New aminopropylphosphinic acids

FIELD: chemistry of organophosphorus compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (1) showing affinity to one or more GABAB receptors and their pharmaceutically acceptable salts, solvates and stereoisomers but with exception for racemate of (3-amino-2-hydroxypropyl)-phosphinic acid. Invention provides increasing the therapeutic index value.

EFFECT: improved and valuable properties of compounds.

14 cl, 1 tbl, 21 ex

 

The scope of the invention

The present invention relates to new compounds having affinity for one or more than one GABAIn(γ-aminobutyric acid) receptor, as well as their pharmaceutically acceptable salts, solvate and stereoisomers. The invention also relates to methods for their preparation, pharmaceutical compositions containing therapeutically active compounds and to the use of these active compounds in therapy.

Prior art

Reflux

Gastroesophageal reflux disease (GORD) is the most common disease of the upper section of the gastrointestinal tract. Modern therapy aims to reduce the secretion of stomach acid or to the reduction of acid exposure in the esophagus by increasing esophageal clearance, the tone of the lower esophageal sphincter and gastric emptying. Previously it was thought that the main mechanism underlying reflux depends on hypotonic conditions in the lower esophageal sphincter. However, recent research (e.g., Holloway & Dent (1990) GastRoenteRol.Clin. N. Amer. 19, 517-535) showed that most of the attacks of reflux occurs during transient relaxation of the lower esophageal sphincter, below referred to as TLOSR, i.e. relaxation, not initiated by pateniemi. It was also shown that patsie the tov with GORD the secretion of gastric acid is usually normal.

Therefore, a need exists for compounds that reduce the number of cases TLOSR and thus prevent reflux.

Pharmaceutical compositions containing a local anesthetic used to inhibit the relaxation of the lower esophageal sphincter, are disclosed in WO 87/04077 and US 5036057. Recently it was shown that agonists of BAWinreceptors inhibit TLOSR, which are disclosed in WO 98/11885.

Agonists GABABreceptors

GABA (4-aminobutyric acid) is an endogenous neurotransmitter in the Central and peripheral nervous systems. Receptors for GABA is traditionally divided into the subtypes of GABAAand GABABthe receptors. GABABthe receptors belong to the superfamily of receptors associated with G-proteins. Agonists GABABreceptors are described as useful in the treatment of disorders of the CNS (Central nervous system), such as muscle relaxation in spinal spasticity, cardiovascular disorders, asthma, disorders of intestinal motility, such as irritable bowel syndrome (IBS), and as prokinetics and antitussive agents. Agonists GABABreceptors have also been described as suitable for the treatment of vomiting (WO 96/11680) and recently, as noted above, for inhibition of TLOSR (WO 98/11885).

The most studied agonist GABABreceptor is baclofen (4-amino-3-(chlorophenyl)oil is islote), disclosed in Swiss patent No. CH 449046. Baclofen for several years been used as an antispasmodic agent. EP 0356128 describes the application of the individual compounds (3-aminopropyl)methylphosphonous acid, as a strong agonist of GABABreceptors in therapy. EP 0181833 discloses substituted 3-aminopropylphosphonic acid, which was found to have very high affinity for the binding sites of GABABthe receptors. By analogy with baclofen, these compounds can be used as, for example, muscle relaxants. EP 0399949 discloses derivatives of (3-aminopropyl)methylphosphonous acid, which are described as strong agonists GABABthe receptors. It is established that these compounds are useful as muscle relaxants. Both applications EP 0463969 and FR 2722192 refer to derivatives of 4-aminobutyric acid with different heterocyclic substituents at the 3-carbon of the butyl chain. The relationship between structure and activity of some analogues of phosphinic acid with respect to their affinity for GABABreceptor, as well as their effect on muscle relaxation, discussed in J. Med. Chem. (1995), 38, 3297-3312. Conclusion in this article is that, compared to baclofen, much stronger muscle relaxation can be achieved by primenenie (S)-enantiomer of 3-amino-2-hydroxypropylmethacrylate to the slots, and without undesirable effects on the Central nervous system.

In the literature phosphinic acid having a hydrogen atom attached to phosphorus, also called phosphonate acid. These are two names for the same compounds, and both names can be used. However, for compounds of the present invention, the authors chose to use the name of phosphinic acid.

Summary of the invention

In the present invention proposed new compounds of formula I

where

R1represents hydrogen, hydroxy, lower alkyl, lower alkoxy or halogen;

R2represents hydroxy, mercapto, halogen or oxoprop;

R3represents hydrogen or lower alkyl (possibly substituted hydroxy, mercapto, lower alkoxy, lower dialkoxy or aryl);

R4represents hydrogen, lower alkyl (possibly substituted aryl)or aryl;

and their pharmaceutically acceptable salt, solvate, and stereoisomers, except:

1) of the racemate of (3-amino-2-hydroxypropyl)phosphinic acid, and

2) (2R/S, 3R)-(3-amino-2-hydroxybutyl)phosphinic acid.

In the preferred embodiment of the

R1represents hydrogen, lower alkyl or halogen;

R2represents halogen, hydroxy or oxoprop;

R3performance is possessing a hydrogen; and

R4represents hydrogen;

except for the racemate of (3-amino-2-hydroxypropyl)phosphinic acid.

Even more preferred compounds are (3-amino-2-forproper)phosphinic acid, (2R)-(3-amino-2-forproper)phosphinic acid, (2S)-(3-amino-2-forproper)phosphinic acid, (3-amino-2-fluoro-1-methylpropyl)phosphinic acid, (3-amino-2-oxopropyl)phosphinic acid, (2S)-(3-amino-2-hydroxypropyl)phosphinic acid, (2R)-(3-amino-2-hydroxypropyl)phosphinic acid and (3-amino-1-fluoro-2-hydroxypropyl)phosphinic acid.

Within the scope of this invention should be understood that when R1is exography, the relationship between R2and carbon is a double bond.

Within the scope of the present invention under the "lower" radicals and connections should be understood, for example, compounds having up to and including 7, especially up to and including 4 carbon atoms. Basic expressions have the following meanings:

Lower alkyl is, for example, With1-C4alkyl, such as methyl, ethyl, n-propyl or n-butyl and isopropyl, isobutyl, secondary butyl or tertiary butyl, but may also be5-C7alkyl group, such as pencilina, exilda or heptylene group.

Lower alkoxy is, for example, With1-C4alkoxy, such as IU is hydroxy, ethoxy, n-propoxy or n-butoxy, also isopropoxy, isobutoxy, secondary butoxy or tertiary, butoxy, but can also be5-C7alkoxygroup, such as pentox, hexose or epoxypropan.

Lower dialkoxy represents, for example, With1-C4dialkoxy, such as dimethoxy, diethoxy, n-dipropoxy or n-dibutoxy, also diisopropoxide, taisabaki, secondary dibutoxy or tertiary, dibutoxy, but can also be5-C7thioalcohol, such as thiopentone, tilecache or tileproxy.

Halogen is a halogen of atomic number up to and including 35, such as fluorine or chlorine, and less preferably bromine.

The compounds of formula I according to the invention are amphoteric in nature and can exist in the form of internal salts. They can also form a salt accession acids and salts with bases. Such salts are in particular pharmaceutically acceptable salts accession acids, 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 acid and carboxylic acid. Salts with bases PR is astavliaut a, for example, alkali metal salts, for example sodium or potassium, or salts of alkaline earth metals such as calcium salt or magnesium, and ammonium salts such as ammonium salts or organic amines. These salts can be obtained by traditional methods.

When the molecule has one or more than one stereocenter, the compounds of formula I can be in the form of mixtures of stereoisomers, that is, a mixture of diastereomers and/or racemate or in the form of single stereoisomers, that is, a single enantiomer and/or diastereoisomer. These compounds can also be in the form of a solvate such as a hydrate.

All the compounds of formula I can be used for inhibition of TLOSR, and thus for the treatment of gastroesophageal reflux disease. Specified inhibition of TLOSR also suggests that these compounds of formula I can be used for the treatment of regurgitation in infants. Effective treatment of regurgitation in infants would be an important way of treatment, not successful due to excessive loss proposinga nutrients. Furthermore, the new compounds can be used to treat associated with GORD or not associated with GORD asthma, belch, cough, pain, addiction to cocaine, hiccups, IBS, dyspepsia, vomiting and nociception.

In contrast to that established in the prior art (J. Med. Chem. (1995) 3297-3312 and The GABA Receptors: Seond Edition. Edited by S. J. Enna and Norman Bowery, Humana PRess (1997) especially str-282), compounds according to the invention have unexpectedly high metabolic stability, despite the presence of the P-N connection. These compounds also possess unexpectedly high therapeutic index.

Getting

The compounds of formula I of the present invention can be obtained in one of the following methods.

A) Compound of formula II,

where R1and R3such as defined above in formula I, X represents hydrogen or a protective group, such as-CLO3(Och2CH3)2Z represents a protective group such as tert-butyloxycarbonyl, and Y represents hydrogen or a protective group such as lower alkyl, the compound of formula II, and this connection may have been synthesized by condensation reaction according to Scheme I, using the appropriate N-protected amino acid of ester in which R3such as defined above, W is a protecting group such as lower alkyl, and Z as defined in formula II, and a suitable protected derivative of phosphinic acid, in which R1such as defined above in formula I, X and Y are such as defined in formula II, and bases, such as diisopropylamide lithium

a) who is one turn by the reaction of N-alkylation to introduce R 4if it is desirable that R4did not represent hydrogen, and then hydrolytic reaction to obtain compounds of formula III

where R1, R3and R4such as defined above in formula I, and may make the above compound III into another chemical compound of the formula III, and/or share the resulting mixture of isomers into individual isomers and/or convert the obtained salt into the free compound of the formula III and/or into another salt, and/or transform obtained free compound of the formula III in salt in accordance with the above definition, or b) turn by a redox reaction, it is possible reactions of N-alkylation, if it is desirable that R4did not represent hydrogen, and finally a hydrolytic reaction to obtain compounds of formula IV

where R1, R3and R4such as defined above in formula I, and may make the above compound IV into another chemical compound of the formula IV and/or share the resulting mixture of isomers into individual isomers and/or convert the obtained salt into the free compound of the formula IV and/or into another salt, and/or transform obtained free compound of the formula IV in g in accordance with the above definition, or

in) prevyshayushchem redox reaction followed by reaction deoxyguanosine, possible reactions of N-alkylation to introduce R4if it is desirable that R4did not represent hydrogen, and finally a hydrolytic reaction to obtain compounds of formula V

where R1, R3and R4such as defined above in formula I and Halo is a halogen atom, and may make the above connection V into another chemical compound of the formula V and/or share the resulting mixture of isomers into individual isomers and/or convert the obtained salt into the free compound of the formula IV and/or into another salt, and/or transform obtained free compound of the formula V in g in accordance with the above definition, or

B) the compound of formula VI

where R1and R3such as defined above in formula I, X represents hydrogen or a protective group, such as - CLO3(Och-CH3)2T represents a group which can be converted in - NH2group, and Y represents hydrogen or a protective group such as lower alkyl, with a compound of formula VI may synthesized by the condensation reaction according to Scheme 2 using 2,3-epoxypropyl derivative, such as a suitable N-protected derivative of 2,3-epoxypropane or epichlorohydrine manufacturing the same, in which R1and R3such as defined above in formula I, and a suitable protected derivative of phosphinic acid, activated O-similarobama, in which X and Y are such as defined in formula VI, and a Lewis acid such as anhydrous ZnCl2,

a) make by reaction where trimethylsilyloxy group replaces the hydrogen atom, the reaction in which T is a group as defined in formula VI is converted into-other4where R4such as defined above in formula I, and finally a hydrolytic reaction to obtain compounds of formula IV

where R1, R3and R4such as defined above in formula I, and may make the above compound IV into another chemical compound of the formula IV and/or share the resulting mixture of isomers into individual isomers and/or convert the obtained salt into the free compound of the formula IV and/or another salt, and/or transform obtained free compound of the formula IV in g in accordance with the above definition,

or

b) transformed by the reaction, in which trimethylsilyloxy group replaces the hydrogen oxidation reaction, a reaction in which T is a group as defined in formula IV is converted into - other4where R4such as defined enter the formula I, and finally a hydrolytic reaction to obtain compounds of formula III

where R1, R3and R4such as defined above in formula I, and possibly make the above compound III into another chemical compound of the formula III, and/or share the resulting mixture of isomers into individual isomers and/or convert the obtained salt into the free compound of the formula III and/or into another salt, and/or transform obtained free compound of the formula III in salt in accordance with the above definition, or

C) turn by reaction where trimethylsilyloxy group replaces the hydrogen reaction deoxyguanosine, reactions in which the T group as defined in formula VI is converted into-other4where R4such as defined above in formula I, and finally a hydrolytic reaction to obtain the formula V,

where R1, R3and R4such as defined above in formula I and Halo is a halogen atom, and may make the above connection V into another chemical compound of the formula V and/or share the resulting mixture of isomers into individual isomers and/or convert the obtained salt into the free compound of the formula V and/or into another salt, and/or turn received a free connection Faure the uly V Sol in accordance with the above definition, or B) the compound of formula VII,

where R1such as defined above in formula I, X represents hydrogen or a protective group, such as - CLO3(Och2CH3)2U represents an electron-acceptor group, such as, for example, -CN, or - CO2Et, which can be turned in-CH2NH2group, and Y represents hydrogen or a protective group such as lower alkyl, and Halo is a halogen atom, with a compound of formula VII may synthesized by the reaction of accession according to the Scheme 3 using unsaturated compounds, in which R1such as defined above in formula I, U and Halo such as defined in formula VII, and a suitable protected derivative of phosphinic acid, activated O-similarobama, where X and Y are such as defined in formula VII,

transformed by the reaction, in which the U group in turn-other4where R4such as defined above in formula I, and a hydrolytic reaction to obtain compounds of formula VIII

where R1and R4such as defined above in formula I and Halo is a halogen atom, and may make the above compound VIII to another chemical compound of the formula VIII, the/or share the resulting mixture of isomers into individual isomers, and/or transform the obtained salt into the free compound of the formula VIII and/or into another salt, and/or transform obtained free compound of the formula VIII in g in accordance with the above definition; or

G) the compound of formula IX, possibly in the form of a single stereoisomer,

where R1, R3and R4such as defined above in formula I, Z represents a protective group such as tert-butyloxycarbonyl, and Halo is a halogen atom, with a compound of formula IX may synthesized by a substitution reaction according to Scheme 4 using electrophilic compounds, in which R1, R3and R4such as defined above, L is a leaving group such as iodide, Z and Halo such as defined above, and phosphinic acid, an activated O-similarobama,

turn by hydrolytic reaction in the compound of formula V

where R1, R3and R4such as defined above in formula I, and may make the above connection V into another chemical compound of the formula V and/or share the resulting mixture of isomers into individual isomers and/or convert the obtained salt into the free compound of the formula V and/or another salt, and/or turn received the second free compound of the formula V in g in accordance with the above definition; or

D) the compound of formula XI,

where R1, R3and R4such as defined above in formula I, X represents hydrogen or a protective group, such as - CLO3(Och2CH3)2and Y represents hydrogen or a protective group such as lower alkyl, with a compound of formula XI may synthesized using the reactions proceed according to Scheme 4, the processing of unsaturated derivative of phosphinic acid, in which R1, R3and R4such as defined above in formula I, H2S, mercaptoethanol (HS-or protected mercaptoethanol, such as benzylthio, in which case the protective group is removed,

turn by hydrolytic reaction to obtain compounds of formula XII

where R1, R3and R4such as defined above in formula I, and may make the above compound XII to another chemical compound of the formula XII, and/or share the resulting mixture of isomers into individual isomers and/or convert the obtained salt into the free compound of the formula XII and/or into another salt, and/or transform obtained free compound of the formula XII in salt in accordance with the above definition.

Detailed OPI is the use of the invention.

The invention is described in more detail in the following non-limiting examples.

Example 1. (3-Amino-2-Forproper)phosphinic acid

It chilled in an ice bath to a solution of ethyl-(3-amino-2-fluoro-3-oxopropyl)(diethoxylate)phosphinate in THF (tetrahydrofuran) was added 1 M NR3-THF in an argon atmosphere. After 10 minutes the solution was heated under reflux for 2.5 hours. The solution was cooled to room temperature, and added 6 N. HCl (200 ml). THF was removed by evaporation on a rotary evaporator, and the aqueous layer was boiled under reflux for 2.5 hours. The solution was cooled and evaporated. The residue was purified ion exchange column chromatography (DOWEX® 50WX-8-200, N.+form, 3,5×4.0 cm). Ion-exchange resin was pre-washed with a mixture of 2:1 methanol/water (400 ml). The crude product is dissolved in a mixture of 1:1 methanol/water was applied on the column and washed with a mixture of 1:1 methanol/water (400 ml). Eluent was changed to a mixture of 3:1 methanol/concentrated ammonium hydroxide. Combined two fractions (150 ml) and evaporated obtaining 645 mg (34%) (3-amino-2-forproper)phosphinic acid as a white solid. Data: melting point 203-207°, Rf=0,35 (60:40:1 methanol, methylene chloride, concentrated ammonium hydroxide);1H NMR (300 MHz, D2O) δ 7.11 (d, J=528 Hz, 1H), 5.18 (dm, J=54 Hz, 1H), 3.28-3.45 (m, 2H). 1.65-2.23 (m, 2H);132O + Dioxane) δ 87.8 (d, J=170 Hz), 44.3 (dd, J=12.6, 21,6 Hz), 35.6 (dd. J=20,2, 86,5 Hz); APIMS (mass spectrometry with ionization at atmospheric pressure): m/z=142 (M+N)+.

Example 2.

(2S)-(3-Amino-2-hydroxypropyl)phosphinic acid

A mixture of ethyl-(2S)-(3-amino-2-hydroxypropyl)(1,1-diatexite)phosphinate (1.0 g, 3.5 mmol) and concentrated HCl (50 ml) was heated under reflux for 2 hours. The solution was cooled to room temperature and was evaporated. The residue was dissolved in methanol (100 ml) and treated with propylene oxide (2 ml) at room temperature. After stirring the mixture for 5 hours, the precipitated solid was collected, decanter solvent. The solid was dried by a stream of argon to obtain 220 mg (45%) of (2S)-(3-amino-2-hydroxypropyl)phosphinic acid as a white solid. Data:1H NMR (300 MHz, D2O) δ 7.1 (d, J=540 Hz, 1H), 4.2 (m, 1H), 2.9-3.2 (m, 2H), 1.7-2.0 (m, 2H);31P NMR (121 MHz, D2O) δ 24.2 (d, J=522 Hz); FABMS (mass spectrometry with bombing bistami atoms): m/z=140 (M+N)+;[α]Dat 20°C=+8° (0.5% in 0.1 M HCl).

Example 3.

(2R)-(3-Amino-2-hydroxypropyl)phosphinic acid

A mixture of ethyl-(2R)-(3-amino-2-hydroxypropyl)(1,1-diatexite)phosphinate (0.9 g, 3.2 mmol) and concentrated HCl (50 ml) was heated under reflux for 2 hours. The solution was cooled to room temperature and upar is Vali. The residue was dissolved in methanol (50 ml) and treated with propylene oxide (3 ml) at room temperature. After stirring the mixture for 5 minutes, the precipitated solid was collected by decantation of the solvent. The solid was dried by a stream of argon to obtain 260 mg (59%) of (2R)-(3-amino-2-hydroxypropyl)phosphinic acid as a white solid. Data:1H NMR (300 MHz, D2O) δ 7.1 (d. J=540 Hz, 1H). 4.2 (m, 1H), 2.9-3.2 (m, 2H), 1.7-2.0 (m, 2H);31P NMR (121 MHz, D2O) δ 23.9 (d, J=525 Hz); FABMS: m/z=140 (M+N)+; [α]Dat 20°C=-8° (0.5% in 0.1 M HCl).

Example 4.

(3-Amino-2-oxopropyl)phosphinic acid

A sample of ethyl-[3-[N-(tert-butoxycarbonyl)amino]-2-oxopropyl](1,1-diatexite)phosphinate (8,11 g, 21,0 mmol) was dissolved in 3 BC HCl (400 ml), which is pre-obezkislorazhivaniya by bubbling N2through the solution. The mixture was stirred for 14 hours at room temperature and then concentrated. The residue was evaporated together with methanol. The residue then was dissolved in methanol (10 ml), was added propylene oxide (10 ml). The mixture was stirred for 6 hours, and the resulting precipitate was isolated by filtration. The solid is washed with cold methanol and dried under vacuum at 50°obtaining 2.1 g (73%) of (3-amino-2-oxopropyl)phosphinic acid in the form of a yellowish solid.

Data: Lockplate 126-127° C; Rf=0,64 (85:15 methanol, water);1H NMR(300 MHz, D2O) δ 7.13 (d, J=551 Hz, 1H), 4.14 (s, 2H), 3.14 (d, J=18 Hz, 2H);13With NMR (75 MHz, D2O+Dioxane) (199.5, 49.2, 47.3 (d, J=69 Hz); FABMS: m/d=138 (M+N)+.

Example 5.

(2R)-(3-Amino-2-forproper)phosphinic acid

Hypophosphite ammonium (73,8 g, 0.89 mol) was added to a 3-necked 2-liter flask equipped with a mechanical stirrer, thermometer, funnel for adding and argon bubbler. The flask was placed in a water bath at room temperature, was added N,O-bis(trimethylsilyl)ndimethylacetamide (215 ml of 0.87 mol - BSA) with such a rate as to maintain the internal temperature below 38°With (approximately 30 minutes), using ice cooling. After adding BSA to the reaction mixture was heated up to 45-48°C and maintained at this temperature for 1 hour. The reaction mixture was cooled to room temperature, and the reaction mixture was added a solution of tert-butyl(2R)-2-fluoro-3-adpropinquabant (27,3 g, 0.09 mol) in methylene chloride (300 ml). The reaction mixture was then allowed to mix at room temperature for 18 hours. The reaction mixture was cooled to 0°and carefully extinguished methanol (275 ml) and then water (32 ml). The reaction mixture was stirred for 30 minutes, after which it was filtered, and the solids were washed with methanol. The filtrate was concentrated, and the residue was placed in a deep VA is uum (0.1 mm, RT. Art. (13,33 PA)) at night. The crude residue triturated with a mixture of methylene chloride, methanol, concentrated aqueous ammonia (80:20:1) and filtered. The filtrate was concentrated under reduced pressure, and rubbing repeated. The crude concentrate was transferred into a 2-liter flask, dissolved in methanol (375 ml) and placed in a water bath at room temperature. Was added a saturated solution of gaseous hydrogen chloride in ethyl acetate (500 ml)and the mixture was stirred for 3 hours. The reaction mixture was filtered, and the solids were washed with a mixture of methanol and ethyl acetate (90:10). The filtrate was concentrated under reduced pressure, and the crude product was passed through a column of Dowex® 50WX8-200 mesh in the N+form (500 g, 8×15 cm), elwira a mixture of 1:1 methanol/water, up until the substance is no longer detected by TLC (thin layer chromatography) analysis. The desired crude product was then suirable a mixture of 1:3 concentrated solution of ammonium hydroxide/methanol. The product is then purified column chromatography, elwira mixture of chloroform, methanol, concentrated ammonium hydroxide solution (6:3:1) to give (2R)-(3-amino-2-forproper)phosphinic acid as a white solid (3.12 g, 24%).1H NMR (300 MHz, D2O) δ 7.90 (s. 0.5 N), 6.15 (s, 0.5 H), 5.12-5.29 (m, 0.5 N). 4.92-5.10 (m, 0.5 H), 3.12-3.42 (m. 2H), 1.74-2.26 m. 2H).

Example 6.

(2S)-(3-Amino-2-forproper)phosphinic acid

Hypophosphite ammonium (58,1 g, 0.70 mol) was added to a 3-necked 2-liter flask equipped with a mechanical stirrer, thermometer, funnel for adding and argon bubbler. Was added N,O-bis(trimethylsilyl)ndimethylacetamide (175,9 ml, 0.71 mol - BSA) with such a rate as to maintain the internal temperature between 35-40°C. after the addition of BSA, the reaction mixture was maintained at 35-40°C for 45 minutes. Added methylene chloride (150 ml)and the mixture was stirred at 35-40°C for another 45 minutes. The reaction mixture was cooled to room temperature, and the reaction mixture was added a solution of tert-butyl(2S)-2-fluoro-3-adpropinquabant (42.5 g, 0.14 mol) in methylene chloride (300 ml). The reaction mixture was then allowed to mix at room temperature over night. The reaction mixture was cooled to 0°and carefully extinguished with methanol (150 ml) and then water (60 ml). The reaction mixture was concentrated, and the residue was placed in a high vacuum (0.1 mm, RT. Art. (13,33 PA)). The residue is brought to about pH 8 by addition of concentrated ammonium hydroxide (50 ml), then was added methylene chloride (400 ml) and methanol (250 ml). The obtained solid substance was filtered, and the filtrate was concentrated. The residue is triturated with a mixture of methylene chloride, methanol, concentrated solution s is iaka (80:20:1, 400 ml) and filtered. The filtrate was concentrated under reduced pressure, and the crude concentrate was dissolved in methanol (400 ml). Was added a saturated solution of gaseous hydrogen chloride in ethyl acetate (600 ml)and the mixture was stirred for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.

The crude product was passed through a column of Dowex® 50WX8-200 mesh in the N+form (450 g), elwira a mixture of 1:1 methanol/water, until the substance is no longer detected by TLC analysis. The desired crude product was then suirable a mixture of 1:3 concentrated solution of ammonium hydroxide/methanol. The product is then purified column chromatography, elwira mixture of methylene chloride, methanol, concentrated ammonium hydroxide solution (6:3:1) to give (2S)-(3-amino-2-forproper)phosphinic acid as a white solid (3.46 in g, 17%).1H NMR (300 MHz, D2O) δ 7.90 (s. 0.5 N), 6.15 (s, 0.5 H), 5.12-5.29 (m. 0.5 N), 4.92-5.10 (m. 0.5 H), 3.12-3.42 (m. 2H), 1.74-2.

Example 7.

(3-Amino-1-fluoro-2-hydroxypropyl)phosphinic acid

Ethyl-(3-(N-(tert-butoxycarbonyl)amino)-1-fluoro-2-hydroxypropyl)(1,1-diatexite)phosphinate (180 mg, 4.5 mmol) was dissolved in methanol (2 ml)was treated with 3 N. hydrochloric acid (20 ml, 60,0 mmol, probabtionary argon immediately prior to use). This mixture is eremetical at room temperature for 6 hours in an argon atmosphere. The reaction mixture was concentrated under reduced pressure, the crude product was re-dissolved in methanol (5 ml);

residual water was removed joint by evaporation under reduced pressure with methanol. The crude product (70 mg) was purified column chromatography (1×10 cm column), elwira mixture of methylene chloride, methanol, concentrated ammonium hydroxide solution (6:3:1). The fractions containing the product were concentrated under reduced pressure, evaporated together with acetonitrile (2×10 ml), then methanol (1×10 ml), and dried overnight in high vacuum (0.1 mm, RT. Art. (13,33 PA). The result of this procedure received (3-amino-1-fluoro-2-hydroxypropyl)phosphinic acid as a white solid (40 mg, 56%).1H NMR (300 MHz, D2O) δ 7.93 (s, 0.5 H), 6.11 (s, 0.5 H), 4.60-4.20 (m. 2 H), 3.42-3.08 (m, 2H).

Example 8.

(3-Amino-2-fluoro-1-methylpropyl)phosphinic acid

It cooled in an ice bath to a solution of ethyl-3-amino-2-fluoro-1-methyl-3-oxopropyl(diethoxylate)phosphinate (1.6 g, 5.3 mmol) in THF (15 ml) was added 1 M NR3-THF (12.3 ml, 12.3 mmol) in argon atmosphere. After 10 minutes the solution was heated under reflux for 3 hours. The solution was cooled to room temperature and was added dropwise 6 N. HCl (100 ml). THF was removed by evaporation on a rotary evaporator and was added another portion of 6 N. HCl (100 ml). The mixture boil is whether under reflux for 3 hours. The solution was cooled, evaporated and evaporated together with water and then with ethanol. The residue was purified ion exchange column chromatography (DOWEX® 50WX-8-200, H+form. 3,5×4.0 cm). Ion-exchange resin was pre-washed with a mixture of 2:1 methanol/water. The crude product is dissolved in a mixture of 1:1 methanol/water was applied on the column and washed with a mixture of 1:1 methanol: water. Eluent was changed to a mixture of 3:1 methanol/concentrated ammonium hydroxide. The appropriate fractions were combined and evaporated to obtain 150 mg (15%) of a mixture of diastereoisomers (3-amino-2-fluoro-1-methylpropyl)phosphinic acid in the form of oil. Data:1H NMR (400 MHz, D2O) (6.2-7.8 (m, 1H), 4.8-5.2 (m, 1H), 3.2-3.5 (m, 2H), 1.8-2.2 (m, 1H); 1.0-1.2 (m, 3 H); m/z=156 (M+N)+.

The following intermediate compounds used in the formation of compounds according to the invention.

Intermediate compounds

Example 11.

Ethyl-3-[(diethoxylate)(ethoxy)phosphoryl]-2-forproposal (intermediate compound for the compounds of Example 1)

A mixture of ethyl-(diethoxylate)phosphinate (26,0 g, 133 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (28 ml, 133 mmol) was heated under reflux for 2 hours in argon atmosphere. The mixture was cooled to room temperature and added ftorakrilata (10.5 g, 89,0 mmol). The reagents were heated to 60°C for three days in an atmosphere of argon. The mixture was cooled to room tempera is URS, was diluted with ethyl acetate (300 ml), washed with 1 N. HCl (2×150 ml) and saturated sodium chloride (100 ml). The organic layer was dried over MgSO4, was filtered and was evaporated obtaining of 32.0 g of yellow oil. The residue was purified column chromatography on a column of wet silica gel gasket (6×30 cm), elwira a mixture of 97:3 methylene chloride/methanol. The appropriate fractions were combined and evaporated to obtain 16.0 g (57%) ethyl-3-[(diethoxylate)(ethoxy)phosphoryl]-2-forproperty in the form of a clear oil. Data:1H NMR (300 MHz, CDCl3) δ 5.32 (dm, 1H), 4.67-4.77 (m. 1H), 4.18-4.32 (m, 2H), 3.58-3.91 (m, 4H), 2.30-2.62 (m. 2H); 1.20-1.41 (m. 9H).

Example 12.

Ethyl-(3-amino-2-fluoro-3-oxopropyl)(diethoxylate)phosphinate (intermediate compound for the compounds of Example 1)

To a solution of ethyl-3-[(diethoxylate)(ethoxy)phosphoryl]-2-forproperty (16.0 g, of 51.1 mmol) in ethanol (22 ml) was added concentrated ammonium hydroxide (14,8 n, 3.5 ml, of 51.1 mmol). The solution was stirred for 16 hours and evaporated. The residue was purified by chromatography on a column of wet silica gel gasket (7×37 cm), elwira mixture of 96.5:3.5 methylene chloride/methanol. The appropriate fractions were combined and evaporated obtaining of 3.43 g (27%) of ethyl-(3-amino-2-fluoro-3-oxopropyl)(diethoxylate)phosphinate in the form of a clear oil. Data:1H NMR (300 MHz, CDCl3) δ 6.43 (s, 1H), 5.70 (s, 1H), 5.21-5.49 (dm. 1H), 4.7 (dd, 1H), 4.18-4.31 (m, 2H), 3.65-3.91 (m, 4H, 2.21-2.81 (m, 2H); 1.30-1.40 (m, 3H), 1.20-1.28 (m, 6H).

Example 13.

Ethyl-(2R)-(3-chloro-2-hydroxypropyl)(1,1-diatexite)phosphinate (intermediate connection connection Example 2)

After a mixture of ethyl-(diatexite)phosphinate (15.0 g, 71 mmol) and toluene was evaporated to dryness, the residue and 1,1,1,3,3,3-hexamethyldisilazane (13,2 g, 82 mmol) was heated under reflux for 3 hours in argon atmosphere. The mixture was cooled to room temperature and was evaporated. Added (R)-epichlorohydrin (6.6 g, 71 mmol) and anhydrous zinc chloride (2.5 g, 18 mmol), and the reactants were heated to 60°C overnight in an argon atmosphere. The mixture was cooled to room temperature, diluted with methylene chloride and water. The organic layer was washed with water, dried over MgSO4, was filtered and was evaporated to obtain 20.7 g of a yellow oil. The residue was dissolved in methanol (150 ml)containing 1% acetic acid, and the solution was stirred over night. The solvent was removed from the receipt of 17.7 g (82%) of ethyl-(2R)-(3-chloro-2-hydroxypropyl)(1,1-diatexite)phosphinate in the form of a clear oil. Data:1H NMR (500 MHz, CDCl3) δ 4.3-4.4 (m, 1H), 4.1-4.3 (m, 2H), 3.5-3.8 (m, 4H), 1.9-2.4 (m, 2H); 1.5 (dd, J=2.3, and 11.4 Hz, MN), 1.32-1.37 (m, 3H), 1.18-1.24(m, 6H).

Example 14.

Ethyl-(2S)-(3-amino-2-hydroxypropyl)(1,1-diatexite)phosphinate (intermediate connection connection Example 2)

A solution of ethyl-(2R)-(3-chloro-2-hydroxypropyl)(1,1-diethoxy the Teal)phosphinate (5.0 g, 17 mmol) in ethanol containing 9% of ammonia was stirred in an autoclave at room temperature for 4 days and at 60°C for another day. The solution was evaporated, and the residue was purified by chromatography on a column of wet silica gel gasket, elwira a mixture of methylene chloride/methanol (5-8% Meon)containing 5% triethylamine. The appropriate fractions were combined, evaporated and diluted with methylene chloride and water. In the aqueous layer pH was brought down by adding a few milliliters of 10%aqueous Na2CO3and re-extracted with methylene chloride. The combined organic layers were dried over Na2SO4and was evaporated to obtain 1.2 g (26%) of ethyl-(2S)-(3-amino-2-hydroxypropyl)(1,1-diatexite)phosphinate in the form of a clear oil. Data:1H NMR (300 MHz, CDCl3) δ 4.40-4.55 (b, 1H), 4.10-4.30 (m, 2H), 3.55-3.80 (m, 4H), 3.20-3.30 (m, 1H), 3.00-3.10 (m, 1H), 2.00-2.40 (m, 2H); 1.45-1.53 (dd. J=3,4. an 11.7 Hz, 3H). 1.30-1.40 (m, 3H),1.15-1.25(m, 6H).

Example 15.

Ethyl-(2S)-(3-chloro-2-hydroxypropyl)(1.1-diatexite)phosphinate (intermediate connection connection Example 3)

After a mixture of ethyl-(diatexite)phosphinate (15.0 g, 71 mmol) and toluene was evaporated to dryness, the residue and 1,1,1,3,3,3-hexamethyldisilazane (13,2 g, 82 mmol) was heated under reflux for 3 hours in argon atmosphere. The mixture was cooled to room temperature and was evaporated. Was added (S)-epichlorohydrin (6.6 g, 71 mmol who) and anhydrous zinc chloride (2.5 g, 18 mmol), and the reactants were heated to 60°C overnight in an argon atmosphere. The mixture was cooled to room temperature, diluted with methylene chloride and water. The organic layer was washed with water, dried over MgSO4, was filtered and was evaporated to obtain 20.7 g of a yellow oil. The residue was dissolved in methanol (150 ml)containing 1% acetic acid, and the solution was stirred over night. The solvent was removed to obtain a 16.8 g (79%) of ethyl-(2S)-(3-chloro-2-hydroxypropyl)(1,1-diatexite)phosphinate in the form of a clear oil. Data:1H NMR (500 MHz, CDCl3) δ 4.4 (m, 1H), 4.2-4.3 (m, 2H). 3.6-3.8 (m, 4H). 1.9-2.4 (m, 2H); 1.5 (dd. J=2.3, and 11.4 Hz, 3H), 1.32-1.37 (m, 3H), 1.18-1.24 (m, 6H).

Example 16.

Ethyl-(2R)-(3-amino-2-hydroxypropyl)(1.1-diatexite)phosphinate (intermediate connection connection Example 3)

A solution of ethyl-(2S)-(3-chloro-2-hydroxypropyl)(1,1-diatexite)phosphinate (5.0 g, 17 mmol) in ethanol containing 9% of ammonia was stirred in an autoclave at room temperature for 6 hours and 55°C for another day. The solution was evaporated, and the residue was purified by chromatography on a column of wet silica gel gasket, elwira a mixture of methylene chloride/methanol (5-8% Meon)containing 5% triethylamine. The appropriate fractions were combined, evaporated and diluted with methylene chloride and water. In the water layer were summed pH by adding a few milliliters of 10%aqueous Na2/sub> CO3and re-extracted with methylene chloride. The combined organic layers were dried over Na2SO4and was evaporated to obtain 0.9 g (19%) of ethyl-(2R)-(3-amino-2-hydroxypropyl)(1,1-diatexite)phosphinate in the form of a clear oil. Data:1H NMR (300 MHz, CDCl3) δ 4.1-4.3 (m, 2H), 4.05 (b, 1H), 3.60-3.80 (m, 4H). 2.4-2.9 (m, 2H). 1.7-2.1 (m, 2H). 1.4-1.5 (dd, 3H), 1.3-1.4 (m, 3H), 1.2 (m, 6H).

Example 17.

Ethyl-[3-[N-(tert-butoxycarbonyl)amino]-2-oxopropyl](1.1-diatexite)phosphinate (intermediate connection connection Example 4)

To a solution of Diisopropylamine (3.0 ml, 21 mmol) in THF (5 ml) at -10°C was added dropwise n-BuLi (n-utility) (2.5 M in hexano, 8.6 ml, 21 mmol). After 10 minutes the reaction mixture was cooled to -78°and was added dropwise a solution of ethyl-(1,1-diatexite)(methyl)phosphinate (4,80 g, 21,0 mmol) in THF (5 ml). After addition the solution was stirred at -78°C for 1 hour. Was added dropwise a solution of methyl ester of N-BOC-glycine (N-butoxycarbonylamino) (810 mg, 4.3 mmol) in THF (15 ml). After the addition, the reaction mixture was stirred for 45 minutes. Was added acetic acid (1.2 ml, 21 mmol)and the reaction mixture was heated to room temperature. The reaction mixture was divided between methylene chloride and water and the layers were separated. The aqueous layer was extracted once with methylene chloride. The combined organic extracts sushi and over MgSO 4, was filtered and was evaporated to obtain 4,89 g of oil. The residue was purified by chromatography on 100 g of silica gel, elwira with ethyl acetate. The appropriate fractions were collected to obtain 1.2 g (74%) of ethyl-[3-[N-(tert-butoxycarbonyl)amino]-2-oxopropyl)(1,1-diatexite)phosphinate in the form of oil. Data:1H NMR (300 MHz, CDCl3) δ 5.48 (s. 1H), 4.10-4.30 (m, 2H), 4.17 (d, 2H), 3.60-3.80 (m, 4H), 3.01-3.30 (m, 2H), 1.52 (d, 3H), 1.43 (s, 9H), 1.32 (t. 3H), 1.19 (t, 6H).

Example 18.

(2R)-3-Dibenzylamino)-2-fluoro-1-propanol (intermediate connection connection Example 5)

Borohydride lithium (5,3 g, 0.24 mol) is suspended in THF (200 ml) under nitrogen atmosphere and cooled to -15°under stirring. Methyl(2R)-3-(dibenzylamino)-2-forproposal (56,6 g at 0.19 mol) suspended in THF (250 ml) and added dropwise to the mixture over 1 hour, the internal temperature during the addition was maintained below -10°C. Upon completion of addition the reaction mixture was allowed to warmed to room temperature and stirred at this temperature for 17 hours. The reaction mixture was cooled to 0°and carefully extinguished saturated aqueous ammonium chloride (300 ml). The reaction mixture was extracted with ethyl acetate (2×200 ml)and the organic phase was concentrated under reduced pressure. The crude residue was dissolved in 2 N. hydrochloric acid (200 ml, pH approximately 2), and the aqueous phase was washed with ether, 2× 200 ml). The aqueous phase was podlachian (approximately pH 10) 80%ammonium hydroxide in brine, extracted with ethyl acetate (3×200 ml), dried over anhydrous sodium sulfate (10 g), filtered and concentrated under reduced pressure to obtain (2R)-3-(dibenzylamino)-2-fluoro-1-propanol (48 g, 93%) as a yellow oil.

1H NMR (300 MHz, CDCl3) δ 7.15-7.38 (m, 10H), 4.65-4.78 (m, 0.5H), 4.48-4.58 (m, N), 3.50-3.82 (m, 6H), 2.70-2.88 (m, 2H).

Example 19.

(2R)-3-Amino-2-fluoro-1-propanol (intermediate connection connection Example 5)

(2R)-3-(Dibenzylamino)-2-fluoro-1-propanol (29,2 g, 0.11 mol) was dissolved in ethanol (300 ml). Added ten percent by weight of the hydroxide, palladium (II) coal (5.0 g)and the mixture was placed on a Parr® shaker, and shaken in a hydrogen atmosphere (55 psi (379,225 kPa)) for 6 hours. When there has been no more hydrogen absorption, the mixture was filtered through a gasket Celite® (20 g). To the ethanol mixture was added to a fresh portion of hydroxide, palladium (II) (5 g) and again subjected to the regime of the hydrogenation described above for 17 hours. The crude reaction mixture was filtered through Celite® and concentrated under reduced pressure to obtain (2R)-3-amino-2-fluoro-1-propanol as a pale yellow oil (9.6 g, 96%).

1H NMR (300 MHz, CDOD) δ 4.78-5.00 (br s, 3H), 4.49-4.62 (m. 0.5H), 4.32-4.46 (m, 0.5H), 3.54-3.70 (m. 2H), 2.70-2.96 (m, 2H).

Example I10.

Tert-Buti is-(2R)-2-fluoro-3-hydroxypropionate (intermediate connection connection Example 5)

(2R)-3-amino-2-fluoro-1-propanol (4.6 g, 49 mmol) was dissolved in 25%aqueous dioxane (160 ml), was added potassium carbonate (7,1 g, 51 mmol)and the mixture was cooled to 0°C. Di-tert-BUTYLCARBAMATE (11.6 g, 53 mmol) was added in two portions. The mixture was then left to warm to room temperature over night. The crude reaction mixture was concentrated to dryness, added water (150 ml), then saturated aqueous potassium hydrosulfate (to a pH of approximately 3). Organic matter was extracted with methylene chloride (2 x 150 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl(2R)-2-fluoro-3-hydroxypropionate (9.5 g, 100%) as a colourless oil.

1H NMR (300 MHz, CDCl3) δ 4.82-5.04 (br s. 1H). 4.62-4.72 (m, 0.5H), 4.48-4.58 (m. 0.5H), 3.62-3.72 (m, 2H), 3.32-3.62 (m, 2H), 3.20-3.44 (br s. 1H), 1.48 (s, 9H).

Example I11.

Tert-butyl(2R)-2-fluoro-3-adpropinquabant (intermediate connection connection Example 5)

The imidazole (26,6 g to 0.39 mol) was dissolved in methylene chloride (400 ml) at room temperature. Was added iodine (102,5 g to 0.39 mol)and the reaction mixture was stirred for 10 minutes at room temperature, and then cooled to 0°C. Triphenylphosphine (102,5 g to 0.39 mol) was added in portions during 10 minutes so that the internal temperature remained below 10°C. was added dropwise a solution of tert-butyl(R)-2-fluoro-3-hydroxypropionate (60,4 g, 0.31 mol) in methylene chloride (100 ml). After adding tert-butyl(2R)-2-fluoro-3-hydroxypropionate added additional methylene chloride (200 ml). The reaction mixture was left to warm to room temperature, and stirring was continued for 17 hours. The reaction mixture was filtered through a gasket Celite® (50 g) and washed with additional methylene chloride. The filtrate was concentrated under reduced pressure and was purified column chromatography on silica gel, elwira with methylene chloride. The result of this procedure was obtained tert-butyl(2R)-2-fluoro-3-adpropinquabant in the form of a white solid (64,7 g, 68%).

1H NMR (300 MHz, CDCl3) δ 4.80-5.10 (br s, 1H). 4.58-4.72 (m, 0.5H), 4.42-4.56 (m, 0,5H), 3.48-3.70 (m, 1H), 3.20-3.46 (m, 3H), 1.48 (s, 9H).

Example I12.

Methyl-(2S)-3-(dibenzylamino)-2-forproposal (intermediate connection connection Example 6)

Methyl(2R)-2-(dibenzylamino)-3-hydroxypropanoate (231,7 g, 0.77 mol) was dissolved in THF (850 ml) and slowly was added dropwise a solution of DAST (TRIFLUORIDE (diethylamino)sulfur) (196 g, 1.2 mol) in THF (400 ml). Once the addition was complete, the reaction mixture was stirred for another 1.5 hours. TLC analysis showed consumption of the original substance. The reaction mixture then was cooled to 0°and extinguished by slow addition of water (1.5 l), followed by neutralization by the addition of solid bicarbonate soda who I am. Immediately after neutralization was added a mixture of 1:1 concatinating ammonium hydroxide/saturated solution of sodium chloride, and the reaction mixture was extracted with ethyl acetate and concentrated under reduced pressure. The crude mixture was purified column chromatography on silica gel, elwira a mixture of ethyl acetate hexane (1:4) to give the desired compounds (of 188.3 g, 62%) as oil.

1H NMR (300 MHz, CDCl3) δ 7.18-7.38 (m. 10H), 5.12-5.17 (m, 0,5H), 4.95-5.00 (m, 0.5H), 3.81-3.87 (m. 2H), 3.69 (s, 3H), 3.49-3.55 (m, 2H), 2.90-3.12 (m. 2H).

Example I13.

(2S)-3-(Dibenzylamino)-2-fluoro-1-propanol (intermediate connection connection Example 6)

Borohydride lithium (17,7 g, 0.81 mol) suspended in THF (400 ml) under nitrogen atmosphere and cooled to -15°under stirring. Methyl-(2S)-3-(dibenzylamino)-2-forproposal (of 188.3 g of 0.62 mol) suspended in THF (400 ml) and added dropwise to the mixture. After the addition was finished the reaction mixture was left to warm to room temperature and stirred at this temperature for 3 hours. TLC analysis showed full consumption of the original substance. The reaction mixture was cooled to 0°and carefully extinguished saturated aqueous ammonium chloride (300 ml). Added additional water (400 ml), then the reaction mixture was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The crude about who's headed the remainder was dissolved in 2 B.C. hydrochloric acid, and the aqueous phase is washed twice with ether. The aqueous phase was podlachian (approximately pH 10) 80%ammonium hydroxide in brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain (2S)-3-(dibenzylamino)-2-fluoro-1-propanol (of 156.6 g, 92%) as a yellow oil.1H NMR (300 MHz, CDCl3) δ 7.15-7.38 (m, J), 4.65-4.78 (m, N), 4.48-4.58 (m, 0.5H), 3.50-3.82 (m, 6H), 2.70-2.88 (m, 2H).

Example I14.

(2S)-3-Amino-2-fluoro-1-propanol (intermediate connection connection Example 6)

(2S)-3-(dibenzylamino)-2-fluoro-1-propanol (39,1 g, 0.14 mol) was dissolved in ethanol (300 ml). Added ten percent by weight of the hydroxide, palladium (II) coal (5.0 g)and the mixture was placed on a Parr® shaker and were shaken in a hydrogen atmosphere (55 psi (379,225 kPa)) during the night. When there was more absorption of hydrogen, the mixture was filtered through a gasket Celite®. To the ethanol mixture was added to a fresh portion of hydroxide, palladium (II) (5 g), and again subjected to the regime of the hydrogenation described above, within 12 hours. Again, when there was more absorption of hydrogen, the mixture was filtered through a gasket Celite®. To the ethanol mixture was added to a fresh portion of hydroxide, palladium (II) (5 g) and again subjected to the regime of the hydrogenation described above, within 12 hours. The crude reaction when ect was filtered through Celite® and concentrated under reduced pressure to obtain (2S)-3-amino-2-fluoro-1-propanol as a pale yellow oil (13.3 g, 100%).1H NMR (300 MHz, CDCl3) δ 4.78-5.00 (bR s, 3H), 4.49-4.62 (m. 0.5H), 4.32-4.46 (m, 0,5H), 3.54-3.70 (m, 2H), 2.70-2.96 (m, 2H).

Example I15.

Tert-butyl(2S)-2-fluoro-3-hydroxypropionate (intermediate connection connection Example 6)

(2S)-3-Amino-2-fluoro-1-propanol (38,6 g, 0.41 mol) was dissolved in 25%aqueous dioxane (1.4 l)was added potassium carbonate (60.1 g, 0.43 mol), then di-tert-BUTYLCARBAMATE (99,5 g, 0.46 mol). The mixture was stirred over night. TLC analysis showed full consumption of the original substance. The crude reaction mixture was concentrated to dryness, added water (300 ml), then saturated aqueous potassium hydrosulfate (to a pH of approximately 3). Organic matter was extracted twice with methylene chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl(2S)-2-fluoro-3-hydroxypropionate (79,5 g, 99%) as a pale yellow oil.1H NMR (300 MHz, CDCl3) δ 4.82-5.04 (bR s, 1H), 4.62-4.72 (m, 0.5H). 4.48-4.58 (m, N), 3.62-3.72 (m, 2H), 3.32-3.62 (m, 2H), 3.20-3.44 (br s, 1H), 1.48 (s, 9H).

Example I16.

Tert-butyl(2S)-2-fluoro-3-adpropinquabant (intermediate connection connection Example 6)

The imidazole (19,8 g, 0.29 mol) was dissolved in methylene chloride (900 ml) at room temperature. Was added iodine (73,9 is, 0.29 mol)and the reaction mixture was stirred for 10 minutes at room temperature and then was cooled to 0°C. Triphenylphosphine (76,3 g, 0.29 mol) was added in portions during 10 minutes so that the internal temperature remained below 10°C. was added dropwise a solution of tert-butyl(2S)-2-fluoro-3-hydroxypropionate (45,0 g, 0.23 mol) in methylene chloride (300 ml). The reaction mixture was left to warm to room temperature, and stirring was continued for 12 hours. The reaction mixture was filtered through a gasket Celite® and washed with additional methylene chloride. The filtrate was concentrated under reduced pressure and was purified column chromatography on silica gel, elwira with methylene chloride. The result of this procedure was obtained tert-butyl(2S)-2-fluoro-3-adpropinquabant in the form of a colorless oil (42.5 g, 62%).1H NMR (300 MHz, CDCl3) δ 4.80-5.10 (br s, 1H), 4.58-4.72 (m, 0.5H), 4.42-4.56 (m, 0.5H), 3.48-3.70 (m, 1H), 3.20-3.46 (m, 3H), 1.48 (s, 9H).

Example I17.

Ethyl-(permitil)(1.1-diatexite)phosphinate (intermediate connection connection Example 7)

Sodium hydride (1.4 g, to 57.1 mmol) suspended in THF (50 ml) in a flask for reactions under pressure in a nitrogen atmosphere and cooled to -10°under stirring. Ethyl-(1,1-diatexite)phosphinate (10.0 g, or 47.6 mmol) in THF (20 ml) was added dropwise to the mixture over 10 minutes, the internal temperature of the support is supported below 0° At the time of adding. After the addition was finished the reaction mixture was allowed to mix at this temperature for 90 minutes. The flask was cooled to -78°and gaseous chloroformate (9.7 g, of 142.8 mmol) are condensed into the reaction mixture. The septum was removed, and the flask is hermetically closed tube with a screw threaded. The flask was then left to warm to room temperature and then was heated at 50°C for 24 hours. The reaction mixture was cooled to 0°and carefully extinguished with water (25 ml). To the reaction mixture were added methylene chloride (50 ml), and the emulsion was filtered through a gasket Celite® (20 g). The aqueous phase was extracted with methylene chloride (2×100 ml), dried over anhydrous magnesium sulfate, and the organic phase was concentrated under reduced pressure to obtain the crude product as a pale yellow oil (6,93 g). The crude product was purified by chromatography on a column of silica gel (6×25 cm column), elwira 20%acetone in hexano. The result of this procedure was obtained ethyl(permitil)(1,1-diatexite)phosphinate in the form of a clear colorless oil (4.4 g, 42%).1H NMR (300 MHz, CDCl3) δ 4.94-4.54 (m, 2H), 4.32-4.20 (m, 2H), 3.82-3.54 (m, 4H), 1.60-1.44 (m, 3H), 1.40-1.28 (m, 3H), 1.26-1.08 (m, 6H).

Example 118.

Ethyl-(3-(N-(tert-butoxycarbonyl)amino)-1-fluoro-2-oxopropyl)(1,1-diatexite)phosphinate (intermediate compound DL the compound from Example 7)

To a solution of Diisopropylamine (2.5 ml, 14.5 mmol, 3.5 equivalents) in THF (30 ml) at -10°With added dropwise (about 10 minutes) of n-BuLi (1.4 M in hexano, 9,0 ml, 14.5 mmol). After 10 minutes the reaction mixture was cooled to -78°and dropwise within 10 minutes was added a solution of ethyl-(permitil)(1,1-diatexite)phosphinate (2.0 g, compared to 8.26 mmol, 2 equivalents) in THF (10 ml). After the addition the reaction mixture was stirred at -78°C for 1 hour. Was added dropwise a solution of methyl ester of N-BOC-glycine (0.8 g, 4.1 mmol) in THF (10 ml) for 10 minutes so as to maintain the internal temperature below -70°C. When the addition was completed, the reaction mixture was stirred at -78°C for 1 hour. The reaction extinguished acetic acid (1 ml, 14.5 mmol) and then warmed to room temperature. Saturated aqueous sodium chloride (75 ml) was added to the reaction mixture, and the organic phase was separated. The aqueous phase was then extracted with ethyl acetate (2×75 ml). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product as a pale yellow oil (2,69 g). The crude product was purified column chromatography (2×35 cm column), elwira 40%ethyl acetate in hexane. The result of this method was obtained ethyl-(3-(N-tert-butoxycarbonyl)amino)-1-fluoro-2-oxopropyl)(1,1-diatexite)phosphinate in the form of a clear colorless oil (0.73 g, 44%).1H NMR (300 MHz, CDCl3) δ 5.78-5.24 (m, 2H), 4.52-4.08 (m, 4H), 3.94-3.50 (m. 4H), 1.62-1.51 (m, 3H). 1.50-1.32 (m, 3H), 1.42 (s. 9H), 1.30-1.12 (m, 6H).

Example I19.

Ethyl-(3-(N-(tert-butoxycarbonyl)amino)-1-fluoro-2-hydroxypropyl)(1.1-diatexite)phosphinate (intermediate connection connection Example 7)

To a solution of ethyl-(3-(N-(tert-butoxycarbonyl)amino)-1-fluoro-2-oxopropyl)(1,1-diatexite)phosphinate (0.7 g, 1.8 mmol) in methanol (30 ml) at -5°C in an atmosphere of nitrogen was added sodium borohydride (76 mg, 2.0 mmol) in one portion. There were some small heat release; however, the internal temperature was maintained below -2°C. the Reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was extinguished with saturated aqueous sodium bicarbonate (5 ml). The crude mixture was concentrated under reduced pressure. The crude residue was extracted with ethyl acetate (30 ml), washed with saturated aqueous sodium chloride (5 ml) and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure was obtained the crude product as a pale yellow oil (580 mg). After purification column chromatography got 2 fractions that were relevant to different diastereomers of ethyl-(3-(N-tert-butoxycarbonyl)amino)-1-fluoro-2-hydroxypropyl)(1,1-diatexite)phosphinate. It turned out that the less polar fraction was a mixture of the 1:1 two diastereomers, (210 mg, 29%), whereas the more polar fraction consisted mainly of one diastereoisomer, as shown1H NMR analysis (190 mg, 26%).1H NMR of less polar compounds (300 MHz, CDCl3) δ 5.32-5.04 (br s, 1H). 4.88-4.82 (m, 0.5H), 4.72-4.68 (m, 0.5H), 4.40-4.08 (m, 4H), 3.90-3.26 (m. 6H), 1.66-1.52 (m, 3H), 1.50-1.32 (m, 3H), 1.44 (s. N), 1.30-1.12 (m, 6H).

Example I20.

Ethyl-3-[(diethoxylate)(ethoxy)phosphoryl-2-verbatimout (intermediate connection connection Example 8)

A mixture of ethyl-(diethoxylate)phosphinate (21,7,0 g, 110 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (23,3 ml, 110 mmol) was heated under reflux for 2 hours in argon atmosphere. The mixture was cooled to room temperature, was added a mixture of diastereomers ethyl-2-Forbot-2-enoate (14.6 g, 110 mmol). The reactants were heated to 80°C for one day and 120°C for 2 hours in argon atmosphere. The mixture was cooled to room temperature, and was added another portion of the activated trimethylsilyl ethyl-(diethoxylate)phosphinate (it was obtained from ethyl-(diethoxylate)phosphinate (21.7,0 g, 110 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (23,3 ml, 110 mmol) in the same way as above). The mixture was heated to 100°within three days, and was added another portion of activated trimethylsilyl ethyl-(diethoxylate)phosphinate. The mixture was heated to 100°C for three days in an argon atmosphere, cooled to room is temperature and then was diluted with ethyl acetate (300 ml). The solution was washed 1 N. HCl (2×200 ml) and saturated sodium chloride. The organic layer was dried over MgSO4, was filtered and was evaporated to obtain 42,0 g yellow oil. The residue was purified column chromatography on a column of wet silica gel gasket, elwira with methylene chloride and then with a mixture of 98:2 methylene chloride/methanol. The appropriate fractions were combined and evaporated to obtain 3.6 g (10%) ethyl-3-[(diethoxylate)(ethoxy)phosphoryl]-2-formetanate in the form of a clear oil.1H NMR (300 MHz, CDCl3) δ 4.9-5.6 (m, 1H), 4.7-4.8 (m. 1H), 4.2-4.4 (m. 4H). 3.6-4.0 (m. 4H), 2.6-2.9 (m, 1H); 1.2-1.4 (m, 12H).

Example I21.

Ethyl-3-amino-2-fluoro-1-methyl-3-oxopropyl(diethoxylate)(phosphinate (intermediate connection connection Example 8)

To a solution of ethyl-3-[(diethoxylate)(ethoxy)phosphoryl]-2-formetanate (1.8 g, 5.5 mmol) in ethanol (3 ml) was added concentrated ammonium hydroxide (14,8 M, 0.5 ml, 7.4 mmol). The solution was stirred for 24 hours at 40°and then evaporated to obtain 1.6 g (97%) of a mixture of diastereomers ethyl-3-amino-2-fluoro-1-methyl-3-oxopropyl(diethoxylate)phosphinate in the form of a clear oil.1H NMR (400 MHz, CDCl3) δ 5.7-6.7 (m, 2H), 4.9-5.5.6 (m, 1H), 4.7-4.8 (m, 1H), 4.1-4.4 (m, 2H), 3.8-4.0 (m, 4H), 2.8-3.0 (m. 1H); 1.2-1.4 (m, 12H).

Pharmaceutical

The compound of formula I according to the present invention can be used as the active ingredient in the pharmacist is logical preparation for oral, rectal, epidural, intravenous, intramuscular, subcutaneous, nasal administration and administration by infusion, or for any other appropriate route of administration. The preferred route of administration is an oral or by injection/infusion.

Pharmaceutical preparations containing the compound of the present invention in combination with one or more pharmaceutically acceptable ingredient. Finished dosage forms are manufactured using known pharmaceutical methods. Usually the number of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.2 to 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 the compound of the present invention, in the form of solid dosage units for oral administration, the selected compound may be mixed with a solid pharmaceutically acceptable ingredients (among them, for example, loosening agents and lubricating agents). The mixture is then processed into granules, tablets, capsules or sachets.

Unit dose for rectal injection can be prepared in the form of suppositories; in the form of a gelatine rectal capsules; in the form of ready microenemas; or in the Orme dry preparation for micro for cultivation in a suitable solvent just before the introduction.

Liquid preparations for oral administration can be prepared in the form of syrups or suspensions, or in the form of a dry mixture for dilution with a suitable solvent before use.

Solutions for parenteral administration can be prepared in the form of a solution of the compounds according to the invention in a pharmaceutically acceptable solvent and poured into ampoules or vials. They can also be prepared as a dry product for reconstitution with a suitable solvent immediately before use.

The usual daily dose of active compound will depend on various factors, such as, for example, an individual need of each patient, the route of administration and the disease. Typically, dosages are in the range of 1 μg to 100 mg per day and kg body weight, preferably from 10 μg to 20 mg per day and kg body weight.

Biological studies

[3H]GABA radioligand analysis linking

Synaptic membranes of rats were prepared from whole brains of male rats Sprague Dawley. essentially similar to that described previously (Zukin, et al. (1974) PRoc. Natl. Acad. USA 71, 4802-4807). [3H]GABA competitive analysis, modified OIpe et al(1990) Eur. J. Pharmacol. 187,27-38) was performed in 200 ál of TCI (Tris-calcium isoguvacine) buffer (50 mm Tris (three(hydroxymethyl)aminomethane), pH 7.4, 2.5 mm CaCl2and 40 μm isoguvacine)containing 20 nm [3H]GABA (specific aktivnosti: 3 tera-Becquerel (TBq)/mmol), the test compound or solvent, and 80 µg protein of synaptic membranes, using 96-well plates. After incubation for 12-20 minutes at room temperature, incubation was finished by rapid filtration through glass fiber filter (Printed filtermat In filters, Wallac), which was pre-treated with 0.3%by polyethylenimine using 96-well harvester cells (Skatron or Tomtec). Filters were washed in a buffer containing 50 mm Tris (Tris(hydroxymethyl)aminomethan) and 2.5 mm CaCl2, pH 7.4 at 4°S, and then dried at 55°C. MeltiLex B/HS scintillator plate (Wallac) was melted on the filter, and the radioactivity was determined in a Microbeta scintillation counter (Wallac).

Results and discussion

It was found that the compounds of the present invention have a high affinity and activity in relation to GABA receptors, as revealed low IC50(median inhibitory concentration) and EC50(median effective concentration) in the analysis of binding and ileum, respectively. It was also found that the compounds reduce TLOSR when administered intravenously and orally in animal models. Contrary to what was stated in the literature for derivatives of 3-aminopropylphosphonic acid having a P-N connection, the authors found that the compounds of the present invention have a high metabolizes the Yu stability in animal models. In addition, adverse effects on the Central nervous system (as determined by the decrease of body temperature in mice) was not observed or were observed only at very high doses. Thus, the difference between therapeutic dose (inhibition of TLOSR in the model in dogs) and the dose that causes adverse effects in the model in mice)was unexpectedly high.

As an indicator of the metabolic stability of the compounds according to the invention is used an indicator of the bioavailability of the compounds, which represents the ratio of the number of connections that have reached the target, not having undergone this transformation, the number of established connections.

In the table below, shows the results of tests on the bioavailability obtained in the in vivo model in rats for five specific representatives of the compounds according to the invention (in brackets the number of sample receipt).

ConnectionBioavailability
[3-amino-2-oxopropyl]phosphinic acid (example 4)97%
[3-amino-2-forproper]phosphinic acid (example 1)81%
[(R)-3-amino-2-forproper]phosphinic acid (example 5)100%
[(S)-3-amino-2-forproper]phosphinic acid (example 6)78%
[(S)-3-amino-2-hydro is sapropel]phosphinic acid (example 2) 78%

The results presented in the table show unexpectedly high degree of bioavailability (80-100%) and, respectively, high metabolic stability of the claimed compounds.

To assess the security profile of the compounds according to the invention was determined by their therapeutic and toxic dose. Therapeutic dose corresponds to the number of new drug compounds, which must be entered to retrieve the target therapeutic effect, namely inhibition of TLOSR. therapeutic dose of the compounds according to the invention was determined by the inhibition of the test compound transient relaxation of the lower esophageal sphincter (TLOSR), which has been evaluated in in vivo models on dogs.

Toxic dose corresponds to the number of connections, which begins the development of unwanted, adverse or toxic effects. While the safety profile of compounds expressed its therapeutic index, which represents the ratio of the dose of compound that causes unwanted side effects, the dose that provides the specified therapeutic effect. The undesirable effects of the compounds according to the invention on the Central nervous system (CNS) has been evaluated for traditional agonists Oavav-receptors - their ability to lower the body temperature of the experimental the tal animal (in vivo model in mice). It is known that the temperature reduction is interconnected with such side effects on the Central nervous system of the medicinal product as sedation and hypothermia.

Baclofen and 3-aminopropyl(methyl)phosphinic acid, described in The GABA Receptors", second edition, Humana press, 1997, page 281 and J. Med. Chem (1995), 3297-3312, had adverse effects on the Central nervous system, such as sedation and hypothermia, at doses close to therapeutic and therapeutic index was not very high in comparison with the compounds according to the invention.

For example, for inhibition of 45% TLOSR in in vivo models on dogs needed 3 µmol/kg of the compounds according to the invention - [(R)-3-amino-2-forproper]phosphinic acid, and to reduce body temperature of the mouse at 2°required 690 μmol/kg of the compound. At the same time, baclofen in the amount of 1.4 mcmol/kg inhibited by 45% TLOSR in in vivo models on dogs, the number of baclofen 41.5 μmol/kg induced a decrease in body temperature of mice 2°C.

Thus, therapeutic index [(R)-3-amino-2-forproper]phosphinic acid was 690/3=230, and therapeutic index of baclofen was 41,5/1,4=29,6, i.e. therapeutic index of the compounds according to the invention was to 7.77 times higher than baclofen.

therapeutic index of all other compounds according to the invention or was the same as in [(R)-3-amino-2-forproper]phosphinic acid or the best is.

1. The compound of the formula I

where R1represents hydrogen,

R2represents hydroxy, fluorescent - or oxoprop;

R3represents hydrogen;

R4represents hydrogen;

and its pharmaceutically acceptable salt, solvate, and stereoisomers,

except for the racemate of (3-amino-2-hydroxypropyl)phosphinic acid.

2. Connection on p. 1, which is (3-amino-2-forproper)phosphinic acid.

3. Connection on p. 2, which is (2R)-(3-amino-2-forproper)phosphinic acid.

4. Connection on p. 2, which is (2S)-(3-amino-2-forproper)phosphinic acid.

5. Connection on p. 1, which is (3-amino-2-oxopropyl)phosphinic acid.

6. Connection on p. 1. which is (2S)-(3-amino-2-hydroxypropyl)phosphinic acid.

7. Connection on p. 1, which is (2R)-(3-amino-2-hydroxypropyl)phosphinic acid.

8. The compound according to any one of paragraphs. 1-7 for use in therapy.

9. The compound according to any one of paragraphs. 1-7 for the manufacture of drugs for the inhibition of transient relaxation of the lower esophageal sphincter.

10. The compound according to any one of paragraphs. 1-7 for the manufacture of drugs for the treatment of gastroesophageal re luxray disease.

11. The compound according to any one of paragraphs. 1-7 for the manufacture of drugs for the treatment of regurgitation in infants.

12. The compound according to any one of paragraphs. 1-7 for the manufacture of drugs for the treatment associated with GORD (gastroesophageal reflux disease) or not associated with GORD asthma, belch, cough, pain, addiction to cocaine, hiccups, IBS (irritable bowel syndrome), dyspepsia, vomiting, or nociception.

13. Pharmaceutical drug that will inhibit transient relaxation of the lower esophageal sphincter, containing as active ingredient a therapeutically acceptable amount of a compound according to any one of paragraphs. 1-7, possibly in combination with diluents, excipients or inert carriers.

14. A compound selected from the group consisting of ethyl-3-[(diethoxylate)(ethoxy)phosphoryl]-2-forproperty, ethyl-(3-amino-2-fluoro-3-oxopropyl)(diethoxylate)phosphinate, ethyl-(2R)-(3-chloro-2-hydroxypropyl)(1,1-diatexite)phosphinate, ethyl-(2R)-(3-amino-2-hydroxypropyl)(1,1-diatexite)phosphinate, ethyl -(2S)-(3-chloro-2-hydroxypropyl)(1,1-detoxation)phosphinate, ethyl-(2R)-(3-amino-2-hydroxypropyl)(1,1-diatexite)phosphinate, ethyl-[3-[N-(tert-butoxycarbonyl)amino]-2-oxopropyl](1,1-diatexite)phosphinate, (2R)-3-(dibenzylamino)-2-fluoro-1-propanol, (2R)-3-amino-2-fluoro-1-propanol, tert-butyl(2R)-2-fluoro-3-hydroxypropionate, tert-butyl(2R)-2-fluoro-3-adpropinquabant methyl-(2S)-3-(dibenzylamino)-2-forproperty, (2S)-3-(dibenzylamino)-2-fluoro-1-propanol, (2S)-3-amino-2-fluoro-1-propanol, tert-butyl(2S)-2-fluoro-3-hydroxypropionate, tert-butyl(2S)-2-fluoro-3-adpropinquabant, ethyl-(permitil)(1,1-diatexite)phosphinate, ethyl-(3-(N-(tert-butoxycarbonyl)amino)-1-fluoro-2-oxopropyl)(1,1-diatexite)phosphinate, ethyl-(3-(N-(tert-butoxycarbonyl)amino)-1-fluoro-2-hydroxypropyl)(1,1-diatexite)phosphinate, ethyl-3-[(diethoxylate)(ethoxy)phosphoryl]-2-formetanate and ethyl-3-amino-2-fluoro-1-methyl-3-oxopropyl(diethoxylate)phosphinate.



 

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