HK1164837B

HK1164837B - Polymorphic forms of 6-(1-methyl-1h-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-benzyl}-2h-pyridazin-3-one dihydrogenphosphate and processes of manufacturing thereof

Info

Publication number: HK1164837B
Application number: HK12105184.1A
Authority: HK
Inventors: Axel Becker; Clemens Kuehn; Christoph Saal; Oliver Schadt; Dieter Dorsch; Eva Kriegbaum; Frank Stieber; Cristina Donini
Original assignee: Merck Patent Gmbh
Priority date: 2008-12-22
Filing date: 2009-11-24
Publication date: 2014-10-17

Description

Polymorphic forms of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate and processes for their preparation

Description

Technical Field

The present invention relates to 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate, its solvates and crystal modifications thereof, as well as their medical uses and methods of preparation.

Prior Art

6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (I)

Was described for the first time in international patent application PCT/EP2008/003473 filed on day 29, 2008, and international patent application PCT/EP2008/005508 filed on day 4, 2008, 7.

In PCT/EP2008/003473, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one was referred to as compound "a 229". Example 38 of PCT/EP2008/003473 describes the first method for the synthesis of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one. P-toluenesulfonate and phosphate are mentioned as possible salt forms. In addition, example 39 of PCT/EP2008/003473 describes an alternative method for the synthesis of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one. Example 1 of PCT/EP2008/005508 describes the same method as the first method for the synthesis of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one, and p-toluenesulphonate and phosphate salts are also mentioned as possible salt forms. Example 2 of PCT/EP2008/005508 mentions as further salt forms sulfate, mesylate, besylate, tosylate, fumarate and maleate salts.

Neither of these prior art documents describes 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one as the dihydrogen phosphate salt, nor the polymorphic forms, crystal modifications, etc. of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate.

Certain crystalline forms, i.e. morphological forms or polymorphs, of a pharmaceutical compound may be important for the pharmaceutical compound involved in developing a suitable pharmaceutical dosage form. This is because if a certain polymorph cannot be kept constant in clinical and stability studies, the exact dose used or measured may not be comparable from one batch to another. Once a pharmaceutical compound is manufactured ready for use, it is important to verify the morphological form or polymorph to be delivered in each dosage form to ensure that the manufacturing process produces the same form and that the same amount of drug is contained in each dose. Thus, it must be ensured that a single morphological form or polymorph or a known combination of morphological forms or polymorphs exists. In addition, certain morphological forms or polymorphs may exhibit enhanced thermodynamic stability and may be more suitable for inclusion in a pharmaceutical formulation than other morphological forms or polymorphs.

Citation of any reference in this application is not an admission that such reference is pertinent prior art to the present application.

Disclosure of Invention

It is an object of the present invention to provide new salt forms of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one and new polymorphs thereof.

The object of the present invention has been surprisingly solved in one aspect by providing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate.

The object of the present invention has been achieved in another aspect by providing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate solvate, preferably 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate.

It has been found that 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate forms solvates in the crystalline modification. Examples of such solvates include: solvates formed in water; solvates formed in alcohols such as methanol, ethanol, 1-propanol or 2-propanol; solvates formed in organic esters such as ethyl acetate; solvates formed in nitriles such as acetonitrile; solvates formed in ketones such as acetone and butanone; solvates formed in ethers such as Tetrahydrofuran (THF); solvates formed in chlorinated hydrocarbons such as chloroform; a hydrocarbon such as n-heptane or toluene. Preferred solvates are formed with polar solvents, preferably water, alcohols, organic esters, nitriles, ketones and ethers.

Preferably, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate forms in the crystalline modification as an anhydrate and as a solvate with water, acetone, tetrahydrofuran, methanol, ethyl acetate or n-heptane, meaning that the combined solvent and 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate form a crystal structure. The molar ratio of solvent to 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate can be varied as known to the person skilled in the art. The molar ratio is preferably between 0.25: 1 and 2.5: 1, more preferably between 0.5: 1 and 1:1, most preferably 1:1 (n-heptane solvate 1/15: 1). It will be appreciated that the anhydrate and solvate of the invention may contain unbound water, i.e. water that is not water of crystallization.

Thus, in a preferred embodiment, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate solvate, preferably 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate is provided in the form of its crystalline modification.

The object of the present invention has in a further aspect surprisingly been solved by providing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate.

In a preferred embodiment, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl]-benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate is provided in its crystalline modification a1 which is characterized by XRD peaks comprising 3.2 °, 6.5 °, 9.8 ° and 13.1 ° 2 θ (all ± 0.1 ° 2 θ, using Cu-ka, K ·₁A radioactive source).

In a preferred embodiment, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl]-benzyl } -2H-pyridazine-3-one dihydrogenphosphate anhydrate is provided in its crystalline modification a1, which crystalline modification a1 is characterized by XRD peaks comprising 18.4 °, 18.8 °, 23.7 °, 24.2 °, 26.4 ° and 28.2 ° 2 Θ (all ± 0.1 ° 2 Θ using Cu-ka₁A radioactive source).

In a preferred embodiment, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl]-benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate is provided in its crystalline modification A1 which is characterized by XRD peaks comprising 14.4 °, 15.8 °, 17.5 °, 19.5 ° and 21.9 ° 2 θ (all ± 0.1 ° 2 θ,using Cu-K alpha₁A radioactive source).

In a preferred embodiment, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate is provided in the form of its crystalline modification a1, which crystalline modification a1 is characterized by the following XRD data:

form a 1:

the object of the present invention has in a further aspect surprisingly been solved by providing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate.

In a preferred embodiment, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl]-benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate is provided in its crystalline modification H1, said crystalline modification H1 being characterized by XRD peaks comprising 3.1 °, 9.4 ° and 18.8 ° 2 Θ (all ± 0.1 ° 2 Θ, using Cu-ka₁A radioactive source).

In a preferred embodiment, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl]-benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate provided in the form of its crystalline modification H1, said crystalline modification H1 being characterized by XRD peaks comprising 19.1 °, 22.8 ° and 26.4 ° 2 Θ (all ± 0.1 ° 2 Θ, using Cu-ka₁A radioactive source).

In a preferred embodiment, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl]-benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate is provided in its crystalline modification H1, which crystalline modification H1 is characterized by XRD peaks comprising 14.4 °, 15.0 ° and 17.8 ° 2 θ (all ± 0.1 ° 2 θ,using Cu-K alpha₁A radioactive source).

In a preferred embodiment, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl]-benzyl } -2H-pyridazine-3-one dihydrogenphosphate dihydrate is provided in its crystalline modification H1, which crystalline modification H1 is characterized by XRD peaks comprising 14.7 °, 18.6 °, 23.2 °, 23.8 °, 26.8 ° and 27.6 ° 2 θ (all ± 0.1 ° 2 θ, using Cu-ka₁A radioactive source).

In a preferred embodiment, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate is provided in its crystalline modification H1, said crystalline modification H1 being characterized by the following XRD data:

form H1:

the object of the present invention has on the other hand been achieved by providing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl in the form of its crystalline modification NF3]-benzyl } -2H-pyridazin-3-one dihydrogenphosphate (crystal modification NF3 which may be hydrate or anhydrate) was surprisingly solved by the fact that the crystal modification NF3 is characterized by XRD peaks comprising 15.3 °, 16.7 °, 21.6 ° and 23.1 ° 2 θ (all. + -. 0.1 ° 2 θ, using Cu-K α 2 θ)₁A radioactive source).

In a preferred embodiment, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate is provided in the form of its crystalline modification NF3, said crystalline modification NF3 being characterized by the following XRD data:

crystalline form NF3:

the object of the present invention has on the other hand been achieved by providing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl in the form of the crystalline modification NF5]-benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate, said crystalline modification NF5 being characterized by XRD peaks comprising 13.9 °, 15.7 °, 16.6 °, 17.3 °, 19.8 ° and 22.1 ° 2 θ (all ± 0.1 ° 2 θ, using Cu-K α, S)₁A radioactive source).

In a preferred embodiment, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate is provided in the form of its crystalline modification NF5, said crystalline modification NF5 being characterized by the following XRD data:

crystalline form NF5:

in the present invention, the term "crystalline modification" is used as a synonym for the terms "crystalline form", "polymorph", "polymorphic modification", "morphological form" and the like.

The crystal modification of the present invention, particularly crystal modification A1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate, crystal modification H1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate, and crystal modifications thereof, The crystal modification NF3 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate (crystal modification NF3 may be a hydrate or anhydrate) and the crystal modification NF5 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate surprisingly have inter alia the following characteristics: reduced hygroscopicity, better compressibility during tableting, extended shelf life, better thermodynamic stability (i.e., stability against heat and humidity), better resistance to light (i.e., ultraviolet light), increased bulk density, improved solubility, maintaining constant bioavailability characteristics from one batch to another, better flow and handling properties during tableting, improved color stability, and better filtration properties during production. Thus, by using the crystalline modification of the present invention, it is possible to obtain pharmaceutical formulations with improved homogeneity, stability, purity and batch-to-batch uniformity.

Furthermore, 6- (1-methyl-1H-pyrazol-4-yl) -2- "was compared to crystal modification NF5 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate crystal modification H1 and 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate crystal modification NF5 Crystalline modification a1 of 3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate exhibits superior properties for drying purposes (no loss of water of hydration) and superior properties in terms of physical stability under different Relative Humidity (RH) conditions (physically stable form in the humidity range from 0% to at least 70% RH). Furthermore, the crystal modification A1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate is believed to be a thermodynamically more stable form compared to the crystal modification NF3 of 6- (1-methyl-1H-pyrazol-4-yl) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate, as shown by competitive slurry transformation experiments performed on binary mixtures of form a1 and NF3 in various organic solvents at 25 ℃ and 50 ℃, respectively (see example 10).

In contrast, 6- (1-methyl-1H-pyrazol-4-yl) -2- The crystalline modification NF3 of {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate exhibits superior properties for drying purposes (no loss of water of hydration) and superior properties in terms of physical stability under different Relative Humidity (RH) conditions (in physically stable form in the humidity range from 0% to at least 70% RH). Furthermore, in contrast to crystalline modification A1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate, crystalline modification NF3 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate in water acetone (30: 70, v: v, after 2 hours) shows lower kinetic solubility in the mixture, which enables a higher yield of the crystallization process in the process-related solvent mixture (see example 14).

On the other hand, crystalline modification NF5 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate is a more stable form at high water activity than crystalline modification A1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate, and thus in aqueous dispersions, as shown by competitive slurry transformation experiments in DI water at 25 c on binary mixtures of crystalline forms NF5 and a1 (see example 11).

Furthermore, crystalline modification H1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate is a more stable form at high water activity than crystalline modification NF5 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate, it is therefore advantageous in aqueous dispersions to obtain form H1 over time as shown by competitive slurry transformation experiments in DI water at 25 ℃ on binary mixtures of forms NF5 and H1 (see example 12). Furthermore, the crystalline modification H1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate is advantageous in aqueous dispersion compared to the crystalline modification NF3 of 6- (1-methyl-1H-pyrazol-4-yl) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate, form H1 is obtained over time as shown by competitive slurry transformation experiments performed on a binary mixture of forms H1 and NF3 in DI water at 25 ℃ (see example 13).

For 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate, the dihydrogen phosphate salt shows significantly better stability in aqueous solution and increased stability of the Active Pharmaceutical Ingredient (API) in solution compared to 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base).

The crystalline modifications of the invention can be characterized according to standard methods which can be found, for example, in Rolf Hilfiker, 'Polymorphism in the Pharmaceutical Industry', Wiley-VCH, Weinheim 2006 and references therein, such as X-ray diffraction (XRD; Chapter 6), IR and Raman spectroscopy (Chapter 5), Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA) (Chapter 3), water vapor adsorption studies (Chapter 9), or in, for example, H.G.Brittain (eds), Polymorphism in Pharmaceutical solutions, Vol.95, Marcel Dekker Inc., New York 1999 (Chapter 6: all mentioned techniques).

6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate solvate, preferably 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin- 4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate, preferably the crystalline modification of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate Crystal modification of dihydrogen phosphate hydrate NF5, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogen phosphate anhydrate, crystal modification of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogen phosphate anhydrate, 6- (1-methyl-1H-pyrazol-4-yl) -2- Crystalline modification A1 of {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate The crystalline modification of the dihydrate of the phenyl } -2H-pyridazin-3-one dihydrogenphosphate, the crystalline modification of the dihydrate of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate H1 and the crystalline modification of the dihydrate of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate NF3 are referred to below as "the product of the invention" NF3 ".

6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base) can be synthesized as described in example 8 of PCT/EP2008/003473 and example 1 of PCT/EP2008/005508 as follows:

a suspension of 7.68g (43.6mmol)6- (1-methyl-1H-pyrazol-4-yl) -2H-pyridazin-3-one in 90ml DMF was reacted with 12.4g (43.6mmol) 5-bromo-2- (3-chloromethyl-phenyl) -pyridine and 14.2g (43.6mmol) cesium carbonate at room temperature under stirring for 24 hours. The reaction mixture was added to 400ml of water. The resulting precipitate of 2- [3- (5-bromopyrimidin-2-yl) -benzyl ] -6- (1-methyl-1H-pyrazol-4-yl) -2H-pyridazin-3-one was filtered off with suction, washed with water and dried in vacuo.

A suspension of 14.0g (33.0mmol)2- [3- (5-bromopyrimidin-2-yl) -benzyl ] -6- (1-methyl-1H-pyrazol-4-yl) -2H-pyridazin-3-one in 65ml DMF was reacted with 10.9g (42.9g) bis (pinacolato) diboron and 9.72g (99.0mmol) potassium acetate and heated to 70 ℃ under nitrogen. After stirring at this temperature for 15 minutes, 695mg (0.99mmol) of bis (triphenylphosphine) -palladium (II) chloride are added and the reaction mixture is stirred at 70 ℃ under nitrogen for 18 hours. Subsequently, the reaction mixture was cooled to room temperature, water and dichloromethane were added, the reaction mixture was filtered over celite, and the organic phase was separated. The organic phase is then dried over sodium sulfate, concentrated and the residue recrystallized from 2-propanol to give 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one.

To a suspension of 13.4g (28.4mmol)6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one in 55ml THF and 55ml water was added 8.50g (85.1mmol) sodium perborate in portions under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours and then filtered off with suction over celite. The filtrate was concentrated in vacuo to about half of the initial volume and titrated to pH 1 with 2N hydrochloric acid. The resulting precipitate of 2- [3- (5-hydroxy-pyrimidin-2-yl) -benzyl ] -6- (1-methyl-1H-pyrazol-4-yl) -2H-pyridazin-3-one was filtered off with suction, washed with water and dried in vacuo.

To a suspension of 360mg (1.00mmol)2- [3- (5-hydroxy-pyrimidin-2-yl) -benzyl ] -6- (1-methyl-1H-pyrazol-4-yl) -2H-pyridazin-3-one in 2ml THF were successively added 394mg (1.50mmol) triphenylphosphine and 242. mu.l (2.00mmol)4- (2-hydroxyethyl) morpholine. 294. mu.l (1.50mmol) of diisopropyl azodicarboxylate was slowly added dropwise under ice-cooling. The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the oily residue was dissolved in 2-propanol. After a period of time the resulting solid 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one was filtered off with suction, washed with 2-propanol and methyl tert-butyl ether and dried in vacuo.

The starting product 6- (1-methyl-1H-pyrazol-4-yl) -2H-pyridazin-3-one can be synthesized as described in PCT/EP2008/003473 (pages 65-66) as follows:

a solution of 815g (3.39mol) 3-chloro-6-iodo-pyridazine in 3.8L 1, 2-dimethoxyethane was reacted with 705g (3.39mol) 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and 1.44kg tripotassium phosphate trihydrate. The resulting suspension was heated to 80 ℃ under nitrogen and stirring and 59.5g (85mmol) of bis (triphenylphosphine) -palladium (II) chloride were added. The reaction mixture was stirred at 80 ℃ for 3 hours. Subsequently, the reaction mixture was cooled to room temperature and 9L of water was added. The resulting 3-chloro-6- (1-methyl-1H-pyrazol-4-yl) -pyridazine precipitate was filtered off with suction, washed with water and dried in vacuo.

A suspension of 615g (2.90mol) 3-chloro-6- (1-methyl-1H-pyrazol-4-yl) -pyridazine in a mixture of 1.86L of formic acid and 2.61L of water was heated to 80 ℃ with stirring and stirring was continued at this temperature for 28 hours. The reaction mixture was cooled to room temperature, activated carbon (activated carbon) was added, and the mixture was filtered with suction. The filtrate was titrated with 40% aqueous caustic soda solution to pH 7 under ice cooling and then incubated at 6 ℃ for 16 hours. The resulting precipitate of 6- (1-methyl-1H-pyrazol-4-yl) -2H-pyridazin-3-one was filtered off with suction, washed with water and dried in vacuo.

The starting product 5-bromo-2- (3-chloromethyl-phenyl) -pyridine can be synthesized as described in example 36 of PCT/EP2008/003473 as follows:

a solution of 95.0g (332mmol) of 5-bromo-2-iodopyridine in 325ml of toluene, kept under nitrogen, is reacted with a solution of 70.0g (660mmol) of sodium carbonate in 325ml of water, and the mixture is heated to 80 ℃. To the reaction mixture was added 2.3g (3.3mmol) of bis (triphenylphosphine) -palladium (II) chloride, followed by dropwise addition of a solution of 50.0g (329mmol) of 3- (hydroxymethyl) -phenylboronic acid in 650ml of ethanol. The reaction mixture was stirred at 80 ℃ for 18 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was reacted with 1L ethyl acetate and 1L water. The organic phase was separated, dried over sodium sulfate and concentrated. The residue of [3- (5-bromopyrimidin-2-yl) -phenyl ] -methanol was recrystallized from 2-propanol.

To 159ml (2.19mol) of thionyl chloride kept at 30 ℃ was added 116g (438mmol) of [3- (5-bromopyrimidin-2-yl) -phenyl ] -methanol in portions with stirring. The reaction mixture was stirred at room temperature for 18 hours. Subsequently, the reaction mixture was concentrated. The residue was dissolved in toluene and concentrated again. This operation was repeated three times. The final 5-bromo-2- (3-chloromethyl-phenyl) -pyridine residue was recrystallized from toluene.

Alternatively, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base) can be synthesized as described in example 39 of PCT/EP2008/003473 as follows:

360mg (1.00mmol) of 2- [3- (5-hydroxy-pyrimidin-2-yl) -benzyl]-6- (1-methyl-1H-pyrazol-4-yl) -2H-pyridazin-3-one, 195mg (1.05mmol) N- (2-chloroethyl) -morpholine chlorideAnd a suspension of 521mg (1.60mmol) of cesium carbonate in 2ml of DMF is heated with stirring to 80 ℃ and stirring is continued at this temperature for 6 hours. Subsequently, the reaction mixture was cooled and 50ml of water was added. The resulting 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl radical is filtered off with suction]-benzyl } -2H-pyridazin-3-one precipitate, washed with water and dried in vacuo.

In another aspect of the invention, a pharmaceutical composition comprising a therapeutically effective amount of at least one product of the invention is provided.

In a preferred embodiment, the pharmaceutical composition further comprises at least one additional compound selected from the group consisting of physiologically acceptable excipients, adjuvants (auxiliary), adjuvants (adjuvant), diluents, carriers and/or additional pharmaceutically active substances other than the product of the invention.

Another embodiment of the invention is a process for the preparation of said pharmaceutical compositions, characterized in that one or more products of the invention and one or more further compounds selected from the group consisting of solid, liquid or semi-liquid excipients, adjuvants, diluents, carriers and/or further pharmaceutically active substances other than the products of the invention are converted into a suitable dosage form.

The term "effective amount" as used herein refers to any amount of a drug or pharmaceutical substance that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for example, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount that results in an improved treatment, cure, prevention or amelioration of a disease, disorder or side effect or a reduction in the rate of progression of a disease or disorder as compared to a corresponding individual not receiving that amount. The term also includes within its scope an amount effective to enhance normal physiological function.

In another aspect of the invention, there is provided a medicament comprising at least one product of the invention or a pharmaceutical composition as described herein.

In a further aspect of the present invention, there is provided an agent as described herein for use in the treatment and/or prevention of a physiological and/or pathophysiological condition which is caused, mediated and/or propagated by the inhibition, regulation and/or modulation of kinase signal transduction, in particular by the inhibition of tyrosine kinases, preferably Met kinase. The corresponding use for the preparation of a medicament for the treatment and/or prophylaxis of the abovementioned conditions is also encompassed by the present invention.

In a further aspect of the invention there is provided an agent as described herein for use in the treatment and/or prevention of a physiological and/or pathophysiological condition selected from the group consisting of: "cancer (cancer), tumor, malignant tumor, benign tumor, solid tumor, sarcoma, carcinoma (carcimoma), hyperproliferative disorder, carcinoid, Ewing's sarcoma, Kaposi's sarcoma, brain tumor, tumor of brain and/or nervous system and/or meninges origin, glioma, glioblastoma, neuroblastoma, gastric cancer, renal cell carcinoma, prostate cancer, connective tissue tumor, soft tissue sarcoma, pancreatic tumor, liver tumor, head tumor, neck tumor, laryngeal cancer, esophageal cancer, thyroid cancer, osteosarcoma, retinoblastoma, thymoma, testicular cancer, lung adenocarcinoma, small cell lung cancer, bronchial cancer, breast cancer (breast cancer), breast cancer (mamma carcinosa), intestinal cancer, colorectal tumor, colon cancer, rectal cancer, gynecological tumor, ovarian tumor/ovarian tumor, Uterine cancer, cancer of the cervix, cervical cancer, cancer of the uterine body, cancer of the uterine corpus, cancer of the endometrial cancer, cancer of the bladder, cancer of the genitourinary tract, cancer of the bladder, cancer of the skin, epithelial tumors, squamous epithelial cancer, basal cell carcinoma, carcinoma of the spinosa (spinoalisma), melanoma, intraocular melanoma, leukemia, monocytic leukemia, chronic myelogenous leukemia (chronic myelogenous leukemia), chronic lymphatic leukemia, acute myeloid leukemia, acute lymphatic leukemia and/or lymphoma ". The corresponding use for the preparation of a medicament for the treatment and/or prophylaxis of the abovementioned conditions is also encompassed by the present invention.

In another aspect of the present invention, there is provided a medicament as described herein, wherein the medicament comprises at least one additional pharmacologically active substance (drug, ingredient).

In a preferred embodiment, the at least one pharmacologically active substance is a substance as described herein.

In a further aspect of the present invention there is provided a medicament as described herein, wherein the medicament is applied before and/or during and/or after treatment with at least one further pharmacologically active substance.

In a further aspect of the invention, a kit is provided comprising a therapeutically effective amount of at least one product of the invention and/or at least one pharmaceutical composition as described herein and a therapeutically effective amount of at least one further pharmacologically active substance other than a product of the invention.

The products of the invention may be used in combination with one or more other pharmacologically active substances (ingredients, drugs) for the treatment, prevention, inhibition or amelioration of diseases or conditions for which the products of the invention or said other substances have a functional effect. Generally, a combination of drugs is safer or more effective than either drug alone or than would be expected based on the additive properties of the drugs. The other drug or drugs may be administered by a commonly used route, in commonly used amounts, simultaneously or sequentially with the product of the invention. When the product of the invention is used contemporaneously with one or more other drugs, a combination product containing the other drug or drugs and the product of the invention is preferred. However, combination therapy also includes therapies in which the product of the invention and one or more other drugs are administered in different staggered regimens. It is contemplated that when used in combination with other active ingredients, the product of the invention or the other active ingredients or both may be effectively used in lower dosages than when each is used alone. Accordingly, the pharmaceutical compositions of the invention (pharmaceutical compositions described herein) include those that contain one or more other active ingredients in addition to the products of the invention.

Examples of pharmacologically active substances (ingredients, drugs) that may be administered in combination with the products of the invention (either separately or in the same pharmaceutical composition) include, but are not limited to, the classes of compounds and specific compounds listed in table 1:

in a preferred embodiment, the products of the invention are administered in combination with one or more known antineoplastic agents, such as the following antineoplastic agents: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxins, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA-reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors.

The products of the invention are particularly well suited for administration in combination with radiotherapy. The synergistic effect of VEGF inhibition in combination with radiotherapy is known to the person skilled in the art (WO 00/61186).

In the present invention, the term "estrogen receptor modulator" refers to a compound that interferes with or inhibits the binding of estrogen to the estrogen receptor-regardless of the mode of action. Non-limiting examples of estrogen receptor modulators are tamoxifen, raloxifene, idoxifene, LY353381, LY 117081, toremifene, fulvestrant, 4- [7- (2, 2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy ] phenyl ] -2H-1-benzopyran-3-yl ] phenyl-2, 2-dimethyl-propionate, 4' -dihydroxybenzophenone-2, 4-dinitrophenylhydrazone, and SH 646.

In the present invention, the term "androgen receptor modulator" refers to a compound that interferes with or inhibits the binding of androgens to the androgen receptor-regardless of the mode of action. Non-limiting examples of androgen receptor modulators are finasteride and other 5 α -reductase inhibitors, nilutamide, flutamide, bicalutamide, liazole and abiraterone acetate.

In the present invention, the term "retinoid receptor modulator" refers to compounds that interfere with or inhibit the binding of retinoids to retinoid receptors-regardless of the mode of action. Non-limiting examples of retinoid receptor modulators are bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α -difluoromethylornithine, ILX23-7553, trans-N- (4' -hydroxyphenyl) tretinoin, and N-4-carboxyphenyltretinoin.

In the present invention, the term "cytotoxin" refers to a compound that mainly causes cell death by directly acting on cell functions or a compound that interferes with or inhibits cell meiosis, such as alkylating agents, tumor necrosis factors, intercalating agents, microtubule inhibitors and topoisomerase inhibitors. Non-limiting examples of cytotoxins are tirapazimin, sertenef, cachectin, ifosfamide, tasolinamine, lonidamine, carboplatin, hexamethaminem, prednimustine, dibromodulcitol, ramustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin (heptaplatin), estramustine, enkephalin tosylate, trofosfamide, nimustine, dibromospiro ammonium chloride, pyrimipide, lobaplatin, satraplatin, mitomycin, cisplatin, irofumevin, dexifosfamide, cis-aminodichloro (2-methylpyridine) platinum (cis-aminodichloro (2-methylpyridine) platine), benzylguanine, glufosfamide, GPX100, (trans ) -bis- μ - (hexane-1, 6-diamine) - μ -diamine (II) bis- [ II (tetrachloro) chloride) ] (II) platinum (tetrachloro), platinum (II) chloride (tetrachloro), and mixtures thereof, Diazopyridinylspermine (Diarizidinylspermine), arsenic trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3, 7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, naphtalen-type, valrubicin, amrubicin, antitumor, 3 '-deamino-3' -morpholino-13-deoxo-10-hydroxycarminomycin, anamycin, calicheacin, eletrinafad, MEN10755 and 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (WO 00/50032).

Non-limiting examples of microtubule inhibitors are paclitaxel, vindesine sulfate, 3 ', 4' -didehydro-4 '-deoxy-8' -norvinblastine, docetaxel, rhizomycin, dolastatin, mitobutrine-isethionate, auristatin, cimadrol, RPR109881, BMS184476, vinflunine, cryptophycine, 2, 3, 4, 5, 6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) -benzenesulfonamide, vinblastine dehydrate, N-dimethyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-tert-butylamide, TDX258 and BMS 188797.

Non-limiting examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ', 4' -O-exo-benzylidene-tebucin (chartreusine), 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3, 4, 5-kl-]Acridine-2- (6H) propylamine, 1-amino-9-ethyl-5-fluoro-2, 3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo- [ de]-pyrano- [3 ', 4': b, 7]Indolizino [1, 2b ]]Quinoline-10, 13(9H, 15H) -dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl]- (20S) camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzosin, 2 '-dimethylamino-2' -deoxy-etoposide, GL331, N- [2- (dimethylamino) ethyl ] etoposide]-9-hydroxy-5, 6-dimethyl-6H-pyrido [4, 3-b]Carbazole-1-carboxamide, asularnine, (5a, 5aB, 8aa, 9b) -9- [2- [ N- [2- (dimethylamino) ethyl group]-N-methylamino radical]Ethyl radical]-5- [ 4-hydroxy-3, 5-dimethoxyphenyl group]-5, 5a, 6, 8, 8a, 9-hexahydrofuro (3 ', 4': 6, 7) naphtho (2, 3-d) -1, 3-dioxol-6-one, 2, 3- (methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenzo [ c ]]Phenanthridines6, 9-bis [ (2-aminoethyl) amino group]-benzo [ g ]]Isoquinoline-5, 10-dione, 5- (3-aminopropylamino) -7, 10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazolo [4, 5, 1-de]-acridin-6-one, N- [1- [2 (diethylamino) ethylamino]-7-methoxy-9-oxo-9H-thia-neAlk-then-4-ylmethyl]Formamide, N- (2- (dimethyl-amino) -ethyl) acridine-4-carboxamide, 6- [ [2- (dimethylamino) -ethyl ] carbonyl]Amino group]-3-hydroxy-7H-indeno [2, 1-c]Quinolin-7-one and dimesna.

Non-limiting examples of antiproliferative agents are antisense RNA-and antisense DNA-oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001 and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, deoxyfluorouridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine octadecyl sodium phosphate (cytarabine ocfosfate), fosetabine sodium hydrate, raltitrexed, palitexiride, ethirimol, thiazoline, decitabine, nolatrexed, pemetrexed, nelarabine, 2 ' -deoxy-2 ' -methylenecytidine, 2 ' -fluoromethylene-2 ' -deoxycytidine, N- [5- (2, 3-dihydrobenzofuranyl) sulfonyl ] -N ' - (3, 4-dichlorophenyl) urea, N6- [ 4-deoxy-4- [ N2- [2(E), 4(E) -Tetradecadienoyl ] glycylamino ] -L-glycero-B-L-manno-heptopyranosyl (heptopyranosyl) ] adenine, aplidine, ecteinascidin, troxacitabine, 4- [ 2-amino-4-oxo-4, 6, 7, 8-tetrahydro-3H-pyrimido [5, 4-B ] [1, 4] thiazin-6-yl- (S) -ethyl ] -2, 5-thiophenoyl-L-glutamic acid, aminopterin, 5-fluorouracil, aragonin, 11-acetyl-8- (carbamoyloxymethyl) -4-formyl-6-methoxy-14-oxa-1, 11-diaza-tetracyclo- (7.4.1.0.0) -tetradeca-2, 4, 6-trien-9-yl acetate, octahydroindolizinetriol, lometrexol, dexrazoxane, methioninase (methioninase), 2 '-cyano-2' -deoxy-N4-palmitoyl-1-B-D-arabinofuranosyl cytosine and 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone.

"antiproliferative agents" also include monoclonal antibodies against growth factors such as trastuzumab and tumor suppressor genes such as p53, which are not listed under "angiogenesis inhibitors".

The pharmaceutical compositions of the present invention (described herein) may be administered by any method that achieves their intended purpose. For example, administration can be by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intra-articular, intraspinal, transtracheal, ocular, subcutaneous, intraperitoneal, transdermal, or buccal routes. Alternatively or concurrently, administration may be by the oral route. The dose administered will depend on the age, health and weight of the recipient, and on the type of concurrent treatment, if any, the frequency of the treatment, and the nature of the effect desired. Parenteral administration is preferred. Oral administration is particularly preferred.

Suitable dosage forms include, but are not limited to, capsules, tablets, pellets, dragees (dragees), semi-solid preparations, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tapes (tape), eye drops, solutions, syrups, aerosols, suspensions, emulsions, which can be prepared according to methods known in the art, for example as described below:

and (3) tablet preparation: the active ingredient is mixed with the auxiliaries, the mixture is compressed into tablets (direct compression), and optionally part of the mixture is granulated before compression.

And (3) capsule preparation: the active ingredient is mixed with adjuvants to give a flowable powder, the powder is optionally granulated, the powder/granulate is filled into open capsules, and the capsules are capped.

Semisolid preparation (ointment, gel, cream): dissolving/dispersing the active ingredient in an aqueous or fatty carrier; the aqueous/fat phase is then mixed with the complementary fat/aqueous phase and homogenized (for cream only).

Suppositories (rectal and vaginal): the active ingredient is dissolved/dispersed in a carrier material which is liquefied by heating (rectal suppository: carrier material is usually a wax; pessary: carrier material is usually a solution of a heated gelling agent), the mixture is poured into suppository moulds, annealed and the suppositories are removed from the moulds.

Aerosol: the active agent is dispersed/dissolved in the propellant and the mixture is charged to the nebulizer.

In general, non-chemical routes for preparing pharmaceutical compositions and/or pharmaceutical formulations include processing steps performed on suitable mechanical means known in the art to convert one or more products of the present invention into a dosage form suitable for administration to a patient in need of such treatment. Typically, converting one or more products of the invention into such dosage forms comprises adding one or more compounds selected from the group consisting of: carriers, excipients, auxiliaries and pharmaceutically active ingredients other than the products of the invention. Suitable processing steps include, but are not limited to, combining, milling, mixing, granulating, dissolving, dispersing, homogenizing, molding, and/or compressing the respective active and inactive ingredients. Mechanical tools for carrying out said process steps are known in the art, for example from Ullmann's Encyclopedia of Industrial Chemistry, fifth edition. In this respect, the active ingredient is preferably at least one product of the invention and one or more further compounds other than the product of the invention, preferably those pharmaceutically active agents other than the product of the invention disclosed herein, which exhibit valuable pharmaceutical properties.

Particularly suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices (juice) or drops, for rectal use are suppositories, for parenteral use are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, for topical use are ointments, creams or powders. The products of the invention may also be lyophilized, the resulting lyophilizates being used, for example, for the preparation of injectable preparations. The given formulations can be sterilized and/or contain adjuvants (assistant), such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for varying the osmotic pressure, buffer substances, dyes, flavorings and/or a multiplicity of further active ingredients, for example one or more vitamins.

Suitable excipients are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical administration and do not react with the products of the invention, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, triacetin, gelatin, carbohydrates such as lactose, sucrose, mannitol, sorbitol or starch (corn starch, wheat starch, rice starch, potato starch), cellulose preparations and/or calcium phosphate salts such as tricalcium phosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and/or vaseline.

If desired, disintegrating agents can be added, such as the starches mentioned above as well as carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate. Adjuvants include, without limitation, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a film-coating solution (lacquer solution) and suitable organic solvents or solvent mixtures. To prepare coatings resistant to gastric juices or to provide dosage forms with the advantage of long-lasting action, tablets, dragees or pills can contain an inner dosage component and an outer dosage component, the latter being in the form of a shell encasing the former. The two components may be separated by an enteric layer which serves to resist disintegration in the stomach and allows the inner component to pass intact through the stomach into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, such materials including a number of polymeric acids and solutions of polymeric acids with such materials as shellac, ethyl alcohol, suitable cellulosics such as acetyl cellulose phthalate, cellulose acetate or hydroxypropylmethyl cellulose phthalate. Dyes or pigments may be added to the coating of the tablets or dragees, for example, for identifying or for identifying combinations of active compound doses.

Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral or topical administration and which do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petrolatum. In particular, tablets, coated tablets, capsules, syrups, suspensions, drops or suppositories are used for enteral administration, solutions, preferably oily or aqueous solutions, also suspensions, emulsions or implants are used for parenteral administration, ointments, creams or powders are used for topical application. The product of the invention may also be lyophilized and the resulting lyophilizate may be used, for example, in the preparation of injectable preparations.

The given formulations may be sterilized and/or may contain excipients such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing osmotic pressure, buffer substances, colorants, taste correctors and/or fragrances. They may also, if desired, contain one or more further active compounds, for example one or more vitamins.

Other pharmaceutical preparations which can be used orally include push-fit (push-fit) capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules can contain the active compounds in the form of granules which can be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers may be added.

Liquid forms in which the novel compositions of the present invention may be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical media. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. Additionally, suspensions of the active compounds may be administered, such as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).

Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran, and may also optionally contain stabilizers.

For administration in the form of an inhalation spray, use is made of a spray in which the active ingredient is dissolved or suspended in a propellant gas or propellant gas mixture (e.g. CO)₂Or chlorofluorocarbons) are possible. The active ingredient is micronizedAdvantageously, one or more additional physiologically acceptable solvents, such as ethanol, may be present in this case. The inhalation solution can be administered by means of a conventional inhaler.

Possible pharmaceutical preparations which can be used rectally include, for example, suppositories which consist of a combination of one or more active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffin hydrocarbons. In addition, gelatin rectal capsules may also be used, which consist of a combination of the active compound with a base. Possible matrix materials include, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For medical use, the product of the invention will be in the form of a pharmaceutically acceptable salt. However, other salts may be used in the preparation of the products of the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the products of the invention include acid addition salts which may be formed, for example, by mixing a product of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the product of the invention carries an acidic group, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, for example sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts with suitable organic bases, such as quaternary ammonium salts.

The pharmaceutical preparations can be used as medicaments in human and veterinary medicine. The term "effective amount" as used herein means an amount of a drug or pharmaceutical substance that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for example, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount that results in an improved treatment, cure, prevention or amelioration of a disease, disorder or side effect or a reduction in the rate of progression of a disease or disorder as compared to a corresponding individual not receiving that amount. The term also includes within its scope an amount effective to enhance normal physiological function. The therapeutically effective amount of the one or more products of the invention is known to those skilled in the art or can be readily determined by standard methods known in the art.

The products of the invention and the additional pharmacologically active substances are generally applied analogously to the commercial preparations. In general, suitable dosages for therapeutic effectiveness lie in the range from 0.0005mg to 1000mg, preferably from 0.005mg to 500mg, in particular from 0.5mg to 100mg per dosage unit. The daily dosage is preferably between about 0.001mg/kg body weight and 10mg/kg body weight.

One skilled in the art will readily appreciate that dosage levels may vary depending on the particular compound, the severity of the symptoms, and the individual's susceptibility to side effects. Some specific compounds are more effective than others. Preferred dosages for a given compound can be readily determined by one skilled in the art using a variety of methods. One preferred method is to determine the physiological potency of a given compound.

For the purposes of the present invention, all mammalian species are included. In a preferred embodiment, the mammal is selected from the group consisting of "primate, human, rodent, equine, bovine, canine, feline, farm animal, bovine, livestock, pet, cow, sheep, pig, goat, horse, pony (pony), donkey, mule, horse mule, rabbit, cat, dog, guinea pig, hamster, rat, mouse". More preferably, the mammal is a human. Animal models are important for experimental studies, providing a model for the treatment of human disease.

However, the specific dose for each individual patient depends on numerous factors, such as the potency of the specific compound used, the age, body weight, general health, sex, dietary type, time and route of administration, rate of excretion, type and dosage form of administration, drug combination and the severity of the particular disorder involved in the treatment. The specific therapeutically effective amount for each patient can be readily determined by routine experimentation, for example, by the physician or physician advised and responsible for the treatment.

In the case of many disorders, the susceptibility of a particular cell to treatment with a subject compound may be determined by in vitro assays. Typically, cell cultures are combined with varying concentrations of the subject compounds for a period of time sufficient for the active agents to exhibit a relevant response, typically about 1 hour to one week. For in vitro assays, cultured cells of a biopsy sample may be used.

The object of the present invention has in a further aspect been surprisingly solved by providing a process for the preparation of crystalline modification a1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate, which comprises the following steps:

(a) dissolving or dispersing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base) or one or more salts thereof in a solvent or solvent mixture, preferably 2-propanol or chloroform, optionally with stirring,

(b) converting 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base) or one or more salts thereof into the corresponding dihydrogen phosphate salt by adding an aqueous or ethanolic solution of phosphoric acid, optionally with stirring,

(c) stirring the dispersion obtained in step (b) at room temperature for one or more hours or for one or more days, preferably for 1 or 2 hours,

(d) the precipitated 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate is recovered by filtration, optionally followed by washing with a solvent or solvent mixture, and optionally followed by drying, preferably in vacuo, optionally at an elevated temperature T, preferably from 30 ℃ to 95 ℃, more preferably 70 ℃.

In the present invention, the terms "elevated temperature" and "elevated temperature" are used anywayT or T_x"(wherein x ═ 1, 2, 3, etc.)" means the particular temperature for a given process step or substep, independently of any other "elevated temperature" and can be any temperature within the range from "above room temperature" to the "boiling temperature" of a given solvent or solvent mixture and/or the "melting temperature" of a given solid, isolate, intermediate or product or mixture thereof.

In the present invention, the term "one or more salts of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base)" refers to any and all salts, preferably pharmaceutically acceptable salts, of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base), including, but not limited to, acetate, adipate, alginate, arginine, aspartate, benzoate, phenylsulfonate (benzenesulfonate), bisulfate, bisulfite, bromide, butyrate, camphorate (bampfeat), camphorsulfonate (campforsulfate), caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galactarate (galactarate), galacturonate, glucoheptonate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, Lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate and phthalate.

In the present invention, the term "solvent or solvent mixture" means any and all solvents, preferably organicSolvents and water, more preferably pharmaceutically acceptable organic solvents and water, including but not limited to methanol, ethanol, 2-propanol, n-butanol, isobutanol, acetone, methyl ethyl ketone, ethyl acetate, 1, 4-diAlkane, diethyl ether, MTBE, THF, acetonitrile, dichloromethane, chloroform, DMF, cyclohexane, cyclopentane, n-hexane, n-heptane, n-pentane, toluene, o-xylene, p-xylene, DMSO, pyridine, acetic acid, anisole, butyl acetate, cumene, ethyl formate, formic acid, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl isobutyl ketone, 2-methyl-1-propanol, 1-pentanol, propyl acetate, ethylene glycol, and 1-methyl-2-pyrrolidone, and mixtures of any and all two or more such solvents, preferably binary mixtures, more preferably binary mixtures of water and pharmaceutically acceptable organic solvents.

(a) dispersing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base) or one or more salts thereof in a solvent or solvent mixture, preferably water, and adding aqueous phosphoric acid, optionally with stirring,

(b) heating the dispersion obtained in step (a) to an elevated temperature T1, preferably 30 ℃ to 95 ℃, more preferably 50 ℃, optionally under stirring, and cooling the resulting solution, preferably to 0 ℃ to 40 ℃, more preferably to 20 ℃, optionally under stirring, before it is diluted with a solvent or solvent mixture, preferably acetone, optionally under stirring,

(c) stirring the dispersion obtained in step (b) at 0 ℃ to 40 ℃, preferably 10 ℃, until crystallization is complete, and/or incubating it at room temperature for one or more hours or one or more days, optionally under stirring,

(d) recovering the precipitated 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate by filtration, optionally cooling the dispersion obtained in step (c) to 0 ℃ to 20 ℃, preferably 5 ℃, followed by filtration, optionally with stirring, optionally followed by washing with a solvent or solvent mixture, preferably acetone, and optionally followed by drying, preferably in vacuo, optionally at an elevated temperature T2, preferably 30 ℃ to 95 ℃, more preferably 70 ℃,

(e) optionally, the dried crystals obtained in step (d) in the form of a dispersion in a solvent or solvent mixture, preferably ethanol, are boiled for one or more minutes, preferably 30 minutes, and they are recovered from the hot dispersion by filtration.

(a) dispersing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base) or one or more salts thereof in a solvent mixture, preferably a water: acetone mixture, and adding aqueous phosphoric acid, optionally with stirring,

(b) heating the dispersion obtained in step (a) to an elevated temperature T1, preferably 30 ℃ to 95 ℃, more preferably 55 ℃, optionally with stirring, and cooling the solution obtained, preferably to 0 ℃ to 50 ℃, optionally with stirring, at a defined cooling rate, preferably 0.1 to 1K/min, more preferably 0.1 to 0.3K/min, optionally with stirring, until crystallization begins,

(c) further cooling the dispersion obtained in step (b), preferably to a temperature of from-20 ℃ to 0 ℃, more preferably to a temperature of from-10 ℃, optionally with stirring, at a given cooling rate, preferably from 0.1 to 1K/min, more preferably from 0.1 to 0.3K/min, optionally with stirring,

(d) stirring the dispersion obtained in step (c) at-20 ℃ to 40 ℃, preferably-10 ℃ until crystallization is complete,

(e) the crystalline 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate is recovered by filtration, optionally followed by washing with a solvent or solvent mixture, preferably acetone, and optionally followed by drying, preferably in vacuo, optionally at an elevated temperature T2, preferably 30 ℃ to 95 ℃, more preferably 70 ℃.

The object of the present invention has in a further aspect been surprisingly solved by providing a process for the preparation of the crystalline modification H1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate, comprising the steps of:

(a) crystalline modification a1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate is spread on a surface, preferably an edge surface of a container, more preferably an edge surface of a petri dish, and subsequently incubated in a sealed desiccator at a defined Relative Humidity (RH), preferably 80-100% RH, more preferably 90-100% RH, on water or an aqueous salt solution for one or more days or one or more weeks.

(a) crystalline modification a1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate is dispersed in a mixture of two or more solvents, preferably a binary mixture of water and an organic solvent, wherein the organic solvent is preferably selected from: "methanol, ethanol, 2-propanol, acetone, TFH and acetonitrile", optionally with stirring, and the resulting dispersion is stirred at an elevated temperature T1, preferably 30 ℃ to 95 ℃, more preferably 50 ℃ for one or more days or weeks,

(b) the precipitated 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate is recovered by filtration, optionally followed by washing with a solvent or solvent mixture, and optionally followed by drying, preferably in vacuo, optionally at an elevated temperature T2, preferably 30 ℃ to 95 ℃, more preferably 70 ℃.

The object of the present invention has in a further aspect been surprisingly solved by providing a process for the preparation of the crystalline modification NF3 of the dihydrogenphosphate salt of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one, comprising the following steps:

(a) mixing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl]-benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate crystalline modification a1 dispersed or dissolved in a mixture of two or more solvents, preferably a binary mixture, wherein the solvents are preferably selected from: "Water, methanol, ethanol, 2-propanol, acetone, TFH, acetonitrile and 1, 4-bisAlkane ", optionally with stirring, and subsequent evaporation of the mixture of two or more solvents at room temperature or at an elevated temperature T1, preferably 30 ℃ to 95 ℃, more preferably 50 ℃, until crystallization occurs,

(b) the precipitated 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate is recovered by filtration, optionally followed by washing with a solvent or solvent mixture, and optionally followed by drying, preferably in vacuo, optionally at an elevated temperature T2, preferably 30 ℃ to 95 ℃, more preferably 70 ℃.

The object of the present invention has in a further aspect been surprisingly solved by providing a process for the preparation of the crystalline modification NF5 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate, comprising the steps of:

(a) crystalline modification A1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate is dissolved in a binary solvent mixture, preferably water: methanol, most preferably water: methanol in the ratio 1:1 (v: v), and the solvent mixture is rapidly evaporated under vacuum at elevated temperature, preferably 40-80 ℃, most preferably 60 ℃, until a precipitate is obtained,

(b) optionally, the precipitate obtained from step (a) in powder form is further spread on a surface, preferably a bordered surface of a container, more preferably a bordered surface of a petri dish, and subsequently incubated on water or an aqueous salt solution in a sealed desiccator at a defined Relative Humidity (RH), preferably 80-100% RH, more preferably 90-100% RH, for one or more days or for one or more weeks.

(a) the crystalline form NF3 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate in powder form is spread on a surface, preferably an edge surface of a container, more preferably an edge surface of a petri dish, and subsequently incubated in a sealed desiccator at a defined Relative Humidity (RH), preferably 80-100% RH, more preferably 90-100% RH, on water or an aqueous salt solution for one or more days or for one or more weeks.

Brief description of the drawings

FIG. 1 depicts a powder X-ray diffraction pattern of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1.

FIG. 2 depicts single crystal X-ray structural data for 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate crystalline modification A1 viewed along the b-axis.

FIG. 3 depicts the FT-IR spectrum of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1.

FIG. 4 depicts the FT-Raman spectrum of crystalline modification A1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate.

FIG. 5 depicts a DSC scan of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1 (Perkin-Elmer Diamond DSC, 5K/min, nitrogen flow 50 mL/min).

FIG. 6 depicts a TGA scan of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1 (Perkin-Elmer Pyris TGA1, 5K/min, nitrogen flow 50 mL/min).

FIG. 7 depicts the water vapor sorption isotherm of form a (25 ℃ C.) (SMS DVS 1) for crystalline modification A1, form a of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate.

FIG. 8 depicts the water vapor sorption isotherm of form b (25 ℃ C.) (SMS DVS 1) for crystalline modification A1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate.

FIG. 9 depicts a powder X-ray diffraction pattern of crystalline modification H1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate.

FIG. 10 depicts single crystal X-ray structural data for 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate in crystal modification H1.

FIG. 11 depicts a FT-IR spectrum of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate in crystalline modification H1.

FIG. 12 depicts a DSC scan of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate in crystal modification H1 (Perkin-Elmer Diamond DSC, 5K/min, nitrogen flow 50 mL/min).

FIG. 13 depicts a TGA scan of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate in crystal modification H1 (Perkin-Elmer Pyris TGA1, 5K/min, nitrogen flow 50 mL/min).

FIG. 14 depicts the water vapor sorption isotherm (25 ℃) of crystalline modification H1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate (SMS DVS Intrinsic).

FIG. 15 depicts a powder X-ray diffraction pattern of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate in crystalline modification NF 3.

FIG. 16 depicts a FT-IR spectrum of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate in crystalline modification NF 3.

FIG. 17 depicts a FT-Raman spectrum of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate in crystalline modification NF 3.

FIG. 18 depicts a DSC scan of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate in crystalline modification NF3 (Perkin-Elmer Diamond DSC, 5K/min, nitrogen flow 50 mL/min).

FIG. 19 depicts a TGA scan of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate in crystalline modification NF3 (Perkin-Elmer Pyris TGA1, 5K/min, nitrogen flow 50 mL/min).

FIG. 20 depicts the water vapor sorption isotherm (25 ℃) of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate in crystalline modification NF3 (SMS DVS Intrinsic).

FIG. 21 depicts a powder X-ray diffraction pattern of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate in crystalline modification NF 5.

FIG. 22 depicts a DSC scan of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate in crystalline modification NF5 (Perkin-Elmer Diamond DSC, 5K/min, nitrogen flow 50 mL/min).

FIG. 23 depicts a TGA scan of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate in crystalline modification NF5 (Perkin-Elmer Pyris TGA1, 5K/min, nitrogen flow 50 mL/min).

FIG. 24 depicts the water vapor sorption isotherm (25 ℃) of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate in crystal modification NF5 (SMS DVS Intrinsic).

Those skilled in the art will be able to utilize the above description to its fullest extent, even if not in any further detail. The preferred embodiments are therefore to be considered in all respects as illustrative and not restrictive.

The contents of all cited references are incorporated herein by reference in their entirety. The present invention is illustrated in more detail by the following examples, which, however, do not limit the invention.

Examples

Example 1:

preparation of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1

Method 1

About 118mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base) was dissolved in about 7mL of warm 2-propanol. After addition of about 0.017mL of aqueous phosphoric acid (85%), a precipitate appeared. The dispersion was stirred at room temperature for 2 hours, followed by filtration. The resulting crystals were dried at 70 ℃ under vacuum.

¹H-NMR(d₆-DMSO)：δ[ppm]＝2.50(m，4H+DMSO)，2.75(t，2H)，3.57(t，4H)，3.87(s，3H)，4.30(t，2H)，5.34(s，2H)，7.05(d，1H)，7.44(m，2H)，7.80(d，1H)，7.89(s，1H)，8.21(m，2H)，8.28(m，1H)，8.65(s，2H).

Ion chromatography: 19.3% by weight of phosphate (corresponding to a molar acid: base ratio of 1.14).

Method 2

About 500mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base) was dissolved in about 10mL of chloroform. After addition of about 2.1mL of an ethanol solution of phosphoric acid (0.5mmol/L), the dispersion was stirred at room temperature for 1 h. The resulting precipitate was filtered and the harvested crystals were dried under vacuum at 70 ℃.

¹H-NMR(d₆-DMSO)：δ[ppm]＝2.55(m，4H)，2.80(t，2H)，3.60(m，4H)，3.88(s，3H)，4.33(t，2H)，5.35(s，2H)，7.07(d，1H)，7.46(m，2H)，7.82(d，1H)，7.90(s，1H)，8.23(m，2H)，8.30(m，1H)，8.65(s，2H).

Ion chromatography: 14.9% by weight of phosphate (corresponding to a molar acid: base ratio of 0.88).

Method 3

About 354g of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base) was dispersed at 23 ℃ in about 450mL of DI water. After addition of about 57.3mL of aqueous phosphoric acid (85%), the dispersion was heated to 50 ℃ to give a clear solution. The solution was cooled to 20 ℃ and diluted with about 1.2L of acetone, resulting in crystallization. The dispersion was stirred at 10 ℃ until crystallization was complete. The dispersion was left at room temperature for several days, then cooled to 5 ℃ and filtered. The crystals obtained were washed with acetone and dried under vacuum at 70 ℃. The dried crystals were subsequently boiled in ethanol for 30 minutes in the form of a dispersion, and the crystals were filtered from the hot dispersion.

¹H-NMR(d₆-DMSO)：δ[ppm]＝2.50(m，4H+DMSO)，2.74(t，2H)，3.58(m，4H)，3.87(s，3H)，4.32(t，2H)，5.34(s，2H)，7.05(d，1H)，7.45(m，2H)，7.82(d，1H)，7.89(s，1H)，8.22(m，2H)，8.28(m，1H)，8.65(s，2H).

Ion chromatography: 19.5% by weight of phosphate (corresponding to a molar acid: base ratio of 1.15).

Method 4

About 1.1kg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base) was dispersed at 23 ℃ in about 1.37L of DI water. After addition of about 240mL of aqueous phosphoric acid (85%), the dispersion was heated to 50 ℃ to give a clear solution. The solution was cooled to 20 ℃ and slowly diluted with about 1L of acetone under agitation, resulting in the onset of crystallization. An additional about 3L of acetone was added slowly to give a white dispersion which was stirred at room temperature overnight. The dispersion was filtered, and the resulting crystals were washed with acetone and dried under vacuum at 70 ℃.

¹H-NMR(d₆-DMSO)：δ[ppm]＝2.50(m，4H+DMSO)，2.74(t，2H)，3.57(m，4H)，3.87(s，3H)，4.30(t，2H)，5.34(s，2H)，7.05(d，1H)，7.45(m，2H)，7.82(d，1H)，7.89(s，1H)，8.22(m，2H)，8.28(m，1H)，8.64(s，2H).

Ion chromatography: 16.8% by weight of phosphate (corresponding to a molar acid: base ratio of 0.99).

Method 5

About 100g of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base) was dispersed at 23 ℃ in about 171.4g of DI water. After addition of about 36.55g of aqueous phosphoric acid (85%), the solution was filtered. The obtained filtrate was diluted with about 331.05g of acetone to obtain a dispersion. The dispersion was heated to 55 ℃ to give a clear solution. The solution was cooled to-10 ℃ at a predetermined cooling rate of 0.3K/min to obtain a dispersion which was slurried for 1 hour at-10 ℃. The dispersion was filtered, and the resulting crystals were washed with acetone and dried under vacuum at 70 ℃.

¹H NMR(500MHz，DMSO)δ＝8.64(s，2H)，8.31-8.26(m，1H)，8.25-8.19(m，2H)，7.89(s，1H)，7.81(d，J＝9.6，1H)，7.53-7.38(m，2H)，7.05(d，J＝9.6，1H)，5.33(s，2H)，4.31(t，J＝5.6，2H)，3.87(s，3H)，3.65-3.52(m，4H)，2.75(t，J＝5.6，2H)，2.50(m，4H)

Ion chromatography: 17.7% by weight of phosphate (corresponding to a molar acid: base ratio of 1.04).

Method 6

About 15.2kg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base) was dispersed in about 31kg of DI water at T < 30 ℃. After addition of about 5.5kg of aqueous phosphoric acid (85%), the solution was slurried for 30 minutes, followed by filtration. The obtained filtrate was diluted with about 55.8kg of acetone at 25 ℃ to obtain a dispersion. The dispersion was heated to 62 ℃ to give a clear solution. The solution was cooled to 50 ℃ (thermostatted jacket temperature) at a given cooling rate of 0.1K/min and slurried for about 6.5 hours until a cloudy dispersion was obtained. The dispersion was further cooled to-10 c (constant temperature jacket temperature) at a given cooling rate of 0.1K/min, and slurried at that temperature for about 1 hour. The dispersion was filtered, and the resulting crystals were washed with acetone and dried under vacuum at 70 ℃.

¹H NMR(500MHz，DMSO)δ＝8.65(s，2H)，8.35-8.26(m，1H)，8.25-8.19(m，2H)，7.89(s，1H)，7.81(d，J＝9.6，1H)，7.53-7.38(m，2H)，7.06(d，J＝9.6，1H)，5.34(s，2H)，4.33(t，J＝5.5，2H)，3.87(s，3H)，3.69-3.52(m，4H)，2.82(t，J＝5.4，2H)，2.64-2.53(m，4H).

Ion chromatography: 17.1% by weight of phosphate (corresponding to a molar acid: base ratio of 1.01).

Example 2:

preparation of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate in crystalline modification H1

Method 1

About 400mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1 was spread on petri dishes and stored in a closed desiccator on pure DI water (100% relative humidity atmosphere) for 2 weeks.

¹H-NMR(d₆-DMSO)：δ[ppm]＝2.50(m，4H+DMSO)，2.74(t，2H)，3.57(m，4H)，3.87(s，3H)，4.30(t，2H)，5.34(s，2H)，7.05(d，1H)，7.45(m，2H)，7.82(d，1H)，7.89(s，1H)，8.22(m，2H)，8.29(m，1H)，8.65(s，2H).

Ion chromatography: 17.1% by weight of phosphate (corresponding to an acid: base molar ratio of 1.08, based on phosphate with the measured water content given below).

Karl-Fischer-titration: 6.5% by weight of water.

Method 2

About 45mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1 was dispersed in about 0.2mL of a binary mixture of DI water/ethanol (1: 1, v/v) and shaken as a slurry at 1000rpm for 7 days at 50 ℃. The dispersion was then filtered and the resulting crystals were dried on the filter at ambient conditions.

Method 3

About 45mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1 was dispersed in about 0.2mL of a binary mixture of DI water/methanol (1: 1, v/v) and shaken as a slurry at 1000rpm for 7 days at 50 ℃. The dispersion was then filtered and the resulting crystals were dried on the filter at ambient conditions.

Method 4

About 50mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1 was dispersed in about 0.2mL of a binary mixture of DI water/2-propanol (1: 1, v/v) and shaken as a slurry at 1000rpm for 7 days at 50 ℃. The dispersion was then filtered and the resulting crystals were dried on the filter at ambient conditions.

Method 5

About 30mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1 was dispersed in about 0.2mL of a binary mixture of DI water/acetone (1: 1, v/v) and shaken as a slurry at 1000rpm for 7 days at 50 ℃. The dispersion was then filtered and the resulting crystals were dried on the filter at ambient conditions.

Method 6

About 65mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1 was dispersed in about 0.2mL of a binary mixture of DI water/THF (1: 1, v/v) and shaken as a slurry at 1000rpm for 7 days at 50 ℃. The dispersion was then filtered and the resulting crystals were dried on the filter at ambient conditions.

Method 7

About 50mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1 was dispersed in about 0.15mL of a binary mixture of DI water/acetonitrile (1: 1, v/v) and shaken as a slurry at 1000rpm for 7 days at 50 ℃. The dispersion was then filtered and the resulting crystals were dried on the filter at ambient conditions.

Example 3:

preparation of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate in crystalline modification NF3

Method 1

About 30mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1 was dissolved in about 3ml of a binary mixture of DI water/ethanol (1: 1, v/v). Crystallization occurs by evaporation of the solvent at ambient conditions. The crystals were isolated by filtration and dried on the filter at ambient conditions.

Method 2

About 155mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl]Crystalline modification A1 of the dihydrogen phosphate monohydrate of (E) -benzyl } -2H-pyridazine-3-one was dissolved in about 15ml DI water/1, 4-bisIn a binary mixture of alkanes (1: 1, v/v). Crystallization occurred by evaporation of the solvent at 50 ℃. The crystals were isolated by filtration and dried on the filter at ambient conditions.

¹H NMR(500MHz，DMSO)d＝8.63(s，2H)，8.31-8.26(m，1H)，8.25-8.18(m，2H)，7.89(s，1H)，7.80(d，J＝9.6，1H)，7.55-7.40(m，2H)，7.05(d，J＝9.6，1H)，5.34(s，2H)，4.31(t，J＝5.6，2H)，3.87(s，3H)，3.80-3.30(m，4H)2.74(t，J＝5.5，2H)，2.50(m，4H)

Ion chromatography: 16.0% by weight of phosphate (corresponding to a molar acid: base ratio of 0.94).

Example 4:

preparation of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate in crystalline modification NF5

Method 1

About 100mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl]Crystalline modification A1 of the dihydrogen phosphate monohydrate of-benzyl } -2H-pyridazine-3-one was dissolved in about 1ml of a binary mixture of DI water/methanol (1: 1, v: v). The solution was heated to 60 ℃ while vacuum was applied to rapidly evaporate the solvent. The resulting precipitate in powder form was spread on a petri dish and subsequently dried in a sealed desiccator under KNO₃For several days on saturated salt solution (94% RH).

¹H NMR(500MHz，DMSO)d＝8.64(s，2H)，8.31-8.25(m，1H)，8.25-8.19(m，2H)，7.88(s，1H)，7.80(d，J＝9.6，1H)，7.52-7.38(m，2H)，7.04(d，J＝9.6，1H)，5.33(s，2H)，4.30(t，J＝5.6，2H)，3.87(s，3H)，3.66-3.50(m，4H)，2.73(t，J＝5.6，2H)，2.50(m，4H)

Ion chromatography: 14.8% by weight of phosphate (corresponding to an acid: base molar ratio of 0.94, based on phosphate with the measured water content given below).

Karl-Fischer-titration: 7.3% by weight of water.

The method 2 comprises the following steps:

about 100mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl in powder form]-benzyl } -2H-pyridazin-3-one dihydrogenphosphate in crystalline modification NF3 spread on a petri dish, followed by KNO in a sealed desiccator₃For several days on saturated salt solution (94% RH).

Example 5:

structural and physicochemical characterization of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystal modification A1

The powder X-ray diffraction (XRD) pattern of crystalline modification a1 was obtained by standard techniques described in european pharmacopeia 6 th edition, chapter 2.9.33. Crystalline modification A1 in the X-ray powder diffraction Pattern (Cu-Ka α) depicted in FIG. 1₁A radioactive source,stoe StadiP611KL diffractometer).

Crystalline modification a1 is characterized by the following XRD data:

list of powder X-ray diffraction pattern peaks:

single crystal X-ray structural data of crystal modification A1 were also obtained (XCalibur diffractometer from Oxford Diffraction, equipped with a graphite monochromator and a CCD detector, Mo K was used at 301K_αA radioactive source). The single crystal structure of crystal modification a1 viewed along the b-axis is shown in fig. 2.

The crystalline modification A1 crystallizes as monoclinic space group C2/C, the unit cell parameters of which areβ 102.2 ° (α γ 90 °). It is evident from the single crystal structure that crystal modification a1 is an anhydrous crystal form.

The crystal modification A1 was further characterized by IR-and Raman-spectroscopy. FT-Raman and FT-IR spectra were obtained by standard techniques described in European pharmacopoeia, 6 th edition, chapters 2.02.24 and 2.02.48. For the determination of FT-IR and FT-Raman spectra, Bruker Vector 22 and Bruker RFS100 spectrometers were used. The FT-IR spectra were baseline corrected using Bruker OPUS software. The FT-raman spectra were vector normalized using the same software.

The FT-IR spectra were obtained using KBr pellets as a sample preparation technique. The FT-IR spectrum is shown in FIG. 3, with band positions given below.

Crystalline modification A1IR band position. + -. 2cm^-1(relative Strength of

2949cm^-1(w)，2885cm^-1(w)，2368cm^-1(w, width), 1661cm^-1(s)，1603cm^-1(s)，1549cm^-1(m)，1446cm^-1(s)，1429cm^-1(s)，1283cm^-1(s)，1261cm^-1(m)，1226cm^-1(m)，1132cm^-1(s)，1068cm^-1(s)，945cm^-1(s)，854cm^-1(s)，713cm^-1(m)

Strong (transmittance less than 50%), "medium (transmittance less than 70%)," medium (transmittance less than 50%), "weak (transmittance greater than 70%)

The FT-raman spectrum is shown in fig. 4, with band positions given below.

Crystal modification A1 Raman band position. + -. 2cm^-1(relative intensity):

3061cm^-1(w)，2951cm^-1(w)，1604cm^-1(s)，1579cm^-1(s)，1568cm^-1(m)，1515cm^-1(w)，1446cm^-1(m)，1430cm^-1(m)，1327cm^-1(m)，1161cm^-1(w)，1001cm^-1(m)，802cm^-1(w)，793cm^-1(w)

strong (relative Raman intensity is greater than or equal to 0.04)'s ' medium (relative Raman intensity is greater than or equal to 0.02) ' w ' weak (relative Raman intensity is less than 0.02) ')

Crystalline modification a1 is an anhydrous crystalline form further characterized by the following physical properties:

thermal behavior shows a melting peak at about 207 ℃ with very little mass loss up to the melting temperature. DSC plots (Perkin-Elmer Diamond DSC, 5K/min, nitrogen flow 50mL/min) and TGA plots (Perkin-Elmer Pyris TGA1, 5K/min, nitrogen flow 50mL/min) are given in FIG. 5 and FIG. 6, respectively.

Water vapor sorption behavior shows small water uptake levels after sorption in the range of 0-70% Relative Humidity (RH) (crystal modification a, form a) and 0-90% RH (crystal modification a, form b), respectively. Significant water uptake levels were observed above 70% RH (crystalline modification a, form a) and above 90% RH (crystalline modification a, form b), respectively, which resulted in the formation of dihydrate crystalline modification H1 (water uptake level of about 6 wt%) at elevated Relative Humidity (RH). The water vapor sorption isotherms [ water vapor sorption isotherms (25 ℃) for crystal modification a1 (type a and b) (SMS DVS 1) ] are given in fig. 7 and fig. 8, respectively.

Example 6:

structural and physicochemical characterization of crystal modification H1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate

The powder X-ray diffraction (XRD) pattern of crystalline modification H1 was obtained by standard techniques described in european pharmacopeia 6 th edition, chapter 2.9.33. Crystal modification H1 in the X-ray powder diffraction pattern (Cu-Ka α) shown in FIG. 9₁A radioactive source,stoe StadiP611KL diffractometer).

Crystalline modification H1 is characterized by the following XRD data:

list of powder X-ray diffraction pattern peaks:

single crystal X-ray structural data of crystal modification H1 were also obtained (XCalibur diffractometer from Oxford Diffraction, equipped with a graphite monochromator and a CCD detector, using MoK at 301K)_αA radioactive source). The single crystal structure of crystal modification H1 is shown in fig. 10. Crystalline modification H1 as monoclinic space group P2₁Crystal of/C, unit cell parameterAnd β ═ 94.1 ° (α ═ γ ═ 90 °). It is evident from the single crystal structure that crystal modification H1 is a stoichiometric dihydrate.

The crystal modification H1 was further characterized by IR spectroscopy. The FT-IR spectrum is obtained by standard techniques described in European pharmacopoeia 6 th edition, chapters 2.02.24 and 2.02.48. For the determination of the FT-IR spectrum, a Bruker Vector 22 spectrometer was used. The FT-IR spectra were baseline corrected using Bruker OPUS software.

The FT-IR spectra were obtained using KBr pellets as a sample preparation technique. The FT-IR spectrum is shown in fig. 11, with band positions given below.

Band position. + -. 2cm of the crystal modification H1IR^-1(relative Strength of

2984cm^-1(s)，2944cm^-1(s)，2451cm^-1(m, width), 1661cm^-1(s)，1603cm^-1(s)，1548cm^-1(s)，1446cm^-1(s)，1430cm^-1(s)，1277cm^-1(s)，1260cm^-1(s)，1226cm^-1(s)，1124cm^-1(s)，1040cm^-1(s)，940cm^-1(s)，852cm^-1(s)，713cm^-1(s)'s' is strong (transmittance is less than or equal to 50%),'m' is medium (transmittance is less than or equal to 70%, 'w' is weak (transmittance is more than 70%)

The FT-raman spectrum of crystalline modification H1 shows the same spectrum as crystalline modification a1, since the loss of water of hydration occurs as a result of laser excitation.

Crystalline modification H1 is a dihydrate crystalline form that is further characterized by the following physical properties:

thermal behavior shows the loss of water of hydration upon heating from about 30-120 ℃ followed by melting of the anhydrous form at about 208 ℃. DSC plots (Perkin-Elmer Diamond DSC, 5K/min, nitrogen flow 50mL/min) and TGA plots (Perkin-Elmer Pyris TGA1, 5K/min, nitrogen flow 50mL/min) are given in FIG. 12 and FIG. 13, respectively.

Water vapor adsorption behavior shows loss of water of hydration at Relative Humidity (RH) < 40%, reconversion to dihydrate crystalline modification H1 after adsorption at > 70% RH. The water vapor adsorption isotherm (25 ℃) of form H1 is given below. The water vapor sorption isotherm for crystal modification H1 [ water vapor sorption isotherm (25 ℃ (SMS DVS Intrinsic) ] is given in fig. 14.

Example 7:

structural and physicochemical characterization of crystal modification NF3 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate

The powder X-ray diffraction (XRD) pattern of the crystalline modification NF3 was obtained by standard techniques described in the european pharmacopeia 6 th edition, chapter 2.9.33. Crystal modification NF3 in the X-ray powder diffraction pattern (Cu-Ka α) shown in FIG. 15₁A radioactive source,stoe StadiP611KL diffractometer).

Crystalline modification NF3 is characterized by the following XRD data:

list of powder X-ray diffraction pattern peaks:

the crystal modification NF3 was further characterized by IR-and Raman-spectra. FT-Raman and FT-IR spectra were obtained by standard techniques described in European pharmacopoeia, 6 th edition, chapters 2.02.24 and 2.02.48. For the determination of FT-IR and FT-Raman spectra, Bruker Vector 22 and Bruker RFS100 spectrometers were used. The FT-IR spectra were baseline corrected using Bruker OPUS software. The FT-raman spectra were vector normalized using the same software.

The FT-IR spectra were obtained using KBr pellets as a sample preparation technique. The FT-IR spectrum is shown in fig. 16, with band positions given below.

Band position of NF3IR crystal modification. + -. 2cm^-1(relative Strength of

2949cm^-1(m)，2873cm^-1(w)，2365cm^-1(w, width), 1661cm^-1(s)，1602cm^-1(s)，1549cm^-1(m)，1445cm^-1(s)，1430cm^-1(s)，1280cm^-1(s)，1262cm^-1(m)，1226cm^-1(m)，1132cm^-1(s)，1072cm^-1(s)，944cm^-1(s)，851cm^-1(s)，713cm^-1(m)

The FT-raman spectrum is shown in fig. 17, with band positions given below.

Crystal modification NF3 Raman band position + -2 cm^-1(relative intensity):

3061cm^-1(m)，2952cm^-1(m)，1604cm^-1(s)，1581cm^-1(s)，1568cm^-1(s)，1515cm^-1(m)，1446cm^-1(s)，1430cm^-1(s)，1327cm^-1(s)，1167cm^-1(m)，1001cm^-1(s)，802cm^-1(w)，793cm^-1(w)

Crystal modification NF3 is a crystalline form, most likely an anhydrous crystalline form, further characterized by the following physical properties:

thermal behavior shows two exotherm events at about 100-. DSC plots (Perkin-Elmer Diamond DSC, 5K/min, nitrogen flow 50mL/min) and TGA plots (Perkin-Elmer Pyris TGA1, 5K/min, nitrogen flow 50mL/min) are given in FIG. 18 and FIG. 19, respectively.

Water vapor sorption behavior shows small water uptake levels after sorption in Relative Humidity (RH) ranging from 0 to 70%. Significant water uptake levels were observed above 70% RH, which resulted in the formation of hydrate crystal modification NF5 at elevated Relative Humidity (RH) (water uptake levels of about 5-6 wt%). The water vapor sorption isotherm for crystal modification NF3 [ water vapor sorption isotherm (25 ℃ (SMS DVS Intrinsic) ] is given in fig. 20.

Example 8:

structural and physicochemical characterization of crystal modification NF5 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate

The powder X-ray diffraction (XRD) pattern of the crystalline modification NF5 was obtained by standard techniques described in the european pharmacopeia 6 th edition, chapter 2.9.33. Crystal modification NF5 in the X-ray powder diffraction pattern (Cu-Ka α) shown in FIG. 21₁A radioactive source,stoe StadiP611KL diffractometer).

Crystalline modification NF5 is characterized by the following XRD data:

list of powder X-ray diffraction pattern peaks:

crystalline modification NF5 is a hydrate crystalline form further characterized by the following physical properties:

thermal behavior shows the loss of water of hydration upon heating from about 30-100 ℃ followed by melting in anhydrous form at about 210 ℃. DSC plots (Perkin-Elmer Diamond DSC, 5K/min, nitrogen flow 50mL/min) and TGA plots (Perkin-Elmer Pyris TGA1, 5K/min, nitrogen flow 50mL/min) are given in FIG. 22 and FIG. 23, respectively.

Water vapor adsorption behavior shows loss of water of hydration at Relative Humidity (RH) < 40% and reconversion to hydrate crystal modification NF5 after adsorption at > 70% RH. The water vapor adsorption isotherm (25 ℃) of form NF5 is given below. The water vapor sorption isotherm for crystal modification NF5 [ water vapor sorption isotherm (25 ℃ (SMS DVS Intrinsic) ] is given in fig. 24.

Example 9:

solubility assay for 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate

For solubility determination, 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one (free base) and its dihydrogenphosphate were weighed into a GC-vial and 300 μ L of solvent vehicle was added to give the maximum possible concentration of 10 mg/mL. The mixture was stirred at ambient temperature at 1000rpm on a magnetic stir plate. At the sampling point 100. mu.L of each solution/suspension was transferred to a 500. mu.L Eppendorff tube and centrifuged for 5min at 14000 rpm. The centrate was analysed by HPLC (dilution may be necessary before analysis).

Table 1 gives the solubility in water of the free base of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one and its corresponding dihydrogen phosphate salt measured after 1 and 2 hours.

TABLE 1

The results clearly demonstrate that 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate has significantly higher solubility in aqueous solution than its free base.

Example 10:

competitive slurry conversion experiments of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate salt crystalline modifications A1 and NF3 in organic solvents

About 10mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1 and 10mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate in crystalline modification NF3 were mixed to a powder blend, dispersed in 1mL of organic solvent in a 4mL glass vial with a PTFE sealing cap. A PTFE coated stir bar was inserted into the dispersion and the vial was sealed. The dispersion was stirred in a closed vial using a magnetic stirrer for 5 days at 25 ℃ and 50 ℃ respectively. The solid residue was filtered and analyzed by XRD to monitor the morphological form after solvent slurrying.

The results of the competitive slurry conversion experiments are compiled in table 2.

TABLE 2

At the end of the slurry experiments starting from a binary 1:1 mixture of form a1 and NF3 at two temperatures, crystalline modification a1 was obtained as the only or preferred crystalline form, clearly demonstrating that a1 can be considered as a more stable crystalline form.

Example 11:

competitive slurry conversion experiments of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate salt crystalline modification A1 and NF5 in water

About 20mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1 and 20mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate in crystalline modification NF5 were mixed to a powder blend, dispersed in 0.3mL of water in a 4mL glass vial with a PTFE sealing cap. A PTFE coated stir bar was inserted into the dispersion and the vial was then sealed. The dispersion was stirred in a closed vial at 25 ℃ for 12 days using a magnetic stirrer. The solid residue was filtered and analyzed by XRD to monitor the morphological form after solvent slurrying.

The results of the competitive slurry conversion experiments are compiled in table 3.

TABLE 3

Experiments show that extended aqueous slurrying of variants a1 and NF5 at 25 ℃ as the preferred crystalline form results in hydrate form NF5, clearly showing that NF5 is a more stable crystalline form in aqueous dispersions.

Example 12:

competitive slurry conversion experiments of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate salt in Water with Crystal modification H1 and NF5

About 20mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate crystalline modification H1 and 20mg of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate crystalline modification NF5 were mixed to a powder blend, dispersed in 0.3mL of water in a 4mL glass vial with a PTFE sealing cap. A PTFE coated stir bar was inserted into the dispersion and the vial was then sealed. The dispersion was stirred in a closed vial at 25 ℃ for 12 days using a magnetic stirrer. The solid residue was filtered and analyzed by XRD to monitor the morphological form after solvent slurrying.

The results of the competitive slurry conversion experiments are compiled in table 4.

TABLE 4

Experiments show that extended aqueous slurrying of the 25 ℃ modifications H1 and NF5 as the preferred crystalline form results in dihydrate form H1, clearly showing that H1 is a more stable crystalline form in aqueous dispersions.

Example 13:

competitive slurry conversion experiments of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate salt in Water with Crystal modification H1 and NF3

Mixing about 10mg of crystalline modification H1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate and 10mg of crystalline modification NF3 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate into a powder blend, dispersed in 0.2mL of water in a 4mL glass vial with a PTFE sealing cap. A PTFE coated stir bar was inserted into the dispersion and the vial was then sealed. The dispersion was stirred in a closed vial at 25 ℃ for 5 days using a magnetic stirrer. The solid residue was filtered and analyzed by XRD to monitor the morphological form after solvent slurrying.

The results of the competitive slurry conversion experiments are compiled in table 5.

TABLE 5

Experiments show that extended aqueous slurrying of the 25 ℃ modifications H1 and NF3 as the preferred crystalline form results in dihydrate form H1, clearly showing that H1 is a more stable crystalline form in aqueous dispersions.

Example 14:

kinetic solubility determination of form A1 (anhydrate) and NF3 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate in a mixture of Water: acetone 30: 70 (v: v) after 2 hours

About 70mg of crystalline modification A1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate was dispersed in 1mL of a binary mixture of water: acetone (30: 70, v: v) in a 5mL Walhtann Uniprep non-syringe-like filter vial. The dispersion was stirred at 450rpm for 2 hours at room temperature. After 2 hours the dispersion was filtered, the filtrate was analyzed by HPLC (dilution may be necessary before analysis). The solid residue was analyzed by powder X-ray diffraction (PXRD).

The results of the kinetic solubility measurements in water: acetone are compiled in table 6.

TABLE 6

The two anhydrous forms underwent transformation to dihydrate form H1 (in the case of form NF3, as a mixture with hydrate form NF 5). The corresponding solubility levels clearly show that form NF3 exhibits a lower solubility level after 2 hours than form a 1.

Claims

1. 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate in crystalline modification A1 characterized by the following XRD data:

form a 1:

the XRD peak is Cu-K alpha₁Obtained from radioactive sources。

2. 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate in the form of crystalline modification H1 characterized by the following XRD data:

form H1:

the XRD peak is Cu-K alpha₁Obtained from radioactive sources.

3. 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate in the form of the crystalline modification NF3, characterized by the following XRD data:

crystalline form NF3:

the XRD peak is Cu-K alpha₁Obtained from radioactive sources.

4. 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate in the crystalline modification NF5 characterized by the following XRD data:

crystalline form NF5:

the XRD peak is Cu-K alpha₁Obtained from radioactive sources.

5. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claims 1 to 4.

6. Pharmaceutical composition as claimed in claim 5, further comprising at least one further compound selected from physiologically acceptable adjuvants and/or further pharmaceutically active substances other than a compound as claimed in any of claims 1 to 4.

7. A pharmaceutical composition as claimed in claim 6 wherein the physiologically acceptable adjuvant is a carrier.

8. A medicament comprising at least one compound according to any one of claims 1 to 4 or a pharmaceutical composition according to any one of claims 5 to 7.

9. The agent according to claim 8, for the treatment and/or prevention of a physiological and/or pathophysiological condition which is caused, mediated and/or propagated by the inhibition of Met kinase.

10. The agent according to claim 8 for use in the treatment and/or prevention of a physiological and/or pathophysiological condition selected from the group consisting of: "cancer, tumor, hyperproliferative disorder".

11. The agent according to claim 8 for use in the treatment and/or prevention of a physiological and/or pathophysiological condition selected from the group consisting of: "Ewing's sarcoma, Kaposi's sarcoma, glioma, glioblastoma, neuroblastoma, renal cell carcinoma, prostate cancer, soft tissue sarcoma, pancreatic tumor, osteosarcoma, retinoblastoma, thymoma, lung adenocarcinoma, small cell lung carcinoma, bronchial carcinoma, breast carcinoma, colon carcinoma, rectal carcinoma, cervical carcinoma, uterine corpus carcinoma, endometrial carcinoma, squamous carcinoma, basal cell carcinoma, echinocyte carcinoma, melanoma, monocytic leukemia, chronic leukemia, acute leukemia and/or lymphoma".

12. The medicament of claim 11 wherein the melanoma is intraocular melanoma.

13. The medicament according to claim 11, wherein the chronic leukemia is chronic myelogenous leukemia, chronic lymphocytic leukemia.

14. The medicament of claim 11, wherein the acute leukemia is acute myelogenous leukemia, acute lymphatic leukemia.

15. A medicament as claimed in any one of claims 8 to 14, wherein at least one additional pharmacologically active substance is included in the medicament.

16. The medicament as claimed in any of claims 8 to 14, wherein the medicament is applied before and/or during and/or after treatment with at least one further pharmacologically active substance.

17. A kit comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 4 and/or at least one pharmaceutical composition as claimed in any one of claims 5 to 7 and a therapeutically effective amount of at least one further pharmacologically active substance other than a compound as claimed in any one of claims 1 to 4.

18. A process for preparing crystalline modification a1 of claim 1, comprising the steps of:

(a) dissolving or dispersing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one free base or one or more salts thereof in a solvent, optionally with stirring,

(b) converting 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one free base or one or more salts thereof into the corresponding dihydrogen phosphate salt by addition of an aqueous or ethanolic solution of phosphoric acid, optionally with stirring,

(c) stirring the dispersion obtained in step (b) at room temperature for one or more hours,

(d) the precipitated 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate is recovered by filtration, optionally followed by washing with a solvent, and optionally followed by drying, optionally at an elevated temperature T.

19. A process for preparing crystalline modification a1 of claim 1, comprising the steps of:

(a) dissolving or dispersing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one free base or one or more salts thereof in a solvent mixture, optionally with stirring,

(d) the precipitated 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate is recovered by filtration, optionally followed by washing with a solvent mixture, and optionally followed by drying, optionally at an elevated temperature T.

20. A process for preparing crystalline modification a1 of claim 1, comprising the steps of:

21. A process for preparing crystalline modification a1 of claim 1, comprising the steps of:

22. The method of claim 18 or 20, wherein step (a) is: 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one free base or one or more salts thereof is dissolved or dispersed in 2-propanol or chloroform, optionally with stirring.

23. The method according to any one of claims 18-21, wherein the temperature T in step (d) is a temperature of from 30 ℃ to 95 ℃.

24. The method according to any one of claims 18-21, wherein the temperature T in step (d) is 70 ℃.

25. A process for preparing crystalline modification a1 of claim 1, comprising the steps of:

(a) dispersing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one free base or one or more salts thereof in a solvent and adding aqueous phosphoric acid, optionally with stirring,

(b) heating the dispersion obtained in step (a) to an elevated temperature T1, optionally with stirring, and cooling the resulting solution, optionally with stirring, before diluting it with the solvent, optionally with stirring,

(c) stirring the dispersion obtained in step (b) at a temperature of between 0 ℃ and 40 ℃ until crystallization is complete, and/or incubating it at room temperature for one or more hours, optionally under stirring,

(d) recovering the precipitated 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate by filtration, optionally cooling the dispersion obtained in step (c) to 0 ℃ to 20 ℃, followed by filtration, optionally with stirring, optionally followed by washing with a solvent, and optionally followed by drying, optionally at an elevated temperature T2,

(e) optionally, the dried crystals obtained in step (d) in the solvent in the form of a dispersion are boiled for one or more minutes and they are recovered from the hot dispersion by filtration.

26. A process for preparing crystalline modification a1 of claim 1, comprising the steps of:

(a) dispersing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one free base or one or more salts thereof in a solvent mixture and adding aqueous phosphoric acid, optionally with stirring,

(b) heating the dispersion obtained in step (a) to an elevated temperature T1, optionally with stirring, and cooling the resulting solution, optionally with stirring, before diluting it with the solvent mixture, optionally with stirring,

(d) recovering the precipitated 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate by filtration, optionally cooling the dispersion obtained in step (c) to 0 ℃ to 20 ℃, followed by filtration, optionally with stirring, optionally followed by washing with a solvent mixture, and optionally followed by drying, optionally at an elevated temperature T2,

(e) optionally, the dried crystals obtained in step (d) in the solvent mixture in the form of a dispersion are boiled for one or more minutes and they are recovered from the hot dispersion by filtration.

27. The method of claim 25, wherein step (a) is: dispersing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one free base or one or more salts thereof in water and adding aqueous phosphoric acid, optionally with stirring.

28. The method according to claim 25 or 26, wherein the temperature T1 in step (b) is a temperature of 30 ℃ to 95 ℃.

29. The method according to claim 25 or 26, wherein the temperature T1 in step (b) is 50 ℃.

30. The method according to claim 25 or 26, wherein the temperature T2 in step (d) is a temperature of 30 ℃ to 95 ℃.

31. The method according to claim 25 or 26, wherein the temperature T2 in step (d) is 70 ℃.

32. The method of claim 25, wherein step (e) is: optionally, the dried crystals obtained in step (d) in ethanol in the form of a dispersion are boiled for one or more minutes and they are recovered from the hot dispersion by filtration.

33. A process for preparing crystalline modification a1 of claim 1, comprising the steps of:

(b) heating the dispersion obtained in step (a) to an elevated temperature T1, optionally with stirring, and cooling the solution obtained, optionally with stirring, at a given cooling rate, optionally with stirring, until crystallization has started,

(c) further cooling the dispersion obtained in step (b), optionally with stirring, at a given cooling rate, optionally with stirring,

(d) stirring the dispersion obtained in step (c) at-20 ℃ to 40 ℃ until crystallization is complete,

(e) the crystalline 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate is recovered by filtration, optionally followed by washing with a solvent, and optionally followed by drying, optionally at an elevated temperature T2.

34. A process for preparing crystalline modification a1 of claim 1, comprising the steps of:

(e) the crystalline 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate is recovered by filtration, optionally followed by washing with a solvent mixture, and optionally followed by drying, optionally at an elevated temperature T2.

35. The method of claim 33 or 34, wherein step (a) is: dispersing 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one free base or one or more salts thereof in a water acetone mixture and adding aqueous phosphoric acid, optionally with stirring.

36. The process according to claim 33 or 34, wherein the temperature T1 in step (b) is a temperature of 30 to 95 ℃.

37. The method according to claim 33 or 34, wherein the temperature T1 in step (b) is 55 ℃.

38. The method of claim 33 or 34, wherein the cooling rate in step (b) is 0.1-1K/min.

39. The method of claim 33, wherein step (e) is: the crystalline 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate is recovered by filtration, optionally followed by washing with acetone, and optionally followed by drying, optionally at elevated temperature T2.

40. The method according to any one of claims 33, 34 and 39, wherein the temperature T2 is a temperature between 30 ℃ and 95 ℃.

41. The method according to any one of claims 33, 34 and 39, wherein the temperature T2 is 70 ℃.

42. A process for preparing crystalline modification H1 of claim 2, comprising the steps of:

(a) crystalline modification a1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate of claim 1 was spread on a surface and subsequently incubated on water or an aqueous solvent mixture in a sealed desiccator for one or more days.

43. A process for preparing crystalline modification H1 of claim 2, comprising the steps of:

(a) dispersing crystalline modification A1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate of claim 1 in a mixture of two or more solvents, optionally with stirring, and stirring the resulting dispersion at an elevated temperature T1 for one or more days,

(b) the precipitated 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate is recovered by filtration, optionally followed by washing with a solvent, and optionally followed by drying, optionally at an elevated temperature T2.

44. A process for preparing crystalline modification H1 of claim 2, comprising the steps of:

(b) the precipitated 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate dihydrate is recovered by filtration, optionally followed by washing with a solvent mixture, and optionally followed by drying, optionally at an elevated temperature T2.

45. The process of claim 43 or 44, wherein the solvent in step (a) is selected from the group consisting of water, methanol, ethanol, 2-propanol, acetone, TFH and acetonitrile.

46. The method according to claim 43 or 44, wherein the temperature T2 in step (b) is a temperature of 30 ℃ to 95 ℃.

47. The method according to claim 43 or 44, wherein the temperature T2 in step (b) is 70 ℃.

48. A process for preparing crystalline modification NF3 of claim 3, comprising the steps of:

(a) dispersing or dissolving crystalline modification A1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate of claim 1 in a mixture of two or more solvents, optionally under stirring, and subsequently evaporating the mixture of two or more solvents at room temperature or at an elevated temperature T1 until crystallization occurs,

(b) the precipitated 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate is recovered by filtration, optionally followed by washing with a solvent, and optionally followed by drying, optionally at an elevated temperature T2.

49. A process for preparing crystalline modification NF3 of claim 3, comprising the steps of:

(b) the precipitated 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate hydrate is recovered by filtration, optionally followed by washing with a solvent mixture, and optionally followed by drying, optionally at an elevated temperature T2.

50. The process of claim 48 or 49, wherein the solvent in step (a) is selected from the group consisting of water, methanol, ethanol, 2-propanol, acetone, TFH, acetonitrile and 1, 4-bisAn alkane.

51. The method according to claim 48 or 49, wherein the temperature T2 in step (b) is a temperature of 30 ℃ to 95 ℃.

52. The method according to claim 48 or 49, wherein the temperature T2 in step (b) is 70 ℃.

53. A process for preparing crystalline modification NF5 of claim 4, comprising the steps of:

(a) the crystalline modification A1 of 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one dihydrogenphosphate anhydrate of claim 1 was dissolved in a binary solvent mixture and the solvent mixture was rapidly evaporated under vacuum at elevated temperature until a precipitate was obtained,

(b) optionally, the precipitate obtained from step (a) in powder form is further spread on a surface and subsequently incubated on water or an aqueous salt solution in a sealed desiccator at a defined relative humidity for one or more days.

54. The process according to claim 53, wherein the binary solvent mixture in step (a) is water methanol.

55. The process of claim 53, wherein the binary solvent mixture in step (a) is 1:1v: v water methanol.

56. The method of claim 53, wherein the relative humidity in step (b) is 80-100% relative humidity.

57. The method of claim 53, wherein the relative humidity in step (b) is 90-100% relative humidity.

58. A process for preparing crystalline modification NF5 of claim 4, comprising the steps of:

(a) the crystalline form NF3 of the dihydrogen 6- (1-methyl-1H-pyrazol-4-yl) -2- {3- [5- (2-morpholin-4-yl-ethoxy) -pyrimidin-2-yl ] -benzyl } -2H-pyridazin-3-one phosphate salt of claim 3 in powder form is spread on a surface and subsequently incubated on water or an aqueous salt solution for one or more days at a defined relative humidity in a sealed desiccator.

59. The method of claim 58, wherein the relative humidity in step (a) is 80-100% relative humidity.

60. The method of claim 58, wherein the relative humidity in step (a) is 90-100% relative humidity.