FIELD OF THE INVENTION

This invention relates to a novel polymorphic form of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid, methods of preparation thereof, and to its use.

BACKGROUND OF THE INVENTION

The invention relates to a novel polymorphic form of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid previously described in WO2009/065406. The compound may be used in treatment of a number of disorders or diseases associated with disturbances of CaSR activity.

Calcimimetics are small molecule allosteric activators of the calcium-sensing receptor (CaSR) [Urena, P. ; Frazao, J. M. Calcimimetic agents: Review and perspectives. Kidney International (2003), 63, pp. s91 -s96; Soudijn, W. et al. Allosteric modulation of G protein- coupled receptors: perspectives and recent developments. DDT (2004), 9, 752-758].

Calcimimetics have already been shown to be commercially useful for the treatment of hyperparathyroidism (HPT): The calcimimetic compound Cinacalcet® [Balfour, J. A. B. et al . Drugs (2005) 65(2), 271 -281 ; Linberg et. al. J . Am. Soc. Nephrol (2005), 16, 800-807, Clinical Therapeutics (2005), 27(1 1 ), 1725-1751 ] has recently been launched for the treatment of secondary HPT in chronic kidney disease patients on dialysis and for the treatment of primary H PT in patients with parathyroid carcinoma. Thus, proof of concept for activators of calcium sensing receptor (CaSR) in humans has been achieved, and the clinical relevance is already well established. Other calcimimetic compounds were for example described in WO 94/018959, WO98/001417, WO05/065050, WO03/099814, WO03/099776, WO00/21 910, WO01 /34562, WO01 /090069, WO97/41090, US6,001 ,884, W096/12697, EP1 203761 , W095/1 1221 , WO93/04373, EP1 281702, WO02/12181 , WO04/069793, US2004242602, WO04/106296 and WO05/1 1 5975.

{4-[(1 R,3S)-3-((f?)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid is part of a new promising class (WO2009/065406) of compounds displaying calcimimetic activity.

l One important aspect of pharmaceutical production is the question of the physical form of the Active Pharmaceutical I ngredient (API). The physical form, such as the crystal form, of a drug substance or API used in a pharmaceutical formulation or medicament is important because different physical forms often display different fundamental properties such as solubility, dissolution rate, hygroscopicity, bioavailability, processability and stability. The existence of various solid forms, such as polymorphism or pseudopolymorphism can thereby affect the properties of the drug product.

Hence, a specific crystal form, including solvates and hydrates, might be preferable over another one. Furthermore certain forms may be preferable depending on the specific formulation and/or application. For example, the properties of a drug, such as the dissolution rate of the active ingredient, may be tuned by the proper choice of a certain crystal form, or mixtures of crystal forms in specific ratios. A crystalline form of an API is usually preferred over a non-crystalline form, e.g. an amorphous form, in a drug formulation or during chemical processing due to its predictable properties. Crystalline forms have inter alia the advantage of greater chemical stability (pressure, heat and light), easier processability and handling. In particular the provision of a crystalline form is an important advantage during drug synthesis, especially on an industrial scale, since crystals are generally easier isolated from a reaction mixture.

Furthermore it is known that the crystallisation of a specific crystalline form of a compound in a particular solvent may result in an advantageous purification of the compound which would not be achieved by crystallisation of another form in a different solvent (partly due to differences in solubility properties of impurities in different solvents). Amorphous compounds, on the contrary, cannot be purified by recrystallisation, but will often require more expensive purification methods such as eg. preparative chromatography.

Various crystalline forms also differ in melting point, density, hardness, grinding properties, etc. and as a consequence a particular polymorphic form is preferred over another one depending on the specific application. Different crystalline forms have different stabilities in pharmaceutical formulations which depend on the excipients, vehicles, and other additives present in the dosage form. The instability of amorphous compounds or polymorphic forms which are not the most stable one represents in particular a problem when the drug substance is in suspension.

Accordingly while crystalline forms are generally preferred over non-crystalline forms of a drug substance, a specific crystalline form of a compound will be preferred depending on the various circumstances, such as its application or the process in which it is being used.

Sometimes a thermodynamically more stable form is preferred over a metastable form, sometime a metastable form which may have an increased dissolution rate is preferred.

WO2009/065406 describes the synthesis of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid, but does not discloses crystalline forms of the compound or the preparation of such forms. The application is silent as regards polymorphism and how to obtain a stable polymorphic form of {4-[(1 R,3S)-3-((f?)-1 - Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid.

WO2010/021351 describes the synthesis of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid derivatives but does not disclose crystalline forms of said derivatives.

SUMMARY OF THE INVENTION

The present invention surprisingly provides a stable crystalline polymorph of {4-[(1 R,3S)-3- ((fi)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid.

In a first aspect, the present invention thus relates to {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid, in crystalline form.

In a preferred aspect, the present invention relates to {4-[(1 R,3S)-3-((f?)-1 -Naphthalen-1 - yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid as a crystalline polymorph exhibiting one or more of the features, or characteristic lines, shapes, or patterns depicted in Graphs 2b, 4b, 6b, 8b, Formula 2 and/or Table 1 -6; or having one or more of the values listed therein, e.g. wavenumbers in cm ^"1 ( ±3 or ±4 cm ^"1 depending on the method used), or angles of reflection in degrees 2Θ (±0.1 ); or being represented by a spectrum or diffractogram substantially similar to that shown in said Graphs or Tables, said crystalline polymorph of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}- acetic acid is hereinafter named "Form X" or "polymorph X".

Form X can be distinguished from other polymorphic forms by several analytical techniques such as X-Ray Powder Diffractometry. Graph 1 shows an overlay XRPD diffractogram of the two polymorphic forms C and X which clearly indicates both regions of similarity and difference.

In an embodiment of the present invention the Form X of {4-[(1 R, 3S)-3-((R)-1 -Naphthalen- 1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid is thus characterized by having an XRPD pattern essentially as shown in Graph 2b, which is an XRPD diffractogram recorded of the pure polymorphic Form X.

In another embodiment the Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)- cyclopentyl]-phenoxy}-acetic acid is characterized by an XRPD pattern exhibiting one or more reflection peaks at approximately 2θ= 8_ , VL3, 1 1 .4, 15.0, 18.2 and/or 21 .5 (±0.05 degrees), (underlined is primary), respectively

Form X can also be distinguished from other polymorphic forms by Differential Scanning Calorimetry (DSC). Graph 3 shows an overlay thermogram of forms C and X which indicates the endothermic events for the two polymorphic forms having onsets at about 240°C and about 255°C (± 2 °C) .

In an embodiment the Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclo- pentyl]-phenoxy}-acetic acid is thus characterized by having a differential scanning calorimetry (DSC) curve essentially as shown in Graph 4b comprising an endothermic event with an onset at about 255°C (± 2 °C). Graph 4b further comprises a TGA trail which indicates that {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}- acetic acid is stable towards degradation at temperatures below 255°C (± 2 °C). Form X can also be distinguished from other polymorphic forms by attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. Graph 5 shows overlay ATR-FTIR spectra of the two polymorphic forms C and X which clearly indicates both regions of similarity and difference.

5

In one embodiment of the present invention the Form X of {4-[(1 f?,3S)-3-((f?)-1 - Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid is characterized by having an ATR-FTIR spectrum essentially as shown in Graph 6b, which is an ATR-FTIR spectrum recorded of the pure polymorphic Form X.

1 0

In another embodiment Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclo- pentyl]-phenoxy}-acetic acid is characterized by an ATR-FTIR spectrum exhibiting one or more attenuated total reflectance peaks at approximately 1409, 1 1 13, 1061 , 939, 841 , and/or 701 (± 3 cm ^"1 ) (underlined is primary), respectively.

I 5

Form X can also be distinguished from other polymorphic forms by Solid State Nuclear Magnetic Resonance (SS-NMR) spectroscopy. Graph 7 shows an overlay ³ C-SS-NMR spectrum of the two polymorphic forms C and X which clearly indicates both regions of similarity and difference.

0

In one embodiment of the present invention Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 - yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid is therefore characterized by having a 3C-SS-NMR spectrum essentially as shown in Graph 8b, which is the ³ C-SS-NMR spectrum recorded of the pure polymorphic Form X.

5

In another embodiment the Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)- cyclopentyl]-phenoxy}-acetic acid is characterized by a ¹³ C-SS-NMR spectrum exhibiting one or more resonance peaks at 5 ¹³ C: 172.7, 155.8. 140.5. 68.5, 5 6, 34.0, 29J3 (±1 ppm) (underlined is primary), respectively

0

In another embodiment of the present invention the Form C and Form X of {4-[(1 R,3S)-3- ((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid are characterized by having single crystal parameters which are substantially the same as provided in Table 1 . Table 1. Single Crystal Parameters for Form C and Form X of {4-[(1 R,3S)-3-((R)-1-Naphthalen- 1-yl-ethylammo)-cyclopentyl]-phenoxy}-acetic acid.

Throughout the present application crystal parameters such as unit cell dimensions, atomic coordinates etc are given in standard crystallographic notation, such that the standard uncertainty for a specific value is stated in brackets. For example, the value of axis a in Table 1 , "a = 8.7299(17) " means that there is a 95% chance that the value of a is 8.7299 ±0.0017 A, i. e. lies between 8.7282 A and 8.7316 A.

Table 2. Crystal data and structure refinement details concerning the Single crystal structure determination of {4-[(1R, 3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phenox y}-acetic acid Form X

Polymorph X

Crystal data

Chemical formula C ₂₅ H ₂₇ N0 ₃

M _r 389.48

Crystal system, space group Orthorhombic, P2 ₁ 2 ₁ 2 ₁

Temperature (K) 120(2)

a, b, c (A) 8.7299(1 7), 14.822(3), 16.353(3)

α, β, V Γ) 90.00, 90.00, 90.00

V (A ³ ) 21 16.0(7)

Z 4 Radiation type Mo Ka

μ (mm ^"1 ) 0.08

Crystal description Cube

Crystal colour Colourless

Crystal size (mm) 0.18 0.15 x 0.15

Data collection

Diffractometer Bruker SMART platform ccd

diffractometer

Absorption correction -

No. of measured, independent and 14231 , 2719, 1946

observed [/ > 2σ(/)] reflections

0.326

Refinement

R[F ² > 2σ(Ρ ² )], wR{F ² ), S 0.079, 0.21 1 , 0.76

No. of reflections 51 1 3

No. of parameters 262

No. of restraints 0

H-atom treatment H-atom parameters constrained

Ap _max , Ap _min (e A ^"3 ) 0.30, -0.52

Absolute structure Flack H D (1983), Acta Cryst. A39, 876-881

Flack parameter 4(3)

In a presently preferred embodiment of the present invention the Form X of {4-[(1 f?,3S)-3- ((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid comprises atoms at atomic positions relative to the origin of the unit cell as set forth below in Table 3, bond lengths as set forth below in Table 4, or bond angles as set forth below in Table 5.

Table 3. {4-[(1 R, 3S)-3-((R)- 1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid Form X. Atomic coordinates, equivalent isotopic displacement parameter [A ² ] and site occupancy factors.

Atom X y z u _eq S. o. f.

C1 0.2501 (7) 0.4585(4) 0.4734(3) 0.0310(14)

C2 0.3558(7) 0.4827(4) 0.5328(3) 0.0410(16)

C3 0.4853(7) 0.4279(4) 0.5510(4) 0.0486(17)

C4 0.5026(7) 0.3476(4) 0.5109(3) 0.0414(16)

C5 0.3975(7) 0.3185(4) 0.4517(3) 0.0362(14)

1 C6 0.4171(7) 0.2356(4) 0.4111(3) 0.0388 15) 1

C7 0.3198(7) 0.2086(4) 0.3511(3) 0.0394 15) 1

C8 0.1958(6) 0.2636(3) 0.3301(3) 0.0334 14) 1

C9 0.1712(7) 0.3442(4) 0.3685(3) 0.0346 14) 1

C10 0.2705(6) 0.3748(3) 0.4309(3) 0.0303 13) 1

C11 0.1158(6) 0.5197(3) 0.4545(4) 0.0340 14) 1

C12 -0.0062(7) 0.5182(4) 0.5216(4) 0.0448 16) 1

C13 0.3030(6) 0.6357(3) 0.3901(3) 0.0314 13) 1

C14 0.3246(6) 0.7399(3) 0.3833(3) 0.0333 13) 1

C15 0.3328(6) 0.7596(3) 0.2914(3) 0.0333 13) 1

C16 0.2295(7) 0.6848(4) 0.2553(3) 0.0418 16) 1

C17 0.2777(7) 0.6010(4) 0.3026(3) 0.0385 15) 1

C18 0.2877(7) 0.8535(4) 0.2645(3) 0.0330 14) 1

C19 0.3866(7) 0.8999(4) 0.2126(3) 0.0364 14) 1

C20 0.3440(6) 0.9826(3) 0.1790(3) 0.0349 14) 1

C21 0.2056(6) 1.0197(3) 0.1995(3) 0.0285 13) 1

C22 0.1098(6) 0.9751(4) 0.2530(3) 0.0317 13) 1

C23 0.1500(6) 0.8926(4) 0.2849(3) 0.0308 13) 1

C24 0.2628(6) 1.1586(3) 0.1297(3) 0.0364 14) 1

C25 0.1886(6) 1.2464(4) 0.1010(3) 0.0328 13) 1

N1 0.1669(5) 0.6172(3) 0.4450(3) 0.0318 11) 1

01 0.1517(4) 1.1013(2) 0.1686(2) 0.0314 9) 1

02 0.0477(4) 1.2469(3) 0.0894(2) 0.0361 9) 1

03 0.2841(4) 1.3089(2) 0.0919(2) 0.0361 10) 1

Table 4. Bond lengths [A] for Form X of {4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclo- pentyl]-phenoxy}-acetic acid.

Polymorph X - Bond lengths [A]

C1-C10 1.432(7) C15-C16 1.546(7)

C1-C11 1.515(7) C15-C18 1.511(7)

C1-C2 1.386(7) C16-C17 1.522(7)

C2-C3 1.424(8) C18-C19 1.392(7)

C4-C3 1.366(7) C20-C19 1.394(7)

C5-C4 1.402(7) C20-C21 1.370(7)

C5-C6 1.407(7) C21-C22 1.378(7)

C6-C7 1.357(7) C23-C18 1.376(7)

C8-C7 1.399(8) C23-C22 1.376(7)

C8-C9 1.366(7) C25-C24 1.528(7)

C10-C5 1.429(7) N1-C11 1.521(6)

C10-C9 1.414(7) N1-C13 1.513(6) C11-C12 1.529(7) 01-C21 1.392(6)

C13-C14 1.560(6) 01- C24 1.438(6)

C13-C17 1.537(7) 02- C25 1.244(6)

C15-C14 1.533(7) 03- C25 1.255(6)

Table 5. Bond angles [°] for Form X of {4-[(1R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclo- pentyl]-phenoxy}-acetic acid .

Polymorph X - Bond angles [°]

C1-C2-C3 121.8(5) C17-C13-C14 106 4

C1-C11-C12 112.6(5) C17-C16-C15 103 3 4)

C1-C11-N1 111.3(4) C18-C15-C14 116 7 4)

C2-C1-C10 118.8(5) C18-C15-C16 113 4 (4)

C2-C1-C11 120.2(5) C18-C19-C20 120 6 '5)

C3-C4-C5 121.8(5) C18-C23-C22 120 4 5)

C4-C3-C2 118.9(6) C19-C18-C15 118 1 5)

C4-C5-C10 119.4(5) C20-C21-C22 119 9 '5)

C4-C5-C6 121.0(5) C20-C21-O1 123 9 k5)

C5-C10-C1 119.2(5) C21-C20-C19 119 5 k5)

C6-C5-C10 119.5(5) C21-01-C24 116 5 4)

C6-C7-C8 119.3(5) C22-C21-01 116 2 .5)

C7-C6-C5 121.5(5) C23-C18-C15 123 0 (5)

C8-C9-C10 121.0(5) C23-C18-C19 118 8 (5)

C9-C10-C1 123.5(5) C23-C22-C21 120 8 (5)

C9-C10-C5 117.4(5) N1-C11-C12 106 9 (4)

C9-C8-C7 121.3(5) N1-C13-C14 108 4 4)

C10-C1-C11 121.1(5) N1-C13-C17 112 3 4)

C13-N1-C11 117.5(4) 01-C24-C25 110 7 4)

C14-C15-C16 102.2(4) 02-C25-C24 118 1 5)

C15-C14-C13 105.3(4) 02-C25-03 129 4 5)

C16-C17-C13 103.9(4) 03-C25-C24 112 5 4)

Table 6. Overview of the determined solubility at room temperature of polymorph Form C and X of {4-[(1R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl ]-phenoxy}-acetic acid as function of pH.

¹ The solubility has been determined twice on two different batches.

In another presently preferred embodiment of the present invention the Form X of {4- [(1 R,3S)-3-((f?)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid has a structure obtained by single crystal X-Ray crystallography (XRC) as shown in Formula 2.

In a further aspect the invention relates to the specific polymorphic Form X of {4-[(1 R,3S)- 3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid, and processes for its preparation.

In yet another aspect, this invention relates to the manufacture of {4-[(1 ft,3S)-3-((R)-1 - Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid Form X using as a starting material an amorphous form of {4-[(1 f?,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclo- pentyl]-phenoxy}-acetic acid.

In a further aspect, the invention relates to the manufacture of {4-[(1 f?,3S)-3-((f?)-1 - Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid Form X using a C,-C ₆ alkyl ester, such as a methyl ester or ethyl ester of {4-[(1 f?,3S)-3-((R)-1 -Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid as a starting material in a two-step, one-pot manufacturing procedure whereby the CrC ₆ alkyl ester is hydrolyzed under alkaline conditions in CVC ₆ alkyl alcoholic solution and the resulting product crystallized directly

i o from the saponification reaction mixture by concentration, neutralization and dilution with water.

The invention in further aspects is directed to pharmaceutical compositions comprising this polymorphic Form X of {4-[(1 f?,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]- phenoxy}-acetic acid, and to methods of its preparation and use.

DEFINITIONS

The term "C^Ce linear or branched alkyl alcohols" includes methanol, ethanol, 1 -propanol,

2- propanol, 1 -butanol, tert-butanol, and 2-butanol.

BRIEF DESCRIPTION OF GRAPHS, FIGURES AND TABLES Graph 1 above shows an overlay XRPD pattern of Form C and Form X.

Graph 2a shows a typical XRPD pattern of Form C.

Graph 2b shows a typical XRPD pattern of Form X.

Graph 3 shows a comparison of the DSC thermograms for Form C and Form X, which shows endothermic events for the two polymorphic forms having onsets at about 240°C and about 255°C (± 2 °C), respectively.

Graph 4a shows a typical DSC + TGA thermogram for Form C.

Graph 4b shows a typical DSC + TGA thermogram for Form X.

Graph 5 above shows overlay ATR-FTIR spectra of Form C and Form X.

Graph 6a, shows an ATR-FTIR spectrum recorded of the pure Form C.

Graph 6b, shows an ATR-FTIR spectrum recorded of the pure Form X.

Graph 7, shows overlay Solid State NMR spectra of Form C and Form X

Graph 8a shows a Solid State NMR spectrum of the pure Form C

Graph 8b shows a Solid State NMR spectrum of the pure Form X

Formula 1 shows the Single Crystal Configuration of the crystalline Form C of {4-[(1 R,3S)-

3- ((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid. Formula 2 shows the Single Crystal Configuration of the crystalline Form X of {4-[(1 R,3S)- 3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid. Table 1 shows the Single Crystal parameters for the crystalline Form C and Form X of {4- [(1 / ^: ?,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid.

Table 2 provides experimental details concerning the determination of the Single Crystal structure of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid Form X.

Table 3 provides selected atomic coordinates and isotropic thermal parameters for the Single Crystal Configuration of Form X of {4-[(1 f?,3S)-3-((f?)-1 -Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid.

Table 4 and Table 5 provide bond lengths and bond angles, respectively, for the Single Crystal Configuration of Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclo- pentyl]-phenoxy}-acetic acid. Table 6 provides solubilities at different pH for Form X and Form C of {4-[(1 f?,3S)-3-((R)-1 - Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid. It can be concluded that at room temperature the solubility of Form X is higher compared to Form C. DETAILED DESCRIPTION OF THE INVENTION

{4-[(1 f?,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid is a zwitterionic molecule with pKa values of 2.9 and 9.3. Salts of the compound are not stable in formulation with a pH between the two pKa values, therefore stable crystalline forms of the zwitterionic form have been sought. Many metastable forms or solvates of {4-[(1 R,3S)- 3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid have been found, but so far only two stable polymorphs have been identified (Form C and Form X). These two forms are enantiotropically related.

It is presently believed that Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)- cyclopentyl]-phenoxy}-acetic acid of the present invention as described above represents a stable polymorphic crystalline form at ambient temperature, which is non-solvated and anhydrous.

A number of methods have been employed for characterizing polymorphs in pharmaceutical solids (H . G. Brittain (ed.) Polymorphism in Pharmaceutical Solids. Marcel Dekker, Inc. , New York, 1 999, pp. 227-278). Polarizing optical microscopy and thermomicroscopy have proven to be useful tools. Thermal analysis procedures, such as differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), can be used to obtain additional information, including phase changes, and to deduce whether each isolated form is a solvate or anhydrate. These thermal methodologies are employed to distinguish between enantiotropic and monotropic systems, as polymorphs are categorized into two types, monotropes and enantiotropes, depending upon their stability with respect to the range of temperatures and pressures. Generally, it is possible to distinguish between monotropes and enantiotropes from their heats of fusion. An endothermic polymorphic transition indicates enantiotropes, whereas an exothermic transition indicates monotropes. Other than Differential Scanning Calorimetric (DSC) analysis, there are a number of efficient ways to characterize polymorphs and distinguish one polymorph from another, as discussed hereinabove.

Crystallisation is a well known technique for the purification of chemical compounds and for obtaining a desired crystalline form of chemical compounds. However, it is known that the crystallisation of polymorphs is affected by a number of effects and the mechanism of these effects is not known and the quantitative relationship between the operational factors and the crystallisation characteristics of the polymorphs is not clearly understood.

The crystallisation process of polymorphous crystals is composed of competitive nucleation, growth, and the transformation from a metastable to a stable form. To selectively crystallise polymorphs, the mechanism of each elementary step in the crystallisation process needs to be in clear relation to the operational conditions and the key controlling factors [Crystal Growth & Design, 2004, Vol. 4, No.6, 1 1 53-1 159]. Crystalline {4-[(1 R,3S)-3-((f?)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid has proven surprisingly difficult to obtain. One obstacle has been the relative stability of the amorphous form due to a high glass transition (significantly above room temperature). Therefore if an attempt is made to precipitate {4-[(1 R,3S)-3-((R)-1- Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid too fast, the amorphous product is often obtained.

{4-[(1 f?,3S)-3-((R)-1-Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid also crystallizes into many metastable forms or solvates. In many cases a solid material obtained by precipitation from a solvent has turned out to be a solvate.

Form X of {4-[(1 R,3S)-3-((f?)-1-Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid can be crystallized from a blank filtered solution in a suitable solvent such as a C-|-C ₆ linear or branched alkyl alcohol, like methanol, without adding seeding crystals thereby rendering Form X simpler to manufacture in large scale than other crystalline forms of {4- [(1 R,3S)-3-((R)-1-Naphthalen-1-yl-ethylamino)-cyclopentyl]-phen oxy}-acetic acid.

Furthermore, it has been found that {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)- cyclopentyl]-phenoxy}-acetic acid can suitably be prepared by saponification of a C Ce alkyl ester thereof in Ci-C ₆ alkyl alcohol solution with aqueous alkali hydroxide such as sodium hydroxide. It has further been found that Form X of {4-[(1 ,3S)-3-((R)-1- Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid can conveniently be crystallized from the saponification mixture by concentration, pH adjustment eg. with 50% acetic acid, and dilution with water which initiates the crystallization of Form X.

In yet another aspect, this invention relates to the isolated Form X of {4-[(1 R,3S)-3-((R)-1- Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid of the present invention as defined herein which has a polymorphic purity of at least 80%, such as 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

In yet another aspect, this invention relates to the isolated Form X of {4-[(1 R,3S)-3-((R)-1- Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid of the present invention as defined herein which has a degree of crystallinity of at least 80%, such as 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In yet another aspect, this invention relates to a mixture or composition of crystalline forms of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid, including pseudopolymorphs of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclo- pentyl]-phenoxy}-acetic acid, comprising a crystalline form of {4-[(1 3S)-3-((R)-1 - Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid of the present invention as defined herein, such as, for example, a mixture of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid Form X with another polymorphic form of {4- [(1 R,3S)-3-((/ ⁼ ?)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid.

The presently preferred Form X of the present invention possesses physical properties which facilitate the manufacture of the compound, especially the readiness by which this particular crystalline polymorph can be isolated in pure form without the need for seeding with Form X crystals. Furthermore, Form X is also well-suited for long-term storage of dosage forms of the compound due to its stability towards interconversion with other solid forms of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid, which typically have different densities and crystal habits than Form X. Polymorphic interconversion of the API in solid dosage forms such as tablets may lead to the formation of cracks in the tablets.

Interconversion between polymorphic forms in solid dosage forms is highly problematic and therefore to be avoided if possible, which is achieved by using the stable polymorph Form X. This has been proven by stability testing; thus polymorph Form C, Form X and mixtures of the two polymorphic forms X+C have all passed the 4 week stress stability test at 60 ^° C, 60 ^° C/75% relative humidity and 80 ^° C/75% relative humidity without any solid state transformation.

In yet another embodiment, the invention thus relates to the isolated Form X of {4- [(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid which does not undergo any solid state transformation during 4 week stress stability testing at 60 ^" C, 60 ^° C/75% relative humidity and 80 ^c C/75% relative humidity.

In yet another embodiment, this invention relates to the crystalline Form X of {4-[(1 R,3S)- 3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid of the present invention, or to mixtures thereof with another stable crystalline polymorphic form of {4- [(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid, as defined herein, for use in therapy. In a specific embodiment, this invention relates to the crystalline Form X of {4-[(1 / ^c ?,3S)-3- ((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid of the present invention, or to mixtures thereof with an amorphous form of {4-[(1 /?,3S)-3-((R)-1 - Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid or with the crystalline Form C of {4-[(1 R,3S)-3-((f?)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid as defined herein, for use in therapy.

In yet another aspect, this invention relates to a pharmaceutical composition comprising the crystalline Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]- phenoxy}-acetic acid of the present invention, or mixtures thereof with another stable crystalline polymorphic form of {4-[(1 f?,3S)-3-((f?)-1 -Naphthalen-1 -yl-ethylamino)-cyclo- pentyl]-phenoxy}-acetic acid, as defined herein, together with a pharmaceutically acceptable excipient or vehicle.

In a specific embodiment, this invention relates to a pharmaceutical composition comprising the crystalline Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)- cyclopentyl]-phenoxy}-acetic acid of the present invention, or mixtures thereof with the crystalline Form C of {4-[(1 ^,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]- phenoxy}-acetic acid or amorphous {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)- cyclopentyl]-phenoxy}-acetic acid as defined herein, or mixtures thereof, together with a pharmaceutically acceptable excipient or vehicle.

In a specific embodiment the invention provides the Form X of {4-[(1 f?,3S)-3-((R)-1 - Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid of the present invention, or mixtures thereof with the crystalline Form C or an amorphous form of {4-[(1 R,3S)-3-((R)-1 - Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid as defined herein for use in the treatment, amelioration or prophylaxis of physiological disorders or diseases associated with disturbances of CaSR activity, such as hyperparathyroidism.

In another specific embodiment the invention provides the Form X of {4-[(1 R,3S)-3-((R)-1 - Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid of the present invention, or mixtures thereof with the crystalline Form C of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid as defined herein, for treating, preventing or ameliorating physiological disorders or diseases associated with disturbances of CaSR activity, such as hyperparathyroidism.

In a further embodiment the present invention is directed to the use of the preferred Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid of the present invention, or mixtures thereof with the crystalline Form C of {4-[(1 R,3S)-3- ((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid as defined herein for the manufacture of a medicament for the prophylaxis, treatment or amelioration of physiological disorders or diseases associated with disturbances of CaSR activity, such as hyperparathyroidism.

In an even further embodiment the present invention is directed to a pharmaceutical composition comprising the preferred Form X of {4-[(1 / ^: ?,3S)-3-((f?)-1-Naphthalen-1 -yl- ethyiamino)-cyclopentyl]-phenoxy}-acetic acid of the present invention, or mixtures thereof with the crystalline Form C of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclo- pentyl]-phenoxy}-acetic acid as defined, together with a pharmaceutically acceptable vehicle or excipient.

The present invention also provides a method of preventing, treating or ameliorating parathyroid carcinoma, parathyroid adenoma, primary parathyroid hyperplasia, cardiac, renal or intestinal disfunctions, diseases of the central nervous system, chronic renal failure, chronic kidney disease, podocyte-related diseases, primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyperparathyroidism, anemia, cardiovascular diseases, osteitis fibrosa, adynamic bone disease, osteoporosis, steroid induced osteoporosis, senile osteoporosis, post menopausal osteoporosis, osteomalacia and related bone disorders, bone loss post renal transplantation, gastrointestinal diseases, endocrine and neurodegenerative diseases, cancer, Alzheimer's disease, hypercalcemia, or renal bone diseases, which method comprising administering to a patient in need thereof an effective amount of the Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid of the present invention, or mixtures thereof with the crystalline Form C of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclo- pentyl]-phenoxy}-acetic acid as defined herein, optionally in combination or as supplement with an active vitamin-D sterol or vitamin-D derivative, such as 1 -a-hydroxycholecalciferol, ergocalciferol, cholecalciferol, 25-hydroxycholecalciferol, 1 -a-25-dihydroxycholecalciferol, or in combination or as supplement with phosphate binders, estrogens, calcitonin or biphosphonates. A presently preferred polymorph of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)- cyclopentyl]-phenoxy}-acetic acid is thus the crystalline Form X characterized by its X-Ray Powder (XRPD) Diffractogram (Graph 2b) its attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrum (Graph 6b), its differential scanning calorimetry (DSC) curve (Graph 4b), its Solid State N R spectrum (SS-NMR) (Graph 8b), its single crystal parameters as defined in Table 1 , and its crystal structure (Formula 2) obtained by single crystal X-Ray crystallography (XRC).

Another specific polymorph of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclo- pentyl]-phenoxy}-acetic acid is the crystalline Form C characterized by its X-Ray Powder (XRPD) Diffractogram (Graph 2a) its attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectrum (Graph 6a), its differential scanning calorimetry (DSC) curve (Graph 4a), its Solid State NMR spectrum (SS-NMR) (Graph 8a), its single crystal parameters as defined in Table 1 , and its crystal structure (Formula 1 ) obtained by single crystal X-Ray crystallography (XRC). As discussed hereinabove, the crystalline composition of matter disclosed herein may be prepared from amorphous (i.e. noncrystalline) {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid. The preparation of amorphous {4-[(1 f?,3S)- 3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid is disclosed in WO 2009/065406, which is incorporated herein by reference.

A specific method of forming crystalline Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid comprises dissolving the amorphous compound in a dry solvent or solvent mixture. Preferred solvents include C Ce linear or branched alkyl alcohols such as methanol and ethanol.

Preferably, the solvent is heated, the amorphous compound dissolved in it to a point approximately equal to saturation, and the resulting solution filtered before allowing it to cool to a temperature at which the full amount of the compound dissolved is no longer soluble in the solvent, at which point crystallization commences. The crystallization is subsequently allowed to proceed, optionally with cooling of the suspension, until deemed complete. Crystals are isolated by filtration and dried, optionally in vacuo at an elevated temperature.

Another specific two-step, one-pot method of forming crystalline Form X of {4-[(1 R,3S)-3- ((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid comprises dissolving a Ci-C ₆ alkyl ester of the compound, such as a methyl or ethyl ester, in a C C ₆ alkyl alcohol such as ethanol followed by adding at least a molar equivalent of aqueous alkali hydroxide such as sodium hydroxide, and stirring the reaction mixture for a prolonged period such as overnight, thereby hydrolyzing the alkyl ester group.

By concentrating the hydrolysis mixture followed by pH adjustment to about 5.3 with a suitable acid such as phosphoric acid, hydrochloric acid or acetic acid followed by dilution with water, the precipitation of crystalline Form X is initiated. The crystallization is subsequently allowed to proceed, optionally with cooling of the suspension, until deemed complete. Crystals are isolated by filtration, washed and dried, optionally in vacuo at an elevated temperature.

The present invention thus in a separate embodiment provides a process for preparing crystalline Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]- phenoxy}-acetic acid which comprises either: a. dissolving an amorphous form of {4-[(1 R,3S)-3-((R)-1-Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid in a dry solvent or solvent mixture, preferably by heating, until an amount approximately equal to saturation has been dissolved,

b. filtering the resulting hot solution before allowing it to cool to a temperature at which the full amount of the compound dissolved is no longer soluble in the solvent, at which point crystallization commences

c. allowing the crystallization to proceed until deemed complete,

d. cooling the resulting suspension of crystals and isolate the crystalline product by filtration and drying it, optionally in vacuo at an elevated temperature, or:

dissolving a C C ₆ alkyl ester of {4-[(1 R, 3S)-3-((R)-1 -naphthalen-1-yl-ethyl- amino)-cyclopentyl]-phenoxy}-acetic acid in a Ci-C ₆ alkyl alcohol such as methanol or ethanol, and adding at least a molar equivalent of aqueous alkali hydroxide such as sodium hydroxide,

stirring the reaction mixture for a prolonged period such as overnight, preferably at room temperature,

concentrating the reaction mixture in vacuo to about half volume followed by adding water to about the original volume,

adjust pH to about 5.3 with 50% acetic acid and stir the resulting mixture for several hours, optionally with cooling, during which period the product slowly crystallizes,

isolate the crystalline product by filtration, washing it with water and drying it, optionally in vacuo at an elevated temperature.

In a specific embodiment, the process for preparing crystalline Form X of {4-[(1 f?,3S)-3- ((R)-1-Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid is carried out in a solvent selected from C^-C _e linear or branched alkyl alcohols such as methanol. PHARMACEUTICAL FORMULATIONS AND METHODS OF TREATMENT

For use in therapy, Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclo- pentyl]-phenoxy}-acetic acid of the present invention is typically in the form of a pharmaceutical composition. The invention therefore relates to a pharmaceutical composition, both for veterinary (including mammals such as horses, cattle, sheep, pigs, dogs and cats) and for human medical use, comprising Form X of {4-[(1 R,3S)-3-((R)-1 - Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid, optionally together with one or more other therapeutically active compound(s), together with a pharmaceutically acceptable excipient or vehicle. The excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

Conveniently, the active ingredient comprises from 10-3000 ppm by weight of the formulation, e.g. 15-2800 ppm, such as 20-2500 ppm, such as 25-2400 ppm, or 30-1000 ppm.

Pharmaceutical compositions of the invention may be in unit dosage form such as tablets, pills, capsules, powders, granules, elixirs, syrups, emulsions, ampoules, suppositories or parenteral solutions or suspensions; for oral, parenteral, opthalmic, transdermal, intra- articular, topical, pulmonal, nasal, buccal or rectal administration or in any other manner appropriate for the formulation of compounds used in nephrology and in accordance with accepted practices such as those disclosed in Remington: The Science and Practice of Pharmacy, 21 ^st ed., 2005, Lippincott Williams & Wilkins. In the composition of the invention, the active component may be present in an amount of from 10-3000 ppm by weight of the composition, e.g. 15-2800 ppm, such as 20-2500 ppm, such as 25-24000 ppm, or 30-1 000 ppm.

For oral administration in the form of a tablet or capsule, Form X of {4-[(1 R,3S)-3-((F?)-1 - Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid may suitably be combined with an oral, non-toxic, pharmaceutically acceptable carrier such as ethanol, glycerol, water or the like. Furthermore, suitable binders, lubricants, disintegrating agents, flavouring agents and colourants may be added to the mixture, as appropriate. Suitable binders include, e.g. , lactose, glucose, starch, gelatin, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes or the like. Lubricants include, e.g. , sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like. Disintegrating agents include, e.g. , starch, methyl cellulose, agar, bentonite, xanthan gum or the like. Additional excipients for capsules include macrogols or lipids.

For the preparation of solid compositions such as tablets, Form X of {4-[(1 f?,3S)-3-((R)-1 - Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid is mixed with one or more excipients, such as the ones described above, and other pharmaceutical diluents such as water to make a solid preformulation composition containing a homogenous mixture of {4- [(1 R,3S)-3-((f?)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid. The term "homogenous" is understood to mean that Form X of {4-[(1 f?,3S)-3-((R)-1 -Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid is dispersed evenly throughout the composition so that the composition may readily be subdivided into equally effective unit dosage forms such as tablets or capsules. The preformulation composition may then be subdivided into unit dosage forms containing from about 0.01 to 0.1 mg Form X of {4- [(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid .

In the form of a dosage unit, Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)- cyclopentyl]-phenoxy}-acetic acid may be administered one or more times a day at appropriate intervals, always depending, however, on the condition of the patient, and in accordance with the prescription made by the medical practitioner. Conveniently, a dosage unit of a formulation contains between 0.005 mg and 0.5 mg Form X of {4-[(1 f?,3S)-3-((ft)- 1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid .

A suitable dosage of Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclo- pentyl]-phenoxy}-acetic acid of the invention will depend, inter alia, on the age and condition of the patient, the severity of the disease to be treated and other factors well known to the practising physician. Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid may be administered either orally, parenterally or topically according to different dosing schedules, e.g. daily or with weekly intervals. In general a single dose will be in the range from 0.0001 to 0.001 mg/kg body weight. Form X of {4-[(1 R,3S)-3-((f?)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}- acetic acid may be administered as a bolus (i.e. the entire daily dosis is administered at once) or in divided doses two or more times a day.

If the treatment involves administration of another therapeutically active compound it is recommended to consult Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9 ^th Ed. , J.G. Hardman and L.E. Limbird (Eds.), McGraw-Hill 1995, for useful dosages of said compounds. The administration of Form X of {4-[(1 f?,3S)-3-((R)-1 - Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid of the present invention with one or more other active compounds may be either concomitantly or sequentially.

Liquid formulations for either oral or parenteral administration of Form X of {4-[(1 f?,3S)-3- ((/ ^c ?)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid, e.g. , aqueous solutions, syrups, aqueous or oil suspensions and emulsion with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose or polyvinylpyrolidone.

For parenteral administration, e.g. intramuscular, intraperitoneal, subcutaneous or intravenous injection or infusion, the pharmaceutical composition preferably comprises Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid dissolved or solubilised in an appropriate, pharmaceutically acceptable solvent. For parenteral administration, the composition of the invention may include a sterile aqueous or non-aqueous solvent, in particular water, isotonic saline, isotonic glucose solution, buffer solution or other solvent conventionally used for parenteral administration of therapeutically active substances. The composition may be sterilised by, for instance, filtration through a bacteria-retaining filter, addition of a sterilising agent to the composition, irradiation of the composition, or heating the composition. Alternatively, Form X of {4- [(1 f?,3S)-3-((f?)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid may be provided as a sterile, solid preparation, e.g. a freeze-dried powder, which is dissolved in sterile solvent immediately prior to use. The composition intended for parenteral administration may additionally comprise conventional additives such as stabilisers, buffers or preservatives, e.g. antioxidants such as methylhydroxybenzoate or the like.

5 Compositions for rectal administration may be in the form of a suppository incorporating Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid and a carrier such as cocoa butter, or in the form of an enema.

Compositions suitable for intra-articular administration may be in the form of a sterile 1 0 aqueous preparation of Form X of {4-[(1 R,3S)-3-((f?)-1 -Naphthalen-1 -yl-ethylamino)-cyclo- pentyl]-phenoxy}-acetic acid which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for both intra-articular and ophthalmic administration.

I 5

Compositions suitable for topical administration, including ophthalmic treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. For topical administration, Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl- 0 ethylamino)-cyclopentyl]-phenoxy}-acetic acid may typically be present in an amount of from 0.01 to 20% by weight of the composition, such as 0.1 % to about 1 0 %, but may also be present in an amount of up to about 50% of the composition.

Compositions for ophthalmic treatment may preferably additionally contain a cyclodextrin. 5

Compositions suitable for administration to the nasal or buccal cavity or for inhalation include powder, self-propelling and spray formulations, such as aerosols and atomizers. Such compositions may comprise Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl- ethylamino)-cyclopentyl]-phenoxy}-acetic acid in an amount of 0.01 -20%, e.g. 2%, by 0 weight of the composition. The composition may additionally comprise one or more other active components conventionally used in the treatment of physiological disorders or diseases associated with disturbances of CaSR activity, such as hyperparathyroidism. A further embodiment of the invention encompasses the use of Form X of {4-[(1 / ^; ?,3S)-3- ((R)-1-Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid as a medicament.

The present invention will be exemplified by the following non-limiting examples.

EXPERIMENTAL In strum en ta tion

X-ray powder diffraction (XRPD): The diffractogram was obtained on a conventional X'pert PRO MPD diffractometer from PANalytical configured with transmission geometry and equipped with a PIXcel detector. A continuous 2Θ scan range of 3-30° was used with a CuKa radiation λ = 1 .5418 A source and a generator power of 40KV and 45mA. A 2Θ step size of 0.0070°/step with a step time of 148.92 s was used. Samples were gently flattened onto a well in a 96-well plate for transmission measurements. The well plate was moved forward and backward in the x direction and all experiments were performed at room temperature.

Single-crystal X-ray diffraction (XRC) data were collected using a Bruker SMART Apex diffractometer with a CCD area detector (Temperature: 120(2) K; Mo Ka Radiation λ = 0.7107 A; data collection method: oj/2q scans). Further details can be found in Example 4. Program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997).

ATR-FTIR spectroscopy (attenuated total reflectance fourier transform infrared spectroscopy): The spectrum was recorded on a FTIR instrument, Equinox 55 or Tensor 27 from Bruker equipped with a GoldenGate ATR unit from SPECAC. A spectral resolution of 3 cm ^"1 was used. Differential scanning calorimetry (DSC): DSC experiments were carried out using a Perkin Elmer DSC8500 system. About 0.5-3 mg of sample was used for the measurements. An aluminium pan was used for the analysis and was sealed by applying pressure by hand and pushing each part of the pan together. The temperature was ramped from -60 to 270°C at 20°C/min. Nitrogen was used as the purge gas with a flow rate of 20 mL/min.

Thermo gravimetric analysis (TGA): TGA experiments were conducted using a Perkin Elmer Pyris 1 TGA instrument. About 1 0-20 mg of sample was loaded into a ceramic pan for the measurements. The sample temperature was ramped from 25 to 350°C at 10°C/min. Nitrogen was used as the purge gas at a flow rate of 40 mL/min.

Solid State Nuclear Magnetic Resonance (SS NMR): The ¹³ C solid-state NMR spectrum was acquired at the Instrument Centre for Solid-State NMR spectroscopy (University of Aarhus). A Varian Unity-I NOVA NMR spectrometer with a magnetic field strength of 7.04 T operating at 75.42 MHz for ¹³ C was used. A 5 mm homebuilt CP/MAS TLT probe using a spinning frequency of 5.0 kHz was used. The ¹³ C spectrum was obtained using a standard cross-polarization pulse sequence using a contact time of 1 .6 ms, a relaxation delay of 4 sec, a dwell time of 10 psec, spectral width of 50 kHz, and at ambient temperature. Proton decoupling was performed using a decoupling field strength of 95 kHz. The 5 mm Si ₃ N ₄ rotor has a sample volume of 1 10 I and contained approximately 100 mg substance. The spectrum was processed with zerofilling (32K real points), exponential multiplication and tine broadening of 1 0 Hz. The spectrum was referenced to an external sample of TMS. The given error ranges in this application for the spectroscopic characteristics, including those in the claims, may be more or less depending on factors well known to a person skilled in the art of spectroscopy and may for example depend on sample preparation, such as particle size distribution, or if the crystal form is part of a formulation, on the composition of the formulation, as well as instrumental fluctuations, and other factors.

An error range of ±5 includes, but is not limited to variations of ±5, ±4, ±3, ±2, ±1 , ±0.5, ±0.4, ±0.3, ±0.2, and ±0.1 ; an error range of ±3 includes, but is not limited to variations of ±3, ±2, ±1 , ±0.5, ±0.4, ±0.3, ±0.2, and ±0.1 ; an error range of ±1 includes, but is not limited to variations of ±0.9, ±0.8, ±0.7, ±0.6, ±0.5, ±0.4, ±0.3, ±0.2, and ±0.1 ; and an error range of ±0.2 includes, but is not limited to variations of ±0.2, ±0.1 5, ±0.1 , ±0.09, ±0.08, ±0.07, ±0.06, ±0.05, ±0.04, ±0.03, ±0.02, and ±0.01 . Characterisation

In addition to the characterizing analyses by XRPD, XRC, DSC, ATR-FTIR and SS NMR discussed hereinabove, the solubility of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)- cyclopentyl]-phenoxy}-acetic acid Form C and X has been determined as function of pH and in MeOH. It can be concluded that at ambient temperature the solubility of Form X is higher compared to Form C (see Table 6)

Stress stability testing

Polymorph Form C, Form X and mixtures of the two polymorphic forms C+X have all been tested at different conditions of temperature and relative humidity for signs of solid state transformation. The stress stability test was carried out at three sets of conditions: 60 ^° C, 60 ^° C/75% relative humidity and 80 C/75% relative humidity, and samples were analyzed after 1 , 2 and 4 weeks, i.e. after 7, 14 and 28 days.

One 1 .8 ml amber screw top vial (27267-U, Supelco) containing between 50 and 100 mg {4-[(1 f?,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid was tested per individual set of conditions. The vials to be tested at 60 ^° C were closed with a PTFE lined black polypropylene solid cap (27416, Supelco) and placed in a thermostated heating cabinet. The vials to be tested at 60 ^° C/75% relative humidity and 80 ^° C/75% relative humidity were placed uncapped in a desiccator containing a saturated NaCI solution. The desiccator was subsequently placed in a thermostatted heating cabinet.

The samples were analyzed at 1 , 2 and 4 weeks for

1 . Visual appearance

2. HPLC assay and impurities

3. Polymorph characterization All the tested samples passed the 4 week stress stability test at 60 ^° C, 60 ^° C/75% relative humidity and 80 ^° C/75% relative humidity without any solid state transformation. Preparative Examples

Example 1 . Preparation of amorphous {4-[(1 f?, 3S)-3-((R)-1 -naphthalen-1 -yl-ethylamino)- cyclopentyl]-phenoxy}-acetic acid. Step l : {4-[(1 R, 3S)-3-((R)-1 -naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid ethyl ester

[4-((1 R)-3-oxo-cyclopentyl)-phenoxy]-acetic acid ethyl ester (see WO2009/065406) (40.0 g, 1 53 mmol) and (R) (+)-1 -naphthalen-1 -yl-ethylamine (28.7 g, 168 mmol) was suspended in acetonitrile (1 .4 I) and cone, acetic acid (87.2 ml) . The clear orange solution was stirred for 1 hour at room temperature before NaBH(OAc) ₃ (51 .7 g, 244 mmol) was added in portions over 30 minutes. After 24 hours HPLC showed 12 % remaining starting material and additional NaBH(OAc) ₃ was added but still some starting material remained. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over MgS0 ₄ and concentrated in vacuo to give a light brown oil. The crude product was purified by column chromatography with a mixture of hexane, ethyl acetate, isopropanol and triethylamine (79.19: 1 .5:0.5) to give the desired diastereoisomer. Yield: 5.9 g. HPLC purity > 96 %.

HPLC conditions: flow=0.8; Column. Ascentis (R) Express C 18; Eluent: 50% 0,025 M acetic acid, 50% acetonitrile pH= 5,5 Step 2: Saponification of {4-[(1 ft, 3S)-3-((/?)-1 -naphthalen-1 -yl-ethylamino)-cyclopentyl]- phenoxy}-acetic acid ethyl ester to afford {4-[(1 R, 3S)-3-((f?)-1 -naphthalen-1 -yl-ethyl- amino)-cyclopentyl]-phenoxy}-acetic acid

{4-[(1 R, 3S)-3-((R)-1 -naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid ethyl ester (0,214 g, 0, 51 mmol) was added to a mixture of methanol (2,35 ml) and water (0,78 ml). To the milk-white mixture was added aqueous 2N LiOH (2.05 ml, 4, 1 mmol). After stirring for about 10 minutes at room temperature the reaction mixture changed into a clear light yellow solution. The solution was stirred overnight at room temperature. After 20 hours the solution was concentrated slightly in vacuo and further 5 ml of water was added. The product was precipitated by adding 4N HCI (2,4 ml) under vigorous stirring. pH was adjusted to 5 with aqueous 2N LiOH. The precipitate was collected by filtration to give crude amorphous {4-[(1 R,3S)-3-((R)-1 -naphthalen-1 -yl-ethylamino)-cyclopentyl] phenoxy}- acetic acid. Yield: 0.1 9 g (95%). Example 2: Crystallisation of Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 -yl-ethylamino)- cyclopentyl]-phenoxy}-acetic acid.

40 mg of amorphous compound (Example 1 , above) were placed in a reaction vial for microwave oven and 1 ml_ of MeOH was added slowly during heating with a heat gun until all material had been dissolved. The hot solution was filtered with 0.45 pm syringe filter (the filter was heated to 50°C before use), and then placed at 5°C for slow formation of crystalline Form X.

Example 3: Two-step, one pot procedure for the crystallisation of Form X of {4-[(1 f?,3S)-3- ((f?)-1 -Naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid directly from a saponification reaction mixture.

{4-[(1 R, 3S)-3-((R)-1 -naphthalen-1 -yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid ethyl ester (20 g, 47.9 mmol) was dissolved in ethanol (160 ml). 2N aqueous sodium hydroxide (160 ml) was added and the solution was stirred at room temperature overnight. The solution was concentrated to about ½ the volume in vacuo and water (1 30 ml) was added. The pH was adjusted to about 5.3 with 50% acetic acid. After several hours of stirring at room temperature during which period the product slowly crystallizes, the reaction mixture was filtered, washed with water and dried in vacuum for two days. Yield: 17 g. Example 4: XRC Single Crystal Structure of Form X of {4-[(1 R,3S)-3-((R)-1 -Naphthalen-1 - yl-ethylamino)-cyclopentyl]-phenoxy}-acetic acid.

A representative crystal obtained by crystallisation from a diluted MeOH solution under slow evaporation conditions was surveyed and a 0.9 A data set was collected at 120K on a Bruker Smart diffracto meter. The crystal structure solution was found and refinement was performed using the SHELXTL-97 system. See, Sheldrick, G.M. , 1990 and 1 997.

Hydrogen atoms on fixed ideal positions were included. The shifts calculated in the final cycle of least squares refinement were all less than 0.1 of their corresponding standard deviations, and the final R index was 7.87 %. A final difference Fourier revealed no missing or misplaced electron density. Details of the crystal are provided by Table 1 above. Experimental details concerning the single crystal structure determination are provided by Table 2. Selected atomic coordinates, equivalent isotopic displacement parameter and site occupancy factors are provided in Table 3. Bond lengths and angles are provided in Table 4 and Table 5.

Example 5: Solubility determination. The aqueous solubility of Form C and Form X was determined as a function of pH at 25°C in 0.1 N HCI (pH 1 .0) and in Sorensen phosphate buffers at pH 2.0, 4.0, 6.0 and 8.0. For each pH value two individual determinations were made. Form C or Form X was weighed out (1 1 mg for pH 1 , 4 mg for pH 2-8) in scintillation vials and 4 ml 0. 1 N HCI or buffer was added. The vials were shaken for 24 hours at 25°C. After 24 hours it was checked that the vial still contained undissolved material. The suspensions were filtered through a 0.45 pm filter, which was first saturated with app. 0.5 ml filtrate. The resulting filtrates were diluted and analyzed by HPLC vs. a standard curve. The results are given in Table 6, from which it can be concluded that at room temperature the solubility of Form X is higher compared to Form C.