3-carbon of the butyl chain. Structure-activity relationships of several phosphinic acid analogues with respect to their affinities to the GABA
B
receptor as well as their muscle relaxant effect are discussed in
J. Med. Chem.
(1995), 38, 3297-3312. The conclusion in said article is that considerably stronger muscle relaxation could be achieved with the (S)-enantiomer of 3-amino-2-hydroxy-propylmethylphosphinic acid than with baclofen and without the occurrence of unwanted CNS effects.
OUTLINE OF THE INVENTION
The present invention provides novel compounds of the formula I
wherein
R
1
represents hydrogen, hydroxy, lower alkyl, lower alkoxy or halogen;
R
2
represents hydroxy, mercapto, halogen or an oxo group;
R
3
represents hydrogen or lower alkyl (optionally substituted with hydroxy, mercapto, lower alkoxy, aryl or lower thioalkoxy);
R
4
represents hydrogen, lower alkyl (optionally substituted with aryl) or aryl;
R
5
represents methyl, fluoromethyl, difluoromethyl or trifluorormethyl;
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof, with the exceptions of:
i) the racemate of (3-amino-2-hydroxypropyl)methylphosphinic acid,
ii) (S)-(3-amino-2-hydroxypropyl)methylphosphinic acid,
iii) (R)-(3-amino-2-hydroxypropyl)methylphosphinic acid,
iv) (3-amino-2-hydroxypropyl)difluoromethylphosphinic acid, and
v) (3-amino-2-oxopropyl)methylphosphinic acid.
Preferrably the compound is one of (3-amino-2-fluoropropyl)(methyl)phosphinic acid, (2R)-(3-amino-2-fluoropropyl)(methyl)phosphinic acid, (2S)-(3-amino-2-fluoropropyl)(methyl)phosphinic acid, (3-amino-2-fluoro-1-methylpropyl)(methyl)phosphinic acid or pharmaceutically acceptable salts, solvates or the stereoisomers thereof.
Within the scope of the invention, it is to be understood that when R
2
is an oxo group the bond between R
2
and the carbon is a double bond.
Furthermore, within the scope of the invention, it is to be understood by “lower” radicals and compounds, for example, those having up to and including 7, especially up to and including 4, carbon atoms. Also the general terms have the following meanings:
Lower alkyl is, for example, C
1
-C
4
alkyl, such as methyl, ethyl, n-propyl or n-butyl, also isopropyl, isobutyl, secondary butyl or tertiary butyl, but may also be a C
5
-C
7
alkyl group such as a pentyl, hexyl or heptyl group.
Lower alkoxy is, for example, C
1
-C
4
alkoxy, such as methoxy, ethoxy, n-propoxy or n-butoxy, also isopropoxy, isobutoxy, secondary butoxy or tertiary butoxy, but may also be a C
5
-C
7
alkoxy group, such as a pentoxy, hexoxy or heptoxy group.
Lower thioalkoxy is, for example, C
1
-C
4
thioalkoxy, such as thiomethoxy, thioethoxy, n-thiopropoxy or n-thiobutoxy, also thioisopropoxy, thioisobutoxy, secondary thiobutoxy or tertiary thiobutoxy, but may also be a C
5
-C
7
thioalkoxy group, such as a thiopentoxy, thiohexoxy or thioheptoxy group.
Halogen is halogen of an atomic number up to and including 35, such as flourine or chlorine, and less prefered bromine.
The compounds according to formula I of the invention are of amphoteric nature and may be presented in the form of internal salts. They can also form acid addition salts and salts with bases. Such salts are particularly pharmaceutically acceptable acid addition salts, as well as pharmaceutically acceptable salts formed with bases. Suitable acids for the formation of such salts include, for example, mineral acids such as hydrochloric, hydrobromic, sulfuric, or phosphoric acid or organic acids such as sulfonic acids and carboxylic acids. Salts with bases are, for example, alkali metal salts, e.g. sodium or potassium salts, or alkaline earth metal salts, e.g. calcium or magnesium salts as well as ammonium salts, such as those with ammonia or organic amines. The salts may be prepared by conventional methods.
When one or more stereocentre is present in the molecule, the compounds according to formula I can be in the form of a stereoisomeric mixture, i.e. a mixture of diastereomers and/or racemates, or in the form of the single stereoisomers, i.e. the single enantiomer and/or diastereomer. The present compounds can also be in the form of solvates, e.g. hydrates.
All of the compounds according to the formula I can be used for the inhibition of TLOSR, and thus for the treatment of gastro-oesophageal reflux disease. The said inhibition of TLOSR also implies that all of the compounds of formula I can be used for the treatment of regurgitation in infants. Effective management of regurgitation in infants would be an important way of managing failure to thrive due to excessive loss of ingested nutrient. Furthermore the novel compounds can be used for the treatment of GORD- or non-GORD related asthma, belching, coughing, pain, cocaine addiction, hiccups, IBS, dyspepsia, emesis and nociception.
The pre
Amin Kosrat
Elebring Thomas
Guzzo Peter
Olsson Thomas
Swanson Marianne
AstraZeneca AB
McKane Joseph K.
Saeed Kamal
White & Case LLP
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