WO2002100871A1 - New compounds useful in reflux disease - Google Patents

New compounds useful in reflux disease Download PDF

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Publication number
WO2002100871A1
WO2002100871A1 PCT/SE2002/001086 SE0201086W WO02100871A1 WO 2002100871 A1 WO2002100871 A1 WO 2002100871A1 SE 0201086 W SE0201086 W SE 0201086W WO 02100871 A1 WO02100871 A1 WO 02100871A1
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acid
aminopropyl
amino
methylphosphinic acid
methylphosphinic
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PCT/SE2002/001086
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French (fr)
Inventor
Kosrat Amin
Thomas Elebring
Peter Guzzo
Anders Lehmann
Sverker Von Unge
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Astrazeneca Ab
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Publication of WO2002100871A1 publication Critical patent/WO2002100871A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
    • C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/48—Phosphonous acids R—P(OH)2; Thiophosphonous acids including RHP(=O)(OH); Derivatives thereof
    • C07F9/4808—Phosphonous acids R—P(OH)2; Thiophosphonous acids including RHP(=O)(OH); Derivatives thereof the acid moiety containing a substituent or structure which is considered as characteristic
    • C07F9/4816—Acyclic saturated acids or derivatices which can have further substituents on alkyl

Definitions

  • 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.
  • Gastro-oesophageal reflux disease 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.
  • TLOSR transient lower oesophageal sphincter relaxations
  • compositions comprising a local anaesthetic, adapted to inhibit relaxation of the lower oesophageal sphicter are disclosed in WO 87/04077 and in US 5,036,057.
  • GAB Ag -receptor agonists have been shown to inhibit TLOSR which is disclosed in WO 98/1 1885.
  • GABA B receptor agonists are disclosed in WO 98/1 1885.
  • 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 96/1 1680) and recently, as mentioned above, in the inhibition of TLOSR (WO 98/11885).
  • 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 present invention provides novel compounds of the formula I
  • Ri represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl
  • R 2 represents hydrogen, hydroxy, C1-C7 alkyl, C1-C7 alkoxy or halogen
  • R 3 represents hydrogen, C1-C7 alkyl (optionally substituted with hydroxy, mercapto, C ⁇ - C ⁇ alkoxy, -C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
  • R represents hydrogen, C1-C7 alkyl (optionally substituted with aryl or heteroaryl), aryl or heteroaryl;
  • 3-aminopropylphosphinic acid the racemate of (3-amino-3-methylpropyl)phosphinic acid the racemate of (3-amino-l-methylpropyl)phosphinic acid the racemate of (3-amino-l-ethylpropyl)phosphinic acid - (N-phenyl-3-aminopropyl)methylphosphinic acid (N- ⁇ -tolyl-3-aminopropyl)methylphosphinic acid (N-(3,5-dimethylphenyl)-3-aminopropyl)methylphosphinic acid (N-(3,4-dimethylphenyl)-3-aminopropyl)methylphosphinic acid (N-(3-chlorophenyl)-3-aminopropyl)methylphosphinic acid - (N-(4-chlorophenyl)-3-aminopropyl)methylphosphinic acid (N-(4-me
  • One embodiment of the invention is a compound of formula I wherein Ri represents hydrogen or methyl;
  • R 2 represents hydrogen, C1-C7 alkyl or halogen
  • R 3 represents hydrogen; and R 4 represents hydrogen or -C7 alkyl (optionally substituted with aryl or heteroaryl);
  • the compound of formula I is (3-amino-l -fluoropropyl)phosphinic acid
  • C1-C7 alkyl can be straight, branched or cyclic alkyl and is, for example, C1-C4 alkyl, such as methyl, ethyl, n-propyl or n-butyl, also isopropyl, isobutyl, secondary butyl or tertiary butyl, but may also be a C5-C7 alkyl group such as a pentyl, hexyl or heptyl group.
  • C1-C7 alkyl can be straight, branched or cyclic alkyl and is, for example, C1-C4 alkyl, such as methyl, ethyl, n-propyl or n-butyl, also isopropyl, isobutyl, secondary butyl or tertiary butyl, but may also be a C5-C7 alkyl group such as a pentyl, hexyl or heptyl group.
  • C1-C7 alkoxy is, for example, C1-C4 alkoxy, such as methoxy, ethoxy, n-propoxy or n- butoxy, also isopropoxy, isobutoxy, secondary butoxy or tertiary butoxy, but may also be a C5-C7 alkoxy group, such as a pentoxy, hexoxy or heptoxy group.
  • C1-C7 thioalkoxy is, for example, -C4 thioalkoxy, such as thiomethoxy, thioethoxy, n- thiopropoxy or n-thiobutoxy, also thioisopropoxy, thioisobutoxy, secondary thiobutoxy or tertiary thiobutoxy, but may also be a C5-C7 thioalkoxy group, such as a thiopentoxy, thiohexoxy or thioheptoxy group.
  • Halogen as used herein is anyone of chlorine, fluorine, bromine or iodine.
  • aryl means aromatic rings with 6-14 carbon atoms including both single rings and polycyclic compounds, such as benzyl or naphtyl, optionally substituted with one or more substituents such as -C7 alkyl, C1-C7 alkoxy, C1-C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amideor nitrile.
  • heteroaryl as used herein means aromatic rings with 5-14 carbon atoms, including both single rings and polycyclic compounds, in which one or several of the ring atoms is either oxygen, nitrogen or sulphur.
  • the heteroaryl is optionally substituted with one or more substituents such as C1-C7 alkyl, -C7 alkoxy, -C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile.
  • 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.
  • 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 compounds can also be in the form of solvates, e.g. hydrates.
  • TLOSR gastro-oesophageal reflux disease
  • the said inhibition of TLOSR also implies that the said 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.
  • the compounds can be used for the treatment of GORD-related or non-GORD related asthma, belching, coughing, pain, cocaine addiction, hiccups, IBS, dyspepsia, emesis and nociception.
  • One aspect of the invention is the use of the compounds of the invention in the manufacture of a medicament for the inhibition of TLOSR and thus for the treatment of gastro-oesophageal reflux disease, regurgitation in infants and also for the treatment of GORD-related or non-GORD related asthma, belching, coughing, pain, cocaine addiction, hiccups, DBS, dyspepsia, emesis and nociception.
  • Another aspect of the invention is a method for the treatment of TLOSR, for the treatment of gastro-oesophageal reflux disease, regurgitation in infants and also for the treatment of GORD-related or non-GORD related asthma, belching, coughing, pain, cocaine addiction, hiccups, IBS, dyspepsia, emesis and nociception, which method comprises treating a subject suffering from said condition with a pharmacuetical preparation comprising a compound of the invention.
  • a further aspect of the invention is a pharmaceutical formulation comprising as active ingredient a therapeutically acceptable amount of a compound according to the invention in association with diluents, excipients or inert carriers.
  • the compounds according to formula I of the present invention may be prepared by one of the following methods.
  • R 2 and R 3 are as defined above in formula I with the exception that possible hydroxy groups in R 2 and R 3 optionally are protected with suitable protecting groups such as C1-C7 alkyl
  • X is a protecting group such as -CCH 3 (OCH 2 CH 3 ) 2 or if desired equal to Ri as defined in formula I
  • Y is a protecting group such as C1-C7 alkyl, which compound of formula II may have been synthesized by a reaction according to Scheme 1 employing an appropriate unsaturated nitro compound in which R is as defined above in formula II, and a suitable protected phosphinic acid derivative in which R 2 is as defined above in formula II, X and Y are as defined in formula II, and a base such as lithium diisopropylamide,
  • Ri, R 2 , R 3 and R 4 are as defined above in formula I, and optionally convert the above resulting compound I into another chemical compound of the formula I and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula I and/or into another salt and/or convert a resulting free compound of the formula I into a salt to correspond to the above definition, or
  • R 2 , and R 3 are as defined above in formula II
  • X is hydrogen or a protecting group such as -CCH 3 (OCH 2 CH 3 ) 2 or if desired equal to Ri as defined in formula I
  • T is a group that can be converted to a-NH 2 group
  • Y is hydrogen or a protecting group such as Cj- C7 alkyl, which compound of formula III may have been synthesized by a condensation reaction according to Scheme 2 employing an 2,3-epoxypropyl derivative, such as an appropriate N-protected 2,3-epoxypropylamine derivative or an epichlorohydrin derivative, in which R and R 3 is as defined above in formula I, and a suitable protected phosphinic acid derivative activated by O-silylation, in which X and Y are as defined in formula III, and a Lewis acid such as anhydrous ZnCl 2 ,
  • R 1 ; R 2 , R 3 and R are as defined above in formula I, and optionally convert the above resulting compound I into another chemical compound of the formula I and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula I and/or into another salt and/or convert a resulting free compound of the formula I into a salt to correspond to the above definition, or
  • R 2 is as defined above in formula I
  • X is hydrogen or a protecting group such as - CCH 3 (OCH 2 CH 3 ) 2 or equal to Ri
  • U is an electron-withdrawing group, such as for instance -CN or -CO 2 Et which can be converted to a -CH 2 NH 2 group
  • Y is hydrogen or a protecting group such as C1-C7 alkyl, which compound of formula IV may have been synthesized by an addition reaction according to Scheme 3 employing an unsaturated compound in which R 2 is as defined above in formula I, U is as defined in formula IV, and a suitable protected phosphinic acid derivative activated by O-silylation, in which X and Y are as defined in formula IV,
  • Ri, R 2 and R are as defined above in formula I, and optionally convert the above resulting compound V into another chemical compound of the formula V and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula V and/or into another salt and/or convert a resulting free compound of the formula V into a salt to correspond to the above definition; or
  • Rj, R 2 , R 3 and R 4 are as defined in formula I and Z is a protecting group such as t- butyloxycarbonyl, which compound of formula VI may have been synthesized by a substitution reaction according to Scheme 4 employing an electrophilic compound in which R 2 , R 3 and R are as defined above, L is a leaving group such as iodo, Z is as defined above, and a phosphinic acid derivative in which Rj is as defined in formula I activated by O-silylation,
  • R l s R 2 , R 3 and R 4 are as defined above in formula I, and optionally convert the above resulting compound I into another chemical compound of the formula I and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula I and/or into another salt and/or convert a resulting free compound of the formula I into a salt to correspond to the above definition; or
  • R 3 and R 4 are as defined above in formula I
  • X is hydrogen or a protecting group such as -CCH 3 (OCH 2 CH 3 ) or if desired equal to Ri
  • Z is a protecting group such as benzyl oxycarbonyl
  • Y is hydrogen or protecting groups such as C1-C7 alkyl, which compound of formula VII may have been synthesized by an addition reaction according to Scheme 5 treating a phosphinic acid derivative, in which X is as defined above in formula VII, with an aldehyde derivative in which R 3 , R and Z are as defined above, and a base such as an a ine
  • a) is optionally converted by an O-alkylation reaction and then a hydrolytic reaction to obtain a compound of formula VIII,
  • R ⁇ , R 3 and R 4 are as defined above in formula I
  • R 5 is hydrogen or C1-C7 alkyl and optionally convert the above resulting compound Vffl into another chemical compound of the formula VIII and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula VIII and/or into another salt and/or convert a resulting free compound of the formula VIE into a salt to correspond to the above definition, or
  • R ⁇ , R 3 and R are as defined above in formula I
  • Halo is a halogen atom and optionally convert the above resulting compound IX into another chemical compound of the formula DC and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula DC and/or into another salt and/or convert a resulting free compound of the formula DC into a salt to correspond to the above definition.
  • the crude 3- amino-1-fluoropropylphosphinic acid was passed through a Dowex ® 50WX8-200 mesh H + form (30 g, 2x15 cm) column eluting with 1 : 1 methanol/water until no further material was detected by TLC analysis.
  • the requisite crude 3-amino- 1-fluoropropylphosphinic acid was eluted with 1:3 concentrated ammonium hydroxide solution/methanol.
  • the crude 3-amino- 1-fluoropropylphosphinic acid was further purified by silica gel column chromatography (20 g, 1x20 cm), eluting with 6:3:1 methylene chloride/methanol/concentrated ammonium hydroxide to afford 3-amino- l-fluoropropylphosphinic acid as a white solid (55 mg, 33%).
  • Trimethylsilyl bromide (2 g, 13 mmol) was added to a solution of ethyl (3- aminopropyl)methylphosphinate (0.75 g, 2.59 mmol) in dichloromethane (10 mL).
  • the reaction mixture was stirred at RT for one hour before it was neutralised by addition of propylene oxid (approx. 10 mL). Evaporation of volatiles gave 3-[(4- chlorobenzyl)amino]propyl(methyl)phosphinic acid (0.61 g, 90%).
  • ⁇ NMR data were in agreement with the expected compound.
  • Ammonium hypophosphite (4.19 g, 50.5 mmol) was added to a three-necked 100-mL flask equipped with a thermometer, addition funnel and an argon bubbler. The flask was placed in a water bath at room temperature and N,O-fr/s-(trimethylsilyl)acetamide (BSA, 12.1 mL, 49.0 mmol) was added at such a rate that the internal temperature was maintained below 38 °C (15 minutes approx.) using ice cooling. During the addition ammonia gas was evolved (during the first 15 min this was rather rapid).
  • BSA N,O-fr/s-(trimethylsilyl)acetamide
  • reaction mixture Upon completing the addition of BSA, the reaction mixture was heated to 45-48 °C and maintained at this temperature for 1 h (during this time the reaction became viscous). The reaction was cooled to room temperature and a solution of tert-buty] 3- ⁇ l-[(tert-butoxycarbonyl)(3-iodopropyl)amino]ethyl ⁇ benzoate (2.40 g, 4.9 mmol) in methylene chloride (25 mL) was added to the reaction mixture. The reaction was then allowed to stir at room temperature for 38 h.
  • the filtrate was concentrated and the residue was purified by flash column chromatography using silica gel (230-400 mesh, 600 g) and chloroform/methanol/ammonium hydroxide (80:19:1) to provide the phosphonous acid intermediate (3.1 g, along with acetamide impurity) as a white solid.
  • the phosphonous acid intermediate (1.4 g, 3.3 mmol) was transferred to a 250- mL flask, dissolved in aqueous HCl (3 N, 100 mL) and stirred at room temperature under argon. The reaction mixture became a colorless clear solution after 2 h. Hydrolysis was complete after 4 h stirring at room temperature, and the reaction mixture was concentrated under reduced pressure.
  • Example II Ethyl 3-amino- l -fluoropropyKLl-diethoxyethvDphosphinate.
  • Tetrahydrofuran 50 mL was added to a pressure flask (350 mL), equipped with a septum and under an Argon atmosphere.
  • Sodium hydride (4.0 g, 0.16 mol, 95 wt %) was added in one portion at room temperature.
  • the flask was cooled to -20 °C and ethyl 1,1- diethoxyethylphosphinate (27.8 g, 0.13 mol) in THF (50 mL) was added dropwise. Stirring was continued for 30 minutes after which the flask was cooled to -78 °C.
  • Chlorofluoromethane gas (30.0 g, 0.44 mol) was bubbled into the THF solution and at this temperature it condensed in the flask. The pressure flask was then sealed with a Teflon screw top and allowed to warm to room temperature over a 30 minute period. After this time the flask was heated to 50 °C for 6 h. The flask was then cooled to room temperature and the chlorofluoromethane gas was vented. An aliquot was taken and analyzed by proton NMR and the conversion was found to be approximately 50%. The reaction mixture was retreated with chlorofluoromethane (20.0 g, 0.29 mol) as previously described, resealed and heated at 50 °C for an additional 17 h.
  • the crude product was purified by flash column chromatography using silica gel (230-400 mesh, 150 g) and chloroform/methanol (99.5:0.5) to provide tert-butyl 3-[l-((tert-butoxycarbonyl) ⁇ 3- [(methylsulfonyl)oxy]propyl ⁇ amino)ethyl]benzoate (1.80 g, 93%) as a pale yellow oil.
  • tert-Butyl 3- ⁇ l-[(3-hydroxypropyl)amino]ethyl ⁇ benzoate (5.1 g, 18.3 mmol) was dissolved in methylene chloride (80 mL) and cooled to 0 °C.
  • Di-tert-butyl dicarbonate (4.4 g, 20.1 mmol) was added in several portions quickly. The mixture was then allowed to warm to room temperature overnight (20 h). TLC analysis indicated complete consumption of tert- butyl 3-[l-((3-hydroxypropyl)amino)ethyl]benzoate (chloroform/methanol 99: 1, uv development). The crude reaction mixture was quenched with aqueous sodium bicarbonate.
  • the organic material was extracted with methylene chloride (3 x 100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a slightly yellow oil.
  • the crude product was purified by flash column chromatography using silica gel (230-400 mesh, 600 g) and chloroform/methanol (99: 1) to provide rert-butyl 3- ⁇ l-[(tert-butoxycarbonyl)(3-hydroxypropyl)amino]ethyl ⁇ benzoate (6.78 g, 98%) as a colorless oil.
  • the flask contents were stirred under nitrogen at room temperature for 16 h.
  • the reaction mixture was cautiously quenched with aqueous ammonium chloride (10 mL), and the aqueous layer was extracted with methylene chloride (3 x 25 mL).
  • the combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure.
  • the crude product was purified by flash column chromatography using silica gel (230-400 mesh, 100 g) and chloroform/methanol/ammoniurn hydroxide (95:4: 1) to provide tert-butyl 3- ⁇ l-[(3- hydroxypropyl)amino]ethyl Jbenzoate (0.74 g, 81 %) as a colorless oil.
  • the compound according to formula I of the present invention can be used as an active ingredient in a pharmaceutical preparation for oral, rectal, epidural, intravenous, intramuscular, subcutanous, nasal administration and administration by infusion or for any other suitable route of administration.
  • a pharmaceutical preparation for oral, rectal, epidural, intravenous, intramuscular, subcutanous, nasal administration and administration by infusion or for any other suitable route of administration.
  • the way of administration is oral or by injection/infusion.
  • the pharmaceutical preparations contain a compound of the present invention in combination with one or more pharmaceutically acceptable ingredients.
  • the finished dosage forms are manufactured by known pharmaceutical processes.
  • the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.2-20% by weight in preparations for parenteral use and preferably between 1-50% by weight in preparations for oral administration.
  • the compound selected may be mixed with solid pharmaceutically acceptable ingredients (among these for instance disintegrating agents and lubricating agents). The mixture is then processed into granules, tablets, capsules or sachets.
  • Dosage units for rectal administration may be prepared in the form of suppositories; in the form of a gelatine rectal capsule; in the form of a ready-made micro enema; or in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, or in the form of a dry mixture to be reconstituted with a suitable solvent prior to use.
  • Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent and are dispensed into ampoules or vials. They may also be prepared as a dry preparation to by reconstituted with a suitable solvent extemporaneously before use.
  • the typical daily dose of the active compound will depend on various factors such as for example the individal requirement of each patient, the route of administration and the disease. In general, dosages will be in the range of 1 ⁇ g to 100 mg per day and kg body weight, preferably 10 ⁇ g to 20 mg per day and kg body weight.
  • Rat synaptic membranes were prepared from the whole brain of Sprague Dawley male rats essentially as described previously (Zukin, et al. (1974) Proc. Natl. Acad. USA 71 , 4802- 4807).
  • the [ 3 H]GABA competition assay modified from Olpe et al ((1990) Eur. J. Pharmacol. 187, 27-38), was performed in 200 ⁇ l TCI (Tris Calcium Isoguvacine) buffer (50 mM Tris (tri(hydroxymethyl)aminomethane), pH 7.4, 2.5 mM CaCl2 and 40 ⁇ M isoguvacine) containing 20 nM [ 3 H]GABA (specific activity: 3 Tera Becquerel
  • the compounds of the present invention were found to have high affinities and potencies for the GABAB receptor as revealed by low IC50 and EC50 me binding and ileum assays, respectively.
  • the compounds have also been found to reduce TLOSR when administered i.v. as well as p.o. in animal models. Contrary to whaf has been claimed in the literature for 3-aminopropylphosphinic acid derivatives having a P-H bond, we found that P-H compounds of the present invention have high metabolic stability in animal models.
  • CNS side-effects (as measured by reduction in body temperature in the mouse) were not observable or only seen at doses higher than the therapeutic doses inhibiting TLOSR in the dog model. Therefore, the difference between therapeutic dose (inhibition of TLOSR in the dog model) and dose causing side-effects (in the mouse model) was unexpectedly high.

Abstract

Novel compounds of formula I having affinity to one or more GABA?B? 191 receptors, their pharmaceutically acceptable salts, solvates and stereoisomers, as well as processes for their preparation, pharmaceutical compositions containing said therapeutically active compounds and the use of said active compounds in therapy.

Description

NEW COMPOUNDS USEFUL IN REFLUX DISEASE
Field of the invention
The present invention is related to novel compounds having affinity to one or more GABAB 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 of the invention 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.
Pharmaceutical compositions comprising a local anaesthetic, adapted to inhibit relaxation of the lower oesophageal sphicter are disclosed in WO 87/04077 and in US 5,036,057. Recently GAB Ag -receptor agonists have been shown to inhibit TLOSR which is disclosed in WO 98/1 1885. GABAB 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 GABAA and GABAB receptor subtypes. GABAB receptors belong to the superfamily of G- protein coupled receptors. GABAB 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. GABAB receptor agonists have also been disclosed as useful in the treatment of emesis (WO 96/1 1680) and recently, as mentioned above, in the inhibition of TLOSR (WO 98/11885).
The most studied GABAB 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 GABAB receptor agonist, in therapy. EP 0181833 discloses substituted 3-aminopropylphosphinic acids which are found to have very high affinities towards GABAB 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 GABAB 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 GABAB 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-hydroxypropyl)methylphosphinic acid than with baclofen and without the occurrence of unwanted CNS effects. In literature the phosphinic acids having a hydrogen atom attached to phosphorus also are named phosphonous acids. These are two names for the same type of compounds and both names can be used. However, we have chosen to use the name phosphinic acids for the compounds according to the present invention.
Outline of the invention
The present invention provides novel compounds of the formula I
Figure imgf000004_0001
wherein
Ri represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl;
R2 represents hydrogen, hydroxy, C1-C7 alkyl, C1-C7 alkoxy or halogen;
R3 represents hydrogen, C1-C7 alkyl (optionally substituted with hydroxy, mercapto, C\- Cη alkoxy, -C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
R represents hydrogen, C1-C7 alkyl (optionally substituted with aryl or heteroaryl), aryl or heteroaryl;
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof,
with the exceptions of: 3-aminopropylphosphinic acid the racemate of (3-amino-3-methylpropyl)phosphinic acid the racemate of (3-amino-l-methylpropyl)phosphinic acid the racemate of (3-amino-l-ethylpropyl)phosphinic acid - (N-phenyl-3-aminopropyl)methylphosphinic acid (N-ρ-tolyl-3-aminopropyl)methylphosphinic acid (N-(3,5-dimethylphenyl)-3-aminopropyl)methylphosphinic acid (N-(3,4-dimethylphenyl)-3-aminopropyl)methylphosphinic acid (N-(3-chlorophenyl)-3-aminopropyl)methylphosphinic acid - (N-(4-chlorophenyl)-3-aminopropyl)methylphosphinic acid (N-(4-methoxyphenyl)-3-aminopropyl)methylphosphinic acid (N-(4-bromopheny])-3-aminopropyl)methylphosphinic acid (N-(2,4-dichlorophenyl)-3-aminopropyl)methylphosphinic acid (N-(3,4-dichlorophenyl)-3-aminopropyl)methylphosphinic acid - (N-(3,4,5-trichlorophenyl)-3-aminopropyl)methylphosphinic acid the racemate of (3-amino-3-(4-chlorophenyl)propyl)phosphinic acid (3-aminopropyl)methylphosphinic acid the racemate of (3-amino-l-methylpropyl)methylphosphinic acid the racemate of (3-amino-l-ethylpropyl)methylphosphinic acid - the racemate of (3-amino-l-hydroxypropyl)methylphosphinic acid (3-aminopropyl)fluoromethylphosphinic acid (3-aminopropyl)difluoromethylphosphinic acid (3-aminopropyl)trifluoromethylphosphinic acid.
One embodiment of the invention is a compound of formula I wherein Ri represents hydrogen or methyl;
R2 represents hydrogen, C1-C7 alkyl or halogen;
R3 represents hydrogen; and R4 represents hydrogen or -C7 alkyl (optionally substituted with aryl or heteroaryl);
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof,
with the exceptions of:
the racemates of (3-amino-l-methylpropyl)methylphosphinic acid; the racemates of (3-amino-l-ethylpropyl)methylphosphinic acid. - the racemates of (3-amino-l-methylpropyl)phosphinic acid the racemates of (3-amino-l -ethylpropyl)phosphinic acid
(N-phenyl-3-aminopropyl)methylphosphinic acid
(N-p-tolyl-3-aminopropyl)methylphosphinic acid
(N-(3,5-dimethylphenyl)-3-aminopropyl)methylphosphinic acid - (N-(3,4-dimethylphenyl)-3-aminopropyl)methylphosphinic acid
(N-(3-chlorophenyl)-3-aminopropyl)methylphosphinic acid
(N-(4-chlorophenyl)-3-aminopropyl)methylphosphinic acid
(N-(4-methoxyphenyl)-3-aminopropyl)methylphosphinic acid
(N-(4-bromophenyl)-3-aminopropyl)methylphosphinic acid - (N-(2,4-dichlorophenyl)-3-aminopropyl)methylphosphinic acid
(N-(3,4-dichlorophenyl)-3-aminopropyl)methylphosphinic acid
(N-(3,4,5-trichlorophenyl)-3-aminopropyl)methylphosphinic acid
According to a further embodiment of the invention the compound of formula I is (3-amino-l -fluoropropyl)phosphinic acid,
3-[(4-chlorobenzyl)amino]propyl(methyl)phosphinic acid or 3-[l-({3-[hydroxy(oxido)phosphino]propyl}amino)ethyl]benzoic acid.
Within the invention C1-C7 alkyl can be straight, branched or cyclic alkyl and is, for example, C1-C4 alkyl, such as methyl, ethyl, n-propyl or n-butyl, also isopropyl, isobutyl, secondary butyl or tertiary butyl, but may also be a C5-C7 alkyl group such as a pentyl, hexyl or heptyl group.
C1-C7 alkoxy is, for example, C1-C4 alkoxy, such as methoxy, ethoxy, n-propoxy or n- butoxy, also isopropoxy, isobutoxy, secondary butoxy or tertiary butoxy, but may also be a C5-C7 alkoxy group, such as a pentoxy, hexoxy or heptoxy group.
C1-C7 thioalkoxy is, for example, -C4 thioalkoxy, such as thiomethoxy, thioethoxy, n- thiopropoxy or n-thiobutoxy, also thioisopropoxy, thioisobutoxy, secondary thiobutoxy or tertiary thiobutoxy, but may also be a C5-C7 thioalkoxy group, such as a thiopentoxy, thiohexoxy or thioheptoxy group.
Halogen as used herein is anyone of chlorine, fluorine, bromine or iodine.
The herein used term aryl means aromatic rings with 6-14 carbon atoms including both single rings and polycyclic compounds, such as benzyl or naphtyl, optionally substituted with one or more substituents such as -C7 alkyl, C1-C7 alkoxy, C1-C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amideor nitrile.
The term heteroaryl as used herein means aromatic rings with 5-14 carbon atoms, including both single rings and polycyclic compounds, in which one or several of the ring atoms is either oxygen, nitrogen or sulphur. The heteroaryl is optionally substituted with one or more substituents such as C1-C7 alkyl, -C7 alkoxy, -C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile.
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 compounds can also be in the form of solvates, e.g. hydrates.
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 the said 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 compounds can be used for the treatment of GORD-related or non-GORD related asthma, belching, coughing, pain, cocaine addiction, hiccups, IBS, dyspepsia, emesis and nociception.
One aspect of the invention is the use of the compounds of the invention in the manufacture of a medicament for the inhibition of TLOSR and thus for the treatment of gastro-oesophageal reflux disease, regurgitation in infants and also for the treatment of GORD-related or non-GORD related asthma, belching, coughing, pain, cocaine addiction, hiccups, DBS, dyspepsia, emesis and nociception.
Another aspect of the invention is a method for the treatment of TLOSR, for the treatment of gastro-oesophageal reflux disease, regurgitation in infants and also for the treatment of GORD-related or non-GORD related asthma, belching, coughing, pain, cocaine addiction, hiccups, IBS, dyspepsia, emesis and nociception, which method comprises treating a subject suffering from said condition with a pharmacuetical preparation comprising a compound of the invention.
A further aspect of the invention is a pharmaceutical formulation comprising as active ingredient a therapeutically acceptable amount of a compound according to the invention in association with diluents, excipients or inert carriers.
Preparation
The compounds according to formula I of the present invention may be prepared by one of the following methods.
A) A compound of formula II
Figure imgf000009_0001
in which R2 and R3 are as defined above in formula I with the exception that possible hydroxy groups in R2 and R3 optionally are protected with suitable protecting groups such as C1-C7 alkyl, X is a protecting group such as -CCH3(OCH2CH3)2 or if desired equal to Ri as defined in formula I, and Y is a protecting group such as C1-C7 alkyl, which compound of formula II may have been synthesized by a reaction according to Scheme 1 employing an appropriate unsaturated nitro compound in which R is as defined above in formula II, and a suitable protected phosphinic acid derivative in which R2 is as defined above in formula II, X and Y are as defined in formula II, and a base such as lithium diisopropylamide,
Figure imgf000010_0001
Scheme 1
is reduced in order to convert the nitro group to -NH2, optionally N-alkylated or N- arylated in order to introduce R if R4 is desired to be not equal to hydrogen, hydrolysed in order to take off the protecting groups, and thereafter optionally P-alkylated if X was not equal to Ri and if Ri is desired to be not equal to hydrogen to obtain a compound of formula I
Figure imgf000010_0002
wherein Ri, R2, R3 and R4 are as defined above in formula I, and optionally convert the above resulting compound I into another chemical compound of the formula I and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula I and/or into another salt and/or convert a resulting free compound of the formula I into a salt to correspond to the above definition, or
B) a compound of formula III
Figure imgf000011_0001
in which R2, and R3 are as defined above in formula II, X is hydrogen or a protecting group such as -CCH3(OCH2CH3)2 or if desired equal to Ri as defined in formula I, T is a group that can be converted to a-NH2 group, and Y is hydrogen or a protecting group such as Cj- C7 alkyl, which compound of formula III may have been synthesized by a condensation reaction according to Scheme 2 employing an 2,3-epoxypropyl derivative, such as an appropriate N-protected 2,3-epoxypropylamine derivative or an epichlorohydrin derivative, in which R and R3 is as defined above in formula I, and a suitable protected phosphinic acid derivative activated by O-silylation, in which X and Y are as defined in formula III, and a Lewis acid such as anhydrous ZnCl2,
Figure imgf000011_0002
Scheme 2
is converted by a reaction where the trimethylsilyl group is replaced by a hydrogen atom, a radical reaction in order to replace the hydroxy group with a hydrogen atom, a reaction where the T group as defined in formula VI is transformed to -NHR wherein R4 is as defined above in formula I, a hydrolytic reaction to take off protecting groups, and thereafter optionally a P-alkylation reaction if X was not equal to Ri and if Rj is desired to be not equal to hydrogen to obtain a compound of formula I
Figure imgf000012_0001
wherein R1 ; R2, R3 and R are as defined above in formula I, and optionally convert the above resulting compound I into another chemical compound of the formula I and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula I and/or into another salt and/or convert a resulting free compound of the formula I into a salt to correspond to the above definition, or
C) a compound of formula IV
Figure imgf000012_0002
in which R2 is as defined above in formula I, X is hydrogen or a protecting group such as - CCH3(OCH2CH3)2 or equal to Ri, U is an electron-withdrawing group, such as for instance -CN or -CO2Et which can be converted to a -CH2NH2 group, and Y is hydrogen or a protecting group such as C1-C7 alkyl, which compound of formula IV may have been synthesized by an addition reaction according to Scheme 3 employing an unsaturated compound in which R2 is as defined above in formula I, U is as defined in formula IV, and a suitable protected phosphinic acid derivative activated by O-silylation, in which X and Y are as defined in formula IV,
Figure imgf000013_0001
Scheme 3
is converted by a reaction where the U group is being transformed to -NHR4 wherein * is as defined above in formula I, and a hydrolytic reaction to obtain a compound of formula V
Figure imgf000013_0002
wherein Ri, R2 and R are as defined above in formula I, and optionally convert the above resulting compound V into another chemical compound of the formula V and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula V and/or into another salt and/or convert a resulting free compound of the formula V into a salt to correspond to the above definition; or
D) a compound of formula VI
Figure imgf000013_0003
in which Rj, R2, R3 and R4 are as defined in formula I and Z is a protecting group such as t- butyloxycarbonyl, which compound of formula VI may have been synthesized by a substitution reaction according to Scheme 4 employing an electrophilic compound in which R2, R3 and R are as defined above, L is a leaving group such as iodo, Z is as defined above, and a phosphinic acid derivative in which Rj is as defined in formula I activated by O-silylation,
Figure imgf000014_0001
Scheme 4 is converted by a hydrolytic reaction to a compound of formula I
Figure imgf000014_0002
wherein Rl s R2, R3 and R4 are as defined above in formula I, and optionally convert the above resulting compound I into another chemical compound of the formula I and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula I and/or into another salt and/or convert a resulting free compound of the formula I into a salt to correspond to the above definition; or
E) a compound of formula VII
Figure imgf000015_0001
in which R3 and R4 are as defined above in formula I, X is hydrogen or a protecting group such as -CCH3(OCH2CH3) or if desired equal to Ri, Z is a protecting group such as benzyl oxycarbonyl and Y is hydrogen or protecting groups such as C1-C7 alkyl, which compound of formula VII may have been synthesized by an addition reaction according to Scheme 5 treating a phosphinic acid derivative, in which X is as defined above in formula VII, with an aldehyde derivative in which R3, R and Z are as defined above, and a base such as an a ine
Figure imgf000015_0002
Scheme 5
a) is optionally converted by an O-alkylation reaction and then a hydrolytic reaction to obtain a compound of formula VIII,
Figure imgf000015_0003
in which R\, R3 and R4 are as defined above in formula I, R5 is hydrogen or C1-C7 alkyl and optionally convert the above resulting compound Vffl into another chemical compound of the formula VIII and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula VIII and/or into another salt and/or convert a resulting free compound of the formula VIE into a salt to correspond to the above definition, or
b) is converted to a halo compound by a deoxohalogenation reaction and then a hydrolytic reaction to obtain a compound of formula DC,
Figure imgf000016_0001
in which R\, R3 and R are as defined above in formula I, Halo is a halogen atom and optionally convert the above resulting compound IX into another chemical compound of the formula DC and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula DC and/or into another salt and/or convert a resulting free compound of the formula DC into a salt to correspond to the above definition.
Detailed description of the invention
The invention is described more in detail by the following non-limiting examples.
Example 1. 3-Amino-l-fluoropropylphosphinic acid.
To a solution of ethyl 3-amino-l -fluoropropyl(l ,l-diethoxyethyl)phosphinate (340 mg, 1.19 mmol) in methanol (5 mL) was added aqueous hydrochloric acid (50 mL, 150 mmol, 3 N HCl). The mixture was deoxygenated by bubbling Argon gas into the solution for 10 minutes; after which the reaction mixture was stirred at room temperature for 6 hours. TLC analysis (6:3: 1 methylene chloride/methanol/concentrated ammonium hydroxide, ninhydrin development) indicated complete consumption of starting material. The crude 3- amino-1-fluoropropylphosphinic acid was passed through a Dowex® 50WX8-200 mesh H+ form (30 g, 2x15 cm) column eluting with 1 : 1 methanol/water until no further material was detected by TLC analysis. The requisite crude 3-amino- 1-fluoropropylphosphinic acid was eluted with 1:3 concentrated ammonium hydroxide solution/methanol. The crude 3-amino- 1-fluoropropylphosphinic acid was further purified by silica gel column chromatography (20 g, 1x20 cm), eluting with 6:3:1 methylene chloride/methanol/concentrated ammonium hydroxide to afford 3-amino- l-fluoropropylphosphinic acid as a white solid (55 mg, 33%). Data for 3-amino- 1-fluoropropylphosphinic acid: mp=178-183 °C dec; APCI mass spectrum m/z=142; 1H NMR (300 MHz, D2O) δ 7.78 (s, 0.5H), 6.00 (s, 0.5H), 4.89-4.53 (m, 1H), 3.27-3.16 (m, 2H), 2.19-2.07 (m, 2H).
Example 2. 3-[(4-Chlorobenzyl)amino1propy](methyl)phosphinic acid.
Trimethylsilyl bromide (2 g, 13 mmol) was added to a solution of ethyl (3- aminopropyl)methylphosphinate (0.75 g, 2.59 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at RT for one hour before it was neutralised by addition of propylene oxid (approx. 10 mL). Evaporation of volatiles gave 3-[(4- chlorobenzyl)amino]propyl(methyl)phosphinic acid (0.61 g, 90%). Η NMR data were in agreement with the expected compound.
Example 3. 3-ri-({3-fHvdroxy(oxido)phosphinolpropyl )amino)ethvI"lbenzoic acid.
Ammonium hypophosphite (4.19 g, 50.5 mmol) was added to a three-necked 100-mL flask equipped with a thermometer, addition funnel and an argon bubbler. The flask was placed in a water bath at room temperature and N,O-fr/s-(trimethylsilyl)acetamide (BSA, 12.1 mL, 49.0 mmol) was added at such a rate that the internal temperature was maintained below 38 °C (15 minutes approx.) using ice cooling. During the addition ammonia gas was evolved (during the first 15 min this was rather rapid). Upon completing the addition of BSA, the reaction mixture was heated to 45-48 °C and maintained at this temperature for 1 h (during this time the reaction became viscous). The reaction was cooled to room temperature and a solution of tert-buty] 3-{ l-[(tert-butoxycarbonyl)(3-iodopropyl)amino]ethyl}benzoate (2.40 g, 4.9 mmol) in methylene chloride (25 mL) was added to the reaction mixture. The reaction was then allowed to stir at room temperature for 38 h. TLC analysis indicated tert- butyl 3-{ l-[(tert-butoxycarbonyl)(3-iodopropyl)amino]ethyl}benzoate was almost consumed (chloroform/methanol/concentrated ammonium hydroxide solution 80: 19: 1, uv development). The reaction mixture was cooled to 0 °C and was cautiously quenched with methanol (17 mL) and then with water (2 mL). The reaction mixture was stirred for 30 min after which the reaction was filtered and the solids were washed with methanol. The filtrate was concentrated and the residue was purified by flash column chromatography using silica gel (230-400 mesh, 600 g) and chloroform/methanol/ammonium hydroxide (80:19:1) to provide the phosphonous acid intermediate (3.1 g, along with acetamide impurity) as a white solid. The phosphonous acid intermediate (1.4 g, 3.3 mmol) was transferred to a 250- mL flask, dissolved in aqueous HCl (3 N, 100 mL) and stirred at room temperature under argon. The reaction mixture became a colorless clear solution after 2 h. Hydrolysis was complete after 4 h stirring at room temperature, and the reaction mixture was concentrated under reduced pressure. The resulting residue was passed through a Dowex® 50WX8-200 mesh H+ form resin (40 g) column eluting with 1 : 1 methanol/water until no further material was detected by TLC analysis (chloroform/methanol/concentrated ammonium hydroxide solution 6:3: 1, ninhydrin development). The requisite crude 3-[l-({3- [hydroxy(oxido)phosphino]propyl}amino)ethyl]benzoic acid was then eluted with 1:3 concentrated ammonium hydroxide solution/methanol. The crude 3-[l-({3- [hydroxy(oxido)phosphino]propyl}amino)ethyl]benzoic acid was further purified by column chromatography (to remove traces of methyl ester byproduct) eluting with chloroform, methanol, concentrated ammonium hydroxide solution (6:3: 1) to afford 3-[l- ({3-[hydroxy(oxido)phosphino]propyl}amino)ethyl]benzoic acid as a white solid (0.12 g, 12% over two steps). Data for 3-[l-({3- [hydroxy(oxido)phosphino]propyl}amino)ethyl]benzoic acid: mp = 194-197 °C; APCI mass spectrum m/z = 272; Η NMR (300 MHz, D2O) δ 7.96 (m, 2H), 7.81 (s, 0.5H), 7.65- 7.57 (m, 2H), 6.11 (s, 0.5H), 4.49 (q, 1H, 7=6.8 Hz), 3.09 (m, 1H), 2.87 (m, 1H), 1.86 (m, 2H), 1.73 (d, 3H, 7=6.8 Hz), 1.58 (m, 2H).
The following intermediates were used in the preparation of the compounds of the invention
Example II . Ethyl 3-amino- l -fluoropropyKLl-diethoxyethvDphosphinate.
Crude ethyl l,l-diethoxyethyl(l-fluoro-3-nitropropyl)phosphinate (0.9g) was dissolved in 10:90 concentrated ammonium hydroxide/methanol (20 mL), and directly reduced in a Parr® apparatus under an atmosphere of hydrogen (50 psi) using Raney Nickel (0.1 g, 50 wt % slurry in water). When no further hydrogen uptake was observed (4 h), the mixture was filtered through a pad of Celite® (5 g). TLC analysis (20:80 methylene chloride/methanol, ninhydrin development) indicated complete consumption of starting material. The crude reaction mixture was filtered through Celite® and concentrated under reduced pressure to afford crude ethyl 3-amino-l-fluoropropyl(l ,l- diethoxyethyl)phosphinate as a green oil (600 mg). This crude product was purified by column chromatography eluting with 20:80 methylene chloride/methanol to start and then the methanol content was increased to 100%. Those fractions, which gave a positive ninhydrin stain, were combined and afforded ethyl 3-amino- 1 -fluoropropyl( 1,1- diethoxyethyl)phosphinate (200 mg, 17%) as a green oil. Note: This general procedure was repeated on the same scale as above substituting lithium diisopropylamide (LDA) for n- butyllithium. In this case an additional amount of ethyl 3-amino- l-fluoropropyl( 1,1- diethoxyethyl)phosphinate (140 mg, 12%) was obtained. The lots were combined and subjected to the hydrolysis conditions below. Data for ethyl 3-aminό-l-fluoropropyl(l,l- diethoxyethyl)phosphinate: 1H NMR (300 MHz, CDC13) δ 5.30-4.78 (m, 1H), 4.40-4.18 (m, 2H), 3.90-3.30 (m, 4H), 2.38-2.20 (m, 2H), 3.20-2.50 (m, 2H), 1.60- 1.48 (m, 3H), 1.48-1.30 (m, 3H), 1.28-1.16 (m, 6H). Example 12. Ethyl l ,l-diethoxyethyl(l-fluoro-3-nitropropyl)phosphinate.
To ethyl l,l-diethoxyethyl(fluoromethyl)phosphinate (1.0 g, 4.13 mmol) in THF (10 mL) at -78 °C, was added n-butyllithium (2.5 mL, 6.19 mmol, 2.5 M solution in hexanes) dropwise with stirring. The solution was stirred at this temperature for an additional 10 minutes. Freshly prepared nitroethene1 (0.4 g, 5.37 mmol), in a solution of THF (10 mL) at -78 °C, was added dropwise over a period of 5 minutes; during this addition bubbling was observed within the flask. The solution was allowed to stir at -78 °C for lh, then allowed to warm to room temperature and stirred for an additional 10 minutes. The reaction was quenched with saturated aqueous ammonium, chloride solution (5 L). Extraction of the organic phase with ethyl acetate (3 x 15 mL), followed by washing with brine, drying over anhydrous sodium sulfate and removal of the solvent under reduced pressure afforded an orange oil (0.9 g). TLC analysis of the crude reaction mixture indicated numerous byproducts present including desired product (ethyl acetate, vanillin development).
Previous attempts to purify ethyl l,l-diethoxyethyl(l-fluoro-3-nitropropyl)phosphinate at this stage had resulted in decomposition. Consequently, the crude product was used in the next step without prior purification.
Example 13. Ethyl l ,l-diethoxyethyl(fluoromethyl)phosphinate.
Tetrahydrofuran (50 mL) was added to a pressure flask (350 mL), equipped with a septum and under an Argon atmosphere. Sodium hydride (4.0 g, 0.16 mol, 95 wt %) was added in one portion at room temperature. The flask was cooled to -20 °C and ethyl 1,1- diethoxyethylphosphinate (27.8 g, 0.13 mol) in THF (50 mL) was added dropwise. Stirring was continued for 30 minutes after which the flask was cooled to -78 °C. Chlorofluoromethane gas (30.0 g, 0.44 mol) was bubbled into the THF solution and at this temperature it condensed in the flask. The pressure flask was then sealed with a Teflon screw top and allowed to warm to room temperature over a 30 minute period. After this time the flask was heated to 50 °C for 6 h. The flask was then cooled to room temperature and the chlorofluoromethane gas was vented. An aliquot was taken and analyzed by proton NMR and the conversion was found to be approximately 50%. The reaction mixture was retreated with chlorofluoromethane (20.0 g, 0.29 mol) as previously described, resealed and heated at 50 °C for an additional 17 h. Another aliquot was taken at this time and analyzed by proton NMR and indicated complete conversion of starting material (ethyl 1,1 -diethoxyethylphosphinate) to product (ethyl 1 ,1- diethoxyethyl(fluoromethyl)phosphinate). The reaction mixture was quenched with water (20 mL) and the organic solvent was concentrated under reduced pressure. The resultant suspension was extracted with methylene chloride (3 x 100 mL), washed with brine and dried over anhydrous sodium sulfate (5 g). Concentration under reduced pressure afforded the desired crude product as a yellow oil. Purification by column chromatography on an 8 x 30 cm column eluting with 15:85 acetone/hexanes afforded the desired product as a colorless oil (5.36 g, 17%). Data for ethyl l,l-diethoxyethyl(fluoromethyl)phosphinate: 1H NMR (300 MHz, CDC13) δ 4.92-4.56 (m, 2H), 4.36-4.18 (m, 2H), 3.80-3.52 (m, 4H), 1.60- 1.40 (m, 3H), 1.38-1.28 (m, 3H), 1.26-1.12 (m, 6H).
Example 14. Ethyl 3-r(4-chlorobenzyl)amino1propyl(methyl)phosphinate.
Ethyl (3-aminopropyl)methylphosphinate (0.95 g, 5.75 mmol) and 4-chlorobenzaldehyde (1.02 g, 7.26 mmol) were dissolved in ethanol (50 mL). Acetic acid was added dropwise until a pH around 6 was achieved and then sodium cyanoborohydride (0.38 g, 6.05 mmol) was added. The resulting mixture was stirred at RT over night. The reaction mixture was quenhed by addition of water and hydrochloric acid (1 M) until a pH around 4 was reached. Evaporation of volatiles gave a solid reaction mixture from which the desired product was isolated by column chromatography (SiO2) eluting first with 5% methanol in dichloromethane and then with 20% methanol in dichloromethane to give ethyl 3-[(4- chlorobenzyl)amino]propyl(methyl)phosphinate (0.85 g) as an oil. Η NMR and FAB-MS data were in agreement with the expected compound. Example 15. tert-Butyl 3-1 l-r(tgrt-butoxycarbonyl)(3-iodopropyl)aminolethyl }benzoate.
tert-Butyl 3-[l-((tørt-butoxycarbonyl){3- [(methylsulfonyl)oxy]propyl}amino)ethyl]benzoate (5.1 g, 1 1.1 mmol) was dissolved in acetone (600 mL) at room temperature. Sodium iodide (16.6 g, 1 11 mmol) was added and the reaction mixture was refluxed for 1.5 h. TLC analysis indicated complete consumption of tert-butyl 3-[l-((tert-butoxycarbonyl){3-
[(methylsulfonyl)oxy]propyl}amino)ethyl]benzoate (chloroform/methanol 99.5:0.5, uv development). The reaction mixture was filtered, concentrated under reduced pressure and purified by silica gel column chromatography eluting with chloroform/methanol (99.5:0.5).
This procedure afforded tert-butyl 3-{ l-[(tert-butoxycarbonyl)(3- iodopropyl)amino]ethyl}benzoate as a pale yellow oil (2.50 g, 46%). Data for terr-butyl 3-
{ l-[(tert-butoxycarbonyl)(3-iodopropyl)amino]ethyl}benzoate: Η NMR (300 MHz, CDC13) δ 7.90 (m, 2H), 7.47-7.32 (m, 2H), 5.42 (m, IH), 2.99 (m, 4H), 1.91 (m, 2H), 1.59
(s, 9H), 1.57 (d, 3H), 1.47 (s, 9H).
Example 16. tert-butyl 3-[l-((tgrt-butoxycarbonyl){3- rCmethylsulfonvDoxylpropyl ) amino)ethvπbenzoate.
To a solution of tert-butyl 3-[l-((tert-butoxycarbonyl)(3- hydroxypropyl)amino)ethyl]benzoate (1.61 g, 4.2 mmol) in methylene chloride (40 mL) at 0 °C was first added triethylamine (1.77 mL, 12.7 mmol), and then followed by dropwise addition of methanesulfonyl chloride (0.49 mL, 6.36 mmol). The reaction mixture was allowed to warm to room temperature and stirring was continued for 2 h. TLC analysis indicated complete consumption of tert-butyl 3-[l-((rert-butoxycarbonyl)(3- hydroxypropyl)amino)ethyl]benzoate (chloroform/methanol 99.5:0.5, uv development). The reaction mixture was quenched with aqueous sodium bicarbonate. The organic material was extracted with methylene chloride (3 x 100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow residue. The crude product was purified by flash column chromatography using silica gel (230-400 mesh, 150 g) and chloroform/methanol (99.5:0.5) to provide tert-butyl 3-[l-((tert-butoxycarbonyl){3- [(methylsulfonyl)oxy]propyl}amino)ethyl]benzoate (1.80 g, 93%) as a pale yellow oil. Data for tert-butyl 3-[l-((fert-butoxycarbonyl){3- [(methylsulfonyl)oxy]proρyl } amino)ethyl]benzoate: Η NMR (300 MHz, CDC13) δ 7.89 (m, 2H), 7.50-7.36 (m, 2H), 5.37 (m, IH), 4.12 (m, 2H), 3.18-3.05 (m, 5H), 1.98-1.35 (m, 23H).
Example 17. terr-Butyl 3-( l-r(tert-butoxycarbonyl)(3- hydroxypropyDaminolethyl lbenzoate.
tert-Butyl 3-{ l-[(3-hydroxypropyl)amino]ethyl}benzoate (5.1 g, 18.3 mmol) was dissolved in methylene chloride (80 mL) and cooled to 0 °C. Di-tert-butyl dicarbonate (4.4 g, 20.1 mmol) was added in several portions quickly. The mixture was then allowed to warm to room temperature overnight (20 h). TLC analysis indicated complete consumption of tert- butyl 3-[l-((3-hydroxypropyl)amino)ethyl]benzoate (chloroform/methanol 99: 1, uv development). The crude reaction mixture was quenched with aqueous sodium bicarbonate. The organic material was extracted with methylene chloride (3 x 100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a slightly yellow oil. The crude product was purified by flash column chromatography using silica gel (230-400 mesh, 600 g) and chloroform/methanol (99: 1) to provide rert-butyl 3- { l-[(tert-butoxycarbonyl)(3-hydroxypropyl)amino]ethyl}benzoate (6.78 g, 98%) as a colorless oil. Data for tert-butyl 3-{ l-[(tert-butoxycarbonyl)(3- hydroxypropyl)amino]ethyl}benzoate: APCI mass spectrum m/z = 380; Η NMR (300 MHz, CDC13) δ 7.90 (m, 2H), 7.46-7.33 (m, 2H), 5.22 (m, IH), 3.51 (m, 2H), 3.41-3.10 ( , 2H), 1.59 (s, 9H), 1.58 (d, 3H), 1.50 (m, 2H), 1.44 (s, 9H). Example 18. tert-butyl 3-( l-[(3-hydroxypropyl)aminolethyl jbenzoate.
To a 100-mL three-necked round bottomed flask equipped with a Dean-Stark trap were added tert-buty] 3-acetylbenzoate (0.75 g, 3.40 mmol), 3-amino-l -propanol (0.55 mL, 7.16 mmol), -toluenesulfonic acid (PTSA, 32 mg, 0.17 mmol) and benzene (40 mL). The reaction mixture was refluxed for 15 h and the solvent was removed under reduced pressure. The resulting residue was dissolved in dichloroethane (15 mL) and treated with sodium triacetoxyborohydride (0.68 g, 3.2 mmol). The flask contents were stirred under nitrogen at room temperature for 16 h. The reaction mixture was cautiously quenched with aqueous ammonium chloride (10 mL), and the aqueous layer was extracted with methylene chloride (3 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography using silica gel (230-400 mesh, 100 g) and chloroform/methanol/ammoniurn hydroxide (95:4: 1) to provide tert-butyl 3-{ l-[(3- hydroxypropyl)amino]ethyl Jbenzoate (0.74 g, 81 %) as a colorless oil. Data for tert-butyl 3-{ l-[(3-hydroxypropyl)amino]ethyl Jbenzoate: APCI mass spectrum m z = 280; Η NMR (300 MHz, CDC13) δ 7.89 (m, 2H), 7.55 (d, IH), 7.42 (m, IH), 3.88 (m, 3H), 3.75 (m, 2H), 2.79 (m, IH), 2.66 ( , IH), 1.73 (m, 2H), 1.60 (s, 9H), 1.44 (d, 3H).
Pharmaceutical preparations
The compound according to formula I of the present invention can be used as an active ingredient in a pharmaceutical preparation for oral, rectal, epidural, intravenous, intramuscular, subcutanous, nasal administration and administration by infusion or for any other suitable route of administration. Preferably the way of administration is oral or by injection/infusion.
The pharmaceutical preparations contain a compound of the present invention in combination with one or more pharmaceutically acceptable ingredients. The finished dosage forms are manufactured by known pharmaceutical processes. Usually the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.2-20% by weight in preparations for parenteral use and preferably between 1-50% by weight in preparations for oral administration.
In the preparation of pharmaceutical preparations containing a compound of the present invention in the form of solid dosage units for oral administration, the compound selected may be mixed with solid pharmaceutically acceptable ingredients (among these for instance disintegrating agents and lubricating agents). The mixture is then processed into granules, tablets, capsules or sachets.
Dosage units for rectal administration may be prepared in the form of suppositories; in the form of a gelatine rectal capsule; in the form of a ready-made micro enema; or in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, or in the form of a dry mixture to be reconstituted with a suitable solvent prior to use.
Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent and are dispensed into ampoules or vials. They may also be prepared as a dry preparation to by reconstituted with a suitable solvent extemporaneously before use.
The typical daily dose of the active compound will depend on various factors such as for example the individal requirement of each patient, the route of administration and the disease. In general, dosages will be in the range of 1 μg to 100 mg per day and kg body weight, preferably 10 μg to 20 mg per day and kg body weight. Biological studies
[ HJGABA radioligand binding assay
Rat synaptic membranes were prepared from the whole brain of Sprague Dawley male rats essentially as described previously (Zukin, et al. (1974) Proc. Natl. Acad. USA 71 , 4802- 4807). The [3H]GABA competition assay, modified from Olpe et al ((1990) Eur. J. Pharmacol. 187, 27-38), was performed in 200 μl TCI (Tris Calcium Isoguvacine) buffer (50 mM Tris (tri(hydroxymethyl)aminomethane), pH 7.4, 2.5 mM CaCl2 and 40 μM isoguvacine) containing 20 nM [3H]GABA (specific activity: 3 Tera Becquerel
(TBq)/mmol), test compound or solvent and 80 μg synaptic membrane protein using 96- well plates. After incubation for 12-20 min at room temperature, incubations were terminated by rapid filtration through a glass fiber filter (Printed filtermat B filters, Wallac), which had been pretreated with 0.3% polyethyleneimine, using a 96-well plate cell harvester (Skatron or Tomtec). The filters were washed with buffer containing 50 mM Tris (tris(hydroxymethyl)aminomethane) and 2.5 mM CaCl2, pH 7.4, at 4 °C and then dried at 55° C. MeltiLex B/HS scintillator sheet (Wallac) was melted onto the filter, and radioactivity was determined in a Microbeta scintillation counter (Wallac).
Results and discussion
The compounds of the present invention were found to have high affinities and potencies for the GABAB receptor as revealed by low IC50 and EC50 me binding and ileum assays, respectively. The compounds have also been found to reduce TLOSR when administered i.v. as well as p.o. in animal models. Contrary to whaf has been claimed in the literature for 3-aminopropylphosphinic acid derivatives having a P-H bond, we found that P-H compounds of the present invention have high metabolic stability in animal models. Moreover, CNS side-effects (as measured by reduction in body temperature in the mouse) were not observable or only seen at doses higher than the therapeutic doses inhibiting TLOSR in the dog model. Therefore, the difference between therapeutic dose (inhibition of TLOSR in the dog model) and dose causing side-effects (in the mouse model) was unexpectedly high.

Claims

1. A compound according to formula I
Figure imgf000028_0001
wherein
R] represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl;
R2 represents hydrogen, hydroxy, C1 -C7 alkyl, -C7 alkoxy or halogen;
R3 represents hydrogen, C1-C7 alkyl (optionally substituted with hydroxy, mercapto, Cj- C7 alkoxy, -C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
R4 represents hydrogen, C1-C7 alkyl (optionally substituted with aryl or heteroaryl), aryl or heteroaryl;
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof,
with the exceptions of:
3-aminopropylphosphinic acid the racemate of (3-amino-3-methylpropyl)phosphinic acid - the racemate of (3-amino- l-methylpropyl)phosphinic acid the racemate of (3-amino- l-ethylpropyl)phosphinic acid (N-phenyl-3-aminopropyl)methylphosphinic acid (N-p-tolyl-3-aminopropyl)methylphosphinic acid (N-(3,5-dimethylphenyl)-3-aminopropyl)methylphosphinic acid (N-(3,4-dimethylphenyl)-3-aminopropyl)methylphosphinic acid (N-(3-chlorophenyl)-3-aminopropyl)methylphosphinic acid - (N-(4-chlorophenyl)-3-aminopropyl)methylphosphinic acid (N-(4-methoxyphenyl)-3-aminopropyl)methylphosphinic acid (N-(4-bromophenyl)-3-aminopropyl)methylphosphinic acid (N-(2,4-dichlorophenyl)-3-aminopropyl)methylphosphinic acid (N-(3,4-dichlorophenyl)-3-aminopropyl)methylphosphinic acid - (N-(3,4,5-trichlorophenyl)-3-aminopropyl)methylphosphinic acid the racemate of (3-amino-3-(4-chlorophenyl)propyl)phosphinic acid (3-aminopropyl)methylphosphinic acid the racemate of (3-amino- l-methylpropyl)methylphosphinic acid the racemate of(3-amino-l-ethylpropyl)methylphosphinic acid - (3-amino- l-hydroxypropyl)methylphosphinic acid (3-aminopropy])fluoromethylphosphinic acid (3-aminopropyl)difluoromethylphosphinic acid (3-aminopropyl)trifluoromethylphosphinic acid.
2. A compound according to claim 1 wherein Ri represents hydrogen or methyl;
R2 represents hydrogen, C1-C7 alkyl or halogen;
R3 represents hydrogen; and
^ represents hydrogen or C]-C7 alkyl (optionally substituted with aryl or heteroaryl);
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof.
3. A compound according to claim 1 which is (3-amino- l-fluoropropyl)phosphinic acid.
4. A compound according to claim 1 which is 3-[(4- chlorobenzyl)amino]propyl(methyl)phosphinic acid.
5. A compound according to claim 1 which is 3-[l-({3- [hydroxy(oxido)phosphino]propyl } amino)ethyl]benzoic acid.
6. A compound according to any one of claims 1-5, for use in therapy.
7. Use of a compound according to formula I
Figure imgf000030_0001
wherein
Ri represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl;
R2 represents hydrogen, hydroxy, C1-C7 alkyl, -C7 alkoxy or halogen;
R3 represents hydrogen, C1-C7 alkyl (optionally substituted with hydroxy, mercapto, Ci - C7 alkoxy, C1-C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
R represents hydrogen, C1-C7 alkyl (optionally substituted with aryl or heteroaryl), aryl or heteroaryl;
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof, with the exceptions of :
3-aminopropylphosphinic acid; (3-aminopropyl)methylphosphinic acid; the racemate of (3-amino- l-hydroxypropyl)methylphosphinic acid; and - (3-aminopropyl)difluoromethylphosphinic acid,
for the manufacture of a medicament for the inhibition of transient lower oesophageal sphincter relaxations.
8. Use according to claim 7, wherein said therapy treatment is gastro-oesophageal reflux disease.
9. Use according to claim 7, wherein said therapy treatment is regurgitation in infants.
10. Use of a compound according to formula I
Figure imgf000031_0001
wherein R] represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl;
R represents hydrogen, hydroxy, -C7 alkyl, C1-C7 alkoxy or halogen;
R3 represents hydrogen, C1-C7 alkyl (optionally substituted with hydroxy, mercapto, C\- C7 alkoxy, C1 -C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl; R4 represents hydrogen, -C7 alkyl (optionally substituted with aryl or heteroaryl), aryl or heteroaryl;
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof,
with the exceptions of:
3-aminopropylphosphinic acid the racemate of (3-amino-3-methylpropyl)phosphinic acid - the racemate of (3-amino- l-methylpropyl)phosphinic acid the racemate of (3-amino- l-ethylpropyl)phosphinic acid (N-phenyl-3-aminopropyl)methylphosphinic acid (N-p-tolyl-3-aminopropyl)methylphosphinic acid (N-(3,5-dimethylphenyl)-3-aminopropyl)methylphosphinic acid - (N-(3,4-dimethylphenyl)-3-aminopropyl)methylphosphinic acid (N-(3-chlorophenyl)-3-aminopropyl)methylphosphinic acid (N-(4-chlorophenyl)-3-aminopropyl)methylphosphinic acid (N-(4-methoxyphenyl)-3-aminopropyl)methylphosphinic acid (N-(4-bromophenyl)-3-aminopropyl)methylphosphinic acid - (N-(2,4-dichlorophenyl)-3-aminopropyl)methylphosphinic acid (N-(3,4-dichlorophenyl)-3-aminopropyl)methylphosphinic acid (N-(3,4,5-trichlorophenyl)-3-aminopropyl)methylphosphinic acid the racemate of (3-amino-3-(4-chlorophenyl)propyl)phosphinic acid (3-aminopropyl)methylphosphinic acid - the racemate of (3-amino- l-methylpropyl)methylphosphinic acid the racemate of(3-amino-l-ethylpropyl)methylphosphinic acid (3-amino- l-hydroxypropyl)methylphosphinic acid (3-aminopropyl)fluoromethylphosphinic acid (3-aminopropyl)difluoromethylphosphinic acid - (3-aminopropyl)trifluoromethylphosphinic acid for the manufacture of a medicament for the treatment of GORD-related or non-GORD related asthma, belching, coughing, pain, cocaine addiction, hiccups, IBS, dyspepsia, emesis or nociception.
1 1. A method for the treatment of transient lower oesophageal sphincter relaxations which method comprises treating a subject suffering from said condition with a pharmaceutical preparation comprising a compound according to formula I
Figure imgf000033_0001
wherein
Ri represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl;
R2 represents hydrogen, hydroxy, C1 -C7 alkyl, C1-C7 alkoxy or halogen;
R3 represents hydrogen, C1-C7 alkyl (optionally substituted with hydroxy, mercapto, Cj- C7 alkoxy, C1-C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
R4 represents hydrogen, C1-C7 alkyl (optionally substituted with aryl or heteroaryl), aryl or heteroaryl;
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof,
with the exceptions of: - 3-aminopropylphosphinic acid;
(3-aminopropyl)methylphosphinic acid; the racemate of (3-amino- l-hydroxypropyl)methylphosphinic acid; and (3-aminopropyl)difluoromethylphosphinic acid.
12. A method according to claim 11 , wherein said therapy treatment is gastro- oesophaegeal reflux disease.
13. A method according to claim 11 , wherein said treatment is regurgitation in infants.
14. A method for the treatment of GORD-related or non-GORD related asthma, belching, coughing, pain, cocaine addition, hiccups, IBS, dyspepsia, emesis or nociception which method comprises treating a subject suffering from said condition with a pharmaceutical preparation comprising a compound according to formula I
Figure imgf000034_0001
wherein
Ri represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl;
R2 represents hydrogen, hydroxy, C1-C7 alkyl, C1-C7 alkoxy or halogen;
R3 represents hydrogen, C1-C7 alkyl (optionally substituted with hydroxy, mercapto, C]- C7 alkoxy, C1-C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
R4 represents hydrogen, -C7 alkyl (optionally substituted with aryl or heteroaryl), aryl or heteroaryl;
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof, with the exceptions of:
3-aminopropylphosphinic acid the racemate of (3-amino-3-methylpropyl)phosphinic acid - the racemate of (3-amino- 1 -methylpropyl)phosphinic acid the racemate of (3-amino- l-ethylpropyl)phosphinic acid
(N-phenyl-3-aminopropyl)methylphosphinic acid
(N-p-tolyl-3-aminopropyl)methylphosphinic acid
(N-(3,5-dimethylphenyl)-3-aminopropyl)methylphosphinic acid - (N-(3,4-dimethylphenyl)-3-aminopropyl)methylphosphinic acid
(N-(3-chlorophenyl)-3-aminopropyl)methylphosphinic acid
(N-(4-chlorophenyl)-3-aminopropyl)methylphosphinic acid
(N-(4-methoxyphenyl)-3-aminopropyl)methylphosphinic acid
(N-(4-bromophenyl)-3-aminopropyl)methylphosphinic acid - (N-(2,4-dichlorophenyl)-3-aminopropyl)methylphosphinic acid
(N-(3,4-dichlorophenyl)-3-aminopropyl)methylphosphinic acid
(N-(3,4,5-trichlorophenyl)-3-aminopropyl)methylphosphinic acid the racemate of (3-amino-3-(4-chlorophenyl)propyl)phosphinic acid
(3-aminopropyl)methylphosphinic acid - the racemate of (3-amino- l-methylpropyl)methylphosphinic acid the racemate of(3-amino-l-ethylpropyl)methylphosphinic acid
(3-amino- l-hydroxypropyl)methylphosphinic acid
(3-aminopropyl)fluoromethylphosphinic acid
(3-aminopropyl)difluoromethylphosphinic acid - (3-aminopropyl)trifluoromethylphosphinic acid.
15. A pharmaceutical formulation comprising as active ingredient a therapeutically acceptable amount of a compound according to formula I
Figure imgf000036_0001
wherein
Ri represents hydrogen, methyl, fluoromethyl, difluoromethyl or trifluoromethyl;
R2 represents hydrogen, hydroxy, C1-C7 alkyl, -C7 alkoxy or halogen;
R3 represents hydrogen, C1-C7 alkyl (optionally substituted with hydroxy, mercapto, C1- C7 alkoxy, C1-C7 thioalkoxy, aryl or heteroaryl), aryl or heteroaryl;
R4 represents hydrogen, C1-C7 alkyl (optionally substituted with aryl or heteroaryl), aryl or heteroaryl;
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof,
with the exceptions of:
3-aminopropylphosphinic acid the racemate of (3-amino-3-methylpropyl)phosphinic acid - the racemate of (3-amino- l-methylpropyl)phosphinic acid the racemate of (3-amino- l-ethylpropyl)phosphinic acid
(N-phenyl-3-aminopropyl)methylphosphinic acid
(N-p-tolyl-3-aminopropyl)methylphosphinic acid
(N-(3,5-dimethylphenyl)-3-aminopropyl)methylphosphinic acid - (N-(3,4-dimethylphenyl)-3-aminopropyl)methylphosphinic acid
(N-(3-chlorophenyl)-3-aminopropyl)methylphosphinic acid
(N-(4-chlorophenyl)-3-aminopropyl)methylphosphinic acid (N-(4-methoxyphenyl)-3-aminopropyl)methy]phosphinic acid
(N-(4-bromophenyl)-3-aminopropyl)methylphosphinic acid
(N-(2,4-dichlorophenyl)-3-aminopropyl)methylphosphinic acid
(N-(3,4-dichlorophenyl)-3-aminopropyl)methylphosphinic acid - (N-(3,4,5-trichlorophenyl)-3-aminopropyl)methylphosphinic acid the racemate of (3-amino-3-(4-chlorophenyl)propyl)phosphinic acid
(3-aminopropyl)methylphosphinic acid the racemate of (3-amino- 1 -methylpropyl)methylphosphinic acid the racemate of(3-amino-l-ethylpropyl)methylphosphinic acid - (3-amino-l-hydroxypropyl)methylphosphinic acid
(3-aminopropyl)fluoromethylphosphinic acid
(3-aminopropyl)difluoromethylphosphinic acid
(3-aminopropyl)trifluoromethylphosphinic acid.
optionally in association with diluents, excipients or inert carriers.
16. A compound selected from the group consisting of ethyl 3-amino-l-fluoropropyl(l,l- diethoxyethyl)phosphinate, ethyl l,l-diethoxyethyl(l-fluoro-3-nitropropyl)phosphinate, ethyl l,l-diethoxyethyl(fluoromethyl)phosphinate, ethyl 3-[(4- chlorobenzyl)amino]propyl(methyl)phosphinate, tert-Butyl 3-{ l-[(tert-butoxycarbonyl)(3- iodopropyl)amino]ethyl Jbenzoate, tert-butyl 3-[l-((tert-butoxycarbonyl){3- [(methylsulfonyl)oxy]propyl}amino)ethyl]benzoate, tert-Butyl 3-{ l-[(tert- butoxycarbonyl)(3-hydroxypropyl)amino]ethyl Jbenzoate and tert-butyl 3-{ l-[(3- hydroxypropyl)amino]ethyl } benzoate.
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