WO2002100869A1

WO2002100869A1 - New napsylate salts i

Info

Publication number: WO2002100869A1
Application number: PCT/SE2002/001083
Authority: WO
Inventors: Lynne Taylor
Original assignee: Astrazeneca Ab
Priority date: 2001-06-08
Filing date: 2002-06-04
Publication date: 2002-12-19
Also published as: UY27324A1; SE0102057D0

Abstract

Novel napsylate salts of formula I, or a solvate thereof, (I) and stereoisomers thereof, as well as a process for the preparation thereof, pharmaceutical compositions containing the therapeutically active napsylate salt and the use of said active compounds in therapy.

Description

NEW NAPSYLATE SALTS I

Field of the invention

The present invention is related to novel salt compounds useful in therapy. The invention is also related to processes for their preparation, pharmaceutical compositions containing said salt compounds and the use of said salt compounds in therapy.

Background of the invention

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, pp. 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 that reduce the incidence of TLOSR and thereby prevent reflux. GAB Ag -receptor agonists having the property to inhibit TLOSR are disclosed in WO 98/ 11885, Al. Further GAB Ag -receptor agonists have recently been shown to have properties to inhibit TLOSR, as disclosed in WO 01/ 42252 Al.

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 GABAB receptor subtypes. GAB A_B receptors belong to the superfamily of G- protein coupled receptors. GABAβ 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. GABAβ receptor agonists have also been disclosed as useful in the treatment of emesis (WO 96/11680, A2) and, as mentioned above, in the inhibition of TLOSR (WO 98/11885, Al).

EP 0356128, Bl, describes the use of the specific compound (3-aminopropyl) methyl phosphinic acid, as a potent GABAβ receptor agonist, in therapy. EP 0181833, Bl, discloses substituted 3-aminopropyl phosphinic acids (or more correctly 3-aminopropyl phosphonous acids having very strong affinities towards GABAB receptor sites. EP 0399949, B l, discloses derivatives of (3-aminopropyl)methyl phosphinic acid which are described as potent GA A_B receptor agonists. These compounds are stated to be useful as muscle relaxants. EP 0463969, B 1 , and FR 2722192, A, are both applications related to 4- aminobutanoic acid derivatives having different heterocyclic substituents at the β-carbon of the butyl chain.

Use of GAB Aβ receptor agonists in form of salts are also proposed in EP 0356128, B 1 , EP 0181833, Bl, and EP 0399949, Bl.

Some of the substances disclosed in the documents above have a relatively high hygroscopicity, i.e. they absorb moisture or water, which in term has an effect to the chemical and physical stability. Therefore there is a need for active substances having a reduced hygroscopicity.

Outline of the invention

The object of the present invention is to provide novel salt compounds of certain GAB Ag receptor agonists. More particularly, the present invention provides novel napsylate salts of compounds of the formula I, or a solvate of said salt, or the stereoisomers thereof,

wherein

R represents hydrogen, hydroxy, C₁-C7 alkyl, C₁-C7 alkoxy or halogen;

R₂ represents hydroxy, mercapto, halogen, or an oxo group;

R₃ represents hydrogen, -C₇ alkyl (optionally substituted with hydroxy, mercapto, C - Cη alkoxy, C1-C7 thioalkoxy, aryl or heteroaryl);

R represents hydrogen, C₁-C7 alkyl (optionally substituted with aryl or heteroaryl), aryl or heteroaryl.

One further aspect of the invention is napsylate salt of compounds of formula I above, or a solvate, wherein

Ri represents hydrogen;

R₂ represents fluoro, hydroxy or an oxo group;

R₃ represents hydrogen; and

R₄ represents hydrogen. The napsylate salt of the invention have improved substance characteristics in relation to hygroscopicity. Further, the salt compounds according to the invention have suitable properties for handling the substances during the preparation of a pharmaceutical dosage form and during storage of the substance or the said dosage form.

The napsylate salt may be formed by an acid addition reaction of the parent substance, i.e. the phosphinic acid according to Formula I, or a solvate, and naphthalene-2-sulphonic acid, or an intermediate substance formed in the synthesis of the parent substance and naphthalene-2-sulphonic acid.

A further aspect of the invention, is a napsylate salt of compounds of formula I, selected from any one of (3-amino-2-fluoropropyl)phosphinic acid; (2R)-(3-amino-2- fluoropropyl)phosphinic acid; (3-amino-2-oxopropyl)phosphinic acid; and (5)-(3-amino-2- hydroxypropyl)phosphinic acid.

In accordance with the invention, it is to be understood that when R2 is an oxo group, the bond between R₂ and the carbon is a double bond.

Examples of the herein used term alkyl means, inter alia, 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.

Examples of the herein used term alkoxy .means, inter alia, 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.

Examples of the herein used term thioalkoxy means, inter alia, C₁-C₄ thioalkoxy, such as thiomethoxy, thioethoxy, n-thiopropoxy, n-thiobutoxy, 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 and iodine.

The herein used term aryl means aromatic rings with 6-14 carbon atoms, including both single rings and polycyclic compounds, such as phenyl and naphtyl, optionally substituted with one or more substituents such as C -Cη alkyl, C1-C7 alkoxy, C1-C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile.

The term heteroaryl as used herein means aromatic rings with 5-14 atoms, including both single rings and polycyclic compounds, in which one or several of the ring atoms is either oxygen, nitrogen or sulphur, inter alia, pyrimidyl. The heteroaryl is optionally substituted with one or more substituents such as C1-C7 alkyl, C1-C7 alkoxy, C1-C7 thioalkoxy, halogen, hydroxy, mercapto, carboxylic acid, carboxylic acid ester, carboxylic acid amide or nitrile. Herein the term halogen can be anyone of chlorine, fluorine, bromine and iodine.

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 napsylate salts of formula I above, or a solvate, or a stereoisomer thereof, have a surprisingly high chemical and physical stability during handling of the substance, as well as formulating into a pharmaceutical dosage form and during storage of the prepared dosage form. By preparing the salt-form of the parent substance and incorporating said substance into a suitable dosage form, the hydrolytic instability due to adsorbed free moisture is improved. If the active compound deliquesces at a low relative humidity, the handling and processing of the compound is made difficult. Therefore, further object of the invention is an aim to reduce the tendency of the compound to deliquesce.

According to the European Pharmacopeia Technical Guide (1999), Appendix E a hygroscopic substance shows an increase in mass which is less than 15 % m/m (mass of water/ mass of drug) and equal to or greater than 2 % m m during a period of 24 hours at 25 °C and 80 % RH. For a very hygroscopic substance the increase in mass is equal or greater than 15 % m/m.

Surprisingly, napsylate salts according to the invention have advantageous properties regarding the processing and handling of the active compound. The hygroscopic properties are improved, the napsylate salt does not deliquesce at as low relative humidity (RH) as the parent compound.

One aspect of the invention is the process for producing a salt compound according to formula I above.

One aspect of the invention is the use of a salt compound according to formula I above, for the manufacture of a medicament for the treatment of anyone of the diseases mentioned above.

One aspect of the invention is the pharmaceutical preparation comprising the pharmaceutically acceptable salt compound according to formula I above.

One aspect of the invention is the method for treatment of anyone of the diseases mentioned above with a pharmaceutical preparation comprising a therapeutic effective amount of a salt compound according to formula I above. Preparation

Preparation of the napsylate salt of compounds of Formula I, or solvate thereof, can be performed from the parent substance according to Formula I. The first step in the formation of the napsylate salt of the parent substances in Formula I, or a solvate thereof, is the addition of a solvent, such as methanol, to the parent substance, which then is let to reflux. A suitable amount of the naphthalene-2-sulphonic acid is added and the acid addition reaction is started. After terminated reaction, the mixture is cooled and the napsylate is crystallised by addition of an antisolvent, such as n-butyl acetate, which lower the solubility of the napsylate salt and further cooling of the mixture follows. Crystals of the napsylate salt are isolated by filtration and following wash.

The crude product is recrystallised by dissolving it in a solvent such as methanol followed by an addition of an antisolvent, such as isopropylalcohol. The solution is then cooled and a slurry is formed which is further cooled. The crystalline napsylate salt is isolated by filtering, washed with a suitable solvent and finally dried.

Preparation of the napsylate salt of Formula I, or solvate thereof, can also be performed from an intermediate compound formed in the synthesis of the parent compound. The formation of the present napsylate salt may start from an ammonium compound of Formula II, or a solvate or a stereoisomer thereof,

wherein Ri represents hydrogen; R₂ represents hydroxy or fluoro; R₃ represents hydrogen; Z represents a protecting group.

The synthesis starts with a neutralization of the intermediate with sulphuric acid, the corresponding phosphinic acid is obtained. Ammonium salt is formed and is filtered off. Naphthalene-2-sulphonic acid is added and the reaction is held for completion, i.e. the phosphinic acid of Formula LI is deprotected by reaction with the added naphthalene-2- sulphonic acid which also form the napsylate salt of the compounds of Formula I. The solvent is evaporated off and a crude product is obtained. The crude product is recrystallised with suitable solvent and antisolvent, for example, methanol and isopropyl alcohol, respectively.

The intermediate compound of Formula II is substituted with a suitable protecting group such as carbamates or other N-protecting groups, which are deprotected under acidic conditions. For details of further suitable protecting groups see Protective groups in organic synthesis, Theodora W. Greene, 1999, 3^rd edition, page 218-287 and page 323-334.

Example

The invention is exemplified by the following non-limiting example.

Example 1:

Preparation of napsylate salt of(2R)-(3-amino-2-fluoropropyl)phosphinic acid from the parent substance according to Formula I.

To (2/?)-(3-amino-2-fluoropropyl)phosphinic acid (6 g, 42.8 mmole) was methanol (24 ml, 4 ml/g parent substance) added at reflux. The naphthalene-2-sulphonic acid (11.3 g, 47.8 mmole) was added and dissolved. To the cooled solution (55°C) n-butyl-acetate was added (72ml, 12 ml/g parent substance). After further cooling of the mixture (0°C), the formed slurry was filtered off. The filter cake was aged at 0°C /overnight. The filter cake was ^• washed with a mixture of methanol and n-butyl-acetate (2x60ml, 2x10 ml/g parent substance). Crystals of the napsylate salt of (2R)-(3-amino-2-fluoropropyl)phosphinic acid were obtained after drying at 40°C/vacuum.

The crude product was recrystallised by dissolving it ( 2.03g, 5.81mmole) in methanol (8 ml, 4 ml/g napsylate salt). When all crude product was dissolved, isopropylalcohol was added (24 ml, 12 ml/g napsylate salt). The solution was cooled slowly to 0°C, a predetermined cooling profile between 35-0°C. The slurry was aged overnight. The obtained slurry was then filtered and washed with a mixture of methanol and isopropylalcohol (2x10 ml methanol/isopropylalcohol (2x5 ml/napsylate salt). The crystals were dried at 40°C/vacuum.

The obtained substance was confirmed by differential scanning calorimetry, DSC. The substance melts at 169 °C.

The improved properties are shown by a comparison of the hygroscopicity of the parent substance and the new napsylate salt. As can be seen from Figure 1 and Figure 2, the napsylate salt does not deliquesce before 90 % relative humidity, the parent substance deliquesces at 65 % relative humidity.

Example 2:

Preparation of napsylate salt of(2R)-(3-amino-2-fluoropropyl)-phosphinic acid from an intermediate substance according to Formula II.

To ammonium (2R)-3-[(tert-butoxycarbonyl)amino]-2-fluoro-propyl phosphinate (10.0 g, 23.2 mmole) was isopropyl alcohol (100 ml) added at ambient temperature. Sulphuric acid (1.3 ml, 23.2 mmol) was added dropwise. The temperature was maintained at 20 °C. The reaction mixture was stirred at ambient temperature for 50 minutes and the temperature was then lowered to 0°C for 1.5 hours. Crystals of ammonium sulfate formed and filtered off, washed with isopropyl alcohol (15 ml) and discarded. Naphthalene sulfonic acid (6.65 g, 25.6 mmol) was added to the solution, which was heated to reflux (Tm=90°C). The reaction is completed after approximately 2 hours. The solvent, isopropyl alcohol, was evaporated off. The crude product was dissolved in methanol (32 ml, 55°C). Isopropyl alcohol (97 ml) being an anti-solvent was added to the solution for one hour. The reaction mixture was cooled to 0°C (10 °C/hour) and left for at least 10 hours. The napsylate salt of (2R)-(3-amino-2-fluoro-propyl)-phosphinic acid was crystallised from the solution. The product was filtered off and washed with 2x32 ml isopropyl: methanol (3:1). The crystals may be recrystallised as above.

When exposed to 65% RH, 22°C the parent compound ceases to be a solid and forms a saturated solution (see Figure 1). It has been shown that the napsylate salt. of the parent compound remains a solid at a relative humidity up to 90% (see Figure 2).

The relative humidity, RH, of a gas is defined as % RH being equal to lOOx (p)/(ps) wherein (p) is the partial pressure of the water vapor present in the gas mixture and (ps) is the saturation pressure, or the partial pressure of water vapor above pure water at the temperature of the gas.

The new compound according to Example 1 is characterised by providing an X-ray powder diffraction pattern (XRPD) (see Figure 3), exhibiting substantially the following d-values and intensities:

The peaks, identified with d-values calculated from the Bragg formula and intensities, have been extracted from the diffractogram of the napsylate salt of (2i?)-(3-amino-2- fluoropropyl)phosphinic acid.

The relative intensities are less reliable and instead of numerical values, the following definitions are used:

% relative Intensity*: Definition:

25-100 vs (very strong)

10-25 s (strong)

3-10 m (medium)

1-3 w (weak)

* the relative intensities are derived from the diffractograms measured with variable slits. The XRPD distance values may vary in the range of ±2 on the last decimal place.

X-ray powder diffractogram (XRPD) analysis was performed on samples of the napsylate salt of (2R)-(3-amino-2-fluoropropyl)phosphinic acid, according to standard methods, for example, those described in Giacovazzo, C. et^'al., (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R.L. (1996),

Introduction to X-ray Powder Diffractometry, John Wiley&Sons, New York; Bunn, C. W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H. P. & Alexander, L. E. (1974), X-ray Diffration Procedures, John Wiley and Sons, New York.. X-ray analyses were performed using a Siemens D 5000 diffractometer.

Alternatively, the compounds of the invention may be characterized by X-ray analyses of the unit cell. Furthermore, the compounds of the invention may be characterized by H- NMR, IR, FTJJR and Raman spectroscopy. Pharmaceutical formulations

In another aspect the present invention provides formulated pharmaceutical formulations comprising, as active ingredient, a therapeutically effective amount of a pharmaceutically acceptable napsylate salt of compounds of formula I, as an enantiomer or a racemate, or a combination of such salts and/or solvates, optionally in association with diluents, excipients or carriers.

According to the present invention the compounds of the invention will normally be administered orally, rectally or parenterally, in the form of a pharmaceutically acceptable non-toxic salt or as a solvate of such salt in a pharmaceutically acceptable dosage form. The dosage form may be a solid, semisolid or liquid preparation. Usually, the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by weight for preparations intended for injection and between 0.2 and 80 % by weight for preparations suitable for oral administration.

The pharmaceutical formulations comprising the salt compounds of the invention are manufactured by conventional pharmaceutical techniques.

Suitable daily doses of the compound of the invention in therapeutical treatment of humans are about 0.001-100 mg/kg bodyweight for parenteral administrations and about 0.01-100 mg/kg bodyweight for other administration routes.

The salts of the compounds according to the invention can be used for the inhibition of TLOSR, and thus for the treatment of gastro-oesophageal reflux diseases. The said inhibition of TLOSR also implies that the said compounds can be used for the treatment of regurgitation in infants. Effective management of regurgitation in infants would be an important way of managing failure to thrive due to excessive loss of ingested nutrient. Furthermore, the novel compounds can be used for the treatment of GORD-related or non- GORD related asthma, belching, coughing, pain, cocaine addition, hiccups, JJBS, dyspepsia, emesis and nociception. Thus, the novel napsylte salts according to the invention are useful in therapy.

A further aspect of the invention is the use of a napsylate salt according to the invention for the manufacturing of any one of the indications mentioned above.

A further aspect of the invention is the method for treatment of the indications mentioned above by administering to a subject suffering from said conditions a pharmaceutical preparation comprising the napsylate salt according to the invention.

Claims

1. A napsylate-salt of a compound according to formula I, or

a solvate, or a stereoisomer of said salt

wherein

R_! represents hydrogen;

R₂ represents hydroxy or fluoro;

R₃ represents hydrogen; and

R represents hydrogen.

2. A napsylate-salt according to claim 1 , selected from any one of the compounds

(3-amino-2-fluoropropyl)phosphinic acid; (3-amino-2-

oxopropyl)phosphinic acid; and (3-amino-2-hydroxyproρyl) phosphinic acid.

3. A napsylate-salt according to claim 1 in form of the racemate.

4. A napsylate-salt according to claim 2 in which the compound of formula I is (3-amino-

2-fluoropropyl)phosphinic acid.

5. A napsylate-salt according to claim 4 in which the compound of formula I is (2R)-(3-

amino-2-fluoropropyl)phosphinic acid.

6. A napsylate-salt according to claim 4 which is (2S)-(3-amino-2-

fluoropropyl)phosphinic acid.

7. A napsylate-salt according to claim 2 in which the compound of formula I is (3-amino-

2-oxopropyl)phosphinic acid.

8. A napsylate-salt according to claim 2 in which the compound of formula I is (3-amino-

2-hydroxypropyl)phosphinic acid.

9. A napsylate-salt according to claim 8 in which the compound of formula I is (2^)-(3-

amino-2-hydroxypropyl)phosphinic acid.

10. A napsylate-salt according to claim 8 in which the compound of formula I is (2R)-(3-

amino-2-hydroxypropyl)phosphinic acid.

11. A napsylate salt according to any one of claims 1-10, for use in therapy.

12. Use of a napsylate-salt according to any one of claims 1-10 for the manufacture of a

medicament for the inhibition of transient lower oesophageal sphincter relaxations.

13. Use of a napsylate-salt according to any one of claims 1-10 for the manufacture of a

medicament for the treatment of gastro-oesophageal reflux disease.

14. Use of a napsylate-salt according to any one of claims 1-10 for the manufacture of a

medicament for the treatment of regurgitation in infants.

15. Use of a napsylate-salt according to any one of claims 1-10 for the manufacture of a

medicament for the treatment of GORD related or non-GORD related asthma, belching

coughing, pain, cocaine addition, hiccups, JJBS, dyspepsia, emesis or nociception. ,

16. A method for the inhibition of transient lower oesophageal sphincter relaxations which

method comprises administering to a subject suffering from said condition a

pharmaceutical preparation comprising a napsylate-salt according to any one of

claims 1-10.

17. A method for the treatment of gastro-oesophageal reflux disease which

method comprises administering to a subject suffering from said condition a

pharmaceutical preparation comprising a napsylate-salt according to any one of

claims 1-10.

18. A method for the treatment of regurgitation in infants which method comprises

administering to a subject suffering from said condition a pharmaceutical preparation

comprising a napsylate-salt according to any one of claims 1-10.

19. 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 administering to a subject suffering from said condition a pharmaceutical preparation comprising a napsylate-salt according to any one of

claims 1-10.

20. A pharmaceutical formulation comprising as active ingredient a therapeutically

acceptable amount of a napsylate-salt of any of claims 1-10 optionally in association with

diluents, excipients or inert carriers.

21. A process for the preparation of a napsylate-salt of a compound of formula I or a

solvate, of said salt according to claim 1, whereby an acid addition

reaction between the compound of formula I, optionally as an individual stereoisomer,

wherein

Ri represents hydrogen;

R₂ represents hydroxy or fluoro;

R₃ represents hydrogen; R represents hydrogen; or the stereoisomers thereof;

and naphthalene-2-sulphonic acid is performed.

22. A process for the preparation of a napsylate salt of a compound of formula I or a

solvate, or a stereoisomer, of said salt according to claim 1 , whereby an acid addition

reaction between the ammonium salt of a compound of formula II, optionally as an

individual stereoisomer,

wherein

R] represents hydrogen;

R₂ represents hydroxy or fluoro;

R₃ represents hydrogen;

Z represents a protecting group

and naphthalene-2-sulphonic acid is performed.

23. A process for the preparation of a napsylate salt of a compound of formula I or a

solvate, or a stereoisomer thereof, according to claim 22 wherein Z represents a carbamate.

24. A process for the preparation of a napsylate salt of a compound of formula I or a

solvate, or a stereoisomer, according to claim 23 wherein Z represents tert-butoxycarbonyl.