WO2012072727A1

WO2012072727A1 - Crystalline modification of n-(3,5-dichloropyridin-4-yl)-[1-(4 -fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide as inhibitor of pde4

Info

Publication number: WO2012072727A1
Application number: PCT/EP2011/071483
Authority: WO
Inventors: Norbert Höfgen; Helge Hartenhauer; Hans-Joachim Lankau
Original assignee: Biotie Therapies Gmbh
Priority date: 2010-12-03
Filing date: 2011-12-01
Publication date: 2012-06-07

Abstract

The present invention relates to N-(3,5-dichloropyridin4-yl)-[1-(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide in crystalline form having crystalline modification II as defined in the claims. The invention also relates to a method for manufacturing the modification II, a pharmaceutical composition comprising said modification II and said modification II for use as a medicament.

Description

CRYSTALLINE MODIFICATION OF N- (3 , 5 -DICHLOROPYRIDIN-4 -YL) - [1 - (4 - FLUOROBENZYL) - 7 - AZAINDOL - 3 - YL) ] GLYOXYLIC ACID AMIDE AS INHIBITOR OF PDE4

Field of the Invention

[0001] The present invention relates to N-(3,5-dichloropyridin- 4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide in crystalline form having crystalline modification II.

Background of the Invention

[0002] N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol- 3-yl)]glyoxylic acid amide is a 7-azaindole.

[0003] N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol- 3-yl]glyoxylic acid amide is a compound which inhibits phosphodiesterase 4 (cf. EP I 330 455). Therefore, this compound can be employed for the treatment of diseases for which the inhibition of phosphodiesterase 4 is therapeutically useful.

[0004] Activation of cell membrane receptors by transmitters leads to activation of the second messenger system. Adenylate cyclase synthesizes the active cyclic AMP (cAMP) and cyclic GMP (cGMP) respectively from AMP and GMP. cAMP and cGMP lead for example in smooth muscle cells to relaxation, and in inflammatory cells to inhibition of mediator release and synthesis. The second messengers cAMP and cGMP are degraded by phosphodiesterases (PDE). To date, 1 1 families of PDE enzymes (PDEI-1 1 ) are known and differ through their substrate specificity (cAMP, cGMP or both) and the dependence on other substrates (e.g. calmodulin). These isoenzymes have different functions in the body and are expressed differently in individual cell types (Beavo, J. A., Conti, M. and Heaslip, R. J., Multiple cyclic nucleotide phosphodiesterases. Mol. Pharmacol. 1994, 46:399-405; Hall, I. P., Isoenzyme selective phosphodiesterase inhibitors: potential clinical uses, Br. J. din. Pharmacol. 1993, 35: 1 -7). Inhibition of the various PDE isoenzyme types results in accumulation of cAMP or cGMP in cells, which can be utilized therapeutically (Torphy, T. J., Livi, G. P., Christensen, S. B. Novel Phosphodiesterase Inhibitors for the Therapy of Asthma, Drug News and Perspectives 1993, 6:203-214).

[0005] The predominant PDE-isoenzyme in cells important for allergic inflammations (lymphocytes, mast cells, eosinophilic granulocytes, macrophages) is that of type 4 (Torphy, J. T. and Undem, B. J., Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. Thorax 1991 , 46:512-523). Inhibition of PDE 4 by suitable inhibitors is therefore regarded as an important approach to the therapy of a large number of allergically induced disorders (Schudt, Ch., Dent, G., Rabe, K, Phosphodiesterase Inhibitors, Academic Press London 1996).

[0006] To be useful as pharmaceuticals, compounds, besides their effectiveness, must be producible in reproducible form. Moreover, in order that they can be marketed as pharmaceuticals, they must have long-term stability.

[0007] Therefore, it was an object of the present invention to provide N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide, in such a form that it can be produced in reproducible form and having longterm stability.

[0008] According to the invention, this object is achieved by the provision of N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]gly- oxylic acid amide having crystalline modification II.

Summary of the Invention

[0009] The present invention relates to N-(3,5-dichloropyridin-4-yl)- [1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide in crystalline form having crystalline modification II showing a powder X-ray diffraction pattern showing peaks at values of diffraction angle in 2.0 Θ of 17.386, 20.947, 22.099, 25.488, 28.320, 31 .560, 32.578, 36.098, 36.661 , 38.522.

[0010] The invention also relates to a method of manufacturing N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide in crystalline form having crystalline modification II as defined above, the method comprising recrystallization of the compound N-(3,5-dichloro- pyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide in a solvent system comprising a solvent selected from the group consisting of acetone, dimethylformamide, formic acid, acetic acid, ethyl acetate and butyl acetate.

[0011] Further, the present invention relates to a pharmaceutical composition comprising an effective amount of N-(3,5-dichloropyridin-4-yl)- [1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide in crystalline form having crystalline modification II as defined above a suitable carrier and conventional excipients.

[0012] The invention also relates to 7. N-(3,5-dichloropyridin-4-yl)- [1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide in crystalline form having crystalline modification II as defined for use as a medicament. Drawings

[0013] Fig.1 shows X-ray diffractograms of N-(3,5-dichloro- pyridin-4-yl)[1 -(4-fluorobenzyl)-7-azaindol-3-yl]glyoxylic acid amide (ELB353)/- form II compared with N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)- 7-azaindol-3-yl)]glyoxylic acid amide (ELB353)/forms I, III and IV.

Detailed Description of the Invention

[0014] N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol- -3-yl]]glyoxylic acid amide has the structural formula

and is also named ELB353 or Ronomilast.

[0015] It has been found that various crystalline modifications of the solid form of N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol3-yl)]- glyoxylic acid amide exist. In particular, four crystalline modifications, herein referred to as crystalline modifications I, II, III and IV, could be identified for N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide. It has now been found that crystalline modification II has special features and advantages as compared to the other crystalline modifications of N-(3,5-di- chloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide. For example, N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)7-azaindol-3-yl)]glyox- ylic acid amide can be obtained in reproducible form in crystalline modification II, for instance, by recrystallization from acetone. The obtained crystals are thereby stable, with no phase change being observed.

[0016] Thus, the invention, in particular, relates to a crystalline form of N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide which has high stability, in particular, thermal stability.

[0017] Crystalline modification II is also heat stable. In DSC experiments, no endoor exothermic effects are observed until the melting point at 201 °C, indicating that no change in crystal structure of crystalline modification II occurs during heating. [0018] The compound N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluoro- benzyl)7-azaindol-3-yl)]glyoxylic acid amide having crystalline modification II show a powder X-ray diffraction pattern at values of diffraction angle (2Θ) as presented below:

Angle in s

d A

2-Theta⁰

17.386 5.0965

20.947 4.2374

22.099 4.0190

25.488 3.4918

28.320 3.1488

31.560 2.8325

32.578 2.7463

36.098 2.4861

36.661 2.4492

38.522 2.3351

[0019] The relative intensity (P(%)) of each of these peaks is preferably above 3%.

[0020] ELB353/Form II is characterized by significant peaks of related diffractogram (relative intensity above 3%) which are not observed in the diffractograms of ELB353/Form I, III and IV. Additionally, ELB353/Form II is characterized by the absence of peaks in the related diffractogram between 2.0 "2-Theta°" and 6.5 "2-Theta°" (relative intensity equal or below 3%) and between 12.0 "2-Theta°" and 13.0 "2-Theta°" (relative intensity equal or below 5%).

[0021] In a preferred embodiment, the compound N-(3,5-dichloro- pyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide having crystalline modification 1 1 has an X-ray powder diffractogram as shown in Table 1 below.

[0022] The invention further relates to a method for manufacturing N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide in crystalline modification II, comprising recrystallization of the compound N-(3,5-dichloropyridin4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide in a solvent comprising acetone, dimethylformamide, formic acid, acetic acid, ethyl acetate or butyl acetate, in particular, acetone.

[0023] Recrystallization is preferably performed in a solvent system comprising at least 40 wt%, more preferably at least 50 wt%, in particular, at least 60 wt%, even more preferably at least 80 wt%, and most preferably at least 90 wt% of acetone, dimethylformamide, formic acid, acetic acid, ethyl acetate or butyl acetate, in particular, acetone, based on wt of the solvent. In a preferred embodiment, recrystallization is performed in a solvent comprising 95 wt% or more, in particular, 100 wt% acetone.

[0024] It has been found that when using specific solvents and, in particular, when using acetone, crystalline modification II is obtained in reproducible form. In particular, the use of acetone results reproducibly in XRD phase II. Thus, acetone is the most suitable solvent for the crystallization process of N-(3,5-dichloropyridin-4-yl)[-1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide.

[0025] The invention also relates to N-(3,5-dichloropyridine- 4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide in crystalline form having crystalline modification II obtainable by a method described herein.

[0026] Thereby, in the crystalline form, preferably at least 90 wt.% of the compound are present in crystalline modification II, more preferably at least 95 wt.% and most preferably at least 99% in crystalline modification II.

[0027] The present invention also relates to a pharmaceutical composition comprising N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol- 3-yl)]glyoxylic acid amide. The pharmaceutical composition may comprise conventional pharmaceutically acceptable carriers and optionally adjuvants. The dosage of the active compound may vary depending on the route of administration, age and weight of the patient, nature and severity of the disorders to be treated, and similar factors. The daily dose may be given as a single dose to be administered once a day or divided into two or more daily doses. The daily dose is usually between 0.001 to 500 mg, preferably from 0.1 to 100 mg. In a particular embodiment, the pharmaceutical composition additionally comprises a further active agent.

[0028] The pharmaceutical composition can be in any suitable dosage form such as solid dosage forms, e.g. tablets, granules or capsules, or liquid dosage forms such as suspensions.

[0029] Suspensions such as suspensions in water or physiological solvents in which the crystalline modification of the compound is maintained are also an embodiment of the invention and can e.g. be used as pharmaceuticals.

[0030] The compound in crystalline form according to the invention is an inhibitor of phosphodiesterase 4. The IC50 value for inhibition of PDE 4 with ELB353 is 0.004 pM/l, using [³H]-cAMP as substrate. The IC50 value towards all other PDEs, in particular, PDE 2, 3 or 5, is at least by factor 250 higher. Phosphodiesterase activity can be determined, for example, according to the method described by Thompson et al. (W. J. Thompson et al., Adv. Cycl. Nucl. Res. 10 (1979), 69-92) (see also EP I 330 455).

[0031] It can therefore be used to inhibit phosphodiesterase 4. The compound in crystalline form having crystalline modification II as well as pharmaceutical compositions comprising said crystalline form can be used for the treatment or/and prophylaxis of diseases for which an inhibition of phosphodiesterase 4 is useful.

[0032] N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol- 3-yl]glyoxylic acid amide is particularly preferred for the treatment or/and prophylaxis of chronic obstructive pulmonary disease (COPD). The pathological condition of chronic obstructive pulmonary diseases (COPD) encompasses various pathological conditions of chronic bronchitis with the symptoms of coughing and expectoration, and progressive and irreversible deterioration in lung function (expiration is particularly affected). The course of the disease is episodic and often complicated by bacterial infections (Rennard, S. I.: COPD: Overview of definitions, Epidemiology, and factors influencing its development. Chest, 1 13 (4) Suppl., 2355-2415, 1998). There is a steady decline in lung function during the disorder, the lung becomes increasingly emphysematous, and the patients' breathing difficulty becomes obvious. This disorder markedly impairs the patients' quality of life (shortness of breath, low exercise tolerance) and significantly shortens their life expectancy.

[0033] Further preferred is use in the case of psoriasis or asthma.

[0034] The compound can be used, in particular, as bronchodilator and for asthma prophylaxis and/or treatment.

[0035] Further, it can be used for the treatment or prophylaxis of inflammation of the joints, including arthritis and rheumatoid arthritis, as well as other arthritic illnesses such as rheumatoid spondylitis and osteoarthritis, en- dotoxic shock, tissue rejection, AIDS and other immunological disorders.

[0036] Further possible applications are the treatment of patients who are suffering from osteoporosis, sepsis, septic shock, gram negative sepsis, toxic shock syndrome, respiratory distress syndrome, asthma or other chronic pulmonary diseases, bone resorprtion diseases or transplant rejection reactions or other autoimmune diseases such as lupus erythematosus, multiple sclerosis, glomerulonephritis and uveitis, insulin-dependent diabetes mellitus and chronic demyelination. [0037] In addition, the compound of the invention can also be used for the treatment of infections such as viral infections and parasite infections, for example, for the treatment of malaria, leishmaniasis, infection-induced fever, infectioninduced muscle pain, AIDS, cachexia and non-allergic rhinitis.

[0038] The compound of the invention can likewise be used for the therapy of hyperproliferative disorders, in particular of cancers, for example for the therapy of melanomas, of breast cancer, lung cancer, bowel cancer, skin cancer and of leukemias.

[0039] The compound in crystalline form, further, is an inhibitor of the release of tumor necrosis factor (TNFct) and can thus be used to inhibit the release of TNFci, in particular, from inflammation cells. The compound in crystalline form can therefore also be used for the treatment of diseases for which an inhibition of TNFci is useful. These diseases, for example, include, inflammations of the respiratory tract, inflammations of the joints, endotoxic shock, tissue rejections, AIDS and many other imunologoical disorders.

[0040] The compound in crystalline form of the present invention furthermore is an inhibitor of the accumulation of eosinophils as well as of their activity. The compound in crystalline form can therefore also be used to treat diseases in which eosinophils play a role. These diseases include, for example, inflammatory diseases of the respiratory tract such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczemas, allergic angiitis, eo- sinophil-mediated inflammations such as eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome (pulmonal infiltration with eosinophils), urticaria, ulcerative colitis, Crohn's disease and proliferative skin diseases such as psoriasis and keratosis.

[0041] The compound of the invention additionally has neuroprotective properties and can be used for the therapy of diseases in which neuroprotection is beneficial. Examples of such disorders are senile dementia (Alzheimer's disease), memory loss, Parkinson's disease, depression, strokes and intermittent claudication.

[0042] Further possible uses of the compound of the invention are the prophylaxis and therapy of prostate disorders such as, for example, benign prostate hyperplasia, polyuria, nocturia, and the treatment of incontinence, of colic induced by urinary calculi, and of male and female sexual dysfunctions.

[0043] Finally, the compound of the invention can likewise be used to inhibit the development of drug dependence on repeated use of analgesics such as, for example, morphine, and to reduce the development of tolerance on repeated use of these analgesics.

[0044] The compound in crystalline form II, further, suppresses the activity of neutrophilic granulocytes.

[0045] The invention is further illustrated by the appended Figures as well as the Examples given below.

Examples

Example 1

Manufacture of N-(3,5-dichloropyrid in-4-yl)-[1-(4-fluorobenzyl)-7-aza- indol-3-yl]glyoxylic acid amide in crystalline form having crystal modification II

[0046] 1 -(4-fluorobenzyl)-7-azaindole (3.57 g, 15 mmoles) is dissolved in 50 ml of t-butyl methyl ether. A solution of 1 .54 ml of oxalyl chloride (18 mmoles) in 10 ml of t-butyl methyl ether is added dropwise at 0°C with stirring. Subsequently, the mixture is refluxed for 2 hours, after which the solvent is distilled off under vacuum. The resulting 1 -(4-fluorobenzyl)-7-azaindol- -3-yl-glyoxylic acid chloride is obtained as a solid residue, which is suspended in 50 ml of tetrahydrofuran (THF).

[0047] To a suspension of 2 g of sodium hydride in 20 ml of THF, 2.4 g of 4-amino-3,5-dichloropyridine (15 mmoles) in 30 ml of THF are added dropwise at -5°C. The mixture is then kept for one hour at 20°C with stirring. Subsequently, the previously prepared suspension of 1 -(4-fluorobenzyl)- 7-azaindol3-yl-glyoxylic acid chloride is added dropwise at about 0°C. Finally, the reaction mixture is refluxed for 4 hours, after which the solvent is removed under vacuum. The residue is stirred with 50 ml of ethyl acetate and 50 ml of water. The phases are separated and the organic phase is washed with water. The solvent is distilled off under vacuum and the residue recrystallized from acetone.

Melting point: 201 -202°C.

[0048] The following Table A shows various solvents and amounts used in the recrystallization as well as the yield obtained. Table A

Solvent Solvent (ml) drug (g) ratio Yield

Aceton 30 ml/g 60%

DMF 3 ml/g 56%

Butyl acetate 24 ml/g 66%

Formic acid 4 ml/g 72%

Ethyl acetate 20 ml/g 69%

Acetic acid 5 ml/g 66%

Comparative Example 2

Manufacture of N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azain- dol-3-yl)]glyoxylic acid amide in crystalline form having crystal modification I (Form I)

[0049] 1 -(4-fluorobenzyl)-7-azaindole (3.57 g, 15 mmoles) is dissolved in 50 ml of t-butyl methyl ether. A solution of 1 .54 ml of oxalyl chloride (18 mmoles) in 10 ml of t-butyl methyl ether is added dropwise at 0°C with stirring. Subsequently, the mixture is refluxed for 2 hours, after which the solvent is distilled off under vacuum. The resulting 1 -(4-fluorobenzyl)-7-azaindol-3-ylglyoxylic acid chloride is obtained as asolid residue, which is suspended in 50 ml of tet- rahydrofuran (THF).

[0050] To a suspension of 2 g of sodium hydride in 20 ml of THF, 2.4 g of 4-amino-3,5-dichloropyridine (15 mmoles) in 30 ml of THF are added drop- wise at -5°C. The mixture is then kept for one hour at 20 °C with stirring. Subsequently, the previously prepared suspension of 1 -(4-fluorobenzyl)- 7-azaindol-3-yl-glyoxylic acid chloride is added dropwise at about 0°C. Finally, the reaction mixture is refluxed for 4 hours, after which the solvent is removed under vacuum. The residue is stirred with 50 ml of ethyl acetate and 50 ml of water. The phases are separated and the organic phase is washed with water. The solvent is distilled off under vacuum and the residue recrystallized from toluene or N-methyl pyrrolidone.

Melting point: 201 -202°C. Comparative Example 3

Manufacture of N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azain- dol-3-yl)]glyoxylic acid amide in crystalline form having crystal modification III (Form III)

[0051] 1 -(4-fluorobenzyl)-7-azaindole (3.57 g, 15 mmoles) is dissolved in 50 ml of t-butyl methyl ether. A solution of 1 .54 ml of oxalyl chloride (18 mmoles) in 10 ml of t-butyl methyl ether is added dropwise at 0°C with stirring for 30 min. Subsequently, the mixture is refluxed for 2 hours, after which the solvent is distilled off under vacuum. The resulting 1 -(4-fluorobenzyl)-7-azaindol-3-yl- glyoxylic acid chloride is obtained as asolid residue, which is suspended in 50 ml of tetrahydrofuran (THF).

[0052] To a suspension of 2 g of sodium hydride in 20 ml of THF, 2.4 g of 4-amino-3,5-dichloropyridine (15 mmoles) in 30 ml of THF are added drop- wise at -5°C. The mixture is then kept for one hour at 20°C with stirring. Subsequently, the previously prepared suspension of 1 -(4-fluorobenzyl)- 7-azaindol-3-yl-glyoxylic acid chloride is added dropwise at about 0°C. Finally, the reaction mixture is refluxed for 4 hours, after which the solvent is removed under vacuum. The residue is stirred with 50 ml of ethyl acetate and 50 ml of water. The phases are separated and the organic phase is washed with water. The solvent is distilled off under vacuum and the residue recrystallized from i-propanol, n-propanol/water, i-propanol/water or n-butanol.

Melting point: 201 -202°C.

Comparative Example 4

Manufacture of N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-aza- indol-3-yl)]glyoxylic acid amide in crystalline form having crystal modification IV (Form IV)

[0053] 1 -(4-fluorobenzyl)-7-azaindole (3.57 g, 15 mmoles) is dissolved in 50 ml of t-butyl methyl ether. A solution of 1 .54 ml of oxalyl chloride (18 mmoles) in 10 ml of t-butyl methyl ether is added dropwise at 0°C with stirring. Subsequently, the mixture is refluxed for 2 hours, after which the solvent is distilled off under vacuum. The resulting 1 -(4-fluorobenzyl)-7-azaindol-3-ylglyoxylic acid chloride is obtained as asolid residue, which is suspended in 50 ml of tetrahydrofuran (THF).

[0054] To a suspension of 2 g of sodium hydride in 20 ml of THF, 2.4 g of 4-amino3,5-dichloropyridine (15 mmoles) in 30 ml of THF are added dropwise at -5°C. The mixture is then kept for one hour at 20°C with stirring. Subsequently, the previously prepared suspension of 1 -(4-fluorobenzyl)-7-aza- indol-3-yl-glyoxylic acid chloride is added dropwise at about 0°C. Finally, the reaction mixture is refluxed for 4 hours, after which the solvent is removed under vacuum. The residue is stirred with 50 ml of ethyl acetate and 50 ml of water. The phases are separated and the organic phase is washed with water. The solvent is distilled off under vacuum and the residue recrystallized from n-propanol.

Melting point: 201 -202°C. Example 5

X-Ray powder diffractometry (XRPD)

[0055] The X-ray diffractogram of N-(3,5-dichloropyridine-4-yl)- -[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide in crystalline form having crystal modification II obtained by recrystallization in acetone according to Example I was recorded on a Siemens X-ray powder diffractometer D5000 at 25°C: Cu anode, variable divergence and anti-scatter slits with 6 mm sample illumination, Ni filter, scanning with 0.02° 2 Θ at 1 s, range 1 ° to 40° (2 Θ) and detector slit 0.2 mm.

Table 1 : Reference X-ray pattern data of N-(3,5-dichloropyridin-4-yl)- [1 -(4-fluorobenzyl)- 7-azaindol-3-yl)]glyoxylic acid amide/form li

Angle in Intensity Intensity Angle in intensity Intensity Angle in Intensity Intensity

2-Theta° d in A in Cps in % 2-Theta" d in A in Cps in % 2-Theta° d in A in Cps in %

7.997 11.04668 138.0 9.6 21.857 4.06315 123.0 8.5 30.771 2.90342 32.4 2.2

9.607 9.19875 129.0 8.9 22.100 4.01898 62.6 4.3 31.231 2.86167 39.0 2.7

10.389 8.50845 231.0 16.0 22.628 3,92645 23.8 1.7 31.599 2.82913 101.0 7.0

10.978 8.05302 137,0 9.5 23.671 3.75571 1442.0 100.0 32.158 2.78124 693.0 48.1

13.642 6.48586 429.0 29.7 24.285 3.66203 47.7 3.3 32.528 2.75046 43.1 3.0

13.932 6,35122 35,1 2.4 24.543 3.62420 176.0 12.2 33.424 2.67875 58.9 4.1

15.173 5.83471 51.6 3.6 24.996 3.55952 112.0 7.8 33.636 2.66234 87.7 6.1

15.501 5.71171 148.0 10.3 25.454 3.49644 333.0 23.1 34.292 2.61287 37.0 2.6

16.016 5.52934 280.0 19.5 25.754 3.45645 224.0 15.5 34.577 2.59201 49.1 3.4

17.360 5.10429 235.0 16.3 26.570 3.35209 94.8 6.6 34.893 2.56925 47.7 3.3

18,101 4.89692 47.1 3.3 27.201 3.27579 464.0 32.2 36.038 2.49018 58.4 4.1

18.794 4.71790 25.0 1.7 28.060 3.17746 460.0 31.9 36.626 2.45155 62.5 4.3

19.391 4.57397 130.0 9.0 28.320 3.14883 172.0 11,9 38.470 2.33816 52.2 3.6

20.592 4.30967 88.2 6.1 28.954 3.08136 54.0 3.7 38.778 2.32034 17.2 1.2

20.905 4.24595 78.8 5,5 30.506 2.92795 33.4 2.3 39.568 2.27579 63.2 4.4

[0056] Identical diffraction pattern was obtain by recrystallization in dimethylformamide, formic acid, acetic acid, ethyl acetate and butyl acetate. [0057] The crystalline form of N-(3,5-dichloropyridine-4-yl)- -[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide/form II obtained by recrystallization in acetone (Example 1 ) was compared to the other crystalline modifications I, 1 1 1 and IV of N-(3,5-dichloropyridin-4-yl)-{1 -(4-fluorobenzyl)- 7-azaindol-3-yl)}glyoxylic acid amide obtained by recrystallization in other solvents (Comparative Examples 2, 3, 4). The results of the comparison are shown in Table 2. Only peaks with intensities above 3% are included.

Table 2: Reference X-ray pattern data of N-(3,5-dichloropyridin- 4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide/form I, III and IV compared with N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenz- yl)-7-azaindol-3-yl)]glyoxylic acid amide/form II

Form II Form III Form IV

Angle in Angle In Angle in Angle in

d in A¹ d in

2-T eta° 2-Theta° 2-Theta" 2-Theta"

5.263 16.778 5.276 16.737 5.269 16.760

7.974 11.079 8.005 11.036

8.341 10.592 8.359 10.568

9.635 9.1723 9.596 9.2095 9.545 9.2586

10.247 8.6252 10.375 8.5193 10.238 8.6332 10.276 8.6013

10.612 8.3299

10.989 8.0447 10.964 8.0629 10.977 8.0536

12.418 7.1219 12.435 7.1123 12.409 7.1271

13.222 6.6905

13.660 6.4773 13.660 6.4771 13.630 6.4912

13.997 6.3220 14.007 6.3174 13.993 6.3237 14.776 5.9902 14.756 5.9982 14.760 5.9969 15.206 5.8218 15.220 5.8165 15.228 5.8136 15.205 5.8222

15.513 5.7075

15.928 5.5596 16.012 5.5304 15.971 5.5447 15.932 5.5580 16.759 5.2856 16.794 5.2748 16.755 5.2871

17.386 5.0965

19.412 4.5688 19.428 4.5652

19.719 4.4984 19.727 4.4986 19.707 4.5011 20.201 4.3922 20.233 4.3854

20.594 4.3093 20.608 4.3064 20.611 4.3058 20.597 4.3086

20.947 4.2374

21.084 4.2102 21.072 4.2125 21.077 4.2115 21.612 4.1086 21.613 4.1082 21.583 4.1140

21.875 4.0596 21.880 4.0588

22.099 4.0190

22.257 3.9908 22.254 3.9914 22.236 3.9946 22.572 3.9360 22.577 3.9351 22.577 3.9351 23.377 3.8021 23.393 3.7996 23.367 3.8038

23.673 3.7552 23.666 3.7564 23.617 3.7640

24.442 3.6389 24.473 3.6343 24.420 3.6420

24.559 3.6218

24.842 3.5812 24.839 3.5816 24.813 3.5853

24.961 3.5643

25.285 3.5193 25.300 3.5174 25.284 3.5196

25.488 3.4918

25.738 3.4584 25.761 3.4555 25.739 3.4583 25.723 3.4604 26.035 3.4197 26.109 3.4102 26.062 3.4162 26.704 3.3356 26.580 3.3508 26.698 3.3362

26.927 3.3084

27.341 3.2593 27.219 3.2735 27.276 3.2669 27.328 3.2607 28.165 3.1657 28.070 3.1762 28.133 3.1693 28.107 3.1721

28.320 3.1488

28.894 3.0875 28.882 3.0887 28.864 3.0906 29.536 3.0219 29.508 3.0246 29.466 3.0288 29.856 2.9902 29.864 2.9894 29.854 2.9904 30.200 2.9569 30.157 2.9610 30.195 2.9574 30.210 2.9559 30.732 2.9069 30.825 2.8983 30.744 2.9058 30.712 2.9088

31.560 2.8325

31.803 2.8114 31.814 2.8105 31.780 2.8134 32.139 2.7828 32.135 2.7831 32.152 2.7817 32.052 2.7901

32.578 2.7463

32.793 2.7288 32.787 2.7292 32.770 2.7306 33.252 2.6921 33.435 2.6778 33.305 2.6879 33.280 2.6899

33.606 2.6646 33.513 2.6718

33.823 2.6479 33.892 2.6428 33.966 2.6372

34.336 2.6096

34.534 2.5950 34.619 2.5889 34.560 2.5932 34.532 2.5952

34.843 2.5727

35.578 2.5213 35.593 2.5203 35.572 2.5217

36.098 2.4861

36.661 2.4492

37.509 2.3958

37.818 2.3769 37.788 2.3787 37.796 2.3783

38.522 2.3351

38.780 2.3201 38.772 2.3206 38.768 2.3209 39.632 2.2722 39.593 2.2744 39.642 2.2716 39.600 2.2740 [0058] Whereas phase II has a completely different diffraction profile, the diffractograms of the phase I, III, and IV are quite similar.

Example 6

Differential scanning calorimetry (DSC)

[0059] DSC was performed with the Perkin Elmer DSC 7 (scan rate: of 10°C/mm).

[0060] Thermogram of ELB353/Form II doesn't show any endo/exo- thermic event prior to the melting peak at approximately 201 °C. In contrast to ELB353/Form II, thermograms of ELB353/Form I, III and IV show significant end/exothermic events between 175°C and 180°C prior to their melting peaks.

Claims

1 . N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]- glyoxylic acid amide in crystalline form having crystalline modification II showing a powder X-ray diffraction pattern showing peaks at values of diffraction angle in 2.0 Θ of 17.386, 20.947, 22.099, 25.488, 28.320, 31 .560, 32.578, 36.098, 36.661 , 38.522.

2. N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]- glyoxylic acid amide having crystalline modification II according to claim 1 or 2, having an X-ray powder diffractogram as shown in Table 1 .

3. A method for manufacturing N-(3,5-dichloropyridin-4-yl)- [1 -(4-fluorobenzyl)-7-azaindol-3-yl)]lglyoxylic acid amide in crystalline modification II according to claim 1 or 2, comprising recrystallization of the compound N-(3,5-dichloropyridin-4-yl)-[l-(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide in a solvent system comprising a solvent selected from the group consisting of acetone, dimethylformamide, formic acid, acetic acid, ethyl acetate and butyl acetate.

4. The method according to claim 3, comprising recrystallization of the compound N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]- glyoxylic acid amide in acetone.

5. N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]- glyoxylic acid amide in crystalline form having crystalline modification II as defined in claim 1 or 2 obtainable by a method according to claim 3 or 4.

6. A pharmaceutical composition comprising an effective amount of N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]glyoxylic acid amide in crystalline form having crystalline modification II according to any one of claims 1 , 2 and 5 and a pharmaceutically acceptable carrier and optionally conventional adjuvants.

7. N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]- glyoxylic acid amide in crystalline form having crystalline modification II according to any one of claims 1 , 2 and 5 for use as a medicament.

8. N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]- glyoxylic acid amide in crystalline form having crystalline modification II according to any of claims 1 ,2 and 5 for use in the treatment and/or prophylaxis of chronic obstructive pulmonary disease (COPD), psoriasis, asthma, inflammation of the joints, including arthritis and rheumatoid arthritis, as well as other arthritic illnesses such as rheumatoid spondylitis and osteoarthritis, endotoxic shock, tissue rejection, AIDS, osteoporosis, sepsis, septic shock, gram negative sepsis, toxic shock syndrome, respiratory distress syndrome, chronic pulmonary diseases, bone resorption diseases or transplant rejection reactions, autoimmune diseases such as lupus erythematosus, multiple sclerosis, glomerulonephritis and uveitis, insulin-dependent diabetes mellitus, chronic demye- lination, infections, such as viral infections and parasite infections, for example malaria, leishmaniasis, infection-induced fever, infection-induced muscle pain, AI DS, cachexia and non-allergic rhinitis, inflammations of the respiratory tract, inflammations of the joints, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczemas, allergic angiitis, eosinophil-mediated inflammations such as eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome (pulmonal infiltration with eosinophils), urticaria, ulcerative colitis, Crohn's disease and proliferative skin diseases such as psoriasis and keratosis, senile dementia (Alzheimer's disease), memory loss, Parkinson's disease, depression, strokes, intermittent claudication, prostate disorders such as benign prostate hyperplasia, polyuria, nocturia, and incontinence, colic induced by urinary calculi, and male and female sexual dysfunctions, or/and drug dependence.

9. N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]- glyoxylic acid amide in crystalline form having crystalline modification II according to any of claims 1 , 2 and 5 for use in the treatment and/or prophylaxis of chronic obstructive pulmonary disease (COPD).

10. N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]- glyoxylic acid amide in crystalline form having crystalline modification II according to any of claims I, 2 and 5 for use in the treatment and/or prophylaxis of asthma.

1 1 . N-(3,5-dichloropyridin-4-yl)-[1 -(4-fluorobenzyl)-7-azaindol-3-yl)]- glyoxylic acid amide in crystalline form having crystalline modification II according to any of claims 1 , 2 or 5 for use in the treatment and/or prophylaxis of psoriasis.