WO2006084757A2 - Combination of ca/mg salt of valsartan with an antidiabetic agent - Google Patents

Combination of ca/mg salt of valsartan with an antidiabetic agent Download PDF

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WO2006084757A2
WO2006084757A2 PCT/EP2006/001285 EP2006001285W WO2006084757A2 WO 2006084757 A2 WO2006084757 A2 WO 2006084757A2 EP 2006001285 W EP2006001285 W EP 2006001285W WO 2006084757 A2 WO2006084757 A2 WO 2006084757A2
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carboxylic acid
methyl
benzenesulfonyl
phenoxy
phenyl
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PCT/EP2006/001285
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French (fr)
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WO2006084757A3 (en
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John Glasspool
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Novartis Ag
Novartis Pharma Gmbh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, which comprises
  • At least one antidiabetic compound preferably selected from the group consisting of a dipeptidyl peptidase IV (DPP IV) inhibitor, insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose- 6-phosphatase (G ⁇ Pase), inhibitors of fructose-1 ,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, ⁇ -glucosidas
  • the calcium or magnesium salt of valsartan can present in crystalline, also partly crystalline and amorphous forms and can be used in the combination of the present invention as amorphous forms, solvates such as salt hydrates, and also the corresponding polymorphous forms thereof.
  • Solvates and also hydrates of the salts according to the invention may be present, for example, as hemi-, mono-, di-, tri-, tetra-, penta-, hexa-solvates or hydrates, respectively.
  • Solvents used for crystallisation such as alcohols, especially methanol, ethanol, aldehydes, ketones, especially acetone, esters, e.g. ethyl acetate, may be embedded in the crystal grating.
  • the description salt hydrates for corresponding hydrates may be preferred, as water molecules in the crystal structure are bound by strong intermolecular forces and thereby represent an essential element of structure formation of these crystals which, in part, are extraordinarily stable.
  • water molecules are also existing in certain crystal lattices which are bound by rather weak intermolecular forces. Such molecules are more or less integrated in the crystal structure forming, but to a lower energetic effect.
  • the water content in amorphous solids can, in general, be clearly determined, as in crystalline hydrates, but is heavily dependent on the drying and ambient conditions. In contrast, in the case of stable hydrates, there are clear stoichiometric ratios between the pharmaceutical active substance and the water.
  • ratios do not fulfil completely the stoichiometric value, normally it is approached by lower values compared to theory because of certain crystal defects.
  • the ratio of organic molecules to water molecules for the weaker bound water may vary to a considerable extend, for example, extending over di-, tri- or tetra-hydrates.
  • the molecular structure classification of water is not stoichiometric; the classification may however also be stoichiometric only by chance.
  • the different resulting crystal gratings are summarised by the term polymorphism.
  • Any reference hereinbefore and hereinafter, to the salts according to the invention is to be understood as referring also to the corresponding solvates, such as hydrates, and polymorphous modifications, and also amorphous forms, as appropriate and expedient.
  • the X-ray diffraction diagram of powders of these two salt hydrates has a number of discrete X-ray reflections, and practically no signs of non-crystalline or amorphous portions.
  • the degree of crystallisation of these defined salt hydrates is therefore surprisingly high.
  • relatively large crystals may be cultured from certain salt hydrates, and in the crystallographic sense these are single crystals. Such single crystals allow the structure of the solid to be determined. It is effected by computer-aided evaluation of the reflection intensities measured by an X-ray diffractometer.
  • This process for determining the structure of a crystal enables, under normal conditions such as high physical, chemical and enantiomeric purity of the gauged crystals, a clear determination of the structure to be carried out on a molecular or atomic level, namely symmetry and size of the elementary cells, atom positions and temperature factors, and from the ascertained cell volume, the X-ray-photographic density is shown on the basis of a molecular weight. At the same time, the X-ray-photographic structure determination supplies details of its quality.
  • the particularly notable salt hydrate is the tetrahydrate of the calcium salt of valsartan.
  • T r 10 K- min ⁇ 1 it has a melting point of 205 ⁇ 1.5 0 C and a melting enthalpy of 98 ⁇ 4 kJ • MoI "1 .
  • the tetrahydrate of the calcium salt of valsartan is not stable at elevated temperatures both in respect of the hydrate water and in respect of the structure of the molecule.
  • the indicated melting point is a hydrate melting - A -
  • Gold containers with a wall thickness of 0.2 mm were used; after weighing in samples of between 2 and 4 mg salt hydrate, they were sealed by cold welding. These gold containers have an internal free volume of ca. 22 microlitres.
  • the amounts of the sample and the volume of the pressurised containers must be suitably adapted, so that strong dehydration of the salt hydrates cannot take place during measurement of the melting point.
  • the partial pressure of the water at 205° Celsius is ca. 18 bar, so that with an open container in DSC (Differential Scanning Calorimeter) during measurement of the melting point, conversion to the anhydrate takes place.
  • thermodynamic characteristics illustrate the advantageous physical properties, compared to the free acid, with the two corresponding data, namely a melting point in the closed system of 90 0 C and a melting enthalpy of 12 kJ • MoI "1 .
  • thermodynamic data together with the X-ray data, prove the high stability of this crystal grating. They are the foundation for the special physical and chemical resistance of the tetrahydrate of the calcium salt of valsartan.
  • a measurement of the infrared absorption spectrum of the tetrahydrate of the calcium salt of valsartan in a potassium bromide compressed tablet shows the following significant bands expressed in reciprocal wave numbers (cm 1 ): 3750 - 3000 (st); 3400 - 2500 (st); 1800 - 1520 (st); 1500 - 1380 (st); 1380 - 1310 (m); 1290 - 1220 (w); 1220 - 1190 (w); 1190 - 1160 (W); 1160 - 1120 (w); 1120 - 1050 (w); 1030 - 990 (m); 989 - 960 (w), 950 - 920 (w); 780 - 715 (m); 710 - 470 (m).
  • the tetrahydrate of the calcium salt of valsartan has the following absorption bands expressed in reciprocal wave numbers (cm "1 ):
  • the error margin for all absorption bands of ATR-IR is ⁇ 2 cm "1 .
  • the water content is in theory 13.2% for the tetrahydrate of the calcium salt of valsartan.
  • thermo-scale TGS-2 Perkin-Elmer Corp. , Norwalk, CT USA .
  • a total formula was calculated from this (C 24 H 27 N 5 O 3 ) 2" Ca 2+ * (3.9 ⁇ 0.1) H 2 O.
  • thermogravimetry in a water-free N 2 atmosphere, the weight loss, i.e. the water loss for the tetrahydrate as a function of temperature, was measured at a heating rate of 10
  • the preferred characterisation of the tetrahydrate of the calcium salt of valsartan is obtained from the interlattice plane intervals d of the ascertained X-ray diffraction diagrams, whereby, in the following, average values are indicated with the appropriate error limits, d in [A] : 16.1 ⁇ 0.3, 9.9 ⁇ 0.2, 9.4 ⁇ 0.2, 8.03 ⁇ 0.1, 7.71 ⁇ 0.1, 7.03 ⁇ 0.1 , 6.50 ⁇ 0.1 , 6.33 ⁇ 0.1, 6.20 ⁇ 0.05, 5.87 ⁇ 0.05, 5.74 ⁇ 0.05, 5.67 ⁇ 0.05, 5.20 ⁇ 0.05, 5.05 ⁇ 0.05, 4.95 ⁇ 0.05, 4.73 ⁇ 0.05, 4.55 ⁇ 0.05, 4.33 ⁇ 0.05, 4.15+0.05, 4.12 ⁇ 0.05, 3.95 ⁇ 0.05, 3.91 ⁇ 0.05, 3.87 ⁇ 0.05, 3.35 ⁇ 0.05.
  • the most intensive reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A] : 16.1 ⁇ 0.3, 9.9 ⁇ 0.2, 9.4 ⁇ 0.2, 7.03 ⁇ 0.1, 6.50 ⁇ 0.1, 5.87 ⁇ 0.05, 5.74 ⁇ 0.05, 4.95 ⁇ 0.05, 4.73 ⁇ 0.05, 4.33 ⁇ 0.05, 4.15 ⁇ 0.05, 4.12 ⁇ 0.05, 3.95 ⁇ 0.05.
  • a preferred method of checking the above-indicated average values of the interlattice plane intervals and intensities measured by experimentation from X-ray diffraction diagrams with a Guinier camera, for a given substance consists in calculating these intervals and their intensities from the comprehensive single crystal structure determination.
  • This structure determination yields cell constants and atom positions, which enable the X-ray diffraction diagram corresponding to the solid to be calculated by means of computer-aided calculation methods (programme CaRine Crystallography, Universite de Compiegne, France).
  • the invention relates to a corresponding combination comprising the crystalline tetrahydrate of the calcium salt of (S)-N-(I -carboxy ⁇ -methylprop-i-yO-N-pentanoyl-N-P'-OH-tetrazol- ⁇ - yl)biphenyl-4-ylmethyl]-amine, a crystalline solid which is clearly characterised by the data and parameters obtained from single crystal X-ray analysis and X-ray powder patterns.
  • An in-depth discussion of the theory of the methods of single crystal X-ray diffraction and the definition of the evaluated crystal data and the parameters may be found in Stout & Jensen, X-Ray Structure Determination; A Practical Guide, Mac Millian Co., New York, N. Y. (1968) chapter 3.
  • the elementary cell is defined by six parameters, namely by the grating constants a, b and c, and by the axial angle, namely by a, ⁇ , und y. In this way, the volume of the elementary cell V c is determined. A differentiated description of these crystal parameters is illustrated in chapter 3 of Stout & Jensen (see above).
  • An essential feature for the quality of a pure active substance both for the physical-chemical procedures such as drying, sieving, grinding, and in the galenic processes which are carried out with pharmaceutical excipients, namely in mixing processes, in granulation, in spray- drying, in tabletting, is the water absorption or water loss of this active substance depending on temperature and the relative humidity of the environment in question.
  • free and bound water is without doubt introduced with excipients and/or water is added to the process mass for reasons associated with the respective formulation process. In this way, the pharmaceutical active substance is exposed to free water over rather long periods of time, depending on the temperature of the different activity (partial vapour pressure).
  • thermogravimetry The measurement error of this sorption method based on thermogravimetry is about 0.1%. Therefore, the tetrahydrate of the calcium salt of valsartan under the conditions employed, which are realistic from a pharmaceutical-galenic point of view, shows no measurable water absorption or loss. This is surprising to a large extent, since the tetrahydrate, which has incorporated about 13% of bound water in the crystal structure, is totally indifferent to water even at extreme values of relative humidity. This property is crucial in the final stages of chemical manufacture and also in practice in all galenic process stages of the different dosage forms. This exceptional stability similarly benefits the patients through the constant availability of the active ingredient.
  • a particularly preferred salt hydrate is the tetrahydrate of the calcium salt of valsartan in the polymorphic form A 1jCa .
  • T r 10 K-min ⁇ 1 it has a melting point of 190 ⁇ 1.5 0 C and a melting enthalpy of 79 ⁇ 4 kJ Mol "1 .
  • Ca is not stable at the melting point both in respect of the hydrate water and therefore in respect of the chemical and physical structure of the molecule.
  • the indicated melting point is a hydrate melting point which can only be measured in a closed specimen container.
  • Gold containers with a wall thickness of 0.2 mm were used; after weighing in samples of between 2 and 4 mg salt hydrate, they were sealed by cold welding. These gold containers have an internal free volume of ca. 22 microlitres.
  • the amounts of the sample and the volume of the pressurised containers must be suitably adapted, so that strong dehydration of the salt hydrates cannot take place during measurement of the melting point.
  • the partial pressure of the water at 191° Celsius is ca. 13 bar, so that with an open container in DSC (Differential Scanning Calorimeter) during measurement of the melting point, conversion to the anhydrate takes place.
  • thermodynamic characteristics illustrate the advantageous physical properties, compared to the free acid, with the two corresponding data, namely a melting point in the closed system of 9O 0 C and a melting enthalpy of 12 kJ-Mol "1 .
  • thermodynamic data together with the X-ray data, prove the high stability of this crystal lattice. They are the base for the special physical and chemical resistance of the tetrahydrate of the calcium salt of valsartan of the polymorphic form A 1iCa .
  • the tetrahydrate of the calcium salt of valsartan A 1t c a has the following absorption bands expressed in reciprocal wave numbers (cm "1 ):
  • a 1iCa of the tetrahydrate of the calcium salt of valsartan are shown by the following values expressed in reciprocal wave numbers (cm "1 ): 3307 (w); 2960 (m); 1621 (st); 1578 (st);
  • the error margin for all absorption bands of ATR-IR is ⁇ 3 cm "1 .
  • the water content is in theory 13.2% for the tetrahydrate of the calcium salt of valsartan.
  • thermobalance TGS-2 Perkin-Elmer Corp. , Norwalk, CT USA ) the water content was determined for the polymorphic form A 1
  • a total formula was calculated from this (C 24 H 27 N 5 O 3 ) 2' Ca 2+ * (3.7 ⁇ 0.2) H 2 O.
  • thermogravimetry in a water-free N 2 atmosphere, the weight loss, i.e. the water loss for the tetrahydrate of the calcium salt of valsartan Ai , c a as a function of temperature, was measured at a heating rate of 10 K-min "1 . The results are illustrated in table 5.
  • the preferred characterisation of the tetrahydrate of the calcium salt of valsartan A 11Ca is obtained from the interlattice plane intervals d of the ascertained X-ray diffraction diagrams, whereby, in the following, average values are indicated with the appropriate error limits.
  • the characteristic reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A]: 16.2 ⁇ 0.3, 11.4 ⁇ 0.2, 9.9 ⁇ 0.2, 9.4 ⁇ 0.2, 8.06 ⁇ 0.1, 7.05 ⁇ 0.1, 6.50 ⁇ 0.05, 5.82 ⁇ 0.05,
  • Another polymorphic form of the tetrahydrate of the calcium salt of valsartan is the solid state form A 2 ,ca-
  • the melting point of form A 2 ,c a is 195 ⁇ 1.5 0 C and the melting enthalpy is 98 ⁇ 8 kJ-Mol '1 .
  • the indicated melting point is a hydrate melting point which can only be measured in a closed specimen container. Gold containers are used and sample weights of between 2 and 4 mg salt hydrate.
  • the theoretical water content is for a tetrahydrate of the calcium salt of valsartan 13.2%.
  • the tetrahydrate of the form A 2 ,c a has a bound water content at 225°C determined as a weight loss of 12.8% and the total formula is calculated from this (C 24 H 27 N 5 O 3 ) 2" Ca 2+ ⁇ (3.9 ⁇ 0.2) H 2 O.
  • Ca is achieved by a X-ray powder pattern and by the evaluation of the reflections into the interlattice plane intervals.
  • the measurements are throughout made without specific explanations with a Guinier camera (FR 552 from Euraf Nonius, Delft, NL) on an X-ray film in transmission geometry, using Cu-Ka 1 radiation at room temperature. Evaluation of the films for calculation of the interlattice plane intervals is made both visually and by a line scanner (Johansson, Taby, S), and the reflection intensities are determined simultanously.
  • the preferred characterization of the tetrahydrate of the calcium salt of valsartan A 2 ,ca is obtained from the interlattice plane intervals d of the ascertained X-ray diffraction diagrams, whereby, in the following, values are indicated with the appropriate error limits.
  • the characteristic reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A]: 16.2 ⁇ 0.3, 9.9 ⁇ 0.2, 9.4 ⁇ 0.2, 8.05 ⁇ 0.1, 7.04 ⁇ 0.1 , 6.49 ⁇ 0.05, 5.82 ⁇ 0.05, 4.94 ⁇ 0.05, 4.13 ⁇ 0.05, 3.93 ⁇ 0.05.
  • a new substance has been found as polymorphic form of a trihydrate of the calcium salt of valsartan assigned with B 1iCa .
  • the water content is in theory 10.24% for the trihydrate of the calcium salt of valsartan.
  • TGS-2 thermogravimetric instrument
  • the water content was determined for the polymorphic form B 1
  • a total formula was calculated from this polymorphic form of the trihydrate of the calcium salt of valsartan (C 24 H 27 N 2 O 3 ) 2" Ca 2+ • (2.9 ⁇ 0.3) H 2 O.
  • a solid state characterization of the trihydrate of the calcium salt of valsartan B 1iCa is preferably performed by X-ray powder patterns with the evaluation of the interlattice plane intervals. The measurements have been performed with two samples of the trihydrate Bi ⁇ Ca of the calcium salt of valsartan and with two different instruments.
  • the first instrument used was a temperature-humidity powder diffraction chamber X'Pert from Philips Analytical X-ray, 7602 Almelo, NL, equipped with a low and medium temperature attachement from Anton Paar GmbH, A-8054 Graz, Austria.
  • the second instrument is a powder diffractometer PW 1710 also from Philips Analytical X-ray, 7602 Almelo, NL.
  • the characteristic reflections in the X-ray diffraction diagram reveal the following interlattice plane intervals for the form B 1iCa : d in [A]: 16.0 ⁇ 0.3, 11.4 ⁇ 0.2, 10.0 ⁇ 0.2, 9.4 ⁇ 0.2, 8.06 ⁇ 0.1 , 7.75 ⁇ 0.1, 7.03 ⁇ 0.1 , 6.48 ⁇ 0.05, 6.10 ⁇ 0.05, 5.16 ⁇ 0.05, 4.75 ⁇ 0.05.
  • the new polymorphic form B 2 ,c a of a trihydrate of the calcium salt of valsartan has a melting point of 197 ⁇ 1.5°C measured in a closed sample cell with a Pyris 1 DSC (Differential Scanning Calorimeter) from Perkin-Elmer Corp., Norwalk, CT USA.
  • the enthalpy of fusion has been determined also from a DSC curve measured also with a heating rate of 10 K-min "1 as 62 ⁇ 6 kJ-Mol '1 .
  • c a of the calcium salt of valsartan also a glass transition was observed, as an unequivocal proof of amorphous substance present in this substance.
  • the amorphicity present in the substance B 2i c a approximated by this value for the change of the specific heat is 18 ⁇ 12%.
  • the crystalline trihydrate B 2 ,c a of the calcium salt of valsartan is according to the heat of fusion measured with the DSC Pyris 1 , the main component is this crystalline product, the amorphous part of the calcium salt of valsartan is a minor part.
  • the water content of the trihydrate B 2, c a of the calcium salt of valsartan is 10.5 ⁇ 0.5%.
  • the value was measured with a thermogravimteric instrument TGS-2 (Perkin-Elmer Corp., Norwalk, CT USA).
  • the total formula was calculated from this bound water content for the polymorph of the trihydrate B 2,Ga as (C 24 H 27 N 5 O 3 ) 2 Oa 2+ • (3.1 ⁇ 0.3)H 2 O.
  • Water may also be present in the amorphous part of the substance B 2 , Ca , which is depending on the concentration of the non-crystalline part. This water is within the amorphous part differently bound compared to the water molecules in the hydrate form of the crystalline part. As a first approximation one can state, that the crystalline and the amorphous part are similar in the water concentration in case the last process of reaching the state of the material is not passing the anhydrous form of the calcium salt of valsartan.
  • the solid state characterization of the trihydrate of the calcium salt of valsartan B 2 ,c a was performed by X-ray powder spectroscopy using two different instruments and two different charges produced with the evaluation of the interlattice plane intervals.
  • the first instrument was a powder diffractometer PW 1710 from Philips Analytical X-ray, 7602 Almelo, NL.
  • the second instrument was a Guinier camera FR 552 from Enraf Nonius, Delft, NL on a X-ray film in transmission geometry, using Cu-Ka 1 radiation.
  • the first instrument has been calibrated with the Guinier camera, the corrections ranging from +0.55A for a d-value of 16 A to +0.02 A for a d-value of 5.7 A. No corrections were necessary for lower d-values.
  • the characterization of the trihydrate of the calcium salt of valsartan B 2 ,c a with the interlattice plane intervals is as such, whereby, in the following values are indicated with the appropriate error limits.
  • the intensities of the d values are given in brackets with the following abbreviations: very strong ⁇ vst; strong ⁇ st; medium ⁇ m; weak ⁇ w; and very weak ⁇ vw.
  • the characteristic reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A]: 16.2 ⁇ 0.3, 11.5 ⁇ 0.2, 9.9 ⁇ 0.2, 9.4 ⁇ 0.2, 7.04 ⁇ 0.1 , 6.50 ⁇ 0.1 , 5.79 ⁇ 0.05, 4.74 ⁇ 0.05, 4.16 ⁇ 0.05.
  • Another polymorph of the trihydrate of the calcium salt of valsartan namely the B 3 , C a has a melting point measured with a heating rate of 10K min ⁇ 1 in a hermetically sealed sample cell of 192 ⁇ 1.5°C. The enthalpy of fusion has been determined also by a DSC measurement with 17 ⁇ 4 kJ-Mol "1 .
  • the water content of the polymorphic form B 3 , Ca for the trihydrate of the calcium salt of valsartan was determined with a thermobalance from Perkin-Elmer Corp., Norwalk, CT USA, named TGS-2 with a value of 9.8 ⁇ 0.5%.
  • the total formula was calculated from this bound water content for the polymorphic from B 3iCa with (C 24 H 27 N 5 O 3 ) 2 Oa 2+ ⁇ (2.9 ⁇ 0.3)H 2 O.
  • the Guinier camera FR552 with a X-ray film in transmission geometry, using a Cu-Ka 1 radiation from Enraf Nonius, Delft, NL has been installed to characterize at room temperature the crystal lattice by the interlattice plane intervals of the calcium salt of valsartan in form of the trihydrate B 3iCa -
  • the characteristic reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A]: 16.1 ⁇ 0.3, 11.4 ⁇ 0.2, 9.9 ⁇ 0.2, 9.4 ⁇ 0.2, 9.0 ⁇ 0.1 , 7.03 ⁇ 0.1 , 6.47+0.05, 5.79 ⁇ 0.05,
  • Ca has the following ATR-IR adsorption bands expressed in reciprocal wave numbers (cm "1 ):
  • the characteristic absorption bands of the ATR-IR spectroscopy for the polymorphic form B 3, ca of the trihydrate of the calcium salt of valsartan are shown by the following values expressed in reciprocal wave numbers (cm 1 ):
  • the bound water content is 3.1 ⁇ 0.3% measured with a thermobalance TGS-2 (Perkin-Emer Corp., Norwalk, CT, USA).
  • the total formula was calculated from the bound water content for the monohydarte C 1
  • the solid state characterization of the monohydrate of the calcium salt of valsartan C 11 Ca was executed by X-ray powder patterns with the evaluation of the interlattice plane intervals.
  • the instrument used was a temperature-humidity powder diffraction chamber X'Pert from Philips Analytical X-ray, 7602 Almelo, NL, equipped with a low and medium temperature attachement from Anton Paar GmbH, A-8054 Graz, Austria.
  • the characteristic reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A]: 16.0 ⁇ 0.3, 15.0 ⁇ 0.3, 11.6 ⁇ 0.2, 9.4 ⁇ 0.2, 7.53 ⁇ 0.1 , 6.11 ⁇ 0.05.
  • the heat of fusion is for the di-(calcium salt of valsartan) pentahydrate for a 100% crystalline di-(calcium salt of valsartan) pentahydrate is approximated with 94kJ-Mol "1 .
  • the water content of the di-(calcium salt of valsartan) as pentahydrate was measured with a thermobalance TGS-2 (Perkin-Elmer Corp., Norwalk, CT USA) and gave the value at the plateau of 225°C of 8.1 ⁇ 0.5%.
  • the total formula was elucidated from this bound water content for the substance D 1
  • the solid state characterization of the di-(calcium salt of valsartan) pentahydrate D 1iCa was achieved with a Guinier camera (FR 522 from Enraf Nonius, Delft, NL) on an X-ray film in transmission geometry, using Cu-Ka 1 radiation at room temperature. Evaluations of the films for calculation of the interlattice plane intervals are made by a line-scanner (Johansson, Taby, S), and the reflection intensities are determined simultaneously. The reflections in the X-ray diffraction diagram could be evaluated to the following interlattice plane intervals d, whereby values are indicated with appropriate error limits.
  • the characteristic reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A]: 15.5 ⁇ 0.3, 11.5 ⁇ 0.2, 9.4 ⁇ 0.2, 9.04 ⁇ 0.1 , 6.46 ⁇ 0.05, 6.09 ⁇ 0.05, 5.82 ⁇ 0.05, 5.16 ⁇ 0.05,
  • a magnesium salt hydrate of valsartan is preferred, in particular the hexahydrate.
  • the thermal behaviour of this salt hydrate in the region of the melting point shows a certain chemical and physical instability.
  • the thermal data are thus dependent on the measurement conditions.
  • the melting point of the hexahydrate of the magnesium salt of valsart is 132 ⁇ 1.5° Celsius and the melting enthalpy is 56 ⁇ 3 kJ Mol "1 .
  • the melting enthalpy which is about 5 times higher than the free acid of valsartan, together with the significantly higher melting point of the hexahydrate of the magnesium salt of valsartan is a measure of the stability of the new- type crystal grating at around room temperature.
  • a measurement of the infrared absorption spectrum of the hexahydrate of the magnesium salt of valsartan in a potassium bromide compressed tablet shows the following significant bands expressed in reciprocal wave numbers (cm "1 ): 3800 - 3000 (st); 3000 - 2500 (st); 1800 - 1500 (st); 1500 - 1440 (m); 1440 - 1300 (m); 1280 - 1240 (w); 1240 - 1190 (w); 1190 - 1150 (w); 1120 - 1070 (w); 1050 - 990 (w); 990 - 960 (w); 960 - 920 (w); 920 - 700 (m); 700 - 590 (w); 590 - 550 (w).
  • the hexahydrate of the magnesium salt of valsartan has the following absorption bands expressed in reciprocal wave numbers (cm "1 ):
  • the most intensive absorption bands of the ATR-IR spectroscopy are shown by the following values expressed in reciprocal wave numbers (cm "1 ): 3378 (m); 3274 (m); 2956 (m); 1619 (st); 1557 (m); 1464 (m); 1419 (m); 1394 (st); 1271 (w); 1175 (m); 1015 (w); 975 (w); 836 (m); 766 (st); 751 (m); 741 (st); 732 (st).
  • the error margin for ail absorption bands of ATR-IR is ⁇ 2 cm '1 .
  • the theoretical water content of the hexahydrate of the magnesium salt of valsartan is 19.1%.
  • TG-FTIR thermogravimetry-Fourier transformation- infrared-spectroscopy
  • IFS 28 thermogravimetry-Fourier transformation- infrared-spectroscopy 28 from the companies Netzsch Geratebau GmbH, SeIb, explanation and Bruker Optik GmbH, Düsseldorf
  • the water content was determined at 18.5 %, conforming well with the theoretical value.
  • Table 11 illustrates the water loss of the hexahydrate of the magnesium salt of valsartan depending on temperature, using the weight loss measured in an N 2 atmosphere on a thermogravimetric thermal analysis instrument for a heating rate of 10 K°min "1 . From the TG-FTIR measurement, the correlation of the weight loss is assured solely by the release of water. Table 11
  • the hexahydrate of the magnesium salt of valsartan has a solubility in distilled water at 22°C of 59 g per litre of solution for a pH value of 9.3.
  • the crystalline form of the hexahydrate of the magnesium salt of valsartan is clearly characterised by the interlattice plane intervals calculated from the lines in an X-ray powder pattern.
  • the measurement and analysis methods used are the same as those used for the tetrahydrate of the calcium salt of valsartan.
  • the most intensive reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A] : 19.7 ⁇ 0.3, 10.11 ⁇ 0.2, 9.8 ⁇ 0.2, 7.28 ⁇ 0.1 , 5.81 ⁇ 0.05, 5.68 ⁇ 0.05, 5.03 ⁇ 0.05, 4.88 ⁇ 0.05, 4.18 ⁇ 0.05, 4.08 ⁇ 0.05, 3.46 ⁇ 0.05.
  • a preferred method of checking the above-indicated average values of the interlattice plane intervals and intensities measured by experimentation from X-ray diffraction diagrams with a Guinier camera, for a given substance, consists in calculating these intervals and their intensities from the comprehensive single crystal structure determination.
  • This structure determination yields cell constants and atom positions, which enable the X-ray diffraction diagram corresponding to the solid to be calculated by means of computer-aided calculation methods (programme CaRine Crystallography, Universite de Compiegne, France).
  • the invention relates in particular to the crystalline hexahydrate of the magnesium salt of (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]- amine, a crystalline solid which is clearly characterised by the data and parameters obtained from single crystal X-ray analysis.
  • An in-depth discussion of the theory of the methods of single crystal X-ray diffraction and the definition of the evaluated crystal data and the parameters may be found in Stout & Jensen, X-Ray Structure Determination; A Practical Guide, Mac Millian Co., New York, N.Y. (1968) chapter 3.
  • SHELXS 86 (Sheldrick, G ⁇ ttingen, 1990)
  • SHELXL 96 (Sheldrick, G ⁇ ttingen, 1996)
  • SCHAKAL 86 (Keller, Freiburg 1986)
  • PLATON (Spek, Acta Cryst, 1990)
  • the elementary cell is defined by six parameters, namely by the grating constants a, b and c, and by the axial angle, namely by a, ⁇ , und y. In this way, the volume of the elementary cell V 0 is determined. A differentiated description of these crystal parameters is illustrated in chapter 3 of Stout & Jensen (see above).
  • Table 14 illustrates the mass change, i.e. the water absorption or loss as a function of relative humidity at 25°C for a sample of 9.5 mg of magnesium -valsartan-hexahydrate and for a period of 4 hours (h). The following cycles of changes in relative humidity are shown: 40-90; 90-0; 0-90; 90-0 % relative humidity:
  • thermogravimetry The measurement error of this sorption method based on thermogravimetry is about 0.1%. Therefore, the hexahydrate of the magnesium salt of valsartan under the conditions employed, which are realistic from a pharmaceutical-galenic point of view, shows weak, reproducible water absorption or water loss in a range of 20 to 80% relative humidity. This is surprising to a large extent, since the hexahydrate, which has incorporated about 19% bound water in the crystal structure, reversibly absorbs or releases water even at extreme values of relative humidity and is relatively insensitive at an average range of relative humidity. This characteristic enables an uncomplicated physical-chemical process to be developed and allows a choice of the best dosage forms for the patients.
  • Another new-type of crystalline, partially amorphous solids are falling into the groups of the magnesium salt hydrate and anhydrate of valsartan.
  • the hexahydrate of the magnesium salt of valsartan in form of the polymorphic substance A 1iMg is a preferred substance.
  • the thermal behaviour of this salt hydrate in the region of the melting point only reveals a certain chemical and physical instability.
  • the thermal data are thus dependent on the measurement conditions.
  • the instrument used for the calorimetric data is throughout a DSC Pyris 1 (Differential Scanning Calorimeter) obtained from Perkin-Elmer Corp., Norwalk, CT USA .
  • Mg is 130 ⁇ 3°C and the enthalpy of fusion is 45 ⁇ 5 kJ-Mol "1 .
  • the hexahydrate of the magnesium salt of valsartan as the polymorphic form A 1 ⁇ Mg reveals the following loss of water as a function of temperature in using the method of thermogravimetry.
  • the instrument used was a TGS-2 (Perkin-Elmer Corp., Norwalk, CT USA) and the measurement was performed in a water free atmosphere.
  • the heating rate selected was 10 K-min '1 .
  • the weight loss is illustrated in table 15.
  • the theoretical water content is for the hexahydrate of the magnesium salt of valsartan 19.1%.
  • the hexahydrate of the magnesium salt of valsartan in form of the polymorph Ai, Mg has a bound water content at 225°C determined as a weight loss of 17.3 ⁇ 0.5%.
  • the total formula is calculated from this as (C 24 H 27 N 5 O 3 ) 2 Mg 2+ • (5.4 ⁇ 0.2)H 2 O.
  • the solid-state characterization of the magnesium salt of valsartan for the polymorphic form of the hexahydrate Ai, Mg is achieved by a X-ray powder pattern and by the evaluation of the reflections into the interlattice plane intervals.
  • the measurements have been made with three different X-ray instruments.
  • the first instrument used is a Guinier camera (FR 522 from Enraf Nonius, Delft, NL) on an X-ray film in transmission geometry, with a Cu-Ka 1 radiation at room temperature. Evaluations of the films for calculation of the interlattice plane intervals are performed with a scanner from Johansson, Taby, S and the reflections intensities are determined simultaneously.
  • the second instrument used for X-ray measurements of the new substance A 1iMg is a temperatur-humidity powder diffraction chamber X'Pert from Philips Analytical X-ray, 7602 Almelo, NL equipped with a low and medium temperature attachement from Anton Paar GmbH, A-8054 Graz.
  • the third instrument applied in the solid state characterization is the powder diffractometer PW1710 from Philips Analytical X-ray. 7602 Almelo, NL.
  • the characterization of the polymorph Ai, Mg of the hexahydrate of the magnesium salt of valsartan is achieved from the interlattice plane intervals d of the ascertained X-ray measurements. In the following d values are listed with the appropriate error limits.
  • the characteristic reflections in the X-ray diffraction diagram reveal the following plane intervals: d in [A]: 19.6 ⁇ 0.3, 16.6 ⁇ 0.3, 10.3 ⁇ 0.2, 9.8 ⁇ 0.2, 7.3 ⁇ 0.1 , 6.01 ⁇ 0.05, 5.92 ⁇ 0.05, 5.55+0.05,
  • the substance in form of the tetrahydrate B 1iMg is a partially amorphous solid of the magnesium salt of valsartan.
  • the tetrahydrate B 1 ⁇ Mg shows the following loss of water as a function of temperature measured with a thermobalance TGS-2 (Perkin-Elmer Corp., Norwalk, CT USA). The heating rate selected was 10K min "1 .
  • the weight loss is tabulated in table 16.
  • the magnesium salt of valsartan in the polymorphic form of the tetrahydrate B 11M g is showing a bound water content at 225°C of 13.0 ⁇ 0.5%, and as shown for 25°C in Table 8 practically no additional free water is present in the substance measurements were performed with a thermobalance TGS-2 of the Perkin-Elmer Corp., CT USA.
  • the total formula is therefore calculated as (C 24 H 27 N 5 O 3 ) Mg • (3.8 ⁇ 0.2)H 2 O.
  • the solid-state characterization of the tetrahydrate of the magnesium salt of valsartan B 1 Mg has been performed with an X-ray instrument by a so-called temperature-humidity powder diffraction chamber X'Pert from Philips Analytical X-ray, 7602 Almelo, NL, equipped with a low and medium temperature attachement from Anton Paar GmbH, A-8054 Graz. Additional X-ray measurements were performed with a powder diffractometer PW 1710 from Philips Analytical X-ray, 7602 Almelo, NL.
  • Mg are characterized in the solid state with the interlattice plane intervals d, which are given with appropriate error limits.
  • the new substance C- ⁇ >Mg is a the trihydrate of the magnesium salt of valsartan.
  • the water content was measured with a thermobalance TGS-2 (Perkin-Elmer Corp., Norwalk, CT USA).
  • the water content for this substance, namely the trihydrate of the magnesium salt of valsartan C 11Mg is 10.7 ⁇ 0.5%.
  • the total formula is calculated from this (C 24 H 27 N 5 O 3 ) ⁇ Mg 2+ • (3.0 ⁇ 0.3)H 2 O.
  • the solid-state characterization of the trihydrate of the magnesium salt of valsartan C 1 M g has been performed with X-ray measurements by use of the temperature-humidity powder diffraction chamber X'Pert from Philips Analytical X-ray, 7602 Almelo, NL equipped with a low and medium temperature attachement from Anton Paar GmbH, A-8054 Graz.
  • Mg of the magnesium salt of the valsartan trihydrate is given with the interlattice plane intervals d obtained with X-ray measurements. In the following, d values are listed with the appropriate error limits.
  • the characteristic reflections in the X-ray diffraction diagram reveal the following plane intervals: d in [A]: 17.9+0.3, 10.2 ⁇ 0.2, 8.96 ⁇ 0.2, 7.18 ⁇ 0.1 , 5.93 ⁇ 0.05, 5.84 ⁇ 0.05, 5.42+0.05, 5.11+0.05, 5.01 ⁇ 0.05, 4.82 ⁇ 0.05, 4.67 ⁇ 0.05, 4.30 ⁇ 0.05, 4.19 ⁇ 0.05, 4.13 ⁇ 0.05, 4.02 ⁇ 0.05.
  • the magnesium salt of valsartan is also forming a substance as a monohydrate which is indicated with Di iMg .
  • the water content was measured with a thermobalance TGS-2 (Perkin- Elmer Corp., Norwalk, CT USA).
  • the water content for the monohydrate D 1 Mg is 2.8 ⁇ 0.3%.
  • the total formula was calculated from this value with (C 24 H 27 N 5 O 3 ) 2 ⁇ Mg 2+ • (0.74+0.2) H 2 O.
  • DPP-IV dipeptidyl peptidase IV, also known as CD26.
  • DPP-IV 1 a serine protease belonging to the group of post-proline/alanine cleaving amino-dipeptidases, specifically removes the two N-terminal amino acids from proteins having proline or alanine in position 2.
  • DPP-IV can be used in the control of glucose metabolism because its substrates include the insulinotropic hormones glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 and GIP are active only in their intact forms; removal of their two N-terminal amino acids inactivates them.
  • GLP-1 and GIP are active only in their intact forms; removal of their two N-terminal amino acids inactivates them.
  • DPP-IV inhibitor is intended to indicate a molecule that exhibits inhibition of the enzymatic activity of DPP-IV and functionally related enzymes, such as from 1-100% or 20- 80% inhibition, and specially preserves the action of substrate molecules, including but not limited to GLP-1 , GIP, peptide histidine methionine, substance P, neuropeptide Y, and other molecules typically containing alanine or proline residues in the second amino terminal position.
  • Treatment with DPP-IV inhibitors prolongs the duration of action of peptide substrates and increases levels of their intact, undegraded forms leading to a spectrum of biological activities relevant to the disclosed invention.
  • CD26/DPP-IV For that purpose, chemical compounds are tested for their ability to inhibit the enzyme activity of purified CD26/DPP-IV. Briefly, the activity of CD26/DPP-IV is measured in vitro by its ability to cleave the synthetic substrate Gly-Pro-p-nitroanilide (Gly-Pro-pNA). Cleavage of Gly-Pro-pNA by DPP-IV liberates the product p-nitroanilide (pNA), whose rate of appearance is directly proportional to the enzyme activity. Inhibition of the enzyme activity by specific enzyme inhibitors slows down the generation of pNA. Stronger interaction between an inhibitor and the enzyme results in a slower rate of generation of pNA.
  • Gly-Pro-pNA Gly-Pro-pNA
  • the degree of inhibition of the rate of accumulation of pNA is a direct measure of the strength of enzyme inhibition.
  • the accumulation of pNA is measured spectrophotometrically.
  • the inhibition constant, Ki, for each compound is determined by incubating fixed amounts of enzyme with several different concentrations of inhibitor and substrate.
  • a DPP-IV inhibitor is also intended to comprise active metabolites and prodrugs thereof, such as active metabolites and prodrugs of DPP-IV inhibitors.
  • An active “metabolite” is an active derivative of a DPP-IV inhibitor produced when the DPP-iV inhibitor is metabolized.
  • a “prodrug” is a compound that is either metabolized to a DPP-IV inhibitor or is metabolized to the same metabolite(s) as a DPP-IV inhibitor.
  • DPP-IV inhibitors are known in the art.
  • DPP-IV inhibitors are in each case generically and specifically disclosed e.g. in WO 98/19998.DE19616486 A1, WO 00/34241, WO 95/15309, WO 01/72290, WO01/52825, WO 9310127, WO 9925719, WO 9938501 , WO 9946272, WO 9967278 and WO 9967279.
  • WO 02053548 especially compounds 1001 to 1293 and examples 1 to 124
  • WO 02067918 especially compounds 1000 to 1278 and 2001 to 2159
  • WO 02066627 especially the described examples
  • WO 02/068420 especially all the compounds specifically listed in the examples I to LXIII and the described corresponding analogues, even preferred compounds are 2(28), 2(88), 2(119), 2(136) described in the table reporting IC50
  • WO 02083128 especially examples 1 to 13, US 2003096846 especially the specifically described compounds
  • WO 2004/037181 especially examples 1 to 33
  • WO 0168603 especially compounds of examples 1 to 109
  • EP1258480 especially compounds of examples 1 to 60
  • WO 0181337 especially examples 1 to 118
  • WO 02083109 especially examples 1A to 1 D
  • WO 030003250 especially compounds of examples 1 to 166, most preferably 1 to 8, WO 03035067 especially the compounds described in the examples, WO 03/0350
  • DE19616 486 A1 discloses val-pyr, val-thiazolidide, isoleucyl-thiazolidide, isoleucyl- pyrrolidide, and fumaric salts of isoleucyl-thiazolidide and isoleucyl-pyrrolidide.
  • WO01 /52825 specially discloses (S)-1 - ⁇ 2-[5-cyanopyridin-2yl)amino]ethyl-aminoacetyl)-2- cyano- pyrrolidine or (S)-1 -[(3-hydroxy-1-adamantyl)amino]acetyl-2- cyano-pyrrolidine.
  • Published patent application WO 9310127 discloses proline boronic esters useful as DPP-IV inhibitors.
  • DPP-IV inhibitors of interest are specially those cited in examples 1 to 19.
  • Published patent application WO 9925719 discloses sulphostin, a DPP-IV inhibitor prepared by culturing a Streptomyces microorganism.
  • Published patent application WO 9938501 discloses N-substituted 4-8 membered heterocyclic rings. DPP-IV inhibitors of interest are specially those cited in claims 15 to 20. Published patent application WO 9946272 discloses phosphoric compounds as inhibitors of DPP-IV. DPP-IV inhibitors of interest are specially those cited in claims 1 to 23.
  • the DPP-IV inhibitor is a N-peptidyl-O-aroyl hydroxylamine or a pharmaceutically acceptable salt thereof.
  • Aroyl is, for example, naphthylcarbonyl; or benzoyl which is unsubstituted or mono- or disubstituted, for example, by lower alkoxy, lower alkyl, halogen or, preferably, nitro.
  • the peptidyl moiety comprises preferably two ⁇ -amino acids, e.g. glycine, alanine, leucine, phenylalanine, lysine or proline, of which the one attached directly to the hydroxylamine nitrogen atom is preferably proline.
  • N-peptidyl-O-aroyl hydroxylamine is a compound of formula VII
  • j is O, 1 or 2;
  • Rs 1 represents the side chain of a natural amino acid
  • Rs 2 represents lower alkoxy, lower alkyl, halogen or nitro; or a pharmaceutically acceptable salt thereof.
  • the N-peptidyl-O-aroyl hydroxylamine is a compound of formula Vila or a pharmaceutically acceptable salt thereof.
  • N-Peptidyl-O-aroyl hydroxylamines e.g. of formula VII or Vila
  • Preferred DPP-IV inhibitors are N-substituted adamantyl-amino- acetyl-2-cyano pyrrolidines, N (substituted glycyl)-4-cyano pyrrolidines, N- (N'-substituted glycyl)-2-cyanopyrrolidines, N- aminoacyl thiazolidines, N-aminoacyl pyrrolidines, L-allo-isoleucyl thiazolidine, L-threo- isoleucyl pyrrolidine, and L-allo-isoleucyl pyrrolidine, 1-[2-[(5-cyanopyridin-2-yl) amino] ethylamino] acetyl-2-cyano-(S)-pyrroIidine and pharmaceutical salts thereof.
  • Preferred DPP-IV inhibitors are those described by Mona Patel and col. (Expert Opinion Investig Drugs. 2003 Apr;12(4):623-33) on the paragraph 5, especially P32/98, K-364, FE- 999011, BDPX, NVP-DDP-728 and others, which publication is hereby incorporated by reference especially the described DPP-IV inhibitors.
  • FE-999011 is described in the patent application WO 95/15309 page 14, as compound No. 18.
  • P32/98 or P3298 also known as 3-[(2S,3S)-2-amino-3-methyl- 1-oxopentyl]thiazolidine can be used as 3-[(2S,3S)-2-amino-3-methyl-1- oxopentyl]thiazolidine and (2E)-2-butenedioate (2:1) mixture such as shown below
  • DPP-IV inhibitors of the invention are described in the International patent application WO 02/076450 (especially the examples 1 to 128) and by Wallace T. Ashton (Bioorganic & Medicinal Chemistry Letters 14 (2004) 859-863 ) especially the compound 1 and the compounds listed in the tables 1 and 2.
  • the preferred compound is the compound 21e (table 1) of formula
  • DPP-IV inhibitors are described in the patent applications WO 2004/037169 especially those described in the examples 1 to 48 and WO 02/062764 especially the described examples 1 to 293, even preferred are the compounds 3-(aminomethyl)-2- isobuthyl-1-oxo-4-phenyl-1 ,2-dihydro-6-isoquinolinecarboxamide and 2- ⁇ [3-(aminomethyl)-2- isobuthyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]oxy ⁇ acetamide described on page 7 and also in the patent application WO2004/024184 especially in the reference examples 1 to 4.
  • DPP-IV inhibitors are described in the patent application WO 03/004498 especially examples 1 to 33 and most preferably the compound of the formula
  • MK-0431 described by the example 7 and also known as MK-0431.
  • Preferred DPP-IV inhibitors are also described in the patent application WO 2004/037181 especially examples 1 to 33 and most preferably the compounds described in the claims 3 to 5.
  • DPP728 and LAF237 are specifically disclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241, respectively.
  • the DPP-IV inhibitor P32/98 (see above) is specifically described in Diabetes 1998, 47, 1253-1258.
  • DPP728 and LAF237 can be formulated as described on page 20 of WO 98/19998 or in WO 00/34241.
  • orally active DPP-IV inhibitors are especially preferred.
  • DPP-IV is responsible for inactivating GLP-1. More particularly, DPP-IV generates a GLP-1 receptor antagonist and thereby shortens the physiological response to GLP-1.
  • GLP-1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose disposal.
  • Non-insulin dependent diabetes mellitus type 2 diabetes mellitus
  • Non-insulin dependent diabetes mellitus is characterized by both increased peripheral insulin resistance and abnormal insulin secretion. At least three abnormalities of insulin secretion are recognized: in the first phase, insulin secretion is lost and in the second phase insulin is both delayed and inadequate in the face of elevated circulating glucose levels.
  • Several metabolic, hormonal, and pharmacological entities are known to stimulate insulin secretion including glucose, amino-acids and gastrointestinal peptides.
  • the Diabetes Control and Complications Trial has established that lowering of blood glucose is associated with decreases in the onset and progression of diabetic microvascular complications (Diabetes Control and Complications Trial Research Group; N. Engl. J. Med. 1993, 329, 977-986).
  • IGT is an impairment of glucose homeostasis closely related to type 2 diabetes mellitus. Both conditions convey a great risk of macrovascular disease. Therefore, one therapeutic focus is on optimizing and potentially normalizing glycemic control in subjects with type 2 diabetes mellitus, conditions of impaired fasting plasma glucose, or IGT. Presently available agents need to be improved in order to better meet this therapeutic challenge.
  • the present invention especially relates to a combination which comprises calcium or magnesium salt of the AT ⁇ receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1-yl)-N- pentanoyl-N-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan), and at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.
  • AT ⁇ receptor antagonist S
  • I -carboxy-2-methyl-prop-1-yl)-N- pentanoyl-N-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine valsartan
  • at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use.
  • a further antidiabetic compound is selected from the group consisting of insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (G ⁇ Pase), inhibitors of fructose- 1 ,6- bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, ⁇ -glucosidase inhibitors, inhibitors of gastric emptying, insulin, and ⁇ 2 -
  • inhibitors of PTPase include, but are not limited to those disclosed in U.S. Patent No. 6,057,316, U.S. Patent No. 6,001,867, WO 99/58518, WO 99/58522, WO 99/46268, WO 99/46267, WO 99/46244, WO 99/46237, WO 99/46236, WO 99/15529 and by Poucheret et al in MoI. Cell Biochem. 1998, 188, 73-80.
  • non-small molecule mimetic compounds include, but are not limited to those disclosed in Science 1999, 284; 974-97, especially L-783,281 , and WO 99/58127, especially CLX-901.
  • inhibitors of GFAT include, but are not limited to those disclosed in MoI. Cell. Endocrinol. 1997,135(1), 67-77.
  • inhibitors of G ⁇ Pase means a compound or composition which reduces or inhibits hepatic gluconeogenesis by decreasing or inhibiting the activity of G6Pase. Examples of such compounds are disclosed in WO 00/14090, WO 99/40062, WO 98/40385, EP682024 and Diabetes 1998, 47, 1630-1636.
  • inhibitors of F-1 ,6-BPase means a compound or composition which reduces or inhibits hepatic gluconeogenesis by decreasing or inhibiting the activity of F-1,6- BPase. Examples of such compounds are disclosed in WO 00/14095, WO 99/47549, WO 98/39344, WO 98/39343 and WO 98/39342.
  • inhibitors of GP means a compound or composition which reduces or inhibits hepatic glycogenosis by decreasing or inhibiting the activity of GP. Examples of such compounds are disclosed in EP 978279, US Patent No. 5998463, WO 99/26659, EP 846464, WO 97/31901, WO 96/39384, WO9639385 and in particular CP-91149 as described in Proc. Natl. Acad Sci USA 1998. 95. 1776-1781.
  • glucagon receptor antagonists as used herein relates in particular to the compounds described in WO 98/04528, especially BAY27-9955, and those described in Bioorg Med. Chem. Lett 1992, 2, 915-918, especially CP-99,711 , J. Med. Chem. 1998, 41, 5150-5157, especially NNC 92-1687, and J. Biol Chem. 1999, 274; 8694-8697, especially L- 168,049 and compounds disclosed in US 5,880,139, WO 99/01423, US 5,776,954, WO 98/22109, WO 98/22108, WO 98/21957 and WO 97/16442.
  • inhibitors of PEPCK means a compound or composition which reduces or inhibits hepatic gluconeogenesis by decreasing or inhibiting the activity of PEPCK. Examples of such compounds are disclosed in U.S. Patent No. 6,030,837 and MoI. Biol. Diabetes 1994, 2, 283-99.
  • PDHK inhibitors as used herein means inhibitors of pyruvate dehydrogenase kinase and include, but are not limited to, those compounds disclosed by Aicher et al in J. Med. Chem. 42 (1999) 2741-2746.
  • Insulin sensitivity enhancer used herein means any and all pharmacological active compounds that enhance the tissue sensitivity towards insulin.
  • Insulin sensitivity enhancers include, e.g., inhibitors of GSK-3, retinoid X receptor (RXR) agonists, agonists of Beta-3 AR, agonists of UCPs, antidiabetic thiazolidinediones (glitazones), non-glitazone type PPAR ⁇ agonists, dual PPAR ⁇ / PPAR ⁇ agonists, antidiabetic vanadium containing compounds and biguanides, e.g., metformin.
  • RXR retinoid X receptor
  • the insulin sensitivity enhancer is preferably selected from the group consisting of antidiabetic thiazolidinediones, antidiabetic vanadium containing compounds and metformin.
  • the insulin sensitivity enhancer is metformin.
  • inhibitors of GSK-3 include, but are not limited to those disclosed in WO 00/21927 and WO 97/41854.
  • RXR agonist is meant a compound or composition which when combined with RXR homodimers or heterodimers increases the transcriptional regulation activity of RXR, as measured by an assay known to one skilled in the art, including, but not limited to, the “co- transfection” or “cis-trans” assays described or disclosed in U.S. Pat. Nos. 4,981 ,784, 5,071,773, 5,298,429, 5,506,102, WO89/05355, WO91/06677, WO92/05447, WO93/11235, WO95/18380, PCT/US93/04399, PCT/US94/03795 and CA 2,034,220, which are incorporated by reference herein.
  • RXR RXR specific agonists
  • RXR RXR specific agonists
  • pan agonists compounds that activate both RXR and RAR
  • RXR pan agonists
  • RXR in a certain cellular context but not others (i.e. partial agonists).
  • Compounds disclosed or described in the following articles, patents and patent applications which have RXR agonist activity are incorporated by reference herein: U.S. Pat. Nos.
  • RXR specific agonists include, but are not limited to, LG 100268 (i.e. 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-cyclopropyl]- py ridine-5-carboxyIic acid) and LGD 1069 (i.e.
  • LG 100268 and LGD 1069 are disclosed in Boehm, et al. J. Med. Chem. 38(16):3146-3155, 1994, incorporated by reference herein.
  • Pan agonists include, but are not limited to, ALRT 1057 (i.e. 9-cis retinoic acid), and analogs, derivatives and pharmaceutically acceptable salts thereof.
  • agonists of Beta-3 AR include, but are not limited to CL-316,243 (Lederle Laboratories) and those disclosed in WO 99/29672, WO 98/32753, WO 98/20005, WO 98/09625, WO 97/46556, WO 97/37646 and U.S. Patent No. 5,705,515.
  • agonists of UCPs means agonists of UCP-1 , preferably UCP-2 and even more preferably UCP-3.
  • UCPs are disclosed in Vidal-Puig et al., Biochem. Biophys. Res. Commun., Vol. 235(1) pp. 79-82 (1997). Such agonists are a compound or composition which increases the activity of UCPs.
  • the antidiabetic thiazolidinedione is, for example, (S)-((3,4-dihydro-2-(phenyl- methyl)-2H-1 -benzopyran-6-yl)methyl-thiazolidine-2,4-dione (englitazone), 5- ⁇ [4-(3-(5-methyl- 2-phenyl-4-oxazolyl)-1-oxopropyl)-phenyl]-methyl ⁇ -thiazolidine-2,4-dione (darglitazone), 5- ⁇ [4-(1 -methyl-cyclohexyOmethoxyVphenylJmethylHhiazolidine ⁇ -dione (ciglitazone), 5- ⁇ [4- (2-(1-indolyl)ethoxy)phenyl]methyl ⁇ -thiazolidine-2,4-dione (DRF2189), 5- ⁇ 4-[2-(5-methyl-2- phenyl-4-oxazolyl
  • the antidiabetic thiazolidinedione is a compound of formula VIII,
  • M represents naphthyl, benzoxazolyl, dihydrobenzopyranyl, indole, phenyl (optionally substituted by halogen) or phenylethynyl (optionally substituted by halogen);
  • Rp 1 represents halogen or a radical -QRp 4 , in which Q can be oxygen, lower alkylen, carbonyl or -NH-, R ⁇ 4 is naphthyl; phenyl, unsubstituted or substituted by 2,4-dioxo-5-thiazolidinyl; or lower alkyl or hydroxy lower alkyl, unsubstituted or substituted by a) indole or 2,3-dihydroindole, b) pyridyl, lower alkyl-pyridyl, N-lower alkyl-N-pyridylamino or halogenphenyl, c) dihydrobenzopyranyl, which is unsubstituted or substituted by hydroxy and lower alkyl, d) oxazolyl, which is substituted by lower alkyl and phenyl, e) cycloalkyl, which is unsubstituted or substituted by lower alky
  • R ⁇ 2 represents hydrogen or trifluoromethylphenyl-lower alkyl carbamoyl
  • R ⁇ 3 represents hydrogen or arylsulfonyl; or a pharmaceutically acceptable salt thereof.
  • the compound of formula VIII is selected from the group consisting of (S)-((3,4- dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione (englitazone), 5- ⁇ [4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl)-phenyl]-methyl ⁇ -thiazolidine-2,4-dione (darglitazone), ⁇ - ⁇ -CI-methyl-cyclohexyOmethoxyVphenyllmethylJ-thiazolidine ⁇ -dione (ciglitazone), 5- ⁇ [4-(2-(1-indolyl)ethoxy)phenyl]methyl ⁇ -thiazolidine-2,4-dione (DRF2189), 5- ⁇ 4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy)]benzyl ⁇ -thiazol
  • the compound of formula VIII is selected from the group consisting of 5- ⁇ [4- (2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl ⁇ -thiazolidine-2,4-dione (rosiglitazone), 5- ⁇ [4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl ⁇ thiazolidine-2,4-dione (pioglitazone) and 5- ⁇ [4- ((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl ⁇ - thiazolidine-2,4-dione (troglitazone), MCC555, T-174 and KRP297, especially rosiglitazone, pioglitazone and troglitazone, or a pharmaceutically acceptable salt thereof.
  • the glitazones 5- ⁇ [4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl ⁇ thiazolidine-2,4-dione (pioglitazone, EP O 193 256 A1), 5- ⁇ [4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl ⁇ - thiazolidine-2,4-dione (rosiglitazone, EP 0 306 228 A1), 5- ⁇ [4-((3,4-dihydro-6-hydroxy- 2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl ⁇ thiazolidine-2,4-dione (troglitazone, EP O 139421), (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6- yl)methyl-thiazoIidine-2,4
  • MCC555 can be formulated as disclosed on page 49, lines 30 to 45, of EP 0 604 983 B1 ; englitazone as disclosed from page 6, line 52, to page 7, line 6, or analogous to Examples 27 or 28 on page 24 of EP 0 207 605 B1; and darglitazone and 5- ⁇ 4-[2-(5-methyl- 2-phenyl-4-oxazolyl)-ethoxy)]benzyl ⁇ -thiazolidine-2,4-dione (BM-13.1246) can be formulated as disclosed on page 8, line 42 to line 54 of EP 0 332 332 Bl AY-31637 can be administered as disclosed in column 4, lines 32 to 51 of US 4,997,948 and rosiglitazone as disclosed on page 9, lines 32 to 40 of EP 0 306 228 A1, the latter preferably as its maleate salt.
  • Rosiglitazone can be administered in the form as it is marketed e.g. under the trademark AVANDIATM.
  • Troglitazone can be administered in the form as it is marketed e.g. under the trademarks ReZulinTM, PRELAYTM, ROMOZINTM (in the United Kingdom) or NOSCALTM (in Japan).
  • Pioglitazone can be administered as disclosed in Example 2 of EP 0 193 256 A1, preferably in the form of the monohydrochloride salt.
  • Ciglitazone can, for example, be formulated as disclosed in Example 13 of US 4,287,200.
  • Non-glitazone type PPAR ⁇ agonists are especially N-(2-benzoylphenyl)-L-tyrosine analogues, e.g. GI-262570, and JTT501.
  • dual PPAR ⁇ / PPAR ⁇ agonists means compounds which are at the same time PPAR ⁇ and PPAR ⁇ agonists.
  • Preferred dual PPAR ⁇ / PPAR ⁇ agonists are especially those ⁇ -[(oxoquinazolinylalkoxy)phenyl]alkanoates and analogs thereof , very especially the compound DRF-554158, described in WO 99/08501 and the compound NC- 2100 described by Fukui in Diabetes 2000, 49(5), 759-767.
  • a preferred "dual PPAR ⁇ / PPAR ⁇ agonist" is compound of the formula (I)
  • L is radical in which R 1 is hydrogen, optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl;
  • R 2 is hydrogen, hydroxy, optionally substituted alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, alkylthio, arylthio or aralkylthio;
  • R 3 is hydrogen or aryl
  • R 2 and R 3 combined are alkylene which together with the carbon atoms they are attached to form a 5- to 7-membered ring; n is zero or an integer from 1 to 2; Y is hydrogen; or Y and R 2 taken together with the carbon atoms they are attached to form a bond provided that n is 1 ;
  • R 4 is hydrogen
  • R 4 and Y taken together with the carbon atoms they are attached to form a bond provided that n is 1 , and R 2 and R 3 taken together with the carbon atoms they are attached to form a bond; or
  • L is radical in which R 1 is hydrogen, optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl;
  • R" is hydrogen, optionally substituted alkyl, alkoxy or halogen; m is an integer from 1 to 2; Y is hydrogen; R 4 is hydrogen; or
  • R and R' are independently hydrogen, halogen, optionally substituted alkyl, alkoxy, aralkyl or heteroaralkyl; or
  • R and R' combined together form a methylenedioxy group provided that R and R' are attached to carbon atoms adjacent to each other;
  • R and R' combined together with the carbon atoms they are attached to form an optionally substituted 5- to 6-membered aromatic or heteroaromatic ring provided that R and R' are attached to carbon atoms adjacent to each other; or
  • R-C and R'-C may independently be replaced by nitrogen
  • X is -Z-(CH 2 )p-Q-W wherein Z is a bond, O, S, -C(O)- or -C(O)NR 5 - in which
  • R 5 is hydrogen, alkyl or aralkyl; p is an integer from 1 to 8;
  • Q is a bond provided that Z is not a bond when p is 1 ; or Q is -O(CH 2 )r or -S(CH 2 ) r -, in which r is zero or an integer from 1 to 8; or
  • Q is -0(CH 2 ) I -BO-, -S(CH 2 ) 1-8 O-, -S(CH 2 )i. 8 S-, -C(O)- or -C(O)NR 6 - in which R 6 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or
  • Q is -NR 6 -, -NR 5 C(O)-, -NR 5 C(O)NH- Or -NR 5 C(O)O- provided that p is not 1;
  • W is cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; or
  • W and R 6 taken together with the nitrogen atom to which they are attached form a 8- to 12-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
  • L is in which R 1 is hydrogen or optionally substituted alkyl
  • R 2 and R 3 are hydrogen;
  • R 2 and R 3 combined are alkylene which together with the carbon atoms they are attached to form a 6-membered ring; n is zero or an integer from 1 to 2; Y is hydrogen; R 4 is hydrogen; or L is radical in which Ri is hydrogen or optionally substituted alkyl;
  • R" is hydrogen, optionally substituted alkyi, alkoxy or halogen; m is an integer from 1 to 2; Y is hydrogen; R 4 is hydrogen;
  • R and R' are independently hydrogen, halogen, optionally substituted C 1-6 alkyl or C 1-6 alkoxy; or
  • R and R' combined together form a methylenedioxy group provided that R and R' are attached to carbon atoms adjacent to each other;
  • Z is a bond, O, S or -C(O)NR 5 - in which R 5 is hydrogen, alkyl or aralkyl; p is an integer from 1 to 5;
  • Q is a bond provided that Z is not a bond when p is 1 ;
  • Q is -O(CH 2 )r or -S(CH 2 ) r - in which r is zero;
  • Q is -C(O)- or -C(O)NR 6 - in which R 6 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or
  • Q is -NR 6 -, -NR 5 C(O)-, -NR 5 C(O)NH- or -NR 5 C(O)O- provided that p is not 1;
  • W is cycloalkyl, aryl or heterocyclyl; or
  • W and R 6 taken together with the nitrogen atom to which they are attached form a 9- to 10-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
  • Preferred is a compound of formula (I A), wherein L is radical in which R 1 is hydrogen or optionally substituted alkyl;
  • R 2 and R 3 are hydrogen; n is zero or an integer from 1 to 2; or
  • L is radical in which R 1 is hydrogen or optionally substituted alkyl
  • R" is hydrogen; m is an integer from 1 to 2;
  • R is hydrogen, halogen, optionally substituted C 1-6 alkyl or C 1-6 alkoxy;
  • R' is hydrogen
  • Z is a bond, O or S; p is an integer from 1 to 5;
  • Q is a bond provided that Z is not a bond when p is 1 ;
  • Q is O, S or -C(O)NR 6 - in which R 6 is hydrogen, optionally substituted alkyl or cycloalkyl; or
  • Q is -NR 6 -, -NR 5 C(O)NH- or -NR 5 C(O)O- in which R 5 is hydrogen, alkyl or aralkyl provided that p is not 1 ;
  • W is cycloalkyl, aryl or heterocyclyl
  • W and R 6 taken together with the nitrogen atom to which they are attached form a 9- to 10-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
  • L is radical in which R 1 is hydrogen or optionally substituted alkyl; n is zero or 1 ; or
  • L is radical in which Ri is hydrogen or optionally substituted alkyl; m is 1;
  • R is hydrogen, halogen, optionally substituted C 1-6 alkyl or C 1-6 alkoxy;
  • Z is a bond, O or S; p is an integer from 1 to 5;
  • Q is a bond provided that Z is not a bond when p is 1 ;
  • Q is O, S or -C(O)NR 6 - in which R 6 is hydrogen, optionally substituted alkyl or cycloalkyl; or
  • Q is -NR 6 -, -NR 5 C(O)NH- or -NR 5 C(O)O- in which R 5 is hydrogen, alkyl or aralkyl provided that p is not 1 ;
  • W is cycloalkyl, aryl or heterocyclyl
  • W and R 6 taken together with the nitrogen atom to which they are attached form a 9- to 10-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
  • Preferred is a compound of formula (I B), wherein L is radical in which R 1 is hydrogen; and n is zero or 1;
  • R is hydrogen, halogen, optionally substituted C 1-6 alkyl or Ci -6 alkoxy;
  • Z is a bond, O or S; p is an integer from 1 to 4;
  • Q is a bond provided that Z is not a bond when p is 1 ;
  • Q is O or S
  • W is aryl or heterocyclyl; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
  • L is radical in which R 1 is hydrogen
  • R is hydrogen, halogen, optionally substituted C 1-6 alkyl or C 1-6 alkoxy;
  • Z is a bond, O or S; p is an integer from 1 to 4;
  • Q is a bond provided that Z is not a bond when p is 1 ;
  • Q is O or S
  • W is aryl or heterocyclyl; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
  • Preferred is a compound of formula (I B) 1 wherein the asymmetric center in radical L is in the (R) configuration; or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen or optionally substituted alkyl
  • R is hydrogen, halogen, optionally substituted C 1-6 alkyl or C 1-6 alkoxy
  • Z is O or S
  • p is 2;
  • Q is a -NR 6 - in which R 6 is lower alkyl; W is aryl or heterocyclyl; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
  • Ri is hydrogen or optionally substituted alkyl
  • R is hydrogen, halogen, optionally substituted C 1-6 alkyl or C 1-6 alkoxy
  • Z is a bond
  • p is 2;
  • Q is a -C(O)NR 6 - in which R 6 is optionally substituted alkyl; W is aryl or heterocyclyl; or
  • W and R 6 taken together with the nitrogen atom to which they are attached form a 9- to 10-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
  • Preferred is a compound of formula (I B), wherein R is hydrogen, chloro, n-propyl or methoxy; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
  • R 1 is hydrogen or optionally substituted alkyl
  • R is hydrogen, halogen, optionally substituted C 1-6 alkyl or C 1-6 alkoxy
  • Z is a bond, O or S
  • p is an integer from 2 to 3
  • Q is O or S
  • W is aryl or heterocyclyl; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
  • R 1 is hydrogen or optionally substituted alkyl
  • R is hydrogen, halogen, optionally substituted Ci -6 alkyl or C 1-6 alkoxy
  • Z is O or S
  • p is an integer from 1 to 2
  • Q is a bond
  • W is aryl or heterocyclyl; or a pharmaceutically acceptable salt thereof; or an optical isomer or a mixture of optical isomers thereof.
  • Preferred is a compound of formula (I B), wherein R 1 is hydrogen or optionally substituted alkyl;
  • R is hydrogen, halogen, optionally substituted Ci -6 alkyl or C 1-6 alkoxy; Z is O or S; p is 2; Q is a bond; W is selected from the group consisting of:
  • the antidiabetic vanadium containing compound is a physiologically tolerable vanadium complex of a bidentate monoprotic chelant, wherein said chelant is an ⁇ - hydroxypyrone or ⁇ -hydroxypyridinone, especially those disclosed in the Examples of US 5,866,563, of which the working examples are hereby incorporated by reference, or a pharmaceutically acceptable salt thereof.
  • metformin dimethyldiguanide
  • hydrochloride salt The preparation of metformin (dimethyldiguanide) and its hydrochloride salt is state of the art and was disclosed first by Emil A. Werner and James Bell, J. Chem. Soc. 121, 1922, 1790- 1794.
  • Metformin can be administered e.g. in the form as marketed under the trademarks GLUCOPHAGETM.
  • Insulin secretion enhancers are pharmacological active compounds having the property to promote secretion of insulin from pancreatic ⁇ cells.
  • insulin secretion enhancers include glucagon receptor antagonists (see above), sulphonyl urea derivatives, incretin hormones, especially glucagon-like peptide- 1 (GLP-1) or GLP-1 agonists, ⁇ -cell imidazoline receptor antagonists, and short-acting insulin secretagogues, like antidiabetic phenylacetic acid derivatives, antidiabetic D-phenylalanine derivatives and BTS 67582 described by T. Page et al in Br. J. Pharmacol. 1997, 122, 1464-1468.
  • the sulphonyl urea derivative is, for example, glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibomuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide or tolcyclamide; and preferably glimepiride or gliclazide.
  • Tolbutamide, glibenclamide, gliclazide, glibomuride, gliquidone, glisoxepid and glimepiride can be administered e.g. in the form as they are marketed under the trademarks RASTINON HOECHSTTM, AZUGLUCONTM, DIAMICRONTM, GLUBORIDTM, GLURENORMTM, PRO-DIABANTM and AMARYLTM, respectively.
  • GLP-1 is a insulinotropic proteine which was described, e.g., by W.E. Schmidt et al. in Diabetologia 28, 1985, 704-707 and in US 5,705,483.
  • GLP-1 agonists used herein means variants and analogs of GLP-1 (7-36)NH 2 which are disclosed in particular in US 5,120,712, US 5,118666, US 5,512,549, WO 91/11457 and by C. Orskov et al in J. Biol. Chem. 264 (1989) 12826.
  • GLP-1 agonists comprises especially compounds like GLP-1 (7-37), in which compound the carboxy-terminal amide functionality of Arg 36 is displaced with GIy at the 37 th position of the GLP-1 (7-36)NH 2 molecule and variants and analogs thereof including GLN 9 -GLP-1(7-37), D-GLN 9 -GLP-1(7-37), acetyl LYS 9 -GLP-1 (7- 37), LYS 18 -GLP-1(7-37) and, in particular, GLP-1 (7-37)OH, VAL 8 -G LP- 1(7-37), GLY 8 -GLP- 1(7-37), THR 8 -GLP-1(7-37), M ET'-G LP- 1(7-37) and 4-imidazopropionyl-GLP-1.
  • Special preference is also given to the GLP agonist analog exendin-4, described by Greig et al in Diabetologia 1999, 42, 45-50.
  • ⁇ -cell imidazoline receptor antagonists as used herein means compounds as those described in WO 00/78726 and by Wang et al in J. Pharmacol. Exp. Ther. 1996; 278; 82-89, e.g. PMS 812.
  • the antidiabetic phenylacetic acid derivative is preferably a compound of formula IX
  • RS 1 is an unbranched C 4 -C 6 alkyleneimino group which is unsubstituted or mono- or disubstituted by C- ⁇ -C 3 alkyl;
  • R ⁇ 2 is hydrogen, halogen, methyl or methoxy;
  • R ⁇ 3 is hydrogen, Ci-C 7 alkyl, or phenyl which is unsubstituted or substituted by halogen, methyl or methoxy;
  • R ⁇ 4 is hydrogen, allyl, acetyl or propionyl or CVCaalkyl which is unsubstituted or substituted by phenyl;
  • W is methyl, hydroxymethyl, formyl, carboxy; or alkoxycarbonyl which comprises between 2 and up to and including 5 carbon atoms and in which the alkyl moiety of the alkoxy group is unsubstituted or substituted by phenyl or a pharmaceutically acceptable salt thereof.
  • the compound of formula IX is repaglinide or a pharmaceutically acceptable salt thereof.
  • the antidiabetic D-phenylalanine derivative is preferably a compound of formula X
  • Ph has the meaning of phenyl
  • R ⁇ i is selected from hydrogen, C 1 to C 5 alkyl, C 6 to C 12 aryl, C 6 to C 12 arylalkyl,
  • Ry 2 is selected from groups comprising C 6 to C 12 aryl, heteroaryl, cycloalkyl, or cycloalkenyl, any of which groups may have one or more substitutents; and Ry 3 is selected from hydrogen and Ci to C 5 alky!, with the proviso that when Ry 1 and Ry 3 are both hydrogen then Ry 2 is other than substituted or unsubstituted phenyl or naphthyl; or a pharmaceutically acceptable salts thereof or a precursor which can be converted thereto in the human or animal body.
  • Ry 2 is preferably quinolynyl, pyridyl or 2-benzofuranyl.
  • the antidiabetic D-phenylalanine derivative is nateglinide or a pharmaceutically acceptable salt thereof.
  • Nateglinide N-[(fra ⁇ 7s-4-isopropylcyclohexyl)-carbonyI]-D-phenylalanine, EP 196222 and EP 526171
  • repaglinide ((S)-2-ethoxy-4- ⁇ 2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]- 2-oxoethyl ⁇ benzoic acid, EP O 147 850 A2, in particular Example 11 on page 61, and EP 0 207 331 A1) are in each case generically and specifically disclosed in the documents cited in brackets beyond each substance, in each case in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications.
  • nateglinide as used herein comprises crystal modifications (polymorphs) such as those disclosed in EP 0526171 B1 or US 5,488,510, respectively, the subject matter of which is incorporated by reference to this application, especially the subject matter of claims 8 to 10 as well as the corresponding references to the B-type crystal modification.
  • the B- or H- type more preferably the H-type, is used.
  • Repaglinde can be administered in the form as it is marketed e.g. under the trademark NovoNormTM.
  • Nateglinide can be administered in the form as it is marketed e.g. under the trademark STARLIXTM.
  • ⁇ -Glucosidase inhibitors are pharmacological active compounds which inhibit small intestinal ⁇ -glucosidase enzymes which break down non-adsorbable complex carbohydrates into absorbable monosaccharides.
  • examples for such compounds are acarbose, N-(1 ,3- dihydroxy-2-propyl)valiolamine (voglibose) and the 1-deoxynojirimycin derivative miglitol.
  • Acarbose is 4",6"-dideoxy-4"-[(1 S)-(I ,4,6/5)-4,5,6-trihydroxy-3-hydroxymethyl-2-cyclo- hexenylamino ⁇ maltotriose.
  • acarbose can as well be described as 0-4,6- dideoxy-4- ⁇ [1S,4R,5S,6S]-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]-amino ⁇ - ⁇ -D- glucopyranosyl-(1 - ⁇ 4)-0- ⁇ -D-glucopyranosyl-(1 -»4)-D-glucopyranose.
  • Acarbose (US 4,062,950 and EP 0 226 121), is generically and specifically disclosed in the documents cited in brackets, in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications.
  • acarbose in the form as it is marketed e.g. under the trademark GLUCOBA YTM.
  • Miglitol can be administered in the form as it is marketed e.g. under the trademark DIASTABOL 50TM
  • the ⁇ -glucosidase inhibitor is preferably selected from the group consisting of acarbose, voglibose and miglitol.
  • inhibitors of gastric emptying include, but are not limited to those disclosed in J. CHn. Endocrinol. Metab. 2000, 85(3), 1043-1048, especially CCK-8, and in Diabetes Care 1998; 21; 897-893, especially Amylin and analogs thereof, e.g. Pramlintide. Amylin is also described e.g. by O.G. Kolterman et al. in Diabetologia 39, 1996, 492-499.
  • ⁇ 2 -adrenergic antagonists include, but are not limited to midaglizole described in Diabetes 36, 1987, 216-220.
  • prevention means prophylactic administration of the combination to healthy patients to prevent the outbreak of the conditions mentioned herein. Moreover, the term “prevention” means prophylactic administration of such combination to patients being in a pre-stage of the conditions, especially diabetes, to be treated.
  • delay of progression used herein means administration of the combination, such as a combined preparation or pharmaceutical composition, to patients being in a pre-stage of the condition, especially diabetes, to be treated in which patients a pre-form of the corresponding condition is diagnosed.
  • inhibitors of PTPases examples include: (a) examples of the preparation and formulation of inhibitors of PTPases, inhibitors of GSK-3, non-small molecule mimetic compounds, inhibitors of GFAT, inhibitors of G ⁇ Pase, glucagon receptor antagonists, inhibitors of PEPCK, inhibitors of F-1, 6-BPase, inhibitors of GP, RXR agonists, agonists of Beta-3 AR, PDHK inhibitors, inhibitors of gastric emptying and agonists of UCPs are disclosed in the patents and applications cited beyond each substance listed herein.
  • the compounds to be combined can be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center.
  • the compounds having an acid group (for example COOH) can also form salts with bases.
  • the compounds to be combined can be present as a sodium salt, as a maleate or as a dihydrochloride.
  • the active ingredient or a pharmaceutically acceptable salt thereof may also be used in form of a hydrate or include other solvents used for crystallization.
  • An antidiabetic compound preferably selected from the group consisting of insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phopshate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (G ⁇ Pase), inhibitors of fructose-1 ,6- bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase (GP) 1 glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, ⁇ -glucosidase inhibitors, inhibitors of gastric emptying, insulin, and ⁇ 2 -
  • a combined preparation which comprises the calcium or magnesium salt of the AT 1 receptor antagonist (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)- biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION and optionally at least one, i.e., one or more, e.g.
  • the two, pharmaceutically acceptable carrier for simultaneous, separate or sequential use is especially a "kit of parts" in the sense that the components, the calcium or magnesium salt of the AT 1 receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1 H- tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION, can be dosed independently or by use of different fixed combinations with distinguished amounts of the components, i.e. at different time points or simultaneously.
  • the parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the time intervals are chosen such that the effect on the treated disease or condition in the combined use of the parts is larger than the effect which would be obtained by use of only any one of the components.
  • there is at least one beneficial effect e.g.
  • lower doses of the individual drugs to be combined according to the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.
  • DPP-IV inhibitor especially (S)-1- ⁇ 2-[5-cyanopyridin-2- yl)amino]ethyl-aminoacetyl ⁇ -2-cyano-pyrrolidine (DPP728) or (S)-1-[(3-hydroxy-1- adamantyl)amino]acetyl-2-cyano-pyrrolidine (LAF237), as further COMBINATION PARTNER OF THE INVENTION results in a more effective prevention or preferably treatment of conditions mediated by DPP-IV, in particular diabetes, especially type 2 diabetes mellitus, conditions of impaired fasting plasma glucose, and conditions of IGT.
  • the person skilled in the pertinent art is fully enabled to select a relevant animal test model to prove the hereinbefore and hereinafter indicated therapeutic indications and beneficial effects.
  • the pharmacological activity may, for example, be demonstrated following essentially an in-vivo test procedure in mice or in a clinical study as described hereinafter.
  • ICR-CDI mice male, five weeks old, body weight: about 20 g are abstained from food for 18 hours, and then used as test subjects.
  • the combination according to the present invention and the active ingredients alone are suspended in 0.5% CMC-0.14M sodium chloride buffer solution (pH 7.4).
  • the solution thus obtained is administered orally in fixed volume amounts to the test subjects. After predetermined time, the percentage decrease of the blood glucose against the control group is determined.
  • the study is, in particular, suitable to compare the effects of monotherapy with a COMBINATION PARTNER OF THE INVENTION with those of a combination of DPP-IV inhibitor plus one of these compounds on glycemic control.
  • HbA 10 Subjects with a diagnosis of type 2 diabetes mellitus who have not achieved near normoglycemia (HbA 10 ⁇ 6.8%) on diet only are chosen for this trial.
  • the effects on glycemic control achieved with DPP-IV monotherapy, monotherapy with one COMBINATION PARTNER OF THE INVENTION, and the combination therapy of DPP-IV plus one COMBINATION PARTNER OF THE INVENTION are determined in this study after 24 weeks with the control achieved on placebo, all subjects continuing with the same diet as in the period before treatment. Measures of glycemic control are validated surrogate endpoints for the treatment of diabetes.
  • HbA 10 is the single most reliable measurement for assessing glycemic control (D.
  • HbA 10 provides an estimate of mean blood glucose for the previous three months.
  • the subjects are administered for four weeks the placebos matching with the DPP-IV inhibitor, e.g. DPP728 and LAF237, before breakfast, lunch and dinner, and the placebos matching with one or more of the COMBINATION PARTNERS OF THE INVENTION (period I).
  • the placebo matching with acarbose is preferably administered together with the first bite of the meals taken for breakfast, lunch and dinner in period I.
  • the placebos matching with repaglinide are preferably administered later on with breakfast, lunch and dinner in period I. If the antidiabetic thiazolidinedione troglitazone is chosen for the study, the placebos matching with troglitazone are preferably administered in period I with breakfast only. If the antidiabetic D-phenylalanine derivative nateglinide is chosen for the study, matching placebos are preferably administered before breakfast, lunch and dinner period I. If metformin is chosen for the study, matching placebos are preferably administered before breakfast and dinner.
  • DPP728 is chosen as the DPP- IV inhibitor and one of the drugs comprising the antidiabetic thiazolidinedione troglitazone, the antidiabetic phenylacetic acid derivative repaglinide, the ⁇ -glucosidase inhibitor acarbose, the antidiabetic D-phenylalanine derivative nateglinide or the biguanide metformin is chosen as the combination partner.
  • the term “synergistic” shall mean that the drugs, when taken together, produce a total joint effect that is greater than the sum of the effects of each drug when taken alone.
  • both active ingredients are administered as a fixed combination, i.e. as a single tablet, in all cases described herein. Taking a single tablet is even easier to handle than taking two tablets at the same time. Furthermore, the packaging can be accomplished with less effort.
  • the combination according to the present invention can be used for the prevention and preferably the treatment of conditions mediated by DPP-IV, in particular type 2 diabetes mellitus.
  • the combination of the present invention can also be used for the prevention and preferably the treatment of other condition mediated by DPP-IV.
  • Pharmaceutical preparations of this kind may furthermore be used for example for the prophylaxis and treatment of diseases or conditions which may be inhibited by blocking the AT 1 receptor for example a disease or condition selected from the group consisting of
  • Atherosclerosis atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension;
  • Primary usages are for the treatment of high blood pressure and congestive heart failure, as well as post-myocardial infarction.
  • the jointly therapeutically effective amounts of a DPP-IV inhibitor in free or pharmaceutically acceptable salt form or an at least one further pharmaceutically active compound are administered simultaneously or sequentially in any order, separately or in a fixed combination.
  • the condition mediated by DPP-IV is preferably selected from the group consisting of diabetes, impaired fasting plasma glucose, impaired glucose tolerance, metabolic acidosis, ketosis, arthritis, obesity and osteoporosis.
  • the condition mediated by DPP-IV is type 2 diabetes mellitus.
  • It is one objective of this invention to provide a pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against conditions mediated by DPP-IV, in particular diabetes, more especially type 2 diabetes mellitus, conditions of impaired fasting plasma glucose, and conditions of IGT, of (i) the calcium or magnesium salt of the ATi receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-i -yl)-N-pentanoyl-N-[2'-(1 H-tetrazol-5- yl)-biphenyl-4-yl-methyl]-amine (valsartan) and (ii) at least one further COMBINATION PARTNER OF THE INVENTION and at least one pharmaceutically acceptable carrier.
  • the ATi receptor antagonist S-N-(I -carboxy-2-methyl-prop-i -yl)-N-pentanoyl-N-[2'-(1 H-tetrazol-5- yl)-biphenyl-4-yl
  • compositions according to the invention can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of the pharmacologically active compound, alone or in combination with one or more pharmaceutically acceptable carries, especially suitable for enteral or parenteral application.
  • novel pharmaceutical preparations contain, for example, from about 10 % to about 100 %, e.g., 80% or 90 %, preferably from about 20 % to about 60 %, of the active ingredient.
  • Pharmaceutical preparations according to the invention for enteral or parenteral administration are, for example, those in unit dose forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. These are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar- coating, dissolving or lyophilizing processes.
  • compositions for oral use can be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, after addition of suitable excipients to give tablets or sugar-coated tablet cores.
  • components (i) and (ii) can be administered together, one after the other or separately in one combined unit dose form or in two separate unit dose forms.
  • the unit dose form is a fixed combination.
  • the components (i) and (ii) are administered in the form of a single galenic formulation, e.g. a single tablet or a single infusion.
  • a further aspect of the present invention is the use of a pharmaceutical composition
  • a pharmaceutical composition comprising the calcium or magnesium salt of the AT ⁇ receptor antagonist (S)-N-(I -carboxy- 2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION, in each case in free form or in form of a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical preparation for the prevention or treatment of conditions mediated by DPP-IV, in particular diabetes, more especially type 2 diabetes mellitus, conditions of impaired fasting plasma glucose, and conditions of IGT.
  • a therapeutically effective amount of each of the components of the combination of the present invention may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination.
  • the method of treatment of the invention may comprise (i) administration of the calcium or magnesium salt of the AT 1 receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1-yl)-N- pentanoyl-N-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) and (ii) adminstration of at least one further COMBINATION PARTNER OF THE INVENTION simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g. in daily dosages corresponding to the ratios described herein.
  • the corresponding active ingredient or a pharmaceutically acceptable salt thereof may also be used in form of a hydrate or include other solvents used for crystallization.
  • the invention relates in particular to a commercial package comprising jointly therapeutically effective amounts of the calcium or magnesium salt of the AT-j receptor antagonist (S)-N-(I- carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan), and at least one further COMBINATION PARTNER OF THE INVENTION together with instructions for use thereof in the treatment of conditions mediated by DPP-IV, in particular diabetes, more especially type 2 diabetes mellitus, conditions of impaired fasting plasma glucose, and conditions of IGT.
  • a further aspect of the present invention is a method of treating a condition mediated by DPP-IV, in particular type 2 diabetes mellitus, comprising administering to a warm-blooded animal in need thereof jointly therapeutically effective amounts of the calcium or magnesium salt of the AT-i receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-i -yl)-N-pentanoyl-N-[2'- (1H-tetrazoi-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan), and at least one further COMBINATION PARTNER OF THE INVENTION.
  • the active ingredients are administered simultaneously or sequentially in any order, separately or in a fixed combination.
  • the jointly therapeutically effective amounts of a calcium or magnesium salt of the ATi receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)- biphenyl-4-yl-methyrj-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION are provided as a combined preparation.
  • the present invention provides a method of treating conditions of impaired glucose tolerance and impaired fasting plasma glucose comprising administering to a warmblooded animal in need thereof jointly therapeutically effective amounts of a calcium or magnesium salt of the AT ⁇ receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1 -yl)-N- pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION.
  • AT ⁇ receptor antagonist S-N-(I -carboxy-2-methyl-prop-1 -yl)-N- pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION.
  • the invention relates to a method of improving the bodily appearance of a mammal which comprises orally administering to said mammal, including man, especially man suffering from a metabolic disorder, in particular type 2 diabetes, a combined preparation or pharmaceutical composition described herein in a dosage effective to influence, e.g., to increase or decrease, the glucose metabolism, or to influence the body weight by other mechanisms, and repeating said dosage until a cosmetically beneficial loss of body weight has occurred.
  • a method of improving the bodily appearance of a mammal which comprises orally administering to said mammal, including man, especially man suffering from a metabolic disorder, in particular type 2 diabetes, a combined preparation or pharmaceutical composition described herein in a dosage effective to influence, e.g., to increase or decrease, the glucose metabolism, or to influence the body weight by other mechanisms, and repeating said dosage until a cosmetically beneficial loss of body weight has occurred.
  • Such combinations described herein can also be used to prevent, for cosmetic reasons, a further increase in body weight in humans experiencing such an increase.
  • the invention relates to the combinations described herein useful for improving the bodily appearance of a mammal, especially a human being, and the use of such combinations in order to improve the bodily appearance of a mammal, especially a human being.
  • Overweight is one of the risk factors for developing a metabolic disorder, in particular type 2 diabetes, and at the same time often the result of such a metabolic disorder, especially type 2 diabetes.
  • a number of antidiabetics are known to cause weight gain.
  • humans suffering from metabolic disorders, especially type 2 diabetes are often faced with overweight. Therefore, the cosmetically beneficial loss of body weight can be effected especially in humans suffering from a metabolic disorder, such as type 2 diabetes.
  • the combinations described herein can also be used to replace or complement an antidiabetic drug taken by a human suffering from type 2 diabetes in order to prevent, for cosmetic reasons, a further increase of the body weight.
  • the dosage range of the combination of a calcium or magnesium salt of the AT-i receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2 ⁇ iH-tetrazol-5-yl)- biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION to be employed depends upon factors known to the person skilled in the art including species of the warm-blooded animal, body weight and age, the nature and severity of the condition to be treated, the mode of administration and the particular substance to be employed.
  • the calcium or magnesium salt of the AT 1 receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1 H- tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION are preferably divided and administered from one to four times per day.
  • the weight ratio of the daily doses of the calcium or magnesium salt of the AT ⁇ receptor antagonist (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N- ⁇ 2'-(1H-tetrazol-5-yl)- biphenyl-4-yl-methyl]-amine (valsartan) to at least one further COMBINATION PARTNER OF THE INVENTION may vary within wide limits depending in particular on the needs of the warm-blooded animal treated.
  • a combination such as a combined preparation or pharmaceutical composition, respectively, which comprises
  • a DPP IV inhibitor especially 1-[[(3-Hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)- pyrrolidine or a pharmaceutically acceptable salt thereof.
  • valsartan of the combination of the present invention is the calcium salt, preferably a hydrate thereof, most preferably the tetrahydrate thereof.
  • the preferred DPP IV inhibitor is 1-[[(3-Hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)- pyrrolidine or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a pharmaceutical preparations of this kind may be used for example for the prophylaxis and treatment of diseases or conditions which may be inhibited by blocking the AT 1 receptor for example a disease or condition selected from the group consisting of
  • Atherosclerosis atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension;
  • the present invention relates to a pharmaceutical preparations of this kind may be used for example for the prophylaxis and treatment of diseases or conditions selected from impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity and osteoporosis, and preferably diabetes, especially type 2 diabetes mellitus.
  • ITT impaired glucose tolerance
  • diabetes especially type 2 diabetes mellitus.
  • the present invention relates to a method for the prevention, delay of progression or treatment of diseases and disorders selected from the group consisting of hyperglycemia, hyperinsulinaemia, hyperlipidaemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, obesity, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, coronary heart disease, hypertension, especially ISH, angina pectoris, myocardial infarction, stroke, vascular restenosis, endothelial dysfunction, impaired vascular compliance, skin and connective tissue disorders, foot ulcerations and ulcerative colitis.
  • diseases and disorders selected from the group consisting of hyperglycemia, hyperinsulinaemia, hyperlipidaemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, obesity, diabetic retinopathy, macular degeneration, cataracts, diabetic
  • said combination may be used for the treatment of hypertension, especially ISH, congestive heart failure, endothelial dysfunction, impaired vascular compliance, hyperlipidaemia, hyperglycemia, hyperinsulinaemia, and type Il diabetes mellitus, comprising administering to a warm-blooded animal, including man, in need thereof jointly therapeutically effective amounts of
  • At least one antidiabetic compound results in a significant response in a greater percentage of treated patients, that is, a greater responder rate results, regardless of the underlying etiology of the condition. This is in accordance with the desires and requirements of the patients to be treated.
  • At least one antidiabetic compound results in a more effective therapy associated with the inhibition of the AT1 receptor and/or associated with the use of an antidiabetic agent through improved efficacy as well as a greater responder rate.

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Abstract

The invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, which comprises (i) the calcium or magnesium salt of the AT1 receptor antagonist (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[21-(1 H-tetrazol-5-yl)-biphenyl-4-yl-rnethyl]-amine (valsartan) and (ii) at least one antidiabetic compound, preferably selected from the group consisting of a dipeptidyl peptidase IV (DPP IV) inhibitor, insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (G6Pase), inhibitors of fructose-1,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, α-glucosidase inhibitors, inhibitors of gastric emptying, insulin, and α2-adrenergic antagonists.

Description

Combination of Ca/Mg salt of valsartan with an antidiabetic agent
The invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, which comprises
(i) the calcium or magnesium salt of_the ATi receptor antagonist (S)-N-(I -carboxy-2-methyl- prop-1 -yl)-N-pentanoyl-Nl-[2'-(1 H-tetrazoI-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) of formula
Figure imgf000002_0001
(ii) at least one antidiabetic compound, preferably selected from the group consisting of a dipeptidyl peptidase IV (DPP IV) inhibitor, insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose- 6-phosphatase (GΘPase), inhibitors of fructose-1 ,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, α-glucosidase inhibitors, inhibitors of gastric emptying, insulin, and α2-adrenergic antagonists.
The calcium or magnesium salt of valsartan can present in crystalline, also partly crystalline and amorphous forms and can be used in the combination of the present invention as amorphous forms, solvates such as salt hydrates, and also the corresponding polymorphous forms thereof. Solvates and also hydrates of the salts according to the invention may be present, for example, as hemi-, mono-, di-, tri-, tetra-, penta-, hexa-solvates or hydrates, respectively. Solvents used for crystallisation, such as alcohols, especially methanol, ethanol, aldehydes, ketones, especially acetone, esters, e.g. ethyl acetate, may be embedded in the crystal grating. The extent to which a selected solvent or water leads to a solvate or hydrate in crystallisation and in the subsequent process steps or leads directly to the free acid is generally unpredictable and depends on the combinations of process conditions and the various interactions between valsartan and the selected solvent, especially water. The respective stability of the resulting crystalline or amorphous solids in the form of salts, solvates and hydrates, as well as the corresponding salt solvates or salt hydrates, must be determined by experimentation. It is thus not possible to focus solely on the chemical composition and the stoichiometric ratio of the molecules in the resulting solid, since under these circumstances both differing crystalline solids and differing amorphous substances may be produced. Especially preferred are solvates formed with a pharmaceutically acceptable solvent.
The description salt hydrates for corresponding hydrates may be preferred, as water molecules in the crystal structure are bound by strong intermolecular forces and thereby represent an essential element of structure formation of these crystals which, in part, are extraordinarily stable. However, water molecules are also existing in certain crystal lattices which are bound by rather weak intermolecular forces. Such molecules are more or less integrated in the crystal structure forming, but to a lower energetic effect. The water content in amorphous solids can, in general, be clearly determined, as in crystalline hydrates, but is heavily dependent on the drying and ambient conditions. In contrast, in the case of stable hydrates, there are clear stoichiometric ratios between the pharmaceutical active substance and the water. In many cases these ratios do not fulfil completely the stoichiometric value, normally it is approached by lower values compared to theory because of certain crystal defects. The ratio of organic molecules to water molecules for the weaker bound water may vary to a considerable extend, for example, extending over di-, tri- or tetra-hydrates. On the other hand, in amorphous solids, the molecular structure classification of water is not stoichiometric; the classification may however also be stoichiometric only by chance.
For the crystalline solids having identical chemical composition, the different resulting crystal gratings are summarised by the term polymorphism. Any reference hereinbefore and hereinafter, to the salts according to the invention is to be understood as referring also to the corresponding solvates, such as hydrates, and polymorphous modifications, and also amorphous forms, as appropriate and expedient.
The X-ray diffraction diagram of powders of these two salt hydrates has a number of discrete X-ray reflections, and practically no signs of non-crystalline or amorphous portions. The degree of crystallisation of these defined salt hydrates is therefore surprisingly high. Equally, relatively large crystals may be cultured from certain salt hydrates, and in the crystallographic sense these are single crystals. Such single crystals allow the structure of the solid to be determined. It is effected by computer-aided evaluation of the reflection intensities measured by an X-ray diffractometer.
This process for determining the structure of a crystal enables, under normal conditions such as high physical, chemical and enantiomeric purity of the gauged crystals, a clear determination of the structure to be carried out on a molecular or atomic level, namely symmetry and size of the elementary cells, atom positions and temperature factors, and from the ascertained cell volume, the X-ray-photographic density is shown on the basis of a molecular weight. At the same time, the X-ray-photographic structure determination supplies details of its quality.
The outstanding properties of these two salt hydrates are based on the crystals, which form these salts by incorporating four or six water molecules per valsartan molecule. Thus, practically perfect three-dimensional crystal gratings are produced. These two salts have water solubility that is several times better than the free acid of valsartan, and this is especially surprisingly at high melting points and melting enthalpies, which are eight or five times greater than the free acid. The extraordinary crystal gratings of these two salt hydrates are the basis for the chemical and physical stability of these two compounds.
The particularly notable salt hydrate is the tetrahydrate of the calcium salt of valsartan. In a closed specimen container, for a heating rate of Tr = 10 K- min ~1 it has a melting point of 205 ± 1.5 0C and a melting enthalpy of 98 ± 4 kJ • MoI"1. The tetrahydrate of the calcium salt of valsartan is not stable at elevated temperatures both in respect of the hydrate water and in respect of the structure of the molecule. The indicated melting point is a hydrate melting - A -
point which can only be measured in a closed specimen container. Gold containers with a wall thickness of 0.2 mm were used; after weighing in samples of between 2 and 4 mg salt hydrate, they were sealed by cold welding. These gold containers have an internal free volume of ca. 22 microlitres. The amounts of the sample and the volume of the pressurised containers must be suitably adapted, so that strong dehydration of the salt hydrates cannot take place during measurement of the melting point. The partial pressure of the water at 205° Celsius is ca. 18 bar, so that with an open container in DSC (Differential Scanning Calorimeter) during measurement of the melting point, conversion to the anhydrate takes place. If the data from several heating rates (Tr= 10, 20, 40 K ■ min "1) are extrapolated to a continuously rapid heating rate, a melting point of 213 ± 2 0C and a melting enthalpy of 124 ± 5 kJ • MoI"1 result. Both the high hydrate melting point and the amount of the melting enthalpy are an expression of the exceptional stability of the crystal grating of the tetrahydrate of the calcium salt of valsartan. These two thermodynamic characteristics illustrate the advantageous physical properties, compared to the free acid, with the two corresponding data, namely a melting point in the closed system of 900C and a melting enthalpy of 12 kJ • MoI"1. These thermodynamic data, together with the X-ray data, prove the high stability of this crystal grating. They are the foundation for the special physical and chemical resistance of the tetrahydrate of the calcium salt of valsartan.
A measurement of the infrared absorption spectrum of the tetrahydrate of the calcium salt of valsartan in a potassium bromide compressed tablet shows the following significant bands expressed in reciprocal wave numbers (cm 1 ): 3750 - 3000 (st); 3400 - 2500 (st); 1800 - 1520 (st); 1500 - 1380 (st); 1380 - 1310 (m); 1290 - 1220 (w); 1220 - 1190 (w); 1190 - 1160 (W); 1160 - 1120 (w); 1120 - 1050 (w); 1030 - 990 (m); 989 - 960 (w), 950 - 920 (w); 780 - 715 (m); 710 - 470 (m). The intensities of the absorption bands are indicated as follows: (w) = weak; (m) = medium; and (st) = strong intensity. Measurement of the infrared spectrum likewise took place by means of ATR-IR (Attenuated Total Reflection-Infrared Spectroscopy) using the instrument Spektrum BX from Perkin-Elmer Corp., Beaconsfield, Bucks, England.
The tetrahydrate of the calcium salt of valsartan has the following absorption bands expressed in reciprocal wave numbers (cm"1):
3594 (W); 3306 (w); 3054 (w); 2953 (w); 2870 (w); 1621 (st); 1578 (m); 1458 (m); 1441 (m); 1417 (m); 1364 (m); 1336 (w); 1319 (w); 1274 (w); 1241 (w); 1211 (w); 1180 (w); 1149 (w); 1137 (W); 1106 (w); 1099 (w); 1012 (m); 1002 (w); 974 (w); 966 (w); 955 (w); 941 (w);
863 (W); 855 (w); 844 (w); 824 (w); 791 (w); 784 (w); 758 (m); 738 (m); 696 (m); 666 (m).
The intensities of the absorption bands are indicated as follows: (w) = weak; (m) = medium and (st) = strong intensity.
The most intensive absorption bands of the ATR-IR spectroscopy are shown by the following values expressed in reciprocal wave numbers (cm'1): 3306 (w); 1621 (st); 1578 (m);
1458 (m); 1441 (m); 1417 (m); 1364 (m); 1319 (w); 1274 (w); 1211 (w); 1180 (w); 1137 (w);
1012 (m); 1002 (w); 758 (m); 738 (m); 696 (m); 666 (m).
The error margin for all absorption bands of ATR-IR is ± 2 cm"1.
The water content is in theory 13.2% for the tetrahydrate of the calcium salt of valsartan. Using the thermo-scale TGS-2 ( Perkin-Elmer Corp. , Norwalk, CT USA ) the water content was determined as 12.9 %. A total formula was calculated from this (C24H27N5O3)2" Ca2+* (3.9 ± 0.1) H2O.
Using thermogravimetry, in a water-free N2 atmosphere, the weight loss, i.e. the water loss for the tetrahydrate as a function of temperature, was measured at a heating rate of 10
K ■ min -1 . The results are illustrated in table 1.
Table 1
Figure imgf000006_0001
Further characterisation of the tetrahydrate of the calcium salt of valsartan is effected using the interlattice plane intervals determined by a X-ray powder pattern. Measurement of the X- ray powder patterns was made with a Guinier camera (FR 552 from Enraf Nonius, Delft, NL) on an X-ray film in transmission geometry, using Cu-Ka1 radiation at room temperature. Evaluation of the films for calculation of the interlattice plane intervals is made both visually and by a Line-Scanner (Johansson Taby, S), and the reflection intensities are determined simultaneously.
The preferred characterisation of the tetrahydrate of the calcium salt of valsartan is obtained from the interlattice plane intervals d of the ascertained X-ray diffraction diagrams, whereby, in the following, average values are indicated with the appropriate error limits, d in [A] : 16.1±0.3, 9.9±0.2, 9.4±0.2, 8.03±0.1, 7.71±0.1, 7.03±0.1 , 6.50±0.1 , 6.33±0.1, 6.20±0.05, 5.87±0.05, 5.74±0.05, 5.67±0.05, 5.20±0.05, 5.05±0.05, 4.95±0.05, 4.73±0.05, 4.55±0.05, 4.33±0.05, 4.15+0.05, 4.12±0.05, 3.95±0.05, 3.91±0.05, 3.87±0.05, 3.35±0.05.
The most intensive reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A] : 16.1 ±0.3, 9.9±0.2, 9.4±0.2, 7.03±0.1, 6.50±0.1, 5.87±0.05, 5.74±0.05, 4.95±0.05, 4.73±0.05, 4.33±0.05, 4.15±0.05, 4.12±0.05, 3.95±0.05.
A preferred method of checking the above-indicated average values of the interlattice plane intervals and intensities measured by experimentation from X-ray diffraction diagrams with a Guinier camera, for a given substance, consists in calculating these intervals and their intensities from the comprehensive single crystal structure determination. This structure determination yields cell constants and atom positions, which enable the X-ray diffraction diagram corresponding to the solid to be calculated by means of computer-aided calculation methods (programme CaRine Crystallography, Universite de Compiegne, France). A comparison of these data, namely the interlattice plane intervals and intensities of the most important lines of the tetrahydrate of the calcium salt of valsartan, obtained from measurements with the Guinier camera and from calculating the single crystal data, is illustrated in Table 2. Table 2
Figure imgf000007_0001
Figure imgf000008_0001
The invention relates to a corresponding combination comprising the crystalline tetrahydrate of the calcium salt of (S)-N-(I -carboxy^-methylprop-i-yO-N-pentanoyl-N-P'-OH-tetrazol-δ- yl)biphenyl-4-ylmethyl]-amine, a crystalline solid which is clearly characterised by the data and parameters obtained from single crystal X-ray analysis and X-ray powder patterns. An in-depth discussion of the theory of the methods of single crystal X-ray diffraction and the definition of the evaluated crystal data and the parameters may be found in Stout & Jensen, X-Ray Structure Determination; A Practical Guide, Mac Millian Co., New York, N. Y. (1968) chapter 3.
The data and parameters of the single crystal X-ray structure determination for the tetrahydrate of the calcium salt of valsartan are contained in Table 3.
Table 3 Crystal data and parameters of the tetrahydrate of the calcium salt of valsartan
Crystal data sum formula ( C24 H27 N5O3) 2Xa 2+ - 4 H2O molecular mass 545.65 crystal colour colourless crystal shape flat prisms crystal system monoclinic space group P2i size of the single crystal 0.42 « 0.39 * 0.17 mm dimensions and angle of elementary cell a = 10.127(2) A b = 8.596(2) A c = 32.214(6) A α = 90 ° β = 95.34(3) °
Y = 90 ° volume of elementary cell Vc = 2792.1(10) A 3 number of molecules in the elementary cell 4
F (000) 1160 measurement range of cell parameters (Θ) 7.47-16.50 ° calculated density 1.298 (g - cm"3) linear absorption coefficient 0.274 mm '1
X-ray measurement data diffractometer Enraf Nonius CAD4
X-radiation ( graphite monochromator ) MoKα wavelength 0.71073 temperature 295 K scan range (θ) 1.27 - 31.99 ° scan mode ω / 2 0 reflections collected/unique 19384 / 18562 number of significant reflections ( I > 2σ(l) ) 10268 variation in intensity 1.7 % absorption correction numeric
Structure refinement method full matrix, least squares, F number of parameters 893 agreement index (R) 6.2 % weighted agreement index (Rw) 14.4 % S factor (Goodness of fit) 1.085 number of reflections used 18562 treatment of all hydrogen atoms in the molecule, all found by difference-Fourier including in the water molecules calculation, almost all isotropically refined, a few theoretically fixed
(riding) extinction correction none maximum/minimum residual electron density in 0.662 / - 0.495 ( e -A"3 ) conclusive difference-Fourier calculation absolute structure parameters 0.00 (4)
Computer programmes used SHELXS 86 ( Sheldrick, Gottingen, 1990 ) SHELXL 96 ( Sheldrick, Gottingen, 1996 ) SCHAKAL 86 ( Keller, Freiburg 1986 ) PLATON ( Spek, Acta Cryst, 1990 )
The elementary cell is defined by six parameters, namely by the grating constants a, b and c, and by the axial angle, namely by a, β, und y. In this way, the volume of the elementary cell Vc is determined. A differentiated description of these crystal parameters is illustrated in chapter 3 of Stout & Jensen (see above). The details for the tetrahydrate of the calcium salt of valsartan from the single crystal measurements, especially the atom coordinates, the isotropic thermal parameters, the coordinates of the hydrogen atoms as well as the corresponding isotropic thermal parameters, show that a monoclinic elementary cell exists, its cell content of four formula units Ca2+ valsartan2' • 4 H2O occurring as a result of two crystallographic independent units on two-fold positions.
Given the acentric space group P2i determined from the single crystal X-ray structure determination, a racemate is ruled out. Thus the enantiomeric purity of the S-configuration for the crystalline tetrahydrate of the calcium salt of (S)-N-(I -carboxy-2-methylprop-1-yl)-N- pentanoyl-N-[2'-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine is verified.
An essential feature for the quality of a pure active substance both for the physical-chemical procedures such as drying, sieving, grinding, and in the galenic processes which are carried out with pharmaceutical excipients, namely in mixing processes, in granulation, in spray- drying, in tabletting, is the water absorption or water loss of this active substance depending on temperature and the relative humidity of the environment in question. With certain formulations, free and bound water is without doubt introduced with excipients and/or water is added to the process mass for reasons associated with the respective formulation process. In this way, the pharmaceutical active substance is exposed to free water over rather long periods of time, depending on the temperature of the different activity (partial vapour pressure).
A clear characterisation of this property is achieved by means of isothermal measurements over predetermined time intervals and predetermined relative humidity using dynamic vapour sorption (DVS-1 from the company Surface Measurement Systems LTD, Marlow, Buckinghamshire, UK). Table 4 illustrates the mass change, i.e. the water absorption or loss as a function of relative humidity at 25°C for a sample of 9.5 mg of the tetrahydrate of the calcium salt of valsartan and for a period of 4 hours. The following cycles of changes in relative humidity are shown: 40-90; 90-0; 0-90; 90-0 % relative humidity:
Table 4
Figure imgf000011_0001
The measurement error of this sorption method based on thermogravimetry is about 0.1%. Therefore, the tetrahydrate of the calcium salt of valsartan under the conditions employed, which are realistic from a pharmaceutical-galenic point of view, shows no measurable water absorption or loss. This is surprising to a large extent, since the tetrahydrate, which has incorporated about 13% of bound water in the crystal structure, is totally indifferent to water even at extreme values of relative humidity. This property is crucial in the final stages of chemical manufacture and also in practice in all galenic process stages of the different dosage forms. This exceptional stability similarly benefits the patients through the constant availability of the active ingredient.
The intrinsic dissolving rates of the calcium salt of valsartan at pH 1, pH 4.5 and pH 6.8 show improved values over those of valsartan.
A particularly preferred salt hydrate is the tetrahydrate of the calcium salt of valsartan in the polymorphic form A1jCa. In a closed specimen container, for a heating rate of Tr = 10 K-min ~1 it has a melting point of 190 ± 1.5 0C and a melting enthalpy of 79 ± 4 kJ Mol"1. The tetrahydrate of the calcium salt of valsartan A1|Ca is not stable at the melting point both in respect of the hydrate water and therefore in respect of the chemical and physical structure of the molecule. The indicated melting point is a hydrate melting point which can only be measured in a closed specimen container. Gold containers with a wall thickness of 0.2 mm were used; after weighing in samples of between 2 and 4 mg salt hydrate, they were sealed by cold welding. These gold containers have an internal free volume of ca. 22 microlitres. The amounts of the sample and the volume of the pressurised containers must be suitably adapted, so that strong dehydration of the salt hydrates cannot take place during measurement of the melting point. The partial pressure of the water at 191° Celsius is ca. 13 bar, so that with an open container in DSC (Differential Scanning Calorimeter) during measurement of the melting point, conversion to the anhydrate takes place. Both the high hydrate melting point and the amount of the melting enthalpy are an expression of the exceptional stability of the crystal lattice of the form A1iGa of the tetrahydrate of the calcium salt of valsartan. These two thermodynamic characteristics illustrate the advantageous physical properties, compared to the free acid, with the two corresponding data, namely a melting point in the closed system of 9O0C and a melting enthalpy of 12 kJ-Mol"1. These thermodynamic data, together with the X-ray data, prove the high stability of this crystal lattice. They are the base for the special physical and chemical resistance of the tetrahydrate of the calcium salt of valsartan of the polymorphic form A1iCa.
Measurement of the infrared spectrum likewise took place by means of ATR-IR (Attenuated
Total Reflection-Infrared Spectroscopy) using the instrument Spektrum BX from
Perkin-Elmer Corp., Beaconsfield, Bucks, England.
The tetrahydrate of the calcium salt of valsartan A1tca has the following absorption bands expressed in reciprocal wave numbers (cm"1):
3594 (W); 3307 (w); 3056 (w); 2960 (m); 2871 (w); 1621 (st); 1578 (st); 1459 (m); 1442 (m);
1417 (m); 1407 (m); 1364 (m); 1357 (m); 1319 (m); 1274 (m); 1242 (w); 1211 (m); 1180 (m);
1149 (w); 1137 (m); 1105 (m); 1099 (m); 1012 (m); 1003 (m); 974 (m); 965 (w); 955 (w);
941 (w); 863 (w); 856 (w); 844 (m); 823 (m); 791 (m); 784 (m); 758 (m); 738 (st); 698 (m).
The intensities of the absorption bands are indicated as follows: (w) = weak; (m) = medium and (st) = strong intensity.
The characteristic absorption bands of the ATR-IR spectroscopy for the polymorphic form
A1iCa of the tetrahydrate of the calcium salt of valsartan are shown by the following values expressed in reciprocal wave numbers (cm"1): 3307 (w); 2960 (m); 1621 (st); 1578 (st);
1459 (m); 1442 (m); 1417 (m); 1407 (m); 1364 (m); 1357 (m); 1319 (m); 1274 (m); 1211 (m);
1180 (m); 1137 (m); 1012 (m); 1003 (m); 974 (m); 758 (m); 738 (st); 698 (m).
The error margin for all absorption bands of ATR-IR is ± 3 cm"1.
The water content is in theory 13.2% for the tetrahydrate of the calcium salt of valsartan. Using the thermobalance TGS-2 (Perkin-Elmer Corp. , Norwalk, CT USA ) the water content was determined for the polymorphic form A1|Ca between 25°C and 225°C as 12.3 %. A total formula was calculated from this (C24H27N5O3)2' Ca2+* (3.7 ± 0.2) H2O.
Using thermogravimetry, in a water-free N2 atmosphere, the weight loss, i.e. the water loss for the tetrahydrate of the calcium salt of valsartan Ai,ca as a function of temperature, was measured at a heating rate of 10 K-min "1 . The results are illustrated in table 5.
Table 5
Figure imgf000013_0001
Figure imgf000014_0001
The preferred characterisation of the tetrahydrate of the calcium salt of valsartan A11Ca is obtained from the interlattice plane intervals d of the ascertained X-ray diffraction diagrams, whereby, in the following, average values are indicated with the appropriate error limits.
The intensities are given in brackets with the following abbreviations: very strong == vst; strong = st; medium = m; weak ≡ w; and very weak ≡ vw. d in [A]: 16.2+0.3 (vst), 11.4±0.2 (vw), 9.9±0.2(w), 9.4±0.2(vw), 8.06±0.1 (vw), 7.73±0.1(vw),
7.05±0.1 (vw), 6.50±0.05(vw), 6.36±0.05(vw), 5.82±0.05(w), 4.94±0.05(vw), 4.73±0.05(vw),
4.33±0.05(vw), 4.17±0.05(vw), 4.13±0.05(vw), 3.93±0.05(vw).
The characteristic reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A]: 16.2±0.3, 11.4±0.2, 9.9±0.2, 9.4±0.2, 8.06±0.1, 7.05±0.1, 6.50±0.05, 5.82±0.05,
4.94±0.05, 4.73±0.05, 4.33±0.05, 4.17±0.05, 4.13±0.05, 3.93±0.05.
Another polymorphic form of the tetrahydrate of the calcium salt of valsartan is the solid state form A2,ca- The melting point of form A2,ca is 195 ± 1.5 0C and the melting enthalpy is 98 ± 8 kJ-Mol'1. The indicated melting point is a hydrate melting point which can only be mesured in a closed specimen container. Gold containers are used and sample weights of between 2 and 4 mg salt hydrate. The heating rate applied is Tr= 10 K-min"1. For details see the explanations given for the form A1|Ca.The tetrahydrate of the calcium valsartan salt A2,ca reveals the following loss of water as a function of temperature using the thermogravimetric instrument TGS-2 (Perkin-Elmer Corp., Norwalk, CT USA) with a heating rate of 10 K-min"1, in a water-free N2 atmosphere, the weight loss is illustrated in Table 6. Table 6
Figure imgf000015_0001
The theoretical water content is for a tetrahydrate of the calcium salt of valsartan 13.2%. The tetrahydrate of the form A2,ca has a bound water content at 225°C determined as a weight loss of 12.8% and the total formula is calculated from this (C24H27N5O3)2" Ca2+ ■ (3.9 ± 0.2) H2O.
A solid state characterization of the calcium salt of valsartan in form of the tetrahydrate A2|Ca is achieved by a X-ray powder pattern and by the evaluation of the reflections into the interlattice plane intervals. The measurements are throughout made without specific explanations with a Guinier camera (FR 552 from Euraf Nonius, Delft, NL) on an X-ray film in transmission geometry, using Cu-Ka1 radiation at room temperature. Evaluation of the films for calculation of the interlattice plane intervals is made both visually and by a line scanner (Johansson, Taby, S), and the reflection intensities are determined simultanously. The preferred characterization of the tetrahydrate of the calcium salt of valsartan A2,ca is obtained from the interlattice plane intervals d of the ascertained X-ray diffraction diagrams, whereby, in the following, values are indicated with the appropriate error limits. The intensities are given in brackets with the following abbreviations: very strong ≡ vst; strong ≡ st; medium = m; weak ≡ w; and very weak ≡ vw. d in [A]: 16.2±0.3(vst), 9.9±0.2(w), 9.4±0.2(vw), 8.05±0.1(vw), 7.72±0.1(vw), 7.04±0.1(vw) 6.49±0.05(w), 6.35±0.05(vw), 5.82±0.05(w), 4.94±0.05(vw), 4.73±0.05(vw), 4.34±0.05(vw), 4.13±0.05(m), 3.93±0.05(w), 3.30±0.05(vw). The characteristic reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A]: 16.2±0.3, 9.9±0.2, 9.4±0.2, 8.05±0.1, 7.04±0.1 , 6.49±0.05, 5.82±0.05, 4.94±0.05, 4.13±0.05, 3.93±0.05.
A new substance has been found as polymorphic form of a trihydrate of the calcium salt of valsartan assigned with B1iCa. The melting point of the substance B1iCa is measured in a closed sample cell with a heating rate of 10 K-min"1 as Tfus = 175±3°C and the melting enthalpy of the partially crystalline sample is 12 ± 4 kJ Mol"1.
The water content is in theory 10.24% for the trihydrate of the calcium salt of valsartan. Using the thermogravimetric instrument TGS-2 (Perkin-Elmer Corp., Norwalk, CT USA) the water content was determined for the polymorphic form B1|Caas 9.9+0.4%. A total formula was calculated from this polymorphic form of the trihydrate of the calcium salt of valsartan (C24H27N2O3)2" Ca2+ • (2.9 ± 0.3) H2O.
Using thermogravimetry, in a water-free N2 atmosphere, the weight loss, i.e. the water loss for the trihydrate of the calcium salt of valsartan in the polymorphic form B1|Ca as a function of temperature, was measured at a heating rate of 10 K-min"1. The results are illustrated in table 7.
Table 7
Figure imgf000016_0001
A solid state characterization of the trihydrate of the calcium salt of valsartan B1iCa is preferably performed by X-ray powder patterns with the evaluation of the interlattice plane intervals. The measurements have been performed with two samples of the trihydrate BiιCa of the calcium salt of valsartan and with two different instruments. The first instrument used was a temperature-humidity powder diffraction chamber X'Pert from Philips Analytical X-ray, 7602 Almelo, NL, equipped with a low and medium temperature attachement from Anton Paar GmbH, A-8054 Graz, Austria. The second instrument is a powder diffractometer PW 1710 also from Philips Analytical X-ray, 7602 Almelo, NL. Two parallel measurements with a reference sample, namely a tetrahydrate of the calcium salt of valsartan have been used to calibrate the powder diffractometer PW 1710 with a Guinier camera (FR 552 from Enraf Nonius, Delft, NL) on a X-ray film in transmission geometry, using Cu-Ka1 radiation. The corrections for the interlattice plane intervals to reach the values of the Guinier camera from the powder diffractometer PW1710 were ranging from +0.55 A for a d -value of 16A to +0.02A for a d-value of 5.7 A . No correction was necessary for lower d-values. The characterization of the trihydrate of the calcium salt of valsartan B1|Ca with the interlattice plane intervals d is as such, whereby, in the following values are indicated with the appropriate error limits. The intensities of the d-values are given in brackets with the following abbreviations: very strong ≡ vst; strong ≡ st; medium ≡ m; weak ≡ w; and very weak ≡ vw. d in [A]: 16.0±0.3(vst), 11.4±0.2(m), 10.0±0.2(vw), 9.4±0.2(vw), 9.1±0.2(vw), 8.06±0.1(vw), 7.75±0.1 (vw), 7.03±0.1 (vw), 6.48±0.05(vw), 6.10±0.05(vw), 5.76±0.05(vw), 5.16±0.05(vw), 4.95±0.05(vw), 4.75±0.05(vw), 4.68±0.05(vw), 4.33±0.05(vw).
The characteristic reflections in the X-ray diffraction diagram reveal the following interlattice plane intervals for the form B1iCa: d in [A]: 16.0±0.3, 11.4±0.2, 10.0±0.2, 9.4±0.2, 8.06±0.1 , 7.75±0.1, 7.03±0.1 , 6.48±0.05, 6.10±0.05, 5.16±0.05, 4.75±0.05.
The new polymorphic form B2,ca of a trihydrate of the calcium salt of valsartan has a melting point of 197±1.5°C measured in a closed sample cell with a Pyris 1 DSC (Differential Scanning Calorimeter) from Perkin-Elmer Corp., Norwalk, CT USA. The enthalpy of fusion has been determined also from a DSC curve measured also with a heating rate of 10 K-min"1 as 62 ± 6 kJ-Mol'1. During the DSC measurements of the melting of the trihydrate B2,ca of the calcium salt of valsartan also a glass transition was observed, as an unequivocal proof of amorphous substance present in this substance. The glass transition temperature was calculated with T9 = 68 ± 200C as the mid point of a change of the specific heat of the substance, namely the trihydrate B2ιca of the calcium salt of valsartan. The value for the change of the specific heat was calculated as Δcp = 0.2 ± 0.1 J (g K)"1. The amorphicity present in the substance B2ica approximated by this value for the change of the specific heat is 18 ± 12%. The crystalline trihydrate B2,ca of the calcium salt of valsartan is according to the heat of fusion measured with the DSC Pyris 1 , the main component is this crystalline product, the amorphous part of the calcium salt of valsartan is a minor part.
The water content of the trihydrate B2,ca of the calcium salt of valsartan is 10.5±0.5%. The value was measured with a thermogravimteric instrument TGS-2 (Perkin-Elmer Corp., Norwalk, CT USA). The total formula was calculated from this bound water content for the polymorph of the trihydrate B2,Ga as (C24H27N5O3)2Oa2+ • (3.1±0.3)H2O.
Water may also be present in the amorphous part of the substance B2,Ca, which is depending on the concentration of the non-crystalline part. This water is within the amorphous part differently bound compared to the water molecules in the hydrate form of the crystalline part. As a first approximation one can state, that the crystalline and the amorphous part are similar in the water concentration in case the last process of reaching the state of the material is not passing the anhydrous form of the calcium salt of valsartan. The explanation for this fact is given with the molecular structure of the calcium salt of valsartan, the same holds for the magnesium salt of valsartan, namely that the salt structure is to a considerable part based on the short range order of the molecular interacting substances valsartan, calcium or magnesium and water which is not free water, however structural bound water. This narrow range molecular structure is rather similar for the crystalline part as for the amorphous part. Of course, in the amorphous material, there is a complete lack of long range order in contrary to the crystalline material were any molecule, in the present case, any molecle in trihydrate B2ιCa calcium salt of valsartan is over neighboring molecules structural interrelated with all the molecules within any single crystal.
Using thermogravimetry, in a water-free N2 atmosphere, the weight loss, i.e. the water loss for the trihydrate B2 Ca as a function of temperature, was measured at a heating rate of 10 K-min"1. The results for the polymorph B2 Ca of the trihydrate of the calcium salt of valsartan are illustrated in table 8. Table 8
Figure imgf000019_0001
The solid state characterization of the trihydrate of the calcium salt of valsartan B2,ca was performed by X-ray powder spectroscopy using two different instruments and two different charges produced with the evaluation of the interlattice plane intervals. The first instrument was a powder diffractometer PW 1710 from Philips Analytical X-ray, 7602 Almelo, NL. The second instrument was a Guinier camera FR 552 from Enraf Nonius, Delft, NL on a X-ray film in transmission geometry, using Cu-Ka1 radiation. The first instrument has been calibrated with the Guinier camera, the corrections ranging from +0.55A for a d-value of 16 A to +0.02 A for a d-value of 5.7 A. No corrections were necessary for lower d-values. The characterization of the trihydrate of the calcium salt of valsartan B2,ca with the interlattice plane intervals is as such, whereby, in the following values are indicated with the appropriate error limits. The intensities of the d values are given in brackets with the following abbreviations: very strong ≡ vst; strong ≡ st; medium ≡ m; weak ≡ w; and very weak ≡ vw. d in [A]: 16.2±0.3(vst), 11.5±0.2(w), 9.9±0.2(w), 9.4±0.2(w), 9.0±0.1(vw), 8.13±0.1(vw), 7.78±0.1(vw), 7.04±0.1(vw), 6.50±0.1(vw), 6.09±0.05(vw), 5.79±0.05(vw), 5.18±0.05(vw), 4.95±0.05(vw), 4.74±0.05(vw), 4.16±0.05(w).
The characteristic reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A]: 16.2±0.3, 11.5±0.2, 9.9±0.2, 9.4±0.2, 7.04±0.1 , 6.50±0.1 , 5.79±0.05, 4.74±0.05, 4.16±0.05. Another polymorph of the trihydrate of the calcium salt of valsartan namely the B3,Ca has a melting point measured with a heating rate of 10K min~1 in a hermetically sealed sample cell of 192±1.5°C. The enthalpy of fusion has been determined also by a DSC measurement with 17±4 kJ-Mol"1.
The glass transition phenomena observed with the DSC at 65°C is revealing a change of the specific heat capacity of scp = 0.3 3g"1- K"1. Compared with the change of the specific heat capacity of a 100% amorphous calcium salt of valsartan as a trihydrate the amorphous content of the B3,ca can be estimated with 50%. Therefore the enthalpy of fusion for the crystalline B3,ca is 34±10 kJ-Mol"1.
The water content of the polymorphic form B3,Ca for the trihydrate of the calcium salt of valsartan was determined with a thermobalance from Perkin-Elmer Corp., Norwalk, CT USA, named TGS-2 with a value of 9.8±0.5%. The total formula was calculated from this bound water content for the polymorphic from B3iCa with (C24H27N5O3)2Oa2+ ■ (2.9±0.3)H2O.
Using thermogravimetry, in a water-free N2 atmosphere, the weight loss, i.e. the water loss for the trihydrate B3 Ca as a function of temperature, was measured at a heating rate of 10 K-min"1. The results for the polymorphic form B3,Ca of the trihydrate of the calcium salt of valsartan are illustrated in table 9.
Table 9
Figure imgf000020_0001
275 10.2 ± 0.5
The Guinier camera FR552 with a X-ray film in transmission geometry, using a Cu-Ka1 radiation from Enraf Nonius, Delft, NL has been installed to characterize at room temperature the crystal lattice by the interlattice plane intervals of the calcium salt of valsartan in form of the trihydrate B3iCa-
The reflections in the X-ray diffraction diagram for the trihydrate of the calcium salt of valsartan B3|Ca reveal the following interlattice plane intervals d, whereby, values are indicated with the appropriate error limits. The intensities of the d-values are given in brackets with the following abbreviations: very strong ≡ vst; strong ≡ st; medium ≡ m; weak ≡ w; and very weak ≡ vw. d in [A]: 16.1±0.3(vst), 11.4±0.2(m), 9.9±0.2(w), 9.4±0.2(w), 9.0±0.1 (vw), 8.04+0.1(vw),
7.73±0.1(vw), 7.03±0.1(vw), 6.47±0.05(vw), 6.33±0.1(vw), 6.09±0.05(vw), 5.79±0.05(w),
5.17±0.05(vw), 4.95±0.05(vw), 4.73±0.05(vw), 4.48±0.05(vw), 4.33±0.05(vw), 4.15±0.05(vw),
4.11±0.05(vw), 3.94±0.05(vw), 3.61±0.05(vw).
The characteristic reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A]: 16.1±0.3, 11.4±0.2, 9.9±0.2, 9.4±0.2, 9.0±0.1 , 7.03±0.1 , 6.47+0.05, 5.79±0.05,
4.15±0.05, 3.94±0.05.
Measurements of the infrared spectrum were performed by means of ATR-IR (Attenuated
Total Reflection-Infrared Spectroscopy) using the instrument Spektrum BX from Perkin-
Elmer Corp., Beaconsfield, Bucks, England.
The trihydrate of the calcium salt of valsartan B3|Ca has the following ATR-IR adsorption bands expressed in reciprocal wave numbers (cm"1):
3594(w); 3309(w); 3053(w); 2959(w); 2930(w); 2870(w); 1621 (m); 1577(m); 1505(w);
1458(m); 1416(m); 1405(m); 1354(w); 1301 (w); 1273(w); 1210(w); 1179(w); 1138(w);
1104(W); 1099(w); 1012(w); 1003(w); 974(w); 941 (w); 906(w); 856(w); 841 (w); 756(m);
737(m); 667(m).
The intensities of the absorption bands are indicated as follows: (w)=weak, (m)=medium, and (st)=strong intensity. The characteristic absorption bands of the ATR-IR spectroscopy for the polymorphic form B3,ca of the trihydrate of the calcium salt of valsartan are shown by the following values expressed in reciprocal wave numbers (cm 1):
3594(w); 2959(w); 1621(st); 1577(m); 1458(m); 1405(m); 1354(w); 1273(w); 1012(w); 756(m); 737(m); 667(m). The error margin for all absorption bands of ATR-IR is ± 3cm"1.
Additionally, a new substance has been found as the monohydrate of the calcium salt of valsartan Ci)Ca.
The bound water content is 3.1 ±0.3% measured with a thermobalance TGS-2 (Perkin-Emer Corp., Norwalk, CT, USA). The total formula was calculated from the bound water content for the monohydarte C1|Ca as (C24H27N5O3)2Oa2+ • (0.8±0.2)H2O.
The solid state characterization of the monohydrate of the calcium salt of valsartan C11Ca was executed by X-ray powder patterns with the evaluation of the interlattice plane intervals. The instrument used was a temperature-humidity powder diffraction chamber X'Pert from Philips Analytical X-ray, 7602 Almelo, NL, equipped with a low and medium temperature attachement from Anton Paar GmbH, A-8054 Graz, Austria.
The characterization of the monohydrate of the calcium salt of valsartan C1ιCa with the interlattice plane intervals d is as such, whereby, in the following values are indicated with the appropriated error limits. The intensities of the d-values are given in brackets with the following abbreviations: very strong ≡ vst; strong ≡ st; medium ≡ m; weak ≡ w; and very weak = vw. d in [A]: 16.0+0.3(m), 15.0±0.3(vst), 11.6±0.2(w), 9.9±0.2(vw), 9.4±0.2(vw), 8.02±0.1(vw),
7.53±0.1(vw), 7.02±0.1(vw), 6.47±0.05(vw), 6.11±0.0.5(vw), 4.50±0.05(vw), 4.34±0.05(vw).
The characteristic reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A]: 16.0±0.3, 15.0±0.3, 11.6±0.2, 9.4±0.2, 7.53±0.1 , 6.11±0.05.
Surprisingly, another new substance has been found, assigned with DiiCa beeing the di- (calcium salt of valsartan) pentahydrate. The melting point of this new substance D1 Ca is Tfus = 210±2°C measured in a closed sample cell with a heating rate of 10K min"1 and with a DSC called Pyris 1 from Perkin-Elmer Corp., Norwalk, CT, USA. With the same instrument and the same procedures as above explained, the heat of fusion was determined. The heat of fusion is for the di-(calcium salt of valsartan) pentahydrate for a 100% crystalline di-(calcium salt of valsartan) pentahydrate is approximated with 94kJ-Mol"1. The water content of the di-(calcium salt of valsartan) as pentahydrate was measured with a thermobalance TGS-2 (Perkin-Elmer Corp., Norwalk, CT USA) and gave the value at the plateau of 225°C of 8.1 ±0.5%. The total formula was elucidated from this bound water content for the substance D1|Ca as [(C24H27N5O3)2"Ca2+]2 • (4.7±0.3)H2O.
Using thermogravimetry, in a water-free N2 atmosphere, the weight loss, i.e. the water loss for the di-(calcium salt of valsartan) pentahydrate D1|Ca as a function of temperature, was measured at a heating rate of 10 K-min"1. The results for the di-(calcium salt of valsartan) pentahydrate are illustrated in table 10.
Table 10
Figure imgf000023_0001
The solid state characterization of the di-(calcium salt of valsartan) pentahydrate D1iCa was achieved with a Guinier camera (FR 522 from Enraf Nonius, Delft, NL) on an X-ray film in transmission geometry, using Cu-Ka1 radiation at room temperature. Evaluations of the films for calculation of the interlattice plane intervals are made by a line-scanner (Johansson, Taby, S), and the reflection intensities are determined simultaneously. The reflections in the X-ray diffraction diagram could be evaluated to the following interlattice plane intervals d, whereby values are indicated with appropriate error limits. The intensities of the d-values are given in brackets with the following abbreviations: very strong = vst; strong ≡ st; medium ≡ m; weak ≡ w; and very weak ≡ vw. d in [A]: 15.5±0.3(vst), 11.5±0.2(st), 9.4±0.2(vw), 9.04±0.1(w), 7.75±0.1(vw), 6.46±0.05(vw),
6.09±0.05(w), 5.82±0.05(vw), 5.66±0.05(vw), 5.1β±0.05(vw), 4.76±0.05(vw), 4.48±0.05(vw),
3.83+0.05(vw), 3.60±0.05(vw), 3.36±0.05(vw).
The characteristic reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A]: 15.5±0.3, 11.5±0.2, 9.4±0.2, 9.04±0.1 , 6.46±0.05, 6.09±0.05, 5.82±0.05, 5.16±0.05,
4.48±0.05, 3.60±0.05.
A magnesium salt hydrate of valsartan is preferred, in particular the hexahydrate. The thermal behaviour of this salt hydrate in the region of the melting point shows a certain chemical and physical instability. The thermal data are thus dependent on the measurement conditions. In the sealed gold specimen container with an internal free volume of ca. 22 microlitres, with a sample of 2 to 4 mg and with a heating rate of Tr = 10 K- min'1, the melting point of the hexahydrate of the magnesium salt of valsarten is 132 ± 1.5° Celsius and the melting enthalpy is 56 ± 3 kJ Mol"1. The melting enthalpy which is about 5 times higher than the free acid of valsartan, together with the significantly higher melting point of the hexahydrate of the magnesium salt of valsartan is a measure of the stability of the new- type crystal grating at around room temperature.
The optical rotation of the hexahydrate of the magnesium salt of valsartan in methanol as a 1% solution at 200C is [α] 20 D = - 14 °.
A measurement of the infrared absorption spectrum of the hexahydrate of the magnesium salt of valsartan in a potassium bromide compressed tablet shows the following significant bands expressed in reciprocal wave numbers (cm"1): 3800 - 3000 (st); 3000 - 2500 (st); 1800 - 1500 (st); 1500 - 1440 (m); 1440 - 1300 (m); 1280 - 1240 (w); 1240 - 1190 (w); 1190 - 1150 (w); 1120 - 1070 (w); 1050 - 990 (w); 990 - 960 (w); 960 - 920 (w); 920 - 700 (m); 700 - 590 (w); 590 - 550 (w).
The intensities of the absorption bands are indicated as follows: (w) = weak; (m) = medium; and (st) = strong intensity. Measurement of the infrared spectrum likewise took place by means of ATR-IR (Attenuated Total Reflection-Infrared Spectroscopy) using the instrument Spektrum BX from Perkin-Elmer Corp., Beaconsfield, Bucks, England.
The hexahydrate of the magnesium salt of valsartan has the following absorption bands expressed in reciprocal wave numbers (cm"1):
3378 (m); 3274 (m); 2956 (m); 2871 (w); 2357 (w); 1684 (w); 1619 (st); 1557 (m); 1464 (m);
1419 (m); 1394 (st); 1374 (m); 1339 (w); 1319 (w); 1300 (w); 1288 (w); 1271 (w) 1255 (w);
1223 (w); 1210 (w); 1175 (m); 1140 (w); 1106 (w); 1047 (w); 1024 (w); 1015 (w); 1005 (w);
989 (W); 975 (w); 955 (w); 941 (w); 888 (w); 856 (w); 836 (m); 820 (w); 766 (st); 751 (m);
741 (st); 732 (st).
The intensities of the absorption bands are indicated as follows: (w) = weak; (m) = medium and (st) = strong intensity.
The most intensive absorption bands of the ATR-IR spectroscopy are shown by the following values expressed in reciprocal wave numbers (cm"1): 3378 (m); 3274 (m); 2956 (m); 1619 (st); 1557 (m); 1464 (m); 1419 (m); 1394 (st); 1271 (w); 1175 (m); 1015 (w); 975 (w); 836 (m); 766 (st); 751 (m); 741 (st); 732 (st). The error margin for ail absorption bands of ATR-IR is ± 2 cm'1.
The theoretical water content of the hexahydrate of the magnesium salt of valsartan is 19.1%. Using a coupled instrument based on thermogravimetry-Fourier transformation- infrared-spectroscopy (TG-FTIR, IFS 28 from the companies Netzsch Geratebau GmbH, SeIb, Bayern and Bruker Optik GmbH, Karlsruhe ), whilst simultaneously measuring the weight loss and identifying the material component given up, using infrared spectroscopy (release of water), the water content was determined at 18.5 %, conforming well with the theoretical value. For the hexahydrate, this corresponds to a molar ratio of 5.8 ± 0.2 mols H2O per mol magnesium salt.
Table 11 illustrates the water loss of the hexahydrate of the magnesium salt of valsartan depending on temperature, using the weight loss measured in an N2 atmosphere on a thermogravimetric thermal analysis instrument for a heating rate of 10 K°min"1. From the TG-FTIR measurement, the correlation of the weight loss is assured solely by the release of water. Table 11
Figure imgf000026_0001
The hexahydrate of the magnesium salt of valsartan has a solubility in distilled water at 22°C of 59 g per litre of solution for a pH value of 9.3.
The crystalline form of the hexahydrate of the magnesium salt of valsartan is clearly characterised by the interlattice plane intervals calculated from the lines in an X-ray powder pattern. The measurement and analysis methods used are the same as those used for the tetrahydrate of the calcium salt of valsartan.
This preferred characterisation of the hexahydrate of the magnesium salt of valsartan is obtained from the interlattice plane intervals d, whereby, in the following, average values are indicated with the appropriate error limits: d in [A]: 19.7±0.3, 10.1±0.2, 9.8+0.2, 7.28±0.1 , 6.48±0.1 , 6.00±0.1, 5.81±0.1 , 5.68±0.1, 5.40±0.05, 5.22 ±0.05, 5.12±0.05, 5.03±0.05, 4.88±0.05, 4.33±0.05, 4.22±0.05, 4.18±0.05, 4.08±0.05, 3.95±0.05, 3.46±0.05, 3.42±0.05.
The most intensive reflections in the X-ray diffraction diagram show the following interlattice plane intervals: d in [A] : 19.7±0.3, 10.11±0.2, 9.8±0.2, 7.28±0.1 , 5.81±0.05, 5.68±0.05, 5.03±0.05, 4.88±0.05, 4.18±0.05, 4.08±0.05, 3.46 ±0.05. A preferred method of checking the above-indicated average values of the interlattice plane intervals and intensities measured by experimentation from X-ray diffraction diagrams with a Guinier camera, for a given substance, consists in calculating these intervals and their intensities from the comprehensive single crystal structure determination. This structure determination yields cell constants and atom positions, which enable the X-ray diffraction diagram corresponding to the solid to be calculated by means of computer-aided calculation methods (programme CaRine Crystallography, Universite de Compiegne, France). A comparison of these data, namely the interlattice plane intervals and intensities of the most important lines of the hexahydrate of the magnesium salt of valsartan, obtained from measurements with the Guinier camera and from calculating the single crystal data, is illustrated in Table 12.
Table 12
Figure imgf000027_0001
The invention relates in particular to the crystalline hexahydrate of the magnesium salt of (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]- amine, a crystalline solid which is clearly characterised by the data and parameters obtained from single crystal X-ray analysis. An in-depth discussion of the theory of the methods of single crystal X-ray diffraction and the definition of the evaluated crystal data and the parameters may be found in Stout & Jensen, X-Ray Structure Determination; A Practical Guide, Mac Millian Co., New York, N.Y. (1968) chapter 3.
The data and parameters of the single crystal X-ray analysis for the magnesium-valsartan- hexahydrate are given in Table 13.
Table 13 Crystal data and parameters of the hexahydrate of the magnesium salt of valsartan
Crystal data sum formula ( C24 H27 N5 O3) 2^Mg 2+ - 6 H2O molecular mass 565.91 crystal colour colourless crystal shape flat prisms crystal system monoclinic space group C2 size of the single crystal 0.013 « 0.50 ' 0.108 mm3 dimensions and angle of elementary cell a = 40.075(8) A b = 7.400(1) A
C = 10.275(2) A α = 90 ° β = 100.85(3) °
Y = 90 ° volume of elementary cell V0 = 2992.6(9) A 3 number of molecules in the elementary cell 4
F (000) 1208 measurement range of cell parameters (Θ) 2.82 -11.15 ° calculated density 1.256 (g«cm-3)
-1 linear absorption coefficient 0.114 mm
X-ray measurement data diffractometer Enraf Nonius CAD4
X-radiation ( graphite monochromator ) MoKa wavelength 0.71073 temperature 295 K scan range (θ) 1.03 - 26.00 ' scan mode ω / 2 Θ reflections collected/unique 5954 / 5868 number of significant reflections ( I > 2σ(l) ) 1341 variation in intensity <1 % absorption correction numeric
Structure refinement method full matrix, least squares, F number of parameters 243 agreement index (R) 10.7 % weighted agreement index (Rw) 13.8 % S factor (Goodness of fit) 1.001 number of reflections used 5868 determination of hydrogen atoms majority according to the "riding" model, nine H-atoms from water molecules isotropically refined from difference-Fourier calculation extinction correction 0.00098 (10) maximum/minimum residual electron density in 0.473 / - 0.614 ( e -A-3 ) final difference-Fourier calculation absolute structure parameters 0.0(10)
Computer programmes used SHELXS 86 (Sheldrick, Gδttingen, 1990) SHELXL 96 (Sheldrick, Gόttingen, 1996) SCHAKAL 86 (Keller, Freiburg 1986) PLATON (Spek, Acta Cryst, 1990)
The elementary cell is defined by six parameters, namely by the grating constants a, b and c, and by the axial angle, namely by a, β, und y. In this way, the volume of the elementary cell V0 is determined. A differentiated description of these crystal parameters is illustrated in chapter 3 of Stout & Jensen (see above).
The details for the hexahydrate of the magnesium salt of valsartan from the single crystal measurements, especially the atom coordinates, the isotropic thermal parameters, the coordinates of the hydrogen atoms as well as the corresponding isotropic thermal parameters, show that a monoclinic elementary cell exists, its cell content occurring from four formula units Mg 2+ Valsartan • 6 H2O .
Given the acentric space group C2 determined from the single crystal X-ray structure determination, a racemate is ruled out. Thus the enantiomeric purity of the S-configuration for the crystalline hexahydrate of the magnesium salt of valsartan is proved.
Table 14 illustrates the mass change, i.e. the water absorption or loss as a function of relative humidity at 25°C for a sample of 9.5 mg of magnesium -valsartan-hexahydrate and for a period of 4 hours (h). The following cycles of changes in relative humidity are shown: 40-90; 90-0; 0-90; 90-0 % relative humidity:
Table 14
Figure imgf000030_0001
The measurement error of this sorption method based on thermogravimetry is about 0.1%. Therefore, the hexahydrate of the magnesium salt of valsartan under the conditions employed, which are realistic from a pharmaceutical-galenic point of view, shows weak, reproducible water absorption or water loss in a range of 20 to 80% relative humidity. This is surprising to a large extent, since the hexahydrate, which has incorporated about 19% bound water in the crystal structure, reversibly absorbs or releases water even at extreme values of relative humidity and is relatively insensitive at an average range of relative humidity. This characteristic enables an uncomplicated physical-chemical process to be developed and allows a choice of the best dosage forms for the patients.
Another new-type of crystalline, partially amorphous solids are falling into the groups of the magnesium salt hydrate and anhydrate of valsartan. In particular, the hexahydrate of the magnesium salt of valsartan in form of the polymorphic substance A1iMg is a preferred substance.
The specific optical rotation of hexahydrates of the magnesium salt of valsartan in water measured with a 1 % solution at 200C is independent of the polymorphic form present as long as it is a hexahydrate [α]D 2o = -38°.
The thermal behaviour of this salt hydrate in the region of the melting point only reveals a certain chemical and physical instability. The thermal data are thus dependent on the measurement conditions. The instrument used for the calorimetric data is throughout a DSC Pyris 1 (Differential Scanning Calorimeter) obtained from Perkin-Elmer Corp., Norwalk, CT USA . The measurements are performed with samples enclosed in a sealed gold specimen container with an internal free volume of ca. 22 microliters, with a sample weight of 2 to 4 mg and with a heating rate of Tr = 10K min"1. The melting point of hexahydrate of the magnesium salt of valsartan in the polymorphic form A1|Mg is 130±3°C and the enthalpy of fusion is 45±5 kJ-Mol"1. The hexahydrate of the magnesium salt of valsartan as the polymorphic form A1ιMg reveals the following loss of water as a function of temperature in using the method of thermogravimetry. The instrument used was a TGS-2 (Perkin-Elmer Corp., Norwalk, CT USA) and the measurement was performed in a water free atmosphere. The heating rate selected was 10 K-min'1. The weight loss is illustrated in table 15.
Table 15
Figure imgf000031_0001
Figure imgf000032_0001
The theoretical water content is for the hexahydrate of the magnesium salt of valsartan 19.1%. The hexahydrate of the magnesium salt of valsartan in form of the polymorph Ai,Mg has a bound water content at 225°C determined as a weight loss of 17.3±0.5%. The total formula is calculated from this as (C24H27N5O3)2 Mg2+ • (5.4±0.2)H2O.
The solid-state characterization of the magnesium salt of valsartan for the polymorphic form of the hexahydrate Ai,Mg is achieved by a X-ray powder pattern and by the evaluation of the reflections into the interlattice plane intervals. The measurements have been made with three different X-ray instruments. The first instrument used is a Guinier camera (FR 522 from Enraf Nonius, Delft, NL) on an X-ray film in transmission geometry, with a Cu-Ka1 radiation at room temperature. Evaluations of the films for calculation of the interlattice plane intervals are performed with a scanner from Johansson, Taby, S and the reflections intensities are determined simultaneously. The second instrument used for X-ray measurements of the new substance A1iMg is a temperatur-humidity powder diffraction chamber X'Pert from Philips Analytical X-ray, 7602 Almelo, NL equipped with a low and medium temperature attachement from Anton Paar GmbH, A-8054 Graz. The third instrument applied in the solid state characterization is the powder diffractometer PW1710 from Philips Analytical X-ray. 7602 Almelo, NL. The characterization of the polymorph Ai,Mg of the hexahydrate of the magnesium salt of valsartan is achieved from the interlattice plane intervals d of the ascertained X-ray measurements. In the following d values are listed with the appropriate error limits. The intensities are given in brackets with the following abbreviations: very strong ≡ vst; strong ≡ st; medium ≡ m; weak ≡ w; and very weak ≡ vw. d in [A]: 19.6±0.3(vst), 16.6±0.3(vw), 10.3±0.2(vw), 9.8±0.2(m), 7.3±0.1(w), 6.9±0.1(vw),
6.01±0.05(w), 5.92±0.05(w), 5.55±0.05(vw), 5.38±0.05(vw), 5.23±0.05(vw), 5.15±0.05(vw),
5.05±0.05(vw), 4.90±0.05(m), 4.54±0.05(vw), 4.22±0.05(vw), 4.13±0.05(vw), 4.07±0.05(w),
3.96±0.05(vw), 3.73±0.05(vw), 3.64±0.05(vw), 3.43±0.05(w), 3.29±0.05(vw), 3.22±0.05(vw),
3.11±0.05(vw).
The characteristic reflections in the X-ray diffraction diagram reveal the following plane intervals: d in [A]: 19.6±0.3, 16.6±0.3, 10.3±0.2, 9.8±0.2, 7.3±0.1 , 6.01±0.05, 5.92±0.05, 5.55+0.05,
5.38±0.05, 4.90±0.05, 4.13±0.05, 4.07±0.05, 3.43±0.05.
The substance in form of the tetrahydrate B1iMg is a partially amorphous solid of the magnesium salt of valsartan. The tetrahydrate B1ιMg shows the following loss of water as a function of temperature measured with a thermobalance TGS-2 (Perkin-Elmer Corp., Norwalk, CT USA). The heating rate selected was 10K min"1. The weight loss is tabulated in table 16.
Table 16
Figure imgf000033_0001
The magnesium salt of valsartan in the polymorphic form of the tetrahydrate B11Mg is showing a bound water content at 225°C of 13.0±0.5%, and as shown for 25°C in Table 8 practically no additional free water is present in the substance measurements were performed with a thermobalance TGS-2 of the Perkin-Elmer Corp., CT USA. The total formula is therefore calculated as (C24H27N5O3) Mg • (3.8±0.2)H2O. The solid-state characterization of the tetrahydrate of the magnesium salt of valsartan B1 Mg has been performed with an X-ray instrument by a so-called temperature-humidity powder diffraction chamber X'Pert from Philips Analytical X-ray, 7602 Almelo, NL, equipped with a low and medium temperature attachement from Anton Paar GmbH, A-8054 Graz. Additional X-ray measurements were performed with a powder diffractometer PW 1710 from Philips Analytical X-ray, 7602 Almelo, NL. The crystalline parts of the substance B1|Mg are characterized in the solid state with the interlattice plane intervals d, which are given with appropriate error limits. The intensities are reported in brackets with the following abbreviations: very strong ≡ vst; strong ≡ st; medium ≡ m; weak ≡ w; and very weak ≡ vw. d in [A]: 15.8±0.3(vst), 11.0±0.2(w), 8.0±0.2(vw).
The new substance C-ι>Mg is a the trihydrate of the magnesium salt of valsartan. The water content was measured with a thermobalance TGS-2 (Perkin-Elmer Corp., Norwalk, CT USA). The water content for this substance, namely the trihydrate of the magnesium salt of valsartan C11Mg is 10.7±0.5%. The total formula is calculated from this (C24H27N5O3)^Mg2+ • (3.0±0.3)H2O.
The solid-state characterization of the trihydrate of the magnesium salt of valsartan C1 Mg has been performed with X-ray measurements by use of the temperature-humidity powder diffraction chamber X'Pert from Philips Analytical X-ray, 7602 Almelo, NL equipped with a low and medium temperature attachement from Anton Paar GmbH, A-8054 Graz. The characterization of the substance Ci|Mg of the magnesium salt of the valsartan trihydrate is given with the interlattice plane intervals d obtained with X-ray measurements. In the following, d values are listed with the appropriate error limits. The intensities are given in brackets with the following abbreviations: very strong ≡ vst; strong ≡ st; medium ≡ m; weak ≡ w; and very weak ≡ vw. d in [A]: 17.9±0.3(m), 10.2±0.2(w), 8.96±0.2(m), 7.18±0.1(w), 6.97±0.1(vw), 6.81±0.1(vw), 6.24±0.05(vw), 5.93±0.05(w), 5.84±0.05(w), 5.72±0.05(vw), 5.59±0.05(vw), 5.42±0.05(m), 5.25±0.05(vw), 5.11±0.05(m), 5.01±0.05(st), 4.82±0.05(w), 4.67+0.05(w), 4.57±0.05(vw), 4.49±0.05(vw), 4.30±0.05(m), 4.19±0.05(vst), 4.13±0.05(vst), 4.02±0.05(vst), 3.88±0.05(vw). The characteristic reflections in the X-ray diffraction diagram reveal the following plane intervals: d in [A]: 17.9+0.3, 10.2±0.2, 8.96±0.2, 7.18±0.1 , 5.93±0.05, 5.84±0.05, 5.42+0.05, 5.11+0.05, 5.01 ±0.05, 4.82±0.05, 4.67±0.05, 4.30±0.05, 4.19±0.05, 4.13±0.05, 4.02±0.05.
The magnesium salt of valsartan is also forming a substance as a monohydrate which is indicated with DiiMg. The water content was measured with a thermobalance TGS-2 (Perkin- Elmer Corp., Norwalk, CT USA). The water content for the monohydrate D1 Mg is 2.8±0.3%. The total formula was calculated from this value with (C24H27N5O3)2^Mg2+ • (0.74+0.2) H2O.
The solid-state characterization of the monohydrate of the magnesium salt of valsartan D1 Mg was achieved with X-ray measurements by use of the temperature-humidity powder diffraction chamber X'Pert from Philips Analytical X-ray, 7602 Almelo, NL. This X-ray instrument is equipped with a low and medium temperature attachement from Anton Paar
GmbH, A-8054 Graz.
The characterization of the new substance, namely the monohydrate of the magnesium salt of valsartan Di,Mg is demonstrated with the interlattice plane intervals d of the X-ray investigations. In the following d values are listed with the appropriate error limits. The intensities are given in brackets with the following abbreviations: very strong ≡ vst; strong = st; medium = m; weak ≡≡ w; and very weak ≡ vw. d in [A]: 15.1±0.2(st), 10.9±0.2(w), 10.3±0.2(vw), 7.66±0.1(vw), 7.21±0.1(vw), 5.12±0.05(vw),
4.75±0.05(vw).
The characteristic reflections in the X-ray diffraction diagram for the monohydrate of the magnesium salt of valsartan reveal the following plane intervals: d in [A]: 15.1 ±0.2, 10.9±0.2, 10.3±0.2, 7.66±0.1 , 5.12±0.05.
Corresponding hydrates and forms of the calcium or magnesium salt, respectively, of valsartan are disclosed and methods of manufacture described in WO02/06253 or WO03/066606, respectively, the corresponding subject of which is herein incorporated by reference.
The term "DPP-IV" as used herein is intended to mean dipeptidyl peptidase IV, also known as CD26. DPP-IV1 a serine protease belonging to the group of post-proline/alanine cleaving amino-dipeptidases, specifically removes the two N-terminal amino acids from proteins having proline or alanine in position 2. DPP-IV can be used in the control of glucose metabolism because its substrates include the insulinotropic hormones glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 and GIP are active only in their intact forms; removal of their two N-terminal amino acids inactivates them.
In vivo administration of synthetic inhibitors of DPP-IV prevents N- terminal degradation of GLP-1 and GIP, resulting in higher plasma concentrations of these hormones, increased insulin secretion and, therefore, improved glucose tolerance.
The term "DPP-IV inhibitor" is intended to indicate a molecule that exhibits inhibition of the enzymatic activity of DPP-IV and functionally related enzymes, such as from 1-100% or 20- 80% inhibition, and specially preserves the action of substrate molecules, including but not limited to GLP-1 , GIP, peptide histidine methionine, substance P, neuropeptide Y, and other molecules typically containing alanine or proline residues in the second amino terminal position. Treatment with DPP-IV inhibitors prolongs the duration of action of peptide substrates and increases levels of their intact, undegraded forms leading to a spectrum of biological activities relevant to the disclosed invention.
For that purpose, chemical compounds are tested for their ability to inhibit the enzyme activity of purified CD26/DPP-IV. Briefly, the activity of CD26/DPP-IV is measured in vitro by its ability to cleave the synthetic substrate Gly-Pro-p-nitroanilide (Gly-Pro-pNA). Cleavage of Gly-Pro-pNA by DPP-IV liberates the product p-nitroanilide (pNA), whose rate of appearance is directly proportional to the enzyme activity. Inhibition of the enzyme activity by specific enzyme inhibitors slows down the generation of pNA. Stronger interaction between an inhibitor and the enzyme results in a slower rate of generation of pNA. Thus, the degree of inhibition of the rate of accumulation of pNA is a direct measure of the strength of enzyme inhibition. The accumulation of pNA is measured spectrophotometrically. The inhibition constant, Ki, for each compound is determined by incubating fixed amounts of enzyme with several different concentrations of inhibitor and substrate.
In the present context "a DPP-IV inhibitor" is also intended to comprise active metabolites and prodrugs thereof, such as active metabolites and prodrugs of DPP-IV inhibitors. An active "metabolite" is an active derivative of a DPP-IV inhibitor produced when the DPP-iV inhibitor is metabolized. A "prodrug" is a compound that is either metabolized to a DPP-IV inhibitor or is metabolized to the same metabolite(s) as a DPP-IV inhibitor.
DPP-IV inhibitors are known in the art. For example, DPP-IV inhibitors are in each case generically and specifically disclosed e.g. in WO 98/19998.DE19616486 A1, WO 00/34241, WO 95/15309, WO 01/72290, WO01/52825, WO 9310127, WO 9925719, WO 9938501 , WO 9946272, WO 9967278 and WO 9967279. Preferred DPP-IV inhibitors are described in the following patent applications; WO 02053548 especially compounds 1001 to 1293 and examples 1 to 124, WO 02067918 especially compounds 1000 to 1278 and 2001 to 2159, WO 02066627 especially the described examples, WO 02/068420 especially all the compounds specifically listed in the examples I to LXIII and the described corresponding analogues, even preferred compounds are 2(28), 2(88), 2(119), 2(136) described in the table reporting IC50, WO 02083128 especially examples 1 to 13, US 2003096846 especially the specifically described compounds, WO 2004/037181 especially examples 1 to 33, WO 0168603 especially compounds of examples 1 to 109, EP1258480 especially compounds of examples 1 to 60, WO 0181337 especially examples 1 to 118, WO 02083109 especially examples 1A to 1 D, WO 030003250 especially compounds of examples 1 to 166, most preferably 1 to 8, WO 03035067 especially the compounds described in the examples, WO 03/035057 especially the compounds described in the examples, US2003216450 especially examples 1 to 450, WO 99/46272 especially compounds of claims 12, 14, 15 and 17, WO 0197808 especially compounds of claim 2, WO 03002553 especially compounds of examples 1 to 33, WO 01/34594 especially the compounds described in the examples 1 to 4, WO 02051836 especially examples 1 to 712, EP1245568 especially examples 1 to 7, EP1258476 especially examples 1 to 32, US 2003087950 especially the described examples, WO 02/076450 especially examples 1 to 128, WO 03000180 especially examples 1 to 162, WO 03000181 especially examples 1 to 66, WO 03004498 especially examples 1 to 33, WO 0302942 especially examples 1 to 68, US 6482844 especially the described examples, WO 0155105 especially the compounds listed in the examples 1 and 2, WO 0202560 especially examples 1 to 166, WO 03004496 especially examples 1 to 103, WO 03/024965 especially examples 1 to 54, WO 0303727 especially examples 1 to 209, WO 0368757 especially examples 1 to 88, WO 03074500 especially examples 1 to 72, examples 4.1 to 4.23, examples 5.1 to 5.10, examples 6.1 to 6.30, examples 7.1 to 7.23, examples 8.1 to 8.10, examples 9.1 to 9.30, WO 02038541 especially examples 1 to 53, WO 02062764 especially examples 1 to 293, preferably the compound of example 95 (2-{{3-(Aminomethyl)-4-butoxy-2-neopentyl-1-oxo-1,2 dihydro-6- isoquinolinyl}oxy}acetamide hydrochloride), WO 02308090 especially examples 1-1 to 1-109, examples 2-1 to 2-9, example 3, examples 4-1 to 4-19, examples 5-1 to 5-39, examples 6-1 to 6-4, examples 7-1 to 7-10, examples 8-1 to 8-8, examples 7-1 to 7-7 of page 90, examples 8-1 to 8-59 of pages 91 to 95, examples 9-1 to 9-33, examples 10-1 to 10-20, US 2003225102 especially compounds 1 to 115, compounds of examples 1 to 121.preferably compounds a) to z), aa) to az), ba) to bz), ca) to cz) and da) to dk), WO 0214271 especially examples 1 to 320 and US 2003096857.
In each case in particular in the compound claims and the final products of the working examples, the subject matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications.
Published patent application WO 9819998 discloses N- (N'-substituted glycyl)-2-cyano pyrrolidines, in particular 1-[2-[5-Cyanopyridin-2-yl] amino]- ethylamino] acetyl-2-cyano- (S)- pyrrolidine (NVP-DPP728).
DE19616 486 A1 discloses val-pyr, val-thiazolidide, isoleucyl-thiazolidide, isoleucyl- pyrrolidide, and fumaric salts of isoleucyl-thiazolidide and isoleucyl-pyrrolidide.
Published patent application WO 0034241 and published patent US 6110949 disclose N- substituted adamantyl-amino-acetyl-2-cyano pyrrolidines and N-(substituted glycyl)-4-cyano pyrrolidines respectively. DPP-IV inhibitors of interest are specially those cited in claims 1 to 4. In particular thes applications describe the compound 1-[[(3-Hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)-pyrrolidine (aslso known as LAF237).
Published patent application WO 9515309 discloses amino acid 2- cyanopyrrolidine amides as inhibitors of DPP-IV Published patent application WO 9529691 discloses peptidyl derivates of diesters of alpha-aminoalkylphosphonic acids, particularly those with proline or related structures. DPP-IV inhibitors of interest are specially those cited in Table 1 to 8.
In WO 01/72290 DPP-IV inhibitors of interest are specially those cited in example 1 and claims 1 , 4, and 6.
WO01 /52825 specially discloses (S)-1 -{2-[5-cyanopyridin-2yl)amino]ethyl-aminoacetyl)-2- cyano- pyrrolidine or (S)-1 -[(3-hydroxy-1-adamantyl)amino]acetyl-2- cyano-pyrrolidine.
Published patent application WO 9310127 discloses proline boronic esters useful as DPP-IV inhibitors. DPP-IV inhibitors of interest are specially those cited in examples 1 to 19. Published patent application WO 9925719 discloses sulphostin, a DPP-IV inhibitor prepared by culturing a Streptomyces microorganism.
Published patent application WO 9938501 discloses N-substituted 4-8 membered heterocyclic rings. DPP-IV inhibitors of interest are specially those cited in claims 15 to 20. Published patent application WO 9946272 discloses phosphoric compounds as inhibitors of DPP-IV. DPP-IV inhibitors of interest are specially those cited in claims 1 to 23.
Published patent applications WO 9967278 and WO 9967279 disclose DPP-IV prodrugs and inhibitors of the form A-B-C where C is either a stable or unstable inhibitor of DPP-IV.
Any of the substances disclosed in the above mentioned patent documents, hereby included by reference, are considered potentially useful as DPP-IV inhibitors to be used in carrying out the present invention.
In a further preferred embodiment, the DPP-IV inhibitor is a N-peptidyl-O-aroyl hydroxylamine or a pharmaceutically acceptable salt thereof. Aroyl is, for example, naphthylcarbonyl; or benzoyl which is unsubstituted or mono- or disubstituted, for example, by lower alkoxy, lower alkyl, halogen or, preferably, nitro. The peptidyl moiety comprises preferably two α-amino acids, e.g. glycine, alanine, leucine, phenylalanine, lysine or proline, of which the one attached directly to the hydroxylamine nitrogen atom is preferably proline.
Preferably, the N-peptidyl-O-aroyl hydroxylamine is a compound of formula VII
Figure imgf000039_0001
wherein j is O, 1 or 2;
Rs1 represents the side chain of a natural amino acid; and
Rs2 represents lower alkoxy, lower alkyl, halogen or nitro; or a pharmaceutically acceptable salt thereof.
In a very preferred embodiment of the invention, the N-peptidyl-O-aroyl hydroxylamine is a compound of formula Vila
Figure imgf000040_0001
or a pharmaceutically acceptable salt thereof.
N-Peptidyl-O-aroyl hydroxylamines, e.g. of formula VII or Vila, and their preparation are described by H. U. Demuth et al. in J. Enzyme Inhibition 1988, Vol. 2, pages 129-142, especially on pages 130-132.
Preferred DPP-IV inhibitors are N-substituted adamantyl-amino- acetyl-2-cyano pyrrolidines, N (substituted glycyl)-4-cyano pyrrolidines, N- (N'-substituted glycyl)-2-cyanopyrrolidines, N- aminoacyl thiazolidines, N-aminoacyl pyrrolidines, L-allo-isoleucyl thiazolidine, L-threo- isoleucyl pyrrolidine, and L-allo-isoleucyl pyrrolidine, 1-[2-[(5-cyanopyridin-2-yl) amino] ethylamino] acetyl-2-cyano-(S)-pyrroIidine and pharmaceutical salts thereof.
Preferred DPP-IV inhibitors are those described by Mona Patel and col. (Expert Opinion Investig Drugs. 2003 Apr;12(4):623-33) on the paragraph 5, especially P32/98, K-364, FE- 999011, BDPX, NVP-DDP-728 and others, which publication is hereby incorporated by reference especially the described DPP-IV inhibitors.
FE-999011 is described in the patent application WO 95/15309 page 14, as compound No. 18.
P32/98 or P3298 (CAS number: 251572-86-8) also known as 3-[(2S,3S)-2-amino-3-methyl- 1-oxopentyl]thiazolidine can be used as 3-[(2S,3S)-2-amino-3-methyl-1- oxopentyl]thiazolidine and (2E)-2-butenedioate (2:1) mixture such as shown below
N
Figure imgf000040_0002
and is described in WO 99/61431 in the name of Probiodrug and also the compound P 93/01.
Other very preferred DPP-IV inhibitors of the invention are described in the International patent application WO 02/076450 (especially the examples 1 to 128) and by Wallace T. Ashton (Bioorganic & Medicinal Chemistry Letters 14 (2004) 859-863 ) especially the compound 1 and the compounds listed in the tables 1 and 2. The preferred compound is the compound 21e (table 1) of formula
Figure imgf000041_0001
Other preferred DPP-IV inhibitors are described in the patent applications WO 2004/037169 especially those described in the examples 1 to 48 and WO 02/062764 especially the described examples 1 to 293, even preferred are the compounds 3-(aminomethyl)-2- isobuthyl-1-oxo-4-phenyl-1 ,2-dihydro-6-isoquinolinecarboxamide and 2-{[3-(aminomethyl)-2- isobuthyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]oxy}acetamide described on page 7 and also in the patent application WO2004/024184 especially in the reference examples 1 to 4.
Other preferred DPP-IV inhibitors are described in the patent application WO 03/004498 especially examples 1 to 33 and most preferably the compound of the formula
Figure imgf000041_0002
MK-0431 described by the example 7 and also known as MK-0431.
Preferred DPP-IV inhibitors are also described in the patent application WO 2004/037181 especially examples 1 to 33 and most preferably the compounds described in the claims 3 to 5.
Especially preferred are 1-{2-[(5-cyanopyridin-2-yl) amino] ethylamino} acetyl-2 (S)- cyano- pyrrolidine dihydrochloride (DPP728), of formula
Figure imgf000042_0001
especially the dihydrochloride thereof, and most preferred (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2- cyano-pyrrolidine
(LAF237) of formula
N
Figure imgf000042_0002
and L-threo-isoleucyl thiazolidine (compound code according to Probiodrug: P32/98 as described above), MK-0431, 3-(aminomethyl)-2-isobuthyl-1-oxo-4-phenyl-1 ,2-dihydro-6- isoquinolinecarboxamide and 2-{[3-(aminomethyl)-2-isobuthyl-4-phenyl-1-oxo-1,2-dihydro-6- isoquinolyl]oxy}acetamide and optionally pharmaceutical salts thereof.
DPP728 and LAF237 are specifically disclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241, respectively. The DPP-IV inhibitor P32/98 (see above) is specifically described in Diabetes 1998, 47, 1253-1258. DPP728 and LAF237 can be formulated as described on page 20 of WO 98/19998 or in WO 00/34241.
Especially preferred are orally active DPP-IV inhibitors.
In each case in particular in the compound claims and the final products of the working examples, the subject matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications.
DPP-IV is responsible for inactivating GLP-1. More particularly, DPP-IV generates a GLP-1 receptor antagonist and thereby shortens the physiological response to GLP-1. GLP-1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose disposal. Non-insulin dependent diabetes mellitus (type 2 diabetes mellitus) is characterized by both increased peripheral insulin resistance and abnormal insulin secretion. At least three abnormalities of insulin secretion are recognized: in the first phase, insulin secretion is lost and in the second phase insulin is both delayed and inadequate in the face of elevated circulating glucose levels. Several metabolic, hormonal, and pharmacological entities are known to stimulate insulin secretion including glucose, amino-acids and gastrointestinal peptides. The Diabetes Control and Complications Trial (DCCT) has established that lowering of blood glucose is associated with decreases in the onset and progression of diabetic microvascular complications (Diabetes Control and Complications Trial Research Group; N. Engl. J. Med. 1993, 329, 977-986). IGT is an impairment of glucose homeostasis closely related to type 2 diabetes mellitus. Both conditions convey a great risk of macrovascular disease. Therefore, one therapeutic focus is on optimizing and potentially normalizing glycemic control in subjects with type 2 diabetes mellitus, conditions of impaired fasting plasma glucose, or IGT. Presently available agents need to be improved in order to better meet this therapeutic challenge.
The present invention especially relates to a combination which comprises calcium or magnesium salt of the AT^ receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1-yl)-N- pentanoyl-N-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan), and at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.
Preferably, a further antidiabetic compound is selected from the group consisting of insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (GβPase), inhibitors of fructose- 1 ,6- bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, α-glucosidase inhibitors, inhibitors of gastric emptying, insulin, and α2- adrenergic antagonists, or the pharmaceutically acceptable salts of such a compound and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use, particularly in the prevention, delay of progression or treatment of conditions mediated by DPP-IV, in particular conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity and osteoporosis, and preferably diabetes, especially type 2 diabetes mellitus. Such a combination is preferably a combined preparation or a pharmaceutical composition.
Examples of "inhibitors of PTPase" include, but are not limited to those disclosed in U.S. Patent No. 6,057,316, U.S. Patent No. 6,001,867, WO 99/58518, WO 99/58522, WO 99/46268, WO 99/46267, WO 99/46244, WO 99/46237, WO 99/46236, WO 99/15529 and by Poucheret et al in MoI. Cell Biochem. 1998, 188, 73-80.
Examples of "non-small molecule mimetic compounds" include, but are not limited to those disclosed in Science 1999, 284; 974-97, especially L-783,281 , and WO 99/58127, especially CLX-901.
Examples of "inhibitors of GFAT" include, but are not limited to those disclosed in MoI. Cell. Endocrinol. 1997,135(1), 67-77.
The term "inhibitors of GδPase" used herein means a compound or composition which reduces or inhibits hepatic gluconeogenesis by decreasing or inhibiting the activity of G6Pase. Examples of such compounds are disclosed in WO 00/14090, WO 99/40062, WO 98/40385, EP682024 and Diabetes 1998, 47, 1630-1636.
The term "inhibitors of F-1 ,6-BPase" used herein means a compound or composition which reduces or inhibits hepatic gluconeogenesis by decreasing or inhibiting the activity of F-1,6- BPase. Examples of such compounds are disclosed in WO 00/14095, WO 99/47549, WO 98/39344, WO 98/39343 and WO 98/39342.
The term "inhibitors of GP" used herein means a compound or composition which reduces or inhibits hepatic glycogenosis by decreasing or inhibiting the activity of GP. Examples of such compounds are disclosed in EP 978279, US Patent No. 5998463, WO 99/26659, EP 846464, WO 97/31901, WO 96/39384, WO9639385 and in particular CP-91149 as described in Proc. Natl. Acad Sci USA 1998. 95. 1776-1781.
The term "glucagon receptor antagonists" as used herein relates in particular to the compounds described in WO 98/04528, especially BAY27-9955, and those described in Bioorg Med. Chem. Lett 1992, 2, 915-918, especially CP-99,711 , J. Med. Chem. 1998, 41, 5150-5157, especially NNC 92-1687, and J. Biol Chem. 1999, 274; 8694-8697, especially L- 168,049 and compounds disclosed in US 5,880,139, WO 99/01423, US 5,776,954, WO 98/22109, WO 98/22108, WO 98/21957 and WO 97/16442.
The term "inhibitors of PEPCK" used herein means a compound or composition which reduces or inhibits hepatic gluconeogenesis by decreasing or inhibiting the activity of PEPCK. Examples of such compounds are disclosed in U.S. Patent No. 6,030,837 and MoI. Biol. Diabetes 1994, 2, 283-99.
The term "PDHK inhibitors" as used herein means inhibitors of pyruvate dehydrogenase kinase and include, but are not limited to, those compounds disclosed by Aicher et al in J. Med. Chem. 42 (1999) 2741-2746.
The term "insulin sensitivity enhancer" used herein means any and all pharmacological active compounds that enhance the tissue sensitivity towards insulin. Insulin sensitivity enhancers include, e.g., inhibitors of GSK-3, retinoid X receptor (RXR) agonists, agonists of Beta-3 AR, agonists of UCPs, antidiabetic thiazolidinediones (glitazones), non-glitazone type PPARγ agonists, dual PPARγ / PPARα agonists, antidiabetic vanadium containing compounds and biguanides, e.g., metformin.
The insulin sensitivity enhancer is preferably selected from the group consisting of antidiabetic thiazolidinediones, antidiabetic vanadium containing compounds and metformin.
In one preferred embodiment, the insulin sensitivity enhancer is metformin.
Examples of "inhibitors of GSK-3" include, but are not limited to those disclosed in WO 00/21927 and WO 97/41854.
By "RXR agonist" is meant a compound or composition which when combined with RXR homodimers or heterodimers increases the transcriptional regulation activity of RXR, as measured by an assay known to one skilled in the art, including, but not limited to, the "co- transfection" or "cis-trans" assays described or disclosed in U.S. Pat. Nos. 4,981 ,784, 5,071,773, 5,298,429, 5,506,102, WO89/05355, WO91/06677, WO92/05447, WO93/11235, WO95/18380, PCT/US93/04399, PCT/US94/03795 and CA 2,034,220, which are incorporated by reference herein. It includes, but is not limited to, compounds that preferentially activate RXR over RAR (i.e. RXR specific agonists), and compounds that activate both RXR and RAR (i.e. pan agonists). It also includes compounds that activate RXR in a certain cellular context but not others (i.e. partial agonists). Compounds disclosed or described in the following articles, patents and patent applications which have RXR agonist activity are incorporated by reference herein: U.S. Pat. Nos. 5,399,586 and 5,466,861 , WO96/05165, PCT/US95/16842, PCT/US95/16695, PCT/US93/10094, WO94/15901 , PCT/US92/11214, WO93/11755, PCT/US93/10166, PCT/US93/10204, WO94/15902, PCT/US93/03944, WO93/21146, provisional applications 60,004,897 and 60,009,884, Boehm, et al. J. Med. Chem. 38(16):3146-3155, 1994, Boehm, et al. J. Med. Chem. 37(18):2930-2941 , 1994, Antras et al., J. Biol. Chem. 266:1157-1161 (1991), Salazar-Olivo et al., Biochem. Biophys. Res. Commun. 204:157-263 (1994) and Safanova, MoI. Cell. Endocrin. 104:201-211 (1994). RXR specific agonists include, but are not limited to, LG 100268 (i.e. 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-cyclopropyl]- py ridine-5-carboxyIic acid) and LGD 1069 (i.e. 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro- 2-naphthyl)-2-carbonyl]-benzo ic acid), and analogs, derivatives and pharmaceutically acceptable salts thereof. The structures and syntheses of LG 100268 and LGD 1069 are disclosed in Boehm, et al. J. Med. Chem. 38(16):3146-3155, 1994, incorporated by reference herein. Pan agonists include, but are not limited to, ALRT 1057 (i.e. 9-cis retinoic acid), and analogs, derivatives and pharmaceutically acceptable salts thereof.
Examples of "agonists of Beta-3 AR" include, but are not limited to CL-316,243 (Lederle Laboratories) and those disclosed in WO 99/29672, WO 98/32753, WO 98/20005, WO 98/09625, WO 97/46556, WO 97/37646 and U.S. Patent No. 5,705,515.
The term "agonists of UCPs" used herein means agonists of UCP-1 , preferably UCP-2 and even more preferably UCP-3. UCPs are disclosed in Vidal-Puig et al., Biochem. Biophys. Res. Commun., Vol. 235(1) pp. 79-82 (1997). Such agonists are a compound or composition which increases the activity of UCPs.
The antidiabetic thiazolidinedione (glitazone) is, for example, (S)-((3,4-dihydro-2-(phenyl- methyl)-2H-1 -benzopyran-6-yl)methyl-thiazolidine-2,4-dione (englitazone), 5-{[4-(3-(5-methyl- 2-phenyl-4-oxazolyl)-1-oxopropyl)-phenyl]-methyl}-thiazolidine-2,4-dione (darglitazone), 5- {[4-(1 -methyl-cyclohexyOmethoxyVphenylJmethylHhiazolidine^^-dione (ciglitazone), 5-{[4- (2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (DRF2189), 5-{4-[2-(5-methyl-2- phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine-2,4-dione (BM-13.1246), 5-(2- naphthylsulfonyl)-thiazoiidine-2,4-dione (AY-31637), bis{4-[(2,4-dioxo-5-thiazolidinyl)- methyl]phenyl}methane (YM268), 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]- benzyl}-thiazolidine-2,4-dione (AD-5075), 5-[4-(1 -phenyl-1 -cyclopropanecarbonylamino)- benzyl]-thiazolidine-2,4-dione (DN-108) 5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl}- thiazolidine-2,4-dione, 5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4- dione, 5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione, 5- {[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (rosiglitazone), 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}thiazoIidine-2,4-dione (pioglitazone), 5-{[4- ((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl}- thiazolidine-2,4-dione (troglitazone), 5-[6-(2-fluoro-benzyloxy)naphthalen-2-ylmethyl]- thiazolidine-2,4-dione (MCC555), 5-{[2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4- dione (T-174) and 5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl- benzyl)benzamide (KRP297).
Preferably, the antidiabetic thiazolidinedione is a compound of formula VIII,
Figure imgf000047_0001
wherein
M represents naphthyl, benzoxazolyl, dihydrobenzopyranyl, indole, phenyl (optionally substituted by halogen) or phenylethynyl (optionally substituted by halogen);
Rp1 represents halogen or a radical -QRp4, in which Q can be oxygen, lower alkylen, carbonyl or -NH-, Rβ4 is naphthyl; phenyl, unsubstituted or substituted by 2,4-dioxo-5-thiazolidinyl; or lower alkyl or hydroxy lower alkyl, unsubstituted or substituted by a) indole or 2,3-dihydroindole, b) pyridyl, lower alkyl-pyridyl, N-lower alkyl-N-pyridylamino or halogenphenyl, c) dihydrobenzopyranyl, which is unsubstituted or substituted by hydroxy and lower alkyl, d) oxazolyl, which is substituted by lower alkyl and phenyl, e) cycloalkyl, which is unsubstituted or substituted by lower alkyl, or f) arylcycloalkylcarbonyl;
Rβ2 represents hydrogen or trifluoromethylphenyl-lower alkyl carbamoyl; and
Rβ3 represents hydrogen or arylsulfonyl; or a pharmaceutically acceptable salt thereof.
Preferably, the compound of formula VIII is selected from the group consisting of (S)-((3,4- dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione (englitazone), 5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl)-phenyl]-methyl}-thiazolidine-2,4-dione (darglitazone), δ-^-CI-methyl-cyclohexyOmethoxyVphenyllmethylJ-thiazolidine^^-dione (ciglitazone), 5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (DRF2189), 5- {4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine-2,4-dione (BM-13.1246), 5- (2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY-31637), bis{4-[(2,4-dioxo-5- thiazolidinyl)methyl]phenyl}methane (YM268), 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2- hydroxyethoxy]benzyl}-thiazolidine-2,4-dione (AD-5075), 5-[4-(1 -phenyl-1 - cyclopropanecarbonylaminoj-benzyll-thiazolidine^^-dione (DN-108) 5-{[4-(2-(2,3- dihydroindol-1-yl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione, 5-[3-(4-chloro-phenyl])-2- propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl])-2-propynyl]-5-(4- fluorophenyl-sulfonyl)thiazolidine-2,4-dione, 5-[6-(2-fluoro-benzyloxy)naphthaIen-2-ylmethyl]- thiazolidine-2,4-dione (MCC555), 5-{[2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4- dione (T-174) and 5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl- benzyl)benzamide (KRP297) or a pharmaceutically acceptable salt thereof.
More preferably, the compound of formula VIII is selected from the group consisting of 5-{[4- (2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (rosiglitazone), 5- {[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}thiazolidine-2,4-dione (pioglitazone) and 5-{[4- ((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl}- thiazolidine-2,4-dione (troglitazone), MCC555, T-174 and KRP297, especially rosiglitazone, pioglitazone and troglitazone, or a pharmaceutically acceptable salt thereof. The glitazones 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}thiazolidine-2,4-dione (pioglitazone, EP O 193 256 A1), 5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}- thiazolidine-2,4-dione (rosiglitazone, EP 0 306 228 A1), 5-{[4-((3,4-dihydro-6-hydroxy- 2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl}thiazolidine-2,4-dione (troglitazone, EP O 139421), (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6- yl)methyl-thiazoIidine-2,4-dione (englitazone, EP 0 207 605 B1), 5-(2,4-dioxothiazo!idin-5- ylmethyl)-2-methoxy-N-(4-trifluoromethyI-benzyl)benzamide (KRP297, JP 10087641-A), 5-[6- (2-fluoro-benzyloxy)naphthalen-2-ylmethyl]thiazolidine-2,4-dione (MCC555, EP 0 604 983 B1 ), 5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1 -oxopropyl)-phenyl]-methyl}-thiazolidine-2,4- dione (darglitazone, EP 0 332 332), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY-31637, US 4,997,948), 5-{[4-(1 -methyl-cyclohexylJmethoxyy-phenylJmethylHhiazolidine^^-dione (ciglitazone, US 4,287,200) are in each case genetically and specifically disclosed in the documents cited in brackets beyond each substance, in each case in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications. The preparation of DRF2189 and of 5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione is described in B.B. Lohray et al., J. Med. Chem. 1998, 41, 1619-1630; Examples 2d and 3g on pages 1627 and 1628. The preparation of 5-[3-(4-chlorophenyl])-2-propynyl]-5-phenylsulfonyl)- thiazolidine-2,4-dione and the other compounds in which A is phenylethynyl mentioned herein can be carried out according to the methods described in J. Wrobel et al., J. Med. Chem. 1998, 41, 1084-1091.
In particular, MCC555 can be formulated as disclosed on page 49, lines 30 to 45, of EP 0 604 983 B1 ; englitazone as disclosed from page 6, line 52, to page 7, line 6, or analogous to Examples 27 or 28 on page 24 of EP 0 207 605 B1; and darglitazone and 5-{4-[2-(5-methyl- 2-phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine-2,4-dione (BM-13.1246) can be formulated as disclosed on page 8, line 42 to line 54 of EP 0 332 332 Bl AY-31637 can be administered as disclosed in column 4, lines 32 to 51 of US 4,997,948 and rosiglitazone as disclosed on page 9, lines 32 to 40 of EP 0 306 228 A1, the latter preferably as its maleate salt. Rosiglitazone can be administered in the form as it is marketed e.g. under the trademark AVANDIA™. Troglitazone can be administered in the form as it is marketed e.g. under the trademarks ReZulin™, PRELAY™, ROMOZIN™ (in the United Kingdom) or NOSCAL™ (in Japan). Pioglitazone can be administered as disclosed in Example 2 of EP 0 193 256 A1, preferably in the form of the monohydrochloride salt. Corresponding to the needs of the single patient it can be possible to administer pioglitazone in the form as it is marketed e.g. under the trademark ACTOS™. Ciglitazone can, for example, be formulated as disclosed in Example 13 of US 4,287,200.
Non-glitazone type PPARγ agonists are especially N-(2-benzoylphenyl)-L-tyrosine analogues, e.g. GI-262570, and JTT501.
The term "dual PPARγ / PPARα agonists" as used herein means compounds which are at the same time PPARγ and PPARα agonists. Preferred dual PPARγ / PPARα agonists are especially those ω-[(oxoquinazolinylalkoxy)phenyl]alkanoates and analogs thereof , very especially the compound DRF-554158, described in WO 99/08501 and the compound NC- 2100 described by Fukui in Diabetes 2000, 49(5), 759-767.
A preferred "dual PPARγ / PPARα agonist" is compound of the formula (I)
wherein
L is
Figure imgf000050_0001
radical in which R1 is hydrogen, optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl;
R2 is hydrogen, hydroxy, optionally substituted alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, alkylthio, arylthio or aralkylthio;
R3 is hydrogen or aryl; or
R2 and R3 combined are alkylene which together with the carbon atoms they are attached to form a 5- to 7-membered ring; n is zero or an integer from 1 to 2; Y is hydrogen; or Y and R2 taken together with the carbon atoms they are attached to form a bond provided that n is 1 ;
R4 is hydrogen; or
R4 and Y taken together with the carbon atoms they are attached to form a bond provided that n is 1 , and R2 and R3 taken together with the carbon atoms they are attached to form a bond; or
L is
Figure imgf000051_0001
radical in which R1 is hydrogen, optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl;
R" is hydrogen, optionally substituted alkyl, alkoxy or halogen; m is an integer from 1 to 2; Y is hydrogen; R4 is hydrogen; or
R4 and Y taken together with the carbon atoms they are attached to form a bond provided that m is 1 ;
R and R' are independently hydrogen, halogen, optionally substituted alkyl, alkoxy, aralkyl or heteroaralkyl; or
R and R' combined together form a methylenedioxy group provided that R and R' are attached to carbon atoms adjacent to each other; or
R and R' combined together with the carbon atoms they are attached to form an optionally substituted 5- to 6-membered aromatic or heteroaromatic ring provided that R and R' are attached to carbon atoms adjacent to each other; or
R-C and R'-C may independently be replaced by nitrogen;
X is -Z-(CH2)p-Q-W wherein Z is a bond, O, S, -C(O)- or -C(O)NR5- in which
R5 is hydrogen, alkyl or aralkyl; p is an integer from 1 to 8;
Q is a bond provided that Z is not a bond when p is 1 ; or Q is -O(CH2)r or -S(CH2)r-, in which r is zero or an integer from 1 to 8; or
Q is -0(CH2)I-BO-, -S(CH2)1-8O-, -S(CH2)i.8S-, -C(O)- or -C(O)NR6- in which R6 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or
Q is -NR6-, -NR5C(O)-, -NR5C(O)NH- Or -NR5C(O)O- provided that p is not 1; W is cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; or
W and R6 taken together with the nitrogen atom to which they are attached form a 8- to 12-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
Preferred is a compound of the formula
Figure imgf000052_0001
wherein
L is
Figure imgf000052_0002
in which R1 is hydrogen or optionally substituted alkyl;
R2 and R3 are hydrogen; or
R2 and R3 combined are alkylene which together with the carbon atoms they are attached to form a 6-membered ring; n is zero or an integer from 1 to 2; Y is hydrogen; R4 is hydrogen; or L is
Figure imgf000053_0001
radical in which Ri is hydrogen or optionally substituted alkyl;
R" is hydrogen, optionally substituted alkyi, alkoxy or halogen; m is an integer from 1 to 2; Y is hydrogen; R4 is hydrogen;
R and R' are independently hydrogen, halogen, optionally substituted C1-6alkyl or C1-6alkoxy; or
R and R' combined together form a methylenedioxy group provided that R and R' are attached to carbon atoms adjacent to each other;
Z is a bond, O, S or -C(O)NR5- in which R5 is hydrogen, alkyl or aralkyl; p is an integer from 1 to 5;
Q is a bond provided that Z is not a bond when p is 1 ; or
Q is -O(CH2)r or -S(CH2)r- in which r is zero; or
Q is -C(O)- or -C(O)NR6- in which R6 is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or
Q is -NR6-, -NR5C(O)-, -NR5C(O)NH- or -NR5C(O)O- provided that p is not 1; W is cycloalkyl, aryl or heterocyclyl; or
W and R6 taken together with the nitrogen atom to which they are attached form a 9- to 10-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
Preferred is a compound of formula (I A), wherein L is
Figure imgf000054_0001
radical in which R1 is hydrogen or optionally substituted alkyl;
R2 and R3 are hydrogen; n is zero or an integer from 1 to 2; or
L is
Figure imgf000054_0002
radical in which R1 is hydrogen or optionally substituted alkyl;
R" is hydrogen; m is an integer from 1 to 2;
R is hydrogen, halogen, optionally substituted C1-6alkyl or C1-6alkoxy;
R' is hydrogen;
Z is a bond, O or S; p is an integer from 1 to 5;
Q is a bond provided that Z is not a bond when p is 1 ; or
Q is O, S or -C(O)NR6- in which R6 is hydrogen, optionally substituted alkyl or cycloalkyl; or
Q is -NR6-, -NR5C(O)NH- or -NR5C(O)O- in which R5 is hydrogen, alkyl or aralkyl provided that p is not 1 ;
W is cycloalkyl, aryl or heterocyclyl; or
W and R6 taken together with the nitrogen atom to which they are attached form a 9- to 10-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
Preferred is a compound of the formula wherein
L is
Figure imgf000055_0001
radical in which R1 is hydrogen or optionally substituted alkyl; n is zero or 1 ; or
L is
Figure imgf000055_0002
radical in which Ri is hydrogen or optionally substituted alkyl; m is 1;
R is hydrogen, halogen, optionally substituted C1-6alkyl or C1-6alkoxy;
Z is a bond, O or S; p is an integer from 1 to 5;
Q is a bond provided that Z is not a bond when p is 1 ; or
Q is O, S or -C(O)NR6- in which R6 is hydrogen, optionally substituted alkyl or cycloalkyl; or
Q is -NR6-, -NR5C(O)NH- or -NR5C(O)O- in which R5 is hydrogen, alkyl or aralkyl provided that p is not 1 ;
W is cycloalkyl, aryl or heterocyclyl; or
W and R6 taken together with the nitrogen atom to which they are attached form a 9- to 10-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
Preferred is a compound of formula (I B), wherein L is
Figure imgf000056_0001
radical in which R1 is hydrogen; and n is zero or 1;
R is hydrogen, halogen, optionally substituted C1-6alkyl or Ci-6alkoxy;
Z is a bond, O or S; p is an integer from 1 to 4;
Q is a bond provided that Z is not a bond when p is 1 ; or
Q is O or S;
W is aryl or heterocyclyl; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
Preferred is a compound of formula (I B), wherein
L is radical in which R1 is hydrogen;
R is hydrogen, halogen, optionally substituted C1-6alkyl or C1-6alkoxy;
Z is a bond, O or S; p is an integer from 1 to 4;
Q is a bond provided that Z is not a bond when p is 1 ; or
Q is O or S;
W is aryl or heterocyclyl; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
Preferred is a compound of formula (I B)1 wherein the asymmetric center in radical L is in the (R) configuration; or a pharmaceutically acceptable salt thereof.
Preferred is a compound of formula (I B), wherein R1 is hydrogen or optionally substituted alkyl; R is hydrogen, halogen, optionally substituted C1-6alkyl or C1-6alkoxy; Z is O or S; p is 2;
Q is a -NR6- in which R6 is lower alkyl; W is aryl or heterocyclyl; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
Preferred is a compound of formula (I B), wherein R is hydrogen, chloro, n-propyl or methoxy; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
Preferred is a compound of formula (I B), wherein Ri is hydrogen or optionally substituted alkyl; R is hydrogen, halogen, optionally substituted C1-6alkyl or C1-6alkoxy; Z is a bond; p is 2;
Q is a -C(O)NR6- in which R6 is optionally substituted alkyl; W is aryl or heterocyclyl; or
W and R6 taken together with the nitrogen atom to which they are attached form a 9- to 10-membered bicyclic ring, which may be optionally substituted or may contain another heteroatom selected from oxygen, nitrogen and sulfur; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof. Preferred is a compound of formula (I B), wherein R is hydrogen, chloro, n-propyl or methoxy; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
Preferred is a compound of formula (I B), wherein R1 is hydrogen or optionally substituted alkyl; R is hydrogen, halogen, optionally substituted C1-6alkyl or C1-6alkoxy; Z is a bond, O or S; p is an integer from 2 to 3; Q is O or S; W is aryl or heterocyclyl; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
Preferred is a compound of formula (I B), wherein R is hydrogen, chloro, n-propyl or methoxy; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
Preferred is a compound of formula (I B), wherein W is selected from the group consisting of:
Figure imgf000058_0001
Figure imgf000059_0001
or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
Preferred is a compound of formula (I B), wherein R1 is hydrogen or optionally substituted alkyl; R is hydrogen, halogen, optionally substituted Ci-6alkyl or C1-6alkoxy; Z is O or S; p is an integer from 1 to 2; Q is a bond; W is aryl or heterocyclyl; or a pharmaceutically acceptable salt thereof; or an optical isomer or a mixture of optical isomers thereof.
Preferred is a compound of formula (I B), wherein R is hydrogen, chloro, n-propyl or methoxy; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
Preferred is a compound of formula (I B), wherein W is selected from the group consisting of:
Figure imgf000060_0001
or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
Preferred is a compound of formula (I B), wherein R1 is hydrogen or optionally substituted alkyl;
R is hydrogen, halogen, optionally substituted Ci-6 alkyl or C1-6 alkoxy; Z is O or S; p is 2; Q is a bond; W is selected from the group consisting of:
Figure imgf000061_0001
or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers thereof.
Preferred is a compound of formula (I B)which is selected from the group consisting of:
(R)-1-{4-[4-(4-Phenoxy-2-propyl-phenoxy)-butoxy]-benzenesulfonyl}-azetidine-2- carboxylic acid;
(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-azetidine-2- carboxylic acid;
(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-azetidine-2- carboxylic acid;
(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxyJ-benzenesulfonyl}- azetidine-2-carboxylic acid;
(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}- azetidine-2-carboxylic acid; (R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzene- sulfonylj-azetidine^-carboxylic acid;
(R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-azetidine-2- carboxylic acid;
(R)-1-{4-[4-(4-Phenoxy-2-propyl-phenoxy)-butoxy]-benzenesulfonyl}-pyrrolidine-2- carboxylic acid;
(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-pyrrolidine-2- carboxylic acid;
(R)-1-(4-{3-[2-Propyl-4-(4-trifluoromethyl-phenoxy)-phenoxy]-propoxy}- benzenesulfonyl)-pyrrolidine-2-carboxylic acid;
(R)-1-{4-[2-(4-Phenoxy-2-propyl-phenoxy)-ethoxy]-benzenesulfonyl}-pyrrolidine-2- carboxylic acid;
(R)-1-(4-{2-[2-Propyl-4-(4-trifluoromethyl-phenoxy)-phenoxy]-ethoxy}- benzenesuIfonyl)-pyrrolidine-2-carboxylic acid;
(R)-1-{3-Methoxy-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}- pyrrolidine-2-carboxylic acid;
(R)-1-{3-Chloro-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}- pyrrolidine-2-carboxylic acid;
(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-3-propyl-benzenesulfonyl}- pyrrolidine-2-carboxylic acid;
{R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propylsulfanyl]-benzenesulfonyl}- pyrroIidine-2-carboxylic acid;
(R)-1-{4-[2-(4-Phenoxy-2-propyl-phenoxy)-ethylsulfanyl]-benzenesulfonyl}-pyrrolidine- 2-carboxylic acid;
(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propyl]-benzenesulfonyl}-pyrrolidine-2- carboxylic acid;
(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-pyrrolidine-2- carboxylic acid;
(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonyl}- pyrrolidine-2-carboxylic acid; (R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}- pyrrolidine-2-carboxylic acid;
(R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzene- sulfonylj-pyrrolidine^-carboxylic acid;
(R)-1-[4-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yimethoxy)-benzenesulfonyl]-pyrroIidine- 2-carboxylic acid;
(R)-1-[3-Methoxy-4-(5-methyl-2-phenyl-oxazoI-4-ylmethoxy)-benzenesulfonyl]- pyrrolidine-2-carboxylic acid;
(R)-1-[3-Chloro-4-(5-methyl-2-phenyI-oxazol-4-ylmethoxy)-benzenesulfonyl]- pyrrolidine-2-carboxylic acid;
(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-3-propyl-benzenesulfonyl]- pyrrolidine-2-carboxylic acid;
(RJ-i-^-Cδ-Methyl^-phenyl-oxazoM-ylmethylsulfanyO-benzenesulfonylJ-pyrrolidine- 2-carboxyIic acid;
(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}- pyrrolidine-2-carboxylic acid;
(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl3- benzenesulfonylJ-pyrrolidiπe-2-carboxylic acid;
(R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]- benzenesulfonylJ-pyrrolidine-2-carboxylic acid;
(R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-pyrrolidine-2- carboxylic acid;
(R)-1-{3-Methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}- pyrrolidine-2-carboxylic acid;
(RJ-i-fS-Chloro^-^-CS-methyl^-phenyl-oxazoM-yO-ethoxyJ-benzenesulfonyl}- pyrrolidine-2-carboxyIic acid;
(R)-1-(4-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}- benzenesulfonyl)-pyrrolidine-2-carboxylic acid;
(R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylsulfanyl]-benzenesulfonyl}- pyrrolidine-2-carboxylic acid; (R)-1-{4-[4-(4-Phenoxy-2-propyl-phenoxy)-butoxy]-benzenesulfonyl}-2,3-dihydro-1H- indole-2-carboxyIic acid;
(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H- indole-2-carboxylic acid;
(R)-1-{4-[2-(4-Phenoxy-2-propyl-phenoxy)-ethoxy]-benzenesulfonyl}-2,3-dihydro-1H- indole-2-carboxylic acid;
(R)-1-{3-Methoxy-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3- dihydro-1 H-indole-2-carboxylic acid;
(R)-1-{3-Chloro-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3- dihydro-1 H-indole-2-carboxylic acid;
(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3-dihydro-1H- indole-2-carboxylic acid;
(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3- dihydro-1 H-indole-2-carboxylic acid;
(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}- 2,3-dihydro-1 H-indole-2-carboxylic acid;
(R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzene- sulfonyl}-2,3-dihydro-1 H-indole-2-carboxylic acid;
(R)-1-[3-Methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3- dihydro-1 H-indole-2-carboxylic acid;
(R)-1-[3-Chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3- dihydro-1 H-indole-2-carboxylic acid;
(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-3-propyl-benzenesulfonyl]-2,3- dihydro-1 H-indole-2-carboxylic acid;
(RJ-i-^-Cδ-MethyW-phenyl-oxazoM-ylmethylsulfanyO-benzenesulfonylJ^.S-dihydro- 1 H-indole-2-carboxylic acid;
(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]-benzenesulfonyl}- 2,3-dihydro-1 H-indole-2-carboxylic acid;
(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]- benzenesulfonyl}-2,3-dihydro-1 H-indole-2-carboxylic acid; (R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]- benzenesulfonyl}-2,3-dihydro-1 H-indole-2-carboxylic acid;
(^-i^-p-Cδ-Methyl-a-phenyl-oxazoM-yO-ethoxyl-benzenesulfonylJ-Σ.S-dihydro-I H- indole-2-carboxylic acid; and
(RJ-I^S-Chloro^-^-Cδ-methyl^-phenyl-oxazoM-yO-ethoxyl-benzenesulfonylJ^.S- dihydro-1 H-indole-2-carboxylic acid; (R)-1 -{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethylsulfanylj-benzene-sulfonyty-pyrrolidine^-carboxylic acid;
(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-benzene- sulfonyl}-2,3-dihydro-1 H-indole-2-carboxylic acid; or a pharmaceutically acceptable salt thereof; or an enantiomer thereof; or a mixture of enantiomers thereof.
Corresponding "dual PPARγ / PPARα agonists" are disclosed and methods of manufacture described in WO03/043985, the corresponding subject of which is herein incorporated by reference.
Preferably, the antidiabetic vanadium containing compound is a physiologically tolerable vanadium complex of a bidentate monoprotic chelant, wherein said chelant is an α- hydroxypyrone or α-hydroxypyridinone, especially those disclosed in the Examples of US 5,866,563, of which the working examples are hereby incorporated by reference, or a pharmaceutically acceptable salt thereof.
The preparation of metformin (dimethyldiguanide) and its hydrochloride salt is state of the art and was disclosed first by Emil A. Werner and James Bell, J. Chem. Soc. 121, 1922, 1790- 1794. Metformin, can be administered e.g. in the form as marketed under the trademarks GLUCOPHAGE™.
Insulin secretion enhancers are pharmacological active compounds having the property to promote secretion of insulin from pancreatic β cells. Examples for insulin secretion enhancers include glucagon receptor antagonists (see above), sulphonyl urea derivatives, incretin hormones, especially glucagon-like peptide- 1 (GLP-1) or GLP-1 agonists, β-cell imidazoline receptor antagonists, and short-acting insulin secretagogues, like antidiabetic phenylacetic acid derivatives, antidiabetic D-phenylalanine derivatives and BTS 67582 described by T. Page et al in Br. J. Pharmacol. 1997, 122, 1464-1468.
The sulphonyl urea derivative is, for example, glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibomuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide or tolcyclamide; and preferably glimepiride or gliclazide. Tolbutamide, glibenclamide, gliclazide, glibomuride, gliquidone, glisoxepid and glimepiride can be administered e.g. in the form as they are marketed under the trademarks RASTINON HOECHST™, AZUGLUCON™, DIAMICRON™, GLUBORID™, GLURENORM™, PRO-DIABAN™ and AMARYL™, respectively.
GLP-1 is a insulinotropic proteine which was described, e.g., by W.E. Schmidt et al. in Diabetologia 28, 1985, 704-707 and in US 5,705,483. The term "GLP-1 agonists" used herein means variants and analogs of GLP-1 (7-36)NH2 which are disclosed in particular in US 5,120,712, US 5,118666, US 5,512,549, WO 91/11457 and by C. Orskov et al in J. Biol. Chem. 264 (1989) 12826. The term "GLP-1 agonists" comprises especially compounds like GLP-1 (7-37), in which compound the carboxy-terminal amide functionality of Arg36 is displaced with GIy at the 37th position of the GLP-1 (7-36)NH2 molecule and variants and analogs thereof including GLN9-GLP-1(7-37), D-GLN9-GLP-1(7-37), acetyl LYS9-GLP-1 (7- 37), LYS18-GLP-1(7-37) and, in particular, GLP-1 (7-37)OH, VAL8-G LP- 1(7-37), GLY8-GLP- 1(7-37), THR8-GLP-1(7-37), M ET'-G LP- 1(7-37) and 4-imidazopropionyl-GLP-1. Special preference is also given to the GLP agonist analog exendin-4, described by Greig et al in Diabetologia 1999, 42, 45-50.
The term "β-cell imidazoline receptor antagonists" as used herein means compounds as those described in WO 00/78726 and by Wang et al in J. Pharmacol. Exp. Ther. 1996; 278; 82-89, e.g. PMS 812.
The antidiabetic phenylacetic acid derivative is preferably a compound of formula IX
(IX)
Figure imgf000067_0001
wherein
RS1 is an unbranched C4-C6alkyleneimino group which is unsubstituted or mono- or disubstituted by C-ι-C3alkyl; Rδ2 is hydrogen, halogen, methyl or methoxy; Rδ3 is hydrogen, Ci-C7alkyl, or phenyl which is unsubstituted or substituted by halogen, methyl or methoxy; Rδ4 is hydrogen, allyl, acetyl or propionyl or CVCaalkyl which is unsubstituted or substituted by phenyl; and W is methyl, hydroxymethyl, formyl, carboxy; or alkoxycarbonyl which comprises between 2 and up to and including 5 carbon atoms and in which the alkyl moiety of the alkoxy group is unsubstituted or substituted by phenyl or a pharmaceutically acceptable salt thereof.
Most preferably, the compound of formula IX is repaglinide or a pharmaceutically acceptable salt thereof.
The antidiabetic D-phenylalanine derivative is preferably a compound of formula X
wherein Ph has the meaning of phenyl,
Rγi is selected from hydrogen, C1 to C5 alkyl, C6 to C12aryl, C6 to C12 arylalkyl,
Figure imgf000068_0001
-CH2CO2Ry3, -CH(CH3)OCO-Ry3, and -CH2-OCO-C(CH3)3;
Ry2 is selected from groups comprising C6 to C12 aryl, heteroaryl, cycloalkyl, or cycloalkenyl, any of which groups may have one or more substitutents; and Ry3 is selected from hydrogen and Ci to C5 alky!, with the proviso that when Ry1 and Ry3 are both hydrogen then Ry2 is other than substituted or unsubstituted phenyl or naphthyl; or a pharmaceutically acceptable salts thereof or a precursor which can be converted thereto in the human or animal body.
If Ry2 represents heteroaryl, Ry2 is preferably quinolynyl, pyridyl or 2-benzofuranyl.
Most preferably, the antidiabetic D-phenylalanine derivative is nateglinide or a pharmaceutically acceptable salt thereof.
Nateglinide (N-[(fraλ7s-4-isopropylcyclohexyl)-carbonyI]-D-phenylalanine, EP 196222 and EP 526171) and repaglinide ((S)-2-ethoxy-4-{2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]- 2-oxoethyl}benzoic acid, EP O 147 850 A2, in particular Example 11 on page 61, and EP 0 207 331 A1) are in each case generically and specifically disclosed in the documents cited in brackets beyond each substance, in each case in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications. The term nateglinide as used herein comprises crystal modifications (polymorphs) such as those disclosed in EP 0526171 B1 or US 5,488,510, respectively, the subject matter of which is incorporated by reference to this application, especially the subject matter of claims 8 to 10 as well as the corresponding references to the B-type crystal modification. Preferably, in the present invention the B- or H- type, more preferably the H-type, is used. Repaglinde can be administered in the form as it is marketed e.g. under the trademark NovoNorm™. Nateglinide can be administered in the form as it is marketed e.g. under the trademark STARLIX™. α-Glucosidase inhibitors are pharmacological active compounds which inhibit small intestinal α-glucosidase enzymes which break down non-adsorbable complex carbohydrates into absorbable monosaccharides. Examples for such compounds are acarbose, N-(1 ,3- dihydroxy-2-propyl)valiolamine (voglibose) and the 1-deoxynojirimycin derivative miglitol. Acarbose is 4",6"-dideoxy-4"-[(1 S)-(I ,4,6/5)-4,5,6-trihydroxy-3-hydroxymethyl-2-cyclo- hexenylamino}maltotriose. The structure of acarbose can as well be described as 0-4,6- dideoxy-4-{[1S,4R,5S,6S]-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]-amino}-α-D- glucopyranosyl-(1 -→4)-0-α-D-glucopyranosyl-(1 -»4)-D-glucopyranose. Acarbose (US 4,062,950 and EP 0 226 121), is generically and specifically disclosed in the documents cited in brackets, in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications. Corresponding to the needs of the single patient it can be possible to administer acarbose in the form as it is marketed e.g. under the trademark GLUCOBA Y™. Miglitol can be administered in the form as it is marketed e.g. under the trademark DIASTABOL 50™
The α-glucosidase inhibitor is preferably selected from the group consisting of acarbose, voglibose and miglitol.
Examples of "inhibitors of gastric emptying" other than GLP-1 include, but are not limited to those disclosed in J. CHn. Endocrinol. Metab. 2000, 85(3), 1043-1048, especially CCK-8, and in Diabetes Care 1998; 21; 897-893, especially Amylin and analogs thereof, e.g. Pramlintide. Amylin is also described e.g. by O.G. Kolterman et al. in Diabetologia 39, 1996, 492-499.
Examples of "α2-adrenergic antagonists" include, but are not limited to midaglizole described in Diabetes 36, 1987, 216-220.
The term "prevention" means prophylactic administration of the combination to healthy patients to prevent the outbreak of the conditions mentioned herein. Moreover, the term "prevention" means prophylactic administration of such combination to patients being in a pre-stage of the conditions, especially diabetes, to be treated. The term "delay of progression" used herein means administration of the combination, such as a combined preparation or pharmaceutical composition, to patients being in a pre-stage of the condition, especially diabetes, to be treated in which patients a pre-form of the corresponding condition is diagnosed.
Examples of the preparation and formulation of inhibitors of PTPases, inhibitors of GSK-3, non-small molecule mimetic compounds, inhibitors of GFAT, inhibitors of GΘPase, glucagon receptor antagonists, inhibitors of PEPCK, inhibitors of F-1, 6-BPase, inhibitors of GP, RXR agonists, agonists of Beta-3 AR, PDHK inhibitors, inhibitors of gastric emptying and agonists of UCPs are disclosed in the patents and applications cited beyond each substance listed herein.
The structure of the active agents identified hereinbefore or hereinafter by generic or tradenames may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g., Patent Focus, e.g. IMS Life Cycle - IMS World Publications. The corresponding content thereof is hereby incorporated by reference.
Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.
The compounds to be combined can be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds having an acid group (for example COOH) can also form salts with bases. For example, the compounds to be combined can be present as a sodium salt, as a maleate or as a dihydrochloride. The active ingredient or a pharmaceutically acceptable salt thereof may also be used in form of a hydrate or include other solvents used for crystallization.
An antidiabetic compound, preferably selected from the group consisting of insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phopshate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (GδPase), inhibitors of fructose-1 ,6- bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase (GP)1 glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, α-glucosidase inhibitors, inhibitors of gastric emptying, insulin, and α2- adrenergic antagonists, or a pharmaceutically acceptable salt of such a compound, will be referred to hereinafter as COMBINATION PARTNER OF THE INVENTION.
A combined preparation which comprises the calcium or magnesium salt of the AT1 receptor antagonist (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)- biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION and optionally at least one, i.e., one or more, e.g. two, pharmaceutically acceptable carrier for simultaneous, separate or sequential use is especially a "kit of parts" in the sense that the components, the calcium or magnesium salt of the AT1 receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1 H- tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION, can be dosed independently or by use of different fixed combinations with distinguished amounts of the components, i.e. at different time points or simultaneously. The parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts. Preferably, the time intervals are chosen such that the effect on the treated disease or condition in the combined use of the parts is larger than the effect which would be obtained by use of only any one of the components. Preferably, there is at least one beneficial effect, e.g. a mutual enhancing of the effect of the calcium or magnesium salt of the AT1 receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1-yl)-N- pentanoyl-N-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION, additional advantageous effects, less side effects, a combined therapeutical effect in a non-effective dosage of one or each of the components, and especially a synergism, e.g. a more than additive effect, between the calcium or magnesium salt of the AT1 receptor antagonist (S)-N-(1-carboxy-2-methyl-prop-1- yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION. All the more surprising is the experimental finding that the combined administration of the calcium or magnesium salt of the AT^ receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-i - yl)-N-pentanoyl-N-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION results not only in a beneficial, especially a synergistic, therapeutic effect but also in additional benefits resulting from combined treatment such as a surprising prolongation of efficacy, a broader variety of therapeutic treatment and surprising beneficial effects on diseases and conditions associated with e.g. diabetes, e.g. less gain of weight.
Further benefits are that lower doses of the individual drugs to be combined according to the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.
It can be shown by established test models and especially those test models described herein that the combination with a DPP-IV inhibitor, especially (S)-1-{2-[5-cyanopyridin-2- yl)amino]ethyl-aminoacetyl}-2-cyano-pyrrolidine (DPP728) or (S)-1-[(3-hydroxy-1- adamantyl)amino]acetyl-2-cyano-pyrrolidine (LAF237), as further COMBINATION PARTNER OF THE INVENTION results in a more effective prevention or preferably treatment of conditions mediated by DPP-IV, in particular diabetes, especially type 2 diabetes mellitus, conditions of impaired fasting plasma glucose, and conditions of IGT.
The person skilled in the pertinent art is fully enabled to select a relevant animal test model to prove the hereinbefore and hereinafter indicated therapeutic indications and beneficial effects. The pharmacological activity may, for example, be demonstrated following essentially an in-vivo test procedure in mice or in a clinical study as described hereinafter.
In-vivo test in mice for blood glucose control
ICR-CDI mice (male, five weeks old, body weight: about 20 g) are abstained from food for 18 hours, and then used as test subjects. The combination according to the present invention and the active ingredients alone are suspended in 0.5% CMC-0.14M sodium chloride buffer solution (pH 7.4). The solution thus obtained is administered orally in fixed volume amounts to the test subjects. After predetermined time, the percentage decrease of the blood glucose against the control group is determined.
Clinical double-blind, randomized, parallel-group study in subjects with type 2 diabetes mellitus inadequately controlled on diet alone
This study proves in particular the synergism of the claimed combined preparation or pharmaceutical composition, respectively. The beneficial effects on conditions mediated by DPP-IV, in particular type 2 diabetes mellitus can be determined directly through the results of this study or by changes in the study design which are known as such to a person skilled in the art.
The study is, in particular, suitable to compare the effects of monotherapy with a COMBINATION PARTNER OF THE INVENTION with those of a combination of DPP-IV inhibitor plus one of these compounds on glycemic control.
Subjects with a diagnosis of type 2 diabetes mellitus who have not achieved near normoglycemia (HbA10 <6.8%) on diet only are chosen for this trial. The effects on glycemic control achieved with DPP-IV monotherapy, monotherapy with one COMBINATION PARTNER OF THE INVENTION, and the combination therapy of DPP-IV plus one COMBINATION PARTNER OF THE INVENTION are determined in this study after 24 weeks with the control achieved on placebo, all subjects continuing with the same diet as in the period before treatment. Measures of glycemic control are validated surrogate endpoints for the treatment of diabetes. HbA10 is the single most reliable measurement for assessing glycemic control (D. Goldstein et al, Tests of Glycemia in Diabetes; Diabetes Care 1995, 18(6), 896-909) and is the primary response variable in this study. Since glycosylation of hemoglobin is determined by the glucose concentration at the time each red blood cell is made, HbA10 provides an estimate of mean blood glucose for the previous three months.
Before starting with the double-blind treatment for 24 weeks, the subjects are administered for four weeks the placebos matching with the DPP-IV inhibitor, e.g. DPP728 and LAF237, before breakfast, lunch and dinner, and the placebos matching with one or more of the COMBINATION PARTNERS OF THE INVENTION (period I). For example, if the α- glucosidase inhibitors acarbose is chosen for the study, the placebo matching with acarbose is preferably administered together with the first bite of the meals taken for breakfast, lunch and dinner in period I. If the antidiabetic phenylacetic acid derivative repaglinide is chosen for the study, the placebos matching with repaglinide are preferably administered later on with breakfast, lunch and dinner in period I. If the antidiabetic thiazolidinedione troglitazone is chosen for the study, the placebos matching with troglitazone are preferably administered in period I with breakfast only. If the antidiabetic D-phenylalanine derivative nateglinide is chosen for the study, matching placebos are preferably administered before breakfast, lunch and dinner period I. If metformin is chosen for the study, matching placebos are preferably administered before breakfast and dinner.
The subjects are then separated into four treatment groups for the 24-week double-blind study (period II) as depicted in Tables 1 to 5 for the case that DPP728 is chosen as the DPP- IV inhibitor and one of the drugs comprising the antidiabetic thiazolidinedione troglitazone, the antidiabetic phenylacetic acid derivative repaglinide, the α-glucosidase inhibitor acarbose, the antidiabetic D-phenylalanine derivative nateglinide or the biguanide metformin is chosen as the combination partner.
The term "synergistic" shall mean that the drugs, when taken together, produce a total joint effect that is greater than the sum of the effects of each drug when taken alone.
Moreover, for a human patient, especially for elderly people, it is more convenient and easier to remember to take two tablets at the same time, e.g. before a meal, than staggered in time, i.e. according to a more complicated treatment schedule. More preferably, both active ingredients are administered as a fixed combination, i.e. as a single tablet, in all cases described herein. Taking a single tablet is even easier to handle than taking two tablets at the same time. Furthermore, the packaging can be accomplished with less effort.
The results of the studies show that the combination according to the present invention can be used for the prevention and preferably the treatment of conditions mediated by DPP-IV, in particular type 2 diabetes mellitus. The combination of the present invention can also be used for the prevention and preferably the treatment of other condition mediated by DPP-IV. Pharmaceutical preparations of this kind may furthermore be used for example for the prophylaxis and treatment of diseases or conditions which may be inhibited by blocking the AT1 receptor for example a disease or condition selected from the group consisting of
(a) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery;
(b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension;
(c) endothelial dysfunction with or without hypertension,
(d) hyperlipidemia, hyperlipoproteinemia, atherosclerosis and hypercholesterolemia, and
(e) glaucoma.
Primary usages are for the treatment of high blood pressure and congestive heart failure, as well as post-myocardial infarction.
The person skilled in the pertinent art is fully enabled to select a relevant and standard animal test model to prove the hereinbefore and hereinafter indicated therapeutic indications and beneficial effects.
Furthermore, in a number of combinations as disclosed herein the side-effects observed with one of the components surprisingly do not accumulate on application of the combination.
Preferably, the jointly therapeutically effective amounts of a DPP-IV inhibitor in free or pharmaceutically acceptable salt form or an at least one further pharmaceutically active compound are administered simultaneously or sequentially in any order, separately or in a fixed combination. The condition mediated by DPP-IV is preferably selected from the group consisting of diabetes, impaired fasting plasma glucose, impaired glucose tolerance, metabolic acidosis, ketosis, arthritis, obesity and osteoporosis.
Very preferably, the condition mediated by DPP-IV is type 2 diabetes mellitus.
It is one objective of this invention to provide a pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against conditions mediated by DPP-IV, in particular diabetes, more especially type 2 diabetes mellitus, conditions of impaired fasting plasma glucose, and conditions of IGT, of (i) the calcium or magnesium salt of the ATi receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-i -yl)-N-pentanoyl-N-[2'-(1 H-tetrazol-5- yl)-biphenyl-4-yl-methyl]-amine (valsartan) and (ii) at least one further COMBINATION PARTNER OF THE INVENTION and at least one pharmaceutically acceptable carrier.
The pharmaceutical compositions according to the invention can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of the pharmacologically active compound, alone or in combination with one or more pharmaceutically acceptable carries, especially suitable for enteral or parenteral application.
The novel pharmaceutical preparations contain, for example, from about 10 % to about 100 %, e.g., 80% or 90 %, preferably from about 20 % to about 60 %, of the active ingredient. Pharmaceutical preparations according to the invention for enteral or parenteral administration are, for example, those in unit dose forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. These are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar- coating, dissolving or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, after addition of suitable excipients to give tablets or sugar-coated tablet cores.
In this composition, components (i) and (ii) can be administered together, one after the other or separately in one combined unit dose form or in two separate unit dose forms. In one preferred embodiment of the invention, the unit dose form is a fixed combination. In a fixed combination the components (i) and (ii) are administered in the form of a single galenic formulation, e.g. a single tablet or a single infusion.
A further aspect of the present invention is the use of a pharmaceutical composition comprising the calcium or magnesium salt of the AT^ receptor antagonist (S)-N-(I -carboxy- 2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION, in each case in free form or in form of a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical preparation for the prevention or treatment of conditions mediated by DPP-IV, in particular diabetes, more especially type 2 diabetes mellitus, conditions of impaired fasting plasma glucose, and conditions of IGT.
A therapeutically effective amount of each of the components of the combination of the present invention may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination. For example, the method of treatment of the invention may comprise (i) administration of the calcium or magnesium salt of the AT1 receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1-yl)-N- pentanoyl-N-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) and (ii) adminstration of at least one further COMBINATION PARTNER OF THE INVENTION simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g. in daily dosages corresponding to the ratios described herein.
The corresponding active ingredient or a pharmaceutically acceptable salt thereof may also be used in form of a hydrate or include other solvents used for crystallization.
The invention relates in particular to a commercial package comprising jointly therapeutically effective amounts of the calcium or magnesium salt of the AT-j receptor antagonist (S)-N-(I- carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan), and at least one further COMBINATION PARTNER OF THE INVENTION together with instructions for use thereof in the treatment of conditions mediated by DPP-IV, in particular diabetes, more especially type 2 diabetes mellitus, conditions of impaired fasting plasma glucose, and conditions of IGT. A further aspect of the present invention is a method of treating a condition mediated by DPP-IV, in particular type 2 diabetes mellitus, comprising administering to a warm-blooded animal in need thereof jointly therapeutically effective amounts of the calcium or magnesium salt of the AT-i receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-i -yl)-N-pentanoyl-N-[2'- (1H-tetrazoi-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan), and at least one further COMBINATION PARTNER OF THE INVENTION. Preferably, in this method of treating the active ingredients are administered simultaneously or sequentially in any order, separately or in a fixed combination. In one preferred embodiment of such method the jointly therapeutically effective amounts of a calcium or magnesium salt of the ATi receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)- biphenyl-4-yl-methyrj-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION are provided as a combined preparation.
Furthermore, the present invention provides a method of treating conditions of impaired glucose tolerance and impaired fasting plasma glucose comprising administering to a warmblooded animal in need thereof jointly therapeutically effective amounts of a calcium or magnesium salt of the AT^ receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1 -yl)-N- pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION.
Furthermore, the invention relates to a method of improving the bodily appearance of a mammal which comprises orally administering to said mammal, including man, especially man suffering from a metabolic disorder, in particular type 2 diabetes, a combined preparation or pharmaceutical composition described herein in a dosage effective to influence, e.g., to increase or decrease, the glucose metabolism, or to influence the body weight by other mechanisms, and repeating said dosage until a cosmetically beneficial loss of body weight has occurred. Such combinations described herein can also be used to prevent, for cosmetic reasons, a further increase in body weight in humans experiencing such an increase. Moreover, the invention relates to the combinations described herein useful for improving the bodily appearance of a mammal, especially a human being, and the use of such combinations in order to improve the bodily appearance of a mammal, especially a human being. Overweight is one of the risk factors for developing a metabolic disorder, in particular type 2 diabetes, and at the same time often the result of such a metabolic disorder, especially type 2 diabetes. Furthermore, a number of antidiabetics are known to cause weight gain. Hence, humans suffering from metabolic disorders, especially type 2 diabetes, are often faced with overweight. Therefore, the cosmetically beneficial loss of body weight can be effected especially in humans suffering from a metabolic disorder, such as type 2 diabetes. The combinations described herein can also be used to replace or complement an antidiabetic drug taken by a human suffering from type 2 diabetes in order to prevent, for cosmetic reasons, a further increase of the body weight.
The dosage range of the combination of a calcium or magnesium salt of the AT-i receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2χiH-tetrazol-5-yl)- biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION to be employed depends upon factors known to the person skilled in the art including species of the warm-blooded animal, body weight and age, the nature and severity of the condition to be treated, the mode of administration and the particular substance to be employed. Unless stated otherwise herein, the calcium or magnesium salt of the AT1 receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1 H- tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) and at least one further COMBINATION PARTNER OF THE INVENTION are preferably divided and administered from one to four times per day.
The weight ratio of the daily doses of the calcium or magnesium salt of the AT^ receptor antagonist (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-{2'-(1H-tetrazol-5-yl)- biphenyl-4-yl-methyl]-amine (valsartan) to at least one further COMBINATION PARTNER OF THE INVENTION may vary within wide limits depending in particular on the needs of the warm-blooded animal treated.
Especially preferred is a combination, such as a combined preparation or pharmaceutical composition, respectively, which comprises
(i) the calcium or magnesium salt of the ATj receptor antagonist (S)-N-(I -carboxy-2-methyl- prop-1 -yl)-N-pentanoyl-N-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) of formula (I) or a pharmaceutically
Figure imgf000080_0001
acceptable solvate thereof, and
(ii) a DPP IV inhibitor, especially 1-[[(3-Hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)- pyrrolidine or a pharmaceutically acceptable salt thereof.
As an especially preferred salt of valsartan of the combination of the present invention is the calcium salt, preferably a hydrate thereof, most preferably the tetrahydrate thereof.
The preferred DPP IV inhibitor is 1-[[(3-Hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)- pyrrolidine or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical preparations of this kind may be used for example for the prophylaxis and treatment of diseases or conditions which may be inhibited by blocking the AT1 receptor for example a disease or condition selected from the group consisting of
(a) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery;
(b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension;
(c) endothelial dysfunction with or without hypertension, (d) hyperlipidemia, hyperlipoproteinemia, atherosclerosis and hypercholesterolemia, and
(e) glaucoma.
The present invention relates to a pharmaceutical preparations of this kind may be used for example for the prophylaxis and treatment of diseases or conditions selected from impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity and osteoporosis, and preferably diabetes, especially type 2 diabetes mellitus.
The present invention relates to a method for the prevention, delay of progression or treatment of diseases and disorders selected from the group consisting of hyperglycemia, hyperinsulinaemia, hyperlipidaemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, obesity, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, coronary heart disease, hypertension, especially ISH, angina pectoris, myocardial infarction, stroke, vascular restenosis, endothelial dysfunction, impaired vascular compliance, skin and connective tissue disorders, foot ulcerations and ulcerative colitis. Preferably, said combination may be used for the treatment of hypertension, especially ISH, congestive heart failure, endothelial dysfunction, impaired vascular compliance, hyperlipidaemia, hyperglycemia, hyperinsulinaemia, and type Il diabetes mellitus, comprising administering to a warm-blooded animal, including man, in need thereof jointly therapeutically effective amounts of
(i) the calcium or magnesium salt of the AT^ receptor antagonist (S)-N-(I -carboxy-2-methyl- prop-1-yl)-N-pentanoyl-N-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) of formula
Figure imgf000082_0001
(ii) at least one antidiabetic compound.
The combined administration of the calcium or magnesium salt of the AT1 receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-i -yl)-N-pentanoyl-N-[2'-(1 H-tetrazol-5-yl)- biphenyl-4-yl-methyl]-amine (valsartan) of formula
Figure imgf000082_0002
(ii) at least one antidiabetic compound results in a significant response in a greater percentage of treated patients, that is, a greater responder rate results, regardless of the underlying etiology of the condition. This is in accordance with the desires and requirements of the patients to be treated.
It can be shown that combination therapy with_the calcium or magnesium salt ofjhe AT1 receptor antagonist (S)-N-(I -carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1 H-tetrazol-5- yl)-biphenyl-4-yl-methyl]-amine (valsartan) of formula
Figure imgf000083_0001
(ii) at least one antidiabetic compound results in a more effective therapy associated with the inhibition of the AT1 receptor and/or associated with the use of an antidiabetic agent through improved efficacy as well as a greater responder rate.

Claims

What we claim is:
1. A pharmaceutical composition, respectively, which comprises
(i) the calcium or magnesium salt of the ATi receptor antagonist (S)-N-(I -carboxy-2-methyl- prop-1-yl)-N-pentanoyl-N-[2'-(1 H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine (valsartan) of formula
Figure imgf000084_0001
(ii) at least one antidiabetic compound.
2. Combination according to claim 1, wherein the calcium or magnesium salt of valsartan is in form or a hydrate.
3. Combination according to claim 2, wherein the calcium salt of valsartan is in form or a tetrahydrate.
4. Combination according to any one of claims 1 to 3, wherein the antidiabetic compound is selected from the group consisting of a dipeptidyl peptidase IV (DPP IV) inhibitor, insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (GδPase), inhibitors of fructose- 1,6- bisphosphatase (F-1 ,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, α-glucosidase inhibitors, inhibitors of gastric emptying, insulin, and α2- adrenergic antagonists.
5. Combination according to any one of claims 1 to 3, wherein the antidiabetic compound is a dipeptidyl peptidase IV (DPP IV) inhibitor.
6. Combination according to claim 4, wherein the DPP IV inhibitor is 1-[[(3-Hydroxy-1- adamantyl) amino]acetyl]-2-cyano-(S)-pyrrolidine or a pharmaceutically acceptable salt thereof.
7. Combination according to any one of claims 1 to 3, wherein the antidiabetic compound is a thiazolidinedione (glitazone).
8. Combination according to claim 7, wherein the glitazone is pioglitazone or rosiglitazone.
9. Combination according to any one of claims 1 to 3, wherein the antidiabetic compound is a non-glitazone type PPARγ agonist.
10. Combination according to claim 9, wherein the non-glitazone type PPARγ agonist is GI-262570 or JTT501.
11. Combination according to any one of claims 1 to 3, wherein the antidiabetic compound is a dual PPARγ / PPARα agonist.
12. Combination according to claim 11 , wherein the dual PPARγ / PPARα agonist is a compound selected from the group consisting of:
(R)-1-{4-[4-(4-Phenoxy-2-propyl-phenoxy)-butoxy]-benzenesulfonyl}-azetidine-2- carboxylic acid;
(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-azetidine-2- carboxylic acid; (R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-azetidine-2- carboxylic acid;
(R)-1-{4-[2-(4-Fluoro-phenyI)-5-methyl-oxazol-4-yImethoxy]-benzenesulfonyl}- azetidine-2-carboxylic acid;
(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-pheπyl)-oxazol-4-ylmethoxy]-benzenesulfonyI}- azetidine-2-carboxylic acid;
(R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzene- sulfonylj-azetidine^-carboxylic acid;
(R)-1-{4-[2-(5-Methyl-2-pheny!-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-azetidine-2- carboxylic acid;
(R)-1-{4-[4-(4-Phenoxy-2-propyl-phenoxy)-butoxy]-benzenesulfonyl}-pyrrolidine-2- carboxylic acid;
(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-pyrrolidine-2- carboxylic acid;
(R)-1-(4-{3-[2-Propyl-4-(4-trifluoromethyi-phenoxy)-phenoxy]-propoxy}- benzenesulfonyl)-pyrrolidine-2-carboxylic acid;
(R)-1-{4-[2-(4-Phenoxy-2-propyl-phenoxy)-ethoxy]-benzenesulfonyl}-pyrrolidine-2- carboxylic acid;
(R)-1-(4-{2-[2-Propyl-4-(4-trifluoromethyl-phenoxy)-phenoxy]-ethoxy}- benzenesulfonyl)-pyrrolidine-2-carboxylic acid;
(R)-1-{3-Methoxy-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}- pyrrolidine-2-carboxylic acid;
(R)-1-{3-Chloro-4-[3-(4-phenoxy-2-propyi-phenoxy)-propoxy]-benzenesulfonyl}- pyrrolidine-2-carboxylic acid;
(R)-1-{4-[3-(4-Phenoxy-2-propyi-phenoxy)-propoxy]-3-propyl-benzenesulfonyl}- pyrrolidine-2-carboxylic acid;
(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propylsulfanyl]-benzenesulfonyl}- pyrrolidine-2-carboxylic acid;
(R)-1-{4-[2-(4-Phenoxy-2-propyl-phenoxy)-ethylsulfanyl]-benzenesulfonyl}-pyrrolidine- 2-carboxylic acid; (R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propyl]-benzenesulfonyl}-pyrroIidine-2- carboxylic acid;
(RJ-i-^-Cδ-Methyl^-phenyl-oxazoM-ylmethoxy^benzenesulfonyll-pyrrolidine-a- carboxylic acid;
(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonyl}- pyrrolidine-2-carboxylic acid;
(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}- pyrrolidine-2-carboxylic acid;
(R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzene- sulfonyl}-pyrrolidine-2-carboxylic acid;
(R)-1-[4-(2-Biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-pyrrolidine- 2-carboxylic acid;
(R)-1-[3-Methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]- pyrrolidine-2-carboxylic acid;
(R)-1-[3-Ch!oro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]- pyrrolidine-2-carboxylic acid;
(R)-1-[4-(5-Methyl-2-phenyI-oxazol-4-ylmethoxy)-3-propyl-benzenesulfonyl]- pyrrolidine-2-carboxylic acid;
(RJ-i-^-Cδ-Methyl^-phenyl-oxazoM-ylmethylsulfanyO-benzenesulfonyll-pyrrolidine- 2-carboxylic acid;
(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazoI-4-ylmethylsulfanyl]-benzenesulfonyl}- pyrrolidine-2-carboxylic acid;
(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]- benzenesulfonyll-pyrrolidine^-carboxylic acid;
(R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]- benzenesulfonylj-pyrrolidine^-carboxylic acid;
(R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-pyrrolidine-2- carboxylic acid;
(R)-1-{3-Methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}- pyrrolidine-2-carboxylic acid; (^-I^S-Chloro^-^-Cδ-methyl^-phenyl-oxazoM-yO-ethoxyl-benzenesulfonyl}- pyrrolidine-2-carboxylic acid;
(R)-1-(4-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}- benzenesulfonyl)-pyrrolidine-2-carboxylic acid;
(R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylsulfanyl]-benzenesulfonyl}- pyrrolidine-2-carboxylic acid;
(R)-1-{4-[4-(4-Phenoxy-2-propyl-phenoxy)-butoxy]-benzenesulfonyl}-2,3-dihydro-1 H- indole-2-carboxylic acid;
(R)-1-{4-[3-(4-Phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3-dihydro-1H- indole-2-carboxylic acid;
(R)-1-{4-[2-(4-Phenoxy-2-propyl-phenoxy)-ethoxy]-benzenesulfonyl}-2,3-dihydro-1H- indole-2-carboxylic acid;
(R)-1-{3-Methoxy-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3- dihydro-1 H-indole-2-carboxylic acid;
(R)-1-{3-Chloro-4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-benzenesulfonyl}-2,3- dihydro-1 H-indole-2-carboxylic acid;
(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesuIfonyl]-2,3-dihydro-1H- indole-2-carboxylic acid;
(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3- dihydro-1 H-indole-2-carboxylic acid;
(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}- 2,3-dihydro-i H-indole-2-carboxylic acid;
(Rj-i^-p-CS.S-Bis-trifluoromethyl-phenyO-δ-methyl-oxazoM-ylmethoxyl-benzene- sulfonyl}-2,3-dihydro-1 H-indole-2-carboxylic acid;
(R)-1-[3-Methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesuIfonyl]-2,3- dihydro-1 H-indole-2-carboxylic acid;
(R)-1-[3-Chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl]-2,3- dihydro-1 H-indole-2-carboxylic acid;
(R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-3-propyl-benzenesulfonyl]-2,3- dihydro-1 H-indole-2-carboxylic acid; (R)-1-[4-(5-Methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonyl]-2,3-dihydro- IH-indole-2-carboxylic acid;
(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-oxazol-4-ylmethylsu!fanyl]-benzenesu!fony!}- 2,3-dihydro-1 H-indole-2-carboxylic acid;
(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]- benzenesulfonyl}-2,3-dihydro-1 H-indole-2-carboxylic acid;
(R)-1-{4-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-oxazol-4-ylmethylsulfanyl]- benzenesulfonyl}-2,3-dihydro-1 H-indole-2-carboxylic acid;
(R)-1-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-2,3-dihydro-1H- indole-2-carboxylic acid; and
(R)-1-{3-Chloro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzenesulfonyl}-2,3- dihydro-1 H-indole-2-carboxylic acid; (R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethylsulfanyl]-benzene-sulfonyl}-pyrrolidine-2-carboxylic acid;
(R)-1-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethylsulfanyl]-benzene- sulfonyl}-2,3-dihydro-1 H-indole-2-carboxylic acid; or a pharmaceutically acceptable salt thereof.
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